Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:35][O:36][CH2:37][CH3:38])[N:23]([CH2:24][C:25]([NH:28][C:29]([NH:31][CH:32]([CH3:34])[CH3:33])=[O:30])([CH3:27])[CH3:26])[C:19]=2[C:18]2[CH:17]=[CH:16][C:15]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][NH2:46])=[CH:14][C:13]=2[N:12]=1.C(N(CC)CC)C>ClCCl>[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:35][O:36][CH2:37][CH3:38])[N:23]([CH2:24][C:25]([NH:28][C:29]([NH:31][CH:32]([CH3:34])[CH3:33])=[O:30])([CH3:26])[CH3:27])[C:19]=2[C:18]2[CH:17]=[CH:16][C:15]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][NH:46][S:2]([CH3:1])(=[O:5])=[O:3])=[CH:14][C:13]=2[N:12]=1
Reactant: CCOCc1nc2c(N)nc3cc(OCCCCCCN)ccc3c2n1CC(C)(C)NC(=O)NC(C)C
Reactant: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc3cc(OCCCCCCNS(C)(=O)=O)ccc3c2n1CC(C)(C)NC(=O)NC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.9 %

Procedure:
Methanesulfonic anhydride (0.34 g, 1.93 mmol) was added to a stirred solution of N-{2-[4-amino-7-[(6-aminohexyl)oxy]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-N′-isopropylurea (prepared as described in Parts A-H of Example 369, 10.9 g, 1.75 mmol) and triethylamine (0.35 mL, 3.5 mmol) in dichloromethane (50 mL) at 0° C. After approximately 30 minutes, the solution was allowed to warm to room temperature and was stirred overnight. The following morning, the solution was cooled to 0° C. and additional methanesulfonic anhydride (0.13 g) was added. After 30 minutes, the solution was allowed to warm to room temperature. After 2 hours, the solution was transferred to a separatory funnel and washed with water (2×) and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, elution with 10% methanol in dichloromethane) followed purification by chromatography on a HORIZON HPFC system (an automated, modular high-performance flash purification product available from Biotage, Inc, Charlottesville, Va., USA) (silica gel, gradient elution with 0-40% CMA in chloroform where CMA is a solution of 80:18:2 chloroform/methanol/concentrated ammonium hydroxide) to yield 0.31 g of N-(6-{[4-amino-2-(ethoxymethyl)-1-(2-{[(isopropylamino)carbonyl]amino}-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}hexyl)methanesulfonamide as an off white solid, mp 190-194° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:21]([N+:25]([O-:27])=[O:26])=[CH:22][C:23]=1[OH:24])[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])[CH2:9][CH2:8]1)=[O:6]>C(OC(=O)C)(=O)C>[C:2]([O:1][C:2]1[CH:3]=[C:4]([C:21]([N+:25]([O-:27])=[O:26])=[CH:22][C:23]=1[O:24][C:5](=[O:6])[CH3:4])[C:5]([N:7]1[CH2:8][CH2:9][CH:10]([C:13]([CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:14])[CH2:11][CH2:12]1)=[O:6])(=[O:1])[CH3:23]
Reactant: O=C(C1CCCCC1)C1CCN(C(=O)c2cc(O)c(O)cc2[N+](=O)[O-])CC1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1cc(C(=O)N2CCC(C(=O)C3CCCCC3)CC2)c([N+](=O)[O-])cc1OC(C)=O
Temperature: 0 °C

