Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]=1[S:20][CH3:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.Cl.[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27]Cl.C([O-])([O-])=O.[K+].[K+]>CCO>[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([C:9]([NH:8][C:1]2[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:10])=[C:12]1[S:20][CH3:21]
Reactant: CN(C)CCCCl
Reactant: CSc1[nH]c2ccccc2c1C(=O)NCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CSc1c(C(=O)Nc2ccccc2)c2ccccc2n1CCCN(C)C

Procedure:
A solution of 2-(methylthio)-N-phenyl-1H-indole-3-carboxamide [XXV: R8 =H] (1.8 g, 6.4 mmol) in EtOH (400 mL) was treated with 3-(dimethylamino)propyl chloride hydrochloride (10.0 g, 64 mmol) and K2CO3 (13 g, 96 mmol ) and heated under reflux for 3 hours. A further 10 equivalents of the reagents were then added, and the mixture was heated under reflux for a further 48 hours. EtOH was removed under reduced pressure, and the residue was diluted with water to give crude product. This was chromatographed on alumina, eluting with CH2Cl2 containing 0.2% MeOH, to give 1-[3-(dimethylamino)propyl]-2-(methylthio)-N-phenyl-1H-indole-3-carboxamide [XXVI: R8 =H, R9 =(CH2)3NMe2 ] (0.49 g, 21%) as an oil.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH2:22][CH2:23][CH:24]([OH:26])[CH3:25]>>[OH:26][CH:24]([CH3:25])[CH2:23][NH:22][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21]
Reactant: CC(O)CN
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: CC(O)CNc1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Yield: 65 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with 1-amino-propan-2-ol according to the GPA affording 23.1 mg (65%) of a red powder. Rt=3.07 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19]Cl)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[OH:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19][O:23][C:24]4[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: CCN1c2ncc(CCl)cc2C(=O)N(C)c2ccc(Cl)nc21
Reactant: COC(=O)c1ccc(O)cc1
Product: CCN1c2ncc(COc3ccc(C(=O)OC)cc3)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 45 %

Procedure:
Using a procedure analogous to that described in Example 98, the title compound, m.p. 196°-197° C., was prepared from 2-chloro-8-chloromethyl5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and methyl 4-hydroxybenzoate. The yield was 45% of theory.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:9][NH:10][NH2:11]>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:10]([CH3:9])[NH2:11])=[CH:6][CH:7]=1
Reactant: CNN
Reactant: Clc1ccc(Cl)nn1
Product: CN(N)c1ccc(Cl)nn1
Reaction time: 16 h
Yield: 39.9 %

Procedure:
3,6-Dichloro-pyridazine (1 g, 6.75 mmol) was placed in a flask fitted with a water condenser and methylhydrazine (1.31 mL, 25 mmol) was added dropwise. An immediate exotherm was observed and methylhydrazine begins to reflux. When the reaction had subsided, the mixture was left for 16 hours, and the excess methylhydrazine was removed under reduced pressure. The cooled residue was stirred with aqueous sodium hydroxide solution (20 ml of 20%), and the resulting solution was extracted with ether (6×100 ml). The combined extracts were dried (K2CO3) and concentrated to give 427 mg of N-(6-Chloro-pyridazin-3-yl)-N-methyl-hydrazine.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:14]=[N:13][N:12]([CH2:15][C@@H:16]2[C@H:19]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18](=[O:31])[N:17]2CC2C=CC(OC)=CC=2OC)[N:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].OP([O-])([O-])=O.[K+].[K+]>CC#N.O>[Si:1]([O:8][CH2:9][C:10]1[CH:14]=[N:13][N:12]([CH2:15][C@@H:16]2[C@H:19]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:18](=[O:31])[NH:17]2)[N:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2Cn2ncc(CO[Si](C)(C)C(C)(C)C)n2)c(OC)c1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cnn(C[C@H]2NC(=O)[C@H]2NC(=O)OCc2ccccc2)n1
Temperature: 90 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To a solution of benzyl ((2R,3S)-2-((4-(((tert-butyldimethylsilyl)oxy)methyl)-2H-1,2,3-triazol-2-yl)methyl)-1-(2,4-dimethoxybenzyl)-4-oxoazetidin-3-yl)carbamate (1.25 g, 2.1 mmol) in CH3CN (20 mL) was added K2S2O8 (0.73 g, 2.7 mmol) followed by a solution of K2HPO4 (0.84 g, 4.8 mmol) in water (10 mL). After stirring at 90° C. for 1 h, more K2S2O8 (0.23 g, 0.84 mmol) was added. After heating at 90° C. for additional 2 h, the reaction mixture was concentrated in vacuo. The residue was extracted with EtOAc (2×30 mL). Combined organic layers were washed with water, brine, dried with Na2SO4, filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (MeOH-DCM, 1-3%) to afford the title compound (0.44 g, 47%) as a pale yellow solid. LCMS: m/z=446.2 (M+1).
Reaction SMILES: [CH3:1][S-:2].[Na+].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])/[CH:9]=[CH:10]/[N+:11]([O-:13])=[O:12].C(O)(=O)C>CO>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:9]([S:2][CH3:1])[CH2:10][N+:11]([O-:13])=[O:12])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COc1ccc(/C=C/[N+](=O)[O-])cc1OC
Reactant: C[S-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(C(C[N+](=O)[O-])SC)cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60.2 %

