Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][C@H:21]4[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:23]([C:34](O)=[O:35])[CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12>C1COCC1>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][C@H:21]4[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[C@H:23]([CH2:34][OH:35])[CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)C[C@H]1C(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)C[C@H]1CO
Temperature: 0 °C
Yield: 57.6 %

Procedure:
(2S,4S)-4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (Example 53; 0.250 g, 0.511 mmol) and THF (5.0 mL) was stirred for 10 minutes (until solution was complete) and cooled to 0° C. BH3—SMe2 (0.242 mL, 2.55 mmol) was added and the mixture was warmed to ambient temperature and for 48 hours. The reaction was carefully quenched with MeOH (1 mL) and concentrated. The residue was taken up in CH2Cl2 (20 mL), water (5 mL) and saturated aqueous Na2CO3 (5 mL). The layers were mixed and separated and the aqueous phase was washed with CH2Cl2 (10 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting solid was slurried in 25% CH2Cl2/Et2O and filtered to provide 0.140 g (57%) of the desired product as a yellow solid.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].CS(O[CH2:39][CH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1)(=O)=O>>[CH:40]1([CH2:39][N:25]([S:26]([CH3:29])(=[O:27])=[O:28])[NH:24][C:22](=[O:23])[C@@H:21]([C@@H:11]([C:9](=[O:10])[NH:8][OH:7])[CH2:12]/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:30][CH:31]([CH3:32])[CH3:33])[CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: CC(C)C[C@@H](C(=O)NNS(C)(=O)=O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Reactant: CS(=O)(=O)OCC1CCCC1
Product: CC(C)C[C@@H](C(=O)NN(CC1CCCC1)S(C)(=O)=O)[C@H](C/C=C/c1ccccc1)C(=O)NO

Procedure:
The starting material was prepared in an analogous manner to that described in Example 15, part (iii), starting from (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-(methanesulphonyl)-4-methylvalerohydrazide and cyclopentylmethyl methanesulphonate.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]([N+]([O-])=O)[CH3:11])=[CH:5][CH:4]=1.Cl.[OH2:16]>C(Cl)(Cl)Cl>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:16])[CH3:11])=[CH:5][CH:4]=1
Reactant: O
Reactant: CSc1ccc(C=C(C)[N+](=O)[O-])cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CSc1ccc(CC(C)=O)cc1
Reaction time: 4 h

Procedure:
A stirred mixture of crude 1-methylsulfanyl-4-(2-nitro-propenyl)-benzene (27a) (28.8 mmol) iron filings (6.25 g, 112 mmol) and ferric chloride hexahydrate (0.155 g, 0.57 mmol) in water (20 ml) is heated to reflux. Concentrated hydrochloric acid (10 ml) is added over 2 hours the reflux continued for 4 hours. After 18 hours at room temperature the reaction is diluted with water and chloroform. The mixture is filtered through celite and the organic extract is separated. The aqueous extract is extracted with chloroform and the combined organic extracts are dried (MgSO4). The solvent is removed and the residue is purified by chromatography on silica eluting with hexane-ethyl acetate (3:1) to afford the title compound (2.65 g).
Reaction SMILES: [CH:1]1([C:5]2[O:9][C:8]([NH:10][C:11]3[CH:12]=[N:13][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]56[CH2:30][CH2:29][C:26]([CH:31]=[CH:32][O:33]C)([CH2:27][CH2:28]5)[CH2:25][O:24]6)=[CH:19][CH:18]=4)=[CH:15][CH:16]=3)=[N:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl>O1CCCC1>[CH:1]1([C:5]2[O:9][C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]56[CH2:28][CH2:27][C:26]([CH2:31][CH:32]=[O:33])([CH2:29][CH2:30]5)[CH2:25][O:24]6)=[CH:19][CH:18]=4)=[N:13][CH:12]=3)=[N:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC=CC12CCC(c3ccc(-c4ccc(Nc5nnc(C6CCC6)o5)cn4)cc3)(CC1)OC2
Agent: Cl
Solvent: C1CCOC1
Product: O=CCC12CCC(c3ccc(-c4ccc(Nc5nnc(C6CCC6)o5)cn4)cc3)(CC1)OC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-cyclobutyl-N-(6-(4-(4-(2-methoxyvinyl)-2-oxabicyclo[2.2.2]octan-1-yl)phenyl)pyridin-3-yl)-1,3,4-oxadiazol-2-amine (10 mg, 0.022 mmol) in tetrahydrofuran (1 ml) at room temperature, was added 1N aqueous HCl solution (0.436 ml, 0.436 mmol). The reaction mixture was stirred for 1 h at room temperature. Most of solvent was removed by evaporation under vacuum, and the residue was purified by flash chromotography to afford 2-(1-(4-(5-((5-cyclobutyl-1,3,4-oxadiazol-2-yl)amino)pyridin-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)acetaldehyde intermediate.
Reaction SMILES: [OH-].[K+:2].[Cl:3][C:4]1[C:8]([Cl:9])=[C:7]([C:10]([OH:12])=[O:11])[S:6][N:5]=1>O.C(O)C>[Cl:3][C:4]1[C:8]([Cl:9])=[C:7]([C:10]([O-:12])=[O:11])[S:6][N:5]=1.[K+:2]
Reactant: O=C(O)c1snc(Cl)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C([O-])c1snc(Cl)c1Cl

