Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:13](=[O:35])[C:14]([F:34])([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:22]=3)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.O>CO>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH:13]([OH:35])[C:14]([F:34])([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:22]=3)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(F)(Cc1cccc(Oc2ccccc2)c1)C(=O)C1(c2ccc(Cl)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)C(F)(Cc1cccc(Oc2ccccc2)c1)C(O)C1(c2ccc(Cl)cc2)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 103.8 %

Procedure:
Sodium borohydride (20 mg, 0.53 mmol) is added to a solution of ethyl 1-(p-chlorophenyl)-α-fluoro-β-oxo-α-(m-phenoxybenzyl)cyclopropanepropionate (214 mg, 0.46 mmol) in methanol at 0° C. The reaction mixture is stirred at 0° C. for 20 minutes, treated with water (2 mL), and concentrated in vacuo to obtain a residue. A solution of the residue in ethyl acetate is washed sequentially with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title product as a colorless gum (224 mg, 100%) which is found to have a 9:1 [R,S and S,R] to [R,R and S,S] ratio by NMR spectral analyses.
Reaction SMILES: [CH:1]1([CH2:6][C:7]2[C:8]([O:13]C)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:5][CH:4]=[CH:3][CH2:2]1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C.C(OCC)(=O)C>[CH:1]1([CH2:6][C:7]2[C:8](=[O:13])[NH:9][CH:10]=[CH:11][CH:12]=2)[CH2:2][CH:3]=[CH:4][CH2:5]1
Reactant: COc1ncccc1CC1CC=CC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1[nH]cccc1CC1CC=CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
To a cloudy dispersion containing 3-(cyclopent-3-en-ylmethyl)-2-(methyloxy)pyridine (Preparation 28, 2.1 g, 11.1 mmol) and sodium iodide (4.1 g, 27.8 mmol) in anhydrous acetonitrile (25 ml) was added chlorotrimethylsilane (3.0 g, 27.8 mmol). A white precipitate formed which was stirred for 30 min at room temperature and then for 1 h at 70° C. The reaction mixture was cooled to room temperature and water was added, followed by ethyl acetate (200 ml), the organic layer washed with water (4×) and then with sodium hydrogen carbonate solution and brine before drying (Na2SO4) to give the title compound as a yellow solid (1.93 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4](Cl)[N:3]=1.Cl.[CH3:13][C@@H:14]1[CH2:19][O:18][CH2:17][CH2:16][NH:15]1.C(N(C(C)C)CC)(C)C>C(O)(C)C.C(Cl)Cl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][C@H:14]2[CH3:13])[N:3]=1
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Reactant: C[C@@H]1COCCN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC(C)O
Product: C[C@@H]1COCCN1c1nc(Cl)nc2[nH]cnc12
Temperature: 75 °C
Reaction time: 18 h
Yield: 90.5 %

Procedure:
2,6-Dichloro-9H-purine (2.36 g, 12.5 mmol), (R)-3-methylmorpholin hydrochloride (1.89 g, 13.8 mmol), and diisopropylethylamine (5.46 mL, 31.3 mmol) were dissolved in 15 mL of isopropanol, and the reaction mixture was stirred for 18 hours at 75° C. The reaction mixture was then diluted with 200 mL of CH2Cl2. The organic solvents were washed with aqueous Na2CO3, followed by water and brine. Drying over Na2SO4, filtering and concentration under reduced pressure gave a residue, which was purified by column chromatography (150 g SiO2, CH2Cl2/EtOH/aq NH3 in a ratio of 96/4/0.1) to give the product as a solid (2.87 g, 91%).
Reaction SMILES: [Na].[C:2]([C:6]1[CH:7]=[C:8]([C:17]2[N:18]=[C:19]([SH:22])[S:20][CH:21]=2)[CH:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]=1[OH:12])([CH3:5])([CH3:4])[CH3:3].[CH3:23]I.O>CO>[C:2]([C:6]1[CH:7]=[C:8]([C:17]2[N:18]=[C:19]([S:22][CH3:23])[S:20][CH:21]=2)[CH:9]=[C:10]([C:13]([CH3:15])([CH3:16])[CH3:14])[C:11]=1[OH:12])([CH3:3])([CH3:4])[CH3:5]
Reactant: CI
Reactant: CC(C)(C)c1cc(-c2csc(S)n2)cc(C(C)(C)C)c1O
Agent: [Na]
Solvent: O
Solvent: CO
Product: CSc1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cs1
Yield: 73 %