Procedure:
To a solution of sodium methanethiolate (0.62 g, 8.8 mmol) in methanol (20 ml), trans-3,4-dimethoxy-β-nitrostyrene (1.42 g, 8 mmol) was added and stirred at room temperature for 5 minutes. Further, acetic acid (0.46 ml) was added and stirred for 5 minutes. After evaporating methanol to a half amount under reduced pressure, water was added and extracted with dichloromethane and the organic layers were combined, washed with water and dried over sodium sulfate. The solvent was distilled out under reduced pressure and the residue was isolated and purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to yield 2-(3,4-dimethoxyphenyl)-2-(methylthio)nitroethane (1.24 g, 60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([OH:21])=O)=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].[CH2:36]([S:38]([NH2:41])(=[O:40])=[O:39])[CH3:37]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:41][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])=[O:21])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23]
Reactant: COc1ccccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)O)cnn12
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccccc3OC)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 50.1 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-methoxyphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.054 g, 0.11 mmol) obtained in step 2 and ethanesulfonamide (0.059 g, 0.55 mmol), the title compound (0.031 g, 34%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: N#Cc1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)c(F)c2)CC1
Temperature: 150 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
2,4-Difluorobenzonitrile (5.00 g, 35.94 mmol), tert-butyl-1-piperazinecarboxylate (6.69 g, 35.92 mmol) and potassium carbonate (10.0 g, 72.4 mmol) were combined in dimethylsulfoxide (40 mL) and stirred at 150° C. overnight. The reaction mixture was cooled to ambient temperature, poured into water (150 mL) and extracted into ethyl acetate (150 mL). The extract was washed twice with water and once with brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography (2″×5″ silica gel). The column was flushed with 500 mL each 10% and 20% ethyl acetate/hexane and the product removed with an additional 500 mL of 20% ethyl acetate/hexane. Concentration gave 4-(4-cyano-3-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester as a white solid (3.28 g, 30%) which had mp 130.5-131.0° C.
Reaction SMILES: I[C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)CCC.CN(C=O)C.[OH-].[Na+]>[Cu]I.C(Cl)(Cl)Cl>[N+:11]([C:4]1[CH:3]=[C:2]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=1)([O-:13])=[O:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: O=[N+]([O-])c1cc(I)c2occc2c1
Agent: [Cu]I
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(-c2ccncc2)c2occc2c1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
7-Iodo-5-nitrobenzofuran (2.00 g, 0.00692 mol), 4-tributylstannylpyridine (2.80 g, 0.00761 mol), copper(I)iodide (132 mg, 0.692 mmol) and dichlorobis(triphenylphosphine) palladium(II) (49 mg, 0.0692 mmol) were added to a 50 mL test tube followed by DMF (20 mL). The mixture was heated at 100° C. overnight in a StemBlock. After cooling to room temperature, aqueous sodium hydroxide (2 M; 4 mL) was added and the solution was stirred for 15 min. Chloroform (20 mL) was added and the mixture was filtered through Celite. The aqueous layer was then extracted with chloroform (3×) and the combined organic phases were evaporated. The residue was then triturated with ether and the precipitate was dried in vacuo overnight to yield a light brown solid. Yield: 686 mg (41%); HLPC (System A) purity=99%, m/z=241 (M+H)+, 1H NMR (270 MHz, DMSO-d6) δ ppm 7.33 (d, J=2.23 Hz, 1H) 7.98 (m, 2H) 8.38 (d, J=2.23 Hz, 1H) 8.50 (d, J=2.47 Hz, 1H) 8.75 (d, J=2.23 Hz, 1H) 8.79 (m, 2H).
Reaction SMILES: O1C2C=CC=CC=2OB1.[Br:10][C:11]1[C:12]([N:27]2[CH2:31][CH2:30][CH:29]([CH:32]3[CH2:34][CH2:33]3)[CH2:28]2)=[C:13]([C:19](=[O:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17].CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1>C1(C)C=CC=CC=1>[Br:10][C:11]1[C:12]([N:27]2[CH2:31][CH2:30][CH:29]([CH:32]3[CH2:34][CH2:33]3)[CH2:28]2)=[C:13]([C@H:19]([OH:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17]
Reactant: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(N2CCC(C3CC3)C2)c1Br
Agent: B1Oc2ccccc2O1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: Cc1ccccc1
Product: Cc1nc(C)c([C@H](O)C(=O)OC(C)C)c(N2CCC(C3CC3)C2)c1Br
Temperature: -50 °C
Reaction time: 18 h
Yield: 73.8 %

