Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=2[O:15][CH2:16][CH:17]2[CH2:19][O:18]2)[CH:6]=[CH:7][CH:8]=1.[CH3:24][NH:25][CH3:26]>O1CCCC1>[CH3:24][N:25]([CH3:26])[CH2:19][CH:17]([OH:18])[CH2:16][O:15][C:14]1[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=1[CH2:12][CH2:11][CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: CNC
Reactant: COc1cccc(CCCCc2ccccc2OCC2CO2)c1
Solvent: C1CCOC1
Product: COc1cccc(CCCCc2ccccc2OCC(O)CN(C)C)c1
Yield: 97 %

Procedure:
Following a procedure similar to that described in Example 1(b), a solution of 300 mg of 2-{2-[4-(3-methoxyphenyl) butyl]phenoxymethyl}oxirane [prepared as described in step (a) above] in tetrahydrofuran was reacted with 50% by volume aqueous dimethylamine. After purification as described in Example 1(b), 335 mg (yield 97%) of the title compound were obtained as a colorless oil.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:9][N:10]2[C:13]2[S:14][CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=2)=[CH:6][CH:5]=1.Br[CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.O>CN(C)C=O>[CH:30]1([O:3][C:4]2[CH:12]=[C:11]3[C:7]([C:8]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[N:9][N:10]3[C:13]3[S:14][CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=3)=[CH:6][CH:5]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: BrC1CCCC1
Reactant: CCOC(=O)c1csc(-n2nc(-c3ccccc3)c3ccc(O)cc32)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(-n2nc(-c3ccccc3)c3ccc(OC4CCCC4)cc32)n1
Reaction time: 0.08 h
Yield: 29.1 %

Procedure:
Sodium hydride (added with 40% mineral oil, 13.5 mg, manufactured by Kanto Chemical Co., Inc.) was added to a solution of ethyl 2-(6-hydroxy-3-phenyl-1H-indazol-1-yl)thiazole-4-carboxylate (20 mg), which had been synthesized from the compound of Reference Example 20 according to the method of Example 3, in N,N-dimethylformamide (1 mL, manufactured by Kanto Chemical Co., Inc.) under ice cooling, and the mixture was stirred for 5 minutes at the same temperature. Subsequently, bromocyclopentane (269 mg, manufactured by Kanto Chemical Co., Inc.) was added, and the mixture was stirred overnight at room temperature. Water (10 mL) was added to the reaction solution, and the mixture was extracted with diethyl ether (3×10 mL), washed with brine (10 mL), and dried (MgSO4). The solvent was then evaporated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:1), to give 6.9 mg of the title compound. LC-MS: HPLC retention time 2.13 minutes, m/z 434 (M+H), condition C-1.
Reaction SMILES: O.CS[C:4]1[NH:9][C:8]2[CH:10]=[CH:11][N:12]=[CH:13][C:7]=2[S:6](=[O:15])(=[O:14])[N:5]=1.[CH2:16]([NH2:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].ClC1C=C(C)C=CC=1>>[CH2:16]([NH:24][C:4]1[NH:9][C:8]2[CH:10]=[CH:11][N:12]=[CH:13][C:7]=2[S:6](=[O:15])(=[O:14])[N:5]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCN
Reactant: CSC1=NS(=O)(=O)c2cnccc2N1
Solvent: Cc1cccc(Cl)c1
Solvent: O
Product: CCCCCCCCNC1=NS(=O)(=O)c2cnccc2N1

Procedure:
A mixture of 3-methylsulfanyl-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide monohydrate (0.5 g), octylamine (0.5 mL) and m-chlorotoluene (3 mL) was refluxed for 2-3 h (until completion of the reaction; t.l.c.). Most of the solvents were removed by distillation and the residue was dispersed in a mixture of water (30 mL) and methanol (30 mL) and supplemented with NaOH 10% w/v in water (2 mL). The mixture was treated with charcoal, filtered, and the filtrate was adjusted to pH 6 with 1N HCl. The resulting precipitate was collected by filtration, washed with water and dried (yield: 0.29 g); m.p. 176°-179° C. (Compound 13).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:14]([C:17]1[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=1)([O-:16])=[O:15].Cl>C(OCC)(=O)C>[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([N:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Yield: 47 %

