Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].C([O-])(=O)C.[NH4+:16]>CC(C)=O.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:16])=[O:7]
Reactant: [NH4+]
Reactant: COc1cccc(C(=O)Cl)c1
Agent: CC(=O)[O-]
Solvent: CC(C)=O
Solvent: ClCCl
Product: COc1cccc(C(N)=O)c1
Temperature: 25 °C
Yield: 49.8 %

Procedure:
17 g of 3-methoxybenzoyl chloride were dissolved in 200 ml acetone. 15.5 g of ammonium acetate were added to the solution and the reaction mixture was stirred for several hours at room temperature. Then it was dissolved in dichloromethane. The dichloromethane phase was dried by adding sodium carbonate and concentrated. 7.5 g of 3-methoxybenzamide were obtained as a colorless solid.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:15][C:16]([C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]3)=[N:22][CH:23]=2)=[O:17])=[N:6][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1)([O-])=O>CO.[Pt](=O)=O>[NH2:1][C:4]1[C:5]([NH:15][C:16]([C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]3)=[N:22][CH:23]=2)=[O:17])=[N:6][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)Nc3nn(-c4ccccc4)cc3[N+](=O)[O-])cn2)CC1
Agent: O=[Pt]=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)Nc3nn(-c4ccccc4)cc3N)cn2)CC1
Reaction time: 0.33 h

Procedure:
A solution of tert-butyl 4-(5-{[(4-nitro-1-phenyl-1H-pyrazol-3-yl)amino]carbonyl}pyridin-2-yl)piperazine-1-carboxylate (50 mg, 0.1 mmol) in methanol (10 mL) was degassed with nitrogen and treated with catalytic platinum(IV) oxide (25 mg). The solution was then placed under a hydrogen atmosphere with stirring for 20 minutes. The reaction was degassed with nitrogen, filtered through celite and evaporated to dryness. Purification by flash chromatography (0-4% methanol/methylene chloride) gave tert-butyl 4-(5-{[(4-amino-1-phenyl-1H-pyrazol-3-yl)amino]carbonyl}pyridin-2-yl)piperazine-1-carboxylate as a light yellow solid. 1H NMR (CDCl3) δ 8.78 (d, J=2.35, 1H), 8.13 (dd, J=9.01, 2.64 Hz, 1H), 7.78 (s, 1H), 7.64 (d, J=8.8 Hz, 2H), 7.42, (t, J=7.33 Hz, 2H), 7.22 (t, J=7.34, 1H), 6.88 (d, J=9.09 Hz, 1H), 3.71 (t, J=5.28 Hz, 2H), 3.54 (bs, 2H), 1.48 (s, 9H); ESIMS calcd 464.2 (M++H), found 464.2 (M++H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[CH:16]=[C:15]([NH:25][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)[N:14]=1>>[CH3:24][O:23][C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[C:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1)=[N:14][C:15]([NH:25][C:26]1[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=1)=[CH:16]2
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: CC(=O)Nc1ccc(O)cc1
Product: COc1ccc2c(Oc3ccc(NC(C)=O)cc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from N-(4-hydroxy-phenyl)-acetamide and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give N-{4-[6-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-yloxy]-phenyl}-acetamide. LC-MS m/e 404(MH+).
Reaction SMILES: [N+]([C:4]1[CH:5]=[CH:6][C:7]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=C(C)C=1)([O-])=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.BrN1C(=O)CCC1=O>O>[CH2:7]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:6][CH2:5][CH3:4]
Reactant: CCCCOc1ccc([N+](=O)[O-])cc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCOCCCC
Reaction time: 8 h

