Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.Cl.[CH2:14]([O:16][C:17](=[O:36])[C@H:18]([CH3:35])[CH2:19][C@H:20]([NH2:34])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)[CH3:15]>C(Cl)Cl>[CH2:14]([O:16][C:17](=[O:36])[C@H:18]([CH3:35])[CH2:19][C@H:20]([N:34]=[C:2]=[O:4])[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:26][CH:27]=1)[CH3:15]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)[C@H](C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)N=C=O
Reaction time: 0.25 h

Procedure:
To a vigorously stirred 1:1 mixture of methylene chloride/8% aqueous NaHCO3 (30 mL) at 0° C. is added triphosgene (114 mg, 0.384 mmol). After stirring the mixture at 0° C. for 5 minutes, (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride (400 mg, 1.15 mmol) is added and stirring is continued for 15 minutes. The organic phase is separated and dried over sodium sulfate. The solvent is removed under reduced pressure to furnish (2R,4S)-5-biphenyl-4-yl-4-isocyanato-2-methyl-pentanoic acid ethyl ester. Next, to a solution of (2R,4S)-5-biphenyl-4-yl-4-isocyanato-2-methyl-pentanoic acid ethyl ester (1.15 mmol) in methylene chloride (10 mL) is added (S)-pyrrolidine-2-carboxylic acid methyl ester (1.15 mmol) and diisopropylethylamine (2.3 mmol). The mixture is stirred at room temperature for 18 hours. The mixture is washed with aqueous 1M HCl and the organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by column chromatography using hexane/methylene chloride to elute the product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:10]=[CH:9]2.[NH2:28][C:29]1[C:30]([C:37]([NH:39][C:40](SC)=[NH:41])=[O:38])=[N:31][C:32]([Cl:36])=[C:33]([NH2:35])[N:34]=1.CCN(C(C)C)C(C)C>CCO>[NH2:28][C:29]1[C:30]([C:37]([NH:39][C:40](=[NH:41])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[CH:12]=[C:11]([O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[CH:10]=[CH:9]3)=[O:38])=[N:31][C:32]([Cl:36])=[C:33]([NH2:35])[N:34]=1
Reactant: CC(C)(C)OC(=O)NCCCOc1ccc2cc(CCCCN)ccc2c1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCOc1ccc2cc(CCCCNC(=N)NC(=O)c3nc(Cl)c(N)nc3N)ccc2c1
Temperature: 70 °C
Yield: 84.2 %

Procedure:
To a solution of carbamate 88 (500 mg, 1.34 mmol) and methyl 3,5-diamino-6-chloropyrazine-2-carbonylcarbamimidothioate (10, 790 mg, 2.01 mmol) in EtOH (30 mL) was added DIPEA (1.75 mL, 9.39 mmol) at room temperature. The reaction mixture was heated at 70° C. in a sealed tube for 2 h, then cooled to room temperature, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 90:9:1 CHCl3/CH3OH/NH4OH) to afford carbamate 89 (660 mg, 84%) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ 7.65 (d, J=7.5 Hz, 2H), 7.56 (s, 1H), 7.31 (dd, J=8.4, 1.5 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 7.08 (dd, J=8.7, 2.4 Hz, 1H), 4.10 (t, J=6.3 Hz, 2H), 2.81 (t, J=6.6 Hz, 2H), 2.01-1.97 (m, 2H), 1.83-1.60 (m, 4H), 1.43 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:12][S:13]([CH2:16][C:17](O)=O)(=[O:15])=[O:14])=[N:7][C:8]=1[N+:9]([O-:11])=[O:10].[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[C:23]=1C=O.C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[N:7][C:6]([CH2:12][S:13](/[CH:16]=[CH:17]/[C:23]2[C:26]([O:32][CH3:33])=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:22]=2[O:21][CH3:20])(=[O:14])=[O:15])=[CH:5][CH:4]=1
Reactant: COc1cc(OC)c(C=O)c(OC)c1
Reactant: COc1ccc(CS(=O)(=O)CC(=O)O)nc1[N+](=O)[O-]
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2ccc(OC)c([N+](=O)[O-])n2)c(OC)c1
Yield: 35.3 %