Procedure:
Potassium hydroxide (0.27 g) dissolved in 3 ml of water was added to a solution of 3,4-dichloroisothiazole-5-carboxylic acid (0.95 g) in 4 ml of ethanol. The solvent was distilled off under reduced pressure. The crystals thus obtained were washed with a small quantity of ethanol.
Reaction SMILES: [C:1]1([C@@H:7]2[C:9]3([CH2:13][CH2:12][CH2:11][CH2:10]3)[C@H:8]2[C:14]([OH:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[NH2:28]>>[C:1]1([C@@H:7]2[C:9]3([CH2:10][CH2:11][CH2:12][CH2:13]3)[C@H:8]2[C:14]([NH:28][C:19]2[CH:20]=[CH:21][C:22]([C:24]([F:25])([F:26])[F:27])=[CH:23][C:18]=2[Cl:17])=[O:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)[C@H]1[C@H](c2ccccc2)C12CCCC2
Reactant: Nc1ccc(C(F)(F)F)cc1Cl
Product: O=C(Nc1ccc(C(F)(F)F)cc1Cl)[C@H]1[C@H](c2ccccc2)C12CCCC2
Yield: 57 %

Procedure:
trans-2-Phenylspiro[2.4]heptane-1-carboxylic acid (300 mg, 1.39 mmol) and 2-chloro-4-trifluoromethyl-phenylamine (272 mg, 1.39 mmol) were reacted as described under General Procedure D to furnish the title compound (312 mg, 57%) as a white solid. 1H NMR (300 MHz, d6-DMSO) δ 9.91 (s, 1H), 8.20 (d, J=8.5 Hz, 1H), 7.89 (d, J=1.6 Hz, 1H), 7.67 (d, J=8.5, 1.6 Hz, 1H), 7.31 (t, J=7.3 Hz, 2H), 7.22-7.16 (m, 3H), 2.80 (d, J=5.7 Hz, 1H), 2.70 (d, J=5.7 Hz, 1H), 1.82-1.73 (m, 2H), 1.66-1.42 (m, 5H), 1.29-1.10 (m, 1H). mp 131-133° C. ESIMS m/z [M+H]+ 394.3.
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH3:16][N:17]([CH3:36])[CH2:18][CH2:19][NH:20][C:21]1[N:22]=[N+:23]([O-:35])[C:24]2[CH:34]=[C:33]3[C:28]([CH2:29][CH2:30][CH2:31][O:32]3)=[CH:27][C:25]=2[N:26]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[O-:35][N+:23]1[C:24]2[CH:34]=[C:33]3[C:28](=[CH:27][C:25]=2[N+:26]([O-:4])=[C:21]([NH:20][CH2:19][CH2:18][N:17]([CH3:36])[CH3:16])[N:22]=1)[CH2:29][CH2:30][CH2:31][O:32]3
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CN(C)CCNc1nc2cc3c(cc2[n+]([O-])n1)OCCC3
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCNc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CCCO3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 25.8 %

