Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N+:15]([O-])=[CH:14][C:13]3[N:20]=[C:21]([CH2:36][O:37][CH2:38][CH3:39])[N:22]([CH2:23][C:24]([NH:27][C:28]([CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[O:29])([CH3:26])[CH3:25])[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C([N:44]=C=O)=O>ClCCl>[NH2:44][C:14]1[C:13]2[N:20]=[C:21]([CH2:36][O:37][CH2:38][CH3:39])[N:22]([CH2:23][C:24]([NH:27][C:28]([CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)=[O:29])([CH3:25])[CH3:26])[C:12]=2[C:11]2[CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CCOCc1nc2c[n+]([O-])c3ccc(OCc4ccccc4)cc3c2n1CC(C)(C)NC(=O)C1CCCCC1
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccc(OCc4ccccc4)cc3c2n1CC(C)(C)NC(=O)C1CCCCC1
Reaction time: 1 h
Yield: 62.7 %

Procedure:
N-{2-[8-(benzyloxy)-2-(ethoxymethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}cyclohexanecarboxamide (2.41 g, 4.55 mmol) was suspended in dichloromethane (75 mL) and trichloroacetyl isocyanate (0.70 mL, 5.92 mmol) was added dropwise. After stirring for 1 hour, the volatiles were removed under reduced pressure. The resulting orange residue was dissolved in methanol (75 mL) and 6 mL of sodium methoxide (21% in methanol) was added. The reaction was stirred overnight and then the methanol was removed under reduced pressure. The residue was dissolved in dichloromethane and washed with water followed by brine. The organic fraction was dried over sodium sulfate, filtered and concentrated under reduced pressure to give an orange foam. The residue was purified by column chromatography on a HORIZON HPFC system. A silica gel cartridge was used eluting with a gradient of 10-20% CMA in chloroform to yield 1.51 g of N-{2-[4-amino-8-(benzyloxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}cyclohexanecarboxamide as a tan solid. A second purification of the product by column chromatography using the conditions described above provided an analytical sample, mp 90° C.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12](O)=[CH:13][CH:14]=[N:15]2)=[CH:10][CH:9]=1>>[Cl:3][C:12]1[C:11]2[C:16](=[CH:17][C:8]([O:7][CH3:6])=[CH:9][CH:10]=2)[N:15]=[CH:14][CH:13]=1
Reactant: COc1ccc2c(O)ccnc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)ccnc2c1
Temperature: 25 °C

Procedure:
To a solution of POCl3 (11 mL, excess), 7-methoxyquinolin-4-ol (1.87 g, 10.67 mmol) was added and heated from RT to 90° C. The mixture was allowed to cool to RT, concentrated in-vacuo and cooled in an ice bath during the slow adjustment to pH 7 by alternating ice and 1N NaOH. The solid was filtered and rinsed with water. The title compound was isolated as a tan solid.
Reaction SMILES: [CH:1]1[C:11]2[C:10](=S)[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][CH:19]([O:22][CH3:23])[CH2:20][NH2:21]>C(O)CCC>[CH3:17][O:18][CH:19]([O:22][CH3:23])[CH2:20][NH:21][C:10]1[C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[NH:6][C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[N:9]=1
Reactant: S=C1Nc2ccccc2Nc2ccccc21
Reactant: COC(CN)OC
Solvent: CCCCO
Product: COC(CNC1=Nc2ccccc2Nc2ccccc21)OC
Temperature: 25 °C

