Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5].[CH2:9](Br)[CH3:10].O.N.C(O)(=O)C>O>[CH2:9]([S:5][CH2:4][C@@H:3]([C:6]([OH:8])=[O:7])[NH2:2])[CH3:10]
Reactant: CCBr
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Agent: N
Solvent: CC(=O)O
Solvent: O
Product: CCSC[C@H](N)C(=O)O
Temperature: 25 °C

Procedure:
SEC is synthesized from L-cysteine hydrochloride (1.58 g, 0.01 mol) and ethyl bromide (1.09 g, 0.01 mol) with the following steps. The reaction mixture is diluted with water in a titration manner until a clear solution is formed. No more than necessary amount of water should be added to further dilute the mixture. Ammonia water was added to PH 9.5-10 with stirring at room temperature. After 2 hours reaction, the mixture is acidified with acetic acid to PH 5-5.5. The desired product was cooled in the refrigerator, filtered and washed successively with water and ethyl ether. The chemical structure of SEC is determined by Proton Nuclear Magnetic Resonance Spectroscopy.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:11].[C:12]1(=[O:16])[O:15][CH2:14][CH2:13]1.Cl>O>[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[O:11][CH2:14][CH2:13][C:12]([OH:16])=[O:15]
Reactant: Oc1cccc(Cl)c1Cl
Reactant: O=C1CCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCOc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.4 g (0.01 mol) of Sodium hydroxide was dissolved in 4 ml of water. To this stirred solution was added 1.63 g (0.01 mol) of 2,3-dichloro phenol was added. Once the solid had dissolved the alkaline solution was kept stirring at 100 C for 1 hour. After that β-propiolactone 0.72 g (0.628 ml, 0.01 mol) was added slowly in drops for 5 minutes. The reaction mixture was further continued heating for 12 h. The reaction mixture was cooled to room temperature and water 10 ml was added. This diluted mixture was acidified by the addition of Con. HCl. The product was extracted twice with diethyl ether (20 ml). The ether layer was then washed with 10% Sodium bicarbonate. The aqueous layer was acidified to pH=2. The precipitated solid was filtered and dried to afford the required product 3-(2,3-dichlorophenoxy)propanoic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1>>[CH3:26][C:24]1[NH:23][N:22]=[C:21]([NH:20][C:12]2[N:11]=[C:10]([O:8][C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][CH:5]=3)[C:19]3[C:14]([CH:13]=2)=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:25]=1
Reactant: Cc1cccc(O)c1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cccc(Oc2nc(Nc3cc(C)[nH]n3)cc3ccccc23)c1

Procedure:
Similar procedure as described in example 10 was used, starting from 3-methyl-phenol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (5-methyl-1H-pyrazol-3-yl)-(1-m-tolyloxy-isoquinolin-3-yl)-amine. LC-MS m/e 331(MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:18][CH2:17][CH2:16][N:15]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.CO.[BH4-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:18][CH2:17][CH2:16][N:15]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: COc1cc(N2CCCN(S(C)(=O)=O)CC2)ccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(N2CCCN(S(C)(=O)=O)CC2)ccc1N
Yield: 50.7 %

