Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][OH:7])([CH3:3])[CH3:2].O[C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1COCC1>N(C(OCC)=O)=NC(OCC)=O>[CH:1]([O:4][CH2:5][CH2:6][O:7][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1)([CH3:3])[CH3:2]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)OCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)OCCOc1ccc(C=O)cc1
Yield: 81.7 %

Procedure:
To a solution of 2-isopropoxyethanol (600 mg, 5.76 mmol), p-hydroxybenzaldehyde (0.78 g, 6.34 mM) and triphenylphosphine in THF (20 ml) (1.6 g, 6.1 mmol), diethyl azodicarboxylate (40% in toluene) was added at 0° C. over 10 minutes while stirring. Then, the mixture was stirred at room temperature for 18 hours until the initial reaction product of 2-isopropoxyethanol and p-hydroxybenzaldehyde disappeared. The resulting solution was concentrated and purified by silica gel chromatography (hexane:ethylacetate=5:1) to obtain 4-(2-isopropoxyethoxy)benzaldehyde as yellow oil (0.98 g, yield: 82%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Cl)=[CH:7][CH:6]=1)[CH:2]=[CH2:3].NC(N)=[S:15].O.N>C(O)C>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][SH:15])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(CCl)cc1
Reactant: NC(N)=S
Agent: N
Solvent: CCO
Solvent: O
Product: C=CCOc1ccc(CS)cc1
Yield: 80.9 %

Procedure:
A mixture of 2.00 g (10.9 mmol) 1-allyloxy-4-chloromethyl-benzene and 917 mg (12.1 mmol) thiourea in 3.0 ml ethanol was heated to reflux for 7 h. Solvents were distilled off and the crystalline residue was washed with cold ethanol and isolated by filtration. After addition of 2.5 ml ethanol, 1.0 ml water and 0.7 ml 25% aqueous ammonia, the mixture was heated to reflux for 1 h. Ethanol was distilled off, then acidified with 0.5 ml half conc. HCl and extracted with ethyl acetate. The solution was dried over MgSO4 and solvents were removed in vacuo to yield 1.59 g (81%) colorless oil, which was used immediately.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:11]1[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:19](=[O:27])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[F:28])[N:12]=1)[CH2:9][CH3:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@H:8]([C:11]1[N:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:19](=[O:27])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[F:28])[N:12]=1)[CH2:9][CH3:10]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)c1nc2cccc(F)c2c(=O)n1-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1ccccc1
Reaction time: 1 h
Yield: 87.1 %

