Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:18][C:19]1[CH:37]=[C:36]([C:38]2[CH:39]([CH3:45])[NH:40][C:41](=[O:44])[NH:42][N:43]=2)[CH:35]=[CH:34][C:20]=1[O:21][CH2:22][C:23]([NH:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:24]>O1CCCC1>[Cl:18][C:19]1[CH:37]=[C:36]([C:38]2[CH:39]([CH3:45])[NH:40][C:41](=[O:44])[NH:42][N:43]=2)[CH:35]=[CH:34][C:20]=1[O:21][CH2:22][C:23]([NH:25][CH2:26][CH2:27][N:28]1[CH2:29][CH2:30][N:31]([C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:32][CH2:33]1)=[O:24]
Reactant: CC1NC(=O)NN=C1c1ccc(OCC(=O)NCCN2CCNCC2)c(Cl)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1NC(=O)NN=C1c1ccc(OCC(=O)NCCN2CCN(C(=O)c3ccc(Cl)cc3)CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
0.43 g of p-chlorobenzoyl chloride and 0.25 g of triethylamine were added to a suspension of 0.5 g of α-[2-chloro-4-(2,3,4,5-tetrahydro-5-methyl-3-oxo-1,2,4-triazin-6-yl)phenoxy-N-[2-(1-piperazinyl)ethyl]acetamide (prepared as described in Example 10) in 10 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 1 hour. The tetrahydrofuran used as the solvent was removed by evaporation under reduced pressure, and the residue was extracted with methylene chloride. The extract was washed with water and dried over anhydrous magnesium sulfate, after which the residue was purified by column chromatography through silica gel, eluted with a 98:2 by volume mixture of methylene chloride and ethanol, to give 0.2 g of a colorless oil. This oil was crystallized from ethanol and then recrystallized, also from ethanol, to give 0.16 g of the title compound as colorless fine crystals melting at 186°-188° C.
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:37])[CH:12]([N:19]2[C:23]3[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:22]=3[N:21]=[C:20]2[C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:6][CH:5]=1.O.[OH-].[Li+]>O.O1CCOCC1>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C:20]2[N:19]([CH:12]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:38])=[O:2])=[CH:5][N:6]=3)=[O:37])[C:23]3[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:22]=3[N:21]=2)=[CH:31][CH:32]=1
Reactant: COC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
6-{2-[2-(4-Chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-acetylamino}-nicotinic acid methyl ester (24 mg, 0.04 mmol) was dissolved in water (0.5 ml) and dioxane (0.5 ml). Lithium hydroxide monohydrate (9 eq, 17 mg) was added and the mixture stirred 3 h at room temperature. The dioxane was removed under reduced pressure and the residue acidified to pH2 with 3M aqueous hydrochloric acid. The precipitate was filtered to afford the title compound as a white solid (20 mg, 84%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][S:11](=[O:14])(=[O:13])[NH:10][CH2:9]2)=[CH:4][CH:3]=1.F[C:16]1[C:25]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH3:30])[CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][S:11](=[O:14])(=[O:13])[N:10]([C:16]3[C:25]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH3:30])[CH:17]=3)[CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=S1(=O)CC(c2ccc(F)cc2)CN1
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(F)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(S(C)(=O)=O)c(N2CC(c3ccc(F)cc3)CS2(=O)=O)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
18.00 g of 4-(4-fluorophenyl)isothiazolidine 1,1-dioxide, 20.59 g of methyl 4-fluoro-5-methanesulfonyl-2-methylbenzoate (Journal of Medicinal Chemistry (1997), 40(13), 2017) and 81.75 g of Cs2CO3 were stirred in 500 ml of anhydrous DMF at RT for 5 hours. Then a further 2.00 g of methyl 4-fluoro-5-methanesulfonyl-2-methylbenzoate were added, and the mixture was stirred at RT for 1 hour and left to stand at RT for 15 hours. The reaction mixture was poured into 1800 ml of water and stirred at RT for 1 hour, and the product was filtered off with suction. The product was then dissolved in 1 l of EA, and the solution was mixed with MgSO4 and activated carbon and stirred at RT for 15 minutes. It was then filtered and the solvent was removed in vacuo. 35.00 g of a colorless foam were obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[F:7][C:8]1[CH:17]=[CH:16][C:11]([C:12](=[O:15])[CH2:13]Br)=[CH:10][CH:9]=1>C(OCC)(=O)C.O>[F:7][C:8]1[CH:17]=[CH:16][C:11]([C:12](=[O:15])[CH2:13][N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])=[CH:10][CH:9]=1
Reactant: Cc1ncc[nH]1
Reactant: O=C(CBr)c1ccc(F)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nccn1CC(=O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 42.3 %

