Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:36].C(O)C.C(=O)([O-])[O-].[NH4+:44].[NH4+]>ClCCl.C(O)C>[ClH:36].[ClH:36].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:44])[NH2:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C#N)cc1)n2C)c1ccccn1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Yield: 90 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[2-(4-cyanophenyl)ethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)amide, ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 90% of theory, C27H28N6O3 (484.6); Rf value: 0.17 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=485; (M+2H)++=243; (M+H+Na)++=254.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([NH:15][CH3:16])=[O:14].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2OC2C=CC=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:7]=[C:6]([NH:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([NH:15][CH3:16])=[O:14])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1cc(I)c(Cl)cn1
Reactant: CNC(=O)c1ccccc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CNC(=O)c1ccccc1Nc1cc(Cl)ncc1Cl
Temperature: 120 °C
Yield: 56.5 %

Procedure:
A 150-mL sealed tube was charged with 2,5-dichloro-4-iodopyridine (3.5 g, 12.78 mmol), 2-amino-N-methylbenzamide (1.919 g, 12.78 mmol) and tripotassium phosphate (8.14 g, 38.3 mmol) in 1,4-dioxane (100 mL). The reaction mixture was degassed with nitrogen for 10 min. Bis(2-diphenylphosphinophenyl)ether (DPEPhos, 0.688 g, 1.278 mmol) and Pd(OAc)2 (0.115 g, 0.511 mmol) were added and the reaction mixture was heated in a 120° C. oil bath over night. The reaction mixture was filtered through celite, which was washed with dioxane. The solvent was evaporated to dryness and the solid was washed with EtOH (10 mL×3) to give 2.14 g (56%) of product as an off white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH3:11])[CH:6]=1)=O.[BH4-].[Na+]>CO>[CH3:11][O:10][C:7]1[CH:6]=[C:5]([CH2:3][OH:2])[O:9][N:8]=1
Reactant: COC(=O)c1cc(OC)no1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CO)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Methoxy-isoxazole-5-carboxylic acid methyl ester (prepared according to Eur. J. Org. Chem., 1998, 473) (1.0 g, 6.4 mmol) was dissolved in methanol (30 ml) and sodium borohydride (300 mg, 8.0 mmol) was added in portions. The mixture was stirred for 1 hour at room temperature, concentrated and the residue dissolved in dichloromethane (30 ml). The solution was washed with water, dried over magnesium sulfate and concentrated to give the product as a concentrated solution in dichloromethane. The solution was used without further purification.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>ClCCl.C(OCC)(=O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)NS(=O)(=O)c1ccc(Br)cc1
Temperature: 0 °C
Yield: 86.2 %

Procedure:
Place t-butylamine (4.32 mL, 41.1 mmol), triethylamine (8.15 mL, 58.7 mmol) and dichloromethane (75 mL) in a 3-neck round bottom flask. Cool this stirring solution to 0° C. and add a solution of 4-bromobenzenesulfonyl chloride (10.0 g, 39.1 mmol) in dichloromethane (50 mL). Add additional dichloromethane (25 mL) and stir the reaction overnight, allowing it to warm to ambient temperature. Evaporate the reaction in vacuo. Suspend the resulting white solid in ethyl acetate and filter it. Concentrate the filtrate in vacuo and purify the resulting residue by flash chromatography (silica gel; 50%-80% gradient CH2Cl2 in hexanes) to provide 9.85 g of 4-bromo-N-tert-butyl-benzenesulfonamide (86%).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][Cl:13].[OH-].[Na+]>C(O)C>[C:1]1([S:7][CH2:9][CH2:10][CH2:11][CH2:12][Cl:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: ClCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: ClCCCCSc1ccccc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
11 g (0.1 mol) of thiophenol and 18.9 g (0.11 mol) of 1-bromo-4-chlorobutane are mixed at ordinary temperature in a 250 ml flask equipped with a condenser, a thermometer and a dropping funnel. 100 ml of ethanol are added, the mixture is heated to 40° C and 20 ml of 5N NaOH are then added dropwise at this temperature. The speed of addition of the sodium hydroxide is regulated so as to have a reaction medium of neutral pH. When the addition is complete, the reactants are left in contact at 40° C for 3 hours, the alcohol is then evaporated, the oil is extracted with ether and the ether solution is washed with 2N NaOH and then with water. Thereafter the organic phase is dried over MgSO4, the ether is evaporated and a yellow oil ia obtained, which crystallises from ethanol. (18.4 g; 0.092 mol; yield: about 92%).
Reaction SMILES: FC1C=C(C=C(F)C=1)C[C@H]1[C@@H]([C@H]2CCCCN2C(C2C=CC=CC=2)C2C=CC=CC=2)OC(=O)N1.[F:35][C:36]1[CH:37]=[C:38]([CH:65]=[C:66]([F:68])[CH:67]=1)[CH2:39][C@H:40]1[C@@H:44]([C@H:45]2[CH2:50][O:49][CH2:48][CH2:47][N:46]2[CH:51]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[O:43][C:42](=[O:64])[NH:41]1.FC1C=C(C=C(F)C=1)C[C@@H]([C@@H]([C@H]1C[C@@H](OCC=C)CN1C(OC(C)(C)C)=O)O)C(O)=O.C(=O)([O-])[O-].[K+].[K+].BrC(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[F:35][C:36]1[CH:37]=[C:38]([CH:65]=[C:66]([F:68])[CH:67]=1)[CH2:39][C@H:40]1[C@@H:44]([C@H:45]2[CH2:50][C@H:48]([OH:49])[CH2:47][N:46]2[CH:51]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[O:43][C:42](=[O:64])[NH:41]1
Reactant: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2COCCN2C(c2ccccc2)c2ccccc2)O1
Agent: BrC(c1ccccc1)c1ccccc1
Agent: C=CCO[C@@H]1C[C@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@H](O)CN2C(c2ccccc2)c2ccccc2)O1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 29 %