Procedure:
A solution of compound 110 (85 mmol) in dichloromethane (60 mL) was treated with trifluoroacetic acid (60 mL). The reaction mixture was stirred for 1 h, concentrated in vacuo, and partitioned between dichloromethane (150 mL) and 10% K2CO3 (sufficient amount to keep the pH greeted than 10). The aqueous layer was extracted with additional dichloromethane (100 mL), and the combined organic layers were washed with water (50 mL) and brine (50 mL). After drying with Mg SO4, the solution was concentrated to provide compound 111 as an off-white solid (22 g, 88%). 1H NMR (300 MHz, CDCl3) δ 7.73-7.65 (m, 1H); 7.62-7.49 (m, 4H), 7.32-7.22 (m, 2H), 7.13-7.06 (m, 1H), 3.42 (dd, J=7.5, 5.2 Hz, 1H), 1.87-1.70 (m, 1H), 1.58-1.43 (m, 1H), 0.80 (t, J=7.4 Hz, 3H). ESI-MS m/z 298.2 (MH+). The reaction described above and compound III are shown below.
Reaction SMILES: [OH:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>CN(C=O)C>[OH:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1O
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: COC(=O)c1cccc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 2-hydroxy-3-nitrobenzoic acid (25 g, 136 mmol) in DMF (125 mL) was added K2CO3 (37.8 g, 273 mmol). Then dimethyl sulfate (48.2 g, 382 mmol) was added dropwise to the mixture at rt. The mixture was stirred at rt overnight. Then the reaction was quenched by the addition of the saturated aqueous NH4Cl (800 mL) at 0° C. The reaction mixture was extracted with EtOAc (500 mL×2). The combined organic layers were washed with water successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound of Step A (26.8 g, 99.6% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.10-8.18 (m, 2H), 7.97-8.03 (br, 1H), 6.95-7.03 (m, 1H), 4.00 (s, 3H).
Reaction SMILES: Cl[CH2:2][S:3][C:4]1[N:5]=[N:6][N:7]([CH3:9])[N:8]=1.[I-:10].[Na+]>CC(C)=O.O>[I:10][CH2:2][S:3][C:4]1[N:5]=[N:6][N:7]([CH3:9])[N:8]=1
Reactant: [I-]
Reactant: Cn1nnc(SCCl)n1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cn1nnc(SCI)n1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of 5-chloromethylthio-2-methyltetrazole (987 mg : 6.0 mMol.) in acetone (10 ml) is added sodium iodide (1.78 g : 12.00 mMol.), and the mixture is stirred at 50° C. for 3 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate, and concentrated to give 5-iodomethylthio-2-methyltetrazole (1.43 9) as yellow oil.
Reaction SMILES: [N:1]1([S:7]([C:10]2[C:18]3[C:13](=[C:14]([N+:19]([O-])=O)[CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[C:22]([NH2:24])=[O:23])(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[NH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[NH:12][C:11]([C:22]([NH2:24])=[O:23])=[C:10]2[S:7]([N:1]1[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1)(=[O:9])=[O:8]
Reactant: [H][H]
Reactant: NC(=O)c1[nH]c2c([N+](=O)[O-])cccc2c1S(=O)(=O)N1CCOCC1
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1[nH]c2c(N)cccc2c1S(=O)(=O)N1CCOCC1
Reaction time: 2 h

Procedure:
To a solution of 3-(morpholin-4-ylsulfonyl)-7-nitro-1H-indole-2-carboxamide (708 mg, 2.00 mmol) in 30 mL of methanol was added 10% palladium on carbon (200 mg), and the reaction was equipped with a balloon of hydrogen gas. After 2 hours, the reaction was filtered through celite, the filter pad was rinsed with ethyl acetate, and the resulting solution was concentrated in vacuo to provide the titled compound as a yellow solid. A portion of this was taken up in dichloromethane, treated with excess ethereal HCl, and concentrated in vacuo to give an off-white solid, used for biological testing. HRMS (ES) exact mass calculated for C13H17N4O4S (M+H+): 325.0965. Found 325.0971.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([Br:15])[CH:12]=[C:11]([C:16]([O:18]C)=O)[C:7]=3[NH:8][C:9]=2[CH:10]=1.[NH3:20]>CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([Br:15])[CH:12]=[C:11]([C:16]([NH2:20])=[O:18])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: N
Reactant: COC(=O)c1cc(Br)nc2c1[nH]c1cc(N)ccc12
Solvent: CO
Product: NC(=O)c1cc(Br)nc2c1[nH]c1cc(N)ccc12
Temperature: 80 °C
Yield: 53 %

