Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(O)O.Br[C:5]1[N:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][CH:6]=1.[O:13]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14]1>>[O:13]1[CH:17]=[CH:16][C:15]([C:5]2[N:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][CH:6]=2)=[CH:14]1
Reactant: OB(O)c1ccoc1
Reactant: O=Cc1cccc(Br)n1
Agent: OBO
Product: O=Cc1cccc(-c2ccoc2)n1

Procedure:
6-(furan-3-yl)picolinaldehyde was prepared using the general boronic acid coupling procedure for 6-bromopicolinaldehyde and furan-3-ylboronic acid (65 mg, 93.2 mg theoretical, 69.8%). LC-MS m/z 174.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:12]=[CH:11][NH:10][C:9]=1[C@H:13]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:14][CH2:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[Na+].[C:38]1([CH3:48])[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1.O>C1COCC1.CCOC(C)=O>[CH2:17]([O:16][CH2:15][CH2:14][C@H:13]([C:9]1[N:10]([S:44]([C:41]2[CH:42]=[CH:43][C:38]([CH3:48])=[CH:39][CH:40]=2)(=[O:46])=[O:45])[CH:11]=[CH:12][C:8]=1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N[C@H](CCOCc1ccccc1)c1[nH]ccc1C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc(C(=O)OC(C)(C)C)c2[C@@H](CCOCc2ccccc2)NC(=O)OC(C)(C)C)cc1
Reaction time: 0.08 h

Procedure:
(R)-tert-Butyl 2-(3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)propyl)-1H-pyrrole-3-carboxylate (724b, 4.31 g, 10.01 mmol) was dissolved in THF (40 mL) under nitrogen and cooled in an ice bath. Sodium tert-butoxide (1M in THF, 10.01 mL, 10.01 mmol) was added and the mixture stirred for 5 min. Toluene-4-sulfonyl chloride (1.91 g, 10.01 mmol) was added to the solution and the mixture was stirred at 0° C. for 30 min. Water (50 mL) and EtOAc (50 mL) were added to the reaction mixture and the organic layer was washed with brine and dried over MgSO4, filtered and concentrated affording crude (R)-tert-butyl-2-(1-amino-3-(benzyloxy)propyl)-1-tosyl-1H-pyrrole-3-carboxylate (724c) as an orange viscous oil. m/z (ESI, +ve) 607.2 (M+Na)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:14][CH3:15])=[C:7](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)[CH:8]=1)#[N:2].C(N(CC)CC)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[NH2:46][C@H:47]([CH2:64][OH:65])[CH2:48][N:49]1[CH2:54][CH2:53][CH:52]([C:55]([C:57]2[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=2)=[O:56])[CH2:51][CH2:50]1>ClCCl>[Cl:63][C:60]1[CH:61]=[CH:62][C:57]([C:55]([CH:52]2[CH2:53][CH2:54][N:49]([CH2:48][C@H:47]([NH:46][C:11](=[O:13])/[CH:10]=[CH:9]/[C:7]3[CH:8]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=3[O:14][CH3:15])[CH2:64][OH:65])[CH2:50][CH2:51]2)=[O:56])=[CH:58][CH:59]=1
Reactant: N[C@H](CO)CN1CCC(C(=O)c2ccc(Cl)cc2)CC1
Reactant: COc1ccc(C#N)cc1/C=C/C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C#N)cc1/C=C/C(=O)N[C@H](CO)CN1CCC(C(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (E)-3-(5-cyano-2-methoxy-phenyl)-acrylic acid (0.31 g, 1.55 mmol), triethylamine (0.2 ml, 1.55 mmol) and 2-(1H benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium tetrafluoroborate (0.49 g 1.55 mmol) in dichloromethane (5 ml), is added to a solution of [1-((S)-2-amino-3-hydroxy-propyl)-piperidin-4-yl]-(4-chloro-phenyl)-methanone hydrochloride and triethylamine (0.4 ml, 3.1 mmol) in dichloromethane (5 ml), and the reaction mixture stirred at ambient temperature for 1 hour. The reaction mixture is diluted with dichloromethane (20 ml), washed successively with saturated sodium bicarbonate solution (25 ml) and brine (25 ml), then dried over magnesium sulphate. The solvent is evaporated and the crude residue purified by flash silica chromatography (methanol:dichloromethane; 5:95) to afford (E)-N-{(S)-2-[4-(4-chloro-benzoyl)-piperidin-1-yl]-1-hydroxymethyl-ethyl}-3-(5-cyano-2-methoxy-phenyl)-acrylamide. [MH]+482.2.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:9]([SH:12])=[N:10][N:11]=2)=[CH:3][CH:2]=1.CI.[C:28](=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:9]([S:12][CH3:28])=[N:10][N:11]=2)=[CH:3][CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccccc1-n1c(S)nnc1-c1ccc(-c2ccccc2)cc1
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CC#N
Product: CSc1nnc(-c2ccc(-c3ccccc3)cc2)n1-c1ccccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.5 %

