Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:31][N:32]([CH3:36])[C:33](Cl)=[O:34]>O1CCCC1>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH2:20][C:33]([N:32]([CH3:36])[CH3:31])=[O:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: CN(C)C(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)C(=O)Cc1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
3-Benzyl-7-chloro-2-methylquinazolin-4 (3H)-one (2 g, 1 eq.) was dissolved in tetrahydrofuran (20 ml). The solution was cooled to −78° C. for 15 minutes. Lithium hexamethyl disilazide (LHMDS) was added slowly and the mixture was stirred at −78° C. for 45 minutes. Dimethylcarbamyl chloride was added and the mixture was stirred at −78° C. for 1 h. The reaction was allowed to warm to room temperature and stirred for 3 h. The solvent was evaporated and the resulting solid was dissolved in ethyl acetate. The ethyl acetate layer was washed with water, saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography to give 2-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-N,N-dimethylacetamide (1.2 g) as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9]CC)=[O:8])=[C:5]([CH3:12])[NH:4][C:3]=1C(OCC)=O>S(=O)(=O)(O)O>[C:7]([CH2:6][CH2:5][N:4]1[C:5]([CH3:12])=[C:6]([C:7]([OH:9])=[O:8])[C:2]([CH3:1])=[CH:3]1)([OH:9])=[O:8]
Reactant: CCOC(=O)c1[nH]c(C)c(C(=O)OCC)c1C
Agent: O=S(=O)(O)O
Product: Cc1cn(CCC(=O)O)c(C)c1C(=O)O
Reaction time: 8 h
Yield: 157.7 %

Procedure:
3,5-Dimethyl-2,4-pyrrole dicarboxylic acid, diethyl ester (200 g, 836 mmol) was placed in a 1 L beaker and treated with 400 mL concentrated sulfuric acid (H2SO4). The mixture was stirred, heated to 45 C with the aid of a heat gun and then maintained at 36–42 C for 25 minutes. The reaction mixture was poured into 3 L crushed ice and stirred for 30 minutes. The yellow solid was recovered by filtration and washed with 200 mL water. The solid was transferred to a 4 L Erlenmeyer flask and treated with 2 L 1 N sodium hydroxide solution (NaOH) followed by 100 mL 10 N NaOH. The basic mixture was filtered and the yellow solid residue was discarded. The filtrate was acidified with H2SO4. The resulting solid was recovered by suction filtration and washed with 2×500 mL water. After suction drying, the material was transferred to a 6 L Erlenmeyer flask and digested briefly in 4 L acetone. After standing overnight at room temperature (RT), the solid was collected by filtration and dried in a vacuum dessicator to afford 139 g, 659 mmol, 79% of the title compound. 1H NMR (DMSO-d6) δ 4.22 (q, 2H), 2.44 (s, 3H), 2.38 (s, 3H), 1.27 (t, 3H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([CH2:10][C:11]1([N:24]2[CH:28]=[C:27]([C:29]3[CH:30]=[N:31][C:32]4[N:33]([C:35]([CH2:38][C:39]5[CH:40]=[C:41]6[C:46](=[CH:47][CH:48]=5)[N:45]=[CH:44][CH:43]=[CH:42]6)=[CH:36][N:37]=4)[N:34]=3)[CH:26]=[N:25]2)[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)#[N:9]>C(Cl)Cl>[N:45]1[C:46]2[C:41](=[CH:40][C:39]([CH2:38][C:35]3[N:33]4[N:34]=[C:29]([C:27]5[CH:26]=[N:25][N:24]([C:11]6([CH2:10][C:8]#[N:9])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]6)[CH:28]=5)[CH:30]=[N:31][C:32]4=[N:37][CH:36]=3)=[CH:48][CH:47]=2)[CH:42]=[CH:43][CH:44]=1.[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(-c3cnc4ncc(Cc5ccc6ncccc6c5)n4n3)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCC1(n2cc(-c3cnc4ncc(Cc5ccc6ncccc6c5)n4n3)cn2)CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic Acid (0.5 mL) was added to a solution of tert-butyl 4-(cyanomethyl)-4-{4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-1H-pyrazol-1-yl}piperidine-1-carboxylate (0.015 g, 0.000027 mol) in methylene chloride (0.5 mL). The mixture was stirred at RT for 0.5 h. The volatiles were removed under reduced pressure to give the desired product as a TFA salt which was directly used in the next step without further purification. LCMS: (M+H)=450.5.
