Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3](=[NH:5])[NH2:4].C(=O)([O-])[O-].[Na+].[Na+].[C:12](OCC)(=[O:17])[CH2:13][C:14]([CH3:16])=O.C(O)(=O)C>O>[OH:17][C:12]1[CH:13]=[C:14]([CH3:16])[N:4]=[C:3]([S:2][CH3:1])[N:5]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: CSC(=N)N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 60 h
Yield: 75.1 %

Procedure:
S-Methylisothiourea (22.26 g, 160 mmol) was added to a solution of sodium carbonate (16.9 g, 160 mmol) in water (50 mL) and stirred at room temperature until complete dissolution of the S-methylisothiourea. Ethyl acetoacetate (10.41 g, 80 mmol) was added to the mixture in one portion. After stirring for 60 hours at room temperature, the reaction was neutralized with acetic acid precipitating a white solid. The solid was collected, washed with water, and dried in vacuo to give 4-hydroxy-6-methyl-2-(methylthio)pyrimidine (9.38 g, 75%), m.p. 218-221° C.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[N+:12]([O-:14])=[O:13].[C:15]1([S:21]([O-:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Na+]>CN(C)C=O>[N+:12]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[CH:3][C:2]([S:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:23])=[O:22])=[CH:11]2)([O-:14])=[O:13]
Reactant: O=S([O-])c1ccccc1
Reactant: O=[N+]([O-])c1cccc2cc(I)cnc12
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2cc(S(=O)(=O)c3ccccc3)cnc12
Temperature: 65 °C
Yield: 57.6 %

Procedure:
3-Iodo-8-nitroquinoline (D3) (135 g, 0.45 mol), was suspended in dimethylformamide (2.4 L) in a 5 L 3-necked flask fitted with an overhead stirrer, under an argon atmosphere. This mixture was treated successively with anhydrous sodium phenylsulfinate (99.6 g 0.608 mol), and bis-(copper (I) triflate) benzene complex (170 g, 0.338 mol). The resulting slurry was heated to 65° C. for 18 h. The mixture was cooled, filtered and the solvent evaporated in vacuo. Acetone (2.5 L) was added to the residue and the solution filtered. The filtrate was evaporated in vacuo, a further 2.5 L of acetone added and the mixture filtered again. The solvent was evaporated in vacuo and the residue dissolved in chloroform (3 L) and washed with 10% aqueous ammonia (2×2 L), and the organic phase was dried over magnesium sulphate and the solvent evaporated in vacuo. The dark brown residue was purified using a Biotage flash-150 chromatography apparatus (5 kg silica gel) eluting with hexane and increasing proportions of ethyl acetate to give the title compound (D4) (81.5 g, 58%) as a yellow solid;
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]([O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:4].[C:13]([O:16][CH2:17][Cl:18])(=[O:15])[CH3:14]>C(OCC)C>[Cl-:18].[C:13]([O:16][CH2:17][N+:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:5][C:3](=[O:4])[N:2]([CH3:12])[CH3:1])[CH:7]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OCCl
Reactant: CN(C)C(=O)Oc1cccnc1
Solvent: CCOCC
Product: CC(=O)OC[n+]1cccc(OC(=O)N(C)C)c1
Product: [Cl-]
Yield: 93.3 %

Procedure:
3-Dimethylcarbamoyloxypyridine (1.66 g) and chloromethyl acetate (2.18 g) were stirred at 90° C. for 1 hr. The hot reaction mixture was poured into 100 ml of anhydrous diethylether with vigorous stirring. The supernatant was removed by decantation followed by addition of 500 ml of diethylether. Again, the supernatant was removed by decantation. These procedures were repeated three times. The solvent was removed under reduced pressure to give 2.56 g of 1-(acetyloxymethyl)-3-(dimethylcarbamoyloxy)pyridinium chloride as oil. The structure was determined by N.M.R.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].C(N(CC)CC)C.[CH2:12]([O:14][C:15](=[O:37])[CH:16]([O:34][CH2:35][CH3:36])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[CH:20][CH:19]=1)[CH3:13].C(OCC)C>ClCCl>[CH2:12]([O:14][C:15](=[O:37])[CH:16]([O:34][CH2:35][CH3:36])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][C:3](=[O:4])[NH:2][CH3:1])=[CH:31][CH:32]=2)=[CH:20][CH:19]=1)[CH3:13]
Reactant: CN=C=O
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(O)cc2)cc1)OCC
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(OC(=O)NC)cc2)cc1)OCC
Yield: 47.1 %

