Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:23]=[C:22]3[N:16]([CH2:17][CH2:18][C:19]4[CH:35]=[CH:34][CH:33]=[CH:32][C:20]=4[CH:21]3[O:24][CH:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)[CH:15]=2)=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O.O.[OH-].[Na+]>C(Cl)Cl>[CH3:31][N:28]1[CH2:27][CH2:26][CH:25]([O:24][CH:21]2[C:20]3[CH:32]=[CH:33][CH:34]=[CH:35][C:19]=3[CH2:18][CH2:17][N:16]3[C:22]2=[N:23][C:14]([C:11]2[CH:10]=[CH:9][C:8]([NH2:7])=[CH:13][CH:12]=2)=[CH:15]3)[CH2:30][CH2:29]1
Reactant: CN1CCC(OC2c3ccccc3CCn3cc(-c4ccc(NC(=O)OC(C)(C)C)cc4)nc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(OC2c3ccccc3CCn3cc(-c4ccc(N)cc4)nc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of {4-[4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenyl}-carbamic acid tert-butyl ester (example 49A) (45 mg, 0.092 mmole) in CH2Cl2 (0.3 mL) is added trifluoroacetic acid (90 μL). The reaction mixture is stirred at room temperature for 1 hour. Water is added and pH adjusted to 9-10 with 1N NaOH. The aqueous phase is extracted three times with CH2Cl2. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using (CH2Cl2:MeOH:NH4OH) as eluent with a gradient from (98:2:0.2) to (95:5:0.5) to give 4-[4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenylamine melting at 197° C.
Reaction SMILES: Cl[C:2]1[C:15]2[C:6](=[C:7]3[C:12](=[CH:13][CH:14]=2)[C:11](Cl)=[CH:10][C:9]([CH3:17])=[N:8]3)[N:5]=[C:4]([CH3:18])[CH:3]=1.C([Mg]Br)C[CH2:21][CH2:22][CH2:23][CH3:24]>>[CH3:17][C:9]1[CH:10]=[C:11]([CH2:15][CH2:2][CH2:3][CH3:4])[C:12]2[C:7](=[C:6]3[C:15](=[CH:14][CH:13]=2)[C:2]([CH2:24][CH2:23][CH2:22][CH3:21])=[CH:3][C:4]([CH3:18])=[N:5]3)[N:8]=1
Reactant: CCCCCC[Mg]Br
Reactant: Cc1cc(Cl)c2ccc3c(Cl)cc(C)nc3c2n1
Product: CCCCc1cc(C)nc2c1ccc1c(CCCC)cc(C)nc12

Procedure:
4,7-dichloro-2,9-dimethyl-1,10-phenanthroline, Phen1, is synthesized according to the literature (M. Schmittel, H. Ammon Eur. J. Org. Chem. 1998, 785.). For the substitution with a n-butyl group, an equimolar amount of n-HexMgBr and CuBr is added. The purification of Phen2 is done using column chromatography over silica gel.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH3:6])[CH2:3][NH2:4].Cl.[CH2:8]([N:10]([CH2:32][CH3:33])[CH2:11][CH:12]([N:14]1[C:27]2[CH:26]=[C:25]([C:28](=[NH:31])OC)[CH:24]=[CH:23][C:22]=2[S:21][C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH3:9].C(OCC)(=O)C>CO>[CH2:8]([N:10]([CH2:32][CH3:33])[CH2:11][CH:12]([N:14]1[C:27]2[CH:26]=[C:25]([C:28]([NH:4][CH2:3][CH:2]([CH3:1])[CH2:5][CH3:6])=[NH:31])[CH:24]=[CH:23][C:22]=2[S:21][C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH3:9]
Reactant: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C(=N)OC)cc21
Reactant: CCC(C)CN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC(C)CNC(=N)c1ccc2c(c1)N(C(C)CN(CC)CC)c1ccccc1S2
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A solution of (2RS)-2-methylbutylamine (3.18 cc) in methanol (5 cc) is added dropwise in the course of 5 minutes to a solution, cooled to 0°-5° C., of methyl 10-[(2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarboximidate hydrochloride (3.49 g) in methanol (21 cc). The mixture is stirred for 2 hours at 5° C. and then concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. to give a residue which is taken up with ethyl acetate (50 cc). The solution is washed with distilled water (50 cc) alkalinized to pH 9 with N sodium hydroxide. The two phases are allowed to settle and the organic phase is separated and washed with half-saturated sodium chloride solution (50 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. The residue is purified by chromatography on a column of neutral alumina (height: 23 cm; diameter: 2.1 cm), eluting with mixtures of ethyl acetate and cyclohexane in proportions (by volume) of 20:80 (850 cc) and 10:90 (500 cc), then with pure ethyl acetate (500 cc) and finally with mixtures of ethyl acetate and methanol in proportions (by volume) of 95:5 (500 cc), 90:10 (500 cc) and 80:20 (500 cc and collecting 50-cc fractions. The first litre is discarded and fractions 40 to 56 are then combined, concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. to give 10-[(2RS)-1-diethylamino-2-propyl]-N-[ (2RS)-2-methylbutyl]-2-phenothiazinecarboxamidine (1.33 g) in the form of a yellow product of meringue-like consistency.
Reaction SMILES: [CH2:1]([CH:8]1[NH:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:25]I>CN(C=O)C.O>[CH2:1]([CH:8]1[N:12]([CH3:25])[C:11](=[O:13])[N:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[C:9]1=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(Cc2ccccc2)C(=O)N1c1cc(F)ccc1F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)N(c2cc(F)ccc2F)C(=O)C1Cc1ccccc1
Reaction time: 1 h
Yield: 56.8 %

