Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([C:23]2([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][N:31](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Zn]>[C:30]([C:2]1[CH:3]=[C:4]([CH:8]([C:23]2([OH:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1)#[N:31]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(c2cccc(Br)c2)C2(O)CCCCC2)CC1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(CC(c2cccc(C#N)c2)C2(O)CCCCC2)CC1
Temperature: 125 °C
Yield: 84 %

Procedure:
A mixture of tert-butyl 4-[2-(3-bromophenyl)-2-(1-hydroxycyclohexyl)ethyl]piperazine-1-carboxylate (see Example 135, step 2) (467 mg, 1.00 mmol), zinc cyanide (141 mg, 1.20 mmol), tris(dibenzylideneacetone)dipalladium (46 mg, 0.0500 mmol), 1,1′-bis(diphenylphosphino)ferrocene (55 mg, 0.100 mmol), and zinc dust (16 mg, 0.25 mmol) in anhydrous N,N-dimethylformamide (5 mL) was heated at 125° C. under nitrogen until all starting material was consumed (5 h). After cooling to room temperature, water (10 mL) and a 2 N aqueous solution of ammonium hydroxide (5 mL) were added and the mixture was extracted with ethyl acetate (1×20 mL). The combined organic extracts were washed with brine (15 mL), dried over sodium sulfate, filtered, and concentrated to give a brown solid, which was purified via flash column chromatography (silica, gradient from 5% ethyl acetate/hexane to 30% ethyl acetate/hexane) to yield 345 mg (84%) tert-butyl 4-[2-(3-cyanophenyl)-2-(1-hydroxycyclohexyl)ethyl]piperazine-1-carboxylate as a yellow solid. MS (ESI) m/z 414 ([M+H]+); HRMS: calcd for C24H35N3O3, 413.2678; found (ESI), 414.2745.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[O:19]([CH2:21][C:22]([OH:24])=[O:23])[NH2:20]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:20][O:19][CH2:21][C:22]([OH:24])=[O:23])=[O:14]
Reactant: NOCC(=O)O
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: O=C(O)CONC(=O)c1ccncc1Nc1ccc(I)cc1F

Procedure:
[({3-[(2-fluoro-4-iodophenyl)amino]isonicotinoyl}amino)oxy]acetic acid was synthesized according to the procedure for General Method 1, outlined above, starting with 0.3 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.51 mmol of aminoxy-acetic acid. LC/MS [5.21 min; 432 (M+1)]
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[NH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27].N1CCOCC1>CN(C=O)C.C(OCC)(=O)C.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>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:27][CH2:26][CH2:25][CH:24]=[CH2:23])[C:4]=2[N:3]=1
Reactant: C=CCCCBr
Reactant: C=CCn1c(Cl)nc2[nH]c(=O)[nH]c(=O)c21
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: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1COCCN1
Product: C=CCCCn1c(=O)[nH]c(=O)c2[nH]c(Cl)nc21
Reaction time: 18 h

Procedure:
8-Chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.10 g, 0.44 mmol) was dissolved in DMF (1.5 ml) containing sodium carbonate (0.12 g, 0.49 mmol) and 5-bromopentene (0.07 g, 0.49 mmol) and the mixture stirred for 18 h. On completion of alkylation, morpholine (0.5 ml) and tetrakis(triphenylphosphine)palladium (0) (0.08 g, 0.07 mmol) were added and stirring continued for 3.5 h. The reaction was diluted with ethyl acetate (10 ml) washed sequentially with 2N hydrochloric acid (2×5 ml) and brine (3×5 ml) and the organic isolated, dried (MgSO4) and concentrated. The crude product was suspended in methanol (2 ml) and purified on an aminopropyl SPE (5 g) eluting with methanol first then 5% acetic acid in methanol to elute the title compound which was isolated as a white solid after concentration (0.039 g, 35%). NMR; (400MHz, d6-DMSO) 1.75 (m, 2H), 2.05 (m, 2H), 3.85 (t, 2H, J=7 Hz), 4.95 (m, 1H), 5.05 (m, 1H), 5.8 (m, 1H), 11.1 (br s, 1H), one exchangeable proton not observed to δH 13; m/z 255[MH+]
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+]>Br>[CH3:1][N:2]([CH3:19])[C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)c2ccc(N(C)C)cc2)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: CN(C)c1ccc(C(=O)c2ccc(O)cc2)cc1
Yield: 77.2 %

