Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:30]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:29][C:5]2[N:6]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[C:37](Cl)(=[O:39])[CH3:38]>ClCCl>[F:1][C:2]1[C:30]([N:31]2[CH2:36][CH2:35][N:34]([C:37](=[O:39])[CH3:38])[CH2:33][CH2:32]2)=[CH:29][C:5]2[N:6]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:22][CH:23]=3)[C:7]([CH2:9][O:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CC(=O)Cl
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(OC(F)(F)F)cc3)c2cc1N1CCNCC1
Solvent: ClCCl
Product: CC(=O)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
80 mg of 5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole (0.16 mmol) and 0.033 ml TEA (0.24 mmol) were dissolved in 1.5 ml dichloromethane and treated with 0.0145 ml acetylchloride (0.2 mmol). After 5 h stirring at rt, the reaction mixture was diluted with dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 85 mg yellow solid (98%). MS (ISP) 543.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][C:15]=1[CH3:23])=[O:13].[H-].[Na+].Br[CH:27]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)[CH3:28]>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH3:28])[C:15]=1[CH3:23])=[O:13]
Reactant: CC(Br)c1ccc(F)cc1
Reactant: Cc1cc(C)c(CNC(=O)c2c(C)[nH]c3ccccc23)c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CNC(=O)c2c(C)n(C(C)c3ccc(F)cc3)c3ccccc23)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 2.5 %

Procedure:
N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1H-indole-3-carboxamide (309 mg, 1.0 mmol) was dissolved in 4 mL DMF, NaH (80 mg, 2.0 mmol) was added, the mixture was stirred at room temperature for 30 min, and then 1-(1-bromoethyl)-4-fluorobenzene (0.404 mg, 2.0 mmol) was added. The mixture was stirred at room temperature overnight and was directly purified by reverse phase HPLC (A:CH3CN, B:water+0.1% HCl. A:B=35:65 ASB C18 150*25 mm) to afford the title compound as a white solid (11 mg, yield 3%). LCMS 432 (M+H+) 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J=8 Hz, 1H), 7.33 (m, 1H), 7.14 (s, 1H), 6.96 (m, 2H), 6.92 (m, 1H), 6.85-6.92 (m, 4H), 5.85 (s, 1H), 5.72 (m, 1H), 4.56 (s, 2H), 2.64 (s, 3H), 2.37 (s, 3H), 2.11 (s, 3H), 1.85 (d, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:3]2([CH2:10][C@@H:9]3[C@@H:5]([CH2:6][C:7](=[O:11])[CH2:8]3)[CH2:4]2)[O:2]1.[CH2:14]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Mg].C(Br)CCCCBr.C(O)C1C=CC=CC=1.[Cl-].[NH4+]>C(OCC)C>[CH2:14]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:7]1([OH:11])[CH2:6][C@@H:5]2[C@@H:9]([CH2:10][C:3]3([O:2][CH2:1][CH2:13][O:12]3)[CH2:4]2)[CH2:8]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1C[C@@H]2CC3(C[C@@H]2C1)OCCO3
Reactant: BrCCCCCOCc1ccccc1
Agent: BrCCCCCBr
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Solvent: OCc1ccccc1
Product: OC1(CCCCCOCc2ccccc2)C[C@@H]2CC3(C[C@@H]2C1)OCCO3
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56.1 %

