Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:7]([O:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[C:6]([O:19][CH3:20])[CH:5]=1)([OH:3])=[O:2].O.[C:22]1(C)[CH:27]=CC(S(O)(=O)=O)=C[CH:23]=1.C(O)C=C>>[C:1]([C:4]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:7]([O:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[C:6]([O:19][CH3:20])[CH:5]=1)([OH:3])=[O:2].[CH3:27][CH:22]=[CH2:23]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OCCC(=O)O
Solvent: O
Solvent: C=CCO
Product: C=CC

Procedure:
A mixture of 3-(4-carboxy-2-methoxy-5-nitrophenoxy)propanoic acid 1 (20 g, 74.3 mmol) and p-toluene sulphonic acid monohydrate (2.3 g, 7.4 mmol) in allyl alcohol (240 mL, 3.5 mol) was refluxed for 7 hours then allowed to cool. The allyl alcohol was then removed in vacuo, and the residue triturated with dilute HCl acid (3×75 ml) and collected by filtration. This solid was taken up in EtOAc, and the resulting solution washed with water (3×50 ml) and brine (3×50 ml) and dried over sodium sulphate. Evaporation in vacuo afforded 2 as a white solid (19.27 g, 84%): mp 128-130° C.; 1H-NMR (270 MHZ, CDCl3) δ2.92 (t, 2H, J=6.35 Hz); 3.94 (s, 3H); 4.38 (t, 2H, J=6.41 Hz); 4.65 (d, 2H, J=5.61 Hz); 5.27 (dd, 1H, J1=1.28 Hz, J2=19.42 Hz); 5.33 (dd, 1H, J1=1.28 Hz, J2=17.04 Hz); 5.92 (m, 1H); 7.15 (s, 1H); 7.45 (s, 1H); 13C NMR (67.8 MHZ, CDCl3): δ34.1, 56.5, 65.0, 65.4, 108.5, 111.3, 118.3, 122.9, 131.8, 141.1, 149.1, 152.6, 167.1, 170.0; IR (Nujol); ν 1730, 1630, 1550, 1430, 1390, 1290, 1230, 1190, 1170, 1070, 1030, 1010 cm−1; MS (EI) m/z (relative intensity): 325 (M+•, 19), 251 (3), 213 (2), 196 (3), 211 (3), 113 (19), 91 (4), 71 (9), 55 (6); HRMS: calcd. for C14H15NO8 325.0798, found 232.0773.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[C:26]([CH3:33])[CH:25]=1>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)=[CH:3][C:2]=1[C:27]1[CH:28]=[CH:29][C:24]([F:23])=[CH:25][C:26]=1[CH3:33]
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: Cc1cc(F)ccc1-c1cc(-c2cnc3c(F)c(C(C)(C)O)ccn23)ccc1F
Yield: 58.2 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol (100 mg, 0.36 mmol) and 4-fluoro-2-methylphenylboronic acid (83 mg, 0.54 mmol) were coupled using the procedure in Example 30 to afford 2-[3-(2,4′-difluoro-2′-methylbiphenyl-5-yl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]propan-2-ol (83 mg, 58%) as a white solid: δH (360 MHz, CDCl3) 1.74 (6H, s), 2.04 (1H, s), 2.26 (3H, s), 6.95-7.05 (2H, m), 7.15-7.33 (3H, m), 7.40 (1H, dd, J 7 and 2), 7.51-7.56 (1H, m), 7.69 (1H, s), 8.06 (1H, d, J 7); m/z (ES+) 397 (100%, [MH]+).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]([OH:14])=[O:13].[CH3:15][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1.CO>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:10])([F:11])[F:9])[C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cn1nc(C(F)(F)F)c(C(=O)O)c1Cl
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1c(C(F)(F)F)nn(C)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (1.00 g, 4.38 mmol) in benzene (5.83 mL) and methanol (2.92 mL) at room temperature was added 2M trimethylsilyldiazomethane (8.75 mL). The resulting solution was stirred at room temperature for 3 hours. Solvent was removed at reduced pressure on a rotary evaporator to yield the title compound (1.06 g, 4.38 mmol, 100% yield) as a white solid. MS m/z 243 (MH+). 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 3.82 (s, 3H) 3.89 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([NH:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:3]=1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](B2OC(C)(C)C(C)(C)O2)=[N:20]1>>[NH:19]1[C:27]2[C:22](=[C:23]([C:2]3[N:7]=[C:6]4[N:8]([CH3:11])[N:9]=[CH:10][C:5]4=[C:4]([NH:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[N:3]=3)[CH:24]=[CH:25][CH:26]=2)[CH:21]=[N:20]1
Reactant: Cn1ncc2c(NC3CCOCC3)nc(Cl)nc21
Reactant: CC1(C)OB(c2n[nH]c3ccccc23)OC1(C)C
Product: Cn1ncc2c(NC3CCOCC3)nc(-c3cccc4[nH]ncc34)nc21

