Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[H-].[Na+].[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]=[C:20]=[O:21]>C1COCC1>[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20](=[O:21])[O:9][CH:3]1[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1
Reactant: O=C=Nc1ccccc1Br
Reactant: OC1CN2CCC1CC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1Br)OC1CN2CCC1CC2
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a solution of quinuclidin-3-ol (382 mg, 3.00 mmol) in THF (15 mL) was added NaH [60% dispersion in mineral oil] (156 mg, 3.90 mmol) at room temperature. The mixture was stirred for 15 min and 2-bromophenyl isocyanate (594 mg, 3.00 mmol) was added under stirring. The resulting mixture was stirred at room temperature for 18 h, quenched with brine and extracted with EtOAc. The organic layers were combined, dried over Na2SO4 and concentrated. The resulting crude product was purified by silica gel column chromatography (EtOAc/methanol 3:1) to give the product quinuclidin-3-yl 2-bromophenylcarbamate as viscous oil (0.80 g, 82%).
Reaction SMILES: [CH2:1](N(CC)CC)C.IC.[OH:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[CH:26]=[C:25]3[C:20]([CH:21]=[C:22]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[N:34]4[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]4)[NH:23][C:24]3=[O:27])=[CH:19][CH:18]=2)[CH2:12]1>C(#N)C>[OH:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[CH:26]=[C:25]3[C:20]([CH:21]=[C:22]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[N:34]4[CH2:39][CH2:38][N:37]([CH3:1])[CH2:36][CH2:35]4)[NH:23][C:24]3=[O:27])=[CH:19][CH:18]=2)[CH2:12]1
Reactant: CCN(CC)CC
Reactant: O=c1[nH]c(-c2ccccc2N2CCNCC2)cc2ccc(N3CCCC(O)C3)cc12
Solvent: CC#N
Solvent: CI
Product: CN1CCN(c2ccccc2-c2cc3ccc(N4CCCC(O)C4)cc3c(=O)[nH]2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.3 %

Procedure:
0.0185 ml (0.133 mmol) of triethylamine and 0.00665 ml (0.107 mmol) of iodomethane were added to an acetonitrile solution (0.4 ml) containing 3.6 mg (0.0089 mmol) of the 7-(3-hydroxypiperidin-1-yl)-3-(2-piperazin-1-ylphenyl)-2H-isoquinolin-1-one obtained in Example 102. The obtained mixture was stirred at a room temperature for 4 hours. Thereafter, the solvent was distilled away under reduced pressure. The obtained residue was developed and purified by thin-layer chromatography (NH2 F254s, Merck, developing solvent; dichloromethane:methanol=10:1, Rf value: 0.8), so as to obtain 1.8 mg (48%) of 7-(3-hydroxypiperidin-1-yl)-3-[2-(4-methylpiperazin-1-yl)phenyl]-2H-isoquinolin-1-one in the form of a yellow solid.
Reaction SMILES: C1COCC1.Cl[Si](C)(C)C.Br[CH2:12]/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16].[CH:20]1([NH:26][C:27]2[CH:36]=[C:35]3[C:30]([C:31](=[O:44])[C:32]([CH:42]=[O:43])=[CH:33][N:34]3[CH:37]([CH2:40][CH3:41])[CH2:38][CH3:39])=[CH:29][C:28]=2[F:45])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>[Zn].O>[CH:20]1([NH:26][C:27]2[CH:36]=[C:35]3[C:30]([C:31](=[O:44])[C:32]([CH:42]([OH:43])[CH2:12]/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:33][N:34]3[CH:37]([CH2:38][CH3:39])[CH2:40][CH3:41])=[CH:29][C:28]=2[F:45])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCC(CC)n1cc(C=O)c(=O)c2cc(F)c(NC3CCCCC3)cc21
Reactant: CCOC(=O)/C=C/CBr
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/CC(O)c1cn(C(CC)CC)c2cc(NC3CCCCC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2.0 ml of THF and 0.071 ml of chlorotrimethylsilane were added to 73 mg of zinc, followed by stirring at room temperature for 15 minutes. Then, 200 mg of ethyl (2E)-4-bromobut-2-enoate was added thereto, followed by stirring at room temperature for 30 minutes. To the reaction mixture was added 7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydro quinoline-3-carbaldehyde, followed by overnight stirring at room temperature. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and then evaporated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 30 mg of ethyl (2E)-5-[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]-5-hydroxypent-2-enoate.
Reaction SMILES: CS(O)(=O)=O.CS(O)(=O)=O.[NH2:11][C:12]1[C:19](=[O:20])[N:15]2[CH2:16][CH2:17][CH2:18][N:14]2[C:13]=1[NH2:21].[NH2:22][C:23]1[CH:24]=[C:25]([OH:30])[CH:26]=[C:27]([CH3:29])[CH:28]=1.N.OO>O.C(O)C>[NH2:21][C:13]1[N:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19](=[O:20])[C:12]=1/[N:11]=[C:28]1\[C:23]([NH2:22])=[CH:24][C:25](=[O:30])[CH:26]=[C:27]\1[CH3:29]
Reactant: Cc1cc(N)cc(O)c1
Reactant: Nc1c(N)n2n(c1=O)CCC2
Agent: CS(=O)(=O)O
Agent: N
Agent: OO
Solvent: CCO
Solvent: O
Product: CC1=CC(=O)C=C(N)/C1=N\c1c(N)n2n(c1=O)CCC2

