Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][S:18][C:19]([CH3:24])([CH3:23])[C:20]([OH:22])=[O:21])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:26][CH2:27]CCCSC(C)(C)C(OCC)=O.COC1C=CC(S(N)(=O)=O)=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][S:18][C:19]([CH3:24])([CH3:23])[C:20]([O:22][CH2:26][CH3:27])=[O:21])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)NCCCCCSC(C)(C)C(=O)O)cc1
Reactant: CCOC(=O)C(C)(C)SCCCCCBr
Agent: COc1ccc(S(N)(=O)=O)cc1
Product: CCOC(=O)C(C)(C)SCCCCCNS(=O)(=O)c1ccc(OC)cc1
Yield: 69 %

Procedure:
In an analogous way, there are obtained: 2. 8-(4-Methoxybenzenesulphonamido)-2,2-dimethyl-3-thiaoctanoic acid by reaction of ethyl 8-bromo-2,2-dimethyl-3-thiaoctanoate with 4-methoxybenzenesulphonamide to give (a) ethyl 8-(4-methoxybenzenesulphonamido)-2,2-dimethyl-3-thiaoctanoate; after chromatography on silica gel/cyclohexane+diethyl ether (2:1 v/v), the yield is 69% of theory; colourless oil; nD20 =1.5280 and subsequent saponification of this ester to give (b) the desired acid; yield 90% of theory; m.p. 57°-59° C. 3. 8-(3-Trifluoromethylbenzenesulphonamido)-2,2-dimethyl-3-thiaoctanoic acid by reaction of ethyl 8-bromo-2,2-dimethyl-3-thiaoctanoate with 3-trifluoromethylbenzenesulphonamide to give
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:13]([C@@:14]([OH:20])([CH3:19])[C:15]([F:18])([F:17])[F:16])[O:12][C@H:11]2[C@H:7]([N:8]=[C:9]([N:21](C)[C:22](=O)OC(C)(C)C)[S:10]2)[C@H:6]1[O:30]CC=C)C=C.CCN(CC)CC.C(O)=O>O1CCOCC1.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>[CH3:22][NH:21][C:9]1[S:10][C@H:11]2[O:12][C@H:13]([C@@:14]([OH:20])([CH3:19])[C:15]([F:16])([F:17])[F:18])[C@@H:5]([OH:4])[C@H:6]([OH:30])[C@H:7]2[N:8]=1
Reactant: C=CCO[C@@H]1[C@H]2N=C(N(C)C(=O)OC(C)(C)C)S[C@H]2O[C@H]([C@](C)(O)C(F)(F)F)[C@H]1OCC=C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O=CO
Solvent: CCN(CC)CC
Product: CNC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H]([C@](C)(O)C(F)(F)F)O[C@@H]2S1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 25.6 %