Procedure:
H2O2 (70%, 0.47 mL, ca. 9.3 mmol) was added dropwise to a stirred solution of TFAA (1.3 mL, 9.3 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 241 (270 mg, 0.9 mmol) and TFA (0.36 mL, 4.7 mmol) in DCM (15 mL) at 0° C. The solution was stirred at 20° C. for 4 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 242 (71 mg, 22%) as a red solid: mp (MeOH/EtOAc) 152-154° C.; 1H NMR δ 7.99 (s, 1H, H-5), 7.61 (s, 1H, H-10), 7.27 (br s, 1H, NH), 4.30 (br dd, J=5.3, 5.2 Hz, 2H, H-8), 3.62 (br t, J=5.9 Hz, 2H, CH2N), 3.05 (br t, J=6.3 Hz, 2H, H-6), 2.62 (t, J=6.0 Hz, 2H, CH2N), 2.31 [s, 6H, N(CH3)2], 2.05-2.12 (m, 2H, H-7); 13C NMR δ 154.7, 148.7, 136.2, 133.2, 130.1, 117.4, 105.2, 67.1, 57.6, 45.1 (2), 38.8, 26.1, 21.3. Anal. calcd for C14H19N5O3.½H2O: C, 52.7; H, 6.5; N, 22.0. Found: C, 53.0; H, 5.9, 21.6%.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]1[C:23]1[C:24]([O:33][CH3:34])=[CH:25][C:26]([O:31][CH3:32])=[C:27]([CH:30]=1)[CH:28]=O>>[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]1[C:23]1[C:24]([O:33][CH3:34])=[CH:25][C:26]([O:31][CH3:32])=[C:27](/[CH:28]=[CH:2]/[C:1]([C:4]2[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=2)=[O:3])[CH:30]=1
Reactant: COc1cc(OC)c(-c2cc3ccccc3[nH]2)cc1C=O
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Product: COc1cc(OC)c(-c2cc3ccccc3[nH]2)cc1/C=C/C(=O)c1ccc(S(N)(=O)=O)cc1
Yield: 70 %

Procedure:
The title compound was prepared by condensing 4-acetyl-benzenesulfonamide (Ex-26A) and 5-(1H-indol-2-yl)-2,4-dimethoxy-benzaldehyde (Ex-61A) in a similar manner as described in Ex-22. Red solid, 70% yield, mp 185–187° C. 1H-NMR (DMSO-d6) δ 11.15 (br, s, 1H), 8.33 (s, 1H), 8.24 (d, J=8 Hz, 2H), 8.07 (d, J=15 Hz, 1H), 7.98 (d, J=8 Hz, 2H), 7.80 (d, J=15 Hz, 1H), 7.41–7.55 (m, 4H), 7.03–7.08 (m, 1H), 6.93–6.99 (m, 2H), 6.83 (s, 1H), 4.04 (s, 3H), 3.99 (s, 3H). MS m/z=463 ([M+H]+). HRMS (ES+) Calcd. for C25H22N2O5S: 463.1327. Found: 463.1316.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[ClH:16].CS(C)=[O:19]>>[ClH:16].[NH2:1][CH:2]([CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=[O:19])[C:13]([OH:15])=[O:14]
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CS(C)=O
Agent: Cl
Product: NC(CC1C(=O)Nc2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.2 Grams of L-tryptophane was suspended in 7.8 g of dimethyl sulfoxide, then 16.6 ml of concentrated hydrochloric acid was added all at once in the suspension, and the mixture was stirred at a room temperature overnight. The crystals formed in the reaction mixture were collected by filtration, then washed with acetone and dried to obtain 9.8 g of 2-amino-3-(oxindol-3-yl)propionic acid hydrochloride. [α]D20 +22.5° (C=1, methanol)
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: COc1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cccc(CN2CC[C@@H](NC(=O)OC(C)(C)C)C2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl (3R)-3-pyrrolidinylcarbamate (450 mg) and 3-methoxybenzaldehyde (352 uL) in CH2Cl2 (4.5 mL) was added sodium triacetoxyborohydride (922 mg), which was stirred at room temperature for 2 hours. To the resultant was added sat. NaHCO3 aq., which was stirred for 20 min. The mixture was extracted with CH2Cl2. The organic phase was washed with brine and dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give tert-butyl [(3R)-1-(3-methoxybenzyl)-3-pyrrolidinyl]carbamate (744 mg) as a off-white solid.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C(N(CC)CC)C.[NH2:17][C:18]1[CH:40]=[CH:39][C:21]([C:22]([N:24]2[CH2:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[CH2:27][C:26]3[CH:35]=[CH:36][CH:37]=[CH:38][C:25]2=3)=[O:23])=[CH:20][CH:19]=1>C(Cl)Cl>[CH:35]1[C:26]2[CH2:27][C:28]3[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=3[CH2:30][N:24]([C:22]([C:21]3[CH:20]=[CH:19][C:18]([NH:17][C:7]([CH:1]4[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]4)=[O:8])=[CH:40][CH:39]=3)=[O:23])[C:25]=2[CH:38]=[CH:37][CH:36]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: O=C(Cl)C1CC=CCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)C1CC=CCC1
Reaction time: 18 h
Yield: 67.1 %