Procedure:
5-Biphenyl-4-yl-4-(2-fluorophenyl)-4H-1,2,4-triazole-3-thiol (2.7 g) was dissolved in acetonitrile (50 ml), followed by addition of methyl iodide (0.967 ml) and potassium carbonate (1.07 g), and stirred at ambient temperature for 3 hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was washed with saturated aqueous saline and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the resulting solid was recrystallized from a mixture solvent of acetonitrile and ethyl acetate, to afford the entitled compound 3-biphenyl-4-yl-4-(2-fluorophenyl)-5-methylsulfanyl-4H-1,2,4-triazole as pale yellow crystal (2.03 g, 72%). The physico-chemical values are as follows.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Cl[C:9]1[N:18]=[C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:16]2[CH2:15][C:14]([Cl:31])(Cl)[CH:13]=[CH:12][C:11]=2[N:10]=1.O.CN(C)[CH:35]=[O:36]>>[N:1]1([C:35]([C:9]2[N:18]=[C:17]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:31])[CH:15]=3)[N:10]=2)=[O:36])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CN(C)C=O
Reactant: Clc1nc2c(c(NCc3ccc4c(c3)OCO4)n1)CC(Cl)(Cl)C=C2
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=C(c1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1)n1ccnc1
Reaction time: 0.17 h

