Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[Cl:2][C:3]1[C:4]([O:24]C)=[N:5][C:6](/[C:9](/[C:16]2[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=2)=[CH:10]/[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:8]=1.O>O1CCOCC1>[Cl:2][C:3]1[C:4](=[O:24])[NH:5][C:6](/[C:9](/[C:16]2[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=2)=[CH:10]/[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:8]=1
Reactant: COc1nc(/C(=C/C2CCCC2)c2ccc(SC)cc2)ccc1Cl
Agent: Br
Solvent: O
Solvent: C1COCCO1
Product: CSc1ccc(/C(=C\C2CCCC2)c2ccc(Cl)c(=O)[nH]2)cc1
Temperature: 85 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
48% hydrobromic acid (1.5 mL) was added to a solution of 3-chloro-6-{(E)-2-cyclopentyl-1-[4-(methylsulfanyl)phenyl]ethenyl}-2-methoxypyridine (250 mg) in 1,4-dioxane (1.5 mL), and the mixture was stirred at 85° C. for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered, after which the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to give a pale brown oil. This was powdered with a hexane/ethyl acetate solution, and filtration operation gave the title compound as a pale brown powder (230 mg, 71%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[NH2:14][CH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]1>O1CCOCC1.[OH-].[Na+]>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:14][CH2:15][C@H:16]1[CH2:17][CH2:18][C@H:19]([C:22]([OH:24])=[O:23])[CH2:20][CH2:21]1)(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)[C@H]1CC[C@H](CNS(=O)(=O)c2ccccc2[N+](=O)[O-])CC1
Reaction time: 0.5 h

Procedure:
A solution of 29.9 g (0.135 mol) of o-nitrobenzenesulfonyl chloride in 150 ml of dioxane and 150 ml of 1 N NaOH was added simultaneously and dropwise at 4° C. (ice bath) to a solution of 14.13 g (0.09 mol) of trans-4-(aminomethyl)cyclohexanecarboxylic acid in a two-phase system comprising 90 ml of 1 N NaOH and 90 ml of dioxane. After the slightly exothermic reaction had died down, stirring was carried out for 30 minutes at room temperature, the precipitate which separated out was filtered off with suction and washed with a little ice water and the filtrate was evaporated down under reduced pressure, further precipitation of salt occurring. The combined amounts of salt were digested with ether, suspended in water, acidified with 1 M KHSO4 solution and extracted with ethyl acetate. The ethyl acetate phase was washed with sodium chloride solution, dried over Na2SO4 and evaporated down under reduced pressure.
Reaction SMILES: [C:1]1(=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.COP([CH2:17][C:18]([C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[C:27]([F:30])([F:29])[F:28])=O)(=O)OC.O.[NH2:32][NH2:33]>>[F:26][C:24]1[CH:23]=[CH:22][C:21]([C:27]([F:30])([F:29])[F:28])=[C:20]([C:18]2[N:33]=[N:32][C:2]3[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:1]=3[CH:17]=2)[CH:25]=1
Reactant: COP(=O)(CC(=O)c1cc(F)ccc1C(F)(F)F)OC
Reactant: O=C1CCCCCCC1=O
Reactant: NN
Solvent: O
Product: Fc1ccc(C(F)(F)F)c(-c2cc3c(nn2)CCCCCC3)c1

Procedure:
yellow oil. MS (EI): 324.2 (M+). Prepared from cyclooctane-1,2-dione, [2-(5-Fluoro-2-trifluoromethyl-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[NH2:9][C@H:10]([C:22](O)=O)CC1C=C2C(C=CC=C2)=CC=1.[CH3:25][C:26](C)=O>>[CH2:25]([N:9]([CH2:10][CH3:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])[CH3:26]
Reactant: CC(C)=O
Reactant: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: OCCCCCCCl
Product: CCN(CC)CCCCCCO
Reaction time: 4 h