Procedure:
5-Benzyl-3-(2,5-difluorophenyl)imidazolidine-2,4-dione (2.0 g, 6.62 mmol) in DMF (10 mL) was added dropwise to a suspension of sodium hydride (166 mg, 6.95 mmol) in DMF (5 mL) at 0° C. The solution was stirred for 1 hour; then methyl iodide (0.62 mL, 9.9 mmol) was added and the mixture was stirred for 5 hours, then diluted with water and extracted with ethyl acetate (3×). The combined extracts were washed with brine (saturated). dried (over MgSO4). filtered and concentrated to give 1.19 grams of 5-benzyl-3-(2,5-difluorophenyl)-1-methylimidazolidine-2,4-dione, as an oil (compound 1 under Table A).
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:26])[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.[OH-].[Na+]>O1CCCC1.O.CO>[Cl:25][C:21]1[CH:20]=[C:19]([CH:12]([CH2:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:27])=[O:2])=[CH:5][N:6]=2)=[O:26])[CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2cccc(Cl)c2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(NC(=O)C(CC2CCCC2)c2cccc(Cl)c2)nc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 44.9 %

Procedure:
A solution of 6-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid methyl ester (146.9 mg, 0.38 mmol) in tetrahydrofuran/water/methanol (10 mL, 3:1:1) at 25° C. was treated with a 2N aqueous sodium hydroxide solution (0.4 mL, 0.80 mmol). The reaction mixture was stirred at 25° C. for 4 d. At this time, the reaction was concentrated in vacuo. The residue was diluted with water (50 mL) and extracted with diethyl ether (1×50 mL). The aqueous layer was acidified to pH=1 by the dropwise addition of a 3N aqueous hydrochloric acid solution. This solution was extracted with a solution of methylene chloride/methanol (3:1, 3×75 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was triturated with diethyl ether/hexanes (2:1) to afford 6-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid (63.6 mg, 44.4%) as a white solid: mp 251-255° C.; EI-HRMS m/e calcd for C20H21ClN2O3 (M+) 372.1240, found 372.1250.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18](I)=[N:17][N:16]=[C:15]3[N:23]([CH3:25])[CH3:24])=[O:11])[CH:6]=[CH:7][CH:8]=1.[C:28]([Cu])#[N:29]>N1C=CC=CC=1>[F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([C:28]#[N:29])=[N:17][N:16]=[C:15]3[N:23]([CH3:25])[CH3:24])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: N#C[Cu]
Reactant: CN(C)c1nnc(I)c2ccc(C(=O)Nc3cccc(C(F)(F)F)c3)cc12
Solvent: c1ccncc1
Product: CN(C)c1nnc(C#N)c2ccc(C(=O)Nc3cccc(C(F)(F)F)c3)cc12
Temperature: 85 °C
Yield: 56.4 %

