Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:22]([C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:33]([N:40]1C=CN=C1)(N1C=CN=C1)=[O:34].CCN(C(C)C)C(C)C.N[OH:55].Cl>C1COCC1.C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:22]([C:23]([CH3:25])([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:33]([NH:40][OH:55])=[O:34])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(CN(CCCCN)Cc2ncccc2C(C)(C)c2ccc(F)cc2)c(C)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NO
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(CN(CCCCNC(=O)NO)Cc2ncccc2C(C)(C)c2ccc(F)cc2)c(C)c1
Temperature: 60 °C
Yield: 60.4 %

Procedure:
To a solution of N1-(3,5-Dimethyl-pyridin-2-ylmethyl)-N1-{3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-butane-1,4-diamine (0.210 g, 0.48 mmol) in dry THF (4 mL) was added 1,1′-carbonyldiimidazole (79 mg, 0.49 mmol), and the resultant solution was stirred room temperature for 30 minutes. The mixture was concentrated and the resultant oil was dissolved in DMF (2 mL), treated with DIPEA (0.50 mL, 2.87 mmol) and NH2OH.HCl (134 mg, 1.93 mmol), and heated at 60° C. overnight. The mixture was cooled to room temperature, diluted with CH2Cl2 (50 mL), washed with brine (3×10 mL), dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (20:21:1 CH2Cl2-MeOH—NH4OH) provided 143 mg (59%) of COMPOUND 149 as a white solid. 1H NMR (CDCl3) δ 1.34 (br s, 4H), 1.65 (s, 6H), 1.93-2.25 (m, 8H), 3.09 (d, 2H, J=5.1 Hz), 3.32 (s, 2H), 3.45 (s, 2H), 6.87-7.09 (m, 5H), 7.21-7.38 (m, 3H), 7.89 (d, 1H, J=7.2 Hz), 8.14 (s, 1H), 8.53 (d, 1H, J=3.3 Hz), 10.27 (br s, 1H); 13C NMR (CDCl3) δ 18.26, 18.75, 23.87, 28.13, 31.51, 39.41, 42.50, 53.98, 57.19, 58.03, 115.56 (d, JC-F=21 Hz), 122.18, 127.72 (d, JC-F=7.5 Hz), 132.12, 132.87, 134.56, 139.50, 143.67, 145.71, 146.71, 146.97, 153.38, 157.78, 161.31 (d, JC-F=243 Hz), 162.84,; ES-MS m/z 494 (M+H). Anal. Calcd. For C28H36N5O2F.0.7H2O: C, 66.43; H, 7.45; N, 13.83; F, 3.75. Found: C, 66.04; H, 7.29; N, 14.22; F, 3.85.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[N:10]([CH3:13])[C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=3[NH:7][C:6]=2[N:18]=1.[H-].[Na+].[CH:21]([N:24]([CH:29]([CH3:31])[CH3:30])[CH2:25][CH2:26][CH2:27]Cl)([CH3:23])[CH3:22]>CN(C)C=O>[CH:21]([N:24]([CH:29]([CH3:31])[CH3:30])[CH2:25][CH2:26][CH2:27][N:7]1[C:8]2[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=2[N:10]([CH3:13])[C:11](=[O:12])[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[N:18][C:6]1=2)([CH3:23])[CH3:22]
Reactant: CC(C)N(CCCCl)C(C)C
Reactant: Cc1ccc2c(n1)Nc1ccccc1N(C)C2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(n1)N(CCCN(C(C)C)C(C)C)c1ccccc1N(C)C2=O
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture consisting of 4.5 gm of 6,11-dihyrdo-2,6-dimethyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one, 60 ml of dimethyl formamide and 1.27 gm of 50% sodium hydride in mineral oil was stirred at 90° C. for 1 hour. Thereafter, 4.6 gm of 3-diisopropylamino-propyl chloride were added dropwise and the mixture was stirred at 120° C. for 2 hours. The reaction solution was then evaporated in vacuo, and the residue was dissolved in a mixture of ether and dilute ammonia. The organic phase was separated, dried over sodium sulfate and evaporated. The oily residue was distilled, and the fraction passing over between 189°-193° C. at 0.13 mm Hg was recrystallized from petroleum ether, yielding 31% of theory of the compound named in the heading, which had a melting point of 118°-119° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[O:17]CC2C=CC=CC=2)[C:6]1=[O:25])(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([O:4][C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[OH:17])[C:6]1=[O:25])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC(=O)N([C@@H]2CCCC[C@H]2OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: CC(=O)O[C@@H]1CC(=O)N([C@@H]2CCCC[C@H]2O)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of acetic acid (1R,2R)-benzyloxycyclohexyl-2,5-dioxo-pyrrolidin-3-(R)-yl ester (3a (1.1 g, 3.18 mmol) in MeOH was added 