Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:15][C@H:14]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][N:12](C(OCC2C=CC=CC=2)=O)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.CCN(C(C)C)C(C)C.Cl[C:46]1[CH:51]=[CH:50][N:49]=[CH:48][C:47]=1[N+:52]([O-:54])=[O:53]>[Pd].CCOC(C)=O>[C:1]([O:9][C@H:10]1[CH2:15][C@H:14]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][N:12]([C:46]2[CH:51]=[CH:50][N:49]=[CH:48][C:47]=2[N+:52]([O-:54])=[O:53])[CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](OC(=O)c2ccccc2)CN(C(=O)OCc2ccccc2)C1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](OC(=O)c2ccccc2)CN(c2ccncc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
To a solution of (3S,5S)-benzyl 3-(benzoyloxy)-5-(tert-butoxycarbonylamino)-piperidine-1-carboxylate (1 eq) in 15 methanol and 15 mL of EtOAc was added 10% Pd/C (0.1 eq). The resulting suspension was stirred at H2 atmosphere for 4 hours. The crude solids were filtered through a pad of Celite on a paper lined Buchner funnel, washed with MeOH, then concentrated in vacuo. The residue was dissolved in 20 mL of isopropanol and DIPEA (1.8 eq) and 4-chloro-3-nitropyridine (1.2 eq) were added. The reaction mixture was stirred at 75° C. for 2 hours, at which point the reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was diluted with 150 mL of EtOAc, washed with brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (EtOAc:hexanes=1:1) to yield (3S,5S)-5-(tert-butoxycarbonylamino)-1-(3-nitropyridin-4-yl)-piperidin-3-yl benzoate (90%). LC/MS (m/z): 443.2 (MH+). HPLC: Rt:2.89 min.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][CH2:12][C:13]1[CH:31]=[CH:30][C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1.[F:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35]Br>>[F:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][N:11]([CH2:12][C:13]1[CH:31]=[CH:30][C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH3:1]
Reactant: COC(=O)CCc1ccc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)cc1
Reactant: Fc1ccccc1CBr
Product: COC(=O)CCc1ccc(Oc2ccc(CN(Cc3ccccc3F)c3cccc([N+](=O)[O-])c3C)cc2)cc1

Procedure:
The product from Example 76C and 2-fluorobenzyl bromide were processed as described in Example 6B to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH3:29][N:30]([CH3:34])[C:31](Cl)=[S:32]>O>[CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][C:31](=[S:32])[N:30]([CH3:34])[CH3:29])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc(O)c2cc(F)ccc2c1
Reactant: CN(C)C(=S)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cc(OC(=S)N(C)C)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 71.4 %

Procedure:
A mixture of (6-fluoro-4-hydroxy-naphthalen-2-yl)-acetic acid methyl ester (500 mg, 2.14 mmol), finely ground potassium carbonate (591 mg, 4.28 mmol), and N,N-dimethylformamide (10 mL) was stirred at room temperature for 20 minutes. Dimethylthiocarbamoyl chloride (290 mg, 2.35 mmol) was added in one portion. After being stirred for 2 hours, the resulting mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with water (15 mL) and brine (20 mL), then dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (gradient elution with 0-30% ethyl acetate in hexanes) to afford (4-dimethylthiocarbamoyloxy-6-fluoro-naphthalen-2-yl)-acetic acid methyl ester (491 mg, 71.5%) as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][NH2:24]>>[ClH:19].[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][NH:24][S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CN(C)CCN
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCN(C)C)s2)c(C)[nH]c1=O
Product: Cl
Yield: 44.3 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 2-(dimethylamino)ethylamine as described in Steps 5 and 6, Example 24 to give the title compound as a solid (44.3% yield). LC/MS: RT 1.97 min; m/e 370 (M+H); 1H NMR (δ, ppm): 11.8 (1H, s), 10.3 (1H, s), 8.3 (1H, t); 7.65 (1H, d); 7.35 (1H, s), 7.2 (1H, d), 4.2 (2H, m), 3.8 (6H, m), 2.4 (2H, q), 2.36 (3H, s), 1.1 (3H, t).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH3:11])[C:5]2=[N:6][CH:7]=1.[NH2:12][C:13]1[C:22]2[C:17](=[C:18](Br)[C:19]([CH3:23])=[CH:20][CH:21]=2)[N:16]=[N:15][C:14]=1[C:25]([NH2:27])=[O:26]>>[NH2:12][C:13]1[C:22]2[C:17](=[C:18]([C:2]3[CH:3]=[C:4]4[N:10]=[CH:9][N:8]([CH3:11])[C:5]4=[N:6][CH:7]=3)[C:19]([CH3:23])=[CH:20][CH:21]=2)[N:16]=[N:15][C:14]=1[C:25]([NH2:27])=[O:26]
Reactant: Cn1cnc2cc(Br)cnc21
Reactant: Cc1ccc2c(N)c(C(N)=O)nnc2c1Br
Product: Cc1ccc2c(N)c(C(N)=O)nnc2c1-c1cnc2c(c1)ncn2C