Procedure:
To 12.5 g (0.07 mol) of mechanically stirred 1-benzylpiperazine was added 10.0 g (0.07 mol) of 4-nitrofluorobenzene. After 10 minutes of a mildly exothermic reaction, the mixture solidified. The yellow solid was suspended in 50 mL of ethyl acetate and ethereal HCl was slowly added to the stirring mixture under a nitrogen atmosphere. The solid was collected (filtration) and partitioned between 10% sodium hydroxide solution and benzene. The benzene layer was washed with ten 100 mL portions of water, dried with anhydrous magnesium sulfate and concentrated under reduced pressure to give a yellow oil. Upon cooling, the oil crystallized. The solid was recrystallized from 2-propanol/petroleum ether (60°-110°) to give 9.8 g (47%) of yellow solid, mp 115°-118° C.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([S:22]([CH:24]5[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]5)=[O:23])[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:33]=2)=[N:7][C:6]([CH3:34])=[N:5]1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=[O:36].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([S:22]([CH:24]5[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:28][CH2:29]5)(=[O:36])=[O:23])[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:33]=2)=[N:7][C:6]([CH3:34])=[N:5]1)([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(S(=O)C4CCN(C(C)C)CC4)ccc2OCC3)n(C(C)C)n1
Reactant: O=C(O)C(F)(F)F
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2cc(S(=O)(=O)C4CCN(C(C)C)CC4)ccc2OCC3)n(C(C)C)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice-cooled solution of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-9-(1-isopropylpiperidine-4-sulfinyl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene 206 (35 mg, 0.0731 mmol) in DCM (6 mL) was added TFA (17 μL, 0.306 mmol) followed by a slow addition of a solution of m-CPBA (16 mg, 0.0951 mmol) in DCM (1 mL) and the resulting mixture was stirred for 2 h at 0° C. Volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (C18, gradient 10-40% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3 in MeOH affording 208 as a white solid (24 mg, 66%). LCMS: RT 2.68 min [M+H]+ 499.1. 1H NMR (DMSO, 400 MHz): δ 8.87 (1H, d, J=2.40 Hz), 7.97 (1H, s), 7.71 (1H, dd, J=10.93, 2.38 Hz), 7.30 (1H, d, J=8.63 Hz), 5.70-5.58 (1H, m), 4.68-4.56 (4H, m), 3.20-3.10 (1H, m), 2.84-2.77 (2H, m), 2.68-2.59 (1H, m), 2.27 (3H, s), 2.09 (2H, bt, J=11.46 Hz), 1.91 (2H, bd, J=12.10 Hz), 1.54-1.34 (8H, m), 0.89 (6H, d, J=6.55 Hz)
Reaction SMILES: [C:1]1(=O)N[C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]1(=[O:18])[NH:16][C:15](=[O:17])[CH:14]=[CH:13]1>>[C:15]1(=[O:17])[N:16]([CH:4]2[C:3]3=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]3[CH2:1]2)[C:12](=[O:18])[CH:13]=[CH:14]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C1C=CC(=O)N1
Product: O=C1C=CC(=O)N1C1Cc2ccccc21

Procedure:
An alternative process is that wherein a 3- or 4-halobenzocyclobutene reactant is treated with a phthalimide or maleimide to produce a 3- or 4-phthalimido-or maleimidobenzocyclobutene. When phthalimide or maleimide is monomeric, for example, phthalide or maleimide themselves, the product can be cleaved by reaction with an amine to produce a corresponding aminobenzocyclobutene. A preferred amine for this purpose is hydrazine, preferably hydrazine hydrate.
Reaction SMILES: Cl.[C:2]1([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][C:16](=[NH:20])OCC)[CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][NH:29][C:30]2[C:31](N)=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:24][CH:23]=1>CO>[CH3:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][N:29]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=3[N:20]=[C:16]2[CH2:15][CH:12]2[CH2:11][CH2:10][N:9]([CH2:8][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:14][CH2:13]2)=[CH:26][CH:27]=1
Reactant: CCOC(=N)CC1CCN(Cc2ccccc2)CC1
Reactant: Cc1ccc(CNc2ccccc2N)cc1
Agent: Cl
Solvent: CO
Product: Cc1ccc(Cn2c(CC3CCN(Cc4ccccc4)CC3)nc3ccccc32)cc1
Reaction time: 4 h
Yield: 63 %