Procedure:
Methyl isocyanate (70 mg; 1.22 mmole) was slowly added to a mixture of triethyl amine (180 mg; 1.17 mmole) and 2-ethoxy-3-{4-[2-(4-hydroxyphenyl)ethoxy]phenyl}propanoic acid ethyl ester (described in Example 26b) (418 mg; 1.17 mmole) in dichloromethane (5 ml). After stirring at room temperature for 2.5 hours the excess of methyl isocyanate was evaporated in vacuo and water and dichloromethane were added. The phases were separated. Water and potassium hydrogensulfate (1 M) were added to the organic phase. The phases were separated, the organic phase was evaporated in vacuo and the residue was purified by chromatography on silica using toluene:diethylether (gradient 4:1 to 3:1) as eluant to give 229 mg (yield 47%) of 2-ethoxy-3-{4-[2-(4-methylcarbamoyloxyphenyl)ethoxy]phenyl}propanoic acid ethyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1.[N+:19]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26]I)=[CH:24][CH:23]=1)([O-:21])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:19]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:18])[C:7]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:8][O:9]3)=[CH:4][CH:3]=2)=[CH:24][CH:23]=1)([O-:21])=[O:20]
Reactant: O=c1c(-c2ccccc2)coc2cc(O)ccc12
Reactant: O=[N+]([O-])c1ccc(CI)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1c(-c2ccccc2)coc2cc(OCc3ccc([N+](=O)[O-])cc3)ccc12

Procedure:
10.5 g of 7-hydroxy-isoflavone in 200 ml of anhydrous acetone are boiled for 2 hours with 11.8 g of p-nitrobenzyl iodide in the presence of 5.7 g of anydrous potassium carbonate under a reflux condenser. On distilling off about half of the volume of acetone, the residue is poured into 1000 ml of water. The precipitating crude product is subjected to suction and recrystallized from glacial acetic acid, affording light yellow plates of 7-p-nitrobenzyloxy-isoflavone, m.p. 225°-226°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[Br:13][CH2:14][CH2:15]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[Br:13][CH2:14][CH2:15][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:9]([F:10])([F:11])[F:12]
Reactant: OCCBr
Reactant: Oc1ccc(F)cc1C(F)(F)F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(OCCBr)c(C(F)(F)F)c1
Reaction time: 0.08 h

