Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[S:14][C:8]=2[C:7]=1[OH:22])=[O:5])C.[NH2:23][CH2:24][C:25]([OH:27])=[O:26]>C[O-].[Na+].CO>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[S:14][C:8]3[C:7]([OH:22])=[C:6]([C:4]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:5])[N:11]=[CH:10][C:9]=3[N:12]=2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1ncc2nc(-c3ccc(Cl)cc3)sc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2nc(-c3ccc(Cl)cc3)sc2c1O
Temperature: 25 °C
Yield: 17.8 %

Procedure:
A mixture of 2-(4-chloro-phenyl)-7-hydroxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (58 mg, 0.17 mmol) and glycine (259 mg, 3.45 mmol) in 0.5 M sodium methoxide/methanol (6.6 mL) was refluxed for three days before it was cooled to room temperature and concentrated in vacuo. Water (20 mL) was added and the mixture was extracted with dichloromethane. The remaining aqueous layer was acidified to pH=2 with 1N HCl. The suspension was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo to give the title compound as a yellow solid (11 mg): 1H NMR (DMSO-d6, 200 MHz): δ=9.44 (br s, 1H), 8.90 (s, 1H), 8.16 (d, J=8.6 Hz, 2H), 7.66 (d, J=8.6 Hz, 2H), 4.02 (d, 2H); MS: (+) m/z 364.0 (M+1)
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1([CH3:16])[O:15][C:13](=[O:14])[CH2:12][C:10](=[O:11])[O:9]1.[C:17](Cl)(=[O:31])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]C>C(Cl)Cl>[OH:31][C:17](=[C:12]1[C:13](=[O:14])[O:15][C:8]([CH3:16])([CH3:7])[O:9][C:10]1=[O:11])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCCC(=O)Cl
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCC(O)=C1C(=O)OC(C)(C)OC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
14.3 mL of pyridine is added at 0° C., to a solution of Meldrum's acid (10.60 g, 73.5 mmol) in 70 mL of anhydrous CH2Cl2. After stirring for 15 min at this temperature, commercial tetradecanoyl chloride (18.16 g, 73.5 mmol) is added dropwise, so that the temperature remains below 10° C. After stirring for 2 h at 0° C. and for 1 h at ambient temperature, the reaction medium is washed with 50 mL of a 2N solution of HCl then 2×50 mL of water. After a last washing with a saturated aqueous solution of NaCl, the organic phase is dried over MgSO4, filtered and concentrated under vacuum. The oil obtained is crystallized by the addition of absolute ethanol then left overnight in the refrigerator. The solid is then filtered then rinsed with cold absolute ethanol before being dried in order to produce compound 17 (21.25 g, 59.9 mmol, 81%) in the form of a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:17][CH2:18][CH2:19][CH2:20]Br>CN(C)C=O.O>[Br:17][CH2:18][CH2:19][CH2:20][O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1
Reactant: COC(=O)c1cc(O)no1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OCCCBr)no1
Temperature: 40 °C
Reaction time: 1 h
Yield: 25.2 %

