Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].[CH:5]1([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:26])=[C:15]([N:19]4[CH2:24][CH2:23][NH:22][CH:21]([CH3:25])[CH2:20]4)[C:16]=3F)[C:11](=[O:27])[C:10]([C:28]([OH:30])=[O:29])=[CH:9]2)[CH2:7][CH2:6]1>CO>[CH:5]1([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:26])=[C:15]([N:19]4[CH2:24][CH2:23][NH:22][CH:21]([CH3:25])[CH2:20]4)[C:16]=3[O:2][CH3:1])[C:11](=[O:27])[C:10]([C:28]([OH:30])=[O:29])=[CH:9]2)[CH2:7][CH2:6]1
Reactant: CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CCN1
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1c(N2CCNC(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reaction time: 70.5 h

Procedure:
To a solution of sodium methoxide prepared from sodium (0.4 g) and absolute methanol (20 ml) was added 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid (1.12 g), and, the mixture in sealed tube was stirred for 70.5 hours at 140° to 150° C. and then concentrated. The residue was dissolved in small amount of water, the resulting solution was adjusted to pH 7 with acetic acid and concentrated. The resulting residue was purified by silica gel column chromatography eluting with chloroform-methanol-concentrated aqueous ammonia (20:6:1) and recrystallized from methanol to give the title compound (0.33 g) as pale yellow prisms, mp 162° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:42])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH:35]([CH3:41])[C:36](OCC)=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[C:11]([F:43])[CH:10]=1)#[N:2].[BH4-].[Li+].[Cl-].[NH4+]>O1CCCC1>[F:43][C:11]1[CH:10]=[C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:14]=[CH:13][C:12]=1[CH2:15][C:16]1[C:17](=[O:42])[N:18]([C@H:28]2[CH2:33][CH2:32][C@H:31]([O:34][CH:35]([CH3:41])[CH2:36][OH:37])[CH2:30][CH2:29]2)[C:19]2[N:20]([N:25]=[CH:26][N:27]=2)[C:21]=1[CH2:22][CH2:23][CH3:24]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC(C)C(=O)OCC)CC2)c2ncnn12
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC(C)CO)CC2)c2ncnn12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl 2-[(trans-4-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]propanoate (1.5 g), lithium tetrahydroborate (0.18 g) and tetrahydrofuran (15 mL) was stirred at 0° C. for 1 hr and then at room temperature for 6 hr. Lithium tetrahydroborate (0.18 g) was further added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was added to saturated aqueous ammonium chloride solution, 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 under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.81 g, 58%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:9]=2)=[N:6][CH:7]=1.[CH2:22]([O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:15]([O:14][C:10]1[CH:9]=[C:8]([C:5]2[N:4]=[CH:3][C:2]([C:34]3[CH:35]=[CH:36][C:31]([O:30][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:32][CH:33]=3)=[CH:7][N:6]=2)[CH:13]=[CH:12][CH:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Brc1cnc(-c2cccc(OCc3ccccc3)c2)nc1
Reactant: CCCCCCCCOc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCCCCCOc1ccc(-c2cnc(-c3cccc(OCc4ccccc4)c3)nc2)cc1
Yield: 97.6 %

