Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([CH2:18]O)[N:9]=[N:8]1.Cl.Cl.[OH:31][NH2:32].O>CS(C)=O>[F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([CH:18]=[N:32][OH:31])[N:9]=[N:8]1
Reactant: NO
Reactant: OCc1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1cccnc1
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: ON=Cc1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1cccnc1
Reaction time: 6 h

Procedure:
Add 3 eq sulfur trioxide pyridine complex (Aldrich) to a solution of [1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazol-4-yl]-methanol in DMSO, then add 10 eq TEA. Stir for 6 hours, pour into 15 ml 1N HCl and extract with EtOAc (2×20 ml). Remove solvent and dissolve the crude aldehyde in MeOH. Add 1.5 eq of hydroxyl amine hydrochloride and stir for 6 hours. Pour into 50 ml water and extract with EtOAc. Purify via radial chromatography 1:1 hexanes:EtOAc to give the title compound. MS (IS) 416.1 (M+1). Rf=0.16 (1:1 hexanes:EtOAc).
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[NH:7][C:8]1([C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[C:25][CH2:26][N:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29]([C:36](=[O:41])[C:37]([F:40])([F:39])[F:38])=[CH:28]3)=[CH:20][CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:42])[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][N:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29]([C:36](=[O:41])[C:37]([F:40])([F:38])[F:39])=[CH:28]3)=[CH:22][CH:23]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(C#Cc2ccc(C#CCn3cc(C(=O)C(F)(F)F)c4ccccc43)cc2)COC(C)(C)OC1
Agent: [Pd]
Product: CC(C)(C)OC(=O)NC1(CCc2ccc(CCCn3cc(C(=O)C(F)(F)F)c4ccccc43)cc2)COC(C)(C)OC1
Reaction time: 16 h

Procedure:
A mixture of the product of Step D (0.6 g, 0.1 mmol) and 10% Pd/C (0.03 g) was stirred for 16 h under H2 (balloon). The catalyst was removed by filtration through Celite pad and filtrate evaporated to give the product (0.019 g; 32%), as pale paste. 1H-NMR (CDCl3) 1.4 (s, 3H); 1.42 (s, 3H); 1.46 (s, 9H); 1.94-2.0 (m, 2H); 2.22-2.29 (m, 2H); 2.51-2.57 (m, 2H); 2.63 (tr, 2H, J=7.30 Hz); 3.67 (d, 2H, J=11.79 Hz); 3.88 (d, 2H, J=11.69 Hz); 4.17 (tr, 2H, J=7.14 Hz); 4.98 (s, 1H); 7.05 (d, 2H, J=8.06 Hz); 7.11 (d, 2H, J=8.06 Hz); 7.30-7.38 (m, 3H); 7.85 (b, 1H); 8.37-8.42 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:24])[C:5]1=[O:34].C(N(C(C)C)CC)(C)C.[CH3:44][N:45]([CH:47]=[O:48])[CH3:46]>>[CH3:44][N:45]([CH3:46])[C:47]([NH:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][N:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)=[O:24])[C:5]1=[O:34])=[O:48]
Reactant: NCCn1c(=O)c(C(=O)NCCN2CCOCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Reactant: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)NCCn1c(=O)c(C(=O)NCCN2CCOCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
A solution of 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[2-(4-morpholinyl)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.025 g, 0.057 mmol) and diisopropyl ethylamine (0.05 mL, 0.29 mmol) in DMF (3 mL) under nitrogen was treated with N,N-dimethyl carbonyl chloride (0.0055 mL, 0.06 mmol) (40° C. After 2½ h the reaction was cooled, concentrated in vacuo, and the resulting residue was triturated with EtOAc and water, filtered, and dried in vacuo to provide the title compound as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.84 (s, 1 H), 2.39-2.47 (m, 4 H), 2.52-2.57 (m, 2 H), 2.71 (s, 6 H), 3.23-3.31 (m, 2 H), 3.44-3.55 (m, 2 H), 3.56-3.62 (m, 4 H), 4.12 (s, 2 H), 4.25 (t, J=6.32 Hz, 2 H), 6.57 (t, J=5.55 Hz, 1 H), 7.09-7.18 (m, 2 H), 7.41 (dd, J=8.70, 5.62 Hz, 2 H), 8.30 (s, 1 H), 8.53 (s, 1 H), 10.40 (t, J=5.90 Hz, 1 H); ES+ MS: 541 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH:26]1[O:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc(-c2cccc(O)c2)n1
Reactant: BrCCCCCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2cccc(OCCCCCCOC3CCCCO3)c2)n1
Temperature: 70 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of methyl 6-(3′-hydroxyphenyl)-pyridine-2-carboxylate (7) (250 mg, 1.1 mmol, 1.0 eq.) and 2-(6′-bromohexyloxy)tetrahydropyran (420 mg, 0.36 mL, 1.6 mmol, 1.5 eq.) in DMF (3 mL) was added K2CO3 (460 mg, 3.3 mmol, 3.0 eq.). The mixture was stirred vigorously overnight at 70° C. and then concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with NaH2PO4 buffer (pH 5, 1M) and brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography on silica using ethyl acetate:hexanes to provide 300 mg (65%) of 12. TLC Rf=0.5 (ethyl acetate:hexanes 1:1), MS m/z 330 (fragment after elimination of the THP group) [M+H]+
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[N:18][CH:19]=[C:20](Br)[CH:21]=1)[CH2:10][C:9]2([CH3:24])[CH3:23])=[O:5])[CH3:2].[C:25]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.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]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[N:18][CH:19]=[C:20]([C:32]3[CH:33]=[CH:34][C:29]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:30][CH:31]=3)[CH:21]=1)[CH2:10][C:9]2([CH3:24])[CH3:23])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cncc(Br)c1)N2
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cncc(-c3ccc(C(C)(C)C)cc3)c1)N2
Temperature: 120 °C
Yield: 70.3 %

