Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: BrCCN1CCCCC1
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(Cl)cc2)c2cc[nH]c2c(=O)n1C
Product: Cn1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccn(CCN3CCCCC3)c2c1=O

Procedure:
The title compound was prepared in a manner similar to that described in Example 2 from methyl 2-(tert-butoxy)-2-(4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate and 1-(2-bromoethyl)piperidine. 1H NMR (400 MHz, METHANOL-d4) ppm 7.62-7.52 (m, 3H), 7.48-7.41 (m, 1H), 7.39-7.31 (m, 1H), 6.09-6.03 (m, 1H), 5.27 (s, 1H), 5.00-4.91 (m, 2H), 3.75 (s, 3H), 3.68-3.53 (m, 4H), 3.12-2.95 (m, 2H), 2.04-1.92 (m, 2H), 1.92-1.75 (m, 2H), 1.62-1.46 (m, 2H), 0.96 (s, 9H); LCMS (m/z) ES+=500 (M+1).
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH3:10])=[CH:4][CH:3]=1.[Cl:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=O)=[CH:18][CH:17]=1>>[Cl:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19](/[C:22](/[C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[C:8](\[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[N:7][CH:6]=2)/[CH2:9][CH3:10])=[CH:18][CH:17]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1
Reactant: CCC(=O)c1ccc(O)nc1
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc(O)nc1

