Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB(/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[C:25]1([C:24]([C:2]2[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=2)=[CH2:23])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC1(C)OB(/C=C/c2ccccc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
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: C1COCCO1
Solvent: O
Product: C=C(c1ccccc1)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 87.7 %

Procedure:
To a solution of tert-butyl 4-bromobenzoate (616 mg, 2.4 mmol) in 1,4-dioxane and water (4:1, 10 mL) were added (E)-4,4,5,5-tetramethyl-2-styryl-1,3,2-dioxaborolane (553 mg, 2.4 mmol), tetrakis(triphenylphosphine)palladium (58.9 mg, 0.05 mmol) and sodium carbonate (164 mg, 1.55 mmol). The mixture was stirred at 90° C. under nitrogen atmosphere for 18 hours. Once the start material was consumed, the resultant mixture was concentrated to give a residue and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=30:1) to give tert-butyl 4-(1-phenylvinyl)benzoate (0.59 g, 87.5%). 1H NMR (300 MHz, CDCl3): δ 7.96 (d, J=4.8 Hz, 2H), 7.41-7.26 (m, 7H), 5.55-5.53 (m, 2H), 1.61 (s, 9H).
Reaction SMILES: C(C[C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)#N.[CH2:9]([N:11](CC)CC)[CH3:10].[SH2:16]>N1C=CC=CC=1>[C:9]([NH:11][C:4]1[NH:8][CH:7]=[CH:6][N:5]=1)(=[S:16])[CH3:10]
Reactant: S
Reactant: N#CCc1ncc[nH]1
Reactant: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(=S)Nc1ncc[nH]1

Procedure:
2-Cyanomethylimidazole (0.83 g, 7.7 mmole) in 20 ml of dry pyridine was added to a medium pressure glass tube and was bubbled with hydrogen sulfide gas for 10 minutes. Then 1.5 equivalents of triethylamine (1.1 ml) was added. The tube was sealed and heated in a steam bath for 4 hours. The pressure tube was cooled and the excess hydrogen sulfide vented. Pyridine was removed under reduced pressure. Recrystallization from ethyl acetate-hexane afforded 0.42 gm of 2-thioacetamidoimidazole. m.p. 174° C. (decomposition).
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]4[CH2:30][CH2:29][C:27](=[O:28])[NH:26][C:24]=4[CH:25]=3)[CH2:11][CH2:10]2)[C:4]([Cl:8])=[C:5]([Cl:7])[CH:6]=1.C(N(CC)CC)C.[CH2:38]([N:40]=[C:41]=[O:42])[CH3:39]>ClCCl>[Cl:8][C:4]1[C:5]([Cl:7])=[CH:6][CH:1]=[CH:2][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[C:24]3[C:23]([CH2:30][CH2:29][C:27](=[O:28])[N:26]3[C:41]([NH:40][CH2:38][CH3:39])=[O:42])=[CH:22][CH:21]=2)[CH2:11][CH2:10]1
Reactant: CCN=C=O
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)N1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a solution of aripiprazole (1.5 g, 3.35 mmol) in dichloromethane (33 mL) was added triethylamine (0.56 mL, 4.01 mmol) and ethyl isocyanate (0.53 mL, 6.69 mmol). The reaction was stirred at room temperature for 5 days. The reaction was quenched with water and extracted with dichloromethane (3×20 mL). The organics were combined, washed with saturated aqueous sodium hydrogen carbonate (20 mL) and brine (20 mL), dried over MgSO4 and concentrated. The product was purified by column chromatography on silica eluting with 0-3% methanol in 1:1 ethyl acetate to dichloromethane. The product was triturated in heptane to remove aliphatic impurities and then filtered and dried. The material was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate (6×15 mL) to afford Compound-72 (0.482 g) as a pink solid.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[OH:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][CH:21]=[N:22]2.C[O:28][C:29](=[O:38])[CH:30](Br)[CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:32]1([CH2:31][CH:30]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:16][C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH:19]=[CH:20][CH:21]=[N:22]4)[CH:6]=[N:5]2)[C:29]([OH:28])=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: Oc1cccc2ncccc12
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Product: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc3ncccc23)cc1=O
Yield: 83 %

