Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([S:23][CH3:24])=[N:19][NH:20]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.CCOC(C)=O>C(Cl)Cl.CCCCCCC.CC([O-])=O.CC([O-])=O.[Cu+2]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([S:23][CH3:24])=[N:19][N:20]3[C:30]3[CH:31]=[C:26]([CH3:25])[CH:27]=[CH:28][CH:29]=3)=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(B(O)O)c1
Reactant: CSc1n[nH]c2cc(C3=CCN(C(=O)OC(C)(C)C)CC3)ccc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CSc1nn(-c2cccc(C)c2)c2cc(C3=CCN(C(=O)OC(C)(C)C)CC3)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 4-(3-methylsulfanyl-1H-indazol-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (63 mg, 0.18 mmol) and 3-methyl phenyl boronic acid (50 mg, 0.36 mmol) in CH2Cl2 (1.5 mL) were added TEA (0.051 mL, 0.36 mmol) and Cu(OAc)2 (33 mg, 0.18 mmol). The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was loaded onto a silica-gel column and chromatography (gradient eluent heptane to 50% EtOAc in heptane) to yield 4-(3-Methylsulfanyl-1-m-tolyl-1H-indazol-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as colorless film stuck on flask wall.
Reaction SMILES: CS([O:5][CH:6]1[CH2:9][N:8]([C:10]2[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:11]=2[C:12]([O:14]C)=[O:13])[CH2:7]1)(=O)=O.[F:24][C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][C:26]=1[C:32]([F:35])([F:34])[F:33]>>[F:24][C:25]1[CH:30]=[CH:29][C:28]([O:5][CH:6]2[CH2:9][N:8]([C:10]3[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:11]=3[C:12]([OH:14])=[O:13])[CH2:7]2)=[CH:27][C:26]=1[C:32]([F:33])([F:34])[F:35]
Reactant: Oc1ccc(F)c(C(F)(F)F)c1
Reactant: COC(=O)c1cc(C(F)(F)F)cnc1N1CC(OS(C)(=O)=O)C1
Product: O=C(O)c1cc(C(F)(F)F)cnc1N1CC(Oc2ccc(F)c(C(F)(F)F)c2)C1
Yield: 98.7 %

Procedure:
The title compound (D125) (108 mg) was prepared according to the experimental procedure described in Description 103A starting from methyl 2-(3-((methylsulfonyl)oxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinate (D68) (100 mg, 0.258 mmol) and 4-Fluoro-3-(trifluoromethyl)phenol (60.98 mg, 0.338 mmol).
Reaction SMILES: C([Li])CCC.[CH2:6]([C@H:13]1[CH2:17][O:16][C:15](=[O:18])[NH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](Cl)=[O:29])=[CH:23][CH:22]=1>C1COCC1>[CH2:6]([C@H:13]1[CH2:17][O:16][C:15](=[O:18])[N:14]1[C:28](=[O:29])[CH2:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
n-Butyllithium (15.4 ml, 24.7 mmol, 1.6 M) was added to a solution of (S)-4-benzyl oxazolidinone (4.00 g, 22.5 mmol) in dry THF (100 ml) at −78° C. and stirred for 30 min. Then p-methoxyphenyl acetyl chloride (6.50 ml, 29.3 mmol) in THF (50 ml) was added to the reaction mixture at −78° C. The reaction mixture was allowed to warm up to room temperature and stirred overnight. It was then quenched with saturated ammonium chloride solution (50 ml) and extracted with ethyl acetate (3×50 ml). The crude compound was purified by column chromatography over silica gel (60-120 mesh) using ethyl acetate (7%) in petroleum ether as eluent to afford 6.0 g (82.5%) of (S)-4-benzyl-3-(2-(4-methoxyphenyl)acetyl)oxazolidin-2-one as an off-white color solid.
