Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[N:11]=[CH:12][N:13]([C:23]=2[N:24]=[CH:25][N:26]=1)[C@@H:14]1[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[C@H:15]1[OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:35])C=1>C(O)(=O)C>[CH2:1]([NH:8][C:9]1[N+:26]([O-:35])=[CH:25][N:24]=[C:23]2[C:10]=1[N:11]=[CH:12][N:13]2[C@@H:14]1[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[C@H:15]1[OH:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(NCc4ccccc4)ncnc32)[C@H](O)[C@@H]1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(=O)O
Product: [O-][n+]1cnc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1NCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 27.9 %

Procedure:
N6 -Benzyladenosine (25 mg, 70 μmol) and m-chloroperbenzoic acid (38 mg, 220 μmol) were dissolved in 1 ml acetic acid. The resulting solution was stirred at room temperature for 2 days. The solvent was evaporated under a stream of nitrogen, and the residue was dissolved in a minimum of methanol and chromatographed on a silica plate (250μ) using acetonitrile:water, 4:1 (v/v). The UV absorbing band at Rf =0.53 was extracted with methanol to provide 7.3 mg (28% yield) of N6 -benzyladenosine-N1 -oxide. Mass and 1H-NMR spectra were consistent with the assigned structure.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[S:5]([CH2:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13]C)=[O:12])(=[O:7])=[O:6]>ClC1C=CC=CC=1>[CH3:1][N:2]([CH3:3])[S:5]([CH2:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([OH:13])=[O:12])(=[O:7])=[O:6]
Reactant: COC(=O)c1ccccc1CS(=O)(=O)Cl
Reactant: CNC
Solvent: Clc1ccccc1
Product: CN(C)S(=O)(=O)Cc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Liquified dimethylamine (73 ml) was added slowly with cooling to a 15% (w/w) solution of methyl 2-[(chlorosulfonyl)methyl]benzoate (42.0 g) in chlorobenzene. When addition was complete, the suspension was stirred 0.5 hour at room temperature, then filtered. The filtrate was concentrated to approximately 250 ml and added dropwise to a mixture of 150 ml of ethanol, 50 ml of water and 40 ml of 50% sodium hydroxide. The resulting suspension was stirred overnight at room temperature. The reaction solution was concentrated to dryness and the residue partitioned between 1000 ml water and 1000 ml of methylene chloride for 1.5 hour. The aqueous phase was separated, washed with 400 ml of methylene chloride, then acidified with concentrated hydrochloric acid. The precipitated solid was collected and dried overnight in vacuo to give 34.9 of 2-[(dimethylamino)sulfonylmethyl]benzoic acid, m.p. 112°-119°.
Reaction SMILES: [CH2:1]([C:3]([C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[C:30]([CH3:43])[CH:29]=1)([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([O:23][CH2:24][O:25][CH3:26])([C:19]([F:22])([F:21])[F:20])[C:15]([F:18])([F:17])[F:16])=[C:8]([CH3:27])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[CH3:44][O:45][C:46](=[O:55])[CH2:47][C:48]1[CH:49]=[N:50][CH:51]=[C:52](Br)[CH:53]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.O>[CH3:44][O:45][C:46](=[O:55])[CH2:47][C:48]1[CH:49]=[N:50][CH:51]=[C:52]([C:31]2[CH:32]=[CH:33][C:28]([C:3]([CH2:1][CH3:2])([C:6]3[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([O:23][CH2:24][O:25][CH3:26])([C:19]([F:22])([F:20])[F:21])[C:15]([F:18])([F:16])[F:17])=[C:8]([CH3:27])[CH:7]=3)[CH2:4][CH3:5])=[CH:29][C:30]=2[CH3:43])[CH:53]=1
Reactant: CCC(CC)(c1ccc(CCC(OCOC)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: COC(=O)Cc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCC(CC)(c1ccc(CCC(OCOC)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 80.3 %

