Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[N:7]=1)O.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[C:30]2[C:25](=[N:26][CH:27]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:29]=2)[N:24]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[N:23]=1.[OH2:48]>O1CCCC1.C(#N)C>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:6]1[CH:11]=[CH:10][C:9]([OH:48])=[C:8]([C:28]2[CH:29]=[C:30]3[C:22]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[O:15][CH3:14])=[N:23][N:24]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:45])([CH3:47])[CH3:46])[C:25]3=[N:26][CH:27]=2)[N:7]=1
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: COC(=O)C(O)c1cccc(Br)n1
Reactant: O
Solvent: C1CCOC1
Solvent: CC#N
Product: COC(=O)Cc1ccc(O)c(-c2cnc3c(c2)c(-c2ccccc2OC)nn3COCC[Si](C)(C)C)n1
Yield: 35 %

Procedure:
In a microwave vial (6-bromo-pyridin-2-yl)-hydroxy-acetic acid methyl ester (430.9 mg, 1.75 mmol), 3-(2-Methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (842.3 mg, 1.75 mmol) in tetrahydrofuran/acetonitrile/1 N aqueous sodium bicarbonate (20 ml) was degassed with nitrogen and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichloromethane adduct (143.0 mg, 0.18 mmol) was added and the vial sealed. This reaction mixture was irradiated to 80° C. for 30 minutes in a microwave reactor. 100 ml water was added and this mixture was extracted with ethyl acetate (3×). The combined organic layers were dried over magnesium sulfate and purified by silica gel chromatography to yield 5-hydroxy-{6-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-pyridin-2-yl}-acetic acid methyl ester as a white solid (319 mg, 35% yield). MS: m/z 521.6 (M+H+).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([S:13]([CH:16]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:17]([CH3:23])([CH3:22])[C:18]([O:20]C)=[O:19])(=[O:15])=[O:14])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]>O.CO>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([S:13]([CH:16]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:17]([CH3:22])([CH3:23])[C:18]([OH:20])=[O:19])(=[O:14])=[O:15])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COC(=O)C(C)(C)C(CCCCc1ccccc1)S(=O)(=O)c1ccc(OC)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(S(=O)(=O)C(CCCCc2ccccc2)C(C)(C)C(=O)O)cc1OC
Yield: 73.1 %

Procedure:
A solution of sodium hydroxide (0.31 g, 7.7 mmol) in water (4 mL) is added to a solution of methyl 3-(3,4-dimethoxybenzenesulfonyl)-2,2-dimethyl-7-phenylheptanoate (0.78 g, 1.7 mmol) in MeOH (6 mL). The reaction is heated at reflux 24 hours. The solvent is then removed in vacuo, CH2Cl2 (20 mL) added and the solution washed with 1 N HCl (2×40 mL). The organic layer is dried over MgSO4 and the solvent removed in vacuo to afford 3-(3,4-dimethoxyphenylsulfonyl)-2,2-dimethyl-7-phenylheptanoic acid (0.54 g, 73%) 1H NMR (300 MHz, CDCl3) δ 7.47 (dd, J=8.5, 2.1 Hz, 1H), 7.36 (d, J=2.1 Hz, 1H), 7.26-7.16 (m, 3H), 7.02 (d, J=7.0 Hz, 2H), 6.90 (d, J=8.4 Hz, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.76-3.73 (m, 1H), 2.46-2.41 (m, 2H), 2.06-2.00 (m, 1H), 1.65-1.60 (m, 2H), 1.48 (s, 3H), 1.45-1.35 (m, 3H), 1.29 (s, 3H); MS (FAB) m/e 434 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1([O:25][CH3:26])[CH2:8][CH2:7][C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:12]=2)([CH:9]=[O:10])[CH2:5][CH2:4]1.[BH4-].[Na+].O>CCCC>[CH3:26][O:25][C:3]1([O:2][CH3:1])[CH2:8][CH2:7][C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)[CH:12]=2)([CH2:9][OH:10])[CH2:5][CH2:4]1
Reactant: COc1ccc(C2(C=O)CCC(OC)(OC)CC2)cc1OC1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCCC
Product: COc1ccc(C2(CO)CCC(OC)(OC)CC2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-formylcyclohexan-1-one dimethyl ketal (0.24 g, 0.66 mmol) in 1,2-dimethyl-ethane (5 mL) under an argon atmosphere was added sodium borohydride (0.05 g, 1.3 mmol) and the mixture was stirred at room temperature for 0.75 h. Water was added, the mixture was partitioned between ether and water, was extracted twice with ether, the organic extract was dried (potassium carbonate) and evaporated to an oil (0.19 g, 79%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Br.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Br-:1].[Br-:1].[CH2:2]([N+:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N+:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCCCCCCCCCCCCBr
Reactant: c1ccncc1
Product: [Br-]
Product: c1cc[n+](CCCCCCCCCCCC[n+]2ccccc2)cc1
Temperature: 65 °C
Yield: 93 %

