Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C(O)=C(CN)C(CO)=CN=1.Cl.Cl.[CH3:15][C:16]1(S([O-])(=O)=O)[C:26](=[O:27])[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:18](=[O:19])[CH2:17]1.O.O.O.[Na+]>O>[CH3:15][C:16]1[C:26](=[O:27])[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:18](=[O:19])[CH:17]=1
Reactant: CC1(S(=O)(=O)[O-])CC(=O)c2ccccc2C1=O
Agent: Cc1ncc(CO)c(CN)c1O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC1=CC(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A solution containing 2.0 grams of pyridoxamine dihydrochloride, purity 98%, (0.00813 moles), in 10 ml of water, at room temperature, was added dropwise during 5 minutes, to a stirred solution of 5.2 grams of menadione sodium bisulfite, purity 95%, (0.01496 moles), in 13 ml of water. After a few minutes of stirring at a temperature of 25° C., a white crystalline precipitate formed. The product was filtered, washed with a few milliliters of ice cold water, then dried in vacuum at 40°-45° C. until constant weight was achieved. The recovered dry product was a white crystalline powder weighing 5.05 grams. The assay gave a combined menadione content equal to 48.5%, with a yield (based on MSB) equal to 95% and a purity of 95.3%. The so obtained compound melted, with decomposition, at 171°-173° C. The product was moderately soluble in water (1.3 g/100 ml of water).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH2:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][Si:10]([CH3:25])([CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH:16]1[CH2:18][O:17]1>C(O)C>[CH3:25][Si:10]([CH3:9])([CH2:19][CH2:20][Si:21]([CH3:22])([CH3:24])[CH3:23])[CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH:16]([OH:17])[CH2:18][NH:8][CH2:7][CH2:6][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CC[Si](C)(C)CCCOCC1CO1
Reactant: NCCN1CCCC1
Solvent: CCO
Product: C[Si](C)(C)CC[Si](C)(C)CCCOCC(O)CNCCN1CCCC1
Temperature: 70 °C

Procedure:
2-Pyrrolidin-1-yl-ethylamine (4.16 g; 36.4 mMol) and 40 mL of ethanol were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 70° C. 2-{3-[Dimethyl-(2-trimethylsilanyl-ethyl)-silanyl]-propoxymethyl}-oxirane 8 (2 g; 7.28 mMol) mixed with 10 g ethanol was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 70° C. for an additional 4 hours. Ethanol was stripped off on the rotovap. The mixture was distilled under vacuum to remove impurities and excess 2-pyrrolidin-1-yl-ethylamine.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl>>[F:23][C:20]([F:21])([F:22])[C:16]1[CH:15]=[C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=[CH:18][CH:17]=1
Reactant: FC(F)(F)c1cccc(C2=CCN(Cc3ccccc3)CC2)c1
Agent: Cl
Product: FC(F)(F)c1cccc(C2CCNCC2)c1
Yield: 96.1 %

Procedure:
Beginning with 1-Benzyl-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine (1.44 g), 1 g of the title compound as HCl salt was recovered by the procedure described in preparation 9. m.p. 202° C. (HCl); MS m/z (rel. intensity, 70 eV) 229 (M+, 44), 228 (33), 83 (12), 57 (54), 56 (bp).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][CH:31]=1)[O:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:32]([F:35])([F:34])[F:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:37][C:38](=[O:47])[C:39]1[CH:44]=[CH:43][C:42]([CH2:45]Br)=[CH:41][CH:40]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][CH:31]=1)[O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:45][C:42]3[CH:43]=[CH:44][C:39]([C:38]([OH:47])=[O:37])=[CH:40][CH:41]=3)=[CH:24][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:32]([F:35])([F:33])[F:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Oc1ccc(Oc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1
Product: O=C(O)c1ccc(COc2ccc(Oc3cccc(-c4c(Cc5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)cc2)cc1

