Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][OH:10].[H-].[Na+].[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][N:22]=[C:21]2I)=[CH:16][CH:15]=1.O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][O:10][C:21]1[N:20]([C:17]2[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=2)[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][N:22]=1
Reactant: OCc1c(F)cccc1Cl
Reactant: CCOC(=O)c1cnc(I)n1-c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cnc(OCc2c(F)cccc2Cl)n1-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a solution of (2-chloro-6-fluorophenyl)methanol (160.5 mg, 0.99 mmol) in THF (8 mL) was added sodium hydride (40 mg, 0.99 mmol) and the reaction was stirred at room temperature. After 25 minutes ethyl 1-(4-fluorophenyl)-2-iodo-1H-imidazole-5-carboxylate (38) (300 mg, 0.83 mmol) was added and the reaction was refluxed overnight. Water was added slowly and the solution was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford ethyl 2-((2-chloro-6-fluorobenzyl)oxy)-1-(4-fluorophenyl)-1H-imidazole-5-carboxylate (39).
Reaction SMILES: [C:1](O)(=O)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[OH:17][NH:18][C:19]([C:21]1[C:22]2[CH:23]=[CH:24][C:25]([NH:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])=[N:26][C:27]=2[CH:28]=[CH:29][CH:30]=1)=[NH:20]>C1COCC1>[CH3:40][O:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[CH2:32][NH:31][C:25]1[CH:24]=[CH:23][C:22]2[C:27](=[CH:28][CH:29]=[CH:30][C:21]=2[C:19]2[N:20]=[C:1]([CH3:2])[O:17][N:18]=2)[N:26]=1
Reactant: COc1ccccc1CNc1ccc2c(C(=N)NO)cccc2n1
Reactant: CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccccc1CNc1ccc2c(-c3noc(C)n3)cccc2n1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 50.3 %

Procedure:
To a stirred solution of acetic acid (48 mg, 0.8 mmol) in THF (7.5 ml) was added at room temperature 1,1′-carbonyl-diimidazole (151 mg, 0.93 mmol). The mixture was allowed to stir for 15 min at room temperature and for 90 min at 70° C., cooled to room temperature and N-hydroxy-2-(2-methoxy-benzylamino)-quinoline-5-carboxamidine (200 mg, 0.62 mmol) was added. The reaction mixture was allowed to stir at room temperature for 30 min, evaporated to dryness and diluted with acetic acid (7.5 ml). The reaction mixture was allowed to stir for 2 h at 100° C., evaporated, poured into saturated NaHCO3 solution (20 ml) and extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel and crystallization (dichloromethane/hexane) to yield the title compound as white solid (108 mg, 50%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][CH:12]3[NH:17][CH:16]([C:5]2=1)[CH2:15][CH2:14][CH2:13]3.[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)#[CH:19]>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](/[CH:19]=[CH:18]\[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=1)[C:6]1[CH2:11][CH:12]3[NH:17][CH:16]([C:5]2=1)[CH2:15][CH2:14][CH2:13]3
Reactant: C#Cc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCC(C3)N1
Product: Cc1ccc2c(c1)c1c(n2/C=C\c2cccc(C(F)(F)F)c2)CC2CCCC1N2

Procedure:
The coupling of 2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (1132 mg, 5.0 mmol; Example 118A) and 1-ethynyl-3-(trifluoromethyl)benzene (1701 mg, 10.0 mmol; Aldrich) was performed according to the procedure described in Example 20 to afford the title compound as the minor isomeric product: 1H NMR (300 MHz, methanol-d4) δ ppm 1.26-1.44 (m, J=27, 14, 4, 4 Hz, 1H), 1.46-1.58 (m, 1H), 1.67 (dd, J=15, 2 Hz, 1H), 1.86-2.18 (m, 3H), 2.40 (s, 3H), 2.68 (d, J=18 Hz, 1H), 3.24-3.31 (m, 1H), 4.01 (t, J=6 Hz, 1H), 5.04 (t, J=3 Hz, 1H), 6.84 (d, J=9 Hz, 1H), 6.92-7.03 (m, 3H), 7.18-7.24 (m, 2H), 7.29-7.39 (m, 2H), 7.44-7.50 (m, 1H); MS (DCI/NH3) m/z 397 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])=[O:8])[CH:2]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]([C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:8])[C:10]1=[O:18])(=[O:21])[CH3:20]
