Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][N:16]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])C(=O)OC(C)(C)C)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH2:8]([O:15][NH:16][CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCC(CC)N(OCc1ccccc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.6 %

Procedure:
Trifluoroacetic acid (42 mL, 544 mmole) was added to a chilled (0° C.) solution of tert-butyl N-benzyloxy-N-(1-ethylpropyl)carbamate (21.6 g, 73.6 mmole) in methylene chloride (300 mL). The reaction was stirred at ambient temperature for about 18 hours then concentrated under vacuum. Saturated aqueous sodium bicarbonate (100 mL) was added to the residue followed by a quantity of solid sodium carbonate sufficient to adjust the pH of the reaction mixture to pH 9. The reaction mixture was extracted with diethyl ether (4×50 mL). The extracts were combined, dried over sodium sulfate then concentrated to provide 10.9 g of N-benzyloxy-N-(1-ethylpropyl)amine as an oil.
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1)=O.C1([CH2:16][O:17]C2C=C([C@@H](O)CC3C(Cl)=C[N+]([O-])=CC=3Cl)C=CC=2OC(F)F)CC1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH:16]([C:8]1[CH:3]=[CH:4][C:5]([CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1)=[O:17]
Reactant: O=Cc1cccc(CC(=O)O)c1
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: O=Cc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.2 %

Procedure:
To a solution of 2-(3-formylphenyl)acetic acid (394 mg, 2.4 mmol) in DMF (5 mL) was added (1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethanol (1.0 g, 2.4 mmol) followed by DMAP (147 mg, 1.2 mmol) and EDC.HCl (930 mg, 4.8 mmol). The mixture was allowed to stir a room temperature for 18 hours. The solvent was removed in vacuo and the residue was partitioned between DCM (10 mL) and waturated sodium bicarbonate solution (10 mL). The organic phase was passed through a hydrophobic fit and the solvent was removed in vacuo. The crude material was purified by silica gel column chromatography, eluting with 0-100% EtOAc in DCM, to afford the title compound as an off-white solid (312 mg, 23%). 1H NMR (400 MHz, CDCl3): δ 10.00 (s, 1H), 8.04 (s, 2H), 7.81 (d, J=7.5 Hz, 1H), 7.72 (s, 1H), 7.52-7.42 (m, 2H), 7.13 (d, J=8.1 Hz, 1H), 6.91-6.85 (m, 2H), 6.62 (t, J=75.3 Hz, 1H), 6.05 (dd, J=9.9, 4.4 Hz, 1H), 3.85-3.76 (m, 2H), 3.72-3.59 (m, 2H), 3.49 (dd, J=14.0, 9.9 Hz, 1H), 3.18 (dd, J=14.0, 4.4 Hz, 1H), 1.32-1.19 (m, 1H), 0.70-0.63 (m, 2H), 0.40-0.34 (m, 2H). LCMS (Method 2): [MH+]=566 at 3.54 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[O:12][N:11]=[C:10]([C:13]([CH3:17])([CH3:16])[CH:14]=O)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][NH2:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>C1COCC1>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[O:12][N:11]=[C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:20][CH3:19])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(C(C)(C)C=O)no1
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: C1CCOC1
Product: CNCC(C)(C)c1cc(NC(=O)OC(C)(C)C)on1
Reaction time: 2 h

Procedure:
[3-(1,1-Dimethyl-2-oxo-ethyl)-isoxazol-5-yl]-carbamic acid tert-butyl ester (150.0 mg, 0.59 mmol) is dissolved in THF (1.0 mL) and 2M methylamine in THF (0.35 mL, 0.71 mmol) is added followed by the addition of MP-triacetoxyborohydride (546.0 mg, 2.70 mmol/g). The reaction mixture is placed on a shaker for 2 h. After this time, the reaction mixture is filtered and the filtrate is concentrated under reduced pressure to provide 163.0 mg of the title compound which is used crude for the next step. m/z 270 [M+H].
Reaction SMILES: Cl.[F:2][C:3]([F:21])([F:20])[C:4]1[CH:19]=[CH:18][C:7]2[NH:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[N:11]=[C:12]([NH2:13])[C:6]=2[CH:5]=1.[CH3:22][O:23][CH2:24][CH2:25][C@H:26]1[CH2:31]N[CH2:29][CH2:28][NH:27]1>CS(C)=O.C1(C)C=CC=CC=1>[F:21][C:3]([F:2])([F:20])[C:4]1[CH:19]=[CH:18][C:7]2[NH:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[N:11]=[C:12]([N:13]3[CH2:29][CH2:28][NH:27][C@@H:26]([CH2:25][CH2:24][O:23][CH3:22])[CH2:31]3)[C:6]=2[CH:5]=1
Reactant: NC1=Nc2ccccc2Nc2ccc(C(F)(F)F)cc21
Reactant: COCC[C@H]1CNCCN1
Agent: Cl
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3ccc(C(F)(F)F)cc32)CCN1
Yield: 61.8 %

