Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][C:6]([NH2:8])=[O:7])[CH2:2][CH2:3][CH3:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)[O-].[K+].C(O[CH2:24][CH3:25])C>O>[CH2:1]([N:5]1[CH:1]=[C:2]([CH2:3][CH2:4][CH2:24][CH3:25])[NH:8][C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCOCC
Reactant: CCCCNC(N)=O
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Product: CCCCc1cn(CCCC)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Under nitrogen, a stirred solution of 10.0 g (36.5 mmol) of N-t-Boc-L-norleucine-N-methoxy-N-methylamide from Step 2 in 100 mL of methylene chloride at 0° C. was treated with 100 mL of trifluoroacetic acid (TFA). The reaction was allowed to warm to ambient temperature and stir. After 2 h, the reaction was concentrated in vacuo to give the TFA salt of L-norleucine-N-methoxy-N-methylamide as a viscous colorless oil: NMR (CDCl3) δ0.88 (t, J=7 Hz, 3H), 1.30-1.40 (m, 4H), 1.88 (t, J=7 Hz, 2H), 3.25 (s, 3H), 3.75 (s, 3H), 4.35-4.46 (m, 1H), 7.55-7.76 (br s, 3H). Under nitrogen, the TFA salt was dissolved in 150 mL of chloroform at 0° C. and sequentially treated with 7.37 g (73 mmol) of triethylamine and 5.42 g (55 mmol) of butyl isocyanate. The reaction was allowed to warm to ambient temperature and stir overnight; concentration in vacuo provided the crude product. Purification by silica gel chromatography (Waters Prep-500A) using ethyl acetate gave 9.0 g (90% from N-t-Boc-L-norleucine-N-methoxy-N-methylamide) of the N-butylurea of L-norleucine-N-methoxy-N-methylamide as a colorless oil: NMR (CDCl3) δ0.83-0.95 (m, 6H), 1.25-1.47 (m, 8H), 1.48-1.60 (m, 1H), 1.63-1.75 (m, 1H), 3.02-3.26 (m, 2H), 3.21 (s, 3H), 3.84 (s, 3H), 4.82-4.93 (m, 1H). Under nitrogen, a 9.0 g (32.5 mmol) sample of the urea was dissolved in 150 mL of anhydrous diethyl ether; the solution was cooled to 0° C. and slowly treated with 41 mL (41 mmol, 1.25 equiv) of a 1.0 M solution of lithium aluminum hydride (LAH) in ether. The reaction was allowed to warm to ambient temperature and stir overnight. A solution of 7.87 g (58 mmol) of potassium bisulfate in 165 mL of water was added cautiously and the reaction stirred for 4 h. The reaction mixture was transferred to a separatory funnel and the phases separated. The aqueous phase was extracted 3 times with additional ether. The combined ether extracts were washed 3 times each with 3N hydrochloric acid, saturated sodium bicarbonate, and brine. The ether extracts were then dried (MgSO4) and concentrated in vacuo to give 5.40 (85%) of 3,5-dibutylimidazol-2-one as a viscous colorless oil which solidified on storage in the refrigerator: NMR (CDCl3) δ0.91 (t,=7 Hz, 3H), 0.93 (t, J=7 Hz, 3H), 1.28-1.41 (m, 4H), 1.47-1.65 (m, 4H), 2.36 (td, J=7 and 1 Hz, 2H), 3.55 (t, J=7 Hz, 2H), 5.84 (t, J=1 Hz, 1H), 9.78 (br s, 1H).
Reaction SMILES: Br[CH2:2][CH3:3].[O:4]=[C:5]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:9]2[CH2:21][CH2:22][C:23](=[O:24])[C:8]=2[CH:7]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=2[S:33]([CH3:36])(=[O:35])=[O:34])[NH:6]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:2]([N:6]1[CH:7]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=2[S:33]([CH3:36])(=[O:34])=[O:35])[C:8]2[C:23](=[O:24])[CH2:22][CH2:21][C:9]=2[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)[C:5]1=[O:4])[CH3:3]
Reactant: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CC2
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1S(C)(=O)=O
Temperature: 25 °C

Procedure:
Bromoethane (20 μL, 0.27 mmol) is added to a solution of 4-(2,5-dioxo-1-(3-(trifluoro-methyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)-3-(methyl-sulfonyl)benzonitrile (example 10, 60 mg, 0.11 mmol based on 90% purity) and cesium carbonate (74 mg, 0.23 mmol) in N,N-dimethylformamide (2.0 mL). The mixture is stirred at room temperature over night and purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 23 mg; ESI mass spectrum [M+H]+=504; Retention time HPLC: 0.86 min (005_CA01).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([O:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:23])[CH3:22]
Reactant: CCOC(=O)c1cc(N=Cc2ccccc2)ccc1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(N=Cc2ccccc2)ccc1OC(C)=O
Reaction time: 48 h
Yield: 73 %

