Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([S:37][CH2:38][C:39]5[N:43]([CH3:44])[CH:42]=[N:41][N:40]=5)=[CH:33][CH:32]=4)=[O:29])=[CH:20][C:19]=3[CH:45]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:54])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([S:37]([CH2:38][C:39]5[N:43]([CH3:44])[CH:42]=[N:41][N:40]=5)=[O:54])=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:45]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nncn4C)cc2)CCN3CCC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nncn4C)cc2)CCN3CCC)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 85416.3 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-methyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.70 mg) in dichloromethane (20 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.41 g) in dichloromethane (5 ml) at −78° C. The mixture was stirred for 1 hour at −78° C., and to the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by basic silica gel column chromatography (ethanol:ethyl acetate ˜1:9), and was further recrystalized from ethyl acetate-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-methyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 133) (613.2 mg) as yellow crystals.
Reaction SMILES: C([O:8][C:9]([C:11]1[N:19]2[C:14]([CH:15]=[CH:16][CH:17]=[CH:18]2)=[C:13]([NH:20][C:21]([N:23]2[CH2:27][CH2:26][CH2:25][C@H:24]2[C:28](=[O:41])[NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]([F:40])([F:39])[F:38])[CH:31]=2)=[O:22])[CH:12]=1)=[O:10])C1C=CC=CC=1>C1COCC1.[Pd]>[F:40][C:37]([F:38])([F:39])[O:36][C:32]1[CH:31]=[C:30]([NH:29][C:28]([C@@H:24]2[CH2:25][CH2:26][CH2:27][N:23]2[C:21]([NH:20][C:13]2[CH:12]=[C:11]([C:9]([OH:10])=[O:8])[N:19]3[C:14]=2[CH:15]=[CH:16][CH:17]=[CH:18]3)=[O:22])=[O:41])[CH:35]=[CH:34][CH:33]=1
Reactant: O=C(OCc1ccccc1)c1cc(NC(=O)N2CCC[C@H]2C(=O)Nc2cccc(OC(F)(F)F)c2)c2ccccn12
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(O)c1cc(NC(=O)N2CCC[C@H]2C(=O)Nc2cccc(OC(F)(F)F)c2)c2ccccn12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 1-{[(S)-2-(3-Trifluoromethoxy-phenylcarbamoyl)-pyrrolidine-1-carbonyl]-amino}-indolizine-3-carboxylic acid benzyl ester (100 mg, 0.177 mmol) dissolved in THF (3 mL) was added Pd/C 10% (20 mg). Air was removed from the flask under vacuum and replaced with nitrogen three times, finally nitrogen was removed and replaced with hydrogen and the mixture was stirred at RT for 5 h. Hydrogen was removed and replaced by nitrogen, the catalyst was removed by filtration through a pad of Celite and washed with THF. Solvents were concentrated to give a mixture containing the desired compound contaminated with 20% of the decarboxylated analog. The mixture was used without further purification in the next step. LC/MS: 475 [M−H]−; tR (HPLC conditions a): 3.41 min.
