Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:21])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[C:16]2[N:15]=[CH:14][NH:13][C:12]=2[CH:11]=[C:10]([C:17]([O:19][CH3:20])=[O:18])[CH:9]=1.[H-].[Na+].[CH2:24](I)[CH3:25]>CN(C=O)C>[O:21]=[S:2]1(=[O:1])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[C:16]2[N:15]=[CH:14][N:13]([CH2:24][CH3:25])[C:12]=2[CH:11]=[C:10]([C:17]([O:19][CH3:20])=[O:18])[CH:9]=1
Reactant: COC(=O)c1cc(N2CCCCS2(=O)=O)c2nc[nH]c2c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cnc2c(N3CCCCS3(=O)=O)cc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 160.2 %

Procedure:
To a solution of methyl 4-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)-1H-benzimidazole-6-carboxylate (D253) (230 mg, 0.74 mmol, 1 equiv) in DMF (10 ml) at room temperature was added NaH (60% dispersion in mineral oil, 33 mg, 0.82 mmol, 1.1 equiv) and the resulting mixture was stirred 5 min at this temperature. Ethyl iodide (66 μl, 0.82 mmol, 1.1 equiv) was added and the resulting solution was stirred for 30 min at 60° C. then cooled to room temperature and concentrated in vacuo. The residue was partitioned between AcOEt and a 5% aqueous citric acid solution. The two layers were separated and the aqueous phase saturated with NaCl and extracted twice with AcOEt. The combined organic phases were dried over MgSO4 and concentrated in vacuo to give methyl 4-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)-1-ethyl-1H-benzimidazole-6-carboxylate (B151) (400 mg, 160%) as a pale yellow viscous oil which was used in the next step without further purification. [M+H]+=338.1, RT=2.43 min.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([CH:9]=O)=[CH:7][N:6]=[C:5]2[C:11]2[CH:16]=[C:15]([Cl:17])[N:14]=[C:13]([Cl:18])[CH:12]=2)[CH2:3][CH2:2]1.C([C:21](CC)(CC)[CH:22](P(O)(O)=O)[C:23]([O-:25])=[O:24])C.[CH2:34]1CCN2C(=NCCC2)C[CH2:35]1>C(#N)C.O>[CH2:34]([O:25][C:23](=[O:24])[C:22]([CH3:21])=[CH:9][C:8]1[N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]([C:11]2[CH:16]=[C:15]([Cl:17])[N:14]=[C:13]([Cl:18])[CH:12]=2)=[N:6][CH:7]=1)[CH3:35]
Reactant: O=Cc1cnc(-c2cc(Cl)nc(Cl)c2)n1C1CC1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCC(CC)(CC)C(C(=O)[O-])P(=O)(O)O
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C(C)=Cc1cnc(-c2cc(Cl)nc(Cl)c2)n1C1CC1
Temperature: 78 °C
Yield: 86.3 %

Procedure:
3-cyclopropyl-2-(2,6-dichloro-pyridin-4-yl)-3H-imidazole-4-carbaldehyde (1.48 g, 5.25 mmol), triethyl-2-phosphonopropionate (1.46 ml, 6.83 mmol) and DBU(1.02 ml, 6.83 mmol) were dissolved in acetonitrile (20 ml). After stirring at 78° C. o.n. the reaction mixture was cooled to r.t, diluted with water and extracted with DCM. The combined organic phase was dried (Na2SO4), filtered and concentrated in-vacuo. The crude was purified on silica gel using 6% EA in DCM, and the isolated residue was triturated with hex. to isolate the title compound (1.66 g, 86%). 1H-NMR: 7.86 (m, 1H), 7.75 (d, 2H), 7.43 (s, 1H), 4.34 (q, 2H), 3.45 (m, 1H), 2.19 (s, 3H), 1.39 (t, 3H), 1.29 (m, 2H), 0.78 (m, 2H).
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:16]=[C:17]([Si:20]([CH3:23])([CH3:22])[CH3:21])[O:18][CH:19]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([O:1][CH:2]([C:15]1[CH:16]=[C:17]([Si:20]([CH3:23])([CH3:22])[CH3:21])[O:18][CH:19]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCC(OC(C)=O)c1coc([Si](C)(C)C)c1
Reaction time: 16 h