Procedure:
A mixture of 2-methylimidazole (8.0 g, 97.5 mmol) and 4-fluorophenacyl bromide (21.16 g, 97.5 mmol) dissolved in ethyl acetate (40 ml) at ambient temperature was treated with tiethylamine (16.4 ml, 117 mmol) and the cloudy mixture heated at reflux for 16 hours. The mixture was cooled to ambient temperature and diluted with ethyl acetate and water, washed with water and brine, dried and evaporated to dryness. The residue was recrystallised (3×) from dichloromethane/methanol/isohexane to give 1-(4-fluorophenyl)-2-(2-methylimidazol-1-yl)ethanone (1, 9.0 g, 42%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:23]=[CH:22][C:10]([CH2:11][CH:12]2[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[C:13]2([OH:21])[CH2:19][OH:20])=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][CH:12]2[CH2:16][CH2:15][C:14]([CH3:17])([CH3:18])[C:13]2([OH:21])[CH2:19][O:20][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:22][CH:23]=1
Reactant: CC1(C)CCC(Cc2ccc(Cl)cc2)C1(O)CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CCC(Cc2ccc(Cl)cc2)C1(O)COS(C)(=O)=O
Reaction time: 2 h
Yield: 79.8 %

Procedure:
2.76 g (1.05 equivalents) methylsulphonyl chloride were added to a solution of 6.42 g (24 mmols) 1-(4-chlorobenzyl)-3,3-dimethyl-2-hydroxy-2-hydroxymethylcyclopentane prepared as described in Example 1 (i) and 2.55 g (1.1 equivalents) triethylamine in 50 ml dichloromethane at 10°-15° C. The reaction mixture was kept at 10°-15° C. for further 2 hours and then washed with 20 ml water, then 20 ml aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulphate and flashed. Trituration with 60/80 petroleum gave 6.64 g 1-(4-chlorobenzyl)-3,3-dimethyl-2-hydroxy-2-methylsulphonyloxymethylcyclopentane (Isomer A) as a white solid, m.pt. 113°-114° C. Yield: 80%.
Reaction SMILES: [CH3:1][C:2]1([CH2:15][NH2:16])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.C(N(CC)CC)C.[CH:24]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1>[CH3:1][C:2]1([CH2:15][NH:16][C:30]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:31])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: CC1(CN)OCCc2c1[nH]c1ccccc21
Reactant: O=C(Cl)C1CCCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(CNC(=O)C2CCCCC2)OCCc2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.8 %

Procedure:
A mixture of 1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indole-1-methanamine(2.6 g, described in Example 3), triethylamine (1.34 g), cyclohexylcarbonyl chloride (1.94 g) and dry tetrahydrofuran (60 ml) is stirred at 25° C. for 18 hours, filtered and evaporated. The residue is crystallized from benzene-hexane to obtain the title compound (3.8 g); mp 174°-175° C.; nmr (CDCl3) δ0.85-2.25(m), 1.55(s), 2.81(m), 3.79(m), 4.00(m), 5.96(t), 6.9-7.2(m) and 9.71(s).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5](Cl)=[O:6].C[O:13][P:14]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]2[CH:24]=[CH:25][CH:26]=[CH:27][C:16]=2[O:15]1>CC(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([P:14]1(=[O:13])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]2[CH:24]=[CH:25][CH:26]=[CH:27][C:16]=2[O:15]1)=[O:6]
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Reactant: COP1Oc2ccccc2-c2ccccc21
Solvent: CC(C)=O
Product: Cc1cc(C)cc(C(=O)P2(=O)Oc3ccccc3-c3ccccc32)c1
Temperature: 115 °C