Procedure:
Following general procedure of McMurry reaction as described in example 1, step B, 1-(6-hydroxypyridin-3-yl)propan-1-one (0.3 g, 1.0 eq) was reacted with (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (1.37 g, 2.5 eq) to give the desired Z-product (Z and E isomer can be separated via column chromatography).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:15][C:7]=1[C:8]([O:10]CC(C)C)=[O:9])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].C(Cl)(Cl)Cl.Cl>C(O)C.O>[CH2:1]([O:5][C:6]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:15][C:7]=1[C:8]([OH:10])=[O:9])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COC(=O)c1cc(OCC(C)C)ccc1OCC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: O
Product: CC(C)COc1ccc(OCC(C)C)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
In 88 ml of ethanol is dissolved 17.48 g of isobutyl 2,5-diisobutoxybenzoate. After adding 33 ml of 5 mol/L sodium hydroxide solution, the mixture is stirred at ambient temperature for 30 minutes. Chloroform and water are added to the reaction mixture, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. Thus, 12.16 g of 2,5-diisobutoxybenzoic acid is obtained as a white solid product.
Reaction SMILES: [CH3:1][O:2][C@H:3]([C@@H:8]([CH3:15])[C@@H:9]([O:13][CH3:14])/[CH:10]=[CH:11]/[CH3:12])[C@@H:4]([CH3:7])[CH2:5][OH:6].[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>N1C=CC=CC=1>[CH3:1][O:2][C@H:3]([C@@H:8]([CH3:15])[C@@H:9]([O:13][CH3:14])/[CH:10]=[CH:11]/[CH3:12])[C@@H:4]([CH3:7])[CH2:5][O:6][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: C/C=C/[C@H](OC)[C@H](C)[C@@H](OC)[C@@H](C)CO
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: C/C=C/[C@H](OC)[C@H](C)[C@@H](OC)[C@@H](C)COC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To (E)-(2S,3S,4S,5S)-3,5-Dimethoxy-2,4-dimethyl-oct-6-en-1-ol (1.5 g, 6.94 mmol) in anhydrous pyridine (20 ml) at 0° C. and under an atmosphere of nitrogen was added pivaloyl chloride (1.33 ml, 10.7 mmol). The reaction was warmed to room temperature and stirred for 2 hours, after which it was quenched with saturated ammonium chloride and extracted with dichloromethane (2×). The combined organic layers were dried by passing through a hydrophobic frit and concentrated in vacuo. The product was purified by flash chromatography (SiO2, iHex/EtOAc, 20:1 then 1:1) to afford 2.0 g (100%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 5.67 (dq, J=15.3 Hz, 6.6 Hz, 1H), 5.21 (m, 1H), 4.23 (dd, J=10.6 Hz, 3.3 Hz, 1H), 4.1 (dd, J=10.6 Hz, 6.0 Hz, 1H), 3.52 (dd, J=10.0 Hz, 2.0 Hz, 1H), 3.42 (s, 3H), 3.34 (t, J=9.3 Hz, 1H), 3.25 (s, 3H), 1.96 (m, 1H), 1.78 (dd, J=6.4 Hz, 1.5 Hz, 3H), 1.68 (m, 1H), 1.24 (s, 9H), 0.90 (d, J=7.1 Hz, 3H), 0.76 (d, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:36]([N:38]2[CH2:43][CH2:42][CH:41]([C:44]([O:46]CC)=[O:45])[CH2:40][CH2:39]2)=[O:37])=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18]/[C:19](/[NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[N:20]/[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].[OH-].[Na+].Cl>O1CCOCC1>[C:1]([NH:4][C:5]1[S:6][C:7]([C:36]([N:38]2[CH2:43][CH2:42][CH:41]([C:44]([OH:46])=[O:45])[CH2:40][CH2:39]2)=[O:37])=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18]/[C:19](/[NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[N:20]/[C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C1CCN(C(=O)c2sc(NC(C)=O)nc2CCc2ccc(N/C(=N/C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(=O)Nc1nc(CCc2ccc(N/C(=N/C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)c(C(=O)N2CCC(C(=O)O)CC2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
Ethyl 1-[(2-(acetylamino)-4-{2-[4-({(Z)-[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)phenyl]ethyl}-1,3-thiazol-5-yl)carbonyl]-4-piperidinecarboxylate (277.9 mg), 1N-NaOH (1.01 ml) and 1,4-dioxane (3 ml) were combined at 0° C., and the reaction mixture was stirred at r.t. for 3 hours. The mixture was neutrallized with 1N-HCl, and the organic solvent was evaporated in vacuo. The residual aqueous solution was extracted with AcOEt. The organic layer was washed with water and brine, dried over anhydrous MgSO4, and concentrated in vacuo to give 1-[(2-(acetylamino)-4-{2-[4-({(Z)-[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)phenyl]ethyl}-1,3-thiazol-5-yl)carbonyl]-4-piperidinecarboxylic acid (262.4 mg) as a pale yellow amorphous substance.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][C:6]1[C:11]([CH3:12])=[N:10][N:9]2[C:13]([Cl:16])=[CH:14][CH:15]=[C:8]2[C:7]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)C.[OH-].[Na+].CO>O1CCCC1>[Cl:16][C:13]1[N:9]2[N:10]=[C:11]([CH3:12])[C:6]([CH2:5][C:4]([OH:24])=[O:3])=[C:7]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C:8]2=[CH:15][CH:14]=1
Reactant: CCOC(=O)Cc1c(C)nn2c(Cl)ccc2c1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nn2c(Cl)ccc2c(-c2ccc(F)cc2)c1CC(=O)O
Reaction time: 8 h
Yield: 90.7 %

Procedure:
To a solution of ethyl[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]acetate (300 mg) in tetrahydrofuran (4 ml) was added 1N sodium hydroxide (1.7 ml), followed by methanol (2 ml). After standing at 20° C. overnight, the mixture was partitioned between 1N hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was triturated with ether to give [7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]acetic acid (250 mg) as an yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH:5]([OH:10])[CH:6]1[CH2:9][O:8][CH2:7]1)[CH3:2].CC1C=CC=C([N+]([O-])=O)C=1C(OC(=O)C1C([N+]([O-])=O)=CC=CC=1C)=O.[CH3:37][C:38]([CH3:44])([CH:42]=[CH2:43])[C:39](O)=[O:40]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([O:3][C:4]([CH:5]([O:10][C:39](=[O:40])[C:38]([CH3:44])([CH3:37])[CH:42]=[CH2:43])[CH:6]1[CH2:7][O:8][CH2:9]1)=[O:11])[CH3:2]
Reactant: C=CC(C)(C)C(=O)O
Reactant: CCOC(=O)C(O)C1COC1
Agent: CN(C)c1ccncc1
Agent: Cc1cccc([N+](=O)[O-])c1C(=O)OC(=O)c1c(C)cccc1[N+](=O)[O-]
Solvent: ClCCl
Product: C=CC(C)(C)C(=O)OC(C(=O)OCC)C1COC1
Reaction time: 4 h
Yield: 72.5 %