Procedure:
To a solution of 119 (4.5 g, 9 mmol) in 1,4-dioxane (50 mL) was added Pd(PPh3)4 (2.1 g, 1.8 mmol), Et3N (23 g, 22.7 mmol) and HCOOH (0.8 g, 18 mmol) at 25° C. under N2 atmosphere. After 20 min at 60° C., additional HCOOH (6.3 g, 136 mmol) was added and the mixture was stirred for additional 12 hours at 60° C., then quenched by H2O (60 mL), extracted with dichloromethane (2×40 mL) to remove the organic impurities. The pH value of aqueous phase was adjusted to 7-8 by saturated aqueous NaHCO3, then concentrated under reduced pressure to give a residue, which was purified by a silica gel column, eluted with 2%-10% methanol in dichloromethane to give the mixture of the two epimer. Further separation by Prep HPLC [(Agilent 1200 prep HPLC): Column, Sun Fire Prep C18*50 mm 5 um; mobile phase, WATER with CH3CN (5% CH3CN up to 40% in 10 min); Detector, UV, 220 nm] to afford (3aR,5S,6S,7R,7aR)-2-(methylamino)-5-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol as white solid (730 mg, 25.4%), Faster eluting isomer. (ES, m/z): 317.0; 1HNMR (300 MHz, D2O) δ 6.27 (d, J=6.9 Hz, 1H), 4.38-4.41 (m, 1H), 4.22-4.23 (m, 1H), 3.94-3.97 (d, J=8.4 Hz, 1H), 3.56-3.60 (d, J=8.4 Hz, 1H), 2.77 (s, 3H), 1.34 (s, 31-1); and (3aR,5S,6S,7R,7aR)-2-(methylamino)-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol as white solid (810 mg, 28.2%), Slower eluting isomer. (ES, m/z): 317.0; 1HNMR (300 MHz, D2O) δ 6.26 (d, J=6.9 Hz, 1H), 4.37-4.39 (m, 1H), 4.18-4.20 (m, 1H), 3.96-3.99 (m, 1H), 3.60-3.62 (d, J=8.4 Hz, 1H), 2.77 (s, 3H), 1.33 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=O.[CH:18]([NH2:20])=[S:19]>C1COCC1.C(OCC)(=O)C>[S:19]1[CH:2]=[C:3]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[N:20]=[CH:18]1
Reactant: NC=S
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CBr)CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2cscn2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
The title compound from Step B above (500 mg, 1.63 mmol) was combined with thioformamide (100 mg, 1.63 mmol) in 5 mL of THF, warmed to 60° C., and stirred overnight. The mixture was cooled to RT and diluted with ethyl acetate. The solution was then washed with water followed by brine. The organics were dried over magnesium sulfate, filtered and concentrated under vacuum. Purification via preparative TLC plates (3×1000 μM) eluting with 60% ethyl acetate/hexane afforded the title compound (282 mg, 63%) as a clear oil. ESI-MS calculated for C13H20N2O2S: Exact Mass: 268.12. Found: 169.12 (M-Boc)+ and 291.14 (MNa)+.
Reaction SMILES: [C:1]1([CH:7]([C:40]([O:42]C(C)(C)C)=[O:41])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O:24]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:23])=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)=O.C(C(CCCC)C([O-])=O)C.[Na+:60].[Na][Na]>C(OCC)(=O)C.C(O)C>[Na+:60].[Na+:60].[C:1]1([CH:7]([C:40]([OH:42])=[O:41])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O-:24])=[O:23])=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([CH:7]([C:40]([OH:42])=[O:41])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O-:24])=[O:23])=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(C(=O)OC(C)(C)C)c3ccccc3)[C@H]2SC1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Agent: [Na][Na]
Solvent: CCOC(C)=O
Solvent: O=CO
Solvent: CCO
Product: COC(=O)C1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(C(=O)O)c3ccccc3)[C@H]2SC1

Procedure:
Benzhydryl 7-(2-phenyl-2-tert-butoxycarbonylacetamido)-3-methoxycarbonyl-3-cephem-4-carboxylate (0.257 g., 0.399 mmol.) was dissolved in 40 ml. 97-100% formic acid and allowed to react for 1 hour at room temperature. The reaction mixture was evaporated to dryness to give a residue which was dissolved in ethyl acetate and extracted with sodium bicarbonate solution. The aqueous extracts were combined, layered with cold ethyl acetate, and acidified with cold 1N.HCl. The organic layer was separated, washed with brine and dried (Na2SO4). Evaporation to dryness gave 0.209 g. of acid which was dissolved in 40 ml. ethanol and treated with 2 equivalents of sodium 2-ethylhexanoate. The solution was evaporated in vacuo until a precipitate was noted. The solution was placed in the refrigerator overnight and filtered to give 27 mg. of the disodium salt: nmr (acetone-d6) 3.75 (m, 5, CO2CH3, C2 --H), 4.85 (2-s, 1, side chain CH), 5.17, 5.28 (2-d, 1, J = 5.0 Hz, C6 --H), and 5.92 ppm (q, 1, J = 5.0 Hz and 9.0 Hz, C7 --H).
Reaction SMILES: C([O:3][C:4](=[O:46])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)[CH:25]=[C:24]([C:33]3[CH:34]=[N:35][CH:36]=[N:37][CH:38]=3)[CH:23]=2)[C:10]=1[CH2:39][CH2:40][C:41]([O:43]CC)=[O:42])C.[OH-].[Na+]>>[C:41]([CH2:40][CH2:39][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)[CH:25]=[C:24]([C:33]3[CH:38]=[N:37][CH:36]=[N:35][CH:34]=3)[CH:23]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:46])=[O:3])([OH:43])=[O:42]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3cncnc3)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(-c3cncnc3)cc(-c3ccsc3)c2)c1CCC(=O)O
Yield: 93 %

