Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[N:14]2)=[CH:9][CH:8]=1)(=O)=O.[CH:19]1(B(O)O)[CH2:21][CH2:20]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:19]1([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[N:14]3)=[CH:9][CH:8]=2)[CH2:21][CH2:20]1
Reactant: O=S(=O)(Oc1ccc2cccnc2c1)C(F)(F)F
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: c1cnc2cc(C3CC3)ccc2c1
Temperature: 105 °C
Yield: 60.9 %

Procedure:
A mixture of quinolin-7-yl trifluoromethanesulfonate (9.28 g, 33.5 mmol), cyclopropylboronic acid (3.74 g, 43.55 mmol), K3PO4 (24.9 g, 117.2 mmol), tricyclohexylphosphine (0.94 g, 3.35 mmol), and Pd(OAc)2 (0.376 g, 1.67 mmol) in toluene (200 mL) and water (10 mL) was heated overnight at 105° C. under an atmosphere of N2. The mixture was filtered through a plug of celite, and the filtrate was collected and extracted with EtOAc/brine. The organic layer was separated, dried over anhydrous Na2SO4, concentrated, and purified by chromatography (SiO2) with a gradient elution of 1-15% EtOAc/CH2Cl2 to yield 7-cyclopropylquinoline (3.45 g, 61% yield).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][Se:15][C:11]=2[C:10]([C:16]2[O:17][C:18]([C:21]([O:23]C)=[O:22])=[CH:19][CH:20]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>[OH-].[Na+]>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][Se:15][C:11]=2[C:10]([C:16]2[O:17][C:18]([C:21]([OH:23])=[O:22])=[CH:19][CH:20]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3cc[se]c23)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(-c2nn(Cc3ccccc3)c3cc[se]c23)o1
Yield: 80.1 %

Procedure:
Compound 55 (0.772 g, 0.002 mole) in 20 ml of 10% NaOH solution was heated under refluxing for 2 h, cooled and acidified with 10% HCl solution in an icewater bath. The precipitates were collected, then recrystallized from ethanol to afford compound 59 (0.595 g). Yield 80.2%; white crystals; mp 243-244° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[C:13]1([C:19]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:20]2[CH:24]=[C:23]([C:25](=[O:27])[CH3:26])[N:22]=[CH:21]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+].Cl>C(O)C>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[CH:26][C:25]([C:23]1[N:22]=[CH:21][N:20]([C:19]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:24]=1)=[O:27]
Reactant: COc1cccc(C=O)c1OC
Reactant: CC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(C=CC(=O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1OC

Procedure:
0.149 mole of 2,3-dimethoxybenzaldehyde is added over 5 hours at room temperature to a solution of 0.149 mole of 1-(1-triphenylmethyl-1H-imidazol-4-yl)-1-ethanone prepared in Example 2.1 in a mixture of 800 ml of ethanol and 186 ml of a 2N aqueous solution of sodium hydroxide. The reaction medium is then brought to pH 7.5 by addition of a 5N aqueous solution of hydrochloric acid. The ethanol is distilled off and a solid is formed, which precipitates. This solid is filtered off and washed with water before drying. The solid is redissolved in 2 liters of boiling 2-propanol and the insoluble salts are filtered off. Half the 2-propanol is evaporated off and the 3-(2,3-dimethoxyphenyl)-1-(1-triphenylmethyl-1H-imidazol-4-yl)-2-propen-1-one is recrystallized.
