Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:29]=[CH:28][C:9]([CH2:10][N:11]3[CH:19]=[C:18]4[C:13]([N:14]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:15](=[O:22])[N:16]([CH3:21])[C:17]4=[O:20])=[N:12]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[CH3:30][S:31]SC.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C(Cl)Cl.C1COCC1>[N:1]1([C:6]2[CH:29]=[CH:28][C:9]([CH2:10][N:11]3[C:19]([S:31][CH3:30])=[C:18]4[C:13]([N:14]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:15](=[O:22])[N:16]([CH3:21])[C:17]4=[O:20])=[N:12]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CSSC
Reactant: Cn1c(=O)c2cn(Cc3ccc(-n4cncn4)cc3)nc2n(CC(C)(C)C)c1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CSc1c2c(=O)n(C)c(=O)n(CC(C)(C)C)c2nn1Cc1ccc(-n2cncn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(4-(1H-1,2,4-triazol-1-yl)benzyl)-5-methyl-7-neopentyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (52 mg, 0.132 mmol) and methyl disulfide (12 μL, 0.13 mmol) are dissolved in 2 mL of anhydrous CH2Cl2, and then 1.0 M LiHMDS (190 μL, 0.19 mmol) in THF is added dropwise. The reaction mixture is stirred at room temperature for 30 min, and then quenched with saturated ammonium chloride aqueous solution. After routine workup, the obtained crude product is purified by silica gel column chromatography to give pure product as off-white solids. MS (ESI) m/z 440.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH:28]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C(Cl)(Cl)Cl>[CH:28]1([NH:34][C:12]([C:9]2[C:8](=[O:15])[N:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]3=[N:11][CH:10]=2)=[O:14])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Reactant: NC1CCCCC1
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cccc2ncc(C(=O)NC3CCCCC3)c(=O)n12
Reaction time: 0.08 h
Yield: 73.2 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate in 40 ml of chloroform is dropped to the above mixture at -10° C. during 20 minutes. After stirring for 5 minutes, 8.73 g (0.088 mol) of cyclohexylamine dissolved in 80 ml of chloroform are dropped to the above solution at -15° C. during 30 minutes. The reaction mixture is stirred for 1 hour below -10° C. and then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each and then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to give 16.7 g (73.2%) of the named product as yellow crystals after recrystallization from ethanol, m.p.: 174°-176° C.
Reaction SMILES: [OH-:1].[Na+].[F:3][C:4]([F:20])([F:19])[C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([N+:15]([O-:17])=[O:16])[C:6]=1Cl.ClCl.O>CO>[F:3][C:4]([F:20])([F:19])[C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([N+:15]([O-:17])=[O:16])[C:6]=1[OH:1]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1Cl
Reactant: [OH-]
Agent: ClCl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1O

Procedure:
To a solution of 168 g (4 moles +5% excess) of sodium hydroxide in 1000 ml methanol there were added portionwise, at 50°-65°C internal temperature, 586 g (2 moles) 2,4-bis-trifluoromethyl-6-nitrochlorobenzene; the reaction mixture, after completion of addition (about 1 hour) of the reactive chlorine compound, was boiled under reflux for one hour. After cooling, 700 ml of water were added to the mixture and unreacted starting materials were extracted once with 400 ml methylene chloride. The aquous phase was separated off, distinct acidification was effected with 20%-strength sulfuric acid; the 2,4-bis-trifluoromethyl-6-nitrophenol which separated was taken up in methylene chloride. The organic phase was dried over sodium sulfate. The 2,4-bis-trifluoromethyl-6-nitro-phenol remaining behind after methylene chloride had been distilled off was subjected to vacuum distillation. 480 g (87%) of the boiling pont 105°-106°C/20 mm Hg were obtained; refractive index nD20 : 1.4580.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].S(Cl)([Cl:13])(=O)=O>C(Cl)Cl>[Cl:13][CH:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C(Cl)C(C)=O

