Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[H-].[Na+].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>CN(C=O)C>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([O:1][C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=2)=[CH:16][CH:17]=1)([O-:23])=[O:22]
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
To a solution of 4-hydroxy-2-nitroaniline (3.08 g, 20.0 mmol) in DMF (30 mL) was added NaH (60% oily, 880 mg, 22.0 mmol) followed by 1-fluoro-4-nitrobenzene (2.33 mL, 22.0 mmol). The mixture was stirred at 90° C. overnight. After cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4 then evaporated. Sequence purification on SiO2 column chromatography gave the title compound (4.56 g, 83%): MS m/e 274 (M−1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)[OH:11].C([O-])([O-])=O.[Na+].[Na+]>O>[CH3:1][C:2]1[C:3]([C:8]([NH2:9])=[O:11])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1cccnc1C#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cccnc1C(N)=O
Temperature: 80 °C
Reaction time: 0.42 h
Yield: 97 %

Procedure:
A mixture of 3-methylpicolinonitrile (2.36 g, 20 mmol) and conc. sulfuric acid (12.5 mL) was stirred at 80° C. for 25 min. The solution was cooled to rt, poured into water (80 mL), followed by addition of sat. Na2CO3 (aq.) until pH ˜7. The resulting mixture was extracted with DCM (3×) and the combined organic layer was dried over MgSO4 and concentrated in vacuo to provide 3-methylpicolinamide as a white solid (2.65 g, 97%). 1H NMR (CDCl3, 400 MHz) δ 8.43 (dd, 1H), 7.93 (brs, 1H), 7.62 (dd, 1H), 7.35 (dd, 1H), 5.44 (brs, 1H), 2.76 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14](OB(C=C)OCCCC)[CH2:15]CC.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O>[N+:11]([C:3]1[CH:4]=[C:5]([C:8](=[O:10])[CH3:9])[CH:6]=[CH:7][C:2]=1[CH:14]=[CH2:15])([O-:13])=[O:12]
Reactant: C=CB(OCCCC)OCCCC
Reactant: CC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1ccc(C(C)=O)cc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 87 %