Procedure:
The benzo[d][1,3,2]dioxaborole (0.66 mL, 2.68 mmol; 50% soln in toluene) was added to a nitrogen purged solution of isopropyl 2-(5-bromo-4-(3-cyclopropylpyrrolidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate (730 mg, 1.78 mmol) and 0.6 ml, of 1M (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (148 mg, 0.54 mmol) in toluene (18 mL) cooled to −50° C. The reaction was allowed to slowly warm to −15° C. and placed in the freezer for 18 h before being quenched with 1M Na2CO3 (5 mL) and stirred for 20 min. The organic layer was washed with brine and dried (MgSO4). The crude product was charged (DCM) to a 40 g ISCO silica gel cartridge and gradient elution (5-50% EtOAc/hexanes) using an Isolera chromatography station gave (2S)-isopropyl 2-(5-bromo-4-(3-cyclopropylpyrrolidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate 540 mg (74%) as a mixture of diastereomers; major isomer. 1H NMR (500 MHz, DMSO-d6) δ 5.52 (s, 1H), 4.96-4.89 (m, 1H), 3.40-3.35 (m, 2H), 3.17-3.09 (m, 1H), 2.94-2.90 (m, 1H), 2.53 (s, 3H), 2.40 (s, 3H), 2.03 (br. s., 1H), 1.82-1.74 (m, 2H), 1.17-1.08 (m, 6H), 0.76-0.75 (m, 1H), 0.43-0.41 (m, 2H), 0.15-0.14 (m, 2H). UPLC (M+H)=413.2.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=3)[N:14]=[C:13]([C:26]([F:29])([F:28])[F:27])[CH:12]=2)=[CH:7][CH:6]=1>O.O1CCOCC1>[OH:3][NH:2][S:22]([C:19]1[CH:20]=[CH:21][C:16]([N:15]2[C:11]([C:8]3[CH:9]=[CH:10][C:5]([CH3:4])=[CH:6][CH:7]=3)=[CH:12][C:13]([C:26]([F:29])([F:28])[F:27])=[N:14]2)=[CH:17][CH:18]=1)(=[O:23])=[O:24]
Reactant: NO
Reactant: Cc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(S(=O)(=O)Cl)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(S(=O)(=O)NO)cc2)cc1
Yield: 74 %

