Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Na+].[Cl-].[Cl-].[Cl-].[Ca+2]>C1N(CCO)CCN(CCS(O)(=O)=O)C1>[C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]
Agent: O=S(=O)(O)CCN1CCN(CCO)CC1
Agent: [Ca+2]
Agent: [Cl-]
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reaction time: 0.5 h

Procedure:
Purified human synovial fluid PLA2 (purified by the procedure of Fawzy, A. A. and Franson, R. C. Biophys. J. 49, 533a 1986!) was obtained from R. C. Franson (Medical College of Virginia, Richmond, Va.). PLA2 activity was measured by using 14C!-oleate labeled autoclaved E. coli as substrate as described by Franson, R. C., Patriarca, P., and Elsbach, P. J., Lipid Res. 15, 380-388 (1974). The assay was performed at 37° C for 30 min. in a final volume of 100 μL 50 mM Hepes buffer (pH 7.0) containing 150 mM NaCl, 5 mM CaCl2, and E. coli cells (corresponding to 10 mmol phospholipid). The test compound or control vehicle was preincubated with PLA2 for 5 min., followed by adding E. coli to initiate the reaction. The reaction was terminated by adding 2 mL tetrahydrofuran. The reaction product, 14C!-oleic acid, was isolated using a 1 mL Bond Elute--NH2 column and counted by liquid scintillation spectrometry.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1C(OC)=O.[C:11](Cl)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]>N1C=CC=CC=1>[S:4]1[CH:5]=[CH:6][C:2]([NH:1][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:3]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)c1sccc1N
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1ccsc1
Temperature: 25 °C
Yield: 44 %

Procedure:
To an oven dried flask was charged with methyl 3-aminothiophene-2-carboxylate (30 g, 191 mmol) and pyridine (300 ml), followed by addition of pivaloyl chloride (25.3 g, 210 mmol) at room temperature. A mild exotherm occurred, and solid was formed. 10 min later, the reaction mixture was refluxed under N2 overnight (˜20 hr), and stirred at rt on weekend. Most of the solvent was removed on rotary vacuo. The brown residue was partitioned between 1N HCl and CH2Cl2(100 mL/150 mL). After seperation, the aqueous solution was extracted with CH2Cl2(100 mL), the combined organic layers were washed with brine (70 mL), dried on MgSO4, concentrated on rotary vacuo, the residue as a brown solid, was triturated with Et2O (30 mL), filtered and washed with Et2O (2×10 mL) to afford the expected product, N-(thiophen-3-yl)pivalamide (15.4 g, 50%) as an off white solid. 1H-NMR (400 MHz, CHLOROFORM-D) δ ppm 1.28 (s, 9 H) 6.98 (dd, J=5.16, 1.39 Hz, 1 H) 7.20 (dd, J=5.29, 3.27 Hz, 1 H) 7.57-7.66 (m, 2 H); Mass spec. C184.05 (MH+) calc. for C9H13NOS 183.07.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13]([CH:15]2[CH2:17][CH:16]2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[O:14])[CH:3]=1.C[N:26]1[C:30](=[O:31])[CH2:29][CH2:28][CH2:27]1>CS(C)=O.CO>[C:30]([NH:26][CH:27]1[CH2:28][CH2:6][N:5]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13]([CH:15]3[CH2:17][CH:16]3[C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[O:14])[CH:3]=2)[CH2:4][CH2:3]1)(=[O:31])[CH3:29]
Reactant: CN1CCCC1=O
Reactant: Cc1cc2nc(NC(=O)C3CC3c3ccc(F)cc3)cc(Cl)n2n1
Solvent: CS(C)=O
Solvent: CO
Product: CC(=O)NC1CCN(c2cc(NC(=O)C3CC3c3ccc(F)cc3)nc3cc(C)nn23)CC1
Temperature: 25 °C
Yield: 44 %

Procedure:
The title compound was prepared by combining N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2-(4-fluorophenyl)cyclopropanecarboxamide (13B, 0.15 g, 0.435 mmol) and the N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2-(4-fluorophenyl)cyclopropanecarboxamide (0.15 g, 0.435 mmol) in NMP (Volume: 1.450 ml) and heating the mixture at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory 60-70% HPLC ([1:1 MeCN/MeOH]/H2O+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a tan solid (86 mg, 44%). 1H NMR (DMSO-d6) δ: 10.95 (s, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.18-7.29 (m, 5H), 7.03-7.17 (m, 4H), 6.08 (s, 1H), 4.30 (d, J=13.1 Hz, 2H), 3.16 (t, J=12.1 Hz, 2H), 2.38-2.48 (m, 2H), 2.35 (s, 3H), 2.24-2.32 (m, 1H), 1.88 (d, J=12.9 Hz, 2H), 1.82 (s, 3H), 1.44-1.62 (m, 4H), 1.35-1.43 (m, 2H), 1.25-1.35 (m, 1H); ESI-MS: m/z 451.3 (M+H)+. It was noted that rotamers were present.