Reaction SMILES: C([O:4][CH2:5][CH:6]([CH2:17][O:18]C(=O)C)[O:7][CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[N+:14]([O-:16])=[O:15])(=O)C.C(O)C.[O-]CC.[Na+]>CO>[OH:18][CH2:17][CH:6]([CH2:5][OH:4])[O:7][CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[N+:14]([O-:16])=[O:15]
Reactant: CC(=O)OCC(COC(C)=O)OCn1ccnc1[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: O=[N+]([O-])c1nccn1COC(CO)CO
Temperature: 25 °C
Yield: 130.4 %

Procedure:
3.01 g of 1-[2-acetoxy-1-(acetoxynethyl)ethoxy]- methyl-2-nitroimidazol (compound (1)) was dissolved in 50 ml of absolute methanol, and stirred at room temperature while being added with 5% absolute ethanol solution of sodium ethoxide dropwise until pH reached 9.0. Stirred at room temperature over 3 hours. Then Dowex 50 W (H+, made by Dow Chemical) was slowly added until the liquid had a pH of 7.0. Dowex 50 W was removed by suction filtration, and the solvent was distilled off under reduced pressure. The residue was subjected to recrystallization by ethanol to obtain 2.83 g of the title compound as light yellow needles (yield: 94%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[NH:13][C:12]3[CH:17]([CH2:20][C:21]([O:23]CC)=[O:22])[CH2:18][CH2:19][C:11]=3[C:10]=2[CH:9]=1)#[N:2].[Li+].[OH-]>O1CCOCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[NH:13][C:12]3[CH:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:18][CH2:19][C:11]=3[C:10]=2[CH:9]=1)#[N:2]
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(C4CCCCC4)c(C#N)c3)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: N#Cc1cc(COc2ccc3[nH]c4c(c3c2)CCC4CC(=O)O)ccc1C1CCCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 56.8 %

Procedure:
To a solution of ethyl 2-(7-(3-cyano-4-cyclohexylbenzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (185.3 mg, 0.406 mmol) in 1,4-dioxane (5M mL) was added 1 M aqueous LiOH solution (1.22 mL, 1.22 mmol). The mixture was stirred at room temperature for 5 h. The mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and then acidified with 1 N aqueous HCl acid solution to pH 4. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was triturated with dichloromethane to provide the title compound as a pink solid (98.9 mg). LCMS m/z=429.6 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21-1.31 (m, 1H), 1.33-1.54 (m, 4H), 1.68-1.74 (m, 1H), 1.74-1.88 (m, 4H), 2.08 (dd, J=4.93, 3.54 Hz, 1H), 2.34 (dd, J=16.04, 8.97 Hz, 1H), 2.61-2.76 (m, 4H), 2.81-2.89 (m, 1H), 3.45 (bs, 1H), 5.07 (s, 2H), 6.70 (dd, J=8.78, 2.46 Hz, 1H), 6.91 (d, J=2.40 Hz, 1H), 7.19 (d, J=8.72 Hz, 1H), 7.52 (d, J=8.08 Hz, 1H), 7.72 (dd, J=8.15, 1.71 Hz, 1H), 7.81 (d, J=1.52 Hz, 1H), 10.46 (s, 1H), 12.18 (bs, 1H).
Reaction SMILES: [CH:1]1([CH:7]2[CH:16]3[CH2:17][CH2:18][CH2:19][O:20][CH:15]3[C:14]3[CH:13]=[C:12]([NH:21]C(=O)[O-])[CH:11]=[CH:10][C:9]=3[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[CH:1]1([CH:7]2[CH:16]3[CH2:17][CH2:18][CH2:19][O:20][CH:15]3[C:14]3[CH:13]=[C:12]([NH2:21])[CH:11]=[CH:10][C:9]=3[NH:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C([O-])Nc1ccc2c(c1)C1OCCCC1C(C1CCCCC1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc2c(c1)C1OCCCC1C(C1CCCCC1)N2
Temperature: 0 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To an ice-cooled solution of tert-butyl(4aSR*,5SR*,10bSR*)-5-cyclohexyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-9-ylcarbamate (prepared according to the method described in example 1) (227 mg, 0.587 mmol) in CH2Cl2 (5 mL) under argon atmosphere was added TFA (1.5 mL) dropwise. The reaction solution was allowed to reach r.t. and stirred overnight. The mixture was cooled down and 0.5 N NaOH solution was added until basic pH. The product was extracted with CH2Cl2 three times. The combined organic fractions were washed with sat. NaCl solution, dried over Na2SO4, and the solvent removed under reduced pressure after filtration giving (4aSR*,5SR*,10bSR*)-5-cyclohexyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-9-amine (145 mg, 86%) as orange viscous solid. The product was used without further purification.