Procedure:
Step L (7): (4S,5S)-4-(3,5-Difluorobenzyl)-5-((R)-4-benzhydrylmorpholin-3-yl)oxazolidin-2-one. To a solution of (4S,5S)-4-(3,5-difluorobenzyl)-5-(morpholin-3-yl)oxazolidin-2-one (step L (6), 180 mg, 0.6 mmol) in acetonitrile (5 mL) were added potassium carbonate (248 mg, 1.8 mmol) and bromodiphenylmethane (296 mg, 1.2 mmol). This mixture was stirred at 100° C. for 1.5 h. Solvent was removed and the crude mixture was purified by silica gel Flash Chromatography (0% to 20% to 40% to 65% EtOAc/Hexane step gradient) to give 85 mg of the title compound (29% yield):
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:13](Cl)=[O:14].Cl>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([N:6]=[C:13]=[O:14])=[O:5]
Reactant: NC(=O)c1c(F)cccc1F
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: O=C=NC(=O)c1c(F)cccc1F
Reaction time: 8 h

Procedure:
36.1 g (0.23 mol) of 2,6-difluorobenzamide are suspended in 360 ml of methylene chloride, and 53.7 g (0.42 mol) of oxalyl chloride are then added dropwise in the course of 20 minutes. After the release of hydrochloric acid has finished, the mixture is well stirred overnight under reflux. The solvent is subsequently distilled off, and the residue is distilled through a 10 cm Vigreux column at about 80° C./0.3 mm; yield 37.4 g (89%) of a slightly yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:19][CH2:20][C:21]([CH3:31])([CH3:30])[CH2:22][O:23]C1CCCCO1.ClC1C=CC2CCN(C(=O)C(F)(F)F)CCC=2C=1OS(C(F)(F)F)(=O)=O.CC(C)(COC1CCCCO1)CN.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:14])([F:13])[F:15])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:19][CH2:20][C:21]([CH3:31])([CH3:30])[CH2:22][OH:23]
Reactant: CC(C)(CNc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)COC1CCCCO1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(CO)CNc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Temperature: 90 °C
Yield: 86 %

Procedure:
7-Chloro-6-[2,2-dimethyl-3-(tetrahydro-pyran-2-yloxy)-propylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine Mix 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.277 g, 3.0 mmol), 2,2-dimethyl-3-(tetrahydro-pyran-2-yloxy)-propylamine (843 mg, 4.5 mmol), palladium acetate (135 mg, 0.6 mmol), BINAP (1.308 g, 2.1 mmol), bis(dibenzylideneacetone)palladium (0) (275 mg, 0.3 mmol) and cesium carbonate (1.955 g, 6.0 mmol) in anhydrous toluene (75 mL), degas, heat at 90° C. for 16 h. Filter off solid through Celite®, concentrate and purify (silica gel chromatography, eluting with 1:7 EtOAc:hexanes) to give the title compound (1.190 g, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[C:10]([O:14][C:15]([NH:17][CH:18]1[CH2:22][CH2:21][NH:20][CH2:19]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>CN(C=O)C>[C:10]([O:14][C:15]([NH:17][CH:18]1[CH2:22][CH2:21][N:20]([CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:19]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: ClCc1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 70 °C
Reaction time: 15 h
Yield: 80.2 %

