Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:17])(O)[CH2:6][CH2:5]2)[O:3]C1.Cl.[H][H]>O1CCOCC1.[Pd]>[CH3:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH:7]1[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]1
Reactant: Cc1ccccc1C1(O)CCC2(CC1)OCCO2
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccccc1C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 35 %

Procedure:
A solution of 4-(2-methylphenyl)-4-hydroxycyclohexanone ethylene ketal from the preceding step in 800 mL dioxane was treated with 16 mL concentrated hydrochloric acid and 30 grams 10% palladium-on-carbon under 35 p.s.i. hydrogen for 24 hours, then filtered through Celite® to remove the catalyst. The filtrate was treated with 230 mL water and stirred at room temperature for 48 hours. The solution was evaporated, the pH adjusted to 8 with saturated aqueous sodium bicarbonate solution, and extracted with methylene chloride. The organic layer was dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/hexane as eluant to afford 33.3 grams (35%) of an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:28])([CH:16]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]([O:26]C)=O)[CH:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.O.[NH2:30][NH2:31]>C(O)(C)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:28])([CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)[CH:16]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]([NH:30][NH2:31])=[O:26])[CH:19]=1)[CH3:17]
Reactant: COC(=O)c1cc(C(C)C(O)(Cn2cncn2)c2ccc(F)cc2F)ccn1
Reactant: NN
Solvent: O
Solvent: CC(C)O
Product: CC(c1ccnc(C(=O)NN)c1)C(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
A solution of the product of part (i) (3.80 g) and hydrazine hydrate (6.0 ml) in isopropanol (20 ml) was heated under reflux for 2.5 hours and then evaporated. Water was added to the residue and the mixture was extracted several times with dichloromethane. The combined extracts were washed with brine and dried (MgSO4). Evaporation of the solvent gave the title compound (3.30 g) as an amorphous foam which was used directly in the next stage.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][O:13]C(C2C=CC=CC=2)[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.O>C(O)C>[CH2:1]([O:8][CH:9]([CH2:10][OH:11])[CH2:14][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COC2COC(c3ccccc3)OC2)cc1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: OCC(CO)OCc1ccccc1
Yield: 87.4 %

Procedure:
A solution of 370 g of 5-benzyloxy-2-phenyl-1,3-dioxane and 35 ml of concentrated sulfuric acid in a medium of 750 ml of water and 1.2 l of ethanol was refluxed for 2 hours. The ethanol was then removed by evaporation under reduced pressure, and by-product benzaldehyde was removed by steam distillation. The aqueous mixture was saturated with potassium carbonate, and the product was extracted from the aqueous medium with ether. The ethereal solution was dried (MgSO4) and evaporated under reduced pressure to give solid product, which upon recrystallization from a benzane/ligroine system gave 218 g of 2-benzyloxy-1,3-propanediol, m.p. 38°-39° C.
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[C:11]([OH:13])=[O:12])=[O:3].C(=O)(O)[O-].[K+:18].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[C:2]([O:4][C:5]1[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:11]([O-:13])=[O:12])(=[O:3])[CH3:1].[K+:18]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Product: CC(=O)Oc1ccccc1C(=O)[O-]

Procedure:
The ˜2 gram dose form soluble aspirin composition of EXAMPLE 1 dissolves in water in less than 30 seconds to constitute a ready to drink dose, when added to 2 ounces of cold water. Upon combination of the dry solids composition with water, a chemical reaction takes place that reacts the aspirin, potassium bicarbonate and citric acid, to yield potassium acetylsalicylate. The potassium acetylsalicylate immediately dissolves in water, leaving no undissolved residue.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]#[C:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]#[C:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:20])=[CH:17][CH:16]=1
Reactant: Cc1onc(-c2ccccc2)c1C#Cc1ccc(C(=O)O)cc1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccccc2)c1C#Cc1ccc(C(=O)NC2CCOCC2)cc1
Yield: 88 %

