Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:14]([OH:16])=[O:15])[CH:4]([C:5]([OH:7])=[O:6])[CH:3]([C:8]([OH:10])=[O:9])[CH:2]1[C:11]([OH:13])=[O:12].C1(C(O)=O)CC(C(O)=O)C(C(O)=O)C1C(O)=O>>[CH2:1]([C:14]([OH:16])=[O:15])[CH:4]([C:5]([OH:7])=[O:6])[CH:3]([C:8]([OH:10])=[O:9])[CH2:2][C:11]([OH:13])=[O:12]
Reactant: O=C(O)C1C(C(=O)O)C(C(=O)O)C1C(=O)O
Agent: O=C(O)C1CC(C(=O)O)C(C(=O)O)C1C(=O)O
Product: O=C(O)CC(C(=O)O)C(CC(=O)O)C(=O)O

Procedure:
1,2,3,4-cyclobutane tetracarboxylic acid; 1,2,3,4-cyclopentane tetracarboxylic acid; dicyclo-(2,2,2)-octane-2,3,5,6-tetracarboxylic acid; 7,8-dichlorodicyclo-(2,2,2)-octane-2,3,5,6-tetracarboxylic acid; 7,8-diphenyldicyclo-(2,2,2)-octane-2,3,5,6-tetracarboxylic acid; dicyclo-(2,2,2)-octene-(7)-2,3,5,6-tetracarboxylic acid;
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:19])([CH2:11][CH2:12][CH2:13][CH2:14][S:15]([O-:18])(=[O:17])=[O:16])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:20]([O-:23])(=[O:22])=[O:21])[CH:8]=2)[N:3]=1.[Na+].[Na+].[CH2:26](OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:27].C1S(=O)(=O)CCC1.CO>CCOC(C)=O>[CH2:26]([N+:3]1[C:4]2[C:9](=[CH:8][C:7]([S:20]([O-:23])(=[O:21])=[O:22])=[CH:6][CH:5]=2)[C:10]([CH3:19])([CH2:11][CH2:12][CH2:13][CH2:14][S:15]([OH:18])(=[O:16])=[O:17])[C:2]=1[CH3:1])[CH3:27]
Reactant: CCOS(=O)(=O)c1ccc(C)cc1
Reactant: CC1=Nc2ccc(S(=O)(=O)[O-])cc2C1(C)CCCCS(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=S1(=O)CCCC1
Solvent: CO
Product: CC[N+]1=C(C)C(C)(CCCCS(=O)(=O)O)c2cc(S(=O)(=O)[O-])ccc21
Yield: 41.6 %

Procedure:
Disodium 2,3-dimethyl-3-(4-sulphonatobutyl)-3H-indole-5-sulphonate (1 g), ethyl-p-toluene sulphonate (0.95 ml; 5.56 mmol) and tetramethylenesulphone (10 ml) were heated together at 140° C. for 12 hrs. TLC (silica; 2:1 MeOH; EtOAc) showed the formation of a new product spot (rf=0.8), which turned magenta on standing. The product was precipitated into ethyl acetate and then filtered off and dried in vacuo to give the crude product as a dark purple solid; 1.5 g. The product was purified in multiple shots by HPLC (Vydac protein & peptide C18 (250 mm×25 mm); flow rate 10 ml/min; gradient of 0 to 25% B over 30 mins; eluant A=0.1% TFA in water and eluant B=0.1% TFA in acetonitrile; detection at 220 nm). The fractions containing the desired product were pooled and the solvent removed under reduced pressure. The product was obtained as a pale pink oil (400 mg).
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=CN=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:26]([CH3:28])[CH3:27].C(Cl)(Cl)Cl.CO.CC([N:38](C)C)=O>>[F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:26]([CH3:28])[CH3:27])=[C:4]([NH:11][C:12]2[CH:13]=[CH:18][CH:17]=[CH:16][N:38]=2)[N:3]=1
Reactant: CC(=O)N(C)C
Reactant: Fc1nc(NCc2ccccn2)c2nc[nH]c2n1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)n1cnc2c(Nc3ccccn3)nc(F)nc21
Temperature: 40 °C
Reaction time: 48 h
Yield: 58 %