Reaction SMILES: [Cl-].[OH:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:12][C:13]2[N:14]=[CH:15][NH2+:16][CH:17]=2)=[CH:5][CH:4]=1.[C:18]([Cl:21])(=[O:20])[CH3:19]>FC(F)(F)C(O)=O>[Cl-:21].[C:18]([O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:12][C:13]2[N:14]=[CH:15][NH2+:16][CH:17]=2)=[CH:5][CH:4]=1)(=[O:20])[CH3:19]
Reactant: Oc1ccc2c(c1)C(CC1=C[NH2+]C=N1)CC2
Reactant: CC(=O)Cl
Agent: [Cl-]
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Oc1ccc2c(c1)C(CC1=C[NH2+]C=N1)CC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-(6-hydroxy-indan-1-ylmethyl)-1H-imidazol-1-ium chloride (100 mg, 0.399 mmol) was dissolved in 1 ml of trifluoroacetic acid (TFA) and acetic acid chloride (0.510 mmol) was added. The mixture was stirred at room temperature for 24 h. TFA was evaporated and the residue was dissolved in water and made basic with 2 M NH3 (aq.). The aqueous phase was extracted with dichloromethane (DCM). The combined extracts were dried (Na2SO4) and evaporated. The residue was dissolved in diethyl ether and the solution was saturated with dry HCl gas. The precipitate was filtered and dried under vacuum. Yield 105 mg (82%) of a white hygroscopic solid. 1H NMR (CDCl3, TMS): δ 1.72 (m, 1H), 2.18-2.26 (m, 4H), 2.72-2.87 (m, 3H), 3.17 (dd, 1H), 3.56 (qui, 1H), 6.85 (m, 2H), 6.92 (s, 1H), 7.16 (d, 1H), 8.61 (s, 1H), 14.44 (s, 2H). 13C NMR (CDCl3, TMS): δ 21.11, 29.60, 30.46, 31.68, 43.93, 115.72, 117.00, 120.29, 125.33, 132.32, 132.40, 141.37, 146.32, 149.39, 170.11. HPLC-MS (EI): m/z=257.2 ((M+H)+—Cl−. Anal.—Calc. for C15H16N2O2.HCl.0.2CH2Cl2: C, 58.94; H, 5.66; N, 9.04. Found C, 58.66; H, 5.78; N, 8.83.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH2:16]([O:18][CH:19](OCC)OCC)[CH3:17]>C(OC(=O)C)(=O)C>[CH2:16]([O:18]/[CH:19]=[C:8](\[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)/[C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:17]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)C(=O)Cc1ccc(F)cc1
Solvent: CC(=O)OC(C)=O
Product: CCO/C=C(/C(=O)C(=O)OCC)c1ccc(F)cc1
Temperature: 25 °C
Yield: 14 %

Procedure:
A solution of ethyl 3-(4-fluorophenyl)-2-oxopropanoate (4 g, 19.03 mmol, 1.00 equiv) and triethoxymethane (16 mL) in acetic anhydride (5 mL) was stirred at 130° C. overnight. The reaction mixture was cooled to room temperature and then concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-10% of ethyl acetate in petroleum ether to give 700 mg (14%) of (E)-ethyl 4-ethoxy-3-(4-fluorophenyl)-2-oxobut-3-enoate as a yellow oil. 1H-NMR (300 MHz, DMSO-d6): δ 7.71 (s, 1H), 7.32-7.28 (m, 2H), 7.09-7.05 (m, 2H), 4.23 (q, J=7.0 Hz, 2H), 4.16 (q, J=8.0 Hz, 2H), 1.37-1.20 (m, 6H) ppm.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[F:17][C:18]([F:36])([C:32]([F:35])([F:34])[F:33])[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][O:28][CH2:29][O:30][CH3:31])[CH:22]=1)=O.O>C1COCC1>[F:17][C:18]([F:36])([C:32]([F:33])([F:34])[F:35])[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][O:28][CH2:29][O:30][CH3:31])[CH:22]=1)=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: COCOCc1cccc(C(=O)C(F)(F)C(F)(F)F)c1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C=C(c1cccc(COCOC)c1)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Under a nitrogen atmosphere, to a suspension of 60% sodium hydride (481 mg) in THF (15 mL) was added ethyl diethylphosphonoacetate (2.55 mL) at 0° C., and the mixture was stirred at room temperature for 5 min. To the obtained colorless solution was added 2,2,3,3,3-pentafluoro-1-(3-((methoxymethoxy)methyl)phenyl)propan-1-one (1.28 g) at room temperature, and the mixture was stirred at 0° C. for 30 min. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.37 g) as a pale-yellow oil.
