Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[F:73][C:74]([F:83])([C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1)[CH2:75][NH2:76].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:76][CH2:75][C:74]([F:73])([F:83])[C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1
Reactant: NCC(F)(F)c1ccccc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: O=C(N1CCc2ccc(Cl)c(NCC(F)(F)c3ccccc3)c2CC1)C(F)(F)F
Temperature: 100 °C
Yield: 60.8 %

Procedure:
Use a method similar to the General Procedure 5-3 to react 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (541 mg, 1.274 mmol), palladium(II) acetate (57 mg, 0.225 mmol), tris(dibenzylideneacetone)dipalladium(0) (117 mg, 0.127 mmol), BINAP (0.506 g, 0.764 mmol), 2,2-difluoro-2-phenyl-ethylamine (400 mg, 2.547 mmol) and cesium carbonate (830 mg, 2.548 mmol) in degassed toluene (35 mL). Degas the mixture with vacuum/nitrogen purge and heat to 100° C. for 16 h. Cool the mixture to room temperature, dilute with EtOAc and filter over Celite®. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1) to obtain 7-chloro-6-(2,2-difluoro-2-phenyl-ethylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as oil (335 mg, 61%). MS (ES+) m/z: 433 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: BrCCCCBr
Reactant: COC(=O)Cc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(N2CCCC2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 24.6 %

Procedure:
Methyl 4-aminophenylacetate (0.4 g, 2.4 mmol), 1,4-dibromobutane (0.29 mL, 2.4 mmol) and potassium carbonate (0.34 g, 2.6 mmol) were dissolved in dimethylformamide (30 mL), and the mixture was stirred overnight at 80° C. The solvent was evaporated, and the residue was worked up according to a conventional method and purified by silica gel column chromatography to give the title compound (0.13 g, 0.59 mmol).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[C@@H:4]2[O:14][C@H:3]12.[Cl:16][C:17]1[CH:26]=[CH:25][C:20]2[NH:21][C:22]([SH:24])=[N:23][C:19]=2[CH:18]=1>>[Cl:16][C:17]1[CH:26]=[CH:25][C:20]2[NH:21][C:22]([S:24][C@@H:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=4)[O:11][C:2]([CH3:15])([CH3:1])[C@@H:3]3[OH:14])=[N:23][C:19]=2[CH:18]=1
Reactant: Sc1nc2cc(Cl)ccc2[nH]1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H]2O[C@@H]21
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](Sc2nc3cc(Cl)ccc3[nH]2)[C@H]1O

Procedure:
Following the procedure in Example 1, using (S,S)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 5-chloro-1H-benzoimidazole-2-thiol as starting material, the title compound was prepared as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]#[N:6].[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=[C:19]1[S:27](Cl)(=[O:29])=[O:28]>N1C=CC=CC=1>[CH2:11]([S:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[NH:1][S:27]([C:19]1[O:18][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=1)(=[O:28])=[O:29])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1ccc(SCc2ccccc2)c(N)c1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Solvent: c1ccncc1
Product: N#Cc1ccc(SCc2ccccc2)c(NS(=O)(=O)c2cc3ccccc3o2)c1
Yield: 64.7 %

Procedure:
Following General Procedure B, the title compound (419 mg, 65%) was prepared from 3-amino-4-(benzylthio)benzonitrile (370 mg, 1.54 mmol) and benzofuran-2-sulfonyl chloride (333 mg, 1.54 mmol) in pyridine (3 ml).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=O.N>>[Br:11][C:12]1[CH:13]=[C:14]([C:15]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Brc1cccc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 1 using N′-hydroxynicotinimidamide (Aldrich) and 3-bromobenzoyl chloride (Aldrich). 1H NMR (300 MHz, DMSO-d6) δ 7.60-7.71 (m, 2H), 7.98 (ddd, J=8.1, 2.0, 1.0 Hz, 1H), 8.22 (ddd, J=7.4, 1.6, 1.3 Hz, 1H), 8.35 (t, J=1.8 Hz, 1H), 8.46 (dt, J=7.9, 2.0 Hz, 1H), 8.83 (dd, J=4.8, 1.6 Hz, 1H), 9.27 (dd, J=2.4, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 302 (M+H)+, 304 (M+H)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:25]1([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Reactant: C1CCNCC1
Product: N#Cc1ccc(-c2ccc3oc(CCN4CCCCC4)cc3c2)cc1