Procedure:
Heat a suspension of 2-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride salt (626 mg) and (S)-2-(2-methoxy-ethyl)-piperazine (863 mg) in DMSO (1.42 mL DMSO per mmol of amine) and toluene (5.68 mL per mmol of amine) at reflux for 48 hours. Evaporate the toluene under vaccuo and pour the resulting solution into water (5.71 mL per mmol of amine). Purify the resulting brown solid by flash chromatography (methylene chloride/methanol (95:5) to afford the title compound as a yellow solid (499 mg, 60%): mp 71-82° C.; 1HNMR (CDCl3) δ 1.75-1.60 (m, 2H), 2.64 (dd, 1H), 3.07-2.94 (m, 4H), 3.31 (s, 3H), 3.48 (ddd, 2H), 3.78 (bs, 2H), 5.09 (s, 1H), 6.69 (dd, 1H), 6.93-6.88 (m, 2H), 7.00 (dt, 1H), 7.10 (dd, 1H), 7.57-7.50 (m, 2H); MS (ESI/pos) m/z (rel intensity) 405.3 (100).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([NH:17][C:18](=[O:21])[CH2:19][CH3:20])[CH:11]=1.[C:22]([C:25]1[C:26](=[O:36])[O:27][C:28]([OH:35])=[C:29]([C:32](=O)[CH3:33])[C:30]=1[OH:31])(=[O:24])[CH3:23]>CO>[C:22]([C:25]1[C:26](=[O:36])[O:27][C:28](=[O:35])[C:29](=[C:32]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([NH:17][C:18](=[O:21])[CH2:19][CH3:20])[CH:11]=2)[CH3:33])[C:30]=1[OH:31])(=[O:24])[CH3:23]
Reactant: CCC(=O)Nc1cc(N)ccc1O
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCC(=O)Nc1cc(NC(C)=C2C(=O)OC(=O)C(C(C)=O)=C2O)ccc1O

Procedure:
Following the procedures of Example 3, 2.0 g. (0.0096 mol) of 4-nitro-2-propionamidophenyl (prepared from propionic acid and 2-amino-4-nitrophenyl) is hydrogenated in a mixture of 100 ml. of ethanol, 0.3 g. of 10% palladium-on-carbon and 1.34 ml. of concentrated hydrochloric acid in a Parr apparatus. Filtration and evaporation of the solvent gives 4-amino-2-propionamidophenol hydrochloride. The latter (2.0 g., 0.0096 mol) in a methanol solution is treated with 1 equivalent of triethylamine under nitrogen atmosphere. The solution of the free amine is added to a refluxing mixture of one equivalent of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one and 30 ml. of methanol under nitrogen. The reaction mixture is refluxed for 18 hours, filtered and the solid is recrystallized from ethanol to yield 5-acetyl-4-hydroxy-3-[1-(4-hydroxy-3-propionamidophenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 228°-229° C. (dec.).
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:12]4.[N:18]1[C:27]2[C:22](=[CH:23][C:24](B3OC(C)(C)C(C)(C)O3)=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>>[N:18]1[C:27]2[C:22](=[CH:23][C:24]([C:2]3[C:10]4[NH:9][C:8]5[CH:11]6[CH2:17][CH2:16][N:14]([CH2:15][C:7]=5[C:6]=4[CH:5]=[CH:4][CH:3]=3)[CH2:13][CH2:12]6)=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Reactant: CC1(C)OB(c2ccc3ncccc3c2)OC1(C)C
Product: c1cnc2ccc(-c3cccc4c5c([nH]c34)C3CCN(CC3)C5)cc2c1

