Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[CH:20]=[C:19](C(O)=O)[S:18][C:17]=2[CH:24]=1.C(OCC)(=O)C.Cl>CC(N(C)C)=O.CCCCCC>[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[CH:20]=[CH:19][S:18][C:17]=2[CH:24]=1
Reactant: O=C(O)c1cc2ccc(Br)cc2s1
Agent: Cl
Solvent: CCCCCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: Brc1ccc2ccsc2c1
Temperature: 200 °C
Yield: 17 %

Procedure:
DBU (1.21 g, 8.00 mmol) was added to a stirred solution of 6-bromo-benzo[b]thiophene-2-carboxylic acid (I-25b: 2.4 g, 8.85 mmol) in DMA (4 mL) at room temperature and the resulting mixture was heated in microwave at 200° C. for 1 hour. The reaction was monitored by TLC (50% ethyl acetate in hexane). The reaction mixture was acidified with 1N HCl and extracted with ethyl acetate. The organic layer was concentrated and purified by column chromatography on silica gel (100% hexane) to afford 320 mg of the product (78% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][C:15]1[CH:28]=[CH:27][C:18]([O:19][CH:20]([CH3:26])[CH:21]=[CH:22][C:23]([OH:25])=[O:24])=[CH:17][CH:16]=1)([O-])=O.[H][H]>O1CCCC1>[NH2:1][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH:20]([CH3:26])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:27][CH:28]=1
Reactant: CC(C=CC(=O)O)Oc1ccc(Nc2ccc(C(F)(F)F)cc2[N+](=O)[O-])cc1
Reactant: [H][H]
Solvent: C1CCOC1
Product: CC(CCC(=O)O)Oc1ccc(Nc2ccc(C(F)(F)F)cc2N)cc1

Procedure:
12D, in solution in tetrahydrofuran, was placed on a Parr shaker and treated with hydrogen (40 psi hydrogen pressure, Parr shaker, 10% palladium-on-charcoal catalyst) to give 4-(4-(2-amino-4-(trifluoromethyl)phenylamino)phenoxy)pentanoic acid (12E), as an oil.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([O:15]C)=O)=[N:5]1)([CH3:3])[CH3:2].O.[NH2:18][NH2:19]>C(O)C>[CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([NH:18][NH2:19])=[O:15])=[N:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1nn(C(C)C)c2ccccc12
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)n1nc(C(=O)NN)c2ccccc21
Yield: 6715.2 %

Procedure:
To a stirred solution of methyl 1-isopropyl-1H-indazol-3-yl carboxylate (40.0 grams, 183.5 mmol, obtained in above step) in ethanol at room temperature hydrazine hydrate (130 mL, 2.56 mmol) was added. The reaction mixture was refluxed for 2 hours. The volatiles were removed under reduced pressure and the crude mass was diluted with dichloromethane, washed with water, brine, dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure to obtain the title compound (37.52 grams).
Reaction SMILES: [F:1][CH:2]([F:33])[O:3][C:4]1[C:13]2[C:8](=[C:9]([F:20])[CH:10]=[CH:11][C:12]=2[O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[N:7]=[C:6]([CH2:21][CH3:22])[C:5]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.[CH:34]1([C:37]2[NH:41][N:40]=[CH:39][CH:38]=2)[CH2:36][CH2:35]1>>[CH3:19][O:18][C:16](=[O:17])[CH2:15][O:14][C:12]1[CH:11]=[CH:10][C:9]([F:20])=[C:8]2[C:13]=1[C:4]([O:3][CH:2]([F:33])[F:1])=[C:5]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:40]3[CH:39]=[CH:38][C:37]([CH:34]4[CH2:36][CH2:35]4)=[N:41]3)=[CH:26][CH:25]=1)[C:6]([CH2:21][CH3:22])=[N:7]2
Reactant: c1cc(C2CC2)[nH]n1
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(B(O)O)cc1
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(-n2ccc(C3CC3)n2)cc1