Procedure:
32.5 g (0.25 mol) of ethyl acetoacetate are dissolved in 64 ml of methylene chloride. 33.74 g (0.25 mol) of sulfuryl chloride are added dropwise to this solution, and the mixture is then (when the evolution of gas is complete) heated at a gentle boil for one hour. After the methylene chloride has been removed by distillation, the residue is distilled at 86°-92° C./12 mmHg. 38.8 g of substance are obtained, 1H NMR: --CH3 1.31 ppm (t, 3H), --CH2 --(ester) 4.28 ppm (q, 2H), --CH3 (acetyl) 2.38 ppm (s, 3H), --CHCl--4.76 ppm (s, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]([C:9]1[NH:10][C:11](=[O:21])[C:12]([OH:20])=[C:13]([C:15]([O:17]CC)=[O:16])[N:14]=1)([CH3:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>CN(C)C=O>[CH2:28]([O:20][C:12]1[C:11](=[O:21])[N:10]2[C:9]([C:6]([CH3:7])([CH3:8])[O:5][CH2:4][CH2:3][CH2:2]2)=[N:14][C:13]=1[C:15]([OH:17])=[O:16])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)c1nc(C(C)(C)OCCCCl)[nH]c(=O)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OCCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Temperature: 60 °C
Reaction time: 5 h
Yield: 135.7 %

Procedure:
A suspension of intermediate 33, ethyl 2-(2-(3-chloropropoxy)propan-2-yl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate, (0.205 g, 0.64 mmol) and anhydrous potassium carbonate (0.361 g, 2.6 mmol) in anhydrous dimethylformamide (4 mL) was stirred at 60° C. for 5 hours. The reaction mixture was treated with benzyl bromide (0.122 g, 0.71 mmol) and stirred for 16 hours. Following this, 2 mL of H2O was added and the mixture stirred for an additional 24 hours. Solvent was removed by rotary evaporator and the resulting residue suspended in 0.5 N hydrochloric acid (16 mL). The crude product was extracted with ethyl acetate (2×15 mL), then dried (sodium sulfate), filtered, and concentrated to dryness by rotary evaporator to give 0.299 g (Yield>100%) of the title compound as a solid. LC/MS [M+H]+=345.21.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:22]=[CH:21][C:15]4[N:16]=[C:17]([S:19][CH3:20])[O:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:22]=[CH:21][C:15]4[N:16]=[C:17]([S:19]([CH3:20])=[O:31])[O:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc2ccc(Cn3cnc4cc(F)cnc43)cc2o1
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cn3cnc4cc(F)cnc43)cc2o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
To a stirred solution of 6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]oxazole (595 mg, 1.89 mmol) from the previous step in DCM (10 mL) at 0° C. was added 70% meta-chloroperbenzoic acid (425 mg, 2.46 mmol). The reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was washed sequentially with aq sodium sulfite and brine. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 50% ethyl acetate in petroleum ether to afford 6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole (509 mg, 82%). 1H NMR (300 MHz, DMSO-d6): δ 8.73 (s, 1H), 8.40 (s, 2H), 7.53 (d, J=7.2 Hz, 1H), 7.37 (s, 1H), 7.15 (d, J=4.5 Hz, 1H), 5.69 (s, 2H), 3.18 (s, 3H); LCMS (ESI) m/z 331 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[S:3]([O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[O:18])=[CH:9][CH:8]=1)(=[O:5])=[O:4].[CH2:21](O)[CH2:22][OH:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:20][C:2]([F:19])([F:1])[S:3]([O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[O:23][CH2:22][CH2:21][O:18]2)=[CH:9][CH:8]=1)(=[O:4])=[O:5]
Reactant: OCCO
Reactant: O=Cc1ccc(OS(=O)(=O)C(F)(F)F)c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=S(=O)(Oc1ccc(C2OCCO2)c2ccccc12)C(F)(F)F

Procedure:
A solution of 4-trifluoromethylsulfonyloxy naphthaldehyde (4.09 g, 13.4 mmol), ethylene glycol (1.5 mL, 1.67 g, 26.9 mmol), and p-toluene sulfonic acid (250 mg) in toluene (250 mL) was refluxed for 16 hr using a Dean-Stark trap. The solution was allowed to reach room temperature, was washed with satd. NaHCO3-sol. (2×80 mL), brine (80 mL), dried (MgSO4), and concentrated to give a yellow oil (4.79 g, quant).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17](O)=[O:18])[CH:15]=2)[C:10]([C:20](=[O:31])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[C:9]1[CH:32]([CH3:34])[CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.[CH2:39]([NH2:42])[C:40]#[CH:41]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH:42][CH2:39][C:40]#[CH:41])=[O:18])[CH:15]=2)[C:10]([C:20]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[O:31])=[C:9]1[CH:32]([CH3:34])[CH3:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CCN
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C(=O)O)cc2n1Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: C#CCNC(=O)c1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1