Procedure:
67.4 g (0.4 mol) of 3,5-dimethylbenzoyl chloride were warmed to 80° C. under a nitrogen atmosphere. 92 g (0.4 mol) of 6-methoxy-(6H)-dibenz[c,e][1,2]oxaphosphorin were added dropwise while stirring. The temperature during the addition was increased in steps to 115° C. When the reaction was complete, 50 ml of acetone were added at room temperature. After crystallization, 113 g (81% of theory) of the abovementioned compound of melting point 120° to 124° C. were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:12])[C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.[CH3:13][CH:14]([S:16](Cl)(=[O:18])=[O:17])[CH3:15]>N1C=CC=CC=1.CCOCC>[CH:14]([S:16]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[C:9]([NH2:11])=[O:10])=[CH:6][CH:7]=1)(=[O:18])=[O:17])([CH3:15])[CH3:13]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: C[C@@H](C(N)=O)c1ccc(N)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C(N)=O)c1ccc(NS(=O)(=O)C(C)C)cc1
Reaction time: 8 h
Yield: 81 %

Procedure:
(2R)-2-(4-Aminophenyl)propanamide (0.5 g, 3.05 mmol) was dissolved in pyridine (2 mL) and 2-propanesulfonyl chloride (0.53 mL, 3.66 mmol) was added. The resulting solution was refluxed for 4 h and left overnight at room temperature. After the complete disappearance of the starting amide, the solution was diluted with Et2O (10 mL) and the organic layer washed with 1N HCl (2×5 mL), with H2O (2×5 mL), dried over Na2SO4, filtered and evaporated under vacuum to give (2R)-2-{(4-[(isopropylsulfonyl)amino]phenyl}propanamide as pale yellow solid (667 mg, 2.47 mmol). Yield 81%. mp 125-127° C.; [α]D25 (c=0.3, CH3OH): −12.7°; 1H-NMR (DMSO-d6) δ 9.65 (bs, 1H, SO2NH), 7.40 (bs, 1H, CONH2), 7.25 (d, 2H, J=7 Hz), 7.12 (d, 2H, J=7 Hz), 6.80 (bs, 1H, CONH2), 3.52 (q, 1H, J=7 Hz), 3.15 (m, 1H), 1.22 (d, 3H, J=7 Hz), 1.18 (d, 6H, J=7 Hz).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[N:20]=[C:21]([CH3:24])[O:22][C:23]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.[NH:27]1[CH2:32][CH:31]=[C:30]([C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][CH:34]=2)[CH2:29][CH2:28]1>CS(C)=O>[NH:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:33]([C:30]2[CH2:31][CH2:32][N:27]([CH2:12][CH:13]3[O:14][C:15]4[C:16](=[CH:17][CH:18]=[C:19]5[N:20]=[C:21]([CH3:24])[O:22][C:23]5=4)[O:25][CH2:26]3)[CH2:28][CH:29]=2)=[CH:34]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)oc4c3O2)cc1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Solvent: CS(C)=O
Product: Cc1nc2ccc3c(c2o1)OC(CN1CC=C(c2c[nH]c4ccccc24)CC1)CO3
Temperature: 77.5 °C