Procedure:
The title compound was prepared by the method of Preparation 23b using (4-{[4-difluoromethoxy-2-ethyl-8-fluoro-5-(2-methoxy-2-oxoethoxy)quinolin-3-yl]methyl}phenyl)boronic acid and 5-cyclopropyl-1H-pyrazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=2)[C:23]([O:25]C)=[O:24])[CH2:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C[Si](C)(C)[O-].[K+]>C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=2)[C:23]([OH:25])=[O:24])[CH2:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(C(CCc2ccc(Cl)cc2)CC(=O)c2ccccc2)c1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: O=C(O)c1cccc(C(CCc2ccc(Cl)cc2)CC(=O)c2ccccc2)c1
Reaction time: 18 h
Yield: 62.6 %

Procedure:
3-[1-(2-(4-Chlorophenyl)ethyl]-3-oxo-3-phenylpropyl]-benzoic acid, methyl ester (0.5 g, 1.22 mmol) is dissolved in diethyl ether (100 mL) and treated with potassium trimethylsilanolate (1 g, 7.8 mmol). After the mixture is stirred 18 hours, the resulting solid is collected by filtration and washed with diethyl ether. The dried cake is dissolved in water, acidified with 1N hydrochloric acid, and the resulting solid collected by filtration. Crystallization in diethyl ether-hexane provides 0.3 g of the title compound as large cottony needles; mp 93°-95° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.Cl[C:21]1[N:26]=[C:25]([Cl:27])[C:24]([C:28]([F:31])([F:30])[F:29])=[CH:23][N:22]=1>CN(C=O)C.O.CCOC(C)=O>[Cl:27][C:25]1[C:24]([C:28]([F:30])([F:29])[F:31])=[CH:23][N:22]=[C:21]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=2)[N:26]=1
Reactant: CC(=O)c1ccc(N)cn1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.8 %

Procedure:
A suspension of 1-(5-aminopyridin-2-yl)ethanone (2.08 g, 15.3 mmol) in DMF (30 mL) and DIPEA (6.65 mL, 38.2 mmol) was stirred at room temperature for 15 minutes. 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (2.47 mL, 18.33 mmol) was added in 4 portions over 5 minutes. The reaction mixture was stirred at 60° C. for 2 hours under a nitrogen atmosphere before it was diluted with water and EtOAc. The aqueous was extracted several times with EtOAc and the combined organic phases were washed with water, brine, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The crude product was adsorbed onto silica gel and purified by column chromatography (CombiFlash Rf, 40 g SiO2 Cartridge, 0-30% EtOAc in cyclohexane) to give 2.17 g of a white solid. The 1:1 regiosiomeric mixture was dissolved in a minimum volume of cold (5° C.) acetonitrile (4-8 mL), sonicated for 10 seconds then filtered and dried to give the title compound (A141) as a white solid (1.14 g, 23%). LCMS-B: rt 7.34 min; m/z 317 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[N:8][OH:9])[NH2:7])=[CH:4][CH:3]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[OH-].[Na+].[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=O>CC1CCCO1.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[N:7]=[C:31]([C:27]3[O:26][CH:30]=[CH:29][CH:28]=3)[O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccco1
Reactant: NC(=NO)c1ccc(Cl)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC1CCCO1
Solvent: O
Product: Clc1ccc(-c2noc(-c3ccco3)n2)cc1
Temperature: 25 °C
Yield: 68.1 %

