Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=O>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:17]([C:13]1[S:12][CH:16]=[CH:15][CH:14]=1)[CH2:9][C:8]2=[O:10]
Reactant: O=Cc1cccs1
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: CCO
Solvent: O
Product: O=C1CC(c2cccs2)Oc2ccc(Br)cc21
Yield: 55.6 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (20 g, 0.093 mol), thiophene-2-carbaldehyde (10.46 g, 0.093 mol) and borax (35.4 g, 0.093 mol) in ethanol (120 mL) and H2O (200 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H2O and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-2-thiophen-2-yl-chroman-4-one (16 g, 50%). 1H-NMR (CDCl3): 3.01 (m, 1H), 3.10 (m, 1H), 5.75 (dd, 1H), 6.94 (d, 1H), 7.02 (t, 1H), 7.05 (d, 1H), 7.32 (d, 1H), 7.54 (dd, 1H), 8.00 (d, 1H).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[F:14])=[O:5])#[N:2].CO/[CH:17]=[CH:18]/[C:19](=O)[CH3:20].N12CCN(CC1)CC2>COCCO.Cl.O1CCCC1.C(OCC)(=O)C>[F:14][C:8]1[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=1[N:6]1[C:19]([CH3:20])=[CH:18][CH:17]=[C:3]([C:1]#[N:2])[C:4]1=[O:5]
Reactant: CO/C=C/C(C)=O
Reactant: N#CCC(=O)Nc1ccc(F)cc1F
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: COCCO
Product: Cc1ccc(C#N)c(=O)n1-c1ccc(F)cc1F
Temperature: 120 °C
Reaction time: 12 h
Yield: 9.4 %

Procedure:
To a solution of 2-cyano-N-(2,4-difluorophenyl)acetamide (5.5 g, 28 mmol) and (3E)-4-methoxybut-3-en-2-one (3.65 g, 36.5 mmol) in dimethyleneglycol monomethylether (50 mL) was added 1,4-diazabicyclo[2.2.2]octane (3.14 g, 28 mmol), and the mixture was stirred at 120° C. for 12 hr. The reaction mixture was diluted with 2N hydrochloric acid, tetrahydrofuran and ethyl acetate, and extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was washed with ethyl acetate to give a slightly yellow solid. The slightly yellow solid was suspended in tetrahydrofuran at 80° C., and the suspension was stirred for 30 min. The suspension was filtrated, and the obtained solid was washed with tetrahydrofuran to give the title compound (650 mg, 9.4%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11])([O-])=O.O.O.Cl[Sn]Cl>CCO>[NH2:1][C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11]
Reactant: N#Cc1cccc(Oc2ccccc2[N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: N#Cc1cccc(Oc2ccccc2N)c1
Yield: 98.9 %

Procedure:
A solution of 3-(2-nitrophenoxy)benzonitrile (1.21 g, 5 mmol, 1.0 equiv) in 30 mL of EtOH was treated with SnCl2.2H2O (3-38 g, 3 equiv) at reflux for 4 h. The volatile was evaporated and the residue was redissolved in EtOAc, washed with saturated aqueous NaHCO3 and 1N NaOH. The organic layer was dried over MgSO4, filtered and evaporated to give 3-(2-aminophenoxy)benzonitrile (1.04 g, 99%). MS found for C13H11N2O (M+H)+: 211.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7][CH2:6]2.[H][H]>[C].[Pd].CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7][CH2:6]2
Reactant: [H][H]
Reactant: CCOC(=O)C=C1CCc2cc(OC)ccc21
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC1CCc2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed ethyl 2-(5-methoxy-2,3-dihydro-1H-inden-1-ylidene)acetate (500 mg, 2.15 mmol, 1.00 equiv), methanol (3 mL), Palladium carbon (500 mg). To the mixture hydrogen was introduced in. The resulting solution was stirred overnight at room temperature. The solids were filtered out. The mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (15:85). This resulted in 300 mg (59%) of ethyl 2-(5-methoxy-2,3-dihydro-1H-inden-1-yl)acetate as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[O:10][CH3:11].[Cl:12][S:13](O)(=[O:15])=[O:14]>C(Cl)Cl>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([CH3:9])[C:6]([S:13]([Cl:12])(=[O:15])=[O:14])=[C:7]([CH3:8])[C:2]=1[CH3:1]
Reactant: COc1cc(C)cc(C)c1C
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1C
Temperature: 0 °C