Procedure:
5,10-Dihydro-11H-dibenzo[b,e][1,4]diazepine-11-thione (33.75 g., 150 mmol.) is suspended in 450 ml. of n-butyl alcohol and treated with 47.25 g. (450 mmol.) of commerical aminoacetaldehyde dimethyl acetal. The reagents are heated for 5.5 hours during which time the solution turns brown. The solution is cooled to room temperature and the solvent is removed in vacuo. The residue is dissolved in 600 ml. of hot ethyl acetate, filtered, concentrated to 400 ml. and cooled to give 36.0 g. (81%) of [(5H-dibenzo[b,e][1,4]diazepin-11-yl)amio]acetaldehyde dimethyl acetal of melting point 181°-182.5° C. A second crop (2.55 g., 5.7%) of melting point 181.5°-184° C. is also collected.
Reaction SMILES: [F:1][CH:2]1[CH:7]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=3)[NH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([CH3:20])[CH2:3]1.O.NN>CO.[Ni]>[F:1][CH:2]1[CH:7]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[NH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([CH3:20])[CH2:3]1
Reactant: CN1CCC(c2c[nH]c3ccc([N+](=O)[O-])cc23)C(F)C1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: CN1CCC(c2c[nH]c3ccc(N)cc23)C(F)C1
Yield: 99.8 %

Procedure:
A solution of compound 135 (0.09 g, 0.324 mmol) in dry methanol (3 mL) was treated with hydrazine hydrate (0.1 mL, 3.245 mmol) followed by Ra—Ni (˜0.05 g) at room temperature. The reaction was placed in a pre-heated oil bath and refluxed for 5 min. The reaction was brought to room temperature, filtered through celite bed and washed with methanol (2×10 mL). The combined methanol layer was evaporated and crude was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 5:95) to obtain compound 136 (0.08 g, quantitative) as a semi-solid. 1H NMR (DMSO-d6) δ 1.78-1.86 (m, 2H), 1.95-2.07 (m, 2H), 2.26 (s, 3H), 2.69-2.78 (m, 2H), 3.11-3.17 (m, 1H), 4.41 (s, 2H), 4.68 (dddd, 1H, J=4.5, 9.9, 9.9, 48.7 Hz), 6.45 (dd, 1H, J=2.1, 8.5 Hz), 6.71 (d, 1H, J=1.5 Hz), 6.93-7.04 (m, 2H), 10.36 (s, 1H); ESI-MS m/z (%): 248 (MH+, 100).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@@H:11]([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:17]([C:19]1[N:20]=[C:21]2[CH:27]=[CH:26][N:25]([S:28]([C:31]3[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[C:22]2=[N:23][CH:24]=1)[NH2:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[S:28]([N:25]1[C:22]2=[N:23][CH:24]=[C:19]([NH:17][NH:18][C:14]([C@@H:11]3[CH2:12][CH2:13][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]3)=[O:16])[N:20]=[C:21]2[CH:27]=[CH:26]1)([C:31]1[CH:32]=[CH:33][C:34]([CH3:35])=[CH:36][CH:37]=1)(=[O:29])=[O:30]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(NNC(=O)[C@@H]4CC[C@@H](NC(=O)OC(C)(C)C)C4)cnc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
To (1R,3R)-3-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (2.25 g, 9.81 mmol, Acros) in DCM (98 mL) was added 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.98 g, 9.81 mmol), HATU (3.73 g, 9.81 mmol) and TEA (5.5 mL, 39 mmol). The reaction mixture was stirred at ambient temperature for about 4 h then diluted with DCM (300 mL). The reaction mixture was washed with water (2×80 mL), saturated aqueous NaHCO3 (80 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The residue was purified using silica gel chromatography (220 g) eluting with a gradient of 50-100% EtOAc in DCM give tert-butyl (1R,3R)-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentylcarbamate (5.03 g, 100%) as a brown solid: LC/MS (Table 1, Method b) Rt=2.18 min; MS m/z: 513 (M−H)−
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])O.[Na+].[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>C(O)C>[CH2:25]([NH:32][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.4 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (300 mg, 1.19 mmol) in ethanol (5 mL) was added sodium hydrogen carbonate (195 mg, 2.32 mmol) and benzylamine (311 mg, 2.90 mmol), and this was heated to reflux with stirring for 4 hours. After the reaction was complete, it was cooled to room temperature and water was added. The precipitated crystals were filtered off, and after washing with water and ethanol the crystals were dried to yield the title compound (347 mg, 84% yield) as orange crystals.
Reaction SMILES: [C:1]([NH:20][C@H:21]([CH2:25][CH3:26])[C:22](=[O:24])[CH3:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][Mg]I.O>CCOCC>[CH3:23][C:22]([OH:24])([C@H:21]([NH:20][C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:25][CH3:26])[CH3:27]
Reactant: C[Mg]I
Reactant: CC[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)=O
Solvent: O
Solvent: CCOCC
Product: CC[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)(C)O