Procedure:
A similar procedure as described in Example 12, step 9 was used, starting from 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(3-pyrimidin-5-yl-5-thiophen-3-yl-phenoxy)-hexyl]-phenoxy}-butyric acid ethyl ester (137 mg, 0.21 mmol) and 1.0 N aqueous NaOH (6 mL) to give 4-{2-(2-carboxy-ethyl)-3-[6-(3-pyrimidin-5-yl-5-thiophen-3-yl-phenoxy)-hexyl]-phenoxy}-butyric acid (115 mg, 93%) as an amorphous light yellow solid: ES(+)-HRMS m/e calculated for C33H36N2O6S (M+H)+ 589.2367, found 589.2366.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:9]([CH3:10])=[CH:8][C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[N+:22]([O-])=O)=[N:6]1)=[O:4].[H][H]>C(O)C.[C].[Pd]>[CH3:1][NH:2][C:3]([N:5]1[C:9]([CH3:10])=[CH:8][C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[NH2:22])=[N:6]1)=[O:4]
Reactant: CNC(=O)n1nc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])cc1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CNC(=O)n1nc(Oc2ccc(C(F)(F)F)cc2N)cc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.9 %

Procedure:
A solution of N-methyl-5-methyl-3-(2-nitro-4-trifluoromethylphenyloxy)pyrazole-1-carboxamide (2.1 g, 6.0 mmol) in ethanol (50 ml) was placed in an autoclave, and 10% palladium carbon (0.7 g) was added. An atmosphere in the autoclave was fully replaced with hydrogen gas, and hydrogen gas was charged up to 5 kg/cm2. Then, the reaction solution was stirred at room temperature for 5 hours. After completion of the reaction, the catalyst was removed by filtration using Celite, and the solvent was distilled off from the filtrate under reduced pressure, to give a yellowish solid of N-methyl-3-(2-amino-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (1.6 g, yield: 82.2%). mp: 93-94; 1H-NMR (CDCl3, TMS, ppm): δ 2.59 (d, J=0.7 Hz, 3H), 2.93 (d, J=5.0 Hz, 1H), 3.90-4.15 (br s, 2H), 5.71 (q, J=0.7 Hz, 1H), 6.80-6.95 (m, 1H), 6.97 (dd, J=1.7 and 8.4 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H).
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][C:6]1[CH:14]=[CH:13][C:9]2[NH:10][N:11]=[N:12][C:8]=2[CH:7]=1)[CH3:4].[H-].[Na+].Br[CH2:18][C:19]1[C:28]([Cl:29])=[C:27]([Cl:30])[CH:26]=[C:25]2[C:20]=1[N:21]=[C:22]([O:33][CH3:34])[C:23]([O:31][CH3:32])=[N:24]2.[Cl-].[NH4+]>CN(C)C=O.O>[Cl:29][C:28]1[C:19]([CH2:18][N:10]2[C:9]3[CH:13]=[CH:14][C:6]([CH2:5][N:3]([CH3:2])[CH3:4])=[CH:7][C:8]=3[N:12]=[N:11]2)=[C:20]2[C:25](=[CH:26][C:27]=1[Cl:30])[N:24]=[C:23]([O:31][CH3:32])[C:22]([O:33][CH3:34])=[N:21]2
Reactant: COc1nc2cc(Cl)c(Cl)c(CBr)c2nc1OC
Reactant: CN(C)Cc1ccc2[nH]nnc2c1
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc2cc(Cl)c(Cl)c(Cn3nnc4cc(CN(C)C)ccc43)c2nc1OC
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 20.1 %