Procedure:
In 500 ml of methylene chloride was dissolved 4.5 g of 2,3,5-trimethylanisole and the solution was cooled to -5° C. to -10° C. A solution of 6.0 ml of chlorosulfonic acid in 400 ml of methylene chloride was added dropwise, and then the temperature was allowed to rise to room temperature. The mixture was poured into an ice--5% aqueous sodium hydrogen carbonate mixture. The methylene chloride layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off, and the residue was crystallized from n-hexane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C:9]([O:13][C:14](=[O:21])[NH:15][C@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)([CH3:12])([CH3:11])[CH3:10].C(N(C(C)C)C(C)C)C.ClCCl>C(#N)C>[C:9]([O:13][C:14](=[O:21])[NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C:5]2[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:17]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: Clc1ncc(Br)cn1
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2ncc(Br)cn2)C1
Yield: 56.1 %

Procedure:
Stir a solution of 5-bromo-2-chloropyrimidine (3.67 g, 19 mmol), (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (3.54 g, 19 mmol), and ethyldiisopropylamine (6.6 mL, 38 mmol) in acetonitrile (50 mL) at room temperature for 4 h. Pour into dichloromethane (200 mL) and wash with water (3×). Dry (sodium sulfate) and concentrate to give (S)-[1-(5-bromopyrimidin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester as a tan solid (3.66 g, 71%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[N:9][CH:10]=1)(=[O:4])=[O:3].Br[C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[N:20][NH:21]2)=[C:17]([NH:24][C:25]([C:27]2[N:28]=[C:29]([CH3:32])[S:30][CH:31]=2)=[O:26])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:32][C:29]1[S:30][CH:31]=[C:27]([C:25]([NH:24][C:17]2[CH:16]=[C:15]([C:7]3[CH:8]=[N:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=3)[CH:23]=[C:22]3[C:18]=2[CH:19]=[N:20][NH:21]3)=[O:26])[N:28]=1
Reactant: CS(=O)(=O)c1cncc(B(O)O)c1
Reactant: Cc1nc(C(=O)Nc2cc(Br)cc3[nH]ncc23)cs1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: Cc1nc(C(=O)Nc2cc(-c3cncc(S(C)(=O)=O)c3)cc3[nH]ncc23)cs1
Temperature: 150 °C
Yield: 5.8 %

Procedure:
To a solution of 5-(methylsulfonyl)-3-pyridinylboronic acid (24 mg, 0.12 mmol, available from Combi-Blocks Inc.) in 1,4-dioxane (1 ml) was added a solution of N-(6-bromo-1H-indazol-4-yl)-2-methyl-1,3-thiazole-4-carboxamide (34 mg, 0.10 mmol), also in 1,4-dioxane (1 ml). A solution of potassium carbonate (17 mg, 0.12 mmol) in water (0.2 ml) was then added, followed by Pd(dppf)Cl2 (10 mg). The reaction vessel was sealed and heated in CEM Discover at 150° C. for 30 min. The mixture was cooled and the solvent was evaporated in vacuo using the Genevac to give the crude products. The sample was loaded in methanol and applied to reverse phase (C18) cartridge (500 mg) and eluted using MeCN/TFA 0.1% (3×3 ml). The appropriate fractions were combined and dried under a stream of nitrogen then the residue was dissolved in (3:1, DMSO:MeOH, 0.5 ml) and purified by MDAP (Method C) to afford the title compound, (2.4 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]([F:16])([F:15])[F:14])[CH:10]=2)[O:5][C:4](=[O:17])[CH:3]=1.[O:18]1[C:22]2[CH:23]=[CH:24][C:25]([CH2:27][N:28]3[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]3)=[CH:26][C:21]=2[O:20][CH2:19]1.C(N(CC)CC)C>CN1CCCC1=O.O>[O:18]1[C:22]2[CH:23]=[CH:24][C:25]([CH2:27][N:28]3[CH2:33][CH2:32][CH:31]([NH:34][C:2]4[C:11]5[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]([F:16])([F:15])[F:14])[CH:10]=5)[O:5][C:4](=[O:17])[CH:3]=4)[CH2:30][CH2:29]3)=[CH:26][C:21]=2[O:20][CH2:19]1
Reactant: O=c1cc(Cl)c2cc(OC(F)(F)F)ccc2o1
Reactant: NC1CCN(Cc2ccc3c(c2)OCO3)CC1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=c1cc(NC2CCN(Cc3ccc4c(c3)OCO4)CC2)c2cc(OC(F)(F)F)ccc2o1
Temperature: 220 °C
Yield: 52.5 %