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 96 using 6-bromo-3-methyl-3H-imidazo[4,5-b]pyridine and 4-amino-8-bromo-7-methylcinnoline-3-carboxamide. 1H NMR (400 MHz, CD3OD) δ ppm 2.34 (s, 3 H), 4.03 (s, 3 H), 7.75 (d, J=8.59 Hz, 1 H), 8.04 (d, J=1.77 Hz, 1 H), 8.28 (d, J=8.59 Hz, 1 H), 8.35 (d, J=1.77 Hz, 1H), 8.45 (s, 1 H); ESI-MS m/z [M+H]+ 334.2.
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([O:7][CH:8]([C:23]([CH3:27])([CH3:26])[CH2:24][OH:25])[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])=[O:10])=[CH:5][C:4]=1[C:30]([F:33])([F:32])[F:31])#[N:2].[CH3:34][S:35](Cl)(=[O:37])=[O:36]>N1C=CC=CC=1>[C:1]([C:3]1[CH:29]=[CH:28][C:6]([O:7][CH:8]([C:9](=[O:10])[NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])[C:23]([CH3:27])([CH3:26])[CH2:24][O:25][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:5][C:4]=1[C:30]([F:32])([F:31])[F:33])#[N:2]
Reactant: COc1ccc(CNC(=O)C(Oc2ccc(C#N)c(C(F)(F)F)c2)C(C)(C)CO)c(OC)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1ccc(CNC(=O)C(Oc2ccc(C#N)c(C(F)(F)F)c2)C(C)(C)COS(C)(=O)=O)c(OC)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 116.8 %

Procedure:
To a clear, colorless solution comprised of 2-(4-cyano-3-trifluoromethyl-phenoxy)-N-(2,4-dimethoxy-benzyl)-4-hydroxy-3,3-dimethyl-butyramide (116.42 g; 250 mmol) in pyridine (160 mL) cooled to 0° C. under a nitrogen atmosphere was added methanesulfonyl chloride (30.2 g; 262 mmol). The mixture turned cloudy yellow with precipitate within 5 minutes of methanesulfonyl chloride addition. The reaction mixture was stirred cold for 1 hour, 20 minutes. The reaction flask was then loaded onto the rotary evaporator over a water bath warmed to 40° C. and the high vacuum was applied. After two hours of rotation, a negligible volume of pyridine had been distilled off and the water bath temperature was raised to 54° C. The pyridine was distilled off as the solution turned to a darker orange color and yielded a dark orange oil. To avoid decomposition, the flask was removed and the contents were partitioned between dichloromethane (1500 mL) and 2N aqueous hydrochloric acid (500 mL.) The unseparated aqueous (top) layer was tested with pH paper to show a pH of 4. The aqueous phase was acidified to pH 0 by the addition of concentrated aqueous hydrochloric acid (10 mL) to the biphasic mixture. The layers were separated and the organic phase was dried over anhydrous magnesium sulfate and vacuum filtered. The vacuum flask containing the clear orange filtrate solution was covered and left at ambient temperature for three days. The solution turned to dark red. Thin layer chromatography analysis of this solution (solvent system: 1:1 v/v hexanes-ethyl acetate) showed the major presence of desired material along with a baseline (Rf=0) species and two higher Rf species. The solution was concentrated in vacuo, keeping the water bath temperature at 35° C., to obtain 159 g of a red foam; 1H-NMR (400 MHz; CDCl3) δ 7.59 (d, 1H, J=2.1 Hz), 7.23 (d, 1H, J=2.5 Hz), 7.05 (d, 1H, J=2.1 Hz), 6.93 (dd, 1H, J=2.2, 0.7 Hz), 6.50 (t, 1H, J=1.5 Hz), 6.36 (dd, 1H, J=2.1, 0.6 Hz), 6.26 (d, 1H, J=0.6 Hz), 5.28 (s, 1H), 4.45 (s, 1H), 4.36-4.24 (m, 2H), 4.11 (dd, 2H, J=6.7, 2.4 Hz), 3.77 (s, 3H), 3.57 (s, 3H), 2.99 (s, 3H), 1.13 (s, 3H), 1.12 (s, 3H); 19F-NMR (376 MHz; CDCl3) δ-62.69 (s, 3F).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8](O)[CH2:9][CH3:10])[CH:5]=[CH:4][CH:3]=1.[Br:12]C(C1C=CC=CN=1)CCC>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]([Br:12])[CH2:9][CH3:10])[N:7]=1
Reactant: CCCC(Br)c1ccccn1
Reactant: CCC(O)c1cccc(Br)n1
Product: CCC(Br)c1cccc(Br)n1