Procedure:
1,12-Dibromododecane (mmol) was added to a solution (30 mL) of dry pyridine, and the solution heated for 24 hours at 65° C. The resulting precipitate was filtered, and the product washed five times with dry diethyl ether. The resulting white solid was isolated in a 93% yield. 1H NMR (300 MHz, DMSO-D6) δ 9.15 (2H, d, C2&C6-H), 8.62 (1H, t, C4-H), 8.19 (2H, t, C3&C5-H), 4.61 (2H, t, C′1-CH2), 1.88 (2H, m, C′2-CH2), 1.22 (8H, m, C′3-6-CH2); 13C NMR (75 MHz, DMSO-D6) δ 145.3, 144.6, 127.9, 60.7, 30.8, 28.9, 28.8, 28.5, 25.4.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#N)=[CH:3][CH:2]=1.C(O)=[O:18]>[Ni]>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=[O:18])=[CH:3][CH:2]=1
Reactant: O=CO
Reactant: N#Cc1cccc(OCc2ccncc2)c1
Agent: [Ni]
Product: O=Cc1cccc(OCc2ccncc2)c1
Yield: 37 %

Procedure:
A mixture of 3-(4-pyridinylmethoxy)benzonitrile (2.5 g, 0.012 mol) in 75% formic acid (35 ml) was treated with raney nickel (2 g) and heated to reflux for 4 hours. The reaction mixture was filtered through SUPERCELL®, the filtrate was brought to a pH of 8-9 with 5N NaOH, extracted with EtOAc (3×150 ml) and the combined organic layers were dried over MgSO4, filtered and stripped. The residue was purified by column chromatography on silica gel eluting with EtOAc (100%) to afford 0.94 g (37%) of 3-(4-pyridinylmethoxy)benzaldehyde.
Reaction SMILES: [N:1]([O-])=O.[Na+].Cl.[Al].[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13]C=C2.[O:17]1[CH2:22][CH2:21]OCC1>>[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:1]=[C:21]2[CH:22]=[O:17]
Reactant: O=N[O-]
Reactant: C1COCCO1
Reactant: Clc1ccc2[nH]ccc2c1
Agent: Cl
Agent: [Al]
Agent: [Na+]
Product: O=Cc1n[nH]c2ccc(Cl)cc12
Reaction time: 2 h

Procedure:
A 0.25 M aqueous solution of NaNO2 (1.0 equivalent) was brought to a pH of 2.5 by the addition of dilute HCl. Dioxane was added to the solution (10% by volume). The flask was protected from light with aluminum foil and 5-chloroindole(1.0 equivalent) was added slowly. The solution was stirred vigorously for 2 hours. The solution was then extracted with three portions of ethyl acetate. The organic layers were combined, washed with water, dried over MgSO4, filtered, and concentrated. The product was purified by flash chromatography (ethyl acetate:hexane, 1:1, v/v) yielding 5-chloro-1H-indazole-3-carbaldehyde as a purple solid. LC/MS (m/z) 181.3 (MH+), Rt 2.7 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.C(OCC)C.[CH:16]1([Mg]Br)[CH2:18][CH2:17]1.O>C1COCC1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([CH:16]2[CH2:18][CH2:17]2)[OH:7])=[C:4]([F:10])[CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1F
Reactant: Br[Mg]C1CC1
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)cc1F)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.00 g (6.31 mmol) of 4-chloro-2-fluorobenzaldehyde were introduced into 20 ml of diethyl ether at 0° C., 19 ml (9.46 mmol) of 0.5N cyclopropylmagnesium bromide solution in THF were added, and the mixture was stirred at RT overnight. The reaction mixture was added to water, the phases were separated, the aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water) to result in 730 mg (58% of theory) of the title compound.
Reaction SMILES: [Si]([NH:8][C:9]1[N:10]=[C:11]([Cl:21])[C:12]2[CH:17]=[CH:16][N:15]([CH:18]([CH3:20])[CH3:19])[C:13]=2[N:14]=1)(C(C)(C)C)(C)C.I[CH2:23][CH2:24][CH3:25].[H-].[Na+].Cl>CN(C=O)C.CCOCC.O>[CH2:23]([NH:8][C:9]1[N:10]=[C:11]([Cl:21])[C:12]2[CH:17]=[CH:16][N:15]([CH:18]([CH3:19])[CH3:20])[C:13]=2[N:14]=1)[CH2:24][CH3:25]
Reactant: CC(C)n1ccc2c(Cl)nc(N[Si](C)(C)C(C)(C)C)nc21
Reactant: CCCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCNc1nc(Cl)c2ccn(C(C)C)c2n1
Reaction time: 0.17 h