Procedure:
As described for example 7b, 4-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-benzoic acid (250 mg; 0.82 mmol) instead of 3-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-benzoic acid was converted using 4-amino-tetrahydropyrane instead of aminomethylcyclopropane to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 281 mg, 88%) which was obtained as a white solid. MS: m/e=387.1 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([NH:15][C:16](=[O:31])[C:17]1[CH:22]=[CH:21][C:20]([C:23]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])=[C:19]([CH3:30])[CH:18]=1)[C:5]1[NH:9][C:8]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:7]=2[N:6]=1.C(N(CC)CC)C.[Cl:39][CH2:40][CH2:41][N:42]=[C:43]=[O:44]>O1CCCC1>[Cl:14][C:12]1[CH:11]=[CH:10][C:8]2[NH:9][C:5]([C@@H:4]([NH:15][C:16](=[O:31])[C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[O:24])=[C:19]([CH3:30])[CH:18]=3)[CH2:3][CH2:2][NH:1][C:43]([NH:42][CH2:41][CH2:40][Cl:39])=[O:44])=[N:6][C:7]=2[CH:13]=1
Reactant: Cc1cc(C(=O)N[C@@H](CCN)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Reactant: O=C=NCCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N[C@@H](CCNC(=O)NCCCl)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
0.3 g (0.528 mmol) of (1S)—N-[3-amino-1-(5-chloro-1H-benzimidazol-2-yl)propyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide is suspended in 10 mL of tetrahydrofuran and 0.1 mL (1.056 mmol) of triethylamine and, after the addition of 56 mg (0.528 mmol) of 2-chloroethyl isocyanate, stirred for 16 hours at ambient temperature. Then the solution is concentrated, the residue is taken up in dichloromethane, washed several times with water, and the combined organic extracts are dried and concentrated by evaporation. Yield: 49%; Rf value: 0.30 (silica gel; dichloromethane/ethanol=9:1); C26H30Cl2N6O3 (545.47); mass spectrum: (M+H)+=545/547 (chlorine isotope).
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:12]([F:13])[C:6]=2[CH2:5][O:4]1.[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21]>CCO>[F:13][C:12]1[C:6]2[CH2:5][O:4][CH:3]([CH2:2][NH:22][CH2:18][CH2:19][CH2:20][CH3:21])[O:8][C:7]=2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=1
Reactant: CCCCN
Reactant: CS(=O)(=O)c1cc(F)c2c(c1)OC(CBr)OC2
Solvent: CCO
Product: CCCCNCC1OCc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 34 using 2-(bromomethyl)-5-fluoro-7-(methylsulfonyl)-4H-1,3-benzodioxine (7 mg, 0.021 mmol), butane-1-amine (0.5 ml) and EtOH (3 ml). MS m/z (rel. intensity, 70 eV) 317 (M+, 0.3), 141 (11), 95 (11), 86 (bp), 72 (13), 57 (9).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1)=O.[CH3:19][C:20](=[O:23])[CH:21]=[CH2:22].[OH-].[K+]>CO.O>[O:23]=[C:20]1[CH2:21][CH2:22][C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:5][CH2:4]2)[CH:1]=[CH:19]1
Reactant: C=CC(C)=O
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1C=CC2(CC1)CCN(C(=O)OCc1ccccc1)CC2

