Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][CH:6]([CH3:10])[C:7](=[O:9])[CH3:8].CC([O-])C.CC([O-])C.CC([O-])C.[Al+3].CC(C)=O>C(O)(C)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:5][CH:6]([CH3:10])[CH:7]([OH:9])[CH3:8])[CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)C(C)Cc1cccc(C)c1
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CC(C)O
Solvent: CC(C)=O
Product: Cc1cccc(CC(C)C(C)O)c1
Reaction time: 8 h

Procedure:
A solution of 1 mol of 3-(3-methylbenzyl)-butanone (86% pure) in 300 ml of isopropanol was added drop-wise in the course of 5 hours to 100 g of aluminum triisopropylate heated to boiling with 300 ml of isopropanol, while a mixture of acetone and isopropanol distilled off slowly through a 50-cm long packed column. After reacting for 8 hours, the distillate no longer contained any acetone. The residual isopropanol was then distilled off and 300 ml of toluene, 300 g of ice and 300 g of conc. hydrochloric acid were added to the residue. The layers were separated, the aqueous phase was extracted with 300 ml of toluene, and the combined organic phases were extracted by shaking with a little water, concentrated and distilled through a Vigreux column at 0.2 mbar. A mixture of 1-(3-methylphenyl)-2-methylbutan3-ol isomers was obtained in 85% yield from 78°-80° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]([NH:5][CH2:6][C:7](=O)[CH3:8])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1>C1C=CC=CC=1>[CH3:8][C:7]1[S:21][C:3]([C:2]([F:11])([F:10])[F:1])=[N:5][CH:6]=1
Reactant: CC(=O)CNC(=O)C(F)(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccccc1
Product: Cc1cnc(C(F)(F)F)s1
Reaction time: 4.5 h

Procedure:
Trifluoroacetamidoacetone (8.45 g, 50 mmol) and 20.2 g (50 mmol) of Lawesson's reagent were slurried in 100 mL of benzene and the mixture was heated at reflux with stirring for 4-5 hours to obtain a clear solution. This was allowed to cool and was washed with 50 mL of 10 percent aqueous sodium hydroxide solution, dried over magnesium sulfate, and filtered. The resulting solution was kugelrohr distilled at 160° C. and the distillate was distilled through a 40 cm column packed with glass helices (to remove the benzene) until the head temperature began to drop. It was then distilled through a 20 cm Vigreaux column to obtain 5.1 g (61 percent of theory) of the title compound as a pale oil boiling at 138°-141° C.
Reaction SMILES: C1O[C:4]2([CH2:21][CH2:20][C@@:19]3([CH3:22])[C:6](=[CH:7][CH2:8][C@@H:9]4[C:18]3=[CH:17][CH2:16][C@@:14]3([CH3:15])[C@H:10]4[CH2:11][C@@H:12]([CH3:35])[C@@H:13]3[C:23](=[O:34])[CH2:24][CH2:25][CH2:26][O:27]C3CCOCC3)[CH2:5]2)[O:3]C1.Cl.C(=O)(O)[O-].[K+]>CC(C)=O>[CH3:35][C@@H:12]1[CH2:11][C@H:10]2[C@H:9]3[C:18](=[CH:17][CH2:16][C@:14]2([CH3:15])[C@H:13]1[C:23](=[O:34])[CH2:24][CH2:25][CH2:26][OH:27])[C@:19]1([CH3:22])[C:6](=[CH:5][C:4](=[O:3])[CH2:21][CH2:20]1)[CH2:7][CH2:8]3
Reactant: C[C@@H]1C[C@H]2[C@@H]3CC=C4CC5(CC[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CCCOC1CCOCC1)OCCO5
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CCCO

