Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:34])([CH3:33])[CH2:13][C:14]([NH:16][C@H:17]1[C:23](=[O:24])[NH:22][C:21]2[CH:25]=[CH:26][C:27]3[C:32]([C:20]=2[CH2:19][CH2:18]1)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]([O:39][C:40]([NH:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[C:50]1[CH:55]=[CH:54][C:53]([CH2:56]O)=[CH:52][CH:51]=1)=[O:41])([CH3:38])([CH3:37])[CH3:36]>>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:34])([CH3:33])[CH2:13][C:14]([NH:16][C@H:17]1[C:23](=[O:24])[N:22]([CH2:56][C:53]2[CH:52]=[CH:51][C:50]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[CH2:43][NH:42][C:40]([O:39][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:41])=[CH:55][CH:54]=2)[C:21]2[CH:25]=[CH:26][C:27]3[C:32]([C:20]=2[CH2:19][CH2:18]1)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2c(ccc3ccccc23)NC1=O)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CO)cc1
Product: CC(C)(CC(=O)N[C@@H]1CCc2c(ccc3ccccc23)N(Cc2ccc(-c3ccccc3CNC(=O)OC(C)(C)C)cc2)C1=O)NC(=O)OCc1ccccc1

Procedure:
The product of Step B is prepared from 3-benzyloxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]butanamide (Step A) and 2′-[(t-butoxycarbonylamino)methyl]-1,1′-biphenyl-4-methanol, methanesulfonate ester (Example 1, Step G) according to the procedure for Example 1, Step H.
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:51])([CH2:49][CH3:50])[CH2:4][C:5]1[N:6]=[C:7]([CH2:29][CH:30]([NH:44][C:45](=[O:48])[O:46][CH3:47])[C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][N:38]=3)=[CH:33][CH:32]=2)[N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1>O1CCOCC1.CO>[CH3:2][C:3]([CH3:51])([CH2:49][CH3:50])[CH2:4][C:5]1[N:6]=[C:7]([CH2:29][CH:30]([NH:44][C:45](=[O:48])[O:46][CH3:47])[C:31]2[CH:32]=[CH:33][C:34]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][N:38]=3)=[CH:35][CH:36]=2)[NH:8][CH:9]=1
Reactant: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(NC(=O)OC)c2ccc(-c3ccc(F)cn3)cc2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCC(C)(C)Cc1c[nH]c(CC(NC(=O)OC)c2ccc(-c3ccc(F)cn3)cc2)n1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Hydrogen chloride (4N, 2 mL) in dioxane was added to a solution of methyl {2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]ethyl}carbamate in methanol (4 mL) at ambient temperature. The solution was stirred at 50° C. for 2 hr. Concentration of the solution afforded the title compound as a white solid. 1H NMR (500 MHz, CD3OD) δ 8.51 (d, J=3.0 Hz, 1H), 7.95 (d, J=8.5 Hz, 2H), 7.88 (dd, J=4.0, 9.0 Hz, 1H), 7.66 (td, J=3.0, 8.5 Hz, 1H), 7.44 (d, J=8.0 Hz, 2H), 7.13 (s, 1H), 5.15 (t, J=7.7 Hz, 1H), 3.59 (s, 3H), 3.51 (dd, J=8.5, 15.0 Hz, 1H), 3.41 (dd, J=7.0, 14.5 Hz, 1H), 2.49 (dd, J=14.7, 18.7 Hz, 2H), 1.20 (q, J=7.5, 15.2 Hz, 2H), 0.84 (t, J=7.5 Hz, 3H), 0.80 (s, 3H), 0.79 (s, 3H).
Reaction SMILES: [CH:1]1([NH:8][C:9]2[O:10][CH2:11][C:12]3[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:20]1([C:23](O)=[O:24])[CH2:22][CH2:21]1>>[CH:1]1([NH:8][C:9]2[O:10][CH2:11][C:12]3[CH:18]=[C:17]([NH:19][C:23]([CH:20]4[CH2:22][CH2:21]4)=[O:24])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Nc1ccc2c(c1)COC(NC1CCCCCC1)=N2
Reactant: O=C(O)C1CC1
Product: O=C(Nc1ccc2c(c1)COC(NC1CCCCCC1)=N2)C1CC1
Yield: 41.3 %