Procedure:
A solution of 0.98 g (3.96 mmol) benzyl 4-formylpiperidine-1-carboxylate (prepared by the method from Eur. J. Med. Chem. 1991, 26, 625) and 0.28 g (4.0 mmol) 3-buten-2-one in a mixture of 1 ml methanol and 1 ml water was added dropwise to a boiling solution of 0.015 g (0.27 mmol) potassium hydroxide in 1 ml methanol. After 1 hour heating with reflux the cooled mixture was poured into 50 ml water, and it was extracted with tert.-butylmethylether. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The title compound was obtained from the remaining oil by HPLC on silica gel with hexane/acetone 4:1.
Reaction SMILES: [CH:1]1([C:6]2[C:7]([O:22]S(C3C=CC(C)=CC=3)(=O)=O)=[N:8][N:9]3[C:14]=2[C:13]([CH3:15])=[N:12][N:11]=[C:10]3[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][N:34]1[C:38]([CH2:39]O)=[N:37][CH:36]=[N:35]1.[H-].[Na+].O>CN(C=O)C>[CH:1]1([C:6]2[C:7]([O:22][CH2:39][C:38]3[N:34]([CH3:33])[N:35]=[CH:36][N:37]=3)=[N:8][N:9]3[C:14]=2[C:13]([CH3:15])=[N:12][N:11]=[C:10]3[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1ncnc1CO
Reactant: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4ccccc4)nnc(C)c3c2C2CCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccccc2)n2nc(OCc3ncnn3C)c(C3CCCC3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To toluene-4-sulfonic acid 3-cyclopentyl-4-methyl-7-phenylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester (Example 5, step a; 300 mg, 0.67 mmol) and (2-methyl-2H-[1,2,4]triazol-3-yl)methanol (90.4 mg, 1.2-molar eq; prepared as described in EP-A-170073) in DMF (10 ml) was added sodium hydride (29.5 mg of a 60% dispersion in mineral oil; 1.2 molar eq) and the mixture was stirred at room temperature for 1 h. Water (90 ml) was added then the solution was extracted with diethyl ether (4×50 ml). The combined ether layers were washed with brine (1×100 ml), dried (Na2SO4), the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel eluting with 0 to 50% ethyl acetate in dichloromethane. 3-Cyclopentyl-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-7-phenylpyrazolo[1,5-d][1,2,4]triazine was isolated as a gum, which solidified upon trituration under diethyl ether (152 mg, mp=159° C.). 1H NMR (360 MHz, CDCl3) δ 1.66-1.96 (8H, m), 2.86 (3H, s), 3.44 (1H, m), 3.87 (3H, s), 5.54 (2H, s), 7.61-7.58 (3H, m), 7.90 (1H, s), 8.24-8.26 (2H, m); MS (ES+) m/e 389 [MH]+. Anal. Found C, 65.02; H, 5.97; N, 25.31%. C21H23N7O requires C, 64.76; H, 5.95; N, 25.18%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:9][CH2:10][C:11]([NH:14][C:15]1[CH:16]=[C:17]([CH:28]=[CH:29][C:30]=1[N+:31]([O-])=O)[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>CO.[Zn]>[NH2:31][C:30]1[CH:29]=[CH:28][C:17]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])=[CH:16][C:15]=1[NH:14][C:11]([CH3:13])([CH2:10][CH2:9][N:8]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH3:12]
Reactant: CC(C)(CCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)Nc1cc(C(=O)OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(CCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)Nc1cc(C(=O)OCc2ccccc2)ccc1N
Reaction time: 0.33 h
Yield: 94.8 %