Procedure:
16α-Methyl-17β-(1-oxo-[4-tetrahydropyranyloxy]butyl)-androsta-5,9(11)-dien-3-one 3-ethylene ketal, step (D), is dissolved in acetone (90 ml) and hydrochloric acid (1N, 10 ml) and allowed to stand at 20°-25° for several hours. Following addition of potassium bicarbonate (1N, 25 ml), the mixture is concentrated and extracted with ethyl acetate. The concentrate is chromatographed on silica gel eluting with acetone/methylene chloride. The appropriate fractions are pooled and concentrated to give 16α-methyl-17β-(1-oxo-[4-hydroxy]butyl)androsta-4,9(11)-dien-3-one.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:26]([N:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]=[C:35]([C:43]([OH:45])=O)[C:34]1=[O:46])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1.C(#N)C.C(N(CC)CC)C>[CH2:26]([N:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]=[C:35]([C:43]([N:3]([CH3:4])[CH3:2])=[O:45])[C:34]1=[O:46])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)c1nc2ccccc2n(Cc2ccccc2)c1=O
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1CCOC1
Product: CN(C)C(=O)c1nc2ccccc2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.4 %

Procedure:
Dimethylamine hydrochloride (0.57 g), WSC (1.33 g) and HOBt (0.86 g) were added to a mixed solution of 4-benzyl-3,4-dihydro-3-oxo-2-quinoxalinecarboxylic acid (1.5 g) in THF (30 ml) and acetonitrile (30 ml), to which was added dropwise triethylamine (2.3 ml) under ice-cooling. The reaction mixture was stirred at room temperature for 15 hours. The precipitated insoluble substances were removed by filtration and the filtrate was concentrated. Water was added to the precipitate, which was extracted with ethyl acetate. The ethyl acetate layer was washed with 1N hydrochloric acid, water, a saturated aqueous sodium hydrogencarbonate solution, and a saturated aqueous sodium chloride solution, then dried and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain the entitled compound (1.47 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C@H:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:13]([N:26]([CH3:28])[CH3:27])[CH:12]=2)=[CH:7][CH:6]=1)=[O:4].[N+:29]([O-])([O-:31])=[O:30].[Na+].Cl.CC(OC(C)=O)=O>C(OC(=O)C)(=O)C.CCOCC.ClCCl.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([N:26]([CH3:28])[CH3:27])[C:14]([O:17][C@H:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][C:16]=2[N+:29]([O-:31])=[O:30])=[CH:7][CH:6]=1)=[O:4]
Reactant: CCCCCC[C@@H](C)Oc1ccc(-c2ccc(C(=O)OC)cc2)cc1N(C)C
Reactant: O=[N+]([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: CCCCCC[C@@H](C)Oc1cc([N+](=O)[O-])c(-c2ccc(C(=O)OC)cc2)cc1N(C)C
Reaction time: 0.25 h
Yield: 43.1 %

Procedure:
Acetic anhydride (3 drops) was added to a stirred solution of compound 63 (75 mg, 0.195 mmol), sodium nitrate (17 mg, 0.205 mmol), water (0.3 ml), concentrated HCl (0.16 ml), dichloromethane (0.5 ml), and ether (3 ml). The reaction mixture was stirred for 15 minutes and then more HCl and Ac2O were added until the solution changed color to a bright yellow. After the color had changed, the reaction mixture was stirred for an additional three hours, and then the organic layer was separated, washed with brine, and dried over MgSO4. The crude product was purified via flash chromatography over silica gel with gradual elutions from 95/5-80/20 (Hex/EtOAc). Evaporation of solvent yielded 36 mg (43%) of a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[CH:5][C:4]=1[NH:18][C:19](=[O:26])[O:20][C@H:21]([CH2:23][CH2:24][CH3:25])[CH3:22].COC(=O)N[CH2:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([C:38]2[N:42]3[CH:43]=[CH:44][N:45]=[C:46]([CH3:47])[C:41]3=[C:40](Br)[N:39]=2)[CH2:34][CH2:33]1>>[CH3:21][O:20][C:19]([CH2:31][C@H:32]1[CH2:33][CH2:34][C@H:35]([C:38]2[N:42]3[CH:43]=[CH:44][N:45]=[C:46]([CH3:47])[C:41]3=[C:40]([C:7]3[CH:6]=[CH:5][C:4]([NH:18][C:19](=[O:26])[O:20][C@H:21]([CH2:23][CH2:24][CH3:25])[CH3:22])=[C:3]([O:2][CH3:1])[CH:8]=3)[N:39]=2)[CH2:36][CH2:37]1)=[O:26]
Reactant: COC(=O)NC[C@H]1CC[C@H](c2nc(Br)c3c(C)nccn32)CC1
Reactant: CCC[C@H](C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1OC
Product: CCC[C@H](C)OC(=O)Nc1ccc(-c2nc([C@H]3CC[C@H](CC(=O)OC)CC3)n3ccnc(C)c23)cc1OC

