Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21]C)[CH:19]=4)[CH2:14][CH2:13][N:12]3[C:25]=2[CH3:26])=[CH:4][C:3]=1[CH3:32].Cl.N1C=CC=CC=1>C(OCC)(=O)C.Cl>[CH3:24][O:23][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][C:18]=1[OH:21])[C:11]1=[C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:9]([C:5]3[CH:6]=[C:7]([CH3:8])[C:2]([OH:1])=[C:3]([CH3:32])[CH:4]=3)=[C:25]([CH3:26])[N:12]1[CH2:13][CH2:14]2
Reactant: CCOC(=O)c1c(-c2cc(C)c(O)c(C)c2)c(C)n2c1-c1cc(OC)c(OC)cc1CC2
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(-c2cc(C)c(O)c(C)c2)c(C)n2c1-c1cc(O)c(OC)cc1CC2
Temperature: 150 °C
Reaction time: 0.33 h

Procedure:
1 g (2.3 mmol) of ethyl 2-(4hydroxy-3,5-dimethylphenyl)-8,9-dimethoxy-3-methyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-1-carboxylate (Example 1) was intimately mixed with 4 g of pyridine hydrochloride and heated to fusion at 150° C. The mixture was stirred at 150° C. for 20 min., then cooled to room temperature and dissolved in a mixture of ethyl acetate and dilute hydrochloric acid. The layers were separated, the aqueous layer was extracted with ethyl acetate, and the combined organic phases were washed with water, dried over Na2SO4, and the solvent was evaporated under reduced pressure. Column chromatography on silica gel using a dichloromethane/ethyl acetate 10:1 mixture as eluant afforded the title compounds ethyl 8-methoxy-9-hydroxy-2-(3,5-dimethyl-4-hydroxyphenyl)-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylate (Example 26):
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:37][CH:38]4[CH2:42][CH2:41][O:40][CH2:39]4)=[C:24]([NH:27][C:28](=[O:36])[CH:29]=[C:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:43]#[N:44])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:45](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:37][CH:38]4[CH2:42][CH2:41][O:40][CH2:39]4)=[C:24]([NH:27][C:28](=[O:36])[CH:29]=[C:30]4[CH2:35][CH2:34][N:33]([CH3:45])[CH2:32][CH2:31]4)[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:43]#[N:44])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: N#Cc1cnc2cc(OC3CCOC3)c(NC(=O)C=C3CCNCC3)cc2c1Nc1ccc(OCc2ccccn2)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CN1CCC(=CC(=O)Nc2cc3c(Nc4ccc(OCc5ccccn5)c(Cl)c4)c(C#N)cnc3cc2OC2CCOC2)CC1
Temperature: 25 °C

Procedure:
To a single-neck reaction flask (50 ml) was added the product of Example 30 (20 mg). The product was dissolved in acetonitrile (10 ml). To the resultant solution were added anhydrous potassium carbonate powders (20 mg) and methyl iodide (5 mg). The resulting mixture was stirred at the room temperature. After the reaction finished, the resultant substance was filtered. The filtrate was rotary-evaporated to dryness to give a crude product. The crude product was purified with thin layer chromatography (developing solvent: chloroform:methanol=92:8).
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]([CH3:10])([CH3:9])[CH2:7][NH2:8].[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:25])[C:20](OCC)=[O:21])=[CH:15][CH:14]=1)#[N:12]>C(Cl)Cl>[CH3:5][C:6]([CH3:10])([CH3:9])[CH2:7][NH:8][C:20]([CH:19]([C:16]1[CH:15]=[CH:14][C:13]([C:11]#[N:12])=[CH:18][CH:17]=1)[CH3:25])=[O:21]
Reactant: CCOC(=O)C(C)c1ccc(C#N)cc1
Reactant: CC(C)(C)CN
Agent: C[Al](C)C
Solvent: ClCCl
Product: CC(C(=O)NCC(C)(C)C)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41 %