Procedure:
A solution of 501 mg of 7,7-ethylenedioxy-3-oxo-cis-bicyclo[3,3,0]octane in 5 ml of diethyl ether was added dropwise at room temperature to 5-benzyloxy-pentamethylene-magnesium bromide, which had been prepared in 5 ml of diethyl ether from 1.00 g of 5-benzyloxypentyl bromide and 100 mg of metallic magnesium at room temperature. The 5-benzyloxypentyl bromide, in turn, had been prepared from pentamethylene bromide and benzyl alcohol according to the method of A. W. Burgstabler et al. [J. Org. Chem. 42, 566 (1977)]. The mixture was stirred for 1.5 hours at room temperature. Upon completion of the reaction, an aqueous solution of ammonium chloride was added to the reaction mixture, which was then extracted with diethyl ether. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, giving 1.47 of residue. On purifying the residues by silica gel column chromatography, 556 mg of the title compound were obtained as an oil from the fractions eluted with hexane containing 25-30% by volume of ethyl acetate.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O.[CH3:15][C:16]1[N:17]=[CH:18][N:19]([C:22]2[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=2)[NH2:25])[C:20]=1[CH3:21].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:15][C:16]1[N:17]=[CH:18][N:19]([C:22]2[CH:23]=[C:24]([NH:25][C:9](=[O:11])[C:8]3[CH:12]=[CH:13][CH:14]=[C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[CH:7]=3)[CH:26]=[CH:27][CH:28]=2)[C:20]=1[CH3:21]
Reactant: O=C(O)c1cccc(-c2cccs2)c1
Reactant: Cc1ncn(-c2cccc(N)c2)c1C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ncn(-c2cccc(NC(=O)c3cccc(-c4cccs4)c3)c2)c1C
Reaction time: 24 h
Yield: 62.4 %

Procedure:
To a suspension of 3-(2-thienyl)benzoic acid (103 mg) and 3-(4,5-dimethylimidazol-1-yl)aniline (94 mg) in dichloromethane (2 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (135 mg) and 4-dimethylaminopyridine (31 mg), and the mixture was stirred for 24 hours. The mixture was diluted with dichloromethane and washed with water and brine. The mixture was dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with methanol, and the insoluble material was collected by filtration and dried to give N-[3-(4,5-dimethylimidazol-1-yl)-phenyl]-3-(2-thienyl)benzamide (117 mg, 62.6%).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][O:15][CH3:16])[CH:10]=[CH:9][C:8]=1[CH:17]1[CH2:22][CH2:21][CH2:20][C:19](=[N:23]O)[CH2:18]1.O>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:3][O:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][O:15][CH3:16])[CH:10]=[CH:9][C:8]=1[CH:17]1[CH2:22][CH2:21][CH2:20][CH:19]([NH2:23])[CH2:18]1
Reactant: COCOc1ccc(C2CCCC(=NO)C2)c(OCOC)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCOc1ccc(C2CCCC(N)C2)c(OCOC)c1
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
Nickel chloride hexahydrate (77 mg) and sodium borohydride (24 mg) were added to a stirred solution of (±)-3-[2,4-bis(methoxymethoxy)phenyl]cyclohexanone oxime (50 mg) in methanol (2 ml). After 0.5 hr, water was added until effervescence ceased, the reaction mixture was filtered, and the residue was washed thoroughly with methanol. The combined filtrate and washings were evaporated in vacuo and the crude residue was purified by flash column chromatography (SiO2, dichloromethane/methanol, 9:1 v/v) to furnish the title compound as a colourless oil (31 mg, 65%) and a mixture of diastereoisomers; m/z (ES+) 295 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH2:21][CH2:22]Cl)[N:9]=2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C([O-])([O-])=O.[K+].[K+].CO.CCOC(C)=O>CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH2:21][CH2:22][N:34]3[CH2:33][CH2:32][N:31]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[F:24])[CH2:36][CH2:35]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(Cl)cc3)nn2CCCCl)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CO
Product: CC(=O)N1CCc2c(c(-c3ccc(Cl)cc3)nn2CCCN2CCN(c3ccccc3F)CC2)C1
Temperature: 25 °C
Reaction time: 168 h
Yield: 40.3 %

