Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C2NC(=O)C(C)(C)N=C(C3C=CC=CC=3F)C=2C=C([N+]([O-])=O)C=1.Cl[C:27]1[C:37]2[NH:36][C:35](=[O:38])[C:34]([CH3:40])([CH3:39])[N:33]=[C:32]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[Cl:47])[C:31]=2[CH:30]=[C:29]([N+:48]([O-:50])=[O:49])[CH:28]=1>CCOCC.CCCCCC>[Cl:47][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[C:32]1[C:31]2[CH:30]=[C:29]([N+:48]([O-:50])=[O:49])[CH:28]=[CH:27][C:37]=2[NH:36][C:35](=[O:38])[C:34]([CH3:40])([CH3:39])[N:33]=1
Reactant: CC1(C)N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])cc(Cl)c2NC1=O
Agent: CC1(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])cc(Cl)c2NC1=O
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1(C)N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2NC1=O

Procedure:
From 10 g (0.029 mol) of 5-(o-chlorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one there is obtained, in analogy to the details in paragraph (a) of Example 13, 9-chloro-5-(o-chlorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one of melting point 105° (ether/n-hexane).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:14]C(=O)OC(C)(C)C)[C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([Br:13])[CH:7]=1)=[N+:2]=[N-:3].[ClH:22]>O1CCOCC1>[ClH:22].[N:1]([CH2:4][C@H:5]([C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([Br:13])[CH:7]=1)[NH2:14])=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])c1cc(F)cc(Br)c1
Agent: Cl
Solvent: C1COCCO1
Product: [N-]=[N+]=NC[C@@H](N)c1cc(F)cc(Br)c1
Temperature: 40 °C
Yield: 99.9 %

Procedure:
To a stirred solution of (S)-tert-butyl (2-azido-1-(3-bromo-5-fluorophenyl)ethyl)carbamate (3.15 g, 8.77 mmol) in dioxane (40 mL) was added hydrochloric acid (10.96 mL, 43.8 mmol) (4N solution in dioxane). The reaction was heated to 40° C. and maintained at this temperature for 2 h. After cooling the reaction mixture was evaporated to dryness, giving (S)-2-azido-1-(3-bromo-5-fluorophenyl)ethanamine hydrochloride (2.59 g, 8.76 mmol, 100% yield) as a white solid.
Reaction SMILES: [ClH:1].[C:2]1(=[O:32])[N:6]([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]3[CH:26]=[CH:25][C:20]([C:21](=[NH:24])OC)=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH3:8])[C:5](=[O:27])[C:4]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:3]12.[NH3:33].CCOCC>CO>[ClH:1].[C:5]1(=[O:27])[N:6]([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([NH2:33])=[NH:24])=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH3:8])[C:2](=[O:32])[C:3]2=[CH:31][CH:30]=[CH:29][CH:28]=[C:4]12
Reactant: N
Reactant: COC(=N)c1ccc(CCc2ccc(C(C)N3C(=O)c4ccccc4C3=O)cc2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CC(c1ccc(CCc2ccc(C(=N)N)cc2)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 1.8 g of methyl 4-{2-[4-(1-phthalimidoethyl)phenyl]ethyl}benzimidate hydrochloride in 30 ml of anhydrous methanol, was added 2.3 ml of a solution of anhydrous ammonia in anhydrous methanol (0.036 g/ml). The mixture was stirred at room temperature for 15 hours. The reaction mixture was stripped of the solvent under reduced pressure. Ether was added to the residue and the precipitated crystals were collected by filtration to yield 1.6 g of 4-{2-[4-(1-phthalimidoethyl)phenyl]ethyl}benzamidine hydrochloride; m.p. 110°-115° C.
Reaction SMILES: [CH2:1]([C:11](Cl)([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:33][Al](C)C>C(Cl)Cl>[CH2:1]([C:11]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH3:33])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C[Al](C)C
Reactant: CCCCCCCCCCC(Cl)(CCCCCCCCCC)CCCCCCCCCC
Solvent: ClCCl
Product: CCCCCCCCCCC(C)(CCCCCCCCCC)CCCCCCCCCC
Temperature: 0 °C
Yield: 75 %