Reaction SMILES: [Na].[SH:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH2:8]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]=[CH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>CO>[C:5]([CH2:4][CH2:3][S:2][CH:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([OH:7])=[O:6]
Reactant: O=C(O)CCS
Reactant: CCCCCCCCCCCCc1ccccc1C=CC(=O)OC(C)(C)C
Agent: [Na]
Solvent: CO
Product: CCCCCCCCCCCCc1ccccc1C(CC(=O)OC(C)(C)C)SCCC(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium (155.5 mmoles) was added slowly to methanol (200 ml ) under an atmosphere of argon. The mixture was cooled to 0° C. in an ice bath and 3-mercaptopropionic acid (78 mmoles) was added dropwise. This mixture was stirred for 30 minutes and the compound of Example 9 (a) (7.8 mmoles) was added dropwise. The reaction mixture was stirred for 24 hours. The solvent was evaporated. The residue was taken up in ice water and acidifed with 10% phosphoric acid to a pH of 6.5. The product was extracted into ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered and evaporated. The resulting residue was flash chromatographed with 1.0% methanol and 1.0% formic acid in methylene chloride. This provided the product as an oil.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].O.[CH2:6]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:7][CH:8]([CH3:10])[CH3:9].C(Cl)(Cl)Cl>C(Cl)(Cl)(Cl)Cl>[CH2:19]([O:18][C:13]1[CH:14]=[C:15]([N+:1]([O-:4])=[O:2])[CH:16]=[CH:17][C:12]=1[O:11][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:20][CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)CCOc1ccccc1OCCC(C)C
Reactant: O=[N+]([O-])O
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC(C)CCOc1ccc([N+](=O)[O-])cc1OCCC(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 300 ml. of conc. HNO3 and 300 ml. of H2O was added dropwise 90 g. (0.36 m.) of o-diisoamyloxybenzene while maintaining a temperature of 19°-21°C. Stirring was continued for an additional 60 minutes at 19°-21°C, then the solution was poured into 3 liters of ice. The crude product was collected by filtration, washed with cold H2O and airdried to give 90 g. It was recrystallized from 300 ml. of MeOH to give 25.5 g. A chromatographic column, 32 inches long with O.D. 3/4 inch, was packed with 20 inches of neutral alumina. The 25 g. of crude product was dissolved in a 250 ml. mixture of 50/50 CHCl3 and CCl4. After the mixture was placed on the column, it was washed several times with the same solvent mixture. The first fraction, very light yellow in color, was collected and concentrated to dryness in vacuo to yield 15 g. m.p. 44°-47°C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH:14]([NH:18][C:19]([C:21]2([NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22]2)=[O:20])[CH2:13][CH2:12]3)O1.Br[C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35]([Cl:40])[C:34]=1[O:41][CH2:42][CH:43]([F:45])[F:44].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:40][C:35]1[C:34]([O:41][CH2:42][CH:43]([F:44])[F:45])=[C:33]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH:14]([NH:18][C:19]([C:21]2([NH:24][C:25](=[O:30])[C:26]([F:27])([F:29])[F:28])[CH2:22][CH2:23]2)=[O:20])[CH2:13][CH2:12]3)[CH:38]=[C:37]([Cl:39])[CH:36]=1
Reactant: CC1(C)OB(c2ccc3c(c2)CCC3NC(=O)C2(NC(=O)C(F)(F)F)CC2)OC1(C)C
Reactant: FC(F)COc1c(Cl)cc(Cl)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC1(C(=O)NC2CCc3cc(-c4cc(Cl)cc(Cl)c4OCC(F)F)ccc32)CC1)C(F)(F)F
Temperature: 25 °C
Yield: 55.6 %

Procedure:
1-(2,2,2-Trifluoro-acetylamino)-cyclopropanecarboxylic acid[(rac)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yl]-amide (intermediate A-1) (0.22 g, 502 μmol), 1-bromo-3,5-dichloro-2-(2,2-difluoro-ethoxy)-benzene (intermediate B-1) (169 mg, 552 μmol) and tri-o-tolylphosphine (30.6 mg, 100 μmol, eq: 0.2) were dissolved in THF (10.0 ml); then palladium(II)acetate (5.64 mg, 25.1 μmol, eq: 0.05) was added, followed by potassium carbonate (173 mg, 1.25 mmol), dissolved in water (1.0 ml). The reaction mixture was stirred at RT over night, then poured into H2O (50 ml) and extracted with EtOAc (2×25 mL). The organic layers were dried over MgSO4, filtered and concentrated in vacuo to give a crude product (0.377 g) which was purified by flash chromatography (silica gel, 20 g, 10% to 50% EtOAc in heptane) to yield the title compound (0.15 g, 56%) as light yellow amorphous solid. MS: 535.1 (M−H−, 2Cl).