Procedure:
To a stirred suspension of benzyl 3-({4-[bis(tert-butoxycarbonyl)amino]-2-methylbutan-2-yl}amino)-4-nitrobenzoate (280 mg, 0.50 mmol) and zinc dust (344 mg, 5.27 mmol) in methanol (9 mL) is added acetic acid (0.34 mL), dropwise. The mixture is stirred for 20 min, methanol (50 mL) is added and the mixture is filtered through Celite. The filtrate is concentrated and partitioned between EtOAc and H2O, adjusting the pH to 5 by adding 1M HCl. The organic layer is washed with NaHCO3 and H2O, dried (MgSO4) and evaporated to afford the title compound (250 mg, 94%) which is used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH3:12])[C:6]=2[NH:5][C:4]1=[O:13])[CH3:2].[H-].[Na+].[CH3:16][Si:17]([CH3:24])([CH3:23])[CH2:18][CH2:19][O:20][CH2:21]Cl.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH3:12])[C:6]=2[N:5]([CH2:21][O:20][CH2:19][CH2:18][Si:17]([CH3:24])([CH3:23])[CH3:16])[C:4]1=[O:13])[CH3:2]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCn1c(=O)[nH]c2c(C)cccc21
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)n(COCC[Si](C)(C)C)c2c(C)cccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 3.500 g of 1-ethyl-4-methyl-1,3-dihydrobenzimidazol-2-one in 40 ml of anhydrous N,N-dimethylformamide is admixed at 0° C. with 0.874 g of sodium hydride dispersion (60%). The reaction mixture is stirred at 0° C. over a further 30 minutes and 4.06 ml of 2-(trimethylsilanyl)ethoxymethyl chloride are added dropwise. The reaction mixture is stirred at 20° C. over 14 hours, poured onto 150 ml of saturated aqueous sodium hydrogencarbonate solution and extracted with tert-butyl methyl ether (2×200 ml). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a brown oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (1:3 EtOAc-heptane); Rt=5.62.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:26]#[N:27])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[Cl:25])[CH:10]=2)=[O:5])C.C([O:32][C:33](=[O:39])[C:34]([CH3:38])([CH3:37])[CH2:35][NH2:36])(C)(C)C.C(O)(=O)C>CO>[Cl:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[O:17][C:11]1[CH:10]=[C:9]2[C:14]([C:15]([OH:16])=[C:6]([C:4]([NH:36][CH2:35][C:34]([CH3:38])([CH3:37])[C:33]([OH:39])=[O:32])=[O:5])[N:7]=[C:8]2[C:26]#[N:27])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)CN
Reactant: CCOC(=O)c1nc(C#N)c2cc(Oc3ccc(F)cc3Cl)ccc2c1O
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(CNC(=O)c1nc(C#N)c2cc(Oc3ccc(F)cc3Cl)ccc2c1O)C(=O)O
Yield: 80 %

Procedure:
A mixture of A mixture of 1-cyano-4-hydroxy-7-(4-fluoro-2-chloro-phenoxy)-isoquinoline-3-carboxylic acid ethyl ester (40 mg, 0.10 mmol) and 3-amino-2,2-dimethyl-propionic acid tert-butyl ester (43 mg, 0.25 mmol) in 1 mL of MeOH was microwaved at 130° C. for 1 h. Reaction mixture was quenched with acetic acid (0.3 mmol) and then concentrated. Residue was purified by silica gel chromatography, eluting with 5-60% EtOAc/hexanes, to provide the title compound 41 mg (0.08 mmol) in 80% yield. 1H NMR (200 MHz) in CDCl3, δ ppm: 14.07 (s, 1H), 8.41 (d, J=9.2 Hz, 1H), 8.32 (br t, 1H), 7.50 (dd J=9.1, 2.6 Hz, 1H), 7.38-7.10 (m, 4H), 3.55 (d, J=6.8, 2 H), 1.23 (s, 6H).
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:22])[CH:14](Cl)[C:15](=O)[C:16]([F:19])([F:18])[F:17])[CH3:11].CCN(CC)CC>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[S:8][C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[N:9][C:15]=1[C:16]([F:17])([F:18])[F:19])=[O:22])[CH3:11]
Reactant: NC(=S)c1cccnc1
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1sc(-c2cccnc2)nc1C(F)(F)F
Temperature: 150 °C

Procedure:
To a 20 mL microwave tube was added thionicotinamide (0.552 g, 4.0 mmol), ethanol (15 mL) and 2-chloro-4,4,4-trifluoro-3-oxo-butyric acid ethyl ester (1.75 g, 8 mmol). The tube was capped and heated in a microwave at 150° C. for 10 min. The reaction mixture was cooled to ambient temperature and Et3N (1.7 mL, 12 mmol) was added. The tube was capped and heated in a microwave at 130° C. for 1 min. After cooling to ambient temperature the solvent was evaporated and the crude reaction mixture was directly subjected to silica gel chromatography (0 to 100% ethyl acetate/hexanes) to give the desired product as an orange oil which subsequently solidified (0.885 g, 73%): IR (KBr) 2988, 1737, 1712 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.21 (dd, J=2.5, 0.8 Hz, 1H), 8.77 (dd, J=5.0, 1.7 Hz, 1H), 8.33 (dt, J=8.0, 2.2 Hz, 1H), 7.47 (ddd, J=11.8, 4.7, 0.8 Hz, 1H), 4.45 (q, J=14.3, 7.1 Hz, 2H), 1.44 (t, J=7.1 Hz, 3H); ESIMS m/z 303 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][N:10]2[CH:14]=[CH:13][S:12][CH:11]2[NH:15][C:16](=[O:18])[CH3:17])=[CH:4][CH:3]=1>C(OCC)(=O)C.C(O)(=O)C.[C].[Pd]>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][S:12][CH:11]2[NH:15][C:16](=[O:18])[CH3:17])=[CH:4][CH:3]=1
Reactant: CC(=O)NC1SC=CN1C=Cc1ccc(O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)NC1SC=CN1CCc1ccc(O)cc1
Yield: 95.8 %

