Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[N+:4]([O-])[CH:5]=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:16]>ClCCl.C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([CH2:12][OH:16])=[N:4][CH:5]=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1c(C)c[n+]([O-])c(C)c1Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1c(C)cnc(CO)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The above 3-chloro-4-methoxy-2,5-dimethylpyridine 1-oxide (530 mg) was suspended in 15 ml of dichloromethane, and trifluoroacetic anhydride (0.39 ml) was then added to the suspension under cooling on ice. The resulting mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with chloroform, and was then washed with a saturated sodium bicarbonate solution. The water layer was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled away, so as to obtain the title compound (521 mg) as an oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].[Cl:10][CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=O)=[CH:14][CH:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1Cl>[Cl:10][CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]2[O:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: Nc1cccc(Cl)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1Cl
Product: ClCc1ccc(-c2nc3cccc(Cl)c3o2)cc1

Procedure:
158.5 g of 2-(4'-chloromethylphenyl)-7-chlorobenzoxazole (produced by condensation of 2-amino-6-chlorophenol with 4-chloromethyl-benzoyl chloride and subsequent cyclisation in o-dichlorobenzene in the presence of p-toluenesulfonic acid, melting point 141° to 142° C.) is heated with 400 ml of triethyl phosphite in the course of 2 hours at 155° C., and the mixture is subsequently stirred at 155° to 158° C. for a further 7 hours. After cooling to 90° C., the unreacted triethyl phosphite is distilled off in vacuo. The reaction product, which is still oily, is stirred into 1000 ml of petroleum ether, and after a short time crystallisation occurs. The product is filtered off, washed with petroleum ether and dried. The yield is 210 g (97% of theory) of 2-(4'-diethylphosphonomethylphenyl)-7-chlorobenzoxazole having a melting point of 92° to 93° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][C:12]1[C:11]([C:15]([F:17])([F:16])[F:18])=[CH:10][C:9]2[NH:19][C:20](=[O:36])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccnc3)c1)=N2

Procedure:
The title compound was prepared from {5-methyl-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M154) (260 mg, 0.506 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (166 mg, 83%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[C:11]([O:19][C:20]1[CH:28]=[C:27]([O:29][C:30](=O)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23])(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:19][C:20]1[CH:28]=[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:26]=[CH:25][C:21]=1[C:22]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:23])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: NCCCN1CCCCC1
Reactant: O=C(Oc1ccc(C(=O)O)c(OC(=O)c2ccccc2)c1)c1ccccc1
Product: O=C(NCCCN1CCCCC1)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Yield: 94.8 %

Procedure:
Condensation between 1-(3-aminopropyl) piperidine (427 mg) and 2,4-dibenzoyloxybenzoic acid (1.0 g) is carried out in the same manner as in Example 7, i) to yield 1-[3-(2,4-dibenzyloxybenzoyl)aminopropyl]piperidine (1.2 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([O:10]C)=O)=[N:6][CH:7]=1.O.[NH2:13][NH2:14]>CCO>[Br:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([NH:13][NH2:14])=[O:10])=[N:4][CH:3]=1
Reactant: COC(=O)c1ncc(Br)cn1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
To a slurry of methyl 5-bromopyrimidine-2-carboxylate (1.0 g, 4.6 mmol) in EtOH (3.6 mL) was added hydrazine monohydrate (0.46 mL, 9.2 mmol). The reaction mixture was stirred at rt for 1 h. The mixture was filtered, and the collected solid was washed with additional EtOH to provide the desired product as a beige solid (720 mg, 72%). MS (ESI): mass calcd. for C5H5N4O, 216.0; m/z found, 217.0 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 10.15 (s, 1H), 9.18-9.08 (s, 2H), 4.67 (s, 2H).
Reaction SMILES: [CH3:1][N:2]([CH2:9][C:10]([O:12]CC)=[O:11])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[ClH:15]>O1CCOCC1>[ClH:15].[CH3:1][N:2]([CH2:9][C:10]([OH:12])=[O:11])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)CN(C)c1ccncc1
Agent: Cl
Solvent: C1COCCO1
Product: CN(CC(=O)O)c1ccncc1
Temperature: 95 °C
Reaction time: 20 h

