Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:18][CH2:19][OH:20])[S:5]([C:8]1[S:12][C:11]([NH:13]C(=O)C)=[N:10][C:9]=1[CH3:17])(=[O:7])=[O:6]>Cl>[OH:1][CH2:2][CH2:3][N:4]([CH2:18][CH2:19][OH:20])[S:5]([C:8]1[S:12][C:11]([NH2:13])=[N:10][C:9]=1[CH3:17])(=[O:6])=[O:7]
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)N(CCO)CCO)s1
Agent: Cl
Product: Cc1nc(N)sc1S(=O)(=O)N(CCO)CCO
Temperature: 80 °C
Yield: 74 %

Procedure:
A stirred suspension of 2-acetamido-4-methyl-thiazole-5-sulfonic acid bis-(2-hydroxy-ethyl)-amide (0.7 g, 2.16 mmol) in 6N hydrochloric acid (8 ml) was heated for 2 h at 80° C., evaporated., and saturated NaHCO3 solution (50 ml) was added. The mixture was extracted with ethyl acetate (3×50 ml), the combined organic layers washed with brine (30 ml) and dried (MgSO4). The crude product was further purified by crystallization (hexane) to yield the title compound (0.45 g, 74%) as a white solid. MS (ISP) 281.9 [(M+H)+]; mp 141° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]1)=O)(C)(C)C.[ClH:26].O1CCOCC1>>[ClH:26].[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCC(CNC(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NCC1CCCNC1)OCc1ccccc1
Reaction time: 3 h

Procedure:
Benzyl (1-(tert-butoxycarbonyl)piperidin-3-yl)methylcarbamate (3.22 g, 9.25 mmol) was treated with a 4.0 M HCl solution in dioxane (11.3 mL, 46.25 mmol). Formation of a white precipitate was observed. After 3 h, the reaction was complete. The solvent and excess HCl were removed under reduced pressure to obtain benzyl (piperidin-3-yl)methylcarbamate hydrochloride as a white solid. LC/MS: m/z 249.3 (M+H)+ at 1.28 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8]([NH2:10])=O)[CH2:4][CH2:3]1.[Li]>>[F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([CH2:8][NH2:10])[CH2:4][CH2:3]1
Reactant: NC(=O)C1CCC(F)(F)CC1
Agent: [Li]
Product: NCC1CCC(F)(F)CC1
Temperature: 25 °C
Yield: 77.3 %

Procedure:
4,4-difluorocyclohexanecarboxamide (1.32 g, 8.10 mmol) was stirred in the solution of lithium borohydrate (1M, 30 ml) under nitrogen overnight. Then, the reaction mixture was refluxed for 4 hours. After cooled to room temperature, it was poured into ice-water slowly. After filtration, the product was extracted with dichloromethane from filtrate. Combined organic layers were water, brine, dried over anhydrous sodium sulphate, filtered and condensed to provide a 934 mg of colorless oil (82%). δ 2.53 (d, 2H), 1.98-2.09 (m, 2H), 1.73-1.82 (m, 6H), 1.17-1.29 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:18]1[CH:19]=[CH:20][C:21]2[N:25]=[C:24]([CH:26]3[CH2:28][C:27]3([F:30])[F:29])[N:23]([CH3:31])[C:22]=2[CH:32]=1.C(=O)([O-])[O-].[K+].[K+].CNCCNC>[Cu](I)I.CS(C)=O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:18]3[CH:19]=[CH:20][C:21]4[N:25]=[C:24]([CH:26]5[CH2:28][C:27]5([F:30])[F:29])[N:23]([CH3:31])[C:22]=4[CH:32]=3)[C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cn1c(C2CC2(F)F)nc2ccc(Br)cc21
Reactant: O=c1cc(OCc2ccc(Cl)cc2)cc[nH]1
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: Cn1c(C2CC2(F)F)nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc21
Temperature: 150 °C
Reaction time: 1 h
Yield: 1.1 %

Procedure:
A mixture of 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (100 mg), 6-bromo-2-(2,2-difluorocyclopropyl)-1-methyl-1H-benzimidazole (122 mg), potassium carbonate (176 mg), N,N′-dimethylethylenediamine (0.046 ml), copper iodide (81 mg) and DMSO (3 ml) was stirred at 150° C. under Ar atmosphere for 1 h. The mixture was quenched with 28% NH3 solution and the precipitate was collected by filtration. The solid was dissolved in THF, passed through NH silica gel pad and concentrated in vacuo. The precipitate was recrystallized from EtOAc/MeOH to give the title compound (2 mg) as a pale orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[O:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[C:9]2=[O:27])=[C:4]([OH:29])[CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[O:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[C:9]2=[O:27])=[C:4]([OH:29])[CH:3]=1
Reactant: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2C1(O)c1ccc(Br)cc1O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C1C(c2ccc(Br)cc2O)c2ccccc2N1Cc1ccc(C(F)(F)F)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.6 %