Procedure:
A mixture of 116.5 parts of O-ethyl 1-(phenylmethyl)-4-piperidineethanimidate hydrochloride, 61.5 parts of N1 -[(4-methylphenyl)methyl]-1,2-benzenediamine and 400 parts of methanol was stirred and refluxed overnight. Another portion of 40 parts of O-ethyl 1-(phenylmethyl)-4-piperidineethanimidate hydrochloride was added and stirring was continued for 4 hours at reflux. The reaction mixture was evaporated. Water was added to the residue. The solution was treated with ammonium hydroxide. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 74.5 parts (63%) of 1-[(4-methylphenyl)methyl]-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-benzimidazole; mp. 124.2° C. (6).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CCCP(=O)=O>O1CCCC1.C(OCC)(=O)C>[CH3:1][N:2]1[C:6]([C:7]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[O:24])=[C:5]([C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:26])[CH:4]=[N:3]1
Reactant: C1COCCN1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Agent: CCCP(=O)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 44.5 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 276 μmol), morpholine (240 μl, 2.76 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 407 μl, 690 μmol) in tetrahydrofurane (7 ml) is stirred for 3 hours at 70° C. The mixture is diluted with ethyl acetate and washed with sat. aqueous sodium hydrogencarbonate solution and brine. The organic layer is separated, dried with magnesium sulfate and the solvent is evaporated. The residue (76 mg white foam) is triturated with diethylether and ethyl acetate affording 1-methyl-4-(morpholine-4-carbonyl)-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide (53 mg, 44.5%) as a white solid. mp.: 203-207° C. MS: m/z=432.4 (M+H+).
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:17]([CH2:18][CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:16]([CH2:25][O:26][CH2:27][CH3:28])=[N:15][C:9]=3[C:10]([NH2:14])=[N:11][C:12]=2[CH:13]=1.C(N(CC)CC)C.[N:36]1([C:42](Cl)=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>C(Cl)(Cl)Cl>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:17]([CH2:18][CH:19]4[CH2:24][CH2:23][N:22]([C:42]([N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[O:43])[CH2:21][CH2:20]4)[C:16]([CH2:25][O:26][CH2:27][CH3:28])=[N:15][C:9]=3[C:10]([NH2:14])=[N:11][C:12]=2[CH:13]=1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CC1CCNCC1
Reactant: O=C(Cl)N1CCOCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CC1CCN(C(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
A solution of 7-bromo-2-ethoxymethyl-1-(piperidin-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine dihydrochloride (4.0 g, 8.1 mmol) and triethylamine (5.67 mL, 40.7 mmol) in chloroform (300 mL) was cooled to 0° C., and 4-morpholinecarbonyl chloride (0.95 mL, 8.1 mmol) was added dropwise. The reaction was allowed to warm to ambient temperature and stirred overnight before it was diluted with chloroform (200 mL); washed sequentially with water (200 mL), 2 M sodium carbonate (2×200 mL), water (200 mL), and brine (200 mL); and concentrated under reduced pressure. The residue was triturated with ethyl acetate and subsequently recrystallized from acetonitrile to provide 3.64 g of 7-bromo-2-ethoxymethyl-1-{[1-(morpholin-4-ylcarbonyl)piperidin-4-yl]methyl}-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 198-199° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH2:14])=[N:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[CH:16]([C:19]1([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:21][CH2:20]1)[CH:17]=O>C(O)(C)C.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:16]([C:19]4([C:22]5[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=5)[CH2:20][CH2:21]4)=[CH:17][N:14]=3)[N:13]=2)=[CH:6][CH:7]=1
Reactant: Nc1ncc(-c2ccc(F)cc2)nn1
Reactant: COc1ccc(C2(C(Cl)C=O)CC2)cc1
Solvent: CO
Solvent: CC(C)O
Product: COc1ccc(C2(c3cnc4ncc(-c5ccc(F)cc5)nn34)CC2)cc1
Temperature: 90 °C

Procedure:
A mixture of 6-(4-fluorophenyl)-1,2,4-triazin-3-amine (20.1 mg, 0.106 mmol) and chloro[1-(4-methoxyphenyl)cyclopropyl]acetaldehyde (53 mg, 0.24 mmol) in isopropyl alcohol (0.6 mL) was heated to 90° C. overnight. After cooling, the mixture was diluted with methanol and was purified by mass-guided RP-HPLC to afford the desired product. LCMS: (M+H)=361.1.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:19])[NH:12][CH2:13][CH2:14][C:15]([O:17]C)=[O:16])[S:2]1.CO.[OH-].[Na+]>O1CCCC1>[S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:19])[NH:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[S:2]1
Reactant: COC(=O)CCNC(=O)NCCCCC1CCSS1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCNC(=O)NCCCCC1CCSS1
Yield: 63.8 %

