Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([CH2:10][C:11]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:23][CH3:24])=[C:19]([NH2:22])[CH:20]=2)[CH2:15][CH2:14]1)=O)[CH3:9].O1CCCC1>C(OCC)C.C(OCC)(=O)C>[CH3:7][N:8]([CH3:9])[CH2:10][CH2:11][N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:23][CH3:24])=[C:19]([NH2:22])[CH:20]=2)[CH2:15][CH2:14]1
Reactant: COc1cc2c(cc1N)N(C(=O)CN(C)C)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N)N(CCN(C)C)CC2
Temperature: 50 °C
Yield: 24.7 %

Procedure:
A 1.0M solution of lithium aluminum hydride in diethyl ether (Aldrich, 11 mL, 11 mmol, 10 equiv.) was added dropwise to a solution of 1-[(dimethylamino)acetyl]-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine (0.280 g, 1.12 mmol) in diethyl ether (10 mL). The solids failed to dissolve, so anhydrous tetrahydrofuran was added (10 mL) and the solution was maintained at 50° C. for 12 hours. The solution was cooled, poured into ice water, diluted with ethyl acetate, and the organic layer was dried, taken to a residue under reduced pressure, and purified by chromatography on SiO2 to afford 1-[2-(dimethylamino)ethyl]-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine (0.065 g, 25% Yield). 1H NMR (400 MHz, CDCl3) δ ppm 6.66 (s, 1 H), 6.05 (s, 1 H), 3.77 (s, 3 H), 3.28 (t, J=8.07 Hz, 2 H), 3.16 (t, J=6.97 Hz, 2 H), 2.86 (t, J=8.25 Hz, 2H), 2.64 (s, 2 H), 2.39 (s, 6 H).
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]([C:10]([OH:12])=O)=[C:8]([CH3:13])[CH:7]=[C:6]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:5]=1)[CH3:2].[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:24][NH2:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C1COCC1.CCOC(C)=O>[F:20][C:21]1[CH:22]=[C:23]([CH2:24][NH:25][C:10]([C:9]2[C:4]([S:3][CH2:1][CH3:2])=[N:5][C:6]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:7][C:8]=2[CH3:13])=[O:12])[CH:26]=[C:27]([F:29])[CH:28]=1
Reactant: CCSc1nc(N2CCOCC2)cc(C)c1C(=O)O
Reactant: NCc1cc(F)cc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCSc1nc(N2CCOCC2)cc(C)c1C(=O)NCc1cc(F)cc(F)c1
Temperature: 70 °C
Yield: 51.7 %