Procedure:
A mixture of 4-dimethylamino-1-iodo-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (85 mg, 0.175 mmol), pyridine (3 mL) and CuCN (46 mg, 0.514 mmol) was heated to 85° C. for 2 h and concentrated. Column chromatography (Hexanes/EtOAc) afforded the desired compound (38 mg, 56.7%) as a yellow solid. 1H-NMR (CDCl3) δ: 3.44 (s, 6H), 7.30-7.34 (m, 1H), 7.42 (t, 1H), 8.00-8.04 (m, 2H), 8.07 (d, 1H), 8.66 (dd, 1H), 8.78 (s, 1H), 10.26 (bs, 1H). m/z (M+1) 386.20.
Reaction SMILES: [O:1]1[CH:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH:10]=[CH:11][CH:12]2[OH:20])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:21][CH2:22][CH2:23][CH2:24][O:25][NH:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1)[CH:4]=[CH:5]2.C(=O)(O)[O-].[Na+].[C:41](Cl)(Cl)=[S:42]>C(Cl)Cl>[O:1]1[CH:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH:10]=[CH:11][CH:12]2[OH:20])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:21][CH2:22][CH2:23][CH2:24][O:25][NH:26][C:27](=[O:35])[C:28]1[CH:29]=[CH:30][C:31]([N:34]=[C:41]=[S:42])=[CH:32][CH:33]=1)[CH:4]=[CH:5]2
Reactant: CN1CC[C@]23c4c5ccc(OCCCONC(=O)c6ccc(N)cc6)c4OC2C(O)C=C[C@H]3[C@H]1C5
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CC[C@]23c4c5ccc(OCCCONC(=O)c6ccc(N=C=S)cc6)c4OC2C(O)C=C[C@H]3[C@H]1C5
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.2 %

Procedure:
A stirred solution of 0.5 g (1.1 mmol) of N-[3-[(7,8-Didehydro-4,5-epoxy-6-hydroxy-17-methylmorphinan-3-yl)oxy]propoxy]-4-aminobenzamide in 10 ml of methylene chloride was treated with 0.5 g of solid anhydrous sodium bicarbonate followed by 150 ul (1.9 mmol) of thiophosgene and stirred at room temperature for 30 minutes. The solvent was removed in vacuo and the residue was chromatographed on 150 g of silica gel using 15% methanol-chloroform to give 230 mg of N-[3-[(7,8-Didehydro-4,5-epoxy-6-hydroxy-17-methylmorphinan-3-yl)oxy]propoxy]-4-isothiocyanatobenzamide as an amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]3[CH2:24][N:23]([CH3:25])[C:22]4[N:26]=[CH:27][CH:28]=[CH:29][C:21]=4[CH:20](O)[C:19]=3[CH:31]=1)[CH:6]=[CH:5]2.Cl.[CH2:33]([O:35][C:36](=[O:41])[C@H:37]([CH2:39][SH:40])[NH2:38])[CH3:34].FC(F)(F)C(O)=O>ClCCl>[CH2:33]([O:35][C:36](=[O:41])[CH:37]([NH2:38])[CH2:39][S:40][CH:20]1[C:19]2[CH:31]=[C:15]([O:14][CH2:13][C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[CH:10][C:11]([F:12])=[C:2]([F:1])[CH:3]=4)[N:8]=3)[CH:16]=[CH:17][C:18]=2[CH2:24][N:23]([CH3:25])[C:22]2[N:26]=[CH:27][CH:28]=[CH:29][C:21]1=2)[CH3:34]
Reactant: CN1Cc2ccc(OCc3ccc4cc(F)c(F)cc4n3)cc2C(O)c2cccnc21
Reactant: CCOC(=O)[C@@H](N)CS
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(N)CSC1c2cc(OCc3ccc4cc(F)c(F)cc4n3)ccc2CN(C)c2ncccc21
Temperature: 45 °C
Reaction time: 16 h

