Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21](O)=[O:22])[CH:19]=3)[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:55]([O:57][C:58](=[O:66])[CH2:59][C:60]1[N:61]=[C:62]([NH2:65])[S:63][CH:64]=1)[CH3:56]>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH2:55]([O:57][C:58](=[O:66])[CH2:59][C:60]1[N:61]=[C:62]([NH:65][C:21]([C:18]2[CH:19]=[C:20]3[C:15]([CH2:14][CH2:13][N:12]3[S:9]([C:4]3[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=3)(=[O:11])=[O:10])=[CH:16][CH:17]=2)=[O:22])[S:63][CH:64]=1)[CH3:56]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: Cc1cc(C)cc(S(=O)(=O)N2CCc3ccc(C(=O)O)cc32)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)Cc1csc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(C)cc(C)c2)CC3)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(3,5-dimethyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid (0.20 g, 0.60 mmol) in dimethylformamide (1.00 mL) under argon was treated with N-methyl morpholine (0.31 g, 0.33 mL, 3.01 mmol), HATU (0.34 g, 0.90 mmol) and (2-amino-thiazol-4-yl)-acetic acid ethyl ester (0.17 g, 0.91 mmol). The mixture was stirred at room temperature for 30 min, then treated with 4-dimethylaminopyridine (0.07 g, 0.60 mmol). The mixture was warmed to 60° C. and stirred for 50 hours. After cooling to room temperature the mixture was partitioned between water and ethyl acetate. The organic phase was washed with brine, dried over magnesium sulphate and evaporated. The residue was purified via flash chromatography (heptane/ethyl acetate gradient) to yield (2-{[1-(3,5-dimethyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-thiazol-4-yl)-acetic acid ethyl ester as an off-white solid, 0.10 g (35%), MS (ISP): m/e=500.4 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:15][N:16]1[CH:21]2[CH2:22][CH2:23][CH:17]1[CH2:18][C:19](=[O:24])[CH2:20]2>O1CCCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:19]2([OH:24])[CH2:20][CH:21]3[N:16]([CH3:15])[CH:17]([CH2:23][CH2:22]3)[CH2:18]2)=[CH:3][CH:4]=1
Reactant: CN1C2CCC1CC(=O)C2
Reactant: COc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CC3CCC(C2)N3C)cc1

Procedure:
The title compound was prepared from 4-bromoanisole (15.1 g, 80.5 mmol), n-butyllithium in hexanes (31.2 mL, 2.5 M; 77.9 mmol) and 8-methyl-8-azabicyclo-[3.2.1]octan-3-one (5 g, 36 mmol) in anhydrous tetrahydrofuran (40 mL). Yield 2.1 g (24%), m.p. 161.8-162.3° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:23][C:24]([F:32])([F:31])[CH:25]([F:30])[C:26]([F:29])([F:28])[F:27])=[N:4][N:5]([C:9]2[CH:14]=[C:13]([S:15][CH2:16][C:17]([F:20])([F:19])[F:18])[C:12]([CH3:21])=[CH:11][C:10]=2[F:22])[C:6]=1[NH:7][CH3:8].ClC1C=CC=C(C(OO)=[O:41])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([O:23][C:24]([F:31])([F:32])[CH:25]([F:30])[C:26]([F:27])([F:28])[F:29])=[N:4][N:5]([C:9]2[CH:14]=[C:13]([S:15]([CH2:16][C:17]([F:20])([F:19])[F:18])=[O:41])[C:12]([CH3:21])=[CH:11][C:10]=2[F:22])[C:6]=1[NH:7][CH3:8]
Reactant: CNc1c(Cl)c(OC(F)(F)C(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CNc1c(Cl)c(OC(F)(F)C(F)C(F)(F)F)nn1-c1cc(S(=O)CC(F)(F)F)c(C)cc1F
Reaction time: 1 h
Yield: 97 %