Procedure:
In 30 ml of methanol was dissolved 0.18 g of metallic sodium and after adding thereto 2.1 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-mercaptothiazole, 1.15 g of methyl iodide was added dropwise to the solution at 0°-5° C. After allowing to stand the mixture for 30 minutes at room temperature, 60 ml of iced water was added to the reaction mixture. The crystals thus precipitated were recovered by filtration and recrystallized from n-hexane to provide 1.6 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylthiothiazole.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[C:7]([C:17]([O:19]C)=[O:18])=[CH:8][C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:10][C:4]=2[N:3]=1.Br[CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=1)[CH3:23].C(=O)([O-])[O-].[K+].[K+].[OH-].[Li+]>CN(C)C=O.O1CCCC1.O>[Cl:30][C:26]1[CH:25]=[C:24]([CH:22]([N:3]2[C:4]3[CH:10]=[C:9]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)[CH:8]=[C:7]([C:17]([OH:19])=[O:18])[C:5]=3[N:6]=[C:2]2[CH3:1])[CH3:23])[CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(C)[nH]c12
Reactant: CC(Br)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1nc2c(C(=O)O)cc(N3CCOCC3)cc2n1C(C)c1cccc(Cl)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 24.27 %

Procedure:
To a solution of methyl 2-methyl-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 26, step d (0.2 g, 0.726 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added 1-(1-bromoethyl)-3-chlorobenzene (0.203 mL, 1.453 mmol) and potassium carbonate (0.301 g, 2.179 mmol). The resulting reaction mixture was stirred for 3 h at 80° C. The solution was cooled to room temperature and poured into water and was extracted with EtOAc. The combined organic phase was washed with Brine and concentrated. The residue was purified on Biotage Isolera purification system using a Biotage 10 g SNAP silica gel cartridge and eluted with a gradient of DCM to 5% MeOH/DCM over 10 column volumes. The expected compound was collected and evaporated to yield a tan solid. The tan solid was dissolved in tetrahydrofuran (THF) (10.00 mL) followed by the addition of 1M lithium hydroxide solution (10 mL, 10 mmol). The reaction was stirred at 50° C. for 2 h. The reaction was cooled to room temperature and the organic solvent was removed in vacuo. The solution was diluted with water (20 mL) and acidified with 1 N HCl. The mixture was then filtered and the grey solid was purified by reversed phase HPLC with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (10-40%) over 10 minutes. The appropriate fractions were collected and evaporated to provide the desired product (70.5 mg, 0.176 mmol, 24.27% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.04 (d, J=6.82 Hz, 3H) 2.78 (br. s., 4H) 3.02 (s, 3H) 3.78 (br. s., 4H) 5.95-6.06 (m, 1H) 6.49 (br. s., 1H) 7.35-7.51 (m, 3H) 7.57 (m, 1H). MS(ES+) m/e 399.8 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][S:12]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[Cl:26])(=[O:14])=[O:13])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].C(N(CC)C(C)C)(C)C.[F:36][CH:37]([F:47])[CH2:38]OS(C(F)(F)F)(=O)=O>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([N:11]([S:12]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:19]=[CH:18][C:17]=2[Cl:26])(=[O:13])=[O:14])[CH2:38][CH:37]([F:47])[F:36])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1nccnc1NS(=O)(=O)Cc1cc(C(F)(F)F)ccc1Cl
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1nccnc1N(CC(F)F)S(=O)(=O)Cc1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 44 h
Yield: 75 %

