Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:13][C@H:14]([C:22]([OH:24])=[O:23])[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[NH:21])[NH2:20]>[Ni].[Pd]>[OH:4][CH:3]([CH:5]([OH:6])[CH:7]([OH:8])[CH:9]([OH:10])[CH2:11][OH:12])[CH2:2][NH:13][C@H:14]([C:22]([OH:24])=[O:23])[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[NH:20])[NH2:21]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: [Ni]
Agent: [Pd]
Product: N=C(N)NCCC[C@H](NCC(O)C(O)C(O)C(O)CO)C(=O)O

Procedure:
The starting materials were D-glucose and L-(+)-arginine. The reductive amination was carried out using Raney nickel or palladium/activated carbon (10%) as a catalyst in the temperature range from 50° to 70° C. and yielded a colorless, resin-like product.
Reaction SMILES: [CH3:1][N:2]([CH2:12][C:13]1[N:14]=[C:15]([NH:18]C(=O)OC(C)(C)C)[S:16][CH:17]=1)[C:3]([C:5]1[C:6]([CH3:11])=[N:7][CH:8]=[CH:9][N:10]=1)=[O:4].Cl>O1CCOCC1>[NH2:18][C:15]1[S:16][CH:17]=[C:13]([CH2:12][N:2]([CH3:1])[C:3]([C:5]2[C:6]([CH3:11])=[N:7][CH:8]=[CH:9][N:10]=2)=[O:4])[N:14]=1
Reactant: Cc1nccnc1C(=O)N(C)Cc1csc(NC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nccnc1C(=O)N(C)Cc1csc(N)n1
Yield: 116 %

Procedure:
A solution of tert-butyl 4-((N,2-dimethylpyrazine-3-carboxamido)methyl)thiazol-2-ylcarbamate (1.30 g, 3.6 mmol) in dioxane (10 mL) was treated with 4N HCl in dioxane (10 mL) for 2 hours. The resulting suspension was concentrated in vacuo to afford N-((2-aminothiazol-4-yl)methyl)-N,3-dimethylpyrazine-2-carboxamide (1.10 g).
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[CH:7]=[CH:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=O)[CH:22]([F:24])[F:23])[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:4][CH2:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>O1CCOCC1>[O:1]=[S:2]1(=[O:28])[CH:7]=[CH:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[S:38])[CH:22]([F:24])[F:23])[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:4][CH2:3]1
Reactant: O=C(NC[C@H]1CN(c2ccc(C3C=CS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: O=C1O[C@@H](CNC(=S)C(F)F)CN1c1ccc(C2C=CS(=O)(=O)CC2)c(F)c1

Procedure:
The product of Example 9 (0.40 g, 0.956 mmol) and Lawesson's reagent (0.290 g, 0.717 mmol) in dioxane (5 ml) are heated at 80° C. overnight. The reaction mixture is evaporated to dryness and the residue purified by PTLC (10% MeOH/DCM) to give the title compound as solid. Rf (10% MeOH/DCM)=0.66.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:25][CH:26]3[CH2:28][O:27]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH3:24])[CH:18]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)#[N:30]>CCO.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:25][CH:26]([OH:27])[CH2:28][N:40]3[CH2:39][CH2:38][N:37]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[C:29]#[N:30])[CH2:42][CH2:41]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH3:24])[CH:18]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(-c2nn(CC3CO3)c3c2CN(C(=O)OC(C)(C)C)CC3)ccc1Cl
Reactant: N#Cc1ccccc1N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(-c2nn(CC(O)CN3CCN(c4ccccc4C#N)CC3)c3c2CN(C(=O)OC(C)(C)C)CC3)ccc1Cl
Temperature: 80 °C
Yield: 83.4 %