Procedure:
Following General Procedure G, 1-benzyl-3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1H-indole-6-carboxylic acid (Compound 56, 35 mg, 0.080 mmol) in in CH2Cl2 (3 ml) was added EDC (25 mg, 0.15 mmol) and DMAP (15 mg, 0.09 mmol), followed by propargyl amine (7 mg, 0.09 mmol). The crude material was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:56][O:57][C:58]([C:60]1[O:61][C:62]2[CH:68]=[CH:67][C:66]([NH2:69])=[CH:65][C:63]=2[CH:64]=1)=[O:59]>ClCCl>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10][C@H:9]2[C:28]([NH:69][C:66]2[CH:67]=[CH:68][C:62]3[O:61][C:60]([C:58]([O:57][CH3:56])=[O:59])=[CH:64][C:63]=3[CH:65]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc2cc(N)ccc2o1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cc2cc(NC(=O)[C@@H]3N[C@@H](CC(C)(C)C)[C@](C#N)(c4ccc(Cl)cc4F)[C@H]3c3cccc(Cl)c3F)ccc2o1
Reaction time: 0.33 h

Procedure:
A solution of chiral-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (60.9 mg, 0.130 mmol) in dichloromethane (3 ml) was reacted with DIPEA (66.8 mg, 0.517 mmol) and DIPHENYLPHOSPHINIC CHLORIDE (75.8 mg, 0.320 mmol) and stirred for 20 min under argon. 5-AMINO-BENZOFURAN-2-CARBOXYLIC ACID METHYL ESTER (26.0 mg, 0.136 mmol, Biofine,) was added and stirred 2.5 hrs. The reaction mixture was diluted with dichloromethane and washed with water, sat. NaHCO3 and brine. After drying over Na2SO4 the crude material was purified by silica gel chromatography with ethyl acetate and n-hexanes giving chiral-methyl 5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)benzofuran-2-carboxylate (46.2 mg., 55.4%) as a white solid. MS (ES+) m/z Calcd: [(M+H)+]: 640.15. found: 640.0.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].CN(C)P(N(C)C)N(C)C>>[CH2:3]=[C:2]([CH2:3][CH2:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: C=CC(=O)OC(C)(C)C
Agent: CN(C)P(N(C)C)N(C)C
Product: C=C(CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 100 °C

Procedure:
Tert-butyl acrylate (465 g, 3.628 mol) was warmed to 100° C. under nitrogen, then hexamethylphosphorous triamide (10 g, 61.2 mmol) was added dropwise and the addition rate was adjusted to maintain the reaction temperature at 100° C. The reaction mixture was allowed to cool, then poured over a plug of silica (~1000 ml) and washed completely off the silica with 4:1 hexane/ethyl acetate. The solvent was removed under reduced pressure and the resulting oil was distilled. Some material was collected from room temperature to 50° C. under high vacuum, and discarded. The temperature was then raised to -80° C. and the product (300 g, 65%, b.p. 67-70° C. at 300μ) was collected as a clear oil. 1H NMR (CDCl3): δ 1.4 (m, 18H), 2.4 (t, 2H), 2.6 (t, 2H), 5.5 (s, 1H), 6.0 (s, 1H).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[CH3:13][C:14]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C(Cl)Cl>[Si:17]([O:1][CH:2]1[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]1)([C:14]([CH3:16])([CH3:15])[CH3:13])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)C1
Yield: 75.4 %

Procedure:
A solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (1 g, 5.77 mmol), TBSCl (6.35 mmol, 956 mg) in DCM (11.5 mL), was stirred for 72 hrs at room temperature. The solvent was removed under reduced pressure, EtOAc was added to the residue, and the solid material was removed by filtration. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography with gradient elution with EtOAc/hexane (9:1) to EtOAc/hexane (1:1), to afford title compound 295 (1.25 g, 75% yield) as a syrup. MS (m/z): 310.1 (M+23).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][CH3:12])=[C:7]([CH:10]=1)[C:8]#[N:9].[CH2:13]([OH:15])[CH3:14]>>[CH2:13]([O:15][C:8](=[NH:9])[C:7]1[CH:10]=[C:3]([Cl:2])[CH:4]=[CH:5][C:6]=1[O:11][CH3:12])[CH3:14]
Reactant: CCO
Reactant: COc1ccc(Cl)cc1C#N
Agent: Cl
Product: CCOC(=N)c1cc(Cl)ccc1OC
Reaction time: 48 h
Yield: 56 %

