Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:6]([CH2:8][C:9]([NH2:11])=[S:10])[CH3:7])([O:3][CH2:4][CH3:5])=[O:2].Br[CH2:13][C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C>[C:1]([N:6]([CH2:8][C:9]1[S:10][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:11]=1)[CH3:7])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)N(C)CC(N)=S
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1csc(CN(C)C(=O)OCC)n1

Procedure:
To a solution of (N-carbethoxy-N-methylamino)thioacetamide (30.7 g; 0.17 mole) [prepared in Step B] in 180 ml of absolute ethanol was added a solution of ethyl bromopyruvate (25.0 ml; 0.20 mole) in 130 ml of absolute ethanol. The reaction mixture was heated at reflux temperature for 17 hours and then evaporated under reduced pressure, and the residue was partitioned between ether and water. The organic layer was washed with water and saturated sodium chloride solution, dried, filtered and evaporated under reduced pressure to give an oil which was placed on silica gel and chromatographed using diethyl ether as the eluting solvent. The appropriate fractions yielded the title compound as an oil; TLC [Silica/CH2Cl2 :CH3CN (85.15)] gave Rf=0.50. The NMR spectrum (60 MHz) in d6 dimethyl sulfoxide gave the following resonances δ: 8.49 (s, 1H); 4.79 (s, 2H); 4.23 (m, 4H); 3.00 (s, 3H); 1.30 (q, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6](Cl)[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[NH3:13]>C1C=CC=CC=1>[NH2:13][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([Cl:1])[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Reactant: N
Solvent: c1ccccc1
Product: CSc1nc(N)c(C=O)c(Cl)n1
Yield: 80 %

Procedure:
To the solution of 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde (2 g, 7.36 mmol) in benzene (20 mL) was introduced NH3 gas for 30 minutes (hereinafter “min”). The formed solid was then filtered and recrystallized from EtOAc (15 mL) to give 1.18 g (80%) of pure 4-amino-6-chloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 2.50 (s, 3H), 7.28 (t, 3H, J=45 Hz, D2O exchangeable), 8.65 (d, 3H, J=41 Hz, D2O exchangeable), 10.11 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N+:3]=1[O-:12].CC(C)([O-])C.[K+].[F:19][C:20]([F:26])([CH:23]([F:25])[F:24])[CH2:21][OH:22]>O>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:22][CH2:21][C:20]([F:26])([F:19])[CH:23]([F:25])[F:24])[CH:5]=[CH:4][N+:3]=1[O-:12]
Reactant: OCC(F)(F)C(F)F
Reactant: Cc1c([N+](=O)[O-])cc[n+]([O-])c1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: Cc1c(OCC(F)(F)C(F)F)cc[n+]([O-])c1C

Procedure:
In 2,2,3,3-tetrafluoropropanol (10 ml) was dissolved 2,3-dimethyl-4-nitropyridine-1-oxide (2 g). To the solution was added potassium t-butoxide (1.6 g) little by little at room temperature. The mixture was then heated at 80°-90° C. for 22 hours. The reaction solution was diluted with water, which was subjected to extraction with chloroform. The extract was dried on magnesium sulfate, and then concentrated. The concentrate was chromatographed on a column of silica gel (70 g). Elution was conducted with methanol-chloroform (1:10), and then subjected to recrystallization from ethyl acetate-hexane to yield 2.6 g of 2,3-dimethyl-4-(2,2,3,3-tetrafluoropropoxy)pyridine-1-oxide as colorless needles, m.p. 138°-139° C.
Reaction SMILES: [Cu](C#N)[C:2]#[N:3].[Cl:6][C:7]1[C:12](I)=[CH:11][N:10]=[C:9]([C:14]([N:16]2[C:24]3[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1>CN(C=O)C>[Cl:6][C:7]1[C:12]([C:2]#[N:3])=[CH:11][N:10]=[C:9]([C:14]([N:16]2[C:24]3[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: N#C[Cu]C#N
Reactant: O=C(c1cc(Cl)c(I)cn1)N1CCc2cc(F)ccc21
Solvent: CN(C)C=O
Product: N#Cc1cnc(C(=O)N2CCc3cc(F)ccc32)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere 45 mg (0.50 mmol) copper cyanide were added to 0.10 g (0.25 mmol) (4-chloro-5-iodo-pyridin-2-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone in 1.5 mL DMF and the mixture was stirred for 2 h at RT. The reaction mixture was stirred overnight at 100° C. and then mixed with d-water. The precipitate formed was suction filtered and dried.
Reaction SMILES: Br[CH:2]([C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:7])[CH2:3][CH2:4]Cl.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].[OH-].[K+]>CN(C)C=O.CO>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([C:2]2([N:19]3[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]3)[CH2:4][CH2:3]2)=[O:7])=[CH:9][CH:10]=1
Reactant: CN1CCNCC1
Reactant: O=C(c1ccc(Cl)cc1)C(Br)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CN1CCN(C2(C(=O)c3ccc(Cl)cc3)CC2)CC1
Reaction time: 3 h
Yield: 50.2 %