Procedure:
3-(4-Chloro-3-methyl-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (5.33 g, 13.2 mmol) and 1-(2-cyanophenyl)-piperazine (2.97 g, 15.86 mmol) were partially dissolved in EtOH (50 mL) and triethylamine (2 mL). The reaction mixture was heated to 80° C. for 18 h. The mixture was concentrated and purified by column chromatography (silica, 20% acetone/CH2Cl2) to give 3-(4-chloro-3-methyl-phenyl)-1-{3-[4-(2-cyano-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (6.51 g, 83%) as a yellow solid. TLC (silica, 20% acetone/CH2Cl2): Rf=0.35. MS (electrospray): m/z 591.3 (591.3, calculated for C32H39ClN6O3, [M+H]+).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].[Cl-].[NH4+]>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: OCCCCCCCCCCCCCCCCBr
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCCCCCCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
16-Bromohexadecan-1-ol (1 g) was dissolved in 20 ml of dichloromethane, and imidazole (317.9 mg) and t-butyldimethylsilyl chloride (701.4 mg) were added to this solution. The reaction mixture was stirred at room temperature for four hours. Saturated ammonium chloride solution was added to the reaction mixture, which was then extracted three times with dichloromethane. The organic layer was washed with saline solution and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by silica gel flash chromatography (heptane:ethyl acetate=7:3) gave (16-bromohexadecyloxy)-t-butyldimethylsilane as a colorless oil at an 81% yield.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Br:7][C:8]1[CH:9]=[N:10][NH:11][CH:12]=1.Br[CH2:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([O:20][CH3:21])=[O:19]>CC(N(C)C)=O>[CH3:21][O:20][C:18](=[O:19])[C:17]1[CH:22]=[CH:23][CH:24]=[C:15]([CH2:14][N:10]2[CH:9]=[C:8]([Br:7])[CH:12]=[N:11]2)[CH:16]=1
Reactant: Brc1cn[nH]c1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cccc(Cn2cc(Br)cn2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
Add sodium carbonate (5.80 g, 41.7 mmol) to a solution of 4-bromopyrazole (3.10 g, 20.9 mmol) and methyl 3-bromomethylbenzoate (4.8 g, 20.9 mmol) in 40 mL of dimethylacetamide. Stir the mixture at 60° C. overnight. Cool the reaction to room temperature and pour into 300 mL of ice water. Collect the resulting solid by filtration and dry to afford 6.0 g, 98% yield of 3-(4-bromo-pyrazol-1-ylmethyl)-benzoic acid methyl ester.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][S:10][C:11]2[NH:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:4][CH2:3]1.[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+]>>[CH2:20]([N:15]1[C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[N:12]=[C:11]1[S:10][CH2:9][CH2:8][N:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCc1ccccc1
Reactant: CN1CCN(CCSc2nc3ccccc3[nH]2)CC1
Agent: [Na+]
Agent: [OH-]
Product: CN1CCN(CCSc2nc3ccccc3n2Cc2ccccc2)CC1

Procedure:
Grams 2 2-[2-(4-methylpiperazin-1-yl)ethylthio] benzimidazole, 0.86 ml benzyl chloride, a 3.5 g aqueous solution containing 1.16 g NaOH and 7.5 ml N,N-dimethylformanide were refluxed for 6 hours, then the solid precipitate was filtered off, and the limpid solution was evaporated almost to dryness. The obtained residue was dissolved in chloroform and water and the extraction was carried out three times; the organic phase was washed, made anhydrous and then evaporated to dryness. The obtained residue was chromatographed on a column eluting with chloroform, methyl alcohol, cyclohexane, ammonium hydroxide (65:15:15:0.1). The fractions, which contained the compound, were evaporated to dryness and the residue which was taken up with boiling petroleum ether (80°-φ° C.) and separated from the insoluble oil, gave, on cooling 0.3 g 1-benzyl-2-[2-4- methylpiperazin-1-ethylthio]benzimidazole melting at 122°-125° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][O:8][C:9]2[C:18]([CH3:19])=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:11][C:10]=2[CH3:20])[CH2:4][O:3]1.[CH2:22](C1C=C(C=C(C)C=1O)C#N)C.CC1(C)O[C@H](CO)CO1>>[CH3:1][C:2]1([CH3:21])[O:6][C@H:5]([CH2:7][O:8][C:9]2[C:10]([CH3:20])=[CH:11][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:17][C:18]=2[CH2:19][CH3:22])[CH2:4][O:3]1
Reactant: CCc1cc(C#N)cc(C)c1O
Reactant: Cc1cc(C(=N)NO)cc(C)c1OCC1COC(C)(C)O1
Agent: CC1(C)OC[C@@H](CO)O1
Product: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H]1COC(C)(C)O1