Procedure:
4-Chlorobenzyl chloride (4.15 g, 25.8 mmol) and 2Pr2NEt (6.67 g, 51.6 mmol) were added to a solution of 3-{(tert-butoxycarbonyl)amino}pyrrolidine (4.81 g, 25.8 mmol) in DMF (50 mL). The reaction mixture was stirred at 70° C. for 15 h and the solvent was removed under reduced pressure. Recrystallization (CH3CN, 50 mL) provided the desired material, 3-(tert-butoxycarbonyl)amino-1-(4-chlorobenzyl)pyrrolidine as a pale yellow solid (6.43 g, 80.2%): 1H NMR (CDCl3, 300 MHz) δ 1.37 (s, 9 H), 1.5-1.7 (br, 1 H), 2.1-2.4 (m, 2 H), 2.5-2.7 (m, 2 H), 2.83 (br, 1 H), 3.57 (s, 2 H), 4.1-4.3 (br, 1 H), 4.9-5.1 (br, 1 H), 7.15-7.35 (br, 4 H); The purity was determined by RPLC/MS (98%); ESI/MS m/e 311.0 (M++H, C16H24ClN2O2).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.S(Cl)(Cl)=O.[CH3:16]O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:16])=[O:7])=[C:4]([OH:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Cl)cc1O
Yield: 95 %

Procedure:
To a solution of 4-chloro-2-hydroxybenzoic acid (20 g, 115.90 mmol) in methanol (500 mL) was added thionyl chloride (26 mL). After refluxing for 3 h, the reaction mixture was concentrated under vacuum, dissolved in petroleum ether (300 mL) and filtered to give methyl 4-chloro-2-hydroxybenzoate as a white solid (21 g, 95%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]([C:13]([O:15]C(C)C)=[O:14])[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8].[OH-].[Na+].[K].Cl>C(O)(C)C.O>[S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]([C:13]([OH:15])=[O:14])[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)OC(=O)C(C(=O)OC(C)C)=C1SC=CS1
Agent: Cl
Agent: [K]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)OC(=O)C(C(=O)O)=C1SC=CS1
Yield: 69 %

Procedure:
After 14.4 g (0.05 mol) of diisopropyl 1,3-dithiol-2-ylidenemalonate was dissolved in 50 ml of isopropanol, 2.95 g (0.074 mol) of sodium hydroxide aqueous solution was dropwise added to the solution at 30° C. The mixture was stirred for an hour and the resulting potassium salt was dissolved in 50 ml of water. The solution was acidified with 6N hydrochloric acid and the aqueous phase was extracted with dichloromethane. The organic phase was washed with water. After drying, the organic phase was concentrated under reduced pressure. The precipitated crystals were filtered to give 8.5 g (yield 70%) of isopropyl hydrogen 1,3-dithiol-2-ylidenemalonate as white crystals. Then, 2.7 g (0.011 mol) of the thus obtained crystals, 3.6 g (0.012 mol) of 2-chloro-1-methylpyridium p-toluenesulfonate were dissolved in 20 ml of dichloromethane. To the solution was dropwise added a solution of 0.51 g (0.011 mol) of ethanol and 3.46 g (0.034 mol) of triethylamine at 10° C. The mixture was stirred at room temperature for 2 hours. After the reaction solution was poured onto ice water followed by extraction with dichloromethane. The extract was washed successively with 2N hydrochloric acid, 10% sodium carbonate solution and then water. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate=2:1) to give 1.0 g (yield 35%) of the objective product. Synthesis Examples 4 to 8
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]2[CH:20]=[CH:21][N:22]=[C:16]2[CH2:15]1)=[O:13].C1C(=O)N([Br:30])C(=O)C1>CN(C)C=O>[Br:30][C:20]1[N:17]2[CH2:18][CH2:19][N:14]([C:12]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:9])([F:10])[F:11])[C:2]=3[Cl:1])=[O:13])[CH2:15][C:16]2=[N:22][CH:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2ccnc2C1
Solvent: CN(C)C=O
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(Br)cnc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (E1) (5.68 g, 17.23 mmol) was dissolved in N,N-dimethylformamide (DMF) (100 mL) and treated with NBS (3.22 g, 18.09 mmol). The solution was stirred at 25° C. for 16 h and the bulk of the DMF was removed in vacuo. The residue was partitioned between dichloromethane (500 ml) and saturated sodium bicarbonate solution (100 ml). The aqueous phase was extracted with dichloromethane (5×100 ml) during which filtration through celite was required to remove emulsions and precipitated succinimide. The combined organic extracts were washed with brine (100 ml), dried over anhydrous sodium sulfate and concentrated to a crude oil. The crude product was purified by flash chromatography (Isolera, 340 g, 0-100% methanol:dichloromethane (1:9)/dichloromethane) to afford an oil that was triturated with hexane to afford a solid of desired product in 5.90 g.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][O:13]C(C2C=CC=CC=2)[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.O.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH2:1]([O:8][CH:9]([CH2:10][OH:11])[CH2:14][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COC2COC(c3ccccc3)OC2)cc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: OCC(CO)OCc1ccccc1
Yield: 81.1 %

