Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[NH2:18][C:19](=[N:25]O)[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)C(C)C)(C)C>ClCCl.CN(C=O)C.N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][C:9]1[O:11][N:25]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:18]=1
Reactant: CCOC(=O)C(N)=NO
Reactant: O=C(O)Cc1cccc(F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1noc(Cc2cccc(F)c2)n1
Yield: 29.3 %

Procedure:
This compound was prepared according to general method 2 with (step I) 2-(3-fluorophenyl)acetic acid (1.03 g; 7.57 mmol) and oxalyl chloride (0.704 mL; 8.33 mmol) in dichloromethane (5 mL) and a few drops of DMF and (step II) ethyl 2-amino-2-(hydroxyimino)acetate (1.0 g; 7.57 mmol) and N,N diisopropylethylamine (2.11 mL; 12.11 mmol) in dichloromethane (10 mL) and (step 110 pyridine (18 mL). The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.555 g (30%) of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:4]=2[S:5][C:6]=1[C:7]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:8].[CH3:23][Al](C)C.C(O)C.Cl>COCCOC.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:20][O:19][C:17]1[C:16]([O:21][CH3:22])=[CH:15][C:4]2[S:5][C:6]([C:7]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[O:8])=[C:2]([CH3:23])[C:3]=2[CH:18]=1
Reactant: C[Al](C)C
Reactant: COc1cc2sc(C(=O)N3CCOCC3)c(Cl)c2cc1OC
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: COc1cc2sc(C(=O)N3CCOCC3)c(C)c2cc1OC

Procedure:
(3-Chloro-5,6-dimethoxybenzo[b]thiophen-2-yl)morpholin-4-yl-methanone (3.0 g) from Example 8, trimethylaluminum (3.2 g) and [1,3-bis(diphenylphosphino)propane]dichloronickel (II) (1.2 g) in 1,2-dimethoxyethane (100 ml) were refluxed under argon for 10 hours. To the cold mixture ethanol (50 ml), water and HCl were added respectively and the mixture was extracted with ethyl acetate. Ethyl acetate was dried and evaporated to dryness. The crude product was purified by flash chromatography eluting with heptane-ethyl acetate (5:5).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][OH:11].N1C=CC=CC=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>CCOCC>[S:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)([O:11][CH2:10][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])(=[O:26])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCc1ccccc1F
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCCCc2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
17.75 gm of the compound prepared in (3) above was dissolved into 200 ml of dry pyridine. To this was slowly added 24.25 gm of p-toluenesulfonyl chloride at 0° C. and the mixture was stirred for 3 hours at room temperature. After the addition of 300 ml of ether, the mixture was washed with water, followed by the addition of 6N hydrochloric acid to acidify it and washing with saturated brine. The product was dried over anhydrous sodium sulfate and the solvent was evaporated to obtain 31.3 gm of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:36])=[C:23]([C:25]4[N:26]=[CH:27][C:28]5[C:33]([C:34]=4[CH3:35])=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:37]>O1CCOCC1>[ClH:37].[ClH:37].[ClH:37].[CH3:35][C:34]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[N:26][C:25]=1[C:23]1[C:22]([NH2:36])=[N:21][CH:20]=[C:19]([C:17]2[CH:16]=[N:15][N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:18]=2)[CH:24]=1
Reactant: Cc1c(-c2cc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)cnc2N)ncc2ccccc12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(-c2cc(-c3cnn(C4CCNCC4)c3)cnc2N)ncc2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-{4-[6-amino-5-(4-methylisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (79.1 mg, 0.163 mmol) in 1,4-dioxane (2.0 mL, 26 mmol) was added 4.0 M of HCl in 1,4-dioxane (2.0 mL), and the mixture was stirred at ambient temperature for 3 h. Almost immediately an off-white solid precipitated. The solid was filtered off, washed with MTBE, and dried in vacuo overnight to give the title compound as an off-white solid. It appeared to be slightly hygroscopic during the filtration; however, after the washing and initial drying it appeared to be non-hygroscopic. 1H NMR (400 MHz, DMSO-d6): δ=14.6 (very brs, 1H), 9.68 (s, 1H), 9.37-9.24 (brm, 1H), 9.24-9.10 (brm, 1H), 8.55 (d, J=2.0 Hz, 1H), 8.47 (d, J=7.6 Hz, 1H), 8.46 (d, J=2.0 Hz, 1H), 8.39 (s, 1H), 8.38 (d, J=7.6 Hz, 1H), 8.14 (t, J=7.2 Hz, 1H), 8.05 (s, 1H), 7.98 (t, J=7.6 Hz, 1H), 7.81 (brs, 2H), 4.54-4.45 (mc, 1H), 3.35 (brd, J=12.6 Hz, 2H), 3.07 (brq, J=11.2 Hz, 2H), 2.59 (s, 3H), 2.26-2.09 (m, 4H). MS(ES+): m/z=385.17 (96) [MH+], 302.1 (100) [MH+-piperidine]. HPLC: tR=0.65 & 1.72 min (peak splitting; polar—5 min, ZQ3).
Reaction SMILES: Cl.[N:2]1([C@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[NH:13]C(=O)C2C=CC=CC=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.C(O)CO.[OH-].[K+]>O>[N:2]1([C@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[NH2:13])[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(N[C@@H]1CCCC[C@@H]1N1CCCC1)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: N[C@@H]1CCCC[C@@H]1N1CCCC1