Procedure:
0.5 g of the product obtained in Example 63 was heated in 10 ml of acetic anhydride for 1 h at 40° C. Ice-water was added and the product was filtered. Yield 0.5 g (87%), m.p. 160°-165° C.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)[C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:34][C:35]1[CH:41]=[C:40]([I:42])[CH:39]=[CH:38][C:36]=1[NH2:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.BrN1C(=O)CCC1=O>ClCCl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16](=[O:17])[NH:18][C@H:19]([C:20](=[O:21])[NH:37][C:36]3[CH:38]=[CH:39][C:40]([I:42])=[CH:41][C:35]=3[F:34])[CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1ccc(I)cc1F
Reactant: O=C(N[C@@H](Cc1ccc2ccccc2c1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(N[C@@H](Cc1ccc2ccccc2c1)C(=O)Nc1ccc(I)cc1F)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-naphthalen-2-yl-propionic acid (1.0 g, 2.30 mmol) and 2-fluoro-4-iodoaniline (434 mg, 1.84 mmol), triphenylphosphine (0.94 g, 3.45 mmol) and pyridine (0.39 mL, 4.60 mmol) in dichloromethane (10 mL) at 0° C. was added N-bromosuccinimide (0.61 mg, 3.45 mmol) in two portions under an atmosphere of dry nitrogen. The mixture was stirred for 2 hours at 0° C. The reaction mixture was purified by chromatography over silica gel gradient eluted from 100% dichloromethane up to 10% methanol/90% dichloromethane over 30 minutes. Concentration of the product containing fractions gave [(S)-1-(2-fluoro-4-iodo-phenylcarbamoyl)-2-naphthalen-2-yl-ethyl]-carbamic acid 9H-fluoren-9-ylmethyl ester as a yellow solid foam (1.05 g, 70%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1.C(OC(=O)C)C.Cl>C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH:9]1[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]1
Reactant: COCCCCCOC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCCCCOC1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
To a solution of 4-(5-methoxypentyloxy)-1-N-t-butyloxycarbonylpiperidine (1.97 g) in ethyl acetate (20 ml) was added 4N-hydrogen chloride ethyl acetate solution (16.3 ml), and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was evaporated in vacuo. The resulting residue was dissolved in a mixture of dichloromethane and methanol (10:1; 50 ml:5 ml). To this solution was added 1N-sodium hydroxide (5 ml) with stirring. The organic layer was separated and evaporated under reduced pressure to give 4-(5-methoxypentyloxy)piperidine (0.62 g).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:13][N:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15](Cl)=[O:16]>>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][C:15](=[O:16])[N:14]([CH3:13])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1ccc(-n2ccnc2)cc1
Product: CN(C(=O)Oc1ccc(-n2ccnc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-imidazol-1-yl-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (4%, clear oil). HPLC-MS m/z=294.1 (M+1), Rt: 2.25 min.
Reaction SMILES: [H-].[Na+].CS(O[CH2:8][CH2:9][CH2:10][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH3:12])(=O)=O.[CH3:20][CH:21]([CH3:24])[CH2:22][SH:23]>O1CCCC1>[CH2:22]([S:23][CH2:8][CH2:9][CH2:10][N:11]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH3:12])[CH:21]([CH3:24])[CH3:20]
Reactant: CC(C)CS
Reactant: CN(CCCOS(C)(=O)=O)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)CSCCCN(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.4 %

Procedure:
To a stirred suspension of sodium hydride (336 mg: 60% dispersion in oil) in anhydrous tetrahydrofuran (12 ml) was added a solution of 3-(N-t-butoxycarbonyl-N-methylamino)propyl methanesulfonate (2.139 g) in tetrahydrofuran (10 ml) dropwise over 5 minutes. After being stirred for 30 minutes, the mixture was cooled to 0° C., and 2-methyl-1-propanethiol (758 mg) was added dropwise at 0°-5° C. The mixture was then allowed to warm to ambient temperature and stirred for 24 hours. Additional 168 mg of sodium hydride and 379 mg of 2-methyl-1-propanethiol was added above the same condition. After being stirred for another 16 hours, the solvent was evaporated and the resulting residue was dissolved in ethyl acetate (100 ml). The solution was washed with 0.5 N hydrochloric acid (100 ml), water (100 ml), aqueous sodium bicarbonate (100 ml), water (100ml), and brine (100 ml) successively, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (6:4 V/V) to give 3-(N-t-butoxycarbonyl-N-methylamino)propyl isobutyl sulfide (595 mg) as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:21][C:22]([O:24][CH2:25][CH:26]2[C:38]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:32]3[C:27]2=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:23])[C:17]([O:19]C)=[O:18])=[C:11]([F:39])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Li+]>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:21][C:22]([O:24][CH2:25][CH:26]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=3[C:33]3[C:38]2=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:23])[C:17]([OH:19])=[O:18])=[C:11]([F:39])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1F)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](Cc1ccc(OCc2ccccc2)cc1F)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Yield: 72.4 %