Procedure:
The title compound was prepared from 4-{3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]-phen-oxy}phenol (0.1 g, 0.0002 mole) and 4-Bromomethyl-benzoic acid methyl ester (0.057 g, 0.00024 mole) with subsequent hydrolysis following the procedure of Example 515: MS (ES) m/z 603.9; HRMS: calcd for C37H26F3NO4+H+, 606.18867; found (ESI, [M+H]+), 606.1894.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.Cl[CH:13]([OH:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C1(C)C=CC=CC=1.O>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[O:1][CH2:14][CH2:13][OH:15])[CH:7]=[CH:8][CH:9]=1
Reactant: Oc1cccc2cccnc12
Reactant: CC(O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: OCCOc1cccc2cccnc12
Yield: 29.1 %

Procedure:
A mixture of 14.5 g (0.10 mole) of 8-hydroxyquinoline, 13.5 ml (0.20 mole) of chloroethanol, 40 g (0.30 mole) of potassium carbonate, and 200 ml of acetone was stirred at reflux temperature for 26 hr. The mixture was filtered and the filtrate concentrated to an oil. The oil was partitioned between toluene and aqueous potassium carbonate solution. When the toluene solution was shaken with a fresh portion of potassium carbonate solution, an off-white solid crystallized out of solution. The solid was collected by filtration and the organic layer of the filtrate extracted twice with potassium carbonate solution. The toluene solution was concentrated to obtain a black oil. The oil was redissolved in toluene and upon treating the solution with a few drops of water, a solid crystallized from solution. This solid was collected by filtration and combined with the previously obtained solid. The solid was dissolved in hot methylene chloride, stirred with magnesium sulfate and charcoal, filtered, and concentrated to an oil. The oil was crystallized by dissolving in toluene and wetting the solution with a few drops of water, affording two crops of solid (5.5 g) which was shown by 1H nmr to be a dihydrate. The dihydrate was dissolved in a mixture of methylene chloride and toluene. The solution was dried (sodium sulfate), and concentrated to give 5.4 g of the anhydrous product as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[C:12]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)([OH:14])=[O:13]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:18]2[CH:19]=[CH:20][C:15]([C:12]([OH:14])=[O:13])=[CH:16][CH:17]=2)=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 100 °C
Yield: 71 %

Procedure:
To a mixed solution of ethylene glycol dimethyl ether (400 ml)-2M aqueous sodium carbonate solution (80 ml), 4-bromobenzotrifluoride (5.0 g), 4-carboxyphenylboronic acid (3.9 g) and tetrakistriphenylphosphinepalladium (2.5 g) were added and stirred at 100° C. for a day and night. Concentrating the reaction liquid under reduced pressure, the residue was extracted with 1N aqueous sodium hydroxide solution, and the aqueous layer was neutralized by gradual addition of conc. sulfuric acid. The precipitated solid was recovered by filtration, washed with water and diethyl ether and dried under reduced pressure to provide the title compound (4.2 g) as white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:6])=[O:5].[Br:14][CH2:15][CH2:16]Br>CN(C=O)C>[Br:14][CH2:15][CH2:16][C:7]([CH3:13])([S:4]([CH3:3])(=[O:5])=[O:6])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: BrCCBr
Reactant: CCOC(=O)C(C)S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(CCBr)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 2.33 g, 58.3 mmol) was washed with hexanes (2×10 mL) in a 100 mL two neck round bottom flask under nitrogen then suspended in DMF (30 mL). The suspension was treated dropwise with ethyl 2-(methylsulfonyl)propanoate (10.0 g, 55.49 mmol) in DMF (10 mL). The mixture was stirred 30 min at RT, cooled to 0° C., and treated drop-wise with 1,2-dibromoethane (5.17 mL, 58.8). The mixture was allowed to warm to room temperature while stirring overnight. The mixture was quenched with saturated aq ammonium chloride (100 mL) and extracted with diethyl ether (4×50 mL). Combined organics were washed with 50% saturated sodium chloride (4×50 mL), dried (MgSO4), and concentrated in vacuo. Crude material was purified via silica chromatography (350 g, 230-400 mesh) and an eluent of EtOAc in hexanes (10-20%) to afford the title compound as a pale yellow oil (7.9 g, 50%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.33 (t, J=7.05 Hz, 3H) 1.64 (s, 3H) 2.49-2.59 (m, 1H) 2.78 (ddd, J=13.89, 10.16, 6.64 Hz, 1H) 3.05 (s, 3H) 3.33-3.41 (m, 1H) 3.46-3.54 (m, 1H) 4.22-4.37 (m, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:38]=[C:39]([N:43]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:44](=[O:46])[CH3:45])[CH:40]=[CH:41][CH:42]=1>>[C:44]([N:43]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:39]1[CH:38]=[C:37]([CH:42]=[CH:41][CH:40]=1)[CH2:36][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1)(=[O:46])[CH3:45]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COCCCN(C(C)=O)c1cccc(CCl)c1
Product: COCCCN(C(C)=O)c1cccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)c1