Procedure:
The product from Example 1C and piperidine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.88 (m, 1H), 7.80 (m, 4H), 7.60 (m, 2H), 6.82 (s, 1H), 3.65 (m, 2H), 3.55 (m, 2H), 3.33 (m, 2H), 3.05 (m, 2H), 2.0 (m, 2H), 1.5-1.9 (m, 4H); MS (DCI) m/z 331 (M+H)+;
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1>CO.C(OCC)(=O)C.[C].[Pd]>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][N:39]2[CH2:40][CH2:41][N:42]([CH3:45])[CH2:43][CH2:44]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])=[O:12]
Reactant: CN1CCN(CCc2ccc(OCc3ccccc3)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1CCN(CCc2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(2-(4-methylpiperazin-1-yl)ethyl)benzamido)-4-phenylbenzoate (0.10 g) in methanol (1.5 mL) and ethyl acetate (1.5 mL), 10% palladium-carbon (0.10 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 1 hour. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-90% chloroform/methanol] to obtain 0.056 g of tert-butyl 2-(2-hydroxy-5-(2-(4-methylpiperazin-1-yl)ethyl)benzamido)-4-phenylbenzoate as a light yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:30][C:31]2[CH:35]=[CH:34][S:33][CH:32]=2)[CH:9]2[CH2:14][CH2:13][N:12]([C@H:15]([CH3:29])[CH2:16][CH2:17][NH:18][C:19]([C:21]3[C:22]([CH3:28])=[N:23][CH:24]=[N:25][C:26]=3[CH3:27])=[O:20])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Br[CH2:37][C:38]([O:40][CH3:41])=[O:39].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:41][O:40][C:38](=[O:39])[CH2:37][O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C@H:15]([CH3:29])[CH2:16][CH2:17][NH:18][C:19]([C:21]3[C:26]([CH3:27])=[N:25][CH:24]=[N:23][C:22]=3[CH3:28])=[O:20])[CH2:13][CH2:14]2)[CH2:30][C:31]2[CH:35]=[CH:34][S:33][CH:32]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: Cc1ncnc(C)c1C(=O)NCC[C@@H](C)N1CCC(N(Cc2ccsc2)c2ccc(O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(N(Cc2ccsc2)C2CCN([C@H](C)CCNC(=O)c3c(C)ncnc3C)CC2)cc1
Temperature: 80 °C
Yield: 43.4 %

Procedure:
A mixture of COMPOUND 296 (290 mg, 0.59 mmol), methyl bromoacetate (141 mg, 0.92 mmol) and K2CO3 (123 mg, 0.89 mmol) in DMF (5.8 mL) was heated at 80° C. overnight to afford {4-[(1-{(R)-3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-thiophen-3-ylmethyl-amino]-phenoxy}-acetic acid methyl ester as a brown oil (145 mg, 42%) following work-up and purification.
Reaction SMILES: [N:1]1([CH:6]([CH3:24])/[C:7](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:8]/[C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.C[O:41][C:42](=[O:49])[C@H:43]([CH2:45][CH2:46][S:47][CH3:48])[NH2:44].CN1CCOCC1.C([O-])(O)=O.[Na+]>CN(C=O)C>[N:1]1([CH:6]([CH3:24])/[C:7](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:8]/[C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH:44][C@@H:43]([CH2:45][CH2:46][S:47][CH3:48])[C:42]([OH:41])=[O:49])=[O:14])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: CC(/C(=C/c1ccc(C(=O)O)cc1)c1ccccc1)n1ccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CSCC[C@H](NC(=O)c1ccc(/C=C(\c2ccccc2)C(C)n2ccnc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 20 %