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:14]3[CH:23]=[C:22]([CH2:24][CH3:25])[O:21][C:15]=3[C:16]([O:19][CH3:20])=[N:17][CH:18]=2)=[O:12])=CC=1)([O-])=O.[F:26][C:27]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[C:28]=1[NH2:29]>>[F:26][C:27]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[C:28]=1[NH:29][C:11]([C:13]1[C:14]2[CH:23]=[C:22]([CH2:24][CH3:25])[O:21][C:15]=2[C:16]([O:19][CH3:20])=[N:17][CH:18]=1)=[O:12]
Reactant: CCc1cc2c(C(=O)Oc3ccc([N+](=O)[O-])cc3)cnc(OC)c2o1
Reactant: Nc1c(F)cc(F)cc1F
Product: CCc1cc2c(C(=O)Nc3c(F)cc(F)cc3F)cnc(OC)c2o1
Yield: 33.2 %

Procedure:
Starting from 2-ethyl-7-methoxyfuro[2,3-c]pyridine-4-carboxylic acid 4-nitrophenyl ester (0.20 g) and 2,4,6-trifluoroaniline (0.18 g). Purification by column chromatography on silica with 30% ethyl acetate in hexane followed by trituration with ether gave the title compound (0.068 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:10]([F:13])([F:12])[CH:9]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][N:15]=3)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[N:3]=1.[H-].[Na+].[CH2:32](Br)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].O>CN(C=O)C>[CH2:32]([O:20][C:17]1[CH:18]=[CH:19][C:14]([CH:9]2[C:10]([F:12])([F:13])[C:11]3[C:2]([F:1])=[N:3][C:4]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:5][C:6]=3[CH2:7][CH2:8]2)=[N:15][CH:16]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCOc1cc2c(c(F)n1)C(F)(F)C(c1ccc(O)cn1)CC2
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCOc1ccc(C2CCc3cc(OCCCCCCCC)nc(F)c3C2(F)F)nc1
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
10 mmol of 1,8,8-trifluoro-7-(5-hydroxypyridin-2-yl)-3-octyloxy-5,6,7,8-tetrahydroisoquinoline are dissolved in 50 ml of DMF, and 11 mmol of sodium hydride are added. After the mixture has been stirred for 30 minutes, 11 mmol of 1-octyl bromide are added dropwise, and the mixture is stirred at 60° C. for a further 140 minutes and poured into water. The mixture is extracted with dichloromethane, the combined organic phases are dried, the solvent is removed in vacuo and the residue is chromatographed on silica gel, giving 7.55 mmol of 7-[5-(octyloxy)pyridin-2-yl]-1,8,8-trifluoro-3-octyloxy-5,6,7,8-tetrahydroisoquinoline.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:32])[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]4[CH2:24][CH2:23][N:22]([CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH2:21][CH2:20]4)=[CH:14][CH:13]=3)=[C:9]([C:33]3[CH:38]=[CH:37][C:36]([O:39]C)=[CH:35][CH:34]=3)[S:8][C:7]=2[CH:41]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:32])[C:12]3[CH:13]=[CH:14][C:15]([O:18][CH:19]4[CH2:24][CH2:23][N:22]([CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH2:21][CH2:20]4)=[CH:16][CH:17]=3)=[C:9]([C:33]3[CH:34]=[CH:35][C:36]([OH:39])=[CH:37][CH:38]=3)[S:8][C:7]=2[CH:41]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OC3CCN(Cc4ccccc4)CC3)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Product: O=C(c1ccc(OC2CCN(Cc3ccccc3)CC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Yield: 56 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)-3-(4-[1-benzylpiperidin-4-oxy]benzoyl)benzo[b]thiophene (846 mg, 1.50 mmol), ethane thiol (7.50 mmol), and aluminum chloride (1.2 g, 9.00 mmol) were converted to 450 mg (56%) of the title compound by the procedure of Example 16. MS(FD) 536(M+). IR (CHCl3) ν max 3311, 3023, 3011, 2953, 1721, 1596, 1469, 1257, 1166.
