Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(/[CH:4]=[C:5]1\[CH2:6][N:7](C(OC(C)(C)C)=O)[CH2:8][CH2:9][C:10]\1=O)C.[CH3:19][CH:20]([NH:22][NH2:23])[CH3:21]>>[CH3:19][CH:20]([N:22]1[CH:4]=[C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:10]2=[N:23]1)[CH3:21]
Reactant: CN(C)/C=C1\CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: CC(C)NN
Product: CC(C)n1cc2c(n1)CCNC2

Procedure:
tert-Butyl (3E)-3-[(dimethylamino)methylidene]-4-oxopiperidine-1-carboxylate was condensed with propan-2-ylhydrazine; removal of the protecting group provided 2-(propan-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.
Reaction SMILES: [CH:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2C(O)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC[N:18]([CH:22](C)C)C(C)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:32])C=CC=CC=1>C1(C)C=CC=CC=1>[CH:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[N:18]=[C:22]=[O:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccccc1C1CCCCC1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C=Nc1ccccc1C1CCCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-cyclohexylbenzoic acid (2 g, 9.8 mmol) and DIPEA (3.45 μL, 14.7 mmol) in toluene (25 mL) under nitrogen was added diphenylphosphoroyl azide (2.1 mL, 9.8 mmol). The reaction mixture was stirred for 4 h at room temperature and then heated at 90° C. for 3 h. Upon cooling, the organic layer was washed with saturated ammonium chloride solution (2×10 mL) and brine (1×10 mL), dried (MgSO4), filtered and the solvent removed under reduced pressure to give the title compound as a clear amber oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([CH3:7])([SH:6])[CH3:5].CCN(CC)CC.[C:15]1(=[O:22])[O:21][C:19](=[O:20])[CH2:18][O:17][CH2:16]1>C(Cl)Cl>[CH3:5][C:4]([SH:6])([CH3:7])[CH2:3][NH:2][C:19]([CH2:18][O:17][CH2:16][C:15]([OH:22])=[O:21])=[O:20]
Reactant: CC(C)(S)CN
Reactant: O=C1COCC(=O)O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(S)CNC(=O)COCC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To an ice-cooled suspension of 1-amino-2-methyl-2-propanethiol hydrochloride (4.21 g, 29.7 mmol) in CH2Cl2 (50 mL) was added Et3N (4.56 mL, 32.7 mmol) followed by diglycolic anhydride (3.43 g, 29.6 mmol). After stirring at room temperature for 30 minutes the reaction was concentrated under vacuum. Cold 2N HCl (50 mL) was added to the residue. The mixture was extracted with EtOAc (5×30 mL). The combined organic extracts were washed with brine (30 mL) and dried over Na2SO4. Concentration and trituration with Et2O:hexane gave the title compound as a white solid (5.50 g, 84.2%). mp 81-82° C.; 1H NMR (300 MHz, CDCl3) δ 8.80 (br s, 1H), 7.48 (br s, 1H), 4.24 (s, 2H), 4.20 (s, 2H), 3.41 (d, J=6.4 Hz, 2H), 1.59 (s, 1H), 1.38 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 172.8, 170.4, 70.8, 68.4, 51.9, 44.9, 29.8; mass spectrum (API-TIS) m/z 239 (M+NH4), 222 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:13])[C:8]=2[CH3:12])[N:3]=1>O.C(O)(=O)C>[CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:13])[C:8]=2[CH3:12])[NH:3]1
Reactant: Cc1ccc2c(C)c(F)ccc2n1
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(F)ccc2c1CCC(C)N2
Reaction time: 20 h