Procedure:
A solution of 29.6 g (0.1 mol) of 4-chlorophenyl 1-bromo-3-chloropropyl ketone in 30 ml of dimethylformamide is added dropwise to a mixture of 10.4 g of N-methyl piperazine and 14 g of potassium carbonate in 30 ml of dimethylformamide at room temperature. Stirring is continued for 3 hours, after which a solution of 9 g of potassium hydroxide in 30 ml of methanol is added dropwise. The reaction mixture is stirred for a further hour at 50° C. and evaporated down in vacuo. The residue is taken up in ethyl acetate/water, and the organic phase is separated off, washed with water, dried over sodium sulphate and evaporated down in vacuo. The residue is chromatographed over silica gel using chloroform/ethanol (97:3). 14 g (50.3% of theory) of 1-(4-chlorobenzoyl)-1-(4-methylpiperazin-1-yl)-cyclopropane are obtained as a reddish oil, which can be directly used further.
Reaction SMILES: [CH2:1]([OH:7])[CH:2]([OH:6])[CH2:3][CH2:4][OH:5].[CH3:8][C:9]([CH3:11])=O.[O-]S([O-])(=O)=O.[Mg+2].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:5][CH2:4][CH2:3][CH:2]1[CH2:1][O:7][C:9]([CH3:11])([CH3:8])[O:6]1
Reactant: OCCC(O)CO
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CO
Product: CC1(C)OCC(CCO)O1
Temperature: 25 °C
Reaction time: 120 h
Yield: 75 %