Procedure:
A mixture of 10 ml (75 mmol) of 6-chlorohexanol and 16.9 g (112 mmole) of Nal dissolved in 100 ml acetone was refluxed for 3.5 days. The reaction mixture was filtered and the filtrate was concentrated to an oil and dissolved in 100 ml of ether. The ether solution was filtered, concentrated to an oil, and dissolved in 30 ml of diethylamine. The solution was stirred for 4 hours and filtered. The filtrate was concentrated to an oil, taken up in acidified water (pH<2) and washed with ethylacetate. The acidic solution was then adjusted to pH 9.5 and extracted twice with ethyl acetate. The organic extract was dried over MgSO4 and concentrated under vacuum to yield 7.5 g of the title compound as an oily product.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[CH:14]OCC)[CH:12]=O)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].Cl.[C:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[O:27])=[CH:24][CH:23]=1)(=[NH:21])[NH2:20].C[O-].[Na+]>CO>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[N:20][C:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[O:27])=[CH:24][CH:23]=3)=[N:21][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C(C=O)=COCC)cc1
Reactant: N=C(N)c1ccc(C(N)=O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCc1ccc(-c2cnc(-c3ccc(C(N)=O)cc3)nc2)cc1

Procedure:
74.2 G. of 2-(4-n-butylphenyl)-3-ethoxy-acrolein, 77.8 g. of the 4-amidinobenzoic acid amide hydrochloride described earlier and 0.546 mol of sodium methylate (obtained by dissolving 12.55 g. of sodium metal in methanol) are suspended in 2500 ml. of methanol and stirred overnight at room temperature under an atmosphere of nitrogen. The yellow suspension is subsequently removed by filtration, washed with a small amount of ethanol and suspended in 4 liters of ether for further purification. The suspension is washed with water and then filtered again. Sparingly soluble 4-[5-(4-n-butylphenyl)-2-pyrimidinyl] benzoic acid amide is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:33]2[CH2:32][CH2:31][N:30]([C:24]3[CH:23]=[C:22]([O:21][CH3:20])[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=3)[CH2:35][CH2:34]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3nc4cc(C)ccc4nc3OC)CC2)c1
Yield: 94 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 43 to obtain the titled compound (yield, 94%). MS(ESI) m/z 438 (M+1).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:20]([N:22]1[CH2:50][CH2:49][CH2:48][C@@H:23]1[C:24]([NH:26][C@H:27]([C:38]([O:40]CC1C=CC=CC=1)=[O:39])[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[NH:37])[NH:33][N+]([O-])=O)=[O:25])=[O:21])[CH2:11][O:12]CC1C=CC=CC=1)=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]>[C].[Pd]>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:20]([N:22]1[CH2:50][CH2:49][CH2:48][C@@H:23]1[C:24]([NH:26][C@H:27]([C:38]([OH:40])=[O:39])[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[NH:33])[NH2:37])=[O:25])=[O:21])[CH2:11][OH:12])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[CH3:27][C:38]([OH:40])=[O:39]
Reactant: N=C(NCCC[C@H](NC(=O)[C@H]1CCCN1C(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)N[N+](=O)[O-]
Agent: [Pd]
Product: CC(=O)O
Product: N=C(N)NCCC[C@H](NC(=O)[C@H]1CCCN1C(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(=O)O