Reaction SMILES: [NH2:1][C:2]([CH3:20])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[C:12]([Cl:19])[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[C:8]2=[N:7]1)[C:3]#[N:4].[F:21][C:22]([F:33])([F:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[S:28])=[CH:25][CH:24]=1>>[Cl:19][C:12]1[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[C:8]2[C:9]([CH:11]=1)=[N:10][N:6]([CH2:5][C:2]([NH:1][C:27](=[S:28])[C:26]1[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:32])[F:33])=[CH:31][CH:30]=1)([C:3]#[N:4])[CH3:20])[N:7]=2
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: CC(N)(C#N)Cn1nc2cc(Cl)cc(C(F)(F)F)c2n1
Product: CC(C#N)(Cn1nc2cc(Cl)cc(C(F)(F)F)c2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(6-chloro-4-trifluoromethyl-2H-benzotriazol-2-yl)-2-methylpropionitrile (100 mg, described in Example 32) and 4-trifluoromethylthiobenzoyl chloride (0.12 mL), the title compound was isolated as a white solid (142 mg, 85%). MS (ES): M/Z [M+H]=508. NMR: (400 MHz, DMSO-d6): 1.77 (s, 3H), 2.47 (s, 3H), 5.46 (d, J=13.3 Hz, 1H), 5.62 (d, J=13.3 Hz, 1H), 7.82-7.88 (m, 4H), 7.96 (s, 1H), 8.57 (s, 1H) and 8.93 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −42.05 (s, 3F) and −61.51 (s, 3F).
Reaction SMILES: Br[C:2]1[C:3]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:26]2)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[CH2:13][CH2:14][O:15][CH3:16])=[CH:9][N:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:5]2=[N:6][CH:7]=1.[CH:39]1(B(O)O)[CH2:41][CH2:40]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.CCOC(C)=O.O.C(O[Pd]OC(=O)C)(=O)C.CC#N.O>[C:35]([O:34][C:32]([NH:31][C@@H:27]1[CH2:28][CH2:29][CH2:30][N:25]([C:3]2[C:2]([CH:39]3[CH2:41][CH2:40]3)=[CH:7][N:6]=[C:5]3[N:8]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH:9]=[C:10]([NH:11][C:12](=[O:17])[CH2:13][CH2:14][O:15][CH3:16])[C:4]=23)[CH2:26]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: OB(O)C1CC1
Reactant: COCCC(=O)Nc1cn(C(=O)OC(C)(C)C)c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Agent: CC(=O)O[Pd]OC(C)=O
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COCCC(=O)Nc1cn(C(=O)OC(C)(C)C)c2ncc(C3CC3)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 80 °C
Reaction time: 22 h
Yield: 22.3 %

Procedure:
A mixture of (R)-tert-butyl 5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-(3-methoxypropanamido)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (370 mg, 0.620 mmol), cyclopropylboronic acid (213 mg, 2.48 mmol), tricyclohexylphosphine (20.9 mg, 0.0744 mmol), K3PO4 (461 mg, 2.17 mmol), and diacetoxypalladium (13.9 mg, 0.0620 mmol) in toluene/water (10:1 mixture, 9 mL) was stirred at 80° C. for 22 hours. The mixture was then diluted with EtOAc (60 mL) and water (10 mL) was added. The layers were separated, and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The oily residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 20%-90% CH3CN/water, 24CV) to provide (R)-tert-butyl 4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-5-cyclopropyl-3-(3-methoxypropanamido)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (77 mg, 22% yield) as a solid. LCMS (APCI+) m/z 558 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.[CH2:20]([O:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42](Cl)=[O:43])=[CH:37][CH:36]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(Cl)Cl>[CH2:20]([O:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42]([NH:1][C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:43])=[CH:37][CH:36]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)Cl)cc1
Reactant: CCOC(=O)c1cccc(N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2cccc(C(=O)OCC)c2)cc1