Procedure:
A mixture of 4-(1-hydroxytridecyl)-2-trimethylsilylfuran (1.32 g, 3.89 mmol), acetic anhydride (4 ml) and pyridine (6 ml) was stirred under argon at ca. 20° for 16 h. After most of the solvent was removed under high vacuum (<40°), the residue was dissolved in ethyl ether (40 ml) and washed thoroughly with aqueous copper sulfate and water. Drying (magnesium sulfate) and evaporation gave a brown oil, which was flash chromatographed on silica using 5% ethyl ether/petroleum ether. Fractions with Rf of about 0.55 (10% ethyl ether/petroleum ether) on evaporation gave the desired trimethylsilylfuran as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)[CH:8]=2)[N:3]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([NH:1][C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)[CH:8]=2)[N:3]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(-c2ccc3nc(N)nc(O)c3c2)cc1OC
Product: COc1ccc(-c2ccc3nc(NC(C)=O)nc(O)c3c2)cc1OC
Yield: 90 %

Procedure:
A suspension of the crude 2-amino-6-(3,4-dimethoxyphenyl)-4-hydroxyquinazoline from example 5 (3.0 g, 10 mmol) in acetic anhydride (20 ml) was refluxed for 40 minutes. After concentration under reduced pressure, the residue was purified by silica gel flash chromatography, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1:40), yielding the title compound as a white solid (3.05 g, yield: 90%) which was characterized by its mass spectrum as follows: MS (m/z): 340 ([M+H]+, 100).
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH3:9])[C:7](=[O:10])[N:6]([CH3:11])[C:5](=[O:12])[CH:4]=1)[NH2:2].[C:13](OC(=O)C)(=[O:15])[CH3:14].Cl.N1C=CC=[CH:23][CH:22]=1>>[C:13]([N:1]1[C:3]2[N:8]([CH3:9])[C:7](=[O:10])[N:6]([CH3:11])[C:5](=[O:12])[C:4]=2[C:22]([CH3:23])=[N:2]1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccncc1
Reactant: Cn1c(NN)cc(=O)n(C)c1=O
Agent: Cl
Product: CC(=O)n1nc(C)c2c(=O)n(C)c(=O)n(C)c21
Temperature: 0 °C

Procedure:
A mixture of Step 2 intermediate (8.0 g, 47.01 mmol) and acetic anhydride (40 ml) in dry pyridine (78 ml) were refluxed for 3 h. The reaction mixture was cooled to 0° C. and acidified with 1N HCl (200 ml). The solid obtained was collected by filtration, washed with 1 N HCl (25 ml), water (25 ml) and dried to give 6.9 g of the product as a white solid; 1H NMR (300 MHz, DMSO-d6): δ 2.71 (s, 3H), 2.96 (s, 3H), 3.37 (s, 3H), 3.50 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([NH:25][C@H:26]([C:31](O)=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:31](=[O:32])[C@H:26]([CH2:27][CH:28]([CH3:29])[CH3:30])[NH:25][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 86.4 %

Procedure:
To a solution of N-benzyl-4-amino piperidine (0.50 g) in CH2Cl2 (10 mL) was added CBZ-leucine (695 mg), EDC (552.5 mg) and HOBT (356.6 mg). The reaction was stirred at room temperature until complete as indicated by TLC analysis. The reaction was dissolved in CHCl3 and washed with 10% Na2CO3, brine, dried (MgSO4), filtered, concentrated and chromatographed (3:1 EtOAc:hexanes) to give 0.99 g of the title compound: MS(ES+) 438 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[F:12][C:13]1[CH:14]=[C:15]([CH2:20][CH2:21][CH:22]=O)[CH:16]=[CH:17][C:18]=1[CH3:19]>>[CH2:1]([C:3]1[N:4]2[CH2:9][CH2:10][NH:11][CH:22]([CH2:21][CH2:20][C:15]3[CH:16]=[CH:17][C:18]([CH3:19])=[C:13]([F:12])[CH:14]=3)[C:5]2=[C:6]([I:8])[N:7]=1)[CH3:2]
Reactant: Cc1ccc(CCC=O)cc1F
Reactant: CCc1nc(I)cn1CCN
Product: CCc1nc(I)c2n1CCNC2CCc1ccc(C)c(F)c1