Procedure:
The title compound was prepared from 1-(6-bromopyridin-2-yl)propan-1-ol (example 239, Step A) following the procedure as described above for the synthesis of 2-(1-bromobutyl)pyridine (Example 231, Step B). Mass Spectrum (ESI) m/z=277.7, 279.7 and 281.7 (M+1).
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][NH:5][C:6]1[N:11]=[C:10](C(Cl)(Cl)Cl)[N:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[N:7]=1>CO.O.Cl>[CH3:1][O:2][C:10]1[N:11]=[C:6]([NH:5][CH3:4])[N:7]=[C:8]([C:16]([F:19])([F:18])[F:17])[N:9]=1
Reactant: CNc1nc(C(F)(F)F)nc(C(Cl)(Cl)Cl)n1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNc1nc(OC)nc(C(F)(F)F)n1

Procedure:
21.8 g of a 30% strength solution of sodium methanolate in methanol (0.12 mol of sodium methanolate) were added dropwise to a solution of 119.4 g (0.40 mol) of 2-methylamino-4-trichloromethyl-6-trifluoromethyl-1,3,5-triazine in 400 ml of methanol. The resulting yellow mixture was then refluxed for 1 hour during which it gradually became cloudy. After addition of a further 7.2 g of the 30% strength solution of sodium methanolate in methanol (0.04 mol of sodium methanolate), the mixture was refluxed for a further 30 minutes and, after cooling to 20° to 25° C., diluted with 150 ml of water and neutralized with 1 normal aqueous hydrochloric acid. The solvent was then removed at 40° C. under reduced pressure, after which the resulting solid was separated off and dried at 40° C. under reduced pressure for 15 hours.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.Cl[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Br:22]>>[Cl-:11].[NH2:1][C:2]1[N:3]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Br:22])[C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N+:6]=1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Br:22]
Reactant: Nc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: ClCOc1ccccc1Br
Product: Nc1n(COc2ccccc2Br)c2cc(Cl)c(Cl)cc2[n+]1COc1ccccc1Br
Product: [Cl-]

Procedure:
Following the procedure of Example 2 and replacing 2-aminobenzimidazole with 2-amino-5,6-dichlorobenzimidazole and replacing 2-bromo-4-chlorophenyl chloromethyl ether with 2-bromophenyl chloromethyl ether, the title compound is obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>C1COCC1.C(Cl)Cl>[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH:13]=2)[CH2:10][CH2:11]1)=[O:29]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCN)CC2)c1
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCNC(=O)c3cccc(Cl)c3)CC2)c1

Procedure:
Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT using N-{3-[1-(4-aminobutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3-chlorobenzoyl chloride: ESMS m/e: 456.0 (M+H)+.
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li].BrC1C=CC=CC=1.[C:16]([CH:24]1[CH2:33][N:32]2[CH:27]([CH2:28][CH2:29][CH2:30][CH2:31]2)[CH2:26][CH2:25]1)(=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCOCC.O>[C:1]1([C:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:24]2[CH2:33][N:32]3[CH:27]([CH2:28][CH2:29][CH2:30][CH2:31]3)[CH2:26][CH2:25]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1ccccc1)C1CCC2CCCCN2C1
Reactant: [Li]c1ccccc1
Agent: [Li]
Solvent: CCOCC
Solvent: O
Solvent: Brc1ccccc1
Product: c1ccc(C(=C2CCC3CCCCN3C2)c2ccccc2)cc1

