Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH2:17][C:16]([CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:15][CH2:14][CH:13]=2)=[N:5][C:4]([NH2:24])=[N:3]1.[N:25]1[CH:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][CH:26]=1>C1C=CC=CC=1>[CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH2:17][C:16]([CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:15][CH2:14][CH:13]=2)=[N:5][C:4]([N:24]=[CH:31][C:28]2[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=2)=[N:3]1
Reactant: Cn1nc(N)nc1NCCCOC1=CCC=C(CN2CCCC2)C1
Reactant: O=Cc1ccncc1
Solvent: c1ccccc1
Product: Cn1nc(N=Cc2ccncc2)nc1NCCCOC1=CCC=C(CN2CCCC2)C1
Yield: 29.1 %

Procedure:
A stirred solution of 1-methyl-N5 -[3-[[5-(1-pyrrolidinylmethyl)-1,4-cyclohexadien-1-yl]oxy]propyl]-1H-1,2,4-triazole-3,5-diamine (0.95 g) and 4-pyridinecarboxaldehyde (0.35 g) in benzene (30 ml) was heated under reflux in a Dean-Stark separator for 30 h. The solution was evaporated in vacuo to give a solid which was recrystallised from ethyl acetate (10 ml) to afford the title compound as a yellow solid (0.35 g). m.p. 166°-167° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)/[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:22]([O:21][C:18]1[CH:17]=[CH:16][C:15](/[CH:14]=[C:11](\[C:12]#[N:13])/[C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:20][CH:19]=1)(=[O:24])[CH3:23]
Reactant: COc1ccc(/C(C#N)=C/c2ccc(O)cc2)cc1OC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(/C(C#N)=C/c2ccc(OC(C)=O)cc2)cc1OC
Yield: 95 %

Procedure:
Compound 1 (0.28 g) was acetylated with acetic anhydride and pyridine in accordance with a customary method, to thereby produce the target product (0.30 g, yield: 95%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:17])[C:15]=1[CH3:16])=[CH:12][CH:11]=[CH:10][C:9]=2[C:18]([OH:20])=[O:19])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[CH2:32][OH:33].Cl>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:17])[C:15]=1[CH3:16])=[CH:12][CH:11]=[CH:10][C:9]=2[C:18]([O:20][CH2:31][CH2:32][OH:33])=[O:19])[CH3:2]
Reactant: OCCBr
Reactant: CCOc1ccccc1-c1oc2c(C(=O)O)cccc2c(=O)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccccc1-c1oc2c(C(=O)OCCO)cccc2c(=O)c1C
Temperature: 0 °C
Yield: 70.4 %

Procedure:
One gram of 2'-ethoxy-3-methylflavone-8-carboxylic acid prepared by the same way as Example 1 is dissolved in 30 ml of dimethyl formamide, 0.5 gram of anhydrous potassium carbonate is added thereto, 2 grams of ethylene bromohydrin is dropped thereinto with stirring, and the mixture is stirred at 50° C. for four hours. Then it is poured into ice water, the mixture is neutralized with 10% hydrochloric acid, extracted with ethyl acetate, the extract is washed with water, dried with anhydrous magnesium sulfate, the solvent is evaporated therefrom, and the residue is recrystallized from a mixture of benzene and n-hexane to give 0.8 gram of beta-hydroxyethyl 2'-ethoxy-3-methylflavone-8-carboxylate, colorless needles, melting point 143° to 144.5° C.
Reaction SMILES: C(OC([O:6][CH:7]1[C:12]2[CH:13]=[C:14]([S:16]([NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])=[O:17])[S:15][C:11]=2[S:10](=[O:25])(=[O:24])[N:9](C(OCC)C)[CH2:8]1)C)C.Cl>C1COCC1>[OH:6][CH:7]1[C:12]2[CH:13]=[C:14]([S:16]([NH:19][C:20]([CH3:21])([CH3:22])[CH3:23])(=[O:17])=[O:18])[S:15][C:11]=2[S:10](=[O:25])(=[O:24])[NH:9][CH2:8]1
Reactant: CCOC(C)OC1CN(C(C)OCC)S(=O)(=O)c2sc(S(=O)(=O)NC(C)(C)C)cc21
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1cc2c(s1)S(=O)(=O)NCC2O
Temperature: 25 °C
Reaction time: 20 h
Yield: 73.8 %