Procedure:
To a stirred solution of (2-fluoro-9H-purin-6-yl)-pyridin-2-ylmethyl-amine (0.4 g, 1.64 mmol) in DMA (5 mL) under Ar, at RT, was added K2CO3 (powdered, anhydrous; 1.1 g, 7.96 mmol) followed 2-bromopropane (1.5 mL, 15.98 mmol). The reaction mixture was stirred at 40° C. for 48 h, when TLC (9:1 CHCl3/MeOH) indicated that the reaction had gone to completion. The solvent was evaporated in vacuo and the residue partitioned between H2O (200 mL) and EtOAc (100 mL), the aqueous phase was separated and extracted with more EtOAc (2×50 mL). The bulked organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo, and the residue was purified by gradient column chromatography on silica gel, eluted with CHCl3/MeOH (100:0→95:5), to afford the title compound as a white solid (0.27 g, 58%). Mp 150-152° C. 1H-NMR (d6-DMSO, 250 MHz): δ 1.49 (2×s, 6H, CH(CH3)2), 4.63 (m, 1H, —CH(CH3)2), 4.71 (d, 2H, J=5.76 Hz, —HNCH2-Pyr), 7.26, 7.71, 8.49 (3×m, 4H, Pyr), 8.26 (s, 1H, —N═CH—N—), 8.78 (bs, 1H, —HNCH2-Pyr). FAB-MS m/z (relative intensity): 287 ([M+H]+, 100), 245 (10), 154 (22), 136 (17). Accurate Mass (M+H): Actual: 287.1420, Measured: 287.1412. Microanalysis (Expected:Measured) C14H15N6F: C, 58.73:58.38; H, 5.28:5.13; N, 29.35:29.36.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH:12]2[CH2:14][CH2:13]2)=[O:10])=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.[C:22](O)(=[O:27])[CH2:23][C:24](O)=[O:25]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:24](=[O:25])[CH2:23][C:22](=[O:27])[N:11]([CH:12]3[CH2:13][CH2:14]3)[C:9]2=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=C(Nc1ccc(Br)cc1)NC1CC1
Solvent: CC(=O)OC(C)=O
Product: O=C1CC(=O)N(C2CC2)C(=O)N1c1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
To 1-(4-bromo-phenyl)-3-cyclopropyl-urea 31 (12.9 g) obtained in Step 1 was added acetic anhydride (25.8 ml), malonic acid 4 (5.79 g) was added under a nitrogen atmosphere, and the mixture was stirred at 100° C. for 3 hrs. After allowing to cool to room temperature, the reaction mixture was concentrated under reduced pressure. Diethyl ether-ethanol [4:1 (volume ratio), 100 ml] was added to the residue and, after stirring, the crystals were collected by filtration and dried to give 1-(4-bromo-phenyl)-3-cyclopropyl-pyrimidine-2,4,6-trione 32 (11.9 g, yield 73%) as pale-yellow crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[O:9].[C:15]1([Mg]Cl)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.S(=O)(=O)(O)O>[Cu]I.C1COCC1>[CH2:11]([O:10][C:8]([N:1]1[CH:6]=[CH:5][CH:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:3]=[CH:2]1)=[O:9])[CH:12]([CH3:14])[CH3:13]
Reactant: c1ccncc1
Reactant: CC(C)COC(=O)Cl
Reactant: Cl[Mg]c1ccccc1
Agent: [Cu]I
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: CC(C)COC(=O)N1C=CC(c2ccccc2)C=C1
Reaction time: 1 h
Yield: 85.2 %

