Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].P(O)([O-])([O-])=O.[Na+].[Na+].Cl[O-].[Na+]>C(Cl)Cl.O.CC1(C)N([O])C(C)(C)CCC1.[Br-].[K+]>[CH:1](=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[O:9]
Reactant: OCCCCCCCCO
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=P([O-])([O-])O
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: O=CCCCCCCC=O
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a heterogeneous mixture of octane-1,8-diol (94.64 g, 0.648 mole), TEMPO (5.08 g, 0.038 mole, available from Aldrich Chemical Company, Milwaukee, Wis.), potassium bromide (3.90 g, 0.033 mole), sodium phosphate (7.80 g, 0.065 mole), disodium phosphate (9.24 g, 0.065 mole) in methylene chloride (1.3 L) and water (500 ml) was added dropwise 12% aqueous sodium hypochlorite (1,225 g) slowly over 2 hours while maintaining the temperature below 35° C. The reaction was stirred for an additional 30 minutes and the two layers were separated. The aqueous layer was extracted with methylene chloride and combined with the organic layer. The combined organic layer was washed with saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride and water. The organic fraction was dried over sodium sulfate, filtered and evaporated. The material was vacuum distilled 82-84° C./0.5 mm Hg to afford octane-1,8-dial (92 g, 100% yield). C8H14O2 (142.20 g/mole). bp: 82° C./0.55 mm Hg. 1HNMR (500 MHz, CDCl3): 1.35 (m, 4H), 1.63 (m, 4H), 2.43 (m, 4H), 9.76 (t, 2H) ppm. 13CNMR (125 MHz, CDCl3): 21.8, 28.9, 43.8, 202.7 ppm. IR (νmax(cm−1)): 2940, 2860, 2740, 1725, 1460, 1420, 1400. MS (m/z): 24(M-18), 98, 95, 81, 67, 57, 54, 44, 41.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl[CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH3:23]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH3:23])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CCCOCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOCCOc1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
In DMF (120 ml) was dissolved 4-bromophenol (20 g). To the mixture were added potassium carbonate (24 g) and sodium iodide (19.1 g) and then was added dropwise 2-chloroethylpropylether (19 ml), and the mixture was stirred at 80° C. for 16 hours and cooled to room temperature. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=10/1) to give 1-bromo-4-(2-propoxyethoxy)benzene (23.1 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[CH:19]=[N:20][NH:21][C:15]=2[CH:14]=1.[I:22]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([I:22])=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]ncc3cn2)c1Cl
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(I)c3cn2)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
At r.t. to a stirring solution of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridine (0.62 g, 1.9 mmol) in methylene chloride (10 mL) was added N-iodosuccinimide (0.47 g, 2.1 mmol). The mixture was stirred at r.t. for 2 h. It was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product 0.50 g.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH:9]1(O)[CH2:13][CH2:12][CH2:11][CH2:10]1.P(=O)(O)(O)O>O.C(OCC)(=O)C>[CH:9]1([C:6]2[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=2[OH:5])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Oc1cccc(O)c1
Reactant: OC1CCCC1
Agent: O=P(O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1ccc(C2CCCC2)c(O)c1
Temperature: 120 °C
Reaction time: 2.5 h