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16]O)=[CH:12][C:11]=2[C:18]2([CH:23]=[CH2:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.S(Cl)([Cl:27])=O>CN(C=O)C.C(Cl)Cl>[Cl:27][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:3]2[C:2]([F:1])=[CH:7][N:6]=[C:5]([O:8][CH3:9])[CH:4]=2)=[C:11]([C:18]2([CH:23]=[CH2:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:12]=1
Reactant: C=CC1(c2cc(CO)ccc2-c2cc(OC)ncc2F)CCCC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CC1(c2cc(CCl)ccc2-c2cc(OC)ncc2F)CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (4-(5-fluoro-2-methoxypyridin-4-yl)-3-(1-vinylcyclopentyl)phenyl)methanol (47.0 mg, 144 μmol) in DMF (0.01 mL) and DCM (4.0 mL) was slowly added thionyl chloride (14.7 μL, 201 μmol) at 0° C. After addition, the resulting mixture was stirred at room temperature for 1 hour. The solvent was removed, and the product thus obtained was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 8.01-8.11 (1H, m), 7.98 (1H, m), 7.47 (1H, s), 6.94 (1H, d, J=7.8 Hz), 6.69-6.82 (1H, m), 5.80 (1H, dd, J=17.2, 10.6 Hz), 4.89 (1H, d, J=10.2 Hz), 4.52-4.69 (3H, m), 3.89 (3H, s), 1.68-1.84 (4H, m), 1.49-1.67 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:21]([O:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH:32]=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[NH4+].[Cl-]>C1COCC1>[CH2:21]([O:28][C:29]1[CH:30]=[C:31]([CH:32]=[CH:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[O:10])[CH:34]=[CH:35][CH:36]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Reactant: CC(=O)c1ccccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(C=Cc1cccc(OCc2ccccc2)c1)c1ccccc1Cl
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2′-chloroacetophenone (1-1) (1.26 mL, 9.70 mmol) in 40 mL of THF at −78° C. was slowly added 10.7 mL (10.7 mmol) of a 1M LiHMDS solution in THF. After stirring for 1 h at −78° C., a solution of 2.05 g (9.70 mmol) of 3-benzyloxy-benzaldehyde (1-2) in 8 mL of THF was added, and stirring was continued at that temperature for an additional hour. The mixture was then dumped into a separatory funnel containing 100 mL of saturated aqueous NH4Cl and extracted twice with 100 mL of EtOAc. The organic phases were combined, washed with 100 mL of brine, and dried over Na2SO4. After filtering off the drying agent, the solvent was removed on a rotary evaporator, and the residue was dissolved in 50 mL of CH2Cl2. After cooling to −78° C., 4 mL of triethylamine and 2 mL of trifluoroacetic anhydride were added sequentially, and the mixture was allowed to warm to rt and stir for 12 h. The reaction was then dumped into a separatory funnel with 100 mL of 1M HCl, the layers were separated, and the aqueous phase extracted again with CH2Cl2. The organic layers were combined, washed again with 1 M HCl, washed with water, and dried over Na2SO4. After concentration, the crude material was purified by chromatography on silica gel with a gradient of 0 to 40% EtOAc in hexanes over 45 min to provide 1-4 as a viscous yellow oil. Data for 1-4: 1HNMR (500 MHz, CDCl3) δ 7.5-7.0 (m, 15H) 5.1 (s, 2H) ppm.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:12][S:13][CH2:14][CH2:15][CH:16]=O>>[CH3:12][S:13][CH2:14][CH:15]=[CH:16][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CSCCC=O
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CSCC=CN1CCCC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 83.8 %

Procedure:
To a dry 1 L round bottom flask equipped with a magnetic stir bar, liquid addition funnel, thermometer, and nitrogen inlet were added potassium carbonate (33.2 g, 240 mmol) and pyrrolidine (136.5 g, 160 mL, 1.92 mol), and the resulting suspension was cooled to 0° C. in an ice bath. 3-(Methylthio)propionaldehyde (K) (50 g, 480 mmol) was added dropwise via the addition funnel at a rate which maintained the reaction temperature at 0-7° C. The resulting light yellow mixture was warmed to room temperature and stirred for 16 hours. The residual potassium carbonate was removed by filtration, the filter cake washed with Et2O, and the filtrate concentrated on the rotary evaporator to give the crude enamine as a viscous, light yellow oil. Fractional distillation (108-110° C. at 4 mm Hg) afforded 63.3 g (83.8%) of 1-[3-(methylthio)prop-1-enyl]pyrrolidine (L) as a colorless liquid. 1H NMR (CDCl3) δ 6.29 (d, 1H), 4.06 (dt, 1H), 3.16 (d, 2H), 3.03 (m, 4H), 2.04 (s, 3H), 1.85 (m, 4H). GC-MS (EI) m/z 157 (M+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.S(Cl)(Cl)=O.[N:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][N:14]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.CN(C)C=O.ClCCl>[N:13]1[CH:18]=[CH:17][C:16]([NH:19][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:8])=[CH:15][N:14]=1
Reactant: Nc1ccnnc1
Reactant: O=C(O)c1ccco1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Nc1ccnnc1)c1ccco1
Temperature: 80 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
2.00 g (17.8 mmol) of furan-2-carboxylic acid were suspended in 25 mL of toluene and one drop of dimethylformamide was added to the mixture. 1.95 ml of thionylchloride (26.8 mmol) were added at room temperature and the reaction mixture was stirred at 80° C. for two hours. After removal of the solvent, toluene was added and the evaporation was repeated. The obtained residue was then dissolved in 5 ml of dichloromethane and the solution was added dropwise to a solution containing 1.70 g of pyridazin-4-yl-amine (17.8 mmol) and 2.73 ml of triethyl amine (19.6 mmol) in 20 ml of dichloromethane. The mixture was stirred at room temperature for 2 days and washed twice with water. The organic layer was dried over Na2SO4, filtered and the solvent was removed under vacuum to give the title compound as a brown solid (1.9 g, 54%, 95% purity).
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[C:10]2=[O:38])=[CH:6][N:7]=1)[CH3:2].[ClH:39]>O1CCOCC1>[ClH:39].[CH2:1]([C:3]1[O:4][C:5]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:10]2=[O:38])=[CH:6][N:7]=1)[CH3:2]
Reactant: CCc1ncc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)o1
Agent: Cl
Solvent: C1COCCO1
Product: CCc1ncc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-butyl 4-{1-[(2-ethyl-1,3-oxazol-5-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (120 mg; compound B9) is dissolved in a solution of hydrogen chloride in 1,4-dioxane (5 ml, 6.8 M). The solution is stirred for 0.5 h at RT. The resulting precipitate is filtered off, washed with diethyl ether and dried in vacuo to give the title compound as a solid.
Reaction SMILES: C([CH:8]([NH2:24])[CH2:9][CH2:10][NH:11][C:12]([P:14]([O:20][CH:21]([CH3:23])[CH3:22])([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])=[O:13])(OC(C)(C)C)=O.CCN(CC)CC.[O:32]([C:39]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[O:32]([C:39]1[CH:44]=[CH:43][C:42]([S:45]([NH:24][CH2:8][CH2:9][CH2:10][NH:11][C:12]([P:14]([O:16][CH:17]([CH3:18])[CH3:19])([O:20][CH:21]([CH3:22])[CH3:23])=[O:15])=[O:13])(=[O:47])=[O:46])=[CH:41][CH:40]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: CC(C)OP(=O)(OC(C)C)C(=O)NCCC(N)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OP(=O)(OC(C)C)C(=O)NCCCNS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