Procedure:
1.28 g (6.60 mmol) of ethyl [N-methyl-N-(pyridine-4-yl)amino]acetate was stirred in 30 ml of dioxane. 26 ml of 1 N hydrochloric acid was added to the resultant mixture, and they were stirred at 95° C. for 20 hours. The solvent was evaporated under reduced pressure to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[F:17].C(=O)(O)[O-].[Na+].O>CS(C)=O>[F:17][C:9]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=1[N:4]1[CH:5]=[N:6][C:2]([CH3:1])=[N:3]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Cc1nc[nH]n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2F)n1
Temperature: 80 °C
Yield: 17 %

Procedure:
Step C (1): A mixture of 3-methyl-1H-1,2,4-triazole (15.0 g, 181 mmol), 1,2-difluoro-4-nitrobenzene (28.7 g, 181 mmol), and sodium bicarbonate (15.2 g, 181 mmol) in DMSO (100 mL) was heated at 80° C. for 48 h. The reaction mixture was allowed to cool to rt and was poured into water (800 mL). The aqueous mixture was extracted with EtOAc (3×200 mL). The combined organic extracts were sequentially washed with water (500 mL) and brine solution (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude reaction mixture was purified using silica gel chromatography (30-80% EtOAc/hexane, linear gradient) to afford two regioisomeric products. Pure fractions of the less polar regioisomer were combined and concentrated to afford 1-(2-fluoro-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (7.2 g, 30.8 mmol, 17% yield) as an off-white solid. Pure fractions of the more polar regioisomer were combined and concentrated to afford 1-(2-fluoro-4-nitrophenyl)-5-methyl-1H-1,2,4-triazole (6.23 g, 28.0 mmol, 15% yield) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([I:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:12]1[C@H:19]2[C@@H:15]([O:16]C(C)(C)[O:18]2)[C@H:14]([C:22]([OH:24])=[O:23])[O:13]1>C(O)=O>[NH2:1][C:2]1[N:10]=[C:9]([I:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:12]1[O:13][C@H:14]([C:22]([OH:24])=[O:23])[C@@H:15]([OH:16])[C@H:19]1[OH:18]
Reactant: CC1(C)O[C@@H]2[C@@H](O1)[C@H](C(=O)O)O[C@H]2n1cnc2c(N)nc(I)nc21
Solvent: O=CO
Product: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](C(=O)O)[C@@H](O)[C@H]1O
Yield: 84.9 %

Procedure:
A solution of 1.72 g (3.85 mmol) of (2R,1R,4R,5R)-4-(6-amino-2-iodopurin-9-yl)-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]octane-2-carboxylic acid (6.7) in 80 mL of 50% HCOOH was stirred at 80° C. for 1.5 hours. The reaction mixture was evaporated under reduced pressure, dissolved in H2O, and the solution was evaporated again. This process was repeated until there was no odor of formic acid in the residue. Recrystallization from water yielded 1.33 g (85%) 6.8 as a white solid, m.p. 221-223° C. dec. 1H NMR (300 MHz, DMSO-d6) δ 8.31 (s, 1H, H-8), 7.68 (s, 2H, NH2), 5.90 (d, J=6.55 Hz, 1H, H-1′), 4.42 (m, 1H, H-2′), 4.35 (d, J=2.31 Hz, 1H, H-4′), 4.22 (m, 1H, H-3′).
Reaction SMILES: CC(C)([O-])C.[K+].Br[C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[NH:18][CH2:19][CH:20]([OH:22])[CH3:21])=[CH:15][CH:14]=[CH:13][CH:12]=2.O>CN(C=O)C>[CH3:21][CH:20]1[O:22][C:8]2[CH:9]=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[NH:18][CH2:19]1
Reactant: CC(O)CNc1c(Br)cnc2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CNc2c(cnc3ccccc23)O1
Temperature: 140 °C
Reaction time: 4 h