Procedure:
A round bottom flask equipped with stirrer bar was charged with resorcinol (150 g, 1.36 moles), cyclopentanol (125 ml, 1.38 moles) and phosphoric acid (85% in water) 500 ml. The flask was fitted with a reflux condenser, purged with nitrogen and the mixture heated at 120° C. (oil bath temperature) for 26 h. After this time, TLC analysis indicated that starting resorcinol was still present. Further cyclopentanol (25 ml, 0.28 moles) was added to the reaction mixture and heating continued for 2.5 hours. On cooling, the mixture was diluted with water (500 ml) and ethyl acetate (600 ml). The organic layer was separated, and the aqueous layer extracted with ethyl acetate (3×500 ml). The combined organic layers were neutralized by careful addition of an excess of saturated aqueous sodium hydrogen carbonate solution, washed with brine (300 ml), dried (magnesium sulfate) and concentrated. The residue was dissolved in toluene (500 ml) and water (20 ml, 1.11 moles, 0.8 eq) added. The solution was stirred for ca. 30 s and cooled in an ice/water batch with periodic stirring. After 4 h the solid was filtered and left to air dry in a crystallizing dish for 16 h to give colored crystals. Recrystallization in toluene afforded the monohydrate form of 4-cyclopentylresorcinol as white plates. An anhydrous toluene solution of 4-cyclopentylresorcinol was prepared via azeotropic distillation. The solution was cooled, and pentane added. Anhydrate A was obtained by filtration. MPt 65-66.5° C. Selected IR Data (υmax/cm−1): 1108.3 s, 1094.7 m, 977.8 s, 971.1 s, 930.4 w, 838.3 m, 826.7 s, 799.8 w, 748.1 w and 628.0 w.
Reaction SMILES: COC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC([O-])=O)C=CC=1OC.[CH2:26]([O:28][C:29]1[CH:30]=[C:31]([CH:40]=[CH:41][C:42]=1[O:43][CH3:44])[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=O)[CH3:27].C([N:47](CC)[C:48]([CH2:50]P(=O)([O-])[O-])=[O:49])C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[C:34]1([C:32]([C:31]2[CH:40]=[CH:41][C:42]([O:43][CH3:44])=[C:29]([O:28][CH2:26][CH3:27])[CH:30]=2)=[CH:50][C:48]([NH2:47])=[O:49])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCN(CC)C(=O)CP(=O)([O-])[O-]
Reactant: CCOc1cc(C(=O)c2ccccc2)ccc1OC
Agent: COc1ccc(C(=CC(=O)[O-])c2ccc(OC)c(OC)c2)cc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CCOc1cc(C(=CC(N)=O)c2ccccc2)ccc1OC

Procedure:
The acrylamide was prepared analogously to 3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3-ethoxy-4-methoxybenzophenone (0.3 g, 1.2 mmol), diethylcarbamoylmethylphosphonate (0.25 g, 1.3 mmol) and lithium hexamethyldisilazide (1 mL, 1.3 mmol, 1.3M) with a reaction time of 54 hours at reflux. The crude mixture was purified by flash column chromatography (silica gel, 45% ethyl acetate/methylene chloride) to afford 0.06 g (17%) of a mixture of the E and Z isomers as an oil: 1H NMR (CDCl3) δ 7.54-7.19 (m, 10 H), 7.00-6.65 (m, 6 H), 6.34 (s, 2 H), 5.54 (s, 1 H), 5.55 (s, 1 H), 5.24 (s, 1 H), 5.04 (s, 1 H), 4.16 (m, 4 H), 3.92 (s, 3 H), 3.87 (s, 3 H), 1.60-1.33 (m, 6 H); 13C NMR (CDCl3) δ 168.7, 168.6, 150.8, 150.4, 149.7, 148.4, 148.0, 140.7, 138.2, 133.0, 130.2, 129.2, 129.1, 128.8, 128.3, 128.0, 121.9, 121.6, 120.0, 113.7, 111.9, 111.4, 110.8, 64.4, 64.3, 55.9, 14.6; Anal. Calcd for C18H19NO3. 0.35H2O. Theoretical: C, 71.19; H, 6.54; N, 4.61. Found: C, 71.19; H, 6.68; N, 4.45.
Reaction SMILES: C([O:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:10]=[C:9]([Cl:17])[CH:8]=1)(C)(C)C>Cl.O1CCOCC1>[ClH:17].[Cl:17][C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:10]=1)[C:6]([OH:18])=[O:5]
Reactant: CC(C)Cc1cc(C(=O)OC(C)(C)C)cc(Cl)n1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)Cc1cc(C(=O)O)cc(Cl)n1
Yield: 102.8 %

