Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:19]([O:26][C:27](=[O:32])[NH:28][CH2:29][CH2:30]Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C.CCOCC>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][CH2:8][N:9]([CH2:30][CH2:29][NH:28][C:27]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:32])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O=C(NCCBr)OCc1ccccc1
Reactant: CCOC(=O)C1(Cc2ccccc2)CCNCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CCOC(=O)C1(Cc2ccccc2)CCN(CCNC(=O)OCc2ccccc2)CC1
Temperature: 80 °C

Procedure:
4-Benzyl-piperidine-4-carboxylic acid ethyl ester (2.5 g, 10 mmol), (2-bromo-ethyl)-carbamic acid benzyl ester (2.58 g, 10 mmol) and DIPEA (1.7 mL, 10 mmol) are dissolved in THF (50 mL) and heated at 80° C. for 15 h. The mixture is poured into Et2O (200 mL) and washed with sat. Na2CO3 (50 mL). The ether phase is extracted with 1M aqueous HCl (3×50 mL), the aqueous extracts washed with ether (50 mL) and adjusted to pH 14 with cooled 33% aqueous NaOH. The aqueous phase is extracted with CH2Cl2 (4×50 mL). The organic extracts are dried (Na2SO4), filtered and evaporated to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:16])/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].S(OCC)(O[CH2:21][CH3:22])(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:16])/[CH:11]=[CH:12]/[C:13]([O:15][CH2:21][CH3:22])=[O:14])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CCOS(=O)(=O)OCC
Reactant: COc1ccc(C(=O)/C=C/C(=O)O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/C(=O)c1ccc(OC)c(Cl)c1
Temperature: 32.5 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
Into a 500 ml four-neck flask were charged 26.5 g (0.11 mol) of (E)-4-(3-chloro-4-methoxyphenyl)-4-oxo-2-butenoic acid obtained in Step 1, 260 ml of dimethylformamide (DMF), 24.7 g (0.16 mol) of diethyl sulfate, and 30.4 g (0.22 mol) of potassium carbonate under a nitrogen atmosphere, followed by 2 hours of reaction at 35 to 45° C. After completion of the reaction was confirmed by HPLC analysis, a mixed solution of 3.6 g (0.06 mol) of acetic acid/3.6 g of DMF was added dropwise and the whole was stirred at 30 to 35° C. for 1 hour to decompose excess diethyl sulfate. Thereafter, extraction with a mixed solution of 400 ml of ethyl acetate/400 ml of water/23.4 g of hydrochloric acid was conducted and the organic layer was washed twice with 400 ml of water. After the solvent was removed by evaporation under reduced pressure, the residue was crystallized from 9 ml of ethanol, and 19 ml of water to obtain 25.4 g (yield 86.0%) of the aimed compound as light yellow crystals. The total yield from 1-chloro-2-methoxybenzene was 52.0% and the purity was found to be 99.6%.
Reaction SMILES: [Cl-].[CH3:2][S:3]([N:6]1[CH2:11][CH2:10][NH2+:9][CH2:8][CH2:7]1)(=[O:5])=[O:4].[C:12]([O:16][C:17](N1CCNCC1)=[O:18])([CH3:15])([CH3:14])[CH3:13].CS(Cl)(=O)=O>>[CH3:2][S:3]([N:6]1[CH2:11][CH2:10][N:9]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:8][CH2:7]1)(=[O:5])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CS(=O)(=O)N1CC[NH2+]CC1
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Product: CC(C)(C)OC(=O)N1CCN(S(C)(=O)=O)CC1