Procedure:
103 mg of imidazole was added to a suspension of 68 mg of sodium hydride in 6 ml of dimethylformamide at 0° C. The obtained mixture was stirred for 10 minutes. 500 mg of 2,6-dichloro-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline was added to the resulting mixture at room temperature. The mixture thus prepared was stirred at 100° C. for 20 minutes, followed by the addition of water. The crystals precipitated were recovered by filtration and washed with water and ethanol/acetone successively to give 325 mg of the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:26][C:10]2([CH:15]=[CH:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32].I[CH3:36]>O1CCCC1>[CH3:36][CH:26]1[C:10]2([CH:11]=[CH:12][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:17])[CH2:14][CH2:15]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:2]1=[O:1]
Reactant: CI
Reactant: C[Si](C)(C)CCOCN1C(=O)CC2(C=CN(C(=O)OCc3ccccc3)CC2)c2cccnc21
Solvent: C1CCOC1
Product: CC1C(=O)N(COCC[Si](C)(C)C)c2ncccc2C12C=CN(C(=O)OCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Lithium hexamethyldisilylazide (1.0 M in THF; 0.135 mL, 0.135 mmol) was added to solution of benzyl 2-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-2,2′,3,3′-tetrahydro-1H,1′H-spiro[1,8-naphthyridine-4,4′-pyridine]-1′-carboxylate (50.0 mg, 0.104 mmol) in tetrahydrofuran (1 mL) at −78° C. After 40 min, iodomethane (8.0 μL, 0.135 mmol) was added and the reaction mixture was slowly warmed to ambient temperature. After 1 h, the mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (3×). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated to give the title compound. MS 494.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:5]2[Cl:19].[CH3:20][C:21]1[CH:25]=[C:24]([CH:26]=[O:27])[O:23][N:22]=1.[Li]CCCC>C1COCC1>[Cl:12][C:7]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([Cl:19])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:26]([C:24]3[O:23][N:22]=[C:21]([CH3:20])[CH:25]=3)[OH:27])[CH:3]=2)[N:8]=1
Reactant: Cc1cc(C=O)on1
Reactant: Clc1nc2ccc(Br)cc2c(Cl)c1-c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C(O)c2ccc3nc(Cl)c(-c4ccccc4)c(Cl)c3c2)on1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 6-bromo-2,4-dichloro-3-phenylquinoline (363 mg, 1.03 mmol, Intermediate 1: step c) and 3-methylisoxazole-5-carbaldehyde (149 mg, 1.34 mmol) in THF (5 mL) at −78° C. was added n-BuLi (1.6 M in hexane, 0.707 mL, 1.13 mmol) dropwise. The mixture was stirred at −78° C. for 30 minutes, then moved to an ice bath and stirred for 30 minutes. The reaction was quenched by addition of saturated aqueous NH4Cl and then diluted with water. The mixture was extracted three times with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated to afford the crude title compound which was used without further purification in the next reaction.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][CH2:5][C:4]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)=[CH:11][CH:10]=2)=[N:3]1.[OH:20][CH2:21][CH2:22][N:23]1[C:28](=[O:29])[CH2:27][CH2:26][C:25]([C:30]2[CH:35]=[CH:34][C:33]([N:36]3[CH:40]=[CH:39][N:38]=[CH:37]3)=[CH:32][CH:31]=2)=[N:24]1.BrBr>C(O)(=O)C>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)=[CH:13][CH:14]=2)=[N:3]1.[OH:20][CH2:21][CH2:22][N:23]1[C:28](=[O:29])[CH:27]=[CH:26][C:25]([C:30]2[CH:31]=[CH:32][C:33]([N:36]3[CH:40]=[CH:39][N:38]=[CH:37]3)=[CH:34][CH:35]=2)=[N:24]1
Reactant: O=C1CCC(c2ccc(-n3ccnc3)cc2)=NN1CCO
Reactant: CN1N=C(c2ccc(-n3ccnc3)cc2)CCC1=O
Agent: BrBr
Solvent: CC(=O)O
Product: Cn1nc(-c2ccc(-n3ccnc3)cc2)ccc1=O
Product: O=c1ccc(-c2ccc(-n3ccnc3)cc2)nn1CCO

Procedure:
Using the procedure of this Example, reaction of 4,5-dihydro-2-methyl-6-[4-(1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinone and 4,5-dihydro-2-[2-hydroxyethyl]-6-[4-(1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinone with bromine in acetic acid gives 2-methyl-6-[4-(1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinone and 2-[2-hydroxyethyl]-6-[4-(1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinone respectively.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:15]=[CH:14][C:7]2[C:8](=[O:13])[NH:9][S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.O>CN(C=O)C>[Br:3][C:4]1[CH:15]=[CH:14][C:7]2[C:8](=[O:13])[N:9]([CH2:22][C:21]3[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)[S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C1NS(=O)(=O)c2cc(Br)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)c3ccc(Br)cc3S2(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 60% NaH (10.1 mg, 0.254 mmol) in DMF (1 mL), 6-bromobenzo[d]isothiazol-3(2H)-one 1,1-dioxide (55.4 mg, 0.212 mmol) was added portionwise at 0° C. The resulting mixture was stirred at rt for 15 min and p-methoxy benzyl chloride (27.6 μL, 0.212 mmol) was added dropwise. The reaction mixture was heated to 70° C. overnight, allowed to cool to rt, and treated with water (20 mL). The aqueous layer was extracted with EtOAc (3×50 mL) and the combined organic layers were dried over Na2SO4, filtered, and concentrated. The resulting solid was recrystallized from hexane/DCM to obtain compound 38a. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.08 (d, J=1.5 Hz, 1H), 7.89 (dd, J=8.2, 1.6 Hz, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.35 (d, J=8.6 Hz, 2H), 6.79 (d, J=8.6 Hz, 2H), 4.76 (s, 2H), 3.71 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=[CH:20][C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][NH:7]1.Br[CH2:29][C:30](Br)=[O:31].[C:33]1([CH2:39][CH2:40][NH2:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=[CH:20][C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:29][C:30]([NH:41][CH2:40][CH2:39][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31]
Reactant: O=C(Br)CBr
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(OC)c(OC)c1OC)NCC2
Reactant: NCCc1ccccc1
Product: COc1cc2c(cc1OC)C(Cc1ccc(OC)c(OC)c1OC)N(CC(=O)NCCc1ccccc1)CC2