Procedure:
A mixture of methyl 7-amino-2-bromo-5H-pyrido[3,2-b]indole-4-carboxylate (700 mg, 2.19 mmol) and 7 N NH3 in MeOH (5 mL) in a sealed microwave vial was heated in an oil bath at 80° C. for 16 h. After cooled to RT, the solid was collected by filtration and washed with MeOH, to afford 7-amino-2-bromo-5H-pyrido[3,2-b]indole-4-carboxamide (500 mg, 1.15 mmol, 53% yield). MS (ESI) m/z 306.96 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.18 (1H, br. s.), 8.33 (1H, br. s.), 7.79 (1H, br. s.), 7.71-7.77 (2H, m), 6.79 (1H, s), 6.52-6.60 (1H, m), 5.70 (2H, br. s.).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([OH:5])[CH2:2]1.CCN(C(C)C)C(C)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>O1CCCC1>[CH3:15][S:16]([O:5][CH:3]1[CH2:4][N:1]([S:16]([CH3:15])(=[O:18])=[O:17])[CH2:2]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CNC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OC1CN(S(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Azetidin-3-ol (3.3 g) and DIPEA (20 mL) are dissolved in dry tetrahydrofuran (40 mL). After 30 min the reaction mixture is cooled to 0° C. and methanesulfonyl chloride (10.9 g) is added dropwise. After stirring for 2 hours at ambient temperature, the mixture is concentrated under vacuum, partitioned between ethyl acetate and water. The organic phase is dried (MgSO4) and concentrated. Chromatography of the residue on silica gel (cyclohexane/ethyl acetate 70:30) gives the title compound. Yield: 5 g.
Reaction SMILES: N[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[O:11])=[CH:4][CH:3]=1.N([O-])=O.[Na+].[BrH:16]>O.[Cu]Br>[Br:16][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: Nc1ccc2c(c1)C(=O)OC2
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C1OCc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 84 %

Procedure:
6-Amino-1(3H)-isobenzofuranone (3.0 g, 20 mmol) obtained from Example 26-(1) was dissolved in a mixture of 47% aqueous hydrobromic acid solution (15 ml) and water (15 ml), then the mixture was cooled to 0° C., and a solution of sodium nitrite (1.45 g, 21 mmol) in water (7 ml) was slowly added thereto. Further, a solution of copper (I) bromide (3.6 g, 25 mmol) dissolved in 47% aqueous hydrobromic acid solution (10 ml) was added to the reaction mixture, and the resulting mixture was stirred at 80° C. for 20 minutes. After cooling the mixture, the liberated product was collected by filtration and then washed with water. The obtained pale brown solid was dissolved in ethyl acetate, then the insoluble material was removed by filtration, and the filtrate was washed successively with a 1N aqueous solution of hydrochloric acid, an aqueous solution of sodium hydrogen carbonate, and an aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to afford the title compound (3.57 g, 84% yield) as a crystalline solid.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:38])[CH:7]([NH:22][CH:23]([C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH2:20])[CH:16]=2)[C:11]1=[O:21])([CH3:4])[CH3:3].ClCCl.[C:42]1([S:48](Cl)(=[O:50])=[O:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>N1C=CC=CC=1>[CH3:1][C:2]([O:5][C:6](=[O:38])[C@H:7]([NH:22][C@H:23]([C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH:20][S:48]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)(=[O:50])=[O:49])[CH:16]=2)[C:11]1=[O:21])([CH3:4])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)CC(NC(CCN1C(=O)c2ccc(N)cc2C1=O)C(=O)OC(C)(C)C)C(=O)NCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C[C@H](N[C@H](CCN1C(=O)c2ccc(NS(=O)(=O)c3ccccc3)cc2C1=O)C(=O)OC(C)(C)C)C(=O)NCc1ccccc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
58 mg of 2-[1-(benzylamino)carbonyl-3-methyl-butylamino]-4-(5-amino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butanoic acid-1,1-dimethylethyl ester, prepared as in Example 73 where the protecting group Rp, 1,1-dimethylethyl, was not removed following the condensation reaction seen in Scheme 2, was added to 4 mL dichloromethane under nitrogen. The mixture was cooled to 0° C. and 0.015 mL benzenesulfonyl chloride was added immediately followed by 0.1 mL pyridine. The mixture was allowed to warm to room temperature and was stirred for 18 h. The solvent was removed by evaporation and the residue was purified by reverse phase H.P.L.C. The solvent was removed by evaporation to afford the title compound; 31.8 mg
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:23]([N:28]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[S:53](=[O:56])(=[O:55])[NH2:54])=[CH:43][CH:42]=1)[C:29]([N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32]1)=[O:30])[CH2:24][CH2:25][CH2:26][CH3:27].N12CCCN=C1CCCCC2>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:54][S:53]([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[C:44]1[CH:43]=[CH:42][C:41]([CH2:40][N:28]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:29]([N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33][CH2:32]2)=[O:30])=[CH:46][CH:45]=1)(=[O:56])=[O:55])=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: CCCCCN(Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1)C(=O)N1CCc2ccccc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCCCCN(Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1)C(=O)N1CCc2ccccc21
Temperature: 55 °C
Reaction time: 29 h
Yield: 67.8 %