Procedure:
1-[3-(methyloxy)-4-nitrophenyl]-4-(methylsulfonyl)hexahydro-1H-1,4-diazepine (0.737g, 2.24 mmol) was suspended in 5 mL THF and 10 mL MeOH in a 100 mL round bottom flask. NiCl2-6H2O (159 mg, 0.672 mmol) was added followed by slow addition of NaBH4 (254 mg, 6.72 mmol). Reaction mixture was adsorbed onto SiO2 and purified via column chromatography to afford 2-(methyloxy)-4-[4-(methylsulfonyl)hexahydro-1H-1,4-diazepin-1-yl]aniline (340 mg, 51%) 1H NMR (400 MHz, DMSO-d6) δ ppm 1.82-1.94 (m, 2 H) 2.80 (s, 3 H) 3.17 (t, J=5.82 Hz, 2 H) 3.36-3.43 (m, 2 H) 3.49 (dd, J=10.68, 3.99 Hz, 4 H) 3.75 (br. s., 3 H) 4.01-4.15 (m, 2 H) 6.10-6.20 (m, 1 H) 6.26-6.35 (m, 1 H) 6.48-6.59 (m, 1 H). ESIMS (M+H)+301
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:10]=2)[C:5](F)=[N:6][CH:7]=1.[F:35][C:36]1[CH:37]=[C:38]([NH2:42])[CH:39]=[N:40][CH:41]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH2:16])[N:10]=2)[C:5]([NH:42][C:38]2[CH:39]=[N:40][CH:41]=[C:36]([F:35])[CH:37]=2)=[N:6][CH:7]=1
Reactant: Nc1cncc(F)c1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3F)n2)cc1
Product: Cc1nc(N)nc(-c2cc(Cl)cnc2Nc2cncc(F)c2)n1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 246 using 4-(5-chloro-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine and 5-fluoropyridin-3-amine (Matrix Scientific), and was isolated as an orange amorphous solid (10%). m/z (ESI, +ve ion) 332.0 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.27 (1H, s); 8.77-8.84 (2H, m); 8.44-8.51 (2H, m); 8.21 (1H, d, J=2.5 Hz); 8.05 (1H, br. s.); 7.91 (1H, br. s.); 2.47 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([F:11])=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.[NH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:25]=1[C:26]([OH:28])=[O:27].Cl>CC(O)C.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:23][C:24]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:25]=2[C:26]([OH:28])=[O:27])[C:5]2[C:10]([F:11])=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: Nc1cccc(F)c1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)n2cc(F)c3c(Cl)nc(Cl)nc32)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(F)c3c(Nc4cccc(F)c4C(=O)O)nc(Cl)nc32)cc1
Temperature: 25 °C
Yield: 41.5 %

Procedure:
A slurry of 2,4-dichloro-5-fluoro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (1.250 g, 3.47 mmol) DIPEA (3.03 mL, 17.35 mmol) and 2-amino-6-fluorobenzoic acid (0.646 g, 4.16 mmol) in iPrOH (30 mL) was heated at 90° C. for 3 h. The resulting mixture was allowed to cool to rt and diluted with EtOAc (100 mL) and a 1N HCl solution (100 mL). The organic layer was washed with a saturated NaHCO3 solution (100 mL) and a saturated NaCl solution (100 mL). The organic layer was diluted with Et2O and the resulting slurry filtered. The solids were washed with Et2O and dried in vacuum to afford 2-({2-chloro-5-fluoro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzoic acid (0.69 g, 41%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.38 (s, 3H), 6.71-6.87 (m, 1H), 7.21-7.36 (m, 1H), 7.48 (d, J=8.06 Hz, 2H), 7.76 (s, 1H), 7.96 (d, J=8.42 Hz, 2H), 8.26 (d, J=8.61 Hz, 1H).
Reaction SMILES: F[C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.CC(C)([O-])C.[K+].O>CN(C=O)C>[N+:8]([C:3]1[C:2]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ncccc1F
Reactant: Nc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ncccc1Nc1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-fluoro-2-nitropyridine (3.32 g, 23.38 mmol) and 2-aminopyridine (2.0 g, 21.25 mmol) in DMF (35.4 mL) was added potassium tert-butoxide (4.77 g, 42.5 mmol). The solution was stirred under nitrogen at rt overnight. After 22 h, the mixture was poured into water (100 mL) and extracted with EtOAc (2×100 mL). After drying with MgSO4, the solution was filtered and concentrated in vacuo to provide the crude material as a orange solid. The orange solid was purified by chromatography through a Redi-Sep™ pre-packed silica gel column (80 g), eluting with a gradient of 0% to 50% EtOAc in hexane, to provide N-(2-nitropyridin-3-yl)pyridin-2-amine as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.53 (1H, s), 8.58 (1H, dd, J=8.4, 1.6 Hz), 8.15 (1H, dd, J=4.3, 1.4 Hz), 8.10-8.14 (1H, m), 7.66-7.76 (2H, m), 7.05 (1H, dt, J=8.4, 0.8 Hz), 6.93 (1H, ddd, J=7.2, 5.0, 0.9 Hz); LC-MS (ESI) m/z 217.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:16]([C:28]2[CH:29]=[CH:30][C:25]([C:24]([F:35])([F:34])[F:23])=[CH:26][CH:27]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
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: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1-c1ccc(C(F)(F)F)cc1
Yield: 35.9 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-(trifluoromethyl)biphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 4-(trifluoromethyl)phenylboronic acid (0.035 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 180° C. for 5 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.028 g (35%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-(trifluoromethyl)biphenyl-2-carboxamide as a white solid.
Reaction SMILES: CS(O[CH2:6][C@H:7]([N:29]1[C:37]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[C:36]2[C:31]([N:32]([CH3:47])[C:33](=[O:46])[N:34]([CH3:45])[C:35]2=[O:44])=[CH:30]1)[CH2:8][S:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)=O.[CH3:48][NH:49][CH3:50]>CN(C=O)C.CCOC(C)=O>[CH3:48][N:49]([CH2:6][C@H:7]([N:29]1[C:37]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[C:36]2[C:31]([N:32]([CH3:47])[C:33](=[O:46])[N:34]([CH3:45])[C:35]2=[O:44])=[CH:30]1)[CH2:8][S:9][C:10]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:50]
Reactant: Cn1c(=O)c2c(-c3ccccc3)n([C@@H](COS(C)(=O)=O)CSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2n(C)c1=O
Reactant: CNC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)n1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C
Temperature: 120 °C