Procedure:
According to the general procedure (GP10), the microwave-assisted Pictet-Spengler reaction (60 W; 100° C.; 8 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (320.7 mg; 1.210 mmol) and 3-(3-fluoro-4-methyl-phenyl)-propionaldehyde (202 mg; 1.210 mmol) afforded 3-ethyl-8-[2-(3-fluoro-4-methyl-phenyl)-ethyl]-1-iodo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine which was Boc-protected and finally purified by HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][CH2:39][C:40]1[S:44][CH:43]=[N:42][C:41]=1[CH3:45])[CH2:24][NH:25][CH:26]1[CH2:32][CH2:31][CH2:30][CH2:29][NH:28][C:27]1=[O:33]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:25]([CH2:24][C:23]2[CH:34]=[CH:35][C:36]([O:37][CH2:38][CH2:39][C:40]3[S:44][CH:43]=[N:42][C:41]=3[CH3:45])=[C:21]([O:20][CH3:19])[CH:22]=2)[CH:26]2[CH2:32][CH2:31][CH2:30][CH2:29][NH:28][C:27]2=[O:33])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COc1cc(CNC2CCCCNC2=O)ccc1OCCc1scnc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)ccc1OCCc1scnc1C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4-chlorobenzenesulfonylchloride (0.26 mmol) was added to a methylene chloride (0.2 M) solution of triethylamine (1.0 mmol) and 3-{3-Methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzylamino)-azepan-2-one (7) (0.26 mmol), and stirred at room temperature for 12 h. The product (8) was obtained by purification upon reverse phase HPLC.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1.Br[CH2:15][C:16]#[CH:17].CCN(C(C)C)[CH:21]([CH3:23])[CH3:22]>C(#N)C>[CH2:15]([N:1]([CH2:23][C:21]#[CH:22])[CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=1)[C:16]#[CH:17]
Reactant: C#CCBr
Reactant: CCN(C(C)C)C(C)C
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Solvent: CC#N
Product: C#CCN(CC#C)CCc1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of 4-(2-aminoethyl)benzenesulfonamide (2.00 g, 10 mmol), 3-bromoprop-1-yne (2.16 mL, 20 mmol, 80% in toluene) in acetonitrile (50 mL) was added DIPEA (3.0 mL). The reaction mixtures were stirred at room temperature for overnight and concentrated under reduced pressure to give a residue. The residue was purified by biotage over silica gel eluting with DCM to 10% MeOH in DCM to afford 4-(2-(di(prop-2-yn-1-yl)amino)ethyl)benzenesulfonamide as a yellow oil (2.40 g, 87%), MS (ESI), 277.1 (M+H)+.
Reaction SMILES: [C:1]([CH:3]1[CH2:5][NH:4]1)#[N:2].C1(C)C=CC=CC=1.[C:13]([N:23]=[C:24]=[O:25])(=[O:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C>C(OCC)(=O)C>[C:13]([NH:23][C:24]([N:4]1[CH2:5][CH:3]1[C:1]#[N:2])=[O:25])(=[O:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#CC1CN1
Reactant: O=C=NC(=O)C=Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: N#CC1CN1C(=O)NC(=O)C=Cc1ccccc1