Procedure:
To a solution of 250 mg (0.89 mmol) 2-ethylsulfanyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid in THF (7 ml), 124 μl (0.97 mmol) 3,5-difluorobenzylamine, 335 mg (0.89 mmol) HATU and 367 μl (2.66 mmol) NEt3 were added and the RM was heated at 70° C. for 5 d. Subsequently the mixture was diluted with EtOAc and washed with a 4M aq. NH4Cl sol., a 1M aq. NaHCO3 sol. and brine. The organic layer was dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 3:2) provided 187 mg (0.46 mmol, 52%) N-[(3,5-difluoro-phenyl)-methyl]-2-ethylsulfanyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example 1). [M+H]+ 408.1.
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[CH2:12][CH2:13][N:14]([C:34](=[O:41])[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:15]1[C:16]([C:29](OCC)=[O:30])=[N:17][CH:18]=[C:19]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:20]=1.C1CCN2C(=NCCC2)CC1.OS([O-])(=O)=O.[Na+]>CCO.O>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][N:14]1[C:15]2[C:16](=[N:17][CH:18]=[C:19]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH:20]=2)[C:29]([OH:30])=[C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:34]1=[O:41]
Reactant: CCOC(=O)CC(=O)N(CCN1C(=O)c2ccccc2C1=O)c1cc(Cc2ccc(F)cc2)cnc1C(=O)OCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of ethyl 3-{[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl][3-(ethyloxy)-3-oxopropanoyl]amino}-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate (2.05 g, 3.65 mmol) in EtOH (75 mL) under nitrogen was treated with DBU (0.709 mL, 4.74 mmol). After stirring at ambient temperature for 15 min., the reaction mixture was treated with 1N NaHSO4 (5.0 mL). The resulting slurry was diluted with water, filtered, the filtered solid was washed with water, EtOH, and Et2O and thoroughly dried under high vacuum to provide the title compound as a white solid: 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.4 (t, J=7.0 Hz, 3 H), 4.0 (t, J=7.0 Hz, 4 H), 4.4 (t, J=6.5 Hz, 2 H), 4.5 (q, J=7.3 Hz, 2 H), 7.0 (t, J=8.5 Hz, 2 H), 7.1 (m, 2 H), 7.7 (dd, J=5.5, 3.1 Hz, 2 H), 7.8 (s, 1 H) 7.8 (m, 2 H), 8.4 (s, 1 H), 13.9 (none, 1 H); ES+ MS: 516 (M+H+).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][O:9][C:10]2[N:15]=[N:14][C:13]([C:16]3[CH:57]=[CH:56][C:19]([CH2:20][C:21]4[N:22]([C:34]5[CH:39]=[CH:38][C:37]([N:40]6[S:44](=[O:46])(=[O:45])[N:43](COCC[Si](C)(C)C)[C:42](=[O:55])[CH2:41]6)=[CH:36][CH:35]=5)[CH:23]=[C:24]([C:26]5[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=5[Cl:33])[N:25]=4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH:1]1([CH2:7][CH2:8][O:9][C:10]2[N:15]=[N:14][C:13]([C:16]3[CH:57]=[CH:56][C:19]([CH2:20][C:21]4[N:22]([C:34]5[CH:39]=[CH:38][C:37]([N:40]6[S:44](=[O:45])(=[O:46])[NH:43][C:42](=[O:55])[CH2:41]6)=[CH:36][CH:35]=5)[CH:23]=[C:24]([C:26]5[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=5[Cl:33])[N:25]=4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(OCCC5CCCCC5)nn4)cc3)cc2)S1(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(OCCC5CCCCC5)nn4)cc3)cc2)S(=O)(=O)N1

Procedure:
5-{4-[2-{4-[6-(2-Cyclohexyl-ethoxy)-pyridazin-3-yl]-benzyl}-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one (17 mg, 0.02 mmol) was treated as described in general procedure W using tetrabutylammonium fluoride (26 mg, 0.1 mmol) to give 5-{4-[2-{4-[6-(2-cyclohexyl-ethoxy)-pyridazin-3-yl]-benzyl}-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [OH-].[Li+].[C:3]([O:7][C:8]([NH:10][CH:11]([CH2:16][C:17]1[CH:18]=[N:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[F:30])=[CH:21][CH:22]=1)[C:12]([O:14]C)=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4]>O.CO>[C:3]([O:7][C:8]([NH:10][CH:11]([CH2:16][C:17]1[CH:18]=[N:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[F:30])=[CH:21][CH:22]=1)[C:12]([OH:14])=[O:13])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)C(Cc1ccc(-c2cccc(F)c2F)nc1)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC(Cc1ccc(-c2cccc(F)c2F)nc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
Lithium hydroxide (10 mg, 0.5 mmol) in water (1 mL) was added to a solution of methyl 2-[(tert-butoxycarbonyl)amino]-3-[6-(2,3-difluorophenyl)pyridin-3-yl]propanoate (70 mg, 0.2 mmol) in methanol (3 mL). The reaction was stirred at rt for 3 h. The reaction was concentrated under reduced pressure to remove methanol and was partitioned between EtOAc and ammonium chloride water. The organic was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give crude 2-[(tert-butoxycarbonyl)amino]-3-[6-(2,3-difluorophenyl)pyridin-3-yl]propanoic acid (0.07 g, 100%) as a semisolid residue. Analytical LCMS (M+H)+: m/z=378.9.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([NH2:17])[CH2:14][CH2:15][CH3:16])=[CH:9][CH:8]=1)[CH3:2].N1(CCOC2C=CC(C(=O)CCC)=CC=2)CCCC1>>[N:3]1([CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]([CH:13]([NH2:17])[CH2:14][CH2:15][CH3:16])=[CH:11][CH:12]=2)[CH2:1][CH2:2][CH2:19][CH2:18]1
Reactant: CCCC(N)c1ccc(OCCN(CC)CC)cc1
Agent: CCCC(=O)c1ccc(OCCN2CCCC2)cc1
Product: CCCC(N)c1ccc(OCCN2CCCC2)cc1
Yield: 45 %