10% Pd—C (110 mg), and the reaction vessel was flushed twice with H2. The reaction mixture was agitated at ambient temperature under H2 (charged balloon). After 4 hours, the reaction mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo to give acetic acid 1R,2R-hydroxycyclohexyl-2,5-dioxopyrrolidin-3-(R)-yl ester (4a) as a white hygroscopic foam (0.82 g, 99% yield); MS (ES+) 256.1 [M+H]+, 278.0 [M+Na]+, 533.1 [2M+Na]+; 1H-NMR (400 MHz, CDCl3) δ 1.11-1.34 (m, 3H), 1.64-1.75 (m, 3H), 2.02-2.09 (m, 2H), 2.12 (s, 3H, CH3), 2.22 (br s, 1H), 2.63 (dd, 1H, J=18.0 Hz, 4.8 Hz), 3.11 (dd, 1H, J=8.8 Hz, J=18 Hz), 3.82 (ddd, 1H, J=4.16 Hz, J=10.6 Hz, J=12.8 Hz), 4.16 (ddd, 1H, J=4.4 Hz, J=10.4 Hz, J=14.8 Hz), 5.34 (dd, 1H, J=8.8 Hz, J=4.8 Hz); 13C-NMR (100 MHz, CDCl3) δ 20.52, 24.16, 24.98, 27.77, 35.03, 35.40, 58.44, 67.43, 68.40, 170.11, 173.89, 174.08.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH:19]=O)[CH:13]=1)[CH2:8][CH2:9][F:10])([CH3:4])([CH3:3])[CH3:2].[CH:22]1([NH2:25])[CH2:24][CH2:23]1.[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:21])[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH2:19][NH:25][CH:22]2[CH2:24][CH2:23]2)[CH:13]=1)[CH2:8][CH2:9][F:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCF)Cc1ccc(Cl)c(C=O)c1
Reactant: NC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCF)Cc1ccc(Cl)c(CNC2CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
A mixture of (4-chloro-3-formyl-benzyl)-(2-fluoro-ethyl)-carbamic acid tert-butyl ester (850 mg, 2.69 mmol) and cyclopropylamine (0.290 mL, 4.05 mmol) in MeOH (27 mL) was heated to reflux for 4 h. The mixture was allowed to cool to rt, and NaBH4 (153 mg, 4.40 mmol) was added in portions. The mixture was stirred for 1 h. The solvents were removed under reduced pressure, and EtOAc was added. The resulting mixture was washed with aq. sat. NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (CH2Cl2/MeOH 95:5) yielded the title compound (845 mg, 88%). LC-MS: tR=0.76 min; ES+: 357.19.
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.C1C(=O)N([Br:24])C(=O)C1>C(Cl)Cl>[Br:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[C:14]([Br:24])[CH:13]=[CH:12][CH:11]=2
Reactant: Brc1cnc2ccccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: Brc1cnc2cccc(Br)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To concentrated H2SO4 (130 ml) was added dropwise at 0° C., over 80 min, 3-bromoquinoline (50 g) at a rate allowing the internal temperature to be maintained between 0° and 10° C. After the addition was complete, NBS (48 g) was added portionwise and the reaction mixture was stirred at rt overnight. The reaction mixture was poured onto ice (2 l) and the resulting solid was dissolved in DCM (600 ml). The aq. layer was further extracted with DCM (600 ml) and the combined extracts were washed with 1M NaOH (300 ml) and concentrated in vacuo. The residue was adsorbed on SiO2 and the resulting dispersal was loaded on the top of a column and eluted with a DCM-Hex (1-1, 3 l) then DCM (3 l) and finally DCM-ether (1-1, 2 l). The title compound was recovered from the last fraction after evaporation to yield 40 g of a white solid.
Reaction SMILES: C(OC([N:11]1[CH:16]2[CH2:17][N:18]([C:20]([C:22]3[CH:23]=[N:24][C:25]([NH:28][C:29]4[N:30]=[CH:31][C:32]5[CH:37]=[C:36]([C:38](=[O:42])[N:39]([CH3:41])[CH3:40])[N:35]([CH:43]6[CH2:47][CH2:46][CH2:45][CH2:44]6)[C:33]=5[N:34]=4)=[CH:26][CH:27]=3)=[O:21])[CH2:19][CH:12]1[CH2:13][O:14][CH2:15]2)=O)C1C=CC=CC=1.C(CC(OC)=O)C.C1COCC1.[H][H]>[Pd].CO>[CH3:40][N:39]([CH3:41])[C:38]([C:36]1[N:35]([CH:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)[C:33]2[N:34]=[C:29]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([C:20]([N:18]4[CH2:17][CH:16]5[NH:11][CH:12]([CH2:13][O:14][CH2:15]5)[CH2:19]4)=[O:21])=[CH:23][N:24]=3)[N:30]=[CH:31][C:32]=2[CH:37]=1)=[O:42]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5COCC(C4)N5C(=O)OCc4ccccc4)cn3)nc2n1C1CCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCCC(=O)OC
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5COCC(C4)N5)cn3)nc2n1C1CCCC1
Yield: 92.8 %