Procedure:
(S)-Pentan-2-yl 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (19 mg) and methyl((trans)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)methylcarbamate (20 mg) were reacted according to the procedure described in example 4 step 4c and purified by prep-HPLC (column Luna C18(2); gradient acetonitrile/water with constant 0.003M trifluoroacetic acid). Proper fractions were collected and made basic with aqueous sodium hydrogencarbonate, extracted with dichloromethane, organic layer dried (Na2SO4) and concentrated in vacuo to give (S)-pentan-2-yl 4-(3-((trans)-4-(methoxycarbonylmethyl)cyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenylcarbamate (16 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([NH:13]C(=O)C)[CH2:7]2)([O-:3])=[O:2].[ClH:17]>>[ClH:17].[NH2:13][CH:8]1[CH2:7][C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:9]1
Reactant: CC(=O)NC1Cc2ccc([N+](=O)[O-])cc2C1
Agent: Cl
Product: NC1Cc2ccc([N+](=O)[O-])cc2C1
Reaction time: 8 h

Procedure:
To N-(5-nitro-indan-2-yl)-acetamide (23.5 g, 107 mmol) is added 2N hydrochloric acid (500 mL). The mixture is heated to reflux for 24 h and then concentrated in vacuo. Methanol (100 mL) is added to the residue and the mixture is concentrated in vacuo. Toluene (100 mL) is added and the mixture is again concentrated. A solution of the residue in methanol (100 mL) is warmed, diethyl ether (500 mL) is added and the mixture is let stand overnight. The solid is collected by filtration and air dried to yield 2-amino-5-nitro-indane hydrochloride as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[C:20]3[C:15](=[C:16]([F:22])[CH:17]=[CH:18][C:19]=3[F:21])[O:14][CH2:13][CH:12]2[CH2:23][CH2:24][CH:25]([OH:29])[CH2:26][CH:27]=[CH2:28])(=[O:10])=[O:9])=[CH:4][CH:3]=1.N1C=CN=C1.[CH3:35][C:36]([Si:39](Cl)([CH3:41])[CH3:40])([CH3:38])[CH3:37]>CN(C=O)C>[C:36]([Si:39]([O:29][CH:25]([CH2:24][CH2:23][CH:12]1[CH:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:9])=[O:10])[C:20]2[C:15](=[C:16]([F:22])[CH:17]=[CH:18][C:19]=2[F:21])[O:14][CH2:13]1)[CH2:26][CH:27]=[CH2:28])([CH3:41])[CH3:40])([CH3:38])([CH3:37])[CH3:35]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCC(O)CCC1COc2c(F)ccc(F)c2C1S(=O)(=O)c1ccc(Cl)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=CCC(CCC1COc2c(F)ccc(F)c2C1S(=O)(=O)c1ccc(Cl)cc1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 36 h
Yield: 88.8 %