Procedure:
(±)-cis-2-(1-Pyrrolidinyl)-N-benzoylcyclohexylamine hydrochloride (10 gm) was combined with ethylene glycol (50 ml) and potassium hydroxide (10 gm) and the solution was heated to reflux for 48 hours. The solution was diluted with water (200 ml) and extracted with ether. The ether was removed on a rotary evaporator and the residue was distilled (94° C. at 0.05 mm Hg) to provide the product.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[N+:14]([O-])=O)[NH:10][CH:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]>CO.[Ni]>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[NH2:14])[NH:10][CH:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc2cc[nH]c2cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)c1cc2cc[nH]c2cc1N
Temperature: 30 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
Raney Ni (3 g) was added to 5-tert-butyl-6-nitro-1H-indole (14.7 g, 67 mmol) in methanol (100 mL). The mixture was stirred under hydrogen (1 atm) at 30° C. for 3 h. The catalyst was filtered off. The filtrate was dried over Na2SO4 and concentrated. The crude dark brown viscous oil was purified by column chromatography (10-20% EtOAc/petroleum ether) to give 5-tert-butyl-1H-indol-6-ylamine (B-24) as a gray solid (11 g, 87%). 1H NMR (300 MHz, DMSO-d6) δ 10.3 (br s, 1H), 7.2 (s, 1H), 6.9 (m, 1H), 6.6 (s, 1H), 6.1 (m, 1H), 4.4 (br s, 2H), 1.3 (s, 9H).
Reaction SMILES: [CH3:1][N:2]([CH2:16][CH:17]([O:20][CH3:21])[O:18][CH3:19])[C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>CCOCC>[CH3:1][N:2]([CH2:3][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6]1)[CH2:16][CH:17]([O:20][CH3:21])[O:18][CH3:19]
Reactant: COc1ccc2c(c1)C(C(=O)N(C)CC(OC)OC)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: COc1ccc2c(c1)C(CN(C)CC(OC)OC)CC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.5 %