Procedure:
The title compound was prepared by using a similar procedure as described for the preparation of 25 except that 1-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)butan-1-one (23) was used instead of 1-(4-(2-(diethylamino)ethoxy)phenyl)butan-1-one (21). This produced crude 27 (188 mg, 45%) as a yellow oil: MS (ES+) m/z 263.2 (M+H)+.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[N:25]=[C:24]([NH2:29])[N:23]=1>>[F:21][C:22]1[CH:27]=[C:26]([F:28])[N:25]=[C:24]([NH:29][CH2:3][C:4]2[N:8]3[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]3=[N:6][C:5]=2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[N:23]=1
Reactant: Fc1ccc(-c2nc3ccc(F)cn3c2CCl)cc1
Reactant: Nc1nc(F)cc(F)n1
Agent: Cl
Product: Fc1ccc(-c2nc3ccc(F)cn3c2CNc2nc(F)cc(F)n2)cc1
Yield: 39 %

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 3-(chloromethyl)-6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridine hydrochloride and 4,6-difluoropyrimidin-2-amine. (0.35 g, 39% yield). M/e+ 374.2 for C18H11F4N5 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:20][C:21]1[N:26]2[CH:27]=[CH:28][N:29]=[C:25]2[CH:24]=[CH:23][CH:22]=1)[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:30][C:31]([Cl:36])([Cl:35])[C:32](Cl)=[O:33]>CN(C1C=CN=CC=1)C.C1COCC1>[Cl:30][C:31]([Cl:36])([Cl:35])[C:32]([C:27]1[N:26]2[C:21]([CH2:20][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[CH:22][CH:23]=[CH:24][C:25]2=[N:29][CH:28]=1)=[O:33]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N(CCCCNC(=O)C(F)(F)F)Cc1cccc2nccn12
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCCCNC(=O)C(F)(F)F)Cc1cccc2ncc(C(=O)C(Cl)(Cl)Cl)n12
Temperature: 0 °C
Yield: 47.9 %

Procedure:
To a solution of 7.69 g (18.56 mmol) of 5-[N-tert-butoxycarbonyl-N-(4-trifluoroacetamidobutan-1-yl)amino methyl]imidazo[1,2-a]pyridine and 10.20 g (83.52 mmol) of 4-(N,N-dimethylamino)pyridine in 100 ml of THF was added 6.21 ml (55.67 mmol) of trichloroacetyl chloride. The reaction mixture was heated for 16 hours under reflux. The reaction mixture was poured into ice-water, and extracted with 100 ml of ethyl acetate. The organic layer was washed with 150 ml of a saturated aqueous saline solution, dried over magnesium sulfate, and distilled off the solvent under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform) to afford 4.98 g of the desired compound (48.0%, a pale yellow amorphous).
Reaction SMILES: BrCBr.[Si:4]([O:11][CH:12]1[CH2:16][C:15](=O)[C:14]([CH:18]([CH3:21])[CH:19]=[CH2:20])=[CH:13]1)([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5].[CH3:22]CCCCC.C(=O)([O-])O.[Na+]>O1CCCC1.ClCCl.O.[Zn].[Ti](Cl)(Cl)(Cl)Cl>[Si:4]([O:11][CH:12]1[CH2:16][C:15](=[CH2:22])[C:14]([CH:18]([CH3:21])[CH:19]=[CH2:20])=[CH:13]1)([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5]
Reactant: CCCCCC
Reactant: C=CC(C)C1=CC(O[Si](C)(C)C(C)(C)C)CC1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: BrCBr
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CC(C)C1=CC(O[Si](C)(C)C(C)(C)C)CC1=C
Yield: 61 %