Procedure:
A solution of 1-[4-(4-chloro-benzenesulfonyl)-5,8-difluoro-chroman-3-yl]-hex-5-en-3-ol (1.30 g, 2.93 mmol) in DMF (29 mL) 0° C. was treated with imidazole (0.41 g, 6.0 mmol), TBSCl (0.66 g, 4.4 mmol) and warmed to ambient temperature. After 36 h, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic extracts were washed H2O (3×), saturated aqueous NaHCO3, brine, dried over MgSO4 and concentrated in vacuo. Flash chromatography (1→10% EtOAc/Hex) afforded the title compound (1.45 g, 89%): 1H NMR (CDCl3 400 MHz) δ 7.71 (dd, J=8.1, 1.5 Hz, 2H), 7.52 (dd, J=8.1, 1.5 Hz, 2H), 7.03 (m, 1H), 6.42 (m, 1H), 5.72 (m, 1H), 5.01-4.89 (m, 3H), 4.33 (dd, J=11.0, 2.2 Hz, 1H), 4.27 (s, 1H), 3.62 (m, 1H), 2.74 (m, 1H), 2.12-2.10 (m, 2H), 1.55-1.24 (m, 4H), 0.78 (s, 4.5H), 0.76 (s, 4.5H), −0.01 (s, 3H), −0.08 (s, 3H).
Reaction SMILES: OC1C(C)=C(O)C=CC=1C=O.C(Cl)C=C.C(N(CC)C(C)C)(C)C.C([O:28][C:29]1[C:36]([CH3:37])=[C:35]([O:38][CH2:39][CH:40]=[CH2:41])[CH:34]=[CH:33][C:30]=1[CH:31]=[O:32])C=C>>[CH2:39]([O:38][C:35]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[C:29]([OH:28])[C:36]=1[CH3:37])[CH:40]=[CH2:41]
Reactant: C=CCOc1ccc(C=O)c(OCC=C)c1C
Agent: Cc1c(O)ccc(C=O)c1O
Solvent: C=CCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOc1ccc(C=O)c(O)c1C

Procedure:
By following Example 2 procedure, 5.0 g of 2,4-dihydroxy-3-methylbenzaldehyde was reacted with 8.35 g of allyl chloride and 5.1 g of N,N-diisopropylethylamine to get 8.41 g of crude title product containing 12% of 2,4-bis(allyloxy)-3-methylbenzaldehyde by GC. Crude product was purified by column chromatography to get the title compound as liquid. IR (neat): 3280, 3088, 3024, 2988, 2926, 2838, 2748, 1645, 1585, 1499, 1452, 1427, 1388, 1353, 1330, 1290, 1250, 1182, 1110, 1022, 990, 928, 891, 788, 758, 715, and 646 cm−1. 1H-NMR (CDCl3, 400 MHz): δ 11.45 (s, 1H, exch. with D2O, OH), 9.70 (s, 1H, CHO), 7.34 (d, J=8.8 Hz, 1H, H-6), 6.53 (d, J=8.8 Hz, 1H, H-5), 6.06 (m, 1H, CH═CH2), 5.44 (dq, J=1.6, 19.2 Hz, 1H, CH═CH2), 5.32 (dq, J=1.2, 10.8 Hz, 1H, CH═CH2), 4.64 (dt, J=1.6, 4.8 Hz, 2H, CH2═CHCH2), 2.13 (s, 3H, ArCH3). 13C NMR (CDCl3, 100 MHz): δ 194.60 (CHO), 163.17 (C-4), 160.99 (C-2), 133.00 (CH2═CH); 132.38 (C-5), 117.55 (CH2═CH), 113.48 (C-1), 103.75 (C-5), 68.90 (OCH2), 7.30 (ArCH3). Mass (EI-MS): 192.1 (M), 191.3 (M−1).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:25][C@H:24]([O:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][C@:19]1(CO)[C:20](O)=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.[Cl-].[NH4+]>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:25][C@H:24]([O:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][C@H:19]1[CH:20]=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@]1(CO)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1C=O
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 84.5 %