Procedure:
A mixture of about 338 g of 5-(benzyloxy)-2-phenyl-m-dioxane, about 1500 ml of ethanol, about 500 ml of water and about 20 ml of sulfuric acid was refluxed for about 2 hours. The ethanol was removed, the acid neutralized with solid bicarbonate, the mixture steam distilled to remove benzaldehyde and then saturated with potassium carbonate. This mixture was extracted three times with ether. The ether extracts were combined, dried and evaporated. Toluene was added and evaporated. The residue was distilled via a Kugelrohr (about 0.1 mm, 170° C.) giving an oil. This oil was dissolved in about 300 ml of toluene, cooled and diluted with two volumes of petroleum ether. Refrigeration produced about 184.69 g of the desired title compound as a solid.
Reaction SMILES: O.N.N.[C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1)#[N:5].[H][H]>[Co]>[NH2:5][CH2:4][C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][CH2:11]1
Reactant: N#C[C@H]1CC[C@H](C(=O)O)CC1
Reactant: [H][H]
Agent: [Co]
Agent: N
Solvent: O
Product: NC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
In 75 ml of ammonia water containing 0.033 mole of ammonia, 5 g. of trans-4-cyanocyclohexane-1-carboxylic acid was dissolved. To this solution, 0.5 g. of Raney cobalt developed by a known method was added. The whole mixture was shaken in an atmosphere of hydrogen under a normal pressure for about 5 hrs. until 0.066 mole of hydrogen had been absorbed. The reduction product was treated as described in Example 1, and 4.1 g. of trans-4-aminomethylcyclohexane-1-carboxylic acid was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:12])[F:11])N.[BrH:14].N([O-])=O.[Na+].NC(N)=O>>[Br:14][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]([F:13])([F:12])[F:11])=[C:2]([Cl:1])[CH:3]=1
Reactant: Br
Reactant: Nc1ccc(OC(F)(F)F)c(Cl)c1
Agent: NC(N)=O
Agent: O=N[O-]
Agent: [Na+]
Product: FC(F)(F)Oc1ccc(Br)cc1Cl
Temperature: 85 °C
Reaction time: 1.75 h
Yield: 29 %