Procedure:
Scheme 2 shows the synthesis of 4-(methylsulfonyl)piperazin-1-ium chloride 8 starting by N-sulfonylation of 1-(tert-butoxycarbonyl)piperazine 6 (BOC-piperazine) with methanesulfonyl chloride to give tert-butyl 4-(methylsulfonyl)piperazine-1-carboxylate 7 which was treated with aqueous hydrogen chloride solution in 1,4-dioxane to give 8.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[C:29]3[C:25]([CH:26]=[N:27][NH:28]3)=[CH:24][CH:23]=2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][N:41]([C:44](=[O:46])[CH3:45])[CH2:40][CH2:39]2)=[CH:34][CH:33]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:28]1[C:29]2[C:25](=[CH:24][CH:23]=[C:22]([NH:21][C:4]3[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:6]=4[N:7]=[C:2]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([N:38]5[CH2:39][CH2:40][N:41]([C:44](=[O:46])[CH3:45])[CH2:42][CH2:43]5)=[CH:36][CH:37]=4)[N:3]=3)[CH:30]=2)[CH:26]=[N:27]1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5cn[nH]c5c4)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(Nc4ccc5cn[nH]c5c4)c4ccn(S(=O)(=O)c5ccc(C)cc5)c4n3)cc2)CC1
Temperature: 116 °C
Reaction time: 48 h
Yield: 26 %

Procedure:
A mixture of 2-chloro-N-(1H-indazol-6-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (340 mg, 0.78 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (204 mg, 0.93 mmol) and trimethylsilyl chloride (TMSCl) (0.200 mL, 1.58 mmol) in n-butyl alcohol (8 mL) was heated at 116° C. overnight. More 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (204 mg, 0.93 mmol) was added. The mixture was then stirred at 116° C. for another 48 h. It was then purified by HPLC to give 1-(4-(4-(4-(1H-indazol-6-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone as a solid (126 mg).
Reaction SMILES: [CH2:1]([C:5]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]#[N:25])=[CH:14][CH:13]=2)[C:9](=[O:26])[C:8]([CH:27]=O)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:29]([NH2:32])([CH3:31])[CH3:30].C(O)C.[BH3-]C#N.[Na+]>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].O>[CH2:1]([C:5]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]#[N:25])=[CH:14][CH:13]=2)[C:9](=[O:26])[C:8]([CH2:27][NH:32][CH:29]([CH3:31])[CH3:30])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)N
Reactant: CCCCc1ccc(C=O)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: CCO
Solvent: O
Product: CCCCc1ccc(CNC(C)C)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 2 h

Procedure:
A mixture of 3.7 g of 6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-3-formyl-1,2-dihydro-2-oxopyridine, 0.59 g of isopropylamine and 3.55 g of titanium tetraisopropoxide is stirred for 2 hours at 20° under N2. 10 ml of absolute ethanol and then 610 mg of NaBH3CN are added, the mixture is stirred for a further 20 hours, 2 ml of water are then added and the mixture is filtered. The filtrate is evaporated. 6-Butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-3-isopropylaminomethyl-1,2-dihydro-2-oxopyridine is obtained after conventional working-up.
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:20]CCl>>[ClH:20].[ClH:20].[C:1]1([NH:7][C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)[CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCl
Agent: c1ccc(Nc2nccc(-c3ccncc3)n2)cc1
Product: Cl
Temperature: 25 °C

Procedure:
A 2.0 g amount of N-phenyl-4-(4-pyridinyl)-2-pyrimidinamine was dissolved in 70 ml of dichloromethane with warming. The solution was cooled to room temperature, then hydrogen chloride gas was bubbled in to give a brick red precipitate. The mixture became very thick and more dichloromethane was added. The precipitate was collected, air dried, then dried in vacuo and gave 2.63 g of the desired product as red-orange crystals, mp 259°-262° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@@H:7]([NH2:24])[C:8]([NH:10][C@@H:11]2[C:14](=[O:15])[N:13]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:12]23)=[O:9])=[CH:5][CH:6]=1.Cl>>[NH2:24][CH:7]([C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[C:8]([NH:10][CH:11]1[C:14](=[O:15])[N:13]2[CH:12]1[S:19][CH2:18][C:17]([Cl:20])=[C:16]2[C:21]([OH:23])=[O:22])=[O:9]
Reactant: N[C@@H](C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1ccccc1
Agent: Cl
Product: NC(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CSC12)c1ccccc1
Temperature: 15 °C
Reaction time: 0.42 h