Procedure:
To a suspension of 4-chloro-6-trifluoromethoxycoumarin (0.04 g, 0.15 mmol) in 1 ml N-methylpyrrolidone in a Smith reaction vial was added 1-benzo[1,3]dioxol-5-ylmethyl-piperidin-4-ylamine (0.039 g, 0.16 mmol) followed by 0.042 ml of triethylamine. The reaction vessel was sealed with a crimper and the reaction heated at 220° C. for 20 minutes in a Smith Synthesizer. The reaction was diluted with 20 ml water and extracted with 3×10 ml ethyl acetate. The combined organic layers were dried over MgSO4, filtered, evaporated and chromatographed using 2% CH3OH:DCM to afford 36.4 mg (52%) of a white solid. MS (ESI (+)) m/e 463 (M+H)+; 1H NMR (300 MHz, MeOD4) δ ppm 1.65-1.75 (m, 2H), 2.0-2.1 (m, 2H), 2.25 (m, 2H), 3.0 (m, 2H), 3.5 (s, 2H), 3.6 (m, 1H), 5.37 (s, 1H), 5.9 (s, 2H), 6.75 (m, 2H), 6.9 (m, 1H), 7.45 (m, 1H), 7.55 (m, 1H), 8.10 (br s, 1H).
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.ClC1C=CC=C[N+]=1C.[CH2:20]([OH:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:28](O)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CCCC)CCCC)CCC>C(Cl)Cl>[C:20]([O:35][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1ccccc1
Agent: C[n+]1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: ClCCl
Solvent: CCCCN(CCCC)CCCC
Product: O=C(OCc1ccccc1)c1ccccc1
Yield: 83 %

Procedure:
To a CH2Cl2 (2 ml) solution of 2-chloro-1-methylpyridinium p-toluenesulfonate (720 mg, 2.4 mmol) was added a mixture of benzyl alcohol (216 mg, 2.0 mmol), benzoic acid (244 mg, 2.0 mmol) and tri-n-butylamine (888 mg, 4.8 mmol) in CH2Cl2, and the resulting mixture was refluxed for 3 hours. After evaporation of the solvent, the residue was separated by silica gel column chromatography, and benzyl benzoate was isolated in 83% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=1)[CH:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)=[O:6]
Reactant: NCC(c1ccc(Cl)cc1)C1CCOCC1
Reactant: O=C(O)c1c(F)cccc1Cl
Product: O=C(NCC(c1ccc(Cl)cc1)C1CCOCC1)c1c(F)cccc1Cl

Procedure:
From 2-chloro-6-fluorobenzoic acid and 2-(4-chlorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine. LCMS (MH+): m/z=396.1, tR (minutes, Method G)=2.36
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[H-].[Na+].[F:14][C:15]([F:23])(S(F)(=O)=O)C(O)=O>C(#N)C>[F:14][CH:15]([F:23])[O:8][C:6]1[N:7]=[C:2]([CH3:1])[C:3]([N+:9]([O-:11])=[O:10])=[CH:4][CH:5]=1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: Cc1nc(O)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1nc(OC(F)F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.5 %