Procedure:
To a mixture of 4′-bromo-3′-nitroacetophenone (600 mg, 2.46 mmol), vinylboronic acid dibutyl ester (680 mg, 3.69 mmol), and sodium carbonate (1.83 g, 17.22 mmol) in THF/H2O (12 mL/4 mL) is added dichlorobis(triphenylphospine) palladium (II) (86 mg, 5% mmol). The reaction tube is sealed and the mixture is purged with N2 for 3 min and heated at 70° C. for 1.5 h. Then the mixture is cooled to room temperature and poured into saturated ammonia chloride aqueous solution. The mixture is extracted with ethyl acetate (3×20 mL). The organic extracts are combined, washed with brine and concentrated. The crude product is purified with silica gel column chromatography (20% ethyl acetate in hexanes) to afford 1-(3-Nitro-4-vinyl-phenyl)-ethanone as a yellow solid, 87% yield: ESMS m/z 192.0 (M+H+).
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11](=[O:21])[NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)([CH3:9])([CH3:8])[CH3:7].CN(C)CCN(C)C.ClCC[I:33]>C(OCC)C>[C:6]([O:10][C:11](=[O:21])[NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][C:18]=1[I:33])([CH3:9])([CH3:8])[CH3:7]
Reactant: COc1ccc(NC(=O)OC(C)(C)C)cn1
Reactant: ClCCI
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1cc(I)c(NC(=O)OC(C)(C)C)cn1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.5M in hexanes, 100 mL, 240 mmol) was added dropwise over 1 h to a cooled (−78° C.) mixture of tert-butyl-6-methoxypyridin-3-ylcarbamate (16 g, 71 mmol) and N,N,N′,N′-tetramethylethylenediamine (34 mL, 221 mmol) in diethyl ether (100 mL). The reaction was stirred at −78° C. for 30 minutes, then warmed to −20° C. and left stirring for 3 h. The reaction mixture was transferred via cannula over fifteen minutes to a cold (−78° C.) solution of 1-chloro-2-iodoethane (48 g, 243 mmol) in diethyl ether (50 mL). On complete addition, the reaction mixture was allowed to warm to room temperature and left stirring at this temperature for 16 h. The reaction was quenched with saturated aqueous ammonium chloride (30 mL) and water (200 mL) then extracted with ethyl acetate (2×100 mL). The combined organic layer was washed with saturated sodium sulfite (50 mL), 1N hydrochloric acid (100 mL), water (100 mL), saturated sodium bicarbonate solution (100 mL) and brine (50 mL), dried over sodium sulfate, and evaporated to give a residue which was purified by flash chromatography (silica, 120 g column, ISCO, 0-40% ethyl acetate in hexanes) to afford the title compound as a white cyrstaline solid (18 g, 72%).
Reaction SMILES: [Cl:1][CH2:2][C:3]#[N:4].[Cl:5][C:6]([Cl:19])([Cl:18])[CH:7](O)[NH:8][C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.S(=O)(=O)(O)[OH:21]>>[Cl:5][C:6]([Cl:19])([Cl:18])[CH:7]([NH:8][C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH:4][C:3](=[O:21])[CH2:2][Cl:1]
Reactant: O=C(NC(O)C(Cl)(Cl)Cl)c1ccccc1
Reactant: O=S(=O)(O)O
Reactant: N#CCCl
Product: O=C(CCl)NC(NC(=O)c1ccccc1)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Chloroacetonitrile (4.1g) was added dropwise to a solution of 1,1,1-trichloro-2-hydroxy-2-benzamidoethane (13.4g) in concentrated sulphuric acid (50 ml). The temperature was kept at 0° during the addition. The mixture was stirred at room temperature for 4 hours, then left overnight. The reaction mixture was poured on to ice. The precipitated solid was collected, washed with water and dried (14.65g). Recrystallisation from nitromethane gave pure 1,1,1-trichloro-2-benzamido-2-(chloroacetamido)ethane (12.7g, m.p. 210°-12°) whose infra red spectrum was identical to that of the product of the preceding Example.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([NH:17][C:18]2[N:50]=[C:21]3[C:22]([C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[CH:41]=4)=[C:23]([CH3:39])[C:24]([C:26]4[N:27]([C:31]5[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=5)[N:28]=[CH:29][CH:30]=4)=[CH:25][N:20]3[N:19]=2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[C:37]([C:34]1[CH:33]=[CH:32][C:31]([N:27]2[C:26]([C:24]3[C:23]([CH3:39])=[C:22]([C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:47])[F:48])[CH:41]=4)[C:21]4[N:20]([N:19]=[C:18]([NH:17][C:15]([NH:14][CH:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[O:16])[N:50]=4)[CH:25]=3)=[CH:30][CH:29]=[N:28]2)=[CH:36][CH:35]=1)#[N:38]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)nc2c1-c1cccc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)NC3CCNCC3)nc2c1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
To a solution of 4-{3-[6-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-ureido}-piperidine-1-carboxylic acid tert-butyl ester (Int. 32, 95 mg, 0.14 mmol) in DCM (2 mL) was added TFA (1 mL) and the solution was stirred at RT for 1 hr, then toluene (10 mL) was added and the reaction mixture concentrated in vacuo. The reaction mixture was partitioned between DCM (15 ml) and aqueous 2 M Na2CO3, and the organic extract was dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a white solid (61 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:4]([CH:5]=[C:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[CH:3]1[C:11](Cl)=[O:12].[OH2:15].[CH:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:14])[C@@H:4]([CH:5]=[C:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[C@H:3]1[C:11]([O:15][CH:4]1[CH2:3][C:2](=[CH2:1])[C:19]([CH2:20][CH:21]=[CH2:16])=[C:18]1[CH3:17])=[O:12]
Reactant: CC1(C)C(C=C2CCCC2)C1C(=O)Cl
Reactant: O
Reactant: c1ccccc1
Solvent: c1ccncc1
Product: C=CCC1=C(C)C(OC(=O)[C@@H]2[C@H](C=C3CCCC3)C2(C)C)CC1=C
Temperature: 20 °C
Reaction time: 17 h