Procedure:
To a round bottom flask was combined 7-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester (0.461 g, 0.722 mmol), methanol ethyl acetate (12 ml), THF (3 ml), methanol (3 ml), and Pd on C/10%. The mixture was put under a balloon of hydrogen and stirred over night. The mixture was purged with nitrogen followed by addition of methylene chloride. The resultant mixture was filtered through a pad of celite. The celite was washed with additional methylene chloride. The organics were combined and concentrated to a residue. The residue was purified by silica gel chromotography which gave 7-Cyclopentyl-2-[5-(3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-7-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (338 mg, 0.67 mmol) in 93% yield. 1H NMR (400 MHz, CDCl3) δ ppm 8.82 (s, 1H), 8.63 (d, J=8.6 Hz, 1H), 8.56 (s, 1H), 8.47 (d, J=2.0 Hz, 1H), 7.87 (dd, J1=8.78 Hz, J2=2.26 Hz, 1H), 6.51 (s, 1H), 4.83 (m, 1H), 4.47 (s, 1H), 4.09 (m, 4H), 3.77 (s, 1H), 3.45-3.21 (m, 4H), 3.19 (s, 6H), 2.59 (m, 2H), 2.11 (m, 5H), 1.77 (m, 2H); HRMS m/z 505.2665 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([CH3:12])[N:4]([CH3:13])[N:3]=1.F[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:13][N:4]1[C:5]([CH3:12])=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]([NH:1][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[N+:22]([O-:24])=[O:23])=[N:3]1
Reactant: CCOC(=O)c1c(N)nn(C)c1C
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Nc2ccc(F)cc2[N+](=O)[O-])nn(C)c1C
Temperature: 0 °C