Procedure:
8.00 g (23.40 mmol) of 5-bromo-2-(3-benzyloxyphenyl)pyrimidine, 7.03 g (28.10 mmol) of 4-octyloxybenzeneboronic acid (preparation analogous to 3-benzyloxybenzeneboronic acid), 7.00 g (65.52 mmol) of sodiumcarbonate and 0.27 g (0.23 mmol) of tetrakis(triphenylphosphine)palladium(0) are heated at 80° C. for 2 hours in 200 ml of toluene, 100 ml of ethanol and 50 ml of water. The reaction mixture is subsequently partitioned between water and ether, the organic phase is washed twice with sodium chloride solution, dried over sodium sulfate and evaporated, and the residue is purified by chromatography (silica gel/dichloromethane: ethyl acetate=98:2), giving 10.66 g of 2-(3-benzyloxyphenyl)-5-(4-octyloxyphenyl)pyrimidine. ##STR15## 10.66 g (22.84 mmol) of 2-(3-benzyloxyphenyl)-5-(4-octyloxyphenyl)pyrimidine are hydrogenated together with 2.00 g of Pd (10%)/C in 100 ml of tetrahydrofuran until the calculated volume of hydrogen has been consumed, the catalyst is subsequently filtered off, and the filtrate is evaporated and dried, giving 8.43 g of 2-(3-hydroxyphenyl)-5-(4-octyloxyphenyl)pyrimidine.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([NH:10][C:11]2[CH:26]=[CH:25][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18](C(N)=O)[CH:17]=3)=[C:13]([F:27])[CH:12]=2)=[O:9])[C:4](=[O:28])[N:3]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C.CC#[N:52].O>CCOC(C)=O.C([O-])(O)=O.[Na+]>[NH2:52][C:18]1[CH:17]=[C:16]([O:15][C:14]2[CH:25]=[CH:26][C:11]([NH:10][C:8]([C:5]3[C:4](=[O:28])[N:3]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:2]([CH3:1])[C:6]=3[CH3:7])=[O:9])=[CH:12][C:13]=2[F:27])[CH:21]=[CH:20][N:19]=1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Reactant: CC#N
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
A solution of 4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2-fluorophenoxy)picolinamide (0.4 g, 0.86 mmol) and PhI(OAc)2 (419 mg, 1.5 mmol) in a mixture of EtOAc (8 mL), MeCN (8 mL) and H2O (4 mL) was cooled to 0° C. and stirred for 30 minutes. The reaction was then allowed to warm to rt, and stirred for another 8 hours. The mixture was diluted with NaHCO3 (aq., 60 mL) and extracted with EtOAc (100 mL×3). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v)=10/1) to give the title compound as a white solid (0.21 g, 56%).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.N1C=CC=CC=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.O>CCCCCCC.C(OCC)(=O)C.C(OCC)(=O)C>[O:4]1[CH2:5][CH2:6][CH:2]([O:1][S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=2)(=[O:21])=[O:20])[CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CCOC1
Solvent: CCCCCCC
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCOC2)cc1
Temperature: 25 °C
Yield: 67.5 %

Procedure:
To a mixture of 3-hydroxytetrahydrofuran (7.00 g, 79.5 mmol) and pyridine (100 mL), was added p-toluenesulfonyl chloride (18.2 g, 95.4 mmol) while stirring at room temperature, and the resulting mixture was stirred for 8.5 hours. To the mixture, were added water and ethyl acetate. After thoroughly shaking the mixture, the organic layer was separated, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The mixture was filtered, and then the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (a mixed solvent of n-heptane and ethyl acetate: n-heptane/ethyl acetate=4/1) to obtain the title compound (13.0 g, 53.7 mmol).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.Cl.[CH3:20][N:21]([CH3:30])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:27][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([N:21]([CH3:30])[CH3:20])=[CH:23][CH:24]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: CN(C)c1ccc(CN)cc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CN(C)c1ccc(CNc2nc(N)nc(-c3ccco3)c2C#N)cc1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 4-dimethylaminobenzylamine dihydrochloride and DBU in DME. ES-MS m/e (%): 335 (M+H+, 100).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH:12](O)[CH2:13][CH3:14])=[CH:5][C:6]2[O:10][CH2:9][O:8][C:7]=2[CH:11]=1)[CH3:2].[SH:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][S:16][CH:12]([C:4]1[C:3]([CH2:1][CH3:2])=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1)[CH2:13][CH3:14])[CH3:22]
Reactant: CCc1cc2c(cc1C(O)CC)OCO2
Reactant: CCOC(=O)CS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)CSC(CC)c1cc2c(cc1CC)OCO2
Yield: 68.8 %