Procedure:
A solution of 10.0 g 1-[4-(dimethylamino)phenyl]-1-(4-methoxyphenyl)-methanone in 30 ml 48% hydrobromic acid was heated at reflux for 21 hours. The reaction mixture was poured into aqueous sodium bicarbonate and the precipitate filtered. Recrystallization from 150 ml of methanol gave 7.3 g of white solid, m.p. 199°-200° C.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[CH:11](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:12]([CH3:14])=[O:13]>ClCCl>[O:13]=[C:12]([CH3:14])[CH:11]=[CH:7][C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc(C=O)cc1
Solvent: ClCCl
Product: CC(=O)C=Cc1ccc(C#N)cc1
Yield: 80 %

Procedure:
By stirring 3.02 g of 4-cyanobenzaldehyde and 7.32 g of acetonylidene-triphenylphosphorane in 50 ml of dichloromethane and then recrystallizing from isopropanol, 3.15 g (80%) of 4-(3-oxobutenyl)-benzonitrile is obtained. 1.71 g of it is mixed in 20 ml of dichloromethane with 20 ml of a 0.5 M solution of bromine in dichloromethane. After decolorization, the solvent is drawn off in a vacuum. The remaining oil is refluxed with 0.95 g of imidazole and 7 ml of triethylamine in 40 ml of toluene for 2 hours. A precipitate is filtered off, the filtrate is distributed in ethyl acetate-2M hydrochloric acid, the hydrochloric acid phase is alkalized with potassium carbonate and extracted with ethyl acetate. 1.2 g of a crude product is obtained, which, after recrystallization from isopropanol, yields the Z-isomer with mp. 131°-135° C. After chromatography of the mother liquor on silica gel (eluant ethyl acetate), the E-isomer is obtained from ethyl acetate/ether as crystals of mp: 123°-126° C.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([CH2:14][Cl:15])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12].Cl[CH2:17][S:18]([C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19].CC(C)([O-])C.[K+].Cl>C1COCC1>[Cl:1][CH2:2][CH:3]([CH2:14][Cl:15])[O:4][C:5]1[C:6]([N+:11]([O-:13])=[O:12])=[C:7]([CH2:17][S:18]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)(=[O:19])=[O:20])[CH:8]=[CH:9][CH:10]=1
Reactant: O=S(=O)(CCl)c1cccc2ccccc12
Reactant: O=[N+]([O-])c1ccccc1OC(CCl)CCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(CS(=O)(=O)c2cccc3ccccc23)cccc1OC(CCl)CCl
Temperature: -40 °C
Reaction time: 5 h
Yield: 66.3 %

Procedure:
A mixture of 1-(2-chloro-1-chloromethyl-ethoxy)-2-nitro-benzene (2) (2.0 g, 8 mmoles) and 1-chloromethane-sulfonyl-naphthalene (2.88 g, 12 mmoles) in THF at −78° C., under nitrogen, was treated dropwise over a 30 minute period with a solution of 1M potassium t-butoxide (18 ml, 18 mmoles). The reaction temperature was allowed to rise to −40° C. The reaction mixture was stirred at −40° C. for 5 hours poured into cold 2N HCl and extracted with EtOAc. The extracts were combined, dried over Na2SO4, and concentrated under vacuum. The resultant solid residue was recrystallized from CH2Cl2/hexane to afford the title compound as an off-white solid (2.4 g, 5.3 mmoles), identified by HNMR analysis.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:37][CH:38]([NH2:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.CS(C)=O>C(#N)C>[CH3:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:45][CH:38]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH3:37])=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: CC(N)c1ccccc1
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Solvent: CC#N
Solvent: CS(C)=O
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NC(C)c4ccccc4)n3Cc3ccccc32)cc1C

