Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]([N:10]=[C:11]=[O:12])([CH3:9])[CH3:8].[Cl:13][C:14]1[C:15]([O:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)=[N:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.Cl>C(OCC)(=O)C>[CH:7]([NH:10][C:11]([N:27]1[C:28]([CH3:30])=[CH:29][C:25]([O:24][C:15]2[C:14]([Cl:13])=[CH:19][C:18]([C:20]([F:23])([F:22])[F:21])=[CH:17][N:16]=2)=[N:26]1)=[O:12])([CH3:9])[CH3:8]
Reactant: CC(C)N=C=O
Reactant: Cc1cc(Oc2ncc(C(F)(F)F)cc2Cl)n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2ncc(C(F)(F)F)cc2Cl)nn1C(=O)NC(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.7 %

Procedure:
Potassium carbonate (0.75 g, 5.4 mmol) and isopropyl isocyanate (0.46 g, 5.4 mmol) were added to a solution of 3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole (1.00 g, 3.6 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a colorless viscous substance of N-isopropyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole-1-carboxamide (0.91 g, yield: 69.7%). 1H-NMR (CDCl3, TMS, ppm): δ 1.25 (d, J=6.5 Hz, 6H), 2.65 (d, J=0.8 Hz, 3H), 3.95-4.20 (m, 1H), 6.04 (q, J=0.8 Hz, 1H), 6.80˜7.00 (m, 1H), 8.02 (d, J=2.3 Hz, 1H), 8.35 (m, 1H).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:4]1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[CH3:30][S:31]([N:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:4]1)(=[O:33])=[O:32]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCNC3)cnc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Product: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)N[C@@H]3CCCN(S(C)(=O)=O)C3)cnc21

Procedure:
1-((R)-1-Methane sulfonyl-piperidin-3-yl)-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea was prepared in the same manner from 1-piperidin-3-yl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea dihydrochloride and methanesulfonyl chloride.
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([N:18]1[CH2:23][CH2:22][N:21]([C:24](=[O:40])[NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=2)[C@@H:20]([CH3:41])[C:19]1=[O:42])[CH2:5][CH2:6][C:7]([N:9]1[CH2:16][CH2:15][C:12]2([CH2:14][CH2:13]2)[C@H:11]([OH:17])[CH2:10]1)=[O:8].[Li+].[BH4-]>CO>[F:39][C:36]([F:37])([F:38])[C:28]1[CH:27]=[C:26]([NH:25][C:24]([N:21]2[CH2:22][CH2:23][N:18]([C@H:4]([CH2:3][OH:2])[CH2:5][CH2:6][C:7]([N:9]3[CH2:16][CH2:15][C:12]4([CH2:14][CH2:13]4)[C@H:11]([OH:17])[CH2:10]3)=[O:8])[C:19](=[O:42])[C@@H:20]2[CH3:41])=[O:40])[CH:31]=[CH:30][C:29]=1[C:32]([F:34])([F:35])[F:33]
Reactant: COC(=O)[C@H](CCC(=O)N1CCC2(CC2)[C@H](O)C1)N1CCN(C(=O)Nc2ccc(C(F)(F)F)c(C(F)(F)F)c2)[C@@H](C)C1=O
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Product: C[C@H]1C(=O)N([C@H](CO)CCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1ccc(C(F)(F)F)c(C(F)(F)F)c1
Yield: 79 %