Reaction time: 2.5 h

Procedure:
A solution of 10.13 g of ethyl 3-amino-benzoate and 6.82 g of triethylamine in 100 ml of methylene chloride is added dropwise to a solution of p-tetradecyloxyphenylacetyl chloride in 100 ml of methylene chloride over 15 minutes. The mixture is stirred for an additional 2.5 hours then washed with dilute hydrochloric acid. The organic layer is evaporated and the residue dissolved in 1.5 liter of ether then washed with dilute sodium hydroxide. The organic layer is dried and evaporated to a residue which is crystallized from carbon tetrachloride:hexane to give 24.4 g of the desired product as a white solid, m.p. 91°-94° C.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6](/[C:10](=[N:12]/[S@:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])/[CH3:11])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].O.[BH4-].[Na+]>C1COCC1>[CH:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][S@:13]([C:15]([CH3:18])([CH3:16])[CH3:17])=[O:14])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: C/C(=N\[S@@](=O)C(C)(C)C)c1cccc(C(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1cccc([C@H](C)N[S@@](=O)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S,E)-N-(1-(3-isopropylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (9.5 g, 0.036 mol) in THF (98 mL)/H2O (2 mL) was added NaBH4, the mixture was stirred at room temperature for 16 hours. The mixture was then partitioned between EtOAc and water, the layers were separated and the organic layer was washed with water, brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography to give the titled compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:21][C:22]([C:24]3([CH2:29][C:30]([O:32]CC4C=CC=CC=4)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[C:16]3[NH:20][N:19]=[N:18][N:17]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1>CO.[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:21][C:22]([C:24]3([CH2:29][C:30]([OH:32])=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[C:16]3[NH:17][N:18]=[N:19][N:20]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(-c2ccc(C[C@H](NC(=O)C3(CC(=O)OCc4ccccc4)CCCC3)c3nnn[nH]3)cc2)c1
Agent: [Pd]
Solvent: CO
Product: Cc1cccc(-c2ccc(C[C@H](NC(=O)C3(CC(=O)O)CCCC3)c3nnn[nH]3)cc2)c1

Procedure:
(S)-benzyl 2-(1-(2-(3′-methylbiphenyl-4-yl)-1-(1H-tetrazol-5-yl)ethylcarbamoyl)cyclopentyl)acetate (175 mg, 0.334 mmol) was hydrogenated with 5% Pd—C (35.6 mg) in MeOH at room temperature for 0.5 hours. The reaction mixture was filtered through celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (Waters SunFire C-18 column, 0.1% TFA in H2O/CH3CN) to give (S)-2-(1-(2-(3′-methylbiphenyl-4-yl)-1-(1H-tetrazol-5-yl)ethylcarbamoyl)cyclopentyl)acetic acid. Retention time=0.76 minutes (condition B); MS (m+1)=434; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33-1.54 (m, 6H), 1.87-2.01 (m, 2H), 2.36 (s, 3H), 2.59 (s, 2H), 3.22-3.77 (m, 2H), 5.43 (dd, J=8.34, 14.91 Hz, 1H), 7.15 (d, J=7.33 Hz, 1H), 7.27-7.35 (m, 3H), 7.38-7.45 (m, 2H), 7.53 (d, J=8.08 Hz, 2H), 8.16 (d, J=7.83 Hz, 1H); HRMS (ES+) m/z for C24H27N5O3 [M+H]+ calcd 433.2. found 433.2
Reaction SMILES: [S:1](OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].[C:13]([O:18][CH3:19])(=[O:17])[C:14]([CH3:16])=[CH2:15].[C:20]([O:24][CH2:25][CH:26]([CH2:31][CH3:32])[CH2:27][CH2:28][CH2:29][CH3:30])(=[O:23])[CH:21]=[CH2:22].[CH2:33](OS(C1C=CC=CC=1)(=O)=O)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].[Na]>O>[C:13]([O:18][CH3:19])(=[O:17])[C:14]([CH3:16])=[CH2:15].[C:20]([O:24][CH2:25][CH:26]([CH2:31][CH3:32])[CH2:27][CH2:28][CH2:29][CH3:30])(=[O:23])[CH:21]=[CH2:22].[CH2:33]([SH:1])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: CCCCCCCCCCCCOS(=O)(=O)c1ccccc1