Procedure:
A solution of 21 mg (0.13 mmole) of 2-chlorobenzoic acid and 22 mg (0.13 mmole) of 1,1'-carbonyldiimidazole (CDI) in 0.8 mL of THF was stirred under N2 at 65° C. for 2.5 hours. Subsequently, a solution of 32 mg (0.067 mmole) of 1-[N-pentyl-N-[(2'-sulfamoylbiphenyl-4-yl)methyl]carbamoyl]indoline (from Step B) and 20 μL (0.13 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in 0.8 mL of THF was added. After stirring for 29 hours at 55° C., the mixture was partitioned between EtOAc and 5% citric acid (aqueous). The organic layer was washed with water and brine, then dried over sodium sulfate. After filtration and removal of volatiles, the crude product was flash chromatographed over silica gel (gradient elution with 0.5-1.0% MeOH in CH2Cl2) to give 28 mg (68%) of the title compound as an off-white solid, mp 83°-85° C.; homogeneous by TLC (95:5 MeOH--CH2Cl2); FAB-MS m/e 616 (M+1)+.
Reaction SMILES: [CH3:1][N:2]([CH2:24][CH2:25][CH3:26])[C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([Sn](CCCC)(CCCC)CCCC)=[CH:6][CH:5]=1.Br[C:28]1[N:29]=[C:30]([N:38]2[CH2:43][CH2:42][N:41]([CH2:44][CH3:45])[CH2:40][CH2:39]2)[C:31]2[C:36]([CH:37]=1)=[CH:35][CH:34]=[CH:33][CH:32]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:44]([N:41]1[CH2:40][CH2:39][N:38]([C:30]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:37]=[C:28]([C:7]3[CH:6]=[CH:5][C:4]([C:3](=[O:23])[N:2]([CH3:1])[CH2:24][CH2:25][CH3:26])=[CH:9][CH:8]=3)[N:29]=2)[CH2:43][CH2:42]1)[CH3:45]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(=O)N(C)CCC)cc1
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCCN(C)C(=O)c1ccc(-c2cc3ccccc3c(N3CCN(CC)CC3)n2)cc1
Yield: 54.3 %

Procedure:
N-Methyl-N-propyl-4-tributylstannylbenzamide (2.36 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (1.02 g) were heated under reflux overnight in the presence of tetrakistriphenylphosphinepalladium(0) (0.15 g) in xylene in nitrogen atmosphere. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 2N hydrochloric acid. The aqueous layer was washed with ethyl acetate and adjusted to pH 10 by a 8N aqueous solution of sodium hydroxide, and then extracted with ethyl acetate, washed with a 10% aqueous solution of sodium carbonate and brine and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 0.72 g of the free compound of the title compound as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7](F)[C:3]=1[C:4]([NH2:6])=[O:5].C([O-])([O-])=O.[K+].[K+].[C:19]([NH:26][CH2:27][CH2:28][NH2:29])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].CC(N(C)C)=O>C(OCC)(=O)C>[C:4]([C:3]1[C:2]([Cl:1])=[C:10]([Cl:11])[CH:9]=[CH:8][C:7]=1[NH:29][CH2:28][CH2:27][NH:26][C:19](=[O:20])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])(=[O:5])[NH2:6]
Reactant: NC(=O)c1c(F)ccc(Cl)c1Cl
Reactant: CC(C)(C)OC(=O)NCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)NCCNc1ccc(Cl)c(Cl)c1C(N)=O
Temperature: 140 °C
Yield: 81.8 %