Reaction SMILES: [C:1]1([CH2:7][C:8](=O)[CH2:9][C:10]([O:12][CH3:13])=[S:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])=O.[NH4+].C([BH3-])#[N:20].[Na+]>CO.CCOC(C)=O>[CH3:13][O:12][C:10](=[S:11])[CH2:9][CH:8]([NH2:20])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [BH3-]C#N
Reactant: COC(=S)CC(=O)Cc1ccccc1
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=S)CC(N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.8 %

Procedure:
To a solution of methyl phenylthioacetoacetate (1.00 g, 4.5 mmol) in MeOH (20 ml), ammonium formate (4.26 g, 6.75 mmol) and sodium cyanoborohydride (0.42 g, 6.7 mmol) were added. The reaction mixture was stirred at room temperature for 18 h, then diluted with EtOAc and partitioned into 1M HCl. The aqueous layer was then basified to pH=8.0 with NaOH. The desired product was extracted out with EtOAc, washed with water and brine, dried over Na2SO4 and concentrated to yield 0.61 g yellow oil; MS (NH3 -CI/DDIP) Calc. for (M+H)+ : 226. Found: 226; 1H NMR (300 MHz, CDCl3)δ 7.39 (d, J=7, 2H), 7.32-7.26 (m, 3H), 7.22 (d, J=10, 1H), 3.74 (s, 3H), 3.39-3.31 (m, 1H), 3.13-3.07 (dd, J=13, J'=9, 1H), 2.91-2.83 (dd, J=12, J'=6, 1H), 2.65-2.58 (dd, J=12, J'=6, 1H), 2.46-2.38 (dd, J=16, J'=8, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]3[C:24](=[O:27])[NH:25][CH2:26][CH:20]3[CH2:19]2)=[O:17])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:32]([N:25]1[C:24](=[O:27])[CH:21]2[CH:20]([CH2:19][N:18]([C:16]([C:8]3[N:7]([CH2:6][C:5]4[CH:28]=[CH:29][C:2]([Cl:1])=[CH:3][CH:4]=4)[C:15]4[C:10]([CH:9]=3)=[CH:11][CH:12]=[CH:13][CH:14]=4)=[O:17])[CH2:23][CH2:22]2)[CH2:26]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C1NCC2CN(C(=O)c3cc4ccccc4n3Cc3ccc(Cl)cc3)CCC12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1cc2ccccc2n1Cc1ccc(Cl)cc1)N1CCC2C(=O)N(Cc3ccccc3)CC2C1
Reaction time: 1 h

Procedure:
5-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)octahydro-1H-pyrrolo[3,4-c]pyridin-1-one (64 mg, 0.245 mmol) was dissolved in anhydrous DMF (5 mL). NaH (60% oil suspension, 29 mg, 0.735 mmol) was added at rt under nitrogen and stirred for 1 h. Benzylbromide (0.035 mL, 0.294 mmol) was added and stirring continued for 18 h under the same conditions. After this time, the solution was diluted with ethyl acetate and washed with 10% aq. sodium carbonate (2×), dried with magnesium sulfate, and concentrated in vacuo. Purification was done via silica gel flash chromatography (25 g silica, 80% EtOAc/hexanes.) The residue was dissolved in DCM, and rapid solvent removal afforded the title compound as a white powder. (Yield: 56 mg, 0.112 mmol, 72%) 1H NMR (400 MHz, CDCl3) 7.69, 7.33-6.99, 5.47, 4.56, 4.38, 4.11, 3.39-3.36, 2.94-2.82, 2.53-2.47, 1.75, 1.39
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[Li]CCCC.[Cl:17][C:18]1[CH:19]=C([CH:27]=[CH:28][CH:29]=1)C(N(OC)C)=O>C1COCC1>[Cl:17][C:18]1[CH:19]=[C:11]([C:10]2[O:9][C:3](=[O:8])[CH:4]=[C:5]([OH:6])[CH:7]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: CON(C)C(=O)c1cccc(Cl)c1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1cc(O)cc(-c2cccc(Cl)c2)o1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 39.4 %