Procedure:
A solution of oxalyl chloride (1.71 g, 13.5 mmol) in methylene chloride (50 ml) was cooled to -78° C. and a solution of dimethyl sulfoxide (2.18 g, 27.1 mmol) in methylene chloride (5 ml) was added thereto. This solution was stirred for 10 minutes. To this solution was added a solution of the alcohol crude product obtained by the above reaction in methylene chloride (10 ml). The mixture was stirred for 10 minutes, and then triethylamine (4.76 ml, 33.9 mmol) was dropwise added at the same temperature. The reaction solution was gradually warmed to 20° C. over a period of 2 h. To the reaction mixture was added saturated aqueous ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (heptane-ethyl acetate=1:4) to give the title compound (829 mg, yield: 84.5%).
Reaction SMILES: [C:1]([O:4][CH:5]=[CH:6][CH:7]=C)(=[O:3])[CH3:2].[C:9]1([SiH:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C>C1(C)C=CC=CC=1>[C:22]1([Si:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:7]=[CH:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: C=CC=COC(C)=O
Reactant: c1ccc([SiH](c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)OCC=C[Si](c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A solution of 1-acetoxy-1,3-butadiene (0.1 mol), triphenylsilane (0.1 mol), and Rh2Cl2 (CO)4 (194.5 mg, 0.625 mol) in 100 mL of toluene was stirred at room temperature under argon for 3 days. The reaction mixture is treated with decolorizing charcoal, and the mixture boiled briefly. After cooling, the reaction mixture is filtered through Celite. Concentration of the solution will afford the title compound.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([C:11]23[CH2:20][CH:15]([CH2:16][CH:17]([NH2:19])[CH2:18]2)[N:14]([CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:13][CH:12]3[CH3:30])[CH:8]=[CH:9][CH:10]=1)(C)C.Br.[OH-].[Na+]>C(O)(=O)C>[NH2:19][C@H:17]1[CH2:16][C@H:15]2[CH2:20][C@:11]([C:7]3[CH:6]=[C:5]([OH:4])[CH:10]=[CH:9][CH:8]=3)([C@H:12]([CH3:30])[CH2:13][N:14]2[CH2:21][CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:18]1
Reactant: CC(C)Oc1cccc(C23CC(N)CC(C2)N(CCCc2ccccc2)CC3C)c1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: C[C@@H]1CN(CCCc2ccccc2)[C@H]2C[C@H](N)C[C@]1(c1cccc(O)c1)C2
Temperature: 25 °C
Yield: 98.5 %

Procedure:
7-amino-4-methyl-5-(3-isopropoxyphenyl)-2-(3-phenylpropyl)-2-aza-bicyclo[3.3.1 ]nonane (2.7) (3.07 g, 7.8 mmole) was dissolved in glacial acetic acid (20 mL), 48% HBr (32.5 ml) was added, and the solution was heated to reflux for 15 h. The reaction mixture was allowed to cool to room temperature, poured into ice (100 g), and the pH was raised to 10 with 50% NaOH. The aqueous layer was extracted with 3:1 CH2Cl2:THF (3×100 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuu. The crude product was purified by flash chromatography using silica gel and eluted with 65:35 CH2Cl2:CMA-80 to yield 2.8 g (88.3%) of the desired product as an off-white solid. The analytical sample was prepared by dissolving the free base in CHCl3, acidifying with HCl in ether, and precipitated with ether. The ether/CHCl3 mixture was decanted and the percipitate taken up in MeOH. The product was then precipitated out of the MeOH with ether. The solvent was decanted and the resultant material was dried under vacuum at 50° C. overnight. [α]D20=−20.5 (c 1.03, MeOH). 1H NMR (CDC13) δ 7.27-7.07 (m, 6H), 6.65-6.58 (m, 3H), 4.33 (br, 2H), 3.54 (br, 1H), 2.79 (m, 1H), 2.66-2.53 (m, 3H), 2.46 (t, J=7.0 Hz, 2H,), 2.31 (m, 3H), 2.04 (br, 1H), 1.77 (t, J=7.2, 2H), 1.53 (m, 1H), 1.14 (m, 1H), 0.98 (m, 1H), 0.70 (d, J=6.9 Hz, 3H,). 13C NMR (CD3OD) δ 159.5, 149.3, 141.9, 131.4, 130.1, 129.9, 127.9, 117.5, 115.1, 114.9, 113.6, 113.4, 89.9, 57.1, 56.2, 55.8, 55.1, 51.4, 46.8, 45.0, 44.1, 40.1, 38.4, 37.4, 34.0, 30.6, 28.4, 27.4, 18.5. Anal. (C24H34Cl2N2O.H2O) C, H, N.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:36])[CH2:15][C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28]CC2C=CC=CC=2)=[CH:24][CH:23]=1)[C:17]1[CH2:21][CH2:20][O:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCO.[Pd]>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:36])[CH2:15][C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[C:17]1[CH2:21][CH2:20][O:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C[C@H](C1=NOCC1)c1ccc(OCc2ccccc2)cc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(C[C@H](C1=NOCC1)c1ccc(O)cc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Yield: 90.3 %