Reaction SMILES: [C:1]([O-])(=O)C.[CH3:5][C:6]([CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[CH:7][C:8](=[O:12])[CH:9]=[CH:10][CH3:11]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(O)(=O)C>[CH3:5][C:6]1[CH:7]([C:8](=[O:12])[CH:9]=[CH:10][CH2:11][CH3:1])[C:16]([CH3:17])([CH3:18])[CH2:15][CH2:14][CH:13]=1
Reactant: CC=CC(=O)C=C(C)CCC=C(C)C
Reactant: CC(=O)[O-]
Agent: [Cu+2]
Solvent: CC(=O)O
Product: CCC=CC(=O)C1C(C)=CCCC1(C)C

Procedure:
248 g. of the acetate prepared according to paragraph (c) were heated at 90° during 5 h. in the presence of 500 ml. of acetic acid and 10 g. of copper acetate. By means of vapour phase chromatography it was shown that the starting acetate had completely reacted. The mixture was concentrated in vacuum and the residue was treated with 300 ml. of water. After extraction with petrol-ether and the usual treatments, 190 g. of a mixture consisting of 7,11-dimethyl-5-oxo-3,6,10-dodecatriene and two isomeric ketones, 7,11-dimethyl-5-oxo-3,7,10-dodecatriene and 11-methyl-7-methylene-5-oxo-3,10-dedacadiene, were obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:12][C:11]2[C:10]([I:13])=[N:9][NH:8][C:7]=2[CH:6]=1)=[O:4].[OH-].[K+].O>O1CCCC1>[I:13][C:10]1[C:11]2[S:12][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[NH:8][N:9]=1
Reactant: COC(=O)c1cc2[nH]nc(I)c2s1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2[nH]nc(I)c2s1
Temperature: 60 °C
Yield: 50.1 %

Procedure:
To a solution of 3-iodo-1H-thieno[3,2-c]pyrazole-5-carboxylic acid methyl ester [4.5 g, 14.60 mmol, Intermediate (26)] in tetrahydrofuran (90 mL) is added potassium hydroxide (2.83 g, 50.44 mmol) and water (20 mL). The resulting reaction mixture is heated at 60° C. oil bath under for 2 hours. The solvent is removed in vacuo and dissolved crude in water (20 mL). The water layer is acidified using 2N hydrochloric acid till pH is 5. White solid precipitated are collected and rinsed with water. The filtrate is extracted three times with ethyl acetate (50 mL). The combined ethyl acetate phases are washed with brine and dried over magnesium sulfate and filtered. Combined solids and stirred in heptane and filtered to obtain 3-iodo-1H-thieno[3,2-c]pyrazole-5-carboxylic acid [2.15 g, 50%, Intermediate (29)] as white solid; 1H NMR [(CD3)2SO)]: δ 13.711 (1H, s), 7.832 (1H, s); LC/MS: 294 (M+H).
