Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S([O-])(O[O-])(=O)=[O:2].[K+].[K+].[NH2:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([S:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)=[CH:17][N:16]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:12]=2[N:13]=[CH:14][N:15]=1.[OH2:36]>CO.C(O)(=O)C>[C:32]([N:16]1[C:12]2[N:13]=[CH:14][N:15]=[C:10]([NH2:9])[C:11]=2[C:18]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:2])=[O:36])=[CH:23][CH:24]=2)=[CH:17]1)([CH3:35])([CH3:34])[CH3:33]
Reactant: O=S(=O)([O-])O[O-]
Reactant: CC(C)(C)n1cc(-c2ccc(Sc3ccccc3)cc2)c2c(N)ncnc21
Reactant: O
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)n1cc(-c2ccc(S(=O)(=O)c3ccccc3)cc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of potassium peroxymonosulphate (4.93g) in water (10 ml) was added dropwise with stirring to a solution of 4-amino-5-[4-(phenylthio)phenyl]-7-(tert-butyl)pyrrolo[2,3-d]pyrimidine (1.0 g) in methanol (5 ml) and glacial acetic acid (5 ml) keeping the temperature below 5° C. The mixture was then stirred at ambient temperature for 3 hours and then diluted with water (50 ml). The mixture was extracted with ethyl acetate to give a solid which was purified by flash column chromatography on silica using ethyl acetate/triethylamine (9:1) as the mobile phase. Appropriate fractions were combined and concentrated to give a solid which was triturated with petroleum ether, boiling point 60-80° C. to give 7-tert-butyl-5-(4-phenylsulphonylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine, m.p. 222-224° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH2:6]([Li])[CH2:7][CH2:8]C.[CH2:11]([Si:14](Cl)(C)[CH3:15])C=C.[NH4+].[Cl-]>C1COCC1>[CH2:6]([C:2]1[S:1][CH:5]=[CH:4][C:3]=1[SiH:14]([CH3:15])[CH3:11])[CH:7]=[CH2:8]
Reactant: C=CC[Si](C)(C)Cl
Reactant: [Li]CCCC
Reactant: c1ccsc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCc1sccc1[SiH](C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
To a solution of thiophene (8.4 g, 0.1 mol) in dried THF (300 mL) at −78° C. was added n-butyllithium (40 mL, 2.5 M solution in hexanes, 0.1 mol) over a period of 5 min. After 30 min of further stirring at −78° C., allylchlorodimethylsilane (13.5 g, 0.1 mol) was added dropwise over a period of 20 min, and the reaction mixture was warmed to room temperature. After 1 h of further stirring at room temperature, concentrated NH4Cl (3 mL) was added, and the reaction mixture was concentrated. Kugelrohr distillation of the crude oil under reduced pressure afforded a colorless oil (16.7 g, 92%); 1H NMR (300 MHz, CDCl3) δ 0.39 (s, 6 H), 1.84 (dd, J=8.10, 1.20 Hz, 2 H), 4.92 (s, 1 H), 4.97 (m, 1 H), 5.85 (m, 1 H), 7.24 (m, 1 H), 7.33 (dd, J=3.30, 1.50 Hz, 1 H), 7.65 (dd, J=5.70, 1.20 Hz, 1 H); 13C NMR (75M Hz, CDCl3) −2.0 (2C), 24.8, 114.2, 128.4, 131.0, 134.4, 134.8, 138.3; HRMS (EI) calcd for C9H15SSi 182.0585, found 182.0583.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].C(C1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([C:19]2[N:20]=[CH:21][C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=1)(O)=O>ClCCl>[ClH:4].[Cl:4][C:2]([C:1]1[C:14]2[C:13](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:12]([C:19]2[N:20]=[CH:21][C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=1)=[O:3]
Reactant: O=C(O)c1cn(-c2cc3ccccc3cn2)c2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cl
Product: O=C(Cl)c1cn(-c2cc3ccccc3cn2)c2ccccc12
Temperature: 22 °C
Reaction time: 15 h
Yield: 79.4 %

Procedure:
0.7 cm3 (8 mmol) of oxalyl chloride is added to a suspension, cooled to a temperature in the region of 5° C., of 0.74 g (2.57 mmol) of 3-carboxy-1-(isoquinol-3-yl)-1H-indole in 15 cm3 of dichloromethane under an argon atmosphere. After stirring at a temperature in the region of 22° C. for 15 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue, dissolved in 15 cm3 of dichloromethane, is again reacted with 1 cm3 (11.46 mmol) of oxalyl chloride. After stirring at a temperature in the region of 22° C. for 48 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give 0.7 g of 3-chlorocarbonyl-1-(isoquinol-3-yl)-1H-indole hydrochloride in the form of a yellow solid which is used directly in the following step.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.C([N:12](CC)CC)C.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>ClCCl>[NH2:12][C:5]1[C:4]2[CH:3]=[CH:2][N:1]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[C:9]=2[CH:8]=[CH:7][N:6]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCN(CC)CC