Procedure:
Ethyl 3-amino-1,5-dimethylpyrazole-4-carboxylate (5.5 g), 2,5-difluoronitrobenzene (6.6 g) and anhydrous potassium carbonate (8.9 g), were stirred in dimethylsulphoxide (60 ml) under dry nitrogen at 70° C. for 20 hours. The mixture was poured on to 300 ml of ice-cold dilute hydrochloric acid, extracted with chloroform (3×), washed with water (2×), dried with magnesium sulphate and the solvent evaporated under reduced pressure. The yellow-brown residue was crystallised from ethanol to give the title compound having a m.p. of 174° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:12])=[CH:9]/[CH2:10][OH:11])=[CH:4][CH:3]=1.N1C=CN=C1.[C:18]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])([CH3:20])[CH3:19]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[CH3:12])=[CH:9]/[CH2:10][O:11][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:24])[CH3:23])=[CH:6][CH:7]=1
Reactant: C/C(=C\CO)c1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Product: C/C(=C\CO[Si](C)(C)C(C)(C)C)c1ccc(Br)cc1

Procedure:
The colourless oil, (E)-[3-(4-bromophenyl)-but-2-enyloxy]-tert-butyl-dimethylsilane was prepared from (E)-3-(4-bromophenyl)-but-2-en-1-ol (example 50b), imidazole and tert-butyl chlorodimethylsilane by a procedure analogous to that described in example 129b.
Reaction SMILES: [C:1](Cl)(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].ON[N:18]=[CH:19][CH:20]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:21]([NH:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][C:27]([O:32][CH3:33])=[CH:26][C:25]=1[O:34][CH3:35])=[O:22].CC[N:44](C(C)C)C(C)C>C1COCC1>[CH2:2]([C:1]1[O:14][N:44]=[C:19]([CH:20]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:21]([NH:23][C:24]2[C:29]([O:30][CH3:31])=[CH:28][C:27]([O:32][CH3:33])=[CH:26][C:25]=2[O:34][CH3:35])=[O:22])[N:18]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: COc1cc(OC)c(NC(=O)C(C=NNO)c2ccccc2)c(OC)c1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCCCCCCCCCCCC(=O)Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1nc(C(C(=O)Nc2c(OC)cc(OC)cc2OC)c2ccccc2)no1
Yield: 40.9 %

Procedure:
Tridecanoyl chloride (15.08 g, 0.061 mol) was added to a mixture of α-[(hydroxyamino)iminomethyl]-N-(2,4,6-trimethoxyphenyl)-benzene acetamide (19.8 g, 0.055 mol), Hunig's base (10.6 mL, 0.061 mol), and THF (200 mL). The mixture was stirred in THF at room temperature for 2 hours, then concentrated in vacuo and dissolved in glacial acetic acid (50 mL) and refluxed for 2 hours, then concentrated in vacuo, azeotroped with toluene (2×250 mL), and columned on silica gel eluting with 35% ethyl acetate in hexanes to yield a white solid (12.1 g, 62%). %(found): C, 68.93; H, 7.96; N, 7.54.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.[F:12][C:13]([F:19])([F:18])[CH2:14][CH2:15][CH2:16]O>>[F:12][C:13]([F:19])([F:18])[CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: OCCCC(F)(F)F
Reactant: COC(=O)c1ccc(O)cc1
Product: O=C(O)c1ccc(OCCCC(F)(F)F)cc1
Yield: 66.6 %

Procedure:
A reaction similar to that described in Example 1 (1a) was conducted using methyl 4-hydroxybenzoate (1.19 g) and 4,4,4-trifluorobutan-1-ol (1.00 g) to give 1.29 g of the title compound (white powder).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([OH:18])(=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>O>[C:5]([Cl:3])(=[O:18])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: O
Product: CCCCCCCCCCCC(=O)Cl
Temperature: 45 °C
Reaction time: 0.75 h