Procedure:
Ethyl 2-hydroxy-5-benzylideneaminobenzoate (21 g, 78 mmole) was dissolved in pyridine (60 ml) and acetic anhydride (8.9 ml) was added after which the reaction mixture was kept at room temperature for 48 hours, evaporated to dryness in vacuo, and the residue recrystallized from hexane to give the title compound (17.8 g, 73%), m.p. 79°-80° C. Found (Calc. for C18H17NO4) C 69.33 (69.45), H 5.51 (5.47), N 4.57 (4.50).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH3:10])[N:8]([CH2:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)[C:7](=[NH:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[F:24][C:25]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:26]=1[C:27](Cl)=[O:28]>C1COCC1>[C:1]([C:5]1[N:9]([CH3:10])[N:8]([CH2:11][CH:12]2[CH2:13][CH2:14][CH2:15]2)/[C:7](=[N:16]/[C:27](=[O:28])[C:26]2[CH:30]=[C:31]([CH3:34])[CH:32]=[CH:33][C:25]=2[F:24])/[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1c(C(C)(C)C)cc(=N)n1CC1CCC1
Reactant: Cc1ccc(F)c(C(=O)Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(F)c(C(=O)/N=c2\cc(C(C)(C)C)n(C)n2CC2CCC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.9 %

Procedure:
To a solution of Example 113C (0.30 g, 1.4 mmol) and Et3N (0.56 mL, 4.1 mmol) in THF (10 mL) was added 2-fluoro-5-methylbenzoyl chloride (0.23 g, 1.4 mmol). The mixture was stirred at ambient temperature for 4 hours then partitioned between saturated aqueous NaHCO3 (10 mL) and EtOAc (10 mL). The layers were separated and the aqueous phase was extracted EtOAc (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 50% hexanes in EtOAc to 100% EtOAc to 9:1:0.1 EtOAc:MeOH:Et3N) afforded the title compound (0.24 g, 0.67 mmol, 50% yield). MS (ESI+) m/z 358 (M+H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH3:14])[C:7]([CH:15]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]1)=[C:6]2[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH3:14])[C:7]([CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:16]1)=[C:6]2[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COc1ccc2c(=O)n(C)c(C3CCCNC3)c(-c3ccccc3)c2c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(=O)n(C)c(C3CCCN(S(C)(=O)=O)C3)c(-c3ccccc3)c2c1

Procedure:
To a methylene chloride (0.100 mL) solution of (±)-6-methoxy-2-methyl-4-phenyl-3-piperidin-3-ylisoquinolin-1(2H)-one (30 mg, 0.086 mmol) and N,N-diisopropylethylamine (0.017 mL, 0.095 mmol) was added methanesulfonyl chloride (0.007 mL, 0.095 mmol). After 24 hours saturated sodium bicarbonate and additional methylene chloride were added. The layers were separated and the organic phase dried with anhydrous magnesium sulfate. Evaporation of the solvent in vacuo followed by trituration with ether-EtOAc gave a white solid which was isolated by vacuum filtration to give the titled product. ESI+MS: 427.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].[F:10][C:11]([F:26])([F:25])[C:12]1[C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[N:14]([CH2:21][C:22](O)=[O:23])[N:13]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>C(Cl)Cl.CN(C=O)C>[F:26][C:11]([F:10])([F:25])[C:12]1[C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[N:14]([CH2:21][C:22]([NH:1][C:2]2[S:3][CH:4]=[CH:5][C:6]=2[C:7]([NH2:9])=[O:8])=[O:23])[N:13]=1
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1CCCC2
Reactant: NC(=O)c1ccsc1N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)c1ccsc1NC(=O)Cn1nc(C(F)(F)F)c2c1CCCC2
Temperature: 120 °C
Yield: 1.7 %