Procedure:
In analogy to the procedure described in Example 53, (S)-2-[(S)-4-(3,4-bis-trifluoromethyl-phenylcarbamoyl)-3-methyl-2-oxo-piperazin-1-yl]-5-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-5-oxo-pentanoic acid methyl ester (example 143) and LiBH4 (2 M in THF)/MeOH gave the titled compound in 79% yield as amorphous white solid. MS: 595.23 (MH+).
Reaction SMILES: C[O-].[Na+].[CH3:4][N:5]([CH3:20])[CH:6]=[CH:7][C:8]([C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][CH:15]=1)=[O:9].[CH2:21](I)[CH3:22]>CN(C)C=O>[CH3:20][N:5]([CH3:4])[CH:6]=[CH:7][C:8]([C:10]1[CH:11]=[C:12]([N:16]([CH2:21][CH3:22])[C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][CH:15]=1)=[O:9]
Reactant: CC(=O)Nc1cccc(C(=O)C=CN(C)C)c1
Reactant: CCI
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(C)=O)c1cccc(C(=O)C=CN(C)C)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
17.5 gm Sodium methoxide was added portion wise to a clear solution of 50 gm N-[3-[3-(Dimethylamino)-1-oxo-2-propenyl]-phenyl] acetamide and 85 gm ethyl iodide in 500 ml dimethyl formamide. After 6 hrs of stirring at room temperature, the reaction mass was quenched in 5 liters of water and extracted in dichloromethane. The dichloromethane layer was washed with water, dried over sodium sulphate and concentrated under vacuum to get oil, which upon trituration in hexane gave the title product as a solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].O.O.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.[Na+]>[Cu]I.CS(C)=O>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccccc1Br
Reactant: O=S([O-])c1ccc(Br)cc1
Agent: [Cu]I
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccccc1S(=O)(=O)c1ccc(Br)cc1

Procedure:
Methyl 2-[(4-bromophenyl)sulfonyl]benzoate was prepared according to the method of Example 135, Step 2 using methyl 2-bromobenzoate (2.8 mL, 20 mmol) in place of (S)-1-(2-iodophenyl)ethanol and sodium 4-bromophenylsulfinate dihydrate (5.6 g, 20 mmol) in place of Intermediate 1, together with CuI (19 g, 100 mmol) and DMSO (40 mL), affording product as a white solid (3.8 g).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:13][N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])=[CH:7][CH:6]=1)=O.[NH2:33][C:34]1[C:39]([CH:40]([OH:42])[CH3:41])=[CH:38][CH:37]=[CH:36][N:35]=1.C(=O)(O)[O-].[Na+]>C(O)(C)C>[O:23]=[C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:24])[N:14]1[CH2:13][C@@H:12]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([C:3]2[N:33]=[C:34]3[C:39]([CH:40]([OH:42])[CH3:41])=[CH:38][CH:37]=[CH:36][N:35]3[CH:2]=2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(=O)CBr)cc1)CN1C(=O)c2ccccc2C1=O
Reactant: CC(O)c1cccnc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(O)c1cccn2cc(-c3ccc(C[C@@H](CN4C(=O)c5ccccc5C4=O)NC(=O)OC(C)(C)C)cc3)nc12
Yield: 87.4 %

Procedure:
A mixture of 1,1-dimethylethyl {(1S)-2-{4-(bromoacetyl)phenyl]-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate (1.90 g, 3.79 mmol), 1-(2-amino-3-pyridinyl)ethanol (0.523 g, 3.79 mmol), and solid sodium bicarbonate (0.398 g, 4.72 mmol) in isopropanol (24 mL) was refluxed for 3.0 h. and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water and saturated sodium chloride, dried (Na2SO4), and concentrated to give the title compound (1.79 g, 87%) as a light pink solid. MS (ES+) m/e 541 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([Br:20])[C:18]=1[OH:19])[CH:14]=O>CN(C=O)C>[Br:10][C:11]1[CH:12]=[C:13]([C:14]2[S:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[N:1]=2)[CH:16]=[C:17]([Br:20])[C:18]=1[OH:19]
Reactant: Nc1cc(Cl)ccc1S
Reactant: O=Cc1cc(Br)c(O)c(Br)c1
Solvent: CN(C)C=O
Product: Oc1c(Br)cc(-c2nc3cc(Cl)ccc3s2)cc1Br
Temperature: 100 °C
Yield: 13 %

Procedure:
In a DMF (3 mL) solvent, a solution including 2-amino-4-chlorobenzenethiol (100 mg, 0.63 mmol) and 3,5-dibromo-4-hydroxybenzaldehyde (127 mg, 0.63 mmol) was heated at a temperature of 100° C. for 8.5 hours. After DMF was evaporated therefrom, the residual was purified by silica gel column chromatography using hexane and ethyl acetate (5:1) as a developer to obtain a solid Compound 96 (34.3 mg, 18.1%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.N1C2C(=CC=CC=2)C=CC=1.[Cl:16][C:17]1[C:18](O)=[N:19][CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1>O>[Cl:3][C:18]1[C:17]([Cl:16])=[CH:22][C:21]([N+:23]([O-:25])=[O:24])=[CH:20][N:19]=1
Reactant: O=[N+]([O-])c1cnc(O)c(Cl)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: c1ccc2ncccc2c1
Product: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Temperature: 120 °C
Yield: 88.9 %