Procedure:
Degassed N,N-dimethylformamide (0.37 mL) was added to 2-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Example 108-(1); 38.4 mg, 0.0623 mmol), (5-bromo-pyridin-3-yl)acetic acid methyl ester (Example 24-(2); 19.9 mg, 0.0865 mmol), tetrakis(triphenylphosphine)palladium (0) (9.0 mg, 0.0078 mmol) and potassium phosphate (28.2 mg, 0.133 mmol). After replacement with nitrogen, the mixture was heated while stirring at an external temperature of 85 to 95° C. for three hours. Water was added to the reaction mixture, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=2/1) to give the title compound (32 mg, 80%).
Reaction SMILES: Cl.Cl.C[O:4][C:5](=[O:53])[C@@H:6]([NH:22][C:23]([C@@H:25]1[CH2:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][C@H:37]([C:39]4[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH:47]5[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]5)=[CH:41][CH:40]=4)[O:38][C:30]3=[CH:29][C:28]=2[CH2:27][NH:26]1)=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=2[CH3:21])=[CH:10][CH:9]=1.[C:54](Cl)(=[O:61])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>CCOC(C)=O.C([O-])(O)=O.[Na+]>[C:54]([N:26]1[C@H:25]([C:23]([NH:22][C@@H:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=3[CH3:21])=[CH:12][CH:13]=2)[C:5]([OH:4])=[O:53])=[O:24])[CH2:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][C@H:37]([C:39]4[CH:40]=[CH:41][C:42]([O:45][CH2:46][CH:47]5[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]5)=[CH:43][CH:44]=4)[O:38][C:30]3=[CH:29][C:28]=2[CH2:27]1)(=[O:61])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCC2CCCCC2)cc1)CO3
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1nccc(-c2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)c3ccccc3)O[C@@H](c3ccc(OCC4CCCCC4)cc3)CO5)C(=O)O)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-2-{[(3S,8S)-3-(4-Cyclohexylmethoxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester dihydrochloride was dissolved in 1:1 EtOAc and saturated aqueous NaHCO3 and benzoyl chloride (3 eq) added. After stirring at room temperature for 1 hour, the layers were separated and the organic layer was dried over Na2SO4 and evaporated. The residue was purified over silica (hexanes to 8:2 hexanes-EtOAc to 6:4 hexanes-EtOAc to 6:4 hexanes-EtOAc+2% MeOH to DCM+3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (17 mg). LCMS (m/z): 781.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[NH:13][C:14]([CH:19]([CH3:21])[CH3:20])([CH3:18])[C:15](=[O:17])[N:16]=1)=[O:5])[CH3:2].[CH2:22]([N:24]=[C:25]=[O:26])[CH3:23].C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:13]([C:25](=[O:26])[NH:24][CH2:22][CH3:23])[C:14]([CH:19]([CH3:20])[CH3:21])([CH3:18])[C:15](=[O:17])[N:16]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccccc1C1=NC(=O)C(C)(C(C)C)N1
Reactant: CCN=C=O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCNC(=O)N1C(c2ccccc2C(=O)OCC)=NC(=O)C1(C)C(C)C
Yield: 98.7 %

Procedure:
9 g (0.031 mole) of 2-(2-ethoxycarbonylphenyl)-5-isopropyl-5-methyl-4-oxo-2-imidazoline are dissolved in 30 ml of absolute methylene chloride, and 2.7 g (0.038 mole) of ethyl isocyanate and 0.5 ml of DBU are added at room temperature. After a reaction time of 1 hour, the mixture is poured onto ice and the organic phase is washed twice with water, dried and evaporated. 11.0 g (98% of theory) of 2-(2-ethoxycarbonylphenyl)-1-N-ethylcarbamoyl-5-isopropyl-5-methyl-4-oxo-2-imidazoline are obtained as colorless tablets of melting point 85°-87° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][Mg]Br)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].CO[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[O:26][CH2:27][C:28]([CH3:31])([CH3:30])[N:29]=1>O1CCCC1>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[O:26][CH2:27][C:28]([CH3:31])([CH3:30])[N:29]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccccc1C1=NC(C)(C)CO1
Reactant: CCCCc1ccc(CCCC[Mg]Br)cc1
Solvent: C1CCOC1
Product: CCCCc1ccc(CCCCc2ccccc2C2=NC(C)(C)CO2)cc1