Reaction SMILES: [Cl-:1].[NH2:2][C:3]([CH3:14])([CH3:13])[CH2:4][CH2:5][N+:6]1([CH3:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(O[Cl:20])(C)(C)C>CO.O>[Cl-:20].[Cl:1][N:2]([Cl:20])[C:3]([CH3:14])([CH3:13])[CH2:4][CH2:5][N+:6]1([CH3:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CC(C)(N)CC[N+]1(C)CCCCC1
Reactant: CC(C)(C)OCl
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: CC(C)(CC[N+]1(C)CCCCC1)N(Cl)Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(3-amino-3-methylbutyl)-1-methylpiperidinium chloride (1.00 g, 3.80 mmol) in a mixture of methanol (6 mL) and water (6 mL) was cooled in an ice bath for 15 min. t-BuOCl (1.3 mL, 3.0 equiv, 11.4 mmol) was added in one portion via syringe to the colorless solution to give a deep yellow solution. The reaction mixture was stirred for 30 min at 0° C. Then the methanol was removed under reduced pressure and the crude solid was purified via reverse phase chromatography on a Shimadzu Prep-LC utilizing water/methanol and 0.05% acetic acid as modifier. Fractions were collected monitoring UV absorbance at 215 nm. Fractions were pooled and concentrated under reduced pressure at 25° C. to give a white solid, (0.92 g, 83%). 1H NMR (D2O, 400 MHz): δ 1.46 (s, 6H), 1.52-1.55 (m, 2H), 1.70-1.95 (m, 4H), 2.20-2.28 (m, 2H), 3.05 (s, 3H), 3.35-3.48 (m, 6H). LRMS (ESI+) for C11H23Cl2N2+ (253.1); Found: 253, 255 (M+, M2H+).
Reaction SMILES: O1CCOCC1.[ClH:7].[F:8][C:9]1([CH3:22])[CH2:13][CH2:12][CH2:11][CH:10]1[NH:14]C(=O)OC(C)(C)C>ClCCl>[ClH:7].[F:8][C:9]1([CH3:22])[CH2:13][CH2:12][CH2:11][CH:10]1[NH2:14]
Reactant: CC(C)(C)OC(=O)NC1CCCC1(C)F
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC1(F)CCCC1N
Reaction time: 1.5 h
Yield: 95.6 %

Procedure:
A 4 M dioxane solution of hydrogen chloride (6.30 mL, 25.2 mmol) was added to a stirred solution of tert-butyl 2-fluoro-2-methylcyclopentylcarbamate (1.0954 g, 5.04 mmol, from Step 4) in dichloromethane (4 mL) at room temperature. After 1.5 h at room temperature, the solvent was evaporated to give 2-fluoro-2-methylcyclopentanamine hydrochloride (740 mg, 96% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-:10])=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:5]=1)([O-])=O>[Pd].O.C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][N+:7]([O-:10])=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:5]=1
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(-c2ccccn2)c1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: Nc1cc[n+]([O-])c(-c2ccccn2)c1
Yield: 84.6 %

Procedure:
A suspension of 2.6 grams (0.012 mole) of 4-nitro-2-(2-pyridinyl)pyridine-N oxide and 0.42 gram of 10% palladium on charcoal in 10 ml of water and 200 ml of ethanol was hydrogenated using a Parr hydrogenator. Upon completion of hydrogenation the reaction mixture was purged with nitrogen gas for one hour, then concentrated under reduced pressure to a residual solid. The solid was triturated with 200 ml of water. The mixture was filtered and the filter cake washed with water. The combined filtrate and wash were concentrated under reduced pressure to a residue. The residue was taken up in 30 ml of ethanol and concentrated under reduced pressure. This procedure was repeated three additional times to remove residual water. The residue was dried under reduced pressure at 60° C. to yield 1.9 grams of 4-amino-2-(2-pyridinyl)pyridine-N oxide as a solid. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[N:10][CH:11]=1.O>S(=O)(=O)(O)O>[F:5][C:6]1[CH:7]=[C:8]([N+:1]([O-:4])=[O:2])[C:9]([OH:12])=[N:10][CH:11]=1