Reaction SMILES: [N:1]1([C:4]2[C:5]3[N:14]([CH3:15])[N:13]=[C:12]([CH3:16])[C:6]=3[N:7]=[C:8]([CH2:10][CH3:11])[N:9]=2)[CH2:3][CH2:2]1.[I-].[Na+].C(OCC)(=O)C>CC(C)=O>[CH2:10]([C:8]1[N:9]2[CH2:2][CH2:3][N:1]=[C:4]2[C:5]2[N:14]([CH3:15])[N:13]=[C:12]([CH3:16])[C:6]=2[N:7]=1)[CH3:11]
Reactant: CCc1nc(N2CC2)c2c(n1)c(C)nn2C
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCC1=Nc2c(C)nn(C)c2C2=NCCN12
Yield: 35.3 %

Procedure:
The above aziridine (6 g, 0.03 mol) is dissolved in 100 ml of acetone and refluxed with 6 g of sodium iodide for two hours. The solution is evaporated in vacuo. The residue is dissolved in methylene dichloride, washed with saturated NaHCO3 solution, dried over MgSO4, and evaporated in vacuo. The resulting solid (2.3 g, 38% yield) melts at 148°-150° C. after recrystallization from ethyl acetate.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH:46][C:47]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=3)=[O:48])[CH:43]=[CH:44][CH:45]=2)=[N:8]1>Cl.O1CCOCC1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:47]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=3)=[O:48])[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)c1ccccn1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
[N-(3-{1-Perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl-2-pyridylcarboxamide was dissolved in 4 mL of 4.0 N HCl in 1,4-dioxane and the reaction was stirred at room temperature overnight. After neutralization with aqueous NaHCO3, the crude product was extracted with ethyl acetate and purified by preparative HPLC. (0.037 g, 39% yield over 2 steps): 1H NMR (CD3OD) δ 8.81 (s, 1H), 8.76 (dt, 1H), 8.55 (t, 1H), 8.45 (br s, 1H), 8.25 (dt, 1H), 8.12 (dd, 1H), 8.09 (td, 1H), 8.00 (dt, 1H), 7.85 (dt, 2H), 7.73 (d, 1H), 7.65 (ddd, 1H), 7.59 (t, 1H); ES-MS (m/z) 382 [M+H]+.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[N:9]=[C:8]([OH:10])[CH:7]=[C:6]([CH3:11])[N:5]=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:1][C:7]1[C:8]([OH:10])=[N:9][C:4]([CH3:3])=[N:5][C:6]=1[CH3:11]
Reactant: BrBr
Reactant: Cc1cc(O)nc(C)n1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1nc(C)c(Br)c(O)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66 %

Procedure:
The solution of bromine (5.1 g, 31.9 mmol) in chloroform (30 mL) was added dropwise to the solution of 2,6-dimethylpyrimidin-4-ol (3.43 g, 27.6 mmol) in chloroform (50 mL) at 0° C. Then the mixture was stirred at 25° C. for 12 hours. Saturated sodium sulfite solution was added to the mixture until the colour of the mixture changed to colourless. The organic phase was separated, dried over sodium sulphate, filtered, and then concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=15:1) to give 5-bromo-2,6-dimethylpyrimidin-4-ol as a white solid (3.7 g, 66%). 1H NMR (300 MHz, d6-DMSO): δ 2.33 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: C(O[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:13][CH:12]1[C:27]([O:29]C)=O)=[O:10])C1C=CC=CC=1.[BH4-].