Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=O)[CH:3]=1.[CH3:12][C:13]([CH3:31])([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21](CC2C=CC=CC=2)[CH2:20][CH2:19]1)=[O:17])[CH3:14]>C(Cl)(Cl)Cl>[CH3:14][C:13]([CH3:31])([O:15][C:16]([N:18]1[CH2:19][CH2:20][N:21]([O:10][CH2:8][C:4]2[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=2)[CH2:22][CH2:23]1)=[O:17])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution of 10.0 g (0.058 mole) m-chloroperbenzoic acid in 100 ml chloroform was added over a one hour period to a cooled (0°-5° C.) solution of 16.1 g (0.058 mole) 1-[1,1-dimethylethoxycarbonyl]-4-phenylmethylpiperazine in 200 ml chloroform. External cooling was removed and the solution stirred for 96 hours at room temperature. The solution was then successively passed through four alumina-packed columns (2.2×16 cm), the eluent evaporated in vacuo, treated with 200 ml acetone and diluted with 50 ml hexane to yield 9.0 g white, crystalline solid, m.p. 123°-126° C. (sealed capillary). An analytical sample from a prior run gave a satisfactory elemental analysis. Calc. for C16H29N2O3.H2O (310.40): C, 61.91; H, 8.44; N, 9.03; O, 20.62. Found: C, 61.91; H, 8.27; N, 9.07; O, 20.55.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[C:10](=[O:12])[CH:11]=2)=[CH:3][CH:2]=1.C1C(=O)N([Br:24])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:24][C:11]1[C:10](=[O:12])[C:9]2([CH2:16][CH2:15][CH2:14][CH2:13]2)[O:8][C:7]=1[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: O=C1C=C(c2ccncc2)OC12CCCC2
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C1C(Br)=C(c2ccncc2)OC12CCCC2
Reaction time: 1 h
Yield: 72.9 %

Procedure:
To a stirred solution of afford 2-(pyridin-4-yl)-1-oxaspiro[4.4]non-2-en-4-one (0.18 g, 0.84 mmol) in CHCl3 (10 mL) was added NBS (0.22 g, 1.25 mmol) portionwise at RT and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with DCM (30 mL), washed with water (10 mL), brine (10 mL), dried over Na2SO4, filtered and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 3-bromo-2-(pyridin-4-yl)-1-oxaspiro[4.4]non-2-en-4-one (0.18 g, 40%) as an oil.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[F:13][C:14]1[C:27]2[CH2:26][CH2:25][C@H:24]3[C@H:19]([CH2:20][CH2:21][CH2:22][NH:23]3)[C:18]=2[CH:17]=[C:16]([F:28])[CH:15]=1>C(Cl)Cl.CO>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:23]3[C@@H:24]4[C@@H:19]([C:18]5[CH:17]=[C:16]([F:28])[CH:15]=[C:14]([F:13])[C:27]=5[CH2:26][CH2:25]4)[CH2:20][CH2:21][CH2:22]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Fc1cc(F)c2c(c1)[C@H]1CCCN[C@H]1CC2
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Solvent: ClCCl
Solvent: CO
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@@H]2c3cc(F)cc(F)c3CC[C@@H]21
Yield: 72 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-7,9-difluoro-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 72% of theory; TLC: rf=0.37 (silica gel, CH2Cl2/MeOH/32% aqueous NH3 90:10:1); Mass spectrum (ESI+): m/z=368 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH:7]=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[CH2:2]1.[NH2-].[Na+].ClC(S(O[CH2:33][C:34]([F:37])([F:36])[F:35])(=O)=O)(Cl)Cl.O>O1CCCC1>[F:35][C:34]([F:37])([F:36])[CH2:33][N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH:7]=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[CH2:2]1
Reactant: C(=C1c2ccccc2CCc2ccccc21)C1CNCCO1
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)CN1CCOC(C=C2c3ccccc3CCc3ccccc32)C1

Procedure:
To 5-(morpholin-2-yl)methylidene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (0.69 g) in anhydrous tetrahydrofuran was added sodium amide (0.20 g) at room temperature, and the resulting mixture was heated under reflux for 1.5 hours. After cooling, 2,2,2-trifluoroethyl trichloromethylsulfonate (0.666 g) in annydrous tetrahydrofuran was added to the mixture under ice-cooling, and then the mixture was heated under reflux for 11.5 hours. After cooling, water (0.2 g) was added thereto and inorganic materials were eliminated by filtration. The filtrate was evaporated and chromatographed to afford 5-[4-(2,2,2-trifluoroethyl)morpholin-2-yl]methylidene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene as oily material. M.P., 174° - 177° C (hydrochloride).