Procedure:
7.0 kg of 2,5-dimethyl-6-fluoroquinoline, 51.5 kg of glacial acetic acid and 350 g of 50% water-wet 5% platinum on carbon catalyst were combined and hydrogenated at 50 psi for 20 hours. Gas chromatography showed residual starting material so an additional 35 g of catalyst was added and the hydrogenation was continued for an additional 2 hours. The mixture was filtered to remove the catalyst and the solvent was then evaporated. The residue was dissolved in 10 gallons of cold water, and the resulting mixture was made basic with ammonium hydroxide to pH 11 while maintaining the temperature below 30° C. The resulting mixture was extracted with 8 gallons of 1,2-dichloroethane and the extract was dried through azeotropic distillation. The dried extract was treated with magnesium sulfate and filtered, and the filtrate was concentrated in vacuo to give a dark oil, 2,5-dimethyl-6-fluoro-1,2,3,4-tetrahydroquinoline, which was used directly in the next step.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:43][CH2:44][CH2:45][NH:46][C:47]1[N:52]=[C:51]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[N:50]=[C:49]([NH:59][CH2:60][CH2:61][NH:62][C:63](=[O:65])[CH3:64])[C:48]=1[CH3:66]>CN1C(=O)CCC1>[C:63]([NH:62][CH2:61][CH2:60][NH:59][C:49]1[N:50]=[C:51]([C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[N:52]=[C:47]([NH:46][CH2:45][CH2:44][NH:43][C:1](=[O:9])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:48]=1[CH3:66])(=[O:65])[CH3:64]
Reactant: O=C(O)c1ccccc1
Reactant: CC(=O)NCCNc1nc(-c2ccccc2)nc(NCCN)c1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(=O)NCCNc1nc(-c2ccccc2)nc(NCCNC(=O)c2ccccc2)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.3 %

Procedure:
Benzoic acid (55.8 mg), N,N-diisopropylethylamine (80 μl) and HATU (160 mg) were stirred in NMP (6851 μl) for 30 min. After this time N-[2-({6-[(2-aminoethyl)amino]-5-methyl-2-phenylpyrimidin-4-yl}amino)ethyl]acetamide (150 mg) was added and the mixture stirred for 16 hrs at room temperature. Purification via SCX resin furnished the title compound (54 mg).
Reaction SMILES: C(C1C=C(C)C=C(C(C)(C)C)C=1[OH:16])(C)(C)C.CN(CCCN1CN(CCCN(C)C)CN(CCCN(C)C)C1)C.[CH3:41][S:42][C:43]1[CH:48]=[CH:47][C:46]([N:49]=[C:50]=[O:51])=[CH:45][CH:44]=1.[C:52]([O:56][CH2:57][CH2:58][CH:59](O)[CH3:60])(=[O:55])[CH:53]=[CH2:54].[N-]=C=O>C(OCC)(=O)C>[C:52]([O:56][CH2:57][CH:58]([O:51][C:50](=[O:16])[NH:49][C:46]1[CH:47]=[CH:48][C:43]([S:42][CH3:41])=[CH:44][CH:45]=1)[CH2:59][CH3:60])(=[O:55])[CH:53]=[CH2:54]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: C=CC(=O)OCCC(C)O
Reactant: CSc1ccc(N=C=O)cc1
Agent: CN(C)CCCN1CN(CCCN(C)C)CN(CCCN(C)C)C1
Agent: [N-]=C=O
Solvent: CCOC(C)=O
Product: C=CC(=O)OCC(CC)OC(=O)Nc1ccc(SC)cc1
Temperature: 60 °C

Procedure:
0.02 g of 2,6-di-tert-butyl-4-methylphenol, 0.01 g of Desmorapid Z, 13.3 g of 4-(methylthio)phenyl isocyanate in 25 g of ethyl acetate were initially introduced into a 100 ml round-bottomed flask and heated to 60° C. Thereafter, 11.6 g of 3-hydroxybutyl acrylate were added dropwise and the mixture was kept further at 60° C. until the isocyanate content had fallen below 0.1%. Thereafter, the ethyl acetate was distilled off at 5 mbar and cooling was effected. The product was obtained as a crystalline solid.
Reaction SMILES: [CH:1]1[N:2]=[C:3]([CH2:10][C:11]#N)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.S(=O)(=O)(O)[OH:14].[C:18](O)(=[O:20])C>>[CH:1]1[N:2]=[C:3]([CH2:10][C:11]([O:20][CH3:18])=[O:14])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=S(=O)(O)O
Reactant: CC(=O)O
Reactant: N#CCc1ncc2ccccn12
Product: COC(=O)Cc1ncc2ccccn12
Temperature: 100 °C
Reaction time: 3 h