Reactant: c1cc2[nH]ccc2cn1
Solvent: ClCCl
Product: Nc1nccc2c1ccn2C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a stirred solution of 1H-pyrrolo[3,2-c]pyridine (500 mg, 4.2 mmol) in dichloromethane (6 mL), triethylamine (1.2 mL, 8.4 mmol) was added. The mixture was cooled to 0° C. and benzyl chloroformate (1.6 mL, 50% solution in dichloromethane, 4.6 mmol) was added drop wise. After complete addition, the reaction mixture was stirred at room temperature for about 1 hour. On completion, the reaction was quenched by addition of saturated aqueous sodium bicarbonate solution and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford benzyl 4-amino-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (1 g, 100%) as viscous liquid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][O:11][C@H:10]([CH2:15][NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[C:25](F)[CH:24]=2)[N:3]=1.O.[NH2:33][NH2:34]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][O:11][C@H:10]([CH2:15][NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]2)[CH:5]=[C:4]([C:23]2[CH:24]=[C:25]3[C:26]([C:29]([NH2:30])=[N:33][NH:34]3)=[CH:27][CH:28]=2)[N:3]=1
Reactant: NN
Reactant: C[C@@H]1CO[C@H](CNC(=O)C(C)(C)C)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Solvent: O
Solvent: CCO
Product: C[C@@H]1CO[C@H](CNC(=O)C(C)(C)C)CN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 100 °C
Reaction time: 17 h
Yield: 63.7 %

Procedure:
A mixture of crude N-({(2R,5R)-4-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-5-methyl-2-morpholinyl}methyl)-2,2-dimethylpropanamide (0.29 mmol theoretical) and hydrazine monohydrate (0.28 mL, 5.78 mmol) in ethanol (3 mL) was stirred at 100° C. in a sealed tube for 17 hours. The mixture was concentrated in vacuo and the residue was purified on a Gilson reverse phase HPLC (CH3CN/water with 0.1% TFA). The product fractions were combined and concentrated in vacuo, taken up in EtOAc (15 mL), washed with saturated aqueous NaHCO3 (2×10 mL) and brine (10 mL), then dried (Na2SO4), filtered, and concentrated in vacuo to afford the title compound (81 mg) as a pale yellow solid. LC-MS (ES) m/z=439 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.13 (s, 9H), 1.17 (d, J=6.6 Hz, 3H), 2.64-2.84 (m, 1H), 3.20-3.30 (m, 2H), 3.42-3.52 (m, 1H), 3.63 (dd, J=11.4, 2.5 Hz, 1H), 3.77 (d, J=11.1 Hz, 1H), 3.98-4.79 (bs, 2H), 5.39 (s, 2H), 6.12 (s, 2H), 6.50 (s, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.63 (t, J=5.7 Hz, 1H), 7.71 (d, J=8.3 Hz, 1H), 7.93 (s, 1H), 11.53 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:25])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].Br[C:33]([CH3:39])([CH3:38])[C:34](C#N)=[O:35]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:25][C:33]([CH3:39])([CH3:38])[C:34](=[O:35])[C:16]=2[C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CC(=O)c2ccc(OCc3ccccc3)cc2)cc1
Reactant: CC(C)(Br)C(=O)C#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(C2=C(c3ccc(OCc4ccccc4)cc3)OC(C)(C)C2=O)cc1
Reaction time: 0.5 h
Yield: 4.1 %

Procedure:
To a pre-cooled 0° C. solution of 1-(4-(benzyloxy)phenyl)-2-(4-methoxyphenyl)-ethanone (2 g, 6.02 mmol) in THF (20 mL) under an inert atmosphere was added t-BuOK (8 mL, 1.0 N solution in THF). The mixture was then stirred for 30 minutes. 2-Bromo-2-methylpropanoyl cyanide (2 g, 12 mmol) was then added to then reaction mixture and stirring was continued for an additional 16 h. The reaction mixture was then quenched with cold water (10 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), and then dried over Na2SO4 concentrated and purified via silica gel column chromatography (10-15% Ethyl acetate in hexanes) to afford 5-(4-(benzyloxy)phenyl)-4-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (100 mg) as a white solid.