Procedure:
A mixture of 3-(4-bromo-2-hydroxyphenyl)-3-hydroxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one (5.5 g, 11.8 mmol), triethylsilane (20.0 mL, excess) and trifluoroacetic acid (20.0 mL, excess) was stirred at ambient temperature for 16 h. The mixture was concentrated under vacuum. The residue was treated with diethyl ether to form a suspension. The filtration gave 3-(4-bromo-2-hydroxyphenyl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one (4.3 g, 82%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.91 (br s, 1H), 7.36 (t, J=7.9 Hz, 1H), 7.26-7.13 (m, 2H), 7.05 (d, J=7.9 Hz, 1H), 6.97 (d, J=2.0 Hz, 1H), 6.92 (dd, J=8.5, 2.0 Hz, 1H), 6.73-6.67 (m, 2H), 6.35 (d, J=3.5 Hz, 1H), 5.08 (s, 1H), 4.95 (s, 2H); MS (ES+) m/z 452.0 (M+1), 450.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13](F)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:21][NH2:22]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([NH:22][CH3:21])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1cccc(Cl)n1)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CN
Product: CNc1ccc(C(=O)Nc2cccc(Cl)n2)cc1[N+](=O)[O-]

Procedure:
Prepared analogously to example 316a from N-(6-chloro-pyridin-2-yl)-4-fluoro-3-nitro-benzamide and methylamine.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[NH:9][C:8]([Cl:13])=[N:7][C:6]=2[N:5]([CH3:14])[C:3]1=[O:4].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>O.[OH-].[Na+]>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH2:20][C:19]3[CH:22]=[CH:23][C:16]([F:15])=[CH:17][CH:18]=3)[C:8]([Cl:13])=[N:7][C:6]=2[N:5]([CH3:14])[C:3]1=[O:4]
Reactant: Fc1ccc(CCl)cc1
Reactant: Cn1c(=O)c2[nH]c(Cl)nc2n(C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1c(=O)c2c(nc(Cl)n2Cc2ccc(F)cc2)n(C)c1=O