Procedure:
The procedure of Koch and Schnatterer, Synthesis ,1990, 499-501 was followed. To 2-hydroxy-5-nitropyridine (70.0 g, 0.5 mol) in 12 N hydrochloric acid was added dropwise a solution of potassium chlorate (21.4 g, 0.18 mol) in H2O (300 mL) at a rate such that the temperature remained ≤60° C. The mixture was allowed to stir for a further 30 minutes at ca. 50° C., then allowed to cool to ambient temperature, then was further cooled in an ice bath. The yellow solid was collected by filtration, washed with cold H2O, and dried under vacuum at 50° C. to afford 3-chloro-2-hydroxy-5-nitropyridine (72.4 g, 83%) as a yellow powder. To phosphorus oxychloride (37.4 mL, 0.4 mol) at 0° C. was added quinoline (23.6 mL, 0.2 mol), followed by 3-chloro-2-hydroxy-5-nitropyridine (70 g, 0.4 mol) from above. The mixture was heated at 120° C. for 2.5 hours, during which time it became a dark liquid. After cooling to 100° C., H2O (150 mL) was added cautiously, and the mixture was cooled to 0° C. The precipitated solid was collected by filtration, washed with cold H2O, and dried under vacuum at 50° C. to afford 2,3-dichloro-5-nitropyridine (68.6 g, 89%). To 2,3-dichloro-5-nitropyridine (68.5 g, 0.39 mol) in a mixture of H2O (800 mL) and acetic acid (160 mL) were added bits of metallic iron with stirring until the starting material was consumed (TLC analysis). The mixture was filtered, and the filter cake was washed repeatedly with EtOAc. The aqueous filtrate was extracted with EtOAc and the organic fractions were combined and concentrated. The residue was chromatographed (silica gel; MeOH: CHCl3, 0.5:99.5 to 1:99) to afford the title compound (44.5 g, 70%) as a light orange powder: MS (CI/NH3) m/z 163 and 165 (M+H+), 180 and 182 (M+NH4)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][CH2:9][NH:10][CH:11]1[CH:15]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:14][N:13]([C:24](=[O:32])[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH2:12]1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Cl:43][CH2:44][C:45](Cl)=[O:46]>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][CH2:9][N:10]([CH:11]1[CH:15]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19])[CH2:14][N:13]([C:24](=[O:32])[C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[CH2:12]1)[C:45](=[O:46])[CH2:44][Cl:43])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)NCCNC1CN(C(=O)c2ccc(Cl)cc2)CC1O[Si](C)(C)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCN(C(=O)CCl)C1CN(C(=O)c2ccc(Cl)cc2)CC1O[Si](C)(C)C(C)(C)C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of {2-[4-(tert-butyl-dimethyl-silanyloxy)-1-(4-chloro-benzoyl)-pyrrolidin-3-ylamino]-ethyl}-carbamic acid tert-butyl ester (389 mg, 0.78 mmol) at 0° C., was added DIPEA (0.150 mL, 0.85 mmol) and chloroacetyl chloride (62 uL, 0.78 mmol). The reaction mixture was stifled at RT for overnight. The organic phase was washed with Sat. NaHCO3, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (Ethyl acetate:Hexane: 1:2) to give the desired product (260 mg, 58% yield) as a colorless oil. MS: (ESI), M/Z, 574 (M+1). Retention time: 2.78 min (FA-polar).