Procedure:
Compound 74.1 (136 mg) and a catalytic amount of Pd/C in EtOH (2 mL) was stirred at room temperature under 1 atm of H2 for 2.5 hours. The catalyst was removed by filtration, and the filtrate was concentrated to give 74.2 (100 mg). MS ESI (pos.) m/e: 395 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([NH:6][C:7]2[CH:19]=[C:18](/[CH:20]=[CH:21]/[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=3)[CH:17]=[CH:16][C:8]=2[C:9]([O:11]C(C)(C)C)=[O:10])=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][C:7]2[CH:19]=[C:18](/[CH:20]=[CH:21]/[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=3)[CH:17]=[CH:16][C:8]=2[C:9]([OH:11])=[O:10])=[CH:29][CH:30]=1
Reactant: Cc1cccc(/C=C/c2ccc(C(=O)OC(C)(C)C)c(Nc3ccc(F)cc3)c2)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(/C=C/c2ccc(C(=O)O)c(Nc3ccc(F)cc3)c2)c1

Procedure:
Trifluoroacetic acid 10 mL solution of the obtained tert-butyl 2-(4-fluoroanilino)-4-((E)-2-(3-methylphenyl)vinyl)benzoate was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, the obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 60-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 2-(4-fluoroanilino)-4-((E)-2-(3-methylphenyl)vinyl)benzoic acid.
Reaction SMILES: C1C=C(O[C:8](OC2N=CC=CC=2)=[S:9])N=CC=1.[NH2:17][C:18]1[CH:26]=[C:25]([CH3:27])[C:21]2[N:22]=[CH:23][NH:24][C:20]=2[C:19]=1[CH3:28]>CN(C)C1C=CN=CC=1.C(Cl)Cl.CO>[CH3:28][C:19]1[C:20]2[NH:24][CH:23]=[N:22][C:21]=2[C:25]([CH3:27])=[CH:26][C:18]=1[N:17]=[C:8]=[S:9]
Reactant: Cc1cc(N)c(C)c2[nH]cnc12
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(N=C=S)c(C)c2[nH]cnc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of di-2-pyridyl thionocarbonate (2.29 g) and 4-dimethylaminopyridine (0.03 g) in CH2Cl2 (150 mL) is added dropwise over 30 minutes a solution of 5-amino-4,7-dimethylbenzimidazole (0.816 g) in methanol (50 mL). The mixture is stirred for 3 hours at room temperature, then rotary evaporated. The residue is purified by flash chromatography on silica gel, eluting with a gradient of 50% to 80% ethyl acetate/hexane to afford 4,7-dimethyl-5-benzimidazolylisothiocyanate as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[Na].[S:18]1(=[O:31])(=[O:30])[C:28]2[C:29]3[C:24]([CH:25]=[CH:26][CH:27]=2)=[CH:23][N:22]=[CH:21][C:20]=3[NH:19]1.BrC1C2C(=CC=CC=2S(N)(=O)=O)C=NC=1.[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C.O>[C:11]1([C:8]2[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][N:19]3[C:20]4[CH:21]=[N:22][CH:23]=[C:24]5[CH:25]=[CH:26][CH:27]=[C:28]([C:29]=45)[S:18]3(=[O:31])=[O:30])[CH2:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=S1(=O)Nc2cncc3cccc1c23
Reactant: ClCCCN1CC=C(c2ccccc2)CC1
Agent: NS(=O)(=O)c1cccc2cncc(Br)c12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=S1(=O)c2cccc3cncc(c23)N1CCCN1CC=C(c2ccccc2)CC1
Temperature: 20 °C