Procedure:
To a stirred solution of hydroxy-oxetan-3-yl-acetic acid ethyl ester (330 mg, 2.06 mmol), 2-methyl-6-nitrobenzoic anhydride (1.42 g, 4.12 mmol) and 4-dimethylamino pyridine (100 mg, 0.82 mmol) in dichloromethane (4 mL) was added a solution of 2,2-dimethyl-but-3-enoic acid (294 mg, 2.58 mmol) in dichloromethane (4 mL). The reaction mixture was stirred for 4 h and then evaporated. The residue was purified by silica gel chromatography using iso-hexanes/diethyl ether 4:1 to give the title compound (383 mg, 73%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.27 (t, J=7.1 Hz, 3H), 1.39 (s, 3H), 1.41 (s, 3H), 3.48-3.61 (m, 1H), 4.20 (q, J=7.1 Hz, 2H), 4.62-4.68 (m, 2H), 4.72-4.85 (m, 2H), 5.12-5.24 (m, 3H), 6.09 (dd, J=17.5, 10.6 Hz, 1H). LCMS (m/z) 257.1[M+H], Tr=2.31 min
Reaction SMILES: [CH2:1]([C:8]1[CH:26]=[CH:25][CH:24]=[CH:23][C:9]=1[C:10]([NH:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl>C1C=CC=CC=1>[CH2:1]([C:8]1[CH:26]=[CH:25][CH:24]=[CH:23][C:9]=1[C:10]1[O:22][C:14]([C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)=[N:13][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C(=O)NNC(=O)c2ccccc2Cc2ccccc2)c1
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: Cc1cccc(-c2nnc(-c3ccccc3Cc3ccccc3)o2)c1
Yield: 95.9 %

Procedure:
To a solution of 19 (1.1 g, 3.194 mmol) in 4 mL benzene was added SOCl2 (2.2 mL, 30.13 mmol). The mixture was heated to reflux overnight and then solvent and excess SOCl2 were evaporated. The yellow residue was dissolved in EtOAc. The organic layer was washed with saturated NaHCO3 aqueous solution, H2O and brine, dried over MgSO4 and concentrated. The crude product was purified by flash column chromatography (8-10% EtOAc in n-hexane) to give 2-(2-benzyl-phenyl)-5-m-tolyl-[1,3,4]-oxadiazole 21 (1.0 g, 3.064 mmol, 96% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[C:3]=1[NH2:4].[Br:13]N1C(=O)CCC1=O.O.[Cl-].[Na+].O>C(#N)C>[Br:13][C:7]1[CH:6]=[C:5]([C:9]([F:10])([F:11])[F:12])[C:3]([NH2:4])=[C:2]([CH3:1])[CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(C(F)(F)F)c1N
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(Br)cc(C(F)(F)F)c1N
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To a room temperature solution of 2-methyl-6-(trifluoromethyl)aniline (3.0 g, 17 mmol) in acetonitrile (85 mL) was added N-bromosuccinimide (3.0 g, 17 mmol) in small portions over 30 minutes. The reaction was allowed to stir for 1 hour. The reaction was poured into a water/brine mixture and was extracted with ethyl acetate (3×). The combined organics were dried over magnesium sulfate, filtered, and concentrated. Purification by flash column chromatography (0-40% ethyl acetate/heptanes) gave the title compound (4.13 g, 95%) as a brown oil. 1H NMR (400 MHz, CDCl3, δ): 7.42 (d, J=2.34 Hz, 1H), 7.31 (s, 1H), 2.17 (s, 3H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=1)[CH2:17][OH:18])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.O1CCCC1>O>[CH3:1][S:2]([O:18][CH2:17][C:16]1[CH:19]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[C:14]([O:13][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:15]=1)(=[O:4])=[O:3]
Reactant: OCc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)OCc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
Methanesulfonyl chloride (5.03 ml) was slowly added to a mixture of 3,5-dibenzyloxybenzyl alcohol (16.0 g), triethylamine (9.06 ml), and tetrahydrofuran (200 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The colorless crystals obtained were collected by filtration to yield 3,5-dibenzyloxybenzyl methanesulfonate (22.20 g, yield: 91%). This was recrystallized from ethyl acetate-hexane. Melting point: 85–86° C.
Reaction SMILES: [N+:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:13])([O-:3])=[O:2].[CH3:14][O:15][CH:16]([O:20][CH3:21])N(C)C.Cl[Si](C)(C)C>CN(C=O)C.CO>[CH3:14][O:15][CH:16]([O:20][CH3:21])[CH2:13][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: Cc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Agent: C[Si](C)(C)Cl
Solvent: CO
Solvent: CN(C)C=O
Product: COC(Cc1cccc([N+](=O)[O-])c1[N+](=O)[O-])OC
Reaction time: 16 h
Yield: 43.5 %