Procedure:
To a stirred solution of (3R)-3-(trityl-amino)-pentan-2-one (0.87 g, 1 eq, 2.54 mmol) in Et2O (100 mL) under an argon atmosphere at room temperature, was added methylmagnesium iodide (3 M in ether, 2.54 mL, 3 eq, 7.62 mmol) dropwise. The solution was placed in a preheated oil bath at 45° C. and refluxed at this temperature for 16 h. The mixture was recooled to 0° C., H2O (100 mL) added, the solution filtered through Celite, and the Celite washed with more Et2O (50 mL). The combined organic phase was separated, the aqueous phase was extracted with Et2O (2×50 mL), and the combined organic phase washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica gel column chromatography, eluted with hexane:ether (100:0→90:10) to afford the title compound as a light yellow oil. Yield: 0.21 g (23%). 1H-NMR (d6-DMSO, 250 MHz): δ 0.26 (t, J=7.42 Hz, —NHCH(CH2CH3)CH(CH3)OH), 1.00 & 1.25 (2×s, 6H, —NHCH(CH2CH3)C(CH3)2OH), 0.72-1.43 (m, 2H, —NHCH(CH2CH3)C(CH3)2OH), 1.84 (m, 1H, —NHCH(CH2CH3)C(CH3)2OH), 2.90 (m, 1H, —NHCH(CH2CH3)C(CH3)2OH), 4.32 (s, 1H, —NHCH(CH2CH3)C(CH3)2OH), 7.17-7.46 (m, 15H, 3×Ph).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([B:8]([OH:10])[OH:9])[CH:7]=1.O[C:13]([C:16](O)([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([B:8]2[O:9][C:16]([CH3:18])([CH3:17])[C:13]([CH3:15])([CH3:14])[O:10]2)[CH:7]=1
Reactant: CC(C)(O)C(C)(C)O
Reactant: OB(O)c1cc(F)ccc1O
Solvent: Cc1ccccc1
Product: CC1(C)OB(c2cc(F)ccc2O)OC1(C)C
Yield: 92 %

Procedure:
To a suspension of (5-fluoro-2-hydroxyphenyl)boronic acid (1.000 g, 0.00641 mol) in toluene (3.0 ml) was added pinacol (0.875 g, 0.007404 mol). This was heated to reflux using a Dean-Stark apparatus for 24 hours before concentrating in vacuo. The residue was suspended in tert-butyl-methyl ether (10.0 ml) and organic layer was washed with saturated aqueous sodium chloride solution (2×10.0 ml), dried over sodium sulphate, filtered and concentrated in vacuo to afford the title compound as a translucent oil, 1.4 g, 92% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:27]COC)=[C:7]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[C:12]=3[N:13]=2)[CH:8]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([OH:27])=[C:7]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[C:12]=3[N:13]=2)[CH:8]=1
Reactant: COCOc1ccc(OC)cc1-c1nc2c(CNCc3ccccn3)cccc2o1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COc1ccc(O)c(-c2nc3c(CNCc4ccccn4)cccc3o2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
A mixture of 2-(5-methoxy-2-methoxymethoxyphenyl)-4-(2-pyridylmethyl)aminomethyl-benzoxazole (F16) (283 mg, 0.70 mmol) and p-toluenesulfonic acid monohydrate (532 mg, 2.8 mmol) in methanol (20 mL) was stirred overnight at room temperature. After the solvent was removed by evaporation, ethyl acetate (20 mL) was added to the resulting residue, neutralized by Na2CO3, washed with brine and water, dried over MgSO4, and concentrated in vacuo. The residue was recrystallized from hot ethanol/hexane to afford the objective compound as a pale yellow crystal (244 mg, 96%); 1H-NMR (500 MHz, CDCl3) δ3.86 (s, 3H), 4.01 (s, 2H), 4.21 (s, 2H), 7.05 (br s, 2H), 7.17 (dd, 1H, J=7.5, 4.5 Hz), 7.33-7.37 (m, 2H), 7.41 (d, 1H, J=7.5 Hz), 7.48-7.51 (m, 2H), 7.66 (t, 1H, J=7.5 Hz), 8.59 (d, 1H, J=4.5 Hz), 11.00 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][S:33]([C:36]3[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=3[F:43])(=[O:35])=[O:34])[C:27]=2[F:44])[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:46]>>[NH2:46][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][S:33]([C:36]3[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=3[F:43])(=[O:35])=[O:34])[C:27]=2[F:44])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Reactant: [NH4+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3F)c(-c3ccnc(N)n3)s2)CC1
Temperature: 90 °C
Yield: 91.8 %