[Li+]>O1CCCC1>[C:21]1([CH2:20][O:19][C:17]([N:14]2[CH2:15][CH2:16][N:11]3[C:9](=[O:10])[O:29][CH2:27][CH:12]3[CH2:13]2)=[O:18])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)C1CN(C(=O)OCc2ccccc2)CCN1C(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCN2C(=O)OCC2C1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a flask containing methyl N,N'-dibenzyloxycarbonylpiperazine-2-carboxylate (Step 2, 12.60 g, 30.60 mmol) and tetrahydrofuran (65 mL) at 0° C. under an inert atmosphere is added lithium borohydride (2 M in THF) (23.00 mL, 45.9 mmol). The solution is warmed to ambient temperature, stirred 19 hours, cooled to 0° C., and quenched with water (50 mL). The mixture is diluted with ethyl acetate (100 mL) and the pH is adjusted to 2 with 1N HCl. The layers are separated and the aqueous phase is extracted with ethyl acetate (50 mL). The organics are combined, washed with water (50 mL) and saline, dried over MgSO4, concentrated in vacuo, and chromatographed on silica gel (70-230 mesh, 500 g), eluting with hexane/ethyl acetate (50/50) then ethyl acetate (100). The appropriate fractions are combined (Rf =0.17, TLC, hexane/ethyl acetate, 50/50) and concentrated in vacuo to give the title compound, mp 85.5-86.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([O:9][CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[S:8][C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([O:9][CH:10]3[CH2:11][CH2:12][N:13]([C:19]4[N:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=4)[CH2:14][CH2:15]3)[S:8][C:4]=2[CH:3]=1
Reactant: Brc1ccc2nc(OC3CCNCC3)sc2c1
Reactant: Fc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cnc(N2CCC(Oc3nc4ccc(Br)cc4s3)CC2)nc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 85.3 %

Procedure:
To a solution of 6-bromo-2-(piperidin-4-yloxy)benzo[d]thiazole (1 g, 3.19 mmol) and 2-chloro-5-fluoropyrimidine (0.508 g, 3.83 mmol) in DMF (15 mL) was added potassium carbonate (1.32 g, 9.58 mmol). The reaction mixture was stirred at 100° C. for 4 h. The reaction mixture was cooled to rt, diluted with water (40 mL), and extracted with EtOAc (3×20 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 40% EtOAc) to afford 6-bromo-2-(1-(5-fluoropyrimidin-2-yl)piperidin-4-yloxy)benzo[d]thiazole (1.112 g, 2.72 mmol, 85% yield) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].N1C=CC=CC=1.[Cl:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>ClCCl>[Cl:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[C:20]([NH:7][C:6]1[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:21]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cccc([N+](=O)[O-])c1)c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
Combine 3-nitroaniline (3.0 g, 21.7 mmol), dichloromethane (100 mL), pyridine (2.11 mL, 26.0 mmol) and 2-chloro-4-fluorobenzoyl chloride (3.07 mL, 23.9 mmol). Stir at room temperature overnight. Filter the white precipitate, rinse with ether (2×10 mL), and dry under vacuum to provide 2-chloro-4-fluoro-N-(3-nitrophenyl)benzamide (4.92 g, 77%). Combine the 2-chloro-4-fluoro-N-(3-nitrophenyl)benzamide (4.92 g, 16.7 mmol) with ethanol (150 mL), SnCl2.2H2O (18.9 g, 83.6 mmol) and concentrated hydrochloric acid (8.24 mL, 83.6 mmol). Stir at reflux under a nitrogen atmosphere for 2 hr. Neutralize with ammonium hydroxide (15 mL). Filter through celite, wash with dichloromethane (2×15 mL), separate the filtrate, extract with dichloromethane (2×80 mL), and dry the combined organic layers over magnesium sulfate. Filter and concentrate to dryness to provide the title intermediate as an off-white solid (3.04 g, 69%): mass spectrum (ion spray): m/z=265.0(M+1); 1H NMR (DMSO-d6): 10.16 (bs, N—H), 7.60 (dd, J=6.2 Hz, 8.6 Hz, 1H), 7.54 (dd, J=2.5 Hz, 9.0 Hz, 1H), 7.30 (td, J=2.5 Hz, 8.5 Hz, 1H), 7.04 (t, J=2.0 Hz, 1H), 6.93 (t, J=8.0 Hz, 1H), 6.74 (bd, J=7.9 Hz, 1H), 6.29 (dd, J=2.2 Hz, 7.9 Hz, 1H), 5.10 (bs, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][C:11]([O:13]CC)=[O:12])[CH:7]=[N:8][C:4]=2[CH:3]=1.