Procedure:
To a solution of 3-(2-chloro-5-trifluoromethyl-phenylmethanesulfonylamino)-pyrazine-2-carboxylic acid methyl ester (Example 2.1) (1.5 g) in acetonitrile (15 ml) was added N,N-diisopropylethylamine (“Hunig's base”) (0.71 ml) at ambient temperature. The mixture was stirred for 5 minutes at ambient temperature before dropwise addition of a solution of 2,2-difluoroethyltrifluoromethanesulfonate (1.2 g) in acetonitrile (5 ml) at ambient temperature. The reaction mixture was stirred at ambient temperature for 44 hours. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (eluent: dichloromethane) to give 3-[(2-chloro-5-trifluoromethyl-phenylmethanesulfonyl)-(2,2-difluoro-ethyl)-amino]-pyrazine-2-carboxylic acid methyl ester as a light yellow solid (1.300 g). 1H-NMR (400 MHz, CDCl3): 8.63 (s, 1H), 8.53 (s, 1H), 7.76 (m, 1H), 7.53-7.59 (m, 2H), 6.15 (tt, 1H), 4.69 (s, 2H), 4.23-4.31 (m, 2H), 4.02 (s, 3H) ppm.
Reaction SMILES: [C:1]([C:3](=[CH:12]OCC)[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2].[F:16][C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:18]=1[NH2:19]>C(O)C>[C:1]([C:3](=[CH:12][NH:19][C:18]1[C:17]([F:16])=[CH:23][CH:22]=[CH:21][C:20]=1[F:24])[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2]
Reactant: CCOC=C(C#N)C(=O)NC(=O)OCC
Reactant: Nc1c(F)cccc1F
Solvent: CCO
Product: CCOC(=O)NC(=O)C(C#N)=CNc1c(F)cccc1F

Procedure:
To 10.0 g of α-cyano-β-ethoxy-N-ethoxycarbonylacrylamide dissolved in about 40 ml of hot ethanol is added 6.45 g of 2,6-difluoroaniline in 15 ml of ethanol. The reaction mixture is stirred at reflux for about 6 hours, cooled and filtered to yield α-cyano-β-(2,6-difluoroanilino)-N-ethoxycarbonylacrylamide, white solid (12.61 g), which is added to 60 ml of tetralin and heated at reflux for 5 hours. The mixture is allowed to cool, filtered and washed with ether to yield 10.21 g of 5-cyano-1-(2,6-difluorophenyl)uracil, white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[C:22]([N+:23]([O-])=O)=[CH:21][C:20]([F:26])=[CH:19][N:18]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CCO.[Pt]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:13][C:17]2[C:22]([NH2:23])=[CH:21][C:20]([F:26])=[CH:19][N:18]=2)=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: O=[N+]([O-])c1cc(F)cnc1Cl
Agent: [Pt]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: Nc1cc(F)cnc1Nc1ccc(OCc2ccccc2)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 24.3 %

Procedure:
A mixture of 4-(benzyloxy)aniline (2.26 g), 2-chloro-5-fluoro-3-nitropyridine (2 g) and K2CO3 (3.13 g) in DMF (20 mL) was stirred at 120° C. for 5 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was suspended in IPE and collected by filtration. The solid obtained above was dissolved in EtOH (20 mL), and Pt/C (2 g) was added. Under H2 atmosphere, the mixture was stirred for 1 h, filtered and evaporated. The residue was chromatographed on silica gel eluting with Hexane/AcOEt to give the title compound (0.85 g).
Reaction SMILES: CCCCO[C@H:6]([CH2:9][OH:10])CC.C(O)CCCO.C(C(CO)(CO)CC)O.O=C=NC1CC(C)(C)CC(C)(CN=C=O)C1.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.N(CCC[Si:85]([O:92][CH2:93][CH3:94])([O:89][CH2:90][CH3:91])[O:86][CH2:87][CH3:88])=C=O>O1CCCC1>[CH3:88][CH2:87][O:86][Si:85]([O:10][CH2:9][CH3:6])([O:92][CH2:93][CH3:94])[O:89][CH2:90][CH3:91]
Reactant: CCCCO[C@@H](CC)CO
Reactant: CCO[Si](CCCN=C=O)(OCC)OCC
Agent: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Agent: CCC(CO)(CO)CO
Agent: CCCCCCCCCCCC(=O)[O-]
Solvent: C1CCOC1
Solvent: OCCCCO
Product: CCO[Si](OCC)(OCC)OCC
Temperature: 60 °C

