Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[CH:11]=[C:10]([C:25]([OH:27])=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH2:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][NH:29]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][N:29]1[C:25]([C:10]1[CH:11]=[C:12]([C:14]([NH:15][CH2:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[O:24])[CH:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:9]=1)=[O:27]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3ccc(C)nc3)c2)cc1
Reactant: c1ccc2c(c1)CNC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C(=O)N3Cc4ccccc4C3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-((6-methylpyridin-3-yl)methylcarbamoyl)biphenyl-3-carboxylic acid (50 mg, 0.14 mmol) in N,N-dimethylformamide (1 mL) were added isoindoline (40 mg, 0.34 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol) and N,N-diisopropylethylamine (120 μL, 0.69 mmol). The reaction mixture was stirred for 16 hours at 25° C. The reaction solution was purified by preparative HPLC to afford the final product as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21][N:22]2C(=O)C3=CC=CC=C3C2=O)=NN=[C:17]1[CH2:33][N:34]([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36].O.[NH2:43][NH2:44]>C(O)C>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]2[N:16]3[C:17]([CH2:33][N:34]([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])=[N:43][N:44]=[C:20]3[CH2:21][N:22]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]=2[CH:14]=1
Reactant: NN
Reactant: CC(C)N(Cc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl)C(C)C
Solvent: CCO
Solvent: O
Product: CC(C)N(Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2)C(C)C

Procedure:
In the manner given in Example 27, 2',5-dichloro-2-[3-[(diisopropylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is heated in ethanol with hydrazine hydrate to give 8-chloro-1-[(diisopropylamino)-methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[O:19]C4C=CC=CC=4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:4]=2[N:5]=[CH:6][N:7]=1.O[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([NH:43]C(=O)OC(C)(C)C)=[CH:39][CH:38]=1>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[O:19][CH2:36][C:37]4[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CO)cc1
Reactant: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)Oc1ccccc1
Solvent: c1ccncc1
Product: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)OCc1ccc(N)cc1
Temperature: 100 °C
Yield: 13.5 %

Procedure:
Phenyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (51 mg, 0.111 mmol) was mixed with tert-butyl N-(4-(hydroxymethyl)phenyl)carbamate (119 mg, 0.533) in pyridine (0.8 mL). The reaction mixture was heated at 100° C. overnight. The solvent was removed and the residue was purified by preparative reverse phase LC/MS to give 4-aminobenzyl N-(4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl)carbamate (9 mg, 0.015 mmol). 1H NMR (CDCl-d) δ 1.52(s, 1H), 2.08(m, 4H), 3.65(m, 2H), 3.90(s, 3H), 4.14(m, 2H), 4.97(m, 1H), 5.17(s, 2H), 5.37(bs, 1H), 6.55(s, 1H), 6.95(s, 1H), 7.03(s, 1H), 7.06(m, 1H), 7.31(s, 1H), 7.38(m, 3H), 8.16(bs, 1H), 8.30(s, 1H). LC/MS: MH+589.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH2:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH3:12].C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[CH2:11]([N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N:3]=2)[CH2:15][CH2:14]1)[CH3:12]
Reactant: CCN1CCNCC1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CCN(c2cc([N+](=O)[O-])ccn2)CC1
Temperature: 100 °C
Yield: 66.1 %