Procedure:
To a stirred and gently refluxing mixture of 256 parts of butyl (5-nitro-o-tolyl) ether, 1 part of benzoyl peroxide and 4800 parts of anhydrous carbon tetrachloride is added, over a one-day period, a mixture of 213.6 parts of N-bromosuccinimide and 1 part of benzoyl peroxide. Upon completion, stirring at gentle reflux is continued overnight. The reaction mixture is cooled and water is added. The organic layer is separated, washed with water, dried, filtered and evaporated. The oily residue is crystallized on standing overnight in 2-propanol, yielding 189.7 parts of (α-bromo-5-nitroo-tolyl) butyl ether; mp. 64° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][OH:9])[CH2:4][CH2:3]1.O.C(N(CC)CC)C.[Cl:18][C:19]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:20]=1[C:21](Cl)=[O:22]>C1COCC1>[Cl:18][C:19]1[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][C:20]=1[C:21]([NH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([CH2:8][OH:9])[CH2:4][CH2:3]1)=[O:22]
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1Cl
Reactant: N[C@H]1CC[C@@H](CO)CC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=C(N[C@H]1CC[C@@H](CO)CC1)c1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of cis-(4-Amino-cyclohexyl)-methanol (Tetrahedron Lett., 1970, 11, 4285-4288) (0.75 g, 5.80 mmol) in THF (10 ml) is added water (1.8 mL), triethylamine (2.023 mL, 14.51 mmol) and 2-chloro-5-(trifluoromethyl)benzoyl chloride (1.411 g, 5.80 mmol). The RM is stirred at RT for 1 hour. The reaction mixture is partitioned between EtOAc and water. The organic phase is washed successively with water, saturated sodium bicarbarbonate and saturated brine, dried over MgSO4, filtered and the solvent removed in vacuo. Purification by chromatography on a pre-packed silica gel column using 0-100% EtOAc in isohexane gradient elution gave the desired product as a colourless solid.
Reaction SMILES: [CH2:1]=[C:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([NH:5][N:6]1[CH2:11][CH2:10][S:9][CH2:8][CH2:7]1)=[O:4].C(Cl)Cl.[C:22]([OH:25])(=[S:24])[CH3:23]>>[C:22]([S:24][CH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([NH:5][N:6]1[CH2:7][CH2:8][S:9][CH2:10][CH2:11]1)=[O:4])(=[O:25])[CH3:23]
Reactant: CC(O)=S
Reactant: C=C(Cc1ccccc1)C(=O)NN1CCSCC1
Solvent: ClCCl
Product: CC(=O)SCC(Cc1ccccc1)C(=O)NN1CCSCC1