Procedure:
A mixture of the product from Step E (158 g, 0.325 mol), THF (700 mL) and 2N HCl (180 mL) were stirred at room temperature for 20 hr. After evaporating the THF, the aqueous mixture was cooled to 0° C. and sodium bicarbonate (50 g) was carefully added followed by water (400 mL) and ethyl acetate (500 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (250 mL). The combined organic extracts were washed with brine, dried (MgSO4) and evaporated to give a foam which was triturated with methylene chloride (200 mL) to give a solid (81.7 g, 75%): mp 144°-147° C. Recrystallization of this solid from methylene chloride gave an off-white solid: mp 163°-165° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)#[N:2].N1C=CN=C1.Cl[Si](C(C)C)(C(C)C)C(C)C.C(=O)([O-])O.[Na+].[C:41](ON1C(=O)CCC1=O)([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42]>CN(C)C=O.O1CCCC1>[CH2:44]([O:43][C:41]([NH:2][CH2:1][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][OH:19])=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)=[O:42])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: N#CCCCc1cccc(-c2ccc(CO)cc2)c1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(NCCCCc1cccc(-c2ccc(CO)cc2)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
[3′-(3-Cyanopropyl)biphenyl-4-yl]methanol (0.44 g) and imidazole (0.30 g) were dissolved in N,N-dimethylformamide (4.3 mL), chlorotriisopropylsilane (0.45 mL) was added, and the resulting mixture was stirred at room temperature for 4 hours. Saturated aqueous sodium hydrogen carbonate (10 mL) was added to the reaction mixture and the whole was extracted with diethyl ether (40 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (7.3 mL) and added dropwise to a solution of lithium alminium hydride (0.1 g) in tetrahydrofuran (10 mL) under ice-cooling, and the resulting mixture was stirred at room temperature for 4 hours. The reaction was quenched by sequential addition of water (0.1 mL), 15% aqueous sodium hydroxide (0.1 mL) and water (0.1 mL). The insoluble material was filtered out and the filtrate was concentrated under reduced-pressure. The residue obtained was dissolved in tetrahydrofuran (6.9 mL), N-carbobenzoxyoxysuccinimide (0.45 g) was added, and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on aminopropylated silica gel (eluent: hexane/ethyl acetate=2/1) to give the title compound as triisopropylated form. The compound obtained was dissolved in tetrahydrofuran (4.1 mL), 1 mol/L tetrabutylammonium fluoride-tetrahydrofuran solution (1.1 mL) was added, and the resulting mixture was stirred at room temperature for 1.5 hours. Saturated aqueous ammonium chloride (10 mL) was added to the reaction mixture and the whole was extracted with ethyl acetate (40 mL). The organic layer was washed with brine (15 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the'title compound (0.40 g).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:8]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6][NH:5][CH2:4]1.Br[C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([O:26][CH3:27])=[O:25].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[NH4+]>O1CCOCC1.CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:12]([O:11][C:10]([NH:9][C@H:8]1[CH2:7][CH2:6][N:5]([C:21]2[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=2)[C:24]([O:26][CH3:27])=[O:25])[CH2:4][C@H:3]1[O:2][CH3:1])=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: CO[C@@H]1CNCC[C@@H]1NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COC(=O)c1cccc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)c1
Temperature: 100 °C
Reaction time: 17 h
Yield: 38.6 %