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:27]=1[C:28]([OH:30])=O>>[CH3:36][O:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:26]([O:25][CH3:24])[C:27]=1[C:28]([NH:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH:9]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[N:8][C:4]=2[CH:3]=1)=[O:30]
Reactant: COc1cccc(OC)c1C(=O)O
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2cc(N)ccc21
Product: COc1cccc(OC)c1C(=O)Nc1ccc2c(c1)ncn2C(CC(=O)O)c1ccccc1

Procedure:
Using the procedure of Preparation 21, the title compound (31 mg) was prepared from ethyl 3-(5-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate and 2,6-dimethoxybenzoic acid. [LCMS (Method C, Mobile Phase I) RT=2.25 min, MH+ 446].
Reaction SMILES: O.O.O.O.O.[O-][Si]([O-])=O.[Na+].[Na+].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Si:19](Cl)(Cl)(Cl)[Cl:20]>>[Cl:20][Si:19].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cl[Si](Cl)(Cl)Cl
Agent: O=[Si]([O-])[O-]
Agent: [Na+]
Solvent: Oc1ccccc1
Solvent: O
Product: [Si]Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
About 0.5 mol of fine granular sodium metasilicate pentahydrate, 0.5 mol of phenol and 1 mol of silicon tetrachloride are slowly added while agitating at ambient temperature and pressure for 1 to 2 hours; the reaction is complete in 2 to 8 hours, thereby producing white granules of phenol chlorosilicon acid resinous product and sodium chloride. To this resinous product, 1 mol of a nitrile, acetonitrile, is added while agitating and keeping the temperature below the boiling temperature of the mixture for 1 to 2 hours; the reaction is complete in 2 to 8 hours, thereby producing an organic silicon acid resinous product. The resinous product is washed with water and filtered to remove the salt.
Reaction SMILES: Cl[CH:2]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([F:15])=[N:13][CH:14]=2)[O:6][C:7]=1[CH3:8].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[O:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH:16]1([CH:2]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])=[CH:27][CH:28]=2)[C:3]2[CH:4]=[C:5]([C:9]3[CH:14]=[N:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:6][C:7]=2[CH3:8])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1oc(-c2ccc(F)nc2)cc1C(Cl)C1CCCCC1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1oc(-c2ccc(F)nc2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
A mixture of 5-{4-[chloro(cyclohexyl)methyl]-5-methylfuran-2-yl}-2-fluoropyridine (0.8 g), ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.7 g), sodium carbonate (0.3 g) and sodium iodide (0.5 g) in N,N-dimethylacetamide (10 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (20% ethyl acetate/hexane to 50% ethyl acetate/hexane). To the residue were added ethanol (3 mL), tetrahydrofuran (3 mL) and 1N lithium hydroxide (3.2 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (753 mg, 62%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH2:8].S.[OH:10][CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH2:17][CH:18]([N:20]1[C:33]2[CH:32]=[C:31]([C:34](=S)N)[CH:30]=[CH:29][C:28]=2[S:27][C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH3:19]>C(OCC)(=O)C>[NH:1]1[CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]2[N:8]=[C:34]1[C:31]1[CH:30]=[CH:29][C:28]2[S:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH:18]([CH3:19])[CH2:17][N:13]3[CH2:14][CH2:15][CH2:16][C@@H:12]3[CH2:11][OH:10])[C:33]=2[CH:32]=1