Procedure:
A mixture of product from step D (0.53 g, 1.67 mmol), EDC (0.32 g, 1.67 mmol) and HOBT(0.23 g, 1.67 mmol) was stirred in DMF (30 ml) until solution. This was then treated with L-methionine methyl ester hydrochloride (0.33 g, 1.67 mmol) and N-methylmorpholine (0.37 ml, 3.34 mmol), stirred for 18 hrs at room temperature and then treated with saturated aqueous NaHCO3. The organic phase was evaporated to give the desired starting material (0.15 g, Yield=19.5%).
Reaction SMILES: C[CH:2]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[CH:12]=[C:13]([C:17]([O:19][CH3:20])=[S:18])[S:14][C:15]=2[CH3:16])[CH:7]=[CH:8][CH:9]=1)C.N[C:22]1C=C(C(OC)=S)S[C:26]=1C.C(C1C=C(B(O)O)C=CC=1)(C)C>>[CH3:2][C:4]1[C:5]([CH2:22][CH3:26])=[C:6]([NH:10][C:11]2[CH:12]=[C:13]([C:17]([O:19][CH3:20])=[S:18])[S:14][C:15]=2[CH3:16])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=S)c1cc(N)c(C)s1
Reactant: COC(=S)c1cc(Nc2cccc(C(C)C)c2)c(C)s1
Agent: CC(C)c1cccc(B(O)O)c1
Product: CCc1c(C)cccc1Nc1cc(C(=S)OC)sc1C
Yield: 19.5 %

Procedure:
Methyl 4-{[3-(methylethyl)phenyl]amino}-5-methylthiothiophene-2-carboxylate: Using a procedure similar to Example 208, step (a), 74.4 mg (0.36 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate was allowed to react with 118 mg (2 equiv, 0.72 mmol) of 3-isopropylphenyl boronic acid to give 22.6 mg (19.5%) of methyl 4-[(3-methylethylphenyl)amino]-5-methylthiothiophene-2-carboxylate. 1H NMR (CDCl3, 400 MHz) δ 1.27 (d, 6H, J=6.9 Hz), 2.40 (s, 3H), 2.89 (m, 1H), 3.88 (s, 3H), 6.15 (s, 1H), 6.86-6.89 (m, 3H), 7.24 (m, 1H), 7.77 (s, 1H).
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19](O)[CH:20]2[CH2:22][CH:21]2[C:23]#[N:24])=[C:15]([O:26][CH3:27])[CH:14]=1.[CH3:28][S:29]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:41]=1[NH:40][CH:39]=[CH:38]2)(=[O:31])=[O:30].[Cl-].[NH4+]>ClCCCl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:38]2[C:37]3[C:41](=[C:33]([CH2:32][S:29]([CH3:28])(=[O:31])=[O:30])[CH:34]=[CH:35][CH:36]=3)[NH:40][CH:39]=2)[CH:20]2[CH2:22][CH:21]2[C:23]#[N:24])=[C:15]([O:26][CH3:27])[CH:14]=1
Reactant: COc1cc(Cl)ccc1C(O)C1CC1C#N
Reactant: CS(=O)(=O)Cc1cccc2cc[nH]c12
Agent: [Cl-]
Agent: [In+3]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Cl)ccc1C(c1c[nH]c2c(CS(C)(=O)=O)cccc12)C1CC1C#N