Procedure:
A mixture of 6.6 g (15.7 mmol) of the product from Example 21, step 5, 6.0 g (32.3 mmol) of L-cystein ethyl ester hydrochloride and 136 ml of trifluoroacetic acid in 198 ml of dichloromethane is stirred at 45° C. for 16 hr. The solvent is evaporated and the residue partitioned between sat. NaHCO3 and chloroform. The organic layer is washed with water, dried and concentrated, giving an oil, which solidifies with the aid of diisopropyl ether/petroleum ether. Yield 7.9 g (91%).
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:4][C:3]=1[CH:18]=O.C(N(CC)CC)C.[C:27]([O:31][CH2:32][CH3:33])(=[O:30])[CH2:28][SH:29].[OH-].[K+]>N1C=CC=CC=1.O>[CH3:17][C:14]1[CH:13]=[CH:12][C:11]([S:8]([N:5]2[CH2:6][CH2:7][C:2]3[S:29][C:28]([C:27]([O:31][CH2:32][CH3:33])=[O:30])=[CH:18][C:3]=3[CH2:4]2)(=[O:9])=[O:10])=[CH:16][CH:15]=1
Reactant: CCOC(=O)CS
Reactant: Cc1ccc(S(=O)(=O)N2CCC(Cl)=C(C=O)C2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2c(s1)CCN(S(=O)(=O)c1ccc(C)cc1)C2
Reaction time: 8 h

Procedure:
To a solution of a 4-chloro-1-[(4-methylphenyl)sulfonyl]-1,2,5,6-tetrahydropyridine-3-carbaldehyde (1 eq) obtained from step II in pyridine was added triethyl amine (1.5 eq.), ethyl thioglycolate (1 eq.) at 0° C. and the reaction mixture was stirred for overnight. A solution of KOH (1.5 eq) in water was added at 0° C. and the reaction was continued at room temperature for 1 h Reaction was quenched with water and the organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded ethyl 5-[(4-methylphenyl)sulfonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].[H-].[Na+].Br[C:12]([CH3:19])([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].O>CN(C)C=O>[CH3:18][C:12]([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1)([CH3:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=[N+]([O-])c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)n1cnc([N+](=O)[O-])c1
Reaction time: 0.33 h

Procedure:
To a solution of 4-nitro-1H-imidazole (10 g) in N,N-dimethylformamide (150 mL) was added sodium hydride (60% in mineral oil, 4.2 g) in an ice bath, and the mixture was stirred at the same temperature for 20 min. To the reaction mixture was added ethyl 2-bromo-2-methylpropanoate (20 mL) at the same temperature, and the mixture was stirred overnight at 50° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (12 g).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:23][CH2:24][C:25]1[CH:39]=[CH:38][C:28]([O:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:27][CH:26]=1)(=O)=O>C(#N)C>[C:34]([O:33][C:31](=[O:32])[CH2:30][O:29][C:28]1[CH:38]=[CH:39][C:25]([CH2:24][CH2:23][O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([O:10][CH3:11])=[O:9])=[CH:26][CH:27]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)COc1ccc(CCOS(C)(=O)=O)cc1
Reactant: COC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccccc1OCCc1ccc(OCC(=O)OC(C)(C)C)cc1
Temperature: -10 °C
Yield: 61.1 %

Procedure:
Methyl salicylate (2.7 ml, 21.187 mmol) was dissolved in acetonitrile, and potassium carbonate (5.856 g, 42.373 mmol) was added. The mixture was cooled to −10° C. then tert-butyl (4-{2-[(methylsulfonyl)oxy]ethyl}phenoxy)acetate was added. The mixture was boiled under reflux for 16 hours, and then the solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc, washed with water and brine, then the organic layer was dried with MgSO4 and the solvent was removed by evaporation. The crude material was purified by flash chromatography (silica gel 60 0.004-0.063 mm) using EtOAc: Toluene 50:50 as the eluant. The fractions which contained the desired product were pooled, and solvent evaporated. This gave 5.0 g of pure product (yield 61.1%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[Na].C1C=CC=CC=1.[CH2:19]([OH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:5]=[CH:4][N:3]=1
Reactant: OCc1ccccc1
Reactant: Nc1ncnc(Cl)c1[N+](=O)[O-]
Agent: [Na]
Solvent: c1ccccc1
Product: Nc1ncnc(OCc2ccccc2)c1[N+](=O)[O-]
Temperature: 130 °C