Procedure:
A solution of 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 (2 mmol), α-methylbenzylamine (4.2 mmol) in dimethylsulfoxide (7 mmol) and acetonitrile (15 mL) was stirred at 80° C. for 18 hours. The solvents were evaporated and the residue was dissolved in dichloromethane, washed with water, dried over anhydrous sodium sulfate and evaporated. The compound was purified by HPLC (normal phase, Luna® CN bonded packing (Phenomenex, Torrance, Calif.)) and crystallized from ethyl acetate/hexane. (0.93 g), m.p. 118-124°C. MS [(+)ESI, m/z]: 538 [M+H]+Anal. Calcd for C36H33N2O2: C, 80.12; H, 6.16; N, 7.79. Found: C, 79.97; H, 6.27; N, 7.78.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH:19]1[CH2:24][CH2:23][N:22]([CH:25]=[O:26])[CH2:21][CH2:20]1)[C:14](=[O:27])[N:13]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=1)[C:12]2=[O:39])C1C=CC=CC=1.C([O-])=O.[NH4+]>CCO.[Pd]>[CH3:38][O:37][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][C:32]=1[O:35][CH3:36])[CH2:28][N:13]1[C:12](=[O:39])[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=2)[N:15]([CH:19]2[CH2:24][CH2:23][N:22]([CH:25]=[O:26])[CH2:21][CH2:20]2)[C:14]1=[O:27]
Reactant: COc1ccc(Cn2c(=O)c3cc(OCc4ccccc4)ccc3n(C3CCN(C=O)CC3)c2=O)cc1OC
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COc1ccc(Cn2c(=O)c3cc(O)ccc3n(C3CCN(C=O)CC3)c2=O)cc1OC
Yield: 100 %

Procedure:
A mixture of 0.618 g of 4-[6-(benzyloxy)-3-(3,4-dimethoxybenzyl)-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde obtained in stage 1.7, 0.44 g of ammonium formate and 0.124 g of Pd/C (10%) in 10 ml of EtOH purged beforehand with nitrogen is irradiated under a microwave field at 80° C. for 2 h 00. The mixture is filtered and the filtrate is evaporated under reduced pressure to give 0.513 g of the expected product.
Reaction SMILES: [O:1]=[C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3]P(=O)(OCC)OCC.[H-].[Na+].[CH2:20]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH:36]=O)[CH2:32][CH2:31]1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH2:20]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH:36]=[CH:3][C:2](=[O:1])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:32][CH2:31]1)=[O:29])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCOP(=O)(CC(=O)c1ccccc1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(C=CC1CCN(C(=O)OCc2ccccc2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Diethyl (2-oxo-2-phenylethyl)phosphonate (0.96 mL,1.1 g, 4.4 mmol) was added in one portion to a stirred suspension of sodium hydride (60% oil dispersion, 158 mg, 3.95 mmol) in THF (20 mL). After 15 min. at RT, the clear solution was cooled in an ice bath and 1-(benzyloxycarbonyl)-4-piperidinecarboxaldehyde (840 mg, 3.40 mmol) was added in THF (1.0 mL) with additional THF (2×1.0 mL) for rinsing. Stirring was continued for a total of 2 h, with slow warming to RT. The mixure was then partitioned between ether (120 ml) and 2.5 N NaOH (60 mL). The organic layer was washed with saturated aq. NaCl (60 mL), dried (Na2SO4), decanted, and evaporated. The crude product was purified by flash column chromatography on silica gel eluting with 85:15 v/v to 80:20 v/v hexanes/EtOAc to give 0-95 g of the title compound as a colorless syrup: 1H NMR (400 MHz) δ 7.82 (d, J=8, 21), 7.57 (t, J=8, 1H), 7.48 (t, J=8, 2H), 7.39-7.29 (m, 51), 6.99 (dd, J=15, 6, 1H), 6.87 (dd, J=15, 1, 1H), 5.15 (s, 2H), 2.97-2.82 (m, 2H), 2.50-2.39 (m, 1H), 1.89-1.77 (m, 2H), 1.54-1.39 (m, 2H); ESI-MS 367 (M+NH3+H).
Reaction SMILES: Cl[CH2:2][C:3]([CH2:5][O:6][C:7](=[O:9])[CH3:8])=[O:4].O.[N-:11]=[N+:12]=[N-:13].[Na+]>O1CCCC1.CCOCC>[N:11]([CH2:2][C:3]([CH2:5][O:6][C:7](=[O:9])[CH3:8])=[O:4])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)OCC(=O)CCl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Chloro-3-acetoxyacetone (15.05 g.) is dissolved in tetrahydrofuran (50 ml.) and water (25 ml.) is added. Sodium azide (8.7 g.) is added and the mixture is allowed to stir overnight at room temperature. The reaction mixture is diluted with ether (200 ml.) and the aqueous phase is separated. The organic phase is washed once with brine, then dried and evaporated to give 1-azido-3-acetoxyacetone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][O:51][C:52](=[O:60])[CH2:53][CH:54]1[CH2:59][CH2:58][CH2:57][CH2:56][NH:55]1>CN(C=O)C.O>[CH3:50][O:51][C:52](=[O:60])[CH2:53][CH:54]1[CH2:59][CH2:58][CH2:57][CH2:56][N:55]1[C:14]([C:9]1[N:10]=[C:11]([CH3:13])[S:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:16]
Reactant: COC(=O)CC1CCCCN1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)CC1CCCCN1C(=O)c1nc(C)sc1-c1ccc(F)cc1
Reaction time: 0.25 h
Yield: 85 %