Procedure:
prepared by reaction of 1-(2,3,4-Trimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-phenyl-ethylamine
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH3:13])[CH:7]=[C:6](/[CH:14]=[CH:15]/[N+:16]([O-:18])=[O:17])[CH:5]=1>C(Cl)(Cl)Cl.C(O)(C)C>[F:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH3:13])[CH:7]=[C:6]([CH2:14][CH2:15][N+:16]([O-:18])=[O:17])[CH:5]=1
Reactant: CCCOc1cc(F)cc(/C=C/[N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: CCCOc1cc(F)cc(CC[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
Add sodium borohydride (1.30 g, 34.46 mmol) to 1-fluoro-3-((E)-2-nitro-vinyl)-5-propoxy-benzene (1.94 g, 8.61 mmol) and silica gel (17 g) in chloroform (86 mL) and isopropanol (25 mL) at room temperature in portions over 5 minutes. Stir at room temperature 2 hours and filter. Concentrate the filtrate and dissolve in ethyl acetate. Wash with water and saturated aqueous sodium chloride, dry over magnesium sulfate, filter and concentrate. Purify on 40 g silica gel eluting with 100:0 to 70:30 hexanes:ethyl acetate to give 1.1 g (56.2%) of the desired compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH2:9][N:10]2[CH:14]=[C:13]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH:12]=[C:11]2[C:20]([O:22]C)=[O:21])=[CH:4][CH:3]=1.O.[OH-].[Li+].[OH-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH2:9][N:10]2[CH:14]=[C:13]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH:12]=[C:11]2[C:20]([OH:22])=[O:21])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(C(=O)N(C)C)cn1CC(=O)c1ccc(Cl)cc1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc(C(=O)O)n(CC(=O)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 103.4 %

Procedure:
To a solution of methyl 1-[2-(4-chlorophenyl)-2-oxoethyl]-4-(dimethylcarbamoyl)-1H-pyrrole-2-carboxylate (90 mg, 0.26 mmol) in THF (1 mL) was added lithium hydroxide monohydrate (22 mg, 0.52 mmol) in water (1 mL). The reaction mixture was stirred at room temperature for 18 h (monitored by LCMS). A aqueous solution of NaOH (1 M) (25 mL) was added and the mixture washed with EtOAc (25 mL) to remove the remaining starting material. The aqueous layer was then acidified to pH 2-3 with an aqueous solution of HCl (1 M) and extracted with a mixture of 20% of propan-2-ol/DCM (2×25 mL). The organic fractions were combined, dried (MgSO4) and concentrated in vacuo to give 1-[2-(4-chlorophenyl)-2-oxoethyl]-4-(dimethylcarbamoyl)-1H-pyrrole-2-carboxylic acid as a yellow solid (90 mg, quantitative yield). ESI-MI m/z [m+H]+ 335.1.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH:13]=[O:14])=[CH:5][CH:4]=1.[BH4-].[Na+]>CO>[F:18][C:2]([F:1])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:11]=[C:12]([CH2:13][OH:14])[CH:15]=[CH:16][CH:17]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1cccc(Sc2ccc(C(F)(F)F)cc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cccc(Sc2ccc(C(F)(F)F)cc2)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 92.5 %