Procedure:
A solution of 7.08 g of (1R, trans) 2,2-dimethyl-3-cyclopentylidenemethyl-cyclopropane-1-carboxylic acid chloride in 3 ml of benzene was added over 10 minutes at 28° C. to a suspension of 5 g of 1S-hydroxy-2-methyl-3-allyl-4-methylene-cyclopent-2-ene in 15 ml of benzene and 2.96 ml of pyridine and the mixture was stirred at 20° C. for 17 hours. 20 ml of water were added to the mixture which was stirred for 10 minutes and the decanted aqueous phase was extracted with benzene. The combined organic phases were washed with water and the wash waters were extracted with benzene. The combined organic phases were dried over magnesium sulfate and were filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 95-5 cyclohexane-ethyl acetate mixture containing 1‰ triethylamine to obtain 8.24 g of (1S) 2-methyl-3-allyl-4-methylene-cyclopent-2-ene-1-yl (1R, trans) 2,2-dimethyl-3-cyclopentylidienemethyl-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =-87°±1° (c=0.9% in ethanol).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[N:13]=[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]2[N:6]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][C:5]2[N:13]=[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][N:7]3[N:6]=2)[CH2:24][CH2:23]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: ClCCCc1nc2ccccn2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCCc2nc3ccccn3n2)CC1
Yield: 60 %

Procedure:
A solution of 3.9 g of 2-(3-chloropropyl)-s-triazolo[1,5-a]pyridine, 3.8 g of 1-o-methoxyphenylpiperazine and 2.8 g of potassium carbonate in 150 ml of dimethylformamide was refluxed for 8 hours. Then the reaction mixture was proceeded by the same manner as described in Example 2. The compound was recrystallized from cyclohexane to give colorless prisms, mp 55°-55.5° C. Yield was 60%. Anal. Calcd. for C20H25ON5 : C, 68.35; H, 7.17; N, 19.53. Found: C, 68.20; H, 6.94; N, 20.21.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[I-].[Na+].[CH2:15](Br)[C:16]#[CH:17].C(N(C(C)C)C(C)C)C>CC(C)=O>[N+:10]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:17][C:16]#[CH:15])=[CH:9][C:6]=1[CH:7]=[O:8])([O-:12])=[O:11]
Reactant: C#CCBr
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: C#CCOc1ccc([N+](=O)[O-])c(C=O)c1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
A mixture of 25 g (150 mmol) 5-hydroxy-2-nitro-benzaldehyde, 44.9 g (299 mmol) sodium iodide, 44.5 g propargyl bromide (80% in toluene), 42 ml N-ethyl-diisopropy-lamine and 400 ml acetone is stirred at rt for 6 d. The reaction mixture is filtered, concentrated, taken up in 1M aqueous hydrochloric acid and extracted with ethyl acetate to yield 2-nitro-5-propargyloxy-benzaldehyde.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C@@H:10]([C:15](O)=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13].O.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25]([OH:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1.O>C1C=CC=CC=1>[S:25]([C:22]1[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=1)([OH:28])(=[O:27])=[O:26].[CH2:1]([O:8][C:15](=[O:16])[C@@H:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: CC(C)C[C@@H](N)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)C[C@@H](N)C(=O)OCc1ccccc1
Yield: 95.1 %