Procedure:
3.9 g of 1-(6-ethyl-1,3-benzodioxol-5-yl)-1-propanol, 0.1 g of p-toluenesulfonic acid and 3.35 g of ethyl mercaptoacetate were dissolved in 80 ml of benzene. The solution was heated under reflux for 12 h while water was removed. Water was added thereto. After extraction with benzene followed by drying over magnesium sulfate and concentration under reduced pressure, the product was purified according to silica gel column chromatography (ethyl acetate/hexane=1:9) to obtain 4.0 g of the intended compound in the form of a colorless, transparent oil.
Reaction SMILES: FC(F)(F)C(O)=O.Br[CH2:9][C:10]1[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=1[CH2:12][O:13][CH2:14][CH:15]([NH2:24])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH:15]2[NH:24][CH2:9][C:10]3[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=3[CH2:12][O:13][CH2:14]2)=[CH:18][CH:19]=1
Reactant: NC(COCc1ccccc1CBr)Cc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccc(CC2COCc3ccccc3CN2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
A mixture of compound 3k (1.6 g, 3.9 mmol) and K2CO3 (1.6 g, 12 mmol) in dry THF (30 mL) was stirred at rt overnight. LCMS indicated the total consumption of compound 3k. The reaction mixture was filtered and the filtrate was evaporated in vacuum to give 3l as a white solid (1.1 g, 86% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]CC)=[O:6].Br[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].Cl>[Cu].O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([O:1][C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([OH:7])=[O:6])=[CH:15][CH:16]=1
Reactant: COc1ccc(Br)cc1
Reactant: CCOC(=O)c1cccc(O)c1
Agent: [Cu]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Product: COc1ccc(Oc2cccc(C(=O)O)c2)cc1
Reaction time: 20 h
Yield: 81.5 %

Procedure:
Ethyl 3-hydroxybenzoate (34.0 grams (g), 0.205 mole) (Aldrich Chemical Company, Milwaukee, Wis.), 4-bromoanisole (26.0 milliliters (ml)), (38.8 g, 0.208 mole) (Aldrich Chemical Company), anhydrous potassium carbonate (17.8 g, 0.129 mole) and copper powder (10.0 g, 0.157 mole), (Fisher Scientific, Pittsburgh, Pa.) were heated under nitrogen to 190° C. with slow stirring. Water generated during the reaction was removed by means of a short-path distillation apparatus attached to the reaction flask. After 20 hours, the reaction mixture was allowed to cool and 20 percent aqueous sodium hydroxide (NaOH) (50 ml) was added. Ester hydrolysis was complete after 1 hour at reflux. The cooled reaction mixture was acidified with concentrated hydrogen chloride (HCl), partitioned between methylene chloride (CH2Cl2 (300 ml)) and water (50 ml), and filtered to remove copper powder. The phases were separated and the organic layer was washed with saturated sodium chloride (NaCl) (2×100 ml), dried with magnesium sulfate (MgSO4), filtered, and solvent evaporated to afford a light brown solid. The crude product was recrystallized from 60 percent aqueous acetic acid to afford 3-(4'-methoxyphenoxy)benzoic acid as off-white crystals (40.77 g, 0.167 mol) with a melting point (m.p.) of 120° C. to 125° C.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CN1CCOCC1>[Cu].C(O)CC(C)C>[N+:11]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:6]([OH:8])=[O:7])([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccccc1
Agent: [Cu]
Solvent: CC(C)CCO
Solvent: CN1CCOCC1
Product: O=C(O)c1ccc(Nc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 144 h
Yield: 42.8 %

Procedure:
A mixture of 4-chloro-3-nitrobenzoic acid (5.70 gm, 23 mmol), aniline (3.17 mL, 35 mmol), N-methylmorpholine (3.24 mL, 25 mmol), copper powder (0.1 gm, 1.57 mmol) and isoamyl alcohol (200 mL) was heated to reflux with stirring for 6 days. The mixture was then cooled to room temperature and filtered through a pad of celite. The filtrate was concentrated in vacuo and the residue taken up in ethyl acetate. The organic phase was washed with 3N HCl (2×1 L). The resulting organic phase was then extracted with saturated aqueous sodium carbonate solution. The aqueous phase was then washed with diethyl ether, followed by ethyl acetate. The aqueous phase was cautiously acidified to pH=1 with 6N HCl, and the resulting precipitate was filtered and dried to afford 2.54 gm of the title compound which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18](=[O:29])[CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1.[C:32](Cl)(=[O:34])[CH3:33].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:31][C:2]([F:1])([F:30])[O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18](=[O:29])[CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([C:32](=[O:34])[CH3:33])[CH:21]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Nc1cccc(OC(F)(F)F)c1)[C@@H]1CCCN1C(=O)Cc1c[nH]c2ccccc12
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Product: CC(=O)n1cc(CC(=O)N2CCC[C@H]2C(=O)Nc2cccc(OC(F)(F)F)c2)c2ccccc21
Temperature: 80 °C