Reactant: O=C1Nc2ccccc2C1C(=O)c1cccnc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1C(=O)C(C(=O)c2cccnc2)c2ccccc21
Temperature: 25 °C

Procedure:
A mixture of 476 mg (2.0 mmole) of 3-(3-pyridylcarbonyl)-2-oxindole and 4 ml of acetic anhydride was heated under reflux for 30 minutes. The reaction mixture was cooled to room temperature, the bulk of the acetic anhydride was removed by evaporation in vacuo and the residue was triturated under 15 ml of water. The solid was recovered by filtration, dried and triturated under isopropanol. The residue (158 mg) was recrystallized from acetonitrile giving 64 mg of the title compound as red-orange crystals, m.p. 142.5°-143.5° C. A second crop of title compound (40 mg) was obtained from the mother liquors from the recrystallization. The two crops were the same by thin-layer chromatography. The first crop was subjected to elemental analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C1N=C[N:13](C(N2C=NC=C2)=O)[CH:12]=1.CN.C1COCC1>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:13][CH3:12])=[O:10])=[N:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ccc(Cl)cn1
Agent: CN
Solvent: ClCCl
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
To a stirred solution of 5-chloropyridine-2-carboxylic acid (315 mg, 2.0 mmol) in DCE (2.5 ml) at 20 to 25° C. was added CDI (324 mg, 2.0 mmol) and the mixture was stirred at RT overnight. The reaction mixture was heated to ca. 50° C. and a solution of methylamine in THF (2 M, 5.0 mmol) was added. The resulting mixture was stirred at 50° C. overnight and then cooled to RT and diluted with DCM (20 mL). the reaction mixture was washed with sat. NaHCO3 (10 ml) and the organic layer dried (Na2SO4), filtered and concentrated in vacuo. Purification by silica flash column chromatography (eluting with DCM/MeOH 95:5) provided the title compound as off-white solid (140 mg, 41%).
Reaction SMILES: [C:1](P(=O)(OCC)OCC)#[N:2].[CH3:11][S:12][C:13]1[CH:14]=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N+:16]([O-])=[CH:17][CH:18]=1.C(N(CC)CC)C>C(#N)C>[CH3:11][S:12][C:13]1[CH:18]=[C:17]([C:1]#[N:2])[N:16]=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1
Reactant: CCOP(=O)(C#N)OCC
Reactant: CSc1cc[n+]([O-])c(-c2ccccn2)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CSc1cc(C#N)nc(-c2ccccn2)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Diethyl cyanophosphonate 90% (1.3 mL, 8.4 mmol) was slowly added at 25° C. to a mixture of 4-Methylsulfanyl-[2,2′]bipyridinyl 1-oxide (650.0 mg, 2.98 mmol) and triethylamine (0.50 mL, 3.58 mmol) in acetonitrile (14 mL) and stirred for 2 hours at 90° C. The reaction mixture was concentrated under reduced pressure, methanol (5 mL) added and the solid formed filtered and washed with methanol (2×5 mL), the filtrate was concentrated and purified by column chromatography on silica gel (0 to 10% Methanol in dichloromethane) to afford 4-methylsulfanyl-[2,2′]bipyridinyl-6-carbonitrile as a white solid that was combined with the previous white solid obtained (500.0 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][C:8]=2[O:14][CH3:15])[N:3]=1.[C:16](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:17]>ClCCl>[Cl:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([N:11]=[C:16]=[S:17])=[CH:9][C:8]=2[O:14][CH3:15])[N:3]=1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: COc1cc(N)ccc1-n1cnc(Cl)n1
Solvent: ClCCl
Product: COc1cc(N=C=S)ccc1-n1cnc(Cl)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.2 %

Procedure:
Step E (4): Dichloromethane (25 mL) was added to a flask charged with 4-(3-chloro-1H-1,2,4-triazol-1-yl)-3-methoxyaniline (0.577 g, 2.57 mmol) and 1,1′-thiocarbonyldi-2(1H)-pyridone (0.597 g, 2.57 mmol). The resulting mixture was stirred for 24 h at rt. The crude reaction mixture concentrated in vacuo and the crude product was purified using silica gel chromatography (0-5% EtOAc/chloroform, linear gradient) to afford 3-chloro-1-(4-isothiocyanato-2-methoxyphenyl)-1H-1,2,4-triazole (529 mg, 1.983 mmol, 77% yield) as a off-white solid. LC-MS (M+H)+ 267.1. 1H NMR (500 MHz, chloroform-d) δ ppm 8.67 (s, 1 H) 7.79 (d, J=8.55 Hz, 1 H) 6.98 (dd, J=8.70, 1.98 Hz, 1 H) 6.91 (d, J=1.83 Hz, 1 H) 3.97 (s, 3 H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([C:13]([OH:15])=[O:14])=[CH:9][NH:8][C:6]=2[N:7]=1.C(N(CC)CC)C.ClC(OC(C)C)=O.O[N:31]1[C:35](=[O:36])[CH2:34][CH2:33][C:32]1=[O:37]>CN(C)C=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([C:13]([O:15][N:31]3[C:35](=[O:36])[CH2:34][CH2:33][C:32]3=[O:37])=[O:14])=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: O=C1CCC(=O)N1O
Reactant: Nc1ncc2c(=O)c(C(=O)O)c[nH]c2n1
Agent: CC(C)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ncc2c(=O)c(C(=O)ON3C(=O)CCC3=O)c[nH]c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A suspension of 2-amino-5,8-dihydro-5-oxopyrido[ 2,3-d]pyrimidine-6-carboxylic acid (1.70 g) and triethylamine (2.5 ml) in dried dimethylformamide (50 ml) was stirred at room temperature for 1 hour and to the suspension was added isopropyl chloroformate (1.90 ml) at 0°-5° C. The mixture was stirred at 5°-10° C. for one hour and a solution of N-hydroxysuccinimide (1.91 g) in dimethylformamide (20 ml) was added to it. The mixture was stirred at room temperature for 1.5 hours. The crystals precipitated were collected and washed with dichloromethane to give N-(2-amino-5,8-dihydro-5-oxopyrido[2,3-d]pyrimidine-6-carbonyloxy)succinimide (1.9 g) m.p. above 300° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[F:10][C:11]([F:21])([F:20])[C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1.O.[BH4-].[Na+].[Cl-:25].[Na+].O>C1(C)C=CC=CC=1>[ClH:25].[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:17][CH2:16][C:15]2[CH:14]=[CH:13][C:12]([C:11]([F:10])([F:20])[F:21])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1
Reactant: [Cl-]
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: O=Cc1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cl
Product: FC(F)(F)c1ccc(CNCc2ccc(Br)cc2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89 %

Procedure:
A solution of 4-bromobenzaldehyde (5.81 g, 31.4 mmol) and 4-(trifluoromethyl)-benzylamine (5.00 g, 28.6 mmol) in toluene (100 mL) was heated at reflux for 75 min with azeotropic removal of water. The toluene was evaporated off under reduce pressure. The residue was taken up in methanol (100 mL) and cooled to 0° C. NaBH4 (2.16 g, 57.1 mmol) was added portionwise and the reaction mixture was stirred at 0° C. for 1.5 h. The reaction mixture was poured into water (200 mL)/brine (200 mL) and extracted with Et2O (500 mL and 200 mL). The organic layers were washed with brine, combined and dried over MgSO4. The solvent was removed under reduce pressure. The residue was diluted with Et2O (200 mL) and HCl (1N in Et2O, 40 mL) was added. A white solid precipitated out. Filtration, washing with Et2O (3×20 mL) and drying under vacuum at 50° C. for 18 hrs gave the title compound as a white solid (9.74 g, 89%). 1H NMR (DMSO-d6, 300 MHz) δ 9.77 (s, 2H), 7.82 (d, 2H, J=8.5 Hz), 7.76 (d, 2H, J=8.5 Hz), 7.64 (d, 2H, J=8.3 Hz), 7.51 (d, 2H, J=8.3 Hz), 4.25 (s, 2H), 4.17 (s, 2H). M+(LC/MS(ESI)): 344.1. HPLC (Condition A), Rt: 3.16 min (HPLC purity: 99.7%).