Procedure:
A mixture of 2-(5-bromo-pyridin-3-yl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.0 g, 2.57 mmol), 4-tert-butylbenzeneboronic acid (0.7 g, 3.86 mmol), tetra(triphenylphosphine)palladium (150 mg, 0.13 mmol) and cesium carbonate (1.7 g, 5.14 mmol) in dimethyl formamide (10 mL) was heated for 3 h at 120° C. After coiling to room temperature, the mixture was treated with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (10% ethyl acetate/hexanes) to afford 2-[5-(4-tert-butyl-phenyl)-pyridin-3-yl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.8 g, 70%) as a white solid: MS (ESI) M+1=443.3.
Reaction SMILES: [C:1]1([S:7][CH2:8]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([O:12][P:13]([O:17]CC)[O:14][CH2:15][CH3:16])[CH3:11]>>[C:1]1([S:7][CH2:8][P:13](=[O:17])([O:14][CH2:15][CH3:16])[O:12][CH2:10][CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCSc1ccccc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CSc1ccccc1)OCC
Yield: 93.9 %

Procedure:
A stirred solution of 40.0 grams (0.25 mole) of phenylthiomethyl chloride and 58.2 grams (0.35 mole) of triethylphosphite was heated at 150°-160° C. for 4 hours, cooled and excess triethylphosphite removed by evaporation under reduced pressure. The residue was purified by distillation to give 61.1 grams (93.1%) of diethyl phenylthiomethylphosphonate; b.p. 155° C./0.6 mm. The nmr and the ir spectra were consistent with the assigned structure.
Reaction SMILES: O=[CH:2][CH2:3][C:4]1([C:20]([O:22]C)=O)[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1.Cl.[NH2:25][C@H:26]1[CH2:31][CH2:30][C@H:29]([OH:32])[CH2:28][CH2:27]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[OH:32][C@H:29]1[CH2:30][CH2:31][C@H:26]([N:25]2[CH2:2][CH2:3][C:4]3([CH2:5][CH2:6][N:7]([C:10]([O:12][CH2:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)=[O:11])[CH2:8][CH2:9]3)[C:20]2=[O:22])[CH2:27][CH2:28]1
Reactant: COC(=O)C1(CC=O)CCN(C(=O)OCc2ccccc2)CC1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC2(CC1)CCN([C@H]1CC[C@H](O)CC1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-benzyl 4-methyl 4-(2-oxoethyl)piperidine-1,4-dicarboxylate (4.80 g, 0.0150 mol), trans-4-aminocyclohexanol hydrochloride (2.5 g, 0.016 mol) and triethylamine (3.3 mL, 0.024 mol) in 1,2-dichloroethane (30.0 mL) was stirred at room temperature for 30 min. To the mixture was added sodium triacetoxyborohydride (7.9 g, 0.038 mol) with stirring. The mixture was stirred at room temperature for 1 h, then was heated at 80° C. for 2 h. After cooling, the mixture was diluted with dichloromethane, and washed with 1N HCl solution, NaHCO3 (7.5%), water, and brine successively, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography to give benzyl 2-(trans-4-hydroxycyclohexyl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (4.20 g, 72.0%).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[C:10](I)=[N:9]1)=O)(C)(C)C.C(OC([N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[C:34]1B1OB(C2CC3C(=CC=CC=3)N2C(OC(C)(C)C)=O)O1)=O)(C)(C)C.C(=O)(O)[O-].[Na+]>>[CH2:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][N:9]=[C:10]2[C:34]1[NH:33][C:41]2[C:36]([CH:35]=1)=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1c2ccccc2CC1B1OB(c2cc3ccccc3n2C(=O)OC(C)(C)C)O1
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(OCc3ccccc3)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Product: c1ccc(COc2ccc3[nH]nc(-c4cc5ccccc5[nH]4)c3c2)cc1
Yield: 80.9 %