Procedure:
A suspension of 1,1-dimethylethyl 4-[5-(2-chloro-4-pyrimidinyl)-4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-1-piperidinecarboxylate (110 mg, 0.165 mmol) in ammonium hydroxide solution (28%, 2 mL, 51.4 mmol) sealed in a 5-mL microwave tube was heated at 90° C. for 3 h under the microwave conditions. The mixture was concentrated and dried under high vacuum to give 98 mg of the title compound. MS (ESI): 647.3 [M+1]+.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[CH3:9][C:10]([CH3:15])([CH2:13]O)[CH2:11][OH:12]>C1(C)C=CC=CC=1>[CH3:9][C:10]1([CH3:15])[CH2:11][O:12][C:3]2([CH2:4][CH2:5][CH2:6][C:1](=[O:8])[CH2:2]2)[O:7][CH2:13]1
Reactant: CC(C)(CO)CO
Reactant: O=C1CCCC(=O)C1
Solvent: Cc1ccccc1
Product: CC1(C)COC2(CCCC(=O)C2)OC1

Procedure:
125 g (630 mmole) 3,3-dimethyl-1,5-dioxa-spiro[5,5]undecan-8-one, which was obtained by the azeotropic acetylation of cyclohexane-1,3-dione with 2,2-dimethylpropane-1,3-diol in toluene as a solvent using p-toluenesulphonic acid as a catalyst, and 59 g (630 mmole) dimethylammonium methylene chloride were stirred at room temperature in 400 ml of dry acetonitrile. After adding 1 ml acetyl chloride the mixture was stirred for a further 3 hours at room temperature, whereupon a clear colourless solution was obtained. 800 ml of dry ether were then added drop-wise to the reaction mixture, whereupon the hydrochloride crystallised out. 158 g of (18) were obtained (98% theoretical).
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[OH:7])=[O:5])[CH3:2].[OH-].[Na+].Cl[C:18](OCC)=[O:19]>>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([N:6]2[C:4](=[O:5])[N:3]([CH2:1][CH3:2])[C:18](=[O:19])[O:7]2)=[CH:13][CH:12]=1
Reactant: CCNC(=O)N(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Product: CCn1c(=O)on(-c2ccc(Cl)cc2)c1=O
Reaction time: 0.5 h

