Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[F:14])[N:5]=[C:4]2[CH2:15][CH2:16][S:17][CH2:18][C:3]=12.P(Cl)(Cl)([Cl:21])=O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Cl:21][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[F:14])[N:5]=[C:4]2[CH2:15][CH2:16][S:17][CH2:18][C:3]=12
Reactant: Oc1c2c(nn1-c1ccc(Cl)cc1F)CCSC2
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Fc1cc(Cl)ccc1-n1nc2c(c1Cl)CSCC2
Reaction time: 16 h

Procedure:
12.4 Parts of 3-hydroxy-2-(4-chloro-2-fluorophenyl)-2,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole was reacted with 6.7 parts of phosphorus oxychloride at 155° C. for 3 hours, the reaction mixture poured into 250 parts of chloroform and 250 parts of saturated aqueous NaHCO3 and stirred for 16 hours. The aqueous portion was extracted with 200 parts of chloroform, the chloroform portions combined and washed twice with 200 parts of water, dried with anhydrous magnesium sulfate, and evaporated under a reduced pressure of 50 to 300 mm Hg. to give 6.0 parts of 3-chloro-2-(4-chloro-2-fluorophenyl)-2,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole as a black-brown oil which when contacted with a mixture of ether and pentane changed into a light brown solid, m.p. 97°-99° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[CH:20]=[CH:21][C:22]([F:37])=[C:23]([NH:25][S:26]([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH3:38][S:39]([N:42]1[CH2:47][CH2:46][CH:45]([NH2:48])[CH2:44][CH2:43]1)(=[O:41])=[O:40]>C1COCC1>[F:36][C:30]1[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:29]=1[S:26]([NH:25][C:23]1[CH:24]=[C:19]([C:9]2[N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:48][CH:45]3[CH2:46][CH2:47][N:42]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:43][CH2:44]3)[N:7]=2)[CH:20]=[CH:21][C:22]=1[F:37])(=[O:28])=[O:27]
Reactant: O=S(=O)(Nc1cc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)ccc1F)c1cc(F)ccc1F
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCC(Nc2nccc(-c3sc(C4CCOCC4)nc3-c3ccc(F)c(NS(=O)(=O)c4cc(F)ccc4F)c3)n2)CC1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (120 mg, 0.212 mmol) and 1-(methylsulfonyl)-4-piperidinamine (377 mg, 2.12 mmol) in THF (1 mL) the title compound was obtained as a light yellow solid (89 mg, 0.12 mmol, 59% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.83 (s, 1H), 8.14 (d, J=4.9 Hz, 1H), 7.46-7.73 (m, 3H), 7.34-7.45 (m, 3H), 7.22-7.34 (m, 1H), 5.99-6.51 (m, 1H), 3.95 (dd, J=11.4, 2.0 Hz, 2H), 3.41-3.58 (m, 4H), 3.18-3.33 (m, 1H), 2.69-2.93 (m, 5H), 1.81-2.06 (m, 5H), 1.66-1.81 (m, 2H), 1.42-1.65 (m, 2H). MS (ESI): 709.18 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][O:10]COC.FC1C=CC2[B:22](O)[O:21]CC=2C=1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[B:22]([OH:21])[O:10][CH2:9][C:3]=2[CH:4]=1
Reactant: COCOCc1cc(Cl)ccc1Br
Reactant: OB1OCc2cc(F)ccc21
Product: OB1OCc2cc(Cl)ccc21

Procedure:
This compound was made from 18d in the same manner as compound 19b: mp 142-144° C. 1H NMR (300 MHz, DMSO-d6) δ (ppm) 4.96 (s, 2H), 7.38 (d, J=7.8 Hz, 1H), 7.49 (s, 1H), 7.71 (d, J=7.8 Hz, 1H), 9.30 (s, 1H); ESI-MS m/z 167 (M−H)−; HPLC purity 99.0%; Anal (C7H6ClO2.0.1H2O)C, H.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.Cl.[OH:13][CH:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[NH2:8][C:6]1[CH:7]=[C:2]([N:16]2[CH2:17][CH2:18][CH2:19][CH:14]([OH:13])[CH2:15]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: OC1CCCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(N2CCCC(O)C2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 18 h
Yield: 53.6 %