Procedure:
Analogously to Method D, 0.238 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 0.128 g of N-(3-chloromethylphenyl)-N-(3-methoxypropyl)acetamide are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.20 (2:1 EtOAc-heptane); Rt=5.80.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:9]([NH:11][N:12]([CH2:28][C@@H:29]([OH:33])[C:30]([OH:32])=[O:31])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[F:27])=[CH:16][CH:15]=2)=[O:10])[NH:7][N:8]=1)(=[O:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(Cl)Cl.[N:51]1([CH2:57][CH2:58]O)[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>>[N:51]1([CH2:57][CH2:58][O:31][C:30](=[O:32])[C@H:29]([OH:33])[CH2:28][N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[F:27])=[CH:16][CH:15]=2)[NH:11][C:9]([C:6]2[NH:7][N:8]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=2)=[O:10])[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1
Reactant: CC(=O)c1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)[nH]n1
Reactant: OCCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(=O)c1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)OCCN2CCOCC2)[nH]n1
Reaction time: 0.17 h
Yield: 14.8 %

Procedure:
(R)-3-[N′-(5-Acetyl-2H-pyrazole-3-carbonyl)-N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydr oxy-propionic acid (41.0 mg, 86 μmol), HOBt (70.0 mg, 518 μmol) and EDC (92 μL, 520 μmol) were combined in DCM (0.7 mL, 10 mmol). The resulting solution was stirred for 10 minutes. 4-Morpholineethanol (84 μL, 691 μmol) was added, and the mixture was stirred at room temperature until the reaction was complete (≈2 hours). The mixture was concentrated by rotary evaporation and purified (reverse phase column) to yield the title compound (7.5 mg, purity 98%) as a TFA salt. MS m/z [M+H]+calc'd for C28H31ClFN5O6, 588.19. found 588.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][CH3:15])=[O:13])[C@@H:7]([CH3:16])[CH2:6][N:5]2[C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18].C1(C(N2C3C(=CC([C:38]4[CH:39]=[N:40][NH:41][CH:42]=4)=CC=3)N(C(OC(C)C)=O)C[C@@H]2C)=O)CC1>>[CH3:16][C@H:7]1[CH2:6][N:5]([C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:38]3[CH:39]=[N:40][NH:41][CH:42]=3)[CH:3]=2)[N:8]1[C:12]([O:14][CH3:15])=[O:13]
Reactant: CC(C)OC(=O)N1C[C@H](C)N(C(=O)C2CC2)c2ccc(-c3cn[nH]c3)cc21
Reactant: COC(=O)N1c2ccc(Br)cc2N(C(=O)OC(C)C)C[C@@H]1C
Product: COC(=O)N1c2ccc(-c3cn[nH]c3)cc2N(C(=O)OC(C)C)C[C@@H]1C