Procedure:
A solution of methyl 3-hydroxyisoxazole-5-carboxylate (3.5 g, 24 mmol) in N,N-dimethylformamide (20 mL) was treated with potassium carbonate (6.8 g, 49 mmol) and 1,3-dibromopropane (2.5 mL, 24 mmol) was added and the mixture was stirred at 40° C. for 1 h. The reaction was diluted with water and extracted with ethyl acetate three times. The combined extracts were dried with magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (0-70% ethyl acetate/hexanes) to give the desired product (1.6 g, 25%). MF=C8H11BrNO4; LCMS calculated for C8H11BrNO4 (M+H)+: m/z=264.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@H:4]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:5][C:6]1[C:9](=O)[C:8](=[O:11])[C:7]=1[O:12]CC.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)C>[CH3:1][O:2][C:3](=[O:22])[C@H:4]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[NH:5][C:6]1[C:7](=[O:12])[C:8](=[O:11])[C:9]=1[NH:30][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOc1c(N[C@@H](Cc2ccccc2)C(=O)OC)c(=O)c1=O
Reactant: NCc1ccccc1
Solvent: CCO
Product: COC(=O)[C@H](Cc1ccccc1)Nc1c(NCc2ccccc2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a stirred solution of [2-ethoxy-3,4-dioxo-cyclobut-1-enyl]-L-phenylalanine methyl ester (0.33 mmol, 100 mg) in absolute ethanol (3 mL) was added neat benzylamine (0.36 mmol, 39 mg; 40 μL) dropwise at room temperature. The resulting solution was stirred at room temperature overnight, during which a white solid precipitated out of solution. The volatiles were removed in vacuo and the residue was taken up in EtOAc and partitioned between EtOAc and water. The organics were dried (Na2SO4), concentrated in vacuo and purified by flash chromatography (SiO2 :EtOAc/hexane) to afford the title compound as a white solid (113 mg; 94%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=3)=[O:18])[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][NH2:40])=[CH:35][CH:34]=1>CS(C)=O.O>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:17](=[O:18])[CH2:16][CH2:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:40][CH2:39][C:36]4[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=4)[N:7]=3)[CH:10]=2)=[CH:21][C:22]=1[C:27]([F:30])([F:29])[F:28]
Reactant: O=C(CCc1cccc(Oc2ccnc(Cl)n2)c1)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: COc1ccc(CN)cc1
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CNc2nccc(Oc3cccc(CCC(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)c3)n2)cc1
Temperature: 95 °C

Procedure:
To a solution of 3-{3-[(2-chloropyrimidin-4-yl)oxy]phenyl}-N-[4-chloro-3-(trifluoromethyl)phenyl]propanamide (0.200 g, 0.44 mmol) in DMSO (1 mL) were added 1-(4-methoxyphenyl)methanamine (0.056 mL, 0.44 mmol) and TEA (0.061 mL, 0.44 mmol). The reaction mixture was heated at 95° C. overnight and then cooled to rt, diluted with water and extracted with EtOAc. The combined organic solutions were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give A-224. 1H NMR (400 MHz, d6 DMSO) δ: 10.35 (s, 1H), 8.11-8.15 (m, 1H), 8.05-8.11 (m, 1H), 7.75-7.81 (m, 1H), 7.62 (d, 1H), 7.30-7.39 (m, 1H), 7.09-7.26 (m, 2H), 7.04-7.07 (m, 1H), 6.67-7.00 (m, 4H), 6.05 (d, 1H), 4.25-4.43 (br m, 1H), 3.96-4.10 (br m, 1H), 3.67 (s, 3H), 2.93 (t, 2H), and 2.67 (t, 2H). LCMS, FA: Rt=1.88 min, [MH+ 557.3].
Reaction SMILES: [C:1]1([CH3:26])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][CH2:13][CH:12](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([SH:35])[CH:32]=[CH:33][CH:34]=1>>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([S:35][CH:12]2[CH2:13][CH2:14][N:10]([S:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:26])=[CH:6][CH:5]=3)(=[O:8])=[O:9])[CH2:11]2)[CH:32]=[CH:33][CH:34]=1
Reactant: COc1cccc(S)c1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(S(=O)(=O)c3ccc(C)cc3)C2)cc1
Product: COc1cccc(SC2CCN(S(=O)(=O)c3ccc(C)cc3)C2)c1

Procedure:
The title compound, MS: m/e=363.1 (M+) was prepared from (RS)-toluene-4-sulfonic acid 1-(toluene-4-sulfonyl)-pyrrolidin-3-yl ester and 3-methoxythiophenol and by using DMF as solvent instead of acetonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH2:13][CH2:14][C:15]([O:17]C2C=CC([N+]([O-])=O)=CC=2)=O)=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:28]1[CH2:35][CH2:34][CH2:33][C@H:29]1[C:30]([OH:32])=[O:31].C(N1CCOCC1)C>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH2:13][CH2:14][C:15]([N:28]2[CH2:35][CH2:34][CH2:33][C@H:29]2[C:30]([OH:32])=[O:31])=[O:17])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(CCC(=O)Oc2ccc([N+](=O)[O-])cc2)=C(C)C1=O
Reactant: O=C(O)[C@@H]1CCCN1
Agent: CCN1CCOCC1
Solvent: CN(C)C=O
Product: COC1=C(OC)C(=O)C(CCC(=O)N2CCC[C@H]2C(=O)O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 46.1 %