Procedure:
Add AlMe3 (1.72 mL, 3.44 mmol, 2M solution in hexane) to a solution of 2,2-dimethyl-propylamine (402 μL, 3.44 mmol) in DCM (0.5 mL) under nitrogen atmosphere. Stir the mixture for 15 min at room temperature and add ethyl 2-(4-cyanophenyl)propanoate. Heat the mixture at 40° C. overnight. Quench the reaction with 10N aqueous HCl and extract twice with DCM. Dry the combined organics extracts over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (7:3) to obtain the desired intermediate (170 mg, 41%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:20][C:21]4[N:26]5[C:27](=[O:30])[NH:28][N:29]=[C:25]5[CH2:24][O:23][C:22]=4[N:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][C:47]#[N:48].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:20][C:21]4[N:26]5[C:27](=[O:30])[N:28]([CH2:46][C:47]#[N:48])[N:29]=[C:25]5[CH2:24][O:23][C:22]=4[N:31]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(n[nH]c3=O)CO4)cc2)CCC1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nn(CC#N)c3=O)CO4)cc2)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
To a solution of tert-butyl(1-(4-(1-oxo-8-phenyl-2,4-dihydro-1H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutyl)carbamate (70 mg, 0.14 mmol) in dry DMF (1 ml) was added potassium carbonate (57 mg, 0.41 mmol) and bromoacetonitrile (29 μl, 0.41 mmol) under nitrogen. The resulting mixture was stirred for 1 hour at room temperature. Water was added and the mixture was extracted with EtOAc (3×10 ml). The combined organic phases were dried over Na2SO4 and concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 35% EtOAc in cyclohexane) to give the title compound (45 mg, 60%). 1H NMR (500 MHz, CDCl3): 8.43 (1H, s), 7.26-7.19 (7H,m), 7.14-7.12 (2H, m), 5.25 (2H, s), 4.96 (1H, br s), 4.72 (2H, s), 2.55-2.25 (4H, m), 2.10-2.03 (1H, m), 1.86-1.78 (1H, m), 1.44-1.15 (9H, br).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]([NH2:15])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:5].Cl.C(N(CC)CC)C.[CH:24]([C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[S:35])=[CH:29][CH:28]=1)([CH3:26])[CH3:25]>CCOCC>[CH:24]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:15][CH:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH2:7][C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)=[S:35])=[CH:29][CH:28]=1)([CH3:26])[CH3:25]
Reactant: CCOC(=O)C(N)Cc1ccc(Cl)cc1
Reactant: CC(C)c1ccc(N=C=S)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc(Cl)cc1)NC(=S)Nc1ccc(C(C)C)cc1
Temperature: 0 °C
Yield: 80 %

Procedure:
DL-4-Chlorophenylalanine ethyl ester hydrochloride(5g, 18.9 mmol) was converted to the free base using triethylamine. A solution of the free base in 75 mL ether was added to a solution of 4isopropylphenylisothiocyanate in 150 mL ether, cooled on an ice-salt bath. The temperature was maintained at about 0° C. during addition. The reaction was stirred for four and one-half hours, at which time the reaction temperature was 12° C. The reaction mixture was filtered, the filtrate concentrated, and the resulting foamy residue triturated with petroleum ether while cooling on ice. This resulted in 6.1 g (15.1 mmol, 80%) N-(4-isopropylphenyl)-N'-[2-(4-chlorophenyl)-1-(ethoxycarbonyl)ethyl]thiourea, mp 73°-75° C.
Reaction SMILES: Br.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:5][CH:4]=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[OH-].[Na+]>[C:16]([NH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:7][CH:8]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: O=C(Nc1ccc(-c2c[nH]c(=O)cn2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5-(4-aminophenyl)-2(1H)-pyrazinone hydrobromide (2.0 g) in aqueous sodium hydroxide (46 ml, 10%) was treated with benzoyl chloride (1.9 ml) and the mixture was agitated for 2 hours at room temperature. The pale yellow precipitate was collected, washed with water and dried. Recrystallisation from glacial acetic acid gave the title compound (0.9 g), m.p.>300° C.; ν(Nujol mull) 1660 (C=0), 1705 (C=0), 3330 (NH)cm-1.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)=[O:4].[N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:13]1([CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=2)=[O:4])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[CH:14]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: O=C(CBr)Nc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Cn1cnc2ccccc21)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
2-Bromo-N-(4-bromophenyl)-acetamide (3.083 g, 10.522 mmol), prepared according to J. Med. Chem., 1996, 4(2), 197-203, benzimidazole (1.24 g, 10.52 mmol) and K2CO3 were combined and dissolved in DMF (60 mL) under nitrogen. The reaction mixture was stirred at room temperature overnight before filtering and purifing by SCX cartridge. The crude product thus obtained was washed with EtOAc to remove excess benzimidazole, yielding the pure product (2.20 g, 63% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 5.17 (2H, s), 7.19-7.28 (2H, m), 7.51 (2H, d, J=12 Hz), 7.51-7.56 (1H, m), 7.57 (2H, d, J=12 Hz), 7.66 (1H, d, J=8 Hz), 8.22 (1H, s), 10.57 (1H, s). MS (ES) m/z: 332.5 [M+H].
Reaction SMILES: [CH2:1]([C@H:8]([NH:32][C:33](=[O:43])[O:34][C@@H:35]1[C@H:42]2[C@H:38]([O:39][CH2:40][CH2:41]2)[O:37][CH2:36]1)[C@H:9]([OH:31])[CH2:10][N:11]([O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C>[Pd].C(OCC)(=O)C>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([N:11]([O:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)[CH2:10][C@@H:9]([OH:31])[C@@H:8]([NH:32][C:33](=[O:43])[O:34][C@@H:35]2[C@H:42]3[C@H:38]([O:39][CH2:40][CH2:41]3)[O:37][CH2:36]2)[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CN(OC1CCCCC1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1)O[C@H]1CO[C@H]2OCC[C@H]21
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)OC2CCCCC2)cc1
Reaction time: 16 h
Yield: 81.1 %