Reaction SMILES: [C:1](=O)([O:34]C1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH2:12][CH2:13][CH2:14][N:15]3[C:20](=[O:33])[CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:26]=2[CH3:32])=[CH:6][CH:5]=1.Cl.[NH2:46][CH2:47][C:48]([O:50][CH3:51])=[O:49]>C(Cl)Cl>[CH3:32][C:26]1[C:27]([CH3:31])=[CH:28][CH:29]=[CH:30][C:25]=1[O:24][CH2:23][CH2:22][CH2:21][C:20]([N:15]1[C:16]2[C:11](=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([CH2:3][O:2][C:1]([NH:46][CH2:47][C:48]([O:50][CH3:51])=[O:49])=[O:34])=[CH:9][CH:8]=3)[CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:13][CH2:14]1)=[O:33]
Reactant: COC(=O)CN
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4ccc(COC(=O)Oc5ccc([N+](=O)[O-])cc5)cc4)cccc32)c1C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)CNC(=O)OCc1ccc(-c2cccc3c2CCCN3C(=O)CCCOc2cccc(C)c2C)cc1
Yield: 62.6 %

Procedure:
A solution of 4-(1-(4-(2,3-dimethylphenoxy)butanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)benzyl 4-nitrophenyl carbonate (0.020 g, 0.034 mmol), methyl 2-aminoacetate hydrochloride (5.07 mg, 0.040 mmol) and TEA (9.38 μL, 0.067 mmol) in DCM (0.200 mL) was stirred at room temperature for 16 h. After this time, the reaction mixture was quenched with 1 N NaOH. The organic layer was washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by preparative HPLC (PHENOMENEX® Axia Luna column, 5μ, C18, 30×100 mm; 10 min gradient from 75% A:25% B to 0% A:100% B (A=90% H2O/10% MeOH+0.1% TFA); (B=90% MeOH/10% H2O+0.1% TFA); detection at 220 nm) to afford the title compound (11.6 mg, 63% yield) as a clear colorless oil. LCMS, [M+H]+=545.2. 1H NMR (400 MHz, MeOD) δ 7.37 (d, J=7.9 Hz, 2H), 7.25 (d, J=7.4 Hz, 2H), 7.13 (d, J=7.5 Hz, 1H), 7.09 (d, J=6.8 Hz, 2H), 6.98 (t, J=7.9 Hz, 1H), 6.72 (d, J=7.5 Hz, 1H), 6.66 (d, J=8.1 Hz, 1H), 5.14 (s, 2H), 3.87 (s, 3H), 3.79-3.63 (m, 6H), 2.82 (t, J=6.9 Hz, 2H), 2.35 (s, 2H), 2.20-2.04 (m, 5H), 1.87-1.66 (m, 5H).