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][C:30]=1[NH:31][CH:32]=[O:33])[NH:27][C:26](=[O:34])[CH2:25]2>>[CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=[C:25]3[C:24]4[C:28](=[CH:29][C:30]([NH:31][CH:32]=[O:33])=[C:22]([F:21])[CH:23]=4)[NH:27][C:26]3=[O:34])=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2]
Reactant: O=CNc1cc2c(cc1F)CC(=O)N2
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4cc(NC=O)c(F)cc43)c(C)c2C1=O
Yield: 69.4 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-formamide as starting materials to give N-{3-[5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-ylmethylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl}-formamide (51 mg, 69.4%) as a red solid.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:9][CH2:8][CH:7]=[CH:6]1)(=O)[CH3:2].[CH:10]1(O)[CH2:15]CC[CH:12]=[CH:11]1.O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>[CH:5]1([O:4][CH:1]2[CH2:12][CH2:11][CH2:10][CH:15]=[CH:2]2)[CH2:9][CH2:8][CH:7]=[CH:6]1
Reactant: OC1C=CCCC1
Reactant: CC(=O)OC1C=CCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: CC(C)=O
Solvent: O
Product: C1=CC(OC2C=CCC2)CCC1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
A two-phase reaction mixture containing 2-cyclopentenyl acetate (0.30 g, 2.4 millimols), 2-cyclohexenol (0.50 g, 5.1 millimols), tetrabutylammonium hydrogen sulfate (0.020 g, 0.06 millimols), and water (0.25 g, 13.9 millimols) was heated at 40° C. with vigorous stirring for four hours. Acetone was then added to give a one-phase system for analytical purposes, and the solution was analyzed by gas chromatography using an Apiezon column programmed from 60° to 220° C. The following relative peak areas were observed for the cyclic components:
Reaction SMILES: C1(O)C=CC=CC=1.II.ClC1C(Cl)=C(C=CC=1)N(Cl)Cl.Cl[C:22]1[C:27]([NH2:28])=[C:26](Cl)[C:25]([Cl:30])=[C:24](Cl)[C:23]=1[Cl:32].[H][H]>O.[Ta]>[Cl:30][C:25]1[CH:26]=[C:27]([CH:22]=[C:23]([Cl:32])[CH:24]=1)[NH2:28]
Reactant: Nc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: [H][H]
Agent: [Ta]
Agent: Clc1cccc(N(Cl)Cl)c1Cl
Agent: II
Solvent: O
Solvent: Oc1ccccc1
Product: Nc1cc(Cl)cc(Cl)c1
Yield: 94 %

Procedure:
200 parts of phenol, 5.7 parts of iodine, 197 parts of a tetrachloroaniline/pentachloroaniline mixture according to the data in Example 3, and 20 parts of ruthenium-on-charcoal catalyst (5% strength) are subjected to a hydrogenating dehalogenation in a tantalum autoclave at 175° C. with hydrogen under a maximum pressure of 50 bars. In the working up process, the hot mixture is dissolved in 450 parts by volume of water at 100° C., the catalyst is separated off through a suction filter and the filtrate is neutralised with sodium hydroxide solution. 3,5-Dichloroaniline and phenol are separated off from the water phase with the aid of toluene, and the organic solution is distilled. After distilling off toluene and water, the phenol is separated off from the 3,5-dichloroaniline by distillation and can be used again. The crude 3,5-dichloroaniline which remains is purified by distillation over a simple distillation bridge. 132 parts of 98% strength 3,5-dichloroaniline is obtained; yield 94% of theory.