Procedure:
To benzyl alcohol (8.2 g) dissolved in benzene (30 mL) was added D-leucine (5.0 g) and p-toluenesulfonic acid monohydrate (8.0 g). The reaction was warmed to reflux with removal of water overnight. Once TLC indicated consumption of starting material, the reaction was cooled, and the resulting solid was filtered and washed with EtOAc to give the title compound as a white powder (14.26 g, 99%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:36])=[C:23]([N:25]4[CH2:34][CH2:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][C:31]=5[Cl:35])[CH2:26]4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO.CCOCC>[Cl:35][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:32]=1[CH2:33][CH2:34][N:25]([C:23]1[C:22]([NH2:36])=[N:21][CH:20]=[C:19]([C:17]3[CH:16]=[N:15][N:14]([CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:18]=3)[CH:24]=1)[CH2:26]2
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(N4CCc5c(Cl)cccc5C4)c3)cn2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1N1CCc2c(Cl)cccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-{4-[6-Amino-5-(5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (26 mg, 0.051 mmol) was dissolved in MeOH (20 mL), 1.0 M of HCl in Et2O (20 mL) was added, and the mixture was stirred at rt overnight. The solvent was removed in vacuo to give the title compound as a brown solid. 1H NMR (400 MHz, CD3OD): δ=2.32-2.39 (m, 4H), 3.11 (t, J=6.0 Hz, 2H), 3.22-3.32 (m, 2H), 3.42 (t, J=6.0 Hz, 2H), 3.59 (d, J=13.2 Hz, 2H), 4.27 (s, 2H), 4.58-4.68 (m, 1H), 7.16 (d, J=7.6 Hz, 1H), 7.22 (t, J=8.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.97 (s, 1H), 7.98 (s, 1H), 8.33 (s, 1H). MS(ES+): m/z=409.10/411.08 (46/18) [MH+]. HPLC: tR=2.25 min (ZQ2, polar—5 min).
Reaction SMILES: [H-].[Na+].C[C:4]1([CH3:11])[O:8][CH:7]([CH2:9][OH:10])C[O:5]1.Br[CH2:13][CH2:14][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][CH3:28].CN(C)[CH:31]=[O:32]>>[C:4]([O:8][CH:7]([CH2:31][OH:32])[CH2:9][O:10][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][CH2:14][CH3:13])(=[O:5])/[CH:11]=[CH:28]\[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=[CH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: CC1(C)OCC(CO)O1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCCCC=CC=CC=CC=CC=C/C=C\C(=O)OC(CO)COCCCCCCCCCCCCCCCC
Reaction time: 72 h
Yield: 57 %

Procedure:
To NaH (1.85 g, 60% dispersed in mineral oil) under argon was added anhydrous N, N-dimethylformamide (DMF, 30 mL) at RT. Solketal (2.20 g, 16.7 mmol) in 10 mL anhydrous DMF was then added dropwise with constant stirring. 1-Bromohexadecane (5.10 g, 16.7 mmol), dissolved in anhydrous DMF (20 mL) was then added to the reaction mixture dropwise and stirred for 72 hours. The reaction was quenched by adding about 5 mL of methanol. It was then poured into cold ice water (100 mL) and extracted with hexane (100 mL, 3×). The solvent was removed under reduced pressure and the residue chromatographed on silica gel using hexane-dichloromethane to obtain 1a (3.363 g, 57% yield); 1H NMR (in CDCl3): δ in ppm 0.83-0.86 (3H, t, J=6.5 Hz), 1.22 (26H, m), 1.33 (3H, s), 1.39 (3H, s), 1.52-1.55 (2H, m), 3.37-3.48 (4H, m), 3.68-3.71 (1H, t, J=6.5 Hz), 4.01-4.03 (1H, t, J=6.5 Hz), 4.20-4.25 (1H, quintet, J=6.0 Hz); 13C NMR (in CDCl3): 8 in ppm 14.3, 22.9, 25.6, 26.2, 27.0, 29.6, 29.7, 29.8, 29.9, 32.1, 67.1, 72.0, 72.1, 74.9, 109.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][C:13]([CH3:15])=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH:27]=1)[N:24]=[CH:23][CH:22]=[CH:21]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[C:26]([N:28]3[CH2:29][CH2:30][N:31]([CH:13]([CH3:15])[CH2:12][C:8]4[C:7]5[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=5[O:10][CH:9]=4)[CH2:32][CH2:33]3)[CH:27]=1)[N:24]=[CH:23][CH:22]=[CH:21]2
Reactant: COc1cc(N2CCNCC2)c2ncccc2c1
Reactant: COc1cccc2c(CC(C)=O)coc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1cc(N2CCN(C(C)Cc3coc4c(OC)cccc34)CC2)c2ncccc2c1