Procedure:
The resultant crude protected Cefaclor mixture is worked up by treating with a mixture of 13.5 ml ice-water and 2.0 ml concentrated HCl and stirred for 25 minutes while cooling with ice. The aqueous phase is separated off and the organic phase is back-extracted with 1.25 ml ice-water. The combined aqueous phases are mixed with 30 ml dimethylformamide, and the resulting suspension is cooled to 15° C., filtered and the solid washed with 8 ml dimethylformamide, which are added to the filtrate. The final solution is treated slowly with concentrated aqueous ammonia to bring the pH to 6.8. The cristalline suspension is stirred at 20° C. for 1 hour, filtered and the crystals washed with 16 ml acetone. After drying, 5.86 g of the title compound were obtained as dimethylformamide solvate.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]=1[C:7]#[N:8].[CH3:13][N:14]=[C:15]=[O:16].C(N(CC)CC)C>CN(C)C=O>[C:7]([C:6]1[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][S:3][C:2]=1[NH:1][C:15]([NH:14][CH3:13])=[O:16])#[N:8]
Reactant: CC(C)(C)c1csc(N)c1C#N
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)Nc1scc(C(C)(C)C)c1C#N
Reaction time: 8 h

Procedure:
A solution of 4 g 2-amino-3-cyano-4-t-butylthiophene, 1.27 g methyl isocyanate and 3 ml triethylamine in 20 ml dimethylformamide was heated at 130°C. for 3 hours and then allowed to stand at about 25°C. overnight. The dimethylformamide was removed by distillation and the residue was crystallized from ether to give the product, as a tan solid, m.p. 212°-214°C. The infrared spectrum of the product showed cyano absorption at 4.6 microns. Sulfur analysis for the product is tabulated in Table I.
Reaction SMILES: CO.[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][N:14]([CH:22]3[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]4[C:39]5[C:34](=[CH:35][CH:36]=[C:37]([N:40]6[CH:44]=[CH:43][N:42]=[CH:41]6)[CH:38]=5)[C:33]([CH3:45])=[CH:32][C:31]4=[O:46])[CH2:24][CH2:23]3)C(=O)OC(C)(C)C)=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1.[ClH:47].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:47].[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][NH:14][CH:22]3[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]4[C:39]5[C:34](=[CH:35][CH:36]=[C:37]([N:40]6[CH:44]=[CH:43][N:42]=[CH:41]6)[CH:38]=5)[C:33]([CH3:45])=[CH:32][C:31]4=[O:46])[CH2:24][CH2:23]3)=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1
Reactant: Cc1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(-n3ccnc3)ccc12
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(=O)n(CCN2CCC(NCc3ccc4c(c3)OCCO4)CC2)c2cc(-n3ccnc3)ccc12
Reaction time: 2 h

Procedure:
To 0.5 mL of methanol solution containing 45 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-(1H-imidazol-1-yl)-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 1 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added at room temperature, and stirred for 2 hours. Ethyl acetate was added, and the resulting solid was filtered to give 32 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-(1H-imidazol-1-yl)-4-methylquinolin-2(1H)-one hydrochloride as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH3:15])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[CH2:16]([NH2:20])[CH2:17][CH2:18][CH3:19]>>[CH2:16]([NH:20][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH3:15])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1)[CH2:17][CH2:18][CH3:19]
Reactant: Cn1cnc2c(Cl)nc3ccccc3c21
Reactant: CCCCN
Product: CCCCNc1nc2ccccc2c2c1ncn2C