Procedure:
7-Bromo-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (146 mg, 0.5 mmol, Example 1B) was coupled with 6-quinolineboronic acid pinacol ester (191 mg, 0.75 mmol, Aldrich) following the procedure described in Example 4. Purification by preparative reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 40-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] gave the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.99-2.18 (m, 4 H) 3.02-3.30 (m, 5 H) 4.29 (s, 2 H) 7.10-7.24 (m, 2 H) 7.36 (d, J=8 Hz, 1 H) 7.58 (dd, J=8, 4 Hz, 1 H) 8.04-8.10 (m, 1 H) 8.13-8.22 (m, 2 H) 8.45 (d, J=8 Hz, 1 H) 8.86 (dd, J=4, 2 Hz, 1 H); MS (DCI/NH3) m/z 340 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][CH2:13][CH2:14][OH:15].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][CH2:13][CH2:14][O:15][S:17]([CH3:16])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CCCCO)c(OC)c1
Solvent: CCN(CC)CC
Product: COc1ccc(CCCCOS(C)(=O)=O)c(OC)c1
Yield: 76 %

Procedure:
Ester 77 was prepared by typical procedure E from alcohol 76 (4.15 g, 0.021 mol), methanesulfonyl chloride (2.4 mL, 0.03 mol) and triethylamine (20 mL). Crude 77 (4.6 g, 80%) was isolated as a yellow oil
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].C(N(CC)CC)C.[C:19]([NH:21][C:22](Cl)=[N:23][CH3:24])#[N:20]>CO>[C:19]([N:21]=[C:22]([NH:11][CH2:10][CH2:9][S:8][CH2:7][C:3]1[N:4]=[CH:5][NH:6][C:2]=1[CH3:1])[NH:23][CH3:24])#[N:20]
Reactant: Cc1[nH]cnc1CSCCN
Reactant: CN=C(Cl)NC#N
Solvent: CCN(CC)CC
Solvent: CO
Product: CNC(=NC#N)NCCSCc1nc[nH]c1C
Reaction time: 7.5 h
Yield: 22.4 %

Procedure:
To a stirred solution of 2-(5-methylimidazol-4-ylmethylthio)ethylamine (1.0 g) and triethylamine (0.71 g) in methanol (20 ml) was added N-cyano-N'-methylchloroformamidine (0.82 g) and stirred for 7.5 hrs. at 50°-55° C. After evaporation, the residue was subjected to chromatography on SiO2 [eluant: CHCl3 -MeOH (10:1)]. The resulting crude product was added to water (3 ml) and extracted repeatedly with ethyl acetate. Ethyl acetate extracts were dried over anhydrous MgSO4 and concentrated under a reduced pressure to small volume. The resulting crystals were collected by filtration and washed with ethyl acetate to give N"-cyano-N-methyl-N'-[2-(5-methylimidazol-4-ylmethylthio)ethyl]guanidine (0.33 g). Yield 22.4%, m.p. 134°-137° C.
Reaction SMILES: [CH3:1][C:2]1[N:11]([CH:12]2[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]2=[O:19])[C:10](=[O:20])[C:9]2[C:4](=[CH:5][C:6]([N+:21]([O-])=O)=[CH:7][CH:8]=2)[N:3]=1>C1CCCCC=1.CN(C=O)C.[OH-].[OH-].[Pd+2]>[NH2:21][C:6]1[CH:5]=[C:4]2[C:9]([C:10](=[O:20])[N:11]([CH:12]3[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]3=[O:19])[C:2]([CH3:1])=[N:3]2)=[CH:8][CH:7]=1
Reactant: Cc1nc2cc([N+](=O)[O-])ccc2c(=O)n1C1CCC(=O)NC1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1=CCCCC1
Product: Cc1nc2cc(N)ccc2c(=O)n1C1CCC(=O)NC1=O
Temperature: 125 °C
Yield: 82.5 %