Procedure:
To a solution of 6-methyl-5-nitropyridin-2-ol (0.5 g, 3.2 mmol) in acetonitrile (10 mL) was added NaH (0.35 g, 8.64 mmol) and the reaction mixture was stirred for 15 minutes at room temperature. To the reaction mixture was added 2,2-difluoro-2-(fluoro-sulfonyl)acetic acid (1.1 mL, 5.5 mmol) dropwise. The reaction mixture was stirred for a further 15 minutes. The reaction mixture was then quenched by the addition of water, and diluted with EtOAc. The organic layer was washed with water and brine, dried over sodium sulphate and concentrated. The crude material obtained was purified by column chromatography (silica: 100-200 mesh, MeOH:DCM 2-4%) to afford the title compound (0.5 g, 75%) as a white solid. LCMS (ES−) 202.85 (M−H)−, RT 2.75 minutes (method 1).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]=[O:15].C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH3:24].CC(=O)OCC>CN(C=O)C>[CH2:23]([N:12]1[C:13]2[CH:1]=[C:2]([CH:14]=[O:15])[CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:24]
Reactant: CCBr
Reactant: O=Cc1ccc2c(c1)[nH]c1ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1c2ccccc2c2ccc(C=O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
A 100-mL round-bottom flask was charged with a solution of 9H-carbazole-2-carbaldehyde (3.7 g, 18.97 mmol, 1.00 equiv) in DMF (50 mL). To this was added K2CO3 (5.23 g, 37.90 mmol, 2.00 equiv) followed by addition of bromoethane (10 g, 91.74 mmol, 4.80 equiv). The resulting solution was stirred overnight at room temperature. The reaction progress was monitored by TLC (EA:PE=1:3). Upon completion, the reaction mixture was quenched with water (100 mL). The resulting mixture was extracted with ethyl acetate (3×100 mL), combined organic layers were dried over sodium sulfate and concentrated on a rotary evaporator. The residue was purified by silica gel column chromatography eluted with ethyl acetate/petroleum ether (1:10) affording 9-ethyl-9H-carbazole-2-carbaldehyde as yellow solid (2.6 g, 61%).
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][C:8]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH3:16])[C:11]=2[O:17][CH3:18])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>CO.Cl.O>[C:1]([CH:5]1[CH2:20][CH2:19][CH:8]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH3:16])[C:11]=2[O:17][CH3:18])[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(Nc2ccc(C(C)(C)C)cc2)ccnc1C
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1c(NC2CCC(C(C)(C)C)CC2)ccnc1C

