Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:15][CH:14]3[C:10]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)([N:11]([C:16]([NH:18][C:19](=[O:26])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[S:17])[O:12][CH2:13]3)[CH2:9]2)=[N:6][CH:7]=1>C(O)(=O)C.[Zn]>[F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:15][CH:14]([CH2:13][OH:12])[C:10]([NH:11][C:16]([NH:18][C:19](=[O:26])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[S:17])([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[CH2:9]2)=[N:6][CH:7]=1
Reactant: O=C(NC(=S)N1OCC2CN(c3ncc(F)cn3)CC21c1cccnc1)c1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C(NC(=S)NC1(c2cccnc2)CN(c2ncc(F)cn2)CC1CO)c1ccccc1
Yield: 26.3 %

Procedure:
A mixture of N-[5-(5-fluoropyrimidin-2-yl)-6a-(3-pyridyl)-3,3a,4,6-tetrahydropyrrolo[3,4-c]isoxazole-1-carbothioyl]benzamide (550 mg, 1.22 mmol) and powdered zinc (798.33 mg, 12.21 mmol) in acetic acid (5 mL) is sonicated for 2 hours at room temperature. The mixture is extracted with ethyl acetate (100 mL) and a saturated aqueous sodium bicarbonate solution (30 mL). The aqueous phase is re-extracted three times with dichloromethane (100 mL). The combined organic extracts are dried over magnesium sulfate, filtered, and concentrated to give a residue. The residue is purified by silica gel chromatography using a 0-10% gradient of 0.14 M ammonia/methanol solution in dichloromethane to give the intermediate N-[[1-(5-fluoropyrimidin-2-yl)-4-(hydroxymethyl)-3-(3-pyridyl)pyrrolidin-3-yl]carbamothioyl]benzamide (145 mg). This is dissolved in dichloromethane (6 mL) and is cooled to 0° C. 1-Chloro-N,N,2-trimethylpropenylamine (0.05 g, 374.19 μmol) is then added and the mixture stirred at 0° C. for 1 hour. A saturated aqueous sodium bicarbonate solution (10 mL) and dichloromethane (100 mL) are added. The phases are separated and the organic phase is dried over magnesium sulfate, filtered, and concentrated. The residue is purified by silica gel chromatography using a 0-5% gradient of 0.14 M ammonia/methanol solution in dichloromethane to give the title product (110 mg, 17%). ES/MS (m/e): 435 (M+1).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CS(O)(=O)=O.[NH2:20][C:21]1[C:26]([NH2:27])=[CH:25][C:24]([Br:28])=[CH:23][N:22]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](O)=O.[OH-].[Na+]>>[Br:28][C:24]1[CH:25]=[C:26]2[NH:27][C:34]([C:33]3[CH:37]=[CH:38][CH:39]=[C:31]([O:30][CH3:29])[CH:32]=3)=[N:20][C:21]2=[N:22][CH:23]=1
Reactant: COc1cccc(C(=O)O)c1
Reactant: Nc1cc(Br)cnc1N
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Product: COc1cccc(-c2nc3ncc(Br)cc3[nH]2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
Phosphorus pentaoxide (23.8 g) was added to methanesulfonic acid (85 ml), the mixture was stirred at 100° C. for 1 hour to give a solution. To the solution were added 2,3-diamino-5-bromopyridine (Compound of Reference Example 1) (15.8 g) and 3-methoxybenzoic acid (12.7 g), and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was poured onto ice, neutralized with 8 N sodium hydroxide, and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with water and dried over MgSO4. The solvent was distilled off under reduced pressure, and crystals were collected by filtration to obtain 6-bromo-2-(3-methoxyphenyl)-1H-imidazo[4,5-b]pyridine (21.3 g, 84%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24](O)=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C(N(CC)CC)C.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[CH3:46][C:47]1[CH:51]=[C:50]([NH2:52])[NH:49][N:48]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([NH:52][C:50]4[NH:49][N:48]=[C:47]([CH3:46])[CH:51]=4)=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Reactant: Cc1cc(N)[nH]n1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)Nc3cc(C)n[nH]3)c2n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 18.6 %