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 5-hydroxy-quinoline and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[6-oxo-4-(quinolin-5-yloxy)-6H-pyridazin-1-yl]-propionic acid (20 g, 83%) as a solid; LC-MS, [M+H+]=380.2; HPLC (0.17% trifluoroacetic acid in acetonitrile/water, 30%-90% acetonitrile, gradient, 1 mL/min, Venusil MP-C18, C18-15 cm×4.6 mm-5 μm) 254 nm, 95.8%; 214 nm, 99.8%. 1H-NMR (300 MHz, CDCl3): δ 1.12-1.25 (m, 2H), 1.50-1.84 (m, 7H), 2.11-2.20 (m, 1H), 2.33-2.43 (m, 1H), 5.54-5.59 (dd, J=10.5, 4.5 Hz, 1H), 5.94-5.95 (d, J=2.7 Hz, 1H), 7.34-7.37 (d, J=7.8 Hz, 1H), 7.48-7.53 (dd, J=8.7, 4.5 Hz, 1H), 7.74-7.80 (t, 1H), 8.00-8.01 (d, J=3.0 Hz, 1H), 8.14-8.16 (d, J=8.4 Hz, 1H), 8.28-8.31 (d, J=8.4 Hz, 1H), 9.02-9.03 (d, J=3.0 Hz, 1H).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[NH:11][C:10]=1[C:18]1[C:30]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23](=O)[C:22]=2[CH:21]=[CH:20][CH:19]=1>C(O)C.O>[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[NH:11][C:10]=1[C:18]1[C:30]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23](=[N:2][OH:3])[C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: O=C1c2ccccc2-c2c1cccc2-c1nc2ccncc2[nH]1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C1c2ccccc2-c2c1cccc2-c1nc2ccncc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
In a 500-ml three-necked flask, dissolve 20 g of 4-(3H-imidazo[4,5-c]pyridin-2-yl)-fluoren-9-one, obtained in Example 1, in 328 ml of ethanol, then add successively 14.02 g of hydroxylamine hydrochloride and 27.59 g of dry sodium acetate. After stirring overnight at room temperature, dilute with 328 ml of water. The precipitate that formed is drained, washed with water and dried in the stove at 500. In this way we obtain 18.6 g of equimolecular mixture of the Z and E oximes of 4-(3H-imidazo[4,5-c]pyridin-2-yl)-fluoren-9-one, in the form of a pale yellow powder, witH-NMR purity over 95%, with the following characteristics:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([S:19][CH3:20])[N:13]=[C:14](SC)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.Cl.[CH2:22]([OH:24])[CH3:23]>>[CH2:22]([O:24][C:14]1[C:15]2[N:16]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[S:9][C:10]=2[N:11]=[C:12]([S:19][CH3:20])[N:13]=1)[CH3:23]
Reactant: CCO
Reactant: CSc1nc(SC)c2nc(-c3ccc(F)cc3)sc2n1
Agent: Cl
Product: CCOc1nc(SC)nc2sc(-c3ccc(F)cc3)nc12
Temperature: 80 °C
Yield: 60 %