Procedure:
2-(Imidazo[1,5-a]pyridin-3-yl)acetonitrile (4.65 g) was dissolved in acetic acid (26 ml). To the solution was added 50%(v/v) sulfuric acid (52 ml), and the mixture was stirred for 3 hours at 100° C., followed by distilling off acetic acid under reduced pressure. To the residue was added, in limited amounts, sodium hydrogencarbonate, and the mixture was concentrated to dryness. To the residue was added methanol (200 ml), then insolubles were filtered off. To the filtrate was added a 4N HCl ethyl acetate solution (40 ml). The mixture was stirred for 15 hours at 25° C., followed by concentration under reduced pressure. To the concentrate were added a 5% aqueous solution of sodium hydrogencarbonate (100 ml) and ethyl acetate (200 ml). The mixture was shaken and left standing to form two layers. The organic layer was dried over anhydrous magnesium sulfate and, then, concentrated to afford the title compound (1.85 g).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.O[C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[N:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][OH:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>O1CCCC1.O>[CH3:21][O:20][C:18]([C:17]1[CH:22]=[CH:23][C:14]2[O:30][CH2:29][C:25]3=[CH:26][CH:27]=[CH:28][N:24]3[C:15]=2[CH:16]=1)=[O:19]
Reactant: COC(=O)c1ccc(O)c(-n2cccc2CO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc2c(c1)-n1cccc1CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.3 %

Procedure:
Diethyl azodicarboxylate (2.3 ml) was added dropwise to the mixture of methyl 4-hydroxy-3-(2-hydroxymethylpyrrol-1-yl)benzoate (2.5 g) and triphenylphosphine (4.0 g) in tetrahydrofuran (50 ml) under ice-cooling and the mixture was stirred for 2 hours at ambient temperature. The mixture was poured into the mixture of ethyl acetate and water. The separated organic layer was washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave the residue, which was purified by column chromatography on silica gel eluting with chloroform. The eluted fractions containing the desired product were collected and evaporated in vacuo to give 8-methoxycarbonyl 4H-pyrrolo[2,1-c][1,4]-benzoxazine (0.61 g).
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([C:21]#[N:22])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1>[C:21]([C:13]1[CH:12]=[C:11]([CH:4]([CH2:5][CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]2)[C:3]([OH:23])=[O:2])[CH:16]=[CH:15][C:14]=1[S:17]([CH3:20])(=[O:18])=[O:19])#[N:22]
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C#N
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 0.1 %

Procedure:
A solution of 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (4.84 g, 14.4 mol) in tetrahydrofuran (25 mL) was treated with a 0.8M aqueous lithium hydroxide solution (27 mL, 21.6 mmol). The reaction mixture was stirred at 25° C. for 2.5 h. The reaction mixture was partitioned between water and ethyl acetate and then acidified to pH=2 with a 10% aqueous hydrochloric acid solution. The layers were shaken and separated. The resulting organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford crude 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (3.80 g, 82%) as a pale yellow oil that solidified to a pale yellow solid. An analytical sample was obtained by recrystallization from ethyl acetate to afford 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid as a white solid: mp 180–181° C.; EI-HRMS m/e calcd for C16H19NO4S (M+) 321.1034, found 321.1039.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][C:9]2[C:23]([O:24][C:25]3[CH:26]=[N:27][C:28]([S:31]([CH2:34][CH3:35])(=[O:33])=[O:32])=[CH:29][CH:30]=3)=[CH:22][C:12]3[NH:13][C:14]([C:16]4[CH:21]=[CH:20]C=C[N:17]=4)=[N:15][C:11]=3[CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:36]1C=CC(C=O)=N1>>[F:1][C:2]1[C:7]([O:8][C:9]2[C:23]([O:24][C:25]3[CH:26]=[N:27][C:28]([S:31]([CH2:34][CH3:35])(=[O:32])=[O:33])=[CH:29][CH:30]=3)=[CH:22][C:12]3[NH:13][C:14]([C:16]4[CH:21]=[CH:20][NH:36][N:17]=4)=[N:15][C:11]=3[CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2cccnc2F)cn1
Reactant: O=Cc1cc[nH]n1
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4cc[nH]n4)nc3cc2Oc2cccnc2F)cn1