Procedure:
0.6 g of the product of Step A was stirred for 24 hours at ambient temperature in 10 ml of thioacetic acid and the excess of acid was eliminated under an inert atmosphere at 40°-45° C. The residue was taken up on 200 ml of methylene chloride, washed with a sodium bicarbonate solution, dried and the solvent was eliminated under reduced pressure. The residue was taken up in isopropyl ether to obtain 0.72 g of the expected product melting at 138° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([NH:14]C(=O)OC(C)(C)C)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1CCC(c2ccc(Cl)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCC(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
To a solution of tert-butyl 4-(4-chlorophenyl)cyclohexylcarbamate (0.760 g, 2.45 mmol) in dichloromethane (5 ml) was added trifluoroacetic acid (5 ml), and the reaction was stirred at ambient temperature for 2 hours. The reaction was concentrated, taken up in water, and 1M NaOH was added until the pH was >13. The aqueous layer was extracted twice with dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to yield 371 mg of the title compound (72.1% yield).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[NH:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH:22]2[O:24][CH2:23]2)=[CH:16][CH:15]=1>O>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][CH:22]([OH:24])[CH2:23][N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:18][CH:19]=1
Reactant: Brc1ccc(CCC2CO2)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OC(CCc1ccc(Br)cc1)Cn1ccnc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
To a sample of pure sodium hydride (1.60 g, 66.58 mmol, 1.4 equiv) under a N2 atmosphere was added DMF (40 mL). The mixture was cooled to 0° C. and imidazole (4.86 g, 71.34 mmol, 1.5 equiv) was added in many small portions over 1 h. Stirring was continued for an additional 0.5 h at 0° C. To the mixture was added dropwise the neat epoxide 12a (10.80 g, 47.56 mmol, 1 equiv); the epoxide container was rinsed with DMF (10 mL) and the rinse solution was added to the reaction mixture. The mixture was stirred at 0° C. for 0.5 h and then at rt for 24 h. Monitoring by TLC (silica gel, EtOAc) confirmed the completion of the reaction. Water (20 mL) was added, the mixture cooled to 0° C., and more water (200 mL) was added without stirring. After 1 h at 0° C. an additional 100 mL of water were added. The white solid was removed by filtration and washed with water (3×250 mL), and then with hexanes (200 mL). High-vacuum drying gave the imidazole-alcohol 13a (11.80 g, 39.98 mmol, 84%) as a white solid: mp 121-122° C., Rf=0.08 (ethyl acetate); 1H NMR (400 MHz, CDCl3): δ 1.68-1.82 (m, 2H), 2.68-2.76 (m, 1H), 2.82-2.89 (m, 1H), 3.75-3.94 (m, 3H), 6.80 (s, 1H), 6.84 (s, 1H), 7.08 (d, J=8.4 Hz, 2H), 7.31 (s, 1H), 7.40 (d, J=8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 31.3, 36.0, 54.1, 69.5, 119.9, 128.5, 130.4, 131.6, 140.6; HRMS (EI) Calcd. for C13H15BrN2O: 294.0368 (M+). Found: 294.0375.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:10]#[N:11])[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[H][H]>C(O)C.[Ni].O>[CH2:1]([O:3][C:4]([C:6]1([CH2:10][NH2:11])[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C#N)CCC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1(CN)CCC1
Temperature: 40 °C
Yield: 71.9 %

Procedure:
1-Cyano-cyclobutanecarboxylic acid ethyl ester (2.00 g, 13.0 mmol) was dissolved in ethanol (30 ml) and treated with Raney Nickel (1 ml as a slurry in water) and hydrogen gas at 4 bar and heating at 40° C. for 18 h. The reaction mixture was filtered through Dicalite and washed through with ethanol (50 ml). The solvent was removed under reduced pressure to give 1-aminomethyl-cyclobutanecarboxylic acid ethyl ester as a yellow oil (1.47 g, 72%).
Reaction SMILES: [CH2:1]([O:19][P:20](=[O:23])([OH:22])[OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(O)C.[OH-].[Na+:28].O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Zn+2:41]>O>[CH2:1]([O:19][P:20]([O-:23])([O-:22])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Zn+2:41].[Na+:28]
Reactant: CCCCCCCCCCCCCCCCCCOP(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOP(=O)([O-])[O-]
Reaction time: 0.5 h

Procedure:
50 g of monostearylphosphoric acid and 100 g of ethanol were put into a 500 ml reaction vessel. Further, a solution of 5.94 g of 96% sodium hydroxide (purity was taken into consideration by calculating it from the degree of neutralization determined by titration) dissolved in 200 g of ion-exchanged water was added thereto. After the temperature was elevated to 80° C., it was confirmed that they were clearly dissolved. The solution was continuously stirred for 30 minutes. A solution of 21.4 g of zinc sulfate heptahydrate dissolved in 100 g of ion-exchanged water was added dropwise thereto to carry out a salt exchange reaction. After the completion of the addition, the mixture was stirred for 30 minutes. 8.85 g of an aqueous solution of 33.33% sodium hydroxide was added dropwise thereto to adjust the pH of the reaction mixture to 3. Further, the mixture was stirred for one hour. After the completion of the reaction, the mixture was cooled and the product was collected by filtration, washed with water and dried, to obtain 51.5 g of the particles of sodium zinc monostearylphosphate.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C([O-])(=O)C.[Ce+3].C([O-])(=O)C.C([O-])(=O)C.[Br-].[Cs+].[C]=O.[C:26](=O)([O:34]C1C=CC=CC=1)[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>[Pd]>[C:26]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:34])[C:2]1[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:7]
Reactant: Oc1ccccc1
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Br-]
Solvent: O
Product: O=C(Oc1ccccc1)c1ccccc1O