Procedure:
One mole of tri-n-decylmethylchloride was added to 0.75 liters of methylene chloride and the solution was blanketed with nitrogen and cooled to 0° C. 0.33 moles of trimethylaluminum was then added and the mixture was allowed to warm to room temperature. The mixture was slowly quenched with 50 ml of water followed by washing with 1 liter of a 10% HCl solution. The organic layer was dried with magnesium sulfate and the solvent was evaporated to give tri-n-decylmethylmethane after vacuum distillation at 225 C/0.5 torr. The yield was 75%.
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[CH:14]=[O:15].O>CS(C)=O>[F:1][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[CH:14]=[O:15]
Reactant: [F-]
Reactant: Cn1nc(C(F)(F)F)c(C=O)c1Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cn1nc(C(F)(F)F)c(C=O)c1F
Temperature: 130 °C
Reaction time: 5 h
Yield: 66.4 %

Procedure:
42.0 g (711.9 mmoles) of potassium fluoride was added to a solution of 60.4 g (282.7 mmoles) of 5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde dissolved in 700 ml of dimethyl sulfoxide. The mixture was stirred at 120 to 140° C. for 5 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 36.8 g (yield: 66.0%) of 5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][C:8]3[CH:14]=[C:13]([CH2:15][C:16](=[O:18])[CH3:17])[CH:12]=[CH:11][C:9]=3[O:10][C:2]=12.C1(C)C=CC(S(O[CH2:29][CH2:30][O:31][CH3:32])(=O)=O)=CC=1>[Na].C(O)(C)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][C:8]3[CH:14]=[C:13]([CH:15]([CH2:29][CH2:30][O:31][CH3:32])[C:16](=[O:18])[CH3:17])[CH:12]=[CH:11][C:9]=3[O:10][C:2]=12
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CC(=O)Cc1ccc2c(c1)Cc1cccnc1O2
Agent: [Na]
Solvent: CC(C)O
Product: COCCC(C(C)=O)c1ccc2c(c1)Cc1cccnc1O2
Temperature: 40 °C
Yield: 53.6 %

Procedure:
3 g of 5H-[1]benzopyrano[ 2,3-b]pyridin-7-yl-acetone is dissolved in a solution of 0.32 g of metallic sodium in 15 ml of absolute isopropyl alcohol by warming to 50°-60°C. The solution is cooled to 40°C, 3.5 g of 2-methoxyethyl p-toluenesulfonate is added, and the mixture is stirred under reflux for 1.5 hours. The reaction mixture is concentrated, chloroform and water are added to the residue, and the mixture is stirred. The chloroform layer is separated, dried over anhydrous magnesium sulfate and concentrated. The oily residue is column chromatographed over silica gel (100 g) with a mixture of chloroform and ethyl acetate (10:1) as eluent to give 2.0 g of 3-(5H-[1]benzopyrano[ 2,3-b]pyridin-7-yl)-5-methoxy-2-pentanone as a pale yellow transparent oil. nD28 = 1.5764
Reaction SMILES: N[C@H]1CCCC[C@H]1[NH:8][C:9](=[O:26])[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1OC.C(=O)([O-])[O-].[K+].[K+].[I-].C([N+]1(C)CCC(=O)CC1)C>C(O)C>[F:21][C:20]([F:22])([F:23])[C:13]1[CH:14]=[C:15]([C:16]([F:19])([F:17])[F:18])[C:10]([C:9]([NH2:8])=[O:26])=[CH:11][CH:12]=1
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N
Agent: CC[N+]1(C)CCC(=O)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCO
Product: NC(=O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Yield: 120 %