Procedure:
Using the general method exemplified in Example 151, 4-chloro-1-methyl-1H-imidazo[4,5-c]quinoline (from Example 114) was reacted with n-butylamine to provide N-butyl-1-methyl-1H-imidazo[4,5-c]quinolin-4-amine, m.p. 98°-100° C.
Reaction SMILES: [OH:1][C:2]1([CH2:21][N:22]([CH3:33])[C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[CH2:7][CH2:6][N:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[CH2:4][CH2:3]1.O1CCCC1.C(Cl)(Cl)Cl.Cl.CO>CO>[OH:1][C:2]1([CH2:21][N:22]([CH3:33])[C:23]2[CH:24]=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=2)[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:14][CH:15]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(N(C)CC2(O)CCN(C(=O)Cc3ccc(S(C)(=O)=O)cc3)CC2)cc1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(N(C)CC2(O)CCN(CCc3ccc(S(C)(=O)=O)cc3)CC2)cc1
Temperature: 25 °C
Yield: 57.6 %

Procedure:
Borane-methylsulfide complex (10M; 0.86 mL) was added to a mixture of the compound (1.36 g) obtained in Step 1, anhydrous tetrahydrofuran (15 mL) and anhydrous chloroform (85 mL) under cooling with ice-water over five minutes under nitrogen atmosphere, and the mixture was stirred at room temperature for twenty four hours. After methanol (10 mL) was added to the mixture under cooling with ice-water, hydrogen chloride-methanol reagent (2.5 M; 5.0 mL) was added to adjust pH to below 1 and the mixture was heated under reflux for two hours. The solvent was removed under reduced pressure and to the residue was added chloroform (50 mL) and saturated aqueous sodium hydrogencarbonate solution (50 mL). The mixture was adjusted to pH 10 by using aqueous 2N sodium hydroxide solution (5 mL) and then separated, and the aqueous layer was extracted with chloroform. The organic layer was combined and washed with water and brine successively, and dried over anhydrous sodium sulfate. After the solvent was removed under reduced pressure, the residue was purified by silica gel column chromatography (Chromatorex NH™) (eluent; dichlorometane:methanol=20:1). The fractions were concentrated and the residue was washed with ethyl acetate and dried to obtain the titled compound (0.76 g) as crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH3:20][O:21][C:22](=[O:29])[C@H:23]([CH2:25][CH:26]([CH3:28])[CH3:27])[NH2:24]>C(Cl)(Cl)Cl.CO>[CH3:20][O:21][C:22](=[O:29])[C@H:23]([CH2:25][CH:26]([CH3:28])[CH3:27])[NH:24][C:16](=[O:18])[C@H:14]([CH3:15])[NH:13][C:11](=[O:12])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)O
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1

Procedure:
Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (from Example D11 above) and L-leucine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.75 in 9:1 CHCl3/MeOH) and the product was purified by silica gel chromatography using 97:3 CHCl3/MeOH as the eluent.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[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(=NO)[CH:39]([F:45])[CH:38]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].C([N:53]1[CH:57]=[CH:56]N=C1)(N1C=CN=C1)=O>C(Cl)(Cl)Cl.C(OCC)(=O)C.O>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[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:56]([C:57]#[N:53])=[C:39]([F:45])[CH:38]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(C4=CC(F)C(=NO)C=C4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4ccc(C#N)c(F)c4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-fluoro-4-formylphenyl)-2-thienylmethyl)benzene (272 mg) obtained in Example 180-(1) was dissolved in N-methyl-2-pyrrolidone (10 ml) and added thereto was hydroxylamine hydrochloride (34 mg). The mixture was heated under stirring at 117° C. overnight. The reaction solution was cooled and diluted with ethyl acetate and water. The organic layer was washed with water and successively washed with brine. After drying over magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1-2:1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-hydroxyimino-3-fluorophenyl)-2-thienylmethyl)benzene (177 mg) as colorless caramel. APCI-Mass m/Z 693/695 (M+NH4). (2) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-hydroxyimino-3-fluorophenyl)-2-thienylmethyl)benzene (175 mg) was dissolved in chloroform (5 ml) and added thereto was 1,1′-carbonyldiimidazole (46 mg). The mixture was stirred at room temperature overnight. 1,1′-Carbonyldiimidazole (92 mg) was further added thereto, and the mixture was stirred at 40° C. for 6 hours. The reaction solution was cooled and diluted with ethyl acetate and water. The organic layer was separated and successively washed with brine. After drying over magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyano-3-fluorophenyl)-2-thienylmethyl)benzene (158 mg) as colorless caramel. APCI-Mass m/Z 675/677 (M+NH4). (3) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyano-3-fluorophenyl)-2-thienylmethyl)benzene was treated in a manner similar to Example 106-(3) to give desired 1-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyano-3-fluorophenyl)-2-thienylmethyl)benzene as pale yellow powder. APCI-Mass m/Z 507/509 (M+NH4).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]=O)[C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[CH3:12][N:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[CH2:18][CH2:19][NH2:20].[Na]>ClCCl>[S:1]1[CH:5]=[C:4]([CH2:6][NH:20][CH2:19][CH2:18][CH:14]2[CH2:15][CH2:16][CH2:17][N:13]2[CH3:12])[C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2
Reactant: CN1CCCC1CCN
Reactant: O=Cc1csc2ccccc12
Agent: [Na]
Solvent: ClCCl
Product: CN1CCCC1CCNCc1csc2ccccc12
Yield: 51 %