Procedure:
To a suspension of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation K, 101 mg, 0.283 mmol) in THF (5 mL) was added triethylamine (34.3 mg, 0.339 mmol), followed by the addition of 2,4,6-trichlorobenzoyl chloride (75.8 mg, 0.311 mmol). The suspension was stirred for 2 hours and then 3-methyl-1H-pyrazol-5-amine (35.7 mg, 0.367 mmol) was introduced. The reaction was heated at 60° C. for 3 hours. After cooling to room temperature, the reaction was partitioned between EtOAc (20 mL) and saturated aqueous NaHCO3 (10 mL). After phase-separation, the aqueous layer was extracted with EtOAc (2×10 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The residue was purified via silica chromatography (EtOAc/MeOH 20:1) to yield the title product (23 mg, 19%). LCMS (apci) m/z=437.0 (M+H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(O)(C)C.[NH2:8][N:9]1[C:14](=[O:15])[CH:13]([F:16])[N:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[N:11]=[C:10]1SC>C(O)(=O)C>[NH2:8][N:9]1[C:14](=[O:15])[CH:13]([F:16])[N:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[N:11]=[C:10]1[N:2]([CH3:3])[CH3:1]
Reactant: CNC
Reactant: CSC1=NN(C(C)(C)C)C(F)C(=O)N1N
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CN(C)C1=NN(C(C)(C)C)C(F)C(=O)N1N
Temperature: 25 °C
Yield: 68.8 %

Procedure:
13.6 g (0.3 mole) of dimethylamine were introduced into a mixture of 350 ml of isopropanol and 12 g of glacial acetic acid, while cooling with ice. 21.8 g (0.1 mole) of 4-amino-6-fluoro-tert.-butyl-3-methylthio-1,2,4-triazin-5-one (obtained as described in Example 2) were then added to this reaction solution. The mixture was allowed to warm to room temperature and was then heated under reflux for 15 hours. Thereafter, the reaction mixture was concentrated and the oily residue was stirred into water. The mixture was extracted with methylene chloride and the extract was dried over sodium sulphate and concentrated. The oily residue was taken up in diisopropyl ether, seed crystals were added and the solid which crystallized out was filtered off and dried. 15.9 g (69% of theory) of 4-amino-3-dimethylamino-6-fluoro-tert.-butyl-1,2,4-triazin-5-one of melting point 86°-87° C. were obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-])=O)[CH2:4][CH2:3]1>Cl>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[CH2:6][CH2:7]1
Reactant: CN1CCN(CCCNc2ccccc2[N+](=O)[O-])CC1
Agent: Cl
Product: CN1CCN(CCCNc2ccccc2N)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a mechanically stirred solution of stannous chloride (1060 g., 4.71 mole) in concentrated hydrochloric acid (1200 ml.), under nitrogen, was added a solution of 2-[3-(4-methyl-1-piperazinyl)propylamino]nitrobenzene (438 g., 1.57 mole) in conc. HCl (800 ml.) at a rate sufficient to maintain the reaction temperature at 55°-60° C. The addition took place over about 1.5 hours. The heavy white precipitate which formed during the course of the addition, was stirred for an additional 1 hour. The reaction mixture was then filtered and the resultant white solid was dissolved in 3 liters of water. An equal volume of chloroform was added, the mixture was cooled to 50° C. and adjusted to pH 10, with 50% KOH. The organic layer was separated, and the cold basic aqueous phase extracted again with chloroform (1l). The organic layers were combined, dried (MgSO4) and evaporated in vacuo to give 334.8 g. of N-[3-(4-methyl-1-piperazinyl)propyl-o-phenylenediamine as a brown oil (yield 97%). A small amount of the oil was triturated with hexane. The hexane layer was cooled to 5° C. forming a tan solid which on recrystallization from benzene-hexane gave an analytical sample, m.p. 65°-67° C.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:23][C:24]([CH3:28])([CH3:27])[CH2:25][NH2:26].CO.C(Cl)Cl>CS(C)=O>[CH3:22][C:3]1[C:2]([NH:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH3:23])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: CC(C)(C)CN
Solvent: CO
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NCC(C)(C)C
Temperature: 80 °C
Yield: 95.6 %