Procedure:
Butane-1,2,4-triol (5.0 g, 47 mmol) was dissolved in MeOH (5 ml). Acetone (20 ml), MgSO4 (ca. 500 mg), and para-toluene sulfonic acid (p-TsOH) (catalytic amount) were added, and the mixture was allowed to stir for 5 days at room temperature. The mixture was filtered and the filtrate concentrated under reduced pressure. Methylene chloride (CH2Cl2) (20 ml) and water (20 ml) were added, the layers were separated, and the organic layer was washed with water (2×20 ml). The organic layer was dried (MgSO4), filtered, and the filtrate concentrated under reduced pressure to afford the product as a clear oil (5.15 g, 75%): 1H NMR (CDCl3) 4.23(dt, 1H, J=6.86 Hz), 4.04(t, 1H, J=6.06 Hz), 3.72(m, 2H), 3.54(t, 1H, J=7.72 Hz), 2.55(broad s, 1H), 1.77(dt, 2H, J=6.67 Hz), 1.34(d, 6H, J=15.68 Hz)ppm; IR (neat) 3420, 2980, 2930, 2870, 1710, 1455, 1370, 1250, 1215, 1155, 1055, 855, 732 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:4]=1[C:5]([OH:7])=[S:6].[CH3:13]O.S(Cl)(Cl)=O>CCCCCC.ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:4]=1[C:5]([O:7][CH3:13])=[S:6]
Reactant: CO
Reactant: COc1ccc(C)cc1C(O)=S
Solvent: O=S(Cl)Cl
Solvent: CCCCCC
Solvent: ClCCl
Product: COC(=S)c1cc(C)ccc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Combine 2-methoxy-5-methylthiobenzoic acid (6.82 g, 34.4 mmol) and methanol (65 mL). Cool in an ice bath. Add slowly dropwise thionyl chloride (2.8 mL, 38 mmol). Warm to ambient temperature. After 18 hours, evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 25% hexane/dichloromethane to give methyl 2-methoxy-5-methylthiobenzoate: Rf=0.06 (silica gel, 65% hexane/dichloromethane).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1.C([Li])CCC.CN(C)[CH:22]=[O:23].COC(C)(C)C>C1COCC1>[CH:22]([C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1)=[O:23]
Reactant: CN(C)C=O
Reactant: CC(C)(C)C(=O)Nc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CC(C)(C)C(=O)Nc1ccc(C=O)cn1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A solution of N-(5-Bromo-pyridin-2-yl)-2,2-dimethyl-propionamide (8.7 g, Kelly, Tetrahedron Lett., 32, 1991, 4263) in THF (200 mL) was cooled to −70° C. under an argon atmosphere and treated dropwise over 30 minutes with n-butyllithium (45.78 mL, 1.6 M in hexane, Acros). The mixture was stirred 1 h at −70° C. and then treated dropwise (over 10 minutes, at −70° C.) with a mixture of N,N-dimethylformamide (5.25 mL) in THF (5 mL), and stirring was continued for further 30 minutes. The reaction mixture was then poured into 2M aqueous KHCO3 (1.2 L), tert-butyl methyl ether (1.2 L) was added, and after stirring for 20 minutes, the layers were separated, the organic layer extracted twice with tert-butyl methyl ether (total volume 0.3 L). The combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo to give N-(5-formyl-pyridin-2-yl)-2,2-dimethyl-propionamide (7 g) as an yellow oil that was used directly in the next step.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5]CC)=O.[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[NH:17][C:18]([NH:20][CH:21]([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[S:19]>ClCCl>[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[N:17]1[C:2](=[O:8])[C:3](=[O:5])[N:20]([CH:21]([CH3:26])[C:22]([CH3:24])([CH3:23])[CH3:25])[C:18]1=[S:19]
Reactant: CC(NC(=S)Nc1ccc(F)cc1F)C(C)(C)C
Reactant: CCOC(=O)C(=O)Cl
Solvent: ClCCl
Product: CC(N1C(=O)C(=O)N(c2ccc(F)cc2F)C1=S)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
Ethyl chlorooxoacetate (0.53 mL, 4.77 mmol) was added to a stirring solution of the above thiourea (1.00 g, 3.67 mmol) in dichloromethane (15 mL) and the resulting mixture was stirred overnight at room temperature. Concentration, trituration of the residue with diethyl ether, and recrystallization from boiling methanol afforded 0.75 g (62%) of 1-(2,4-difluoro-phenyl)-2-thioxo-3-(1,2,2-trimethyl-propyl)-imidazolidine-4,5-dione as a yellow solid: mp 155.2–156.0° C.; 1H NMR (DMSO-d6): δ 7.55 (m, 2H), 7.30 (m, 1H), 4.80 (m, 1H), 1.51 (d, 3H), 0.99 (s, 9H); IR (KBr): 3550, 2970, 2230, 1770 cm1; MS (m/z) 326 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([OH:23])=O)[C:9]=2[CH3:24])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:32]([NH:34][C:35]1([C:41]([NH2:43])=[O:42])[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[CH3:33].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:38]3[CH2:37][CH2:36][C:35]([NH:34][CH2:32][CH3:33])([C:41]([NH2:43])=[O:42])[CH2:40][CH2:39]3)=[O:23])[C:9]=2[CH3:24])=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CCNC1(C(N)=O)CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC1(C(N)=O)CCN(C(=O)c2nn(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)c2C)CC1
Yield: 46.7 %