Procedure:
A solution of 2-chloro-6-isobutylisonicotinic acid tert.-butyl ester (1.70 g, 6.3 mmol) in 4 N HCl in dioxane (50 mL) is stirred at 60° C. for 30 h. The solvent is evaporated and the crude product is purified by MPLC on silica gel (heptane:EA gradient) to give 2-chloro-6-isobutylisonicotinic acid hydrochloride (0.81 g) as a beige resin; LC-MS: tR=0.89 min, [M+1]+=214.02.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([CH:25]=[CH:26][CH:27]=1)[O:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:24])[CH2:15][S:16]([CH2:18][C:19]1[O:23][CH:22]=[CH:21][CH:20]=1)=[O:17].Cl.C(=O)([O-])O.[Na+]>CC(C)=O>[CH:2]([C:6]1[CH:7]=[C:8]([CH:25]=[CH:26][CH:27]=1)[O:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:24])[CH2:15][S:16]([CH2:18][C:19]1[O:23][CH:22]=[CH:21][CH:20]=1)=[O:17])=[O:1]
Reactant: O=C(CS(=O)Cc1ccco1)NCCCOc1cccc(C2OCCO2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: O=Cc1cccc(OCCCNC(=O)CS(=O)Cc2ccco2)c1
Yield: 95.7 %

Procedure:
N-{3-[3-(1,3-dioxolan-2-yl)phenoxy]propyl}-2-(furfurylsulfinyl)acetamide (20 g) was dissolved in 300 ml of acetone, and 60 ml of a 1N aqueous solution of HCl was added. The mixture was heated under reflux for 8 hours. After cooling, the solution was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, concentrated and extracted with ethyl acetate. The organic layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give 17 g (yield 81%) of N-[3-(3-formylphenoxy)propyl]-2-(furfurylsulfinyl)acetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[CH3:20][C:21]1[CH:22]=[C:23]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:24]=[C:25]([CH3:27])[CH:26]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:31]1[CH2:32][CH2:33][N:28]([C:23]3[CH:24]=[C:25]([CH3:27])[CH:26]=[C:21]([CH3:20])[CH:22]=3)[CH2:29][CH2:30]1)=[O:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Product: COc1nc2ccc(Cl)cc2nc1NC(=O)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 79 %

Procedure:
Ethyl N-(6-chloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound (yield, 79%). 1H NMR (300 MHz, CDCl3): δ 2.29 (s, 6H), 3.19-3.29 (m, 4H), 3.73-3.89 (m, 3H), 4.11-4.14 (m, 4H), 6.58 (s, 3H), 7.19-7.25 (m, 1H), 7.36-7.64 (m, 2H), 7.67-7.81 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([CH:16]1[O:18][CH2:17]1)[Cl:15].C([O-])(O)=O.[Na+]>CCO>[Cl:15][CH2:14][CH:16]([OH:18])[CH2:17][N:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1
Reactant: ClCC1CO1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: OC(CCl)CN1CCN(Cc2ccccc2)CC1
Yield: 75.3 %

Procedure:
1-Benzylpiperazine (8.66 mL, 50 mmol) in EtOH (100 mL) was added dropwise to epichiorohydrin (3.92 mL, 50 mmol) in EtOH (25 mL) with NaHCO3 (4.2 g, 50 mmol) over 30 min at 0° C. under nitrogen. After 16 h the EtOH was removed in vacuo and the crude product eluted through silica gel (5% methanol: methylene chloride) to give pure product (10.12 g, 75.3%) as an amber oil. DCI/MS (M+1) 269. 400 HMz 1H NMR (CDCl3) δ:7.3 (m, 5H), 4.95 (m, 1H),4.& 4.6(m,2H), 3.95(m,1H),3.6(m,2H),3.5(s,2H),2.7(m,4H),2.4(m, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CN1C(=O)CCC1>[N+:15]([C:5]1[CH:4]=[CH:3][C:2]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(Br)cc1Nc1ccccc1
Reactant: C1CNCCN1
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(N2CCNCC2)cc1Nc1ccccc1
Yield: 86.3 %