Procedure:
To a solution of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-{(cyclohexyloxy)[(4-nitrophenyl)sulfonyl]amino}-2-hydroxypropylcarbamate (115 mg, 0.186 mmol) in a 1:1 mixture of ethanol:ethyl acetate (6 mL) was added Palladium on charcoal (10 wt %, 30 mg). The starting material was reduced under an atmosphere of Hydrogen gas over 16 hrs. The reaction mixture was filtered and evaporated in vacuo. The residue was purified on a preparative TLC plate (20×20 cm, 500 uM) eluting with 3:1 ethyl acetate:hexane. The product band was removed, eluted with 3:1 methylene chloride:methanol, filtered, and evaporated in vacuo. The residue was triturated with water, filtered and dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[[(4-aminophenyl)sulfonyl](cyclohexyloxy)amino]-1-benzyl-2-hydroxypropylcarbamate (89 mg, 81%). H1-NMR (chloroform-D3): 1.26 (m, 6H), 1.58 (m, 5H), 2.05 (m, 2H), 2.90 (m, 4H), 3.09 (b, 2H), 3.68 (m, 2H), 3.88 (m, 4H), 4.16 (m, 1H), 4.24 (b, 1H), 4.81 (d, 1H), 5.00 (m, 1H), 5.63 (d, 1H), 6.66 (d, 2H), 7.23 (m, 5H), 7.56 (d, 2H). MS(ESI): 612(M+Na).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5](=[O:28])[CH2:6][C:7]([CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)([OH:22])[CH2:8][CH2:9][C:10]#[C:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([S:18](=[O:21])(=[O:20])[NH2:19])[CH:13]=1.COC(=O)CC(=O)CC(C1CCCC1)(O)CCC#CC1C=C(C)C(O)=CC=1C>>[CH:23]1([C:7]2([CH2:8][CH2:9][C:10]#[C:11][C:12]3[CH:13]=[C:14]([S:18]([NH2:19])(=[O:20])=[O:21])[CH:15]=[CH:16][CH:17]=3)[CH2:6][C:5](=[O:28])[CH2:4][C:3](=[O:2])[O:22]2)[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: COC(=O)CC(=O)CC(O)(CCC#Cc1cccc(S(N)(=O)=O)c1)C1CCCC1
Agent: COC(=O)CC(=O)CC(O)(CCC#Cc1cc(C)c(O)cc1C)C1CCCC1
Product: NS(=O)(=O)c1cccc(C#CCCC2(C3CCCC3)CC(=O)CC(=O)O2)c1

Procedure:
The desired product was prepared analogously to example F(1), substituting 5-cyclopentyl-5-hydroxy-3-oxo-9-(3-sulfamoyl-phenyl)-non-8-ynoic acid methyl ester (80 mg, 0.19 mmol) from Step 2 below in place of 5-cyclopentyl-5-hydroxy-9-(4-hydroxy-2,5-dimethyl-phenyl)-3-oxo-non-8-ynoic acid methyl ester. Yield: 17 mg, 23%.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([O:25][CH3:26])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22](O)=[O:23])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN.C(Cl)CCl.C1C=CC2N(O)N=[N:39][C:37]=2C=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([O:25][CH3:26])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22]([NH:39][CH3:37])=[O:23])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: On1nnc2ccccc21
Reactant: COc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CC(=O)O)CS3)cc2c1
Agent: CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CNC(=O)C[C@@H]1CSC(c2cc3cc(OC)cc(NC4CCCC4)c3[nH]2)=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
The compound (83 mg, 0.22 mmol) prepared in Example 48 was dissolved in N,N-dimethylformamide (3 ml). Methylamine (0.17 ml, 2M in THF, 0.33 mmol), EDC (72 mg, 0.38 mmol) and HOBT (60 mg, 0.44 mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and concentrated. The residue was purified by column chromatography to give the title compound (39 mg, Yield 46%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].S(Cl)([Cl:19])(=O)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1([Cl:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:3]1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CC(=O)c1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CC(=O)C1C=CC=CC1(Cl)Cl