Procedure:
1.9 g (0.01 mole) of CuI was added to a mixture of 18.7 g (0.236 mole) of pyridine and 150 ml of tetrahydrofuran under a N2 atmosphere, with stirring. The mixture was stirred at room temperature until the mixture became a homogeneous solution, and thereafter a solution of 28.7 g (0.21 mole) of isobutyl chloroformate and 20 ml of tetrahydrofuran was added dropwise, on an ice bath, so that the inner temperature of the reactor could not exceed 20° C. Further, 100 ml of 2M phenyl magnesium chloride solution (0.2 mole; a THF solution) was added to the mixture dropwise, over 1 hour, at the inner temperature of 0±3° C. (i.e., −3° C. to 3° C.). The mixture was stirred for 20 minutes at the temperature of 0±3° C., and further stirred for 1 hour 25° C. After removing about 60 ml of tetrahydrofuran by vacuum distillation, 180 ml of toluene was added, and then 60 g (0.061 mole) of 10% sulfuric acid was added dropwise. The resulting precipitate was removed by filtration through celite, and then the celite was washed with 40 ml of toluene. After removing the aqueous layer of the filtrate, the organic layer of the filtrate was washed twice with 180 ml each of 10% hydrochloric acid, and twice with 180 ml each of water. The organic layer was concentrated under a reduced pressure to obtain Compound I-2: obtained amount 51.0 g; purity 86.0% (determined by HPLC); yield 85.2%.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[N:8]=[CH:9][N:10]3[C:19]4[C:14](=[C:15](C(F)(F)F)[CH:16]=[CH:17][CH:18]=4)[C:13](=[O:24])[N:12]([CH3:25])[C:11]=23)[N:3]=1.[CH3:26][C:27]1ON=C(C[N+]#[C-])N=1>>[CH:1]1([C:2]2[O:6][N:5]=[C:4]([C:7]3[N:8]=[CH:9][N:10]4[C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:13](=[O:24])[N:12]([CH3:25])[C:11]=34)[N:3]=2)[CH2:27][CH2:26]1
Reactant: Cc1nc(-c2ncn3c4cccc(C(F)(F)F)c4c(=O)n(C)c23)no1
Reactant: [C-]#[N+]Cc1noc(C)n1
Product: Cn1c(=O)c2ccccc2n2cnc(-c3noc(C4CC4)n3)c12

Procedure:
3-(5-methyl-1,2,4-oxadiazol-3-yl)-4,5-dihydro-4-methyl-5-oxo-6-trifluoromethyl-imidazo(1,5-a)quinazoline, M.p. 251.5°-251.9° C., by reaction between 3-methyl-5-trifluoromethyl 1 2,3,4-tetrahydro-2,4-dioxo-quinazoline and 5-methyl-3-isocyanomethyl-1,2,4-oxadiazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[H-].[Na+].[CH3:17]I>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([N:11]([CH3:17])[C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CC(=O)Nc1cc(Br)cc([N+](=O)[O-])c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
31.0 g (0.1197 mol) of N-(3-bromo-5-nitrophenyl)-acetamide were dissolved in 240 ml of dimethylformamide and added dropwise within 20 min. to a suspension, cooled at 5° C., of 5.8 g (0.1325 mol) of NaH (60%) in 120 ml of dimethylformamide. Subsequently, the mixture was stirred at room temperature for 1 hr., again cooled to 0-5° C. and 22.30 ml (0.358 mol) of MeI were added thereto. The mixture was stirred at room temperature for 18 hrs., then freed from solvent and the residue was partitioned in water and dichloromethane. The organic phase was washed with sat. sodium chloride solution, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel with ethyl acetate/hexane. There were obtained 29.0 g (88.7%) of N-(3-bromo-5-nitrophenyl)-N-methylacetamide as a brown oil. MS (El): me/e=274,272 (C9H9BrN2O3+).
Reaction SMILES: C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1.[Cl:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[S:46](Cl)(=[O:48])=[O:47]>O1CCCC1>[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][N:34]([S:46]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[Cl:39])(=[O:48])=[O:47])[CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1
Reactant: COC(=O)Cc1cc(C2CCNCC2)c2cc(F)ccc2c1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3ccccc3Cl)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
Diisopropylethylamine (0.6 mL, 3.4 mmol) was added at 0° C. to a solution of (6-fluoro-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt (which may be prepared as described above; 150 mg, 0.36 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 30 min. 2-Chlorobenzenesulfonyl chloride (available from Sigma-Aldrich; 114 mg, 0.54 mmol) was added and the mixture was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure. Ethyl acetate was added and the mixture was washed with aqueous NaHCO3 (5 mL) and water (5 mL). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using a Biotage purification system, eluting with 10% ethyl acetate/hexanes, to give {4-[1-(2-chloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-naphthalen-2-yl}-acetic acid methyl ester (94 mg, 55%) as a white solid. MS cald. for C24H24ClFNO4S [(M+H)+]: 476, obsd. 476.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[CH3:9][C:10]1([CH3:13])[CH2:12][O:11]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:9][C:10]([OH:11])([CH3:13])[CH3:12])[C:4](=[O:8])[CH:3]=1
Reactant: CC1(C)CO1
Reactant: O=c1cc(Br)cc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1ccc(Br)cc1=O
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-bromo-1H-pyridin-2-one (0.25 g), 2,2-dimethyl-oxirane (0.26 mL), and potassium carbonate (0.40 g) in dimethylformamide (2.5 mL) was stirred under microwave irradiation at 120° C. for 30 min. After cooling to ambient temperature, the mixture was concentrated and purified by HPLC on reversed phase (acetonitrile/water) to afford the title compound. Yield: 0.34 g (96% of theory); Mass spectrum (ESI+): m/z=246/248 (Br) [m+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])/[CH:5]=[CH:6]/[C:7]1[N:8]([CH3:26])[C:9](=[O:25])[C:10]2[C:15]([C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:14][C:13]([CH3:23])=[C:12]([CH3:24])[CH:11]=2)[CH3:2].C1COCC1>[C].[Pd].C(O)C>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][C:7]1[N:8]([CH3:26])[C:9](=[O:25])[C:10]2[C:15]([C:16]=1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[CH:14][C:13]([CH3:23])=[C:12]([CH3:24])[CH:11]=2)[CH3:2]
Reactant: CCOC(=O)/C=C/c1c(-c2ccccc2)c2cc(C)c(C)cc2c(=O)n1C
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c(-c2ccccc2)c2cc(C)c(C)cc2c(=O)n1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.5 %