Procedure:
2-aminothiophene-3-carboxamide (23 mg, 0.16 mmol) and 2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-1-yl)acetic acid (40 mg, 0.16 mmol) were dissolved in DCM/DMF (2 mL/50 μL) and polymer supported carbonyldiimidazole (264 mg, 1.2 mmol/g, 0.32 mmol) added. The reaction mixture was heated at 120° C. for 10 min in a Biotage SmithCreator microwave. The reaction mixture was filtered washing with MeOH (10 mL), EtOAc (10 mL), and MeCN (10 mL). The filtrate was concentrated in vacuo to give a yellow gum. Purification by preparative reverse phase HPLC gave desired product (1 mg, 2%).
Reaction SMILES: [S:1]([N:11]1[CH2:13][C@H:12]1[C:14]([O:16]C)=[O:15])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[OH-].[Na+].[NH2:20][C@H:21]([C:28]([OH:30])=[O:29])[CH2:22][C:23]1[N:27]=[CH:26][NH:25][CH:24]=1>CO>[C:28]([C@@H:21]([NH:20][CH2:13][C@H:12]([NH:11][S:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:2])=[O:3])[C:14]([OH:16])=[O:15])[CH2:22][C:23]1[N:27]=[CH:26][NH:25][CH:24]=1)([OH:30])=[O:29]
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: COC(=O)[C@@H]1CN1S(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N[C@@H](CN[C@@H](Cc2c[nH]cn2)C(=O)O)C(=O)O)cc1
Reaction time: 0.83 h
Yield: 30 %

Procedure:
A solution of methyl (2S)-1-tosyl-2-aziridinecarboxylate (1.04 g) in methanol was added to 1N aqueous sodium hydroxide (4.1 ml) in an ice bath and the mixture was stirred for 50 minutes at the same temperature. To the resulting solution were added L-histidine (2.11 g) and sodium hydroxide (730 mg) and the mixture was refluxed for 1.5 hours. After removal of the solvent in vacuo, the residue was dissolved in water and adjusted to pH 4 with 2N sulfuric acid. The solution was subjected to a column of "Diaion HP-20" (150 ml) and the column was washed with water. The elution was carried out with a mixture of water and methanol (1:1 400 ml). The eluate was evaporated in vacuo and the residue was chromatographed on a silica gel (100 g) column with a mixutre of chloroform, methanol and 28% aqueous ammonia (5:3:1) as an eluent to give (2S)-3-[[(1S)-1-carboxy-2 -(4-imidazolyl)ethyl]amino]-2-tosylaminopropionic acid (485 mg).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH2:13][CH3:14])=[N:9][NH:10]2)=[CH:6][CH:5]=1.[CH:15]1(Br)[CH2:19][CH2:18][CH2:17][CH2:16]1.O>CN(C=O)C>[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH2:13][CH3:14])=[N:9][N:10]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:6][CH:5]=1
Reactant: CCc1n[nH]c2cc(Br)ccc12
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nn(C2CCCC2)c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61.8 %

Procedure:
2.46 g (61.4 mmol, 1.05 equiv) sodium hydride, 60% oil dispersion, was added in 0.5 g portions to a 10° C. solution of 13.17 g (58.5 mmol, 1.0 equiv) 6-bromo-3-ethyl-1H-indazole in 500 mL anhydrous DMF. The mixture was stirred at room temperature for 20 minutes, then a solution of 8.8 mL (81.9 mmol, 1.4 equiv) cyclopentyl bromide in 10 mL anhydrous DMF was added dropwise. After 18 hours, the reaction mixture was poured into 2 L H2O and extracted 2×1 L ethyl acetate. The organic extracts were combined, washed 2×750 mL H2O, 1×500 mL brine, and dried over Na2SO4. Filtration, concentration of filtrate and drying gave 20.7 g of crude product, which was purified on a silica gel column (1.1 kg silica gel, 3% ethyl acetate/hexanes) to give 10.6 g (62%) of an amber liquid: IR (CHCl3)2972, 2875, 1606, 1501, 1048 cm−1 ; 1H NMR (300 MHz, CDCl3) d 7.56 (d, 1H, J=1.3 Hz), 7.52 (d, 1H, J=8.7 Hz), 7.17 (dd, 1H, J=1.5, 8.5 Hz), 4.83 (quintet, 1H, J=7.6 Hz), 2.96 (q, 2H, J=7.6 Hz), 2.15 (m, 4H), 2.0 (m, 2H), 1.65 (m, 2H), 1.36 (t, 3H, J=7.7 Hz); MS (thermospray, NH4OAc) m/z 295/293 (M+H+, base); Anal. calcd for C14H17N2Br: C, 57:35; H, 5.84; N, 9.55. Found: C, 57.48; H, 5.83; N, 9.90.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:22]O>>[CH3:22][O:15][C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)=[O:16]
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(-c2ccc(O)cc2)cc1