Procedure:
A slurry of 60% NaH (0.790 g, 19.7 mmol) in THF (50 mL) under a N2 atmosphere was cooled to 0° C. and treated with ethyl acetoacetate (2.51 mL, 19.7 mmol). The resulting solution was subsequently treated with n-BuLi (12.3 mL, 19.7 mmol) and stirred for 20 min. at 0° C. to provide an orange solution which was treated via cannula with a solution of 3-chloro-N-methoxy-N-methylbenzamide (2.50 g, 15.15 mmol) in THF (5.0 mL). The mixture was allowed warm to ambient temperature where it was stirred for 14 h before being quenched with 2.0N HCl. The product was extracted with ethylacetate (3×50 mL), the layers combined, dried with Na2SO4, and the solvent removed in vacuo. The residue was then treated with conc. H2SO4 (20 mL) and the resulting mixture stirred for 18 h at room temperature before being diluted with H2O (200 mL). The product was then extracted with ethylacetate (3×100 mL) being sure to collect all solids. The layers were then combined and diluted with acetone to provide a homogenous solution which was dried with Na2SO4. The solvent was then removed in vacuo and the resulting solid recrystallized from acetone-hexane to provide the title compound (1.33 g, m.p. 254°-256° C.). 1H NMR (400 MHz, DMSO-d6) δ 11.957 (bs, 1 H), 7.889 (t, 1 H, J=1.5 Hz), 7.839-7.813 (m, 1 H), 7.598-7.524 (m, 2 H), 7.876 (d, 1 H, J=2 Hz), 5.450 (d, 1 H, J=2 Hz).
Reaction SMILES: Cl.[CH:2]1([C:5]([N:7]2[CH2:13][CH2:12][CH:11]3[CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][CH2:17][N:10]3[C:9]3[N:25]=[CH:26][CH:27]=[CH:28][C:8]2=3)=[O:6])[CH2:4][CH2:3]1>C(Cl)Cl>[CH:2]1([C:5]([N:7]2[CH2:13][CH2:12][CH:11]3[CH2:14][NH:15][CH2:16][CH2:17][N:10]3[C:9]3[N:25]=[CH:26][CH:27]=[CH:28][C:8]2=3)=[O:6])[CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCN2c3ncccc3N(C(=O)C3CC3)CCC2C1
Agent: Cl
Solvent: ClCCl
Product: O=C(C1CC1)N1CCC2CNCCN2c2ncccc21
Temperature: 25 °C
Reaction time: 70 h

Procedure:
A solution of HCl (4 M in dioxane, 250 μl, 1 mmol) was added to a solution of the product of Example 72B (26.3 mg, 0.071 mmol) in CH2Cl2 (1.3 mL), and the mixture was stirred at room temperature for 70 hours. The mixture was concentrated under vacuum, and the residue was crystallized from ethyl acetate-ethanol (4 mL, 2:1) to provide the title compound as the bis-hydrochloride salt: 1H NMR (400 MHz, pyridine-d5, 110° C.) δ ppm 0.41 (dd, J=7.8, 3.5 Hz, 2H), 0.85-0.97 (m, 2H), 1.06-1.21 (m, 1H), 1.51-1.64 (m, 1H), 1.66-1.77 (m, 1H), 2.91 (t, J=11.0 Hz, 1H), 3.25-3.45 (m, 3H), 3.53-4.09 (m, 5H), 6.77 (dd, J=7.6, 4.9 Hz, 1H), 7.37 (dd, J=7.6, 1.5 Hz, 1H), 8.16 (dd, J=4.6, 1.5 Hz, 1H); MS (DCI) m/z 273 (M+H)+. Elemental analysis is calculated for C15H20N4O.2HCl.0.5H2O.0.4 EtOAc: C, 51.19; H, 6.78; N, 14.38. Found: C, 51.23; H, 6.57; N, 14.12.