Procedure:
5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carb oxylic acid (1 eq, 20 mg, 0.052 mmol), triethylamine (3 eq, 0.02 mL, 0.157 mmol), 4-(ethylamino)-4-piperidinecarboxamide (1 eq, 9 mg, 0.052 mmol), and benzotriazole-1-yl-oxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (1 eq, 23 mg, 0.052 mmol) was stirred in tetrahydrofuran (5 mL) for 16 h. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-100% CMA 80/ethyl acetate and precipitated from ethyl acetate with hexane to yield pure 1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-(ethylamino)piperidine-4-carboxamide (13 mg, 46%). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.10 (t, J=6.97 Hz, 3H) 1.61-1.80 (m, 2H) 2.08-2.26 (m, 5H) 2.45-2.63 (m, 2H) 3.68 (td, J=8.85, 4.43 Hz, 2H) 3.96-4.19 (m, 2H) 5.40 (br. s., 1H) 7.07 (d, J=8.29 Hz, 2H) 7.12-7.19 (m, 1H) 7.20-7.36 (m, 3H) 7.44 (d, J=1.98 Hz, 1H).
Reaction SMILES: [C:1]([O:4][CH2:5]I)(=[O:3])[CH3:2].[Cl:7][C:8]1[C:9]([F:48])=[C:10]([C@@H:14]2[C@:18]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[F:28])([C:19]#[N:20])[C@H:17]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:16][C@H:15]2[C:34]([NH:36][C:37]2[CH:45]=[CH:44][C:40]([C:41]([OH:43])=[O:42])=[CH:39][C:38]=2[O:46][CH3:47])=[O:35])[CH:11]=[CH:12][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:4][CH2:5][O:43][C:41](=[O:42])[C:40]1[CH:44]=[CH:45][C:37]([NH:36][C:34]([C@H:15]2[C@H:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([Cl:7])[C:9]=3[F:48])[C@:18]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[F:28])([C:19]#[N:20])[C@H:17]([CH2:29][C:30]([CH3:32])([CH3:33])[CH3:31])[NH:16]2)=[O:35])=[C:38]([O:46][CH3:47])[CH:39]=1)(=[O:3])[CH3:2]
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: CC(=O)OCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)OCOC(C)=O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reaction time: 8 h
Yield: 19.1 %

Procedure:
A portion of this iodomethyl acetate (661 mg, 3.31 mmol) was added to a suspension of chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (200.1 mg, 0.325 mmol) and cesium carbonate (964.4 mg, 2.93 mmol) in dimethylformamide (8 mL) and the reaction was stirred in the dark overnight. It was then taken up in ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash chromatography (hexane/ethyl acetate, 80/20 to 10/90) to give chiral-4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid acetoxymethyl ester as a white solid (42.8 mg, 19% yield). MS (ES+) m/z calcd. for C34H34Cl2F2N3O6: [(M+H)+]: 688, found: 688
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6](=[O:17])(=[O:16])[C:5]=2[CH:4]=[C:3]([CH:18]=O)[CH:2]=1.[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23]>C1C=CC=CC=1>[CH2:20]([N:24]=[CH:18][C:3]1[CH:2]=[CH:1][C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6](=[O:17])(=[O:16])[C:5]=2[CH:4]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCN
Reactant: O=Cc1ccc2c(c1)S(=O)(=O)c1ccccc1C=C2
Solvent: c1ccccc1
Product: CCCCN=Cc1ccc2c(c1)S(=O)(=O)c1ccccc1C=C2
Reaction time: 0.75 h

Procedure:
Reflux a mixture of 200 mg of dibenzo[b,f]thiepin-3-carboxaldehyde-5,5-dioxide (0.74 mmole) and 82 mg of n-butylamine (1.11 mmole) in 0.30 ml of benzene, with azetropic removal of water, for 45 minutes. Evaporate the mixture to remove the benzene and excess butylamine and obtain the title product as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=3)=[N:11][C:10]=2[C:23]([O:25]CC)=[O:24])=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=3)=[N:11][C:10]=2[C:23]([OH:25])=[O:24])=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1nc(-c2cccc([N+](=O)[O-])c2)[nH]c1-c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2[nH]c(-c3cccc([N+](=O)[O-])c3)nc2C(=O)O)cc1
Yield: 77.3 %