Procedure:
1-Ethyl-3-(4'-chlorophenyl)-3-hydroxyurea (8.0 g; 0.037 mole) prepared above was dissolved in cooled (10° C.) 2 N aqueous sodium hydroxide (21 ml.). Ethyl chloroformate (3.9 ml; 0.041 mole) was added dropwise at 10°-15° C. with stirring and the stirring was continued for about 1/2 hour after addition was completed. The desired compound precipitated as formed and was removed by filtration, washed with water, air dried, and recrystallized from methanol to yield solid 2-(4'-chlorophenyl)-4-ethyl-1,2,4-oxadiazolidine-3,5-dione as tan needle-like crystals melting 84°-86° C. and having the following elemental analysis as calculated for C10H9ClN2O3 :
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.F[C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17]>CS(C)=O>[N:3]1([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1
Reactant: N#Cc1cccc(F)c1
Reactant: c1ccc2c(c1)CCN2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1cccc(N2CCc3ccccc32)c1
Temperature: 25 °C
Reaction time: 1.08 h

Procedure:
4.63 g (0.0193 mole, 1.1 equiv.) 99% NaH was added in one portion to a stirred solution of 19.8 ml (0.175 mole) indoline in 90 ml sieve dried DMSO under nitrogen at room temperature. After 65 minutes, the mixture was cooled in an ice bath and treated dropwise with a solution of 23.43 g (0.193 mole, 1.1 equiv.) 3-fluorobenzonitrile in 34 ml dry DMSO. The product was permitted to stir overnight at room temperature, poured onto 300 ml ice and extracted with CHCl3. The organic layer was washed five times with water (800 ml portions), dried over MgSO4, and concentrated to give 42.75 g (38.6 g theory) of oil. 2.0 g of the crude product was chromatographed on silica gel (104 g) using ether-hexane thus affording a 0.99 g sample of an oil of pure 3-(1-indolinyl)benzonitrile.
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[NH2:13][C:14]1[C:15]([OH:28])=[C:16]([S:21]([N:24]([O:26][CH3:27])[CH3:25])(=[O:23])=[O:22])[C:17]([Cl:20])=[CH:18][CH:19]=1>C(O)C>[Cl:20][C:17]1[C:16]([S:21]([N:24]([O:26][CH3:27])[CH3:25])(=[O:22])=[O:23])=[C:15]([OH:28])[C:14]([NH:13][C:4]2[C:5](=[O:12])[C:6](=[O:11])[C:7]=2[O:8][CH2:9][CH3:10])=[CH:19][CH:18]=1
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: CON(C)S(=O)(=O)c1c(Cl)ccc(N)c1O
Solvent: CCO
Product: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)OC)c2O)c(=O)c1=O
Temperature: 45 °C
Reaction time: 1 h

Procedure:
A solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (2.83 g, 1.2 equiv) in ethanol (30 ml) was treated with TEA (1.54 g, 1.1 equiv) and the reaction mixture was heated to 45° C. 3-Amino-6-chloro-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide (3.7 g, 1 equiv) was added portion wise over 30 minutes, with vigorous stirring, maintaining the reaction mixture at 45′C. The reaction mixture was stirred at 45° C. for 1 hour and then allowed to cool to RT. The solvent was removed in vacuo and the residue was partitioned between EtOAc (600 ml) and water (2×200 ml). The aqueous portion was separated and extracted with EtOAc (3×200 ml) and the combined organic extracts were washed with water (3×200 ml) and allowed to stand over night. The resulting solid was collected by filtration and dried in vacuo to afford the title compound. The mother liquor was evaporated to give a yellow/brown oily solid which was triturated with ethanol (100 ml). The solid was collected by filtration, washed with EtOH and dried in vacuo to afford the title compound; [M+H]+ 390.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:30](OCC)=[O:31])[N:18]([CH2:28][CH3:29])[C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])=[CH:11][CH:10]=1>>[CH:1]1([NH:7][C:30]([C:17]2[N:18]([CH2:28][CH3:29])[C:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])=[C:15]([C:12]3[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=3)[N:16]=2)=[O:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1CC
Reactant: NC1CCCCC1
Product: CCn1c(C(=O)NC2CCCCC2)nc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1Cl