Procedure:
6-methoxy-8-{4-[2-(7-methoxy-1-benzofuran-3-yl)-1-methylethyl)piperazin-1-yl]quinoline was prepared by generally following the procedure outlined in example 35, step 2, starting from the 1-(7-methoxy-1-benzofuran-3-yl)acetone (204 mg, 1 mmol) and 6-methoxy-8-piperazino quinoline (243.0 mg, 1 mmol) in 1,2-dichloroethane (100 ml) and acetic acid (1 ml), sodium triacetoxyborohydride (422 mg, 2 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methanol:ethyl acetate, yielding a brown semi-solid. Yield: 75 mg (17%); (M+H): 432.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3=[N:19][N:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:21]=[C:11]3[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:37][C:38]1[CH:46]=[C:45]([Cl:47])[CH:44]=[CH:43][C:39]=1[C:40](Cl)=[O:41]>C(Cl)Cl>[Cl:37][C:38]1[CH:46]=[C:45]([Cl:47])[CH:44]=[CH:43][C:39]=1[C:40]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3=[N:19][N:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:21]=[C:11]3[CH2:10][CH2:9]2)=[O:7])=[CH:28][CH:29]=1)=[O:41]
Reactant: CCOC(=O)Cn1cc2c(n1)-c1ccccc1N(C(=O)c1ccc(N)cc1)CC2
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1cc2c(n1)-c1ccccc1N(C(=O)c1ccc(NC(=O)c3ccc(Cl)cc3Cl)cc1)CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 0.940 g of ethyl 6-(4-aminobenzoyl)-5,6-dihydropyrazolo[4,3-d][1]benzazepine-2(4H)-acetate in 25 ml of methylene chloride is added 369 μl of triethylamine followed by the dropwise addition of 373 μl of 2,4-dichlorobenzoyl chloride in 3.5 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours, washed with water, saturated NaHCO3, brine and the organic layer treated with activated carbon, and filtered through is MgSO4. The filtrate is concentrated in vacuo to a residue which is purified by flash chromatography on silica gel using 25% ethyl acetate in methylene chloride to give 380 mg of the desired product as white crystals, m.p. 164°-167° C. The mother liquors are combined, evaporated in vacuo to a residue which is dissolved in 25% ethyl acetate in chloroform to give 535 mg of off-white solid, m.p. 160°-163.5° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:16][C:15](=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[CH:3][N:2]=1.N.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[N:2][CH:3]=2)[N:16]=1
Reactant: O=c1[nH]c(-c2ccnnc2)nc2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Product: Clc1nc(-c2ccnnc2)nc2ccccc12
Temperature: 0 °C