Procedure:
[(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-yl]methyl 4-methylbenzenesulfonate (0.50 g, 1.31 mmole) and 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.97 g, 4.92 mmole) were combined in 30 mL of DMSO under nitrogen. This solution was heated to 75-80° C. under nitrogen. After completion, the reaction was cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuum. The crude residue was column chromatographed on silica gel using 85% hexane/methylene chloride to remove impurities and methylene chloride to elute the product, the (S)-enantiomer of the title compound, which was a yellow solid (m.p. 196° C.) after evaporation of the solvent (0.21 g, 40%). MS (ESI) m/z 402(M+H)+.
Reaction SMILES: C(=O)(OC)[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([F:12])=[CH:5][C:4]=1[C:13]([CH3:16])([CH3:15])[CH3:14].N1CCCCC1>C(Cl)Cl>[C:13]([C:4]1[CH:5]=[C:6]([F:12])[C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[OH:2])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1C(C)(C)C
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(C)(C)c1cc(F)c([N+](=O)[O-])cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
To a solution of 2-tert-butyl-4-fluoro-5-nitrophenyl methyl carbonate (C-7-a) (1.08 g, 4 mmol) in CH2Cl2 (40 mL) was added piperidine (3.94 mL, 10 mmol). The mixture was stirred at room temperature for 1 h and extracted with 1N NaOH (3×). The aqueous layer was acidified with 1N HCl and extracted with diethyl ether. The ether extract was washed with brine, dried (MgSO4) and concentrated to give 2-tert-butyl-4-fluoro-5-nitrophenol (530 mg, 62%). 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 7.49 (d, J=6.8 Hz, 1H), 7.25 (d, J=13.7 Hz, 1H), 1.36 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(Cl)[Cl:11]>>[Cl:11][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[OH:1])[CH:6]=[O:7]
Reactant: ClCCl
Reactant: O=Cc1ccc(O)cc1
Product: O=Cc1ccc(O)c(Cl)c1
Reaction time: 14 h
Yield: 79.8 %

Procedure:
To a stirred solution of 4-hydroxybenzaldehyde (5.0 g, 40.0 mmol) in DCM (50 mL) SOCl2 (3.30 mL, 40.0 mmol) was added slowly at 0° C. After the addition was completed, the reaction mixture was brought to RT and stirred for 14 h. The reaction mixture was then quenched with water (50 mL), neutralized with a saturated NaHCO3 solution and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to obtain crude product. The crude material was purified via silica gel column chromatography to afford 3-chloro-4-hydroxybenzaldehyde (5.0 g, 77%) as a brown solid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([CH3:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][N:34]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([CH3:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:40][CH:37]5[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7-fluoro-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid and 1-methylpiperidin-4-amine as described in the General procedure for amide bond synthesis using HATU. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41-1.65 (m, 6 H) 1.65-1.86 (m, 6 H) 1.93 (d, J=3.3 Hz, 1 H) 2.07 (s, 1 H) 2.04 (d, J=13.1 Hz, 1 H) 2.81 (d, J=5.1 Hz, 1 H) 2.78 (d, J=4.6 Hz, 3 H) 2.99-3.17 (m, 2 H) 3.27 (s, 4 H) 3.48 (d, J=11.6 Hz, 2 H) 4.83 (t, J=7.8 Hz, 1 H) 7.53 (dd, J=8.3, 1.8 Hz, 1 H) 7.55 (s, 1 H) 8.08 (d, J=8.3 Hz, 1 H) 8.17 (s, 1 H) 8.43 (d, J=7.3 Hz, 1 H) 8.98 (br. s., 1 H) 9.54 (br. s., 1 H). [M+H] calc'd for C28H38FN7O3, 540; found 540.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.O=[C:24]1[C@@:29]([O:35][C:36]2[CH:41]=[C:40]([F:42])[C:39]([F:43])=[C:38]([F:44])[CH:37]=2)([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:28][CH2:27][CH2:26][NH:25]1>C1(C)C=CC=CC=1>[S:10]=[C:24]1[C@@:29]([O:35][C:36]2[CH:41]=[C:40]([F:42])[C:39]([F:43])=[C:38]([F:44])[CH:37]=2)([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:28][CH2:27][CH2:26][NH:25]1
Reactant: CCOC(=O)[C@@]1(Oc2cc(F)c(F)c(F)c2)CCCNC1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@]1(Oc2cc(F)c(F)c(F)c2)CCCNC1=S
Temperature: 100 °C
Yield: 142.8 %