Reaction SMILES: [Cl:1][CH2:2][C:3]([OH:5])=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:48][N:49]([CH3:53])[CH2:50][CH2:51][NH2:52]>C(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:52][CH2:51][CH2:50][N:49]([CH3:53])[CH3:48])=[O:5]
Reactant: CN(C)CCN
Reactant: O=C(O)CCl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)CCNC(=O)CCl
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
A suspension of 2-chloroacetic acid (214 mg, 2.27 mmol), PyBOP® (1.18, 2.27 mmol), DIEA (1.18 mL, 6.81 mmol) in CH2Cl2 (1 mL) was stirred at RT for 10-15 minutes. This solution of activated acid was added to a suspension of N1,N1-dimethylethane-1,2-diamine (249 μL, 2.27 mmol) and CH2Cl2 (4 mL). The reaction mixture was stirred at RT for 1.5 h. Diluted with more CH2Cl2 and extracted with H2O (3×). Organic layer was dried under Na2SO4 and concentrated in vacuo to give the desired product 2-chloro-N-(2-(dimethylamino)ethyl)acetamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:30][N:21]4[N:22]=[C:23]5[C:28]([CH:27]=[CH:26][CH:25]=[C:24]5Br)=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.[CH3:45][N:46](C)C(=O)C>[Zn].[C-]#N.[Zn+2].[C-]#N>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:30][N:21]4[N:22]=[C:23]5[C:28]([CH:27]=[CH:26][CH:25]=[C:24]5[C:45]#[N:46])=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c5cccc(Br)c5nn4cc3-c3ccccc3)cc2)CCC1
Reactant: CC(=O)N(C)C
Agent: [C-]#N
Agent: [Zn+2]
Agent: [Zn]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c5cccc(C#N)c5nn4cc3-c3ccccc3)cc2)CCC1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
150 mg (0.26 mmol) {1-[4-(7-Bromo-3-phenylpyrimido[1,2-b]indazol-2-yl)phenyl]-cyclobutyl}carbamic acid tert-butyl ester (intermediate example Int-2-1), 1.7 mg (0.026 mmol) zinc, 21.6 mg (0.026 mmol) bis(diphenylphosphino)ferrocenedichloropalladium(II) and 61.8 mg (0.53 mmol) zinc cyanide in 2.2 mL N,N-dimethylacetamide, (degassed) were stirred in the microwave for four hours at 110° C. After addition of a further equivalent of zinc cyanide and a spatelspitze of zinc and bis(diphenylphosphino)ferrocenedichloropalladium(II) stirring was continued for three hours at 110° C. Despite an incomplete reaction the mixture was worked up. After addition of ethyl acetate the organic phase was washed twice with water and saturated ammonium chloride, dried over sodium sulfate, filtrated, and the solvent was removed. 274 mg {1-[4-(7-Cyano-3-phenylpyrimido[1,2-b]indazol-2-yl)-phenyl]cyclobutyl}carbamic acid tert-butylester were obtained which were used without purification in the next step (cleavage of the protecting group).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[CH:13]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)=[O:14]>C(Cl)Cl>[CH:13]([C:15]1[CH:16]=[CH:17][C:18]([S:21]([N:2]([CH2:3][CH2:4][OH:5])[CH3:1])(=[O:23])=[O:22])=[CH:19][CH:20]=1)=[O:14]
Reactant: O=Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CNCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCO)S(=O)(=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 80 h
Yield: 92.3 %