Procedure:
(6-Chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-(tetrahydro-pyran-4-yl)-amine was reacted with indazole boronic acid pinacol ester in General Procedure A. Purification on silica yielded 154. NMR (CDCl3) 1.70-1.80 (m, 2H, CH2), 2.24-2.27 (m, 2H, CH2), 3.67-3.73 (m, 2H, CH2), 4.11-4.14 (m, 2H, CH2), 4.18 (s, 3H, CH3), 4.55 (m, H, CH), 5.32 (sbr, H, NH), 7.55 (t, H, ArH, J=7.76 Hz), 7.63 (d, H, ArH, J=8.27 Hz), 7.92 (s, H, ArH), 8.40 (d, H, ArH, J=7.23 Hz), 9.16 (s, H, ArH), 10.22 (sbr, H, NH). MS: (ESI+) MH+=350.16
Reaction SMILES: [C@H:1]12[NH:8][CH2:7][C@H:6]1[CH2:5][CH2:4][N:3]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2]2.C([O-])([O-])=O.[Na+].[Na+].[C:22](Cl)([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C1COCC1.O>[C@H:1]12[N:8]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:7][C@H:6]1[CH2:5][CH2:4][N:3]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2]2
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2CN[C@@H]2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H]2CN(C(=O)OCc3ccccc3)[C@@H]2C1
Reaction time: 18 h
Yield: 101.9 %

Procedure:
To (1S,6R)-tert-butyl 3,8-diazabicyclo[4.2.0]octane-3-carboxylate (1.4 g, 6.8 mmol) in THF (35 mL) and H2O (35 mL) was added Na2CO3 (1.4 g. 13.6 mmol) and CbzCl (1.1 mL, 7.5 mmol). After 18 h, the reaction mix was diluted with H2O and extracted with CH2Cl2 (2×). The combined organics were dried (Na2SO4) to give 2.4 g of the title compound as a clear oil that was used without further purification.
Reaction SMILES: Br[C:2]1[C:29]([Cl:30])=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:13]([N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:25]3[CH2:27][CH2:26]3)[CH2:17][CH2:16]2)=[O:14])=[C:4]([Cl:31])[CH:3]=1.C([O:35]B(OC(C)C)OC(C)C)(C)C.C([Li])CCC.C(=O)=O.C(O)(=O)C.OO>O1CCCC1>[CH:25]1([N:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:15]([C:13]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]3[CH:28]=[C:29]([Cl:30])[C:2]([OH:35])=[CH:3][C:4]=3[Cl:31])=[O:14])[CH2:16][CH2:17]2)[CH2:27][CH2:26]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: O=C(c1cnccc1Oc1cc(Cl)c(Br)cc1Cl)N1CCN(C2CC2)c2ccccc21
Agent: O=C=O
Agent: OO
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(c1cnccc1Oc1cc(Cl)c(O)cc1Cl)N1CCN(C2CC2)c2ccccc21
Temperature: -75 °C
Reaction time: 1.5 h
Yield: 65.3 %