Procedure:
3.0 g (32 mmol) of phenol, 25.8 mg (0.012 mmol Pd) of 5%-palladium/carbon, 4.2 mg (0.012 mmol) of cerium (III) acetate monohydrate, and 5.18 mg (0.24 mmol) of cesium bromide were charged in a 30-ml Hastelloy autoclave. After air in the system was replaced by carbon monoxide, 60 Kg/cm2 of carbon monoxide and 30 Kg/cm2 of dry air were introduced into the autoclave, followed by reaction at 100° C. for 3 hours. As a result of gas chromatographic analysis of the reaction solution, the yield of diphenyl carbonate was 9.4% (1.5 mmol). The yields of phenyl salicylate and p-phenoxyphenol which were produced as by-products were 0.32% (0.05 mmol) and 0.13% (0.02 mmol), respectively. After the completion of reaction, the gas phase contained 0.4% of carbon dioxide.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH3:7][S:8][C:9]1[C:14]2[N:15]=[C:16]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1>ClC1N=C(N2CCS(=O)CC2)C2N=CN=C(Cl)C=2N=1>[C:4]([N:28]1[CH2:29][CH2:30][N:25]([C:16]2[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)[C:13]3[N:12]=[CH:11][N:10]=[C:9]([S:8][CH3:7])[C:14]=3[N:15]=2)[CH2:26][CH2:27]1)(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: C=C1CC(=O)O1
Reactant: CSc1ncnc2c(N3CCSCC3)nc(N3CCNCC3)nc12
Agent: O=S1CCN(c2nc(Cl)nc3c(Cl)ncnc23)CC1
Product: CSc1ncnc2c(N3CCSCC3)nc(N3CCN(C(=O)CC(C)=O)CC3)nc12
Reaction time: 0.5 h

Procedure:
1.6 gm (0.02 mol) of diketene were slowly poured, while stirring, into a solution of 3.6 gm (0.01 mol) of 8-methylthio-2-piperazino-4-thiomorpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 177°-179° C.) in 50 ml of dioxane. After stirring for 30 minutes more, the solvent was evaporated in vacuo, and the residue was taken up in about 100 ml of water. The precipitated reaction product was suction-filtered off, washed with water and dried.
Reaction SMILES: [CH2:1]([N:3]1[CH2:26][CH2:25][C:6]2[N:7]([CH2:15][CH:16]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)O)[C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].S(=O)(=O)(O)O.[OH-].[K+]>>[CH2:1]([N:3]1[CH2:26][CH2:25][C:6]2[N:7]([CH:15]=[CH:16][C:18]3[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=3)[C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: CCN1CCc2c(c3cc(C)ccc3n2CC(O)c2ccc(C)cc2)C1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: CCN1CCc2c(c3cc(C)ccc3n2C=Cc2ccc(C)cc2)C1
Temperature: 5 °C

Procedure:
2-(2-Ethyl-1,2,3,4-tetrahydro-8-methylpyrido[4,3-b]indol-5-yl)-1-p-tolylethanol (1 equiv.) is refluxed with 25% sulfuric acid for 2 h. The reaction mixture is cooled to 5° C. with an ice-water bath. KOH (15% aq. solution) is added dropwise to the reaction mixture until pH 9-10 is achieved. The reaction mixture is extracted with EtOAc. The combined organic layers are washed with water followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product is purified by column chromatography over silica gel (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%).
Reaction SMILES: [OH-].[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N+:9]3[C:15]([OH:16])=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)S[C:10]=32)=[CH:5][CH:4]=1.[C:23]([O:27][CH3:28])(=[O:26])[C:24]#[CH:25]>C1(C)C=CC=CC=1>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][CH2:8][N:9]3[C:10](=[C:24]([C:23]([O:27][CH3:28])=[O:26])[CH:25]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:15]3=[O:16])[C:11]=2[CH:12]=1
Reactant: Oc1c(-c2ccccc2)sc2[n+]1CCc1ccc(Cl)cc1-2
Reactant: C#CC(=O)OC
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1cc(Cl)ccc1CC2