Procedure:
A solution of 43 g 1,3-dimethyl 8-chloro xanthine in 200 ml water and 20 ml sodium hydroxide 10N is heated to 70°-80° C., to which 27.6 ml 4-fluorobenzyl chloride are portion-wise added at this temperature within 4 hours. During this addition, 20 ml sodium hydroxide 10N are added by small portions to maintain the pH at an alkaline value. After achievement of this addition, the solution is further heated at 70°-80° for 2 hours then let to revert to room temperature under stirring. The precipitate is filtered, dried, washed with water until neutral, then dried. Thereafter it is recrystallized from acetone to recover 19 g of pure compound. It melts at 183°-184° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[CH:12][CH:11]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=2)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccc(F)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(Oc3ccc(Cl)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-chlorophenol and N-(3-{1-[5-(4-fluorophenyl)-5-hydroxypentyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 537.3 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:23]=[C:22]3[C:18]([CH2:19][CH2:20][N:21]3[C:24](=[O:26])[CH3:25])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:36]1([C@@H:42]2[CH2:44][C@H:43]2[C:45](Cl)=[O:46])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(#N)C>[C:24]([N:21]1[C:22]2[C:18](=[CH:17][CH:16]=[C:15]([N:14]([CH:11]3[CH2:12][CH2:13][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:9][CH2:10]3)[C:45]([C@@H:43]3[CH2:44][C@H:42]3[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:46])[CH:23]=2)[CH2:19][CH2:20]1)(=[O:26])[CH3:25]
Reactant: CC(=O)N1CCc2ccc(NC3CCN(Cc4ccccc4)CC3)cc21
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCc2ccc(N(C(=O)[C@@H]3C[C@H]3c3ccccc3)C3CCN(Cc4ccccc4)CC3)cc21
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To a solution of 1-[6-(1-benzyl-piperidin-4-ylamino)-2,3-dihydro-indol-1-yl]-ethanone (0.353 g, 1.01 mmol) in 50 mL of acetonitrile was added diisopropylethylamine (0.193 mL, 1.11 mmol) and trans-2-phenyl-1-cyclopropanecarbonyl chloride (90%, 0.174 mL, 1.01 mmol). The reaction mixture was stirred overnight, and then was filtered through diatomaceous earth. The filtrate was evaporated and the residue was chromatographed over silica gel (acetone/MeOH/CH2Cl2) to provide the desired product as a tan solid (0.30 g, 61%). 1H NMR (400 MHz, CDCl3): 8.04 (s, 1H), 7.38-6.98 (m, 9H), 6.97-6.82 (m, 2H), 6.76 (dd, J=12.5, 6.2 Hz, 1H), 4.65 (br t, J=12.7 Hz, 1H), 4.12 (t, J=9.5 Hz, 1H), 4.09-3.87 (m, 1H), 3.44 (s, 2H), 3.26-3.07 (m, 2H), 2.97-2.79 (m, 2H), 2.51-2.47 (m, 1H), 2.29-1.98 (m, 5H), 1.92-1.66 (m, 2H), 1.65-1.29 (m, 4H), 1.08-0.96 (m, 1H). MS: exact mass calculated for C32H35N3O2, 493.27; m/z found, 494.3 [M+H]+.
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][S:3][S:4][CH2:5][CH2:6][OH:7].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(OCC)(=O)C>[CH3:16][S:17]([O:8][CH2:1][CH2:2][S:3][S:4][CH2:5][CH2:6][O:7][S:17]([CH3:16])(=[O:19])=[O:18])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: OCCSSCCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCSSCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
10 g of 2,2′-dithiodiethanol and 14.44 g of triethylamine (TEA) are diluted in 100 ml of ethyl acetate (EtOAc). At 0° C., 16.35 g of methanesulphonyl chloride diluted in 35 ml of EtOAc are added dropwise to the reaction medium with rapid stirring. 7.22 g of TEA are introduced, and the stirring is continued at ambient temperature for 4 h 30. 8.2 g of methanesulphonyl chloride are added dropwise at 15° C., and then the stirring is maintained at ambient temperature for 17 h. The precipitate is filtered off and washed with 3 times 50 ml of EtOAc. The organic phases are extracted with 100 ml of ice-cold water, 100 ml of water, 3 times 50 ml of a saturated solution of sodium bicarbonate (NaHCO3), with twice 20 ml of a saturated solution of sodium chloride (NaCl), and are then dried over anhydrous sodium sulphate (Na2SO4). The EtOAc is evaporated off, and 17.49 g of pale yellow translucent oil are recovered and stored at −25° C. The analyses indicate that the product is in conformity and pure.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([C:11]2[CH:26]=[CH:25][C:14]([CH2:15][N:16]3[CH2:21][CH2:20][CH:19]([C:22](O)=[O:23])[CH2:18][CH2:17]3)=[CH:13][CH:12]=2)[CH2:2]1.[NH:27]1[CH2:30][CH:29]([OH:31])[CH2:28]1>>[O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([C:11]2[CH:12]=[CH:13][C:14]([CH2:15][N:16]3[CH2:21][CH2:20][CH:19]([C:22]([N:27]4[CH2:30][CH:29]([OH:31])[CH2:28]4)=[O:23])[CH2:18][CH2:17]3)=[CH:25][CH:26]=2)[CH2:2]1
Reactant: O=C(O)C1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Reactant: OC1CNC1
Product: O=C(C1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1)N1CC(O)C1