Procedure:
A mixture of 5-chloro-2-nitrophenylamine (1.3 g, 7.0 mmol), 3-hydroxypiperidine hydrochloride (3.0 g, 20 mmol), and K2CO3 (3.0 g, 22 mmol) in DMF (10 mL) was stirred at 120° C. for 18 h. The reaction mixture was cooled to room temperature, poured into water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography (silica gel, 4×7.5 cm, eluted with 50:50 CHCl3/EtOAc) to yield the product as an orange solid (0.89 g, 54%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[CH2:19][C:18](=O)[NH:17][CH2:16][C@H:15]2[CH2:21]CC(O)=O)=[CH:10][CH:9]=1.[O:26]1CCCC1>>[F:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH:15]2[CH2:21][OH:26])=[CH:12][CH:13]=1
Reactant: O=C(O)CC[C@@H]1CNC(=O)C[C@H]1c1ccc(F)cc1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCC1CNCCC1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Lithium aluminum hydride (1.0 molar solution in tetrahydrofuran, 0.75 ml, 0.75 mmol) was added gradually to a solution of trans-4-(4-fluorophenyl)-3-carboxyethylpiperidin-6-one (0.25g, 0.836 mmol) in tetrahydrofuran (3 ml) keeping the temperature below 25° C. The reaction mixture was stirred for 1 hour at 25° C., then quenched with 1 drop of water, followed by 2 drops 15% sodium hydroxide solution, and finally with 5 drops of water. Extraction with dichloromethane (35 ml) followed by evaporation of the dichloromethane phase gave 0.21 g of the title compound. Yield 76%.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[CH:9])[CH2:3]1.[F:10][C:11]1[C:12](I)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[F:10][C:11]1[C:12]([C:9]#[C:8][CH2:7][N:4]2[CH2:5][CH2:6][C@H:2]([OH:1])[CH2:3]2)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: C#CCN1CC[C@H](O)C1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CCN3CC[C@H](O)C3)c21

Procedure:
Using Method C above, (S)-3-hydroxy-1-prop-2-ynyl-pyrrolidine (60 mg, 0.48 mmol) (Example 96A) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (60 mg, 0.16 mmol) (Starting Material 6) using (Ph3P)4Pd (18 mg, 0.02 mmol) and a catalylic amount of CuI in a mixture of DMF (4 mL) and Et3N (4 mL) as solvent at 80° C. for 6 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4 and concentrated. (S)-(Z)-1,3-Dihydro-5-fluoro-4-[3-(3-hydroxy-pyrrolidin-1-yl)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-20% MeOH in CH2Cl2 gradient and precipitation out of THF with excess of pentane. (Yield 42 mg, 71%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:32]=1>>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:22][CH:23]=2)[S:37]([C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)(=[O:39])=[O:38])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Agent: Cl
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2cccnc2)c1

Procedure:
The title compound of Step B was prepared from {3-[(4-pyrazol-1-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester of Step A and pyridine-3-sulfonyl chloride hydrochloride, of Preparation 2, following the method described in Example 3, Step B with a reaction time of 2 h. 1H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.78 (d, 1H), 8.03 (dd, 1H), 7.88 (m, 1H), 7.69 (m, 1H), 7.55 (d, 2H), 7.42 (m, 1H), 7.13 (m, 3H), 6.76 (d, 1H), 6.66 (m, 2H), 6.45 (m, 1H), 4.39 (s, 2H), 4.38 (s, 2H), 4.33 (s, 2H), 1.47 (s, 9H); MS 535(M+1).
Reaction SMILES: [I-].[Na+].Br[CH:4]([CH2:16]Br)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.II.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)C.O.CC(C)=O>[CH2:6]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[CH2:5][CH:4]=[CH2:16]
Reactant: O=[N+]([O-])c1ccc(CCC(Br)CBr)cc1
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [I-]
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: O
Product: C=CCCc1ccc([N+](=O)[O-])cc1
Yield: 89.1 %

Procedure:
A mixture of 52.1 g of sodium iodide, 300 ml of acetone and 28.6 g of 1-(3,4-dibromobutyl)-4-nitrobenzene was stirred under reflux for 3.5 hours. After cooling the brown suspension was freed from solvent in vacuo and the brown residue was taken up in diethyl ether and water. The separated iodine was reduced by adding solid sodium thiosulphate. The colourless ether solutions were washed with water, dried with sodium sulphate and concentrated in vacuo. The residue (14.9 g) was distilled in a high vacuum, whereby 13.4 g of 1-(3-butenyl)-4-nitrobenzene were obtained as an almost colourless liquid; b.p. 86°-89° C./0.2 Torr.
Reaction SMILES: FC(F)(F)C([NH:5][C@H:6]1[CH2:11][CH:10]=[CH:9][CH2:8][C@@H:7]1[C:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]1)=[O:13])=O.Cl>CO.[Pd]>[CH2:20]=[C:17]1[CH2:18][CH2:19][N:14]([C:12]([C@@H:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C@@H:6]2[NH2:5])=[O:13])[CH2:15][CH2:16]1
Reactant: CC1CCN(C(=O)[C@H]2CC=CC[C@@H]2NC(=O)C(F)(F)F)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: C=C1CCN(C(=O)[C@@H]2CCCC[C@@H]2N)CC1
Reaction time: 20 h
Yield: 115.6 %