Procedure:
Prepared similar to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 40 mg, 0.090 mmol) and 2,2-dimethylpropan-1-amine (TCI America, Portland, Oreg.; 0.032 mL, 0.271 mmol) in DMSO (0.8 mL), heating at 80° C. for 2 h. Chromatographic purification (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) furnished 2-(2-methyl-3-(neopentylamino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (31.4 mg, 0.086 mmol, 96% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.05 (1H, br. s.), 7.85 (1H, dd, J=7.7, 0.8 Hz), 7.55 (1H, dd, J=8.0, 0.9 Hz), 7.30 (1H, t, J=7.7 Hz), 7.21 (1H, d, J=2.2 Hz), 7.02 (1H, t, J=6.4 Hz), 6.92 (1H, br. s.), 3.41-3.48 (4H, m), 2.88 (2H, t, J=6.8 Hz), 2.57 (3H, s), 0.99 (9H, s). m/z (ESI, +ve) 364.2 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:2]1.[C:15]([O:24][CH3:25])(=[O:23])[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH2:18].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[C:15]([O:24][CH3:25])=[O:23])=[O:14])=[CH:2]1
Reactant: COC(=O)c1ccccc1N
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1NC(=O)CCc1c[nH]c2ccccc12
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
To a solution of 3-(3-indolyl)propionic acid (6.0 g, 32 mmol) in 100 ml THF at room temperature was added 1,1-carbonyldiimidazole (5.14 g, 32 mmol). The reaction mixture was stirred under a dry atmosphere for 30 minutes, after which methyl anthranilate (4.79 g, 32 mmol) was added, and the reaction mixture was stirred at reflux for 30 minutes. No reaction was detected by thin layer chromatography (TLC). Pyridinium p-toluenesulfonate (PPTS) [6.36 g, 25 mmol] was added, and the mixture was stirred at reflux for two days. The reaction mixture was allowed to cool, and the solvent was removed in vacuo. The resulting product was taken up in ethyl acetate and washed (1N HCl, H2O, saturated NaHCO3, and brine) and dried over anhydrous magnesium sulfate. Concentration in vacuo provided a light yellow solid which, when triturated with ethyl acetate/hexane, gave, upon filtration, 7.19 g (70% yield) of 3-(3-indolyl)-N-(2-methoxycarbonylphenyl)propionamide as an off white granular solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:32])[C:13]3[CH:14]=[CH:15][C:16]([O:18][CH2:19][O:20][CH3:21])=[CH:17][C:12]=3[O:11][CH2:10][CH:9]2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][Cl:39].[OH-].[Na+].O>CC(C)=O>[Cl:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][O:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:32])[C:13]3[CH:14]=[CH:15][C:16]([O:18][CH2:19][O:20][CH3:21])=[CH:17][C:12]=3[O:11][CH2:10][CH:9]2[C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:26][CH:27]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2cccc(O)c2)cc1
Reactant: ClCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2cccc(OCCCCCCl)c2)cc1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
4-(3-Hydroxyphenyl)-4-hydroxy-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-2,3-dihydro-4H-benzopyran (283 mg, 0.6 mmol), 1-bromo-5-chloropentane (598 mg, 3.2 mmol) and aqueous 2N-NaOH solution (1 ml) were dissolved in acetone (3 ml) and then refluxed for 6 hours. The reaction mixture was cooled to room temperature and then water was added thereto. The reaction solution was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to remove the organic solvent. The concentrate was separated by column chromatography (n-hexane:ethyl acetate=8:1) to obtain 307 mg (yield: 94%) of the title compound as a colorless oil.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:22]=[C:21]4[C:15]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20]4)=[N:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]1(=O)[CH2:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.CO>[CH:23]1([N:18]2[CH2:19][CH2:20][C:21]3=[CH:22][N:13]([C:10]4[CH:11]=[CH:12][C:7]([N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)=[CH:8][CH:9]=4)[N:14]=[C:15]3[CH2:16][CH2:17]2)[CH2:26][CH2:25][CH2:24]1
Reactant: O=C1CCC1
Reactant: c1cc(-n2cc3c(n2)CCNCC3)ccc1N1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: c1cc(-n2cc3c(n2)CCN(C2CCC2)CC3)ccc1N1CCCCC1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of 2-[4-(1-piperidinyl)phenyl]-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine (may be prepared as described in Description 43) (42 mg, 0.14 mmol) in dichloromethane (4 ml) was added cyclobutanone (30 μl, 0.42 mmol) followed by acetic acid (3 drops). The mixture was stirred at room temperature for 50 min, then treated with sodium triacetoxyborohydride (89 mg, 0.42 mmol). The mixture was stirred at room temperature for 2.5 hours, then it was diluted with methanol and purified by SCX cartridge to afford the title compound (E40). MS (ES+) m/e 351 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=O)[N:11]=[N:10]2)=[CH:5][CH:4]=1.[NH2:18][C:19]1[C:20](=[O:32])[N:21]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[N:22]([CH3:25])[C:23]=1[CH3:24].C(N(CC)C(C)C)(C)C>C(Cl)Cl.CO>[CH:26]1([N:21]2[C:20](=[O:32])[C:19]([NH:18][C:15]([C:12]3[N:11]=[N:10][N:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[C:13]=3[CH3:14])=[O:17])=[C:23]([CH3:24])[N:22]2[CH3:25])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: Cc1c(N)c(=O)n(C2CCCCC2)n1C
Reactant: COc1ccc(-n2nnc(C(=O)O)c2C)cc1
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-n2nnc(C(=O)Nc3c(C)n(C)n(C4CCCCC4)c3=O)c2C)cc1
Reaction time: 4 h