Procedure:
In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 13.13 ml (180 mmol) of thionyl chloride, and a water condenser, is placed 20.03 g (100 mmol) of dodecanoic acid. Addition of the thionyl chloride is completed with heating to about 45° C. over the course of about 30 minutes. When addition of the thionyl chloride is complete the mixture is heated and stirred for an additional 45 minutes. The water condenser is then replaced with a distillation side arm condenser and the crude mixture is distilled. The crude distillate in the receiving flask is then fractionally distilled to obtain the acyl chloride, dodecanoyl chloride. This acyl chloride, 7.65 g (35 mmol), is put into a dry separatory funnel and combined with 50 ml of dry dichloromethane for use in the next step of the reaction.
Reaction SMILES: [CH:1]([C:3]1([CH2:7][O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]5[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]4[N:40]=[CH:41][N:42]=[C:16]34)[CH2:11][CH2:10]2)[CH2:6][CH2:5][CH2:4]1)=[O:2].Cl([O-])=[O:44].[Na+].P([O-])(O)(O)=O.[Na+].CC(=CC)C>O.O1CCCC1.C(O)CCC>[C:35]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C:19]2[C:20](=[O:21])[N:15]([C@H:12]3[CH2:13][CH2:14][C@H:9]([O:8][CH2:7][C:3]4([C:1]([OH:44])=[O:2])[CH2:6][CH2:5][CH2:4]4)[CH2:10][CH2:11]3)[C:16]3[N:17]([N:40]=[CH:41][N:42]=3)[C:18]=2[CH2:37][CH2:38][CH3:39])=[CH:28][CH:27]=1)#[N:36]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3(C=O)CCC3)CC2)c2ncnn12
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CCCCO
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3(C(=O)O)CCC3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4′-[(4-{trans-4-[(1-formylcyclobutyl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.7 g), sodium chlorite (0.21 g), sodium dihydrogen phosphate (0.15 g), 2-methyl-2-butene (0.53 mL), n-butanol (10 mL), tetrahydrofuran (5 mL) and water (5 mL) was stirred at room temperature for 16 hr. The reaction mixture was extracted with 1 N hydrochloric acid and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.47 g, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([OH:18])=O)=[C:4]([F:19])[CH:3]=1.[H-].[Na+].COS([O:27][CH3:28])(=O)=O.[CH3:29]N(C=O)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[N:11]([CH3:29])[C:10]([CH3:15])=[C:9]2[C:16]([O:27][CH3:28])=[O:18])=[C:4]([F:19])[CH:3]=1
Reactant: CC1=C(C(=O)O)C(c2ccc(Cl)cc2F)CC(=O)N1
Reactant: COS(=O)(=O)OC
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1=C(C)N(C)C(=O)CC1c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 73 %

Procedure:
The product of Example 3 Step 2 (3.0 g, 10.08 mmol, 1.0 equiv) was dissolved in 100 mL DMF and NaH (806 mg, 20.15 mmol, 2.0 equiv) was added slowly to the reaction mixture. Me2SO4 (1.9 mL, 20.15 mmol, 2.0 equiv) was added and the reaction was stirred at room temperature for 45 min. The reaction was quenched with water and filtered. The precipitate was washed with water and air dried to provide 2.29 g (73%) of the title compound as a light yellow solid. MS (ES+) m/e 312 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10](Cl)(=[O:12])=[O:11].[OH:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].CCN(CC)CC>CCOCC>[C:2]1([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([O:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:11])=[O:12]
Reactant: CC(C)(C)OC(=O)NO
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1cc(C)c(S(=O)(=O)ONC(=O)OC(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.4 %

Procedure:
To a solution of 2,4,6-trimethylbenzene-1-sulfonyl chloride (30 g, 0.148 mol) and tert-butyl hydroxycarbamate (18 g, 0.148 mol) in Et2O (500 mL) was added Et3N (15 g, 0.148 mol) dropwise over 1 h. The reaction mixture was stirred at room temperature for 4 h, then filtered. The filtrate was concentrated. The product was purified by silica gel column chromatography (5% v/v EtOAc in PE) to give tert-butyl mesitylsulfonyloxycarbamate as a white solid (31 g, yield 72%). ESI MS: m/z 338 [M+Na]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[I:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][C:2]1[N:3]([CH2:12][C:11]2[CH:14]=[CH:15][C:8]([I:7])=[CH:9][CH:10]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: BrCc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nccn1Cc1ccc(I)cc1
Yield: 44 %