Reactant: Oc1ccc(F)cn1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1cc(F)cnc1O
Temperature: 85 °C
Yield: 60 %

Procedure:
A mixture of nitric acid (70%, 15 ml) and sulfuric acid (15 ml) was slowly added at 5° C.˜10° C. to a solution of 5-fluoro-2-hydroxypyridine (13.0 g, 115 mmol) prepared in Step 2 in sulfuric acid (31 ml). The reaction mixture was heated for 2 hours at 85° C. and then cooled to room temperature. Water was added to the reaction mixture, which was then filtered. The resulting yellow solid was dried to give 11 g of the titled compound as yellow solid. (Yield: 60%).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][OH:9])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=1[C:28]([F:31])([F:30])[F:29].O>CN(C=O)C>[F:29][C:28]([F:30])([F:31])[C:19]1[CH:20]=[C:21]([C:24]([F:27])([F:25])[F:26])[CH:22]=[CH:23][C:18]=1[CH2:17][N:1]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][OH:9])[CH2:3][CH2:2]1
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: OCC1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCC1CCCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of azepan-4-ylmethanol (1.40 g) and potassium carbonate (3.00 g) in DMF (54.2 mL) was added 1-(bromomethyl)-2,4-bis(trifluoromethyl)benzene (2.03 mL). The reaction mixture was stirred at room temperature overnight, poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.901 g).
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([O:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17]([CH:28]([CH3:30])[CH3:29])=[CH:16][C:15]=1[N:31]1[C:35]([C:36]2[CH:41]=[CH:40][C:39]([CH2:42]O)=[CH:38][CH:37]=2)=[CH:34][N:33]=[N:32]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>C(Cl)Cl.CN(C=O)C>[CH2:6]([O:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:17]([CH:28]([CH3:30])[CH3:29])=[CH:16][C:15]=1[N:31]1[C:35]([C:36]2[CH:41]=[CH:40][C:39]([CH2:42][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:38][CH:37]=2)=[CH:34][N:33]=[N:32]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C1COCCN1
Reactant: CC(C)c1cc(-n2nncc2-c2ccc(CO)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)c1cc(-n2nncc2-c2ccc(CN3CCOCC3)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
TEA (160 μl, 1.17 mmol) and MsCl (90 μl, 1.17 mmol) were added to a solution of {4-[3-(2,4-bis-benzyloxy-5-isopropyl-phenyl)-3H-[1,2,3]triazol-4-yl]-phenyl}-methanol (200 mg, 0.39 mmol) in DCM (5 ml) at 0° C. The solution was stirred for 30 minutes at 0° C. and for 12 hours at RT. The solvent was removed under reduced pressure and the reaction crude was dissolved in DMF (3 ml). Morpholine (1.17 mmol) and TEA (160 μl, 1.17 mmol) were added and the reaction mixture was stirred for 12 hours at RT. After standard work-up with AcOEt (4×30 ml) and washing with H2O (2×30 mL) and brine (2×30 ml), the solvent was evaporated under reduced pressure and the crude reaction mixture was purified by column chromatography (PE/AcOEt:20/80) to obtain the desired adduct as an oil.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:14](O)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:14]([N:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2)CC1
Yield: 95.7 %

Procedure:
General procedure A was followed using 1-Boc-piperazine (50 mg, 0.27 mmol), benzoic acid (43 mg, 0.35 mmol), HATU (0.14 g, 0.35 mmol), DIPEA (0.23 ml 1.4 mmol) and DMF (2 mL) to furnish the title compound as a beige solid (75 mg, 98%), m.p. 105-107° C.; umax (CHCl3)/cm−1 3011, 2930, 2866, 1691, 1626, 1421, 1249, 1158; m/z (ESI) C16H22N2NaO3 requires 313.1523, found [M+Na]+ 313.1528.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6](=[O:59])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([NH:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([S:29]([C:32]3[CH:36]=[C:35]([C:37]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[NH:38])[S:34][C:33]=3[S:47][CH3:48])(=[O:31])=[O:30])[CH:24]=2)=[C:18]([NH:49][C:50](=[O:58])[CH2:51][CH2:52][CH2:53][C:54]([O:56]C)=[O:55])[CH:17]=1)=[O:14])C>CO.O>[C:43]([O:42][C:40]([NH:39][C:37](=[NH:38])[C:35]1[S:34][C:33]([S:47][CH3:48])=[C:32]([S:29]([C:25]2[CH:24]=[C:23]([C:19]3[C:20]([CH3:22])=[CH:21][C:16]([NH:15][C:13](=[O:14])[NH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:59])=[O:5])=[CH:17][C:18]=3[NH:49][C:50](=[O:58])[CH2:51][CH2:52][CH2:53][C:54]([OH:56])=[O:55])[CH:28]=[CH:27][CH:26]=2)(=[O:30])=[O:31])[CH:36]=1)=[O:41])([CH3:46])([CH3:44])[CH3:45]
Reactant: CCOC(=O)CCCCCNC(=O)Nc1cc(C)c(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)c(NC(=O)CCCC(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(NC(=O)NCCCCCC(=O)O)cc2NC(=O)CCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.6 %

Procedure:
Lithium hydroxide (53.8 μL, 0.215 mmol, 4N aqueous) was added to a solution of 6-{3-[3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-2-(4-methoxycarbonyl-butyrylamino)-6-methyl-biphenyl-4-yl]-ureido}-hexanoic acid ethyl ester (45.5 mg, 53.8 μmol, Example 278: step d) in MeOH/H2O (10 mL, 2:1) at 0° C. The reaction mixture was warmed to rt and stirred overnight. The solvents were removed in vacuo to afford the title compound as a yellow solid (50 mg, quantitative). ESI-MS (m/z): Calcd. for C36H45N5O1OS3: 804.2 (M+1); found: 803.9.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]([CH3:24])[C:9]2[N:14]=[C:13]3[S:15][C:16]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])=[N:17][C:12]3=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][C:27]=1[C:35]([F:38])([F:37])[F:36].C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:1][C:2]2[CH:3]=[C:4]([N:8]([CH3:24])[C:9]3[N:14]=[C:13]4[S:15][C:16]([NH:18][C:19]([CH:21]5[CH2:22][CH2:23]5)=[O:20])=[N:17][C:12]4=[CH:11][CH:10]=3)[CH:5]=[CH:6][CH:7]=2)=[O:34])=[CH:28][C:27]=1[C:35]([F:36])([F:37])[F:38]
Reactant: CN(c1cccc(N)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1cccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
To a solution of N-{5-[(3-aminophenyl)(methyl)amino][1,3]thiazolo[5,4-b]pyridin-2-yl}cyclopropanecarboxamide (100 mg, 0.295 mmol) produced in Example 8(x) in N,N-dimethylformamide (1.0 mL) was added 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (78.4 mg, 0.354 mmol), and the mixture was stirred at room temperature for 1 hr. Aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The precipitate was collected by filtration and recrystallized from hexane/tetrahydrofuran to give the title compound (118 mg, 72%) as a colorless powder.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[CH:19]1([CH2:25][C:26](O)=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([CH2:25][C:26]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(O)CC1CCCCC1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: O=C(CC1CCCCC1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-cyclohexylacetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (dd, J=7.8, 1.4 Hz, 1H), 8.03 (dd, J=8.1, 1.3 Hz, 1H), 7.97-8.00 (m, 1H), 7.91 (td, J=7.5, 1.3 Hz, 1H), 3.75-3.83 (m, 4H), 3.08-3.10 (m, 4H), 2.16 (d, J=7.0 Hz, 2H), 1.61-1.83 (m, 6H), 0.96-1.28 (m, 5H); MS (ESI−) M/Z 369 (M−H)−.