Procedure:
To a solution of phenyl lithium, which had been prepared by the reaction of 1.23 g. of lithium and 16.80 g. of bromobenzene, in 50 ml. of absolute ether was dropwise added a solution of 120 g. of 3-benzoylquinolizidine in absolute ether. The mixture was refluxed for 30 mins. with stirring. After the excess of phenyl lithium was decomposed with water, the reaction mixture was extracted with ether. The thus obtained etheral layer was washed with water and dried. After removing the solvent by distillation, α,α-diphenyl-quinolizidine-3-methanol showing a melting point of 166° to 167° C. was obtained.
Reaction SMILES: [CH:1]1[CH:6]=CC=CC=1.[H-].[Na+].Br[CH2:10][CH2:11][CH2:12][C:13]1(OCC)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[C:22]=[O:23])[C:14]1=[O:24].[OH2:28]>>[CH2:6]([O:28][C:22]([C:15]12[CH2:10][CH2:11][CH2:12][CH:13]([C:21]3[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:14]2=[O:24])=[O:23])[CH3:1]
Reactant: O
Reactant: c1ccccc1
Reactant: CCOC1(CCCBr)C(=O)C(=C=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C12CCCC(C1=O)c1ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of benzene (400 ml.) and sodium hydride (5.3 g. of a 57% suspension in nujol), which is free of nujol, is added dropwise, under dry nitrogen, 1-(3-bromopropyl)-1-ethoxy-carbonyl-2-indanone (39.3 g.) in 100 ml. of benzene. The mixture is stirred at room temperature for 18 hours. Water is added and the organic layer is separated, washed with aqueous sodium chloride, dried, concentrated and distilled to give after a small forecut, 20.5 g. of the title product with b.p. 130°-145° at 0.5 mm.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[N:19]=[C:9]2[NH:10][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][C:13](=O)[N:8]2[N:7]=1)(=[O:3])[CH3:2].P(Cl)(Cl)([Cl:22])=O>>[C:1]([O:4][CH2:5][C:6]1[N:19]=[C:9]2[N:10]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[C:13]([Cl:22])[N:8]2[N:7]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(=O)n2nc(COC(C)=O)nc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc(Cl)n2nc(COC(C)=O)nc2n1

Procedure:
Methyl 2-(acetoxymethyl)-4,7-dihydro-7-oxo-s-triazolo[1,5-a]pyrimidine-5-carboxylate (500 mg) (1.87 mmol) are suspended in 20 l of phosphorus oxychloride. The suspension is held under reflux for 5 hours. The mixture is concentrated in a water-jet vacuum, the residue is treated with dichloromethane and ice/water and extracted several times with dichloromethane. After drying and evaporation of the extract the product is crystallized from methanol. There are obtained 400 mg of methyl 2-(acetoxymethyl)-7-chloro-s-triazolo[1,5-a]pyrimidine-5-carboxylate.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:15]=[C:16]([CH3:35])[C:17]2[NH:18][C:19](=[O:34])[C:20]3[CH:30]=[C:29]([CH2:31][CH2:32][OH:33])[CH:28]=[N:27][C:21]=3[N:22]([CH2:25][CH3:26])[C:23]=2[N:24]=1.O[C:37]1[CH:46]=[CH:45][CH:44]=[C:43]2[C:38]=1[CH:39]=[CH:40][CH:41]=[N:42]2.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.CCOC(C)=O>[Cl:13][C:14]1[CH:15]=[C:16]([CH3:35])[C:17]2[NH:18][C:19](=[O:34])[C:20]3[CH:30]=[C:29]([CH2:31][CH2:32][O:33][C:37]4[CH:46]=[CH:45][CH:44]=[C:43]5[C:38]=4[CH:39]=[CH:40][CH:41]=[N:42]5)[CH:28]=[N:27][C:21]=3[N:22]([CH2:25][CH3:26])[C:23]=2[N:24]=1
Reactant: Oc1cccc2ncccc12
Reactant: CCN1c2ncc(CCO)cc2C(=O)Nc2c(C)cc(Cl)nc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN1c2ncc(CCOc3cccc4ncccc34)cc2C(=O)Nc2c(C)cc(Cl)nc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 21.7 %