Procedure:
0.24 g of 4-chloro-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(1,1,2,3,3,3-hexafluoropropoxy)-5-methylaminopyrazole was dissolved in 10 mL of chloroform, and 120 mg of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for one hour under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogen carbonate solution, and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 0.24 g of 4-chloro-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-3-(1,1,2,3,3,3-hexafluoropropoxy)-5-methylaminopyrazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:4]=1[CH2:10][CH:11]=[CH:12][CH2:13][O:14][CH3:15]>O1CCCC1.[Pt]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:4]=1[CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: COCC=CCc1cc(Br)ccc1OC
Agent: [Pt]
Solvent: C1CCOC1
Product: COCCCCc1cc(Br)ccc1OC

Procedure:
A solution of 50 g of 4-methoxy-3-(4-methoxy-2-butenyl)-bromobenzene in 700 ml of tetrahydrofuran is hydrogenated for 2 hours under normal pressure and at room temperature in the presence of 2.5 g of 5% Pt/C. The reaction mixture is filtered. The filtrate is concentrated by evaporation. The evaporation residue obtained from the filtrate is purified by FC (1.6 kg of silica gel, hexane/ethyl acetate=20:1). Distillation under a high vacuum yields the title compound: Rt (hexane/ethyl acetate=10:1)=0.38; HPLC Rt =19.92 minutes; FAB-MS (M+H)+ =273.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.[F:21][C:22]1[CH:36]=[CH:35][C:25]2[C:26]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:27][O:28][C:24]=2[CH:23]=1>CN(C)C=O.C(O)C>[F:21][C:22]1[CH:36]=[CH:35][C:25]2[C:26]([CH:29]3[CH2:30][CH2:31][N:32]([CH2:3][C@@H:2]([OH:1])[CH2:4][O:5][C:6]4[CH:11]=[CH:10][CH:9]=[C:8]([C:12]5[C:20]6[C:15](=[N:16][CH:17]=[CH:18][CH:19]=6)[O:14][N:13]=5)[CH:7]=4)[CH2:33][CH2:34]3)=[N:27][O:28][C:24]=2[CH:23]=1
Reactant: c1cc(OC[C@H]2CO2)cc(-c2noc3ncccc23)c1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@@H](COc1cccc(-c2noc3ncccc23)c1)CN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
The title compound is prepared from a mixture of (R)-3-(3-oxiranylmethoxy-phenyl)-isoxazolo[5,4-b]pyridine in dimethylformamide and ethanol and 6-fluoro-3-piperidine-4-yl-benzo[d]isoxazole (Table No. 1, SM 8) in ethanol essentially as described above in Example 102. Purity by LC/MS=100%, [M+H]+=489.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=2[O:13][C:12]1=[O:21].[OH-].[Na+]>>[CH3:20][C:18]1[CH:17]=[CH:16][C:15]2[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:22])=[O:2])[C:12](=[O:21])[O:13][C:14]=2[CH:19]=1
Reactant: COC(=O)CCCCCCCn1c(=O)oc2cc(C)ccc21
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc2c(c1)oc(=O)n2CCCCCCCC(=O)O

Procedure:
The product is produced as described in example 22 from 31 g. of 8-(6-methyl-2-oxo-benzoxazolin-3-yl)-caprylic acid methyl ester and 4.4 g. of NaOH. Eluant in chromatographic purification: chloroform.
Reaction SMILES: CO.[CH2:3]([N:10]([CH2:29][CH2:30][C:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:11][CH2:12][C:13]1[CH:28]=[CH:27][C:16]([O:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=2)=[CH:15][CH:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[BH4-].[Na+]>[Cl-].[Na+].O>[CH2:3]([N:10]([CH2:29][CH2:30][CH:31]([OH:38])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:11][CH2:12][C:13]1[CH:28]=[CH:27][C:16]([O:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=2)=[CH:15][CH:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NC(=O)c1ccc(Oc2ccc(CCN(CCC(=O)c3ccccc3)Cc3ccccc3)cc2)nc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CCN(CCC(O)c3ccccc3)Cc3ccccc3)cc2)nc1
Temperature: 0 °C
Yield: 12.7 %