Procedure:
A mixture of 2,3-dichloro-6-fluorobenzamide (4.0 g, 19.32 mmol.), K2CO3 (5.33 g, 38.64 mmol), and N-Boc-ethylenediamine (3.41 g, 21.25 mmol) and dimethylacetamide (50 mL). was heated at 140° C. for 18 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL) and washed with a solution of aqueous saturated sodium bicarbonate (3×100 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated to give the title compound (5.50 g, 82% yield) as a brown gum.
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]([S:8][C:9]1[S:13][C:12]([NH:14][C:15]([N:17]([CH2:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[O:16])=[N:11][CH:10]=1)([CH3:7])[CH3:6])C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC(S(C)(=O)=O)=CC=2)CCCC1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[CH:29]1([CH2:28][N:17]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:20][CH:19]=2)[C:15](=[O:16])[NH:14][C:12]2[S:13][C:9]([S:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:34])=[O:3])=[CH:10][N:11]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CCOC(=O)C(C)(C)Sc1cnc(NC(=O)N(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)s1
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: CS(=O)(=O)c1ccc(NCC2CCCC2)cc1
Product: CC(C)(Sc1cnc(NC(=O)N(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)s1)C(=O)O

Procedure:
The title compound was prepared via 2-{2-[3-cyclopentylmethyl-3-(4-methanesulfonylphenyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(4-methanesulfonyl-phenyl)-amine and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: C([O:4][C:5]1[C:15]([O:16][C:17](=[O:19])[CH3:18])=[CH:14][C:8]2[C:9](=[O:13])[N:10]([CH3:12])[S:11][C:7]=2[CH:6]=1)(=O)C>N1CCOCC1.CN(C)C=O>[OH:4][C:5]1[C:15]([O:16][C:17](=[O:19])[CH3:18])=[CH:14][C:8]2[C:9](=[O:13])[N:10]([CH3:12])[S:11][C:7]=2[CH:6]=1
Reactant: CC(=O)Oc1cc2sn(C)c(=O)c2cc1OC(C)=O
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: CC(=O)Oc1cc2c(=O)n(C)sc2cc1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of acetic acid 6-acetoxy-2-methyl-3-oxo-2,3-dihydro-benzo[d]isothiazol-5-yl ester (0.21 g) in dimethylformamide morpholine (0.070 g) was added at 0° C. The mixture was stirred at 0° C. for one hour and then poured to ice water. The precipitated product was filtered.
Reaction SMILES: [CH3:1][Mg]Cl.[CH3:4][N:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8](=[O:15])[N:7]([C:16]2[CH:17]=[CH:18][C:19]3[S:23][N:22]=[C:21]([CH:24]=[O:25])[C:20]=3[CH:26]=2)[C:6]1=[O:27]>O1CCCC1>[OH:25][CH:24]([C:21]1[C:20]2[CH:26]=[C:16]([N:7]3[C:8](=[O:15])[CH:9]=[C:10]([C:11]([F:12])([F:13])[F:14])[N:5]([CH3:4])[C:6]3=[O:27])[CH:17]=[CH:18][C:19]=2[S:23][N:22]=1)[CH3:1]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C=O)c3c2)c1=O
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(O)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Temperature: 25 °C
Yield: 711.3 %

Procedure:
Methyl magnesium chloride (14.1 ml, 0.0422 mol) is added dropwise to a solution of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-carboxaldehyde (6.00 g, 0.00170 mol) in tetrahydrofuran at -78° C. over 15 minutes. The resultant mixture is stirred at -78° C. for 30 minutes, quenched with saturated ammonium chloride and allowed to warm to room temperature. After dilution with ethyl acetate, the mixture is washed with saturated ammonium chloride, water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to a solid. The solid is chromatographed on silica gel with hexanes/ethyl acetate to give the title compound as a white crystalline solid (4.49 g, 71.1%) which is identified by NMR spectral analysis.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH:9]([CH3:20])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:21][CH:22]1[CH2:27][NH:26][CH2:25][CH2:24][NH:23]1>>[CH3:21][CH:22]1[NH:23][CH2:24][CH2:25][N:26]([C:2]2[C:7]([O:8][CH:9]([CH3:20])[CH2:10][O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:27]1
Reactant: COc1ccccc1OCC(C)Oc1nccnc1Cl
Reactant: CC1CNCCN1
Product: COc1ccccc1OCC(C)Oc1nccnc1N1CCNC(C)C1