Procedure:
To an ice-cooled solution of 2-(methylamino)ethanol (0.196 mL, 2.44 mmol) and triethylamine (0.407 mL, 2.93 mmol) in DCM (10 mL) was added 4-formylbenzenesulfonyl chloride (0.500 g, 2.44 mmol). The reaction mixture was warmed slowly to RT and stirred at RT for 80 hours. The reaction mixture was diluted with DCM and was washed with 10% aqueous potassium hydrogen sulfate and dried (magnesium sulfate). The mixture filtered and the solvent evaporated at reduced pressure to afford the title compound (0.548 g, 92%).
Reaction SMILES: [CH2:1](I)[CH3:2].[CH3:4][O:5][CH:6]1[C:11](=[O:12])[NH:10][C:9](=[S:13])[NH:8][C:7]1=[O:14].[OH-].[Na+]>O>[CH2:1]([S:13][C:9]1[NH:8][C:7](=[O:14])[CH:6]([O:5][CH3:4])[C:11](=[O:12])[N:10]=1)[CH3:2]
Reactant: COC1C(=O)NC(=S)NC1=O
Reactant: CCI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCSC1=NC(=O)C(OC)C(=O)N1

Procedure:
Ethyl iodide (11.2 ml) was added dropwise to a stirred mixture of the product from step (i) (23 g) and sodium hydroxide (6 g) in water (400 ml). After 16 h the mixture was filtered, the filtrate acidified to pH1 and the precipitate filtered, washed with water and dried. Yield 17.8 g
Reaction SMILES: [SH2:1].C(O)C.[C:5]([CH:7]([C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)[NH:8][C:9]([C:11]1[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=1)=[O:10])#[N:6]>C(N(CC)CC)C>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[CH:7]([C:5](=[S:1])[NH2:6])[NH:8][C:9]([C:11]1[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=1)=[O:10]
Reactant: Cn1cc(C(=O)NC(C#N)c2ccco2)cn1
Reactant: S
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cn1cc(C(=O)NC(C(N)=S)c2ccco2)cn1
Reaction time: 1 h

Procedure:
Hydrogen sulfide was blown into an ethanol solution containing 1.4 g of the N-(cyano-2-furanylmethyl)-1-methyl-1H-pyrazol-4-carboxamide as obtained in the above process and 0.7 g of triethylamine, for 1 hour, and the whole was stirred for 1 hour under cooling with ice and then for a further 2 hours at room temperature. Afterwards, the crystal formed was taken out by filtration, washed with chloroform and then dried, to obtain 1.1 g of the intended N-[2-furanyl(thiocarbamoyl)-methyl]-1-methyl-1H-pyrazole-4-carboxamide.
Reaction SMILES: [NH2:1][CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[OH-].[Na+].[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[C:11]([NH:1][CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)C(N)C(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)C(NC(=O)c1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
A solution of 2-amino-3-methylbutanoic acid (500 mg, 4.27 mmol) in 2N NaOH (2.35 ml, 4.69 mmol) was stirred at RT for 30 minutes, then the reaction mixture was cooled at 0° C., and benzoyl chloride (471 μl, 4.05 mmol) and 2N NaOH (2.35 ml, 4.69 mmol) were simultaneously added dropwise from two different syringes. The reaction was stirred at RT for 3 hours. Water was added, the aqueous phase was washed with Et2O, then acidified with 1M HCl and back-extracted with Et2O, dried over Na2SO4 and evaporated. The residue was triturated with i-Pr2O to obtain 2-benzamido-3-methylbutanoic acid (780 mg, 83% yield).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][C@H:3]([OH:5])[CH3:4].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.O>N1C=CC=CC=1>[OH:5][C@H:3]([CH3:4])[CH2:2][CH2:1][O:6][S:13]([C:10]1[CH:11]=[CH:12][C:7]([CH3:17])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: C[C@@H](O)CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC[C@@H](C)O)cc1
Temperature: -25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
After adding pyridine (100 ml) to (R)-1,3-butanediol (86.0 g), the solution was cooled to −25° C. under nitrogen atmosphere. A solution of p-toluenesulfonyl chloride (200 g) in pyridine (200 ml) was slowly added dropwise thereto at a temperature ranging from −20 to −10° C. The mixture was stirred for 1 hour at a temperature ranging from −20 to −10° C. A small amount of water was added to the reaction mixture to stop the reaction and the solution was extracted with toluene and water. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to obtain (R)-3-hydroxy-1-(p-toluenesulfonyloxy)butane (209 g) as light brown oil. The oil thus obtained was used in the next step as such without purification.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[NH:12][C:11]3[C:13]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([F:28])=[C:23]([F:29])[CH:22]=4)=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:10]=3[N:9]=2)[CH2:3]1.[Br:30][C:31]1[C:32](Cl)=[N:33][CH:34]=[CH:35][CH:36]=1>>[Br:30][C:31]1[C:32]([N:7]2[CH2:6][CH2:5][N:4]([C:8]3[NH:12][C:11]4[C:13]([C:21]5[CH:26]=[C:25]([F:27])[C:24]([F:28])=[C:23]([F:29])[CH:22]=5)=[CH:14][C:15]([C:17]([F:18])([F:19])[F:20])=[CH:16][C:10]=4[N:9]=3)[CH2:3][C@@H:2]2[CH3:1])=[N:33][CH:34]=[CH:35][CH:36]=1
Reactant: Clc1ncccc1Br
Reactant: C[C@H]1CN(c2nc3cc(C(F)(F)F)cc(-c4cc(F)c(F)c(F)c4)c3[nH]2)CCN1
Product: C[C@H]1CN(c2nc3cc(C(F)(F)F)cc(-c4cc(F)c(F)c(F)c4)c3[nH]2)CCN1c1ncccc1Br