Procedure:
To a stirred suspension of hydroxylamine hydrochloride (2.74 g, 40 mmol) in dioxane (25 ml) sodium acetate (3.25 g, 40 mmol) in water (15 ml) was added dropwise at room temperature, followed by dropwise addition of 4-(5-p-methylphenyl-3-trifluoromethyl-pyrazol-1-yl)-benzenesulfonyl chloride (4.11 g, 10 mmol) in dioxane (40 ml). The obtained reaction mixture was poured into water (100 ml), extracted with ethyl acetate (2×50 ml), the organic layers were washed with water (3×50 ml) and brine (1×50 ml), dried over MgSO4, filtered and concentrated in vacuo. The obtained oil was crystallized from 75% aqueous ethanol (75 ml) to yield 2.94 g (75%) of the title compound as white crystals. Mp: 203° C.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C:7](=[CH:9][CH:10]=O)[CH3:8])[CH3:3].[CH3:12][C:13]([CH3:15])=[O:14]>CCOCC>[CH3:8][C:7]([CH2:6][CH2:5][CH:4]=[C:2]([CH3:1])[CH3:3])=[CH:9][CH:10]=[CH:12][C:13](=[O:14])[CH3:15]
Reactant: CC(C)=O
Reactant: CC(C)=CCCC(C)=CC=O
Solvent: CCOCC
Product: CC(=O)C=CC=C(C)CCC=C(C)C
Temperature: 67.5 °C
Yield: 91 %

Procedure:
1.00 mL (5.84 mmoles) of citral (purchased from Aldrich Chemical Co., Milwaukee, Wis.), 20 mL of acetone (HPLC-grade, purchased from Aldrich Chemical Co.), and 1.66 g of alumina (weakly acidic, activated, Brockmann I, 150 mesh, Aldrich catalog #26,774-0) were added to a 200 mL glass pressure bottle containing a Teflon-coated spin bar. After sweeping the bottle briefly with a stream of nitrogen gas, the bottle was closed; and the mixture was subsequently heated at 65-70° C. (external oil bath temperature) for 20 hours. After cooling the mixture to room temperature, the product was isolated by dilution of the reaction mixture with 160 mL of 3:1 (v/v) ether: dichloromethane and removal of the alumina by filtration through a small pad of Hyflo Super-Cel® filtering aid. For large-scale reactions, fractional distillation of this filtrate would be the only requirement to complete the process of isolating the product. For convenience in a small-scale reaction, the filtrate was washed three times with 140 mL portions of 5% (w/v) aqueous sodium chloride to remove 4-hydroxy-4-methyl-2-pentanone (formed in minor amounts by the self-aldol condensation of acetone), then dried over anhydrous magnesium sulfate, and filtered. Removal of the ether and dichloromethane by evaporation at reduced pressure and subsequent evaporative ("Kugelrohr oven") distillation afforded 1.03 g (91% yield) of the named unsaturated ketone: boiling point 102-110° C. (bath temperature, 0.40 mm). The identity and purity of this compound was ascertained by IR and proton NMR analysis (recorded at 400 MHz). The latter spectrum exhibited a multiplet at δ 7.42 (C-4 vinyl H), a doublet (J=14.8 Hz) at δ 6.08 (C-3 vinyl H), a doublet (J=12 Hz) at δ 6.004 (C-5 vinyl H), a multiplet at δ 5.09 (C-9 vinyl H), a singlet at δ 2.27 (CH3C=O), and signals for three vinyl methyl groups at δ 1.90 (CH3 bonded to C-6), 1.676, and 1.606.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[S:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[NH2:24]>>[Cl:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])[CH:25]=[CH:26][C:27]=1[S:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Reactant: Nc1ccc(Sc2ccccc2)c(Cl)c1
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(Sc4ccccc4)c(Cl)c3)c2cc1OCC