Procedure:
The 4-chlorobenzamidoxime (1.24 g, 7.25 mmol) was dissolved in 2-methyltetrahydrofuran (10.0 mL) and water (1.0 mL). A 40% aqueous solution of benzyltrimethylammonium hydroxide (100 uL) and 50% aqueous solution of sodium hydroxide (736 mg, 9.20 mmol) were added. The mixture was stirred and a precipitate formed. Furoyl chloride (1.24 g, 7.25 mmol) was added dropwise and an exotherm was noted. The mixture was stirred at 70° C. for 1 hour and cooled to room temperature. The solution was poured into water (25 mL) and the 2-methyltetrahydrofuran removed at reduced pressure. The resulting solids were isolated by vacuum filtration. The 3-(4-chlorophenyl)-5-(2-furanyl)-1,2,4-oxadiazole (1.22 g, 4.94 mmol) was obtained as a white solid. (68% yield).
Reaction SMILES: ClC1C=CC=CC=1NC(=O)NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=NC=1.[CH3:35][C:36]1[CH:37]=[C:38]([NH:43][C:44](=[O:71])[NH:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:60]=[C:59]4[C:55]([CH2:56][N:57]([C@@H:62]([CH:67]([CH3:69])[CH3:68])[C:63]([O:65]C)=[O:64])[C:58]4=[O:61])=[CH:54][CH:53]=3)=[CH:48][C:47]=2[F:70])[CH:39]=[CH:40][C:41]=1[CH3:42]>>[CH3:35][C:36]1[CH:37]=[C:38]([NH:43][C:44](=[O:71])[NH:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:60]=[C:59]4[C:55]([CH2:56][N:57]([C@@H:62]([CH:67]([CH3:68])[CH3:69])[C:63]([OH:65])=[O:64])[C:58]4=[O:61])=[CH:54][CH:53]=3)=[CH:48][C:47]=2[F:70])[CH:39]=[CH:40][C:41]=1[CH3:42]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(C)c(C)c4)c(F)c3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4Cl)cn3)cc2C1=O
Product: Cc1ccc(NC(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)cc2F)cc1C
Yield: 82 %

Procedure:
The compound of example 436 was prepared analogous to the compound of example 394 by hydrolysis of the compound of example 435.
Reaction SMILES: C(O)(=O)C.[BH4-].[Na+].[H][H].[NH2:9][C:10]1[CH:23]=[CH:22][CH:21]=[CH:20][C:11]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].C(=O)(O)[O-].[Na+]>C1COCC1.O.CCCCCC.CCOC(C)=O>[NH2:9][C:10]1[CH:23]=[CH:22][CH:21]=[CH:20][C:11]=1[CH:12]([OH:13])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [H][H]
Reactant: Nc1ccccc1C(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1ccccc1C(O)c1ccccc1

Procedure:
Acetic acid (2.28 mL, 2.4 g, 40.4 mmol) was added slowly to sodium borohydride (0.76 g, 20.2 mmol) in THF (20 mL) stirred in an ice bath. The mixture was stirred in the cold until hydrogen evolution had ceased. 2-Aminobenzophenone (2.0 g, 10.1 mmol) was added as the solid. The mixtuire was stirred under nitrogen at ambient temperature for 20 hours, after which time, TLC assay (silica gel, 1:9 EtOAc:hexane) indicated reaction was complete. The reaction mixture was treated with water (40 mL), then neutralized with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layers were combined, dired over sodium sulfate, filtered, and evaporated to dryness in vacuo to give 2-aminobenzhydrol.
Reaction SMILES: Cl[CH2:2][C:3]1[CH2:8][C:7](=[O:9])[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][N:4]=1.O1CCCC1.Cl.[CH3:24][NH:25][CH3:26].[OH-].[Na+]>O>[CH2:11]([O:10][C:6]1[C:7](=[O:9])[CH2:8][C:3]([CH2:2][N:25]([CH3:26])[CH3:24])=[N:4][CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CC(CCl)=NC=C1OCc1ccccc1
Reactant: CNC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CC1=NC=C(OCc2ccccc2)C(=O)C1
Reaction time: 1.5 h
Yield: 96.7 %