Procedure:
Aldehyde 31.2 (162 mg, 0.574 mmol) was dissolved in MeOH (6 mL) and cooled to 0° C. Sodium borohydride (22.0 mg, 0.574 mmol) was added to the reaction. The solution was allowed to slowly warm to room temperature and was stirred for 1.5 hours. The reaction was quenched with dilute hydrochloric acid and then concentrated to dryness under reduced pressure. Water (20 mL) was added to the residue, and the mixture was extracted with EtOAc (2×50 mL). The organic layers were combined, washed with brine (1×30 mL), and dried over magnesium sulfate. The filtrate was concentrated to give 31.3 (151 mg). 1H NMR (400 MHz, CDCl3) δ ppm 7.38-7.43 (3 H, m), 7.27-7.32 (3 H, m), 7.20 (2 H, d, J=8.2 Hz), 4.61 (2 H, s).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl.[C:11]([O:14][CH2:15][CH3:16])(=[O:13])[CH3:12]>O1CCCC1>[OH:3][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:2])[CH2:12][C:11]([O:14][C@@H:15]1[CH2:5][C@H:4]([CH3:9])[CH2:1][CH2:2][C@H:16]1[CH:7]([CH3:8])[CH3:6])=[O:13]
Reactant: CC(=O)c1ccccc1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)CC(C)(O)c1ccccc1
Reaction time: 4 h
Yield: 92 %

Procedure:
20.4 mL (20 mmol, 2 equivalents) of the solution of (−)-menthyl bromozincacetate in tetrahydrofuran obtained in Example 63 was added dropwise to a solution of 0.58 mL (5 mmol) of acetophenone in 3 mL of THF at 5˜7° C. The mixture was stirred at 3˜7° C. for 4 hours. 10 mL of 1H hydrochloric acid was added at 20° C. or lower, followed by dilution with 20 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL of 1N hydrochloric acid, 5 mL of water, 10 mL and 5 mL of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure, purification with silica gel column (developing solvent; ethyl acetate/n-hexane=1/5, 1/3) afforded 1.69 g of the desired product (NMR yield 92%; internal standard dioxane). Recrystallization with n-hexane afforded 0.74 g of the desired product (yield 47%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[N+:17]([O-])=O.[H][H]>[Pd]>[NH2:17][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:8]=1[N:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]1[CH3:1])[C:12]([OH:14])=[O:13]
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Product: CC1CCCCN1c1ccc(C(=O)O)cc1N
Yield: 100 %

Procedure:
A methanolic solution of 4-(2-methylpiperidin-1-yl)-3-nitrobenzoic acid obtained in step 1 (500 mg; 1.89 mmol; 0.01 M) was pumped through an H-Cube (1 mL/min) fitted with a 10 mol % Pd/C catalyst cartridge (30×4 mm) and heated to 25° C. with the full hydrogen option enabled. Solvent was evaporated under vacuum to give the title compound as a pinkish oil (443 mg, 99%). 1H NMR (DMSO-d6, 300 MHz) δ 12.39 (bs, 1H), 7.28 (d, J=1.86 Hz, 1H), 7.14 (dd, J=8.1, 2.1 Hz, 1H), 6.99 (d, J=8.1 Hz, 1H), 5.01 (bs, 1H), 3.07-3.03 (m, 1H), 2.91-2.88 (m, 1H), 2.43-2.35 (m, 1H), 1.79-1.70 (m, 2H), 1.62-1.61 (m, 2H), 1.41-1.31 (m, 2H), 0.79 (d, J=6 Hz, 3H). HPLC (Method A) Rt 1.66 min (Purity: 99.2%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][CH:30]=[CH:29]3)=[CH:22][C:21]=1[CH:35]=O.[CH3:37][N:38]1[CH2:43][CH2:42][CH:41]([NH2:44])[CH2:40][CH2:39]1>ClCCCl.ClCCl>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][CH:30]=[CH:29]3)=[CH:22][C:21]=1[CH2:35][NH:44][CH:41]1[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]1
Reactant: CN1CCC(N)CC1
Reactant: O=Cc1cc(-c2ccc3[nH]ccc3c2)ccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN1CCC(NCc2cc(-c3ccc4[nH]ccc4c3)ccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 117.6 %