Procedure:
A suspension of 3-(2-methyl-7-nitro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (4.8 g, 13 mmol) and 20% Pd(OH)2/C (1.0 g) in cyclohexene (15 mL) and DMF (60 mL) was heated in a 125° C. oil bath overnight. The suspension was filtered thru a pad of Celite, and washed with DMF (30 mL). To the filtrate, was added water (150 mL) to give a suspension. The suspension was filtered and washed with water (50 mL) to give 3-(7-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as an off-white solid (3.07 g, 71% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 5/95 grad 95/5 in 5 min CH3CN/0.1% H3PO4, 4.08 min (97.3%) [sample was dissolved in 0.1% H3PO4]; mp: 305-307° C.; 1H NMR (DMSO-d6) δ 2.05-2.16 (m, 1H, CHH), 2.53 (s, 3H, CH3), 2.58-2.69 (m, 2H, 2CHH), 2.75-2.86 (m, 1H, CHH), 5.10 (dd, J=6, 11 Hz, 1H, NCH), 6.11 (brs, 2H, NH2), 6.54 (d, J=2 Hz, 1H, Ar), 6.68 (dd, J=2, 8 Hz, 1H, Ar), 10.93 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.36, 23.43, 30.63, 55.97, 106.12, 109.17, 114.70, 127.28, 148.95, 154.42, 154.61, 159.85, 169.87, 172.67; LCMS: MH=287; Anal Calcd for C14H14N4O3: C, 58.74; H, 4.93; N, 19.57. Found: C, 58.60; H, 4.83; N, 19.40.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:9]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:10]([S:12][CH3:13])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[H-].[Na+].I[CH2:25][CH2:26][CH3:27].O>CN(C)C=O>[Br:1][C:2]1[C:3]2[N:4]([C:9]([N:14]([CH2:25][CH2:26][CH3:27])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[C:10]([S:12][CH3:13])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CCCI
Reactant: CSc1nc2c(Br)cc(C)cn2c1NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(C(=O)OC(C)(C)C)c1c(SC)nc2c(Br)cc(C)cn12
Reaction time: 0.17 h
Yield: 97.1 %

Procedure:
tert-Butyl N-[8-bromo-6-methyl-2-(methylsulfanyl)imidazo[1,2-a]pyridin-3-yl]carbamate (123 mg) was dissolved in N,N-dimethylformamide (10 mL), then sodium hydride (65% in oil; 15 mg) was added thereto under ice-cooling, and the mixture was stirred for 10 minutes. Iodopropane (67 mg) was added thereto under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The extracted organic layers were combined, dried over anhydrous magnesium sulfate and evaporated, to give the title compound (133 mg) as a brown oil.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:11]([NH:13][C@H:14]([C:19]([NH:21][C@H:22]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[C@H:15]([CH2:17][CH3:18])[CH3:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1>C(O)C.[Pd]>[NH2:1][C@H:2]([C:11]([NH:13][C@H:14]([C:19]([NH:21][C@H:22]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[C@H:15]([CH2:17][CH3:18])[CH3:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C

Procedure:
In ethanol (50 ml) is dissolved Z-Tyr-Ile-Leu-OBut (2.09 g, 3.5 m.mols) and catalytic reduction is carried out with palladium black as the catalyst for 4 hours. The catalyst is removed by filtration and the solvent is distilled off, whereby H-Tyr-Ile-Leu-OBut is obtained.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[H-].[Na+].Cl[C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[CH:14][N:13]=1>CS(C)=O>[C:3]1([CH3:8])[CH:4]=[CH:5][C:6]([O:7][C:12]2[C:17]([C:18]#[N:19])=[CH:16][N:15]=[CH:14][N:13]=2)=[CH:1][CH:2]=1
Reactant: N#Cc1cncnc1Cl
Reactant: Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc(Oc2ncncc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 41.6 %