Procedure:
The cyclohexene VI (0.57 g) is dissolved in methanol (50 ml) in the presence of 10% Pd/C (50 mg) and of 3N HCl (0.85 ml). The reaction mixture is stirred under a slight hydrogen pressure for 20 h. The catalyst is removed by filtration and the solvent is driven off under vacuum. The residue is taken up in a saturated K2CO3 solution and the aqueous phase is extracted with ethyl acetate. The organic phase is dried over Na2SO4 and then evaporated under vacuum to provide the reduced derivative VIII (0.46 g) in the form of an oil.
Reaction SMILES: [Cl:1][Si:2](Cl)([C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:24][C:25]1[CH:26]=[C:27]([Li])[CH:28]=[C:29]([CH3:31])[CH:30]=1>C(OCC)C>[Cl:1][Si:2]([C:9]1[CH:14]=[C:13]([C:15]([CH3:17])([CH3:16])[CH3:18])[CH:12]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:10]=1)([C:27]1[CH:26]=[C:25]([CH3:24])[CH:30]=[C:29]([CH3:31])[CH:28]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)c1cc(C(C)(C)C)cc([Si](Cl)(Cl)c2ccccc2)c1
Reactant: [Li]c1cc(C)cc(C)c1
Solvent: CCOCC
Product: Cc1cc(C)cc([Si](Cl)(c2ccccc2)c2cc(C(C)(C)C)cc(C(C)(C)C)c2)c1
Temperature: 25 °C
Yield: 86.5 %

Procedure:
Under a nitrogen atmosphere, to a diethyl ether solution (70 mL) of dichloro(3,5-di-tert-butylphenyl)(phenyl)silane (7.00 g, 19.16 mmol), a solution of 3,5-dimethylphenyllithium (2.15 g, 19.16 mmol) dissolved in diethyl ether (22 mL) was added dropwise at −20° C. After the mixture was gradually warmed to room temperature, stirring was performed at room temperature. 3,5-Dimethylphenyllithium (1.26 g, 11.24 mmol) was added and further stirred at room temperature. After completion of the reaction, the solvent was removed under reduced pressure. Thereafter, hexane was added to the residue, and insoluble materials were removed by filtration. The solvent was removed from the filtrate under reduced pressure to obtain chloro(3,5-di-tert-butylphenyl)(3,5-dimethylphenyl)(phenyl)silane (7.21 g, yield 86.5%) as yellow oil.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][N:7]([C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)[C:8](=[O:11])[CH2:9][Cl:10])([CH3:3])[CH3:2].[CH3:21][C:22]1[CH:34]=[CH:33][CH:32]=[CH:31][C:23]=1[CH2:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH:1]([O:4][CH2:5][CH2:6][N:7]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([N:28]2[CH2:29][CH2:30][N:25]([CH2:24][C:23]3[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=3[CH3:21])[CH2:26][CH2:27]2)=[O:17])=[CH:14][CH:13]=1)[C:8](=[O:11])[CH2:9][Cl:10])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1CN1CCNCC1
Reactant: CC(C)OCCN(C(=O)CCl)c1ccc(C(=O)Cl)cc1
Product: Cc1ccccc1CN1CCN(C(=O)c2ccc(N(CCOC(C)C)C(=O)CCl)cc2)CC1

Procedure:
Analogously to Example 55, 1.5 g of 4-[N-(2-isopropyloxyethyl)-N-chloroacetylamino]benzoyl chloride are reacted with 0.76 g of 2-methylbenzylpiperazine, yielding 1-{4-[N-(2-isopropyloxyethyl)-N-chloroacetylamino]benzoyl}-4-(2-methylbenzyl)piperazine. The hydrochloride thereof melts at 142°-143°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C:9](=[O:25])[C@@:10]2([N:22]=[N+]=[N-])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5])[CH3:2].[C:26]([OH:29])(=S)[CH3:27]>>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C:9](=[O:25])[C@@:10]2([NH:22][C:26](=[O:29])[CH3:27])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1[C@@H]2CC(=O)[C@@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Reactant: CC(O)=S
Product: CCOC(=O)[C@H]1[C@@H]2CC(=O)[C@@](NC(C)=O)(C(=O)OCc3ccccc3)[C@@H]21
Yield: 71 %