Procedure:
A mixture of the compound (1.0 g) obtained in Step 2, 10% palladium-carbon (300 mg), THF (15 ml) and ethanol (15 ml) was stirred for 1.5 hours at room temperature under hydrogen atmosphere. The catalyst was filtered off. From the filtrate was distilled off the solvent. The residue was dissolved in ethyl acetate, which was washed with 2N-HCl, an aqueous solution of sodium hydrogencarbonate and water, successively, followed by drying (MgSO4). The solvent was distilled off to leave 3-(1,2-dihydro-2,6,7-trimethyl-1-oxo-4-phenylisoquinolin-3-yl)propionic acid ethyl ester as colorless crystals (0.85 g).
Reaction SMILES: [C:1]([CH2:4][NH:5][CH2:6][CH2:7][OH:8])([OH:3])=[O:2].[C:9](#[N:12])[CH2:10]O>>[C:1]([CH2:4][N:5]([CH2:6][CH2:7][OH:8])[CH2:10][C:9]#[N:12])([OH:3])=[O:2]
Reactant: O=C(O)CNCCO
Reactant: N#CCO
Product: N#CCN(CCO)CC(=O)O

Procedure:
The hydrolysis of (1) with base gives N-carboxymethylamino-2-ethanol (II). Compound (II) is then reacted with additional glycolonitrile to form N-carboxymethyl-N-cyanomethylamino-2-ethanol (III). The molar ratio of (II) to glycolonitrile is generally about 1:1. In the above reactions, hydrogen cyanide and formaldehyde can be substituted for glycolonitrile.
Reaction SMILES: Cl[C:2]1([NH2:20])[N:19]=[CH:18][N:17]=[C:16]2[C:3]1=[N:4][CH2:5][N:6]2[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].[CH:21]1(N)[CH2:25][CH2:24][CH2:23][CH2:22]1.C(O)C>CO>[CH:21]1([NH:20][C:2]2[C:3]3[N:4]=[CH:5][N:6]([C:16]=3[N:17]=[CH:18][N:19]=2)[C@@H:7]2[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]2[OH:9])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NC1CCCC1
Reactant: NC1(Cl)N=CN=C2C1=NCN2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: CCO
Solvent: CO
Product: OC[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)ncnc32)[C@H](O)[C@@H]1O
Temperature: 25 °C