Procedure:
5-(N,N-Dimethylaminomethyl)-1H-1,2,3-benzotriazole hydrochloride (383 mg 1.8 mmol) was added to a suspension of sodium hydride (108 mg, 80% dispersion in oil, 3.6 mmol) in dry dimethylformamide (20 mL) at room temperature and stirred for 15 minutes. The mixure was cooled to -30° C., 5-bromomethyl-6,7-dichloro-2,3-dimethoxy quinoxaline (Preparation 1, 528 mg, 1.5 mmol) was added, and the mixture was stirred at -30° C. for 1 hour, and then allowed to warm slowly to 0° C. Saturated aqueous ammonium chloride (5 mL) was added, followed by water (50 mL). The product was extracted into ethyl acetate, the extracts were washed with water, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with hexane/ethyl acetate, then ethyl acetate/methanol) to give 6,7-dichloro-2,3-dimethoxy-5-[5-(N,N-dimethylaminomethyl)-1,2,3-benzotriazol-1-yl] methylquinoxaline (135 mg, 28%), Rf =0.4 (silica gel, ethyl acetate/methanol=4:1), as the slowest eluted product isomer.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][CH2:7][N:8]2[CH2:14][CH2:13][CH2:12][CH:11]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=4)[C:18](=O)[C:16]3=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.O>O1CCCC1>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][CH2:7][N:8]2[CH2:14][CH2:13][CH2:12][CH:11]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=4)[CH:18]=[CH:16]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)N(C1CCCN(CCc3ccc(F)cc3)CC1)C(=O)C2=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2ccn(C3CCCN(CCc4ccc(F)cc4)CC3)c2c1
Temperature: 25 °C
Reaction time: 11 h

Procedure:
1-(4-Fluorophenethyl)-4-(6-methoxyisatin-1-yl)homopiperidine (0.4 g) was dissolved in tetrahydrofuran (1.0 ml). Under nitrogen atmosphere, a 2.0 M solution (4.0 ml) of borane-tetrahydrofuran complex in tetrahydrofuran was added dropwise thereinto in a water bath followed by heating under reflux for 3 hr. The reaction solution was ice cooled and water was added thereto. Next, the reaction solution was partitioned between water and ethyl acetate and the organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in pyridine (5.0 ml) and stirred at room temperature for 11 hr. After adding water, the reaction solution was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Then the resulting residue was purified by NH-silica gel column chromatography (hexane/ethyl acetate system) to give 1-(4-florophenethyl)-4-(6-methoxyindol-1-yl)homopiperidine as a yellow oil. Then this product was treated as in Production Example 64 to give the free title compound (0.095g) asayellowoil (yield: 27.2%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=O.[CH:11]1([NH:16][NH2:17])[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC([O-])(C)C.[K+]>CN1C(=O)CCC1.C(OCC)(=O)C.C(#N)C.CN(C=O)C>[CH:11]1([N:16]2[C:2]3[C:3](=[CH:6][C:7]([I:10])=[CH:8][CH:9]=3)[CH:4]=[N:17]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=Cc1cc(I)ccc1F
Reactant: NNC1CCCC1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Solvent: CC#N
Product: Ic1ccc2c(cnn2C2CCCC2)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 2-fluoro-5-iodobenzaldehyde (500 mg, 2 mmol), cyclopentylhydrazine (273 mg, 2 mmol), and cesium carbonate (1.91 g, 5 mmol) in NMP (5 ml) was stirred at 100° C. overnight. Then KOtBu (560 mg, 5 mmol) and DMF (10 ml) were added, and the mixture was stirred at 150° C. for 5 h. After cooling to r.t., the mixture was diluted with ethyl acetate (100 ml), and washed with water (3×50 ml), and dried. Evaporation of solvent afforded batch residue, which was dissolved in acetonitrile (50 ml), and the insoluble material was removed by filtration. Flash chromatography on silica gel (n-heptane/ethyl acetate) afforded yellow oil, 158 mg (25%).
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[CH:8]=[C:9]([O:13][B:14]([OH:16])[OH:15])[CH:10]=[CH:11][CH:12]=1.NC1[CH:19]=[C:20]([O:24]B(O)O)C=CC=1.[OH-].[Na+].C([CH:32]([C:36](Cl)=[O:37])[C:33](Cl)=[O:34])C>O.O1CCCC1>[CH2:20]([O:24][C:36]([CH2:32][C:33]([NH:6][C:7]1[CH:8]=[C:9]([O:13][B:14]([OH:16])[OH:15])[CH:10]=[CH:11][CH:12]=1)=[O:34])=[O:37])[CH3:19]
Reactant: CCC(C(=O)Cl)C(=O)Cl
Reactant: Nc1cccc(OB(O)O)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)Nc1cccc(OB(O)O)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45 %