Procedure:
Under nitrogen atmosphere, 2-(t-butyl-dimethylsilanyl)amino-4-chloro-7-i-propyl-pyrrolo[2,3-d]pyrimidine (5.7 g, 17.6 mmol) and 1-iodopropane (4.5 g (26.4 mmol) were dissolved in DMF (20 mL). The reaction mixture was cooled to 0° C. with vigorous stirring, and NaH (1.06 g of a 60% dispersion in mineral oil, 26.4 mmol) of (60%) was added. The mixture was stirred for 10 min, and then water (50 mL) was slowly added to quench the reaction. The mixture was extracted with EtOAc (300 mL) and the organic layer was washed with water (50 mL) and then with a brine solution (50 mL), and lastly, dried over anhydrous Na2SO4. After evaporation of the solvents, a yellow oily residue was isolated (6.5 g). The residue was dissolved in Et2O (50 mL), concentrated hydrochloric acid (10 mL) was added at 0° C. with stirring, and the mixture was stirred for an additional 10 min. After the reaction was completed, the solution was extracted with EtOAc (200 mL) and 1N NaOH (200 mL). The organic layer was washed with H2O (150 mL) and then with a brine solution (150 mL) and dried over Na2SO4. The solvents in vacuo and the residue was purified by flash column chromatography (PE/EtOAc=10/1 to 5/1) to yield 2-(n-propyl)amino-4-chloro-7-i-propyl-pyrrolo[2,3-d]pyrimidine (CXXXIV, 4.5 g, !00%) as a yellow solid. LCMS (ESI) m/z=253 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][S:8][C:9]2[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[C:20](N1C=CN=C1)(N1C=CN=C1)=O.C[O-].[Na+]>CN(C)C=O.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C:9]2[C:14]([C:15]([O:17][CH3:20])=[O:16])=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(CSc2ccncc2C(=O)O)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1cnccc1SCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 2.2 g (0.008 mole) of 4-(4-methoxybenzylthio)-nicotinic acid in 30 mL of dry N,N-dimethylformamide was reacted with 1.78 g (0.011 mole) of 1,1'-carbonyldiimidazole. This was stirred at room temperature for 2 hours, then 0.5 mL of 4.3M sodium methoxide in methanol and 5 mL of methanol. The reaction was stirred for 1 hour at room temperature, then partitioned between 75 mL of ether and 30 mL of water. The ether layer was extracted with 2×30 mL of water, dried, concentrated to a small volume, and hexane added to crystallize methyl 4-(4-methoxybenzylthio) nicotinate; yield 1.66 g (72% of theory), m.p. 108°-110° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:11](=[O:25])[C@@H:10]([CH2:26][C:27]([OH:29])=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[CH3:34]COC(C)=O.C([O-])(O)=O.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:23][CH2:24]3)[C:11](=[O:25])[C@@H:10]([CH2:26][C:27]([O:29][CH3:34])=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Reactant: CCOC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)C[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O