Procedure:
Compound 286 is synthesized from Intermediate K and azetidin-3-ol according to the procedure used to synthesize Example 255. (LC/MS method 16: ES+ m/z 410.4 [M+H]+, Rt=0.35 min)
Reaction SMILES: [N:1]1([CH2:7][C:8]2[O:12][C:11]([CH2:13][NH:14][CH2:15][CH2:16][N:17]3[CH2:21][CH2:20][NH:19][C:18]3=[C:22]([C:25]#[N:26])[C:23]#[N:24])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:27](OC(=O)C)(=[O:29])[CH3:28].CO>N1C=CC=CC=1>[C:27]([N:14]([CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][NH:19][C:18]1=[C:22]([C:23]#[N:24])[C:25]#[N:26])[CH2:13][C:11]1[O:12][C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:9][CH:10]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: N#CC(C#N)=C1NCCN1CCNCc1ccc(CN2CCCCC2)o1
Solvent: c1ccncc1
Solvent: CO
Product: CC(=O)N(CCN1CCNC1=C(C#N)C#N)Cc1ccc(CN2CCCCC2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
In 12 ml of pyridine was dissolved 0.6 g (1.69 mmol) of Compound 28, and 260 mg (2.55 mmol) of acetic anhydride was added dropwise. The reaction mixture was stirred at room temperature for 0.5 hour and, after addition of 1 ml of methanol, the solvent was distilled off. The residue was diluted with 20 ml of water, adjusted to pH 13 with 5N sodium hydroxide solution and extracted with methylene chloride. The extract was washed with saturated aqueous sodium chloride solution twice and dried over anhydrous magnesium sulfate. Finally the solvent was distilled off to give 0.66 g (97.9%) of Compound 44 as colorless oil.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:37]=[C:36]([N:38]4[CH2:43][CH2:42][N:41]([CH2:44][C:45]5[CH2:50][CH2:49][C:48]([CH3:52])([CH3:51])[CH2:47][C:46]=5[C:53]5[CH:58]=[CH:57][C:56]([Cl:59])=[CH:55][CH:54]=5)[CH2:40][CH2:39]4)[CH:35]=[CH:34][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH2:26][CH:27]4[CH2:30][NH:29][CH2:28]4)=[C:21]([N+:31]([O-:33])=[O:32])[CH:20]=3)(=[O:18])=[O:17])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:74][CH2:75][C:76](=O)[CH2:77][F:78]>ClCCl>[Cl:59][C:56]1[CH:55]=[CH:54][C:53]([C:46]2[CH2:47][C:48]([CH3:52])([CH3:51])[CH2:49][CH2:50][C:45]=2[CH2:44][N:41]2[CH2:42][CH2:43][N:38]([C:36]3[CH:35]=[CH:34][C:12]([C:13]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][CH2:26][CH:27]5[CH2:30][N:29]([CH:76]([CH2:77][F:78])[CH2:75][F:74])[CH2:28]5)=[C:21]([N+:31]([O-:33])=[O:32])[CH:20]=4)(=[O:18])=[O:17])=[O:14])=[C:11]([O:10][C:8]4[CH:9]=[C:4]5[CH:3]=[CH:2][NH:1][C:5]5=[N:6][CH:7]=4)[CH:37]=3)[CH2:39][CH2:40]2)=[CH:58][CH:57]=1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NCC5CNC5)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Reactant: O=C(CF)CF
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NCC5CN(C(CF)CF)C5)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1

Procedure:
A solution of EXAMPLE 161B (0.118 g), sodium triacetoxyborohydride (0.035 g) and 1,3-difluoropropan-2-one (0.012 g) were stirred together in dichloromethane (1 mL) overnight. The reaction was quenched with saturated aqueous NaHCO3 solution (10 mL) and extracted into dichloromethane (30 mL). The organic layer was dried and concentrated. Silica gel chromatography (Reveleris 12 g) eluting with a gradient of 0.5% to 3.5% methanol/dichloromethane over 30 minutes (Flow=36 ml/min) gave the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ 11.67 (s, 1H), 11.47-11.21 (m, 1H), 8.85 (s, 1H), 8.55 (d, 1H), 8.03 (d, 1H), 7.80 (dd, 1H), 7.54-7.45 (m, 3H), 7.33 (s, 2H), 7.04 (d, 3H), 6.67 (d, 1H), 6.38 (dd, 1H), 6.20 (d, 1H), 4.43 (dt, 4H), 3.56 (t, 2H), 3.46 (s, 2H), 3.12 (m, 6H), 2.74 (m, 3H), 2.17 (m, 7H), 1.95 (s, 2H), 1.39 (d, 2H), 0.92 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13](Cl)=[O:14])=[CH:10][CH:9]=2)[C:4]=1[CH3:16].Cl.[NH:20]1[CH2:25][CH2:24][CH2:23][C@H:22]([CH2:26][OH:27])[CH2:21]1>>[OH:27][CH2:26][C@@H:22]1[CH2:23][CH2:24][CH2:25][N:20]([C:13]([C:11]2[S:12][C:8]([C:5]3[C:4]([CH3:16])=[C:3]([C:2]([F:18])([F:17])[F:1])[O:7][N:6]=3)=[CH:9][CH:10]=2)=[O:14])[CH2:21]1
Reactant: Cc1c(-c2ccc(C(=O)Cl)s2)noc1C(F)(F)F
Reactant: OC[C@H]1CCCNC1
Agent: Cl
Product: Cc1c(-c2ccc(C(=O)N3CCC[C@@H](CO)C3)s2)noc1C(F)(F)F