Procedure:
1.86 g of 3-aminophenyl-boric acid hemisulphate are suspended are suspended in 20 ml of water and treated with 5 ml of a 2N sodium hydroxide solution. The clear, yellowish solution is treated dropwise while cooling with ice with a solution of monoethyl malonyl chloride in 7 ml of tetrahydrofuran. The mixture is stirred at room temperature for a further 15 min. and the precipitate is filtered off under suction. It is recrystallized in 50 ml of water. 1.12 g (45%) of 3-(2-ethoxycarbonylacetylamino)-phenylboric acid are isolated. M.p. 247°.
Reaction SMILES: [C:1]([C:5]1[O:6][CH:7]=[C:8]([C:10]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][C:21]1[CH:27]=[C:26]([O:28][C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:24][C:22]=1[NH2:23].CCOC(OC(OCC)=O)=O.C(N(CC)CC)C>O1CCCC1.O>[C:1]([C:5]1[O:6][CH:7]=[C:8]([C:10]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:23][C:22]2[CH:24]=[CH:25][C:26]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:27][C:21]=2[CH3:20])=[O:14])[N:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nc(-c2c(Cl)cccc2C(=O)O)co1
Reactant: Cc1cc(OC(F)(F)F)ccc1N
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(OC(F)(F)F)ccc1NC(=O)c1cccc(Cl)c1-c1coc(C(C)(C)C)n1
Yield: 28 %

Procedure:
0.4 Gram of 2-(2-t-butyloxazol-4-yl)-3-chlorobenzoic acid was dissolved in 30 ml of tetrahydrofuran, then 0.3 g of 2-methyl-4-trifluoromethoxyaniline, 0.4 g of DEPC and 0.3 g of triethylamine were added thereto, the resulting mixture was heated under reflux for 3 hours with stirring. After completion of the reaction, the reaction mixture was poured into water, and the objective product was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, the residue obtained by removal of the solvent by distillation under reduced pressure was purified by the silica gel column chromatography to obtain 0.18 g (yield: 28%) of the objective product.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]([C:21]#[C:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32]C)=[O:31])=[CH:25][CH:24]=2)[CH:10]=[C:11]2[C:16]=1[O:15][C:14]([CH3:18])([CH3:17])[CH2:13][C:12]2([CH3:20])[CH3:19])=[O:6])([CH3:3])[CH3:2].[OH-].[Li+]>C(O)C.O1CCCC1.O>[CH:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]([C:21]#[C:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]([OH:32])=[O:31])=[CH:25][CH:24]=2)[CH:10]=[C:11]2[C:16]=1[O:15][C:14]([CH3:17])([CH3:18])[CH2:13][C:12]2([CH3:20])[CH3:19])=[O:6])([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1ccc(C#Cc2cc(C(=O)OC(C)C)c3c(c2)C(C)(C)CC(C)(C)O3)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)OC(=O)c1cc(C#Cc2ccc(CC(=O)O)cc2)cc2c1OC(C)(C)CC2(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
A solution of 6-(4-methoxycarbonylmethyl-phenylethynyl)-2,2,4,4-tetramethyl-chroman-8-carboxylic acid isopropyl ester (Intermediate 45, 0.019 g, 0.043 mmol) in ethanol (0.3 mL), tetrahydrofuran (0.3 mL) and water (0.3 mL) was treated with 1N lithium hydroxide (0.086 mL, 0.086 mmol) and the resulting reaction mixture was stirred at ambient temperature for 30 minutes. The volatiles were evaporated in vacuo to a residue that was washed with hexane:ethyl acetate (3:1), neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a brown oil (0.015 g, 80%). 1H NMR (300 MHz, CDCl3): δ 7.69 (d, 1H, J=2.4 Hz), 7.55 (d, 1H, J=2.4 Hz), 7.50-7.26 (m, 4H), 5.25 (heptet, 1H), 3.67 (s, 2H), 1.88 (s, 2H), 1.39 (s, 6H), 1.37 (s, 6H), 1.39-1.35 (d, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)=[C:6]([F:27])[C:5]=1[F:28])[CH3:2].[OH-].[Na+].O.Cl>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][CH:15]=2)=[C:6]([F:27])[C:5]=1[F:28])[CH3:2]
Reactant: CCOC(=O)c1ccccc1-c1ccc(-c2ccc(OCC)c(F)c2F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOc1ccc(-c2ccc(-c3ccccc3C(=O)O)cc2)c(F)c1F
Temperature: 30 °C
Yield: 48.2 %