Procedure:
Following the procedures of Example 1(a), (b) and (c), to 4-(4-butylphenyl)butylmagnesium bromide (from 21.47 mmoles of 4-(4-butylphenyl)butyl bromide and 18.96 mmoles of magnesium) in distilled tetrahydrofuran (35 ml) was added 2-(2-methoxyphenyl)-4,4-dimethyloxazoline (16.32 mmoles) in tetrahydrofuran (15 ml). Workup of the reaction mixture furnished 2-[2-(4-(4-butylphenyl)butyl)phenyl]-4,4-dimethyloxazoline as an oil. A solution of the oxazoline (14.41 mmoles) in methyl iodide (20 ml) was refluxed under argon for 18 hours. Removal of the volatiles afforded the corresponding 3,4,4-trimethyloxazolinium iodide as a white solid (mp 91°-94° C.). To an ice cold solution of the iodide (14.07 mmoles) in methanol was added in portions sodium borohydride (14.30 mmoles). Similar treatment of the reaction mixture resulted in the isolation of the desired benzaldehyde product as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[C:12](O)(=O)[CH2:13][OH:14].[NH4+].[OH-]>>[N+:9]([C:5]1[CH:6]=[C:7]2[N:8]=[C:12]([CH2:13][OH:14])[NH:1][C:2]2=[N:3][CH:4]=1)([O-:11])=[O:10]
Reactant: Nc1cc([N+](=O)[O-])cnc1N
Reactant: O=C(O)CO
Agent: [NH4+]
Agent: [OH-]
Product: O=[N+]([O-])c1cnc2[nH]c(CO)nc2c1
Temperature: 145 °C
Reaction time: 0.62 h
Yield: 57.9 %

Procedure:
Solid 2,3-Diamino-5-nitropyridine (prepared according to J. Med. Chem. 1997, 40, 3679-3686; 610 mg, 0.0040 mol) and solid glycolic acid (750 mg, 0.0099 mol) were combined in a sealed tube (left open) and heated to 145° C. and stirred for approx. 30-45 min (solid fuses together, liquifies then re-solidifies). After allowing to cool to rt the solid was extracted with 1N HCl. The aqueous mixture was concentrated under vacuum to leave a crude solid that was basified using conc. NH4OH solution. The ammonia solution was concentrated under vacuum to leave a crude solid that was dry-loaded on to silica and purified by column chromatography (using the ISCO system) to give a solid (450 mg) that was used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][CH2:18][CH3:19])[C:11](=[O:20])[N:10]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=4)[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.O.NN.[H][H]>[Pd]>[NH2:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][CH2:21][N:10]2[C:9]3[N:8]=[C:7]([CH2:6][C:5]4[CH:32]=[CH:33][C:2]([F:1])=[CH:3][CH:4]=4)[NH:15][C:14]=3[C:13](=[O:16])[N:12]([CH2:17][CH2:18][CH3:19])[C:11]2=[O:20])=[CH:28][CH:27]=1
Reactant: CCCn1c(=O)c2[nH]c(Cc3ccc(F)cc3)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Reactant: [H][H]
Agent: [Pd]
Agent: NN
Solvent: O
Product: CCCn1c(=O)c2[nH]c(Cc3ccc(F)cc3)nc2n(CCc2ccc(N)cc2)c1=O

Procedure:
By the method of Example 2, 4-fluorophenylacetic acid is reacted with 5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield 8-(4-fluorobenzyl)-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine. By methods well known in the art, 8-(4-fluorobenzyl)-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-8-(4-fluorobenzyl)-1-propylxanthine.
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].C([Li])CCC.COCN[C:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:21]>O1CCCC1>[CH3:4][O:3][C:2]1[C:1]([O:9][CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:21]
Reactant: COc1ccccc1OC
Reactant: COCNC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1OC
Temperature: 0 °C

Procedure:
A suitable reactor maintained under nitrogen is charged with veratrole (12.5 kg, 90.0 mol) and about 87 kg of tetrahydrofuran. The solution is cooled and maintained below −10° C. while adding n-butyl lithium (22.9 kg, 83.3 mol, 23.3% solution in hexane). The mixture is warmed to about 0° C. for 1 hour, then to about 25° C. for at least 2 hours. In a separate reactor maintained under nitrogen is charged with 4-[(methoxymethylamino)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15) as a heptanes wet cake (15.6 kg, 57.3 mol, dry weight basis) and about 66 kg of tetrahydrofuran. The mixture is cooled below −10° C.1 and the lithiated veratrole solution is added at such a rate to maintain the temperature below −10° C. The mixture is warmed to about 25° C. for at least 6 hours.2 When complete, the title compound may be utilized in Scheme H, step a, Example 108 as the reaction solution.
Reaction SMILES: [CH2:1]([O:5][C:6]([CH2:8][S:9][C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:7])[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:27])C=1.C(OCC)(=O)C>C(Cl)Cl>[CH2:1]([O:5][C:6]([CH2:8][S:9]([C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:27])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOC(=O)CSc1nc2cccnc2s1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCOC(=O)CS(=O)c1nc2cccnc2s1
Temperature: -10 °C
Reaction time: 0.67 h
Yield: 68.5 %