Procedure:
To a solution of Na (2.0 mg, 0.08 mmol) in ethanol (1 ml) was added 2-(4-fluorophenyl)-5,7-bis(methylthio)thiazolo[5,4-d]pyrimidine (50 mg, 0.15 mmol). The reaction mixture was heated at 80° C. for 3 hours. After cooling, the mixture was neutralized with 1N HCl and the solvent was removed under reduced pressure. The crude residue was redissolved in ethyl acetate, extracted with brine and dried over Na2SO4. After removing the solvents in vacuo, the residue was purified by flash chromatography on silica (EtOAc/Hex 1:50), yielding the title compound as a white solid (30 mg, 60%).
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]([F:18])([F:17])[F:16])[C:9]=1[O:19][CH2:20][CH2:21][CH3:22])[C:3](=[O:6])[CH:4]=[CH2:5].C(N(C(C)C)CC)(C)C.Br[C:33]1[CH:46]=[N:45][C:36]2[NH:37][C:38](=[O:44])[C:39]([CH3:43])([CH3:42])[NH:40][CH2:41][C:35]=2[CH:34]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:42][C:39]1([CH3:43])[C:38](=[O:44])[NH:37][C:36]2[N:45]=[CH:46][C:33](/[CH:5]=[CH:4]/[C:3]([N:2]([CH3:1])[CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]([F:18])([F:16])[F:17])[C:9]=3[O:19][CH2:20][CH2:21][CH3:22])=[O:6])=[CH:34][C:35]=2[CH2:41][NH:40]1
Reactant: CC1(C)NCc2cc(Br)cnc2NC1=O
Reactant: C=CC(=O)N(C)Cc1cccc(OC(F)(F)F)c1OCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCOc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CNC(C)(C)C(=O)N3)cccc1OC(F)(F)F
Yield: 44.5 %

Procedure:
A solution of N-methyl-N-(2-propoxy-3-trifluoromethoxybenzyl)acrylamide (0.468 g, 1.47 mmol) in propionitrile (5 mL) and DMF (1 mL) was deoxygenated with Ar for 20 min. The solution was treated sequentially with diisopropylethylamine (0.40 mL, 2.3 mmol) and 7-bromo-3,3-dimethyl-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one (0.300 g, 1.11 mmol). The solution was deoxygenated with Ar for 20 min. Pd(OAc)2 (0.024 g, 0.111 mmol) and P(o-tol)3 (0.067 g, 0.222 mmol) were added and the solution was deoxygenated with Ar for 20 minutes. The mixture was heated to reflux for 18 h, then allowed to cool. The mixture was diluted with EtOAc (30 mL) and then washed with H2O (3×50 mL) and brine (2×100 mL), dried (Na2SO4) and concentrated to a yellow-orange solid. Purification by column chromatography (silica gel, CH2Cl2/MeOH, 100 to 98:2) gave the title compound (0.25 g, 31%) as an off-white solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 9.80-9.78 (m, 1H), 8.41-8.36 (m, 1H), 8.01-7.92 (m, 1H), 7.56-7.49 (m, 1H), 7.36-7.08 (m, 4H), 4.87-4.69 (m, 2H), 3.96-3.83 (m, 4H), 3.16-2.88 (m, 4H), 1.78-1.71 (m, 2H), 1.31-1.29 (m, 6H), 1.03-0.98 (m, 3H); MS (ESI) m/e 507 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:4]=1[OH:5].C(O[C:14](OCC)(OCC)[CH2:15][CH3:16])C.O>C(O)C>[CH2:15]([C:16]1[O:5][C:4]2[CH:6]=[CH:7][CH:8]=[C:9]([OH:10])[C:3]=2[N:2]=1)[CH3:14]
Reactant: CCOC(CC)(OCC)OCC
Reactant: Nc1c(O)cccc1O
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCc1nc2c(O)cccc2o1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-aminoresorcinol hydrochloride (5.0 g) and triethylorthopropionate (13.7 ml) was heated to 150° C. for 2 h before being poured into a mixture of water (140 ml) and ethanol (35 ml). The mixture was stirred vigorously for 30 minutes at room temperature. The resulting precipitate was removed by filtration and dried to give the title compound as a beige solid (4.11 g).
Reaction SMILES: N(C(OCC)=O)=N[C:3](OCC)=[O:4].[OH:13][C@H:14]1[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[C@@H:16]([C:32]([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][O:42][C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=3)=[O:44])[CH2:36][CH2:35]2)=[O:33])[CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)=O>O1CCCC1>[CH:3]([O:13][C@@H:14]1[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)=[O:20])[C@@H:16]([C:32]([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][O:42][C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=3)=[O:44])[CH2:36][CH2:35]2)=[O:33])[CH2:15]1)=[O:4]
Reactant: O=C(OCCN1CCN(C(=O)[C@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=CO
Solvent: C1CCOC1
Product: O=CO[C@H]1C[C@H](C(=O)N2CCN(CCOC(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.17 h
Yield: 45.2 %