Procedure:
To a solution of 1.0 g (1.93 mmol) [4-(4-bromo-2,5-dichloro-phenoxy)-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone (Example 26) in 20 mL dry tetrahydrofuran was added 0.85 mL (3.72 mmol) triisopropylborate (commercially available, CAS RN 5419-55-6). The solution was cooled to −75° C. using a dry ice bath and 1.50 mL (2.4 mmol) n-butyllithium solution (1.6M in n-hexane) was added over 3 min. to the reaction mixture. Stirring was continued for another 1.5 hours. The dry-ice bath was replaced by an ice bath and 0.98 g (8.17 mmol) acetic acid (50% solution in water) and 0.28 g (2.89 mmol) hydrogen peroxide (35% solution in water) were added. The reaction mixture was stirred at 0° C. for 1 hour, the cooling batch was removed and stirring was continued at room temperature for 20 hours. The solution was poured on 10% aqueous sodium thiosulfate solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated to dryness. The resulting powder was purified by silica gel chromatography using a MPLC system (20 g silica gel column, CombiFlash Companion, Isco Inc.) with a gradient of n-heptane:ethyl acetate (100:0 to 40:60) to give 0.575 g (65%) of the title compound as a light brown solid. MS (ESI): m/z=456.2 [M+H]+.
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][C:4]#[N:5].[OH-].[Na+].Cl.[NH2:15]O.Cl>O.CCO>[C:6]1([C:2]2[O:1][N:5]=[C:4]([NH2:15])[CH:3]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#CCC(=O)c1ccccc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc(-c2ccccc2)on1
Temperature: 80 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
To a stirred solution of 3-oxo-3-phenylpropanenitrile (1.5 g, 10.3 mmol) and NaOH (452 mg, 11.3 mmol) in water (10 mL)/EtOH (10 mL) was added hydroxylamine hydrochloride (785 mg, 11.3 mmol). The mixture was stirred at 80° C. for overnight. At this point, conc. HCl (1.3 mL, 15.5 mmol) was added and the resulting mixture was heated at 80° C. for 2 h. It was then basified to pH 10 and extracted with ethyl acetate. The combined extract was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with ethyl acetate/petroleum ether (1:50 to 1:10) to afford 299a as a yellow solid (1.1 g, 68%). MS-ESI: [M+H]+ 161.3.
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][O:9][C:10](=[O:25])[C@H:11]([CH2:23]Br)[NH:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10](=[O:25])[C:11](=[CH2:23])[NH:12][C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])=[CH:26][CH:27]=1)([O-:3])=[O:2]
Reactant: O=C(N[C@@H](CBr)C(=O)OCc1ccc([N+](=O)[O-])cc1)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(NC(=O)OCc1ccccc1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101 %

Procedure:
To 20 ml solution of 2.18 g (5 mmols) N-carbobenzoxy-β-bromoalanine p-nitrobenzyl ester in tetrahydrofuran, 1.01 g (10 mmols) triethylamine was added and the mixture was stirred at room temperature for 30 minutes. Solvent was removed under reduced pressure, water was added and the crystals which formed were filtered to obtain 1.80 g (yield 100%) of the desired compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.Cl.[CH2:20]([N:22]([CH2:32][CH3:33])[C:23]1[CH:31]=[CH:30][C:26]([CH2:27][NH:28][NH2:29])=[CH:25][CH:24]=1)[CH3:21].C(N(CC)CC)C>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[OH:9])[N:28]([CH2:27][C:26]2[CH:30]=[CH:31][C:23]([N:22]([CH2:32][CH3:33])[CH2:20][CH3:21])=[CH:24][CH:25]=2)[N:29]=1
Reactant: CCN(CC)c1ccc(CNN)cc1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCN(CC)c1ccc(Cn2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1

Procedure:
5.0 g of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one are boiled under reflux for 18 h with 5.4 g of 4-diethylaminobenzylhydrazine hydrochloride and 6.7 ml of triethylamine in 50 ml of ethanol. The mixture is poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from isopropanol. After drying, 3,5-bis(2-hydroxyphenyl)-1-(4-diethylaminobenzyl)-1H-[1,2,4]triazole remains as colorless crystals of m.p. 125-127° C.
Reaction SMILES: [O:1]=[C:2]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)/[CH:3]=[CH:4]/[C:5]1[O:6][CH:7]=[CH:8][C:9](=[O:22])[C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C([BH-](CC)CC)C.[Li+]>O1CCCC1>[OH:1][CH:2]([CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)/[CH:3]=[CH:4]/[C:5]1[O:6][CH:7]=[CH:8][C:9](=[O:22])[C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CCCCCOc1c(/C=C/C(=O)CCc2ccccc2)occc1=O
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CCCCCOc1c(/C=C/C(O)CCc2ccccc2)occc1=O
Reaction time: 0.5 h
Yield: 28.2 %