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carbonyl chloride (74 mg, 0.25 mmol, as prepared in Example 2 Method B) and (S)-1-piperidin-3-yl-methanol, hydrochloride (76 mg, 0.5 mmol) in the same manner as the S isomer (Example 69). Gummy solid (56 mg, 60%). LC/MS 5.86 min, [M+1]+ 375.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:13]#[CH:14])=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].CC(C)([O-])C.[K+]>CN1CCCC1=O.[Cl-].[Na+].O>[Br:1][C:2]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[C:4]2[C:3]=1[CH:13]=[CH:14][NH:5]2
Reactant: C#Cc1c(N)cc(C(F)(F)F)cc1Br
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1cc(Br)c2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 3-bromo-2-ethynyl-5-(trifluoromethyl)aniline (7.54 g, 28.6 mmol) in N-methylpyrollidinone (50 mL) was added dropwise to a 0° C. solution of potassium tert-butoxide (6.41 g, 57.1 mmol) in N-methylpyrollidinone (200 mL). The reaction was stirred at ambient temperature for 4 h. The reaction was poured into brine (500 mL) and extracted with ethyl acetate (4×50 mL). The combined organic layers were washed with brine (100 mL), dried with magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel with a gradient of 10% to 25% ethyl acetate/hexanes to give 7.16 g (95%) as a brown oil. 1H-NMR (CDCl3, 400 MHz) δ 8.54 (bs, 1H), 7.63 (s, 1H), 7.53 (s, 1H), 7.40 (t, J=2.8 Hz, 1H), 6.66 (t, J=2.8 Hz, 1H); LC/MS (HPLC method 4): tR=3.280 min, 264.12(MH)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][CH3:10])[C:5]([CH3:11])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:3]=1.C(OCC)(=O)C.[CH3:28][N:29](C)C=O>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:11][C:5]1[C:6]([CH2:8][CH2:9][CH3:10])=[N:7][C:2]([C:28]#[N:29])=[N:3][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1
Reactant: CN(C)C=O
Reactant: CCCc1nc(Cl)nc(-c2cccc(C(F)(F)F)c2)c1C
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CCCc1nc(C#N)nc(-c2cccc(C(F)(F)F)c2)c1C
Temperature: 150 °C

Procedure:
To a solution of 2-chloro-5-methyl-4-propyl-6-(3-trifluoromethylphenyl)-pyrimidine (50 mg) in dimethylformamide (1 mL), was added zinc(II) cyanide (16 mg) and tetrakis(triphenylphosphine)-palladium(0) (16 mg). The suspension was heated in the microwave at 150° C. for 5 min, then poured into ethyl acetate (50 mL) and washed with water (2×10 mL). The organic layer was separated, dried over sodium sulphate and evaporated at reduced pressure. Preparative-HPLC afforded 5-methyl-4-propyl-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile as a yellow gum (11 mg). 1H NMR (CDCl3): δ 7.63-7.81 (m, 4H), 2.87 (t, 2H), 2.39 (s, 3H), 1.80-1.90 (m, 2H), 1.07 (t, 3H). MS m/z 306.4 (M+1), 100%.
Reaction SMILES: [CH2:1]([N:4]([CH3:11])[C:5]1[S:6][CH2:7][C:8](=[O:10])[N:9]=1)[CH:2]=[CH2:3].[Cl:12][C:13]1[CH:30]=[CH:29][C:16]([CH2:17][N:18]2[C:26]3[C:21](=[CH:22][C:23]([CH:27]=O)=[CH:24][CH:25]=3)[CH:20]=[N:19]2)=[C:15]([C:31]([F:34])([F:33])[F:32])[CH:14]=1>>[CH2:1]([N:4]([CH3:11])[C:5]1[S:6][C:7](=[CH:27][C:23]2[CH:22]=[C:21]3[C:26](=[CH:25][CH:24]=2)[N:18]([CH2:17][C:16]2[CH:29]=[CH:30][C:13]([Cl:12])=[CH:14][C:15]=2[C:31]([F:34])([F:32])[F:33])[N:19]=[CH:20]3)[C:8](=[O:10])[N:9]=1)[CH:2]=[CH2:3]
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Reactant: C=CCN(C)C1=NC(=O)CS1
Product: C=CCN(C)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
2-(Allyl-methyl-amino)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one was prepared from 2-(allyl-methyl-amino)-thiazol-4-one and 1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde following General Procedure E.
Reaction SMILES: [C:1]1([C@@H:13]2[CH2:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]2)[N:5]2[C:6]3[CH:12]=[CH:11][NH:10][C:7]=3[N:8]=[CH:9][C:4]2=[CH:3][N:2]=1.O1CCOCC1.[ClH:32]>CCOCC>[ClH:32].[NH:15]1[CH2:16][CH2:17][CH2:18][C@@H:13]([C:1]2[N:5]3[C:6]4[CH:12]=[CH:11][NH:10][C:7]=4[N:8]=[CH:9][C:4]3=[CH:3][N:2]=2)[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](c2ncc3cnc4[nH]ccc4n23)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: c1cc2c(ncc3cnc([C@@H]4CCCNC4)n32)[nH]1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 105.4 %