Procedure:
A mixture of 4-fluoro-2-(trifluoromethyl)phenol (1.05 g, 5.83 mmol), 2-bromoethanol (0.62 mL, 8.7 mmol) and triphenylphosphine (2.29 g, 8.73 mmol) in tetrahydrofuran (20 mL) was stirred for 5 minutes. Diisopropyl azodicarboxylate (94%, 1.84 mL, 8.71 mmol) was then added drop-wise over 20 minutes, and the reaction was stirred at room temperature for 16 hours. Water (50 mL) was added, and the mixture was extracted with dichloromethane (2×75 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 10% ethyl acetate in heptane) afforded the title compound as a white solid. Yield: 600 mg, 2.09 mmol, 36%. GCMS m/z 286. 1H NMR (400 MHz, CDCl3) δ 3.66 (dd, J=6.6, 6.4 Hz, 2H), 4.35 (dd, J=6.5, 6.4 Hz, 2H), 6.97 (br dd, J=9.0, 4.1 Hz, 1H), 7.18-7.24 (m, 1H), 7.32 (br dd, J=8.3, 3.2 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.Cl[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12].[CH3:17][C:18]1[NH:19][C:20]([CH3:23])=[CH:21][CH:22]=1>ClCCl>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH:1][C:15]([NH:14][S:11]([C:22]2[CH:21]=[C:20]([CH3:23])[NH:19][C:18]=2[CH3:17])(=[O:13])=[O:12])=[O:16])[N:3]=1
Reactant: Cc1cc(C)nc(N)n1
Reactant: Cc1ccc(C)[nH]1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2cc(C)[nH]c2C)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mechanically stirred suspension of 12.3 g (0.1 mole) of 2-amino-4,6-dimethylpyrimidine in 200 ml of dry dichloromethane maintained at 0° to 5° C. under a nitrogen atmosphere was added dropwise over 30 minutes a solution of 9.2 ml (0.1 mole) of chlorosulfonyl isocyanate in 50 ml of ice-cold dichloromethane. After 30 minutes at 0° to 5° C. the resulting yellow solution was treated dropwise over 15 minutes with 20 ml (0.197 mole) of 2,5-dimethylpyrrole. This mixture was stirred 30 minutes at 0° to 5° C. and allowed to stand overnight at room temperature.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[C:6]([C:15](=[O:17])[CH3:16])[CH:5]=[C:4]([Cl:18])[C:3]=1[CH3:19].[CH2:20]([O:23][C:24](Cl)=[O:25])[CH2:21]Cl.CC(C)([O-])C.[K+]>CN(C)C1C=CN=CC=1.O1CCCC1>[C:15]([C:6]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[C:2]([N:1]2[CH2:21][CH2:20][O:23][C:24]2=[O:25])[C:3]([CH3:19])=[C:4]([Cl:18])[CH:5]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)c1cc(Cl)c(C)c(N)c1-c1cccc(F)c1
Reactant: O=C(Cl)OCCCl
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccncc1
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c(C)c(N2CCOC2=O)c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.1 %

Procedure:
To a mixture of 1-(6-amino-4-chloro-3′-fluoro-5-methylbiphenyl-2-yl)ethanone (100 mg, 0.4 mmol) and 4-dimethylaminopyridine (53 mg, 0.43 mmol) in tetrahydrofuran (1 mL) was added 2-chloroethyl chloridocarbonate (0.041 mL, 0.40 mmol). The mixture was stirred at room temperature overnight. To the mixture was added 1.0 M potassium tert-butoxide in tetrahydrofuran (0.79 mL) at 0° C., and the resulting mixture stirred at room temperature for 2 hours, then quenched with aq. ammonium chloride, extracted with ethyl acetate. The combined organic layers were washed with brine, dried, and evaporated. The filtrate was applied on silica gel, eluting with 0 to 60% ethyl acetate in hexane, to give the desired product (14 mg, 10%). LCMS calculated for C18H16ClFNO3 (M+H)+: m/z=348.1. found: 348.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]2[N:23]([CH3:24])[CH:11]([CH2:12][C:13]=1[C:14]1[O:18][N:17]=[C:16]([CH2:19][CH2:20][CH2:21][OH:22])[CH:15]=1)[CH2:10][N:9]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:8]2)=[O:5])[CH3:2].N1C=CN=C1.[CH3:37][C:38]([Si:41](Cl)([CH3:43])[CH3:42])([CH3:40])[CH3:39]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]2[N:23]([CH3:24])[CH:11]([CH2:12][C:13]=1[C:14]1[O:18][N:17]=[C:16]([CH2:19][CH2:20][CH2:21][O:22][Si:41]([C:38]([CH3:40])([CH3:39])[CH3:37])([CH3:43])[CH3:42])[CH:15]=1)[CH2:10][N:9]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:8]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2cc(CCCO)no2)CC2CN(C(=O)OC(C)(C)C)CC1N2C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(c2cc(CCCO[Si](C)(C)C(C)(C)C)no2)CC2CN(C(=O)OC(C)(C)C)CC1N2C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
A mixture of compound B3 (3.56 g, 8.17 mmol), imidazole (1.39 g, 20.4 mmol), and TBDMS-Cl (1.85 g, 12.2 mmol) in DMF (70 mL) was stirred at 0° C. for 30 min, then at rt for 1 h. The mixture was diluted with EtOAc and washed with aq. 10% Na2CO3 (2×), and brine (1×). The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:6→1:3→1:1) yielded the title compound (2.47 g, 55%). LC-MS: tR=0.94 min; ES+: 550.40.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][N:9]=2)[C:4]1=[O:18].C(N(CC)CC)C.[CH3:26][C:27]([CH3:33])([CH3:32])[CH2:28][C:29](Cl)=[O:30]>ClCCl>[CH3:26][C:27]([CH3:33])([CH3:32])[CH2:28][C:29]([N:2]([CH3:1])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][N:9]=2)[C:4]1=[O:18])=[O:30]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CNC1CCN(c2cc(C(F)(F)F)ccn2)C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)CC(C)(C)C)C1CCN(c2cc(C(F)(F)F)ccn2)C1=O
Reaction time: 1 h
Yield: 75 %