Procedure:
A mixture of 208 mg of 3-cyclohexene-1-carbonyl chloride (prepared from 3-cyclohexene-1-carboxylic acid and thionyl chloride) and 145 mg of triethylamine in 3 ml of methylene chloride is added to a solution of 377 mg of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine in 7 ml of methylene chloride. The mixture is stirred for 18 hours, washed with water, 1N HCl, water, 1M NaHCO3 and brine then dried with Na2 SO4. The organic layer is passed through a short column of hydrous magnesium silicate and hexane added to the filtrate at the boil to give 340 mg of the desired product as a crystalline solid, m.p. 234°-236° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]1[C:13]([O:15]CC)=O.[O-]CC.[Na+]>C(O)C>[C:13]1(=[O:15])[C:5]2=[CH:6][C:7]3[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=3[N:4]2[CH2:3][CH2:2][NH:1]1
Reactant: CCOC(=O)c1cc2c(n1CCN)CCCC2
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1NCCn2c1cc1c2CCCC1
Temperature: 55 °C
Reaction time: 5 h
Yield: 41.7 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was purged with nitrogen and charged with 101d (1.80 g, 7.63 mmol), sodium ethoxide (1.55 g, 22.8 mmol) and ethanol (50 mL). The mixture was stirred at 55° C. for 5 h. After that time, the reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (200 mL) and water (100 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to afford a 42% yield (605 mg) of 3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one 101e as a white solid: mp 207-209° C.; 1H NMR (500 MHz, DMSO-d6) δ 7.41 (s, 1H), 6.36 (s, 1H), 3.84 (t, 2H, J=6.0 Hz), 3.42 (m, 2H), 2.51 (t, 2H, J=6.0 Hz), 2.42 (t, 2H, J=6.0 Hz), 1.76 (m, 2H), 1.65 (m, 2H); (APCI+) m/z 191.3 (M+H)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][N:11]2[CH:15]=[N:14][N:13]=[CH:12]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:10]([N:11]2[CH:15]=[N:14][N:13]=[CH:12]2)[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(Nn2cnnc2)cc1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N(Cc2ccc(Br)cc2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.8 %

Procedure:
8 Milliliters of acetonitrile was added to 0.63 g of 4-[N-(4-nitrophenyl)amino]-4H-1,2,4-triazole, 0.82 g of 4-bromobenzyl bromide and 0.62 g of anhydrous potassium carbonate and the mixture was stirred for 3 hours at room temperature. The solvent was removed by distillation under reduced pressure, and water was added to the residue obtained, which was then extracted with chloroform. The chloroform layer separated was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography to give crude crystals from the chloroform/methanol (100/1) eluate. The crude crystals were recrystallized from acetone to give 0.71 g of 4-[N-(4-bromobenzyl)-N-(4-nitrophenyl)amino]-4H-1,2,4-triazole.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)=[O:4].[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.[K]>CN(C)C=O>[Cl:11][C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][N:16]2[C:12](=[O:22])[C:13]3[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:15]2=[O:17])[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CBr)c1cccc(Cl)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)c2ccccc2C1=O)c1cccc(Cl)c1
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of 2-bromo-3′-chloroacetophenone (0.9271 g, 3.971 mmol, 1.0 equiv) and potassium phthalimide (0.8129 g, 4.389 mmol, 1.1 equiv) in N,N-dimethylformamide (15 mL) was heated at 50° C. After 1 hour, the solvent was removed by rotary evaporation. The resultant solids were triturated with ethyl acetate and filtered. The collected solids were dried under vacuum to yield 1.19 g (117%) of 2-(2-(3-chlorophenyl)-2-oxoethyl)isoindoline-1,3-dione, which was carried forward without purification. 1H NMR (400 MHz, DMSO-d6) δ: 8.13 (s, 1H), 8.05 (d, 1H), 7.96 (m, 2H), 7.93 (m, 2H), 7.83 (d, 1H), 7.65 (t, 1H), 5.29 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][C:12]=3[Cl:19])[O:10][C:6]=2[CH:5]=[C:4]([O:20]C)[CH:3]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=3[Cl:19])[O:10][C:6]=2[CH:5]=[C:4]([OH:20])[CH:3]=1
Reactant: COc1ccc(-c2nc3c(Cl)cc(OC)cc3o2)c(Cl)c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Oc1ccc(-c2nc3c(Cl)cc(O)cc3o2)c(Cl)c1
Yield: 73.7 %