Procedure:
1-[N-methyl-N-(2,2-dimethoxyethyl)aminocarbonyl]-6-methoxy-indane 3.5 g (12 mmol), an amidoacetal compound of Formula 5, was dissolved in 20 ml of ether and added to 1.0 g (26 mmol) of LAH in 100 ml of ether. The reaction mixture was stirred at ambient temperature for 48 hours and then treated dropwise with 1 ml of water, 1 ml of 15% NaOH, and finally 3 ml of water. The insoluble inorganic materials were removed by filtration and the filtrate was concentrated to give the 3.1 g of 1-[N-methyl-N-(2,2-dimethoxyethyl)aminomethyl]-6-methoxy-indane, an aminoacetal of Formula 6, which is used without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:16]2[N:17]([CH3:42])[C:18]3[C:23]([N:24]=2)=[C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:21]=[C:20]([N:31]2[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[N:33]=[C:32]2[CH2:40][CH3:41])[N:19]=3)([O:14][CH3:15])[CH2:9]1)=O)(C)(C)C.[ClH:43]>C(Cl)Cl.CO.O1CCOCC1>[ClH:43].[ClH:43].[CH2:40]([C:32]1[N:31]([C:20]2[N:19]=[C:18]3[C:23]([N:24]=[C:16]([C:10]4([O:14][CH3:15])[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]4)[N:17]3[CH3:42])=[C:22]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:21]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=1)[CH3:41]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CCCN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CCCNC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-3-methoxypiperidine-1-carboxylic acid tert-butyl ester in DCM (10 mL) and MeOH (10 mL) was added 4M HCl in dioxane (10 mL). The resulting mixture was allowed to stir at r.t. for 16 h then concentrated in vacuo. The resulting residue was triturated with Et2O, the solid collected by filtration and dried in vacuo affording 2-(2-Ethylbenzoimidazol-1-yl)-8-(3-methoxypiperidin-3-yl)-9-methyl-6-morpholin-4-yl-9H-purine dihydrochloride (1.0 g, quant.). LCMS (method H): RT 2.05 min [M+H]+ 477.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][NH:6][C:7]1[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[C:9]([N:16]2[CH2:24][C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:17]2)[N:8]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:63][C@H:64]1[CH2:69][CH2:68][C@H:67]([OH:70])[CH2:66][CH2:65]1>CN(C=O)C.O>[OH:70][C@H:67]1[CH2:68][CH2:69][C@H:64]([NH:63][C:13]([C:12]2[C:7]([NH:6][CH2:5][C:4]3[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:2]([Cl:1])[CH:3]=3)=[N:8][C:9]([N:16]3[CH2:24][C:23]4[C:18](=[N:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)=[N:10][CH:11]=2)=[O:15])[CH2:65][CH2:66]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: COc1ccc(CNc2nc(N3Cc4cccnc4C3)ncc2C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc(CNc2nc(N3Cc4cccnc4C3)ncc2C(=O)N[C@H]2CC[C@H](O)CC2)cc1Cl
Reaction time: 0.33 h

Procedure:
In DMF (10 mL) was dissolved 4-((3-chloro-4-methoxybenzyl)amino)-2-(5H-pyrrolo[3,4-b]pyridin-6(7H)yl)-5-pyrimidine formic acid (0.8 g, 1.94 mmol). The solution was cooled in an ice bath. HATU (1.11 g, 2.91 mmol) and DIPEA (0.37 g, 2.87 mmol) were added. After 20 min, trans-4-aminocyclohexanol (0.27 g, 2.3 mmol) was added in batches. The reaction was conducted overnight. LC-MS was used to monitor the reaction. The reaction mixture was poured into water (50 mL) and filtrated. The solid was recrystallized with acetone (20 mL) to give N-((trans)-4-hydroxycyclohexan-1-yl)-4-((3-chloro-4-methoxybenzyl)amino)-2-(5H-pyrrolo[3,4-b]pyridin-6(7H)yl)-5-pyrimidine formamide (300 mg, 30.3% yield).
Reaction SMILES: [F:1][C@H:2]1[O:10][C@H:9]([C:11]([O-:13])=[O:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[F:1][C@H:2]1[O:10][C@H:9]([C:11]([O:13][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: O=C([O-])[C@H]1O[C@H](F)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: BrCc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)[C@H]1O[C@H](F)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Sodium 1-deoxy-1-fluoro-α-D-glucuronate (6.22 g, 28.51 mmol) was suspended in DMF (350 ml), and benzyl bromide (4.89 g, 28.59 mmol) was added. The reaction mixture was stirred at 60° C. for 24 h and then evaporated. The residue was dissolved in 3:1 chloroform/methanol, and magnesium sulfate (12 g) was added. The suspension was stirred for 2 h and then filtered, and the filtrate was evaporated. The residue was purified by column chromatography on silica gel (160 g) with 4:1 dichloromethane/acetone.
Reaction SMILES: [N+](C1C=CSC=1C1C=CC(Cl)=CC=1)([O-])=O.[N+:16]([C:19]1[CH:23]=[CH:22][S:21][C:20]=1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)([O-])=O>>[NH2:16][C:19]1[CH:23]=[CH:22][S:21][C:20]=1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1
Reactant: Cc1ccc(-c2sccc2[N+](=O)[O-])cc1
Agent: O=[N+]([O-])c1ccsc1-c1ccc(Cl)cc1
Product: Cc1ccc(-c2sccc2N)cc1
Yield: 68 %