Reaction SMILES: [CH:1]1([NH2+]C2CCCCC2)CCCC[CH2:2]1.[CH2:14]([O:21][C:22]([NH:24][C@@H:25]([CH2:29][CH2:30][C:31]#[N:32])[C:26]([O-:28])=[O:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(O)C>C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:14]([O:21][C:22]([NH:24][C@@H:25]([CH2:29][CH2:30][C:31]#[N:32])[C:26]([O:28][CH2:1][CH3:2])=[O:27])=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: N#CCC[C@H](NC(=O)OCc1ccccc1)C(=O)[O-]
Reactant: C1CCC([NH2+]C2CCCCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](CCC#N)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5.00 g (11.3 mmol) dicyclohexylammonium-(2S)-2-(benzyloxycarbonyl-amino)-4-cyano-butanoate are stirred into in 100 ml of 5% citric acid solution and then extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and the solvent is distilled off i. vac. The residue is dissolved in 70 ml THF, 4.35 g (13.5 mmol) TBTU and 6.35 ml (33.8 mmol) DIPEA are added and the mixture is stirred for 10 minutes at ambient temperature. Then 50 ml of ethanol are added and the mixture is refluxed for 16 hours. Then the reaction mixture is evaporated down i. vac., taken up in ethyl acetate, washed with semisaturated sodium hydrogen carbonate solution and water, dried over sodium sulphate and evaporated down i. vac.
Reaction SMILES: [N:1]1([C:6]([C@@H:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]3[N:19]=[C:18]4[NH:20][C:21]([C:23]5[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=5)[C:26]#[N:27])=[N:22][C:17]4=[CH:16][CH:15]=3)[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N-:31]=[N+:32]=[N-:33].[Na+].II>CN(C)C=O>[N:27]1[NH:31][N:32]=[N:33][C:26]=1[C:25]1[CH:24]=[C:23]([C:21]2[NH:20][C:18]3=[N:19][C:14]([N:10]4[CH2:11][CH2:12][CH2:13][C@@H:8]([C:6]([N:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)=[O:7])[CH2:9]4)=[CH:15][CH:16]=[C:17]3[N:22]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cccc(-c2nc3ccc(N4CCC[C@@H](C(=O)N5CCCC5)C4)nc3[nH]2)c1
Agent: II
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C([C@@H]1CCCN(c2ccc3nc(-c4cccc(-c5nn[nH]n5)c4)[nH]c3n2)C1)N1CCCC1
Temperature: 120 °C
Yield: 116 %

Procedure:
To a solution of (R)-3-(5-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)benzonitrile (30 mg, 0.07 mmol) in N,N-dimethylformamide (2 mL) were added sodium azide (6 mg, 0.09 mmol) and iodine (3 mg). The reaction mixture was heated for 12 h at 120° C., then was cooled. The mixture was filtered, and the filtrate was concentrated. The resulting residue was triturated with diethyl ether to afford (R)-(1-(2-(3-(2H-tetrazol-5-yl)phenyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone as yellow solid (36 mg, 92%). MS (ES+APCI) (M+H) 444.1; HPLC retention time 3.551 min (Method C1). 1H NMR (400 MHz, DMSO-d6) δ 1.50-2.00 (m, 8H), 2.60-2.68 (m, 1H), 2.83-2.97 (m, 3H), 3.25-3.31 (m, 1H), 3.42-3.50 (m, 1H), 3.52-3.60 (m, 1H), 4.32 (d, 1H), 4.42 (d, 1H), 6.83 (d, 1H), 7.47 (t, 1H), 7.81 (d, 1H), 7.94-8.02 (m, 2H), 8.79 (s, 1H), 13.02 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][S:19]([O-])(=O)=O)[CH:15]=[CH:14][CH:13]=2)=[N:3]1.C[S-].[Na+].[C:26](OCC)(=O)C.O>CN(C=O)C>[CH3:26][S:19][CH2:18][C:16]1[N:17]=[C:12]([C:4]2[S:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2](=[O:1])[N:3]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: O=c1nc(-c2cccc(CS(=O)(=O)[O-])n2)sc2ccccc12
Reactant: CCOC(C)=O