Procedure:
A solution of 1.31 g of diethyl azodicarboxylate in 5 ml of tetrahydrofuran was added dropwise, whilst ice-cooling, to a solution of 3.0 g of (2R,4R)-4-hydroxy-2-{4-[2-(4-nitrobenzyloxycarbonyl)oxyethyl]-1-piperazinylcarbonyl}-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in Preparation 57(i)] and 1.97 g of triphenylphosphine in 25 ml of tetrahydrofuran, and the resulting mixture was stirred at the same temperature for 10 minutes. 283 μl of formic acid were then added dropwise to the mixture, and the mixture was stirred at the same temperature for 5 minutes and at room temperature for 1 hour. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 20:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 1.42 g of the title compound, as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[C:20]3[CH:27]=[CH:26][O:25][C:21]3=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[C:21]5[O:25][CH:26]=[CH:27][C:20]5=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2c1ccc1occc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2ccc3occc3c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-Methyl-6,7,8,9-tetrahydro-furo[3,2-f]isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][CH:16]=[C:15]2[C:20]2[O:21][C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:24]=2)[CH:8]=1)(=O)=O.B([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[C:48]1[N:49]=[N:50][N:51]([C:53]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[N:52]=1)(O)O.C([O-])([O-])=O.[K+].[K+]>ClCCl.CN(C=O)C.O.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>[C:25]1([C:23]2[N:24]=[C:20]([C:15]3[C@H:14]([CH2:13][C:9]4[CH:8]=[CH:7][CH:12]=[C:11]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=5[C:48]5[N:49]=[N:50][N:51]([C:53]([C:66]6[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=6)([C:60]6[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=6)[C:54]6[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=6)[N:52]=5)[CH:10]=4)[CH2:19][CH2:18][CH2:17][CH:16]=3)[O:21][C:22]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=S(=O)(Oc1cccc(C[C@@H]2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1)C(F)(F)F
Reactant: OB(O)c1ccccc1-c1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
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: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: C1=C(c2nc(-c3ccccc3)c(-c3ccccc3)o2)[C@H](Cc2cccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)c2)CCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
To a solution of (S)-3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}phenyl trifluoromethanesulfonate (1.17 g) in dichloromethane (100 ml) were added 5-(2-boronophenyl)-2-(triphenylmethyl)-2H-tetrazole (1.16 g), tetrakis(triphenylphosphine)palladium (600 mg), and K2CO3 (630 mg) in a mixture of DMF and water. After being stirred for 8 hours at 100° C., the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give (S)-2-(4,5-diphenyloxazol-2-yl)-1-{3-{2-[2-(triphenyl-methyl)tetrazol-5-yl]phenyl}benzyl}-2-cyclohexene (0.83 g).
Reaction SMILES: [C:1]1([C:7]2([CH2:13][C:14]([NH2:16])=[NH:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:18][C:19](=O)/[C:20](/[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[C:21](\O)/[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C[O-].[Na+]>CO.ClCCl>[C:25]([O:24][C:22]([C:21]1[C:20]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:19]([OH:18])[N:16]=[C:14]([CH2:13][C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[N:15]=1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: COC(=O)/C(OCc1ccccc1)=C(\O)C(=O)OC(C)(C)C
Reactant: N=C(N)CC1(c2ccccc2)CCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)c1nc(CC2(c3ccccc3)CCCCC2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.2 %