Procedure:
p-Cresol (1.0 equiv.) was placed in a round bottom flask with DMSO (1.0 M) and sodium hydride (0.9 equiv). The reaction mixture was stirred at ambient temperature for 5 min. To the mixture was added 4-chloropyrimidine-5-carbonitrile (1.0 equiv.). The reaction was stirred at 25° C. for 2 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine (3×) and dried over sodium sulfate. Volatile organic solvents were removed under reduced pressure to give 4-(p-tolyloxy)pyrimidine-5-carbonitrile (41.6% yield) as a light brown solid which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.24 (s, 1H), 8.94 (s, 1H), 7.29 (dd, J=0.8, 8.6 Hz, 2H), 7.21-7.16 (m, 2H), 2.34 (s, 3H). MS (ESI) m/z 211.7 [M+1]+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1N.N([O-])=O.[Na+].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.N1C=CC=CC=1>Cl.O>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH:25]=1
Reactant: COc1ccncc1
Reactant: Nc1ccccc1Sc1nc2ccccc2[nH]1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: COc1ccnc(-c2ccccc2Sc2nc3ccccc3[nH]2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice cold solution of 2-(1H-benzimidazol-2-yl thio)benzenamine (1.70 g) in dilute hydrochloric acid (11 ml) was added dropwise a solution of sodium nitrite (0.53 g) in water (5 ml), keeping the temperature below 0°. The reaction mixture was stirred at this temperature for 0.5 hours then added portionwise to a mixture of 4-methoxypyridine (42.40 g) and pyridine (0.57 g) stirring at 80° for 1 hour. The pyridines were distilled off, replaced with 880 ammonia which was in turn distilled off. The residue was treated with water, extracted into dichloromethane, washed, dried, evaporated and the residue was purified by flash column chromatography using ethyl acetate as eluant to give the sub-title product as a creamish foam, 0.20 g.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:27])[N:19]([CH2:23][C:24]([OH:26])=O)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.[S:34]([NH2:38])([NH2:37])(=[O:36])=[O:35]>>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:27])[N:19]([CH2:23][C:24]([NH:37][S:34](=[O:36])(=[O:35])[NH2:38])=[O:26])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:30]([F:33])([F:31])[F:32])[CH:3]=1
Reactant: NS(N)(=O)=O
Reactant: O=C(O)CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Product: NS(=O)(=O)NC(=O)CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
2-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]-N-sulfamoylacetamide was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]acetic acid (Example 4) and sulfamide following General Procedure L.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH3:17])=[O:14].[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[C:20]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:20]3[C:21]([O:25][CH3:26])=[CH:22][CH:23]=[CH:24][C:19]=3[F:18])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH3:17])=[O:14]
Reactant: COc1cccc(F)c1B(O)O
Reactant: CCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCNC(=O)c1nnc2c(-c3c(F)cccc3OC)cccc2c1N

Procedure:
Using Method A, 4-amino-8-bromo-N-ethyl-cinnoline-3-carboxamide and 2-fluoro-6-methoxy-phenyl boronic acid were reacted to afford the title compound as a off-white solid. 1H NMR (500 MHz, CDCl3) δ 8.50 (br, 1H), 7.90 (m, 1H), 7.74 (m, 2H), 7.36 (m, 1H), 6.84 (m, 2H), 3.70 (s, 3H), 3.52 (m, 2H), 1.25 (t, J=7.0 Hz, 3H). MS APCI, m/z=341 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:32]([Cl:33])=[CH:31][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][N:20]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:34][CH3:35])[CH:3]=1.O.NN>C(O)C>[NH2:1][C:2]1[C:32]([Cl:33])=[CH:31][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:34][CH3:35])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCN)CC1
Yield: 71.7 %