Procedure:
Benzyl cis(±)-4-(3-methoxypiperidin-4-yl)-carbamate obtained by the method described in Example (40b) (0.5 g, 1.89 mmol) was dissolved in dioxane (20 ml) and DMF (6 mL). Methyl 3-bromobenzoate (0.35 g, 1.63 mmol), palladium acetate (39 mg, 0.17 mmol), BINAP (214 mg, 0.34 mmol) and cesium carbonate (1.35 g, 4.14 mmol) were added, and the mixture was stirred at 100° C. for 17 hours. Aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Thereafter, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=90/10, 80/20, 0/100) to obtain 250.9 mg of the title compound as a yellow oily substance (39%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:10]([CH2:11][C:12]([OH:14])=[O:13])[O:9][CH2:8][CH2:7][C:6]=2[CH:15]=1.CC1C=CC([C@H](N)C)=CC=1.Cl>C(#N)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C@H:10]([CH2:11][C:12]([OH:14])=[O:13])[O:9][CH2:8][CH2:7][C:6]=2[CH:15]=1
Reactant: O=C(O)CC1OCCc2cc(Br)ccc21
Agent: Cc1ccc([C@@H](C)N)cc1
Agent: Cl
Solvent: O
Solvent: CC#N
Product: O=C(O)C[C@@H]1OCCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-(6-bromo-3,4-dihydro-1H-2-benzopyran-1-yl)acetic acid (55 g, 203 mmol) in acetonitrile (375 mL) and water (40 mL) was added a solution of (R)-1-(4-methylphenyl)ethylamine (27.45 g, 203 mmol) in acetonitrile (370 mL). The mixture was heated to reflux and the resulting solution cooled to room temperature. A precipitate appeared upon cooling. After stirring for 2 h the salt was filtered off, washed with 95/5 acetonitrile/water (80 mL), and dried in vacuo. The salt was recrystallized in 95/5 acetonitrile/water to give a solid which was suspended in water (390 mL) and treated with 6N HCl (17 mL). After stirring for 1.5 h, filtration, washing, and drying gave the title compound (98% e.e.) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[CH:21][N:20]=[C:19]3[C:15]=2[N:16]=[CH:17][N:18]3[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:32]I.O>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:29])[N:7]([CH3:32])[CH:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]=[CH:21][N:20]=[C:19]3[C:15]=2[N:16]=[CH:17][N:18]3[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ncnc3c2ncn3C2CCCCO2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ncnc3c2ncn3C2CCCCO2)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 74.1 %

Procedure:
The {1-[9-(tetrahydro-pyran-2-yl)-9H-purin-6-yl]-piperidin-4-yl}-carbamic acid tert-butyl ester (107.7 mg, 0.27 mmol) of Example 1A was dissolved in anhydrous dimethylformamide (1 ml) and the solution was cooled to 0° C. in an ice bath. Sodium hydride (13 mg, 60% suspension in oil, 0.33 mmol) was added in small portions. The suspension was stirred vigorously for an additional 20 minutes at 0° C. and then the methyl iodide (0.020 ml, 0.32 mmol) was added drop wise. After stirring the reaction mixture for 30 minutes at 0° C. this was brought to room temperature and left stirring additionally overnight. Water (1.2 ml), followed by ethyl acetate (5 ml) was added to the reaction mixture. The organic layer was separated, washed with water, 0.1 M HCl, a saturated aqueous NaHCO3 solution, and brine before being dried and concentrated in vacuo. The crude product was purified by flash silica column chromatography eluting with 5% methanol in dichloromethane to afford the required compound as a white solid (83 mg, 0.2 mmol, 73%) LC-MS (LCT) Rt 7.07 [M+H]+417.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[OH-].[Na+].Cl.[NH2:18][C@@H:19]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:20][C:21]([OH:23])=[O:22].CN1CCOCC1>O1CCOCC1.C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:18][C@@H:19]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:20][C:21]([OH:23])=[O:22])(=[O:13])=[O:12]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: N[C@H](CC(=O)O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CN1CCOCC1
Product: O=C(O)C[C@@H](NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Reaction time: 3 h