Procedure:
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-[2-(2-methoxyphenoxy)-1-methylethoxy]pyrazine* (150 mg, 0.51 mmol) and 2-methylpiperazine (260 mg, 2.6 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 118 mg (65%) of the title product. HRMS m/z calcd for C19H26N4O3M)+358.2005, found 358.2018. Anal. (C19H26N4O3) C, H, N.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[CH3:11])([O-:3])=[O:2].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16].CN(C)C=O>CO>[CH3:14][N:15]([CH3:17])/[CH:16]=[CH:11]/[C:5]1[CH:6]=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: Cc1ccc(C)c([N+](=O)[O-])c1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(/C=C/N(C)C)c([N+](=O)[O-])c1
Yield: 82.6 %

Procedure:
A 12-l. three-necked flask, equipped with a thermometer, a mechanical stirrer and a 60 cm. vacuum-jacketed silvered column with glass helice packing connected to a total-condensation, variable take-off still head with receiver was charged under nitrogen with 675 g (4.46 moles) of 2-nitro-1,4-dimethylbenzene, 736 g (6.17 moles) of N,N-dimethyl formamide dimethyl acetal and 3.0 l of N,N-dimethylformamide. The mixture was stirred and heated with a heating mantle for 37 hours. The pot temperature was gradually raised from 130° to 144° while the formed methanol was removed by distillation. The fractionating column was replaced by a distilling head with condenser and receiver (cooled in a dry ice-acetone bath). The dimethylformamide was removed by distillation, first at aspirator vacuum and then at high vacuum (water bath 70°), giving a residue of 924 g (100%) of crude product as a dark red viscous oil. This material was poured into a beaker and mixed thoroughly with 640 ml of methyl alcohol. The mixture was stirred in an ice bath until the product crystallized in mass and was then refrigerated overnight. The precipitate was collected by suction filtration, washed with 320 ml of methyl alcohol and dried in vacuo at room temperature (constant weight) to afford 760 g (83%) of product as a free-flowing, dark-red crystalline solid, m.p. 41.5-43.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19]([NH:21][NH2:22])=[O:20])=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([CH3:23])[CH:3]=1.[C:24](=S)=[S:25].[OH-].[K+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19]3[O:20][C:24]([SH:25])=[N:22][N:21]=3)=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([CH3:23])[CH:3]=1
Reactant: S=C=S
Reactant: Cc1cc(Cl)ccc1Nc1c(C(=O)NN)cc2[nH]cnc2c1F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Cl)ccc1Nc1c(-c2nnc(S)o2)cc2[nH]cnc2c1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6-(4-Chloro-2-methyl-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid hydrazide 20b (0.050 g, 0.150 mmol) is suspended in 3 mL absolute EtOH and cooled to 0° C. under N2. CS2 is added (26 mg, 0.346 mmol) followed by powdered KOH (8 mg, 0.150 mmol). After stirring at 0° C. for 30 minutes, the reaction mixture is heated to reflux. After 3.5 hours, the reaction mixture is quenched by the addition of water, followed by the addition of ethyl acetate and 1N HCl. The layers are separated and the aqueous layer is extracted with ethyl acetate. The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure to give the desired product as a yellow solid: LC/MS ESI (+) m/z 376, 378 (M+ Cl pattern) detected; 1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.92 (s, 1H), 7.19 (s, 1H), 7.12 (s, 1H), 6.98 (d, 1H), 6.29 (d, 1H), 2.28 (s, 3H).