Agent: C=C(C)C(=O)OC
Agent: C=CC(=O)OCC(CC)CCCC
Agent: [NH4+]
Solvent: O
Product: CCCCCCCCCCCCS

Procedure:
To a mixture of 250 parts of deionized water and 25 parts of the seed emulsion of Manufacturing Example 1, were added an aqueous solution of 0.1 part of ammonium persulfate and 17 parts of deionized water, and then the same procedures as stated in Manufacturing Example 14 were repeated, excepting using as the first stage pre-emulsion a mixture of 195 parts of methyl methacrylate, 100 parts of 2-ethylhexyl acrylate, 200 parts of deionized water, 0.4 part of sodium dodecylbenzene sulfonate and 0.9 part of ammonium persulfate and as the second stage monomer mixture a composition of 135 parts of methyl methacrylate, 65 parts of 2-ethylhexyl acrylate and 6 parts of n-dodecylmercaptan, to obtain an emulsion having a non-volatile content of 50.0%, average grain diameter of resinous particles being 2.8μ and the maximum diameter being 4.0μ.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:17]([C:19]1[CH:20]=[C:21]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:22]=[CH:23][C:24]=1F)#[N:18].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[C:17]([C:19]1[CH:20]=[C:21]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:22]=[CH:23][C:24]=1[N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)#[N:18]
Reactant: COC(=O)Cc1ccc(F)c(C#N)c1
Reactant: CC(C)(C)OC(=O)c1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(-n2ccc3cc(C(=O)OC(C)(C)C)ccc32)c(C#N)c1
Temperature: 95 °C
Reaction time: 24 h
Yield: 31.7 %

Procedure:
tert-Butyl 1H-indole-5carboxylate (0.800 g, 3.68 mmol), methyl 2-(3-cyano-4-fluorophenyl)acetate (0.593 g, 3.07 mmol), and potassium carbonate (0.509 g, 3.68 mmol) were combined in 15 mL of DMSO and the reaction mixture was stirred at 95° C. for 24 hours. Reaction was diluted with ethyl acetate washed twice with water, dried over magnesium sulfate and concentrated. Silica gel chromatography eluting with a gradient of 5% ethyl acetate/hexanes to 60% ethyl acetate/hexanes gave tert-butyl 1-(2-cyano-4-(2-methoxy-2-oxoethyl)phenyl)-1H-indole-5-carboxylate (0.380 g, 0.973 mmol, 32%). MS (APCI)=390.9 (M+1).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-:18].O.[CH2:20]([O:27][C:28]1[CH:51]=[C:50]([Cl:52])[C:31]([CH2:32][C@@H:33]2[CH2:37][CH2:36][N:35]([C@H:38]3[CH2:43][CH2:42][C@H:41](OS(C)(=O)=O)[CH2:40][CH2:39]3)[C:34]2=[O:49])=[C:30]([Cl:53])[CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[CH2:20]([O:27][C:28]1[CH:51]=[C:50]([Cl:52])[C:31]([CH2:32][C@@H:33]2[CH2:37][CH2:36][N:35]([C@H:38]3[CH2:43][CH2:42][C@@H:41]([F:18])[CH2:40][CH2:39]3)[C:34]2=[O:49])=[C:30]([Cl:53])[CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: [F-]
Reactant: CS(=O)(=O)O[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(OCc4ccccc4)cc3Cl)C2=O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CC#N
Product: O=C1[C@H](Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1[C@H]1CC[C@@H](F)CC1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
Dissolve TBAF.3H2O (1.595 g, 1.30 mmol) in 10 ml of acetonitrile. Add water (0.18 ml, 9.91 mmol) and stir for 10 minutes. Add (R)-trans-Methanesulfonic acid 4-[3-(4-benzyloxy-2,6-dichloro-benzyl)-2-oxo-pyrrolidin-1-yl]-cyclohexyl ester (Preparation 14) (1.30 g, 2.48 mmol). Stir at 80° C. for 12 hours. Quench with saturated NaHCO3 and extract with ethyl acetate. Wash the extract with brine. Dry over magnesium sulfate, filter, and concentrate. After flash column chromatography receive 0.230 g (21%) of the title compound: Mass spectrum (apci) m/z=450 (M+H).