Procedure:
1 g of 4-(4-tert-butylanilino)-3-methoxy-2-methylpyridine in 20 ml of methanol, 3.7 ml of 2N HCl and 1.3 ml of water are hydrogenated at room temperature and normal pressure until absorption of hydrogen has ended using 1 g of rhodium on alumina (5% strength). After filtering and concentrating 1 g of syrup remains=100% isomer mixture.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:17])[CH2:5][CH:6]1[CH2:15][CH2:14][C:13](=[O:16])[N:7]12.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].CS(O[CH:34]([CH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:35])(=O)=O>C(OCC)(=O)C>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH:34]([CH2:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:35])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:17])[CH2:5][CH:6]1[CH2:15][CH2:14][C:13](=[O:16])[N:7]12
Reactant: CC(CCCc1ccccc1)OS(C)(=O)=O
Reactant: O=C1CC2CCC(=O)N2c2cc(O)cc(O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(CCCc1ccccc1)Oc1cc(O)c2c(c1)N1C(=O)CCC1CC2=O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Under anhydrous conditions and in a nitrogen atmosphere, 70 g. (0.30 mole) 6,8-dihydroxy-3a,4-dihydro-(2H,3H)-pyrrolo[1,2-a]quinolin-1,5-dione was dissolved in 750 ml. dimethylformamide by warming to 60° C. To the resulting deep red solution was added 51.6 g. (0.675 mole) potassium carbonate. The mixture was heated to 70° C., a solution of 2-methylsulfonyloxy-5-phenylpentane in 250 ml. dimethylformamide was added in a fast stream, and heated at 75°-80° C. for 12 hours. Additional portions of 2-methylsulfonyloxy-5-phenylpentane (5.3 g.) and potassium carbonate (3.8 g.) and heating continued at 75°-80° C. for two hours. The mixture was poured over a mixture (one liter each) ethyl acetate and ice and, after shaking in a separtory funnel, the layers were separated. The aqueous phase was extracted with 5×1000 ml. ethyl acetate. The combined organic layers were washed with 3×4 liters water, 3×2 liters of 0.5N hydrochloric acid, dried (MgSO4) and concentrated to a volume of about 2.5 liters. Upon cooling, the precipitated product which formed was collected: 9.0 g., M.P. 151°-153° C. The mother liquor was concentrated to half volume, cooled, and a second crop, 34.2 g., M.P. 148°-151° C., was collected. Total yield by crystallization: 52.2 g. This material was shown to be primarily a single diastereomer, designated as "Diastereomer B." Upon recrystallization from ethyl acetate, colorless crystals were obtained, M.P. 159°-161° C. This was found to be about 90% diastereomer B. 1H--NMR (CDCl3) ppm (delta): 1.33 (d, 3H, J=6 Hz).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[N:9]([CH2:11][C:12]2[CH:16]=[C:15]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[O:14][N:13]=2)[CH:10]=1)=[O:5])C.[OH-].[Na+].O.Cl>O1CCOCC1>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:8]2[N:9]([CH2:11][C:12]3[CH:16]=[C:15]([C:17]4[S:18][C:19]([Cl:22])=[CH:20][CH:21]=4)[O:14][N:13]=3)[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cn(Cc2cc(-c3ccc(Cl)s3)on2)c(-c2ccc(Cl)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cn(Cc2cc(-c3ccc(Cl)s3)on2)c(-c2ccc(Cl)cc2)n1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
480 mg (1.1 mg) of 2-(4-Chloro-phenyl)-1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-imidazole-4-carboxylic acid ethyl ester was dissolved in 10 ml of dioxan and 10 ml of 2 N aqueous NaOH was added. The solution was stirred at 60° C. for 3 h. The solution was poured into water and the pH was adjusted to 3 by the addition of 2 N aqueous HCl. The precipitated product was filtered off and dried. Yield: 258 mg; MS (LCMS-ES+): m/e=420.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].C(O)(=O)C.[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[C:17]([CH:19]=O)[CH:18]=1)[NH:15][CH:14]=[CH:13]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+].[OH-].[Na+]>ClCCCl>[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[C:17]([CH2:19][NH:1][CH2:2][CH2:3][OH:4])[CH:18]=1)[NH:15][CH:14]=[CH:13]2
Reactant: O=Cc1cc(F)cc2cc[nH]c12
Reactant: NCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: OCCNCc1cc(F)cc2cc[nH]c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
Add 2-aminoethanol (1.93 mL, 32.0 mmol) followed by acetic acid (2.01 mL, 48.0 mmol) to a solution of 5-fluoro-1H-indole-7-carbaldehyde (2.6 g, 16.0 mmol) in 1,2-dichloroethane (40 mL). Stir at room temperature for 15 minutes. Add sodium triacetoxyborohydride (4.07 g, 19.2 mmol) portion wise. Stir the reaction mixture at room temperature for 3 hours. Add saturated aqueous sodium bicarbonate (100 mL) slowly followed by 1 N NaOH to pH ˜9. Extract with ethyl acetate (100 mL×3). Wash the organic phase with saturated aqueous sodium chloride (200 mL×2), dry over sodium sulfate, and concentrate under reduced pressure to provide the desired compound as a pale yellow solid (3.2 g, 96%).
Reaction SMILES: CS(O)(=O)=O.[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[S:18]([C:21]2[CH:26]=[CH:25][C:24]([NH:27]C(=O)C)=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:7]=1.C(=O)(O)[O-].[Na+]>CO>[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[S:18]([C:21]2[CH:22]=[CH:23][C:24]([NH2:27])=[CH:25][CH:26]=2)(=[O:20])=[O:19])[CH:7]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N2CCCCC2c2cccnc2)cc1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Nc1ccc(S(=O)(=O)N2CCCCC2c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
A 1.81 ml portion of methanesulfonic acid was added to a methanol solution (10 ml) of 1.0 g N-(4-{[2-(pyridin-3-yl)piperidin-1-yl]sulfonyl}phenyl)acetamide and stirred overnight at room temperature. The reaction liquid was poured into ice water and neutralized with sodium bicarbonate, and then layer separation operation was carried out by adding ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried with anhydrous sodium sulfate and then concentrated under a reduced pressure to obtain 695 mg of 4-{[2-(pyridin-3-yl)piperidin-1-yl]sulfonyl}aniline as pale yellow crystals.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=1)=[O:7].[N:16]1([C:22]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[C:31]([F:34])([F:33])[F:32])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:19]2[CH2:20][CH2:21][N:16]([C:22](=[O:23])[C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[C:31]([F:34])([F:33])[F:32])[CH2:17][CH2:18]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: O=C(c1cc(F)ccc1C(F)(F)F)N1CCNCC1
Reactant: CC(C)CCNC(=O)c1ccc(Cl)nn1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3cc(F)ccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (3-methylbutyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(5-fluoro-2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (28.3% yield). 1H NMR (400 MHz, CDCl3) δ8.05, 7.86, 7.78-7.75, 7.28-7.22, 7.12-7.08, 7.02, 4.08-4.01, 3.91-3.86, 3.82-3.68, 3.55-3.46, 3.38, 1.73-1.65, 1.56-1.48, 0.94.
Reaction SMILES: [C:1]([C:4]1[C:8]([CH3:9])=[C:7](Br)[NH:6][C:5]=1[CH3:11])(=[O:3])[CH3:2].O.C(=O)(O)[O-].[Na+].[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>C(COC)OC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.N1C=CC(B(O)O)=CC=1>[C:1]([C:4]1[C:8]([CH3:9])=[C:7]([C:21]2[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=2)[NH:6][C:5]=1[CH3:11])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C)[nH]c(Br)c1C
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(=O)c1c(C)[nH]c(-c2ccncc2)c1C
Yield: 25 %