Procedure:
A suspension prepared by suspending 3.7 g of zinc dust in 30 ml of tetrahydrofuran was mixed with 1.4 ml of dibromomethane in an atmosphere of argon at a temperature of -20° to -10° C. After stirring for fifteen minutes, 12.5 ml of a dichloromethane solution of 1M titanium tetrachloride was added dropwise to the suspension and stirred at the above temperatures for thirty minutes and at 4° C. for three days. A solution prepared by dissolving 3.33 g of (RS)-3-(1-methyl-2-propenyl)-4-oxocyclopent-2-en-1-yl t-butyldimethylsilyl ether in 15 ml of dichloromethane was added dropwise to the reaction solution in an atmosphere of argon at a temperature of -20° to -10° C. After stirring at an ambient temperature for six hours, 30 ml of hexane was further added to the reaction solution. Under stirring, a suspension prepared by suspending 15 g of sodium hydrogencarbonate in 100 ml of water was added gradually to the reaction solution. After stirring at an ambient temperature for two hours, the reaction solution was filtered through celite, extracted with hexane, and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the obtained oily substance was subjected to silica gel column chromatography to yield 2.02 g of (RS)-3-(1-methyl-2-propenyl)-4-methylidenecyclopent-2-en-1-yl t-butyldimethylsilyl ether. Yield 61%
Reaction SMILES: [CH:1]1([CH2:6][C:7]2([CH3:11])[CH2:10][O:9][CH2:8]2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[BrH:12]>C1COCC1>[Br:12][CH2:8][C:7]([CH2:6][CH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)([CH3:11])[CH2:10][OH:9]
Reactant: CC1(CC2C=CC=C2)COC1
Reactant: Br
Solvent: C1CCOC1
Product: CC(CO)(CBr)CC1C=CC=C1
Temperature: -70 °C
Reaction time: 2 h

Procedure:
In a 500 ml Schlenk tube (8 cm diameter), 4.5 g (30 mmol) of 2 were dissolved in 150 ml of THF and cooled to -70° C. An aqueous solution of HBr was added dropwise over a period of 5 minutes and the solution was stirred further for 2 hours at this temperature. After removing the cooling bath, the solution thawed to -15° C. over a period of 1.5 hours. The reaction solution was hydrolyzed at this temperature by addition of 40 ml of 10% strength sodium hydroxide solution and was stirred for 1 hour without cooling. During this time, the solution came to room temperature. The aqueous phase was separated off and shaken three times with 30 ml of diethyl ether. The combined organic phases were subsequently washed with saturated sodium chloride solution and dried over sodium sulfate. Removal of the solvent gave a yellow oil. The crude product obtained in this way (6.97 g) can be reacted further without further purification. To characterize the material, part of the crude product was flash-chromatographed on a silica gel column (4*25 cm; eluant: PE/THF in a ratio of 9:1;
Reaction SMILES: [CH:1]1([CH:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([N:32]([CH3:40])[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[O:31])=[CH:26][CH:25]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][S:21][CH3:22])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([N:32]([CH3:40])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:31])=[CH:26][CH:25]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][S:21][CH3:22])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OCCSC)cc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSCCOc1ccc2oc(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)c(C)c2c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
Ethyl 3-[({4-[(cyclohexyl{3-methyl-5-[2-(methylsulfanyl)ethoxy]-1-benzofuran-2-yl}methyl)amino]phenyl}carbonyl)(methyl)amino]propanoate (0.33 g) synthesized in the above-mentioned (3) was dissolved in ethanol (2 mL), 1N aqueous sodium hydroxide solution (1.5 mL) was added to the solution at room temperature, and the mixture was stirred at 50° C. for 0.5 hr. Ethanol was evaporated under reduced pressure, 1N hydrochloric acid (1.5 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with ethanol-water to give the title object compound (0.20 g, 63%) as a colorless solid.
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[NH:19]1[CH2:27][CH2:26][CH2:25][C@H:20]1[C:21]([O:23][CH3:24])=[O:22].Cl>C(Cl)Cl>[N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([N:19]1[CH2:27][CH2:26][CH2:25][C@H:20]1[C:21]([O:23][CH3:24])=[O:22])=[O:5]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Z-Pro-OH (1 equivalent), H-Pro-OMe hydrochloride (1 equivalent) and TEA (1 equivalent) were dissolved in dry methylene chloride, and WSCD (1 equivalent) was added under cooling with ice. Thereafter, the mixture was stirred at room temperature for 20 hours, and the reaction mixture was washed successively with IN HCl, water, saturated aqueous sodium bicarbonate, water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under vacuum. The resulting crude product was purified by medium-pressure liquid column chromatography on silica gel to obtain the end compound. Z-Pro-Pro-OMe (1 equivalent) thus obtained was dissolved in ethanol, and boron trifluoride-ether complex (1 equivalent) and palladium on carbon (a small amount) were added. The mixture was subjected to catalytic reduction in a hydrogen atmosphere to remove the Z grup, and the solvent was distilled off under vacuum to obtain the end compound as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[NH:8][C:9](=[O:13])[CH2:10][CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].[H-].[Na+].BrC[CH2:20][CH2:21][O:22][CH3:23]>CN(C=O)C>[CH3:23][O:22][CH2:21][CH2:20][N:8]1[C:9](=[O:13])[CH2:10][CH2:11][CH2:12][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:15]=[CH:14][C:7]1=2
Reactant: O=C1CCCc2cc([N+](=O)[O-])ccc2N1
Reactant: COCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCN1C(=O)CCCc2cc([N+](=O)[O-])ccc21
Reaction time: 0.25 h