Procedure:
Prepared from N2-cycloheptyl-4H-benzo[d][1,3]oxazine-2,6-diamine (example 92) (200 mg, 0.77 mmol) and cyclopropanecarboxylic acid (80 mg, 0.93 mmol) according to the procedure described for example 93. Obtained the title compound as an off-white foam (104 mg, 41%), MS (ISP) m/e=328.4 [(M+H)+].
Reaction SMILES: [N:1]([CH2:4][CH:5]([O:14][CH3:15])[CH:6]([OH:13])[CH:7]([OH:12])[C:8](=O)[CH2:9][OH:10])=[N+]=[N-].[H][H]>>[OH:10][CH2:9][CH:8]1[CH:7]([OH:12])[CH:6]([OH:13])[CH:5]([O:14][CH3:15])[CH2:4][NH:1]1
Reactant: [H][H]
Reactant: COC(CN=[N+]=[N-])C(O)C(O)C(=O)CO
Product: COC1CNC(CO)C(O)C1O

Procedure:
Then, the above 6-azido-5-methoxy-1,3,4-trihydroxy-2-hexanone intermediate is cyclized using reductive amination conditions with hydrogen and a catalyst for producing the 2-hydroxymethyl-3,4-dihydroxy-5-methoxypiperidine with the formula:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:8][C:9]1[C:10](Cl)=[N:11][CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Br:8][C:9]1[C:10]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:11][CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cnc(Oc2ccccc2)c(Br)c1
Temperature: 80 °C
Yield: 91 %

Procedure:
Phenol (0.416 g, 4.42 mmol), 3-bromo-2-chloro-5-nitropyridine (Combi-Blocks, CAS [5470-17-7], 1 g, 4.21 mmol) and cesium carbonate (1.372 g, 4.21 mmol) were combined in DMSO (8 mL) and heated at 80° C. for 30 minutes. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. Purification of the residue by chromatography (silica gel, 0-30% ethyl acetate in hexanes) afforded the title compound (1.13 g, 91%).
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[C:7]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]#[N:32])=[CH:21][CH:20]=2)=[C:8]([CH:14]=[CH:15][CH:16]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:33]([O-])([O-])([O-])[O:34][CH3:35]>>[C:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:17]2[C:7]3[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][CH:15]=[CH:16][C:6]=3[N:5]=[C:33]2[O:34][CH3:35])=[CH:20][CH:21]=1)#[N:32]
Reactant: CCOC(=O)c1cccc(N)c1NCc1ccc(-c2ccccc2C#N)cc1
Reactant: COC([O-])([O-])[O-]
Solvent: CC(=O)O
Product: CCOC(=O)c1cccc2nc(OC)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Acetic acid (0.2 g) was added to a solution of ethyl 3-amino-2-[(2'-cyanobiphenyl-4-yl)methyl)aminobenzoate (1.1 g) in methyl orthocarbonate (5 ml). The mixture was stirred at 80° C. for one hour. The reaction mixture was concentrated, and the concentrate was extracted with ethyl acetate. The organic layer was then washed with an aqueous solution of sodium hydrogen carbonate and water. The solvent was evaporated in vacuo to give crystals. Recrystallization from ethyl acetate--benzene afforded colorless crystals (1.09 g, 90%), m.p. 160-161° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:19][CH:18]=2)[CH:10]=1)=[O:2].[BH4-].[Na+]>CO.O1CCCC1>[OH:2][CH2:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:21][CH:22]=2)[CH:10]=1
Reactant: CC(C)(C)OC(=O)CCc1ccc(OCc2cccc(-c3ccccc3C=O)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)CCc1ccc(OCc2cccc(-c3ccccc3CO)c2)cc1
Reaction time: 2 h
Yield: 83 %

Procedure:
tert-Butyl 3-(4-(2′-formylbiphenyl-3-ylmethoxy)phenyl)propanoate (0.30 g, 0.72 mmol) was dissolved in a mixed solution of methanol (6 mL) and tetrahydrofuran (6 mL), and sodium borohydride (14 mg, 0.36 mmol) was added under ice-cooling, and the mixture was stirred at the same temperature for 2 hrs. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-1/1) to give the title compound (0.25 g, yield 83%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([O:21][C:22]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[O:23])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:30])=[N:9]2)=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH:46]1([C:52](O)=[O:53])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1>C(Cl)Cl>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([O:21][C:22]([N:24]4[CH2:25][CH2:26][N:27]([C:52]([CH:46]5[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]5)=[O:53])[CH2:28][CH2:29]4)=[O:23])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:30])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCCCC1
Reactant: O=C(OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1)N1CCNCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1)N1CCN(C(=O)C2CCCCC2)CC1
Yield: 69.4 %