Procedure:
To a cold (5° C.) mixture of 55.0 g (0.423 mole) of ethyl acetoacetate, 70 ml. of benzene, 18.3 ml. of 33% sodium hydroxide, and 141 ml. of water was added simultaneously with vigorous stirring 80.0 g (0.457 mole) of o-chlorobenzoyl chloride and 76 ml. of 33% sodium hydroxide in 1 hour. The aqueous solution of the sodium salt of ethyl o-chlorobenzoylacetoacetate was stirred with 22.5 g (0.424 mole) of ammonium chloride for 18 hours. The aqueous solution was then saturated with 25.0 g of sodium chloride. At this moment, some precipitate formed which was filtered. The analysis indicated this material was mainly the sodium salt of ethyl o-chlorobenzoylacetoacetate. The sodium salt and the aqueous filtrate were combined and acidified with dilute hydrochloric acid. The oil which separated was extracted with ether. The ether solution was dried (MgSO4) and concentrated under reduced pressure. The residue was Kugelrohr distilled to give 30.0 g of oil which contained mainly ethyl o-chlorobenzoylacetoacetate. This material was stirred with a mixture of 7.2 g of ammonium chloride, 14 ml. of concentrated ammonium hydroxide and 150 ml. of water and worked up as described in Example 4 to give 16.6 g (15% ) of crude ethyl o-chlorobenzoylacetate which was about 92% pure. A mixture of 15.0 g. (0.065 mole) of ethyl o-chlorobenzoylacetate, 9.5 (0.070 mole) of sulfuryl chloride and 20 ml. of chloroform was held at reflux for 6 hours and concentrated to give 17.3 g of crude ethyl 2-chloro-o-chlorobenzoylacetate. A mixture of 17.0 g (0.065 mole) of ethyl 2-chloro-o-chlorobenzoylacetate, 4.94 g (0.065 mole) of thiourea and 65 ml. of ethanol was held at reflux for 2 hours and worked up as described in Example 4 to give 15.0 g of solid, m.p. 114°-136° C. which was recrystallized twice from ethanol to give 5.8 g (31%) of ethyl 2-amino-4-(o-chlorophenyl)- 5-thiazolecarboxylate, m.p. 165°-166° C.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[C:10]([O:17][CH3:18])=[N:11][C:12]([O:15][CH3:16])=[N:13][CH:14]=2)[C:6]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:5]=2[N:4]([CH3:24])[C:3]1=[O:25].[C:26](Cl)(Cl)=[S:27]>>[Cl:23][C:20]1[CH:21]=[CH:22][C:5]2[N:4]([CH3:24])[C:3](=[O:25])[CH:2]([N:1]=[C:26]=[S:27])[N:8]=[C:7]([C:9]3[C:10]([O:17][CH3:18])=[N:11][C:12]([O:15][CH3:16])=[N:13][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: COc1ncc(C2=NC(N)C(=O)N(C)c3ccc(Cl)cc32)c(OC)n1
Reactant: S=C(Cl)Cl
Product: COc1ncc(C2=NC(N=C=S)C(=O)N(C)c3ccc(Cl)cc32)c(OC)n1
Yield: 43.6 %

Procedure:
As illustrated in the scheme above and following General Procedure 2, 3-amino-7-chloro-5-(2,4-dimethoxy-5-pyrimidinyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (1.15 g, 3.18 mmol) and thiophosgene (0.49 mL, 6.4 mmol) were combined. Purification of the crude product by silica gel column chromatography (9:1 CH2Cl2:EtOAc) provided the title compound as a viscous dark yellow oil (0.560 g, 44%). 1H-NMR (CDCl3): δ 8.60 (s, 1H), 7.55 (dd, J=2.5 Hz, J=8.8 Hz, 1H), 7.33 (d, J=8.8 Hz, 1H), 7.17 (d, J=2.5 Hz, 1H), 5.16 (s, 1H), 4.07 (s, 3H), 3.78 (s, 3H), 3.49 (s, 3H). MS (ESI) (M+H)+=404.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23]([O:25]C)=O)[CH:5]=[CH:6][CH:7]=1.Cl.[OH-].[NH4+:29]>C1COCC1.C(OCC)(=O)C>[I:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(I)c1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(I)c1
Yield: 37 %