Agent: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 70 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]methanesulfonate (0.55 g, 1.58 mmol) was dissolved in DMF (30 ml), and sodium thiomethoxide (0.13 g, 1.74 mmol) was added thereto. The mixture was stirred at 70° C. for 3 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was recrystallized from ethanol to give the titled compound (0.35 g, 75%) as pale yellow crystals.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][N:9]1[CH:13]([C:14]([O:16]C(C)(C)C)=[O:15])[CH2:12][N:11]([C:21]2[CH:22]=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[C:10]1=[O:29]>ClCCl>[OH:5][C:3]([C:2]([F:7])([F:6])[F:1])=[O:4].[CH3:8][N:9]1[CH:13]([C:14]([OH:16])=[O:15])[CH2:12][N:11]([C:21]2[CH:22]=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[C:10]1=[O:29]
Reactant: COc1ccc(N2CC(C(=O)OC(C)(C)C)N(C)C2=O)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(N2CC(C(=O)O)N(C)C2=O)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (400 mg, 1.998 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 5-bromo-2-(methyloxy)pyridine (0.259 ml, 1.998 mmol) in 1,4-dioxane (20 ml) was added cesium carbonate (2604 mg, 7.99 mmol), Xantphos™ (87 mg, 0.150 mmol) and tris(dibenzylideneacetone)dipalladium(0) (91 mg, 0.100 mmol) and the reaction was stirred at reflux overnight. After cooling the solvent was removed under vacuum and the residue was partitioned between dichloromethane and water. The organic layer was separated, washed with saturated sodium hydrogen carbonate solution, water and then brine and passed through a hydrophobic frit. The organic layer was reduced under vacuum and the residue was purified by Flashmaster automated silica gel chromatography eluting with 0-30% ethyl acetate in isohexane to give 1,1-dimethylethyl 3-methyl-1-[6-(methyloxy)-3-pyridinyl]-2-oxo-4-imidazolidinecarboxylate (272 mg, 43.4% yield). LC/MS [M+H]+=308. (ii) Trifluoroacetic acid (1 ml) was added to a solution of 1,1-dimethylethyl 3-methyl-1-[6-(methyloxy)-3-pyridinyl]-2-oxo-4-imidazolidinecarboxylate (270 mg, 0.878 mmol) in dichloromethane (2 ml) and the solution was stirred at room temperature overnight. The reaction mixture reduced to dryness under vacuum azeotroping with toluene and then dried under heated vacuum overnight to give 3-methyl-1-[6-(methyloxy)-3-pyridinyl]-2-oxo-4-imidazolidinecarboxylic acid TFA salt (assume ˜0.88 mmol). LC/MS [M+H]+=252.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9](S(C3C=CC(C)=CC=3)(=O)=O)[CH:8]=[CH:7][C:6]=2[C:5]([C:21]([C:23]2[N:27](COCC[Si](C)(C)C)[C:26]3[CH:36]=[CH:37][C:38]([C:40]#[N:41])=[CH:39][C:25]=3[N:24]=2)=[O:22])=[C:4]([C:42]([F:45])([F:44])[F:43])[CH:3]=1.[CH3:46]C1C2N(S(C3C=CC(C)=CC=3)(=O)=O)C=CC=2C(C(C2N(COCC[Si](C)(C)C)C3C=C(C#N)C=CC=3N=2)=O)=C(C(F)(F)F)C=1>>[OH:22][C:21]([C:23]1[NH:27][C:26]2[CH:36]=[CH:37][C:38]([C:40]#[N:41])=[CH:39][C:25]=2[N:24]=1)([C:5]1[C:4]([C:42]([F:43])([F:44])[F:45])=[CH:3][C:2]([CH3:1])=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2)[CH3:46]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(=O)c4nc5ccc(C#N)cc5n4COCC[Si](C)(C)C)c(C(F)(F)F)cc(C)c32)cc1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(=O)c4nc5cc(C#N)ccc5n4COCC[Si](C)(C)C)c(C(F)(F)F)cc(C)c32)cc1
Product: Cc1cc(C(F)(F)F)c(C(C)(O)c2nc3cc(C#N)ccc3[nH]2)c2cc[nH]c12

Procedure:
The title compound was synthesized from a mixture of 2-(7-methyl-1-tosyl-5-(trifluoromethyl)-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and 2-(7-methyl-1-tosyl-5-(trifluoromethyl)-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile using the same procedures as described in Example 64-B and 64-C. 1H NMR (400 MHz, DICHLOROMETHANE-d2 with 5% of METHANOL-d4) δ ppm 9.24 (br. s., 1H) 7.92 (s, 1H) 7.57-7.65 (m, 1H) 7.51-7.55 (m, 1H) 7.47 (s, 1H) 6.99-7.12 (m, 1H) 5.96 (dd, J=3.41, 1.89 Hz, 1H) 2.53 (s, 3H) 2.34 (s, 3H). HRMS calcd. for C20H15F3N4O (M+H)+ 385.1271. found 385.1277.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:43])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[CH:37]=2)[CH:31]=1)=O)(C)(C)C>>[CH3:14][C:12]1[C:11]([C:15]([F:16])([F:17])[F:18])=[CH:10][C:9]2[NH:19][C:26](=[O:43])[CH2:27][C:28]([C:30]3[CH:35]=[CH:34][N:33]=[C:32]([C:36]4[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[CH:37]=4)[CH:31]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1cc(-c2cc(C(=O)CC(=O)OC(C)(C)C)ccn2)ccn1
Product: Cc1cc(-c2cc(C3=Nc4cc(C)c(C(F)(F)F)cc4NC(=O)C3)ccn2)ccn1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (102 mg, 0.35 mmol) and 3-(2′-methyl-[2,4′]bipyridinyl-4-yl)-3-oxo-propionic acid tert-butyl ester (Example K59) (109 mg, 0.35 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (80 mg).
Reaction SMILES: Cl[CH2:2][CH:3]=[O:4].[CH3:5][C:6]1[N:11]=[C:10]([NH:12][C:13](=[S:15])[S-:14])[CH:9]=[CH:8][CH:7]=1.C([NH+](CC)CC)C.C(O)C>O>[OH:4][CH:3]1[CH2:2][S:15][C:13](=[S:14])[N:12]1[C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:5])[N:11]=1
Reactant: Cc1cccc(NC(=S)[S-])n1
Reactant: O=CCCl
Agent: CC[NH+](CC)CC
Solvent: O
Solvent: CCO
Product: Cc1cccc(N2C(=S)SCC2O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A 50% aqueous solution of chloroacetaldehyde (28.4 g) is added, at between 20° and 30° C., to a solution of triethylammonium 6-methylpyrid-2-yldithiocarbamate (51.5 g) in distilled water (225 cc). The reaction mixture is stirred for 2 hours at 25° C. The crude product is filtered off, washed five times with distilled water (total 125 cc) and dried in air. The product obtained (37.0 g; m.p. 128° C.) is dissolved in boiling ethanol (250 cc). After filtering the boiling solution and cooling the filtrate for 2 hours at 2° C., the resulting crystals are filtered off, washed three times with ice-cooled ethanol (total 30 cc) and dried under reduced pressure (0.2 mm Hg) at 40° C. 4-Hydroxy-3-(6-methylpyrid-2-yl)-thiazolidine-2-thione (29.8 g), melting at 128° C., is thus obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].C1OCCOCCOCCOCCOCCOC1.Br[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][C:39]([O:41][CH3:42])=[O:40]>CN(C=O)C>[C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[O:12][CH:38]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:32]=1)[C:39]([O:41][CH3:42])=[O:40])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1ccccc1Br
Reactant: Cc1ccc(O)c(C(C)(C)C)c1
Agent: C1COCCOCCOCCOCCOCCO1
Solvent: CN(C)C=O
Product: COC(=O)C(Oc1ccc(C)cc1C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 26.2 %

Procedure:
To a suspension of 1.05 g (9.15 mmol) of a 35% oil dispersion of KH in 15 mL of DMF was added 1.50 g (9.15 mmol) of 2-tert-butyl-4-methylphenol and the mixture was stirred under N2 at room temperature. After 10 minutes, 2.41g (91.5 mmol) of 18-crown-6 and then a solution of 2.30 g (10.1 mmol) of methyl 2-bromophenylacetate dissolved in 10 mL of DMF were added. The reaction mixture was stirred 17 hours, then partitioned between ethyl acetate and water. The organic layer was separated, washed with water, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 5% ethyl acetate/hexane to afford 0.750 g (26%) of the title compound.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].[CH3:5][C:6]1[N:11]=[C:10]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:9]2=[CH:8][C:7]=1[C:17](OCC)=[O:18]>CC(O)C>[CH3:5][C:6]1[N:11]=[C:10]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:9]2=[CH:8][C:7]=1[C:17]([NH:3][C:2]([NH2:4])=[NH:1])=[O:18]