Procedure:
The piperazine from step (a) above (41 mg, 0.1 mmol) reacted with 3-bromo-2-chloropyridine (19 mg, 0.1 mmol, Aldrich) under the conditions of Example 48b to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 570 (M+1).
Reaction SMILES: ClCC[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[SH:28]>>[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[S:28][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2
Reactant: Sc1ccc2ccccc2c1
Reactant: O=C1CCc2cc(OCCCCCl)ccc2N1
Product: O=C1CCc2cc(OCCSc3ccc4ccccc4c3)ccc2N1

Procedure:
Prepared analogous to Example 1 from 6-(4-chlorobutoxy)-3,4-dihydro-carbostyril (m.p.: 147°-148° C.) and 2-naphthyl-mercaptan.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C(OCC)(=O)C>[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24]([O:1][N:2]=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: CCOC(=O)C(C#N)=NO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C#N)=NOS(=O)(=O)c1ccc(C)cc1
Reaction time: 8 h
Yield: 94.1 %

Procedure:
In ethyl acetate (50 ml) are dissolved ethyl 2-hydroxyimino-2-cyanoacetate (7.1 g) and triethylamine (7.0 ml). To the solution is added p-toluenesulfonyl chloride (9.5 g) with stirring under ice-cooling, and the mixture is stirred for 2 hours and allowed to stand overnight. The reaction mixture is filtered and the filtrate is concentrated. To the residue is added cyclohexane and the resulting crystals are separated by filtration and dried to give ethyl 2-(p-toluenesulfonyloxyimino)-2-cyanoacetate (13.9 g), melting point: 84°-87° C.
Reaction SMILES: [Li]C(CC)C.CN(CCN(C)C)C.[CH3:14][O:15][C:16]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19].[Br:29]C(Cl)(Cl)C(Cl)(Cl)Br>C1CCCCC1.C1COCC1>[Br:29][C:21]1[CH:22]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:24]=[C:16]([O:15][CH3:14])[C:17]=1[C:18]([OH:20])=[O:19]
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: COc1cc(C(F)(F)F)ccc1C(=O)O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: COc1cc(C(F)(F)F)cc(Br)c1C(=O)O
Temperature: -75 °C
Reaction time: 2 h
Yield: 12 %

Procedure:
To −75° C. cooled THF (70 ml) was added dropwise 36 ml (50.0 mmol) of a 1.4 M sec-BuLi solution in cyclohexane within 5 minutes keeping the temperature below −70° C. 7.5 ml (50.0 mmol) TMEDA were added dropwise at temperature below −70° C. within 5 minutes. A solution of 5.0 g (22.71 mmol) 2-methoxy-4-(trifluoromethyl)benzoic acid (commercial) in THF (25 ml) was added dropwise at over a period of 20 minutes. The dark green solution was stirred at −75° C. for 2 hours. A solution of 29.6 g (90.84 mmol) 1,2-dibromotetrachloroethane in THF (30 ml) was added dropwise. The off-white suspension was stirred at −75° C. for 1 hour and then allowed to warm to room temperature. The yellow solution was quenched by dropwise addition of 60 ml water under ice bath cooling. The mixture was diluted with ethyl acetate (70 ml) and water (30 ml). The aqueous layer was extracted with ethyl acetate (50 ml), acidified with HCl 25% and extracted with ethyl acetate (3×50 ml). The extracts were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was stirred in heptane, filtered and dried. The solid was recrystallized from heptane (7 ml) and ethyl acetate (2 ml) to provide 815 mg (12%) of the title compound as a white solid. MS (m/e): 298.9 (M−H).