Procedure:
A mixture of 2 g (13 mmol) 2-chloro-4-nitropyridine, 1.73 g (15 mmol) 1-ethyl-piperazine and 0.81 g (6 mmol) N,N-diisopropylethylamine (DIPEA) in 19 ml DMF and 20 ml water was heated to 100° C. for 24 h. The precipitate was filtered off and washed three times with 4 ml of water and dried for 24 h under vacuum to yield 2.03 g (68%) of the title compound as yellow oil (m/e): 236.7 (MH+; 100%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[CH:5][N:4]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][O:24][C@H:23]([C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][C:28]=2[F:34])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(C(C)C)C(C)C)C>C(Cl)Cl.CN(C=O)C>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][O:24][C@H:23]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([C:2]([F:1])([F:13])[F:12])[CH:8]=3)=[O:11])=[CH:29][C:28]=2[F:34])[CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(N)cc2F)C1
Reactant: O=C(O)c1ccnc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(NC(=O)c3ccnc(C(F)(F)F)c3)cc2F)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under N2, 2-(trifluoromethyl)-4-pyridinecarboxylic acid (CAS 131747-41-6) (64.4 mg, 337 μmol, Eq: 1.00) was dissolved in CH2Cl2 (1 ml). 1-chloro-N,N2-trimethypropenylamine (51.8 mg, 51.3 μl, 388 μmol, Eq: 1.15) was added dropwise. After 30 minutes at RT, a solution contained (R)-2-(4-Amino-2-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (100 mg, 337 μmol, Eq: 1.00) and ethyldiisopropylamine (109 mg, 140 μl, 842 μmol, Eq: 2.5) in DMF (1.00 ml) was added. The RM was stirred at RT over 1 hour. Control with TLC: the reaction was finished. The RM was extracted with EtOAc and 1M citric acid solution; the organic phase was dried over MgSO4; filtered; concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 10% to 50% EtOAc in heptane) leading to 149 mg (82%) of a white foam. MS (EIC): 468.1 ([M−H]−)
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([NH:12][C:13]2[N:14]([CH3:21])[N:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:17]=2)=[CH:10][CH:9]=[C:8]([CH3:22])[N:7]=1)=[O:5])C.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([CH3:31])[N:25]=1>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:4]([C:6]2[C:11]([NH:12][C:13]3[N:14]([CH3:21])[N:15]=[C:16]([CH:18]4[CH2:19][CH2:20]4)[CH:17]=3)=[CH:10][CH:9]=[C:8]([CH3:22])[N:7]=2)=[O:5])=[N:25][C:26]=1[CH3:31]
Reactant: Cc1nc(N)ccc1F
Reactant: CCOC(=O)c1nc(C)ccc1Nc1cc(C2CC2)nn1C
Product: Cc1ccc(Nc2cc(C3CC3)nn2C)c(C(=O)Nc2ccc(F)c(C)n2)n1

Procedure:
The title compound, was prepared from 3-(5-Cyclopropyl-2-methyl-2H-pyrazol-3-ylamino)-6-methyl-pyridine-2-carboxylic acid ethyl ester and 2-Amino-5-fluoro-6-methylpyridine in accordance with the general method of Example 78, step 2 to yield the final compound as a yellow cristalline solid, MS (ISP): m/e=381.4 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:14]([OH:16])=[O:15])=[C:6]2[C:10]=1[O:9][CH:8]([CH2:11][O:12][CH3:13])[CH2:7]2.Cl[C:18]1[N:27]=[CH:26][C:25]2[N:24]([CH3:28])[C:23](=[O:29])[C@@H:22]([CH2:30][CH3:31])[N:21]([CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[C:20]=2[N:19]=1.Cl>C(O)C.O>[CH:32]1([N:21]2[C:20]3[N:19]=[C:18]([NH:1][C:2]4[CH:3]=[CH:4][C:5]([C:14]([OH:16])=[O:15])=[C:6]5[C:10]=4[O:9][CH:8]([CH2:11][O:12][CH3:13])[CH2:7]5)[N:27]=[CH:26][C:25]=3[N:24]([CH3:28])[C:23](=[O:29])[C@H:22]2[CH2:30][CH3:31])[CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: COCC1Cc2c(C(=O)O)ccc(N)c2O1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OC(COC)C4)nc2N1C1CCCC1
Yield: 44.5 %

Procedure:
7-Amino-2-(methoxymethyl)-2,3-dihydrobenzofuran-4-carboxylic acid 40d (160 mg, 0.70 mmol) and (7R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydro-5H-pteridin-6-one 1o (232 mg, 0.80 mmol) were dissolved in 34 mL of the mixture solvent of ethanol and water (V:V=1:2.4) followed by the addition of 0.4 mL of concentrated hydrochloric acid. The reaction solution was heated to reflux for 16 hours with stirring, then cooled down resulting in the formation of precipitate. The precipitate was filtered to obtain the title compound 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2-(methoxymethyl)-2,3-dihydrobenzofuran-4-carboxylic acid 40e (0.15 g, yield: 43.0%) as a yellow solid.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1>CO.[Pd]>[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Agent: [Pd]
Solvent: CO
Product: c1ccc2c(C3CCNCC3)c[nH]c2c1