Procedure:
Ethyl 5-(4-methoxyphenyl)-2-(3-nitrophenyl)imidazole-4-carboxylate (13.3 g), ethyl alcohol (266 ml) and 1M aqueous sodium hydroxide solution (127 ml) were reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 5-(4-methoxyphenyl)-2-(3-nitrophenyl)imidazole-4-carboxyic acid (9.5 g), melting point 234-235° C.
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([F:31])=[C:16]2[C:21]=1[NH:20][CH:19]=[C:18]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:17]2=[O:30])C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[F:31][C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][OH:8])=[C:21]2[C:16]=1[C:17](=[O:30])[C:18]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)=[CH:19][NH:20]2
Reactant: COc1ccc(-c2c[nH]c3c(OCCOCc4ccccc4)ccc(F)c3c2=O)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2c[nH]c3c(OCCO)ccc(F)c3c2=O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 105.3 %

Procedure:
20% palladium hydroxide/carbon (5.0 g) was added to an ethanol solution (50 ml) of 8-(2-benzyloxyethoxy)-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin-4-one (6.3 g, 15.0 mmol), followed by hydrogen substitution. The mixture was stirred at room temperature for 4 hours. After completion of the reaction, the catalyst was removed and the mixture was concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane:methanol=100:0→20:1). The purified material was concentrated to dryness under reduced pressure, giving a pale yellow powder of 5-fluoro-8-(2-hydroxyethoxy)-3-(4-methoxyphenyl)-1H-quinolin-4-one (5.2 g, yield: 99%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4](Cl)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:20])([CH3:19])[O:13][SiH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:8][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][SH:38])=[CH:32][CH:31]=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:22])[CH:4]([S:38][CH2:37][CH2:36][C:33]1[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:20])([CH3:19])[O:13][SiH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:8][CH:7]=1
Reactant: COC(=O)C(Cl)Cc1ccc(C(C)(C)O[SiH2]C(C)(C)C)cc1
Reactant: Fc1ccc(CCS)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(C(C)(C)O[SiH2]C(C)(C)C)cc1)SCCc1ccc(F)cc1
Reaction time: 18 h

Procedure:
To a solution of 3-[4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-2-chloro-propionic acid methyl ester (6.56 g, 42 mmol) in anhydrous DMF (200 mL) was added Cs2CO3 (14.34 g, 44 mmol) at 0° C. After stirring for 30 min 2-(4-fluoro-phenyl)-ethanethiol (13.72 g, 40 mmol), dissolved in anhydrous DMF (100 mL), was added dropwise and the resulting organe mixture was stirred for 18 h without removing the cooling bath. The mixture was diluted with Et2O and extracted with three times with H2O. The organic phase was concentrated under reduced pressure and the residue was dissolved in Et2O again and repeatedly extracted with H2O. After drying the separated organic layer over MgSO4, the solvent was removed under reduced pressure to afford the crude product as an orange oil which was purified by chromatography using n-heptane/EtOAc 20:1 as the eluent. The desired product was obtained as an oil (4.93 g, 25.4%). 1H NMR (400 MHz, CDCl3): δ 7.16 (d, 2H), 7.06-6.99 (m, 4H), 6.88 (t, 2H), 4.62 (s, 2H), 3.58 (s, 3H), 3.41 (dd, 1H), 3.10 (dd, 1H), 2.82 (dd, 1H), 2.74-2.76 (m, 4H), 0.85 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:20]=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].[OH-].[Na+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:20]([C:21](=[O:23])[CH3:22])=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:18])([F:17])[F:19])=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Fc1ccc(-c2cc3ccc(C(F)(F)F)cn3n2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)c1c(-c2ccc(F)cc2)nn2cc(C(F)(F)F)ccc12
Temperature: 25 °C