Procedure:
(ba) 4.2 g of 9-chloro-2-phenyl-5,6-dihydro-3-hydroxythiazolo[2,3-a]isoquinolinium hydroxide (internal salt) were heated under reflux for 4 hours in 100 ml of toluene together with 1.32 ml of methyl propiolate. After concentration in vacuo, the residue was chromatographed on silica gel with toluene/acetone (9:1). There was obtained methyl 10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-benzo[a]quinolizine-1-carboxylate of m.p. 139°-141° (from ethyl acetate).
Reaction SMILES: Cl[CH2:2][CH:3]1[CH:5]([C:6]([O:8]CC)=O)[C:4]1([CH3:20])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1.[CH:21]1([CH2:27][CH2:28][CH2:29][NH2:30])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>Cl>[CH:21]1([CH2:27][CH2:28][CH2:29][N:30]2[CH2:2][CH:3]3[CH:5]([C:4]3([CH3:20])[C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)[C:6]2=[O:8])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NCCCC1CCCCC1
Reactant: CCOC(=O)C1C(CCl)C1(C)c1cccc([N+](=O)[O-])c1
Agent: Cl
Product: CC1(c2cccc([N+](=O)[O-])c2)C2CN(CCCC3CCCCC3)C(=O)C21
Yield: 72.6 %

Procedure:
A solution of ethyl 3-(chloromethyl)-2-methyl-2-(3-nitrophenyl)cyclopropane carboxylate (Preparation 5, 1 g, 3.36 mmol) in 3-cyclohexylpropylamine ([Preparation—Eur. J. Med. Chem. (1992), 27, 321–330], 2.9 g, 20.5 mmol) was heated to 160° C. for 16 h. The mixture was cooled, 2N hydrochloric acid solution (20 ml) was added and the mixture was extracted with dichloromethane (3×20 ml). The combined extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica (200 g) column chromatography eluting with dichloromethane then diethyl ether. Appropriate fractions were combined and concentrated in vacuo to give the title compound as an amber oil (870 mg, 73%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[S:7][C:8]([CH2:15][OH:16])=[CH:9][C:10]=1[Si:11]([CH3:14])([CH3:13])[CH3:12])=[O:5])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH2:1]([NH:3][C:4]([C:6]1[S:7][C:8]([CH:15]=[O:16])=[CH:9][C:10]=1[Si:11]([CH3:14])([CH3:13])[CH3:12])=[O:5])[CH3:2]
Reactant: CCNC(=O)c1sc(CO)cc1[Si](C)(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCNC(=O)c1sc(C=O)cc1[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
To the compound of step b (1.3 g, 5 mmol) in 40 mL CH2Cl2 containing 1.8 g celite was added 2.4 g pyridinium chlorochromate and the resulting reaction mixture was stirred at RT for 2 h. The CH2 Cl2 solution was filtered through celite, washed with water, brine, dried and concentrated in vacuo. The residue was purified by flash chromatography with 10% ethyl acetate-hexane to give 1.1 g of the desired product as a light yellow solid, m.p. 62°-65° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].I[CH3:29]>C1COCC1.C(OCC)(=O)C>[CH3:29][O:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1OC