Procedure:
19.03 g (0.096 mol) of 3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole were hydrogenated in a Parr apparatus during 18 h at 40 psi with 2.2 g of Pd/C 10% in 600 ml of methanol. After standard work-up, 16.76 g (87% of yield) of the desired product were obtained.
Reaction SMILES: [OH-].[Na+].[C:3]12([C:13]3[CH:14]=[C:15]([C:23]4[CH:24]=[C:25]5[C:30](=[CH:31][CH:32]=4)[CH:29]=[C:28]([C:33]([O:35]C)=[O:34])[CH:27]=[CH:26]5)[CH:16]=[CH:17][C:18]=3[C:19]([O:21][CH3:22])=[O:20])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2>CO>[C:3]12([C:13]3[CH:14]=[C:15]([C:23]4[CH:24]=[C:25]5[C:30](=[CH:31][CH:32]=4)[CH:29]=[C:28]([C:33]([OH:35])=[O:34])[CH:27]=[CH:26]5)[CH:16]=[CH:17][C:18]=3[C:19]([O:21][CH3:22])=[O:20])[CH2:12][CH:7]3[CH2:6][CH:5]([CH2:11][CH:9]([CH2:8]3)[CH2:10]1)[CH2:4]2
Reactant: COC(=O)c1ccc2cc(-c3ccc(C(=O)OC)c(C45CC6CC(CC(C6)C4)C5)c3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccc(-c2ccc3cc(C(=O)O)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
0.34 g of sodium hydroxide is added to 1.92 g (4.22 mmol) of the diester obtained in Example 14 in 25 ml of methanol and the mixture is kept under reflux for 24 hours. After the same treatment as in Example 8 and recrystallization from the isopropyl ether-ethyl acetate mixture, 1.7 g (91%) of the expected derivative are isolated, which derivative melts at 272°-273° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]3[S:22][C:21]([C:23]([O:25]C)=[O:24])=[CH:20][CH:19]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH-].[Na+].O.[ClH:30]>O1CCOCC1>[ClH:30].[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]3[S:22][C:21]([C:23]([OH:25])=[O:24])=[CH:20][CH:19]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(CCc2ccc(N3CCN(C(C)=O)CC3)cn2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N1CCN(c2ccc(CCc3ccc(C(=O)O)s3)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 5-{2-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]ethyl}thiophene-2-carboxylate (550.0 mg, 1.473 mmol) in dioxane (4.5 ml) were added 1M aqueous sodium hydroxide solution (5.15 ml, 5.15 mmol) and water (2.2 ml) at 0° C. After stirring at room temperature for 1 hr, the mixture was cooled to 0° C., and 1M hydrochloric acid (8.84 ml, 8.84 mmol) was added. The mixture was concentrated to dryness to give crude 5-{2-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]ethyl}thiophene-2-carboxylic acid hydrochloride as a pale-yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[C:8]([CH3:15])[CH:7]=2)[CH2:3][CH2:2]1.[Br:16]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:16][C:11]1[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)=[CH:7][C:8]([CH3:15])=[C:9]([C:12](=[O:14])[CH3:13])[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1ccc(OCC2CC2)cc1C
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cc(Br)c(OCC2CC2)cc1C
Temperature: 50 °C

Procedure:
A suspension of 1-(4-cyclopropylmethoxy-2-methyl-phenyl)-ethanone from example A24 (6.4 g, 31.3 mmol) and N-bromosuccinimide (6.20 g, 34.5 mmol) in dry dimethylformamide (50 mL) is heated for 3 h at 50° C. After cooling to ambient temperature, water (200 mL) is added and the mixture is extracted with ethyl acetate (3×60 mL). The combined organic extracts are dried over sodium sulfate. The solvent is removed under reduced pressure. The crude is purified by column chromatography on silica gel using dichloromethane as eluent to give the title compound as a off-white solid. Yield: 4.80 g.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:5]2=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].S(=O)(=O)(O)[OH:19].O.[Cr](O)(O)(=O)=O>C(O)(=O)C.CC(O)C>[CH3:1][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:19])[C:5]2=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)c1cc2c(nc1C)CCCCC2
Agent: O=[Cr](=O)(O)O
Solvent: CC(C)O
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2c(nc1C)CCCCC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.8 %