Procedure:
The entitled compound was obtained as a colorless solid in the same method as in Example 202 or in accordance with the method or by combining it with an ordinary method but using 4-(2-fluoropyridin-3-yloxy)-5-(6-ethanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 239, and 1H-pyrazole-3-carboxaldehyde.
Reaction SMILES: [CH:1]([CH:4]1[C:9]2=[CH:10][C:11]3[CH:12]=[CH:13][C:14]([S:17][CH3:18])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6][NH:5]1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:29]1[N:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[C:32]([C:39](=[O:41])[CH3:40])=[CH:31][N:30]=1>CC(O)C>[CH:1]([CH:4]1[C:9]2=[CH:10][C:11]3[CH:12]=[CH:13][C:14]([S:17][CH3:18])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6][N:5]1[C:29]1[N:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[C:32]([C:39](=[O:41])[CH3:40])=[CH:31][N:30]=1)([CH3:3])[CH3:2]
Reactant: CSc1ccc2cc3n(c2c1)CCNC3C(C)C
Reactant: CC(=O)c1cnc(Cl)nc1C(F)(F)F
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ccc2cc3n(c2c1)CCN(c1ncc(C(C)=O)c(C(F)(F)F)n1)C3C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To a solution of 1-isopropyl-7-(methylthio)-1,2,3,4-tetrahydropyrazino[1,2-a]indole (100 mg, 0.38 mmol) and DIPEA (246.72 mg, 1.91 mmol) in i-PrOH (2 mL) was added 1-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (172.50 mg, 0.76 mmol). The reaction mixture was stirred at rt overnight. The mixture was concentrated and purified by preparative TLC on silica gel eluting with PE/EtOAc 1:1 to afford 1-(2-(1-isopropyl-7-(methylthio)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (120 mg, 69.67% yield) as a colorless oil. LC-MS MS (ESI) m/z 449.2 [M+H]+. 1H NMR (CDCl3 400 MHz): δ 8.66 (s, 1H), 7.44-7.40 (m, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.27-6.25 (m, 1H), 5.79-577 (m, 1H), 5.13-5.02 (m, 1H), 4.21-4.16 (m, 1H), 3.97-3.91 (m, 1H), 3.82-3.71 (m, 1H), 2.48 (s, 3H), 2.46 (s, 3H), 2.21-2.15 (m, 1H), 1.12-1.08 (m, 3H), 0.96-0.93 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:9]=1[CH3:10])=[O:4].C1C(=O)N([Br:35])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O.CCCCCC>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)=[C:8]([C:11]2[CH:12]=[CH:13][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[CH:15][CH:16]=2)[C:9]=1[CH2:10][Br:35])=[O:4]
Reactant: COC(=O)c1sc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)c1C
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1sc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)c1CBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
A solution of 404 mg of the product of Step 5, 200 mg of NBS, and 5 mg of benzoylperoxde in 10 mL of CCl4 was heated in a 80° C. oil bath under light from a W-lamp. After 30 min, the reaction mixture was cooled to room temperature, diluted with 10 mL of 3:1 EtOAc/hexane, and filtered through a pad of silica gel. The filtrate was concentrated in vacuo to give 400 mg of the crude title compound which was used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl.[F:49][C:50]1[CH:58]=[C:57]([F:59])[C:56]([F:60])=[CH:55][C:51]=1[CH:52]([OH:54])[CH3:53]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38](=[O:40])[O:54][CH:52]([C:51]2[CH:55]=[C:56]([F:60])[C:57]([F:59])=[CH:58][C:50]=2[F:49])[CH3:53])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(O)c1cc(F)c(F)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OC(C)c4cc(F)c(F)cc4F)cc3)c2cc1OC
Temperature: 25 °C
Yield: 34.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (89 mg) was added to toluene/triethylamine=10/1 (9 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (130 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2,4,5-trifluoro-α-methylbenzyl alcohol (80 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (51 mg, yield 32%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.F[C:8]1[CH:18]=[CH:17][C:11]([C:12](OCC)=[O:13])=[CH:10][CH:9]=1>>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:8]2[CH:18]=[CH:17][C:11]([CH2:12][OH:13])=[CH:10][CH:9]=2)[CH:6]=1
Reactant: Cc1c[nH]cn1
Reactant: CCOC(=O)c1ccc(F)cc1
Product: Cc1cn(-c2ccc(CO)cc2)cn1