Procedure:
Potassium tertiary butoxide (5 g) was added to a solution of 3-bromo-N-(2-hydroxypropyl)-4-quinolinamine (9 g) in 30 ml of DMF and the mixture stirred at 140° C. for 4 hours. The mixture was cooled to room temperature and poured into 200 ml of water. The product was extracted with dichloromethane and purified by HPLC (solvent: DCM:MeOH=10:1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][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]([F:21])[CH:3]=1.Cl[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N+:29]([O-:31])=[O:30].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.O>[Cl:1][C:2]1[C:7]([O:8][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-:31])=[O:30])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[NH:11][C:10]2=[O:20])=[C:4]([F:21])[CH:3]=1
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(O)c(Cl)cc1F
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(Oc2ccccc2[N+](=O)[O-])c(Cl)cc1F

Procedure:
A mixture of 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (2.2 g), 2-chloronitrobenzene (1.3 g) and potassium carbonate (1.4 g) in N,N-dimethylformamide (100 ml) was heated at reflux for 3 hours under an atmosphere of nitrogen. The resulting mixture was poured into water (200 ml) and acidified by the addition of a small portion of conc. hydrochloric acid. The solution was extracted with a mixed solvent (ethyl acetate:hexane, 1:1,400 ml) and the organic phase dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue chromatographed on silica gel eluting with ethyl acetate:hexane, 1:1, to give 3-[4-chloro-2-fluoro-5-(2-nitrophenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-18) as an amorphous solid (1.0-g).
Reaction SMILES: [NH3:1].[Br:2][C:3]1[C:4](=[O:17])[C:5]2[C:10]([C:11](=[O:14])[C:12]=1Br)=[CH:9][C:8]([CH3:15])=[C:7]([CH3:16])[CH:6]=2>[N+](C1C=CC=CC=1)([O-])=O>[NH2:1][C:12]1[C:11](=[O:14])[C:10]2[C:5]([C:4](=[O:17])[C:3]=1[Br:2])=[CH:6][C:7]([CH3:16])=[C:8]([CH3:15])[CH:9]=2
Reactant: Cc1cc2c(cc1C)C(=O)C(Br)=C(Br)C2=O
Reactant: N
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1cc2c(cc1C)C(=O)C(Br)=C(N)C2=O
Yield: 86 %

Procedure:
Dry ammonia was passed through a refluxing solution of 2,3-dibromo-6,7-dimethyl-1,4-naphthoquinone (10 g; mp 237°-238° C.) in dry nitrobenzene (65 ml) for 30 mins. and the orange solid which separated on cooling was filtered off and washed with light petroleum. After removal of ammonium bromide with water, 6.96 g. (86%) of material of mp 228° C. was obtained. Recrystallisation from glacial acetic acid gave analytically pure material of the same melting point. ν max(mull) 3400, 3300, 1680, 1610, 1585, 1570 cm-1. δ(DMSO) 2.35 (6H,s); 7.35 (2H, exchangeable broad singlet); 7.74 (2H,s). (Found; C, 51.50; H, 3.38; N, 4.79; C12H10BrNO2 requires; C, 51.45; H, 3.60; N, 5.00%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:25][CH2:26][C:27]2[CH:31]=[CH:30][O:29][CH:28]=2)=[C:8]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][C:13]=3[N:14]=2)[CH:9]=1)([O-])=O>[Zn]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:25][CH2:26][C:27]2[CH:31]=[CH:30][O:29][CH:28]=2)=[C:8]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:15][C:13]=3[N:14]=2)[CH:9]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccoc2)c(-c2nc3cc(-c4ccccc4)ccc3o2)c1
Agent: [Zn]
Product: Nc1ccc(OCc2ccoc2)c(-c2nc3cc(-c4ccccc4)ccc3o2)c1