Procedure:
In the manner of Example 105 reaction of 4-chloro-6,7-diethoxy-3-quinolinecarbonitrile with 3-chloro-4-(phenylthio)aniline gave the title compound as a tan solid, mp 88-94° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:31])=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C@@H:17]3[C@@H:22]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=4[F:30])[CH2:21][CH2:20][NH:19][CH2:18]3)=[O:16])[CH2:11][CH2:10]2)[CH:8]=1.Cl.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:34]=1>C(Cl)(Cl)Cl>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:31])=[C:7]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C@@H:17]3[C@@H:22]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=4[F:30])[CH2:21][CH2:20][N:19]([S:39]([C:35]4[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=4)(=[O:41])=[O:40])[CH2:18]3)=[O:16])[CH2:13][CH2:14]2)[CH:8]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: Cc1ccc(Cl)cc1N1CCN(C(=O)[C@H]2CNCC[C@@H]2c2ccc(F)cc2F)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(Cl)cc1N1CCN(C(=O)[C@H]2CN(S(=O)(=O)c3cccnc3)CC[C@@H]2c2ccc(F)cc2F)CC1

Procedure:
In analogy to example 63, step 4, from (3S,4R) or (3R,4S)-[4-(5-chloro-2-methyl-phenyl)-piperazin-1-yl]-[4-(2,4-difluoro-phenyl)-piperidin-3-yl]-methanone hydrochloride and pyridine-3-sulfonyl chloride hydrochloride was prepared (3S,4R) or (3R,4S)-[4-(5-chloro-2-methyl-phenyl)-piperazin-1-yl]-[(3S,4R)-4-(2,4-difluoro-phenyl)-1-(pyridine-3-sulfonyl)-piperidin-3-yl]-methanone as a white foam, MS: 575.4 ([M+H, 1Cl])+; [α]D=−66.76 (c=0.454 g/100 mL, CHCl3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])[N:3]=1.[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>O1CCOCC1.CO>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])[N:3]=1)=[O:21]
Reactant: CN1CCC(C(=O)c2cccc(N)n2)CC1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: C1COCCO1
Solvent: CO
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccccc3Cl)n2)CC1
Yield: 85.2 %

Procedure:
Mix 2-Amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine (0.223 g) and 2-chlorobenzoyl chloride (0.175 g) in 1,4-dioxane (10 mL) and heat at reflux for 1 hour. Dilute with methanol (10 mL) and load on a SCX column (10 g). Wash the column with methanol, elute the product with 2 M NH3 in methanol, evaporate and purify the product on a silica gel column (CH2Cl2 with 2 M NH3 in methanol) to obtain 0.305 g (84%) of the title compound: mass spectrum (electric spray) m/z=358 (M+1) and 360 (M+2+1); 1H NMR (CDCl3): 8.60 (br s, 1H), 8.54 (d, 1H), 7.90 (dd, 1H), 7.81 (d, 1H), 7.76 (dd, 1H), 7.45 (m, 3H), 3.63 (m, 1H), 2.90 (m, 2H), 2.29 (s, 3H), 2.07 (m 2H), 1.85 (m, 4H).
Reaction SMILES: FC(F)(F)C([O:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])=O.[F:14][CH2:15][C:16]([NH:18]O)=[O:17]>>[F:14][CH2:15][C:16]([NH:18][O:5][C:6](=[O:11])[C:7]([F:8])([F:9])[F:10])=[O:17]
Reactant: O=C(CF)NO
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C(CF)NOC(=O)C(F)(F)F
Yield: 93 %