Procedure:
The same procedures as described in Example 3 were carried out except that 3-nitro-2-(4-chlorophenyl)thiophene was replaced by 3-nitro-2-(4-tolyl)thiophene. The yield was 68%. 1H-NMR(CDCl3, δ value):2.37(3H, s), 3.79(2H, brs), 6.54(d, J=5.1), 7.09(1H, d, J=5.1), 7.22(2H, d, J=8.1), 7.41(2H, d, J=8.1)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].BrC[C:20]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21]>C(#N)C>[CH:22]1([C:20]([C:9]2[O:11][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=3[C:8]=2[OH:10])=[O:21])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(=O)c1cc(F)ccc1O
Reactant: O=C(CBr)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(c1oc2ccc(F)cc2c1O)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
1-(5-Fluoro-2-hydroxyphenyl)ethanone (4.0 g) was dissolved in acetonitrile (80 mL). To the reaction mixture were added potassium carbonate (4.8 g) and 2-bromo-1-cyclohexylethanone (7.3 g) synthesized in Example A51(1) at room temperature, and the mixture was stirred at room temperature for 8 hr. The reaction mixture was filtered through celite, rinsed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (50 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (5.3 mL) was added to the solution, and the mixture was stirred with heating at 110° C. for 1 hr. After cooling to room temperature, the reaction mixture was quenched with 1N hydrochloric acid, and the mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure, and the precipitated compound was recrystallized from diisopropyl ether-ethanol to give the title object compound (4.7 g, 76%) as a colorless solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[ClH:38]>CC(=O)CC.C(O)(C)C.C(O)C>[ClH:38].[ClH:38].[O:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:4]([CH2:3][CH2:2][N:27]2[CH2:26][CH2:25][N:24]([C:18]3[CH:17]=[C:16]([O:15][CH3:14])[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=3)[CH2:29][CH2:28]2)[CH2:5][CH2:6]1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: BrCCC1CCOc2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)O
Solvent: CCO
Solvent: CCC(C)=O
Product: COc1cc(OC)cc(N2CCN(CCC3CCOc4ccccc43)CC2)c1

Procedure:
The procedure of Example 1 is followed, starting 4-(2-bromoethyl)-3,4-dihydro(2H)-benzopyran (2 g), 1-(3,5-dimethoxyphenyl)piperazine (1.84 g) and dry potassium carbonate (0.56 g), followed by potassium iodide (1.4 g) in 2-butanone (70 cc). The residue obtained is chromatographed on a column 4.4 cm in diameter, containing silica gel (100 g), using a dichloromethane-ethyl acetate mixture (50-50 by volume) as eluent and collecting 20-cc fractions. The fractions between 200 and 400 cc are concentrated to dryness. The oil obtained is taken up with ethanol (30 cc) and a 5N solution of hydrochloric acid in isopropanol (1.8 cc) is added. The crystals formed are filtered off and 1-[2-(3,4-dihydro-1(2H)-benzopyran-4-yl)ethyl]-4-(3,5-dimethoxyphenyl)piperazine dihydrochloride (1.9 g) is thus obtained in the form of a solid melting at 208° C.
Reaction SMILES: C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(O)(=O)[C:15]1[CH:23]=[CH:22][C:20]([OH:21])=[C:17]([O:18][CH3:19])[CH:16]=1.C([O-])(=O)C1C=CC=CC=1.[Na+]>>[C:17]1([O:18][CH3:19])[C:20](=[CH:22][CH:23]=[CH:15][CH:16]=1)[OH:21]
Reactant: COc1cc(C(=O)O)ccc1O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])c1ccccc1
Agent: [Na+]
Product: COc1ccccc1O