Procedure:
Ethyl methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate (2.50 g, 10.1 mmol) was dissolved in acetic acid (7.0 ml), the solution was mixed with concentrated sulfuric acid (1.4 ml), and then 11% acetic acid aqueous solution (4.8 ml) of chromic anhydride (1.41 g, 14.1 mmol) was added thereto at 10 to 15° C. spending about 1 hour. After 6 hours of stirring at room temperature, water was added to the reaction solution to which was subsequently added dropwise 2-propanol at 0° C. to decompose excess chromic acid. The solvent was evaporated under reduced pressure, the thus obtained residue was neutralized with 20% sodium hydroxide aqueous solution at 0° C. and mixed with chloroform, and then the insoluble matter was removed by celite filtration and washed with chloroform. The resulting filtrate was extracted with chloroform, washed with water and saturated brine in that order and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (ether:hexane=1:1) to obtain the title compound (284.7 mg, 10.8%) as colorless oil.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[NH:8][C:7]3[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=3[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=1.[OH-].[K+].C1C2C(CCCC2)CCC1>[Cu].C(Cl)(Cl)Cl>[I:27][C:24]1[CH:25]=[CH:26][C:21]([N:8]2[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[CH:19]=[CH:18][CH:17]=[CH:16][C:7]2=3)=[CH:22][CH:23]=1
Reactant: c1ccc2c(c1)Nc1ccccc1-c1ccccc1-2
Reactant: Brc1ccc(I)cc1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: C1CCC2CCCCC2C1
Solvent: ClC(Cl)Cl
Product: Ic1ccc(N2c3ccccc3-c3ccccc3-c3ccccc32)cc1
Temperature: 200 °C
Yield: 52.1 %

Procedure:
Eighteen point two (18.2) grams (75 mmol) of 9H-tribenz[b,d,f]azepin, 63.7 g (225 mmol) of 1-bromo-4-iodo-benzene, 5.0 g (90 mmol) of potassium hydroxide, and 2.0 g (31 mmol) of a copper powder were mixed with 50 ml of decalin and stirred by heating under a nitrogen gas current for about one week at outer temperature of 200° C. After the temperature of the reaction solution was lowered to near room temperature, chloroform was added thereto, and the solution was filtered through Celite to remove insoluble matters. Water was added to the filtrate, and the solution was subjected to extraction. The obtained concentrated reaction product was purified by silica gel column chromatography to obtain 17.4 g of 9-(4-iodophenyl)-tribenz[b,d,f]azepin (yield: 52%, a small amount of 4-bromophenyl compound was contained).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:20])[CH:13](Cl)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:9]([O:11][C:12](=[O:20])[CH:13]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:10]
Reactant: CCOC(=O)C(Cl)C(=O)OCC
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(Oc1ccc(Cl)cc1)C(=O)OCC
Yield: 84.4 %

Procedure:
A mixture of 38.6 g (0.3 mole) of 4-chlorophenol, 70 g (0.36 mole) of diethylchloromalonate and 69.1 g (0.5 mole) of anhydrous potassium carbonate in 750 ml of acetone was heated at reflux for 48 hr, cooled, filtered and the filtrate concentrated. The residue was diluted with 250 ml of ethyl ether and was washed successively with two 100 ml portions of a 1% NaOH solutoin, once with H2O and once with brine, dried (sodium sulfate) and concentrated to give an oil which gradually crystallized. The solid was triturated with petroleum ether (30°-60° C.), collected by filtration and dried to yield 72.6 g (84%) of white solid. An analytical sample, mp 43.5°-45° C. (lit. 1 mp 58°-60° C.), was recrystallized from petroleum ether (60°-110° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10](=[N:12][OH:13])[NH2:11])=[CH:4][CH:3]=1.[Cl:14][CH2:15][C:16](Cl)=O>C1(C)C=CC=CC=1>[Cl:14][CH2:15][C:16]1[O:13][N:12]=[C:10]([CH2:9][S:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:11]=1
Reactant: O=C(Cl)CCl
Reactant: NC(CSc1ccc(Cl)cc1)=NO
Solvent: Cc1ccccc1
Product: ClCc1nc(CSc2ccc(Cl)cc2)no1

Procedure:
2-(4-Chlorophenylthio)acetamidoxime (21.7 g, 0.1 mol) was stirred in toluene (150 ml) whilst a solution of chloroacetyl chloride (11.3 g, 0.1 mol) in toluene (50 ml) was added dropwise over 20 minutes. The thick suspension was refluxed for 1 hour to give a black mixture which was cooled and then extracted with water and ether. The ether extracts were evaporated to give a brown oil which was chromatographed on silica gel (200 g) and eluted with ether/hexane (2:3) to give 5-chloromethyl-3-(4-chlorophenylthiomethyl)-1,2,4-oxadiazole.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([O-:8])=O)[N:3]=[C:2]1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[NH2:14][C@H:15]([CH3:31])[CH2:16][N:17]1[CH:21]=[CH:20][C:19]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([Cl:30])[CH:23]=2)=[N:18]1>>[Cl:30][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][N:17]([CH2:16][C@H:15]([NH:14][C:6]([C:4]3[N:3]=[C:2]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[S:1][CH:5]=3)=[O:8])[CH3:31])[N:18]=2)[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]
Reactant: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: CCOC(=O)c1nc(C(=O)[O-])cs1
Product: CCOC(=O)c1nc(C(=O)N[C@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cs1
Yield: 66.3 %