Procedure:
4-Amino-6-chloro-5-nitropyrimidine (Boon et al., J. Chem. Soc., 96-102 (1951)) (1.5 g, 8.6 mmol) was added to a solution of sodium (0.23 g, 9.9 mmol) in benzyl alcohol (14 mL). The solution was heated in a 130° C. oil bath for 3.5 h, and was poured into benzene (50 mL). A. yellow solid was collected by filtration and washed with benzene. Crystallization from benzene/ether afforded an analytically pure sample of 3a: yield, 0.71 g (34%); mp 149-150° C.; UV (pH 1) λmax 284 nm (ε=0.368×104), 333 (0.488×104); (pH 6.9) 284 (0.329×104), 336 (0.470×104); (pH 13) 290 (0.344×104), 333 (0.494×104); 1H NMR δ 5.50 (s, 2H, ArCH2), 7.33-7.49 (m, 5H, ArH), 8.12-8.24 (br d, 2H, NHa and NHb, exchange with D2O), 8.24 (s, 1H, H-2); MS (EI) calcd. m/z for C11H10N4O3 246.0752, found 246.0751; Anal. (C11H10N4O3) C, H, N.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13](C2C=CC=CC=2)(C2C=CC=CC=2)[O:14][SiH2]C(C)(C)C)[CH2:11][C@@H:10]([CH2:32][CH3:33])[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][OH:14])[CH2:11][C@@H:10]([CH2:32][CH3:33])[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@@H]1C[C@@H](C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)N(C(=O)OC(C)(C)C)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC[C@@H]1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of the compound obtained from step A (5.2 g, 10.8 mmol) in THF (20 mL) and acetic acid (1.36 mL, 2.2 equiv.) at 0° C. was added TBAF (1.0 M in THF, 17.8 mL, 1.65 equiv). The mixture was stirred at rt for 2.0 h. It was then diluted with ethyl acetate and washed with 5% KHSO4 and brine. Evaporation of solvent and a column chromatography (EtOAc: hexane=1:1) gave the desired product as viscous oil (yield, 95%). 1HNMR (400 MHz, CDCl3) δ 4.11 (m, 1 H), 3.78 (dd, 2 H), 2.63 (m, 1 H), 2.15 (dd, 1 H), 1.99 (m, 1 H), 1.82 (m, 1 H), 1.55 (s, 9 H), 1.54 (m, 1 H), 0.97 (t, 3 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=2[N+:21]([O-])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=2[NH2:21])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccnc(N)c2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccnc(N)c2N)CC1
Reaction time: 18 h
Yield: 76.5 %

Procedure:
4-(2-Amino-3-nitro-pyridin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (5) (260 mg, 0.81 mmol) was dissolved in MeOH (10 ml) with 10% Pd/C (40 mg). It was stirred under a hydrogen atmosphere for 18 hours. It was filtered through CELITE to remove the palladium, and the solvent was removed under vacuum to yield the title product 6 (200 mg (85%), 0.62 mmol). 1H NMR (DMSO-d6): δ 7.29 (d, J=5 Hz, 1H), 6.29 (d, J=5 Hz, 1H), 5.30 (s, 2H), 4.21 (s, 2H), 3.48 (m, 4H), 2.74 (m, 4H), 1.41 (s, 9H). MS (ESI-POS): [M+H]+=294.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:14](Br)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>[I-].[Na+].C(O)CCC>[CH2:14]([N:1]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)c1ccccc1
Yield: 53.8 %

Procedure:
A mixture of freshly distilled aniline (93 g, 1 mol), potassium carbonate (210 g, 1.5 mol), octadecyl bromide (840 g, 2.5 mol), sodium iodide (7.5 g, 0.05 mol), and 1 liter of butanol was heated at reflux for 72 hours under nitrogen with vigorous stirring. The hot solution was filtered and the filtrate was evaporated under reduced pressure. The residue was recrystallized from absolute ethanol to yield 322 g (54%) of off-white crystals mp 110°-111° C.
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][C:5]1[CH:18]=[C:8]2[N:9]=[CH:10][C:11]([C:13]([O:15]CC)=[O:14])=[CH:12][N:7]2[N:6]=1.O>O1CCCC1>[OH:3][CH2:4][C:5]1[CH:18]=[C:8]2[N:9]=[CH:10][C:11]([C:13]([OH:15])=[O:14])=[CH:12][N:7]2[N:6]=1
Reactant: CCOC(=O)c1cnc2cc(CO)nn2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc2cc(CO)nn2c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 66.3 %