Procedure:
To 4-chloro-2-(2-chloro-4-methoxy-phenyl)-6-methoxybenzooxazole (52 mg) in CH2Cl2 (2 mL) placed in and ice water bath was added drop wise 1.0 M BBr3 in CH2Cl2 (0.96 mL, 6 eq). After the reaction stirred over night, the mixture was placed in an ice water bath and excess MeOH was added drop wise to quench excess BBr3 and the mixture was stirred for an additional 20 min and concentrated. Flash chromatography on silica gel eluting with 0% to 40% ethyl acetate-hexane afforded 35 mg (74%) of the title compound as a solid. MS: 296 (MH+), HPLC tR: 2.32 min.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1.[OH:49][CH:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>>[OH:49][CH:50]1[CH2:55][CH2:54][N:53]([C:30]([C:29]2[CH:33]=[CH:34][C:26]([Br:25])=[CH:27][C:28]=2[NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])=[O:31])[CH2:52][CH2:51]1
Reactant: OC1CCNCC1
Reactant: O=C(O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nccnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc(Br)cc1NS(=O)(=O)c1cccc2nccnc12)N1CCC(O)CC1

Procedure:
The title compound was prepared from the HATU-mediated coupling of 4-bromo-2-(quinoxaline-5-sulfonylamino)benzoic acid (EXAMPLE 1, Step G) and 4-hydroxypiperidine and purified as described in EXAMPLE 1, Step K. MS (ESI): mass calculated for C20H19BrN4O4S, 490.0; m/z found, 491/493 [M+H]+, 513/515 [M+Na]+. HPLC (reverse phase): RT=7.68 min. 1H NMR (400 MHz, CDCl3, rotameric broadening): 9.08 (d, J=1.8 Hz, 1H), 9.02 (d, J=1.8 Hz, 1H), 8.95 (br s, 1H), 8.52-8.50 (m, 1H), 8.38-8.36 (m, 1H), 7.92-7.88 (m, 1H), 7.75 (d, J=1.6 Hz, 0.7H), 7.68 (d, J=1.6 Hz, 0.3H), 7.20-7.17 (m, 1H), 6.96-6.92 (m, 1H), 3.96-3.91 (m, 1H), 3.85-3.75 (m, 1H), 3.2-2.8 (m, 3H), 2.05-1.95 (m, 2H), 1.7-1.3 (m, 3H).
Reaction SMILES: [C:1]([CH:3]1[CH2:7][S:6][CH2:5][C:4]1=O)#[N:2].[ClH:9].[NH2:10]O.CCOCC>C(#N)C>[ClH:9].[NH2:10][C:4]1[C:3]([C:1]#[N:2])=[CH:7][S:6][CH:5]=1
Reactant: NO
Reactant: N#CC1CSCC1=O
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Product: N#Cc1cscc1N