Procedure:
(S)-2-(1,3-Dimethyl-2,4-dioxo-5-phenyl-3,4-dihydro-1H-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)-3-(tritylthio)propyl methanesulfonate (step 3)(1.7 g, 2.55 mmol) was dissolved in DMF (12 mL) and dimethylamine (40% wt. aqueous solution) (1.455 mL, 11.49 mmol) was added. The mixture was heated under microwave irradiation at 120° C. for 15 h. The reaction mixture was diluted with EtOAc and washed with brine (4×). The organic phase was dried over sodium sulphate and evaporated under vacuum. The residue was redissolved in DCM and evaporated onto silica. Purification by chromatography on silica, eluting with 20-100% EtOAc in iso-hexane gave the title compound.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:21])([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:19]=[CH:18][NH:17][C:16]2=[O:20])=[CH:11][CH:10]=1)[CH:5]([F:7])[F:6].[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[C@@:30]1([CH2:34][N:35]2[CH:39]=[N:38][CH:37]=[N:36]2)[C@H:32]([CH3:33])[O:31]1>>[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[C@@:30]([OH:31])([CH2:34][N:35]1[CH:39]=[N:38][CH:37]=[N:36]1)[C@H:32]([N:17]1[CH:18]=[CH:19][N:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][C:4]([F:3])([F:21])[CH:5]([F:6])[F:7])=[CH:10][CH:11]=2)[C:16]1=[O:20])[CH3:33]
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=c1[nH]ccn1-c1ccc(OC(F)(F)C(F)F)cc1
Agent: [H-]
Agent: [Na+]
Product: C[C@@H](n1ccn(-c2ccc(OC(F)(F)C(F)F)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
60% Sodium hydride in oil (2.4 g) was added portionwise to a stirred solution of 1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone (16.6 g) and the resulting mixture was stirred for 30 minutes at room temperature. (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane (10 g) was added and the mixture was stirred at 80° C. for 20 hours. After cooling, the mixture was concentrated into a volume of about 50 ml under reduced pressure and diluted ice-water (400 ml) and ethyl acetate (500 ml). The ethyl acetate layer was separated, washed with a 10% aqueous phosphoric acid solution (400 ml) and an aqueous solution of sodium chloride (400 ml×2) successively and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/1 to 2/1) to give 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone (7.56 g) as an oily substance, which was identical with the compound obtained in the Reference Example 47.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:32])[NH:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=4)=[O:20])[CH2:15][CH2:14]3)[N:10]=2)[CH2:3]1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>C(Cl)Cl>[CH3:33][S:34]([O:1][CH:2]1[CH2:3][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:32])[NH:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=4)=[O:20])[CH2:15][CH2:14]3)[N:10]=2)[CH2:5]1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NC1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)c1csc(N2CC(O)C2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)NC3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)cs2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a solution of 3-hydroxy-1-{4-[1-(p-nitrobenzyloxycarbonyl)-piperidin-4-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (360 mg, 0.780 mmol) (obtained as described in Reference Example 51(6)) in methylene chloride (18 ml) were added methanesulfonyl chloride (181 μl, 2.34 mmol) and triethylamine (328 μl, 2.34 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 1 hour. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate→ethyl acetate:methanol (98:2) as the eluant to afford 3-methanesulfonyloxy-1-{4-[1-(p-nitrobenzyloxycarbonyl)-piperidin-4-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (390 mg, yield 93%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([OH:8])[CH:7]=1.Br[CH:12]([CH:14]1[CH2:16][CH2:15]1)O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([O:8][CH2:12][CH:14]2[CH2:16][CH2:15]2)[CH:7]=1
Reactant: OC(Br)C1CC1
Reactant: OCc1ccc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCc1ccc(Cl)cc1OCC1CC1
Temperature: 80 °C
Yield: 13.1 %