Reaction SMILES: [OH-].[K+].[I-].[CH3:4][S+](C)(C)=O.[F:9][C:10]([F:15])([F:14])[C:11](=[O:13])[CH3:12].[C:16]1([S:22]([C:25]2[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O.ClCCl>[F:9][C:10]([F:15])([F:14])[C:11]([CH3:4])([OH:13])[CH2:12][S:31][C:28]1[CH:27]=[CH:26][C:25]([S:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:24])=[O:23])=[CH:30][CH:29]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(S)cc1
Reactant: CC(=O)C(F)(F)F
Reactant: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(O)(CSc1ccc(S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
Potassium hydroxide (0.129 g, 2.3 mmol) in water (2 mL) was added dropwise to a stirred suspension of trimethylsulfoxonium iodide (0.476 g, 2.2 mmol), trifluoroacetone (0.258 g, 2.3 mmol) in dichloromethane (5 mL) under nitrogen at 0° C. The mixture was stirred for 0.5 hours and was then refluxed for a further 0.5 hour. After cooling to room temperature a solution of 4-(phenylsulfonyl)thiophenol (0.5 g, 2 mmol), potassium hydroxide (0.112 g, 2 mmol), and water (5 mL) was added in one portion and the mixture was stirred for 2 hours. The reaction mixture was diluted with dichloromethane, washed (saturated aqueous ammonium chloride solution, water, brine), and dried (Na2SO4). Evaporation gave an oil that crystallized from ether/ethyl acetate/hexane to give a white solid. The filtrate was evaporated to give a solid which was recrystallized from ether/hexane to give the title compound (0.24 g); mp 100°-102° C.; NMR: 1.35 (s,3 , CH3), 3.35 (m,2, SCH2), 6.41 (s,1, OH), 7.57 (d,2, J=9, Ar), 7.67 (m,3, Ar), 7.83 (d,2, J=8.7, Ar), 7.94 (d,2, J=6.9, Ar). MS: m/z=377 (M+1). Analysis for C16H15F3O3S2 : Calculated: C, 51.06; H, 4.02; Found: C, 51.50: H, 3.94.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[O:13][CH2:14][C:15](=O)[CH3:16].[C-:23]#[N:24].[Na+].[NH3:26]>C(O)C>[NH2:26][C:15]([C:23]#[N:24])([CH3:16])[CH2:14][O:13][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:5]=1[O:4][C:3]1[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:2]=1[Cl:1])[C:9]#[N:10]
Reactant: CC(=O)COc1cc(C#N)ccc1Oc1ccc(Cl)cc1Cl
Reactant: N
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: CC(N)(C#N)COc1cc(C#N)ccc1Oc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
20.2 g of 4-(2,4-dichlorophenoxy)-3-(2-oxopropoxy)-benzonitrile and 4.4 g of sodium cyanide are suspended in 300 ml of a 2M solution of ammonia in ethanol and stirred overnight at room temperature, then filtered and concentrated under vacuum. The residue is dissolved in ethylacetate and washed with water and brine. The organic phase is dried over magnesium sulfate and evaporated under vacuum and the residue recrystallized from ether to yield 3-(2-amino-2-cyano-1-propoxy)-4-(2,4-dichlorophenoxy)-benzonitrile.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5](=[O:15])[C:4]1([F:17])[F:16].N12CCCN=C1CCCCC2>O1CCCC1>[F:17][C:4]1([F:16])[C:3](=[CH2:2])[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[C:5]1=[O:15]
Reactant: CC(C)(C)OC(=O)N1CC(CBr)C(F)(F)C1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: C=C1CN(C(=O)OC(C)(C)C)C(=O)C1(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