Procedure:
1-[3-(4-Chloro-phenyl)-1-(3-chloro-propyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (0.053 g, 0.15 mmol) was dissolved in CH3CN (0.5 mL) and a solution of 1-(2-fluorophenyl)piperazine (0.053 g, 0.30 mmol) in CH3CN (0.5 mL) was added, followed by K2CO3 (0.031 g, 0.22 mmol) and Bu4Nl (0.018 g, 0.05 mmol). The mixture was stirred at room temperature for 7 d. Preparative TLC (silica, 5% MeOH/EtOAc) afforded 30 mg (41%) of the title compound. MS (electrospray): exact mass calculated for C27H31ClFN5O, 495.22; m/z found, 496.3 [M+H]+. 1H NMR (500 MHz, CDCl3, a mixture of 1:1 rotamers): 7.60 (d, J=8.3 Hz, 1H), 7.54 (d, J=8.3 Hz, 1H), 7.39 (d, J=8.3 Hz, 1H), 7.35 (d, J=8.3 Hz, 1H), 7.06-6.90 (m, 4H), 4.77 (s, 1H), 4.60 (s, 1H), 4.10 (t, J=6.8 Hz, 2H), 3.92 (t, J=5.7 Hz, 1H), 3.74 (t, J=5.7 Hz, 1H), 3.08 (br s, 4H), 2.83 (t, J=5.6 Hz, 1H), 2.77 (t, J=5.7 Hz, 1H), 2.58 (br s, 4H), 2.41-2.38 (m, 2H), 2.19 (s, 1.5H), 2.13 (s, 1.5H), 2.10-2.07 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]([CH3:21])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]([CH3:21])[CH2:13][CH2:12][NH:11][CH2:10][C:9]1=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CCN(C(=O)OC(C)(C)C)CC(=O)N(Cc2ccccc2)c2ccccc21
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC1CCNCC(=O)N(Cc2ccccc2)c2ccccc21

Procedure:
A solution of 1-benzyl-4-tert-butyloxycarbonyl-7-methyl-2-oxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine (160 mg, 0.41 mmol) in chloroform (2 ml) was stirred with trifluoroacetic acid (3 ml) at room temperature for 30 minutes. The mixture was evaporated to dryness and the residue partitioned between chloroform and saturated potassium carbonate solution (30 ml/1:2). The organic layer was separated and dried (MgSO4). Filtration and evaporation of the solvent gave the product. (98 mg, 81%).
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2](OCC)=O.C[O-].[Na+].[NH2:14][C:15]1[C:24]([C:25]([NH2:27])=[O:26])=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1>>[N:14]1[C:15]2[C:24](=[CH:23][C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH:16]=2)[C:25](=[O:26])[NH:27][C:2]=1[C:1]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(=O)OCC
Reactant: NC(=O)c1cc2ccccc2cc1N
Agent: C[O-]
Agent: [Na+]
Product: CCOC(=O)c1nc2cc3ccccc3cc2c(=O)[nH]1
Yield: 79 %

Procedure:
Diethyl oxalate (2.35 g., 16.1 millimoles), sodium methoxide (10 m and 2-aminonaphthalene-3-carboxamide (1.50 g., 8.05 millimoles) are mixed together and heated at reflux for two days. The mixture is then cooled in an ice bath and the brown precipitate recovered by filtration. It is recrystallized from ethanol to give 1.76 g. (79% yield) of the desired ester. M.P. 240°-242° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][S:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27](=[O:47])[CH2:28][C:29]1([C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:33]=2)[CH2:31][CH2:30]1)[CH3:25]>>[CH2:24]([O:26][C:27](=[O:47])[CH2:28][C:29]1([C:32]2[CH:37]=[CH:36][C:35]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH2:14][S:15][CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:34][CH:33]=2)[CH2:31][CH2:30]1)[CH3:25]
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CSCCc1ccccc1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4CSCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 5-(4-bromo-phenyl)-3-methyl-4-phenethylsulfanylmethyl-isoxazole and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[N:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1.CO.[BH4-].[Na+]>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([NH:1][CH2:29][C:28]3[CH:27]=[CH:26][C:25]([O:24][C:19]4[N:18]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:32][CH:31]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Reactant: O=Cc1ccc(Oc2ncccn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: CCO
Solvent: CO
Product: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1NCc1ccc(Oc2ncccn2)cc1
Yield: 17.9 %