Procedure:
To a mixture of 2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridine (10.30 g, 36.76 mmol) and acetic anhydride (100 mL) was added conc. sulfuric acid (10 drops) and the mixture was stirred and heated at reflux for 1 hour. The reaction mixture was cooled to room temperature and poured into ice water (300 mL). 2N Aqueous sodium hydroxide solution was added to raise the pH of the solution to about 10 and the resulting orange precipitate was collected by filtration. The solid was washed with water, air-dried, and then dried under vacuum to afford the title compound as an orange solid, 11.87 g (quant.). 1H NMR (DMSO-d6): δ 9.58 (s, 1H), 8.41 (d, 1H. J=9.3 Hz), 7.89 (d, 1H, J=9.5 Hz), 7.74 (m, 2H), 7.39 (m, 2H), 2.22 (s, 3H). MS (ES) 323 (M+1).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([O:16][CH:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)=[CH:15][C:9]=2[C:8]2[N:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.O1CCOCC1.Cl>O1CCOCC1>[NH:20]1[CH2:19][CH2:18][CH:17]([O:16][C:14]2[CH:13]=[CH:12][C:10]3[NH:11][C:2](=[O:1])[C:3]4[CH:4]=[CH:5][CH:6]=[N:7][C:8]=4[C:9]=3[CH:15]=2)[CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3[nH]c(=O)c4cccnc4c3c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]c2ccc(OC3CCNCC3)cc2c2ncccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.8 %

Procedure:
The compound (110 mg, 0.28 mmol) prepared in step 3 was dissolved in 1,4-dioxane, added with 3.7 N hydrochloric acid 1,4-dioxane solution. The resulting mixture was stirred overnight at room temperature and the precipitate was collected by filtration to obtain the title compound (90 mg, yield: 98%, yellow solid).
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C@:12]([C:21]3[CH:26]=[C:25]([O:27][C:28]([F:33])([F:32])[CH:29]([F:31])[F:30])[CH:24]=[C:23]([F:34])[CH:22]=3)([NH2:20])[CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=[CH:9][C:10]=2[F:11])[CH2:3][CH2:2]1.[CH3:35][C:36]1[O:37][C:38]([C:44]([F:47])([F:46])[F:45])=[C:39]([C:41](O)=[O:42])[N:40]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C@@:12]([NH:20][C:41]([C:39]3[N:40]=[C:36]([CH3:35])[O:37][C:38]=3[C:44]([F:47])([F:45])[F:46])=[O:42])([C:21]3[CH:26]=[C:25]([O:27][C:28]([F:33])([F:32])[CH:29]([F:31])[F:30])[CH:24]=[C:23]([F:34])[CH:22]=3)[CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=[CH:9][C:10]=2[F:11])[CH2:2][CH2:3]1
Reactant: Cc1nc(C(=O)O)c(C(F)(F)F)o1
Reactant: N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(OC2CC2)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(C(=O)N[C@@](Cc2ccccc2)(c2cc(F)cc(OC(F)(F)C(F)F)c2)c2ccc(F)c(OC3CC3)c2)c(C(F)(F)F)o1
Temperature: 25 °C
Reaction time: 72 h
Yield: 70 %

Procedure:
To a solution of (R)-1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamine, prepared as described in Procedure 109, 110, 111, 112, 113, 114, 161, (24 mg, 0.05 mmol) in CH2Cl2 (0.5 mL) was added 2-methyl-5-(trifluoromethyl)-oxazole-4-carboxylic acid (12 mg, 0.06 mmol), followed by PyBrOP (28 mg, 0.06 mmol) and iPr2NEt (9 mg, 0.065 mmol). The reaction mixture was stirred at rt for 72 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by prep HPLC (Phenomenex Luna 5μ 30×100 mm, eluting with 10%-90% MeOH/H2O containing 0.1% TFA, gradient time 10 min, flow rate 40 mL/min) to yield (R)—N-(1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methyl-5-(trifluoromethyl)oxazole-4-carboxamide (Example 347) as a white solid (23 mg, 70% yield). HPLC: RT=2.18 min [M+H] 659.5 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); 1H NMR (400 MHz, CDCl3) δ ppm 7.79, s, 1H, 7.10-7.20, m, 3H, 6.90-7.03, m, 5H, 6.70, s, 1H, 6.68, s, 1H, 6.55-6.58, m, 1H, 5.74-6.00, t, J=52; 4.15, 4.19, d, J=16, 1H, 3.66-3.69, d, J=12, 1H, 3.51-3.54, m, 1H, 0.73-0.80, m, 1H, 0.61-0.69, m, 2H, 0.55-0.60, m, 1H.