Procedure:
100 mg of Z-Asn-Ser(Bzl)-D-Pro-Arg(NO2)-OBzl was reduced in the presence of palladium-carbon in the same manner as in Example 7-(4). The resulting product was purified by high-performance liquid chromatography at 12 ml/min.(flow rate), 0 to 10% (B) 20 min. linear gradient (A) (mobile phase), subjected to Dowex 1×2 (acetate type) treatment and freeze-dried to obtain the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([C:16]([C:18]3[CH:19]=[CH:20][C:21]4[O:26][CH2:25][C:24](=[O:27])[NH:23][C:22]=4[CH:28]=3)=[O:17])[C@@H:7]([CH2:10][C:11]([O:13]CC)=O)[CH2:8][O:9][C:4]=2[CH:3]=1.[CH3:31][NH2:32].C(O)C>CO.CC(O)C>[F:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([C:16]([C:18]3[CH:19]=[CH:20][C:21]4[O:26][CH2:25][C:24](=[O:27])[NH:23][C:22]=4[CH:28]=3)=[O:17])[C@@H:7]([CH2:10][C:11]([NH:32][CH3:31])=[O:13])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CCOC(=O)C[C@H]1COc2cc(F)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Reactant: CN
Solvent: CCO
Solvent: CO
Solvent: CC(C)O
Product: CNC(=O)C[C@H]1COc2cc(F)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl {(3S)-7-fluoro-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}acetate (Intermediate 14a, 1648 g) was taken up in methanol (10 L). Methylamine in ethanol (33 wt %, 20 eq., 7490 mL) was added at <30° C. The resulting solution was stirred at rt for 18 h. LCMS analysis indicated the reaction was not complete. The reaction was stirred for a further 4 h at rt after which HPLC indicated that <1% Intermediate 14a and its corresponding methyl ester remained (combined). The solvent was removed in vacuo to give the crude product as a tan solid (1719.2 g). This was combined with 376 g crude product from another batch and the combined crude product (2095 g) was taken up in IPA (20950 mL) and heated to reflux. A solution was not obtained. The suspension was sampled and the sample cooled and filtered for XRPD analysis. This indicated the product was of the desired form (type 2). HPLC analysis of the filtered material indicated a purity of 99.2% confirming purification had been successful. The suspension was cooled to room temperature over night. The solid was filtered, washed with IPA (3×2 L) and pulled dry. Further drying in a vacuum oven at 60° C. yielded the title product as an off-white solid (1632.5 g). 1H NMR indicated a purity of >95% (0.18% residual IPA). This material was combined with the product from another smaller scale recrystallisation (input 250 g crude) to give a total of 1820.7 g of the title compound.
Reaction SMILES: C([O:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][N:15]1[CH:23]=[N:22][C:21]2[C:20](=[O:24])[NH:19][C:18]([NH2:25])=[N:17][C:16]1=2)(=O)C1C=CC=CC=1>CN>[OH:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][N:15]1[CH:23]=[N:22][C:21]2[C:20](=[O:24])[NH:19][C:18]([NH2:25])=[N:17][C:16]1=2
Reactant: Nc1nc2c(ncn2COCCCOC(=O)c2ccccc2)c(=O)[nH]1
Agent: CN
Product: Nc1nc2c(ncn2COCCCO)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
A mixture of 9-(3-benzoyloxypropoxymethyl)guanine (0.5 g) and aqueous 45% methylamine (10 ml) was stirred overnight at room temperature. Excess methylamine and water was evaporated at <30° C. under reduced pressure and the residue recrystallized from ethanol to give 9-(3-hydroxypropoxymethyl)guanine (0.24g), m.p. 223° C. (with resolidification), as the .1/2 hydrate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[CH:15]=[C:16]([C:18]3[N:19]=[C:20]4[N:24]([CH:25]=3)[N:23]=[C:22](Br)[S:21]4)[O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][O-:28].[Na+]>ClCCl.CO>[CH2:1]([O:8][C:9]1[C:14]2[CH:15]=[C:16]([C:18]3[N:19]=[C:20]4[N:24]([CH:25]=3)[N:23]=[C:22]([O:28][CH3:27])[S:21]4)[O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1nn2cc(-c3cc4c(OCc5ccccc5)cccc4o3)nc2s1
Reactant: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1nn2cc(-c3cc4c(OCc5ccccc5)cccc4o3)nc2s1
Reaction time: 0.67 h