Procedure:
To a mixture of HCl-salt of 2-(1-phenyl-cyclohexyl)-acetamidine (254) (2.0 g, 7.91 mmol) and (E)-2-benzyloxy-3-hydroxy-but-2-enedioic acid 4-tert-butyl ester 1-methyl ester (9) (3.66 g, 11.86 mmol) in methanol (50.0 mL) was added sodium methoxide (1.28 g, 23.73 mmol, 25% in methanol) at 0° C. Then the reaction mixture was allowed to warm up to room temperature and was stirred for 16 h. After completion of the reaction, the solvent was reduced and the crude product was dissolved in dichloromethane and the resultant mixture extracted with dichloromethane. The organic layer was washed with 1N HCl and with water and brine. It was then dried over Na2SO4 and concentrated. The crude product was purified by normal silica gel column chromatography (using 10% ethyl acetate in hexane) to get 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclohexylmethyl)-pyrimidine-4-carboxylic acid tert-butyl ester (255) (3.2 g, 85.0%) as a yellowish thick liquid which turned into a solid after storing at room temperature.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]=[C:5]=[O:6].[C:7]1([CH3:14])[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1.CO>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][NH:4][C:5]([NH:13][C:9]1[CH:8]=[C:7]([CH3:14])[CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: O=C=NCCCl
Reactant: Cc1cccc(N)c1
Solvent: ClCCl
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1cccc(NC(=O)NCCCl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95753.2 %

Procedure:
1-Chloro-2-isocyanato-ethane (2.36 g, 0.02239 mmol) was added dropwise to a stirred solution of m-tolylamine (2 g, 0.01866 mmol) in toluene (50 mL) over a period of 30 minutes at 0° C. The reaction mixture was stirred at room temperature for 12 hours. The reaction was monitored by TLC (5% MeOH in DCM). The reaction mixture was filtered, washed with toluene and dried under reduced pressure to afford 3.8 g (97% yield) of 1-(2-chloro-ethyl)-3-m-tolyl-urea.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]#N)=[N:8][C:7]([C:15]#[N:16])=[C:6]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-:23].[Na+].Cl.[OH2:26]>CCO>[C:15]([C:7]1[N:8]=[C:9]([C:13]([OH:26])=[O:23])[C:10]2[C:5]([C:6]=1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)#[N:16]
Reactant: O
Reactant: COc1ccc2c(C#N)nc(C#N)c(-c3ccccc3)c2c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2c(C(=O)O)nc(C#N)c(-c3ccccc3)c2c1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a suspension of 6-methoxy-4-phenylisoquinoline-1,3-dicarbonitrile in 25 mL EtOH was added 2(N) aq NaOH (15 mL), and the reaction was stirred at 40° C. for 2 h. Then concentrated aq HCl (18 mL) and water (29 mL) were added to the reaction mixture and heated at 100° C. for 16 h. After cooling to rt, it was extracted with DCM (4×). The combined organic layers were dried over Na2SO4 and concentrated to a tan solid (470 mg, 85%). This crude product was used without further purification.
Reaction SMILES: [C:1]([OH:16])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][S:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][CH3:14].C(Cl)(=O)CCCCSCCCCCSCC.COCCCCCCCCCCCC(Cl)=O.COCCCCCCCCCCCC([NH2:64])=O>>[C:1]([NH2:64])(=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][S:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][CH3:14]
Reactant: COCCCCCCCCCCCC(N)=O
Reactant: CCSCCCCCSCCCCC(=O)O
Agent: CCSCCCCCSCCCCC(=O)Cl
Agent: COCCCCCCCCCCCC(=O)Cl
Product: CCSCCCCCSCCCCC(N)=O