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide (100 mg) was then suspended in EtOH (4 mL) and 4-(pyrimidin-2-yloxy)benzaldehyde (80 mg, 1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain product as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr (104 mg, 60% yield). Resulting imine (104 mg) was suspended in 5 ml, MeOH and sodium borohydride (10 eq, 100 mg) was added. HPLC confirmed reaction was complete (absence of imine). After completion (1 hr), precipitate was filtered to obtain D32 as a light yellow powder. Product was washed with deionized water to remove excess sodium borohydride. Product was allowed to dry under vacuum for 18 hrs. 31 mg (30% yield) of final product was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.[CH2:11](I)[CH3:12].C(=O)([O-])O.[Na+].C(O)C>O>[CH3:10][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([NH:8][CH2:11][CH3:12])=[CH:6][C:5]=1[OH:9]
Reactant: CCI
Reactant: Cc1cc(Cl)c(N)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCNc1cc(O)c(C)cc1Cl

Procedure:
A mixture of 3 g of 4-chloro-2-methyl-5-aminophenol (0.016 mol), 2.6 g of ethyliodide (0.017 mol), 1.35 g of sodium hydrogen carbonate (0.016 mol) and 30 ml of ethanol was refluxed for 7 hours. After cooling and dilution with 50 ml of water, the solution was neutralized with a sodium hydrogen carbonate solution and then extracted three times with 50 ml of ethylacetate. The extract was dried over sodium sulfate and concentrated to dryness. The residue was recrystallized from toluene. Beige crystals melting at 205° C. were obtained.
Reaction SMILES: [CH3:1][N:2]([S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:24])=[O:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19](O)=[O:20])=[CH:15][N:16]=1)=[CH:8]2.[N:30]1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N>O.CN(C)C=O>[CH3:1][N:2]([S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:24])=[O:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19]([NH2:30])=[O:20])=[CH:15][N:16]=1)=[CH:8]2
Reactant: CN(c1cccc2cc(-c3ncc(CCC(=O)O)s3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1cccc2cc(-c3ncc(CCC(N)=O)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 127.2 %