Procedure:
0.5 mmol of 2,3-diamino-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-1-one dimethane sulfonate was dissolved in a mixture of water and ethanol (7.5 ml/1.5 ml). This solution was admixed with 0.05 mmol of 3-amino-5-methylphenol, then with 1.8 ml of concentrated aqueous ammonia, then with 9 ml of hydrogen peroxide.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[N:11]=[C:12]([C:14]1[N:19]=[C:18]([C:20](=O)[CH3:21])[CH:17]=[CH:16][CH:15]=1)[CH3:13])([CH3:3])[CH3:2].[CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH2:32])([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[N:11]=[C:12]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([C:20](=[N:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH:23]([CH3:25])[CH3:24])[CH3:21])[N:19]=1)[CH3:13])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1N
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cccc2C(C)C)n1
Solvent: Cc1ccccc1
Product: CC(=Nc1ccccc1C(C)C)c1cccc(C(C)=Nc2c(C)cccc2C(C)C)n1

Procedure:
4.0 g (0.0135 mol) of 1-{6-[1-(2-isopropyl-6-methyl-phenylimino)-ethyl]-pyridin-2-yl}-ethanone 15, 2.76 g (0.0204 mol) of 2-Isopropyl-phenylamine 9 (4.0 g, 0.0135 mol), 100 g of fresh molecular sieves, and 100 ml of toluene were kept at 100° C. for 3 days under a flow of nitrogen. The solvent was removed in a rotary evaporator and the residue was recrystallized from 10 ml of ethanol. The yield of (2-Isopropyl-6-methyl-phenyl)-(1-{6-[1-(2-isopropyl-phenylimino)-ethyl]-pyridin-2-yl}-ethylidene)-amine 16 was 4.83 g (87%) as a yellow solid. 13C NMR (500 MHz, CD2Cl2, TMS (selected signals)): δ 166.9 (C═N), 166.2 (C═N).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[Br:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccc(Br)cc1
Yield: 81.1 %

Procedure:
1.79 g (0.00931 mol) of 1-benzyl-4-hydroxy-piperidine and 2.3 ml (0.0164 mol) of triethylamine were dissolved in 20 ml of toluene and treated with 1.63 g (0.00745 mol) of 4-bromobenzoyl chloride. The mixture was boiled at reflux for 6 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 2.26 g (81%) of 1-benzyl-piperidin-4-yl 4-bromo-benzoate were obtained as white crystals; m.p. 71°-72°.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[CH:4][N:3]=1.CC(C)([O-])C.[K+].CN(C)C(=O)C.[CH3:31][N:32]1[CH:36]=[CH:35][C:34]([NH:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([OH:48])[CH:46]=3)[N:41]=[CH:40][N:39]=2)=[N:33]1>O>[CH3:31][N:32]1[CH:36]=[CH:35][C:34]([NH:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([O:48][C:2]4[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][O:12][CH:13]5[CH2:18][CH2:17][CH2:16][CH2:15][O:14]5)=[CH:4][N:3]=4)[CH:46]=3)[N:41]=[CH:40][N:39]=2)=[N:33]1
Reactant: Fc1ccc(OCCCOC2CCCCO2)cn1
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cn1ccc(Nc2ncnc3ccc(Oc4ccc(OCCCOC5CCCCO5)cn4)cc23)n1
Temperature: 180 °C
Reaction time: 14 h
Yield: 96.5 %