Procedure:
104 mg (0.47 mmol) of indium(III) chloride and 0.05 ml (0.70 mmol) of trifluoroacetic acid were added to 93.0 mg (0.39 mmol) of the compound from Example 163A and 112 mg (0.47 mmol) of the compound from Example 86A with a purity of 88% under argon in 5 ml of 1,2-dichloroethane, and the mixture was heated under reflux for 2 h. Addition of the reaction mixture to saturated aqueous ammonium chloride solution was followed by extraction with dichloromethane, drying over magnesium sulfate, filtration and concentration. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 30.5 mg (18% of theory) of diastereomer 1 and 28.0 mg (17% of theory) of diastereomer 2 of the title compound.
Reaction SMILES: [CH2:1]([N:4]([CH2:14][CH2:15][CH3:16])[C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][N:13]=1)[C:8]([OH:10])=O)[CH2:2][CH3:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:29][C@@H:30]([CH2:46][C:47]1[CH:52]=[C:51]([F:53])[CH:50]=[C:49]([F:54])[CH:48]=1)[C@H:31]([OH:45])[CH2:32][NH:33][C:34]1([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43]#[CH:44])[CH:38]=2)[CH2:36][CH2:35]1>ClCCl>[F:53][C:51]1[CH:52]=[C:47]([CH:48]=[C:49]([F:54])[CH:50]=1)[CH2:46][C@H:30]([NH:29][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][N:13]=[C:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:14][CH2:15][CH3:16])[CH:6]=1)[C@H:31]([OH:45])[CH2:32][NH:33][C:34]1([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43]#[CH:44])[CH:38]=2)[CH2:36][CH2:35]1
Reactant: CCCN(CCC)c1cc(C(=O)O)ccn1
Reactant: C#Cc1cccc(C2(NC[C@@H](O)[C@@H](N)Cc3cc(F)cc(F)c3)CC2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: C#Cc1cccc(C2(NC[C@@H](O)[C@H](Cc3cc(F)cc(F)c3)NC(=O)c3ccnc(N(CCC)CCC)c3)CC2)c1
Reaction time: 8 h
Yield: 60 %

Procedure:
2-(Dipropylamino)isonicotinic acid (0.206 g) was dissolved in dichloromethane (10 mL). 1,1′-Carbonyldiimidazole was added (0.142 g) and the mixture was stirred for 2 h at room temperature, at which time (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-{[1-(3-ethynylphenyl)cyclopropyl]amino}butan-2-ol (0.284 g) in dichloromethane was added. The mixture was allowed to stir overnight and then was partitioned between dichloromethane, water, and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was chromatographed on silica gel using methanol/dichloromethane (4/96) to give N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethynylphenyl)cyclopropyl]amino}-2-hydroxypropyl)-2-(dipropylamino)isonicotinamide (0.268g). MS (ESI+) for C33H38F2N4O2+H1 m/z 561.30 (M+H)+.
Reaction SMILES: CO[N:3]=[CH:4][C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=1[S:12][CH3:13].O1CCCC1.B.[ClH:20].[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[ClH:20].[Br:11][C:9]1[CH:8]=[CH:7][C:6]([S:12][CH3:13])=[C:5]([CH2:4][NH2:3])[CH:10]=1
Reactant: CON=Cc1cc(Br)ccc1SC
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1ccc(Br)cc1CN
Temperature: 80 °C
Reaction time: 3 h

Procedure:
(Step 3) To a solution of 5-bromo-2-(methylsulfanyl)benzaldehyde O-methyloxime obtained in Step 2 (11.8 g) in tetrahydrofuran (200 ml) was added tetrahydrofuran-borane (113.4 ml, 1M tetrahydrofuran solution) at 0° C. The mixture was stirred at 80° C. for 3 hr, and treated with ice, and 1N hydrochloric acid (200 ml) was added. The mixture was stirred at 90° C. for 1 hr, and ethyl acetate was added to the mixture. The separated aqueous layer was basified with 8N sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (15 ml) was added, and the obtained precipitate was collected by filtration, and washed with ethyl acetate to give 1-[5-bromo-2-(methylsulfanyl)phenyl]methanamine hydrochloride (7.25 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.F[C:28]1[CH:33]=[CH:32][N:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:28]5[CH:33]=[CH:32][N:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: Fc1ccnc(C(F)(F)F)c1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccnc(C(F)(F)F)c5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-fluoro-2-trifluoromethyl-pyridine following a procedure analogous to that described for Intermediate 12. LC (method 2): tR=1.10 min; Mass spectrum (ESI+): m/z=504 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:14]3[CH:15]=[C:16]([C:19](OC)=[O:20])[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.O.[NH2:26][NH2:27]>C(O)C>[F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:14]3[CH:15]=[C:16]([C:19]([NH:26][NH2:27])=[O:20])[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: NN
Reactant: COC(=O)c1ccc2occ(-c3cccc(OC(F)(F)F)c3)c2c1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc2occ(-c3cccc(OC(F)(F)F)c3)c2c1