Procedure:
A solution of 5-bromo-2-nitro-N-phenylbenzenamine (4.0 g, 13.6 mmol) and piperazine (4.7 g, 54.6 mmol) in 40 ml NMP was heated at 100° C. for 16 hours. The reaction was quenched with 100 ml water. The mixture was extracted with ethyl acetate (3×30 ml) and dried over anhydrous sodium sulfate. 2-Nitro-N-phenyl-5-(piperazin-1-yl)benzenamine (3.5 g, 86%) was obtained by flash column chromatograph (10% methanol in dichoromethane). A solution of 2-nitro-N-phenyl-5-(piperazin-1-yl)benzenamine (0.5 g, 1.7 mmol), benzyl bromide (0.2 g, 1.7 mmol) and triethylamine (0.60 ml, 4.19 mmol) in 20 ml dichloromethane was stirred at 0° C. for 2 hours. The mixture was washed with water (2×10 ml) and dried over anhydrous sodium sulfate before removing the solvents. N-(5-(4-benzylpiperazin-1-yl)-2-nitrophenyl)benzenamine (0.30 g, 43%) was obtained by flash column chromatograph (50% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 2.54 (t, J=5.0 Hz, 4H), 3.32 (t, J=2.0 Hz, 4H), 3.56 (s, 2H), 6.34 (dd, J=9.7, 2.1 Hz, 1H), 6.42 (d, J=2.5 Hz, 1H), 7.22-7.44 (m, 9H), 8.14 (d, J=9.7 Hz, 1H), 9.90 (s, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 47.3, 53.0, 63.3, 96.2, 106.2, 124.9, 125.8, 127.8, 128.9, 129.3, 129.6, 130.1, 138.0, 139.5, 145.9, 156.1.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH:6][C:7]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)=[NH:8])C>FC(F)(F)C(O)=O>[NH:6]1[CH:5]=[CH:4][N:8]=[C:7]1[N:9]1[C:17]2[C:12](=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1
Reactant: CCOC(CNC(=N)N1CCc2cc([N+](=O)[O-])ccc21)OCC
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc2c(c1)CCN2c1ncc[nH]1
Temperature: 60 °C

Procedure:
470 mg N-(2,2-diethoxy-ethyl)-5-nitro-2,3-dihydro-indole-1-carboxamidine are dissolved in 8 ml trifluoroacetic acid and the mixture is heated to 60° C. for 3 hours. Then the solvent is eliminated in vacuo and the residue is chromatographed on aluminium oxide (dichloromethane/methanol 99:1 to 70:30).
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)=[CH:13][CH:12]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2.Br[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29]>>[CH3:31][O:30][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][N:20]1[CH2:21][CH2:22][CH2:23][C@@H:19]1[CH2:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([N:3]2[C:2]([Cl:1])=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]3)=[N:4]2)=[CH:16][CH:15]=1
Reactant: Clc1c2ccccc2nn1-c1ccc(OC[C@H]2CCCN2)cc1
Reactant: COC(=O)CCCBr
Product: COC(=O)CCCN1CCC[C@@H]1COc1ccc(-n2nc3ccccc3c2Cl)cc1
Yield: 80.7 %

Procedure:
The title compound was prepared from product from 3-chloro-2-[4-((R)-1-pyrrolidin-2-ylmethoxy)-phenyl]-2H-indazole (0.4 g, 1.1 mmol) and methyl 4-bromobutyrate (0.25 g, 1.4 mmol) using the procedure of step 7 of the Example 5 to provide the title compound (0.38 g, 79%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH:26]([CH3:29])[CH2:27][OH:28])=[O:24])[C:5]1=[O:30].[N:31]1([C:37](Cl)=[O:38])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:11]2[CH:12]=[C:13]3[C:8]([C:7]([OH:22])=[C:6]([C:23]([NH:25][CH:26]([CH3:29])[CH2:27][OH:28])=[O:24])[C:5](=[O:30])[N:4]3[CH2:3][CH2:2][NH:1][C:37]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:38])=[N:9][CH:10]=2)=[CH:20][CH:19]=1
Reactant: CC(CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN)c1=O
Reactant: O=C(Cl)N1CCOCC1
Product: CC(CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCNC(=O)N2CCOCC2)c1=O