Procedure:
To a solution of (S)-1-(2-1H-indol-3-yl-acetyl)-pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl)-amide (100 mg, 0.232 mmol) in DMF (1.5 mL) under nitrogen atmosphere were added acetyl chloride (148 μl, 2.09 mmol) followed by DMAP (85 mg, 0.7 mmol) and the reaction mixture was heated at 80° C. for 18 h. After completion of the reaction, the mixture was poured into citric acid (10% solution), and extracted three times with EtOAc. The combined organic layers were washed twice with water, dried over Na2SO4, filtered and concentrated. The crude material was purified by preparative HPLC (Waters SunFire C18-ODB, 5 μm, 19×50 mm, 20% CH3CN/H2O 2.5 min, 20-100% CH3CN/H2O in 10 min, CH3CN/H2O containing 0.1% HCOOH flow: 20 mL/min) to give after lyophilization of the purified fractions the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[NH:11][C:10]2=[O:20])=[C:4]([N+:21]([O-:23])=[O:22])[C:3]=1[NH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].S(OC)(O[CH3:34])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[N:11]([CH3:34])[C:10]2=[O:20])=[C:4]([N+:21]([O-:23])=[O:22])[C:3]=1[NH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)Nc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Nc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1[N+](=O)[O-]

Procedure:
3-(4-chloro-3-ethoxycarbonylamino6-fluoro-2-nitrophenyl)-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (0.96 g) was stirred with dimethyl sulfate (0.72 ml) and potassium carbonate (0.33 g) in N,N-dimethylformamide (10 ml) at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate, evaporated to give the title compound (1.1 g, oil).
Reaction SMILES: [CH:1]1([N:7]2[C:12](=[O:13])[CH:11]3[CH2:14][C:9]([C:15]4[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=4)([CH2:10]3)[C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCOCC>COCCO.[Pd]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:9]23[CH2:10][CH:11]([CH2:14]2)[C:12](=[O:13])[N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]3=[O:24])=[CH:16][CH:17]=1
Reactant: O=C1C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C(=O)N1C1CCCCC1
Agent: [Pd]
Solvent: COCCO
Solvent: CCOCC
Product: Nc1ccc(C23CC(C2)C(=O)N(C2CCCCC2)C3=O)cc1

Procedure:
In a manner analogous to that described in Example 1a, 6.0 g of 3-cyclohexyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]-heptane-2,4-dione are dissolved in 120 ml of 2-methoxyethanol, hydrogenated in the presence of 0.6 g of 5% palladium-on-carbon and worked up. Melting point 139°-14020 (from ether).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19](C)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>C1(C)C=CC=CC=1>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CN1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Clc1ccnc(Cl)n1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2nccc(Cl)n2)CC1
Temperature: 25 °C
Yield: 56.9 %

Procedure:
To a suspension of 2,4-dichloropyrimidine (1.00 g, 6.71 mmol) in 13.4 mL of toluene was added 4-methyl-piperazine-1-carboxylic acid tert-butyl ester (1.34 g, 6.71 mmol). The reaction was heated to reflux overnight, then cooled to room temperature and concentrated in vacuo. The residue was taken up in 20 mL of water and extracted with ethyl acetate (2×40 mL). The combined organic layers were washed with brine (25 mL), then dried over sodium sulfate, filtered, and concentrated in vacuo to an off-white solid. Flash column chromatography (silica gel, gradient elution from 5% ethyl acetate-hexanes to 20% ethyl acetate-hexanes) yielded 1.14 g of the title compound (I-2a).
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][CH2:7][S:6](=[O:10])(=[O:9])[NH:5]1)([CH3:3])[CH3:2].Br[C:12]1[N:17]=[CH:16][C:15]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([C:26](=[O:34])[C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[CH2:22][CH2:21]2)=[O:19])=[CH:14][CH:13]=1>>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:26]([CH:23]2[CH2:22][CH2:21][N:20]([C:18]([C:15]3[CH:16]=[N:17][C:12]([N:5]4[C@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][CH2:7][S:6]4(=[O:10])=[O:9])=[CH:13][CH:14]=3)=[O:19])[CH2:25][CH2:24]2)=[O:34])=[CH:32][CH:31]=1
Reactant: O=C(c1ccc(Cl)cc1)C1CCN(C(=O)c2ccc(Br)nc2)CC1
Reactant: CC(C)[C@@H]1CCS(=O)(=O)N1
Product: CC(C)[C@@H]1CCS(=O)(=O)N1c1ccc(C(=O)N2CCC(C(=O)c3ccc(Cl)cc3)CC2)cn1
Yield: 25.7 %