Procedure:
To a mixture of 2-chloromethyl-5-benzyloxy-4-pyridone (1.0 g), tetrahydrofuran (10 ml) and water (10 ml) were added dimethylamine hydrochloride (1.31 g) and sodium hydroxide (0.64 g). After being stirred for 1.5 hours, the mixture was concentrated under reduced pressure to dryness. The residue was dissolved in methanol and the insoluble material was filtered off. The filtrate was evaporated in vacuo to give 5-benzyloxy-2-(N,N-dimethylamino)methyl-4-pyridone (1.0 g) as a powder.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[N:22]2[CH:26]=[C:25]([CH2:27][OH:28])[CH:24]=[N:23]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[N:22]2[CH:26]=[C:25]([CH:27]=[O:28])[CH:24]=[N:23]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2cc(CO)cn2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2cc(C=O)cn2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-tert-butyl-N-[4-chloro-2-(4-hydroxymethyl-pyrazol-1-yl)-phenyl]-benzenesulfonamide (synthesized according to general procedure LL, 31 mg, 0.074 mmol) in CH2Cl2 (3 mL) was added Dess-Martin periodinane (34 mg, 0.33 mmol) and the reaction was stirred for 3 hours at room temperature. 10% Na2S2O3 (5 mL) and saturated aqueous NaHCO3 (5 mL) were added sequentially and the mixture was stirred an additional 30 minutes. The aqueous layer was subsequently separated and extracted with EtOAc (2×25 mL). The combined organic layers were washed with saturated aqueous NaHCO3 solution (20 mL) and brine (20 mL), dried (anhydrous Na2SO4), and concentrated in vacuo to afford 4-tert-butyl-N-[4-chloro-2-(4-formyl-pyrazol-1-yl)-phenyl]-benzenesulfonamide which was used for further transformation without purification.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].C(OCC)(=O)CC(OCC)=O.[F:16][C:17]1[CH:18]=[CH:19][C:20]([O:28][CH3:29])=[C:21]([CH:23]=[CH:24][C:25](=[O:27])[CH3:26])[CH:22]=1>C(O)C>[F:16][C:17]1[CH:18]=[CH:19][C:20]([O:28][CH3:29])=[C:21]([CH:23]2[CH2:3][C:2](=[O:1])[CH2:26][C:25](=[O:27])[CH2:24]2)[CH:22]=1
Reactant: COc1ccc(F)cc1C=CC(C)=O
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(=O)CC(=O)OCC
Product: COc1ccc(F)cc1C1CC(=O)CC(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 20% sodium ethoxide in ethanol (21.4 g) was added at room temperature diethyl malonate (11.2 g) and then was added little by little 4-(5-fluoro-2-methoxyphenyl)-3-buten-2-one (13 g), and the reaction mixture was stirred at room temperature for 30 minutes, refluxed for 2 hours and cooled. The solvent was evaporated, and to the residue was added water. The aqueous layer was washed with ethyl acetate and concentrated. To the residue was added 2M sodium hydroxide (50 ml), and the mixture was refluxed for 2 hours and cooled. To the mixture was added 2.5M sulfuric acid (50 ml) for 15 minutes, and the mixture was refluxed for 15 minutes and cooled. Precipitated crystals were washed with ethyl acetate to give 5-(5-fluoro-2-methoxyphenyl)cyclohexane-1,3-dione (9.6 g) as pale yellow crystals.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([NH:18][CH:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20]3)=[O:17])=[CH:10][C:9]=2[O:28][CH3:29])[CH:7]=1>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[CH:2]([C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([NH:18][CH:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20]3)=[O:17])=[CH:10][C:9]=2[O:28][CH3:29])[CH:7]=1)=[O:1]
Reactant: COc1cc(/C=C/C(=O)NC2CCc3ccccc32)ccc1-n1cnc(CO)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COc1cc(/C=C/C(=O)NC2CCc3ccccc32)ccc1-n1cnc(C=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 201 %