Procedure:
A mixture of 2-((5-methoxy-6-nitropyridin-2-yl)methylsulfonyl)acetic acid (0.29 g, 1.0 mmol) in dry toluene (2 mL) was added 2,4,6-trimethoxybenz-aldehyde (0.196 g, 1.0 mmol) and acetic anhydride (0.38 mL). After refluxing for 5 hrs, the reaction mixture was evaporated to dryness. The residue was precipitated by adding methanol (15 mL). The precipitate was filtered to give 150 mg (35%) the titled compound as grey coloured powder. 1H-NMR (Acetone-D6): δ 3.92 (s, 9H, 3×OCH3), 4.07 (s, 3H, OCH3), 4.52 (s, 2H, CH2), 6.32 (s, 2H, Ph-H), 7.20 (d, J=15.6 Hz, 1H, CH), 7.74 (d, 1H, J=15.6 Hz, CH), 7.87 (d, 1H, J=8.4 Hz, Py-H), 7.95 (d, 1H, J=8.8 Hz, Py-H); HR-MS (ESI+) m/z 425.1053 [M+1]+ C18H20N2O8S requires 424.0940.
Reaction SMILES: [CH3:1][C:2]([NH2:10])([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH3:22])=[O:20]>C(#N)C>[CH3:1][C:2]([NH:10][CH2:18][C:19]([O:21][CH3:22])=[O:20])([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)CBr
Reactant: CC(C)(N)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CNC(C)(C)c1ccccc1
Reaction time: 24 h
Yield: 58.4 %

Procedure:
13.5 g (0.1 mol) of α,α-dimethylbenzylamine was dissolved in 200 ml of acetonitrile, and 15 g (0.11 mol) of potassium carbonate was added thereto. 15.3 g (0.1 mol) of methyl bromoacetate was gradually dropwise added thereto under cooling with ice. After completion of the dropwise addition, reaction mixture was returned to room temperature and stirred for one day and night. Salts were removed by filtration, and acetonitrile was distilled off under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The ethyl acetate layer was thoroughly washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to distillation to obtain 12.1 g (yield: 60%) of the desired compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH2:16][NH2:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:18](C(OC(C)(C)C)=O)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=O>C1COCC1.CCOC(C)=O>[C:22]([O:21][C:19](=[O:18])[NH:17][CH2:16][C:10]1([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NCC1(c2ccc([N+](=O)[O-])cc2)CCOCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC1(c2ccc([N+](=O)[O-])cc2)CCOCC1

Procedure:
A solution of C-[4-(4-nitro-phenyl)-tetrahydro-pyran-4-yl]-methylamine (as prepared in the previous step) in THF is treated with BOC2O at RT. The mixture is diluted with EtOAc and washed with water. The organic layer is dried (MgSO4) and concentrated in vacuo. The residue is purified by silica gel chromatography with the appropriate solvent to afford the title compound.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.[F:21][CH:22]([F:28])[C:23](OCC)=[O:24]>O1CCCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:23](=[O:24])[CH:22]([F:28])[F:21])[CH:15]=1
Reactant: CCOC(=O)C(F)F
Reactant: Fc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(c1cc(Br)ccc1F)C(F)F
Temperature: -10 °C
Reaction time: 2.5 h
Yield: 91.6 %

Procedure:
A solution of diisopropylamine (12.7 g, 17.9 ml, 126 mmol) and tetrahydrofuran (375 ml) was cooled to −78° C. and n-BuLi (1.6 M in hexane) (78.6 ml, 126 mmol) was added dropwise. After stirring for 10 min commercially available 1-bromo-4-fluorobenzene {CAS[460-00-4]} (20 g, 12.4 ml, 114 mmol) was added dropwise at max. −60° C. Stirring was continued at −70° C. for 2.5 hours. Then ethyl difluoroacetate (17.0 g, 13.7 ml, 137 mmol) was added dropwise and the mixture was warmed to −10° C. and then quenched by pouring the mixture onto 1 M HCl. The mixture was extracted twice with ethyl acetate, dried over sodium sulphate, filtered and evaporated to give a yellow liquid (34 g; 118%). The residue was chromatographed on 200 g silica gel with cyclohexane/ethyl acetate 3:1 to give 1-(5-bromo-2-fluorophenyl)-2,2-difluoroethanone (26.5 g, 105 mmol, 91.6% yield) as a yellow liquid. MS (EI): m/z=252.0 [M]+ and 254.0 [M+2]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl.Cl[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]Cl>C1(C)C(C)=CC=CC=1>[N:1]1([C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: ClCCNCCCl
Reactant: CCOC(=O)c1cccc(N)c1
Agent: Cl
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cccc(N2CCNCC2)c1
Reaction time: 48 h
Yield: 68.4 %