Procedure:
To a solution of 2,3-dinitrotoluene (3.02 g, 16.6 mmol) in 25 mL of DMF was added dimethylformamide dimethylacetal (6.0 mL, 5.4 g, 45 mmol), and the solution was brought to 140° C. and stirred for 16 hours. The solvent was removed under reduced pressure to afford a dark red solid mass. This crude enamine was dissolved in 40 mL of MeOH and 4.0 mL of chlorotrimethylsilane (3.4 g, 31.7 mmol) was added. The solution was brought to reflux and stirred for 16 hours at reflux. The solvent was removed under reduced pressure and the crude material chromatographed directly to afford the 1-(2,2-dimethoxy-ethyl)-2,3-dinitro-benzene (1.85 g, 44%). 1H NMR (CDCl3) δ 2.96 (2H, d, J=5.2 Hz), 3.35 (6H, s), 4.49 (1H, t, J=5.2 Hz), 7.60 (apparent t, 1H, J=8.0 Hz), 7.76 (d, 1H, J=6.5 Hz), 8.05 (dd, 1H, J=1.3, 8.0).
Reaction SMILES: [O:1]1[CH2:5]CCC1.C([N-]C(C)C)(C)C.[Li+].[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[Cl:25])[N:21]=[C:20]([O:26][CH3:27])[C:19]([O:28][CH3:29])=[N:18]2.[O:30]1CCCC1>>[Cl:25][C:24]1[C:15]([Cl:14])=[CH:16][C:17]2[N:18]=[C:19]([O:28][CH3:29])[C:20]([O:26][CH3:27])=[N:21][C:22]=2[C:23]=1[C:5]([OH:1])=[O:30]
Reactant: C1CCOC1
Reactant: COc1nc2cc(Cl)c(Cl)cc2nc1OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: COc1nc2cc(Cl)c(Cl)c(C(=O)O)c2nc1OC
Reaction time: 1 h
Yield: 68 %

Procedure:
Lithium diisopropylamide mono(tetrahydrofuran) (1.5M in cyclohexane, 15.5 mL, 23.3 mmol) was added to a stirred suspension of 6,7-dichloro-2,3-dimethoxyquinoxaline (Preparation 1, 5.0 g, 19.3 mmol) in dry tetrahydrofuran (150 mL) at −78° C. under nitrogen. The reaction mixture was stirred at this temperature for 1 hour, then anhydrous carbon dioxide was bubbled through the solution at −78° C. for 1 hour. Saturated aqueous ammonium chloride solution (80 mL) was added and the resulting mixture was allowed to reach room temperature, acidified to pH 1 using 2M aqueous hydrochloric acid solution and extracted with ethyl acetate (3×50 mL). The combined organic extracts were then extracted with 1M aqueous sodium hydroxide solution. The aqueous solution was acidified to pH 1 using 2M aqueous hydrochloric acid solution and extracted with dichloromethane (3×50 mL). The combined dichloromethane extracts were dried (MgSO4) and concentrated under reduced pressure to give the title compound (4.0 g, 68%) as a pale brown solid, mp 230-232° C.
Reaction SMILES: C([O:5][C:6](=[O:23])[CH:7]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:15]([C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH:7]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:6]([OH:23])=[O:5])=[CH:14][CH:13]=1)#[N:16]
Reactant: CC(C)(C)OC(=O)C(Cc1ccc(C#N)cc1)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(CC(C(=O)O)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 69 h
Yield: 101.3 %