Procedure:
Trifluoroacetic anhydride, 71 ml (0.5 mol), was added dropwise to a 37.22 g (0.4 mol) sample of powdered 2-fluoroacetohydroxamic acid. The reaction mixture became liquid and warmed spontaneously to 60°. After cooling, the reaction mixture was evaporated to dryness under reduced pressure to give 70.3 g (93%) of N--(fluoroacetyl)--O--(trifluoroacetyl)hydroxylamine as a colorless, crystalline residue: mp 56°-59°; 1H NMR (CDCl3) δ5.05 ppm (d, J=47 Hz, 2H) and 9.8 ppm (NH); 19F NMR (CDCl3) δ-233.8 ppm (t, J=47 Hz, 1F) and 73.8 ppm (s, 3F).
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH3:6])[CH2:3][CH2:4][OH:5].[F:8][C:9]([F:21])([F:20])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16](Cl)(=[O:18])=[O:17].C(OCC)(=O)C>C(Cl)Cl>[F:21][C:9]([F:8])([F:20])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([O:5][CH2:4][CH2:3][C:2]([OH:7])([CH3:6])[CH3:1])(=[O:17])=[O:18]
Reactant: CC(C)(O)CCO
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(O)CCOS(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 7 h
Yield: 66.7 %

Procedure:
To a solution of 3-methyl-1,3-butane diol (2.5 g, 21 mmol) and TEA (1.63 g, 16 mmol) in CH2Cl2 (15 mL) was added o-(trifluoromethyl)benzenesulfonyl chloride (2.03 g, 8.3 mmol) dissolved in CH2Cl2 (20 mL). The solution was stirred at rt for 7 h. The reaction mixture was diluted with CH2Cl2 (75 mL) and washed with 1 M HCl (2×25 mL), saturated aqueous NaHCO3 (1×25 mL) and saturated aqueous NaCl (1×25 mL). The organics were dried over Na2SO4 and concentrated to give a crude mixture. Silica gel chromatography with ethyl acetate in hexanes yielded the desired product (1.73 g, 66%). 1H NMR (400 MHz CDCl3) δ 8.23 (m, 1H), 7.91 (m, 1H), 7.75 (m, 2H), 4.32 (t, 2H, J=7.0 Hz), 1.91 (t, 2H, J=7.0 Hz) 1.22 (s, 6H). Anal. Calcd. For C12H15F3O4S: C, 46.15; H, 4.84. Found: C, 45.73; H, 4.88.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]3[C:11]4([CH2:21][O:22][C:8]3=[CH:7][C:5]=2[N:6]=1)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:13][C:12]4=[O:20].Br[CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27].BrCC1CCCCO1.N1C2C(=CC=CC=2)C2(C3=CC4SC=NC=4C=C3OC2)C1=O>>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]3[C:11]4([CH2:21][O:22][C:8]3=[CH:7][C:5]=2[N:6]=1)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[N:13]([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:12]4=[O:20]
Reactant: CC(C)CCBr
Reactant: Cc1nc2cc3c(cc2s1)C1(CO3)C(=O)Nc2ccccc21
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3ncsc3cc12
Product: Cc1nc2cc3c(cc2s1)C1(CO3)C(=O)N(CCC(C)C)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-methylspiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and 1-bromo-3-methylbutane to replace 2-(bromomethyl)tetrahydro-2H-pyran, methylbutyl)spiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one was obtained (71%) as a colorless solid: mp 137-138° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ7.60 (d, J=8.6 Hz, 1H), 7.32-7.27 (m, 1H), 7.13-7.08 (m, 1H), 7.03-6.92 (m, 3H), 5.03 (d, J=8.8 Hz, 1H), 4.78 (d, J=8.8 Hz, 1H), 4.12-4.01 (m, 1H), 3.71-3.60 (m, 1H), 2.56 (s, 3H), 1.93-1.61 (m, 3H), 1.06-1.00 (m, 6H); 13C NMR (75 MHz, CDCl3) δ176.8, 169.3, 160.4, 149.4, 142.8, 132.9, 129.1, 128.7, 123.6, 122.8, 122.2, 120.4, 108.6, 108.4, 81.1, 58.2, 39.2, 36.1, 26.0, 23.0, 22.5, 20.3; MS (ES+) m/z 378.5 (M+1).