Procedure:
(R)-ethyl 4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-carbamoyl)thiazole-2-carboxylate was prepared using the method of Example 34(d) starting from 2,4-thiazoledicarboxylic acid, 2-ethyl ester (0.528 g, 2.62 mmol) and (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.6 g, 2.186 mmol). The product triturated diethyl ether. Yield 66.3%. 1H-NMR (400 MHz; DMSO-d6): δ 1.17 (d, 3H), 1.34 (t, 3H), 4.34 (dd, 1H), 4.39-4.47 (m, 3H), 4.47-4.56 (m, 1H), 6.94 (d, 1H), 7.83 (d, 1H), 7.95-7.96 (m, 2H), 8.02 (dd, 1H), 8.55 (s, 1H), 8.61 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[CH:11][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C([O-])([O-])=O.[Na+].[Na+].Br[C:31]1[CH:36]=[CH:35][N:34]([CH2:37][CH2:38][CH:39]2[CH2:41][CH2:40]2)[C:33](=[O:42])[C:32]=1[C:43]#[N:44]>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:14]=[C:13]([C:31]2[CH:36]=[CH:35][N:34]([CH2:37][CH2:38][CH:39]3[CH2:41][CH2:40]3)[C:33](=[O:42])[C:32]=2[C:43]#[N:44])[CH:12]=[CH:11][C:3]=1[O:4][CH:5]1[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: N#Cc1c(Br)ccn(CCC2CC2)c1=O
Reactant: CC1(C)OB(c2ccc(OC3CCOCC3)c(Cl)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: N#Cc1c(-c2ccc(OC3CCOCC3)c(Cl)c2)ccn(CCC2CC2)c1=O
Yield: 15.9 %

Procedure:
To a solution of intermediate 18 (0.57 g, 1.7 mmol) in 1,4-dioxane (2 ml) and a saturated solution of Na2CO3 (2 ml) was added intermediate 9 (0.45 g, 1.7 mmol). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.19 mg, 0.17 mmol). The reaction was then microwaved in a sealed tube at 150° C. for 10 minutes. The resulting cooled reaction mixture was then diluted with EtOAc and filtered through a pad of diatomaceous earth. The filtrate was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM/EtOAc up to 30% as eluent). The desired fractions were collected and evaporated in vacuo to yield compound 4 (0.108 g, 17%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7](O)=O.Cl.CN(C)CCCN=C=NCC.N1C=CC=CC=1.[F:28][C:29]([F:64])([F:63])[C:30]([N:32]1[CH2:36][CH2:35][CH2:34][CH:33]1[C:37]1[C:51]([O:52][C:53]2[CH:58]=[CH:57][C:56]([S:59]([CH3:62])(=[O:61])=[O:60])=[CH:55][CH:54]=2)=[CH:50][C:40]2[N:41]=C(C3C=CC=CN=3)[NH:43][C:39]=2[CH:38]=1)=[O:31]>C(OCC)(=O)C>[F:64][C:29]([F:28])([F:63])[C:30]([N:32]1[CH2:36][CH2:35][CH2:34][CH:33]1[C:37]1[C:51]([O:52][C:53]2[CH:58]=[CH:57][C:56]([S:59]([CH3:62])(=[O:61])=[O:60])=[CH:55][CH:54]=2)=[CH:50][C:40]2[N:41]=[C:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)[NH:43][C:39]=2[CH:38]=1)=[O:31]
Reactant: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2C(=O)C(F)(F)F)cc1
Reactant: O=C(O)c1cnccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4cnccn4)[nH]c3cc2C2CCCN2C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
14.5 mg of pyrazine-2-carboxylic acid and 27.0 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride were added in order to a pyridine (1 ml) solution of 53 mg of 1-(2-(4,5-diamino-2-(4-methanesulfonyl-phenoxy)-phenyl)-pyrrolidin-1-yl)-2,2,2-trifluoro-ethanone obtained in Example 162 (step 6), and the reaction liquid was stirred at room temperature for 3 hours. The reaction liquid was diluted with saturated saline, and extracted with ethyl acetate. The organic layers were combined, washed with aqueous saturated ammonium chloride and aqueous saturated sodium bicarbonate in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was dissolved in 1 ml of toluene. 9.9 mg of p-toluenesulfonic acid monohydrate was added to it, and the reaction liquid was stirred at 120° C. for 6 hours. After cooled, the reaction liquid was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=9/1) to obtain the entitled compound as an oily substance.