Procedure:
2-Fluoro-5-[3-(tetrahydro-2H-pyran-2-yloxy)propoxy]pyridine (305 mg, 1.10 mmol) and potassium tert-butoxide (140 mg, 1.24 mmol) were added to an N,N-dimethylacetamide solution (1 ml) of 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (120 mg, 0.50 mmol), and stirred at 180° C. for 14 hours under a nitrogen atmosphere in a sealed tube. The reaction solution was cooled with ice, then saline water was added, and extracted with chloroform. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage, chloroform:methanol=100:3) to obtain N-(1-methyl-1H-pyrazol-3-yl)-6-({5-[3-(tetrahydro-2H-pyran-2-yloxy)prop oxy]pyridin-2-yl}oxy)quinazoline-4-amine (230 mg, yield: 97%) as a pale orange amorphous solid.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[N:5][N:6]([CH2:8]Cl)[CH:7]=1.[F:10][C:11]([F:20])([F:19])[CH2:12][CH2:13][CH:14]([C:17]#[N:18])[C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:2][C:3]1[CH:4]=[N:5][N:6]([CH2:8][C:14]([CH2:13][CH2:12][C:11]([F:10])([F:19])[F:20])([C:15]#[N:16])[C:17]#[N:18])[CH:7]=1
Reactant: ClCn1cc(Br)cn1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cc(Br)cn1
Yield: 72.4 %

Procedure:
3.27 g of 4-bromo-1-(chloromethyl)-1H-pyrazole hydrochloride and 2.29 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 28 ml of N,N-dimethylformamide. 3.89 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 3.28 g of [(4-bromo-1H-pyrazole-1-yl)methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (21), hereinafter) shown by below formula.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][C@H:11]1[CH2:19][OH:20])=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:21]I>C1COCC1.[Cl-].[Na+].O>[C:3]([O:7][C:8]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][C@H:11]1[CH2:19][O:20][CH3:21])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1c2ccccc2C[C@H]1CO
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC[C@@H]1Cc2ccccc2N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
To a slurry of sodium hydride (60%) (1.623 g, 40.5 mmol, 1.3 eq) in THF (15 mL) was added (S)-2-hydroxymethyl-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (7.760 g, 31.1 mmol, 1 eq) (J. Org. Chem, 62, 7679, 1997) in THF (100 mL) and the mixture was stirred at room temperature for 1 hr. Methyl iodide (3 mL, 48.2 mmol, 1.5 eq) was added and the reaction was stirred at room temperature overnight. It was then poured into brine and extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate and concentrated. The crude residue purified by column chromatography using ethyl acetate/hexanes (10/90) as an eluent to give the title compound as a colorless oil (3.863 g, 47% ). NMR (400 Mz, DMSO-d6): consistent.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7](#[N:11])[CH2:8][C:9]#[N:10].[C:12]1([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25](=O)[CH2:26][Cl:27])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[Cl:27][C:26]1[CH:25]=[CH:20][CH:21]=[CH:22][C:23]=1[C:24]1[C:8]([C:9]#[N:10])=[C:7]([NH2:11])[N:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:19]=1
Reactant: N#CCC#N
Reactant: O=C(CCl)c1ccccc1Nc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: N#Cc1c(-c2ccccc2Cl)cn(-c2ccccc2)c1N
Temperature: 65 °C
Reaction time: 2 h