Procedure:
A solution of (1S,2R,5R,6S)-2-Azido-3-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (IX) (974 mg, 2.84 mmol) in thioacetic acid (6.5 mL) was stirred at 70° C. for 2 d. The reaction mixture was concentrated in vacuum and subjected to silica gel column chromatography with hexane/ethyl acetate 3:2->1:1 to yield (1S,2R,5R,6S)-2-acetylamino-3-oxo-bicyclo [3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XVI) (726 mg, 71%) as a pink oil. 1H-NMR (250 MHz, CDCl3) □1.25 (3H, t, 1=7.1 Hz), 1.63 (1H, t, J=3.5 Hz), 2.05 (3H, s), 2.32 (1H, ddd,J=7, 6,3.5 Hz), 2.54 (1H, d,J=19 Hz), 2.90 (1H, dd,J=19, 6 Hz), 3.06 (1H, dd, J=7, 3.5 Hz), 4.12 (2H, m), 5.16 (1H, d, J=12 Hz), 5.25 (1H, d, J=12 Hz), 7.24-7.35 (5H, m); MS[ISP] 360 (M+H+); □D20 +44.33° (c=0.97, CHCl3).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:29][OH:30])[N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]2[C:23](=[O:24])[N:22]3[CH2:25][CH2:26][S:27][C:21]3=[N:20][C:19]=2[CH3:28])[CH2:12][CH2:11]1.O1CCCC1.[H-].[Na+].[OH-].[NH4+]>C(O)(=O)C.C(O)C.CC1C=CC=CC=1>[F:8][C:6]1[CH:5]=[CH:4][C:3]2[C:9]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]4[C:23](=[O:24])[N:22]5[CH2:25][CH2:26][S:27][C:21]5=[N:20][C:19]=4[CH3:28])[CH2:12][CH2:11]3)=[N:29][O:30][C:2]=2[CH:7]=1
Reactant: Cc1nc2n(c(=O)c1CCN1CCN(C(=NO)c3ccc(F)cc3F)CC1)CCS2
Agent: [H-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cc1nc2n(c(=O)c1CCN1CCN(c3noc4cc(F)ccc34)CC1)CCS2
Reaction time: 18 h
Yield: 91.4 %

Procedure:
A solution of 4.4 parts of 6-[2-[4-[(2,4-difluorophenyl)(hydroxyimino)methyl]-1-piperazinyl]ethyl]-2,3-dihydro-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one in 45 parts of tetrahydrofuran was stirred at room temperature. 0.5 Parts of a sodium hydride dispersion 50% were added portionwise. Upon complete addition, 108 parts of methylbenzene were added and the reaction mixture was stirred for 18 hours at reflux temperature. After cooling, 16 parts of ethanol were added, followed by the addition of 3 parts of acetic acid. The whole was stirred for 10 minutes. The mixture was treated with ammonium hydroxide and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 3.8 parts (91.4%) of 6-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperazinyl]-ethyl]-2,3-dihydro-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one; mp. 193.0° C. (compound 3).
Reaction SMILES: C1C=C[NH+]=CC=1.[Br:7][Br-]Br.[Cl:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[C:16](=[O:20])[NH:17]2)=[CH:13][CH:12]=1>CC(O)(C)C.O>[Br:7][C:15]1([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[C:14]2[C:18](=[CH:19][C:11]([Cl:10])=[CH:12][CH:13]=2)[NH:17][C:16]1=[O:20]
Reactant: O=C1Nc2cc(Cl)ccc2C1Cc1cccc(Cl)c1
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: O
Product: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Yield: 100.3 %