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C:8]2=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:17].[Na+].C([Li])CCC.C1CCCCC1.[CH3:30][O:31][C:32](=O)[O:33]C.Cl>O1CCCC1.O>[CH3:30][O:31][C:32]([N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:9][C:8]([OH:16])=[O:17])=[O:33]
Reactant: [OH-]
Reactant: COC(=O)OC
Reactant: O=C1Cc2ccccc2N1c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: C1CCCCC1
Product: COC(=O)N(c1ccccc1)c1ccccc1CC(=O)O
Temperature: 67 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
A mixture of 1-phenyl-1,3-dihydro-indol-2-one (80 g, 382 mmol), sodium hydroxide (16.06 g, 402 mmol) and tetrahydrofuran (113 ml) is heated to reflux (67° C.) for S hours. The solution is diluted with another portion of tetrahydrofuran (169 ml) and cooled to −10° C. A 20% solution of butyllithium in cyclohexane (122.3 g, 382 mmol) is added at this temperature followed by dimethylcarbonate (51.7 g, 573 mmol). Afterwards, the solution is stirred at −10° C. for 2 hours. Concentrated hydrochloric acid (38 ml) and water (125 ml) are added and the organic solvents are distilled off at reduced pressure. After addition of toluene (345 ml) to the suspension, the pH of the water phase is adjusted to 1.5 using hydrochloric acid (34 ml). After phase separation at 75° C., the organic phase is washed with another portion of water (120 ml), concentrated at reduced pressure and allowed to crystallize at 0° C. to yield 81.2 g of pure title compound (75%).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.Br[CH2:13][CH:14]([CH3:16])[CH3:15]>>[CH2:13]([O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH:2]=[O:1])[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)CBr
Reactant: COc1ccc(C=O)cc1O
Product: COc1ccc(C=O)cc1OCC(C)C

Procedure:
The title compound was prepared by reaction of isovanillin with 1-bromo-2-methyl propane as described in WO 04/000 806 A1 (Elbion A G).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12](=[O:26])[CH:11]([CH3:27])[CH2:10]1.I[CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:29][CH2:30][CH3:31])[C:3]=1[CH:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:17][CH:16]=2)[C:12](=[O:26])[CH:11]([CH3:27])[CH2:10]1
Reactant: CC1CC(c2c(O)cccc2F)N(Cc2ccc(OC(F)(F)F)cc2)C1=O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1cccc(F)c1C1CC(C)C(=O)N1Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 5-(2-fluoro-6-hydroxyphenyl)-3-methyl-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one (preparation described in example 413; 50 mg; 0.13 mmol), 1-iodopropane (22 mg; 0.13 mmol), potassium carbonate (36 mg; 0.26 mmol), and cesium carbonate (8.5 mg; 0.026 mmol) in anh. DMF (0.7 ml) was stirred at rt, under nitrogen, for 17 h. Subsequent filtration and purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=1.01 min.; [M+H]+: 425.99 g/mol.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[O:28][CH2:29][O:30][CH3:31])[OH:20].C(N(CC)CC)C>ClCCl>[CH3:31][O:30][CH2:29][O:28][C:22]1[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:21]=1[C:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][CH3:11])=[O:20]
Reactant: COCOc1c(C)cccc1C(O)c1ccccc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COCOc1c(C)cccc1C(=O)c1ccccc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 8.72 ml of oxalyl chloride in 300 ml of dichloromethane was cooled with a dry ice-acetone bath and a solution of 13.9 ml of dimethyl sulfoxide in 50 ml of dichloromethane was added dropwise with stirring. After 30 min, (2-methoxyphenyl)(3-methyl-2-methoxymethoxyphenyl)methanol (26.4 g) dissolved in 100 ml of dichloromethane was added slowly with stirring and the mixture allowed to react for 1 hour. Triethylamine (64 ml) was then added and the resulting mixture was stirred another 30 min cold and then allowed to warm to room temperature. The product mixture was extracted sequentially with water, 5 percent hydrochloric acid, water, and 5 percent sodium carbonate. It was then dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain an oil. This was purified by preparative liquid chromatography to obtain the title compound as an oil. The assigned structure was consistent with the proton NMR spectrum.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=O)[C:11]([C:15]#[N:16])=[CH:10][C:9]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:12]1[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:10][C:11]=1[C:15]#[N:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc(-c2[nH]c(=O)c(C#N)cc2-c2ccccc2)cc1
Product: Cc1ccc(-c2nc(Cl)c(C#N)cc2-c2ccccc2)cc1
Temperature: 100 °C

Procedure:
A mixture of 6-(4-methylphenyl)-2-oxo-5-phenyl-1,2-dihydropyridine-3-carbonitrile (11-3) (5.73 g, 20.01 mmol) in POCl3 (50 mL) was heated to 100° C. overnight. Cooled and concentrated in vacuo. The residue was basified with sat. aqueous Na2CO3 solution and then extracted with CH2Cl2. The combined organic layers was dried, filtered and concentrated to give 2-chloro-6-(4-methylphenyl)-5-phenylnicotinonitrile (11-4) as a solid. LRMS m/z (M+H) Calcd: 305.1, found: 305.2.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([OH:13])[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14](OCC)[CH3:15].C(N(CC)CC)C.C[Si](Cl)(C)C.Br[CH2:32][C:33]([OH:35])=[O:34]>C(Cl)(Cl)Cl>[CH2:14]([O:12][P:11]([CH2:32][C:33]([OH:35])=[O:34])([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:13])[CH3:15]
Reactant: CCOCC
Reactant: O=C(O)CBr
Reactant: OP(O)CCCCc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOP(=O)(CCCCc1ccccc1)CC(=O)O
Temperature: 0 °C
Reaction time: 5 h
Yield: 97 %

Procedure:
To a solution of 4-phenylbutyl phosphonous acid, ethyl ether (0.5 g, 0.0022 mole) in chloroform (10 ml) was added triethylamine (0.68 ml, 0.0048 mole) and the solution was cooled in an ice bath to 0° C. Trimethyl silyl chloride (0.6 ml, 0.0048 mole) was added to the above solution dropwise, followed by bromoacetic acid (0.34 g, 0.0024 mole). The ice bath was removed and the mixture stirred at room temperature for 5 hours and poured into 10% aqueous HCl (30 ml) and crushed ice (20 g). After shaking the mixture in a separatory funnel, the chloroform layer was separated and the aqueous layer extracted with dichloromethane (2×50 ml). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and the solvents removed on a rotavap. The resulting crude thick oil was vacuum dried to get 0.61 g (97%) of title compound in the form of an oil, TLC: Silica gel, CH2Cl2 :MeOH:HOAc shows one main spot at Rf =0.37.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])=[CH:16][CH:15]=3)[CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:31]N1C(=O)CCC1=O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([O:20][Si:21]([CH:22]([CH3:23])[CH3:24])([CH:28]([CH3:29])[CH3:30])[CH:25]([CH3:27])[CH3:26])=[CH:18][CH:19]=3)[C:10]=2[Br:31])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2cc(-c3ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc3)no2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2onc(-c3ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc3)c2Br)CC1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
A solution of 1-[3-(4-triisopropylsilanyloxy-phenyl)-isoxazol-5-yl]-cyclopropanecarboxylic acid ethyl ester (288 g) in 3 L DMF was cooled to 5° C. under an atmosphere of N2. The reaction solution was treated with N-bromosuccinimide (131.5 g) and allowed to slowly warm to room temperature over 20 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (2 L), cooled to −15° C., and quenched with 10% sodium metabisulfite solution (150 mL) with stirring. The organic layer was separated, washed with sat. NaHCO3 (250 mL) and brine (250 mL), dried over Na2SO4, filtered, and evaporated. The residue was purified by column chromatography (0 to 20% ethyl acetate in hexanes) to afford 1-[4-bromo-3-(4-triisopropylsilanyloxy-phenyl)-isoxazol-5-yl]-cyclopropanecarboxylic acid ethyl ester (285 g) as a light-brown thick liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[CH2:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C[N+]1([O-])CC[O:20]CC1.S([O-])(O)=O.[Na+].[OH2:29]>C(#N)C.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:20])([C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:15][OH:29])=[CH:4][CH:3]=1
Reactant: C=C(CCc1ccc(Cl)cc1)C(C)(C)C
Reactant: O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)C(O)(CO)CCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3.0 g of 1-(4-chlorophenyl)-3-methylene-4,4-dimethylpentane prepared as described above (1) was dissolved in a mixture solvent of 40 ml of acetonitrile and 10 ml of water, and 3.2 g of 4-methylmorpholine-N-oxide was added thereto. After addition of 10 ml of a 4% aqueous solution of osmium tetroxide, the mixture was stirred at room temperature for 24 hours. After adding an aqueous solution of sodium hydrogen sulfite, the mixture was stirred for 1 hour, and insoluble substances were removed by filtration, and the filtrate was extracted with ethyl acetate. The separated organic layer was washed with water and dried, followed by removing the solvent under vaccum to obtain an oily product. It was then purified by column chromatography on a silica gel column to obtain 1.4 g of the target compound as a white solid.