Procedure:
A solution of 6-(4-(benzyloxy)benzofuran-2-yl)-2-bromoimidazo[2,1-b][1,3,4]thiadiazole (Example 38E, 3.22 g, 7.55 mmol) in a mixture of dichloromethane (400 mL) and methanol (50 mL) was treated at 22° C. with 6.3 mL of a 25 wt. % solution of sodium methoxide in methanol (30.2 mmol) added in one portion. More methanol (45 mL) was added and the mixture was stirred for 40 min. The reaction mixture was quenched by the addition of 40 mL of 1 N hydrochloric acid followed by 10 ml of saturated sodium bicarbonate. The solvent was evaporated under reduced pressure and the residue was diluted with dichloromethane (400 mL), washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. Crystallization of the white solid residue from 1,2-dichloroethane (30 mL) gave 2.19 g of the title material as a white solid. Chromatography of the mother liquors on silica gel (3×10 cm, elution with dichloromethane-ethyl acetate 0-1%) gave another 0.46 g of product (total yield 2.65 g, 93%). LC (Method A): 2.379 min. HRMS (ESI) calcd for C20H16N3O3S [M+H]+ m/z 378.0907. found 378.0911. 1H NMR (CDCl3, 600 MHz) δ ppm: 4.18 (s, 3H), 5.21 (s, 2H), 6.71 (dd, J=7.4 Hz and J=0.95 Hz, 1H), 7.12-7.17 (m, 3H), 7.32 (broad t, 1H), 7.38 (broad t, 2H), 7.47 (broad d, 2H), 7.88 (s, 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][C:22](=[O:34])[C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:25][CH:24]=2)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>O1CCCC1>[CH2:7]([N:14]1[CH2:15][CH2:16][CH:17]([CH2:20][CH2:21][CH:22]([OH:34])[C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:25][CH:24]=2)[CH2:18][CH2:19]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(CCC1CCN(Cc2ccccc2)CC1)c1ccc(N2CCCC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OC(CCC1CCN(Cc2ccccc2)CC1)c1ccc(N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
To a solution (10 mi) of 0.6 g of lithium aluminum hydride (0.6 g) in tetrahydrofuran was added 0.6 g of the 1-benzyl-4-[2-(4-pyrrolidinobenzoyl)ethyl]piperidine synthesized in Example 59 and the mixture was stirred at room temperature for 30 minutes. Then, water was added cautiously thereto for decomposing the excess reagent and the reaction product was then extracted into dichloromethane. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to give crude crystals. Recrystallization from ether-hexane yielded 0.5 g of colorless crystals melting at 93°-95° C.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13](=O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[CH3:16])[C:6]=2[CH:5]=[C:4]([CH3:17])[CH:3]=1.I.[OH-].[Na+]>C(O)(=O)CC.O>[CH3:1][C:2]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[CH3:16])[C:6]=2[CH:5]=[C:4]([CH3:17])[CH:3]=1
Reactant: Cc1cc(C)c2c(c1)-c1cccc(C)c1C2=O
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(=O)O
Solvent: O
Product: Cc1cc(C)c2c(c1)-c1cccc(C)c1C2