Procedure:
To a chloroform (5 mL) solution of (E)-3-(4-(4-hydroxymethyl-1H-imidazol-1-yl)-3-methoxyphenyl)-N-indan-1-ylacrylamide (15 mg) obtained in Example 45, activated manganese dioxide (280 mg) was added, and the reaction mixture was agitated at room temperature overnight. The reaction solution was filtered through a filter paper and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate), and 30 mg of the title compound was obtained.
Reaction SMILES: C([O:5][C:6]1[C:7](=[O:37])[C:8](=[O:36])[C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=2)[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:12]=1)(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[F:35][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][C:31]=1[F:34])[CH2:27][NH:26][CH:17]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:13]1[CH:12]=[C:11]([NH:10][C:9]2[C:6](=[O:5])[C:7](=[O:37])[C:8]=2[OH:36])[CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(C(NCc2ccc(F)c(F)c2)c2cccc(Nc3c(OC(C)(C)C)c(=O)c3=O)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(NCc2ccc(F)c(F)c2)c2cccc(Nc3c(O)c(=O)c3=O)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.09 g of 3-t-butoxy-4-{3-[(3,4-difluorobenzylamino)-(4-methoxyphenyl)methyl]phenylamino}-3-cyclobutene-1,2-dione [prepared as described in step (c) above] was dissolved in 30 ml of dichloromethane. 2 ml of trifluoroacetic acid were added to the resulting solution. The mixture was stirred at room temperature for 30 minutes, and then the solvent was distilled off under reduced pressure. Toluene was added to the residue, followed by azeotropic distillation twice. The resulting white solid was suspended in diethyl ether and collected by filtration, to obtain 830 mg of the title compound as a white solid.
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:7]=2[O:6][C:5]=1[C:16]([O:18]CC)=[O:17])(=[O:3])N.[OH2:21]>S(=O)(=O)(O)O>[OH:15][C:13]1[CH:12]=[CH:11][C:8]2[C:9](=[O:10])[C:4]([C:1]([OH:3])=[O:21])=[C:5]([C:16]([OH:18])=[O:17])[O:6][C:7]=2[CH:14]=1
Reactant: CCOC(=O)c1oc2cc(O)ccc2c(=O)c1C(N)=O
Reactant: O
Agent: O=S(=O)(O)O
Product: O=C(O)c1oc2cc(O)ccc2c(=O)c1C(=O)O

Procedure:
A mixture of 2.0 g (7.2 mmol) of ethyl 3-carbamoyl-7-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylate in 10 ml of 80% sulfuric acid was heated over a steam bath for 1 hr. and then poured into 50 ml of water. This was filtered and the filtrate evaporated in vacuo. The gummy residue was triturated with a minimum amount of water, the solid filtered and dried, mp 255°-257°C.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:23]=[N:24][N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:26]=3)=[CH:12][CH:11]=2)[C:7]2[CH:46]=[C:47]([C:51]3[N:52]=[C:53]([CH3:56])[O:54][CH:55]=3)[CH:48]=[C:49]([CH3:50])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-]=[N+]=[N-].[Na+]>CN(C)C=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:12][CH:11]=2)[C:7]2[CH:46]=[C:47]([C:51]3[N:52]=[C:53]([CH3:56])[O:54][CH:55]=3)[CH:48]=[C:49]([CH3:50])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3coc(C)n3)cc2n1Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)cc(-c3coc(C)n3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 103 from 4'-[(2-n-propyl-4-methyl-6-(2-methyl-oxazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]2[CH2:15][CH2:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH2:27][CH2:26][CH:25]([C@H:28]5[CH2:33][CH2:32][C@H:31]([CH2:34][CH2:35][CH3:36])[CH2:30][CH2:29]5)[CH2:24][CH:23]=4)=[CH:18][CH:17]=3)=[CH:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]>[Ni].C1(C)C=CC=CC=1>[CH2:1]([C@H:4]1[CH2:5][CH2:6][C@H:7]([C@H:10]2[CH2:11][CH2:12][C@H:13]([C:16]3[CH:21]=[CH:20][C:19]([C@H:22]4[CH2:27][CH2:26][C@H:25]([C@H:28]5[CH2:29][CH2:30][C@H:31]([CH2:34][CH2:35][CH3:36])[CH2:32][CH2:33]5)[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)[CH2:14][CH2:15]2)[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](C2CC=C(c3ccc(C4=CCC([C@H]5CC[C@H](CCC)CC5)CC4)cc3)CC2)CC1
Agent: [Ni]
Solvent: Cc1ccccc1
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc([C@H]4CC[C@H]([C@H]5CC[C@H](CCC)CC5)CC4)cc3)CC2)CC1