Procedure:
5 N Sodium hydroxide solution (0.1 ml) was added to a solution of the thus obtained ethyl 2-hydroxymethylpyrazolo[1,5-a]pyrimidine-6-carboxylate (19 mg) in tetrahydrofuran (1 ml), and stirred for 17 hours at room temperature. After water was added, the reaction mixture was washed with ethyl acetate. The aqueous phase was acidified by 2 N hydrochloric acid, extracted with ethyl acetate and dried over sodium sulfate anhydrous. The resulting product was concentrated under reduced pressure, and the residue was dissolved in hot ethyl acetate and then filtered. The filtrate was concentrated under reduced pressure to give the title compound (11 mg, Y.:65%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]([CH3:13])[C:10](=[O:12])[CH3:11])=[N:7][CH:8]=1)#[N:2].[OH-].N>CO.[Ni]>[NH2:2][CH2:1][C:3]1[CH:4]=[N:5][C:6]([N:9]([CH3:13])[C:10](=[O:12])[CH3:11])=[N:7][CH:8]=1
Reactant: CC(=O)N(C)c1ncc(C#N)cn1
Agent: [Ni]
Agent: N
Agent: [OH-]
Solvent: CO
Product: CC(=O)N(C)c1ncc(CN)cn1
Reaction time: 2 h

Procedure:
A solution of N-(5-cyano-pyrimidin-2-yl)-N-methyl-acetamide (0.08 g, 0.45 mmol) in MeOH and 28% aqueous ammonia hydroxide (0.80 mL, 0.45 mmol) was hydrogenated over Raney-Ni catalyst using a continuous flow hydrogenation apparatus (conditions: flow rate 1 mL/minute, 25° C., 10 bar). After 2 hours, the solvent was concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 5% MeOH in CH2Cl2. The major fractions were combined and the solvent was concentrated in vacuo to afford the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]([NH:16][C:17]2[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=2)[C:20]([O:22]CC)=[O:21])=[O:15])[O:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[OH-].[Li+]>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]([NH:16][C:17]2[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=2)[C:20]([OH:22])=[O:21])=[O:15])[O:7][C:8]=1[CH:9]([CH3:10])[CH3:11])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cccc(NC(=O)C=Cc2cc(C(C)C)c(C(C)C)o2)c1
Agent: [Li+]
Agent: [OH-]
Product: CC(C)c1cc(C=CC(=O)Nc2cccc(C(=O)O)c2)oc1C(C)C
Yield: 95 %

Procedure:
The ester obtained above (76 mg, 0.206 mmol) was hydrolyzed with lithium hydroxide in a conventional manner, and the residue was recrystallized to obtain the title compound (28, 67 mg, 95%) as pale yellow prisms.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](=[O:41])[CH:7]=[C:8]([CH2:11][NH:12][C:13]([CH:15]2[CH2:20][N:19]([S:21]([C:24]3[NH:25][C:26]4[C:31]([CH:32]=3)=[CH:30][C:29]([Cl:33])=[CH:28][CH:27]=4)(=[O:23])=[O:22])[CH2:18][CH2:17][N:16]2C(OC(C)(C)C)=O)=[O:14])[O:9][CH:10]=1)(=[O:3])[CH3:2].[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>C(Cl)Cl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[C:1]([O:4][C:5]1[C:6](=[O:41])[CH:7]=[C:8]([CH2:11][NH:12][C:13]([CH:15]2[NH:16][CH2:17][CH2:18][N:19]([S:21]([C:24]3[NH:25][C:26]4[C:31]([CH:32]=3)=[CH:30][C:29]([Cl:33])=[CH:28][CH:27]=4)(=[O:23])=[O:22])[CH2:20]2)=[O:14])[O:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1coc(CNC(=O)C2CN(S(=O)(=O)c3cc4cc(Cl)ccc4[nH]3)CCN2C(=O)OC(C)(C)C)cc1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Oc1coc(CNC(=O)C2CN(S(=O)(=O)c3cc4cc(Cl)ccc4[nH]3)CCN2)cc1=O

Procedure:
In methylene chloride (5 ml), 2-[N-[(5-acetoxy-4-oxo-4H-pyran-2-yl)methyl]carbamoyl]-1-(tert-butoxycarbonyl)-4-[(5-chloroindol-2-yl)sulfonyl]piperazine was treated with trifluoroacetic acid (5 ml), followed by concentration to dryness under reduced pressure, whereby the title compound (224 mg) was obtained.