Procedure:
Add methanol (10 mL) to 6-(4-{2-[benzyl-(3-oxo-3-phenyl-propyl)-amino]-ethyl}-phenoxy)-nicotinamide (0.1871 g, 0.3901 mmol) and cool to 0° C. Add sodium borohydride (0.0664 g, 1.756 mmol) and stir for 1.5 h at 0° C. under nitrogen. Pour the reaction into brine (50 mL) and extract with diethyl ether (3×50 mL). Dry the diethyl ether extracts over magnesium sulfate, filter, and concentrate on a rotary evaporator to give the crude product. The crude product is purified by flash chromatography on silica gel eluting with 100% ethyl acetate to yield 0.0239 g (13%) of 6-(4-{2-[benzyl-(3-hydroxy-3-phenyl-propyl)-amino]-ethyl}-phenoxy)-nicotinamide: HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron: Retention time: 8.07 minutes, Purity: 99.9%; mass spectrum (ion spray): m/z=482.3 (M+1).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:37]=[CH:36][C:17]([CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH2:28][C:29]([O:31]CC)=[O:30])[C:20]=2[CH2:34][CH3:35])=[CH:16][CH:15]=1)=[O:12].O.[OH-].[Li+].O1CCCC1.Cl>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH2:28][C:29]([OH:31])=[O:30])[C:20]=2[CH2:34][CH3:35])=[CH:36][CH:37]=1)=[O:12]
Reactant: CCOC(=O)Cn1c(CC)c(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1c(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ccccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
Into a dry reaction vessel, ethyl 2-[3-[4-(2-naphthamido)benzyl]-2-ethyl-1H-indol-1-yl]acetate (340 mg, 0.69 mmol), lithium hydroxide monohydrate (117 mg, 2.79 mmol), 5 mL tetrahydrofuran, 5 mL water were weighed, and stirred at room temperature for 2 h. The reaction was monitored to be complete by TLC, the system was added 10 mL water, and adjusted to pH=5 with 2 N HCl solution. A solid precipitated, it was pumping filtered, washed with dichloromethane to obtain the product as a light yellow solid 240 mg, at a yield of 75.2%.
Reaction SMILES: [H-].[Na+].C([O:7][C:8](=[O:35])[C:9]([S:12][C:13]1[S:14][CH:15]=[C:16]([CH:18]([OH:34])[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[N:17]=1)([CH3:11])[CH3:10])(C)(C)C.[CH3:36]I.O>CN(C=O)C>[F:33][C:30]1[CH:29]=[CH:28][C:27]([C:24]2[CH:25]=[CH:26][C:21]([O:20][CH2:19][CH:18]([C:16]3[N:17]=[C:13]([S:12][C:9]([CH3:10])([CH3:11])[C:8]([OH:7])=[O:35])[S:14][CH:15]=3)[O:34][CH3:36])=[CH:22][CH:23]=2)=[CH:32][CH:31]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(C(O)COc2ccc(-c3ccc(F)cc3)cc2)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(COc1ccc(-c2ccc(F)cc2)cc1)c1csc(SC(C)(C)C(=O)O)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% oil suspension, 24 mg) was suspended in DMF (5 mL), and a solution of 2-[(4-{2-[(4′-fluorobiphenyl-4-yl)oxy]-1-hydroxyethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (331 mg) obtained in Example 2-2 in DMF (1.5 mL) was added. After cease of foaming, methyl iodide (0.12 mL) was added, and the mixture was stirred at room temperature for 30 min. Water (20 mL) was added, and the mixture was stirred, extracted with ethyl acetate (50 mL), washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by column chromatography (Fuji Silysia silica gel BW300 was used. elution solvent: hexane/ethyl acetate-9/1-7/3) to give tert-butyl ester of the title compound (222 mg). By an operation similar to that in Example 2-3 and using the compound, the title compound (177 mg) was obtained.
Reaction SMILES: CC(C)(OC([NH:7][CH:8]([CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)[C:9]([O:11][CH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=1)=[O:10])=O)C.[ClH:32]>O1CCCC1>[ClH:32].[NH2:7][CH:8]([CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)[C:9]([O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH3:20])[CH:16]=[C:17]([CH3:19])[CH:18]=1)=[O:10]
Reactant: Cc1cc(C)cc(COC(=O)C(Cc2c[nH]c3ccccc23)NC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(C)cc(COC(=O)C(N)Cc2c[nH]c3ccccc23)c1
Reaction time: 16 h