Procedure:
This compound was prepared from 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxy-1-methylethyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide and 4-morpholinecarbonyl chloride employing methods similar to those described in Example 450 and was obtained as an orange solid: ES+ MS: 528 (M+H+).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([N:10]1[CH2:16][C:15]2([O:23][CH:12]([C:13]3[CH:27]=[CH:26][CH:25]=[CH:24][C:14]=32)[CH2:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=O)[CH3:8].O.[OH-].[Na+]>C1COCC1>[CH2:7]([N:10]1[CH2:16][C:15]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:23][CH:12]([C:13]3[CH:27]=[CH:26][CH:25]=[CH:24][C:14]=32)[CH2:11]1)[CH3:8]
Reactant: CC(=O)N1CC2OC(c3ccccc3)(C1)c1ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCN1CC2OC(c3ccccc3)(C1)c1ccccc12
Yield: 89.6 %

Procedure:
To a suspension of LiAlH4 (910 mg, 23.95 mM) in dry THF (40 ml) under N2 was added the compound from Example 8 (2.22 g, 7.96 mM) in one portion and the resulting mixture refluxed for one hour. The mixture was then cooled in an ice bath and treated successively with distilled water (0.9 ml), 15% NaOH solution (0.9 ml) and water (2.7 ml) in a dropwise manner. The resulting white suspension was filtered through Celite, the filtrate washed thoroughly with THF, and the combined washings concentrated in vacuo. The residue was recrystallized from hexane to give the titled compound (1.89 g, 90% yield) as white crystals, mp 132°-134° C. NMR (CDCl3) δ 0.90 ppm (t, 3H, NCH2CH3), 2.43 (q, 2H, J=7 Hz, NCH2CH3), 2.63 (AB doublet, 1H, J=11 Hz, ##STR19## 2.72 (m, 2H, ##STR20## 3.25 (AB doublet, 1H, J=11 Hz, ##STR21## 5.20 (broad t, 1H, ##STR22## 6.70-7.70 (m, 9H, aromatic H). MS: 265 (M+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][CH2:15][NH:16][C:17]([C:19]2[S:29][C:28]3[N:30]4[C:21](=[CH:22][N:23]=[C:24]4[CH:25]=[CH:26][CH:27]=3)[CH:20]=2)=[O:18])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:31]>C(O)C>[ClH:31].[ClH:31].[NH:8]1[CH2:13][CH2:12][C:11](=[CH:14][CH2:15][NH:16][C:17]([C:19]2[S:29][C:28]3[N:30]4[C:21](=[CH:22][N:23]=[C:24]4[CH:25]=[CH:26][CH:27]=3)[CH:20]=2)=[O:18])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(=CCNC(=O)C2=Cc3cnc4cccc(n34)S2)CC1
Agent: Cl
Solvent: CCO
Product: O=C(NCC=C1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
While 1.56 g (7.17 mM) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid and 0.83 g (7.17 mM) of N-hydroxysuccinimide were stirred together in 50 ml of acetonitrile, 1.51 g (7.89 mM) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added and the mixture was stirred at room temperature for 2 hours. To this reaction mixture was added 1.50 ml (10.8 mM) of triethylamine as well as a solution of the above crude 2-[1-(tert-butoxycarbonyl)piperidin-4-ylidene]ethylamine in 20 ml of acetonitrile and the mixture was stirred at room temperature for 2 hours. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 3 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate to ethyl acetate-methanol=9/1) to provide crude N-[2-(1-(tert-butoxycarbonyl)piperidin-4-ylidene]ethyl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide. To this crude N-[2-(1-(tert-butoxycarbonyl)piperidin-4-ylidene)ethyl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide was added 4 ml of concentrated hydrochloric acid and the mixture was stirred at room temperature for 0.5 hour. After addition of ethanol, the mixture was stirred and the resulting precipitate was recovered and rinsed serially with ethanol and diethyl ether to provide the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.C1C([NH2:18])=CC=C(N)C=1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH2:18]
Reactant: Oc1ccc2ccccc2c1
Reactant: Nc1ccc(N)cc1
Product: Nc1ccc2ccccc2c1