Procedure:
To a 0° C. solution consisting of 3-chloro-4-trifluoromethoxy-aniline (2.12 g, 10.0 mmol) and HBr (48% aq, 50 mL) was added NaNO2 (2 M aq., 917.7 mg, 13.3 mmol) dropwise at a rate such that the reaction temperature remained below 5° C. After stirring for 1.75 h, urea (330 mg, 5.5 mmol) was added and the mixture stirred for 20 min. A solution consisting of Cu(I)Br (2.96 g, 20.6 mmol) and HBr (48% aq., 13.1 mL) was then added while keeping the reaction temperature in the range of 0-5° C. Upon complete addition, the reaction mixture was heated to 85° C. for 2.5 h. After cooling to rt, the reaction mixture was poured into ice water (150 mL) and extracted with hexanes (100 mL). The aqueous layer was washed with CH2Cl2 (100 mL) and the combined organic phases washed with satd. aq. NaHCO3 (150 mL×2), dried (Na2SO4) and concentrated. The crude material was purified (FCC) to yield the title compound (806 mg, 29%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:16]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1>>[Br:1][CH2:2][CH2:3][O:4][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][O:16]1
Reactant: OCCBr
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: BrCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.29 ml of 2-bromoethanol was dissolved in 27.8 ml of dry dichrolomethane, and 7.21 ml of dihydropyran and then 48.1 mg of dry p-toluenesulfonic acid were added thereto. The mixture was stirred at room temperature for 3 hours. Then, the reaction mixture was partitioned with 150 ml of chloroform and 75 ml of a 4% sodium hydrogen-carbonate aqueous solution. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (50 g of Kieselgel 60) by using a mixture of hexane/ethyl acetate (20/1). The product-containing fractions were put together, and the solvent was distilled off under reduced pressure to obtain 5.4 g of 2-bromo-1-(2-tetrahydropyranyloxy)ethane as a oily substance.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])[CH:5]=[CH:4][N:3]=1.[O:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[S:32](Cl)(=[O:34])=[O:33]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([NH:22][S:32]([C:28]3[O:27][CH:31]=[CH:30][CH:29]=3)(=[O:34])=[O:33])[CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1ccco1
Reactant: Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1ccco1
Yield: 63 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline (3.0 g, 7.6 mmol) and furan-2-sulfonyl chloride (1.4 g, 8.4 mmol) the title compound of Step A was obtained (2.5 g, 63% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.07 (d, J=5.5 Hz, 1H), 7.59-7.66 (m, 1H), 7.42-7.75 (br, 1H), 7.13-7.20 (m, 2H), 7.02 (d, J=5.5 Hz, 1H), 6.93-6.98 (m, 1H), 6.37-6.42 (m, 2H), 3.50-3.57 (m, 4H), 3.72-3.78 (m, 4H). MS (ES+): 522 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([NH:22][S:38]([C:34]3[O:33][CH:37]=[CH:36][CH:35]=3)(=[O:40])=[O:39])[CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1ccco1
Reactant: Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1ccco1
Temperature: 0 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of 3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline (3 g, 7.6 mmol) in DCM (50 mL) was added pyridine (10 mL). The mixture was cooled to 0° C. Furan-2-sulfonyl chloride (1.4 g, 8.4 mmol) in DCM (5 mL) was added dropwise to the mixture. The reaction was stirred at rt overnight. Then the reaction was washed with water (100 mL), and extracted with DCM (2×100 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether:EtOAc 4:1) to afford the title compound of Step A (2.5 g, 63% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.07 (d, J=5.5 Hz, 1H), 7.59-7.66 (m, 1H), 7.42-7.75 (br, 1H), 7.13-7.20 (m, 2H), 7.02 (d, J=5.5 Hz, 1H), 6.93-6.98 (m, 1H), 6.37-6.42 (m, 2H), 3.50-3.57 (m, 4H), 3.72-3.78 (m, 4H). MS (ES+): 522 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1>N.CO.[Ni]>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][NH2:11])=[CH:7][CH:8]=1
Reactant: N#CCc1ccc(C(F)(F)F)cc1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCCc1ccc(C(F)(F)F)cc1
Reaction time: 20 h

Procedure:
[4-(Trifluoromethyl)phenyl]acetonitrile (10.0 g, 54 mmol) was dissolved in a 2.00 M solution of ammonia in methanol (100 mL) in a Parr flask. To it was added Raney Nickel (approx. 1 g). The mixture was shaken under hydrogen (50 psi) for 20 h and filtered through celite which was then washed with methylene chloride several times. The filtrate was concentrated to afford the title compound as a solid. MS calculated for C9H10F3N: (M+H)+190; found 173.1 (M+H−NH3)+.
Reaction SMILES: [CH:1]([N:4]1[CH2:8][CH2:7][N:6]=[C:5]1[CH3:9])([CH3:3])[CH3:2]>[Ni]>[CH:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[CH3:9])([CH3:3])[CH3:2]
Reactant: CC1=NCCN1C(C)C
Agent: [Ni]
Product: Cc1nccn1C(C)C
Yield: 84 %

Procedure:
The procedure of Example 1 was followed except that 40 g of 1-isopropyl-2-methylimidazoline and 5 g of Raney nickel were charged. GLC analysis showed that an 84% yield of 1-isopropyl-2-methyl imidazole was obtained with 98% conversion of imidazoline.