Procedure:
A stirred solution of 3-methylamino-1(4-trifluoromethylpyridin-2-yl)pyrrolidin-2-one (0.30 g, prepared as described in Example 7, Step 3, above) in dichloromethane (20 ml) was treated successively with triethylamine (0.13 g) and 3,3-dimethylbutanoyl chloride (0.16 g). After one hour, the mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica, using hexane-ethyl acetate (1:1) as eluant, to give Compound 28 (0.31 g, m.p. 47°-53° C.). NMR (CDCl3): δ 1.31(9H,s); 2.31(4H,m+s); 3.09(3H,s); 3.88(1H,m); 4.32(1H,m); 5.22(1H,t); 7.26(1H,dd); 8.52(1H,d); 8.78(1H,s). MS: M+357.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[C:5](/[CH:11]=[CH:12]/[C:13](OCC)=[O:14])=[C:4]([CH3:18])[N:3]=1.C1CCN2C(=NCCC2)CC1>O>[NH2:1][C:2]1[N:3]=[C:4]([CH3:18])[C:5]2[CH:11]=[CH:12][C:13](=[O:14])[N:8]([CH2:9][CH3:10])[C:6]=2[N:7]=1
Reactant: CCNc1nc(N)nc(C)c1/C=C/C(=O)OCC
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1c(=O)ccc2c(C)nc(N)nc21
Temperature: 165 °C
Reaction time: 24 h
Yield: 73.5 %

Procedure:
(E)-Ethyl 3-(2-amino-4-(ethylamino)-6-methylpyrimidin-5-yl)acrylate (4.50 g, 18.0 mmol) was added to DBU (10.95 g, 4.0 equiv.) and the mixture was heated to 165° C. and stirred for 24 h. After that, the mixture was cooled to 70° C. followed by the addition of H2O (20 mL) to precipitate crystal and stirred for 1 h at room temperature. The crystal was collected and washed with H2O and acetone and dried under vacuum to afford 2.70 g (73.5% yield of 2-amino-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one as a light yellowish brown solid. LC/MS: Calculated for C10H12N4O (204.2). Found: 205.31 (M+1); HPLC analytical purity: 98.5%. 1H NMR (400 MHz, DMSO-d6): δ 7.9 (d, 1H), 7.20 (bs, 2H), 6.20 (m, 1H), 4.20 (q, 2H), 2.50 (s, 3H), 1.20 (t, 3H); MS (EI) for C10H12N4O: 205.11 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[NH2:23]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[NH:23][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccc2)n1
Reactant: COc1ccc(N)cc1OC
Product: COc1ccc(Nc2cc(C(F)(F)F)nc(-c3ccccc3)n2)cc1OC