Procedure:
The title compound is prepared in analogy to rac-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-N-hydroxy-3,5-dimethyl-benzamidine from 3-ethyl-4-hydroxy-5-methyl-benzonitrile and (R)-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol; LC-MS**: tR=0.46 min, [M+H]+=309.23; 1H NMR (D6-DMSO): δ1.17 (t, J=7.5 Hz, 3H), 1.33 (s, 3H), 1.38 (s, 3H), 2.25 (s, 3H), 2.57-2.69 (m, 2H), 3.73-3.84 (m, 3H), 4.12 (t, J=7.0 Hz, 1H), 4.39-4.45 (m, 1H), 5.76 (s br, 2H), 7.34 (s, 1H), 7.36 (s, 1H), 9.47 (s, 1H).
Reaction SMILES: C([O:5][C:6](=O)[C@H:7]([CH3:30])[O:8][C:9]1[C:14]([NH:15][CH:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)=[CH:13][C:12]([F:29])=[CH:11][N:10]=1)(C)(C)C>FC(F)(F)C(O)=O>[F:29][C:12]1[CH:11]=[N:10][C:9]2[O:8][C@@H:7]([CH3:30])[C:6](=[O:5])[N:15]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:14]=2[CH:13]=1
Reactant: C[C@H](Oc1ncc(F)cc1NC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1Oc2ncc(F)cc2N(C2CCNCC2)C1=O
Yield: 83.5 %

Procedure:
A trifluoroacetic acid solution (10 ml) of tert-butyl 4-({2-[(1S)-2-tert-butoxy-1-methyl-2-oxoethoxy]-5-fluoropyridin-3-yl}amino)piperidine-1-carboxylate (861 mg) was stirred at room temperature for 24 hours, and then concentrated under reduced pressure. To the residue were added dichloromethane and a saturated aqueous sodium hydrogen carbonate solution, and the solution was separated. The aqueous layer was saturated with salt, and then extracted with dichloromethane. The collected organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford (3S)-7-fluoro-3-methyl-1-piperidin-4-yl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (434 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:14]=[C:13]([C:15]([NH:17][C:18]3[CH:22]=[C:21]([C:23]([NH:25][CH2:26][CH2:27][C:28]([NH2:30])=[NH:29])=[O:24])[N:20]([CH3:31])[CH:19]=3)=[O:16])[N:12]([CH3:32])[CH:11]=2)=[O:8])=[CH:5][C:4]([NH:33][CH:34]=[O:35])=[CH:3]1.N[OH:37]>CN(C=O)C>[CH3:31][N:20]1[CH:19]=[C:18]([NH:17][C:15]([C:13]2[N:12]([CH3:32])[CH:11]=[C:10]([NH:9][C:7]([C:6]3[N:2]([CH3:1])[CH:3]=[C:4]([NH:33][CH:34]=[O:35])[CH:5]=3)=[O:8])[CH:14]=2)=[O:16])[CH:22]=[C:21]1[C:23]([NH:25][CH2:26][CH2:27][C:28](=[N:30][OH:37])[NH2:29])=[O:24]
Reactant: NO
Reactant: Cn1cc(NC(=O)c2cc(NC(=O)c3cc(NC=O)cn3C)cn2C)cc1C(=O)NCCC(=N)N
Solvent: CN(C)C=O
Product: Cn1cc(NC(=O)c2cc(NC(=O)c3cc(NC=O)cn3C)cn2C)cc1C(=O)NCCC(N)=NO