Procedure:
Charged 5-chloro-2-(hydroxymethyl)phenol (616 mg, 3.88 mmol, PREPARATION 7), bromocyclopropylmethanol (525 mg, 3.88 mmol), K2CO3 (1.07 g, 7.77 mmol) and DMF (6 mL) to a flask, purged with nitrogen and heated to 80° C. overnight. Poured into ice water, and extracted with ethyl acetate twice, and washed the organic phase with water twice, brine and dried with anhydrous Na2SO4, removed the solvent for silica gel chromatograph to give 108 mg of the title compound (13%). 1H NMR (400 MHz, CDCl3): δ 0.33-0.37 (2H, m), 0.63-0.68 (2H, m), 1.26-1.28 (1H, m), 3.84 (2H, d, J=7.2 Hz), 4.67 (2H, s), 4.86 (1H, s), 6.84 (1H, d, J=1.2 Hz), 6.91 (1H, dd, J=2.0 Hz, 8.0 Hz), 7.19 (1H, d, J=7.6 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[Cl:14]N1C(=O)CCC1=O>C(Cl)Cl.O>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([Cl:14])=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc2c(Cl)c[nH]c2c1
Reaction time: 2 h
Yield: 630.5 %

Procedure:
To a solution of 1H-indole-6-carboxylic acid methyl ester (5.86 g, 33.5 mmol) in 30 mL of CH2Cl2 is added N-chlorosuccinimide (0.58, 4.33 mmol) portionwise over 1.5 hours. The mixture is stirred for 2 h, then diluted with water. The layers are separated and the organic phase is washed with water and saturated NaCl solution. The organic layer is dried over MgSO4, filtered and concentrated in vacuo to give the title compound (5.74 g, 27.3 mmol). The crude product is used in the next step without further purification. 1H NMR (CDCl3, 300 MHz) δ8.46 (bs, 1H), 8.19 (s, 1H), 7.90 (dd, 1H), 7.69 (d, 1H), 7.36 (d, 1H), 3.97 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1F.[NH:13]1[C:17]2[N:18]=[CH:19][CH:20]=[C:21]([OH:22])[C:16]=2[CH:15]=[CH:14]1>>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[O:22][C:21]1[CH:20]=[CH:19][N:18]=[C:17]2[NH:13][CH:14]=[CH:15][C:16]=12
Reactant: Oc1ccnc2[nH]ccc12
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Product: O=[N+]([O-])c1cc(F)c(Oc2ccnc3[nH]ccc23)cc1F
Yield: 40 %

Procedure:
Following a similar procedure as described in Step A of Example 313 and using 1,2,4-trifluoro-5-nitrobenzene, 1H-pyrrolo[2,3-b]pyridin-4-ol (268 mg, 2.0 mmol) was converted to the title compound (230 mg, 40%). MS(ESI) m/z 292.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:20](O)=[O:21])=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.C(N1C=CN=C1)([N:26]1C=CN=C1)=O.[OH-].[NH4+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:20]([NH2:26])=[O:21])=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)O)s1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(N)=O)s1
Temperature: 60 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To a solution of 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-thiazole-5-carboxylic acid (83 mg, 0.25 mmol) in DMF (2.5 mL) was added 1,1′-carbonyldiimidazole (49 mg, 0.3 mmol). The resulting reaction mixture was stirred for 1 h at 60° C. and then treated with an ammonium hydroxide solution (25%, 385 μL, 2.5 mmol) and stirred for 2 h at room temperature. The reaction mixture was then evaporated. Purification by trituration from water/methanol afforded the title compound (64 mg, 77%) as an off white solid after. MS: m/e=331.0 [M+H]+.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[OH:21][C:22]1[C:23]([C:32](Cl)=[O:33])=[CH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2>>[OH:21][C:22]1[C:23]([C:32](=[O:33])[CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2
Reactant: CC(=O)OC(C)(C)C
Reactant: O=C(Cl)c1cc2ccccc2cc1O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)CC(=O)c1cc2ccccc2cc1O