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-phenyl-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3,4-dimethoxyaniline (44 mg, 0.290 mmol) similar to Example 75. The mixture was extracted with ethyl acetate (75 ml), washed with water (2×25 ml), washed with aqueous saturated NaCl (1×25 ml), and dried over anhydrous sodium sulfate. The ethyl acetate solution was rotary evaporated to dryness. The residual was purified by column chromatography and isolated as a yellow oil (35 mg, 48%). 1H NMR (CDCl3): 8.45–8.42 (m, 2H), 7.50–7.44 (m, 3H), 7.25 (s, 1H), 7.02 (s, 1H), 6.90 (s, 2H), 6.74 (s, 1H), 3.91 (s, 3H), 3.87 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]3)=[O:13])[C:6]=2[CH:21]=1.[C:22]1(=[O:28])[O:27][C:25](=[O:26])[CH:24]=[CH:23]1>N1C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:15][CH2:16][CH:17]([O:20][C:22]([CH:23]=[CH:24][C:25]([OH:27])=[O:26])=[O:28])[CH2:18][CH2:19]3)=[O:13])[C:6]=2[CH:21]=1
Reactant: O=C1C=CC(=O)O1
Reactant: O=C(Cn1c(=O)sc2ccc(Cl)cc21)N1CCC(O)CC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(O)C=CC(=O)OC1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Reaction time: 8 h
Yield: 50.5 %

Procedure:
A solution of 5-chloro-3-(4-hydroxypiperidinocarbonylmetyl)benzothiazolin-2-one (3.2 g) in dry pyridine (2.5 ml) and dry tetrahydrofuran (50 ml) was cooled, to which a solution of maleic anhydride (1.0 g) in dry tetrahydrofuran (5 ml) was gradually dropwise added under stirring. The mixture was refluxed for two hours and then left overnight. The solvent was evaporated off under vacuum from the reaction mixture, and the residue was dissolved in 5% aqueous sodium bicarbonate (20 ml). The solution was cooled and adjusted to pH 2 with 1% hydrochloric acid. The precipitated crystals were collected by filtration, washed with water and then subjected to chromatography on silica gel eluting with ethanol/benzene (1:1). The solvent was evaporated off under vacuum from the eluate at below 50° C. The residue was recrystallized from isopropyl alcohol to yield the title compound as colorless crystals (2.1 g). m.p. 197°-198° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:13][O:14][CH2:15][C:16]1[CH:24]=[N:23][CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>O.CN(C=O)C>[OH:12][C:3]1[C:2]([NH:1][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][N:23]=[CH:24][C:16]=2[CH2:15][O:14][CH3:13])=[CH:7][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:5][N:4]=1
Reactant: Nc1cc(C(F)(F)F)cnc1O
Reactant: COCc1cnccc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCc1cnccc1C(=O)Nc1cc(C(F)(F)F)cnc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
A mixture of 0.51 g of 3-amino-2-hydroxy-5-trifluoromethylpyridine, 0.48 g of 3-methoxymethyl isonicotinic acid, 1.65 g of BOP reagent, 0.38 g of triethylamine and 6 ml of DMF was stirred at room temperature for one hour, and further stirred while heating at 50° C. for two hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.58 g of N-[2-hydroxy-5-(trifluoromethyl)pyridin-3-yl]-3-(methoxymethyl)isonicotinamide.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:6]=CC=CC=1.[CH2:16]([N:18]=[C:19]=[O:20])[CH3:17].[O:21]1CCCC1>>[CH2:16]([NH:18][C:19]([NH:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][C@@H:1]2[CH2:6][O:21]2)=[CH:14][CH:13]=1)=[O:20])[CH3:17]
Reactant: C1CCOC1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: CCN=C=O
Product: CCNC(=O)Nc1ccc(OC[C@@H]2CO2)cc1
Reaction time: 24 h

Procedure:
4-(Phenylmethoxy)-benzenamine (5.1 g, 25.5 mmol) was dissolved in anhydrous tetrahydrofuran and ethyl isocyanate (2.00 g, 28.1 mmol) added. The solution was heated to reflux. After 24 hours ethyl isocyanate (2.00 g, 28.1 mmol) was again added to the reaction mixture and refluxing continued for a further 24 hours. The reaction mixture was taken to dryness in vacuo and the residue purified by flash chromatography on silica gel Merck-60 (eluant: 3:1 hexane-ethyl acetate) to yield the title compound (6.3 g, 23.30 mmol).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].Br[CH2:14][C:15]#[N:16].[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CC#N>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[C:6]([NH:7][CH2:14][C:15]#[N:16])[CH:8]=[CH:9][CH:10]=1
Reactant: Nc1cccc(OC(F)(F)F)c1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: N#CCNc1cccc(OC(F)(F)F)c1
Yield: 74.2 %