Procedure:
4-Benzyloxybenzoic acid chloride and an optically active 1,1,1-trifluoro-2-alkanol were allowed to react to give 1,1,1-trifluoro-2-alkyl 4-benzyloxybenzoate, which was subjected to hydrogenolysis to give 1,1,1-trifluoro-2-alkyl 4-hydroxybenzoate. An alkyl bromide and 2-hydroxynaphthalene-6-carboxylic acid methyl ester were allowed to react in the presence of potassium carbonate in a solvent such as dimethylformamide and then subjected to hydrolysis with an aqueous sodium hydroxide. The hydrolyzed product was allowed to react with 1,1,1-trifluoro-2-alkyl 4-hydroxybenzoate in the presence of dicyclohexylcarbodiimide to give 6-alkyloxynaphthalene-2-carboxylic acid 4-(1,1,1-trifluoro-2-alkyloxycarbonyl)phenyl ester. ##STR17## (B) 4-Hydroxybiphenyl-4'-carboxylic acid was dissolved in methanol and heated under refluxing in the presence of concentrated sulfuric acid to give 4-hydroxy-biphenyl-4'-carboxylic acid methyl ester. Then the ester and benzyl bromide were dissolved in a solvent such as DMF and the solution was allowed to react in the presence of anhydrous potassium carbonate to give 4-benzyloxybiphenyl-4'-carboxylic acid methyl ester. The compound obtained was subjected to hydrolysis with an aqueous sodium hydroxide solution to give 4-benzyloxy-biphenyl-4'-carboxylic acid. The compound was further allowed to react with thionyl chloride to give 4-benzyloxy-biphenyl-4'-carboxylic acid chloride.
Reaction SMILES: [Cl-].[Li+].Br[C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[C:6]([Cl:12])[CH:5]=1.[C:13]1([Sn](CCCC)(CCCC)CCCC)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[Cl:12][C:6]1[CH:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][C:7]=1[CH2:8][OH:9]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: OCc1ccc(Br)cc1Cl
Agent: [Pd]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: O
Product: OCc1ccc(-c2ccccc2)cc1Cl
Reaction time: 5 h
Yield: 21.2 %

Procedure:
To a suspension of lithium chloride (482 mg) in anhydrous 1,4-dioxane (12 ml) were added 4-bromo-2-chlorobenzyl alcohol (1.05 g), phenyl tributyl tin (1.74 g) and tetrakis(triphenylphosphine)palladium(O) (110 mg) under a nitrogen atmosphere, and the mixture was refluxed under heating. After 5 hr, the reaction mixture was cooled and water was added. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The filtrate was concentrated, and the residue was subjected to flash silica gel column chromatography (silica gel, 50 ml, eluent: hexane-ethyl acetate=2-1). The eluate was washed with hexane to give the objective compound (220 mg) as colorless crystals.
Reaction SMILES: O[C:2]1([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:22])[CH3:21]>C(OCC)(=O)C.CCCCCC>[CH3:21][C:3]1([CH3:22])[CH:2]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4]1
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2(O)c1cccs1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2c1cccs1
Yield: 65 %

Procedure:
Using N-(3-hydroxy-2,2,6,7-tetramethyl-3-(2-thienyl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 248, the title compound was synthesized in the same manner as in Example 271. Yield: 65%. Melting point: 137-138° C. (ethyl acetate-hexane).
Reaction SMILES: O.[NH2:2]N.C[N:5](/[CH:7]=[N:8]/[C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([I:17])[CH:11]=1)C>C(O)(=O)C>[I:17][C:12]1[CH:11]=[C:10]([C:9]2[NH:8][CH:7]=[N:5][N:2]=2)[CH:15]=[CH:14][C:13]=1[CH3:16]
Reactant: NN
Reactant: Cc1ccc(C(=O)/N=C/N(C)C)cc1I
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(-c2nnc[nH]2)cc1I
Temperature: 90 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
Hydrazine monohydrate (0.30 g, 6.0 mmol) was added to a stirred solution of (E)-N-((dimethylamino)methylene)-3-iodo-4-methylbenzamide (preparation 48b, 1.20 g, 3.8 mmol) in acetic acid (6 mL) and the mixture was stirred and heated to 90° C. After 2 hours, the mixture was concentrated in vacuo and water and 2N aqueous sodium hydroxide solution were added to the residue. The solid that formed was filtered, washed with water and dried in vacuo to give the title compound (0.98 g, 91%) as a solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[NH:34][C:33](=[O:35])[C:20]3([CH2:25][CH2:24][N:23](CC4C=CC=CC=4)[CH2:22][CH2:21]3)[N:19]=[C:18]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:17]=2[CH:42]=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[NH:34][C:33](=[O:35])[C:20]3([CH2:25][CH2:24][N:23]([C:2]([O:4][CH2:5][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=4)=[O:3])[CH2:22][CH2:21]3)[N:19]=[C:18]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:17]=2[CH:42]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=NC12CCN(Cc1ccccc1)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(OCc1ccccc1)N1CCC2(CC1)N=C(c1ccccc1)c1cc(Cl)ccc1NC2=O
Reaction time: 3 h