1-Boc-amino-3-[diisopropylphosphonoformamido]propane (0.7 g, 4 mmol) was dissolved in 5 ml TFA. The reaction was stirred for 30 min. The excess of TFA was removed by evaporation in vacuo with toluene. To the residue in 15 ml DCM were added Et3N (5 eq, 2.8 ml, 20 mmol) and 4-phenoxybenzenesulfonyl chloride (1 g, 45 mmol). The reaction was stirred overnight at room temperature. The mixture was washed with 1N HCl; the organic layer was dried over Na2SO4 and the solvent was evaporated. The product was purified by silica gel chromatography [eluent: CHCl3/1-2% MeOH] to yield 1 g (50%) yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]([C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:26]=2[O:25][C:24]([CH3:27])=[CH:23][C:22]3=[O:28])[C:5]([C:11]([O:13][CH2:14][CH2:15][CH3:16])=[O:12])=[C:6]([CH3:10])[NH:7][C:8]=1[CH3:9])#[N:2].CCCC(C)C.C(O)C.C(NCC)C>>[C:1]([C:3]1[C@@H:4]([C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:26]=2[O:25][C:24]([CH3:27])=[CH:23][C:22]3=[O:28])[C:5]([C:11]([O:13][CH2:14][CH2:15][CH3:16])=[O:12])=[C:6]([CH3:10])[NH:7][C:8]=1[CH3:9])#[N:2]
Reactant: CCCOC(=O)C1=C(C)NC(C)=C(C#N)C1c1cccc2c(=O)cc(C)oc12
Solvent: CCO
Solvent: CCNCC
Solvent: CCCC(C)C
Product: CCCOC(=O)C1=C(C)NC(C)=C(C#N)[C@H]1c1cccc2c(=O)cc(C)oc12

Procedure:
430 mg (1.13 mmol) of racemic propyl 5-cyano-2,6-dimethyl-4-(2-methyl-4-oxo-4H-chromen-8-yl)-1,4-dihydropyridine-3-carboxylate (example 4) are separated into the enantiomers by preparative HPLC on a chiral phase [column: Chiralpak AD-H, 250 mm×4.6 mm; eluent: isohexane/ethanol 3:1 (v/v)+0.2% diethylamine; flow rate: 1 ml/min; UV detection: 220 nm]:
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]2[O:6][C:7]3[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=3[C@@H:9]3[C@H:13]([C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)[O:12][C:11](=[O:20])[N:10]3[C:4]=2[CH:3]=1>O>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]2[O:6][C:7]3[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=3[C@H:9]3[C@H:13]([C:14]4[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=4)[O:12][C:11](=[O:20])[N:10]3[C:4]=2[CH:3]=1
Reactant: O=C1O[C@@H](c2ccncc2)[C@H]2c3ccccc3Oc3ccc(Cl)cc3N12
Solvent: O
Product: O=C1O[C@@H](c2ccncc2)[C@@H]2c3ccccc3Oc3ccc(Cl)cc3N12

Procedure:
(-)-trans-6-chloro-1,13b-dihydro-1-(4-pyridyl)-3H-dibenz[b,f]oxazolo[3,4-d][1,4]oxazepin-3-one 6b specific rotation -50.2° @ 589 nM; Analysis Calculated for C20H13N2O3Cl×1.5 H2O: C, 61.31; H, 4.12; N, 7.15. Found: C, 61.38; H, 4.13; N, 6.82.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH:9]([NH:10][C:11]2[N:16]=[C:15]([N:17]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:14]=[CH:13][N:12]=2)[CH2:8][CH2:7][CH2:6][N:5]1[CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.N=C=N.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([C:46](O)=[O:47])[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].OC1C2N=NNC=2C=CC=1.C(=O)([O-])[O-]>ClCCl.CN(C)C=O>[N:17]1([C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH:10][CH:9]3[CH2:8][CH2:7][CH2:6][N:5]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[CH:4]3[CH2:3][CH2:2][NH:1][C:46]([CH:43]3[CH2:44][CH2:45][N:40]([C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])[CH2:41][CH2:42]3)=[O:47])[N:16]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NCCC1C(Nc2nccc(N3CCCCCC3)n2)CCCN1C1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: N=C=N
Agent: O=C([O-])[O-]
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCCC2C(Nc3nccc(N4CCCCCC4)n3)CCCN2C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[(2RS,3SR)-2-(2-aminoethyl)-1-cyclohexylpiperidin-3-yl]-4-azepan-1-ylpyrimidin-2-amine (63 mg) was dissolved in dichloromethane (3 mL), PS-carbodiimide (327 mg) was added and then 0.5 M of a solution (0.47 mL) of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid in dimethylformamide:dichloromethane=1:1 and 0.5 M of a mixture solution (0.53 mL) of hydroxybenzotriazole in dimethylformamide:dichloromethane=1:1 were added and stirred at room temperature for overnight. MP-carbonate (271 mg) was added into the reaction solution, stirred for 1 hour and then filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=90:10) to obtain the title compound (81 mg) having the following physical properties.