Procedure:
4-Isopropyl 1-methyl (S)-2-methyl-6-(1H-pyrazol-4-yl)-2,3-dihydroquinoxaline-1,4-dicarboxylate was synthesized from 4-isopropyl 1-methyl (S)-6-bromo-2-methyl-2,3-dihydroquinoxaline-1,4-dicarboxylate according to the procedure outlined above for (S)-isopropyl 4-(cyclopropanecarbonyl)-3-methyl-7-(1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate. MS (ESI, pos. ion) m/z 359 [M+1]+.
Reaction SMILES: C(OC([N:8]1[C@@H:12]([CH2:13][N:14]([CH:21]([CH3:23])[CH3:22])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][O:10]C1(C)C)=O)(C)(C)C.[ClH:26]>O1CCOCC1>[ClH:26].[ClH:26].[NH2:8][C@@H:12]([CH2:13][N:14]([CH:21]([CH3:23])[CH3:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][OH:10]
Reactant: CC(C)N(C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)N(C[C@H](N)CO)c1ccccc1
Reaction time: 8 h

Procedure:
To a stirred solution of (S)-4-[(isopropyl-phenyl-amino)-methyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (650 mg) in dioxane (5 ml) under an argon atmosphere was added HCl solution (4M in dioxane; 9.33 ml). The mixture was stirred overnight. The mixture was concentrated and the residue was dried to give (S)-2-amino-3-(isopropyl-phenyl-amino)-propan-1-ol dihydrochloride (616 mg, quant.) as off-white amorphous solid. MS (ISP): 209.3 ([M+H]+)
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([N+:22]([O-])=O)=[C:7]([NH:9][C@@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]([NH:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:8]=1>CCO.[Pd]>[NH2:22][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][OH:1])=[CH:8][C:7]=1[NH:9][C@@H:10]1[CH2:11][CH2:12][C@H:13]([C:16]([NH:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(CO)ccc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(CO)ccc2N)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of cis-4-(5-(hydroxymethyl)-2-nitrophenylamino)-N-isopropylcyclohexane-carboxamide (2.0 g, 5.96 mmol) in EtOH (25 mL) was added 10% palladium on carbon (0.635 g, 0.596 mmol). The reaction was stirred under a hydrogen atmosphere (1 atm) at RT. After 3 hours, the reaction mixture was filtered through Celite® brand filter aid and concentrated to afford cis-4-(2-amino-5-(hydroxymethyl)phenylamino)-N-isopropylcyclohexanecarboxamide as a brown oil.
Reaction SMILES: C[O-].[Na+].Cl.[CH3:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([NH2:11])=[NH:10].[N:16](=[C:18]([C:24]#[N:25])[C:19](OCC)=[O:20])[OH:17].O>CO.C(O)(=O)C>[NH2:25][C:24]1[N:10]=[C:9]([C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[O:6][CH3:5])[NH:11][C:19](=[O:20])[C:18]=1[N:16]=[O:17]
Reactant: COc1ccccc1C(=N)N
Reactant: CCOC(=O)C(C#N)=NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: COc1ccccc1-c1nc(N)c(N=O)c(=O)[nH]1
Reaction time: 4.5 h
Yield: 67.4 %

Procedure:
A stirred solution of sodium methoxide in dry methanol [prepared from sodium (10.7 g.) and dry methanol (150 ml.)] maintained at 0° C. was treated with 2-methoxybenzamidine hydrochloride (21.6 g.) followed by ethyl α-oximinocyanoacetate (16.5 g.). The mixture was then heated to reflux with stirring for 4.5 hours, and then poured into water (1000 ml.) and brought to pH6 by the addition of glacial acetic acid. The resultant green solid was filtered off and recrystallised from aqueous acetic acid to give 4-amino-2-(2-methoxyphenyl)-5-nitrosopyrimid-6-one (19.2 g.), m.p. 210°-211° C. (with decomposition). A further quantity of less pure 4-amino-2-(2-methoxyphenyl)-5-nitrosopyrimid-6-one (2.9 g.) was obtained by concentration of the mother liquors of the recrystallisation.
Reaction SMILES: BrCCCCC[N:7]1[C:18](=[O:19])[C:17]2[N:15]([CH3:16])[CH:14]=[N:13][C:12]=2[N:10]([CH3:11])[C:8]1=[O:9].C(N(CC)CC)C.[ClH:27]>C1(C)C=CC=CC=1>[ClH:27].[NH:7]1[C:18](=[O:19])[C:17]2[N:15]([CH3:16])[CH:14]=[N:13][C:12]=2[N:10]([CH3:11])[C:8]1=[O:9]
Reactant: Cn1cnc2c1c(=O)n(CCCCCBr)c(=O)n2C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cn1cnc2c1c(=O)[nH]c(=O)n2C