Procedure:
A solution of 6-chloroadenosine (43 g) and cyclopentylamine (5 eq.) in ethanol (50 eq.) was heated at reflux for 3 hours then cooled to room temperature. The resultant reaction mixture was concentrated in vacuo and the resultant residue was diluted with water (400 ml) and ethyl acetate (400 ml). The eoganic layer was separated and the aqueous layer was extracted into ethyl acetate (2×400 ml). The combined organic layers were washed with water (2×200 ml), dried over sodium sulfate, concentrated in vacuo and dried under vacuum to provide a solid which was suspended in MeOH (400 mL), filtered and dried to provide N6-cyclopentyladenosine (43.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([CH2:13][OH:14])=[CH:8][C:7]=1[F:15].Cl[C:20]1[CH:30]=[C:24]2[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]2[C:22](=[O:31])[N:21]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([CH2:13][O:14][C:20]2[CH:30]=[C:24]3[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]3[C:22](=[O:31])[N:21]=2)=[CH:8][C:7]=1[F:15]
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1cc(F)c(Oc2cccc(Cl)c2)c(F)c1
Product: CN1CCCn2c1cc(OCc1cc(F)c(Oc3cccc(Cl)c3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (4-(3-chlorophenoxy)-3,5-difluorophenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][CH2:9][OH:10].C(N(CC)CC)C.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C(#N)C>[OH:10][CH2:9][CH2:8][CH2:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][N:1]1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OCCCC1CCCCN1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCCCC1CCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
3-(2-Piperidinyl)-1-propanol (8.69 g, 60.7 mmol) was stirred in acetonitrile (90 ml) with triethylamine (10.40 mL, 74.6 mmol) under N2 and cooled in an ice bath. Benzyl chloroformate (9.53 ml, 66.7 mmol) was added dropwise. After complete addition the reaction was allowed to warm to ambient temperature and stirring then continued overnight. The suspension was filtered and the filtrate evaporated to dryness. The residue was partitioned between ethyl acetate and water. The organic phase was washed with saturated brine, passed through a hydrophobic frit and evaporated to dryness. The residue was purified by chromatography on silica (330 g silica RediSep column, loaded in DCM) using a 0-50% ethyl acetate in cyclohexane gradient over 40 mins. with a 50-100% flush of ethyl acetate on an ISCO Companion. No peaks were detected (254 nm, 280 nm) so the waste was evaporated in vacuo to recover the material. The material was re-columned using identical conditions as before but detecting at 220 nm and collecting all the eluent. The main product peak was collected and evaporated in vacuo to give the title compound as a yellow oil (6.15 g).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[C:22]([C:23]([OH:25])=[O:24])=[CH:21][NH:20][N:19]=1.C([BH3-])#N.[Na+]>>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:10][NH:17][C:18]2[C:22]([C:23]([OH:25])=[O:24])=[CH:21][NH:20][N:19]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: Nc1n[nH]cc1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: COc1ccc(CNc2n[nH]cc2C(=O)O)cc1OC1CCCC1
Yield: 48 %

Procedure:
The condensation of 3-cyclopentyloxy-4-methoxybenzaldehyde with 3-amino-4-pyrazolecarboxylic acid in the presence of sodium cyanoborohydride produces 3-(3-cyclopentyloxy-4-methoxybenzyl-amino)-4-pyrazolecarboxylic acid in 48% yield. Treatment with excess borane-tetrahydrofuran complex in tetrahydrofuran solution gives 3-(3-cyclopentyloxy-4-methoxybenzylamino)-4-hydroxymethylpyrazole (Example 1) in 40% yield.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[C:6](=[O:18])[C:5]=2[NH:4][N:3]=1.[C:19](=[O:22])([O-])[O-].[K+].[K+].[CH3:25][C:26]1[CH:43]=[C:42]([CH3:44])[CH:41]=[C:40]([CH3:45])[C:27]=1[CH2:28][N:29]1[CH2:34][CH2:33][N:32]([C:35](=O)[CH2:36]CCl)[CH2:31][CH2:30]1>>[NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[C:6](=[O:18])[C:5]=2[N:4]([C:19](=[O:22])[CH2:36][CH2:35][N:32]2[CH2:33][CH2:34][N:29]([CH2:28][C:27]3[C:40]([CH3:45])=[CH:41][C:42]([CH3:44])=[CH:43][C:26]=3[CH3:25])[CH2:30][CH2:31]2)[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(N2CCc3c(N)n[nH]c3C2=O)cc1
Reactant: Cc1cc(C)c(CN2CCN(C(=O)CCCl)CC2)c(C)c1
Agent: [K+]
Product: Cc1ccc(N2CCc3c(N)nn(C(=O)CCN4CCN(Cc5c(C)cc(C)cc5C)CC4)c3C2=O)cc1