Procedure:
3,5-Dimethylbenzyl 2-(1,1-dimethylethoxycarbonylamino)-3-(3-indolyl)propionate (1.0 g) was dissolved in dry tetrahydrofuran (20 ml). Saturated methanolic hydrochloric acid (10 ml) was added and the reaction was stirred for 16 hours. The solvent was removed in vacuo and the residue was recrystallised from ethanol/diethyl ether to yield 3,5-dimethylbenzyl 2-amino-3-(3-indolyl)propionate hydrochloride (0.71 g), m.p. 213°-214° C. 1H NMR (360 MHz D6DMSO) δ11.09 (1H, s), 8.64 (1H, s), 7.51 (1H, d, J=7 Hz), 7.38 (1H, d, J=7 Hz), 7.20 (1H, d, J=2 Hz), 7.10 (1H, t, J=7 Hz), 6.98 (1H, t, J=7 Hz), 6.94 (1H, s), 6.76 (2H, s). Found: C, 66.25; H, 6.67; N, 7.71, C20H22N2O2. HCl. 0.25(H2O) requires C, 66.11; H, 6.52; N, 7.71%.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[Br:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[N:12]2.OS(O)(=O)=O>>[Br:6][C:7]1[CH:16]=[CH:15][C:14]([N+:1]([O-:4])=[O:2])=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[N:12]2
Reactant: O=[N+]([O-])[O-]
Reactant: Brc1cccc2ncccc12
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1ccc(Br)c2cccnc12
Yield: 92.2 %

Procedure:
KNO3 (1.58 g, 15.6 mmol) was added portionwise to a solution of 5-bromoquinoline (2.0 g, 12.0 mmol) conc.H2SO4 (7.5 ml) at 0° C. and the mixture was stirred at room temperature for 16 h. The mixture was poured onto ice and the resulting solid was extracted into DCM. The organic phase was washed with brine, dried (Na2SO4) and concentrated in vacuo to give the title compound (2.8 g, 92%) which was used in the next step without further purification.
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].[NH2:16][CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].Cl.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([NH:16][CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:8])[CH:3]([CH3:4])[CH3:5]
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
Boc-Val-OH (8.69 g, 40.0 mmol) and Gly-OBzl.HCl (8.07 g, 40.0 mmol) were dissolved in methylene chloride (100 ml), and the solution was maintained at 0° C. Triethylamine (6.13 ml, 44.0 mmol), HOBt (1-hydroxybenzotriazole, 6.74 g, 44.0 mmol), and WSC.HCl (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 8.44 g, 44.0 mmol) were added to the solution, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (200 ml). The solution was washed with water (50 ml), 5% citric acid aqueous solution (50 ml×twice), saturated brine (50 ml), 5% sodium hydrogencarbonate aqueous solution (50 ml×twice), and saturated brine (50 ml). The organic layer was dried over anhydrous magnesium sulfate, then the magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to obtain white crystals of Boc-Val-Gly-OBzl (13.2 g, 36.2 mmol).
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10]([N:13]=[C:14]=[O:15])(=[O:12])=[O:11])(=[O:4])=[O:3].[CH3:16][O:17][C:18]1[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH2:25])[N:19]=1.C1N2CCN(CC2)C1>C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH:25][C:14]([NH:13][S:10]([C:9]2[CH:8]=[CH:7][S:6][C:5]=2[S:2]([CH3:1])(=[O:4])=[O:3])(=[O:11])=[O:12])=[O:15])[N:19]=1
Reactant: CS(=O)(=O)c1sccc1S(=O)(=O)N=C=O
Reactant: COc1cc(C)nc(N)n1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccsc2S(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The crude 2-methylsulfonyl-3-thiophenesulfonyl isocyanate described above was dissolved in 100 ml of methylene chloride and 10 ml of this solution (0.3 g of crude isocyanate) was added to 200 mg of 4-methoxy-6-methyl-2-pyrimidinamine in methylene chloride containing a few crystals of DABCO. After stirring 3 days at room temperature, the precipitate was filtered and washed with ether to afford 250 mg of product, m.p. 204.5°-206° d. The IR spectrum showed a carbonyl absorption at 1680 cm-1 indicative of a sulfonylurea.
Reaction SMILES: [ClH:1].[N:2]1([C:8]2[S:9][CH2:10][C:11](=[NH:13])[N:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[NH:14]=[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=N)[NH:16]1>CO>[ClH:1].[NH:14]=[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[C:10]2[S:9][C:8]([N:2]3[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)=[N:12][C:11]2=[NH:13])[NH:16]1
Reactant: N=C1CSC(N2CCCCC2)=N1
Reactant: N=C1NC(=N)c2ccccc21
Agent: Cl
Solvent: CO
Product: N=C1N=C(N2CCCCC2)SC1=C1NC(=N)c2ccccc21
Temperature: 0 °C