Procedure:
4.0 g of potassium tertiary butoxide are dissolved in 80 ml of ethanol and subsequently first 3.0 g of malononitrile and then 9 g of 2'-phenylamino-2-chloroacetophenone are added at RT and the mixture is stirred at 65° C. for 2 h. The mixture is then cooled and concentrated in an RE. The residue is partitioned between water and methylene chloride and the aqueous phase is extracted once more with methylene chloride. The combined organic phases are dried over MgSO4 and concentrated. The product is chromatographed on silica gel using methylene chloride and the product-containing fractions are concentrated, 4-(2-chlorophenyl)-1-phenyl-2-amino-3-cyanopyrrole being obtained as a reddish, viscous oil which is directly further processed.
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[NH:8][CH2:7][C@@H:6]([OH:9])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:17](Cl)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>C(Cl)Cl>[OH:9][C@@H:6]1[CH2:7][N:8]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C@@H:3]([CH3:2])[CH2:4][CH2:5]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@H]1CC[C@H](O)CN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CC[C@H](O)CN1C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
A mixture of ±trans-6-methylpiperidin-3-ol hydrochloride (14.0 g, 0.092 mol) in CH2Cl2 (150 mL) was cooled to 0° C. Triethylamine (51.5 mL, 0.369 mol) was added slowly. CbzCl (13.59 mL, 0.092 mol) was added dropwise, keeping the temperature below 20° C. The reaction was allowed to warm overnight to room temperature. The reaction was quenched by addition of water and diluted further with additional CH2Cl2. The layers were separated and the organics were dried over MgSO4 and concentrated. The crude material was purified by silica gel gradient chromatography (0-75% ethyl acetate in hexanes), providing ±Benzyl trans-5-hydroxy-2-methylpiperidine-1-carboxylate.
Reaction SMILES: O[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13]([S:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1)=[S:14])[CH3:11].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:10]([O:12][C:13]([S:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([C:31]([O:33][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[O:32])=[CH:34][CH:35]=1)=[S:14])[CH3:11]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCOC(=S)SCCCCCCCCCCOc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=S)SCCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
p-Hydroxybenzaldehyde (0.37 g, 3.0 mmol), 8 (1.2 g, 3.0 mmol), and DMAP (0.04 g, 0.3 mmol) were dissolved in 300 mL of CH2Cl2. DCC (1.24 g, 6.0 mmol) was added to reaction flask which was stirred at room temperature for three days. The solvent was removed under reduced pressure, and the residue purified using column chromatography (CH2Cl2:EtOH, 10:0.05). The product was then recrystallized from ethanol. Yield 0.3 g (20%). 1HNMR: δH (CDCl3; 300 MHz): 1.24-1.52 (15 H, m, CH2/O—CH2—CH3), 1.69 (2 H, m, S—CH2—CH2), 1.81 (2 H, m, O—CH2—CH2), 3.11 (2 H, t, 3J=7.3 Hz, SCH2), 4.02 (2 H, t, 3J=6.5 Hz, O—CH2), 4.65 (2 H, q, 3J=7.1 Hz, O—CH2—CH3), 6.99 (2 H, d, 3J=8.9 Hz, Ar—H), 7.40 (2 H, d, 3J=8.5 Hz, Ar—H), 7.96 (2 H, d, 3J=8.6 Hz, Ar—H), 8.14 (2 H, d, 3J=8.9 Hz, Ar—H), 10.0 (1 H, s, COH). 13C NMR: δC (CDCl3; 75 MHz): 13.8, 25.9, 28.1, 28.3, 28.8, 29.1, 29.3, 29.4, 35.9, 68.4, 69.7, 114.4, 120.8, 122.6, 131.2, 132.4, 133.9, 155.9.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.O>N1C=CC=CC=1>[S:19]([O:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCCO
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCNC(=O)OC(C)(C)C)cc1
Reaction time: 8 h
Yield: 55 %

Procedure:
Into 50 mL of pyridine was dissolved 2.95 g (16.9 mmoles) of 3-tert-butoxycarbonylamino-1-propanol. To the solution, while being cooled in ice under an argon atmosphere, was added dropwise over a period of 40 minutes a solution of 3.36 g (17.7 mmoles) of p-toluenesulfonyl chloride in pyridine. The mixture was left standing overnight at 7° C., then admixed with a small volume of water, and evaporated to dryness. The residue was dissolved in 200 mL of chloroform, washed successively with 5% aqueous potassium hydrogensulfate solution, saturated aqueous sodium hydrogencarbonate solution, and water, then dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography using 120 g of silica gel (Wako-Gel®C-200) and a toluene-ethyl acetate (8:1 by volume) mixture as developing solvent. Fraction Nos. 35 to 68 (each 15 mL in volume) were combined and evaporated to dryness to yield 3.06 g (55% yield) of O-tosyl-3-tert-butoxycarbonylamino-1-propanol in colorless oily form.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[CH3:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[NH:20]C1C=CC=CC=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:13]=1[CH3:12])=[O:7]
Reactant: Cc1cccc(Nc2ccccc2)c1C
Reactant: O=C(Cl)c1cccc(CCl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(NC(=O)c2cccc(CCl)c2)c1C
Reaction time: 18 h