Procedure:
Using A. acidoterrestris-proliferative acid sport drink (comprising 1% fruit juice, 0.18% citric acid, 9% isomerized sugar and 0.25% flavor) containing 100 ppm of vanillic acid added therein, two steps of preparations containing 103 and 105 spores/ml of A. acidoterrestris spores were prepared therein and cultured at 45° C. with shaking. As a control, a sample prepared by adding 300 ppm of sodium benzoate having the effect of inhibiting the growth of the same bacteria to the same solution was used. The resulting solution was sampled with a lapse of time and the amount of guaiacol produced was measured by the Peroxidase method.
Reaction SMILES: C(OC1C=CC(C2C3C(N)=NC=NC=3NC=2)=CC=1)C1C=CC=CC=1.[CH2:25]([O:32][C:33]1[CH:34]=[C:35]([C:39]2[C:47]3[C:46]([NH2:48])=[N:45][CH:44]=[N:43][C:42]=3[NH:41][CH:40]=2)[CH:36]=[CH:37][CH:38]=1)C1C=CC=CC=1.[C:49]([O:53][C:54]([N:56]1[CH2:60][CH2:59][CH:58](CS(C2C=CC(C)=CC=2)(=O)=O)[CH2:57]1)=[O:55])([CH3:52])([CH3:51])[CH3:50]>>[C:49]([O:53][C:54]([N:56]1[CH2:60][CH2:59][CH:58]([N:41]2[C:42]3[N:43]=[CH:44][N:45]=[C:46]([NH2:48])[C:47]=3[C:39]([C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([O:32][CH3:25])[CH:34]=3)=[CH:40]2)[CH2:57]1)=[O:55])([CH3:52])([CH3:50])[CH3:51]
Reactant: Nc1ncnc2[nH]cc(-c3cccc(OCc4ccccc4)c3)c12
Reactant: Cc1ccc(S(=O)(=O)CC2CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: Nc1ncnc2[nH]cc(-c3ccc(OCc4ccccc4)cc3)c12
Product: COc1cccc(-c2cn(C3CCN(C(=O)OC(C)(C)C)C3)c3ncnc(N)c23)c1

Procedure:
Examples 63 and 64 are prepared analogously to Example 20/21 starting from 5-(4-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl-amine or 5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl-amine and 3-(toluene-4-sulfonylmethyl)-pyrrolidine-carboxylic acid tert-butyl ester.
Reaction SMILES: I.[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8](=[NH:11])SC.[NH2:17][CH2:18][C:19]1[S:20][CH:21]=[CH:22][CH:23]=1.C(O)C>O.[OH-].[Na+]>[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8]([NH:17][CH2:18][C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)=[NH:11]
Reactant: NCc1cccs1
Reactant: CSC(=N)NN=Cc1c(Cl)cccc1Cl
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N=C(NCc1cccs1)NN=Cc1c(Cl)cccc1Cl