Procedure:
To a solution of 21.9 parts of 2-piperidino-4-imino-2-thiazoline hydrochloride in 240 parts of methyl alcohol there was added 14.5 parts of 1,3-diiminoisoindoline. The resultant mixture was heated at reflux for six hours, then chilled to 0° C and filtered. The collected solid was washed with methyl alcohol and dried at 50° C to obtain 27 parts of 1-imino-3-(2-piperidino-4-imino-2-thiazolin-5-ylidene)isoindoline hydrochloride melting at 320°-321° C (dec). The assigned chemical structure was completely corroborated by a concordant nuclear magnetic resonance spectrum. The hydrochloride salt is readily converted to the free base, a colorless solid melting at 226°-227°C, by treatment with dilute ammonium hydroxide. This compound, which corresponds to Formula VIII wherein R, R1, R2 and R3 are each hydrogen and N=B is piperidino, was found on testing in vitro by standard serial dilution procedures to be bacteriostatic versus: Staphylococcus aureus 209 at a minimal concentration of 6.3 parts per million; Esherichia coli at 62.5 parts per million; Pseudomonas aeruginosa 211 at 125 parts per million; and fungicidal versus Tricophyton mentogrophytes at 62.5 parts per million; Aspergillus niger at > 125 parts per million; and Candida albicans at 125 parts per million.
Reaction SMILES: [CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[C:27](=[O:28])[CH:26]=[CH:25][CH:24]=[N:23]5)=[CH:18][CH:17]=4)=[CH:12][CH:11]=3)[CH2:6][CH2:7]2)[CH2:3]1.[OH:29]O>C(Cl)Cl.CO>[CH3:1][N@+:2]1([O-:29])[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[C:27](=[O:28])[CH:26]=[CH:25][CH:24]=[N:23]5)=[CH:18][CH:17]=4)=[CH:12][CH:11]=3)[CH2:6][CH2:7]2)[CH2:3]1
Reactant: CN1C[C@H]2CCN(c3ccc(-c4ccc(-n5ncccc5=O)cc4)cc3)[C@H]2C1
Reactant: OO
Solvent: CO
Solvent: ClCCl
Product: C[N@+]1([O-])C[C@H]2CCN(c3ccc(-c4ccc(-n5ncccc5=O)cc4)cc3)[C@H]2C1
Temperature: 50 °C