To a solution of tert-butyl 4-(bromomethyl)-3,3-difluoro-2-oxopyrrolidine-1-carboxylate (50.1 g) in tetrahydrofuran (400 mL) was added dropwise 1,8-diazabicyclo[5.4.0]undec-7-ene (25.0 mL) at 0° C. over 15 min. After the completion of the dropwise addition, the mixture was stirred at room temperature for 1 hr. Insoluble materials were filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=4:1). The obtained crystals were washed with diisopropyl ether to give the title compound as colorless crystals (yield 28.1 g, 76%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[O:5][C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[C:8]=1[CH3:9].[O:14]=[C:15]1[CH2:20][O:19][C:18]2[CH:21]=[C:22]([CH:25]=[CH:26][C:27](O)=[O:28])[CH:23]=[N:24][C:17]=2[NH:16]1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH3:1][N:2]([CH2:3][C:4]1[O:5][C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[C:8]=1[CH3:9])[C:27](=[O:28])/[CH:26]=[CH:25]/[C:22]1[CH:23]=[N:24][C:17]2[NH:16][C:15](=[O:14])[CH2:20][O:19][C:18]=2[CH:21]=1
Reactant: CNCc1oc2ccccc2c1C
Reactant: O=C(O)C=Cc1cnc2c(c1)OCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)OCC(=O)N3)oc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
To a solution of methyl-(3-methyl-benzofuran-2-ylmethyl)-amine (152 mg, 0.87 mmol) in DMF (5 mL) were added in sequential order 3-(3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-acrylic acid (175 mg, 0.79 mmol), 1-hydroxybenzotriazole (121 mg, 0.87 mmol), diisopropylethylamine (412 uL, 2.37 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (174 mg, 0.87 mmol). The mixture was stirred at room temperature overnight, cooled in an ice bath and treated with water under rapid stirring. The precipitated product was filtered and dried, triturated with diethyl ether to yield the title compound (150 mg, 50%) as a light brown solid and as a mixtures of amide rotamers. 1H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 8.19 (s, 1H), 7.89 (s, 1H), 7.5-7.59 (m, 3H), 7.24-7.32 (m, 3H), 4.8-5.02 (m, 2H), 4.70 (s, 2H), 2.95-3.19 (m, 3H), 2.28 (s, 3H); MS (ESI) m/e 378 (C21H19N3O4+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]=[CH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH3:2].[CH3:18][CH:19]([N+:30]#[C-:31])S(C1C=CC(C)=CC=1)(=O)=O.CC(C)([O-])C.[K+].O>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]1[C:6]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)=[C:19]([CH3:18])[NH:30][CH:31]=1)=[O:17])[CH3:2]
Reactant: CCOC(=O)C=Cc1cccc2ccccc12
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c[nH]c(C)c1-c1cccc2ccccc12
Yield: 66 %

Procedure:
4.3 g(18.9 mmol) of 3-(naphthalen-1-yl)-acrylic acid ethylester prepared in Preparation 6-1) and 3.95 g(18.9 mmol) of α -methyltosylmethylisocyanide disclosed in A. M. van Leusen, et al., Tetrahedron Letter, 1975, 40, 3487 were dissoved in 100 ml of tetrahydrofuran. 2.55 g(22.7 mmol) of potassium t-butoxide dissolved in 100 ml of tetrahydrofuran was slowly added thereto, which was then refluxed for 30 minutes. To the reaction solution was added 100 ml of water to stop the reaction and the solvent was removed under reduced pressure. The residue was extracted with diethylether, washed with saturated sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was subjected to silica gel column chromatography using a solvent mixture of ethyl acetate/n-hexane(1/3, v/v) as an eluent to give 3.50 g(12.5 mmol, Yield 66%) of the title compound.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH:12][C:13]([CH:15]3[CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=4[CH3:27])[C:18]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[F:37])([C:28]#[N:29])[CH:17]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:16]3)=[O:14])[CH:9]=[CH:10][CH:11]=2)=[N:4][N:3]=[N:2]1.[C:43](=O)(O)[O-].[Na+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:43][N:4]1[C:5]([C:6]2[CH:7]=[C:8]([NH:12][C:13]([CH:15]3[CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=4[CH3:27])[C:18]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[F:37])([C:28]#[N:29])[CH:17]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:16]3)=[O:14])[CH:9]=[CH:10][CH:11]=2)=[N:1][N:2]=[N:3]1