Procedure:
Using (S)-3-isopropylisothiazolidine 1,1-dioxide (320 mg) described in Preparation Example 6 and (6-bromopyridin-3-yl)[4-(4-chlorobenzoyl)piperidin-1-yl]methanone (408 mg) described in Preparation Example 190 and by the reaction and treatment in the same manner as in Example 4, the title compound (126 mg) was obtained.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([NH:18][C:19]([CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=O)=[C:11]([CH3:27])[CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]>[CH3:27][C:11]1[C:12]2[NH:18][C:19]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[N:15][C:13]=2[CH:14]=[C:9]([OH:8])[CH:10]=1
Reactant: [H][H]
Reactant: Cc1cc(OCc2ccccc2)cc([N+](=O)[O-])c1NC(=O)C1CCOCC1
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1cc(O)cc2nc(C3CCOCC3)[nH]c12

Procedure:
0.33 g (0.84 mmol) N-(4-(benzyloxy)-2-methyl-6-nitrophenyl)tetrahydro-2H-pyran-4-carboxamide were placed in 10 mL acetic acid and hydrogenated under a hydrogen atmosphere and with the addition of 0.10 g palladium/charcoal (10%) at 50° C. and a hydrogen pressure of 5 bar until all the hydrogen had been taken up. The catalyst was filtered off and the filtrate was evaporated down i.vac.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:13]C1C=C(C=CC=1)C#N>>[Cl:13][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cccc(Cl)c1
Reactant: Brc1cccc(-c2nn[nH]n2)c1
Product: Clc1cccc(-c2nn[nH]n2)c1

Procedure:
Following the procedure in COMPOUND 3 for the synthesis of intermediate 5-(3-bromophenyl)-2H-tetrazole, 3-chlorobenzonitrile (1.88 g, 13.67 mmol) was employed to obtain 5-(3-chlorophenyl)-2H-tetrazole.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[S:5][CH:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:16][N:17]1[C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=[N:18]1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][N:17]1[C:21]([C:2]2[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[S:5][CH:6]=2)=[CH:20][CH:19]=[N:18]1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(O)c1cc(Br)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nccc1-c1csc(C(=O)O)c1
Temperature: 85 °C

Procedure:
To a solution of 4-bromo-2-thiophenecarboxylic acid (3.91 g, 18.9 mmol) in dioxane/H2O (4:1, 100 mL) was added Cs2CO3 (21.7 g, 66.6 mmol), tetrakistriphenylphosphine Pd(0) (1.1 g, 0.95 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.94 g, 18.94 mmol) [prepared according to the procedure of Preparation 7]. The reaction mixture was heated to 85° C. in a sealed tube for 12 hours and partitioned between H2O and CHCl3. The pH of the aqueous phase was adjusted to ˜3 with 6N HCl and washed several times with CHCl3. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification (2.84 g, 13.64 mmol, 72%): LC-MS (ES) m/z=209 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.Cl.Cl[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[C:4]([F:9])[CH:3]=1
Reactant: CCN(CC)CCCl
Reactant: Oc1ccc(Br)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc(Br)cc1F

Procedure:
4-Bromo-2-fluorophenol (1.0 g, 5.24 mmol), 2-chloro-N,N-diethylethanamine HCL (0.90 mg, 5.24 mmol) and Cs2CO3 (8 g, 25 mmol) were combined in DMF (20 mL) and the mixture was heated at reflux over night. H2O was added and the mixture was extracted with EtOAc, then washed with 2N NaOH and brine. The organic layers were combined, dried over Na2SO4 and concentrated to a brown oil. Flash chromatography (gradient eluent: 10-50% EtOAc in hexanes) of the crude concentrate afforded title compound 56.