Procedure:
To a suspension of 250 mg (0.578 mmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetic acid (Example 35) in MeOH (3 mL) was added thionyl chloride (78.0 μl, 1070 μmol) dropwise at 0° C. After being stirred at 25° C. for 14h, the reaction was diluted (EtOAc), basified (sat NaHCO3), extracted (2×EtOAc). The combined organic layers were washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to provide the title compound as a colorless liquid.
Reaction SMILES: [CH2:1]([C:4]([CH2:13][C:14]#[CH:15])(C(OC)=O)[C:5]([O:7][CH3:8])=[O:6])[C:2]#[CH:3].[Cl-].[Na+]>CS(C)=O.O.COC(C)(C)C>[CH2:1]([CH:4]([CH2:13][C:14]#[CH:15])[C:5]([O:7][CH3:8])=[O:6])[C:2]#[CH:3]
Reactant: C#CCC(CC#C)(C(=O)OC)C(=O)OC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: COC(C)(C)C
Product: C#CCC(CC#C)C(=O)OC
Reaction time: 15 h

Procedure:
Dimethyl 2,2-di(2-propynyl)malonate (71 g) was treated to a Krapcho decarboxylation by heating at 170° C. with with sodium chloride (25 g) and water (23 ml) in dimethylsulfoxide (341 ml). After 15 hr, the solution was cooled and diluted with water and t-butyl methyl ether and extacted. The organic layer was washed with water (4×), brine, and then dried over sodium sulfate. Solvent removal afforded a liquid which was distilled, collecting the title compound at 109° C. (28 mm Hg).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][OH:27])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[F:28][C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][O:27][C:32]2[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Oc1ccc(F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Over the course of 30 minutes, 10.5 ml of diethyl azodicarboxylate are poured onto a mixture of 13.5 g of N-tert-butyloxycarbonyl-4-hydroxymethylpiperidine, 7.45 g of p-fluorophenol, 17.4 g of triphenylphosphine and 140 ml of tetrahydrofuran. After stirring for 12 hours at ambient temperature, the reaction mixture is concentrated, taken up in ether, washed with water and then 1N sodium hydroxide solution, and then washed with water. After drying, filtration and evaporation under reduced pressure, chromatography over silica gel (cyclohexane/ethyl acetate: 90/10) allows the expected product to be isolated.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([N:8]([CH3:12])[C:9](Cl)=[O:10])=[N:6][N:7]=1.[S:13]1[CH2:19][CH2:18][CH2:17][CH2:16][S:15][CH:14]1CNC.C([N:25]([CH2:28]C)[CH2:26]C)C>C1C=CC=CC=1>[CH3:1][S:2][C:3]1[S:4][C:5]([N:8]([CH3:12])[C:9]([NH:25][CH:14]2[S:15][CH2:16][CH2:17][CH2:18][CH2:19][S:13]2)=[O:10])=[N:6][N:7]=1.[CH3:1][S:2][C:3]1[S:4][C:5]([N:8]([CH3:12])[C:9]([N:25]([CH3:26])[CH:28]2[S:15][CH2:16][CH2:17][CH2:18][CH2:19][S:13]2)=[O:10])=[N:6][N:7]=1
Reactant: CNCC1SCCCCS1
Reactant: CSc1nnc(N(C)C(=O)Cl)s1
Reactant: CCN(CC)CC
Solvent: c1ccccc1
Product: CSc1nnc(N(C)C(=O)N(C)C2SCCCCS2)s1
Product: CSc1nnc(N(C)C(=O)NC2SCCCCS2)s1
Temperature: 25 °C

Procedure:
N-(2-Methylthio-1,3,4-thiadiazol-5-yl)-N-methylcarbamoyl chloride (0.05 mole), N-(1,3-dithiepan-2-ylmethyl)-N-methylamine (0.05 mole), triethylamine (0.07 mole) and benzene (200 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is then heated at reflux for a period of about 5 hours. After this time the mixture is cooled to room temperature and is filtered. The filtrate is washed with water and dried over anhydrous magnesium sulfate. The dried solution is then stripped of benzene under reduced pressure to yield the desired product N-(2-methylthio-1,3,4-thiadiazol-5-yl)-N-methyl-N'-methyl-N'-(1,3-dithiepan-2-yl)urea.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.O1CCOCC1.[OH-].[Na+].Cl[CH:24]([F:26])[F:25]>O>[F:25][CH:24]([F:26])[O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)C(C(=O)O)c1ccc(O)cc1
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)C(C(=O)O)c1ccc(OC(F)F)cc1
Temperature: 0 °C
Yield: 43 %