Procedure:
To a stirred solution of 3-acetyl-5-bromo-2,4-dimethyl-1H-pyrrole (5.33 g, 21.1 mmol, including water) in dimethoxyethane (DME; 60 mL) added water (20 mL), sodium bicarbonate (5.32 g, 63.3 mmol), 4-pyridineboronic acid [prepared according to the method of Fischer F. C. et al., J. Red. Trav. Chim. Pays-Bays, 1965, 84, 439. ] (3.11 g, 25.3 mmol) and bis(triphenylphosphine)palladium(II)chloride (1.48 g, 2.11 mmol) at room temperature under nitrogen. The mixture was heated at reflux temperature for 8 hours, 4-pyridineboronic acid (0.5 g, 4.07 mmol) and bis(triphenylphosphine)palladium(II)chloride (1.48 g, 2.11 mmol) were additionally added to the reaction mixture and stirred at reflux temperature for 6 hours. After cooling, the reaction mixture was filtered through celite pad. The filtrate was diluted with ethyl acetate (150 mL), and the whole was washed with water (50 mL). The aqueous layer was extracted with ethyl acetate (150 mL), and the combined organic layers were washed with brine (50 mL) and 10% aqueous HCl solution (100 mL×2). The combined acidic aqueous layers were neutralized with saturated aqueous NaHCO3 solution. The whole was extracted with ethyl acetate (100 mL×3), and the combined organic layers were dried over MgSO4, and concentrated in vacuo. The resulting solids were washed with diethylether to give 2.00 g of crude product, which was recrystallized from MeOH to give the title product (1. 13 g, 25% yield).