Procedure:
To a mixed solution of methyl(2S)-3-(4-(benzyloxy)-2-fluorophenyl)-2-(((9H-fluoren-9-ylmethoxy)carbonyl)amino)propanoate (60.0 g, 114 mmol) described in Production Example 1-2-6 and ethyl acetate (1331 mL) was added lithium iodide (92.0 g, 685 mmol) at room temperature. The resultant mixture was stirred under reflux for 23 hours and 45 minutes. The reaction mixture was cooled to 0° C., and a precipitate was collected by filtration. To the resultant solid was added 1 N hydrochloric acid (228 mL). The resultant solution was extracted with ethyl acetate. An organic layer was dried over anhydrous magnesium sulfate and then filtrated. The solvent was evaporated under a reduced pressure to give the title compound (42.2 g, yield: 72%).
Reaction SMILES: [H-].[Na+].O1CC[CH2:5][CH2:4]1.[NH2:8][C:9]1[CH:10]=[C:11]([SH:15])[CH:12]=[CH:13][CH:14]=1.ICC>O.CN(C)C=O>[CH2:4]([S:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[NH2:8])[CH3:5]
Reactant: C1CCOC1
Reactant: Nc1cccc(S)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCI
Product: CCSc1cccc(N)c1
Reaction time: 0.08 h
Yield: 82 %

Procedure:
Sodium hydride (60% in oil, 2.3 g) was suspended in a mixed solvent of tetrahydrofuran (35 mL) and N,N-dimethylformamide (15 mL), and 3-aminobenzenethiol (5.0 g) was added dropwise at room temperature. The mixture was stirred at the same temperature for 5 min, iodoethane (6.86 g) was added, and the mixture was stirred for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→4:1) to give the title compound as a yellow oil (yield 5.0 g, 82%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@H:16]2[CH3:21])[N:11]([CH2:22][C:23]([OH:25])=O)[CH2:10][C@H:9]1[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:45]=[CH:44][C:31]([CH2:32][C:33]2[CH:34]=[C:35]3[NH:41][CH2:40][C:39]([CH3:43])([CH3:42])[C:36]3=[N:37][CH:38]=2)=[CH:30][CH:29]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@H:16]2[CH3:21])[N:11]([CH2:22][C:23]([N:41]2[C:35]3[C:36](=[N:37][CH:38]=[C:33]([CH2:32][C:31]4[CH:44]=[CH:45][C:28]([F:27])=[CH:29][CH:30]=4)[CH:34]=3)[C:39]([CH3:43])([CH3:42])[CH2:40]2)=[O:25])[CH2:10][C@H:9]1[CH3:26])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC1(C)CNc2cc(Cc3ccc(F)cc3)cnc21
Reactant: C[C@@H]1COCCN1C[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1COCCN1C[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)N1CC(C)(C)c2ncc(Cc3ccc(F)cc3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.1 %

Procedure:
To (2R,5S)-4-carboxymethyl-2-methyl-5-((R)-3-methyl-morpholin-4-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (1.5 g, 4.04 mmol) and 6-(4-fluoro-benzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (1.14 g, 4.4 mmol) in DMF (20.2 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (2.31 g, 6.1 mmol) and N,N-diisopropylethylamine (1.41 mL, 8.1 mmol) at room temperature. The reaction was stirred at room temperature for 18 h, then saturated aqueous sodium hydrogen carbonate was added and the mixture extracted with diethyl ether (3×). The combined organic extracts were washed with water (3×) and brine (3×), then dried with sodium sulfate, filtered and concentrated. Chromatography (silica gel, gradient elution, 0-100%, EtOAc in petrol 40-60) gave the title compound (1.9 g, 77%), MS: [M+H]+=610.
Reaction SMILES: CC(C)=O.[OH:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>O>[O:5]=[C:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Nc1ccccc1OC1CCCCC1O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Solvent: CC(C)O
Product: CS(=O)(=O)Nc1ccccc1OC1CCCCC1=O
Yield: 42.3 %