Procedure:
Stage Ib: A suspension of 3.23 g of 5-benzyloxy-3-iodoindazole-1-carboxylic acid tert-butyl ester, 7.31 g of 2-[4-(1-tert-butoxycarbonyl-2,3-dihydro-1H-indol-2-yl)-1,3,2,4-dioxadiboretan-2-yl]indole-1-carboxylic acid tert-butyl ester, 2.07 g of palladium tetrakistriphenylphosphine and 11 ml of a saturated aqueous sodium bicarbonate solution is heated at reflux for approximately two hours and then at ambient temperature overnight. The reaction medium is filtered through paper, and the filtrate is then diluted with 150 ml of ethyl acetate. The organic phase is washed with 200 ml of distilled water. The aqueous phase is extracted with 2×150 ml of ethyl acetate. The organic phases are combined and washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and filtered. The solvent is evaporated off under vacuum in a rotary evaporator. The resulting crude product is purified by flash chromatography on silica 70-200 μm, eluent: cyclohexane/ethyl acetate gradient 95:5 to 70:30 to obtain 1.97 g of 5-benzyloxy-3-(1H-indol-2-yl)-1H-indazole.
Reaction SMILES: CC(C)(O[C:5]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O)C.[CH3:14][C:15]([C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:25]=1[OH:26])C=O)([CH3:17])[CH3:16].C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+].FC(F)(F)C(O)=O>CO.C1COCC1>[CH3:17][C:15]([C:18]1[CH:19]=[C:20]([CH2:5][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)[CH:23]=[C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:25]=1[OH:26])([CH3:14])[CH3:16]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1cc(CN2CCNCC2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Commercially available (1,1-dimethylethoxy)carbonylpiperazine (12.47 g) and 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzaldehyde (15.67 g) were dissolved in 1:1 mixture of methanol and THF (200 ml). The solution was cooled in an ice-bath, and sodium cyanoborohydride (6.2 g) was added portionwise over 2 h. The reaction mixture was allowed to warm to room temperature and stirred for 48 h. At this time 50 ml of a saturated solution of NaHCO3 was added, and the mixture was concentrated in vacuo. The residue was diluted with water and extracted with dichloromethane. The organic fractions (3×500 ml) were washed with water, brine and dried over sodium sulphate. After removal of the solvent in vacuo, the viscous material was dissolved in trifluoroacetic acid (100 ml) and stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was triturated with diethyl ether to afford a white solid. A small amount of this trifluoroacetic acid salt was converted into the corresponding free base and analysed as the required product. The product can be isolated as its free base by simple modification of the above described procedure.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH:7][C:8]([C:10]2[CH:11]=[CH:12][C:13]([N:16]3[CH2:21][CH2:20][CH:19](C4C=CC=C(C(F)(F)F)C=4)[CH2:18][CH2:17]3)=[N:14][CH:15]=2)=[O:9])=[N:4][C:3]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CN(C1CCN(C2C=CC(C(=O)NC3SC(C)=C(C4C=CC=CC=4)N=3)=CN=2)CC1)C(=O)O.ClC1C=CC(C(NC2SC(C)=C(C3C=CC=CC=3)N=2)=O)=CN=1.[C:92]([O:96][C:97](=[O:106])[N:98](C)[CH:99]1CCNCC1)([CH3:95])([CH3:94])[CH3:93]>>[C:92]([O:96][C:97](=[O:106])[N:98]([CH3:99])[CH:19]1[CH2:18][CH2:17][N:16]([C:13]2[CH:12]=[CH:11][C:10]([C:8](=[O:9])[NH:7][C:5]3[S:6][C:2]([CH3:1])=[C:3]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:4]=3)=[CH:15][N:14]=2)[CH2:21][CH2:20]1)([CH3:95])([CH3:94])[CH3:93]
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Reactant: Cc1sc(NC(=O)c2ccc(N3CCC(c4cccc(C(F)(F)F)c4)CC3)nc2)nc1-c1ccccc1
Agent: Cc1sc(NC(=O)c2ccc(Cl)nc2)nc1-c1ccccc1
Agent: Cc1sc(NC(=O)c2ccc(N3CCC(N(C)C(=O)O)CC3)nc2)nc1-c1ccccc1
Product: Cc1sc(NC(=O)c2ccc(N3CCC(N(C)C(=O)OC(C)(C)C)CC3)nc2)nc1-c1ccccc1