Procedure:
A solution of methyl 3-[3-(trifluoromethoxy)phenyl]-1-benzofuran-5-carboxylate (6.80 g, 20.2 mmol) and hydrazine monohydrate (9.92 mL, 202.2 mmol) in ethanol (70 mL) was heated under reflux overnight. After cooling, the precipitate was collected by filtration to give 3-[3-(trifluoromethoxy)phenyl]-1-benzofuran-5-carbohydrazide.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[C:13](=[O:14])[N:12]([CH3:15])[CH:11]=[C:10]2[C:16](=[O:32])[N:17]([CH2:20][CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[C:18](=[O:19])[C:9]=12>CCO>[CH3:15][N:12]1[C:13](=[O:14])[C:8]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[C:9]2[C:18](=[O:19])[N:17]([CH2:20][CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[C:16](=[O:32])[C:10]2=[CH:11]1
Reactant: C1COCCN1
Reactant: Cn1cc2c(c(Cl)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2=O
Solvent: CCO
Product: Cn1cc2c(c(N3CCOCC3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2=O
Temperature: 90 °C
Reaction time: 16 h
Yield: 123 %

Procedure:
Morpholine (0.355 ml, 4.08 mmol) was added to a solution of 7-chloro-5-methyl-2-(2-quinolin-2-yl-ethyl)-5H-pyrrolo[3,4-c]pyridine-1,3,6-trione (0.5 g, 1.36 mmol, see Example c1)) in EtOH (30 ml) and the reaction was stirred at 90° C. for 16 h. The solvent was removed to give the title compound (0.7 g, 123% yield), which was used in the next steps without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:13]([CH2:14][C:15]3[C:16]([F:32])=[N:17][C:18]([NH:21][CH2:22][C:23]4[C:24]([O:30][CH3:31])=[N:25][CH:26]=[C:27]([F:29])[CH:28]=4)=[CH:19][CH:20]=3)=[CH:12][NH:11][C:8]2=[N:9][CH:10]=1)=O.[CH3:33][NH2:34]>>[CH3:33][NH:34][C:3]([C:5]1[CH:6]=[C:7]2[C:13]([CH2:14][C:15]3[C:16]([F:32])=[N:17][C:18]([NH:21][CH2:22][C:23]4[C:24]([O:30][CH3:31])=[N:25][CH:26]=[C:27]([F:29])[CH:28]=4)=[CH:19][CH:20]=3)=[CH:12][NH:11][C:8]2=[N:9][CH:10]=1)=[O:2]
Reactant: COC(=O)c1cnc2[nH]cc(Cc3ccc(NCc4cc(F)cnc4OC)nc3F)c2c1
Reactant: CN
Product: CNC(=O)c1cnc2[nH]cc(Cc3ccc(NCc4cc(F)cnc4OC)nc3F)c2c1
Temperature: 50 °C

Procedure:
3-{2-Fluoro-6-[(5-fluoro-2-methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester (P-1693, 1 equivalent) is slurried with methylamine (2N in methanol, 15 equivalents) in a sealable vial, sealed and heated at 50° C. overnight. Additional methylamine (2N in methanol, 15 equivalents) is added and heated at 50° C. overnight. The reaction is concentrated under vacuum, the residue dissolved in tetrahydrofuran for purification on a C18 reverse phase column, eluting with 0-100% methanol (with 10% tetrahydrofuran)/water. Appropriated fractions are combined and concentrated under vacuum. The resulting material is triturated with ethyl acetate/heptane and filtered, washing with heptane. The solid is dried under vacuum to provide the desired compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][C:16]=2[C:24]([F:27])([F:26])[F:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][C:30]=1[NH:36][C:37]1[CH:42]=[C:41]([C:43]2[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=2)[CH:40]=[CH:39][N:38]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH:33][C:32]3[CH:34]=[CH:35][C:29]([CH3:28])=[C:30]([NH:36][C:37]4[CH:42]=[C:41]([C:43]5[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=5)[CH:40]=[CH:39][N:38]=4)[CH:31]=3)=[O:21])=[CH:17][C:16]=2[C:24]([F:27])([F:26])[F:25])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1ccc(N)cc1Nc1cc(-c2cccnc2)ccn1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(=O)O)cc2C(F)(F)F)CC1
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(C(F)(F)F)c2)cc1Nc1cc(-c2cccnc2)ccn1