Reactant: NC1CCCCC1N
Reactant: CC(CN1CCC[C@@H]1CO)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Agent: S
Solvent: CCOC(C)=O
Product: CC(CN1CCC[C@@H]1CO)N1c2ccccc2Sc2ccc(C3=NC4CCCCC4N3)cc21
Temperature: 150 °C
Reaction time: 2 h

Procedure:
1,2-Diaminocyclohexane (10.57 g) is added to an ethanolic solution (40 cc), saturated with hydrogen sulphide, of 10-{1-[(2R)-2-hydroxymethyl-1-pyrrolidinyl]-2-propyl}-2-phenothiazinecarbothioamide, D series (3.65 g). The mixture is heated in an autoclave to 150° C. for 11 hours, then diluted with ethyl acetate (250 cc) and washed with distilled water (4×200 cc). The organic phase is separated after settling has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is diluted in boiling absolute ethanol (200 cc) and a small amount of insoluble matter is filtered off. The filtrate is stirred at 25° C. for 2 hours and then cooled to 5° C. for 12 hours. The precipitate formed is filtered off, washed with cold ethanol (3×10 cc) and dried under reduced pressure (5 mm Hg; 0.67 kPa) at 40° C. to give 2-(3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl)-10-{1-[(2R)-2-(hydroxymethyl)pyrrolidinyl]-2-propyl}phenothiazine, D series (1.1 g) in the form of a cream-coloured solid.
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[N:17][CH:18]=3)[N:13]=[CH:12][C:11]=2[C:20]([O:22]CC)=O)=[CH:4][CH:3]=1>C(O)CCC>[ClH:1].[N:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:20](=[O:22])[C:11]3=[CH:12][NH:13][C:14]4[CH:15]=[CH:16][N:17]=[CH:18][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2ccncc2c1NNc1ccncc1
Agent: Cl
Solvent: CCCCO
Product: O=c1c2c[nH]c3ccncc3c-2nn1-c1ccncc1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A suspension of ethyl 4-[2-(4-pyridyl)hydrazino]-1,6-naphthyridin-3-carboxylate hydrochloride (1.76 g) in 50 ml of n-butanol is refluxed for 20 hours. The mixture is cooled down to room temperature and filtered. Collected solid is dissolved in aqueous sodium hydroxide and stirred at room temperature for 21 hours, then filtered. The filtrate is acidified with 1N hydrochloric acid to precipitate a solid, which is collected, washed successively with aqueous methanol, methanol and acetone to yield 2-(4-pyridyl)-pyrazolo[4,3-c][1,6]naphthyridin-3(5H)-one hydrochloride, m.p. above 345°; IR (KBr) 726, 746, 791, 833, 898 cm-1.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([OH:24])[C:5]2[CH:11]=[C:10]([CH2:12][CH2:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1.[OH-].[Na+].C(O)(=O)C.O>CO>[NH2:1][C:2]1[N:3]=[C:4]([OH:24])[C:5]2[CH:11]=[C:10]([CH2:12][CH2:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: COC(=O)c1ccc(CCc2cnc3nc(N)nc(O)c3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: Nc1nc(O)c2cc(CCc3ccc(C(=O)O)cc3)cnc2n1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A mixture of 0.46 g of methyl 4-[2-(2-amino-4-hydroxypyrido[2,3,d]pyrimidin-6-yl)ethyl]benzoate and 30 mL of 1N sodium hydroxide is stirred at room temperature for 36 hours and then acidified with glacial