Procedure:
A solution of 1-(3-chloropropyl)-4-phenyl-1,2,3,6-tetrahydropyridine (4.9 g) in dimethylformamide (20 cc) is added to a solution of the sodium salt of 2H-isothiazolo[3,4,5-de]isoquinoline 1,1-dioxide (obtained by heating, after the evolution of gas has ceased, a solution of 4-bromo-5-isoquinolylsulphonamide (4.1 g) in dimethylformamide (25 cc) and a suspension of sodium hydride (0.85 g) in an 80% dispersion in vaseline oil in dimethylformamide (50 cc) at 110° C. for 2 hours and 30 minutes) cooled to 20° C. The reaction medium is heated for 2 hours at 100° C., then poured into a mixture of water (300 cc) and ethyl acetate (300 cc). The organic phase is washed with water (3×300 cc), dried over magnesium sulphate and concentrated to dryness. The residue is purified by chromatography on a silica column under a slight overpressure of nitrogen, eluting with ethyl acetate and then with a mixture of ethyl acetate and ethanol vol). 2-[3-(4-Phenyl-1,2,3,6-tetrahydropyridyl)propyl]-2H-isothiazolo[3,4,5-de]isoquinoline 1,1-dioxide (1.4 g) is obtained in the form of a yellow oil. 1.8 g of this product are purified with a second, similar chromatography stage to give 2-[3-(4-phenyl-1,2,3,6-tetrahydropyridyl)propyl]-2H-isothiazolo[3,4,5-de]isoquinoline 1,1-dioxide (1.6 g) (Rf =0.27; support: silica gel; eluant: ethyl acetate-ethanol (9-1 vol)). This product is dissolved in ethyl acetate (100 cc) before adding a 3 N solution of hydrochloric acid in isopropyl oxide (5 cc). The precipitate is centrifuged, washed with ethyl acetate and dried under vacuum (0.1 mm Hg) at 35° C. 2-[3-(4-Phenyl-1,2,3,6-tetrahydropyridyl)propyl]-2H-isothiazolo[3,4,5-de]isoquinoline 1,1-dioxide dihydrochloride (1.6 g) is obtained in the form of a yellow (amorphous) solid.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[C:15]([F:18])([F:17])[F:16].CC(O)=O.O.N>[Fe].CCO>[CH3:19][N:2]([CH3:1])[CH2:3][C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[C:15]([F:16])([F:17])[F:18]
Reactant: CN(C)CC#Cc1ccc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Fe]
Agent: N
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CN(C)CC#Cc1ccc(N)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of dimethyl-[3-(4-nitro-2-trifluoromethyl-phenyl)-prop-2-ynyl]-amine (2.0 g, 7.4 mmol), iron powder (1.65 g, 29.4 mmol, 4 equiv), AcOH (5 mL), H2O (10 mL), and EtOH (40 mL) is stirred for 30 min at 80° C. The reaction mixture is allowed to cool to rt, basified by addition of a 1 M aqueous solution of NH3, and filtered through Celite. The filtrate is partially concentrated and extracted with EtOAc. The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (CH2Cl2/NH3 (2 N in MeOH), 95:5) to provide the title compound as a brown oil: ES-MS: 243.0 [M+H]+; single peak at tR=2.49 min (System 1); Rf=0.10 (CH2Cl2/NH3 (2 N in MeOH), 95:5).