Procedure:
cis-N-(2-Amino-cyclohexyl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide (intermediate H) (400 mg, 1.04 mmol) was dissolved in 27 mL ethanol. Potassium carbonate (86 mg, 0.062 mmol) and 1-ethyl-1-methyl-4-oxo-piperidinium iodide (420 mg, 1.56 mmol) were added. The reaction mixture was refluxed for 2 h. The solvent was evaporated off. The residue was extracted with saturated sodium bicarbonate solution and ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (dichloromethane/ethyl acetate 1:0->1:1) yielded cis 2-methoxy-N-2-(4-oxo-piperidin-1-yl)-cyclohexyl]-4,6-bis-trifluoromethyl-benzamide as a light yellow solid (321 mg, 66%), MS: m/e=467.2 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([CH:14]3[O:19][CH2:18][CH2:17][NH:16][CH2:15]3)[NH:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[C:23]([NH2:28])[N:22]=1.CCN(C(C)C)C(C)C.O>C(O)C>[Cl:20][C:21]1[CH:26]=[C:25]([N:16]2[CH2:17][CH2:18][O:19][CH:14]([C:11]3[NH:12][CH:13]=[C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)[N:10]=3)[CH2:15]2)[N:24]=[C:23]([NH2:28])[N:22]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: COc1cccc(-c2c[nH]c(C3CNCCO3)n2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCO
Product: COc1cccc(-c2c[nH]c(C3CN(c4cc(Cl)nc(N)n4)CCO3)n2)c1
Reaction time: 8 h
Yield: 42.3 %

Procedure:
To a stirred solution of 2-{4-[3-(methyloxy)phenyl]-1H-imidazol-2-yl}morpholine (1.5 g, 5.07 mmol) and 4,6-dichloro-2-pyrimidinamine (0.832 g, 5.07 mmol) in ethanol (100 mL) was added Hunig's base (4.5 mL, 25.4 mmol), and the reaction mixture was stirred overnight at reflux. Water (150 mL) was added, and the resulting mixture was extracted with EtOAc (3×100 mL). The organic was dried (Na2SO4), filtered, and concentrated. Purification by silica gel chromatography, eluting with EtOAc in PE from 50% to 80% afforded the title compound (830 mg) as a brown solid. LC-MS (ES) m/z=387 [M+H]+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][N:12]3[CH:15]=[CH:16][N:17]=[C:11]3[CH:10]=2)O1.[CH3:19][O:20][C:21]([C:23]1[CH:28]=[CH:27][C:26](Br)=[CH:25][N:24]=1)=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+].O>COCCOC.CS(C)=O>[CH3:19][O:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:9]2[CH:14]=[CH:13][N:12]3[CH:15]=[CH:16][N:17]=[C:11]3[CH:10]=2)=[CH:25][N:24]=1)=[O:22]
Reactant: COC(=O)c1ccc(Br)cn1
Reactant: CC1(C)OB(c2ccn3ccnc3c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc(-c2ccn3ccnc3c2)cn1
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
To a stirred mixture of 7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-imidazo[1,2-a]pyridine (732 mg, 3 mmol), 5-bromopyridine-2-carboxylic acid methyl ester (650 mg, 3 mmol) and cesium carbonate (2.0 g, 6 mmol) in dry DME (15 ml) was added PdCl2dppf (220 mg, 0.3 mmol) and H2O (55 μl, 3 mmol). The reaction mixture was deoxygenated and then heated at 80° C. for 3 h. The mixture was allowed to cool, then partitioned between CH2Cl2/H2O and stirred for 20 min. The solid material was filtered off and washed with MeOH (100 ml). The CH2Cl2 layer was separated, combined with the MeOH washings and the solvent removed in vacuo. The residue was purified by silica column chromatography (0-3% 2M NH3. MeOH/CH2Cl2) to afford a dark yellow solid, which was used directly in the next reaction (492 mg). MS: [M+H]+=254. 1H NMR d6 DMSO: 9.21 (1H, d), 8.71 (1H, d), 8.44 (1H, dd), 8.20-8.10 (2H, m), 8.04 (1H, s), 7.69 (1H, s), 7.43 (1H, dd), 3.92 (3H, s).
Reaction SMILES: [ClH:1].C(OCC)C.[F:7][C:8]1([F:23])[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH:15]C(=O)OC(C)(C)C)[CH2:9]1>>[ClH:1].[ClH:1].[F:7][C:8]1([F:23])[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH2:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)NCCN1CCC(F)(F)C1
Agent: Cl
Solvent: CCOCC
Product: NCCN1CCC(F)(F)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8.6 ml of a 2 N solution of hydrogen chloride in diethyl ether (17.22 mmol, 10 equivalents) were added to 431 mg of tert-butyl [2-(3,3-difluoropyrrolidin-1-yl)ethyl]carbamate (Example 164A, 1.72 mmol, 1 equivalent), and the reaction mixture was stirred at RT overnight. The solvent was then decanted off, the residue was triturated three times with diethyl ether and the residue obtained in this manner was dried under reduced pressure. This gave 410 mg (99% of theory; purity 93%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(OCC)C.O>[S:26]([O:17][CH2:16][CH2:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)(=[O:28])(=[O:27])[CH3:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CCCO)CC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCCOS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4.87 g (20.0 mM) of 3-(1-tert-butoxycarbonyl-4-piperidyl)-1-propanol and 5.6 ml (40.0 mM) of triethylamine in 50 ml of diethyl ether was added 1.86 ml (24.0 mM) of methanesulfonyl chloride at 0° C. and the mixture was stirred at 0° C. for 30 minutes. This reaction mixture was then poured in iced water and extracted with ether. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4 and the solvent was distilled off under reduced pressure to provide 3-(1-tert-butoxycarbonyl-4-piperidyl)-1-propyl mesylate. To a solution of the above mesylate in 100 ml of N,N-dimethylformamide was added 3.70 g (20.0 mM) of potassium phthalimide and the mixture was heated at 100° C. for 90 minutes. After cooling to room temperature, this reaction mixture was poured in iced water and the resulting precipitate was collected by filtration, rinsed with water, and dried in vacuo to provide the title compound as white solid (20.24 g, 90%).
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH:27]([C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=1[F:45])[S:28]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)(=[O:30])=[O:29])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1.C(OC(C)C)(C)C>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([S:28]([CH:27]([C:38]2[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=2[F:45])[CH2:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][OH:18])(=[O:30])=[O:29])=[CH:36][CH:35]=1
Reactant: CC(C)(C)[Si](OCc1ccccc1CC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Solvent: O
Product: O=S(=O)(c1ccc(Cl)cc1)C(Cc1ccccc1CO)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 84.9 %