Procedure:
The procedure of Example 14 is followed but starting with 2-(7-chloro-1,8-naphthyridin-2-yl)-3-(piperazin-1-yl)carbonyloxy-isoindolin-1-one (4.23 g.), N,N'-dicyclohexylcarbodiimide (3.1 g.) in anhydrous methylene chloride (100 cc.) and cyclohexylcarboxylic acid (1.92 g.). After having filtered off the precipitate, the organic solution is washed with an 8% aqueous solution of sodium bicarbonate (20 cc.) and then dried over anhydrous potassium carbonate (10 g.). After the solution has been filtered and the filtrate concentrated to dryness, the residue is recrystallised from ethanol (300 cc.). 2-(7-Chloro-1,8-naphthyridin-2-yl)-3-(4-cyclohexylcarbonylpiperazin-1-yl)carbonyloxy-isoindolin-1-one (3.7 g.), which melts at 240° C., is thus obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH:10]([OH:14])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH:10]([OH:14])[C:11]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(O)C(=O)N1CCOCC1

Procedure:
To a solution of 200 mg of (2RS, 3S)-3-tertbutoxycarbonylamino-4-cyclohexyl-2-hydroxybutyric acid which was prepared in Reference Example 4, 0.06 ml of morpholine and 13 mg of 1-hydroxybenzotriazole in 6 ml of ethyl acetate was added 150 mg of dicyclohexylcarbodiimide with stirring under ice-cooling, and the mixture was stirred for 16 hours at room temperature. The reaction mixture was cooled, and filtered to remove insoluble materials. The filtrate was washed successively with an aqueous citric acid solution, a 5% aqueous sodium bicarbonate solution and a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to obtain 296 mg of 4-[(2RS, 3S)-3-(tertbutoxycarbonyl)amino-4-cyclohexyl-2-hydroxybutyryl]morpholine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[C:5]([I:17])=[CH:4][N:3]=1.[CH:18]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C>[CH:18]1([NH:23][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=3)[C:5]([I:17])=[CH:4][N:3]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NC1CCCC1
Reactant: COc1ccc(Nc2nc(Cl)ncc2I)cn1
Solvent: CCO
Product: COc1ccc(Nc2nc(NC3CCCC3)ncc2I)cn1
Temperature: 140 °C
Yield: 91.6 %

Procedure:
A glass microwave reaction vessel was charged with 2-chloro-5-iodo-N-(6-methoxypyridin-3-yl)pyrimidin-4-amine (181 mg, 0.499 mmol), cyclopentylamine (85 mg, 0.998 mmol) and ethanol (3 mL). The reaction mixture was stirred and heated in a Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 140° C. for 30 min. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with 50% EtOAc/hexanes to give N2-cyclopentyl-5-iodo-N4-(6-methoxypyridin-3-yl)pyrimidine-2,4-diamine (188 mg, 0.457 mmol, 92% yield). 1H NMR (300 MHz, CDCl3) δ 8.30 (s, 1H); 8.14 (s, 1H); 7.82 (d, J=10.38 Hz, 1H); 6.75 (d, J=8.92 Hz, 1H); 6.66 (s, 1H); 4.79-4.96 (m, 1H); 4.10 (dd, J=13.15, 4.53 Hz, 1H); 3.94 (s, 3H); 1.97 (dd, J=11.62, 5.19 Hz, 2H); 1.56-1.78 (m, 4H); 1.35-1.50 (m, 2H). m/z (ESI, +ve ion) 412.0 (M+H)+.
Reaction SMILES: CO[CH:3]=[C:4]([C:9]([O:11]C)=O)[C:5]([O:7][CH3:8])=[O:6].[CH3:13][O:14][CH:15]([O:26][CH3:27])[CH2:16][NH:17][C:18]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)=[NH:19].CO>C(OCC)C>[CH3:27][O:26][CH:15]([O:14][CH3:13])[CH2:16][N:17]1[C:9](=[O:11])[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][N:19]=[C:18]1[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(CNC(=N)c1cccnc1)OC
Reactant: COC=C(C(=O)OC)C(=O)OC
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1cnc(-c2cccnc2)n(CC(OC)OC)c1=O