Procedure:
This compound was prepared in the same manner as in Example 34, except that 4-[4-(t-butoxycarbonyl)piperazin-1-ylmethyl]-3-trifluoromethylbenzoic acid (Reference Example 13) and 4-methyl-3-[4-(3-pyridyl)pyridin-2-ylamino]aniline (Reference Example 23) were used, and that the resulting crude crystals obtained by purification with silica gel column chromatography were recrystallized from n-hexane-ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6](=[O:12])[N:5]3[CH2:13][CH:14]([CH2:15][N:16]4[CH2:21][CH2:20][CH:19]([NH:22][CH2:23][C:24]5[N:40]=[CH:39][C:27]6[O:28][CH2:29][CH2:30][N:31](C(OC(C)(C)C)=O)[C:26]=6[CH:25]=5)[CH2:18][CH2:17]4)[C:3]=1[C:4]=23.[ClH:41]>ClCCl.CO.O1CCOCC1>[ClH:41].[ClH:41].[NH:31]1[CH2:30][CH2:29][O:28][C:27]2[CH:39]=[N:40][C:24]([CH2:23][NH:22][CH:19]3[CH2:18][CH2:17][N:16]([CH2:15][CH:14]4[C:3]5[C:4]6[N:5]([C:6](=[O:12])[CH:7]=[N:8][C:9]=6[CH:10]=[CH:11][C:2]=5[F:1])[CH2:13]4)[CH2:21][CH2:20]3)=[CH:25][C:26]1=2
Reactant: CC(C)(C)OC(=O)N1CCOc2cnc(CNC3CCN(CC4Cn5c(=O)cnc6ccc(F)c4c65)CC3)cc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: O=c1cnc2ccc(F)c3c2n1CC3CN1CCC(NCc2cc3c(cn2)OCCN3)CC1
Reaction time: 2.5 h

Procedure:
1,1-Dimethylethyl 7-[({1-[(7-fluoro-3-oxo-5,6-dihydro-3H-pyrrolo[1,2,3-de]quinoxalin-6-yl)methyl]-4-piperidinyl}amino)methyl]-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine-1-carboxylate (91 mg, 0.165 mmol) in dichloromethane (2 ml) and methanol (1.5 ml) was treated with 4M hydrogen chloride in 1,4-dioxane (3.5 ml). After standing at room temperature for 2.5 h, the mixture was evaporated. The residue was triturated twice with ether and dried to give the title compound (89 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[C:4]([CH3:10])[CH:3]=1.[CH2:11]([O:13][C:14]([C:16]1[CH:20]=[CH:19][N:18]([CH:21]([CH3:23])[CH3:22])[C:17]=1[CH:24]=[O:25])=[O:15])[CH3:12]>C1COCC1>[CH2:11]([O:13][C:14]([C:16]1[CH:20]=[CH:19][N:18]([CH:21]([CH3:22])[CH3:23])[C:17]=1[CH:24]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[CH3:10])[OH:25])=[O:15])[CH3:12]
Reactant: CCOC(=O)c1ccn(C(C)C)c1C=O
Reactant: Cc1cc(Cl)ccc1[Mg]Br
Solvent: C1CCOC1
Product: CCOC(=O)c1ccn(C(C)C)c1C(O)c1ccc(Cl)cc1C
Reaction time: 2 h

Procedure:
A solution (0.5 M in THF) of 4-chloro-2-methylphenylmagnesium bromide [480438-47-9] (68.8 mmol) was added to a mixture of 2-formyl-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester (Step A5) (68.8 mmol) in THF (160 mL) at 0° C. After stirring for 2 h, the reaction mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with MTBE (2×). The combined organic phases were successively washed with water and brine, dried (Na2SO4), filtered and concentrated. The residue was suspended in hexanes, stirred for 30 min and then filtered to afford the title compound as a white solid. tR: 7.74 min (HPLC 2); ESI-MS: tR=1.26 min, [M]+318/320 (i.e. fragmented pyrrolium ion) (LC-MS 1); TLC: Rf=0.20 (1:6 EtOAc/hexanes).