Procedure:
To a vial was added 1-(4-methoxyphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (0.040 g, 0.170 mmol) and a solution of Ghosez reagent (0.047 ml, 0.340 mmol) in DCM (0.95 ml). The mixture was sonicated and heated to aid dissolution. The vial was placed on the IKA shaker for 4 hours. To this mixture was added a solution of 4-amino-2-cyclohexyl-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate A) (10.043 g, 0.204 mmol) and N,N-diisopropylethylamine (0.030 ml, 0.170 mmol) in DCM (0.97 ml) and the vial was shaken for 16 hrs. A few drops of MeOH were added and the solvent was removed using a Genevac HT-4X evaporator. The crude mixture was purified by reverse phase chromatography and the product fraction was concentrated using a Genevac HT-4X evaporator. The crude product was dissolved in MeOH (1 ml) and eluted through a SiCO3 cartridge using MeOH as the eluent. The collected eluent was concentrated to give the title compound.
Reaction SMILES: C[N:2](/[CH:4]=[N:5]/[C:6]([C:8]1[N:12]2[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C:11]2=[N:10][N:9]=1)=[S:7])C.N1C=CC=CC=1>C(O)C.CO>[S:7]1[C:6]([C:8]2[N:12]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C:11]3=[N:10][N:9]=2)=[N:5][CH:4]=[N:2]1
Reactant: CN(C)/C=N/C(=S)c1nnc2n1CCN(C(=O)OC(C)(C)C)C2
Solvent: CO
Solvent: c1ccncc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCn2c(nnc2-c2ncns2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
A mixture of 1,1-dimethylethyl 3-({[(1E)-(dimethylamino)methylidene]amino}carbonothioyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (I113)(0.118 g, 0.349 mmol) and pyridine (0.056 ml, 0.698 mmol) in ethanol (2 ml) was stirred at 25° C. and hydroxylamine O-sulfonic acid (0.043 g, 0.384 mmol) in methanol (1.2 ml) was added in one batch. The mixture was stirred at RT and after a few minutes the solution became clear. After 1 h, the mixture had changed from orange to pale yellow in colour. The solvents were evaporated and the concentrated mixture was diluted with DCM (50 ml) and washed with water (5 ml), 0.2M NaOH (5 ml) and water (5 ml) and the organic layer was dried and concentrated. Chromatography (SP4, 0-100% ethyl acetate in isohexane) gave a white foam (58 mg). NMR showed some high field impurities therefore the foam was triturated with isohexane to give a white solid in 51.2 mg of desired product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:27]=1[C:28](Cl)=[O:29]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:28](=[O:29])[C:27]5[C:31]([O:35][CH3:36])=[CH:32][CH:33]=[CH:34][C:26]=5[O:25][CH3:24])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: COc1cccc(OC)c1C(=O)Cl
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4c(OC)cccc4OC)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-2,6-dimethoxy-benzamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 2,6-dimethoxybenzoyl chloride (178 mg, 0.87 mmol). The title compound was obtained as light brown powder (180 mg, 47%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH2:18])=O)=[CH:11][CH:10]=2)[CH2:5]CC[CH2:2]1.N(C1C=CC(OCCN(C)C)=CC=1)=C=[S:21]>>[CH3:2][N:1]([CH3:5])[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH2:18])=[S:21])=[CH:11][CH:10]=1
Reactant: CN(C)CCOc1ccc(N=C=S)cc1
Reactant: NC(=O)Nc1ccc(OCCN2CCCC2)cc1
Product: CN(C)CCOc1ccc(NC(N)=S)cc1