Procedure:
Lawesson's reagent (4.46 g) was added to a mixture of ethyl (3R)-2-oxo-3-(3,4,5-trifluorophenoxy)piperidine-3-carboxylate (5.00 g) in toluene (50 mL) at room temperature, and the mixture was stirred with heating at 100° C. for 1 hr. After cooling to room temperature, the reaction mixture was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give ethyl (3S)-2-thioxo-3-(3,4,5-trifluorophenoxy)piperidine-3-carboxylate (5.25 g). To a mixture of ethyl (3S)-2-thioxo-3-(3,4,5-trifluorophenoxy)piperidine-3-carboxylate (5.25 g) in acetonitrile (25 mL) was added methyl iodide (2.94 mL) at room temperature, and the mixture was stirred under a nitrogen atmosphere at 50° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, to the residue was added 10% aqueous potassium carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (NH, ethyl acetate) to give the title compound (5.65 g).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH:7]([C:9]([OH:11])=[O:10])[O:8][C:4]=2[C:3]=1[Cl:14].[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20](Cl)=[O:21].[Cl-].[Al+3].[Cl-].[Cl-]>Cl>[Cl:1][C:2]1[C:13]([C:20](=[O:21])[C:16]2[S:15][CH:19]=[CH:18][CH:17]=2)=[CH:12][C:5]2[CH2:6][CH:7]([C:9]([OH:11])=[O:10])[O:8][C:4]=2[C:3]=1[Cl:14]
Reactant: O=C(O)C1Cc2ccc(Cl)c(Cl)c2O1
Reactant: O=C(Cl)c1cccs1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1cccs1)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)C2
Temperature: 0 °C

Procedure:
To a well stirred mixture of 6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid (2.6 g.) and thiophene-2-carbonyl chloride (4 ml.) protected from the atmosphere with a calcium chloride tube is added anhydrous aluminum chloride (6.0 g.) over a one-hour period. The reaction mixture is heated at 80°-90° C. for 31/2 hours then poured into ice water (100 ml.) and hydrochloric acid (10 ml.). The product is extracted into ether, washed with water, then extracted into aqueous sodium bicarbonate (100 ml.) from which the sodium salt of the product precipitates. The sodium salt of the product is placed in a separatory funnel with dilute hydrochloric acid (100 ml.) and ether (100 ml.) and shaken until the solid dissolves. The ether solution is washed with water, brine, dried over magnesium sulfate and the ether distilled at reduced pressure. The (±)6,7-dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carboxylic acid melts at 187° C. after crystallization from butyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](C)=[CH2:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[C:20]1(C)C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]3[C:11](=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: C=C(C)CCc1ccc(-c2ccc(OC)cc2)cc1
Reactant: Cc1ccccc1
Product: COc1ccc(-c2ccc3cc(C)ccc3c2)cc1