Procedure:
Raney Ni catalyst (0.5 g) was added to a solution of 1,4-bis[4-(trans-4-propylcyclohexyl)cyclohexen-1-yl]benzene (0.9 g) dissolved in toluene (70 ml), followed by subjecting to catalytic reduction at ordinary temperature under ordinary pressure, tracing the reaction by gas chromatography and stopping the reaction when the raw material disappeared. Since the product was a mixture of cis-form and trans-form substances, it was recrystallized from toluene to obtain an objective product, 1,4-bis[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]benzene (yield: 0.3 g, C-Sm point: room temperature or lower, Sm-I point: 300° C. or higher).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([F:20])=[C:7]2[O:11][C:10]([CH:12]3[CH2:14][CH2:13]3)=[N:9][C:8]2=[C:15]([C:18]#[N:19])[C:16]=1[CH3:17])=O.C(=O)([O-])[O-].[Cs+].[Cs+].[C:27]([NH2:30])(=[S:29])[CH3:28]>C1(C)C=CC=CC=1>[CH:12]1([C:10]2[O:11][C:7]3[C:8](=[C:15]([C:18]#[N:19])[C:16]([CH3:17])=[C:5]([C:3]4[N:30]=[C:27]([CH3:28])[S:29][CH:2]=4)[C:6]=3[F:20])[N:9]=2)[CH2:14][CH2:13]1
Reactant: Cc1c(C(=O)CBr)c(F)c2oc(C3CC3)nc2c1C#N
Reactant: CC(N)=S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: Cc1nc(-c2c(C)c(C#N)c3nc(C4CC4)oc3c2F)cs1
Temperature: 100 °C
Reaction time: 6 h
Yield: 44.2 %

Procedure:
6-(2-Bromoacetyl)-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-79) (39.98 g, 28.6 mmol) was dissolved in toluene (270 ml), then cesium carbonate (13.02 g, 39.90 mmol) and thioacetamide (2.58 g, 34.28 mmol) were added, followed by stirring at 100° C. for 6 hours under nitrogen atmosphere. The reaction liquid was cooled, the insoluble matter was separated by filtration through Celite, ethyl acetate was added to the filtrate, followed by washing with water and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure. The resulting residue was recrystallized and purified with n-hexane/ethyl acetate to obtain the entitled compound (3.96 g, 44%) as a white solid.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:8][CH2:7][C@@H:6]2[CH2:9][C@H:3]1[C:4](=[O:10])[O:5]2.[CH3:11][CH2:12][O-:13].[Na+]>C(O)C>[OH:13][C@H:12]1[CH2:9][C@@H:3]([C:4]([O:5][CH2:6][CH3:7])=[O:10])[C@H:2]([CH3:8])[CH2:1][CH2:11]1
Reactant: C[C@@H]1CC[C@@H]2C[C@H]1C(=O)O2
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)[C@@H]1C[C@H](O)CC[C@H]1C

Procedure:
reacting said (1R,2R,5R)-2-methyl-6-oxabicyclo[3.2.1]octan-7-one (9) with with EtONa and ethanol, or with Na and ethanol to produce ethyl (1R,2R,5R)-5-hydroxy-2-methylcyclohexane-1-carboxylate (10),
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CN=C1[C:24](C1NC=CN=1)=[O:25]>C1COCC1>[CH3:16][O:15][CH:14]([O:17][CH3:18])[CH2:13][N:12]1[C:3]2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:24]1=[O:25]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: COC(=O)c1cccc(N)c1NCC(OC)OC
Solvent: C1CCOC1
Product: COC(=O)c1cccc2[nH]c(=O)n(CC(OC)OC)c12
Yield: 59.5 %

Procedure:
The solution of methyl 3-amino-2-(2,2-dimethoxyethylamino)benzoate (0.7 g, 2.4 mmol) from Step C of Example 13 in THF (23 mL) with di(1H-imidazol-2-yl)methanone (0.4 g, 2.6 mmol) was refluxed overnight. The reaction mixture was washed with saturated aqueous sodium bicarbonate, re-extracted with methylene chloride, dried (Na2SO4), filtered, and concentrated under reduced pressure to give the crude material which was purified by column chromatography (silica gel, 0% to 100% ethyl acetate in hexanes) to afford methyl 3-(2,2-dimethoxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate (0.4 g, 60%): 1H NMR (300 MHz, DMSO-d6) δ 11.29 (s, 1H), 7.30 (dd, J=7.8, 1.2 Hz, 1H), 7.17 (dd, J=7.8, 1.5 Hz, 1H), 7.05 (t, J=7.8 Hz, 1H), 4.31 (t, J=5.4 Hz, 1H), 4.23-4.22 (m, 2H), 3.85 (s, 3H), 3.18 (s, 6H).