Procedure:
A solution of 0.98 g. 2-cyanoaziridine in 20 ml. toluene is added dropwise, while stirring, at 20° to 30° C. to 2.5 g. cinnamoyl isocyanate dissolved in 20 ml. toluene. The resultant suspension is stirred for 1 hour at ambient temperature, then filtered off with suction and washed with toluene. The crystals obtained are triturated with anhydrous diethyl ether and dried for 1 hour at 50° C. in a vacuum to give 1.9 g. of crude product; m.p. 134°-136° C. This crude product is boiled with 50 ml. ethyl acetate for a short time, mixed with active charcoal and then filtered. The hot ethyl acetate filtrate is evaporated in a vacuum and the evaporation residue triturated with anhydrous diethyl ether. There is thus obtained 1.2 g. 1-(N-cinnamoyl-carbamoyl)-2-cyanoaziridine; m.p. 163°-164° C. The compound is practically insoluble in water but goes into solution upon the addition of excess 2 N aqueous sodium hydroxide solution.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C:13]2([CH2:15][CH2:14]2)[C:12](=[O:16])[N:11]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([O:25][CH3:26])[CH:18]=2)[C@H:10]1[CH3:27])(C(C)(C)C)(C)C.CO.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[OH:8][C@@H:9]1[C:13]2([CH2:15][CH2:14]2)[C:12](=[O:16])[N:11]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([O:25][CH3:26])[CH:18]=2)[C@H:10]1[CH3:27]
Reactant: COc1cc(N2C(=O)C3(CC3)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]2C)ccc1C#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(N2C(=O)C3(CC3)[C@@H](O)[C@@H]2C)ccc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
To a solution of 4-[(6S,7R)-7-(tert-butyldimethylsilyloxy)-6-methyl-4-oxo-5-azaspiro[2.4]hept-5-yl]-2-methoxybenzonitrile (320 mg) in tetrahydrofuran (8 mL)-methanol (8 mL) was added 6 mol/L hydrochloric acid (6 mL), and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=30/1→1/3) to give the title compound as a colorless solid (yield: 49.7 mg, 22%).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]([C:16]2[C:17]([CH:22]([F:24])[F:23])=[N:18][N:19]([CH3:21])[CH:20]=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>C1(C)C=CC=CC=1>[CH:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]([C:16]2[C:17]([CH:22]([F:24])[F:23])=[N:18][N:19]([CH3:21])[CH:20]=2)=[S:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1cc(C(=O)Nc2ccccc2C2CCCCC2)c(C(F)F)n1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cn1cc(C(=S)Nc2ccccc2C2CCCCC2)c(C(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
N-(2-cyclohexylphenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide (2.0 g) and Lawesson's reagent (2.4 g) were refluxed in toluene (100 mL) for 1 h. Contents were stirred overnight at RT and filtered. The filtrate was concentrated in vacuo leaving a yellow solid which was chromatographed on silica gel eluting with 35% EtOAc/hexanes to give a yellow solid. The solid was recrystallized from EtOAc to give the desired compound as a yellow solid (1.1 g).
Reaction SMILES: C[O:2][C:3](=[O:46])[CH2:4][CH2:5][C:6]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]=2)=[C:29]([Cl:45])[CH:28]=1)([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)=[C:10]([Cl:26])[CH:9]=1)[CH3:7].COC(=O)CCC(C1C=CC(OCC2C=CC3C(=CC=CC=3)N=2)=CC=1)(C1C=CC(OCC2C=CC3C(=CC=CC=3)N=2)=CC=1)C.N>O>[Cl:45][C:29]1[CH:28]=[C:27]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)=[C:10]([Cl:26])[CH:9]=2)([CH3:7])[CH2:5][CH2:4][C:3]([OH:46])=[O:2])[CH:32]=[CH:31][C:30]=1[O:33][CH2:34][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]=1
Reactant: COC(=O)CCC(C)(c1ccc(OCc2ccc3ccccc3n2)c(Cl)c1)c1ccc(OCc2ccc3ccccc3n2)c(Cl)c1
Agent: COC(=O)CCC(C)(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: N
Solvent: O
Product: CC(CCC(=O)O)(c1ccc(OCc2ccc3ccccc3n2)c(Cl)c1)c1ccc(OCc2ccc3ccccc3n2)c(Cl)c1