Procedure:
Into the reactor were fed a solution of 12.4 g (0.049 mol) of the four isomers of 4-methoxy-4'-isopentenyl biphenyl of Example 6 in 237.6 g of toluene at a rate of 10 g/hour. Lower boiling point compounds were removed by distillation from the reaction mixture. The reaction mixture was concentrated to 30 g. The reaction mixture was left to stand. The deposited crystal was filtered to separate it off. The product was recrystallized with toluene for purification. As a result, 2-(4'-methoxyphenyl)-6-methyl naphthalene (5.0 g) was obtained. The yield of the product was 45 mol % on the basis of the olefin compound (4-methoxy-4'-isopentenyl biphenyl).
Reaction SMILES: [C:1]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2/[C:7](=[CH:14]\[C:15]2[C:20]([CH2:21][O:22]C3CCCCO3)=[CH:19][C:18]([Cl:29])=[CH:17][N:16]=2)/[C:6]1=[O:30])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C>[C:1]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH:7]([CH2:14][C:15]2[C:20]([CH2:21][OH:22])=[CH:19][C:18]([Cl:29])=[CH:17][N:16]=2)[C:6]1=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N1C(=O)/C(=C/c2ncc(Cl)cc2COC2CCCCO2)c2cccnc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)N1C(=O)C(Cc2ncc(Cl)cc2CO)c2cccnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a suspension of 55 (3.0 g, 7.0 mmol) in ethanol (25 mL) was added NaBH4 (0.37 g) in one portion. The resulting suspension was stirred at room temperature for 1 h. The reaction was quenched by adding water (10 mL) followed by 6 N HCl solution in isopropanol (5 mL) slowly. The solution was warmed up to 40° C. and stirred for 3 h. The reaction mixture was mixed with MTBE (50 mL) and saturated aqueous NaCl (50 mL). The organic was separated and washed with water (50 mL). The solution was concentrated under vacuum at 50° C. and residue was triturated with hexane (30 mL). The resulting suspension was stirred at room temperature for 30 min. The precipitates were collected by filtration to give 56 (2.2 g, 86%) as a solid. 1H NMR (CDCl3, 400 MHz): δ 8.34 (s, 1H), 8.15 (d, J=4.9 Hz, 1H), 7.74 (s, 1H), 7.30 (d, J=7.1 Hz, 1H), 6.83 (t, J=5.7 Hz, 1H), 4.73 (dd, J=13.4, 4.9 Hz, 1H), 4.63 (dd, J=13.4, 5.7 Hz, 1H), 4.01 (t, J=6.1 Hz, 1H), 3.44 (dd, J=15.4, 5.2 Hz, 1H), 3.17 (dd, J=15.4, 7.2 Hz, 1H), 2.94 (t, J=5.5 Hz, 1H), 1.79 (s, 9H); 13C NMR (CDCl3, 100 MHz): δ 178.72, 159.12, 153.82, 146.45, 145.83 135.72, 135.32, 130.63, 130.27, 124.04, 117.33, 61.40, 58.70, 44.12, 34.01, 28.81.
Reaction SMILES: [CH3:1][CH:2]1[N:7]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1>FC(F)(F)C(O)=O.ClCCl>[CH3:1][CH:2]1[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccc2ccccc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CNCCN1c1ccc2ccccc2n1

Procedure:
A solution of 0.15 g (0.458 mmol) of tert.butyl 3-methyl-4-quinolin-2-yl-piperazine-1-carboxylate in 1 ml of trifluoroacetic acid and 20 ml of dichloromethane is stirred for ten hours at ambient temperature. Then the solution is concentrated by evaporation, the residue is taken up in water and made alkaline with dilute sodium hydroxide solution. The aqueous phase is extracted with dichloromethane and the organic phase is dried over sodium sulphate.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5](OC)[C:6]2[C:7](=[N:9][O:10][N+:11]=2[O-:12])[N:8]=1.[CH2:15]([N:17]([CH2:20][CH2:21][NH2:22])[CH2:18][CH3:19])[CH3:16]>CO>[CH2:15]([N:17]([CH2:18][CH3:19])[CH2:20][CH2:21][NH:22][C:5]1[C:6]2[C:7](=[N:9][O:10][N+:11]=2[O-:12])[N:8]=[C:3]([O:2][CH3:1])[N:4]=1)[CH3:16]
Reactant: COc1nc(OC)c2c(no[n+]2[O-])n1
Reactant: CCN(CC)CCN
Solvent: CO
Product: CCN(CC)CCNc1nc(OC)nc2no[n+]([O-])c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3.0 g (15 mmol) of 5,7-dimethoxy-[1,2,5]oxadiazolo[3,4-d]pyrimidine-1-oxide (J. Chem. Soc. Perkin Trans. 1, 1976, 1327), 1.75 g (15 mmol) of diethylaminoethylamine and 120 ml of methanol is stirred at room temperature for 2 hours and then concentrated in a rotary evaporator. The residue is dissolved hot in isopropanol, and the solution is filtered and treated with the same amount of hot petroleum ether. Overnight, 2.5 g (59%) of 7-(2-diethylaminoethylamino)-5-methoxy-[1,2,5]oxadiazolo[3,4-d]pyrimidine-1-oxide crystallise out.