Procedure:
A stirring solution of 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (3.00 g, 12.5 mmol) in DMF (50 ml), under argon was treated sequentially with N,N-diisopropylethylamine (6.8 ml), HATU (4.77 g, 12.5 mmol) then after stirring for 0.25 h, piperidin-2-yl-acetic acid methyl ester (Beckett et al, J. Med. Chem., 563, 1969) (1.83 g, 12.5 mmol) was added. The mixture was stirred for 16 h at room temperature and was then diluted with water. The product was extracted into diethyl ether. The organic phase was washed with water (3×) and brine, was dried (MgSO4) and the solvent removed in vacuo to afford the title compound as a yellow gum (4.00 g, 85%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(N(CC)CC)C.O>C(Cl)(Cl)Cl>[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21]([O:1][CH:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC2CCCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 70 °C
Reaction time: 9 h
Yield: 28.3 %

Procedure:
To a solution of tert-butyl 3-hydroxypiperidine-1-carboxylate (2.00 g, 9.94 mmol) in chloroform (20 ml) were successively added p-toluenesulfonyl chloride (2.27 g, 11.9 mmol) and triethylamine (1.66 ml, 11.9 mmol) at 0° C., and the mixture was stirred at 70° C. for 9 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was successively washed with water and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate:hexane=1:1) to give tert-butyl 3-(toluene-4-sulfonyloxy)piperidine-1-carboxylate (1.00 g, yield 28%).
Reaction SMILES: CO.O.[Cl:4][C:5]1[CH:32]=[CH:31][C:8]([O:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=O)=[CH:7][CH:6]=1>O1CCCC1>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH2:11][NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][S:21]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)(=[O:22])=[O:23])=[CH:31][CH:32]=1
Reactant: O=C(COc1ccc(Cl)cc1)Nc1ccccc1NS(=O)(=O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=S(=O)(Nc1ccccc1NCCOc1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
In a 2-L three-neck flask, the product of step (2) (100.00 g) was dissolved in tetrahydrofuran (500 ml) by using a stirrer and cooled on a water bath so that the inside temperature became 2-3° C. To the resultant solution, a borane-tetrahydrofuran complex—1 M tetrahydrofuran solution (532 ml) was added by using a syringe. After stirring for one hour at 5° C., the mixture was further stirred for four hours at room temperature, to thereby obtain an almost colorless reaction mixture. The reaction mixture was cooled again on a water bath, and methanol (100 ml) was added gradually thereto by using a pipette, to dissolve the excessive borane-tetrahydrofuran complex. After completion of hydrogen gas generation, the reaction mixture was removed from the water bath and stirred for one hour during the temperature was returned to room temperature. Extremely small quantities of impurities such as fibers of filter were removed through suction-filtered and the solvent was removed under reduced pressure. To the residue was added methanol (300 ml) before drying, to thereby crystallize the residue. About one half in volume of methanol was removed under reduced pressure, to thereby yield a colorless mud-like product. The product was added to water (1 L) and the resultant solution was stirred. Crystals in the solution were suction-filtered, washed with water, and air-dried for three days, to thereby yield the target product (97.12 g). This product was submitted directly to the next reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[C:23]1([CH3:40])[CH:28]=[CH:27][C:26]([S:29]([NH:32][C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:37][C:36]2[CH:35]=[CH:34][C:33]([NH:32][S:29]([C:26]3[CH:27]=[CH:28][C:23]([CH3:40])=[CH:24][CH:25]=3)(=[O:31])=[O:30])=[CH:39][CH:38]=2)=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(N)cc2)cc1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(NC(=O)c3ccc(-c4cc(-c5nnc(C)o5)ccc4C)cc3)cc2)cc1