Procedure:
Prepared from 4-methylimidazole and ethyl 4-fluorobenzoate.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[SH:6][C:7]1[S:11][C:10]([C:12]([O:14]CC)=O)=[N:9][N:8]=1.[CH2:17]1[CH2:21]OC[CH2:18]1>>[CH:1]1([C:12]([CH:18]2[CH2:17][CH2:21]2)([C:10]2[S:11][C:7]([SH:6])=[N:8][N:9]=2)[OH:14])[CH2:3][CH2:2]1
Reactant: Br[Mg]C1CC1
Reactant: CCOC(=O)c1nnc(S)s1
Reactant: C1CCOC1
Product: OC(c1nnc(S)s1)(C1CC1)C1CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of cyclopropylmagnesiumbromide (37 ml, 0.5 M/THF, 18.4 mmol at 0° C. was slowly added a THF solution of ethyl 5-mercapto-1,3,4-thiadiazole-2-carboxylate (1 g, 5.3 mmol). When half the solution was added, the cooling bath was removed and the rest of the solution was added. The mixture was stirred at room temperature for 4 hours then partitioned between aqueous NH4Cl and Et2O. The layers were separated and the aqueous phase was extracted with Et2O. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated and the residue chromatographed on silica gel (hexanes:acetone, 95:5) to give the title compound. 1H NMR (400 MHz, acetone-d6): 4.75 (s, 1H), 1.39-1.26 (m, 2H), 0.67-0.38 (m, 8H).
Reaction SMILES: CC1(C)CO[CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([OH:30])[CH2:20][C@@H:21]3[OH:29])=[CH:16][CH:15]=4)[CH2:12][CH2:11]2)[CH3:9])[O:4]C1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C.CCCCCC>CC(C)=O>[OH:29][C@@H:21]1[C@@:22]2([CH3:23])[C:17](=[CH:16][CH:15]=[C:14]3[C@@H:24]2[CH2:25][CH2:26][C@@:27]2([CH3:28])[C@H:13]3[CH2:12][CH2:11][C@@H:10]2[CH:8]([CH:5]=[O:4])[CH3:9])[CH2:18][C@@H:19]([OH:30])[CH2:20]1
Reactant: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C=O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 81.3 %