Procedure:
Prepared by the method of Example 47b), from 2-(5-nitro-2-(3-furanylmethoxy)phenyl)-5-phenylbenzoxazole (392 mg, 0.95 mmol) and zinc (622 mg, 9.5 mmol) the subtitle compound was obtained (382 mg, 93%). The product was used directly in the next step without purification.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[N:6]=1.[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[CH:21]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N:20]1([C:2]2[O:3][C:4]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=3)[N:6]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[CH:21]1
Reactant: COC(=O)CCc1oc(Cl)nc1-c1cccc(Cl)c1
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1oc(-n2cnc3ccccc32)nc1-c1cccc(Cl)c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
A mixture of methyl 3-[2-chloro-4-(3-chlorophenyl)-5-oxazolyl]propionate (2.31 g), 1H-benzoimidazole (1.82 g), potassium carbonate (3.19 g) and N,N-dimethylformamide (12 mL) was stirred at 120° C. for 2 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[2-(1H-benzoimidazol-1-yl)-4-(3-chlorophenyl)-5-oxazolyl]propionate (1.85 g, 63%) was obtained as a solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][OH:19].C([O-])([O-])=O.[K+].[K+].O>CC(=O)CC>[OH:19][CH2:18][CH2:17][N:10]1[CH2:9][CH2:8][C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:15][CH:14]=2)([OH:13])[CH2:12][CH2:11]1
Reactant: OCCBr
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: Cc1ccc(CC2(O)CCN(CCO)CC2)cc1
Yield: 69 %

Procedure:
A mixture containing 4-(4-methyl-benzyl)-piperidin-4-ol (5.1 g, 25 mmol), 2-bromoethanol (1.8 ml, 25 mmol) and K2CO3 (5.2 g, 37.5 mmol) in 2-butanone (120 ml) was refluxed for 22 hours. H2O (30 ml) was added and the aqueous phase was extracted with ethylacetate. Combined organic phases were dried over Na2SO4, and concentrated. The residue was chromatographed over silica gel (CH2Cl2 --MeOH, 9:1 +NH4OH (1%)) to provide 1-(2-hydroxy-ethyl)-4-(4-methyl-benzyl)-piperidin-4-ol (4.3 g, 73%) as a yellow oil, MS: m/e=235.3 (M+).
Reaction SMILES: [CH:1]([C:4]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:25](=[O:27])[NH2:26])[N:5]1[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]([NH:12][C:13]([C:15]2[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[C:6]1=[O:24])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:37][C:38]([O:40]C(C)(C)C)=[O:39].O>CN(C)C=O>[CH:1]([C:4]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)([C:25](=[O:27])[NH2:26])[N:5]1[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]([NH:12][C:13]([C:15]2[N:16]([CH2:37][C:38]([OH:40])=[O:39])[C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[C:6]1=[O:24])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)C(C(N)=O)(c1ccccc1)N1CCCC[C@@H](NC(=O)c2cc3ccccc3[nH]2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C(C(N)=O)(c1ccccc1)N1CCCC[C@@H](NC(=O)c2cc3ccccc3n2CC(=O)O)C1=O