Procedure:
Ethyl 3-aminobenzoate (1.65 g) was dissolved in xylene (20 ml), and bischloroethylamine hydrochloride (1.79 g) was added to the solution. The mixture was heated under reflux with stirring for two days. The solvent was removed from the reaction solution by distillation under the reduced pressure. Water and a saturated aqueous sodium hydrogencarbonate solution were added to the residue, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=9:1-5:1) to give 1.60 g (70.0%) of ethyl 3-piperazin-1-yl-benzoate.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:23](Cl)(=[O:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].Cl>C(Cl)Cl>[C:23]([C:4]1[CH:3]=[CH:2][C:1]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:9][CH:8]=2)=[CH:6][CH:5]=1)(=[O:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: c1ccc(-c2ccc(-c3ccccc3)cc2)cc1
Reactant: CCCCCCCCCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCCCCC(=O)c1ccc(-c2ccc(-c3ccccc3)cc2)cc1
Temperature: 0 °C
Yield: 71.4 %

Procedure:
A reaction vessel was charged with 5.7 g of p-terphenyl and 40 ml of methylene chloride. To this mixture was added 4 g of anhydrous aluminum chloride with stirring at 0° C. A solution of 5.2 g of decanoyl chloride in 10 ml of methylene chloride was added dropwise. After the dropwise addition, the mixture was stirred for 5 hours. The reaction liquid was poured into diluted hydrochloric acid and the mixture was stirred well. Insolubles were collected by filtration, washed and dried to obtain 6.8 g (71%) of 4-decanoyl-p-terphenyl.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13]O)=[N:11][CH:10]=[N:9]2)=[CH:5][CH:4]=1.[CH2:17]([N:19](CC)CC)C.CS(Cl)(=O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13][NH:19][CH3:17])=[N:11][CH:10]=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2ncnc2CO)cc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CNCc1ncnn1Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
[2-(4-Methoxybenzyl)-2H-[1,2,4]triazol-3-yl]methanol (0.50 g, 2.28 mmol) was dissolved in dichloromethane (10 ml), then triethylamine (0.36 ml, 2.60 mmol) was added. With cooling with ice, methanesulfonyl chloride (0.20 ml, 2.58 mmol) was added, followed by stirring at room temperature for 2 hours. The reaction liquid was concentrated, ethyl acetate was added, followed by washing. After drying over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure, and the resulting residue was dissolved in tetrahydrofuran (25 ml), then aqueous methylamine solution (40%, 5 ml) was added. After stirring at room temperature for 3 days, the reaction liquid was concentrated. This was diluted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure to obtain a pale yellow oil (0.44 g, 83%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([O:22][CH:23]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:21])=[C:15]([CH2:18]Cl)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[I-:39].[C:40]1([P:46]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CC(C)=O>[I-:39].[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([O:22][CH:23]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:21])=[C:15]([CH2:18][P+:46]([C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=4)([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12

Procedure:
32.5 g (0.0609 mol) of benzhydryl 7-phenylacetamido-3-chloromethyl-3-cephem-4-carboxylate are dissolved in 330 ml of acetone, and 10.1 g (0.0674 mol) of NaI and 17.6 g (0.0671 mol) of triphenylphosphine are added in succession, with stirring. After the mixture has been stirred at room temperature for 1.5 hours, the insoluble material is removed by filtration with suction and the clear mother liquor is stirred into 1,000 ml of ether. The white flocculent material which precipitates out is filtered off with suction, washed with 300 ml of ether and dried in vacuo.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH2:10][CH2:9]1.[NH2:28][CH2:29][CH2:30][CH2:31][OH:32]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:14]=3[N:13]=[C:12]([NH:28][CH2:29][CH2:30][CH2:31][OH:32])[C:11]=2[CH2:10][CH2:9]1
Reactant: Cc1ccccc1N1CCc2c(Cl)nc3c(OCC(F)(F)F)cccc3c21
Reactant: NCCCO
Product: Cc1ccccc1N1CCc2c(NCCCO)nc3c(OCC(F)(F)F)cccc3c21