Reaction SMILES: F[C:2]1[C:10]2[S:9][C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[CH:21]=4)[CH:16]=3)=[N:7][C:6]=2[C:5]([C:29]([F:32])(F)F)=C[CH:3]=1.FC1C=CC2SC(I)=NC=2C=1>>[F:32][C:29]1[CH:3]=[CH:2][C:10]2[S:9][C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[CH:21]=4)[CH:16]=3)=[N:7][C:6]=2[CH:5]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(C(F)(F)F)ccc(F)c2s1
Agent: Fc1ccc2sc(I)nc2c1
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2cc(F)ccc2s1

Procedure:
Following the procedure for 3-(7-fluoro-4-trifluoromethylbenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine, using 5-fluoro-2-iodo-1,3-benzothiazole and conducting the Suzuki coupling at 55° C. for 3 h, the title compound was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=9.20-9.09 (brm, 1H), 9.04-8.92 (brm, 1H), 8.71 (very brs, 1H), 8.58 (d, J=2.0 Hz, 1H), 8.55 (brs, 1H), 8.47 (s, 1H), 8.28 (dd, J=5.2, 9.0 Hz, 1H), 8.10 (s, 1H), 8.01 (dd, J=2.6, 9.4 Hz, 1H), 7.47 (dt, J=2.4, 9.0 Hz, 1H), 4.58-4.48 (mc, 1H), 3.40 (brd, J=12.5 Hz, 2H), 3.11 (brq, J=12.0 Hz, 2H), 2.30-2.12 (m, 4H). MS(ES+): m/z=395.09 (73) [MH+], 312.05 (100) [MH+-piperidine]. HPLC: tR=2.06 min (polar—5 min, ZQ2).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[C:13]([O:19][CH3:20])=[N:14][CH:15]=[C:16]([F:18])[CH:17]=2)=[N:6][CH:5]=1.[AlH4-].[Li+].[OH-].[Na+].Cl>O1CCCC1>[F:18][C:16]1[CH:17]=[C:12]([CH2:11][NH:10][C:7]2[N:6]=[CH:5][C:4]([CH2:3][OH:2])=[CH:9][CH:8]=2)[C:13]([O:19][CH3:20])=[N:14][CH:15]=1
Reactant: COC(=O)c1ccc(NCc2cc(F)cnc2OC)nc1
Agent: Cl
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ncc(F)cc1CNc1ccc(CO)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
To 6-[(5-fluoro-2-methoxy-pyridin-3-ylmethyl)-amino]-nicotinic acid methyl ester (91, 0.825 g, 2.83 mmol) in 11 mL of tetrahydrofuran, lithium tetrahydroaluminate (5.66 mL, 1.0 M in tetrahydrofuran, 5.66 mmol) was added at −40° C. under nitrogen. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was poured into aqueous 1M sodium hydroxide, then neutralized with aqueous 1M hydrochloric acid. The solids were filtered out through celite, the celite washed with ethyl acetate and tetrahydrofuran. The isolated aqueous layer was extracted with ethyl acetate and all organic layers were combined, washed with brine, then dried over sodium sulfate, filtered and the filtrate was concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (92, 357 mg). MS (ESI) [M+H+]+=264.4.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:5]([CH3:8])[C:6]=1[CH3:7].[Si:16]([O:23][C@@H:24]([CH3:40])[C@H:25]([C:31]1[O:35][N:34]=[C:33]([C:36](O)=[O:37])[C:32]=1[CH3:39])[O:26][CH2:27][C:28]([CH3:30])=[CH2:29])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Si:16]([O:23][C@@H:24]([CH3:40])[C@H:25]([C:31]1[O:35][N:34]=[C:33]([C:36]([NH:1][C:2]2[C:3](=[O:15])[N:4]([CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]3)[N:5]([CH3:8])[C:6]=2[CH3:7])=[O:37])[C:32]=1[CH3:39])[O:26][CH2:27][C:28]([CH3:30])=[CH2:29])([C:19]([CH3:22])([CH3:20])[CH3:21])([CH3:18])[CH3:17]
Reactant: C=C(C)CO[C@@H](c1onc(C(=O)O)c1C)[C@H](C)O[Si](C)(C)C(C)(C)C
Reactant: Cc1c(N)c(=O)n(C2CCCCC2)n1C