Reaction SMILES: Cl.[CH:2]1([NH:8][NH2:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:10]([O:12][C:13](=[O:21])[C:14]([C:19]#[N:20])=[CH:15]OCC)[CH3:11].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[CH:15]=[N:9][N:8]([CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[C:19]=1[NH2:20])=[O:21])[CH3:11]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: NNC1CCCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnn(C2CCCCC2)c1N
Temperature: 80 °C

Procedure:
To a round bottom flask is added cyclohexyl-hydrazine hydrochloride (4.5 g, 30 mmol), 2-cyano-3-ethoxy-acrylic acid ethyl ester (5.1 g, 30 mmol), sodium bicarbonate (2.6 g, 30.9 mmol) and 40 mL of ethanol. The mixture is heated to 80° C. for 1 hour, cooled down to room temperature and concentrated. The residue is dissolved in chloroform and washed with water, dried over sodium sulfate. After removal of the solvent, the solid is recrystallized from ethyl acetate: 1HNMR (CDCl3): δ 7.40 (1 H, s), 4.77 (2 H, brs), 4.05 (2 H, q, J=7.2 Hz), 3.50 (1 H, m), 1.61-1.71 (6 H, m), 1.50 (1 H, m), 1.02-1.21 (3 H, m), 1.13 (3 H, t, J=7.2 Hz).
Reaction SMILES: [C@@H:1]1([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21]C)=[O:20])=[CH:13][CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO>[C@@H:1]1([O:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)CCc1ccc(O[C@H]2CCc3ccccc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCc1ccc(O[C@H]2CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 54.3 %

Procedure:
Methyl (S)-4-[(2,3-dihydro-1H-inden-1-yl) oxy]benzenepropanoate (4.4 g, 15 mmol) was dissolved in methanol (50 mL), 1N aqueous sodium hydroxide solution (25 mL) was added and the mixture was stirred at room temperature for 18.5 hrs. 1N Hydrochloric acid (25 mL) was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over sodium sulfate. The mixture was concentrated under reduced pressure and the obtained crystals were washed with hexane to give colorless crystals (4.2 g, 96% ee). The crystals were recrystallized from a mixed solvent of diisopropyl ether (70 mL) and hexane (70 mL) to give the title compound (2.3 g, 99.4% ee, yield 56%) as colorless crystals. As the secondary crystals, 0.67 g (yield 16%, 97% ee) of the title compound was obtained and as the tertiary crystals, 0.16 g (yield 4%, 92% ee) of the title compound was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].Cl>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)OCC
Reactant: CCOC(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(NC(=O)OCc1ccccc1)(C(=O)OCC)C(=O)OCC
Temperature: 50 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
A suspension of diethyl 2-benzyloxycarbonylaminomalonate (5.0 g), potassium carbonate (2.7 g), potassium iodide (0.27 g), and ethyl 2-chloroacetate (2.6 g) in DMF (50 mL) was stirred at 50° C. for 1 hour. The reaction mixture was cooled, and then poured into diluted hydrochloric acid, the mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from ethyl acetate/n-hexane to obtain the title compound (5.5 g, yield: 86%) as colorless crystals.