Procedure:
The desired compound was prepared according to the method of Example 1, step 3, except substituting 4,4-bis(3-chloro-4-(2-quinolylmethoxy)phenyl)pentanoic acid methyl ester, prepared as in step 1, for 4,4-bis(4-(2-quinolylmethoxy)phenyl)pentanoic acid methyl ester: mp 91°-94° C.; 1H NMR (300 MHz, DMSO-d6) d 1.53 (s, 3H), 1.96 (m, 2H), 2,30 (m, 2H), 5.44 (s, 4H), 7.09 (dd, 2H, J=3, 9 Hz), 7.20 (d, 2H, J=9 Hz), 7.24 (d, 2H, J=3Hz), 7.62 (m, 2H), 7.71 (d, 2H, J=9 Hz), 7.80 (m, 2H), 8.00 (m, 4H), 8.44 (d, 2H, J=9 Hz), 12.08 (bs, 1H); MS (DCl--NH3) m/e 637 (M+H)+. Anal. Calc'd. for C37H30Cl2N2O4 ×H2O: C, 67.79; H, 4.92; N, 4.27. Found: C, 68.02; H, 4.85; N, 3.94.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:23]([C:27]1[C:31]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[S:45](=[O:48])(=[O:47])[NH2:46])=[CH:35][CH:34]=2)=[C:30]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[N:29]([C:54]2[CH:59]=[C:58]([N+:60]([O-:62])=[O:61])[CH:57]=[CH:56][C:55]=2[Cl:63])[N:28]=1)[CH2:24][CH2:25][CH3:26].N12CCCN=C1CCCCC2>C1COCC1>[CH2:23]([C:27]1[C:31]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[S:45](=[O:48])(=[O:47])[NH:46][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])=[CH:35][CH:34]=2)=[C:30]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[N:29]([C:54]2[CH:59]=[C:58]([N+:60]([O-:62])=[O:61])[CH:57]=[CH:56][C:55]=2[Cl:63])[N:28]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(C(=O)OCC)c1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reactant: O=C(O)c1ccccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(C(=O)OCC)c1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 47.8 %

Procedure:
A mixture of 675 mg (4.28 mmol) of 2-chlorobenzoic acid, 695 mg (4.28 mmol) of 1,1'-carbonyldiimidazole (CDI), and 2 mL of dry THF was stirred at 50° C. under N2 for 3 hours. Then a solution of 851 mg (1.43 mmol) of ethyl 3-n-butyl-1-(2-chloro-5-nitrophenyl)-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-1H-pyrazole-5-carboxylate (from Step G) and 640 μL (651 mg, 4.28 mmol) of 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU) in 5 mL of dry THF was added, and stirring under N2 at 50° C. was continued overnight. The cooled reaction mixture was partitioned between 75 mL of 5% citric acid (aqueous) and 75 mL of ethyl acetate. The organic phase was washed with H2O, dried (Na2SO4), filtered, and concentrated. The orange residue was flash chromatographed on silica gel (elution with 1% MeOH in CH2Cl2) to yield 503 mg (48%) of the title compound as a solid, mp>60° C. (gradual); homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 736 (M+1)+. 400 MHz 1H NMR (CDCl3) δ0.88 (t, J=7.3 Hz, 3H), 1.05 (t, J=7.1 Hz, 3H), 1.34 (m, 2H), 1.59 (m, 2H, partially obscured by H2O peak), 2.56 (t, J=7.8 Hz, 2H), 4.14 (q, J=7.1 Hz, 2H), overlapping 4.16 (s, 2H), 7.07 (d, J=8.1 Hz, 2H), 7.25-7.45 (m, 6H), 7.55-7.69 (m, 4H), 8.26 (dd, J=8.8, 2.6 Hz, 1H), 8.35 (dd, J=8.1, 1.3 Hz, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][N:12]=1)[C:7]([NH2:9])=[O:8])([O-:3])=[O:2].[CH:13]([N:16]=[C:17]=[O:18])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[CH:13]([NH:16][C:17](=[O:18])[NH:9][C:7]([C:6]1[CH:10]=[CH:11][N:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:8])([CH3:15])[CH3:14]
Reactant: NC(=O)c1ccnc([N+](=O)[O-])c1
Reactant: CC(C)N=C=O
Solvent: Cc1ccccc1
Product: CC(C)NC(=O)NC(=O)c1ccnc([N+](=O)[O-])c1