Procedure:
The reaction was effected as described in Example 48, but using 115 mg of methyl 3-{3-[4-(1,2-dithiolan-3-yl)butyl]ureido}propionate (prepared as described in Example 54), 3 ml of methanol, 2 ml of tetrahydrofuran and 1.40 ml of a 1N aqueous solution of sodium hydroxide. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue. The resulting mixture was neutralized by the addition of 2N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure and the crystals so precipitated were collected by filtration, to give 70 mg of the title compound as a yellow powder, melting at 108 to 110° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[O:9].C([O-])(=S)C.[K+].O>CC(C)=O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9]
Reactant: O=CCCCCCCBr
Agent: CC([O-])=S
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: OCCCCCCCBr
Temperature: 25 °C

Procedure:
To a solution of crude 7-bromoheptanal (Enders and Bartzen (1991) Liebigs Ann. Chem, 569–574) (3.32 g, 17.2 mmol) in acetone (50 mL) was added potassium thioacetate (2.36 g, 21 mmol) under stirring at rt. Then the mixture was refluxed, yielding a precipitate after a few minutes. The reaction was monitored by TLC and cooled to rt when no starting material was detectable (4 h). Water (50 mL) was added, the mixture was extracted with ethyl ether until the organic phase was colorless, and the combined organic phases were dried (Na2SO4) and evaporated. Distillation at 98° C. with a water suction pump afforded 1.66 g (51%, 42% from 7-bromoheptanol) of a yellow oil. IR (neat): {tilde over (v)} 2938, 2857, 2721, 1725, 1694; 1H NMR δ 1.28–1.43 (m, 4H), 1.53–1.69 (m, 4H), 2.33 (s, 3H), 2.43 (dt, 3J=7.3 Hz, 3J=1.5 Hz, 2H), 2.86 (t, 3J=7.3 Hz, 2H), 9.77 (t, 3J=1.5 Hz, 1H); 13C NMR (APT) δ 21.6 (+), 28.1 (+), 28.3 (+), 28.6 (+), 29.0 (+), 30.3 (−), 43.3 (+), 195.4 (+), 202.0 (−); GC-MS (EI) obsd 188, 187, 145, 128, 112, 94, 43.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C([OH:15])C.[ClH:16]>CCOCC>[ClH:16].[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11](=[NH:12])[OH:15])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(CC#N)cc1
Reactant: CCO
Agent: Cl
Solvent: CCOCC
Product: CC(C)c1ccc(CC(=N)O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of 4-isopropylphenylacetonitrile (2 g, 12.5 mmol) in anhydrous ether (50 mL) was added absolute ethanol (0.5 g, 12.5 mmol) and an excess of HCl gas was passed into the solution with cooling in an ice bath. The resulting solution was allowed to stir at 0° C. for 1.5 hours and at room temperature overnight. The white solid was collected by filtration, washed with ether (2×20 mL) and dried to give 2.52 g (84%) of 4-isopropylphenylacetimidate hydrochloride as white crystals, mp 118-120° C. A solution of ethylenediamine (1.25 g, 20 mmol) in absolute ethanol (5 mL) was added to a solution of the imidate hydrochloride (2.5 g, 10 mmol) in absolute ethanol (15 mL) cooled at ice-bath temperature. After stirring at 0° C. for 1 hour, the solution was heated at reflux for 20 minutes. The solvent was evaporated and the oily residue was washed with water (2×3 mL) and extracted with methylene chloride (3×15 mL). The solution was dried (MgSO4), filtered and evaporated under reduced pressure to afford 2 g of the free base of the title compound. A solution of the free base in anhydrous ether was treated with dry HCl gas. The crude salt was collected and recrystallized from ethanol/ether to give 1.95 g (79%) of the title compound as a white solid. mp 176-178° C.; Anal. C13H18N2.HCl: C, H, N.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH3:23][NH2:24]>C(Cl)Cl.CCOCC>[CH3:23][NH:24][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN
Reactant: O=C(O)CCCCCCCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CNC(=O)CCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 8-phenyl octanoic acid (28.6 g, 129.8 mmol, 1 eq) in CH2Cl2 (100 mL) cooled to 0° C. was added oxalyl chloride (17 mL, 195 mmol, 1.5 eq) dropwise via an addition funnel over 30 minutes. Upon the completion of the addition, the ice bath was removed and the reaction was stirred at rt for 2 h. It was then heated at reflux for 30 minutes. The reaction was cooled to rt and concentrated in vacuo to afford a yellow oil. It was added as a solution in Et2O (100 mL) to a solution of condensed methyl amine (˜20 mL) in Et2O (200 mL) at −78° C. Immediately, a white precipitate formed. The cold bath was removed and the reaction was allowed to stir overnight warming to rt under a stream of N2. The residue was washed with Et2O and concentrated to afford N-methyl-8-phenyloctanamide (25.2 g, 83%) as a yellow-white solid. 1H NMR.(CDCl3) δ 7.68-7.10 (m, 5H); 5.42 (bs, 1H); 3.80 (m, 3H); 2.60 (m, 2H); 2.18 (m, 2H); 1.60 (m, 4H); 1.30 (m, 8H).
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=3)[NH:12][C:11]=2[C:20]([NH2:22])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][S:24]([CH3:23])(=[O:26])=[O:25])[CH:17]=3)[NH:12][C:11]=2[C:20]([NH2:22])=[O:21])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: NC(=O)c1[nH]c2ccc(N)cc2c1S(=O)(=O)c1ccccc1
Product: CS(=O)(=O)Nc1ccc2[nH]c(C(N)=O)c(S(=O)(=O)c3ccccc3)c2c1