Procedure:
To a mixture of 3-(2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazol-5-yl)propanoic acid (1.15 g), 1H-1,2,3-benzotriazol-1-ol (0.54 g) and N,N-dimethylformamide (14 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.77 g) at room temperature. The mixture was stirred at room temperature for 1 hr, and 28% aqueous ammonia (1.0 mL) was added. The reaction mixture was stirred at room temperature overnight, and water was added. The resulting crystals were filtrated, washed with water and ethyl acetate, and dried to give the title compound (1.46 g, yield 98%) as yellow crystals. melting point 246-247° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]=[C:10]3[S:12][C:13]([NH2:15])=[N:14][C:9]3=[CH:8][CH:7]=2)[CH:3]=[N:2]1.[CH:16]1([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[CH2:18][CH2:17]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC>CN(C=O)C>[NH:1]1[CH:5]=[C:4]([C:6]2[N:11]=[C:10]3[S:12][C:13]([NH:15][C:23](=[O:24])[C:22]4[CH:26]=[CH:27][C:19]([CH:16]5[CH2:18][CH2:17]5)=[CH:20][CH:21]=4)=[N:14][C:9]3=[CH:8][CH:7]=2)[CH:3]=[N:2]1
Reactant: Nc1nc2ccc(-c3cn[nH]c3)nc2s1
Reactant: O=C(O)c1ccc(C2CC2)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1nc2ccc(-c3cn[nH]c3)nc2s1)c1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
5B (25.0 mg, 1.0 equivalent) and 4-cyclopropylbenzoic acid (1.1 equivalent) were dissolved in DMF, followed by addition of HOBt (1.0 equivalent), EDC (1.0 equivalent), Et3N (2.0 equivalents). The mixture was stirred for 12 h at room temperature. The crude mixture was filtered and purified by LCMS to give the titled compound 5 as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.77-0.87 (m, 2H) 1.04-1.13 (m, 2H) 2.01-2.10 (m, 1H) 7.28 (d, J=8.34 Hz, 2H) 7.68 (t, J=7.58 Hz, 1H) 7.82-7.91 (m, 3H) 7.99 (d, J=8.34 Hz, 2H) 8.47 (s, 1H) 9.03 (s, 1H); ESI-MS: m/z 362.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[N:23]=[CH:24][N:25]([CH3:27])[CH:26]=3)(=[O:21])=[O:20])=[CH:15][CH2:14][N:13]2[C:28](O)=[O:29])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.Cl.[NH2:43][OH:44].C(N(CC)CC)C.ON.Cl>C(Cl)Cl.O.C1COCC1>[OH:44][NH:43][C:28]([N:13]1[CH2:14][CH:15]=[C:16]([S:19]([C:22]2[N:23]=[CH:24][N:25]([CH3:27])[CH:26]=2)(=[O:20])=[O:21])[CH:17]=[CH:18][N:12]1[S:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)(=[O:11])=[O:10])=[O:29]
Reactant: NO
Reactant: COc1ccc(S(=O)(=O)N2C=CC(S(=O)(=O)c3cn(C)cn3)=CCN2C(=O)O)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N2C=CC(S(=O)(=O)c3cn(C)cn3)=CCN2C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The 1-[(4-methoxyphenyl)sulfonyl]-5-(1-methyl-1H-imidazole-4-sulfonyl)-diazepine-2-carboxylic acid (0.35 g, 0.76 mmol) is dissolved in methylene chloride (10 mL) at room temperature followed the addition of oxalyl chloride (0.14 mL, 1.56 mmol) and the slow addition of DMF (0.058 mL, 0.76 mmol). This mixture is stirred for 30 minutes at room temperature. In a separate flask, hydroxylamine hydrochloride (0.21 g, 1.56 mmol) in water (2 mL) and THF (5 mL) are stirred at 0° C., and then triethylamine (0.634 mL, 4.56 mmol) is added. This mixture is stirred for 15 minutes. The acid chloride solution is added to the hydroxyl amine solution at 0° C. and the resulting solution is warmed to room temperature and stirred for 3 hours. The solution is acidified to pH~1 with 1N HCl, poured into water, and extracted with methylene chloride. The organic extracts are dried (Na2SO4) and concentrated down to an oil. The oil is purified by HPLC with a reverse phase column using 80% (95% water, 5% acetonitrile, 0.1 % formic acid) and 20% (80% acetonitrile, 20% water) as the eluent.
Reaction SMILES: O[Li].O.[CH2:4]([O:11][N:12]([C@H:25]1[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@H:28]([C:38]([O:40]CC)=[O:39])[CH2:27][CH2:26]1)[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23])(=[O:15])=[O:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl>C1COCC1.O>[CH2:4]([O:11][N:12]([C@H:25]1[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:32])[C@H:28]([C:38]([OH:40])=[O:39])[CH2:27][CH2:26]1)[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23])(=[O:14])=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)[C@@H]1CC[C@@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])CC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 36 h
Yield: 95.7 %

Procedure:
LiOH.H2O (2.7 g, 64 mmol) was added to a solution of (2S,5R)-1-tert-butyl 2-ethyl 5-(N-(benzyloxy)-2-nitrophenylsulfonamido)piperidine-1,2-dicarboxylate (9.0 g, 16 mmol) in THF (60 mL) and H2O (60 mL) at rt. The mixture was stirred at rt for 36 hrs., then the reaction mixture was adjusted to pH 4 with 1N HCl, and extracted with EtOAc (3×). The combined organic layer was washed with saturated sodium chloride, dried over Na2SO4 and concentrated to give (2S,5R)-5-(N-(benzyloxy)-2-nitrophenylsulfonamido)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (8.2 g, 95%) as a yellow solid. ESI-MS (EI+, m/z): 558 [M+Na]+.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[CH:16]=O)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[CH2:16][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=Cc1cccc(N2CCC(CN3CCCC3)CC2)c1
Product: c1cc(CN2CCOCC2)cc(N2CCC(CN3CCCC3)CC2)c1