Procedure:
N-{3-[2-(4-Hydroxyphenyl)vinyl]-1,3-thiazol-2-yl}acetamide (1.900 g, 7.299 mmol) was dissolved in a mixture of ethyl acetate (300 ml) and acetic acid (50 ml), and 10% palladium carbon (760 mg, containing 50% water) was added. The mixture was hydrogenated at room temperature under 4-5 atm. After the completion of the reaction, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate by heating, and recrystallized by cooling to give N-{3-[2-(4-hydroxyphenyl)ethyl]-1,3-thiazol-2-yl}acetamide (1.834 g, 6.993 mmol, yield 95.8%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([C@H:11]3[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[CH2:12]3)[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.[CH3:20][S:21]([C:24]1[C:32]2[C:27](=[CH:28][N:29]=[CH:30][CH:31]=2)[NH:26][N:25]=1)(=[O:23])=[O:22].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([C@@H:11]3[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[CH2:12]3)[C:7]([CH2:9][N:26]3[C:27]4=[CH:28][N:29]=[CH:30][CH:31]=[C:32]4[C:24]([S:21]([CH3:20])(=[O:22])=[O:23])=[N:25]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1n[nH]c2cnccc12
Reactant: O=S1(=O)CC[C@H](n2c(CCl)nc3cc(Cl)ccc32)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2[C@@H]2CCS(=O)(=O)C2)c2cnccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.7 %

Procedure:
A mixture of compound 5-chloro-2-chloromethyl-1-((S)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-1H-benzoimidazole(115 mg, 0.36 mmol), 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine (60 mg, 0.36 mmol) and Cs2CO3 (236 mg, 0.76 mmol) in 4 mL of DMF was stirred at room temperature for 1 h. The mixture was filtered, the filtrate was collected, then to the filtrate was added oxone (300 mg). The mixture was stirred for 4 hrs and purified by prep-HPLC to give the product (60 mg, yield: 34.6%) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]([OH:12])=O)=[O:4].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[N:38]1([CH2:44][C:45]2[CH:46]=[C:47]([CH:53]=[CH:54][CH:55]=2)[O:48][CH2:49][CH2:50][CH2:51][NH2:52])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>ClCCl>[N:38]1([CH2:44][C:45]2[CH:46]=[C:47]([CH:53]=[CH:54][CH:55]=2)[O:48][CH2:49][CH2:50][CH2:51][NH:52][C:10](=[O:12])[CH2:9][S:8][CH2:7][CH2:6][NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: COC(=O)NCCSCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COC(=O)NCCSCC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
There was dissolved 2.07 g (0.011 mol) of 2-[2-(methoxycarbonylamino)ethylthio]acetic acid in 50 ml of dichloromethane and added 1.68 g (0.011 mol) of HOBt and 2.27 g (0.011 mol) of DCC under cooling with ice, and the mixture was stirred for 30 minutes under cooling with ice. Thereto was added 2.7 g (0.011 mol) of 3-[3-(piperidinomethyl)phenoxy]propylamine and the mixture was stirred for 18 hours at room temperature. The precipitate was filtrated off, and the filtrate was washed with 5% aqueous solution of sodium hydroxide and with water and dried over Glauber's salt. Then the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=5:1) to give 3.69 g of the titled compound as oily matter.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]3[CH:19]=[CH:20][CH:21]=[C:11]3[CH2:10][CH2:9]2)=[O:7])=[C:4]([Cl:24])[CH:3]=1.C(N(CC)CC)C.[F:32][C:33]1[C:34]([CH3:42])=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36](Cl)=[O:37].[OH-].[Na+]>ClCCl>[CH:18]1[C:13]2[N:12]3[CH:19]=[CH:20][CH:21]=[C:11]3[CH2:10][CH2:9][N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:36](=[O:37])[C:35]4[CH:39]=[CH:40][CH:41]=[C:33]([F:32])[C:34]=4[CH3:42])=[CH:3][C:4]=3[Cl:24])=[O:7])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1c(F)cccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2CCc3cccn3-c3ccccc32)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(F)cccc1C(=O)Nc1ccc(C(=O)N2CCc3cccn3-c3ccccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.9 %