Procedure:
In a prior art process, 3 mols of β-naphthol and 1 mol of p-phenylenediamine were heated together at 343° C. for 1.5 hours. 1259 ppm of undesirable β-naphthylamine was formed. It is difficult to remove this much material from the desired reaction product. When the reaction was conducted at 304° C. for 4 hours, 715 ppm of β-naphthylamine were formed. The yield for this 4 hour reaction was 94.3%. When this reaction was conducted for 4 hours at 232° C. the yield was only 68.9%.
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]CCCCCCCC>CO>[CH2:4]([O:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:30][CH:31]=1)/[CH:5]=[CH:6]/[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCC/C=C/COc1ccc(C(=O)O)cc1

Procedure:
The ester 35 g 565 mg, 1.95 mmol), and lithium hydroxide monohydrate (817 mg, 19.5 mmol) in 20 ml methanol were reacted according to the procedure for compound 36a. The yield was 482 mg (89% of a white powder.
Reaction SMILES: [C:1]([C:4]1[C:31]([OH:32])=[CH:30][CH:29]=[CH:28][C:5]=1[O:6][CH2:7][CH:8]([OH:27])[CH2:9][O:10][C:11]1[C:16]2[C:17](=[O:26])[CH:18]=[C:19]([C:21]([O:23]CC)=[O:22])[O:20][C:15]=2[CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+:37]>O>[C:1]([C:4]1[C:31]([OH:32])=[CH:30][CH:29]=[CH:28][C:5]=1[O:6][CH2:7][CH:8]([OH:27])[CH2:9][O:10][C:11]1[C:16]2[C:17](=[O:26])[CH:18]=[C:19]([C:21]([O-:23])=[O:22])[O:20][C:15]=2[CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2].[Na+:37]
Reactant: CCOC(=O)c1cc(=O)c2c(OCC(O)COc3cccc(O)c3C(C)=O)cccc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)c1c(O)cccc1OCC(O)COc1cccc2oc(C(=O)[O-])cc(=O)c12

Procedure:
32.0 parts of ethyl 5-(3-[2-acetyl-3-hydroxyphenoxy]-2-hydroxypropoxy)-4-oxo-4H-1-benzopyran-2-carboxylate were refluxed with a solution of 6.08 parts of sodium bicarbonate in 200 parts of water for eighteen hours. The solution was filtered hot and cooled. The solid obtained was collected by filtration and crystallised from water containing a small quantity of ethanol to give 9.2 parts of sodium 5-(3-[2-acetyl-3-hydroxyphenoxy]-2-hydroxypropoxy)-4-oxo-4H-1-benzopyran-2-carboxylate, m.pt. 178°-180°.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]=2[C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:31][CH2:32][CH2:33][OH:34]>CN(C=O)C.O>[CH2:1]([N:8]1[C:16]2[CH2:15][CH2:14][N:13]([CH2:31][CH2:32][CH2:33][OH:34])[CH2:12][C:11]=2[C:10]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2cn(Cc3ccccc3)c3c2CNCC3)cc1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCCN1CCc2c(c(-c3ccc(Cl)cc3)cn2Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1-benzyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (Example 25; 0.51 g) in DMF (14 mL) was added 1.39 g of Cs2CO3 and 142 μL of 3-bromo-1-propanol. The mixture was stirred at RT for 12 h and then was diluted with water. The aqueous layer was extracted with Et2O and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography on SiO2 (2% 2 M NH3 in MeOH/CH2Cl2) afforded 0.15 g of the title compound. The product was dissolved in Et2O and treated with excess 1.0 M HCl in Et2O to afford 0.16 g the corresponding HCl salt. MS (ESI): exact mass calculated for C23H25ClN2O, 380.17. found, m/z 381.2 [M+H]+, 383.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.37-7.27 (m, 7H), 7.19-7.17 (m, 3H), 5.15 (s, 2H), 4.47 (br s, 2H), 3.93-3.25 (m, 6H), 2.94-2.93 (m, 2H), 2.01-1.96 (m, 2H).