Procedure:
To a solution of p-nitrophenyl 3-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)propionate (187 mg, 0.5 mmol) and L-proline (57 mg, 0.5 mmol) in N,N-dimethylformamide (5 ml) was added N-ethylmorpholine (128 μl, 1.0 mmol). The mixture was stirred at room temperature for 2 days. Thereafter, the reaction mixture was further treated in the same manner as Example 1 to give 3-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)propionyl-L-proline (81 mg), melting at 131° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[N:7][C:8]([O:24][C@@H:25]2[CH2:30][CH2:29][NH:28][CH2:27][C@H:26]2[F:31])=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH2:1]([C:5]1[N:6]=[N:7][C:8]([O:24][C@@H:25]2[CH2:30][CH2:29][N:28]([CH3:34])[CH2:27][C@H:26]2[F:31])=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc(O[C@@H]2CCNC[C@H]2F)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCc1nnc(O[C@@H]2CCN(C)C[C@H]2F)cc1-c1ccc(OC2CCCCC2)cc1

Procedure:
To a stirred solution of (±)-trans-3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(3-fluoro-piperidin-4-yloxy)-pyridazine (20 mg, 0.047 mmol) in DCM (4 mL) was added 37% aqueous formaldehyde (0.1 mL, 1 mmol) and sodium triacetoxyborohydride (106 mg, 0.5 mmol). After 2 hrs the mixture was diluted with saturated aqueous NaHCO3 and extracted with DCM. The organics were dried over sodium sulfate, filtered, concentrated, and purified by column chromatography using 2-5% methanolic solution of ammonia (2.0 M ammonia in methanol) in DCM to give (±)-trans-3-Butyl-4-(4-cyclohexyloxy-phenyl)-6-(3-fluoro-1-methyl-piperidin-4-yloxy)-pyridazine. The free base was dissolved in DCM, treated with 4.0 M HCl in dioxane and concentrated. The resultant salt was washed with ether and dried to provide the title compound (20 mg). LCMS: m/z 443 [M+1]. 1H NMR (400 MHz, CD3OD) δ 7.93 (1H, s), 7.51 (2H, d), 7.14 (2H, d), 5.54-5.60 (1H, m), 5.29 (1H, d), 4.41-4.50 (1H, m), 3.64-3.94 (2H, m), 3.46-3.53 (2H, m), 3.14-3.21 (2H, m), 3.00 (3H, t), 2.40-2.50 (2H, m) 1.96-2.05 (2H, m), 1.77-1.86 (2H, m), 1.23-1.66 (10H, m), 0.82 (3H, t).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14](F)[CH:13]=2)=[O:9])=[C:6]([CH3:20])[CH:5]=[C:4]([Cl:21])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:28]([SH:30])[CH3:29].O>CN(C=O)C>[Cl:21][C:4]1[N:3]=[C:2]([S:30][CH2:28][CH3:29])[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([F:18])[CH:17]=2)=[O:9])=[C:6]([CH3:20])[CH:5]=1
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)NCc1cc(F)cc(F)c1
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1nc(Cl)cc(C)c1C(=O)NCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.8 %