Procedure:
With a method similar to that used for the preparation of 4-(3-trifluoromethyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (5-methyl-4-phenyl-thiazol-2-yl)-amide, methyl-[5′-(5-methyl-4-phenyl-thiazol-2-ylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-carbamic acid tent-butyl ester was prepared from 6-chloro-N-(5-methyl-4-phenyl-thiazol-2-yl)-nicotinamide and methyl-piperidin-4-yl-carbamic acid tert-butyl ester. LCMS calcd for C27H33N5O3S (m/e) 507, obsd 508 (M+H).
Reaction SMILES: C[Al](C)C.[CH2:5]([NH2:8])[CH2:6][NH2:7].C(O[C:12]([CH:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=O)C>C1(C)C=CC=CC=1>[NH:7]1[CH2:6][CH2:5][N:8]=[C:12]1[CH:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)C1Cc2ccccc2N1c1ccccc1
Reactant: NCCN
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: c1ccc(N2c3ccccc3CC2C2=NCCN2)cc1

Procedure:
To a stirring solution of 2 molar trimethylaluminum in toluene (13.1 ml) at 10° C. under argon is added ethylenediamine (1.75 ml) dropwise under cooling to maintain a temperature of +10° C. It is allowed to ware to room temperature and then ethyl-2,3-dihydro-1-phenylindole-2-carboxylate (3.5 g) in toluene (15 ml) is added under argon. The whole is heated gradually to reflux and maintained at this temperature under argon for 18 hours. This cooled mixture is quenched in water (40 ml) and treated with methanol (40 ml) and methylene chloride (40 ml). The aqueous layer is separated and extracted further with methylene chloride (3×100 ml). The combined organic extracts are dried over sodium sulfate and concentrated to dryness at reduced pressure. The residue is dissolved in boiling ethyl acetate (150 ml), filtered through sodiumsulfate and concentrated to reduced pressure to a small volume from which yellow solid precipitates. The pure dl-2,3-dihydro-2-(4,5-dihydroimidazol-2-yl)-1-phenylindole, mp. 141° -144°, is thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH:21]=O)[CH:6]=1.[CH2:24]([NH2:26])[CH3:25]>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][NH:26][CH2:24][CH3:25])[CH:6]=1
Reactant: COC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2C=O)c1
Reactant: CCN
Product: CCNCc1cc(Br)ccc1Oc1cc(CC(=O)OC)ccc1OC

Procedure:
Prepared according to the procedure described in Example 3, Step 2, using the following starting materials: [3-(4-bromo-2-formyl-phenoxy)-4-methoxy-phenyl]-acetic acid methyl ester and ethylamine (2M in THF).
Reaction SMILES: [CH2:1]([C:5]1[NH:21][C:8]2=[N:9][C:10]([CH2:19][OH:20])=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:22]([O:24][CH:25]([N:27]1[C:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]2[CH:43]=[CH:42][C:41]([CH2:44]Br)=[CH:40][CH:39]=2)=[N:30][N:29]=[N:28]1)[CH3:26])[CH3:23].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:5]1[N:21]([CH2:44][C:41]2[CH:40]=[CH:39][C:38]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[C:31]3[N:27]([CH:25]([O:24][CH2:22][CH3:23])[CH3:26])[N:28]=[N:29][N:30]=3)=[CH:43][CH:42]=2)[C:8]2=[N:9][C:10]([CH2:19][OH:20])=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(C)n1nnnc1-c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc2cc(-c3ccccc3)c(CO)nc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc2cc(-c3ccccc3)c(CO)nc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(C)OCC)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.7 %