Procedure:
In toluene, 7.9 g of 1-(5-bromo-n-pentyl)theobromine, 5.0 g of N-benzyhydrylpiperazine and 4 g of triethylamine are stirred under reflux for 30 hours. The subsequent treatments are carried out in the same manner as described in Example 96. The obtained crude crystal is converted to a hydrochloride according to customary procedures to obtain 4.7 g of intended 1-}5-[4-benzhydrylpiperazinyl-(1)]-n-pentyl}-theobromine hydrochloride (the yield being 40.9%).
Reaction SMILES: [Na].C([NH:5][C:6]1[C:14]2[CH:13]3[CH2:15][CH2:16][CH2:17][CH2:18][CH:12]3[O:11][C:10]=2[C:9]([C:19]([O:21]C)=[O:20])=[CH:8][C:7]=1[Cl:23])(=O)C>CO.[OH-].[Na+]>[NH2:5][C:6]1[C:14]2[CH:13]3[CH2:15][CH2:16][CH2:17][CH2:18][CH:12]3[O:11][C:10]=2[C:9]([C:19]([OH:21])=[O:20])=[CH:8][C:7]=1[Cl:23]
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)c2c1OC1CCCCC21
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CO
Product: Nc1c(Cl)cc(C(=O)O)c2c1C1CCCCC1O2
Reaction time: 48 h

Procedure:
To a solution of 0.3 g of sodium in 15 ml methanol is added 0.6 g of methyl 1-acetylamino-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylate. Stirring is continued at 60° C. for two days. This is then diluted with 5 ml 1N sodium hydroxide and stirring continued at 60° C. overnight. The methanol is removed in vacuum, diluted with water, filtered, acidified with acetic acid, filtered, extracted with ethyl acetate, washed with water, dried over magnesium sulfate and evaporated to dryness to obtain 1-amino-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylic acid. This is purified by crystallization from ethyl acetate/ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[CH:10][N:9]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]2=[N:7][CH:8]=1.[CH:21]([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.CI>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([CH3:21])[N:9]([S:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:13])[C:6]2=[N:7][CH:8]=1
Reactant: CC(C)[N-]C(C)C
Reactant: COc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: CI
Solvent: C1CCOC1
Product: COc1cnc2c(c1)cc(C)n2S(=O)(=O)c1ccccc1
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A solution of 5-methoxy-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (900 mg, 3.12 mmol) in THF (22.5 ml) was added dropwise to a solution of lithium diisopropylamide (prepared from nBu-Li (2.5M in hexane); 2.5 ml) and diisopropylamine (874 μl) in THF (13.5 ml)) cooled at −25° C. and the mixture was stirred for 30 minutes. Methyl iodide (215 μl, 3.44 mmol) in THF (9 ml) was then added dropwise and the mixture was stirred for 10 minutes at −25° C., left to warm up to ambient temperature and stirred for 15 minutes. The mixture was then poured onto ice/water. The mixture was then extracted with ethyl acetate. The organic layer was separated, washed with water, brine, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography, eluting with ethyl acetate/petroleum ether (20/80 followed by 30/70). The fractions containing the expected product were combined and evaporated to give 5-methoxy-2-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (805 mg, 85%).
Reaction SMILES: [C:1]1([C:7]([SH:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.C(N(CC)CC)C.[C:33]([NH:36][C:37](=[O:40])[CH2:38]Cl)(=[O:35])[CH3:34]>O>[C:33]([NH:36][C:37](=[O:40])[CH2:38][S:20][C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)NC(=O)CCl
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)NC(=O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To a suspension of 100.4 g. (0.40 mole) of triphenylmethylmercaptan in 500 ml. of dry dimethylformamide was added 40.4 g. (0.40 mole) of dry triethylamine. The reaction mixture was cooled in ice and stirred as portions of 54.2 g. (0.40 mole) of the product of Step A above were added over 10 minutes. The reaction mixture was stirred an additional hour with ice cooling and then overnight at room temperature. Water was then added carefully to the reaction mixture until just before the cloud point, when the mixture was seeded and crystallization began. Yield of product was 98.5 g. with an m.p. of 147°-149° C.
Reaction SMILES: [CH3:1][C@@:2]1([OH:20])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[C:14]2[N:15]=[CH:16][N:17]=[C:18]([NH2:19])[C:13]=2[CH:12]=[CH:11]1.C1C2=C(N)N=CN=C2N([C@@H]2[O:35][C@H:34](CO)[C@@H](O)[C@H]2O)C=1>>[CH3:1][C@@:2]1([OH:20])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[C:14]2[N:15]=[CH:16][N:17]=[C:18]([NH2:19])[C:13]=2[C:12]([CH:34]=[O:35])=[CH:11]1
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(N)ncnc21
Reactant: Nc1ncnc2c1ccn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc(C=O)c2c(N)ncnc21