Procedure:
5 wt % Fluorinated Masterbatch. To a 500 mL, three-neck round bottom flask containing dry tetrahydrofuran (THF) (150 mL) under nitrogen was added Terathane™ 650 polytetramethylene glycol (20.62 g, 0.032 mol), 1,4-butanediol (4.50 g, 0.050 mol), Polyfox™ PF-6320 (2.84 g, 0.0008 mol) and trimethylolpropane (1.38 g, 0.010 mol). The mixture was stirred under nitrogen until a solution was obtained; then isophorone diisocyanate (20.66 g, 0.093 mol) was added, and then the mixture was degassed under reduced pressure (0.1 mm Hg). Dibutyltin dilaurate (0.10 g, 0.0002 mol) was added, and the mixture was heated at 60° C. under nitrogen for 5 hours. To the above solution was added 3-isocyanatopropyltriethoxysilane (2.11 g, 0.0085 mol) and additional THF (35 mL). The mixture was heated at 60° C. for 15 hours, yielding a solution containing 24 wt % dissolved solids.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][N:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[N:32][CH:33]=1>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[N:12]=[CH:13][C:14]([C:30]2[CH:31]=[N:32][CH:33]=[C:28]([F:27])[CH:29]=2)=[CH:15][CH:16]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(Br)cn1)c1ccc(Cl)c(Cl)c1
Reactant: OB(O)c1cncc(F)c1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(-c2cncc(F)c2)cn1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[2-(5-bromo-pyridin-2-yl)-1-(3,4-dichloro-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and 5-fluoropyridine-3-boronic acid in analogy to Example 1b): MS (ISP): 476.1 and 478.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:18][OH:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.CCN(CC)CC.[S:33](Cl)([CH3:36])(=[O:35])=[O:34]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:18][O:19][S:33]([CH3:36])(=[O:35])=[O:34])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: OCC(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 104 %

Procedure:
To a solution of [rac]-2-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-2-cyclohexyl-ethanol (example 37.1) (400 mg, 1.1 mmol) in dry DCM (15 ml) was added Et3N (0.64 ml, 3.32 mmol) at room temperature. Mesyl chloride (0.16 ml, 2.22 mmol) was then added to this reaction mixture dropwise at 0° C.; and the reaction mixture was stirred at room temperature for 2 hours. TLC shows complete consumption of [rac]-2-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-2-cyclohexyl-ethanol. The reaction mixture was diluted with H2O (10 ml) and the aqueous layer was extracted with DCM (3×10 ml). Combined organic layers were washed with ice water (10 ml), 10% NaHCO3 (10 ml), brine (10 ml) and finally dried over Na2SO4. Organic layer was distilled under reduced pressure to get light yellow oil (500 mg), which was purified by column chromatography [SiO2 (230-400 mesh), EtOAc:Hexane 10/90] to give the title compound (370 mg, 76%) as a light yellow liquid.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=3[CH3:23])[C:6]=2[CH:5]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:3]=1.[O:30]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31]1.C(=O)([O-])[O-].[Na+].[Na+].C(O)(C(F)(F)F)=O>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.C(#N)C>[O:30]1[CH:34]=[CH:33][C:32]([C:2]2[C:10]3[N:9]=[C:8]([CH3:11])[N:7]([CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=4[CH3:23])[C:6]=3[CH:5]=[C:4]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[CH:3]=2)=[CH:31]1
Reactant: OB(O)c1ccoc1
Reactant: Cc1c(Cn2c(C)nc3c(Br)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Cn2c(C)nc3c(-c4ccoc4)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Yield: 14.11 %