Procedure:
A solution of 2 g of distamycin A in 35 ml DMF was heated to 80° C. and treated with 0.46 ml of hydroxylamine 1M in DMF. After 30′ additional 1 equivalent of hydroxylamine 1M in DMF was added. The solution was evaporated to dryness and the crude residue was purified by flash chromatography (methylene chloride/methanol: 9/1) to give 1.50 g of 3-[1-methyl-4[1-methyl-4[1-methyl-4-formamidopyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidoxime which was dissolved in 50 ml of methanol and added of 10 ml of HCl 2N. The solution was stirred at room temperature for 2 days, the solvent evaporated in vacuo and the solid residue suspended in 200 ml of ethyl acetate, yielding, after filtration 1.4 g of the intermediate.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:30]=[O:31])=[C:5]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH3:15])=[O:9].[BH4-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[NH:3][C:4]([CH2:30][OH:31])=[C:5]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH3:15])=[O:9]
Reactant: CCOCCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOCCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Yield: 79.3 %

Procedure:
To a suspension of 2-ethoxyethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate (1.13 g) in ethanol (15 ml) was added sodium borohydride (80 mg) with stirring under ice-cooling, and this mixture was further stirred for an hour at the same temperature. The reaction mixture was adjusted with dilute hydrochloric acid to pH 6 under ice-cooling and then the solvent was distilled off. To the residue was added water and the aqueous mixture was extracted with diethyl ether. The extract was washed with water and dried over magnesium sulfate. Removal of the solvent gave an oil, which was crystallized by treating with n-hexane. These were recrystallized from a mixture of diethyl ether and n-hexane to give pure crystals (900 mg) of 2-ethoxyethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-1,4-dihydropyridine-3-carboxylate, m.p. 99° to 100° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[CH3:16][CH:17]([CH3:21])[CH2:18][C:19]#[N:20].Cl.O>O1CCOCC1>[CH2:18]([C:19]1[NH:20][C:4](=[O:6])[C:3]2[C:2](=[CH:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=2)[N:1]=1)[CH:17]([CH3:21])[CH3:16]
Reactant: CC(C)CC#N
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2c(=O)[nH]c(CC(C)C)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of dimethyl 2-aminoterephthalate (3.0 g, 14.4 mmol), 3-methylbutanenitrile (1.2 g, 14.4 mmol), and saturated HCl solution in dioxane (20 mL) in sealed tube was stirred at 100° C. overnight. After it was cooled to room temperature, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layer was concentrated and the residue was purified by silica gel chromatography give the desired product. MS (ESI): 260 (MH+).
Reaction SMILES: [O:1]1[CH:6]2[CH:2]1[CH2:3][O:4][CH2:5]2.[CH2:7]([NH:10][CH2:11][CH:12]=[CH2:13])[CH:8]=[CH2:9]>C(O)C>[CH2:7]([N:10]([CH2:11][CH:12]=[CH2:13])[C@@H:6]1[CH2:5][O:4][CH2:3][C@H:2]1[OH:1])[CH:8]=[CH2:9]
Reactant: C=CCNCC=C
Reactant: C1OCC2OC12
Solvent: CCO
Product: C=CCN(CC=C)[C@@H]1COC[C@H]1O
Temperature: 75 °C
Reaction time: 48 h