Procedure:
To a solution, cooled under nitrogen to -78°, of 0.823 g (1.99 mmol) of 2-(3-oxo-5-phenyl-trans-1-pentenyl)-3-(5-carboethoxypentyloxy)-4-pyrone in 4 ml of tetrahydrofuran was added dropwise keeping the internal temperature at -70° to -75°, 1.89 ml (1.89 mmole) of lithium triethylborohydride. After being stirred for an additional 30 min the cold reaction was quenched by the addition of 2.0 ml of 40% aqueous acetic acid and then partially concentrated under reduced pressure. The residue was dissolved in methylene chloride and washed successively with aqueous sodium bicarbonate and brine solution. The organic solution was dried over magnesium sulfate and evaporated to give an oil. Chromatographic purification on silica gel eluting with ether furnished 0.233 g (28%) of 2-[(3RS)-3-hydroxy-5-phenyl-trans-1-pentenyl]-3-(5-carboethoxypentyloxy)-4-pyrone. NMR (CDCl3, 100 M Hz): δ1.26 (3H, t, J = 7.0 Hz), 2.32 (2H, t, J = 6 Hz).
Reaction SMILES: CO[C:3](=[O:20])[C@@H:4]([NH2:19])[CH2:5][CH2:6][CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[NH3:21]>CO>[CH2:12]([O:11][C:9](=[O:10])[NH:8][CH2:7][CH2:6][CH2:5][C@H:4]([NH2:19])[C:3](=[O:20])[NH2:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)[C@@H](N)CCCNC(=O)OCc1ccccc1
Reactant: N
Solvent: CO
Product: NC(=O)[C@@H](N)CCCNC(=O)OCc1ccccc1

Procedure:
(S)-2-Amino-5-benzyloxycarbonylamino-pentanoic acid methyl ester (2.80 g, 9.99 mmol) and 7M NH3 in MeOH (20 ml) is stirred at room temperature for 72 hours. The reaction mixture is evaporated to dryness in vacuo to yield a white solid. The white solid is suspended in diethyl ether before filtration and drying to yield ((S)-4-Amino-4-carbamoyl-butyl)-carbamic acid benzyl ester.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:23][CH3:24]>CN(C)C=O.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([O:9][CH2:23][CH3:24])=[O:8]
Reactant: O=C(O)Cc1ccco1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccco1
Temperature: 25 °C
Reaction time: 14 h
Yield: 56.1 %

Procedure:
24.8 g of 2-(furan-2-yl)acetic acid was dissolved in 590 mL of N,N-dimethylformamide and mixed with 32.6 g (0.236 mol) of potassium carbonate and 6.42 g (19.7 mmol) cesium carbonate successively. The reaction mixture was further mixed with 19 mL (0.24 mol) of iodoethane under cooling with ice and stirred at room temperature for 14 hours. After completion of the reaction, the reaction mixture was diluted with distilled water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give 17.0 g of the desired product as a brown liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[S:23]1[CH:27]=[CH:26][N:25]=[C:24]1[NH2:28].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([NH:28][C:24]2[S:23][CH:27]=[CH:26][N:25]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Nc1nccs1
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)Nc2nccs2)cc1Cl
Reaction time: 2 h
Yield: 61.5 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid (prepared as in Example 1, 93 mg, 0.27 mmol), thiazol-2-ylamine (27 mg, 0.27 mmol) and N,N-diisopropylethylamine (141 μL, 0.82 mmol) were combined in acetonitrile (1.25 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (103 mg, 0.27 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 60% ethyl acetate/hexanes) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-N-thiazol-2-yl-acetamide (71 mg, 62%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C17H18ClN3O4S2 [M+] 427.04, found 428 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.68 (m, 4 H, 2×CH2), 1.90 (m, 4 H, 2×CH2), 3.32 (s, 3 H, SO2CH3), 4.96 (m, 1 H, OCH), 7.05 (d, J=3.5 Hz, 1 H, Ar), 7.52 (d, J=3.5 Hz, 1 H, Ar), 7.60 (dd, Jo=8.2, Jm=1.2 Hz, 1 H, Ar), 7.71 (d, Jm=1.2 Hz, 1 H, Ar), 8.20 (d, Jo=8.2 Hz, 1 H, Ar), 10.20 (s, 1 H, NH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([S:17]([CH3:19])=O)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.SC[CH2:22][C:23]([OH:25])=[O:24].C1CCN2C(=NCCC2)CC1>C1COCC1.C([O-])(O)=O.[Na+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([S:17][CH2:19][CH2:22][C:23]([OH:25])=[O:24])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)CCS
Reactant: CS(=O)c1ncc(C(=O)Nc2ccc(F)cc2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)CCSc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reaction time: 0.42 h
Yield: 80.2 %