Procedure:
In tetrahydrofuran (20 ml) was dissolved 2-[2-[2-[(t-butyldiphenylsilyloxy)methyl]phenyl]-1-[(4-chlorophenyl)sulfonyl]ethyl]-1,4-difluorobenzene (1.10 g, 1.66 mmol), followed by the dropwise addition of a tetrahydrofuran solution (1.0M, 5.0 ml, 5.0 mmol) of tetrabutylammonium fluoride under ice cooling. The resulting mixture was stirred at room temperature for 14 hours. After addition of water (3 ml), the residue obtained by concentrating the resulting mixture under reduced pressure was subjected to flash silica gel chromatography. The fraction obtained from the hexane:ethyl acetate=1:1 eluate was concentrated under reduced pressure to give a white solid. The white solid was washed with diisopropyl ether, whereby the title compound (595 mg, 1.41 mmol, 85%) was obtained as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C[Al](C)C.C([O:15][C:16]([C:18]1[N:19]=[C:20]([CH3:34])[S:21][C:22]=1[NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([S:30](=[O:33])(=[O:32])[NH2:31])[CH:25]=1)=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1.O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:16]([C:18]2[N:19]=[C:20]([CH3:34])[S:21][C:22]=2[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([S:30](=[O:33])(=[O:32])[NH2:31])[CH:25]=2)=[O:15])=[N:3][CH:4]=1
Reactant: Nc1ccc(F)cn1
Reactant: CCOC(=O)c1nc(C)sc1Nc1cccc(S(N)(=O)=O)c1
Agent: C[Al](C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(C(=O)Nc2ccc(F)cn2)c(Nc2cccc(S(N)(=O)=O)c2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 2.8 %