Procedure:
A mixture of 2-methylimidazole (0.66 g, 8.0 mmol), 4-iodobenzyl bromide (J. Am. Chem. Soc, 1949, 71, 3360) (2.38 g, 8.0 mmol) and potassium carbonate (2.21 g, 16 mmol) in acetonitrile (100 ml) was stirred at reflux for 15 hrs. After cooling, precipitates were filtered off and the filtrate was concentrated to dryness. The residue was partitioned between ether (100 ml) and water (100 ml). The ethereal layer was separated, washed with brine (100 ml), dried (magnesium sulfate) and concentrated. Purification by column chromatography (silica-gel, 50 g; methanol in dichloro-methane, increasing the ratio of methanol from 0% to 5%) yielded the titled compound (1.05 g, 44%).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:11]([C:14]1[C:22]2[NH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[N:19][C:18]=2[CH:17]=[C:16]([C:27]([F:30])([F:29])[F:28])[CH:15]=1)([O-:13])=[O:12].[Na]>C(#N)C>[N+:11]([C:14]1[C:22]2[N:21]=[C:20]([C:23]([F:24])([F:25])[F:26])[N:19]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[C:18]=2[CH:17]=[C:16]([C:27]([F:30])([F:29])[F:28])[CH:15]=1)([O-:13])=[O:12]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc2nc(C(F)(F)F)[nH]c12
Agent: [Na]
Solvent: CC#N
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc2c1nc(C(F)(F)F)n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3.5 g. of phenylsulfonyl chloride in 20 m. of anhydrous acetonitrile was added to a solution of 6.4 g. of 4-nitro-2,6-bis(trifluoromethyl)benzimidazole, sodium salt in 50 ml. of anhydrous acetonitrile. The mixture was stirred at room temperature for 2 hours, and the reaction mixture was filtered. The filtrate was evaporated to dryness under vacuum, and the residue was recrystallized from benzenepentane to yield 4-nitro-1-phenylsulfonyl-2,6-bis(trifluoromethyl)benzimidazole, m.p. 183°-185°C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C(N(CC)CC)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(Cl)Cl>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:40])=[O:39])=[CH:34][CH:33]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)CC(CCCCCN)CCCCc1cccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(CCCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCCc1cccnc1

Procedure:
To a solution of 1.0 g of ethyl 8-amino-3-[4-(3-pyridyl)-butyl]-octanoate in 100 ml of methylene chloride is added 3 g of triethylamine followed by the dropwise addition of a solution of 1.5 g of p-chlorophenylsulfonyl chloride in 15 ml of methylene chloride. The reaction mixture is concentrated then directly purified by chromatography on silica gel using 25% ethyl acetate in methylene chloride as eluent to yield ethyl 8-(p-chlorophenylsulfonamido)-3-[4-(3-pyridyl)-butyl]-octanoate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[NH:12][C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].O1CC[CH2:24][CH2:23]1.C(OC(OCC)N(C)C)C>O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH2:23][CH3:24])[C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ccccc12
Reactant: C1CCOC1
Agent: CCOC(OCC)N(C)C
Solvent: O
Product: CCn1c(=O)c2ccccc2n(-c2cccc([N+](=O)[O-])c2)c1=O

Procedure:
A mixture of 2.8 g of 1-(m-nitrophenyl)quinazoline-2,4(1H, 3H)-dione, 40 ml of dry tetrahydrofuran and 4.4 g of N,N-dimethylformamide diethyl acetal was refluxed for 6 hours. After the reaction was complete, the solvent was distilled off from the reaction mixture under reduced pressure. To the residue obtained was added water to precipitate a crude product, which was then recrystallized from methanol to produce 2.8 g of 1-(m-nitrophenyl)- 3-ethylquinazoline-2,4(1H, 3H)-dione as colorless prisms, melting at 193°-194° C.