Procedure:
Pyridinium bromide perbromide (0.659 g, 2.06 mmol) (Aldrich) was added in one portion to a solution of 6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (0.5 g, 1.72 mmol) (from Example 30b supra) in t-BuOH (16.2 mL) and H2O (74 uL) at room temperature with stirring. After stirring at room temperature for 4 hours, the crude was diluted with water, extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over MgSO4. After filtration, the solvent was removed to obtain rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one as a pale yellow solid (yield: 0.64 g, 84%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[Cl:11])=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19]N)=[CH:15][CH:14]=1>O>[Cl:12][C:13]1[CH:14]=[C:15]2[C:16](=[CH:17][CH:18]=1)[NH:19][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[Cl:11])=[CH:1]2
Reactant: NNc1ccc(Cl)cc1
Reactant: CC(=O)c1ccc(Cl)cc1Cl
Solvent: O
Product: Clc1ccc(-c2cc3cc(Cl)ccc3[nH]2)c(Cl)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
A mixture of 2,4-dichloroacetophenone (378 mg, 2.0 mmol), p-chloro-phenylhydrazine (358 mg, 2.0 mmol and polyphosphoric acid (PPA) (0.5 mL) is heated at 100° C. for 8 h, cooled to room temperature, diluted with water, stirred briefly, allowed to stand at room temperature for 16 h and filtered. The filtercake is washed with water and air-dried to afford the title compound, 320 mg (54% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[N:20]([CH2:21][C:22]3[O:23][CH:24]=[CH:25][CH:26]=3)[C:19]3[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=3[N:17]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[O:23]1[CH:24]=[CH:25][CH:26]=[C:22]1[CH2:21][N:20]1[C:19]2[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=2[N:17]=[C:16]1[C:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3n2Cc2ccco2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1nc2ccccc2n1Cc1ccco1)C1CCNCC1
Reaction time: 0.25 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazole-2-carbonyl)piperidine (1.16 mmol), furfuryl alcohol (0.10 mL, 1.16 mmol), and triphenylphosphine (0.33 g, 1.28 mmol) in tetrahydrofuran (5 mL). Add diethyl azodicarboxylate (0.20 mL, 1.28 mmol). After 18 hours, evaporate the reaction mixture in vacuo to give a residue. Partition the residue between ethyl acetate and water. Separate the organic layer and extract with water and saturated aqueous sodium chloride solution. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound. Chromatograph the residue on silica gel eluting with 5% acetone/dichloromethane to give 1-(t-butoxycarbonyl)-4-(1-(fur-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine. Cool 1-(t-butoxycarbonyl)-4-(1-(fur-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine (1.0 mmol), and dichloromethane (5 mL). Slowly add a cold solution of trifluoroacetic acid (1 mmol) in dichloromethane (2 mL). After 15 minutes, partition the reaction mixture between dichloromethane and saturated aqueous sodium bicarbonate solution. Separate the organic layer and extract with brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: C(SC1C=C(O)C(=O)NC=1)C1C=CC=CC=1.C[O:18][C:19]1[C:24]([O:25]C)=[CH:23][C:22]([S:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)=[CH:21][N:20]=1>>[OH:25][C:24]1[C:19](=[O:18])[NH:20][CH:21]=[C:22]([S:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[CH:23]=1
Reactant: COc1cc(SCc2ccc(C)cc2)cnc1OC
Agent: O=c1[nH]cc(SCc2ccccc2)cc1O
Product: Cc1ccc(CSc2c[nH]c(=O)c(O)c2)cc1

Procedure:
Prepared as described for 5-(benzylsulfanyl)-3-hydroxypyridin-2(1H)-one (Example 1) from 2,3-dimethoxy-5-[(4-methylbenzyl)sulfanyl]pyridine (Intermediate 3).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13].[N:19]1([CH2:25][CH2:26][C@@H:27]([NH2:36])[CH2:28][S:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[N:19]1([CH2:25][CH2:26][C@@H:27]([NH:36][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])[CH2:28][S:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1
Reactant: NS(=O)(=O)c1ccc(F)c(S(=O)(=O)C(F)(F)F)c1
Reactant: N[C@H](CCN1CCOCC1)CSc1ccccc1
Product: NS(=O)(=O)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1

Procedure:
reacting 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, (1R)-3-morpholin-4-yl-1-((phenylthio)methyl)propylamine and a sixth base to provide 4-(((1R)-3-morpholin-4-yl-1-((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide and isolating or not isolating the 4-(((1R)-3-morpholin-4-yl-1-((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide; and
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:34][C:35]([CH:37]([CH3:39])[CH3:38])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:34][C:35]([CH:37]([CH3:38])[CH3:39])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(NC(=O)C(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(NC(=O)C(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-isopropylcarbonylamino-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [Cl:1][SiH2:2][Cl:3].[CH2:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[CH2:4]([SiH:2]([Cl:3])[Cl:1])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cl[SiH2]Cl
Reactant: C=Cc1ccccc1
Product: Cl[SiH](Cl)CCc1ccccc1

Procedure:
Cyclohexylphenethydichlorosilane having the general formula ##STR12## which is produced by reacting a dichlorosilane and styrene in the presence of the catalyst of claim 6 at a temperature of 30°-150° C. for 0.1-60 hours to produce a monophenethyldichlorosilane and reacting said monosubstitute with cyclohexene at a temperature of 80°-150° C. for 5-20 hours.