Procedure:
To 30 ml. of toluene were added 0.8 g. of 2-nitroisonicotinamide and 1.7 g. of isopropyl isocyanate, and the mixture was refluxed for 6 hours. The reaction mixture was cooled and filtered removing 0.4 g. of the insoluble starting material. The filtrate was concentrated, and the residue was purified by silica gel chromatography and recrystallized from ethyl acetate-n-hexane to yield 0.08 g. of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O>[CH3:14][N:11]1[CH2:12][CH2:13][CH:8]([C:4]2[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=2)[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(N)c2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: CN1CCC(c2cccc(N)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A dried flask was charged with tert-butyl 4-(3-aminophenyl)piperidine-1-carboxylate (0.553 g, 2.00 mmol). Lithium aluminium hydride (1M in THF, 10 mL, 10.0 mmol) was added slowly through a syringe under N2. The resulting mixture was stirred overnight at rt. Water (0.5 mL) was cautiously added to quench the reaction. The resulting mixture was filtered. The filtrate was concentrated to dryness to give the title compound as a white solid, which was used without further purification in the next step. 1H-NMR (CDCl3, 400 MHz): δ=1.80-1.85 (m, 2H), 2.04 (dt, J=4.0, 11.6 Hz, 2H), 2.33 (s, 3H), 2.40 (m, 1H), 2.98 (m, 2H), 3.64 (s, br, 2H), 6.54-6.59 (m, 2H), 6.66 (d, J=7.6 Hz, 1H), 7.10 (t, J=7.6 Hz, 1H). MS (ES+): m/z 191.26 [MH+]. HPLC: tR=0.49 min (ZQ2000, polar—5 min).
Reaction SMILES: [H][H].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13]1[C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[N:26]O)[C:17]=2[CH:16]=[CH:15][CH:14]=1>C(O)C.O1CCCC1.[Ni]>[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13]1[C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]([NH2:26])[C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: ON=C1c2ccccc2-c2c1cccc2-c1ccc2ccccc2n1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: NC1c2ccccc2-c2c(-c3ccc4ccccc4n3)cccc21
Temperature: 60 °C

Procedure:
In a 100 mL autoclave, dissolve 0.9 g of equimolecular mixture of the Z and E isomers of 4-(quinolin-2-yl)-fluoren-9-one oxime, obtained in Stage 3, in a mixture of 40 mL of ethanol and 40 mL of tetrahydrofuran, add a spatula tip of Raney nickel, then submit to an initial hydrogen pressure of 1 bar and heat the autoclave at 60° C. for 2 hours. After cooling, filter the catalyst on Celite and concentrate the filtrate at reduced pressure. After purification by flash chromatography on silica gel (20-40 μm), eluting with a mixture of dichloromethane and methanol (95-05 by volume), we obtain 0.72 g of 4-(quinolin-2-yl)-9H-fluoren-9-(R,S)-yl-amine in the form of a white meringue with the following characteristics:
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=2)=[CH:6][CH:5]=1.[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22].[C:33]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])(=[O:36])[NH:34][NH2:35].Cl>O1CCCC1.C(OCC)(=O)C.O>[C:18]([NH:17][C:14]1[S:15][CH:16]=[C:12]([CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][S:1][C:21]([NH:35][NH:34][C:33]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:22])=[CH:5][CH:6]=2)[N:13]=1)(=[O:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(=O)Nc1nc(CCc2ccc(CCS)cc2)cs1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc(CCc2ccc(CCSC(=O)NNC(=O)OC(C)(C)C)cc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
To a solution of N-(4-{2-[4-(2-sulfanylethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (368.0 mg, 1.201 mmol) in anhydrous tetrahydrofuran (30 ml) was added 1,1′-carbonyldiimidazole (291.4 mg, 1.797 mmol), and the mixture was stirred at room temperature for 1 hr. tert-Butyl carbazate (477.9 mg, 3.616 mmol), anhydrous tetrahydrofuran (2 ml) was added, and the mixture was stirred at room temperature for 19 hr. Water (20 ml), 1M hydrochloric acid (10 ml) and ethyl acetate (30 ml) were added, and the mixture was stirred, stood still and partitioned. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. BW-300SP 30 g, ethyl acetate:hexane=1:1) to give tert-butyl 2-({[2-(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenyl)ethyl]sulfanyl}carbonyl)hydrazinecarboxylate (469.9 mg, 1.011 mmol, yield 84.2%) as a white solid.