Reactant: Cc1c(Cl)cccc1C1C(C(=O)Nc2cccc(-c3nnn[nH]3)c2)NC(CC(C)(C)C)C1(C#N)c1ccc(Cl)cc1F
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: Cc1c(Cl)cccc1C1C(C(=O)Nc2cccc(-c3nnnn3C)c2)NC(CC(C)(C)C)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 11.2 %

Procedure:
To a stirred solution of rac (2R,3R,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-(1H-tetrazol-5-yl)-phenyl]-amide (44 mg, 0.172 mmol) in acetone (5 mL), sodium bicarbonate (84 mg, 1 mmol) and dimethyl sulfate (30 uL, 0.22 mmol) was added and the mixture was stirred at rt for 5 hrs. The solvent was removed and the residue was suspended in 3 mL of methylene chloride. The mixture was filtered and the filtrate was loaded on a silica gel column. Eluting with 35-70% EtOAc/Hexanes on an ISCO machine gave the desired product (12 mg) and the other regioisomer (26 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][Mg]Br.CCOCC>C1COCC1.CN1C(=O)CCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH3:10])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: Cc1nc(Cl)ncc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a solution of 2,4-dichloro-5-fluoropyrimidine (1.02 g, 6.08 mmol) in THF/NMP (38 mL/3 mL) was added Fe(acac)3 (215 mg, 0.61 mmol) and the mixture was cooled to 0° C. 3.0 M methylmagnesium bromide in Et2O (3.04 mL, 9.12 mmol) was added dropwise. After 30 min at 0° C., the reaction was complete and quenched with saturated aqueous NH4Cl solution. Et2O was added and the layers were separated and the aqueous layer was further extracted with several portions of Et2O. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. Chromatography (Hexanes to 10% EtOAc/Hexanes) gave the desired product as a waxy white solid (430 mg, 48%). 1H NMR (400 MHz, CDCl3): 8.35 (s, 1H), 2.55 (d, J=2.5 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[C:27]([CH2:29][O:30][C:31]2[C:35](/[CH:36]=[CH:37]/[C:38]3[N:39]=[C:40]([N:44]4[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]4)[S:41][C:42]=3[CH3:43])=[CH:34][N:33]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[N:32]=2)[CH:26]=[CH:25][C:4]=1[O:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]CC)=[O:21])=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH3:1][O:2][C:3]1[CH:28]=[C:27]([CH2:29][O:30][C:31]2[C:35](/[CH:36]=[CH:37]/[C:38]3[N:39]=[C:40]([N:44]4[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]4)[S:41][C:42]=3[CH3:43])=[CH:34][N:33]([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[N:32]=2)[CH:26]=[CH:25][C:4]=1[O:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4nc(N5CCCCC5)sc4C)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/c2nc(N3CCCCC3)sc2C)ccc1OCc1nc(-c2ccc(CC(=O)O)cc2)oc1C
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 57.7 %

Procedure:
To a mixture of ethyl [4-{4-[(2-methoxy-4-{[(4-{(E)-2-[5-methyl-2-(piperidin-1-yl)-1,3-thiazol-4-yl]ethenyl}-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}phenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl]acetate (0.36 g), tetrahydrofuran (9 mL) and ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at 50° C. for 1.5 hrs. To the reaction mixture were added 1N hydrochloric acid (1 mL) and water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give [4-{4-[(2-methoxy-4-{[(4-{(E)-2-[5-methyl-2-(piperidin-1-yl)-1,3-thiazol-4-yl]ethenyl}-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}phenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl]acetic acid as crystals (0.20 g, yield 58%). Recrystallization from ethyl acetate-hexane gave brown prism crystals. melting point: 146-148° C.