Reactant: N=C(N)N
Reactant: CCOC(=O)c1cc2c(nc1C)CCCCC2
Solvent: CC(C)O
Product: Cc1nc2c(cc1C(=O)NC(=N)N)CCCCC2
Yield: 31.2 %

Procedure:
In an atmosphere of argon, metallic sodium (325.2 mg, 0.014 g atom) was dissolved in anhydrous methanol (20.0 ml) at room temperature, and the solution was mixed with guanidine hydrochloride (1.35 g, 14.1 mmol) at 0° C. After 1 hour of stirring at room temperature, the thus precipitated sodium chloride was removed by filtration using a glass filter and the resulting filtrate was evaporated under reduced pressure to obtain free guanidine. Guanidine and ethyl 2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate (500.0 mg, 2.02 mmol) were suspended in 2-propanol (12.0 ml) and heated under reflux for 18 hours. After cooling, the solvent was evaporated under reduced pressure, and the resulting residue was mixed with water and extracted with ethyl acetate. The thus obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and then the thus formed crystals were washed with ether to obtain the title compound (165.1 mg, 31.2%) as white powder.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=O)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([NH:25][NH2:26])[CH3:24].C(#N)C>O>[CH2:23]([N:25]1[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10]2)=[C:16]2[C:17]([CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:26]1)[CH3:24]
Reactant: O=C1CCCCC1C(=O)C1CCN(Cc2ccccc2)CC1
Reactant: CCNN
Solvent: O
Solvent: CC#N
Product: CCn1nc2c(c1C1CCN(Cc3ccccc3)CC1)CCCC2

Procedure:
The title compound was prepared from the semi-crude (1-benzylpiperidin-4-yl)-(cyclohexanon-2-yl)ketone from step A and 34% aqueous ethylhydrazine in 4:1 acetonitrile and water at room temperature. This provided 8:1 ratio of isomeric ethyl pyrazoles in favor of the title compound. (Note: Use of ethyl hydrazine oxalate in the presence of DIEA gave about 2:1 ratio of the same isomers.) The 1-benzylpiperidine-4-carboxylic acid ethyl ester present in the starting β-diketone was removed after saponification of the crude product with sodium hydroxide in water ethanol mixture followed by extractive work-up. The desired ethyl isomer is the higher Rf isomer. It was isolated on silica gel chromatography (60˜100% ethyl acetate in hexanes and 5˜20% methanol in ethyl acetate, both with 1% triethylamine).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20]([C:22]1[N:23]=[CH:24][N:25](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:26]=1)=[O:21])[CH:14]=[CH:13]2>>[NH:25]1[CH:26]=[C:22]([C:20]([C:15]2[CH:14]=[CH:13][C:12]3[C:17](=[CH:18][CH:19]=[C:10]([O:9][CH3:8])[CH:11]=3)[CH:16]=2)([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[OH:21])[N:23]=[CH:24]1
Reactant: Brc1ccncc1
Reactant: COc1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Product: COc1ccc2cc(C(O)(c3ccncc3)c3c[nH]cn3)ccc2c1

Procedure:
In a similar manner to that described in Example 6-(i), the reaction of 4-bromopyridine (0.92 ml) with (6-methoxynaphthalen-2-yl)-(1-trityl-1H-imidazol-4-yl)ketone (1.0 g) was carried out to give the titled compound (0.88 g) as a colorless solid.