Procedure:
Dissolved in 50 ml of methylene chloride was 18.5 g of the compound obtained in Example 1, and the solution was cooled down to -10° C. 16.2 g of m-chloroperbenzoic acid (with a 70% purity) was added to the solution, which was in turn stirred at that temperature for 40 minutes. Ethyl acetate (600 ml) was added to the solution, which was then washed once with an aqueous solution of sodium thiosulfate, three times with sodium hydrogencarbonate and once with water, dried over magnesium sulfate, and distilled to remove the solvent. The residue was purified by silica gel column chromatography, and eluting with n-hexane-ethyl acetate (5:3 to 3:1) to obtain the title compound (13.4 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:29]3[C:24](=[CH:25][C:26](F)=[CH:27][CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>CS(C)=O.O>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([N:1]4[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]4)=[CH:27][CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)ccc23)CC1
Reactant: C1CNCCN1
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(N4CCNCC4)ccc23)CC1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A mixture of piperazine (5 mmol) and 4-(7-fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (1 mmol) in DMSO (1 mL) was stirred at 120° C. for 1 h. It was then diluted with water and extracted with DCM. The combined extracts were washed with water, brine, dried (anhydrous MgSO4), filtered and concentrated in vacuo to obtain 4-(7-piperazin-1-yl-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [OH:1][C@:2]1([CH3:27])[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12]2(OCC[O:14]2)[CH3:13])[CH2:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[OH:1][C@:2]1([CH3:27])[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1
Reactant: CC1([C@H]2CC[C@H]3[C@@H]4CC[C@H]5C[C@](C)(O)CC[C@]5(C)[C@H]4CC[C@]23C)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@](C)(O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A solution of 3α-hydroxy-3β-methyl-20,20-ethylenedioxy-5α-pregnane and p-toluene sulfonic acid (catalytic) in wet acetone was heated at reflux overnight. The reaction was concentrated in vacuo and taken up in chloroform. The organic phase was washed with sodium bicarbonate, dried over magnesium sulfate, concentrated, and recrystallized from methanol to give the titled compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH:12]=[C:13]1[NH:17][C:16](=[O:18])[NH:15][C:14]1=O)([O-])=O.CO.II>CN(C)C=O.[Pd]>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]2[N:1]=[C:14]3[NH:15][C:16](=[O:18])[NH:17][C:13]3=[CH:12][C:5]=2[CH:6]=1
Reactant: COc1ccc([N+](=O)[O-])c(C=C2NC(=O)NC2=O)c1
Agent: [Pd]
Agent: II
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc2nc3[nH]c(=O)[nH]c3cc2c1
Yield: 44 %

Procedure:
A solution of 5-[(2-nitro-5-methoxyphenyl)methylene]-2,4-imidazolidinedione (4.5 g, 17 mmol) in dimethylformamide (120 mL) was hydrogenated over 10% palladium on charcoal (0.45 g) at 60 psi. After 42 hours the mixture was filtered through infusorial earth and the solvent evaporated to leave a brown solid. A mixture of this material and methanol (150 mL) was heated to reflux and iodine (3.65 g, 14 mmol) introduced portionwise over 15 minutes. The reaction mixture was refluxed 45 minutes, cooled and concentrated to 20 mL before adding a solution of sodium thiosulfte (10 g) and sodium carbonate (10 g) in water (200 mL). The precipitate was filtered off, suspended in hot (80° C.) water (200 mL) and filtered. Recrystallization from aqueous dimethylformamide afforded 7-methoxy-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (1.61 g, 43%), m.p.>360° C.
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1[CH:28]=[CH:27][C:10]([O:11][CH2:12][CH:13]([OH:26])[CH2:14][NH:15][CH:16]([CH3:25])[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][CH:8]=1)=O)C.O.[NH2:30][NH2:31]>C(O)C>[NH:30]([C:4]([CH2:6][C:7]1[CH:28]=[CH:27][C:10]([O:11][CH2:12][CH:13]([OH:26])[CH2:14][NH:15][CH:16]([CH3:25])[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][CH:8]=1)=[O:3])[NH2:31]
Reactant: CCOC(=O)Cc1ccc(OCC(O)CNC(C)CCc2ccccc2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(CCc1ccccc1)NCC(O)COc1ccc(CC(=O)NN)cc1
Yield: 41.5 %