Procedure:
A solution of 4.0 g (12.8 mmol) 2,6-dichloro-N-(3,5-difluorobenzyl)-4-methyl-pyridine-3-carboxylic acid amide in DMF (30 ml) was treated with 2.6 g (19.2 mmol) K2CO3 and 1.2 ml (16.0 mmol) ethanethiol, followed by stirring in a closed vessel at RT for 16 h. Then water (35 ml) was added and the mixture was extracted with EtOAc (2×70 ml). The combined organic layers were washed with water, a 2M aq. NaOH sol. and brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 3:1) provided 3.3 g (9.7 mmol, 76%) 6-chloro-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine-3-carboxylic acid amide.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][CH:29]=1)[O:8][C:9]1[C:17]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[NH:22][CH2:23][CH2:24][CH2:25][CH3:26])(=O)C.[OH-].[Na+]>>[NH2:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][CH:29]=1)[O:8][C:9]1[C:17]([S:18](=[O:20])(=[O:21])[NH2:19])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[NH:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1cccc(NC(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Product: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1cccc(N)c1

Procedure:
The mixture of 1.5 g of 4-(3-acetamidophenoxy)-3-n-butylamino-5-sulfamoylbenzoic acid and 15 ml of 2 N aqueous sodium hydroxide is refluxed for 5 hours under nitrogen. After cooling it is filtered, the filtrate acidified with glacial acetic acid and hydrochloric acid to a pH of 2 - 3, the precipitate collected and recrystallized from ethanol, to yield the 4-(3-aminophenoxy)-3-n-butylamino-5-sulfamoylbenzoic acid of the formula ##SPC16##
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:7]=1[CH:8]=[O:9])([CH3:4])[CH3:3].[OH:15]P([O-])(O)=O.[K+].[Mn]([O-])(=O)(=O)=O.[K+]>C(O)(C)(C)C>[CH3:4][C:2]([O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:7]=1[C:8]([OH:15])=[O:9])([CH3:1])[CH3:3]
Reactant: CC(C)(C)Oc1cccc(Cl)c1C=O
Reactant: O=P([O-])(O)O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)(C)Oc1cccc(Cl)c1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To a solution of 2-[(1,1-dimethylethyl)oxy]-6-chlorobenzaldehyde (8.40 g, 40.0 mmol) in t-butanol (200 mL) was added 1.25M KH2PO4 (pH 7, 200 mL) and 0.4M aqueous potassium permanganate (200 mL, 80 mmol). The reaction was stirred at room temperature for 3 h and was quenched by the addition of saturated aqueous sodium sulfite (200 mL). The brown suspension was acidified with 2N HCl with ice-cooling until the MnO2 dissolved (pH 4). The reaction was extracted with ethyl acetate (3 times) and the organic layers were washed with brine, dried (MgSO4) and concentrated to a white solid. The crude product was recrystallized from hexanes at 0° C. to afford 7.14 g (78%) of 2-[(1,1-dimethylethyl)oxy]-6-chlorobenzoic acid as white crystals: mp 117°-119° C.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][NH2:4].Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[I-].[K+].C(N(C(C)C)CC)(C)C>C(#N)C>[F:1][CH:2]([F:5])[CH2:3][NH:4][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: NCC(F)F
Reactant: CCOC(=O)CBr
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CNCC(F)F
Temperature: 25 °C
Reaction time: 25 h

Procedure:
2,2-difluoroethylamine (4.0 g) was added to a suspension of ethyl bromoacetate (5.4 mL), potassium iodide (0.82 g), diisopropylethylamine (9.8 mL) in acetonitrile (100 mL) and the mixture was stirred at RT for 25 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford the sub-title compound (7.0 g) as a colorless oil; 1H NMR (300 MHz, CDCl3); 5.82 (1H, tt), 4.18 (2H, q), 3.46 (2H, s), 3.00 (2H, dt), 1.26 (3H, t).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[C:8]2[CH:9]=[C:10]([CH2:13][N:14]3[C:18]([C:19]([OH:21])=[O:20])=[C:17]([Cl:22])[N:16]=[C:15]3[CH2:23][CH2:24][CH2:25][CH3:26])[CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([O:35]CC)=[O:34]>O.C(O)C>[Br:3][C:4]1[C:8]2[CH:9]=[C:10]([CH2:13][N:14]3[C:18]([C:19]([OH:21])=[O:20])=[C:17]([Cl:22])[N:16]=[C:15]3[CH2:23][CH2:24][CH2:25][CH3:26])[CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([OH:35])=[O:34]
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc2oc(-c3ccccc3C(=O)OCC)c(Br)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc2oc(-c3ccccc3C(=O)O)c(Br)c2c1