Procedure:
Experimental condition analogous to Example 5, from benzo[b]thiophen-3-carbaldehyde 0.16 g (1 mmol), 2-(1-methyl-pyrrolidin-2-yl)-ethylamine 0.14 g (1.1 mmol), and sodium triacethoxyborohydride 0.31 g (1.5 mmol), in 10 mL Dichloromethane. Purification using silica chromatography, elution with dichloromethane-methanol-ammonium hydroxide, 9-1-0.25, gave 140 mg of compound.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH2:12][CH2:13][CH2:14][NH2:15])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[Br:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[Br:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:15][CH2:14][CH2:13][CH2:12][N:10]2[CH:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[CH:9]2)=[O:24])=[CH:21][CH:20]=1
Reactant: NCCCn1cnc(-c2ccccc2)c1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCCCn1cnc(-c2ccccc2)c1)c1ccc(Br)cc1

Procedure:
A mixture of 2.0 g. of 4-phenyl-1H-imidazole-1-propanamine, 50 ml. of methylenechloride and 10 ml. of 1N sodium hydroxide was stirred and 2.2 g. of 4-bromobenzoyl chloride was added. The mixture was stirred for eighteen hours, methylene chloride was added and the layers were separated. The organic layer was washed with water, dried over magnesium sulfate and concentrated. The residue was washed onto a filter with ether, giving the desired product, m.p. 132°-135° C.
Reaction SMILES: C[O-].[Na+].[F:4][C:5]([F:12])([F:11])[C:6]([O:8]CC)=O.[C:13]([C:16]1[S:17][C:18]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:19]=2[N:20]=1)(=[O:15])[CH3:14]>C1COCC1>[F:25][C:23]1[CH:22]=[CH:21][C:19]2[N:20]=[C:16]([C:13](=[O:15])[CH2:14][C:6](=[O:8])[C:5]([F:4])([F:11])[F:12])[S:17][C:18]=2[CH:24]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)c1nc2ccc(F)cc2s1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CC(=O)C(F)(F)F)c1nc2ccc(F)cc2s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42.4 %