Procedure:
Naphthalene-2-sulfonyl chloride (18.18 g, 80.2 mmol) and NaOH (60 mL, 2 N) were added portion-wise over 1 h to a mixture of (R)-3-amino-3-phenyl-propionic acid HCl salt (14.70 g, 72.9 mmol) and N-methylmorpholine (4.0 mL, 36.5 mmol) in dioxane (250 mL). The pH was maintained at pH 11 with the 2N NaOH solution during the addition. After stirring for an additional 3 h, the mixture was diluted with CH2Cl2 (1 L), acidified, washed with water, dried over MgSO4, filtered, and concentrated in vacuo. Crystallization from CH2Cl2/hexane furnished the title compound. MS (-ESI, m/z) 354 (M−H)−.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([C:19]#[CH:20])[CH2:16][CH:17]=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[N:32]=[C:31]([CH3:33])[O:30][N:29]=2)[CH:23]=1>C(N(CC)CC)C.[Cu]I>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([C:19]#[C:20][C:26]3[CH:27]=[CH:22][CH:23]=[C:24]([C:28]4[N:32]=[C:31]([CH3:33])[O:30][N:29]=4)[CH:25]=3)[CH2:16][CH:17]=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C#CC(CC=O)c1ccc(OC)c(OC2CCCC2)c1
Reactant: Cc1nc(-c2cccc(I)c2)no1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COc1ccc(C(C#Cc2cccc(-c3noc(C)n3)c2)CC=O)cc1OC1CCCC1
Temperature: 80 °C
Yield: 70 %

Procedure:
A mixture (+/-)-3-(3-cyclopentyloxy-4-methoxyphenyl)pent-4-ynal (0.20 g, 0.73 mmol) and 1-iodo-3-(5-methyl-[1,2,4]oxadiazol-3-yl)benzene (0.21 g, 0.73 mmol) and trace tetrakistriphenylphosphine palladium (0) and trace copper(I)iodide in triethylamine (5 mL)under an argon atmosphere was heated at 80° C. for 0.25 h. The mixture was cooled to room temperature and was evaporated. The residue was purified by flash chromatography (silica gel, 35% EtOAc/Hex) to provide the title compound as a yellow oil (0.22 g, 71%).1H NMR (250 Mhz, CDCl3) δ 9.86 (t, J=1.7 Hz, 1 H), 8.15, (d, J=1.4 Hz, 1 H), 8.01 (dt, J=7.8 and 1.4 Hz, 1 H), 7.54 (dt, J=7.8 and 1.4 Hz, 1 H), 7.42 (t, J=7.8 Hz),lH), 6.95 (m. 2 H), 6.84 (d, J=8.5 Hz, 1 H), 4.8 (m, 1 H), 4.40 (t, J=7 Hz, 1 H), 3.85 (s, 3 H), 2.86-3.10 (m, 2 H), 2.66 (s, 3 H), 1.80-2.05 (m, 6 H), 1.60-1.69 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[N+:7]([O-])[CH:8]=[CH:9][CH:10]=1.COS(OC)(=O)=O.ClC1C=CC=CC=1OC1[CH:28]=[N+:29](OC)C=CC=1.[C-]#N.[Na+]>O>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[C:6]([C:28]#[N:29])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: [O-][n+]1cccc(Oc2ccccc2Cl)c1
Reactant: CO[n+]1cccc(Oc2ccccc2Cl)c1
Agent: [C-]#N
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: N#Cc1ncccc1Oc1ccccc1Cl
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 22 g of 3-(2-chlorophenoxy)pyridine 1-oxide and 22 g of dimethylsulfate is heated at 100° C. for 4 hours. The 3-(2-chlorophenoxy)-1-methoxypyridinium methosulfate is cooled and dissolved in 100 ml of water. This solution is added dropwise with stirring to a 0°-5° C. solution of 50 g of sodium cyanide in 100 ml under a nitrogen atmosphere. The mixture is stirred 16 hours and extracted with 250 ml of chloroform. The extract is dried, concentrated and distilled to yield 3-(2-chlorophenoxy)-2-pyridine-carbonitrile, bp 125°-135° C. at 01. mM, mp 90°-92° C. after recrystallization from isopropanol.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>CS(C)=O.O>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:1]2[CH2:5][CH2:4][NH:3][C:2]2=[O:6])=[CH:18][CH:17]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: O=C1NCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1NCCN1Cc1ccc(Cl)cc1
Reaction time: 1.3 h
Yield: 92 %