Procedure:
A mixture of 3-(trifluoromethoxy)aniline (1.00 g, 5.64 mmol), bromoacetonitrile (745 mg, 6.21 mmol), sodium iodide (1.86 g, 12.4 mmol), and sodium carbonate (858 mg, 6.21 mmol) in CH3CN (15 mL) was heated at reflux for 18 h, then partitioned between water and EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; heptane/EtOAc gradient) afforded the title compound (904 mg, 74%). Brown liquid, MS: 215.2 (M+H)+.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][OH:31])[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]([CH3:36])=C.[CH2:37](Cl)Cl>>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH:34]([O:33][CH3:32])[CH2:36][CH3:37])[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(=NO)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: ClCCl
Reactant: C=C(C)OC
Product: CCC(OC)ON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 12.9 g of the syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-hydroxyimino-acetic acid, 120 ml of methylene chloride and 12 ml of 2-methoxy-propene was stirred for 20 minutes at room temperature and was then evaporated to dryness. The residue was stirred for another 30 minutes in 60 ml of methylene chloride and 12 ml of 2-methoxypropene and the mixture was evaporated to dryness under reduced pressure to obtain the syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-(2-methyl-1-methoxyethoxyimino)-acetic acid which was used as is for the next step.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13](B1OC(C)(C)C(C)(C)O1)=[CH:12][CH:11]=2.[OH:26][NH:27][C:28](=[O:45])[C@:29]([CH3:44])([S:40]([CH3:43])(=[O:42])=[O:41])[CH2:30][CH2:31][N:32]1[CH:37]=[CH:36][C:35](I)=[CH:34][C:33]1=[O:39].O>O1CCOCC1.[Pd]>[OH:26][NH:27][C:28](=[O:45])[C@:29]([CH3:44])([S:40]([CH3:43])(=[O:42])=[O:41])[CH2:30][CH2:31][N:32]1[CH:37]=[CH:36][C:35]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[NH:9][C:8]([CH3:7])=[CH:16]3)=[CH:34][C:33]1=[O:39]
Reactant: Cc1cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2[nH]1
Reactant: C[C@@](CCn1ccc(I)cc1=O)(C(=O)NO)S(C)(=O)=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc2cc(-c3ccn(CC[C@](C)(C(=O)NO)S(C)(=O)=O)c(=O)c3)ccc2[nH]1
Temperature: 80 °C
Yield: 21.4 %

Procedure:
Pd EnCat™ (93 mg, 0.03 mmol) was added to a mixture of potassium carbonate (115 mg, 0.83 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (86 mg, 0.33 mmol), and (2R)—N-hydroxy-4-(4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (115 mg, 0.28 mmol) in dioxane:water (2.5 mL, 5:1 mixture). The reaction mixture was heated overnight at 80° C. The reaction was cooled to ambient temperature, filtered through a nylon filter and concentrated. The material was dissolved in a minimal amount of DMSO and loaded onto a 13 g c18 column. The gradient was run from 25-45% acetonitrile in water. The desired material was concentrated yielding 25 mg (22%) of a light brown solid. LCMS m/z 418.5 (M+1) 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 (s, 3H) 2.13-2.24 (m, 1H) 2.32-2.46 (m, 1H) 2.39 (s, 3H) 3.12 (s, 3H) 3.69-3.78 (m, 1H) 4.06-4.16 (m, 1H) 6.20 (s, 1H) 6.65 (d, J=1.95 Hz, 1H) 6.70 (dd, J=7.22, 1.95 Hz, 1H) 7.31-7.39 (m, 2H) 7.70 (d, J=7.22 Hz, 1H) 7.79 (s, 1H) 9.25 (br. s., 1H) 11.11 (br. s., 1H) 11.23 (br. s., 1H)