Procedure:
Sodium hydroxide (89 mg) in water (0.2 ml) was added to a suspension of the product of Example 51 (0.5 g) in ethanol (5 ml). The solution was heated under reflux for 16 h, cooled, then evaporated in vacuo. The residue was dissolved in water (5 ml), and HCl (2N; 1 ml) was added dropwise resulting in the precipitation of the title compound which was filtered off, washed with water (2×5 ml) and dried to give the title compound as a colourless solid (391 mg). m.p. 148°-152° C.
Reaction SMILES: O.O.[Sn](Cl)Cl.[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[CH:17]=[CH:18][C:19]2[C:25](=[O:26])[C:24]3[CH:27]=[CH:28][C:29]([N+:31]([O-])=O)=[CH:30][C:23]=3[CH2:22][O:21][C:20]=2[CH:34]=1)([O-])=O>C(O)C>[NH2:6][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[CH:17]=[CH:18][C:19]2[C:25](=[O:26])[C:24]3[CH:27]=[CH:28][C:29]([NH2:31])=[CH:30][C:23]=3[CH2:22][O:21][C:20]=2[CH:34]=1
Reactant: O=C1c2ccc([N+](=O)[O-])cc2COc2cc(Nc3ccccc3[N+](=O)[O-])ccc21
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)COc1cc(Nc3ccccc3N)ccc1C2=O

Procedure:
In accordance with general method Y, 2.40 g (10.66 mmol) of tin(II) chloride dihydrate are dissolved in 15 ml of ethanol, and 0.35 g (0.89 mmol) of (9) is added. Yield: 0.20 g (67.9%);
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:37]3[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=O)C.[OH-:45].[Na+].OO.O>C(O)C>[C@@H:6]1([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]3[S:33][C:34]([C:37]4[CH:42]=[CH:41][C:40]([C:43](=[O:45])[NH2:44])=[CH:39][CH:38]=4)=[CH:35][CH:36]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: [OH-]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4ccc(C#N)cc4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=O)c1ccc(-c2ccc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)s2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyanophenyl)-2-thienylmethyl)benzene (282 mg) obtained in Example 191-(1) was suspended in ethanol (5 ml) and added thereto was a 6N aqueous sodium hydroxide solution (0.37 ml). The mixture was stirred at room temperature for 10 minutes. To the mixture was added a 30% aqueous hydrogen peroxide solution (0.2 ml), and the mixture was stirred at room temperature for 1.5 hours and at 45° C. for 3 hours. To the mixture was added water (20 ml) and the mixture was cooled. The powder was collected by filtration and washed with diethyl ether and dried to give the desired 1-(β-D-glucopyranosyl)-3-(5-(4-carbamoylphenyl)-2-thienylmethyl)-4-chlorobenzene (176 mg) as colorless powder. APCI-Mass m/Z 507/509 (M+NH4).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:8]([CH2:9][OH:10])=[CH:7][N:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:5]=1.F[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1.O>CN(C)C=O>[CH3:3][C:4]1[C:8]([CH2:9][O:10][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=2)=[CH:7][N:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:5]=1
Reactant: Cc1nn(-c2ccccn2)cc1CO
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccccn2)cc1COc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
Sodium hydride (60%, oily, 0.80 g) was added to a solution of [3-methyl-1-(2-pyridyl)-1H-pyrazol-4-yl]methanol (3.20 g) in N,N-dimethylformamide (50 ml) at 0° C., and the mixture was stirred at room temperature for one hour. 4-fluorobenzaldehyde (2 ml) was added to the reaction mixture, and the mixture was stirred overnight at 50° C. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and 4-[3-methyl-1-(2-pyridyl)-1H-pyrazol-4-ylmethoxy]benzaldehyde (4.26 g, yield: 86%) was obtained as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 84–85° C.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[O:20]=[C:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([N:24]3[CH2:25][CH2:26][C:21](=[O:20])[CH2:22][CH2:23]3)=[O:19])[CH:16]=2)[CH:4]=1)[CH3:2]
Reactant: O=C1CCNCC1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)N3CCC(=O)CC3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 4-oxo-piperidine to afford the title compound. MS: m/e=340 (M+H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([Br:23])[CH:21]=4)[N:16]([CH3:24])[CH:15]=3)[C:11]([O-])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:25][O:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[S:34]([NH2:37])(=[O:36])=[O:35].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([Br:23])[CH:21]=4)[N:16]([CH3:24])[CH:15]=3)[C:11]([NH:37][S:34]([C:28]3[CH:29]=[CH:30][C:31]([CH3:33])=[CH:32][C:27]=3[O:26][CH3:25])(=[O:35])=[O:36])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cn1cc(C(C(=O)[O-])c2ccc3c(c2)OCO3)c2cc(Br)ccc21
Reactant: COc1cc(C)ccc1S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2ccc(Br)cc12
Reaction time: 20 h