Procedure:
Reaction of 3-phenylsulfonyl-5-aminoindole-2-carboxamide with methanesulfonyl chloride under the conditions of Example 47 provides the title compound.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].[NH2:16][OH:17].C([O-])(=O)C.[Na+]>C(O)C.O>[C:1](=[N:16][OH:17])([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: NO
Reactant: CC(=O)c1nccc(-c2ccccn2)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=NO)c1nccc(-c2ccccn2)n1
Yield: 91.1 %

Procedure:
A solution of 2-acetyl-4-(pyrid-2-yl)-pyrimidine (1.0 g), hydroxylamine (0.39 g) and sodium acetate (0.62 g) in a mixture of ethanol (10 ml) and water (2 ml) was heated to reflux for 1.5 hours. The reaction was then poured into water the precipitate filtered and washed with hexane to give 2-acetyl-4-(pyrid-2-yl)-pyrimidine oxime (0.98 g, 91% yield) as a white crystalline solid m.p. 196°-8° C.; 1H NMR: 2.50(3H,s); 7.42(1H,m); 7.88(1H,m); 8.30(1H,d); 8.59(1H,d); 8.74(1H,d); 8.90(1H,d); 10.85(1H,brs) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C@@H:17]([CH3:21])[C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH3:22][NH:23][CH3:24]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([C@@H:17]([CH3:21])[C:18]([N:23]([CH3:24])[CH3:22])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CNC
Reactant: C[C@@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Solvent: C1CCOC1
Product: C[C@@H](C(=O)N(C)C)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
A solution of (S)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0166 mole), 1,1'-carbonyldiimadazole (3.21 g, 0.0198 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for 3 hours with nitrogen bubbling through it. A solution of dimethylamine (2.26 g, 0.050 mole) in tetrahydrofuran (20 ml) was added and the reaction mixture was stirred at room temperature under nitrogen overnight. The mixture was evaporated to an oil and partitioned between ethyl acetate (50 ml) and water (50 ml). The layers were separated and the aqueous layer was re-extracted with ethyl acetate. The combined organic layers were washed once with water (50 ml), twice with 5% potassium hydroxide solution (50 ml portions), and once more with water (50 ml). Drying over magnesium sulfate, treatment with charcoal, filtration and evaporation of the solvents gave a residue which upon recrystallization from hot isopropyl ether and drying under high vacuum gave 3.20 g (59%) of title compound, mp 124°-126° C.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[C:7](Br)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]>CC(C)=O>[CH2:7]([O:8][C:11]1[CH:10]=[C:9]([CH:14]=[C:13]([O:4][CH2:1][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:12]=1)[CH:7]=[O:8])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(Br)c1ccccc1
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Yield: 34 %

Procedure:
To a mixture of DHBD (24.4 g, 177 mmol) and potassium carbonate (12.2 g, 88.5 mmol) heated at reflux under argon in dry acetone (200 ml) was added dropwise over 12 hours a solution of BzBr (43.4 g, 30.2 ml, 248 mmol) in dry acetone (30 ml). Thin layer chromatography showed very little DHBD after the addition was complete. The reaction mixture was evaporated to dryness and the residue partitioned between dichloromethane/water. The aqueous layer was further extracted with dichloromethane (3×100 ml) and the combined dichloromethane layers extracted with aqueous sodium hydroxide (1N, 3×100 ml). Evaporation of the dichloromethane layers gave 18.1 g of essentially pure 3,5-dibenzyloxybenzaldehyde (34.0% based on DHBD). The sodium hydroxide extracts were acidified with glacial acetic acid, extracted with chloroform (3×100 ml), and the combined chloroform extracts dried and evaporated to dryness. The residue was recrystallized from methanol/water to give 14.5 g of compound XVI (36.0% based on DHBD).