Procedure:
1,3,8-Trimethylfluoren-9-one (53) was reduced according to the general procedure of Carruthers et al. (W. Carruthers, D. Whitmarsh, J. Chem. Soc. Perkin Trans, I 1973, 1511). 1,3,8-Trimethylfluoren-9-one (53) (2.74 g, 12.3 mmol) was dissolved in propionic acid (235 ml). Red phosphorus (3.0 g) and concentrated HI (40 ml) were added and the reaction mixture was refluxed for 24 h. Quantitative conversion was shown by TLC. The reaction mixture was diluted with water (250 ml), neutralized with NaOH and extracted with Et2O (4×125 ml). The combined organic layers were washed with brine (2×125 ml), dried over MgSO4, filtered and the volatiles removed in vacuo to afford 2.56 g (quant.) 54 as a white solid.
Reaction SMILES: Cl[C:2]([Cl:12])(OC(=O)OC(Cl)(Cl)Cl)Cl.C[N:14](C)[NH:15][C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=1)=[O:17].[C:33](OCC)(=O)C>C(Cl)Cl>[Cl:12][C:2]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:21]=2)[C:16](=[O:17])[N:15]([CH3:33])[N:14]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(C)=O
Reactant: CN(C)NC(=O)NCc1cccc(-c2ccccc2)c1
Solvent: ClCCl
Product: Cn1nc(Cl)n(Cc2cccc(-c3ccccc3)c2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2.75 g (9.28 mmol) of triphosgene in 15 ml of methylene chloride was added dropwise a solution of 1.25 g (4.64 mmol) of 1,1-dimethyl-4-(3-phenylbenzyl)semicarbazide (produced in the following Reference Production Example 1) in 10 ml of methylene chloride with ice-cooling. The mixture was removed from an ice bath, allowed to warm to room temperature, and heated under reflux for 4 hours. After allowing to cool to room temperature, the reaction mixture was poured into an about 5% aqueous solution of sodium bicarbonate, and the mixture was stirred for 1 hour. The organic layer was washed with water, dried and concentrated. The residue was subjected to silica gel column chromatography (eluted with n-hexane:ethyl acetate=5:1 and then 3:1) to obtain 0.59 g (2.0 mmol) of 5-chloro-2-methyl-4-(3-phenylbenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (the compound 2 of the present invention).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][O:17]C)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:19]([C:22]1[O:26][C:25]([CH:27]=O)=[CH:24][CH:23]=1)([O-:21])=[O:20]>C1C=CC=CC=1.C(OCC)C.FB(F)F>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15](=[CH:27][C:25]2[O:26][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][CH:24]=2)[CH:16]=[O:17])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: COC=Cc1ccc(OCc2ccccc2)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: c1ccccc1
Product: O=CC(=Cc1ccc([N+](=O)[O-])o1)c1ccc(OCc2ccccc2)cc1
Reaction time: 2 h

Procedure:
6.4 g of 1-(4-benzyloxyphenyl)-2-methoxyethylene, diluted with 10 cc of benzene, are added dropwise at 0°-5° to 11.15 g of 5-nitrofuran-2-aldehyde in 30 cc of dry benzene after the addition of a few drops of diethyl ether/trifluoroborane. The mixture is stirred at 40° for 11/2 hours, is washed with a 5% aqueous sodium acetate solution and with water, dried with magnesium sulphate and concentrated by evaporation. The residue is heated to 90° for 4 hours with 10% hydrochloric acid and glacial acetic acid. The mixture is again concentrated by evaporation, is taken up in ether and the acid salt portion is filtered off. After concentration, orange crystals having a M.P. of 145°-155°, crystallize from the ether solution.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)Cl.CO>[Br:11][C:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[NH:8][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ncnc2[nH]ccc12
Solvent: ClCCl
Solvent: CO
Product: Clc1ncnc2[nH]cc(Br)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.2 %

Procedure:
To a suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (3.99 g, 26.0 mmol, 1.0 eq) in dry DCM (150 mL) under argon, N-bromosuccinimide (6.02 g, 33.8 mmol, 1.3 eq) was added and the resulting mixture was stirred at RT for 3 h. The reaction mixture was diluted with MeOH (30 mL) and then concentrated in vacuo to yield a slight brown solid. The residue was triturated with H2O (150 mL). The solid was collected by filtration and then re-crystallized in MeOH to afford 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (4.0 g, 66% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=[O:12])[CH:6]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:5]2.C[O-:18].[Na+].[CH:20]([C:22]([CH3:24])=O)=[CH2:21]>C(O)C.C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=[O:12])[C:6]([CH2:21][CH2:20][CH2:22][CH3:24])([CH2:13][CH2:14][C:15](=[O:18])[CH3:16])[CH2:5]2
Reactant: CCCCC1Cc2cc(N)c(F)cc2C1=O
Reactant: C[O-]
Reactant: C=CC(C)=O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCCCC1(CCC(C)=O)Cc2cc(N)c(F)cc2C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 221.9 %