Procedure:
2.1 g(0.0075 mole) of the compound obtained in step 9 and 3.6 g(0.009 mole) of 2'-[1-(1-ethoxyethyl)-1H-tetrazol-5-yl]-biphenyl-4-ylmethyl bromide were dissolved in 20 ml of dimethyl formamide and to the resulting solution was added 2.1 g(0.015 mole) of K2CO3. The resultant was stirred for 5 hours at room temperature and diluted with 100 ml of ethyl acetate, and washed with water(50 ml×3). The organic layer was dried over Na2SO4, concentrated under reduced pressure and purified with column chromatography(5% MeOH/CH2Cl2) to obtain 2.85 g of the title compound(yield 65%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:30]2[C:31](/[CH:34]=[CH:35]/[C:36]3[CH:41]=[CH:40][C:39](Br)=[CH:38][CH:37]=3)=[CH:32][O:33][C:29]=2[CH:28]=[CH:27][CH:26]=1)(=[O:3])[CH3:2].[C:43]([OH:48])(=[O:47])[CH2:44][CH:45]=[CH2:46].C(N(CC)CC)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:30]2[C:31](/[CH:34]=[CH:35]/[C:36]3[CH:41]=[CH:40][C:39](/[CH:46]=[CH:45]/[CH2:44][C:43]([OH:48])=[O:47])=[CH:38][CH:37]=3)=[CH:32][O:33][C:29]=2[CH:28]=[CH:27][CH:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3occ(/C=C/c4ccc(Br)cc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C=CCC(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3occ(/C=C/c4ccc(/C=C/CC(=O)O)cc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C

Procedure:
A mixture of 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-[(E)-2-(4-bromophenyl)vinyl]benzofuran (0.2 g), 3-butenoic acid (0.053 mL), triethylamine (0.22 mL), palladium (II) acetate (7 mg) and tris(2-methylphenyl)phosphine (19 mg) in acetonitrile (4 mL) was heated for reflux under an argon atmosphere for 8 hours. The reaction mixture was cooled to room temperature, and the insoluble material was removed by filtration. The filtrate was diluted with ethyl acetate. The solution was washed with 0.5 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1-dichloromethane/methanol=20/1) to give the title compound (0.17 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH:11]1([Mg]Br)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C1(Br)CCCCC1.[Mg].C(O)(=O)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[OH:8])[CH:9]=1
Reactant: Br[Mg]C1CCCCC1
Reactant: O=Cc1cc(Br)ccc1O
Agent: [Mg]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: BrC1CCCCC1
Product: Oc1ccc(Br)cc1C(O)C1CCCCC1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 147 %

Procedure:
A solution of 3.35 g (0.0167 mole) 5-bromo-2-hydroxybenzaldehyde in 15 ml dry tetrahydrofuran (HF) was cooled to -78° C. To this was added dropwise over seven minutes, a solution of 9.37 g (0.050 mole) cyclohexylmagnesium bromide (prepared by reaction of cyclohexylbromide with an equimolar amount of magnesium turnings in THF under anhydrous conditions) in THF (50 ml). The reaction mixture was stirred at -78° C. for 1.5 hours, then at -10° C. for another hour. The reaction was quenched by addition of 3.0 g (0.050 mole) acetic acid, the mixture allowed to warm slowly to room temperature and stirred for 70 hours. Evaporation of solvent gave a viscous oil which was partitioned between 500 ml ethyl acetate and 300 ml 1N hydrochloric acid. The organic layer was washed with saturated sodium bicarbonate (2×300 ml), brine, dried (MgSO4), filtered and solvent evaporated in vacuo to yield 7.0 g of product as a viscous oil. The oil was purified by silica gel chromatography, eluting with 4:1 hexane/ethyl acetate to obtain 3.7 g (78%) of product which crystallized upon standing, m.p. 110-113° C. M.S. m/e): 286, 284, 268, 266, 201 (base).
Reaction SMILES: O.[C:2]([O-:9])(=[O:8])[C:3]([C:5]([O-:7])=[O:6])=O.[Na+].[Na+].[C:12]1([NH:18][NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>Cl>[C:12]1([NH:18][N:19]=[C:3]([C:5]([OH:7])=[O:6])[C:2]([OH:9])=[O:8])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C([O-])C(=O)C(=O)[O-]
Reactant: NNc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)C(=NNc1ccccc1)C(=O)O

Procedure:
Sodium mesoxalate monohydrate (5.00 g, 27.8 mmol) was dissolved in 1 M hydrochloric acid (50 ml) to give a colourless cloudy solution. Phenylhydrazine (3.00 g, 2.72 ml, 27.8 mmol) was added dropwise at room temperature to the stirred mixture. A yellow precipitate formed, was collected by filtration after 90 min and washed with water (50 ml). The filter cake was triturated with ethyl acetate/hexane [1:1], filtered and dried under vacuum. The title compound was isolated as a yellow powder (4.74 g, 22.7 mmol, 82%). LCMS: m/z 207 [M−H]+.