Procedure:
A solution of 2-amino-5-fluoro pyridine (0.15 g, 1.38 mmol) in 10 ml dry dioxane was treated at 0° C. with trimethylaluminium (2M in hexane, 0.69 ml, 1.38 mmol). The mixture was stirred at room temperature for 1 h. 2-Methyl-5-(3-sulfamoyl-phenylamino)-thiazole-4-carboxylic acid ethyl ester (0.12 g, 0.35 mmol) was added and the reaction mixture was refluxed for 4 h. 1 ml water and 2 g sodium sulfate were sequentially added and filtered. The filtrate was evaporated and the residue purified by flash chromatography (hetane, ethyl acetate) to yield 2-methyl-5-(3-sulfamoyl-phenylamino)-thiazole-4-carboxylic acid (5-fluoro-pyridin-2-yl)-amide (0.004 g, 3%) as an off-white solid, MS (ISP): m/e=408.4 (M+H+).
Reaction SMILES: C(OC([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]4[C:24]5[CH:36]=[CH:35][CH:34]=[N:33][C:25]=5[NH:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:22]4=[N:21][C:20]=3[C:37]3[CH:46]=[CH:45][C:40]([C:41]([O:43][CH3:44])=[O:42])=[CH:39][CH:38]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:47].O1CCOCC1>CO>[ClH:47].[ClH:47].[ClH:47].[NH2:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]4[C:24]5[CH:36]=[CH:35][CH:34]=[N:33][C:25]=5[NH:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:22]4=[N:21][C:20]=3[C:37]3[CH:38]=[CH:39][C:40]([C:41]([O:43][CH3:44])=[O:42])=[CH:45][CH:46]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)c1ccc(-c2nc3n(c2-c2ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2nc3n(c2-c2ccc(C4(N)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
Methyl 4-[3-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-2-yl]benzoate (28 mg, 0.046 mmol) in MeOH (0.5 mL) was added 4N HCl-dioxane (2 mL) and stirred at room temperature for 18 hours. The mixture was concentrated to afford the desired product (28 mg, 97%) as a yellow solid. 1HNMR (DMSO-d6) 400 MHz δ: 8.80 (s, 2H), 8.65 (s, 1H), 8.12 (dd, J=4.6 Hz and 1.7 Hz, 1H), 7.98 (dd, J=7.4 Hz and 1.7 Hz, 1H), 7.89-7.87 (m, 2H), 7.59 (dd, J=12.0 Hz and 8.6 Hz, 4H), 7.40-7.30 (m, 4H), 7.14 (t, J=7.2 Hz, 1H), 6.92 (dd, J=8.0 Hz and 1.7 Hz, 1H), 6.76 (dd, J=4.6 Hz and 4.6 Hz, 1H), 3.84 (s, 3H), 2.59 (t, J=7.4 Hz, 4H), 2.26-2.17 (m, 1H), 1.87-1.78 (m, 1H). LCMS: 514 [M+H].
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[N-:8]=[N+:9]=[N-:10].[Na+].C(Cl)Cl.[Cl-].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[N:8]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N+:9]=[N-:10]
Reactant: CCOC(=O)CCl
Reactant: [N-]=[N+]=[N-]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CN=[N+]=[N-]

Procedure:
A solution of 55.7 grams (0.45 moles) of 99% pure ethyl chloroacetate (Aldrich Chemical Company, Milwaukee, Wis.), 0.64 grams(1.6 millimoles) of Aliquat 336 and 30.16 grams (0.46 moles) of sodium azide (Aldrich) in 50 ml. of methylene chloride and 50 ml. of water was heated to reflux for 16 hours in a 250 ml. round bottom 3-neck flask. The mixture was allowed to cool, whereupon an additional 30 ml. of water was added to dissolve the precipitated sodium chloride. The organic phase was separated and the aqueous phase was washed twice with 10 ml. aliquots of methylene chloride. The aqueous phase was discarded and the organic phases were combined and used as a solvent for the following reaction.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14](=O)[NH2:15])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>ClCCl.O>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]#[N:15])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H](C(N)=O)C1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H](C#N)C1
Temperature: -10 °C
Reaction time: 3 h
Yield: 86.7 %