Procedure:
In 10 ml of acetone was dissolved 4.3 mg (0.010 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)pregna-5,7-diene-1α,3β-diol, followed by addition of 1 ml of a 1 mmole/l solution of p-toluenesulfonic acid in acetone (containing 0.001 mmole of p-toluenesulfonic acid). The mixture was refluxed for 2 hours. The reaction mixture thus obtained was cooled to room temperature and the solvent was distilled off under reduced pressure. The residue was dissolved in 40 ml of methylene chloride and this methylene chloride solution was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution in that order and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1:5, v/v) to give 2.8 mg of 1α,3β-dihydroxypregna-5,7-diene-20-carbaldehyde (yield: 82%).
Reaction SMILES: [NH2:1][C:2]1(OC)[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)=[CH:9][CH:10]=2)[N:5]=[CH:4][NH:3]1.[H-].[Na+].[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:27]=1[N:33]=[C:34]=[S:35].CN([CH:39]=[O:40])C>>[CH3:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([CH3:25])[C:27]=1[NH:33][C:34]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]3)=[C:9]([O:40][CH3:39])[CH:10]=2)[N:5]=[CH:4][N:3]=1)=[S:35]
Reactant: Cc1cccc(C)c1N=C=S
Reactant: CN(C)C=O
Reactant: COC1(N)NC=Nc2cc(OCC3CCN(C)CC3)ccc21
Agent: [H-]
Agent: [Na+]
Product: COc1cc2c(NC(=S)Nc3c(C)cccc3C)ncnc2cc1OCC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 4-amino-4-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (150 mg) in DMF (4.5 ml) was added to sodium hydride (60% dispersion in mineral oil, 0.03 g) and the reaction mixture was stirred at ambient temperature for 20 minutes. 2,6-Dimethylphenyl isothiocyanate (0.162 g) was added and the mixture was stirred at ambient temperature for 20 hours. The action mixture was evaporated and the residual solid was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and a 2M solution of ammonia in methanol as eluent. There was thus obtained the title compound (0.112 g); NMR Spectrum: (CDCl3) 1.44-1.61 (m, 2H), 1.87-2.08 (m, 5H), 2.32 (s, 3H), 2.36 (s, 6H), 2.94 (d, 2H), 4.04 (m, 5H), 7.1 (s, 1H), 7.19 (m, 3H), 7.29 (s, 1H), 8.69 (s, 1H), 8.9 (s, 1H), 13.37 (s, 1H); Mass Spectrum: M+H+ 466.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:24][O:25][C:26]1[C:27](=[O:50])[C:28]([CH3:49])=[C:29]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:45]C(=O)C)=[C:40]([CH:44]=2)[C:41](O)=[O:42])[C:30](=[O:34])[C:31]=1[O:32][CH3:33]>C(Cl)Cl>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:41](=[O:42])[C:40]2[CH:44]=[C:36]([CH2:35][C:29]3[C:30](=[O:34])[C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[C:27](=[O:50])[C:28]=3[CH3:49])[CH:37]=[CH:38][C:39]=2[OH:45])=[CH:3][CH:4]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: Nc1ccncc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccncc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 12.3 %

Procedure:
4-Aminopyridine (0.282 g, 3.000 mmol), triethylamine (0.304 g, 3.000 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.507 g, 3.000 mmol) were added to a methylene chloride solution (50 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.374 g, 1.000 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.050 g, 0.123 mmol, 12%).
Reaction SMILES: [K+].[CH2:2]([N:4]1[C:12](=[O:13])[C:11]2[NH:10][C:9]([C:14]3[CH:15]=[C:16]([S:20]([O-:23])(=[O:22])=O)[CH:17]=[CH:18][CH:19]=3)=[N:8][C:7]=2[N:6]([CH2:24][CH3:25])[C:5]1=[O:26])[CH3:3].S(Cl)(Cl)=O.[CH3:31][N:32]([CH2:34][CH2:35][NH2:36])[CH3:33]>CN(C=O)C>[CH2:2]([N:4]1[C:12](=[O:13])[C:11]2[NH:10][C:9]([C:14]3[CH:15]=[C:16]([S:20]([NH:36][CH2:35][CH2:34][N:32]([CH3:33])[CH3:31])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[N:8][C:7]=2[N:6]([CH2:24][CH3:25])[C:5]1=[O:26])[CH3:3]
Reactant: CN(C)CCN
Reactant: CCn1c(=O)c2[nH]c(-c3cccc(S(=O)(=O)[O-])c3)nc2n(CC)c1=O
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCn1c(=O)c2[nH]c(-c3cccc(S(=O)(=O)NCCN(C)C)c3)nc2n(CC)c1=O
Temperature: 0 °C
Yield: 18 %

Procedure:
A mixture of 3-(1,3-diethyl-2,3,6,7-tetrahydro-2,6-dioxo-1H-purin-8-yl)benzenesulfonic acid monopotassium salt (4.6 g, 0.01 moles) and DMF (250 ml) is prepared and cooled to 0° C. To this solution is added thionyl chloride (7.14 g, 0.06 mole) and the mixture allowed to come to ambient temperature with vigorous stirring. To this slurry is added unsym dimethylethylenediamine (17.6 g, 0.2 moles). The resulting solution is concentrated on a rotary evaporator, the residue taken up in water, filtered, recrystallized twice from ethanol and dried at 48° to yield 0.78 grams of 3-(1,3-diethyl-2,3,6,7-tetrahydro-2,6-dioxo-1H-purin-8-yl)-N-[2-(dimethylamino)ethyl]benzenesulfonamide, mp, 250°-251° C.