Procedure:
A 100-mL round-bottom flask was charged with 2-(pyridazin-4-yl) quinazolin-4(3H)-one (30 mg) which was suspended in 3 mL of POCl3. The reaction mixture was heated to reflux for 1 h. The reaction mixture turned to a clear brown solution. After cooling, 50 mL of ice/water was carefully added. An aqueous ammonia solution (25% by weight in water) was added dropwise to the mixture with stirring until the pH of the mixture was adjusted to 7˜8. An internal temperature of 0° C. was maintained by the addition of ice. The mixture was warmed to room temperature and extracted with DCM (50 ml×3). The combined organic layers were washed with brine, dried over Na2SO4. After filtration and evaporation, 32 mg was obtained as a light brown solid. LCMS m/z=242.9 (M+1) (Method B) (retention time=1.65 min). The solid was used directly in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7]4=[C:8]([C:17](=[O:20])[NH:18][N:19]=[C:6]4[C:5]=2[CH:4]=1)[CH:9]=[CH:10][CH:11]=3.[P:21](Cl)([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])=[O:22]>CN(C=O)C>[CH2:24]([O:23][P:21]([NH:1][CH2:2][C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7]4=[C:8]([C:17](=[O:20])[NH:18][N:19]=[C:6]4[C:5]=2[CH:4]=1)[CH:9]=[CH:10][CH:11]=3)(=[O:22])[O:26][CH2:27][CH3:28])[CH3:25]
Reactant: NCc1ccc2c(c1)-c1n[nH]c(=O)c3cccc(c13)O2
Reactant: CCOP(=O)(Cl)OCC
Solvent: CN(C)C=O
Product: CCOP(=O)(NCc1ccc2c(c1)-c1n[nH]c(=O)c3cccc(c13)O2)OCC
Yield: 50 %

Procedure:
To a solution of compound 49 (0.5 mmol) in anhydrous DMF (20 mL) was added diethyl chlorophosphate (1.5 mmol). After 3 hours solution was concentrated in vacuo, and 50 mL of water was added. The aqueous layer was extracted with 30 mL of EtOAc twice. Organic layers were combined and washed with 30 mL of brine. Organic layer was dried with MgSO4. Solvent was removed to afford a white solid, which was recrystallized in 10% of EtOAc in hexanes to afford a white solid 54 in 50% yield. MS (ES−): 400; Mp: 222.3-224.5° C.; 1H-NMR (CDCl3, 400 MHz): 10.21 (s, 1H), 8.10 (d, J=2.5 Hz, 1H), 8.03 (d, J=7.5 Hz, 1H), 7.79 (t, J=8.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.47 (dd, J=8.5 and 2.0 Hz, 1H), 7.22 (d, J=8.5 Hz, 1H), 4.12 (m, 6H), 1.32 (t, J=6.5 Hz, 6H); Anal. Calcd. for C19H20N3O5P.(0.3H2O): C, 56.10; H, 5.10; N, 10.33. Found: C, 56.00; H, 5.03; N, 10.13.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]2)[CH:5]=[C:6]([CH3:9])[C:7]=1[OH:8].[CH2:20]=O>C(O)=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([CH3:20])[C:12]([CH3:19])([CH3:18])[CH2:11]2)[CH:5]=[C:6]([CH3:9])[C:7]=1[OH:8]
Reactant: C=O
Reactant: Cc1cc(C2CC(C)(C)NC(C)(C)C2)cc(C)c1O
Solvent: O=CO
Product: Cc1cc(C2CC(C)(C)N(C)C(C)(C)C2)cc(C)c1O

Procedure:
3.0 Parts by weight of 4-(3',5'-dimethyl-4'-hydroxyphenyl)-2,2,6,6-tetramethylpiperidine was dissolved in formic acid and treated with 1.0 part by weight of formaldehyde on a steam bath. After heating for 12 hours the solution was cooled and basified in aqueous solution. The basification liquor was extracted into ether, the ethereal layer dried with magnesium sulphate and evaporated under reduced pressure. Crystallisation of the residue from petroleum (b.p. 80°-100°) have 1.9 parts by weight of product melting at 144°-6°.
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:14](OCC)=[O:15].[Na:19]>C(OCC)C>[Na:19].[CH:14]([CH:2]([CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:1]([O:11][CH2:12][CH3:13])=[O:10])=[O:15]
Reactant: CCOC=O
Reactant: CCOC(=O)CCCC(=O)OCC
Agent: [Na]
Solvent: CCOCC
Product: CCOC(=O)CCC(C=O)C(=O)OCC

Procedure:
Prepared from diethyl glutarate and ethyl formate in the presence of sodium metal in diethyl ether according to the literature procedure (J. Bigs, P. Sykes, J. Chemical Society (1959), 1849-55). Obtained solid (28 g; 45%). LCMS (ES+) m/z 238 (MH+).