Procedure:
7-(2′-C-methyl-β-D-ribofuranosyl)-4-amino-5-(formyl)-pyrrolo[2,3-d]pyrimidine was synthesized according to the procedure described by Shin-ichi Watanabe and Tohru Ueda in Nucleosides and Nucleotides (1983) 2(2), 113–125. In the synthesis of the title compound however, 7-(2′-C-methyl-β-D-ribofuranosyl)-4-amino-pyrrolo[2,3-d]pyrimidine (See Carroll, et al.,11,12) was substituted in place of tubercidin.
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.[CH2:6]([O:8][C:9](=[O:19])[CH2:10][CH:11]=[CH:12][CH2:13][C:14](OCC)=[O:15])[CH3:7]>>[CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[CH2:13][CH2:12][CH:11]2[CH2:10][C:9]([O:8][CH2:6][CH3:7])=[O:19])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC=CCC(=O)OCC
Reactant: NCC1CC1
Product: CCOC(=O)CC1CCC(=O)N1CC1CC1
Temperature: 165 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
78 g of cyclopropylmethylamine (1.1 mole) and 220 g of 3-hexenedioic acid diethyl ester are introduced into a liter autoclave. The mixture is heated to 165° C. and then kept at that temperature for 8 hours. After cooling, the product is distilled under vacuum, first eliminating the alcohol, then obtaining 155 g of a compound which distils at 157°-160° C. under 3 mm of Hg.
Reaction SMILES: [Cl:1]/[C:2](/[C:11]([O:13][CH2:14][CH2:15][CH3:16])=[O:12])=[C:3](\Cl)/[C:4]([O:6][CH2:7][CH2:8][CH3:9])=[O:5].C([O-])(=O)C.[NH4+:21]>CN(C)C=O>[NH2:21]/[C:3](/[C:4]([O:6][CH2:7][CH2:8][CH3:9])=[O:5])=[C:2](\[Cl:1])/[C:11]([O:13][CH2:14][CH2:15][CH3:16])=[O:12]
Reactant: [NH4+]
Reactant: CCCOC(=O)/C(Cl)=C(/Cl)C(=O)OCCC
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CCCOC(=O)/C(N)=C(/Cl)C(=O)OCCC
Yield: 96.5 %

Procedure:
26.9 g (0.1 mol) of dipropyl dichloromaleate, 19.27 g (0.25 mol) of ammonium acetate and 40 ml of dimethylformamide were reacted under the same conditions as described in Example 1. 24.1 g (87.4% yield) of dipropyl aminochloromaleate were obtained as a reddish, viscous liquid (purity according to GC analysis 90.5%)