Procedure:
A solution of 5-amino-2-butyl-6-fluoro-1-indanone (0.98 g, 4.64 mmol) in ethanol (17 mL) was treated with sodium methoxide (0.5M solution in MeOH, 1.86 mL, 0.928 mmol) and methyl vinyl ketone (0.579 mL, 6.97 mmol). The resulting solution was stirred at room temperature and under a nitrogen atmosphere for 2 days. The mixture was diluted with CH2Cl2 and filtered through a pad of silica gel. The product washed off with EtOAc and the filtrate was evaporated under vacuum. The residue was purified by flash chromatography on a Biotage 40M KP-Sil column, eluting with 3:1 to 2.5:1 hexanes-EtOAc. The product containing fractions were evaporated under vacuum to provide to afford 5-amino-2-butyl-6-fluoro-2-(3-oxobutyl)-1-indanone(0.6 g, 46%) as a yellow foam.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1([CH3:28])[C:13]2[CH:12]=[CH:11][C:10]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)=[CH:9][C:8]=2[C:7](=[O:27])[CH2:6][CH2:5]1>C1COCC1.C(O)C.O>[OH:27][CH:7]1[CH2:6][CH2:5][C:4]([CH3:3])([CH3:28])[C:13]2[CH:12]=[CH:11][C:10]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=3)=[CH:9][C:8]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CCC3(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(O)CCC3(C)C)cc1
Reaction time: 6 h

Procedure:
1 g (2.88 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoate (Compound 9) was converted into the title compound using 60 mg (1.6 mmol) of sodium borohydride. The procedure was as follows: To a cold solution (0° C.) of Compound 9 in 5 ml of THF and 10 ml of ethanol was added sodium borohydride. The mixture was stirred for 6 hours, diluted with water (10 ml) and extracted with Et2O (4×40 ml). The combined organic layers were washed with 10% HCl (5 ml), 10% aqueous NaHCO3 (10 ml) and brine (10 ml), dried over MgSo4 and concentrated in vacuo to give the title compound as a white solid.
Reaction SMILES: [CH:1]([C:3]1[C:4]([N+:13]([O-:15])=[O:14])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCCCCC.CCOC(C)=O>CCO>[N+:13]([C:4]1[C:3]([CH:1]=[N:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])([O-:15])=[O:14]
Reactant: COC(=O)c1cccc(C=O)c1[N+](=O)[O-]
Reactant: Nc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1cccc(C=Nc2ccccc2)c1[N+](=O)[O-]

Procedure:
A mixture of (A3) (1.0 eq.) and aniline (1.05 eq.) in EtOH (0.2 M) was stirred at reflux under N2 atmosphere for 2 hr until TLC revealed completation of the reaction (Hexane/EtOAc=75:25). Evaporation of the solvent gave (A4) as a white solid which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3, 300K) δ 8.51 (1H, d, J=7.3 Hz), 8.41 (1H, s), 8.11 (1H, d, J=7.8 Hz), 7.67 (1H, t, J=7.8 Hz), 7.43 (2H, t, J=7.8 Hz), 7.31 (1H, t, J=7.3 Hz), 7.16 (2H, d, J=7.8 Hz), 3.94 (3H, s).
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:4]=2[CH2:3]1.[C:19]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([O:21][CH2:22][CH3:23])=[O:20]>C(Cl)(Cl)Cl>[C:19]([N:24]1[CH2:29][CH2:28][N:27]([CH:2]2[C:8]3[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=3[S:6][C:5]3[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:4]=3[CH2:3]2)[CH2:26][CH2:25]1)([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)N1CCNCC1
Reactant: Cc1ccc2c(c1)CC(Cl)c1cc(F)ccc1S2
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCN(C2Cc3cc(C)ccc3Sc3ccc(F)cc32)CC1
Temperature: 0 °C

Procedure:
24 G. of 10-chloro-8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin in 80 ml. of chloroform are heated under reflux for 20 hours with 38.4 g. of 1-carbethoxy-piperazine. The mixture is poured on to ice-water and extracted with chloroform. The organic phase is dried over magnesium sulfate, evaporated under reduced pressure, and there is obtained crude, oily 1-carbethoxy-4-[8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl]-piperazine.