Reaction SMILES: FC(F)(F)C([NH:5][C@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]1[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=O.[OH-].[Na+]>CCO.O>[NH2:5][C@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]1[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1NC(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the mixture of cis-tert-butyl 2-(2,2,2-trifluoroacetamido)cyclohexylcarbamate in EtOH from Step B, was added a solution of NaOH (500.0 g of a 50 wt % solution in water, 1.42 eq) in water (1.0 L) portion wise over a period of 15 minutes, while maintaining a reaction temperature <15° C. Once the addition was complete, the reaction temperature was allowed to rise to room temperature, and the reaction mixture was stirred at RT overnight (16 hours). The batch (6 L) was distilled under reduced pressure (˜200 mBar) to a volume of ˜3.4 L. Water (2.0 L) was added and the distillation was continued (at ˜200 mBar) until the volume of the mixture was about 4.0 L and the solution had turned milky in appearance. The batch was cooled to 25° C., diluted with IPAc (3.5 L) and stirred for 10 minutes. Following phase separation, the aqueous phase was extracted with IPAc (1.5 L) and the phases separated. The combined organic extracts were washed with water (1.5 L) and then with an aqueous solution of NaCl (5 wt %, 1.5 L). The organic phase (5.8 L) was distilled under reduced pressure (˜200 mBar) until the volume of the mixture was ˜2.0 L. This afforded the title compound as a crude racemic product in IPAc, which was carried forward into the next step. Proton NMR analysis showed the presence of EtOH (2.3 mole %) and KF analysis indicated the presence of water (0.58%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20]C)=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.I[Si](C)(C)C.Br.Br.[CH:29]12[CH2:35][CH:32]([NH:33][CH2:34]1)[CH2:31][NH:30]2.C(#N)C>ClCCl>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:30]4[CH2:31][CH:32]5[CH2:35][CH:29]4[CH2:34][NH:33]5)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C1NC2CNC1C2
Reactant: COC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Br
Agent: C[Si](C)(C)I
Solvent: ClCCl
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC4CC3CN4)c(F)cc2c1=O
Temperature: 25 °C
Yield: 92 %

Procedure:
To a solution of 1.0 g (3.4 mmole) of methyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate in 25 ml dichloromethane was added 0.6 ml (0.8 g, 4.2 mmole) of iodotrimethylsilane while stirring at room temperature under a blanket of nitrogen. The reaction was warmed to reflux and stirred overnight. An additional 0.23 ml (1.6 mmole) of iodotrimethylsilane was added and the solution was refluxed for another two hours, cooled to room temperature, and concentrated. The residue was taken up in 20 ml of acetonitrile. To this solution was added a mixture of 2.2 g (8.5 mmole) of 2,5-diazabicyclo[2.2.1]heptane, dihydrobromide, 2.7 g (17.9 mmole) 1,8-diazobicyclo[5.4.0]undec-7-ene and 20 ml acetonitrile. The reaction was refluxed for 2.5 hours then cooled to room temperature. The formed precipitate was filtered, washed with acetonitrile and ethyl ether, yielding 1.13 g (92%) of the title compound, mp 288°-290° C.