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: C=C(C)CO[C@@H](c1onc(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)c1C)[C@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-Amino-2-cyclohexyl-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate D) (2.63 g, 12.55 mmol) was added portionwise to 5-((1R,2S)-2-((tert-butyldimethylsilyl)oxy)-1-((2-methylallyl)oxy)propyl)-4-methylisoxazole-3-carboxylic acid (4.14 g, ˜70% w/w) in DMF (100 mL) followed by DIPEA (7.8 ml, 44.8 mmol) and HATU (4.8 g, 12.55 mmol). After stirring at room temperature for 18 h the reaction mixture was partitioned between EtOAc and brine. The aqueous phase was extracted with EtOAc and the combined organic extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 50-100% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:13]1[O:14][C:15]2[C:20]([C:21](=[O:23])[CH:22]=1)=[C:19]([O:24]C)[CH:18]=[C:17]([O:26]C)[C:16]=2[C@@H:28]1[CH2:32][CH2:31][N:30]([CH3:33])[C@H:29]1[CH2:34][OH:35].Cl.N1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CO>[Cl:1][C:2]1[C:7]([N:8]2[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:13]1[O:14][C:15]2[C:20]([C:21](=[O:23])[CH:22]=1)=[C:19]([OH:24])[CH:18]=[C:17]([OH:26])[C:16]=2[C@@H:28]1[CH2:32][CH2:31][N:30]([CH3:33])[C@H:29]1[CH2:34][OH:35]
Reactant: COc1cc(OC)c2c(=O)cc(-c3cccc(N4CCCC4)c3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4cccc(N5CCCC5)c4Cl)oc23)[C@@H]1CO
Temperature: 180 °C

Procedure:
A mixture of compound of example 48 (0.650 g, 1.30 mmol) and pyridine hydrochloride (1.5 g, 12.90 mmol) was heated at 180° C. for a period of 2.5 hours. The reaction mixture was diluted with methanol (60 mL) and basified with solid Na2CO3 to pH 10. The reaction mixture was filtered, and washed with methanol. The organic layer was concentrated and the residue purified by column chromatography using 0.01% ammonia and 4.5% methanol in chloroform as eluent to yield the title compound as a yellow solid.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]([OH:39])[CH2:23][O:24][C:25]2[CH:38]=[CH:37][C:28]([CH2:29][CH:30]3[S:34][C:33](=[O:35])[NH:32][C:31]3=[O:36])=[CH:27][CH:26]=2)[CH:19]=[CH:20][CH:21]=1.CS(C)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:15][C:16]1[CH:17]=[C:18]([C:22](=[O:39])[CH2:23][O:24][C:25]2[CH:38]=[CH:37][C:28]([CH2:29][CH:30]3[S:34][C:33](=[O:35])[NH:32][C:31]3=[O:36])=[CH:27][CH:26]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: O=C1NC(=O)C(Cc2ccc(OCC(O)c3cccc(Cl)c3)cc2)S1
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C1NC(=O)C(Cc2ccc(OCC(=O)c3cccc(Cl)c3)cc2)S1
Reaction time: 0.25 h
Yield: 47.2 %

Procedure:
To a stirring solution of phosphorus pentoxide (0.38 g, 1.30 mmol) in DCM (8 mL) at 0° C. was added a solution of 5-{4-[2-(3-chlorophenyl)-2-hydroxyethoxy]benzyl}-1,3-thiazolidine-2,4-dione (0.25 g, 0.66 mmol) in DCM (8 mL) followed by dimethyl sulfoxide (0.23 mL, 3.30 mL). After stirring for 15 minutes N,N-diiisopropylethylamine (0.34 mL, 2.00 mmol) was added. After 45 minutes the reaction was poured into cold saturated NaHCO3 and the mixture was extracted with EtOAc (×2). The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was chromatographed on a small silica gel column eluting with 0-15% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 117 mg (47%) of a white solid. MS (ESI−) for C18H14ClNO4S m/z 374.1 (M−H)−
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CN=C1.[C:21]1(=[O:27])[CH2:26][CH2:25][CH2:24][CH:23]=[CH:22]1>CO.O>[Cl:1][C:2]1[C:3]([CH:4]([OH:5])[C:22]2[C:21](=[O:27])[CH2:26][CH2:25][CH2:24][CH:23]=2)=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][N:9]=1
Reactant: O=Cc1cc(-c2ccccc2)cnc1Cl
Reactant: O=C1C=CCCC1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CO
Product: O=C1CCCC=C1C(O)c1cc(-c2ccccc2)cnc1Cl
Yield: 95 %

Procedure:
The clear solution of 2-Chloro-5-phenylnicotinaldehyde (10 mmol, 2.17 g) and imidazole (10 mmol) in 50 ml. of MeOH was slowly charged with 50 ml. of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclohexen-1-one (10.2 mmol., 1.0 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl3 thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 95% yield (2.25 g).