Procedure:
In this example, 4 g of 1-(4-ethoxycarbonylmethylphenoxy)-3-(1-methyl-3-phenylpropylamino)-2-propanol (Compound 14) is dissolved in 30 ml of ethanol and 6.1 g of 85% hydrazine hydrate is added thereto. The mixture is heated under reflux for2 hours. The solvent is distilled away from the reaction solution under reduced pressure. The residue is recrystallized from tetrahydrofuran-etherto obtain 1.6 g of 1-(4-hydrazinocarbonylmethylphenoxy)-3-(1-methyl-3-phenylpropylamino)-2-propanol. (Yield: 42%)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:36].C(O)C.C(=O)([O-])[O-].[NH4+:44].[NH4+]>ClCCl.C(O)C>[ClH:36].[ClH:36].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:44])[NH2:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(COc1ccc(C#N)cc1)n2C)c1ccccn1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(COc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Yield: 44 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[(4-cyanophenyl)oxymethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 44% of theory, C26H26N6O4 (486.5); Rf value: 0.12 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=487; (M+2H)++=244; (M+H+Na)++=255.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH2:9][C:10]3[CH:16]=[C:15]([CH3:17])[S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2].C1(C=CC(O)=CC=1)O.C1C(=O)N([Br:33])C(=O)C1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CC(O)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH2:9][C:10]3[C:16]([Br:33])=[C:15]([CH3:17])[S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)N1CC2Cc3cc(C)sc3C2C1
Agent: O=C([O-])O
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)N1CC2Cc3c(sc(C)c3Br)C2C1
Temperature: 40 °C

Procedure:
The product of Example 15, step c) (69.1 mg, 0.30 mmol) was placed in a vial and diluted with CHCl3 (740 μl) and AcOH (740 μl). Next, hydroquinone (˜5 mg) was added followed by NBS (51.4 mg, 0.31 mmol) and the contents were heated to 40° C. for 6 hours. The crude reaction mixture was carefully poured into saturated NaHCO3 (10 ml) and extracted with EtOAc (3×5 ml). The organic layer was dried (MgSO4) and purified by preparative TLC using hexanes/EtOAc 50:50 providing the subtitled product. MS calculated for C13H16BrNO2S+H 330, observed 330, 332.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C@@H:12]3[O:27][C@H:26]([CH2:28][O:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=4[Cl:38])[C@@H:15]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[C@@:13]3([CH3:39])[OH:14])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH4+:40].[OH-]>O1CCOCC1>[NH2:40][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C@@H:12]3[O:27][C@H:26]([CH2:28][O:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=4[Cl:38])[C@@H:15]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[C@@:13]3([CH3:39])[OH:14])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: [NH4+]
Reactant: C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1cc(I)c2c(Cl)ncnc21
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1cc(I)c2c(N)ncnc21
Yield: 88 %

Procedure:
To a compound 6.2 (5 g, 6.7 mmol) in dioxane (100 mL) was added conc. NH4OH (100 mL). The mixture was heated in a stainless steel autoclave at 100° C. for 3 h, then cooled and evaporated in vacuo. The crude mixture was dissolved in 100 mL of CH2Cl2 and washed with water and brine, dried over MgSO4, filtered and concentrated to provide crude product. The crude product was then purified on a silica gel column with 5% MeOH in CH2Cl2 as eluent to give 4.32 g of 6.3 as white foam (yield 88%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl>C1COCC1.O1CCOCC1>[Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][NH:13][CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Clc1ncnc2sc3c(c12)CCNC3
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.8 %

Procedure:
To a solution of tert-butyl 4-chloro-5,8-dihydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7(6H)-carboxylate (3500 mg, 10.7 mmol) in THF (100 mL) was added 4 N HCl in 1,4-dioxane (4 N, 6 mL). The reaction mixture was stirred at room temperature for 24 h. The white precipitate was collected and dried under reduced pressure and gave 2000 mg (82%) of the desired product. LCMS RT=0.21 min, [M+1]+=226.