Procedure:
To a solution of 3-chloromethylbenzoyl chloride (2.0 g) in methylene chloride (20 mL) was added 2,3- dimethylphenylaniline (1.28 g) and triethylamine (1.47 mL). The solution was stirred 18 h, concentrated in vacuo, and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was extracted w/50 mL each of 2% potassium hydrogen sulfate, saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate and concentrated in vacuo. Upon concentration a precipitated formed which was collected and dried to obtained the product. NMR (300 MHz, DMSO-d6) δ 10.0 (1H, s), 8.02 (1H, s), 7.94 (1H, d, J=7 Hz), 7.63 (1H, d, J=7 Hz), 7.52 (1H, t, J=7 Hz). 7.10 (3H, s), 4.83 (2H, s), 2.27 (3H, s), 2.07 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.Cl[C:13]1[C:22]2[C:17](=[C:18]([CH3:23])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[C:13]1[C:22]2[C:17](=[C:18]([CH3:23])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1
Reactant: Cc1cccc2c(Cl)ccnc12
Reactant: Cc1cc2cc(F)ccc2[nH]1
Product: Cc1[nH]c2ccc(F)cc2c1-c1ccnc2c(C)cccc12

Procedure:
The sub-title compound was prepared from 5-fluoro-2-methylindole and 4-chloro-8-methylquinoline by the method of Example 31, step a).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[O:11])[C:3]=1[C:4]#[N:5].[NH4+:20].[OH-]>CO.CCO>[NH2:20][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[O:11])[C:3]=1[C:4]#[N:5]
Reactant: [NH4+]
Reactant: COc1cccc(S(=O)c2cccc(F)c2C#N)c1
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: COc1cccc(S(=O)c2cccc(N)c2C#N)c1
Temperature: 130 °C

Procedure:
To a solution of 0.73 g (2.7 mmol) of 2-fluoro-6-[(3-methoxyphenyl)sulfinyl]benzonitrile (Example 16) in 65 ml of MeOH/EtOH (2.5:4) was added 20 mL of concentrated NH4OH. This mixture was sealed in a glass-lined bomb and heated at 130° C. for 3 h. After solvent removal, the resultant concentrate was purified by flash column chromatography on silica gel with 5% MeOH in methylene chloride as the eluent. This resulted in 0.36 g (53%) of 2-amino-6-[(3-methoxyphenyl)sulfinyl]benzonitrile as a solid: mp 110°-114° C.; NMR. (Me2SO-d6, 200 MHz): δ 3.8 (s, 3H), 6.5 (br s, 2H); 7.1 (apparent d, 1H), 7.0 (apparent d, 2H), 7.2-7.3 (m, 2H), 7.5 (apparent t, 2H); mass spec (CI) 273 (M+ +1, 100%). Anal. Calc. for C14H12N2O2S: C, 61.75; H, 4.44; N, 10.29; S, 11.77. Found: C 61.65; H, 4.46; N, 10.21; S, 11.69.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=O)=[CH:3][CH:2]=1.[NH2:12][C:13]1[S:14][C:15]([CH3:18])=[CH:16][N:17]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:18][C:15]1[S:14][C:13]([NH:12][C:8](=[O:10])[CH2:7][C:4]2[CH:3]=[CH:2][C:1]([CH3:11])=[CH:6][CH:5]=2)=[N:17][CH:16]=1
Reactant: Cc1cnc(N)s1
Reactant: Cc1ccc(CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(CC(=O)Nc2ncc(C)s2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.2 %

Procedure:
To a suspension of p-tolylacetic acid (1.00 g, 6.66 mmol) and 2-amino-5-methylthiazole (0.760 g, 6.66 mmol) in dichloromethane (10 mL) was added at 0° C. under a nitrogen atmosphere 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.40 g, 7.32 mmol), 1-hydroxybenzotriazole (90 mg, 0.67 mmol) and N,N-diisopropyl ethyl amine (1.8 mL, 10 mmol). The ice bath was removed and the resulting solution was stirred for 3 h at ambient temperature. The reaction mixture was diluted with dichloromethane (20 mL) and washed with aqueous sodium carbonate (half-concentrated, 20 mL) and water (20 mL). The aqueous layers were extracted with dichloromethane (20 mL) and the combined organic layers were dried over sodium sulfate. The filtrate was concentrated and the residue was suspended in TBME (20 mL) and filtered. Washing with TBME (10 mL) afforded the title compound (1.48 g, 90%) as a white solid. MS m/e: 247.2 [M+H]+.