Procedure:
To a mixture of 0.10 g of 6,7-dihydro-5-(4-amino-2-chlorobenzoyl)-5H-pyrrolo-[1,2-a][1,5]benzodiazepine and 0.06 g of triethylamine in 6 ml of dichloromethane is added 0.08 g of 3-fluoro-2-methylbenzoyl chloride in 0.5 ml of dichloromethane. The mixture is stirred for 2 hours at room temperature and then 2 ml of 1 N NaOH added. The volatiles are evaporated under vacuum and the residue dissolved in 2 ml of tetrahydrofuran and 1 ml of methanol. The mixture is stirred for 2 hours and evaporated and the residue diluted with 2 ml of 1 N NaOH and 5 ml of water. The mixture is extracted with ethyl acetate (15 ml) and the extract washed with brine and dried (Na2SO4). The solvent is removed and the residue triturated with diethyl ether-hexane to give 0.15 g of white solid: Mass Spectrum (CI)474(M+H, Cl35); 476(M+H, Cl37).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Li]CCCC.[CH2:16]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH2:16]([N:23]1[CH2:28][CH2:27][C:26]2([C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4](=[O:5])[O:6]2)[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1OC2(CCN(Cc3ccccc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.5 %

Procedure:
A solution of 2-bromobenzoic acid (20.12 g, 0.1 mol) in THF (200 mL) was treated dropwise with n-BuLi (2.5 M, 80 mL) at −78° C. The mixture was stirred at this temperature for 30 min, followed by dropwise addition of a solution of N-benzylpiperdine-4-one (26 g, 137 mmol) in THF (100 mL). The resulting mixture was stirred at −78° C. for 30 min, and was then allowed to warm to room temperature and stirred overnight. The reaction was quenched with water (100 mL) and the resulting mixture was washed with ether (100 mL). The aqueous layer was refluxed for 1 hr and then acidified to pH 2.5. The mixture was extracted with CHCl3 (3×50 mL), the combined organic layers were washed with brine, dried over Na2SO4 and concentrated to dryness to obtain 1′-benzyl-3H-spiro[isobenzofuran-1,4′-piperidin]-3-one 1b (6 g).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.CCN(CC)CC.Cl[C:23]([O:25][CH3:26])=[O:24].OS([O-])(=O)=O.[K+]>C(Cl)Cl>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:23]([O:25][CH3:26])=[O:24])[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 638.8 %

Procedure:
A solution of 4.00 g (2.00 mmol) of 4-amino-1-BOC-piperidine and 4.18 ml (3.00 mmol) of Et3N in 50 ml of CH2Cl2 was treated at 0° C. with 1.62 ml (2.10 mmol) of methyl chloroformate. The reaction was stirred for 16 h at RT, neutralized with aqueous 10% KHSO4 and extracted with CH2Cl2 (3×). The organic phases were washed with aqueous 10% NaCl, dried over Na2SO4 evaporated and purified by flash silica gel column (n- heptane/EtOAc 1:1 to 1:2) to yield 3.30 g (64%) of the title compound as white solid. MS: 259.2 (MH+).