Procedure:
To a solution of 3,4-epoxytetrahydrofuran (57.4 g, 0.67 mol) in ethanol (344 mL) was added diallylamine (194 g, 2.00 mol). The reaction mixture was heated to 75° C. After 2 days, the reaction mixture was cooled and concentrated under reduced pressure to afford trans-4-(diprop-2-en-1-ylamino)tetrahydrofuran-3-ol. The material was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]([C@@H:8]2[O:30][C@H:29]([CH2:31][O:32]C(=O)C3C=CC=CC=3)[C@@H:19]([O:20]C(=O)C3C=CC=CC=3)[C@H:9]2[O:10]C(=O)C2C=CC=CC=2)[C:4]2=[N:41][C:42](=[O:44])[S:43][C:3]=12.C[O-].[Na+]>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]([C@@H:8]2[O:30][C@H:29]([CH2:31][OH:32])[C@@H:19]([OH:20])[C@H:9]2[OH:10])[C:4]2=[N:41][C:42](=[O:44])[S:43][C:3]=12
Reactant: Nc1ncn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c2nc(=O)sc1-2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2nc(=O)sc1-2
Temperature: 5 °C
Reaction time: 5 h

Procedure:
Compound 31 (310 mg, 0.51 mmol) was dissolved in dry methanol (35 mL) and cooled to 5° C. To this solution was added solid sodium methoxide (82 mg, 1.5 mmol) and the solution was stirred at room temperature for 5 h. The mixture was neutralized with Dowex-50 H+ resin, filtered and evaporated to dryness. The residue was triturated with ethyl ether and then recrystallized from aqueous ethanol to yield colorless needles: 120 mg, 80%: mp 132°-134° C.: UV λmax (pH 1) 227 nm (ε17230), 301 (15750): UV λmax (pH 7, 11) 233 nm (ε22300), 305 (19100): 1H NMR (DMSO-d6) δ5.96 (d, J=3.51 Hz, 1H, C1,H), 7.75 (b, 2H, NH2), and other sugar protons. Anal. Calcd. for C10H 12 N4O5S.O.2H2O: C, 35.71: 9.53. Found: C, 35.45: H, 4.88: N, 16.44: S, 9.50.
Reaction SMILES: [NH2:1][C:2]1[C:32]([Cl:33])=[CH:31][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22](OC4C=CC=CC=4)=[O:23])[CH2:18][CH2:17]3)[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:34][CH3:35])[CH:3]=1.ClC(OC1C=CC=CC=1)=O.[NH:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1>>[NH2:1][C:2]1[C:32]([Cl:33])=[CH:31][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([N:46]4[CH2:50][CH2:49][CH2:48][CH2:47]4)=[O:23])[CH2:18][CH2:17]3)[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:34][CH3:35])[CH:3]=1
Reactant: C1CCNC1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCN(C(=O)Oc3ccccc3)CC2)CC1
Agent: O=C(Cl)Oc1ccccc1
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCN(C(=O)N3CCCC3)CC2)CC1

Procedure:
To 4-amino-5-chloro-2-methoxy-N-[1-(1-phenoxycarbonyl-4-piperidinylmethyl)-4-piperidinyl]benzamide (1 g), which is prepared in the same manner as in Example 1 except that phenyl chloroformate is used instead of dimethylcarbamoyl chloride, is added pyrrolidine (3 ml), and the mixture is heated under reflux for 10 hours. The mixture is concentrated to dryness under reduced pressure, and to the residue is added chloroform. The solution is washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform:methanol=40:1) to give the desired compound (790 mg) as white amorphous.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([O:20]C)=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH:22]([CH3:24])[CH3:23])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:25])[CH:5]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([OH:20])=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH:22]([CH3:23])[CH3:24])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:25])[CH:5]=1
Reactant: COC(=O)COc1cc2c(c(Cl)c1Cl)C1=CC(=O)CCC1(C(C)C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2