Procedure:
To a stirred mixture of 2-(4-hydroxyphenyl)-3-methylbutyric acid (10.0 g; 0.0515 mol), dioxane (65 ml), sodium hydroxide (19.08 g, 18.56 g real; 0.464 mol), and water (30 ml) is bubbled chlorodifluoromethane (46 g; 0.532 mol) at 80° C. over a four-hour period. The reaction mixture is then poured into 250 ml of ice water, washed with ether, acidified with concentrated hydrochloric acid to pH 3, and extracted with 200 ml of ether. The ether extract is washed with 100 ml of water, dried with sodium sulfate, filtered, and evaporated to a white paste. A mixture of hexane and methylene chloride is added. The resulting mixture is filtered to remove the solid which is the starting material. The filtrate is evaporated to give 5.41 g of product as a clear brown oil. The product is at least 85% pure as calculated by NMR. NMR (CDCl3 -d5 pyridine): δ6.57 (t, J=74.3 Hz, 1 H); δ3.63 (s, imp.); δ3.25 (d, J=10 Hz, 1H); δ2.37 (m, 1H); δ1.19 (d, J=6.5 Hz, 3H); δ0.78 (d, J=6.5 Hz, 3H); δ13.82 (s, 1H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[Cl:13][C:14]1[CH:15]=[C:16]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:34][CH:33]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]=[C:25]2[CH3:49])[CH:17]=[CH:18][C:19]=1[O:20][CH:21]([CH3:23])[CH3:22]>O.C(OCC)(=O)C>[Cl:13][C:14]1[CH:15]=[C:16]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[C:44]4[NH:3][C:4](=[O:7])[O:5][N:45]=4)=[CH:34][CH:33]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]=[C:25]2[CH3:49])[CH:17]=[CH:18][C:19]=1[O:20][CH:21]([CH3:23])[CH3:22]
Reactant: CCCc1nc(C)n(-c2ccc(OC(C)C)c(Cl)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC(C)C)c(Cl)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
A mixture of hydroxylammonium chloride (1.63 g), sodium hydrogen carbonate (2.46 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[1-(3-chloro-4-isopropoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.00 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.41 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.39 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.63 g, 57%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]2[OH:16].[CH2:17](O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(Cl)Cl.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]2[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1[nH]c2ccc(Br)cc2c1O
Reactant: OCc1ccccc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2ccc(Br)cc2c1OCc1ccccc1
Temperature: 0 °C
Yield: 79.3 %

Procedure:
To a solution containing 2.04 g of ethyl 5-bromo-3-hydroxyindole-2-carboxylate, 3.94 g of benzyl alcohol and 3.34 g of di-tert-butyl azodicarboxylate in 30 mL of THF and 15 mL of CH2Cl2 at −78° C. was treated dropwise with a solution containing 3.81 g of triphenylphosphine in 15 mL of CH2Cl2. The resulting reaction mixture was warmed slowly to 0° C. upon consumption of the starting material (monitored by TLC). 800 μL of acetic acid was added and after 30 min the solvents were removed under vacuum and the excess of acetic acid was removed by coevaporation with toluene. The crude product was filtered over a pad of silica gel eluting with CH2Cl2. The organic phase was concentrated to dryness and the solid was swished with hexane to give 2.13 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([NH:26]C(=O)OC(C)(C)C)=[CH:22][CH:21]=3)[N:16]=2)[CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[N:5]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=3)[N:16]=2)[CH:3]=1
Reactant: Cc1ccc(Cn2nc(-c3nc(-c4ccc(NC(=O)OC(C)(C)C)cc4)no3)cc2C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(Cn2nc(-c3nc(-c4ccc(N)cc4)no3)cc2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (4-{5-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-1,2,4-oxadiazol-3-yl}phenyl)carbamate (Example 101, 1.0 g, 2.25 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (5 mL). The reaction mixture was stirred at rt for 1 h. The solvent was removed in vacuo and the residue was re-dissolved in ethyl acetate. After washing with saturated aqueous sodium bicarbonate, the solvent was removed and the title compound was obtained as an off-white solid (770 mg, 99%): 1H NMR (400 MHz, CDCl3) 8.00 (d, 2H), 7.13 (d, 2H), 7.07 (d, 2H), 6.76 (s, 1H), 6.73 (d, 2H), 5.40 (s, 2H), 3.92 (broad, 2H), 2.32 (s, 3H), 2.23 (s, 3H); ES-MS m/z 346, HPLC RT (Method D) 2.48 min.