Procedure:
A solution of 5.85 g. of methyl 3-(2,6-dichlorobenzylidene)thiocarbazimidate hydriodide and 3.39 g. of 2-(aminomethyl)thiophene in 25 ml. of absolute ethanol is heated under reflux for 16 hours, diluted with water and excess 10N sodium hydroxide is added. After standing, crystallization occurs, and filtration gives 3.50 g. of nearly colorless crystals. Recrystallization from aqueous ethanol gives the desired product as colorless crystals, m.p. 135°-137° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]=[CH2:10].C([Li])CCC.CN(C)[CH:18]=[O:19].O>C1COCC1>[F:8][C:4]1[C:3]([CH:9]=[CH2:10])=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:18]=[O:19]
Reactant: C=Cc1c(F)cccc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1c(F)cccc1C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1-bromo-3-fluoro-2-vinylbenzene (900 mg) in THF (40 ml) was added dropwise, at −78° C., n-butyllithium (3.4 ml 1.6 M/hexane). After 60 minutes, N,N-dimethylformamide (0.69 ml) was added dropwise at −78° C. After stirring at −78° C. for 60 minutes, the reaction mixture was admixed with water and then warmed to room temperature. Then the mixture was admixed with water and extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated. Purification by column chromatography gives 3-fluoro-2-vinylbenzaldehyde (160 mg).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([OH:14])=O)=[O:9].C1C=CC2N(O)N=NC=2C=1.[S:28]1[CH2:32][CH2:31][NH:30][CH2:29]1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C=O)C>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([N:30]1[CH2:31][CH2:32][S:28][CH2:29]1)=[O:14])=[O:9]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CN1CCCC1=O
Reactant: C1CSCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1CCCN1CC(=O)N1CCC[C@H]1C(=O)N1CCSC1
Temperature: -25 °C
Reaction time: 12 h

Procedure:
N-[(2-Oxo-1-pyrrolidinyl)acetyl]-L-proline as prepared in Example 1-B) (623 mg) was suspended in a mixture of methylene chloride (3 ml) and DMF (5 ml), to which were added HOBt (530 mg) and thiazolidine (0.21 ml). The mixture was cooled to -25° C. and DCC (588 mg) was added thereto. The mixture was stirred at a temperature of -25°-0° C. for 3 hours and at room temperature for 12 hours. The precipitated dicyclohexylurea was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform-methanol) to give 468 mg of 3-{N-[(2-oxo-1-pyrrolidinyl)acetyl]-L-prolyl}thiazolidine.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[C:5]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])=[C:4]([F:27])[CH:3]=1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:29].[K+].[K+].C(OCC)(=O)C.CCCCCC>C(#N)C.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[Cl:1][C:2]1[C:7]2[C:8](=[O:29])[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[C:5]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:22])[F:23])[N:16]([CH3:25])[C:15]2=[O:26])=[C:4]([F:27])[CH:3]=1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3c2OC(C)(C)CC3)c1=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3c2OC(C)(C)CC3=O)c1=O
Yield: 47.5 %

Procedure:
By the method of Example 3, Step A, 1.8 grams (0.004 mole) of 3-(5-chloro-3,4-dihydro-2,2-dimethyl-7-fluoro-2H-1-benzopyran-8-yl)-1-methyl-6-trifluoromethyluracil was reacted with 3.5 grams (0.013 mole) of potassium persulfate and 1.1 grams (0.004 mole) of copper(II) sulfate pentahydrate in 30 mL of acetonitrile and 30 mL of water. The crude reaction mixture was subjected to column chromatography on silica gel, with 1:4 ethyl acetate:hexane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.8 gram of 3-(5-chloro-3,4-dihydro-2,2-dimethyl-7-fluoro-2H-1-benzopyran-4-on-8-yl)-1-methyl-6-trifluoromethyluracil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[N:9]=[CH:10]/[CH:11]=O)=[CH:4][CH:3]=1.[C:13](OCC)(=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].N1CCCCC1.CCOC(C)=O>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:20])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C/C=N/Nc1ccc(F)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: CCOC(=O)c1ccnn(-c2ccc(F)cc2)c1=O
Yield: 17.1 %

Procedure:
Crude (E)-2-(2-(4-fluorophenyl)hydrazono)acetaldehyde (0.97 g, 5.8 mmol) is dissolved in EtOH (50 mL), and diethyl malonate (0.93 g, 5.8 mmol) and piperidine (0.2 mL, 2.0 mmol) are added. The mixture is heated at reflux overnight. The reaction mixture is then cooled and concentrated. The residue is diluted with water and extracted with EtOAc twice. The combined organic extracts are dried over Na2SO4 and concentrated. The residue is purified by column chromatography on silica gel, eluting with PE:EtOAc (from 3:1 to 1:1), to afford title compound (0.26 g, 17% yield of two steps) MS (m/z): 263 (M+H).