Procedure:
Prepared from the product of Example 20 and morpholine.
Reaction SMILES: CS(NCCN[C@@:9]1(CCN)[CH2:18][C@@H:17]2[N:12]([CH2:13][CH2:14][C:15]3[CH:22]=[C:21]([O:23]C)[CH:20]=[CH:19][C:16]=32)[CH2:11][CH2:10]1)(=O)=O.C(Cl)Cl.N1C=CC=[CH:33][CH:32]=1.C(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH:18]1[CH2:9][CH:10]=[CH:11][N:12]2[C:17]=1[C:16]1[O:23][C:21]3[CH:20]=[CH:19][CH:33]=[CH:32][C:22]=3[C:15]=1[CH:14]=[CH:13]2
Reactant: COc1ccc2c(c1)CCN1CC[C@@](CCN)(NCCNS(C)(=O)=O)C[C@@H]21
Reactant: c1ccncc1
Agent: O=C(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C1=CN2C=Cc3c(oc4ccccc34)C2=CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.50 grams (11.35 mmol) of (2R,11bS) 2-(2-methanesulfonamidoethylamino)-2-(2-aminoethyl)-9-methoxy-1,3,4,6,7,11b-hexahydrobenzo[a]quinolizine and 600 milliliters of methylene chloride containing 6.02 milliliters (25.01 mmol) of dry pyridine was cooled to 0° C. and 6.02 milliliters (11.91 mmol) of a 1.98M solution of phosgene in toluene was added dropwise over two hours. The mixture was stirred overnight at room temperature, washed with saturated aqueous NaHCO3 and brine, dried, filtered and concentraed in vacuo. The residue was chromatographed on 80 grams of silica gel using 1:4 methanolethyl acetate as eluant to obtain 1 gram of (2R,11bS) 9-methoxy-1,3,4,5',6,6',7,11b-octahydro-3'-(2-methanesulfonamidoethyl)-spiro-benzo[a]quinolizine-2,4'-(1'H-pyrimidin-2'-(3'H)-one as the free base. The HCl salt was prepared from 2-propanol and concentrated HCl. The HCl salt has a melting point 170°-174° C. with decomposition. The specific rotation for the HCl salt was -32.2°, c=0.012 g/ml, methanol.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][C:2]1=[CH2:3].[OH-].[NH4+:10]>O1CCCC1>[C:5]([CH2:4][C:2](=[CH2:3])[C:1]([OH:7])=[O:8])(=[O:6])[NH2:10]
Reactant: [NH4+]
Reactant: C=C1CC(=O)OC1=O
Agent: [OH-]
Solvent: C1CCOC1
Product: C=C(CC(N)=O)C(=O)O
Reaction time: 1 h
Yield: 40 %

Procedure:
To a mixture of 3 g (0.027 mol) of itaconic anhydride in 30 ml of tetrahydrofuran, 3 ml of 28% ammonium hydroxide was added. After 1 hr. the reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in 15 ml of water, then acidified to pH 2 with concentrated hydrochloric acid and allowed to stay overnight at 4°. The precipitate formed was filtered off, washed with a small portion of cold water and dried to give 1.4 g (40% yield) of the title compound melting at 153-154° C.; NMR (DMSO-d6): 3.11 (s, 2H, CH2); 5.67,6.13 (s, s, 1H, 1H, CH); 6.7, 7.9 (broad s, s 1H, 1H, NH); 12.15 (broad s, 1H, OH).