Procedure:
Dimethyl methoxymethylenemalonate and N-(2,2-dimethoxy-ethyl) -3-pyridinecarboxamidine were subjected to a procedure similar to that described in Example 1.b. Chromatography, with methanol:diethyl ether (gradient, 0:100, 10:90) as the eluent, gave methyl 1-(2,2-dimethoxy-ethyl)-2-(3-pyridyl)pyrimidin-6(1H)-one-5-carboxylate as an oil; MS: m/z=320(M+1); TLC: Rf =0.4, methanol:diethyl ether (5:95).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[C:25]([C:27](=[O:33])[NH:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:24]=[CH:23][C:22]=4[O:34][CH2:35]C4CCCNC4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.[C:42](O)([C:44](F)(F)F)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[C:25]([C:27](=[O:33])[NH:28][CH2:29][CH:30]([CH3:31])[CH3:32])[CH:24]=[CH:23][C:22]=4[O:34][CH2:35][C:44]4[CH:42]=[CH:16][N:15]=[CH:13][CH:12]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NCC(C)C)ccc3OCC3CCCNC3)cc12
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NCC(C)C)ccc3OCc3ccncc3)cc12

Procedure:
2-(4-Fluorophenyl)-5-(5-(isobutylcarbamoyl)-2-(piperidin-3-ylmethoxy)phenyl)-N-methyl benzofuran-3-carboxamide, TFA. 1H NMR (400 MHz, THF-d8) δ ppm 0.93 (d, J=6.78 Hz, 6 H), 1.40-1.57 (m, 1 H), 1.75-2.00 (m, 4 H), 2.33 (br. s., 1 H), 2.80-3.00 (m, 5 H), 3.18 (t, J=6.40 Hz, 2 H), 3.32 (d, J=12.05 Hz, 1 H), 3.45 (d, J=10.79 Hz, 1 H), 3.90-4.12 (m, 2 H), 7.03 (d, J=8.53 Hz, 1 H), 7.22 (t, J=8.78 Hz, 2 H), 7.47 (dd, J=8.53, 1.51 Hz, 1 H), 7.58 (d, J=8.53 Hz, 1 H), 7.71 (t, J=5.65 Hz, 1 H), 7.75-7.86 (m, 2 H), 7.92 (s, 2 H), 8.01 (dd, J=8.78, 5.52 Hz, 2 H). LCMS m/z 558.20 (M+H), Rt 1.595 min. HPLC Rt 6.443 min. (Sunfire C18), 99.2% purity and 10.418 min. (XBridge Phenyl C18), 99.2% purity.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]([CH3:41])[C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=2[NH:27][C:28]([C:30]2[CH:38]=[C:37]([Cl:39])[C:36]([Cl:40])=[CH:35][C:31]=2[C:32]([OH:34])=[O:33])=[O:29])=[CH:12][CH:11]=1)=O)(C)(C)C.Cl>CO>[NH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]([CH3:41])[C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:19][C:18]=2[NH:27][C:28]([C:30]2[CH:38]=[C:37]([Cl:39])[C:36]([Cl:40])=[CH:35][C:31]=2[C:32]([OH:34])=[O:33])=[O:29])=[CH:14][CH:15]=1
Reactant: CN(c1ccc(CNC(=O)OC(C)(C)C)cc1)c1ccc(C(F)(F)F)cc1NC(=O)c1cc(Cl)c(Cl)cc1C(=O)O
Agent: Cl
Solvent: CO
Product: CN(c1ccc(CN)cc1)c1ccc(C(F)(F)F)cc1NC(=O)c1cc(Cl)c(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a vial is placed 2-({[2-[(4-{[(tert-butoxycarbonyl)amino]methyl}phenyl)(methyl)amino]-5-(trifluoromethyl)phenyl]amino}carbonyl)-4,5-dichlorobenzoic acid (34 mg, 0.056 mmol) and MeOH (5 mL) saturated with HCl. The mixture is stirred at rt for 2 h. The solution is concentrated and the product purified by preparative thin layer chromatography. The yield is 12 mg of 2-({[2-[[4-(aminomethyl)phenyl](methyl)amino]-5-(trifluoromethyl)phenyl]amino}carbonyl)-4,5-dichlorobenzoic acid, 42%. DMSO: 13.3 (s, 1 H), 8.48 (s, 1 H), 7.76 (s, 2 H), 7.51 (m, 1 H), 7.41 (m, 1 H), 7.16 (m, 2 H), 6.60-6.58 (m, 2 H), 3.81 (s, 2 H), 3.22 (s, 3 H). ESI+ for C23H18Cl2F3N3O3 497 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[N:7]([C:10](=[O:34])[C@@H:11]([NH:16]C(=O)C3C=CC(N4CCN(CCC)CC4)=CC=3)[CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:8][CH2:9][C@H:5]2[O:4][CH2:3]1.[ClH:35].O1CCOCC1.O[C@@H]1[C@H]2N(C(=O)[C@@H](NC(=O)OC(C)(C)C)CC(C)C)CC[C@H]2OC1>>[ClH:35].[NH2:16][C@@H:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:10]([N:7]1[CH2:8][CH2:9][C@H:5]2[O:4][CH2:3][C@H:2]([OH:1])[C@@H:6]12)=[O:34]
Reactant: CCCN1CCN(c2ccc(C(=O)N[C@@H](CC(C)C)C(=O)N3CC[C@H]4OC[C@H](O)[C@H]43)cc2)CC1
Agent: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H]2OC[C@H](O)[C@H]21
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)C[C@H](N)C(=O)N1CC[C@H]2OC[C@H](O)[C@H]21
Reaction time: 2.5 h