Procedure:
Hydrogen chloride gas (˜200 mmol) was passed into a solution of 5-chloro-2-methoxy-benzonitrile(1.68 g, 10.0 mmol) in ethanol (50 ml). After stirring for 48 hours, the mixture was concentrated under reduced pressure. The residue was treated with ethyl acetate (25 ml) and stirred for 1 hour. Filtration provided 5-chloro-2-methoxy-benzimidic acid ethyl ester (1.20 g, 56% yield) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:27]2[CH2:29][CH2:28]2)=[C:9]([F:26])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:13]=2)=[CH:4][CH:3]=1.[Mg]>CO.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:27]2[CH2:29][CH2:28]2)[C:9]([F:26])=[CH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: FC(C=Cc1ccc(F)c(Oc2ccccc2)c1)=C(c1ccc(Cl)cc1)C1CC1
Agent: [Mg]
Solvent: CO
Solvent: C1CCOC1
Product: FC(=CCc1ccc(F)c(Oc2ccccc2)c1)C(c1ccc(Cl)cc1)C1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.4 %

Procedure:
A solution of 1-(p-chlorophenyl)-1-cyclopropyl-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-1,3-butadiene (26 g, 0.064 mol) in a methanol/tetrahydrofuran solution (15:1) is treated with magnesium turnings (7.72 g, 0.317 mol), stirred at room temperature for 4 hours, quenched with hydrochloric acid, and extracted with ethyl acetate. The organic extracts are combined, washed sequentially with water, 2N hydrochloric acid and water, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a residue. Flash column chromatography of the residue using silica gel and an ethyl acetate/hexanes solution (5:95) gives the title product as an oil (21.4 g, 82%) which is identified by NMR spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]#[N:7])=[C:4]([S:11][CH2:12][CH3:13])[CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:19]>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]#[N:7])=[C:4]([S:11]([CH2:12][CH3:13])=[O:19])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1cc(Cl)cc(C)c1C#N
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCS(=O)c1cc(Cl)cc(C)c1C#N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 37 %

Procedure:
To a stirred solution of 4-chloro-2-ethylsulfanyl-6-methyl-benzonitrile (synthesized according to the method described in section a) of example 2) (1.00 g, 4.73 mmol) in dichloromethane (20 ml) is added meta-chloroperoxybenzoic acid (0.58 g, 2.36 mmol, 70% suspension) portion wise at 0° C. The resulting mixture is stirred at 0° C. for 15 min. The white suspension is dissolved in ethyl acetate (25 ml) and the solvent is distilled off. The residue is again diluted with ethyl acetate (15 ml) and washed with 10% sodium sulphite solution (3×15 ml), saturated sodium hydrogen sulfate solution (3×15 ml), brine (15 ml), dried over anhydrous sodium sulfate and evaporated to get the crude product, which is purified by column chromatography (silica gel, 8% ethyl acetate/hexane) to yield 4-chloro-2-(ethylsulfinyl)-6-methyl-benzonitrile (0.4 g, 1.76 mmol, 37%).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:12]=2)[CH:10]=1)CCC.[C:39]([NH:43][S:44]([C:47]1[S:51][C:50](Cl)=[N:49][CH:48]=1)(=[O:46])=[O:45])([CH3:42])([CH3:41])[CH3:40].[F-].[K+].O>C1(C)C=CC=CC=1>[C:39]([NH:43][S:44]([C:47]1[S:51][C:50]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[N:16]=[C:15]([C:17]([F:18])([F:20])[F:19])[CH:14]=[C:13]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][CH:22]=4)[N:12]=3)[CH:10]=2)=[N:49][CH:48]=1)(=[O:45])=[O:46])([CH3:42])([CH3:40])[CH3:41]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(-c3ccc(C(F)(F)F)cc3)cc(C(F)(F)F)n2)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1cnc(Cl)s1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)NS(=O)(=O)c1cnc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)s1

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (Example G.1) (0.265 g, 0.41 mmol), 2-chloro-thiazole-5-sulfonic acid tert-butylamide (Example H.1) (0.115 g, 0.45 mmol), tetrakis(triphenyl-phosphine)palladium (0.028 g, 0.024 mmol) in toluene (5 mL) was heated under reflux conditions for 15 h. The mixture was poured into saturated potassium fluoride solution (5 mL), water (20 mL) was added and the water layer was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (heptane/ethyl acetate) and crystallization (THF/hexane) to yield N-tert-butyl-2-{1-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiazole-5-sulfonamide (0.081) as a light brown solid. Mp 281° C.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH2:17]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[CH2:27]O)[C:22]#[N:23])[CH3:18]>>[C:22]([C:21]1[CH:24]=[CH:25][C:26]([CH2:27][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:19]([CH2:17][CH3:18])[CH:20]=1)#[N:23]
Reactant: CCc1cc(C#N)ccc1CO
Reactant: COC(=O)c1ccnc(-n2nccc2O)c1
Product: CCc1cc(C#N)ccc1COc1ccnn1-c1cc(C(=O)OC)ccn1