Procedure:
To a solution of 7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one solid (566.6 mg, 2.75 mmol) in DMF (5 mL) was added NaH (200 mg, 60% dispersion in mineral oil, 5.0 mmol). After stirring for 15 min, 1-bromo-3-methoxy-propane (764 mg, 5.5 mmol) was added and the mixture stirred at room temperature for 1 hour prior to quenching with 10% aqueous NH4Cl solution. Solvent was removed by rotary evaporation and the residue extracted into EtOAc, washed with water (2×), brine and dried by passing through a plug of MgSO4. The resulting filtrate was evaporated onto Florisil and purified by chromatography (silica gel, DCM→15% EtOAc/DCM gradient). The appropriate fractions were combined and evaporated to afford 1-(2-methoxy-ethyl)-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as an oil that was carried onto the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]C)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:27][NH:28][O:29][CH3:30].C(=O)=O.C([Mg]Cl)(C)C>C1COCC1>[CH3:30][O:29][N:28]([CH3:27])[C:22](=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNOC
Reactant: COC(=O)CCCCCCCCCCNC(=O)OCc1ccccc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Agent: O=C=O
Solvent: C1CCOC1
Product: CON(C)C(=O)CCCCCCCCCCNC(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
A solution of 19 (2.25 g, 6.44 mmol), methyl methoxyamine hydrochloride (1.26 g, 12.88 mmol) and THF (anhydrous, 30 mL) was cooled to −15 to −20° C. with an ice/methanol bath containing a few pieces of dry ice. To this cold solution was added dropwise i-PrMgCl (3M solution in pentane, 11.27 mL, 22.54 mmol) over 15 min and temperature was then raised to −10° C. and stirring continued at the temperature for additional 2 h. After this time the reaction was quenched by the slow addition of saturated aqueous NH4Cl (50 mL). The aqueous layer was separated and washed with dichloromethane (2×50 mL). Organics were combined, dried over anhydrous Na2SO4, concentrated and further dried under high vacuum overnight to afford the desired product 20 (2.04 g, 84% yield) as a colorless, viscous oil: 1H NMR (300 MHz, CDCl3) δ 1.27 (m, 12H), 1.48 (m, 2H), 1.60 (m, 2H), 2.40 (m, 2H), 3.18 (m, 5H), 3.68 (s, 3H), 5.09 (s, 2H), 7.34 (m, 5H); m/z (ESI) 379 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=S)[CH2:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:8]=2[CH:22]=1)([O-:3])=[O:2].[OH:23][CH2:24][C:25]([NH:27][NH2:28])=O>C(O)CCC>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:25]([CH2:24][OH:23])=[N:27][N:28]=[C:12]3[CH2:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:8]=2[CH:22]=1)([O-:3])=[O:2]
Reactant: NNC(=O)CO
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCC(=S)N2
Solvent: CCCCO
Product: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CO)n1-2