Procedure:
To 10 ml of an acetone solution containing 0.50 g of N-[2-(2-hydroxycyclohexyloxy)phenyl]methanesulfonamide was added 0.5 g of 8N Jones reagent (chromic acid-sulfuric acid) under ice cooling with stirring, and the mixture was stirred for 1 hour. Then, to the reaction solution was added 1 ml of isopropyl alcohol and water, and the mixture was extracted with dichloromethane. The dichloromethane layer was washed, in turn, with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (eluent; n-hexane:dichloromethane=1:1) and then recrystallized from ethanol-n-hexane to give 0.21 g of N-[2-(2-oxocyclohexyloxy)phenyl]methanesulfonamide.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:14])=[N:4][CH:5]=[C:6]([CH:13]=1)[C:7]([N:9]([O:11][CH3:12])[CH3:10])=[O:8].[CH2:15](I)[CH3:16]>C(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[C:3]([O:14][CH2:15][CH3:16])=[N:4][CH:5]=[C:6]([CH:13]=1)[C:7]([N:9]([O:11][CH3:12])[CH3:10])=[O:8]
Reactant: CON(C)C(=O)c1cnc(O)c(Br)c1
Reactant: CCI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CCOc1ncc(C(=O)N(C)OC)cc1Br
Temperature: 25 °C
Reaction time: 40 h
Yield: 30 %

Procedure:
A mixture of 5-bromo-6-hydroxy-N-methoxy-N-methyl-nicotinamide (Preparation 239, 1.80 g, 6.90 mmol), ethyl iodide (2.8 mL, 34.5 mmol) and silver carbonate (3.8 g, 13.8 mmol) in DCM (10 mL) was stirred at room temperature for 40 hours. The reaction mixture was diluted with DCM (50 mL), washed with water (2×30 mL), brine (20 mL), dried (Na2SO4) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (EtOAc:petroleum ether 2:5) to afford the title compound as a yellow sticky solid in 30% yield, 600 mg.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[C:9](O)(=[O:12])[CH:10]=[CH2:11]>C(Cl)(Cl)Cl>[C:9]([O:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8])(=[O:12])[CH:10]=[CH2:11]
Reactant: O=C1CCC(=O)N1O
Reactant: C=CC(=O)O
Solvent: ClC(Cl)Cl
Product: C=CC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Yield: 68.6 %

Procedure:
To a mixture of 400 ml of chloroform, 115 g of N-hydroxysuccinimide and 72 g of acrylic acid in a reaction vessel, 206 g of N,N-dicyclohexylcarbodiimide dissolved in 100 ml of chloroform was added dropwise over a period of 2 hours under cooling with ice water. Following a 2-hour stirring at room temperature, the precipitate was filtered off and the filtrate concentrated at low temperature for crystallization. The resulting crystals were filled to give 116 g of N-acryloyloxysuccinimide (mp=61°-62° C., yield=68%). The active ester content was determined by the method of Ronald L. Schnaar and Yuan Chuan Lee described in Biochemistry, p. 1535 (1975) as 5.2×10-3 eq./g.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][N:6]=1>Br>[O:11]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: OCCCc1ncccc1O
Agent: Br
Product: c1cnc2c(c1)OCCC2
Temperature: 25 °C
Yield: 30.2 %