Procedure:
In a 25 mL round bottomed flask (cis-3-carbamoyl-cyclohexyl)-carbamic acid tert-butyl ester (1.00 g, 4.13 mmol) was suspended in dichlormethane (7 mL). The suspension was cooled to −10° C. in an acetone-dry ice bath. To the cooled suspension was added slowly triethylamine (1.15 mL, 8.25 mmol) and subsequently TFAA (0.62 mL, 4.39 mmol) so that the temperature is maintained. The reaction mixture was stirred at that temperature for 3 h and then diluted with water and dichloromethane. The organic layer was washed with water, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 60% EtOAc in heptane) to afford 0.803 g (87%) of cis-(3-cyano-cyclohexyl)-carbamic acid tert-butyl ester as a white crystalline solid. 1H NMR (300 MHz, DMSO-d6) δ: 6.86 (d, J=7.9 Hz, 1H), 3.09-3.30 (m, 1H), 2.77 (tt, J=12.0, 3.3 Hz, 1H), 2.04 (d, J=12.1 Hz, 1H), 1.90 (d, J=9.1 Hz, 1H), 1.61-1.80 (m, 2H), 1.37 (s, 9H), 1.21-1.35 (m, 3H), 0.98-1.20 (m, 1H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][N:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11](Cl)=[O:12].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:11](=[O:12])[N:10]([CH3:9])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1ccc(I)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)Oc1ccc(I)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.7 %

Procedure:
To a solution of 4-iodophenol (30 mmol) in CH2Cl2 (100 mL) was added N-methyl-N-phenylcarbamoyl chloride (27 mmol) and diisopropylethylamine (60 mmol) at room temperature. The reaction mixture was stirred for 16 hours at rt, added CH2Cl2 (20 mL) and washed with aqueous citric acid (5%), aqueous Na2CO3 and brine. The organic phase was dried (MgSO4) and evaporated to give the crude product which was purified by FC (Quad flash 40 EtOAc-Heptane) to give 6.55 g (69%) of the title compound as light brown crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][S:13](Cl)(=[O:15])=[O:14].N1C=CC=CC=1>C1COCC1.Cl>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:13]([CH3:12])(=[O:15])=[O:14])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(Cl)c([N+](=O)[O-])c1
Reaction time: 24 h
Yield: 92.2 %

Procedure:
A mixture of 4-chloro-3-nitroaniline (5.0 g, 29 mmol), methanesulfonyl chloride (2.37 mL, 30.4 mmol) and pyridine (5.9 mL, 72.4 mmol) in THF (100 mL) was stirred for 24 h. Poured in 1M HCl (500 mL). The resulting precipitate was filtered and air-dried to provide the title compound as a solid (6.7 g, 92%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:14])=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([CH:12]=[O:13])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:24][C:25]([CH3:27])=[CH2:26]>CN(C)C=O.O>[CH3:14][C:3]1[C:2]([O:1][CH2:26][C:25]([CH3:27])=[CH2:24])=[CH:10][C:9]([CH3:11])=[C:8]2[C:4]=1[CH2:5][CH2:6][N:7]2[CH:12]=[O:13]
Reactant: Cc1cc(O)c(C)c2c1N(C=O)CC2
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)COc1cc(C)c2c(c1C)CCN2C=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
2,3-Dihydro-5-hydroxy-4,7-dimethyl-1H-indole-1-carbaldehyde (5.74 g, 30 mmol) was dissolved in N,N-dimethylformamide (100 ml) and to the solution were added potassium carbonate (8.29 g, 60 mmol), potassium iodide (0.50 g, 3 mmol) and 3-chloro-2-methyl-1-propene (4.41 ml, 45 mmol). The mixture was stirred at 80° C. for 3 hours. The reaction mixture was poured into cold water (300 ml), and extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel. (hexane:ethyl acetate=6:1) to obtain 6.00 g of the title compound.