Procedure:
10 g (0.029 mole) of a 50% strength solution of benzyl chloroformate in toluene are added to a mixture of 4.0 g (0.0093 mole) of 7-chloro-5-phenyl-1'-benzyl-spiro[1H-1,4-benzodiazepine-3,4'-piperidin]-2-(3H)-one and 2.4 g (0.029 mole) of finely powdered NaHCO3 in 80 ml of absolute chloroform. The reaction mixture is boiled for 3 hours, with reflux cooling. It is then poured onto ice and the organic phase is separated off and washed twice with 10% strength NaHCO3 solution. After drying over Na2SO4, the mixture is filtered and the solvent is evaporated off. A pale brown-colored remains, and is crystallized with petroleum ether. The compound is filtered off with suction, washed with petroleum ether and dried at 60° C. in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[ClH:26]>C(OCC)(=O)C>[ClH:26].[ClH:26].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccc(F)cc3)cs2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2csc(N3CCNCC3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.3 %

Procedure:
To a solution of tert-butyl 4-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]piperazine-1-carboxylate (3.29 g, 9.05 mmol) in ethyl acetate (100 ml) was added a 4N solution (100 ml) of hydrogen chloride in ethyl acetate, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure to give 2.32 g (76.3%) of the desired product as a solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][C:3]=1OS(C(F)(F)F)(=O)=O.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Sn](CCCC)(CCCC)CCCC>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][C:3]=1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[F:21]
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)c(F)cc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1F
Product: O=C1CCCc2cc(-c3ccccc3F)c(F)cc21
Yield: 53.2 %

Procedure:
Using 1.50 g (4.80 mmol) of 3,4-dihydro-7-fluoro-6-trifluoromethylsulfonyloxy-1(2H)-naphthalenone and 2.22 g (5.78 mmol) of 2-fluorophenyltributyltin, the same reaction as described in Reference Example 1 was carried out to obtain 0.66 g of the above-mentioned compound (yield 53%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH3:37])[O:5][C:6]1[CH:7]=[C:8]([O:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21]([O:23]CC)=[O:22])[CH2:18][N:19]=1)=[CH:11]2.O1CCCC1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][CH2:3][CH:4]([CH3:37])[O:5][C:6]1[CH:7]=[C:8]([O:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:18][N:19]=1)=[CH:11]2
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OC(C)COC)c3[nH]2)S1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COCC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
To a mixture of ethyl (2-{7-(2-methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (134 mg), tetrahydrofuran (1 mL) and ethanol (1 mL) was added 1M aqueous sodium hydroxide solution (0.51 mL). The whole was stirred at room temperature for 2 h, and then concentrated in vacuo. The residue was acidified by 1M hydrochloric acid, and then extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed successively with water and brine, dried (MgSO4), filtered, and concentrated in vacuo to give the title compound (57 mg, 43%) as a yellow amorphous solid. MS 519 (MH+).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:6])[CH2:4][NH2:5].S=[C:8]1[CH2:12][S:11][C:10](=[O:13])[NH:9]1>C(O)C>[CH3:1][NH:2][C:3](=[O:6])[CH2:4][NH:5][C:8]1[CH2:12][S:11][C:10](=[O:13])[N:9]=1
Reactant: O=C1NC(=S)CS1
Reactant: CNC(=O)CN
Solvent: CCO
Product: CNC(=O)CNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.2 %

Procedure:
To a solution of N-methylglycinamide (4.06 g) in ethanol (22 mL) was added 4-thioxo-1,3-thiazolidin-2-one (5.11 g), and the mixture was stirred at room temperature for 4 hr. The precipitate was collected by filtration and washed with ethanol to give the title compound (6.26 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH2:8][CH:7]=[C:6]2[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.[H][H]>C(O)C.[Pd]>[CH3:13][O:12][C:11]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH:6]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[CH2:7][CH2:8]2
Reactant: COc1ccc(C2=CCc3cc(OC)c(OC)cc32)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C2CCc3cc(OC)c(OC)cc32)cc1

Procedure:
A solution of 5,6-dimethoxy-3-(4-methoxyphenyl)indene (1.5 g, 5.32 mmol) in 60 ml of ethanol is hydrogenated in an autoclave in the presence of palladium on carbon (10%, 25 mg) under 5 bars of hydrogen for 1.5 h. After filtration of the catalyst, the evaporation of the solvent gives an oil which gradually solidifies (1.5 g, 100%).