Procedure:
The title compound was prepared from methyl 2-(5-hydroxypyrazol-1-yl)pyridine-4-carboxylate (PREPARATION 6) and 3-ethyl-4-(hydroxymethyl)benzonitrile according to the procedure for the preparation of Example 125, part B. 1H NMR (400 MHz, CDCl3): δ 1.26 (3H, t, J=7.6 Hz), 2.73 (2H, q, J=7.6 Hz), 3.96 (3H, s), 5.28 (2H, s), 5.77 (1H, d, J=1.2 Hz), 7.53-7.67 (4H, m), 7.77 (1H, d, J=4.8 Hz), 8.31 (1H, s), 8.67 (1H, d, J=4.8 Hz). [M+H] Calc'd for C20H18N4O3, 363; Found, 363.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([NH2:18])=[C:13]([CH:17]=2)C(O)=O)[CH:6]=[CH:7][CH:8]=1.C[N:20]1CCC[C:21]1=[O:25].C(N(CC)CC)C>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]3[NH:18][C:21](=[O:25])[NH:20][C:13]=3[CH:17]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2ccc(N)c(C(=O)O)c2)c1
Reactant: CN1CCCC1=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1cccc(-c2ccc3[nH]c(=O)[nH]c3c2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 5-(3-methoxyphenyl)-2-aminobenzoic acid (2.0 g) in 1,4-dioxane (20 mL) add N-methylpyrolidinone (NMP, 5 mL) and triethylamine (1.4 mL), followed by diphenyl phosphoric azide (DPPA, 2.5 g). After stirring at ambient temperature for 30 minutes, heat the mixture to 100° C. for 2 hours, until gas evolution fully subsided. Cool the mixture to ambient temperature and concentrate in vacuo. Dissolve the residue in MeOH and leave to stand for 18 hours. Filter the precipitate and air dry to obtain 5-(3-methoxyphenyl)benzimidazolidin-2-one as a pale yellow solid. C. 2-Chloro-5-(3-methoxyphenyl)benzimidazole
Reaction SMILES: [NH:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:2]([NH2:4])=[O:3].[CH3:13][Si](C=[N+]=[N-])(C)C>CO.C1C=CC=CC=1>[NH:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:2]([NH2:4])=[O:3]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: NC(=O)NCCCCCC(=O)O
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)CCCCCNC(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6-ureidohexanoic acid (0.996 g, 5.72 mmol, 1.0 equiv) in methanol/benzene (2:7, 60 mL) was cooled to 0 degrees C., and a solution of trimethylsilyldiazomethane in hexanes (2.0 M, 3.43 mL, 6.86 mmol, 1.2 equiv) was added. The reaction mixture was warmed to room temperature and stirred for 1 h prior to removing all volatile components in vacuo. The crude methyl ester (1.06 g, 5.61 mmol, 98%) was used without further purification in the Biginelli reaction.
Reaction SMILES: [C@@H:1]12[CH2:7][NH:6][C@@H:5]1[CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2]2.[Br:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23](Br)[CH:24]=1>>[Br:18][C:19]1[CH:24]=[C:23]([N:6]2[CH2:7][C@@H:1]3[C@H:5]2[CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:2]3)[CH:22]=[N:21][CH:20]=1
Reactant: O=C(OCc1ccccc1)N1C[C@@H]2CN[C@@H]2C1
Reactant: Brc1cncc(Br)c1
Product: O=C(OCc1ccccc1)N1C[C@@H]2CN(c3cncc(Br)c3)[C@@H]2C1
Yield: 47 %

Procedure:
The product of Example 52D (230 mg, 1.0 mmol) and 3,5-dibromopyridine were processed as described in Example 1E. The crude product was purified by chromatography (SiO2, ethyl acetate, Rf 0.2) to provide the title compound (180 mg, 47% yield). 1H NMR (MeOH-d4, 300 MHz) δ 3.20 (dd, J=12.5, 4.0 Hz, 1H), 3.30 (m, 2H), 3.40 (m, 1H), 3.64 (dd, J=7.8, 3.4 Hz, 1H), 3.95-4.10 (m, 3H), 4.75 (m, 1H), 5.15 (m, 2H), 7.05 (t, J=2.1 Hz, 1H), 7.24 (m, 3H), 7.35 (m, 2H), 7.70 (d, J=2.3 Hz, 1H), 7.93 (d, J=1.7 Hz, 1H); MS (DCI/NH3) m/z 390 (M+2+H)+, 388 (M+H)+.