Procedure:
To a suspension of sodium methoxide (0.581 mg, 1.08 mmol) in THF (15 ml) was added a solution of ethyl trifluoroacetate (1.456 g, 10.2 mmol) in THF (7 ml) under nitrogen atmosphere. To the resulting mixture was added a solution of 2-acetyl-6-fluorobenzothiazole (2.00 g, 10.2 mmol) in THF (25 ml) dropwise along with ice cooling. The mixture was stirred at room temperature for 1.5 hours, and then concentrated. The resultant residue was subjected to purification using column chromatography on silica gel to afford 1-(6-fluorobenzothiazol-2-yl)-4,4,4-trifluorobutane-1,3-dione (1.26 g, 42%). NMR(CDCl3 -DMSO-d6) δ: 6.85 (1H, s), 7.23 (1H, app dt, J=2.6 Hz, 8.9 Hz), 7.59 (1H, dd, J=2.6 Hz, 8.2 Hz), 8.05 (1H, dd, J=4.6 Hz, 8.9 Hz); mp 175-178° C.
Reaction SMILES: [C:1]([O:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14](=[O:31])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]=[C:25](S(C)(=O)=O)[N:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].NCCC[N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>C1COCC1.CN(C)C(=O)C>[C:1]([O:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14](=[O:31])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]=[C:25]([CH2:9][CH2:8][CH2:7][NH:6][N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)[N:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCCN1CCOCC1
Reactant: CC(C)(C)ONc1ccccc1NC(=O)c1ccc(-c2ccnc(S(C)(=O)=O)n2)cc1
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)ONc1ccccc1NC(=O)c1ccc(-c2ccnc(CCCNN3CCOCC3)n2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 193.7 %

Procedure:
N-(2-t-Butoxyaminophenyl)-4-(2-methylsulfonyl-pyrimidin-6-yl)benzamide (Method 21, 62.5 mg, 0.133 mmol) was dissolved in a mixture of THF (2 ml) and N,N-dimethylacetamide (2 ml) and N-(3-aminopropyl)morpholine (60 μl 0.411 mmol) added. The reaction mixture was heated to 50° C. and stirred for 2 hours. The reaction mixture was then cooled and solvents removed under reduced pressure. The resultant oil was purified by elution through silica with a 5% methanol in dichloromethane, to yield the title compound as a colourless solid (65 mg, 92%); NMR Spectrum: (DMSO-d6) 1.45 (s, 9H), 1.74 (m, 2H), 2.37 (m, 6H), 3.40 (br, 2H), 3.59 (m, 4H), 7.20 (m, 2H), 7.23 (d, 1H), 7.34 (t, 1H), 7.57 (d, 1H), 8.08 (d, 2H), 8.26 (d, 2H), 8.40 (m, 1H), 8.72 (s, 1H), 9.94 (s, 1H); Mass Spectrum: M+H+ 534.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:3]=1[CH2:4][CH:5]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH2:7][CH2:6]1.[Br:20]N1C(=O)CCC1=O>C(Cl)Cl.C(O)(=O)C>[Br:20][C:12]1[CH:13]=[C:14]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH:5]2[CH2:4][C:3]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Fc1ccc(F)c(CC2CCNc3ncccc32)c1
Solvent: ClCCl
Solvent: CC(=O)O
Product: Fc1ccc(F)c(CC2CCNc3ncc(Br)cc32)c1

Procedure:
To a solution of 4-(2,5-difluorobenzyl)-1,2,3,4-tetrahydro-[1,8]naphthyridine (23 mg) in CH2Cl2/acetic acid (5.5 mL, 10:1, v/v) was added N-bromosuccinimide (18.8 mg, 1.2 eq). The reaction was stirred at room temperature for one (1) hour, concentrated under reduced pressure, and purified by silica gel chromatography using a gradient of 0-60% ethyl acetate/hexane as the eluting solvent to give the title compound as a clear, colorless oil (30% yield). LCMS: m/z=339 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.66-1.75 (m, 1H), 1.75-1.86 (m, 1H), 2.73 (dd, J=9.6 and 13.4 Hz, 1H), 2.95 (dd, J=6.0 and 13.4 Hz, 1H), 2.99-3.08 (m, 1H), 3.34-3.43 (m, 1H), 3.45-3.55 (m, 1H), 5.22 (bs, 1H), 6.80-6.86 (m, 1H), 6.88-6.96 (m, 1H), 6.98-7.05 (m, 1H), 7.16 (d, J=1.9 Hz, 1H), 7.91 (d, J=1.9 Hz, 1H).