Procedure:
To a solution of example 46 (1.200 g) under nitrogen in anhydrous dimethylformamide (10 mL) at 0°-5° C. was added sodium hydride (60% dispersion in mineral oil, 0.113 g). After stirring until the reaction mixture was homogeneous, tert-butyl bromoacetate (0.434 mL) was added. The reaction mixture was maintained at 0°-5° C. for 1.5 h and then added to water (100 mL). The resulting slurry was cooled to 0°-5° C., filtered and the filter cake was dried under high vacuum to provide the title compound as an off-white solid (1.482 g). MS(ESI): [M+H]+ =561.2. 1H NMR (300 MHz, CDCl3) d=1.07 (d, J=6.8 Hz, 6H), 1.47-2.20 (m, 6H), 1.56 (s, 9H), 3.17 (m, 1H), 3.64-3.77 (m, 2H), 3.85 (d, J=16.6 Hz, 1H), 4.75 (m, 1H), 4.98 (m, 1H), 5.27 (m, 2H), 7.01 (b, 1H), 7.13 (m, 1H): 7.19-7.31 (m, 3H), 7.41-7.50 (m, 4H), 7.63 (m, 1H), 7.71 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][C:12]=1[CH3:13].[NH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.O>C(O)(=O)C>[CH3:13][C:12]1[CH:11]=[C:5]2[C:4](=[CH:3][C:2]=1[CH3:1])[C:9](=[O:10])[N:14]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[C:6]2=[O:8]
Reactant: Cc1cc2c(cc1C)C(=O)OC2=O
Reactant: Nc1cccnc1
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc2c(cc1C)C(=O)N(c1cccnc1)C2=O
Yield: 82.9 %

Procedure:
4,5-dimethylphthalic anhydride (2.0 g, 11 mmol) and 3-aminopyridine (1.0 g, 11 mmol) were heated under reflux in acetic acid (30 ml) for 1.5 hrs. After standing to cool, water was added thereto, the precipitated crystals were collected by filtration, washed with water, followed by drying to give 2.3 g of 5,6-dimethyl-2-(3-pyridyl)isoindolin-1,3-dione.
Reaction SMILES: C(S[C:4](=[N:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:5]([CH3:7])[CH3:6])C.[C:15]([NH:23][NH2:24])(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)CCC>[CH:5]([C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:23][N:24]=1)([CH3:7])[CH3:6]
Reactant: CCSC(=Nc1ccccc1)C(C)C
Reactant: NNC(=O)c1ccccc1
Solvent: CCCCO
Product: CC(C)c1nnc(-c2ccccc2)n1-c1ccccc1
Temperature: 130 °C
Reaction time: 7 h
Yield: 24 %

Procedure:
First, 6.1 g of N-[1-(ethylsulfanyl)isobutylidene]aniline, 3.4 g of benzoylhydrazine, and 30 mL of 1-butanol were put in a 200 mL recovery flask, and heated and stirred at 130° C. for 7 hours to be reacted. After the reaction, 1-butanol was distilled off under a reduced pressure to give an oily substance. This oily substance was purified by silica gel column chromatography. As developing solvents, first, dichloromethane was used, and then ethyl acetate was used. The resulting fraction was concentrated to give a white solid. The given solid was recrystallized from a mixed solvent of ethanol and hexane, so that 1.6 g of 3-isopropyl-4,5-diphenyl-4H-1,2,4-triazole was prepared as a white solid with a yield of 24%. The synthetic scheme of Step 1 is shown by (a-8).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][P:6]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])=[O:7])C.[Si:17]([O:34][CH2:35][CH:36]([OH:39])[CH2:37][SH:38])([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC1C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Si:17]([O:34][CH2:35][C@@H:36]1[O:39][C@@H:4]([CH2:5][P:6]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])=[O:7])[S:38][CH2:37]1)([C:30]([CH3:33])([CH3:31])[CH3:32])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(CP(=O)(OCC)OCC)OCC
Reactant: CC(C)(C)[Si](OCC(O)CS)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOP(=O)(C[C@@H]1O[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CS1)OCC
Temperature: 25 °C
Yield: 84.2 %