Procedure:
A 21.5 g (0.25 mole) portion of 2-imidazolidinone in 300 ml of dimethylsulfoxide was treated with 34.5 g (0.25 mole) of potassium carbonate, 10 g (0.06 mole) of potassium iodide and 40.5 g (0.25 mole) of 4-chlorobenzyl chloride. The reaction mixture was heated to 100° over 0.3 hours, held at 100° with rapid stirring for 1.3 hours and poured into 1.3 l of water. The aqueous mixture was extracted with 1.3 l of chloroform. The chloroform extract was washed with 150 ml of water, dried over magnesium sulfate for 3 hours and filtered. The filtrate was concentrated to dryness to give 49 g (92%) a light yellow oil which crystallized.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@@H:4]([NH:20][C:21](=[O:30])[C:22]1[CH:27]=[C:26](Br)[CH:25]=[CH:24][C:23]=1[OH:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]CC2C=CC=CC=2)=[CH:8][CH:7]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:31])[C@@H:4]([NH:20][C:21](=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[OH:29])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)c1cc(Br)ccc1O
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1ccccc1O
Reaction time: 2.5 h
Yield: 86.5 %

Procedure:
(S)-3-(4-benzyloxy-phenyl)-2-(5-bromo-2-hydroxy-benzoylamino)-propionic acid methyl ester (750 mg, 1.5 mmol) was dissolved in 30 mL of MeOH, 100 mg of 10% Pd/C added, and the mixture stirred for 2.5 h under 40 psi of H2. The mixture was filtered and solvent evaporated. The resulting residue was dissolved in DCM, washed with saturated NaHCO3, dried over sodium sulfate and evaporated to give (S)-2-(2-hydroxy-benzoylamino)-3-(4-hydroxy-phenyl)-propionic acid methyl ester (409 mg).
Reaction SMILES: C(O[C:6]([CH:8]1[N:13]([CH3:14])[CH2:12][C:11]2[S:15][C:16]([C:18]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([C:29]4[NH:30][C:31]5[C:36]([CH:37]=4)=[CH:35][C:34]([Cl:38])=[CH:33][CH:32]=5)(=[O:28])=[O:27])[CH2:22][CH:21]3[C:39](=[O:42])[NH:40][CH3:41])=[O:19])=[N:17][C:10]=2[CH2:9]1)=O)(C)(C)C.C(OCC)C>Cl.C(O)C>[ClH:38].[Cl:38][C:34]1[CH:35]=[C:36]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29]([S:26]([N:23]1[CH2:24][CH2:25][N:20]([C:18]([C:16]3[S:15][C:11]4[CH2:12][N:13]([CH3:14])[CH:8]([CH3:6])[CH2:9][C:10]=4[N:17]=3)=[O:19])[CH:21]([C:39](=[O:42])[NH:40][CH3:41])[CH2:22]1)(=[O:28])=[O:27])=[CH:37]2
Reactant: CNC(=O)C1CN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CCN1C(=O)c1nc2c(s1)CN(C)C(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CNC(=O)C1CN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CCN1C(=O)c1nc2c(s1)CN(C)C(C)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a saturated solution of hydrochloride in ethanol (2 ml) was dissolved 1-[[6-(tert-butoxycarbonyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl)piperazine (40 mg), followed by stirring at room temperature for 1 hour. Diethyl ether was added to the reaction mixture. The precipitate so formed was collected by filtration and washed with diethyl ether. Methylene chloride (7 ml) and triethylamine (81 μl) were added, followed by the addition of acetic acid (34 μl). To the resulting mixture were added a 30% aqueous solution (21 μl) of formaldehyde and sodium triacetoxyborohydride (64 mg), followed by stirring at room temperature for 30 minutes. The solvent was distilled off under reduced pressure. Methylene chloride was added and the resulting mixture was washed with water and saturated aqueous NaCl solution. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was dissolved in a 1N ethanol hydrochloride solution. After stirring at room temperature for 5 minutes, the solvent was distilled off under reduced pressure. The precipitate so formed was collected by filtration and washed with diethyl ether, whereby the title compound (68 mg) was obtained as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])NC2C=CSC=2C=1Cl)=[O:5])[CH3:2].[CH3:17][O:18][C:19]([C:21]1[S:22][CH:23]=[CH:24][C:25]=1[NH2:26])=[O:20].C(C(C(Cl)=O)C(Cl)=O)C>>[CH3:17][O:18][C:19]([C:21]1[S:22][CH:23]=[CH:24][C:25]=1[NH:26][C:11](=[O:12])[CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:20]
Reactant: CCOC(=O)c1c(Cl)c2sccc2[nH]c1=O
Reactant: COC(=O)c1sccc1N
Agent: CCC(C(=O)Cl)C(=O)Cl
Product: CCOC(=O)CC(=O)Nc1ccsc1C(=O)OC