Procedure:
To a solution of solution of 2-methanesulfinylpyrimidine-5-carboxylic acid (4-fluorophenyl)amide (141 mg, 0.50 mmol) in THF (3 mL) was added 3-mercaptopropionic acid (88 μL, 1.0 mmol) followed by DBU (320 μL, 2.1 mmol). The solution was stirred for 25 min, diluted with 1% NaHCO3, and extracted with ethyl acetate. The aqueous layer was acidified with 3% HCl to afford a white precipitate. The solids were collected by filtration, washed with water and dried to afford 128.8 mg (79% yield) of the titled compound as a white solid. API-MS m/z 322 (MH+), 320 (M−H)−.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]([SH:22])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CS(O[C@H:28]1[CH2:32][N:31]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=2)=[O:34])[C@H:30]([C:46]([O:48][CH3:49])=[O:47])[CH2:29]1)(=O)=O.Cl>CN(C)C=O.C(OCC)(=O)C>[C:3]1([C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[S:22][C@@H:28]2[CH2:32][N:31]([C:33]([O:35][CH2:36][C:37]3[CH:38]=[CH:39][C:40]([N+:43]([O-:45])=[O:44])=[CH:41][CH:42]=3)=[O:34])[C@H:30]([C:46]([O:48][CH3:49])=[O:47])[CH2:29]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.4 %

Procedure:
To a suspension of sodium hydride (1.26 g) (60% dispersion in oil) in dimethylformamide (50 ml) under ice cooling is added triphenylmethylmercaptan (10.9 g) in small portions and stirred for 5 minutes at room temperature. A solution of crude (2S,4R)-4-methanesulfonyloxy-2-methoxycarbonyl-1-p-nitrobenzyloxycarbonylpyrrolidine (2:10.6 g) in dimethylformamide (80 ml) is added to this mixture, and the whole mixture is stirred in an oil bath at 50° C. overnight. The reaction mixture is diluted with ethyl acetate and mixed with ice water containing 1N-hydrochloric acid (35 ml). The organic layer is taken, washed with water and satd. brine, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by silica gel chromatography (toluene-ethyl acetate) to give (2S ,4S)-4-triphenylmethylthio-2-methoxycarbonyl-1-p-nitrobenzyloxycarbonylpyrrolidine (3:9.12 g) an orange foam (Yield: 52% from hydroxyproline) and the starting compound (2:3.11 g: Yield: 29%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]3)=[CH:17][CH:18]=2)=[CH:5][CH:4]=1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Reactant: CSc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CSc1ccc(-c2ccc(OCC3CCN(C(=O)OC(C)C)CC3)cc2)cc1
Temperature: 80 °C
Yield: 18.5 %

Procedure:
A mixture of [4-(methylthio)phenyl]boronic acid (16.8 mg, 0.1 mmol) and 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (36 mg, 0.10 mmol), Pd(PPh3)4 (5 mg, 0.004 mmol), 2M Na2CO3 (1 mL) and DME (1 mL) was heated at 80° C. overnight. The reaction was cooled to ambient temperature, transferred onto a 1 mL Varian Chem Elut column, eluted with EtOAc, and the filtrate concentrated. The crude product was purified by reverse-phase preparative HPLC using a MeOH:H2O gradient (20:80 to 100:0) with 0.1% formic acid as a modifier to afford the title compound (7.4 mg, 12%). LRMS (ESI), m/z 422 (M+Na).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>COCCOC>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])=[CH:35][CH:34]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CSc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2ccccc2SCC(=O)N(NC(=O)c2ccccc2)C(C)C)cc1
Yield: 73 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-phenylsulfanyl)-acetyl]-N′-isopropyl-hydrazide (100 mg, 0.246 mmol) in DME (5 ml)/2M Na2CO3 (0.43 ml, 0.86 mmoles) was treated with 4-methoxyphenylboronic acid (75 mg, 0.49 mmol) and Pd[PPh3]4 (28 mg, 0.025 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was adsorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexane gradient to afford the product as a solid (78 mg, 72%). MS m/e 435.24 (M+H+)