Procedure:
Preparation of N—((S)-1-((3R,3aR,6aR)-3-Hydroxydihydro-2H-furo[3,2-b]pyrrol-4(5H, 6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide A solution of HCl in 1,4-dioxane (4.0M, 22 mL, 88 mmol) was added to tert-butyl(S)-1-((3R,3aR,6aR)-3-hydroxydihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-ylcarbamate (1.335 g, 3.90 mmol). The solution was stirred for 2.5 hours then the solvents were removed in vacuo and the residue azeotroped with toluene (3×30 mL) to leave (S)-2-amino-1-((3R,3aR,6aR)-3-hydroxydihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methylpentan-1-one hydrochloride as an off-white solid which was used without further purification. TLC (Rf=0.0, EtOAc:heptane 3:1), analytical HPLC main peak, Rt=3.54 min., HPLC-MS 243.2 [M+H]+, 507.3 [2M+Na]+.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.Cl>C1COCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCC.C(O)C>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C(O)c1ccc(Br)cc1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCO
Product: O=C(O)c1ccc(-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution of 4-bromobenzoic acid (5 g, 0.025 mol) in THF (150 mL) under an atmosphere of argon were added tetrakis(triphenylphosphine) palladium(0) (862 mg, 0.75 mmol), 2 M aqueous Na2CO3 (30 mL), and a solution 4-fluorophenyboronic acid (3.48 g, 0.025 mol) in a minimal amount of ethanol (˜10 mL). The resulting reaction mixture was stirred at reflux under an argon atmosphere for overnight. The reaction mixture was cooled to ambient temperature and acidified with addition of 1 M HCl aqueous. The aqueous layer was extracted with Et2O (three times). The organic layers were combined, dried over MgSO4, filtered and concentrated. The resulting precipitate was crystallized in Et2O and hexane to give 4′-fluoro-biphenyl-4-carboxylic acid (4.4 g, 0.020 mol, 82%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[CH:10][CH:9]=[N:8][C:7]=3[C:6]=2[C:5]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:4]=2[N:3]=1.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH:26][C:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[CH:10][CH:9]=[N:8][C:7]=3[C:6]=2[C:5]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:4]=2[N:3]=1
Reactant: CN(C)CCN
Reactant: COc1ccc2c3c(c(Cl)nc2c1)C(=O)c1cccnc1-3
Product: COc1ccc2c3c(c(NCCN(C)C)nc2c1)C(=O)c1cccnc1-3