Procedure:
4-Amino-5-chloro-N-(1-(4-(2,3-dihydro-1,3-dioxo-1H-isoindol-2-yl)butyl)piperidin-4-ylmethyl)-2-methoxybenzamide (8.3 g) was dissolved in ethanol (100 ml) and hydrazine hydrate (1.1 ml) was added at room temperature with stirring. The mixture was refluxed with stirring for 3 hr. The precipitated crystals were filtered off and the filtrate was concentrated under reduced pressure to give 4.4 g of 4-amino-N-(1-(4-aminobutyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:5]=[C:6]([Cl:21])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:12]C(=O)C1C=CC=CC=1.[OH-].[K+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:5]=[C:6]([Cl:21])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][OH:12]
Reactant: O=C(OCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: OCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
A reaction vessel was charged with 3.75 g of 3,5-dichloro-4-(3-benzoyloxypropyloxy)-1-(benzyloxy)benzene, 5.0 g of 10% aqueous potassium hydroxide solution and 50 ml of methanol. After stirring at room temperature for 24 hours, the reaction mixture was concentrated. The concentrate was poured into water, and extracted twice with 150 m of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 2.56 g of 3-(2,6-dichloro-4-(benzyloxy)phenoxy)-1-propyl alcohol (90% yield).
Reaction SMILES: C(=O)([O-])O[CH2:3][CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[I:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[C:4]([CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH:19][C:18]1[CH:20]=[CH:21][C:15]([I:14])=[CH:16][CH:17]=1)#[CH:3]
Reactant: Nc1ccc(I)cc1
Reactant: O=C([O-])OCC=Cc1ccccc1
Product: C#CC(Nc1ccc(I)cc1)c1ccccc1
Reaction time: 12 h
Yield: 92.9 %

Procedure:
The general procedure was followed with cinnamyl carbonate (0.188 g, 0.979 mmol) and p-iodoaniline (0.220 g, 1.04 mmol). The reaction was conducted at room temperature for 12 h. 1H NMR analysis of the crude reaction mixture indicated the ratio of regioisomers to be 98/2. The mixture was purified by flash column chromatography on silica gel (1.5% ethyl acetate in hexanes) to give the title compound (0.303 g, 92%). HPLC analysis indicated the enantiomeric excess of the product was 96% [Diacel CHIRALCEL OD-H (0.46 cm×25 cm); hexane/2-propanol=99/1; flow rate=0.6 mL/min; detection wavelength=254 nm; TR=18.4 (major), 23.1 (minor) min]: [α]DRT=(c, CHCl3). 1H NMR (400.13 MHz, CDCl3) δ 7.48-7.40 (m, 6H), 7.36 (s, J=4.6 Hz, 1H), 6.43 (dt, J=8.8, 2.4 Hz, 2H), 6.09 (ddd, J=16.8, 10.4, 6.0 Hz, 1H), 5.34 (dt, J=12.0, 1.3 Hz, 1H), 5.31 (dt, J=5.2, 1.2 Hz, 1H), 4.97 (d, J=5.6 Hz, 1H), 4.15 (br s, 1H). 13C NMR (100.59 MHz, CDCl3) δ 146.53, 141.10, 138.35, 137.51, 128.72, 127.53, 126.99, 116.28, 115.69, 78.32, 60.46. Anal. Calcd for C15H14NI: C, 53.75; H, 4.21; N, 4.18; I, 37.86. Found: C, 53.59; H, 4.27; N, 4.17; I, 38.04.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][NH2:5].[S:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=S.CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][NH:5][C:12]1[S:11][CH2:17][C:15](=[O:16])[N:14]=1
Reactant: Cc1cccc(Cl)c1CN
Reactant: O=C1CSC(=S)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cccc(Cl)c1CNC1=NC(=O)CS1
Temperature: 0 °C
Reaction time: 72 h
Yield: 28.5 %

Procedure:
To a solution of 2-chloro-6-methylbenzylamine (650 mg, 4.2 mmol) and Rhodanine (559 mg, 4.2 mmol) in acetonitrile (25 mL) was added DIPEA (1.74 mL, 10 mmol) at room temperature. Then, this solution was cooled to 0° C. and mercuric chloride (1.22 g, 4.5 mmol) was added in one portion. After addition, the suspension was allowed to warm to room temperature and stirred for 3 days. The resulting black solids were filtered through a plug of celite and washed with dichloromethane (500 mL) and methanol (250 mL). The combined solvents were removed under the vacuum and the crude residue was dissolved in ethyl acetate (25 mL) at hot condition and stored in the refrigerator overnight. Then, the solids were collected by filtration and washed with ethyl acetate. After drying in air, 305 mg (28.5% yield) of 2-(2-chloro-6-methylbenzylamino)-thiazol-4-one was isolated as a white amorphous solid: EI-HRMS m/e calcd for C11H11ClN2OS (M+) 254.0281. found 254.0282.