Procedure:
1-(2-Methylphenyl)-4-chloro-6-β,β,β-trifluoroethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(500 mg, 1.3 mmol) was dissolved in 3-amino-1-propanol(5.0 ml), and reacted at the same condition of Step 6 in the Example 30 to obtain 496 mg of desired compound as solid in 90% of yield.
Reaction SMILES: [CH2:1]1[CH2:5]OC[CH2:2]1.[H-].[Na+].[C:8]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].C(Br)C=C>O>[CH2:5]([CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:8]([O:16][CH2:17][CH3:18])=[O:15])[CH:1]=[CH2:2]
Reactant: C1CCOC1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C=CCBr
Solvent: O
Product: C=CCC(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a THF suspension (50 ml) containing sodium hydride (0.92 g, 21 mmol, 55% in oil) was added dropwise at 0° C. diethyl malonate (3.2 g, 20 mmol). The reaction liquid was heated to room temperature and stirred for 1 hour. The reaction liquid was stirred overnight together with allyl bromide (2.9 g, 24 mmol). With water added, the reaction liquid was extracted with ether. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried with anhydrous magnesium sulfate. After solvent removal, the residues were purified by silica gel chromatography. Thus there was obtained 2.88 g of diethyl allylmalonate (yields: 72%). This product was identical with commercial one.
Reaction SMILES: [CH2:1]([S:3]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:23])OC2C=CC=CC=2)=[CH:10][CH:9]=1)(=[O:5])=[O:4])[CH3:2].[C:24]1([CH3:42])[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=[C:32]([C:38]([F:41])([F:40])[F:39])[N:31]=2)[CH:25]=1>C(#N)C.CN(C)C1C=CN=CC=1>[C:24]1([CH3:42])[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[C:35]([CH2:36][NH:37][C:15](=[O:23])[NH:14][C:11]3[CH:10]=[CH:9][C:8]([CH2:7][NH:6][S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])=[CH:13][CH:12]=3)=[CH:34][CH:33]=[C:32]([C:38]([F:40])([F:39])[F:41])[N:31]=2)[CH:25]=1
Reactant: CCS(=O)(=O)NCc1ccc(NC(=O)Oc2ccccc2)cc1
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CN)c1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CCS(=O)(=O)NCc1ccc(NC(=O)NCc2ccc(C(F)(F)F)nc2-c2cccc(C)c2)cc1
Temperature: 50 °C
Yield: 44.9 %

Procedure:
To a solution of phenyl 4-(ethylsulfonamidomethyl)phenylcarbamate (74 mg, 0.22 mmol) in acetonitrile (3 mL) was added 4-dimethylaminopyridine (27 mg, 0.22 mmol) and (2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methanamine (59 mg, 0.22 mmol) at room temperature. The reaction mixture was heated to 50° C. for 15 h. TLC showed complete consumption of starting material. The reaction mixture was diluted with water and extracted with ethylacetate. The organic part was washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude was purified by column chromatography to give N-(4-(3-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)ureido)benzyl)ethanesulfonamide (example 82) (50 mg, 45%).
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].C(N(CC)CC)C>C(OCC)C>[CH3:1][C:2]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: CCOCC
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(S(=O)(=O)ONC(=O)OC(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.5 %

Procedure:
A stirred solution of 25.0 grams (0.114 mole) of 2,4,6-trimethylbenzenesulfonyl chloride and 15.3 grams (0.114 mole) of 1,1-dimethylethyl N-hydroxycarbamate in 350 mL of diethyl ether was cooled in an ice-water bath, and 11.4 grams (0.114 mole) of triethylamine was added dropwise. Upon completion of the addition, the reaction mixture was allowed to warm to ambient temperature as it stirred for about 18 hours. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure to a residue, which was slurried with toluene and petroleum ether. The resultant solid was collected by filtration, yielding 25.0 grams of 1,1-dimethylethyl N-(2,4,6-trimethylphenylsulfonyloxy)carbamate. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.[CH2:14]([NH2:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[CH2:14]([NH:32][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: CCCCCCCCCCCCCCCCCCN
Product: CCCCCCCCCCCCCCCCCCNc1ncc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
The synthesis is carried out analogously to Example 1 using 2-chloro-3,5-dinitropyridine (Fluka) and octadecylamine as the starting materials. Octadecylamine is recrystallized several times from ethanol before the synthesis.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[C:6]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[CH:5]2.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH2:28])=[CH:23][CH:22]=1.O>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:28][CH2:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=1)[C:6]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[CH:5]2
Reactant: Clc1nc2ccc(Br)cc2cc1C1CCOCC1
Reactant: COc1ccc(CN)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(CNc2nc3ccc(Br)cc3cc2C2CCOCC2)cc1
Temperature: 130 °C