Reaction SMILES: [OH:1][C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:11]([OH:13])=O.Cl.[C:15]([O:19][C:20](=[O:25])[C:21]([NH2:24])([CH3:23])[CH3:22])([CH3:18])([CH3:17])[CH3:16].C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[C:15]([O:19][C:20](=[O:25])[C:21]([NH:24][C:11]([C:3]1[CH:4]=[CH:5][C:6]2[S:7][CH:8]=[CH:9][C:10]=2[C:2]=1[OH:1])=[O:13])([CH3:23])[CH3:22])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)C(C)(C)N
Reactant: O=C(O)c1ccc2sccc2c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C(C)(C)NC(=O)c1ccc2sccc2c1O
Yield: 64.5 %

Procedure:
To a solution of 300 mg 4-Hydroxy-benzo[b]thiophene-5-carboxylic acid in 5 ml N,N-dimethylformamide were added 42 mg 1-hydroxy-benzotriaziole and 285 mg 2-amino-2-methyl-propionic acid tert-butyl ester hydrochloride. At 0° C. 0.77 ml (600 mg) ethyl-diisopropyl-amine and 444 mg (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride were added. After 16 h at room temperature 0.51 ml (400 mg) ethyl-diisopropyl-amine and 444 mg (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride were added, and after additional 16 h the reaction was diluted with ethyl acetate and washed with brine. The organic layer was dried over magnesium sulphate and concentrated. The resulting residue was purified by flash chromatography (silica, heptane/ethyl acetate) to afford 315 mg 2-[(4-hydroxy-benzo[b]thiophene-5-carbonyl)-amino]-2-methyl-propionic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Br:9])[C:3]=1[OH:10].[Br:11][CH2:12][CH2:13]Br.[OH-].[K+]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Br:9])[C:3]=1[O:10][CH2:13][CH2:12][Br:11]
Reactant: Cc1cc(Br)c(O)c(Br)c1
Reactant: BrCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Br)c(OCCBr)c(Br)c1
Yield: 65.7 %

Procedure:
A mixture of 2,6-dibromo-4-methylphenol (18) (26.59 g, 0.1 mol), 1,2-dibromoethane (11.2 ml, 0.13 mol) and potassium hydroxide (8.42 g, 0.15 mol) in 200 ml of absolute ethanol was heated under reflux for 24 hours. The inorganic salt was collected on a filter and the filtrate taken to dryness. The resulting mixture was treated with ethyl ether, chilled, and the solid, which proved to be recovered phenol, collected on a filter. The filtrate was evaporated to afford the ether 19 (24.5 g, 65.7%) as a liquid. This was purified by distillation (0.5 torr, 120°-124° C.) to yield 19.79 g (53.0%) of product. NMR (CDCl3) δ 7.25 (s, 2H, aromatic protons), 3.55-4.38 (m, 4H, 2CH2), and 2.27 (s, 3H, CH3).
Reaction SMILES: O=[C:2]1[C@@H:8]2[CH2:9][CH2:10][CH2:11][C@@:7]2([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH3:20].COCCO[AlH2-]OCCOC.[Na+]>C1C=CC=CC=1>[CH3:20][N:3]1[CH2:4][CH2:5][CH2:6][C@:7]2([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[CH2:11][CH2:10][CH2:9][C@H:8]2[CH2:2]1
Reactant: COc1cccc([C@@]23CCC[C@H]2C(=O)N(C)CCC3)c1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: c1ccccc1
Product: COc1cccc([C@@]23CCC[C@H]2CN(C)CCC3)c1

Procedure:
Following the procedure set out in Example 7, dl-trans-1-oxo-2-methyl-5a-(3-methoxyphenyl)-decahydrocyclopent[c]azepine was reacted with Red-al® in benzene to provide dl-trans-2-methyl-5a-(3-methoxyphenyl)-decahydrocyclopent[c]azepine. B.P. 130°-140° C. at 0.05 torr.