Procedure:
Prepared according to above procedure using diisopropylamine (2.0 mL, 15 mmol), nBuLi (11.4 mL, 1.2 M), tert-butyl acetate (3.4 mL, 12 mmol), 3-hydroxynaphthalene-2-carbonyl chloride (3.9 mmol, prepared from 730 mg of 3-hydroxy-2-naphthoic acid and SOCl2, 0.9 mL, heated to 40° C. in 9 mL toluene for 4 h) yielding 666 mg (57%) as yellow needles. mp=80-84° C.; IR (film) 2981.9; 2919.0; 1732.1; 1642.5; 1261.4; 1147.6 cm−1; 1H NMR (500 MHz, CDCl3) δ 11.17 (s, 1H); 8.29 (s, 1H); 7.78 (d, J=8.0 Hz, 1H); 7.65 (d, J=8.2 Hz, 1H); 7.50 (t, J=7.0, 1H); 7.33-7.27 (m, 2H); 4.05 (s, 2H); 1.42 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 199.3, 166.2, 157.2, 138.5, 133.7, 130.2, 129.6, 127.1, 126.5, 124.5, 120.9, 112.7, 82.9, 47.8, 28.1; LRMS (electrospray): Mass calculated for C17H18O4, [M]+, 286.12. Found [M]+, 285.8.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[N:7][S:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])[N:3]=[N:2]1.[CH3:14][Mg]Br.C(OCC)C>C1COCC1>[NH:1]1[CH:5]=[C:4]([CH:6]([NH:7][S:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])[CH3:14])[N:3]=[N:2]1
Reactant: C[Mg]Br
Reactant: CC(C)(C)S(=O)N=Cc1c[nH]nn1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(NS(=O)C(C)(C)C)c1c[nH]nn1
Temperature: -70 °C

Procedure:
N-((1H-1,2,3-triazol-4-yl)methylene)-2-methylpropane-2-sulfinamide (Preparation 64, 2 g, 10 mmol) was dissolved in THF (80 mL) under nitrogen and cooled to −70° C. A solution of methylmagnesium bromide in diethyl ether (3.5M, 7.5 mL, 22.5 mmol) was added dropwise over a period of 15 minutes, keeping the reaction temperature below −60° C. The reaction was stirred with cooling for a further 40 minutes then the cooling bath was removed and the mixture was stirred at room temperature for 18 hours. The reaction was quenched by the addition of saturated aqueous sodium chloride solution (0.5 mL) followed by 2M (aq) HCl (12 mL). The THF was removed in vacuo and the residue acidifed to pH=4 with 2M (aq) HCl. The solution was extracted with EtOAc (110 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 40-100% EtOAc in heptanes to afford the title compound as a 4:1 mixture of diastereomers (1.09 g, 50%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:38]=[CH:39][CH:40]=1)[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[C:20]([O:22][CH:23]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:45]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:38]=[CH:39][CH:40]=1)[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[C:20]1[O:22][C:23]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:45]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)C(OC(=O)C1CCCCN1C(=O)c1cccc(OCc2ccccc2)c1)c1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: O=C(c1cccc(OCc2ccccc2)c1)N1CCCCC1c1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Yield: 37.4 %

Procedure:
A mixture of 2-oxo-1,2-diphenylethyl 1-(3-benzyloxybenzoyl)-2-piperidinecarboxylate (288 mg) and ammonium acetate (427 mg) in acetic acid (1.4 ml) was stirred under reflux for 3 hours, cooled to room temperature, and partitioned between ethyl acetate and aqueous NaHCO3. The organic layer was washed with aqueous NaHCO3 (twice) and brine, dried over MgSO4, and evaporated in vacuo. The residue was chromatographed over silica gel to afford 1-(3-benzyloxybenzoyl)-2-(4,5-diphenyl-2-oxazolyl)piperidine (104 mg) as amorphous powder.