Procedure:
In the manner given in Example 11, a solution of 1,3-dihydro-7-nitro-5-(o-chlorophenyl)-2H-1,4-benzodiazepine-2-thione and hydroxyacetic acid hydrazide in n-butylalcohol was refluxed to give 8-nitro-1-(hydroxymethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]#[N:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH:13](OCC)=[O:14]>C1COCC1>[Cl:1][C:2]1[C:7]([CH:8]([CH:13]=[O:14])[C:9]#[N:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCOC=O
Reactant: N#CCc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC(C=O)c1cccnc1Cl
Reaction time: 0.25 h

Procedure:
A solution of 2-(2-chloropyridin-3-yl)acetonitrile (2.0 g, 13 mmol) in THF (5 mL) was slowly added to a suspension of sodium hydride, 60% in mineral oil (1.31 g, 33.0 mmol) in THF (10 mL) at 0° C. The mixture was stirred for 15 minutes, and ethyl formate (1.1 mL, 13 mmol) was slowly added. The mixture was stirred at RT, and monitored by LCMS. Upon completion, the reaction was extracted into EtOAc, washed organics 2×H2O, dried with Mg2SO4, filtered through fritted funnel, and lyophilized to yield 2-(2-chloropyridin-3-yl)-3-oxopropanenitrile as reddish brown solid. The crude was used without further purification. MS m/z=181 [M+1]+. Calc'd for C8H5ClN2O: 180.59.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:21][C@H:20]([OH:22])[CH2:19][C@@H:18]1[C:23]([N:25]1[CH2:31][CH2:30][CH2:29][N:28]([CH:32]2[CH2:35][CH2:34][CH2:33]2)[CH2:27][CH2:26]1)=[O:24])=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15]([N:17]1[CH2:21][C@H:20]([O:22][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:19][C@@H:18]1[C:23]([N:25]1[CH2:31][CH2:30][CH2:29][N:28]([CH:32]2[CH2:33][CH2:34][CH2:35]2)[CH2:27][CH2:26]1)=[O:24])=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: N#Cc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1C(=O)N1CCCN(C2CCC2)CC1
Product: CC(C)(C)OC(=O)N1C[C@H](Oc2ccc(C#N)cc2)C[C@@H]1C(=O)N1CCCN(C2CCC2)CC1

Procedure:
The title compound was prepared from 4-bromobenzonitrile and (2R,4R)-2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester as described for Example 59. MS (ESI): mass calcd. for C26H36N4O4, 468.27; m/z found, 469.4 [M+H]+. 1H NMR (CDCl3): 7.66-7.51 (m, 2H), 6.99-6.86 (m, 2H), 5.05-4.85 (m, 1H), 4.79-4.54 (m, 1H), 4.12-3.96 (m, 1H), 3.84-3.41 (m, 4H), 2.93-2.77 (m, 1H), 2.75-2.13 (m, 5H), 2.10-1.54 (m, 10H), 1.50-1.40 (m, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](O)=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:21])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@H:17]([CH2:18][OH:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:21])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(O)ccc2C[C@H]1C(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1Cc2cc(O)ccc2C[C@H]1CO

Procedure:
(S)-2-t-Butoxycarbonyl-1,2,3,4-tetrahydro-7-hydroxyisoquinoline-3-carboxylic acid (100 mmol) is dissolved in THF (1 L). Borane methyl sulfide complex (200 mmol) is added carefully, and the solution heated at reflux for 1 hour. The solution is cooled, quenched with MeOH, and 1 N HCl to pH 2. The solution is neutralized to pH 7-8 with NaHCO3 and the solvent evaporated. The oily residue is diluted with water, extracted with EtOAC, washed with NaHCO3 and brine, then dried with MgSO4 and evaporated to give the title compound.