Procedure:
To a solution of diethylphosphonoacetaldehyde diethylacetal (12.23 g, 48.1 mmol, 1.2 eq.) and t-butyldiphenylsilyloxy-3-mercapto-2-propanol (13.63 g, 38.1 mmol, 1.2 eq.) in toluene (500 mL) was added pTSA (0.73 g, 3.8 mmol, 0.1 eq.). The mixture was stirred at reflux for 72 hr and was cooled to room temperature. A saturated solution of sodium bicarbonate was added and the aqueous phase was extracted with dichloromethane. The organic phase was dried with anhydrous magnesium sulphate and evaporated under reduced pressure. The crude material was purified by flash chromatography with ethyl acetate:hexane (2:1), and gave 16.31 g of the compound in a 87% yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH2:15])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3.[CH3:18][N:19]=[C:20]=[S:21]>ClCCl>[CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH:15][C:20]([NH:19][CH3:18])=[S:21])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3
Reactant: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Reactant: CN=C=S
Solvent: ClCCl
Product: CNC(=S)NC1c2cc3nonc3cc2OC(C)(C)C1O
Reaction time: 23 h
Yield: 46.5 %

Procedure:
200 mg (0.850 mmol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazole and 20 ml of dichloromethane were stirred at room temperature, and 68 mg (0.935 mmol) of methyl isothiocyanate were added thereto and stirred for 23 hours. The crystals precipitated were filtered off to obtain 122 mg of the intended compound as colorless crystals. (yield: 47%)
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:17]1[CH:25]=[C:24]2[C:20]([C:21]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][C:22]=3[N:23]2[CH3:26])=[CH:19][CH:18]=1>>[CH3:26][N:23]1[C:24]2[C:20](=[CH:19][CH:18]=[C:17]([N:12]3[CH:13]=[CH:14][C:9]([CH2:1][CH2:2][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)=[CH:10][C:11]3=[O:15])[CH:25]=2)[C:21]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][C:22]1=2
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)C2
Reactant: O=c1cc(CCc2ccccc2)cc[nH]1
Product: Cn1c2c(c3ccc(-n4ccc(CCc5ccccc5)cc4=O)cc31)CCN(C(=O)OC(C)(C)C)C2
Yield: 60.5 %

Procedure:
4-Phenethylpyridin-2(1H)-one (817 mg, 4.10 mmol) and tert-butyl 7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (1.5 g, 4.1 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (1.2 g, 60%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.53 (d, J=8.1 Hz, 1H), 7.34-7.29 (m, 4H), 7.26-7.20 (m, 3H), 7.03 (dd, J=8.2, 1.5 Hz, 1H), 6.50 (s, 1H), 6.09 (dd, J=6.9, 1.6 Hz, 1H), 4.63 (br s, 2H), 3.74 (br s, 2H), 3.63 (s, 3H), 2.98-2.91 (m, 2H), 2.84-2.79 (m, 4H), 1.51 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)=O)=[CH:4][C:3]=1[F:17].[C:18]1(=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:10]2[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=2)=[CH:4][C:3]=1[F:17]
Reactant: O=C(c1cccc(O)c1)c1ccc(Br)c(F)c1
Reactant: O=C1CCCCCC1
Product: Oc1cccc(C(=C2CCCCCC2)c2ccc(Br)c(F)c2)c1
Yield: 93 %

Procedure:
The general McMurry protocol, described for 14 was followed. Reaction of (4-bromo-3-fluorophenyl)(3-hydroxyphenyl)methanone (196 (0.860 g, 2.3 mmol) and cycloheptanone (0.814 mL, 6.87 mmol) afforded 0.80 g, (93%) of the title compound 197 as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.89 (app t, J=7.5 Hz, 1H), 7.17 (app t, J=7.8 Hz, 1H), 6.96 and 6.92 (dd, J1=9.6 Hz, J2=1.8 Hz, 1H), 6.86 and 6.84 (dd, J1=8.1 Hz, J2=1.8 Hz, 1H), 6.73 (app br d, J=8.1 Hz, 1H), 6.70 and 6.68 (dd, J1=8.4 Hz, J2=2.4 Hz, 1H), 6.61 (app t, J=1.8 Hz, 1H), 4.86 (s, 1H), 2.31 (br s, 4H), 1.59 (br s, 8H).