Procedure:
A round bottom flask was charged with (R)-tert-butyl 3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate (2.8 g, 8.20 mmol), 1,4-dioxane (24 mL) and HCl (4 N in 1,4-dioxane, 6.2 mL, 24.6 mmol). The reaction mixture was heated at about 60° C. for about 18 h. The reaction mixture was cooled to ambient temperature, Et2O (40 mL) was added and the mixture was stirred for about 15 min. The solid was collected by vacuum filtration and washed with Et2O (50 mL) then dried in a vacuum oven at about 60° C. to afford (R)-1-(piperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine hydrochloride as an off-white solid (2.4 g, 94%): LC/MS (Table 1, Method b) Rt=0.81 min; MS m/z 242 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][N:15]2[N:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[NH:16]2)[C:5]=1[C:6]([O:8][CH3:9])=[O:7])(=O)[CH3:2].Cl.[CH3:26][O:27][NH2:28].C([O-])(=O)C.[K+].CO>O>[CH3:22][O:21][C:19]1[CH:18]=[C:17]([O:23][CH3:24])[NH:16][N:15]([O:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:4]([C:1](=[N:28][O:27][CH3:26])[CH3:2])[C:5]=2[C:6]([O:8][CH3:9])=[O:7])[N:20]=1
Reactant: CON
Reactant: COC(=O)c1c(ON2N=C(OC)C=C(OC)N2)cccc1C(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: CON=C(C)c1cccc(ON2N=C(OC)C=C(OC)N2)c1C(=O)OC
Yield: 48 %

Procedure:
0.9 of methyl 2-acetyl-6-[(4,6-dimethoxytriazin-2-yl)oxy]benzoate, 0.68 g of methoxyamine hydrochloride and 0.80 g of potassium acetate were added to 30 ml of methanol, and the resultant mixture was stirred for one day and one night at room temperature. The resultant reaction liquor was poured into water, and was extracted with ethyl acetate. After washing the extracted product with water, the washed product was dried and concentrated to obtain an oily product. This was then purified by column chromatography to obtain 0.47 g of the aimed compound (melting point=131° to 135° C.) at a yield of 48%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][N:6]=[C:5]([CH2:11][S:12][C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])=[CH:21][C:15]=3[N:14]=2)[C:4]=1[CH3:29].ClC1C=C(C=CC=1)C(OO)=[O:35]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][N:6]=[C:5]([CH2:11][S:12]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:25])[F:26])=[CH:21][C:15]=3[N:14]=2)=[O:35])[C:4]=1[CH3:29]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cnc(CSc2nc3cc(OC(F)(F)C(F)F)ccc3[nH]2)c(C)c1OC
Solvent: ClCCl
Product: COc1cnc(CS(=O)c2nc3cc(OC(F)(F)C(F)F)ccc3[nH]2)c(C)c1OC

Procedure:
0.8 g of a pale yellow oil is obtained by the procedure described in Example 2 by oxidation of 0.99 g of 2-[(4,5-dimethoxy-3-methyl-2-pyridyl)methylthio]-5-(1,1,2,2-tetrafluoroethoxy)-1H-benzimidazole with 12 ml of a 0.2M solution of m-chloroperoxybenzoic acid in methylene chloride at -40° C. for a reaction time of 1.5 hours. Recrystallization twice from methylene chloride/diisopropyl ether gives 0.30 g (34% of theory) of the title compound in the form of colorless crystals of m.p. 125° C. (decomp.).