Procedure:
A solution of 2-(3-hydroxypropyl)pyridin-3-ol (0.90 g) in 48% hydrobromic acid (20 mL) in a sealed tube was heated at 150° C. for 5 h. The reaction mixture was cooled to rt, concentrated in vacuo and poured into a solution of NaOH in MeOH (1 M). The mixture was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 2:1 (v/v) PE/EA) to afford the title compound as pale yellow oil (0.24 g, 30.00%), HPLC: 92.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 136.3 (M+1); 1H NMR (400 MHz, CDCl3) δ: 7.99-7.98 (m, 1H), 7.19-7.11 (m, 2H), 4.19 (t, J=7.8 Hz, 2H), 2.91 (t, J=7.8 Hz, 2H), 2.12-2.07 (m, 2H) ppm.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[O:12][C:13](=[CH2:17])[C:14]([OH:16])=[O:15].[C:18]1([C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N+]=[N-])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[O:12][C:13](=[CH2:17])[C:14]([O:16][CH:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:15]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: C=C(ON1C(=O)c2ccccc2C1=O)C(=O)O
Solvent: CC#N
Product: C=C(ON1C(=O)c2ccccc2C1=O)C(=O)OC(c1ccccc1)c1ccccc1
Yield: 70.3 %

Procedure:
2-[(1,3-Dioxo-2H-isoindol-2-yl)oxy]-2-propenoic acid (39.6 g, 0.17 mole) was dissolved in 800 ml of acetonitrile and a solution of diphenyldiazomethane (43.4 g, 0.224 mole/1000 ml acetonitrile) was added dropwise over 3 hours at 0° C. The reaction solution was evaporated to a solid which was triturated with hexane. The resulting solid was dissolved in dichloromethane and filtered through a pad of silica gel (Kieselgel 60). Addition of hexane produced 47.7 g of the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.[Cl:15][C:16]1[CH:17]=[C:18]([CH:27]([NH2:29])[CH3:28])[CH:19]=[N:20][C:21]=1[O:22][CH2:23][CH:24]1[CH2:26][CH2:25]1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:29]([CH:27]([C:18]3[CH:19]=[N:20][C:21]([O:22][CH2:23][CH:24]4[CH2:26][CH2:25]4)=[C:16]([Cl:15])[CH:17]=3)[CH3:28])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: CC(N)c1cnc(OCC2CC2)c(Cl)c1
Product: CC(c1cnc(OCC2CC2)c(Cl)c1)N1Cc2c(ccnc2Cl)C1=O
Yield: 35 %

Procedure:
The title compound is prepared in 35% yield (263 mg, yellow oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (561 mg, 2.02 mmol, Step-1 of Intermediate-1) and 1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethanamine (457 mg, 2.02 mmol, Amine-74, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [CH2:1]([N:8]1[CH2:20][C@@H:19]2[C@H:10]([NH:11][C:12](=[O:22])[C:13]3[C:14]([CH3:21])=[CH:15][CH:16]=[CH:17][C:18]=32)[CH2:9]1)C1C=CC=CC=1.[C:23]1([CH2:29]C=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO.[Pd]>[CH3:21][C:14]1[C:13]2[C:12](=[O:22])[NH:11][C@@H:10]3[CH2:9][N:8]([CH2:1][CH2:29][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][C@H:19]3[C:18]=2[CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cccc2c1C(=O)N[C@@H]1CN(Cc3ccccc3)C[C@@H]21
Reactant: O=CCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Cc1cccc2c1C(=O)N[C@@H]1CN(CCc3ccccc3)C[C@@H]21