Procedure:
To a solution of 3-(4-cyanophenyl)-2-(R,S)-cyclohexyl-propionic acid t-butyl ester (8.2 g, 26.2 mmol) in dichloromethane (70 ml) was added trifluoroacetic acid (14.1 ml, 183.0 mmol) with stirring at room temperature. A gentle gas evolution ensued. After 69 h, solvent and excess trifluoroacetic acid were evaporated under reduced pressure. The solid was taken up in ethyl acetate and washed with water and brine, then dried (magnesium sulfate), filtered, and evaporated to dryness. The crude product was dissolved in methanol, treated with decolorizing carbon, filtered through celite, and concentrated. The resultant solid was recrystallized from toluene to afford the desired product as an off-white powder (6.83 g, 58%). mp.: 115-117° C., MS m/z: 258 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:5]([OH:7])[CH3:6].[C:17]([Si:21](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:20])([CH3:19])[CH3:18].N1C=CN=C1>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:16])[C@@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:5]([O:7][Si:21]([C:17]([CH3:20])([CH3:19])[CH3:18])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:6]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 72 h
Yield: 95.2 %

Procedure:
(2S,3R)-2-tert-Butoxycarbonylamino-3-hydroxy-butyric acid methyl ester (1.85 g, 7.93 mmol) was dissolved in N,N-dimethylformamide (10 mL), under an atmosphere of nitrogen. tert-Butyl(chloro)diphenylsilane (2.89 mL, 11.1 mmol) was added followed by imidazole (1.08 g, 15.9 mmol) and the reaction was left to stir for 72 h. The reaction mixture was diluted with water and then extracted with ethyl acetate. The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using a stepwise gradient iso-hexanes/ethyl acetate from 1:0 to 4:1 to afford the title compound (3.56 g, 95%) as a pale Greene oil. 1H NMR (300 MHz, CDCl3) δ 0.89 (d, J=6.6 Hz, 3H), 1.04 (s, 9H), 1.10 (s, 9H), 3.64 (s, 3H), 4.18-4.26 (m, 1H), 4.39-4.50 (m, 1H), 5.34 (d, J=9.9 Hz, 1H), 7.36-7.50 (m, 6H), 7.60-7.69 (m, 2H), 7.71-7.77 (m, 2H). LCMS (m/z) 472.2 [M+H], Tr=4.13 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH2:11][CH2:10][C:9](=[O:12])[CH:8]=1>CCO.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8]1
Reactant: O=C1C=C(c2ccccn2)CC1
Agent: [Pd]
Solvent: CCO
Product: O=C1CCC(c2ccccn2)C1
Reaction time: 6.5 h
Yield: 225.2 %

Procedure:
A mixture of 3-(2-pyridyl)-2-cyclopenten-1-one (1.43 g, 8.98 mmol) and 10% Pd/C (142 mg) in EtOH (30 mL) was stirred under hydrogen atmosphere (0.3 MPa) for 6.5 h. The catalyst was removed by filtration over Celite and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography (Hexane/EtOAc=1/1) to yield 3-(2-pyridyl)cyclopentan-1-one (3.26 g, 94%) as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][NH2:5].[CH3:7][S:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O>>[CH3:7][S:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][NH:5][CH2:4][C:3]([O:2][CH3:1])=[O:6]
Reactant: CSc1ccccc1C=O
Reactant: COC(=O)CN
Product: COC(=O)CNCc1ccccc1SC
Yield: 50 %