Procedure:
Methyl 2-hydroxy-4-(1-Boc-4-piperidyloxy)benzoate (6.7 g, 19.1 mmol) was dissolved in THF (20 ml) and stirred in an ice bath under nitrogen. Sodium hydride (1.17g of a 60% suspension in mineral oil, 29.5 mmol) was added and the mixture was stirred for 15 min in the cold, then for 15 min at ambient temperature. Iodomethane (2.4 ml, 5.47 g, 38.1 mmol) was added and the mixture was allowed to stir at ambient temperature under nitrogen for 72 hours. An additional 0.51 g of 60% sodium hydride suspension was added and the mixture stirred an additional 7 hours, then an additional 1.2 ml of iodomethane was added and the mixture stirred another 18 hours. An additional 0.53 g of sodium hydride suspension was added, the mixture was stirred 1.5 hours, then an additional 1 ml of iodomethane was added and the mixture stirred 6 hours. An additional 1 ml of iodomethane was added and the mixture stirred 18 hours at ambient temperature. The mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and with brine. The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness in vacuo to give methyl 2-methoxy-4-(1-Boc-4-piperidyloxy)-benzoate.
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].C([Li])CCC.[Si:13]([N:20]1[C@H:23]([C:24]([OH:26])=[O:25])[C@@H:22]([CH3:27])[C:21]1=[O:28])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(I)C.Cl>C1COCC1.CCCCCC.CCOCC>[Si:13]([N:20]1[C@H:23]([C:24]([OH:26])=[O:25])[C@:22]([CH2:1][CH3:2])([CH3:27])[C:21]1=[O:28])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: C[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1C(=O)O
Reactant: CC(C)NC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CCI
Product: CC[C@@]1(C)C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1C(=O)O
Temperature: -70 °C

Procedure:
To a solution of 13 mL of diisopropylamine in 75 mL of THF at -20° C. was added 35 mL of 2.4M n-butyl lithium in hexane. After 15 minutes the solution was cooled to -70° C. and a solution of 10 gms of (3R,4S)-1-t-butyldimethylsilyl-3-methylazetidin-2-one-4-carboxylic acid in 50 mL of THF was added. The solution was warmed to -20° C. for 15 minutes and a solution of 6.7 mL of ethyl iodide in 10 mL of THF was added. After 30 minutes at -20° to 0° C. the reaction was diluted with ether and poured into a mixture of ice and 1N HCl. The layers were separated and the aqueous layer extracted with ether. The ether layers were each washed with brine, dried over sodium sulfate and evaporated. The residue was crystallized from a minimum amount of hexane to give 8.8 gms of (3R,4S)-1-t-butyldimethylsilyl-3-ethyl-3-methylazetidin-2-one-4-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:12][Br:13])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](OC)=[O:6].CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([CH2:12][Br:13])=[C:4]([CH2:5][OH:6])[CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1cccc(Br)c1CBr
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: OCc1cccc(Br)c1CBr
Temperature: 0 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
A solution of methyl 3-bromo-2-(bromomethyl)benzoate in dry toluene (0.45 M) was added dropwise to a solution of DIBAL-H (2 eq., 1 M in toluene) in dry toluene (0.9 M) at 0° C. The reaction mixture was stirred at 0° C. for 2 h. Then, the reaction mixture was quenched with a solution of 1N HCl until pH 1 and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine and dried (Na2SO4). Evaporation of the solvent yielded (96%) the title compound as a white powder, which was used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6, 300K) δ 7.66 (1H, d, J=8.0 Hz), 7.56 (1H, d, J=7.4 Hz), 7.32 (1H, t, J=7.6 Hz), 5.51 (1H, bt, J=5.4 Hz), 4.83 (2H, s), 4.70 (2H, bd, J=4.6 Hz).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=O.[NH2:12]CC1C=CC=C(C(C)(C)C)C=1O>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH2:4][NH2:12]
Reactant: CC(C)(C)c1cccc(CN)c1O
Reactant: COc1cccc(F)c1C=O
Product: COc1cccc(F)c1CN

Procedure:
(2-fluoro-6-methoxyphenyl)methanamine was synthesized from 2-fluoro-6-methoxybenzaldehyde using a similar procedure to the described synthesis of 2-(aminomethyl)-6-tert-butylphenol.