Procedure:
4-Cyano-3-oxotetrahydrothiophene (1.27 g) was dissolved in acetonitrile (15 ml) with heating and stirring. Hydroxylamine hydrochloride (0.69 g) was added to the refluxing solution and the mixture was refluxed for 11/2hour. After cooling, ether (25 ml) was added and the title compound was filtered off and air-dried. Yield 1.35 g (84%); mp 244°-246°. δ'H nmr (CDCl3 /DMSO-d6) 9.2(br s) 8.55 (d, J=4Hz) 7.85 (d, J=4Hz).
Reaction SMILES: [C:1]([S:4][CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[C:6]([OH:8])=O)(=[O:3])[CH3:2].[CH3:18][O:19][C:20](=[O:37])[C@@H:21]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[OH:32])[N:22]1[C:33](=[O:36])[CH2:34][NH2:35]>CCCCCC.C(OCC)(=O)C>[CH3:18][O:19][C:20](=[O:37])[C@@H:21]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[OH:32])[N:22]1[C:33](=[O:36])[CH2:34][NH:35][C:6](=[O:8])[CH:5]([S:4][C:1](=[O:3])[CH3:2])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1
Reactant: COC(=O)[C@@H]1CCC(c2ccccc2O)N1C(=O)CN
Reactant: COc1ccc(CC(SC(C)=O)C(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)[C@@H]1CCC(c2ccccc2O)N1C(=O)CNC(=O)C(Cc1ccc(OC)cc1)SC(C)=O
Yield: 50 %

Procedure:
Condensation of 2-acetylthio-3-(para-methoxyphenyl)propanoic acid with N-glycyl-5-(ortho-hydroxyphenyl)proline methyl ester, obtained in accordance with the same protocols as those described in Preparation G, yields the expected product in the form of an oil after chromatography in an n-hexane/ethyl acetate mixture, 4:6.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Product: O=S(=O)(c1cccc(Br)c1)N1CCOCC1
Yield: 96.3 %

Procedure:
Prepared by general procedure III from 3-bromobenzenesulfonyl chloride (5.0 g, 20 mmol) and morpholine (1.89 g, 22 mmol) to give the title compound (5.9 g, 98%) as a white solid. MS (ISP) 306.1[(M+H)+].
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[NH:20][C:19]3[C:18](=[O:21])[N:17]([CH2:22][CH2:23][CH3:24])[C:16](=[O:25])[N:15]([CH2:26][CH2:27][CH3:28])[C:14]=3[CH:13]=2)=[CH:8][CH:7]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1>C1COCC1>[F:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:38])[N:5]([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[NH:20][C:19]4[C:18](=[O:21])[N:17]([CH2:22][CH2:23][CH3:24])[C:16](=[O:25])[N:15]([CH2:26][CH2:27][CH3:28])[C:14]=4[CH:13]=3)=[CH:10][N:11]=2)[CH2:4][CH2:3][O:2][CH3:1])=[CH:32][CH:31]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CCCn1c(=O)c2[nH]c(-c3ccc(NCCOC)nc3)cc2n(CCC)c1=O
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(-c3ccc(N(CCOC)C(=O)Nc4ccc(F)cc4)nc3)cc2n(CCC)c1=O
Temperature: 94 °C
Reaction time: 72 h
Yield: 26.6 %

Procedure:
9a (25 mg) was suspended in THF (2 ml) in a pressure tube, 4-fluorophenyl isocyanate (200 mg) was added and the mixture was stirred at 94° C. for 3 days. After cooling to room temperature, the mixture was evaporated to almost dry and the solid was filtered and washed with ether (two peaks shown in HPLC, rt=8.0 min, rt=1.6 min). The solid was stirred with DCM, the solid (rt=8.0 min) was removed and the mother liquid was collected. After removal of the solvent, the residue was purified by column (14 g silica gel, RT Scientific) (CH2Cl2: MeOH=100:0 to 98:2) to give the product (11a) (9 mg). HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH 95%. Retention Time=11.60 min. 1H NMR (DMSO, d6): 0.83-0.95 (m, 6H), 1.53-1.75 (m, 4H), 3.26 (s, 3H), 3.60 (t, 2H), 3.87 (t, 2H), 4.17 (t, 2H), 6.85 (s, 1H), 7.16 (t, 2H, J=8.7 Hz), 7.48 (m, 3H), 8.30 (dd, 1H, J1=8.7 Hz, J2=2.4 Hz), 8.95 (d, 1H, J=2.4 Hz), 10.87 (s, 1H), 12.50 (s, 1H). MS: m/z 523 (M+H)+.