Procedure:
A mixture of 4-bromo-2-methyl-1-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-1H-benzimidazole, prepared as described in Example 62 (200 mg, 0.427 mmol), 3-furanyl boronic acid (47.8 mg, 0.427 mmol), sodium carbonate (91 mg, 0.854 mmol) and PdCl2(dppf)-CH2Cl2 adduct (34.9 mg, 0.043 mmol) in 1,2-Dimethoxyethane (DME) (2.5 mL) and Water (0.5 mL) was irradiated in a microwave reactor for 1 h at 100° C. The mixture was poured into water and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4 and evaporated. Only partial conversion (ca. 50%) was observed by LC/MS analysis. The residue was purified by RP-HPLC (Gilson, 25-65% Acetonitrile in water plus 0.1% TFA) to the desired product (28 mg, 0.060 mmol, 14.11% yield) as a white powder (separation from impurity was difficult. The head of the peak was discarded decreasing the overall yield, in addition to the partial conversion observed). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.57 (s, 1H), 7.58 (d, J=7.58 Hz, 1H), 7.55 (t, J=1.52 Hz, 1H), 7.09-7.15 (m, 2H), 7.02 (d, J=1.26 Hz, 1H), 6.52 (d, J=7.83 Hz, 1H), 6.48 (d, J=2.02 Hz, 1H), 5.29 (s, 2H), 3.80-3.97 (m, 4H), 3.07-3.21 (m, 4H), 2.57 (s, 3H), 2.52 (s, 3H). MS (ES+) m/e 456.0 [M+H]+
Reaction SMILES: C1(C)C=CC(S(O[CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:15]=2)[C:12]#[N:13])(=O)=O)=CC=1.CO.[CH3:31][S-:32].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH3:31][S:32][CH:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:15]=1)[C:12]#[N:13]
Reactant: Cc1ccc(S(=O)(=O)OC(C#N)c2cccc(C(=O)c3ccccc3)c2)cc1
Reactant: C[S-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CSC(C#N)c1cccc(C(=O)c2ccccc2)c1
Yield: 80 %

Procedure:
979 mg of O-(p-toluenesulfonyl)-m-benzoylmandelonitrile was dissolved in 2 ml of DMF, and the mixture was stirred in an argon atmosphere under ice cooling. Then, 1.08 ml of a 2.3 M methanol solution of sodium methanethiolate was added dropwise to the solution over 5 minutes, and the mixture was further stirred under ice cooling. An aqueous solution of ammonium chloride (0.2 g/30 ml) was added, and the mixture was extracted with methylene chloride. The extract was washed with 10 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The oily residue was separated by column chromatography (silica gel; methylene chloride) to afford 533 mg (yield 80%) of alpha-(methylthio)(m-benzoylphenyl)acetonitrile as a pale orange oil.
Reaction SMILES: [CH3:1][C@H:2]1[C:10]2[C:9](O)=[N:8][CH:7]=[N:6][C:5]=2[CH2:4][CH2:3]1.O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:9]1[C:10]2[C@H:2]([CH3:1])[CH2:3][CH2:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: C[C@@H]1CCc2ncnc(O)c21
Product: C[C@@H]1CCc2ncnc(Cl)c21
Yield: 49 %