Procedure:
A target compound (130.2 mg, 0.253 mmol, 56.7%) was yielded as yellow solid in the same manner as Example 1 by reacting 3-amino-5,6-dihydro-6-N-(p-tolyl)-1H-pyrazolo[3,4-c]pyridin-7(4H)-one (108.2 mg, 0.446 mmol) with potassium carbonate (92.4 mg, 0.669 mmol) and 1-{4-(2,4,6-trimethylbenzyl)piperazin-1-yl}-3-chloropropan-1-one (151.3 mg, 0.490 mmol).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=2)[N:4]=[C:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22](=[O:31])(=[O:30])[NH:23][CH:24]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25]2)[CH:17]=1>CO.O1CCCC1.[Pd]>[CH3:1][C:2]1([CH3:32])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22](=[O:31])(=[O:30])[NH:23][CH:24]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25]2)[CH:17]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)NC3CCN(C)C3)c1)=N2
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)NC3CCN(C)C3)c1)N2
Yield: 92.7 %

Procedure:
A mixture of methyl 3,3-dimethyl-2-(3-(N-(1-methylpyrrolidin-3-yl)sulfamoyl)phenyl)-3,4-dihydroquinoline-6-carboxylate (152 mg, 0.33 mmol) and 10% Pd/C (100 mg) in methanol (3 mL) and tetrahydrofuran (3 mL) was hydrogenated by a H2 balloon at 30° C. After filtration, the filtrated was concentrated and purified on preparative Thin layer chromatography to afford 140 mg of methyl 3,3-dimethyl-2-(3-(N-(1-methylpyrrolidin-3-yl)sulfamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate as a white solid. (Yield: 92%).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[CH:6][C:7]1[C:12]([Br:13])=[CH:11][N:10]=[CH:9][C:8]=1[Br:14])C.[BH4-].[Na+].C(O)(=O)C>CCO>[Br:13][C:12]1[CH:11]=[N:10][CH:9]=[C:8]([Br:14])[C:7]=1[CH2:6][CH2:5][CH2:4][OH:3]
Reactant: CCOC(=O)C=Cc1c(Br)cncc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: OCCCc1c(Br)cncc1Br
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-(3,5-dibromo-pyridin-4-yl)-acrylic acid ethyl ester (1 eq, 17.0 mmol, 5.7 g) in EtOH (100 ml) at −18° C. is added NaBH4 (2 eq, 34.0 mmol, 1.29 g). The cooling bath is removed and the mixture is stirred at r.t. for 1.5 h. Then additional NaBH4 (0.78 eq, 13.2 mmol, 0.5 g) is added and the mixture is heated at 50° C. for 6 h. After cooling to r.t., glacial acetic acid is added, then the mixture is concentrated under reduced pressure. The residue is taken up in EtOAc, and washed with aqueous HCl (1M), sat. aqueous NaHCO3 solution, and sat. aqueous NaCl solution. The organic layer is dried with MgSO4, filtered, and concentrated in vacuo. The crude product is purified using column chromatography (hexane/EtOAc) to give the title compound; [M+H]+=295.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:15][CH3:16])[C:9]=2[O:13][CH3:14])[C:4]1=[O:17].[C:18]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19]1>>[ClH:1].[CH:18]1([NH:2][CH:3]2[CH2:12][CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([O:15][CH3:16])[C:9]=3[O:13][CH3:14])[C:4]2=[O:17])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C1CCCC1
Reactant: COc1ccc2c(c1OC)CCC(N)C2=O
Agent: Cl
Product: COc1ccc2c(c1OC)CCC(NC1CCCC1)C2=O

Procedure:
In a manner similar to that of Reference Example 3, 10 parts of 2-amino-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride is reacted with 300 volume parts of cyclopentanone. The procedure yields 10.2 parts of 2-cyclopentylamino-5,6-dimethoxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride as colorless crystals melting at 158°-167° C (decomposition).