Procedure:
Using essentially the same procedure as Example 42, Step C, but using neat cyclohexylamine (2 mL), ethyl 4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-1-ethylimidazole-2-carboxylate (30 mg, 0.073 mmol) from Example 42, Step B was converted to the title compound after purification by Prep TLC (25% ethyl acetate in hexanes).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=O)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:17])[CH:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].S(Cl)([Cl:20])=O>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:20])=[CH:13][C:12]([F:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1c[nH]c2ccc(F)cc2c1=O
Product: CCOC(=O)c1cnc2ccc(F)cc2c1Cl
Reaction time: 0.25 h

Procedure:
A mixture of 6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (4.4 g, 18.7 mmol) in thionyl chloride (50 mL) was heated at reflux for 3 hours (at 30 min. mixture changed to a clear solution). The resultant solution was cooled to room temperature, and the excess thionyl chloride was evaporated in vacuo. The residue was added to ammonium hydroxide on ice (note: highly exothermic). Let resultant mixture stir for 15 minutes, and the product was collected by filtration and washed generously with water. The solid was purified by flash chromatography, on silica gel, eluted with a gradient of ethyl acetate (0% to 30%) in heptane, to give the product, 4.24 g (89%) as a colorless solid. MS: m/z 253.8 (MH+).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:15]=[CH:14][C:10]3[NH:11][N:12]=[N:13][C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[N+:16]([O-])([OH:18])=[O:17]>>[N:1]1([CH2:6][C:7]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:10]3[NH:11][N:12]=[N:13][C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1cn(Cc2ccc3[nH]nnc3c2)cn1
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1cc2[nH]nnc2cc1Cn1ccnc1
Reaction time: 8 h
Yield: 1.6 %

Procedure:
2.47 Parts of 5-(1H-imidazol-1-ylmethyl)-1H-benzotriazole were added portionwise to 30 parts of fuming nitric acid while stirring. Upon complete addition, stirring was continued overnight at room temperature. The reaction mixture was poured into 100 parts of crushed ice and nitrogen was bubbled through the mixture during 30 minutes. The precipitated product was filtered off, washed with water and purified by reversed phase chromatography (HPLC) over Li Chroprep RP 18 using a mixture of methanol, acetonitrile and an ammonium acetate solution 0.5% (17:8:75 by volume) as eluent. The desired fraction was collected and the eluent was evaporated. The residue was stirred in methanol and 2,2'-oxybispropane. The precipitated product was filtered off and boiled in methanol. The product was filtered off, washed with methanol and 2,2'-oxybispropane and dried in vacuo at 50°-60° C., yielding 0.05 parts (1.6%) of 5-(1H-imidazol-1-ylmethyl)-6-nitro-1H-benzotriazole; mp. 286.0° C. (decomp.) (compound 235).
Reaction SMILES: C([O:3][C:4]1[CH:5]=[C:6]([C@H:11]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:27][C:28](=[O:31])[CH2:29][OH:30])[C:18]2=[O:32])[CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:7]=[CH:8][C:9]=1[OH:10])C.[Al+3].[Cl-].[Cl-].[Cl-].O>C(Cl)Cl>[OH:3][C:4]1[CH:5]=[C:6]([C@H:11]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:27][C:28](=[O:31])[CH2:29][OH:30])[C:18]2=[O:32])[CH2:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2C(=O)c3cccc(NC(=O)CO)c3C2=O)ccc1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)C[C@H](c1ccc(O)c(O)c1)N1C(=O)c2cccc(NC(=O)CO)c2C1=O
Reaction time: 1 h

Procedure:
To a stirred solution of (S)—N-{2-[1-(3-ethoxy-4-hydroxy-phenyl)-2-methanesulfonyl-ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-2-hydroxy-acetamide (0.55 mmol) in anhydrous CH2Cl2 is added AlCl3 (2.20 mmol) at room temperature. After stirring for 1 hour, water is added. The product is extracted into CH2Cl2. The solvent is removed in vacuo to give crude (S)—N-{2-[1-(3,4-dihydroxy-phenyl)-2-methanesulfonyl-ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-2-hydroxy-acetamide. The product is purified by column chromatography or recrystallization.