Procedure:
Sodium triacetoxyborohydride (400 mg, 1.88 mmol) and then enough acetic acid to bring the pH to 5 were added to a solution of 5-(4-fluoro-3-formylphenyl)-1H-indole (150 mg, 0.63 mmol) and 1-methyl-piperidin-4-ylamine (144 mg, 1.23 mmol) in 15 mL of 1,2-dichloroethane. The mixture was stirred at ambient temperature overnight, and then it was diluted with dichloromethane and washed with water. The aqueous phase extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated to leave the crude product, which was eluted through an SCX cation exchange column (elution with methanol, followed by 2M ammonia in methanol) to give 250 mg of product.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[C:8](=[O:11])[CH:9]=[CH2:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[S:22]1[CH:26]=[CH:25][N:24]=[C:23]1[CH:27]=[O:28].C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH:1]1([CH2:6][CH:7]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[C:8](=[O:11])[CH2:9][CH2:10][C:27]([C:23]2[S:22][CH:26]=[CH:25][N:24]=2)=[O:28])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)cc1
Reactant: O=Cc1nccs1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)CCC(=O)c2nccs2)cc1
Temperature: 25 °C
Yield: 79 %

Procedure:
To a solution (5 mL) of 5-cyclopentyl-4-[4-(methylsulfonyl)phenyl]pent-1-en-3-one (790 mg) in ethanol were added 1,3-thiazole-2-carbaldehyde (275 μL), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (80 mg) and triethylamine (160 μL), and the mixture was stirred with heating under reflux for 8 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (850 mg, yield 79%) was obtained as colorless amorphous crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 420 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9]N)[CH:5]=[N:6][CH:7]=1.C([N:14](CC)C(C)C)(C)C.[CH2:20]([S:22](Cl)(=[O:24])=[O:23])[CH3:21]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C@H:8]([NH:14][S:22]([CH2:20][CH3:21])(=[O:24])=[O:23])[CH3:9])[CH:5]=[N:6][CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: NCCc1cncc(Br)c1
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Product: CCS(=O)(=O)N[C@H](C)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
To a vial is added (1R)-1-(5-bromo(3-pyridyl)ethylamine (300 mg, 1.26 mmol) in 3 ml of CH2Cl2, followed by the addition of N,N-diisopropylethylamine (490 mg, 3.79 mmol). Then ethanesulfonyl chloride (195 mg, 1.52 mmol) is added. The reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is diluted with DCM, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. Purification by the flash column chromatography affords 278 mg of ethanesulfonic acid [(R)-1-(5-bromo-pyridin-3-yl)-ethyl]-amide.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[CH3:11][C:12]1[C:18]([CH3:19])=[CH:17][C:15]([NH2:16])=[C:14]([N+:20]([O-:22])=[O:21])[CH:13]=1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:16][C:15]2[CH:17]=[C:18]([CH3:19])[C:12]([CH3:11])=[CH:13][C:14]=2[N+:20]([O-:22])=[O:21])=[O:7])=[CH:9][CH:10]=1
Reactant: Cc1cc(N)c([N+](=O)[O-])cc1C
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: Cc1cc(NC(=O)c2ccc(Cl)nc2)c([N+](=O)[O-])cc1C

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 4,5-dimethyl-2-nitroaniline and was obtained as an orange solid as described in Example 1. 1H NMR (CDCl3): 11.38 (s, 1H), 9.03 (d, J=2.1, 1H), 8.72 (s, 1H), 8.24-8.21 (m, 1H), 8.07 (s, 1H), 7.52 (d, J=8.7, 1H), 2.41 (s, 3H), 2.34 (s, 3H).