Procedure:
When 6,12-dithiatetradecanoic acid is substituted for an equivalent amount of 12-methoxydoecanoic acid in Example 11 and then the resulting 6,12-dithiatetradecanoyl chloride is substituted for an equivalent amount of the 12-methoxydodecanoyl chloride in Example 12, the compound 6,12-dithiatetradecanamide is prepared and can be used in place of the 12-methoxy-dodecanamide with substantially similar antiviral results.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[N:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]([F:19])([F:18])[F:17])[C:5]=1[CH2:20][O:21][C:22]1[N:27]=[C:26]([CH3:28])[C:25]([NH2:29])=[CH:24][CH:23]=1)([CH3:3])[CH3:2].[CH3:30][O:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH:39]=O)[CH:34]=1.[B][B][B][B][B][B][B][B][B][B].[CH2:52]=O>CO>[CH3:30][O:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][N:29]([C:25]2[C:26]([CH3:28])=[N:27][C:22]([O:21][CH2:20][C:5]3[N:6]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[O:15][C:16]([F:19])([F:17])[F:18])[N:7]=[CH:8][C:4]=3[CH:1]([CH3:3])[CH3:2])=[CH:23][CH:24]=2)[CH3:52])[CH:34]=1
Reactant: C=O
Reactant: Cc1nc(OCc2c(C(C)C)cnn2-c2ccccc2OC(F)(F)F)ccc1N
Reactant: COC(=O)c1cccc(C=O)c1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: COC(=O)c1cccc(CN(C)c2ccc(OCc3c(C(C)C)cnn3-c3ccccc3OC(F)(F)F)nc2C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69 %

Procedure:
To an ambient temperature solution of 6-[4-isopropyl-2-(2-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-2-methyl-pyridin-3-ylamine (100 mg, 0.246 mmol) in MeOH (3 mL) is added 3-formyl-benzoic acid methyl ester (40 mg, 0.246 mmol). The reaction mixture is stirred at room temperature for 10 min. Decaborane (12 mg, 0.0738 mmol) is added and the reaction mixture is stirred at room temperature. After 2 h, formaldehyde (2.0 mL, 37 wt % in water) is added and the reaction mixture is stirred at room temperature for 10 min. Decaborane (12 mg, 0.0738 mmol) is added and the reaction is stirred at room temperature. After 2 h, the reaction mixture is concentrated and the residue is chromatographed (SiO2 40 g, 0% to 20% EtOAc/Hex) to yield the title compound (97 mg, 69%). 1H NMR (400 MHz, DMSO) δ 7.91-7.88 (m, 1H), 7.81 (dt, 1H, J=4.6, 2.5 Hz), 7.63 (s, 1H), 7.59-7.50 (m, 4H), 7.48-7.41 (m, 3H), 6.39 (d, 1H, J=7.9 Hz), 5.13 (s, 2H), 4.00 (s, 2H), 3.82 (s, 3H), 3.03 (sept, 1H, J=6.6 Hz), 2.46 (s, 3H), 2.32 (s, 3H), 1.18 (d, 6H, J=6.6 Hz).
Reaction SMILES: [C:1]1([C:7]2[N:11]([CH2:12][CH2:13][CH3:14])[C:10]3[CH:15]=[CH:16][C:17]([CH2:19]O)=[CH:18][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:21].S(Cl)([Cl:24])=O>ClC(Cl)Cl>[ClH:24].[Cl:21][CH2:19][C:17]1[CH:16]=[CH:15][C:10]2[N:11]([CH2:12][CH2:13][CH3:14])[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:8][C:9]=2[CH:18]=1
Reactant: CCCn1c(-c2ccccc2)nc2cc(CO)ccc21
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCCn1c(-c2ccccc2)nc2cc(CCl)ccc21
Reaction time: 0.5 h
Yield: 96 %

Procedure:
(a-5) A solution of 70.5 parts of 2-phenyl-1-propyl-1H-benzimidazole-5-methanol in 300 parts of trichloromethane was saturated with gaseous hydrogen chloride. Then there are added dropwise 55.9 parts of thionyl chloride (exothermic reaction). Upon completion, stirring was continued for 30 minutes at reflux temperature. The reaction mixture was evaporated, the residue was taken up in 90 parts of methylbenzene and the latter was evaporated again. The residue was crystallized from 320 parts of 4-methyl-2-pentanone, yielding 80 parts (96%) of 5-(chloromethyl)-2-phenyl-1-propyl-1H-benzimidazole monohydrochloride; mp. 138.5° C. (int. 61).