acetic acid. The resulting suspension is centrifuged with fresh water several times and then combined with methanol. The water is removed azeotropically under reduced pressure to yield 4-[2-(2-amino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoic acid, m.p. >300° C.; IR (KBr) ν max 3220, 2855, 1680, 1607, 1483, 1398, 1253, 1179, 1016, and 812 cm-1 ; 1H NMR (dTFA, d6DMSO) delta 8.38 (s, 1H (7)-H), 8.02 (s, 1H, (5)-H), 7.62 (d, J=8.0 Hz, 2H, Ar), 6.87 (s, 1H, (3)-H), 6.82 (d, J=8.0 Hz, 2H, Ar), 2.79 (m, 2H, (6)-CH2 --), 2.70 (m, 2H, benzyl).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[C:6](=[O:34])([O:10][CH2:11][O:12][C:13](=[O:33])[CH2:14][CH2:15][CH:16]([P:25]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26])[P:17]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:18])SCC>>[CH2:20]([O:19][P:17]([CH:16]([P:25]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26])[CH2:15][CH2:14][C:13]([O:12][CH2:11][O:10][C:6]([Cl:4])=[O:34])=[O:33])([O:22][CH2:23][CH3:24])=[O:18])[CH3:21]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOP(=O)(OCC)C(CCC(=O)OCOC(=O)SCC)P(=O)(OCC)OCC
Product: CCOP(=O)(OCC)C(CCC(=O)OCOC(=O)Cl)P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Sulfuryl chloride (687 μL, 8.49 mmol) was added drop-wise to 61 (2.03 g, 4.24 mmol). The neat reaction was stirred at room temperature for 2.5 hr. The excess sulfuryl chloride was removed under reduced pressure resulting in chloroformate 62 (1.87 g, 97%) that was used without purification. 1H NMR (400 MHz, CDCl3): δ 1.35 (t, J=7.1, 12H), 2.17-2.36 (m, 2H), 2.53 (tt, J=23.8, 6.5, 1H), 2.80 (t, J=7.5, 2H), 4.15-4.24 (m, 8H), 5.82 (s, 2H). 31P NMR (162 MHz, CDCl3) δ 23.72 (s, 2P).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[CH:5]=[N:6][CH:7]=1.[CH:16]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)=[CH2:17].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)(O)[O-].[Na+]>C(#N)C.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:21]1[CH:22]=[CH:23][C:18]([CH:16]=[CH:17][C:2]2[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]3[CH2:14][CH2:13][CH2:12][N:11]3[CH3:15])[CH:5]=[N:6][CH:7]=2)=[CH:19][CH:20]=1
Reactant: CN1CCC[C@H]1COc1cncc(Br)c1
Reactant: C=Cc1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN1CCC[C@H]1COc1cncc(C=Cc2ccncc2)c1
Temperature: 100 °C
Yield: 87.7 %

Procedure:
To a solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine (272.0 mg, 1.0 mmol) in acetonitrile (3.0 mL) and triethylamine (2.5 mL) was added 4-vinylpyridine (0.227.0 mL, 2.0 mmol), palladium acetate (23.0 mg, 0.1 mmol) and tri-o-tolylphosphine (122.0 mg). After being heated in a sealed tube at 100° C. overnight, the reaction mixture was cooled to room temperature. A minimum amount of saturated sodium bicarbonate was added to free the amine, and the mixture was extracted with EtOAc, dried (MgSO4), and concentrated. The residue was chromatographed on a silica gel column, eluting with CHCl3/MeOH 10:1 to afford a light yellowish oil (259 mg, 88%). MS (CI/NH3) m/z 295 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 1.70-2.13 (m, 3H), 2.27-2.41 (m, 1H), 2.53 (s, 3H), 2.66-2.70 (m, 1H), 3.12-3.20 (m, 1H), 3.97-4.14 (m, 2H), 7.07 (d, J=16.6 Hz, 1H), 7.27 (d, J=16.6 Hz, 1H), 7.38 (d, J=5.5 Hz, 2H), 7.39 (dd, J=2.1 Hz, J=3.0 Hz, 1H), 8.28 (d, J=3.0 Hz, 1H), 8.36 (d, J=2.1 Hz, 1H), 8.62 (d, J=5.5 Hz, 2H).