Procedure:
The compounds (3) (29.1 g), sodium hydroxide (11.4 g), Solmix A-11 (100 ml) and water (100 ml) were mixed, and the mixture was heated under reflux for 2 hours. The reaction mixture was cooled to 30° C., and then aqueous 6N-hydrochloric acid solution (100 ml) and toluene (200 ml) were added hereto and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and extraction into an organic phase was carried out. The organic phase obtained was fractionated, washed sequentially with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate, giving 13.0 g of 4-ethoxy-2,3-difluoro-4′-biphenylbenzoic acid (44). The yield based on the compound (3) was 49.2%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][C:6]([CH2:8][S:9][CH2:10][CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:5][CH:4]=1.CN>C(O)C>[OH:1][CH2:2][C:3]1[O:7][C:6]([CH2:8][S:9][CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1
Reactant: O=C1c2ccccc2C(=O)N1CCSCc1ccc(CO)o1
Agent: CN
Solvent: CCO
Product: NCCSCc1ccc(CO)o1
Yield: 45.8 %

Procedure:
A solution of 2-[2-[[5-(hydroxymethyl)-2-furanylmethyl]thio]ethyl]-1H-isoindole-1,3(2H)-dione, (5.0 g) in ethanol (50 ml) was stirred in the presence of methylamine (33% in ethanol) (15 ml) for 15 mins. The residue was subjected to column chromatography (silica/methanol-ethyl acetate 1:1, then methanol) and the appropriate eluates were evaporated. Chloroform (50 ml) was added to the oily product, the solution dried (anhyd. magnesium sulphate) and evaporated yielding the title compound as a pale yellow oil (1.35 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([CH2:11][CH2:12]O)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.CS(Cl)(=O)=O.C([O-])([O-])=O.[K+].[K+].[SH:32][C:33]1[N:47]=[CH:46][CH:45]=[CH:44][C:34]=1[C:35]([NH:37][CH2:38][C:39]1[S:40][CH:41]=[CH:42][CH:43]=1)=[O:36]>C(Cl)Cl.CN(C=O)C.CC(=O)OCC.C(Cl)Cl.CC(=O)OCC>[F:1][C:2]1[CH:3]=[C:4]([S:8]([CH2:11][CH2:12][S:32][C:33]2[N:47]=[CH:46][CH:45]=[CH:44][C:34]=2[C:35]([NH:37][CH2:38][C:39]2[S:40][CH:41]=[CH:42][CH:43]=2)=[O:36])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(CCO)c1cccc(F)c1
Reactant: O=C(NCc1cccs1)c1cccnc1S
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCc1cccs1)c1cccnc1SCCS(=O)(=O)c1cccc(F)c1
Reaction time: 16 h
Yield: 22 %

Procedure:
A solution of 408 mg (2.0 mmol) of 2-(3-fluorophenylsulfonyl)ethanol in DCM (5 ml) was cooled to 0° C.; 304 μl (2.2 mmol) of NEt3 and 154 μl (2.0 mmol) of methanesulfonic acid chloride were added thereto, and stirring was carried out for 16 hours at RT. In another vessel, 275 mg (2.0 mmol) of K2CO3 were added to a solution of 500 mg (2.0 mmol) of 2-mercapto-N-(thiophen-2-ylmethyl)nicotinamide in DMF (6 ml), and stirring was carried out for 30 min at RT. The DCM reaction solution was added to this solution, and stirring was continued for 72 hours at RT. The mixture was then diluted with EA and washed with 1 N aqueous NaHCO3 solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. CC (DCM/EA 4:1) of the residue yielded 194 mg (0.44 mmol, 22%) of 2-[2-(3-fluorophenyl)sulfonylethylthio]-N-(2-thienylmethyl)-nicotinamide. MS: m/z 437.0 [M+H]+