Procedure:
To a solution of (±)-trans-2-benzyl-6-methyl-2,3,3a,4-tetrahydro-1H-pyrrolo[3,4-c]isoquinolin-5(9bH)-one, from Example 101, Part A (57 mg, 0.2 mmol) in 10 mL of methanol was added phenylacetaldehyde (24 mg, 0.2 mmol) and 10% Pd/C catalyst (6 mg). The reaction mixture was purged several times with hydrogen and stirred under 1 atm of hydrogen, maintained by a balloon, for 18 h. The reaction mixture was filtered through a pad of Celite and concentrated in vacuo. The residue was purified (ISCO, elution with 0-8% methanol/methylene chloride) to afford the title compound of Example 102 as a solid. 1H NMR (CDCl3): δ 7.36-7.20 (m, 6H), 7.18 (d, 1H, J=7.7 Hz), 6.88 (d, 1H, J=7.7 Hz), 6.22 (broad s, 1H), 3.66-3.58 (m, 1H), 3.41 (app t, 1H, J=8.3 Hz), 3.30-3.22 (m, 1H), 3.14 (app t, 1H, J=7.7 Hz), 3.05-2.93 (m, 4H), 2.88-2.81 (m, 2H), 2.70 (s, 3H). LRMS (ESI): 307.3 (M+H)+.
Reaction SMILES: BrBr.[C:3]([C:5]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:6][CH:7]=[C:8](N1CCOCC1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[N:4].C(Cl)Cl.N>C(O)C>[C:3]([C:5]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:6][CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[N:4]
Reactant: CCOC(=O)C(C#N)=NC=C(c1ccccc1)N1CCOCC1
Agent: BrBr
Agent: N
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(C#N)=NC=Cc1ccccc1

Procedure:
A reactor provided with a stirring device, a bromine feed and a calcium chloride tube, is filled with a solution of 6.3 parts of 1-cyano-1-ethoxycarbonyl-4-morpholino-4-phenyl-2-aza-1,3-butadiene in 63 parts by volume of dry methylene chloride. 1.4 parts by weight of ammonia (in the form of a concentrated solution in ethanol) are added at the ambient temperature over a period of three days.
Reaction SMILES: [Cl:1][CH:2](P(OCC)(OCC)=O)[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[OH-].[Ca+2].[OH-].[CH3:21][O:22][C:23]1[N:27]([C:28]2[CH:32]=[CH:31][S:30][C:29]=2[CH:33]=O)[C:26](=[O:35])[N:25]([CH3:36])[N:24]=1>C(OCC)(=O)C>[Cl:1][C:2](=[CH:33][C:29]1[S:30][CH:31]=[CH:32][C:28]=1[N:27]1[C:26](=[O:35])[N:25]([CH3:36])[N:24]=[C:23]1[O:22][CH3:21])[C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4]
Reactant: CCOP(=O)(OCC)C(Cl)C(=O)OC(C)(C)C
Reactant: COc1nn(C)c(=O)n1-c1ccsc1C=O
Agent: [Ca+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COc1nn(C)c(=O)n1-c1ccsc1C=C(Cl)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
A solution of the title compound of Step C (0.026 g, 0.0009 mol) in ethyl acetate (2 mL) was added to a mixture of calcium hydroxide (0.068 g, 0.0009 mol) and the title compound of Step A (0.220 g, 0.0009 mol) in ethyl acetate (5 mL). The resulting mixture was stirred at 60° C. overnight. Three additional 0.026 g (0.0009 mol) portions of the title compound of Step C were added at 3 h intervals and then the temperature of the mixture was increased to 70° C. and heating was continued overnight. After 40 h of total reaction time, the reaction mixture was poured into ice water and extracted three times with ethyl acetate. The combined organic phase was washed successively with saturated aqueous NaCl and then with a 1/1 mixture of saturated aqueous NaCl and saturated aqueous sodium hydrogen carbonate, dried (Na2SO4), filtered and concentrated to a pale yellow oil. The crude product was purified by flash column chromatography on silica gel to give a preliminary fraction of 0.170 g of the title compound of Step D, a compound of the invention, as a white solid (m.p. 105-115° C.) consisting of a 7:3 ratio of Z- and E-isomers, respectively, followed by a final fraction of 0.04 g of the title compound of Step D, a compound of the invention, as a white solid (m.p. 104° C.) consisting of a 5:1 ratio of Z- and E-isomers, respectively. 1H NMR (300 MHz, CDCl3 : for the Z/E mixture): δ 7.77 and 7.00 (2d,1H total, J=0.8 Hz), 7.62 and 7.46 (2dd,1H total, J=0.8, 5.4 Hz), 7.09 and 6.98 (2dd,1H total, J=0.9, 5.4 Hz), 3.97 (s,3H), 3.45 (s,3H), 1.54 (s,9H).