Procedure:
A solution of the 9-[(3-iodophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (170 mg, 0.37 mM) in 10 mL THF and 30 mL concentrated aqueous ammonium hydroxide was stirred vigorously at room temperature for 120 hours. The mixture was diluted with ethyl acetate and acidified to pH 2 with 5 N HCl. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 61 mg (37%) of the 9-[(3-iodophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (dd, 1H, J=1 and 8 Hz), 7.6-7.4 (m, 4H), 7.3 (t, 1H, J=8 Hz), 7.1-6.9 (m, 3H), 6.6 (d, 1H, J=8 Hz), and 5.7 (s, 2H). IR (CHCl3, cm−1) 3423, 3201 (br), 1630, 1600, 1579, 1564, 1445, 1330, 1261, and 775. MS (ES) m/e 441, 443.
Reaction SMILES: NS(N)(=O)=O.Cl[CH2:7][CH2:8][CH2:9][S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:33]([NH2:35])=[O:34])[CH:24]=[C:25]([C:28]4[CH:32]=[CH:31][S:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11].[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C([O-])([O-])=O.[K+].[K+]>>[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([CH2:7][CH2:8][CH2:9][S:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[C:27]4[C:22](=[C:23]([C:33]([NH2:35])=[O:34])[CH:24]=[C:25]([C:28]5[CH:32]=[CH:31][S:30][CH:29]=5)[CH:26]=4)[NH:21][CH:20]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:39][CH2:38]1
Reactant: CN1CCNCC1
Reactant: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Agent: NS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN1CCN(CCCS(=O)(=O)N2CCC(c3c[nH]c4c(C(N)=O)cc(-c5ccsc5)cc34)CC2)CC1
Yield: 16.3 %

Procedure:
Following the general procedure for aminosulfonamide formation outlined in example 2, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(3-thienyl)-1H-indole-7-carboxamide (40 mg, 0.13 mmol) and 1-methylpiperazine (0.068 mL, 0.65 mmol) were allowed to react in the presence of K2CO3 (74 mg, 0.65 mmol). The resulting residue was purified by reverse phase HPLC eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give the title compound (11.2 mg, 17.2%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C@H:13]([NH:24][C:25]3[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([Cl:33])[C:26]=3[CH3:34])[C@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH3:15])=[N:10][N:9]=2)=[CH:4][CH:3]=1.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl.N1C=CC=CC=1>[Si:17]([O:16][C@H:14]([CH3:15])[C@H:13]([C:11]1[O:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:35](=[O:42])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:7][CH:6]=2)=[N:9][N:10]=1)[NH:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([Cl:33])[C:26]=1[CH3:34])([C:20]([CH3:22])([CH3:23])[CH3:21])([CH3:19])[CH3:18]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(N)cc3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(NC(=O)c4ccccc4)cc3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Yield: 99.9 %

Procedure:
To a solution of 4-((1R,2R)-1-(5-(4-aminophenyl)-1,3,4-oxadiazol-2-yl)-2-(tert-butyldimethylsilyloxy)propylamino)-2-chloro-3-methylbenzonitrile (306 mg, 0.61 mmol) in CH2Cl2 (10 mL) and pyridine (1.5 mL) was added benzoylchloride (0.10 mL, 0.86 mmol) at room temperature. The resultant solution stirred for 24 hours and quenched with 2N aq. HCl (15 mL). The mixture was further partitioned between H2O (40 mL) and CH2Cl2 (40 mL). The aqueous layer was extracted with CH2Cl2 (30 mL). The combined organic extracts were washed with sat. aq. NaHCO3 (2×40 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a colourless oil (367 mg, 100%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 9.84 (s 1H), 8.10-7.98 (m, 6H), 7.67-7.48 (m, 4H), 6.96 (d, J=8.6 Hz, 1H), 5.76 (d, J=9.0 Hz, 1H), 5.05 (dd, J=6.5, 9.0 Hz, 1H), 4.67 (pentet, J=6.3 Hz, 1H), 2.36 (s, 3H), 1.45 (d, J=6.3 Hz, 3H), 0.83 (s, 9H), 0.11 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[CH:21]=O>C(O)C>[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[CH:21]=[N:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccccc1
Reactant: O=Cc1ccc2ccccc2n1
Solvent: CCO
Product: O=C(NN=Cc1ccc2ccccc2n1)c1ccccc1
Temperature: 25 °C
Yield: 49.2 %

Procedure:
A mixture of 4.08 gm (0.03 mole) of benzhydrazide, 4.72 gm (0.03 mole) of 2-quinolinecarboxaldehyde and 100 ml of absolute ethanol is refluxed 4 hr. The hot solution is filtered and cooled slowly to room temperature. The mixture is chilled. The crystals which separate are collected, washed with ether and dried to give 4.06 gm (50%) of the title compound having a melting point of 170.7° C.