Procedure:
Prepared as in example 10-10a from glycine methyl ester and 2-(methylthio)benzaldehyde. Yield 50%. MS M+H calculated 226.1. found 226.1.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:13][CH:12]2[N:7]([CH2:8][CH2:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=32)[CH2:6][CH2:5]1.C(N(CC)CC)C.[CH2:25]([S:27]([Cl:30])(=[O:29])=[O:28])[CH3:26].Cl>ClCCl.C(O)C.CO>[ClH:30].[CH2:25]([S:27]([NH:3][CH:4]1[CH2:13][CH:12]2[N:7]([CH2:8][CH2:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=32)[CH2:6][CH2:5]1)(=[O:29])=[O:28])[CH3:26]
Reactant: NC1CCN2CCc3ccccc3C2C1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: CCO
Solvent: CO
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)NC1CCN2CCc3ccccc3C2C1
Temperature: 0 °C
Reaction time: 0.1 h

Procedure:
2-Amino-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizine dihydrochloride (3.65g) was dissolved in dichloromethane (30 ml), and the solution ice-cooled and stirred whilst a solution of triethylamine (2.83 g) in dichloromethane (10 ml) was added. The ice-cooling and stirring were maintained whilst a solution of ethanesulphonyl chloride (2.20 g) in dichloromethane (10 ml) was added dropwise. The reaction was stirred at room temperature for a further 3 hours before washing the solution twice with aliquots of water (50 ml). The dichloromethane solution was evaporated to yield a yellow oil, which was dissolved in ethanol (10 ml) and ethanol saturated with hydrogen chloride was added dropwise until the solution was acidic (pH2). On standing for 0.1 hour white crystals were produced, which, after standing for a further 0.1 hour were removed by filtration to constitute a first crop. After allowing the filtrate to stand for 1 hour the solution was filtered again to produce a second crop of white crystals. A third crop was obtained by evaporation of the filtrate. Thin-layer-chromatography indicated that two products had been formed. The two products were isolated by fractional crystallisation of the three crops from hot methanol to give chromatographically pure 2-ethanesulphonamido-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizine hydrochloride, isomer A (1.13g) and chromatographically pure 2-ethanesulphonamido-1,3,4,6,7,11b-hexahydro-2H-benzo[a]-quinolizine hydrochloride, isomer B (1.05 g). The isomer A hydrochloride had m.p. 234°-6° C (C15H22N2O2S.HCl requires C, 54.45; H, 7.01; N, 8.47%. Found: C, 54.25; H, 6.97; N, 8.18%) and isomer B hydrochloride had m.p. 227°-8° C (C15H22N2O2S.HCl requires C, 54.45; H, 7.01; N, 8.47%. Found: C, 54.46; H, 7.09; N, 8.16%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([O:20][CH:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[CH3:22])[CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH:21]([O:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:19]=1)[CH3:22]
Reactant: CC(Oc1ccnc(N2CCN(C(=O)OC(C)(C)C)CC2)n1)c1ccccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(Oc1ccnc(N2CCNCC2)n1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 121.7 %

Procedure:
To a solution of 4-{4-[1-(2-chloro-phenyl)-ethoxy]-pyrimidin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester (I-2b) (64.3 mg, 0.15 mmol) in 2.0 mL of dichloromethane was added trifluoroacetic acid (177.4 μL, 2.30 mmol) and the mixture was stirred for 1.5 h at ambient temperature. The reaction was concentrated, and the residue dissolved in 1 M HCl(aq) (10 mL). This was extracted with ethyl acetate (10 mL), separated, and the aqueous layer was adjusted to a pH of 12 using 5 M KOH(aq). This aqueous mixture was extracted with ethyl acetate (2×15 mL) and the combined organic extracts were dried over sodium sulfate and concentrated to give 58.2 mg of the title product (2-A).