Procedure:
In a similar manner to Example 1-d, the desired product was prepared starting from 6-chloro-3-methoxy-5,11-diaza-benzo[c]fluoren-7-one (Example 14c-1) and N,N-dimethylethylenediamine. The product was obtained as an orange solid. ESI−MS: m/z 349 (MH+); 1H-NMR (CDCl3): δ2.37 (6H, s), 2.67 (2H, t, J=6.5 Hz), 3.79 (2H, dt, J=5.5 Hz, 6.5 Hz), 3.96 (3H, s), 6.96 (1H, dd, J=9 Hz, 2.5 Hz), 7.04 (1H, d, J=2.5 Hz), 7.25 (1H, brt, J=ca 5.5 Hz), 7.28 (1H, dd, J=4.5 Hz, 7.5 Hz), 7.85 (1H, dd, J=7.5 Hz, 1.5 Hz), 8.67 (1H, dd, 4.5 Hz, 1.5 Hz), 8.96 (1H, d, J=9 Hz).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:40])[CH2:7][S:8][C:9]1[N:14]=[C:13]([NH:15][CH2:16][CH2:17][NH:18][C:19](=[O:29])[C:20]2[CH:25]=[CH:24][C:23]([N:26]=[N+:27]=[N-:28])=[CH:22][CH:21]=2)[C:12]([C:30](=[O:39])[NH:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[CH:11][N:10]=1)C.Cl>C1COCC1>[N:26]([C:23]1[CH:22]=[CH:21][C:20]([C:19]([NH:18][CH2:17][CH2:16][NH:15][C:13]2[C:12]([C:30](=[O:39])[NH:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)=[CH:11][N:10]=[C:9]([S:8][CH2:7][C:6]([OH:40])=[O:5])[N:14]=2)=[O:29])=[CH:25][CH:24]=1)=[N+:27]=[N-:28]
Reactant: CCOC(=O)CSc1ncc(C(=O)Nc2ccc(F)cc2)c(NCCNC(=O)c2ccc(N=[N+]=[N-])cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: [N-]=[N+]=Nc1ccc(C(=O)NCCNc2nc(SCC(=O)O)ncc2C(=O)Nc2ccc(F)cc2)cc1
Reaction time: 1 h
Yield: 52.2 %

Procedure:
1 M NaOH (0.5 mL, 0.5 mmol) was added to a solution of [4-[2-(4-Azido-benzoylamino)-ethylamino]-5-(4-fluorophenylcarbamoyl)pyrimidin-2-ylsulfanyl]acetic acid ethyl ester (8 mg, 0.015 mmol) in THF (0.5 mL) at ambient temperature. The reaction was stirred for 1 h, then acidified with 1 N HCl to pH 3. The reaction mixture was concentrated by rotary evaporation, and the resulting solid was filtered, washed with water and dried to yield the titled product (4 mg, 53%) as a white solid. 1H NMR: (d6-DMSO) δ 10.22 (s, 1H), 8.63 (m, 1H), 8.56 (s, 1H), 7.82 (d, 2H), 7.60 (m, 2H), 7.13 (m, 3H), 3.89 (s, 2H), 3.62 (m, 2H), 3.34 (m, 2H); HPLC: Rt=4.13 min; MS (ESI): m/z 509.07 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][C:26]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[C:29]3[CH3:37])[CH2:25][CH2:24]2)=[O:22])=[CH:4][CH:3]=1.[CH3:38][S:39]([NH2:42])(=[O:41])=[O:40]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:42][S:39]([CH3:38])(=[O:41])=[O:40])=[O:20])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][C:26]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[C:29]3[CH3:37])[CH2:25][CH2:24]2)=[O:22])=[CH:4][CH:3]=1
Reactant: CC1=Cc2ccccc2C12CCN(C(=O)c1cnc3c(C(=O)O)cnn3c1Nc1ccc(F)cc1)CC2
Reactant: CS(N)(=O)=O
Product: CC1=Cc2ccccc2C12CCN(C(=O)c1cnc3c(C(=O)NS(C)(=O)=O)cnn3c1Nc1ccc(F)cc1)CC2
Yield: 71.3 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(4-fluorophenylamino)-6-(2-methylspiro[inden-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.040 g, 0.083 mmol) obtained in step 2 and methanesulfonamide (0.040 g, 0.417 mmol), the title compound (0.034 g, 71%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13]>>[Cl:13][CH2:12][CH2:11][CH2:10][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: ClCCCBr
Reactant: Oc1cccc(F)c1
Product: Fc1cccc(OCCCCl)c1

Procedure:
Prepared by Procedure U and Scheme AK using 3-fluorophenol and 1-bromo-3-chloropropane.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][OH:5].[CH3:6][CH:7]([CH3:23])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:12]=1)=[O:9]>>[OH:5][CH2:4][CH2:3][CH2:2][N:20]1[CH2:21][CH2:22][CH:17]([C:13]2[CH:12]=[C:11]([NH:10][C:8](=[O:9])[CH:7]([CH3:6])[CH3:23])[CH:16]=[CH:15][CH:14]=2)[CH2:18][CH2:19]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: OCCCCl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCO)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 3-chloro-1-propanol and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 305.3 (M+H)+.