Procedure:
A mixture of (R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (5.8 g, 38.62 mmol) in POCl3 (20 mL) was refluxed for 5 minutes. Excess POCl3 was removed under vacuum and the residue was dissolved in DCM (50 mL). The mixture was then added to saturated NaHCO3 (200 mL). The aqueous phase was extracted with DCM (3×100 mL), and the combined organic phases were dried and concentrated. The residue was purified by silica gel chromatography, eluting with ethyl acetate to give (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (3.18 g, 49%). 1H NMR (CDCl3, 400 MHz) δ 8.81 (s, 1H), 3.47 (m, 1H), 3.20 (m, 1H), 3.05 (m, 1H), 2.41 (m, 1H), 1.86 (m, 3H), 1.47 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[N:9]2[CH2:12][CH:11]([C:13](C)([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=3)[C:14]([NH:16]C3CCCCC3)=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.N[CH2:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1.Cl.CN(C)CCCN=C=NCC.O.OC1C2N=NNC=2C=CC=1.Cl.ClC1C=CC(C(C2C=CC(Cl)=CC=2)N2CC(C(C3C=C(F)C=C(F)C=3)C(O)=O)C2)=CC=1>ClCCl.C(N(CC)CC)C>[Cl:38][C:35]1[CH:34]=[CH:33][C:32]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]2[CH2:12][CH:11]([CH:13]([C:23]3[CH:24]=[C:25]([F:30])[CH:26]=[C:27]([F:29])[CH:28]=3)[C:14]([NH:16][CH2:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)=[O:15])[CH2:10]2)=[CH:37][CH:36]=1
Reactant: NCC1CCCCC1
Reactant: CC(C(=O)NC1CCCCC1)(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC1CCCCC1)C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: 20 °C
Reaction time: 12 h

Procedure:
(RS)-2-{1-[Bis(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyclohexyl-methylacetamide may be prepared in the following manner: 0.016 cm3 of aminomethylcyclohexane, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added to a solution of 50 mg of {1-[bis(4-chlorophenyl)methyl]-azetidin-3-yl}-(3,5-difluorophenyl)acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane, at a temperature in the region of 20° C. The solution obtained is stirred at a temperature in the region of 20° C. for about 12 hours. The reaction medium is deposited on a Varian cartridge (6 cm3) filled with 3 g of fine silica (0.040-0.063 mm), conditioned and then eluted with dichloromethane with the aid of a Duramat pump, collecting 2-cm3 fractions. Fractions 2 to 3 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. 49 mg of (RS)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluoro-phenyl)-N-cyclohexylmethylacetamide are thus obtained in the form of a white foam [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): from 0.75 to 1.75 (mt: 11H); 2.65 (mt: 1H); from 2.85 to 3.15 (mt: 5H); 3.42 (broad t, J=7.5 Hz: 1H); 3.57 (d, J=10.5 Hz: 1H); 4.27 (s: 1H); 5.40 (mt: 1H); 6.71 (broad t, J=9 Hz: 1H); 6.83 (mt: 2H); from 7.15 to 7.40 (mt: 8H)].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][NH2:9].[CH3:10][C:11](=[O:18])[C:12](=[N:16]O)[C:13](=O)[CH3:14]>C(#N)C>[CH3:14][C:13]1[NH:9][C:8]([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[CH3:1])=[N:16][C:12]=1[C:11](=[O:18])[CH3:10]
Reactant: CC(=O)C(=NO)C(C)=O
Reactant: Cc1cnccc1CN
Solvent: CC#N
Product: CC(=O)c1nc(-c2ccncc2C)[nH]c1C
Temperature: -10 °C
Reaction time: 5 h
Yield: 41 %

Procedure:
A mixture consisting of 7.1 g (0.058 mole) of 3-methyl-4-pyridylmethylamine, 6.25 g (0.051 mole) of 2,3,4-pentanetrione 3-oxime, and 125 ml of acetonitrile was stirred at the reflux temperature for five hours. After cooling at -10° C., a precipitate formed. This was collected, washed with a little cold acetonitrile, and dried. Recrystallization from a mixture of chloroform and hexane gave 4.5 g of the desired product, mp 185°-187° C.