Procedure:
A solution of the product from Example 1G (5 g, 13.44 mmol) in DCM (80 mL) and MeOH (40 mL) was treated with hydrogen peroxide (5.2 mL, 30% in H2O, 53.8 mmol). The mixture was heated to 50° C. for 48 hours. The mixture was concentrated under reduced pressure to a smaller volume while still in a solution. The solution was loaded onto an ANALOGIX SuperFlash silica gel column (ANALOGIX is a registered trademark of Analogix Inc. of Burlington, Wis.) and eluted with NH4OH /MeOH/DCM (1/10/90) to obtain the slower moving component (comparing with Example 1H) as the title product. 1H NMR (300 MHz, DMSO) δ ppm 8.07 (m, 1 H), 7.70 (d, J=9 Hz, 2 H), 7.57 (d, J=9 Hz, 4 H), 7.50 (d, J=6 Hz, 1 H), 7.08 (dd, dd, J=9, 4.0 Hz, 1 H), 6.65 (d, J=9 Hz, 2 H), 4.48-4.54 (m, 1 H), 3.81-3.87 (m, 1 H), 3.66-3.74 (m, 2 H), 3.36-3.42 (m, 2 H), 3.24 (m, 1 H), 3.09 (s, 3 H), 2.11-2.17 (m, 1 H); MS (DCI,) M+=388.
Reaction SMILES: [H-].[Na+].O1CCCC1.[CH3:8][O:9][C:10](=[O:28])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][S:18][C:19]1[NH:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.[C:29]([O:33][C:34](=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41]Br)([CH3:32])([CH3:31])[CH3:30]>O>[CH3:8][O:9][C:10](=[O:28])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][S:18][C:19]1[N:20]([CH2:41][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:43])[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1
Reactant: CC(C)(C)OC(=O)c1ccccc1CBr
Reactant: COC(=O)c1ccccc1CSc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1CSc1nc2ccccc2n1Cc1ccccc1C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 0.83 h
Yield: 70.8 %

Procedure:
Sodium hydride (104 mg, 2.86 mmol) and tetrahydrofuran (16 ml) were added to a previously dried reaction vessel. To the mixture were added 2-(benzimidazole-2-ylthiomethyl)benzoic acid methyl ester (428 mg, 1.43 mmol) and 2-(bromomethyl)benzoic acid t-butyl ester (466 mg, 3.46 mmol), and then the mixture was stirred at 60° C. for 50 minutes. Water was added thereto, followed by extraction with ethyl acetate. After the ethyl acetate phase was dried with anhydrous sodium sulfate, it was concentrated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate=3:1) to obtain 2-((1-((2-((t-butyl)oxycarbonyl)phenyl)methyl)benzimidazole-2-ylthio)methyl)benzoic acid methyl ester (495 mg, yield 71%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([C:13]2[CH:14]=[N:15][C:16]([N:19]([CH3:21])[CH3:20])=[N:17][CH:18]=2)[C:5]([O:11][CH3:12])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+]>CO.C(#N)C>[NH2:29][CH:8]([C:6]1[C:5]([O:11][CH3:12])=[C:4]([C:13]2[CH:14]=[N:15][C:16]([N:19]([CH3:21])[CH3:20])=[N:17][CH:18]=2)[C:3]([CH3:22])=[C:2]([Cl:1])[CH:7]=1)[CH3:9]
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1-c1cnc(N(C)C)nc1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: COc1c(C(C)N)cc(Cl)c(C)c1-c1cnc(N(C)C)nc1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-3-[2-(dimethylamino)pyrimidin-5-yl]-2-methoxy-4-methylphenyl}ethanone (60 mg, 0.2 mmol), ammonium acetate (150 mg, 1.9 mmol) and sodium cyanoborohydride (24 mg, 0.38 mmol) in methanol (0.7 mL) and acetonitrile (0.7 mL) was heated at 65° C. overnight in a sealed tube. The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step (60 mg, 100%). LCMS calculated for C16H22ClN4O (M+H)+: m/z=321.1. found: 321.1.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH2:12]=[C:13]([CH3:15])[CH3:14]>C(OCC)C>[Br:6][CH2:7][CH2:8][C:9]([O:11][C:13]([CH3:15])([CH3:14])[CH3:12])=[O:10]
Reactant: C=C(C)C
Reactant: O=C(O)CCBr
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CCBr
Temperature: -20 °C

Procedure:
7 ml of sulfuric acid were added to a solution of 100 g of 3-bromopropionic acid in 200 ml of diethyl ether, and the reaction mixture was cooled to -20° C. Then 123 ml of liquified isobutene were added. The reaction mixture was stirred at room temperature in a pressure vessel for several hours. Subsequently, for working up, the reaction mixture was poured into dilute ice-cold aqueous sodium hydroxide solution. The ether phase was separated and the aqueous phase was extracted once more with ether. The combined organic phases were washed with aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. The resulting crude product was distilled under reduced pressure. 100 g of tert-butyl 3-bromopropionate were obtained, boiling point (20)=75° to 77° C.