Procedure:
A preferred intermediate in the preparation of compound of structure (I) is 7-chloro-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester, depicted by formula (4) below. To prepare this intermediate, methyl-3-amino-thiophene-2-carboxylate was reacted with ethylmalonyl chloride to yield intermediate 3-(2-ethoxycarbonyl-acetylamino)-thiophene-2-carboxylic acid methyl ester, depicted by formula (1). This intermediate was converted to 7-hydroxy-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester, depicted by formula (2), by reacting with sodium ethoxide, and was then converted into 5,7-dihloro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester, depicted by formula (3). Hydrolysis of 5,7-dihloro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester, depicted by formula (3), yielded 7-chloro-5-oxo-4,5-dihydro-thieno[3,2-b]pyrdine-6-carboxylic acid ethyl ester, depicted by formula (4) as shown in Scheme 1.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13]([S:19](Cl)(=[O:21])=[O:20])=[CH:14]2.C(N(C(C)C)CC)(C)C.ClC1C=CC=C2C=1C=CC=C2S(Cl)(=O)=O>C(Cl)(Cl)Cl>[CH:1]1([NH:7][S:19]([C:13]2[CH:12]=[CH:11][C:10]3[C:15](=[CH:16][CH:17]=[CH:18][C:9]=3[Cl:8])[CH:14]=2)(=[O:20])=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: O=S(=O)(Cl)c1ccc2c(Cl)cccc2c1
Agent: O=S(=O)(Cl)c1cccc2c(Cl)cccc12
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(NC1CCCCC1)c1ccc2c(Cl)cccc2c1
Reaction time: 8 h

Procedure:
The title compound was prepared from the coupling of cyclohexylamine and 5-chloro-2-naphthalenesulfonyl chloride. Cyclohexylamine (1.0 g, 3.8 mmol) and diisopropyl ethylamine (1.35 ml, 7.7 mmol) were dissolved in 30 ml chloroform. 5-Chloro-1-naphthalenesulfonyl chloride (0.88 m., 7.7 mmol) in 20 ml chloroform was added dropwise to the solution. After stirring overnight, the CHCl3 solution was washed with saturated sodium bicarbonate solution and brine. Drying over magnesium sulfate and evaporation of the CHCl3 followed by recrystallization with isopropyl ether/methanol gave 0.92 g (75% yield) of a yellow solid: mp 133°-134° C.; 1H NMR (CDCl3): 8.48 (d, J=1.8, 1 H, H1), 8.38 (d, J=9.0, 1 H, H3), 8.00 (d, J=9.0, 1 H, H4), 7.88 (d, J=8.3, 1 H, H6), 7.71 (d, J=7.5, 1 H, H8), 7.51 (t, J=7.8, 1 H, H7), 5.07 (d, J=7.7, 1 H, NH), 3.23-3.15 (m, 1 H, NHCH, 1.77-1.72 (m, 2 H, ring H's), 1.61-1.55 (m, 2H, ring H's), 1.51-1.45 (m, 1H, ring H), 1.22-1.10 (m, 6H ring H's); anal. calcd. for C16H18NO2SCl; C, 59.34; H, 5.60; N, 4.33; found: C, 59.27; H, 5.60; N, 4.30.