Procedure:
4 -Dimethylaminopyridine (151 mg) was added to a solution of 2-(1,3-benzodioxol-5-yl)-2-(5-bromo-1-methyl-1H-3-indolyl)acetate acid (the product of Example 68, 480 mg. 1.24 mmol) in anhydrous dichloromethane (10 ml) at ambient temperature. 2-Methoxy-4-methyl-1-benzenesulfonamide (from Preparation 11, 300 mg, 1.48 mmol) was added to the solution, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (355 mg. 1.85 mmol), and stirring was continued for 20 hours. The solution was washed twice with 2N hydrochloric acid, and dried (magnesium sulphate) and the solvents removed in vacuo. The residue was flash chromatographed using 1% methanol in dichloromethane as eluant, and crystallised from dichloromethane and diethyl ether mixture to give the subtitle compound (535 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH3:21])[C:7]([NH:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=O)=[O:8])[CH3:2].[CH2:22]([C:29]1[S:33][C:32]([NH2:34])=[N:31][C:30]=1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(#N)C.O>[CH2:22]([C:29]1[S:33][C:32]([NH:34][C:11]([C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:16]=[CH:17][C:18]([O:19][CH2:20][CH3:21])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)([CH3:15])[CH3:14])=[O:13])=[N:31][C:30]=1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOc1ccc(C(=O)NC(C)(C)C(=O)O)cc1OCC
Reactant: Nc1nc(-c2ccccc2)c(Cc2ccccc2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: CCOc1ccc(C(=O)NC(C)(C)C(=O)Nc2nc(-c3ccccc3)c(Cc3ccccc3)s2)cc1OCC
Temperature: 50 °C
Reaction time: 48 h

Procedure:
150 mg of 2-(3,4-Diethoxy-benzoylamino)-2-methyl-propionic acid and 130 mg of 5-Benzyl-4-phenyl-thiazol-2-ylamine (WO2006082952) were stirred in 2 ml of acetonitrile at room temperature. 120 mg of EDCl and 100 mg of HOBT were added and the reaction mixture was stirred at 50° C. for 2 days and cooled to room temperature. It was diluted with water and the resulting precipitates were collected by filtration followed by washing with water. The filter cake was then purified by column chromatography (heptane/ethyl acetate=3/1) to provide the title compound. 1H NMR (400 MHz. CD3OD) δ 1.34-1.54 (m, 3H) 1.44 (d, J=5.31 Hz, 3H) 1.65 (s, 7H) 4.14 (qd, J=6.95, 2.53 Hz, 4H) 4.23 (s, 2H) 7.01 (d, J=8.46 Hz, 1H) 7.16-7.26 (m, 3H) 7.26-7.45 (m, 6H) 7.47-7.67 (m, 4H). m/z 545.1 (MH+).