Procedure:
Methyl [(5,6-dichloro-9a-isopropyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetate (4.2 gm., 0.011 mole) is added to a solution composed of 20% aqueous sodium hydroxide solution (4.32 ml., 0.022 mole) and methanol (45 ml.). The mixture is stirred and heated at reflux for two hours and then concentrated in vacuo at 50° C. The residue is dissolved in water (50 ml.) and made acid to Congo red paper with 6 normal hydrochloric acid. The solid that separates is removed by filtration, washed with water, then with a little methanol and finally with a little ether. After drying, the product is recrystallized from acetic acid to give pure [(5,6-dichloro-9a-isopropyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetic acid. Using a procedure similar to that described in Example 25, except that in Step A there is substituted for the [(6,7-dichloro-2-isopropyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]acetic acid, an equimolar amount of:
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=O.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][C:14]=1[CH3:22].[OH-].[K+].Cl>CO.O>[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])/[CH:20]=[CH:1]/[C:3]2[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=2)=[CH:15][C:14]=1[CH3:22]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CC(=O)c1ccc(O)c(C)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C(=O)/C=C/c2ccc(C(=O)O)cc2)ccc1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
Commercially available 4-formylbenzoic acid (15.0 g, 0.1 mol) and commercially available 4′-hydroxy-3′-methylacetophenone (15.0 g, 0.1 mol) were dissolved in 150 mL of methanol and 50 mL of water. The solution was cooled with an ice-water bath, to which was added potassium hydroxide (28.0 g, 0.5 mol). The reaction mixture was stirred overnight. The resulted mixture was poured on to 600 mL of ice-water, acidified to pH=4-5 with 1 M HCl, filtered, washed with water (200 mL), and dried in the air. 25 g (87%) of a yellowish solid was obtained.
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(O)(=O)C.[N:19]([O-])=[O:20].[Na+]>O>[N:19](=[CH:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:6])[OH:20]
Reactant: O=N[O-]
Reactant: CC(=O)CC(=O)OCc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(C=NO)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a three necked one liter flask, fitted with a thermometer, a dropping funnel and a magnetic stirrer were placed 173 g. (0.9 mole) of benzyl acetoacetate [The benzyl acetoacetate was prepared as described by Baker et al., J. Org. Chem. 17, 91 (1952)] and 130 ml. of glacial acetic acid. The contents were cooled in an ice-salt bath and a solution of 69 g. (1 mole) of sodium nitrite in 130 ml. of water was added over a period of half an hour; the temperature was kept at 0° to 10° C. After the reaction mixture was stirred for one hour at room temperature, 400 ml. of water was added and the stirring was continued for an additional two hours. The reaction mixture was extracted three times with 200 ml. portions of diethyl ether. The diethyl ether extracts were combined, washed once with water, three times with saturated sodium bicarbonate solution and once with brine. After drying over anhydrous sodium sulfate, the diethyl ether solution was evaporated leaving 16 as a clear oil which solidified upon trituration with petroleum ether (30° - 60°) to give 186.5 g. (93.2%) of white solid. Its NMR spectrum was consistent with the assigned structure. Generally the product was used as such in subsequent reaction but it can be recrystallized from toluene, m.p. 81° - 82° C. ##STR153##
Reaction SMILES: [CH:1]([CH:3]=O)=O.[CH3:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([O:11][CH3:12])=[C:9]([NH2:15])[C:8]=1[NH2:16]>O>[CH3:12][O:11][C:10]1[CH:13]=[CH:14][C:7]([O:6][CH3:5])=[C:8]2[C:9]=1[N:15]=[CH:1][CH:3]=[N:16]2
Reactant: O=CC=O
Reactant: COc1ccc(OC)c(N)c1N
Solvent: O
Product: COc1ccc(OC)c2nccnc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
A mixture of 10 g (0.17 mol) of glyoxal in 50 ml of water was added to 5 g (0.03 mol) of 2,3-diaminohydroquinone dimethyl ether, and stirred at 50° C. for 1 hour. After allowing to cool to room temperature, the reaction solution was extracted with chloroform, and the extract was dried and concentrated. Recrystallization of the residue from benzene gave 4.3 g (75%) of the title compound. m.p. 145°-150° C.