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-[4-(p-toluenesulphonamido)phenyl]-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 4-(p-toluenesulphonamido)aniline using method I. NMR; δH [2H6]—DMSO 10.26,(1H, s), 10.08,(1H, b), 8.01,(2H, d), 7.90,(1H, dd), 7.77,(1H, d), 7.63,(4H, m), 7.56,(3H, m), 7.33,(2H, d), 7.06,(2H, d), 2.56,(3H, s), 2.33-2.32,(6H, m). LCMS; retention time 3.52 min, MH+ 539.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:26][C@H:25]([CH2:27][O:28]C(=O)C)[C@@H:20]([O:21]C(=O)C)[C@H:15]([O:16]C(=O)C)[C@H:10]2[O:11]C(=O)C)[OH:9])=[CH:4][C:3]=1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]2([CH2:45][O:46][CH3:47])[CH2:44][CH2:43][CH2:42][CH2:41]2)=[CH:35][CH:34]=1.N1CCCC1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:26][C@H:25]([CH2:27][OH:28])[C@@H:20]([OH:21])[C@H:15]([OH:16])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]2([CH2:45][O:46][CH3:47])[CH2:41][CH2:42][CH2:43][CH2:44]2)=[CH:35][CH:34]=1
Reactant: COCC1(Oc2ccc(Cc3cc([C@@]4(O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)ccc3Cl)cc2)CCCC1
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: COCC1(Oc2ccc(Cc3cc([C@@]4(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)cc2)CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-chloro-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-[4-(1-methoxymethyl-cyclopent-1-yloxy)-benzyl]-benzene (0.39 g) in tetrahydrofuran (3 mL) is added pyrrolidine (0.22 mL). The solution is stirred at ambient temperature for 16 h. After dilution with ethyl acetate, the resulting solution is washed with aqueous hydrochloric acid (1 mol/l), dried (Na2SO4) and the solvent is removed under reduced pressure. The residue is purified by HPLC on reversed phase (YMC C18; water/acetonitrile 95:5→2:98).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:11]([NH:15][C:16]([NH2:18])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH3:19][CH2:20][O:21][C:22]([CH:24]1[C:28](=O)[CH2:27][CH2:26][CH2:25]1)=[O:23]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:11]([NH:15][C:16]([NH:18][C:25]2[CH2:26][CH2:27][CH2:28][C:24]=2[C:22]([O:21][CH2:20][CH3:19])=[O:23])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)OC(=O)c1cc(NC(N)=O)c(Cl)cc1Br
Reactant: CCOC(=O)C1CCCC1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(NC(=O)Nc2cc(C(=O)OC(C)C)c(Br)cc2Cl)CCC1

Procedure:
using isopropyl 2-bromo-4-chloro-5-ureidobenzoate and ethyl cyclopentanone-2-carboxylate in toluene there is obtained isopropyl 2-bromo-4-chloro-5-{3-[2-(ethoxycarbonyl)-1-cyclopenten-1-yl]ureido}-benzoate, m.p. 131°-132° C.,
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:17]([CH3:19])=O)[C:15]=2[OH:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]1[CH:30]=[C:29]([C:31]([NH:33][NH2:34])=[O:32])[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24].O.S(C1C=CC(C)=CC=1)(O)(=O)=O>>[F:20][C:21]1[CH:30]=[C:29]([C:31]([NH:33][N:34]=[C:17]([C:14]2[C:15]([OH:16])=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)[S:12][CH:13]=2)[CH3:19])=[O:32])[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: CC(=O)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Reactant: COC(=O)c1ccc(C(=O)NN)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2csc(-c3ccc(C(C)(C)C)cc3)c2O)cc1F
Yield: 94.2 %

Procedure:
From 2-(4-t-butylphenyl)-3-hydroxy-4-methylcarbonylthiophene (59.0 mg, 0.215 mmol), methyl 2-fluoro-4-hydrazinocarbonylbenzoate (45.6 mg, 0.215 mmol) and tosylic acid monohydrate (12.3 mg, 0.0645 mmol), 94.9 mg of the desired product was obtained in the same manner as in Synthetic Example 65 as a pale yellow solid (yield 94%).