Procedure:
The title compound is prepared as described in Example 1 for [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-urea but using [2-(4-isothiocyanato-phenoxy)-ethyl]-dimethyl-amine. The title compound: ES-MS: 240.0 [M+H]+; single peak at tR=3.52 min (System 1).
Reaction SMILES: F[C:2](F)(F)[C:3]([O-])=[O:4].[C:8]([C:11]1[C:12]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:13][N:14]([C:16]2([CH2:20][C:21]#[N:22])[CH2:19][NH2+:18][CH2:17]2)[CH:15]=1)(=[O:10])[NH2:9].N1C=CC=CC=1.C(OC(=O)C)(=O)C>C(Cl)Cl>[C:3]([N:18]1[CH2:17][C:16]([N:14]2[CH:15]=[C:11]([C:8]([NH2:9])=[O:10])[C:12]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:13]2)([CH2:20][C:21]#[N:22])[CH2:19]1)(=[O:4])[CH3:2]
Reactant: O=C([O-])C(F)(F)F
Reactant: N#CCC1(n2cc(C(N)=O)c(Nc3ccccc3)n2)C[NH2+]C1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CC(CC#N)(n2cc(C(N)=O)c(Nc3ccccc3)n2)C1
Reaction time: 0.5 h

Procedure:
To a suspension of 3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidinium trifluoroacetate (Intermediate #38-2) (50 mg, 0.17 mmol) in DCM (2 mL) was added pyridine (0.050 mL, 0.62 mmol), followed by acetic anhydride (0.030 mL, 0.32 mmol). The reaction mixture was allowed to stir for 30 minutes before the solvent was removed in vacuo. Saturated aqueous NaHCO3 solution was added and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 50-100% EtOAc/hexanes followed by 10% MeOH/EtOAc) to afford the title compound, Example #32.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10](O)[C:4]=2[CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[CH2:6][CH2:7][CH2:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:4]=2[CH:3]=1
Reactant: COC(=O)C1CCCc2ccc(Br)cc2C1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C1=Cc2cc(Br)ccc2CCC1
Yield: 80.9 %

Procedure:
To a solution of methyl 3-bromo-5-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6-carboxylate from step A3 (230 mg, 0.769 mmol) in toluene (3 mL) was added p-toluenesulfonic acid monohydrate (29.2 mg, 0.154 mmol). The mixture was heated at reflux for 4 h. The solvent was removed in vacuo, and the residue was purified using silica gel column chromatography (hexanes-10% EtOAc) to give methyl 2-bromo-6,7-dihydro-5H-benzo[7]annulene-8-carboxylate (175 mg, 0.622 mmol, 81% yield). 1H NMR (500 MHz, chloroform-d) δ 7.61 (s, 1H), 7.44 (d, J=1.8 Hz, 1H), 7.32 (dd, J=8.1, 2.0 Hz, 1H), 7.02 (d, J=7.9 Hz, 1H), 3.83 (s, 3H), 2.79-2.72 (m, 2H), 2.63 (t, J=6.6 Hz, 2H), 2.09-2.00 (m, 2H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14]([N+:21]([O-])=O)[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]>CO.CCOC(C)=O>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([NH2:21])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: CNC(=O)c1cc(Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)ccn1
Solvent: CO
Solvent: CCOC(C)=O
Product: CNC(=O)c1cc(Oc2ccc(N)c(N)c2)ccn1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
4-(3,4-Dinitro-phenoxy)-pyridine-2-carboxylic acid methylamide (Step A) (0.71 g, 2.23 mmol) was dissolved in 40 mL MeOH and 80 mL EtOAc. To the argon-degassed solution was added 10% Pd/C (0.20 g). The reaction was vigorously stirred for 42 h at RT under 1 atm of H2 gas. The reaction was filtered through a Celite® plug. The solvent was removed under reduced pressure to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([F:31])[CH:22]=2)([NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][C:10]([O:12]C)=[O:11])=[N:6][CH:7]=1.[Li+].[OH-].Cl>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=[C:23]([F:31])[CH:22]=2)([NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][C:10]([OH:12])=[O:11])=[N:6][CH:7]=1
Reactant: COC(=O)C[C@](NC(=O)C(C)(C)C)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)N[C@@](CC(=O)O)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 14 h
Yield: 88.7 %

Procedure:
(S)-methyl 3-(5-chloropyridin-2-yl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)-3-pivalamidopropanoate (1.04 g, 2.16 mmol, prepared as described in Procedure 11) was dissolved in THF (30 mL) at room temperature. A4M LiOH solution was added (20 mL) and the reaction mixture stirred at RT for 14 h. The RM was diluted with EtOAc (ca. 100 mL) and the pH adjusted to pH1-2 by addition of 1 M HCl. The organic portion was separated and the aqueous washed with EtOAc (ca.2×20 mL). The combined organic portions were dried over anhydrous Na2SO4, decanted and concentrated yielding (S)-3-(5-chloropyridin-2-yl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)-3-pivalamidopropanoic acid as a colorless oil (0.856 g, 85% yield) LCMS: 1.90 min [M+1] 467.2 (2 min gradient, MeOH/H2O 0.1% TFA).