Procedure:
A glass microwave reaction vessel was charged with 6-bromo-2-chloro-3-(tetrahydro-2H-pyran-4-yl)quinoline (1.46 g, 4.47 mmol) and (4-methoxyphenyl)methanamine (5.80 mL, 44.7 mmol) in N-methyl-2-pyrrolidinone (5.80 mL). The reaction mixture was stirred and heated in a microwave reactor at 130° C. for 180 min. The reaction mixture was poured into water and extracted with EtOAc and DCM. The combined organic extracts were washed with saturated ammonium chloride, water, saturated sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material as a yellow oil. The crude material was purified by silica gel chromatography by eluting with 1:4 to 1:1 EtOAc in hexane, to provide 6-bromo-N-(4-methoxybenzyl)-3-(tetrahydro-2H-pyran-4-yl)quinolin-2-amine as yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:6][C:7]=1[CH3:8].[P:15]([O:22]CC)([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]>C(OCC)(=O)C.CO>[CH3:8][C:7]1[S:6][C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:4][C:3]=1[CH2:2][P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]
Reactant: Cc1sc(N2CCOCC2)nc1CCl
Reactant: CCOP(OCC)OCC
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1nc(N2CCOCC2)sc1C)OCC
Temperature: 160 °C
Reaction time: 20 h
Yield: 98.6 %

Procedure:
A mixture of 4-(4-chloromethyl-5-methyl-1,3-thiazol-2-yl)morpholine (1.2 g), triethyl phosphite (2.1 g) was stirred at 160° C. for 20 hrs. Excess triethyl phosphite was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (2:1, v/v), then ethyl acetate-methanol (10:1, v/v) to give diethyl {[5-methyl-2-(morpholin-4-yl)-1,3-thiazol-4-yl]methyl}phosphonate as a yellow oil (1.7 g, yield 95%). NMR (CDCl3) δ: 1.30 (6H, t, J=7.1 Hz), 2.27 (3H, d, J=4.1 Hz), 3.11 (2H, d, J=20.9 Hz), 3.31-3.43 (4H, m), 3.72-3.85 (4H, m), 3.99-4.20 (4H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)([O-])=O>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1
Reactant: O=[N+]([O-])c1ccncc1N1CCc2ccccc21
Solvent: CCO
Product: Nc1ccncc1N1CCc2ccccc21

Procedure:
A solution of 2,3-dihydro-1-(4-nitro-3-pyridinyl)-1H-indole, N-oxide (4.5 g) in 250 ml ethanol containing 0.5 g platinum oxide was hydrogenated at 50 psi (pounds per square inch) for five hours and thereafter filtered and concentrated to an oil. This oil was purified by flash chromatography (silica, 10% methanol in dichloromethane) to give 4 g oil. This oil was converted to the hydrochloride salt and recrystallized twice from ethanol/ether to give 3 g crystals, d 274°.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([Br:20])=[CH:13]3)[C:5]([NH2:21])=[N:4][CH:3]=1.[N:22]([O-])=O.[Na+]>C(O)(=O)C.O>[Br:20][C:14]1[CH:15]=[N:16][C:17]2[C:12]([CH:13]=1)=[CH:11][C:10]([CH2:9][N:8]1[C:6]3=[N:7][C:2]([Br:1])=[CH:3][N:4]=[C:5]3[N:21]=[N:22]1)=[CH:19][CH:18]=2
Reactant: O=N[O-]
Reactant: Nc1ncc(Br)nc1NCc1ccc2ncc(Br)cc2c1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Brc1cnc2ccc(Cn3nnc4ncc(Br)nc43)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
To a solution of 6-bromo-N2-((3-bromoquinolin-6-yl)methyl)pyrazine-2,3-diamine (300 mg, 0.73 mmol) in 5 mL of acetic acid was added dropwise a solution of NaNO2 (150 mg, 2.17 mmol) in 0.5 mL of water at 20° C. The mixture was stirred at rt overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with DCM/methanol gradient to afford the title compound (130 mg, 42%). 1H-NMR (400 MHz, CDCl3) δ ppm 8.84 (s, 1H), 8.71 (s, 1H), 8.24 (s, 1H), 8.01 (d, 1H), 7.74 (s, 2H), 5.99 (s, 2H). LCMS (method E): [MH]+=421, tR=5.50 min.