Procedure:
Diethyl azodicarboxylate (DEAD) (77 μL, 0.49 mmol) was added drop wise to a solution of 2-chloro-5,11-dihydro-11-ethyl-8-(2-hydroxyethyl)4methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (125 mg, 0.38 mmol), 5-hydroxyquinoline (70.9 mg, 0.49 mmol) and Ph3P (128 mg, 0.49 mmol) in THF (2.5 mL) at room temperature. After 1.5 h, additional amounts of DEAD (35 μL, 0.22 mmol) and PPh3 (59 mg, 0.22 mmol) were added to the mixture. The mixture was stirred at room temperature for 1 h then was diluted in EtOAc (50 mL) and the solution was successively washed with aqueous 1 N NaOH (4×10 mL) and brine (15 mL) then was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (CH2Cl2:acetone, 85:15). The resulting solid was triturated with Et2O to give the title compound (38 mg, 22% yield) as a white solid: MS (ESI) m/z 460/462 (MH)+.
Reaction SMILES: [ClH:1].[CH:2]1([C:5](=[O:35])[CH:6]([N:14]2[CH2:19][CH2:18][CH:17]([SH:20])/[C:16](=[CH:21]/[C:22]3[N:23]=[N:24][N:25]([CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[N:26]=3)/[CH2:15]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[CH2:4][CH2:3]1.Cl>C(#N)C>[ClH:1].[C:30]([CH2:29][CH2:28][CH2:27][N:25]1[N:24]=[N:23][C:22](/[CH:21]=[C:16]2\[CH2:15][N:14]([CH:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[F:13])[C:5]([CH:2]3[CH2:4][CH2:3]3)=[O:35])[CH2:19][CH2:18][CH:17]\2[SH:20])=[N:26]1)([OH:32])=[O:31]
Reactant: CCOC(=O)CCCn1nnc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2S)n1
Agent: Cl
Solvent: CC#N
Product: O=C(O)CCCn1nnc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2S)n1
Yield: 99.1 %

Procedure:
(E)-1-[2-Cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-({2-[3-(ethoxycarbonyl)propyl]-2H-tetrazol-5-yl}methylidene}-4-sulfanylpiperidine hydrochloride (854 mg) was treated with 3 N aqueous hydrochloric acid solution (16 ml) at 50° C. for one hour in a similar manner to that described in Example 134. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: acetonitrile/0.024 N aqueous hydrochloric acid, 30/70 to 35/65, v/v) to afford the title compound as a colourless amorphous solid (801 mg, yield: 99%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH2:6])[CH3:5].[Cl:7][CH2:8][CH2:9][N:10]=[C:11]=[O:12]>C1COCC1>[Cl:7][CH2:8][CH2:9][NH:10][C:11]([NH:6][C@@H:4]([CH3:5])[CH2:3][O:2][CH3:1])=[O:12]
Reactant: O=C=NCCCl
Reactant: COC[C@H](C)N
Solvent: C1CCOC1
Product: COC[C@H](C)NC(=O)NCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of (S)-1-methoxypropan-2-amine (500 mg, 5.61 mmol) in THF (15 mL) was treated with 2-chloroethylisocyanate (592 mg, 5.61 mmol), stirred at RT overnight, then concentrated to dryness. The residue was treated with toluene and concentrated to dryness (twice) to afford (S)-1-(2-chloroethyl)-3-(1-methoxypropan-2-yl)urea (100% yield assumed) as a white solid which was used without further purification. MS (ESI) m/z: 195.1 (M+H+).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]1([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][NH:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])O.[Na+]>CCOC(C)=O.O>[Cl:1][CH2:2][C:3]([N:13]1[CH2:14][CH2:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@H:12]1[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:4]
Reactant: c1ccc([C@@H]2NCCc3ccccc32)cc1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CCl)N1CCc2ccccc2[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
A mixture of chloroacetyl chloride (1.03 g) and EtOAc (5 mL) was added dropwise with stirring to a mixture of (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (1.58 g), sodium hydrogen carbonate (960 mg), water (25 mL) and EtOAc (25 mL), followed by stirring at room temperature for 2 hours. The reaction liquid was extracted with EtOAc, and the extract was washed sequentially with saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-AcOEt, 4:1) to obtain (1S)-2-(chloroacetyl)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (2.14 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]1=[N:13][CH:14]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16](=[O:17])[N:8]1[CH2:7][CH2:6]2>CC1C=CC(C(C)C)=CC=1.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]1=[N:13][CH:14]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16](=[O:17])[N:8]1[CH:7]=[CH:6]2
Reactant: CCOC(=O)c1cnc2n(c1=O)CCc1cc(OC)ccc1-2
Agent: [Pd]
Solvent: Cc1ccc(C(C)C)cc1
Product: CCOC(=O)c1cnc2c3ccc(OC)cc3ccn2c1=O
Yield: 81 %

Procedure:
A stirred mixture of ethyl 6,7-dihydro-9-methoxy-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (510 mgs.) in p-cymene (25 ml.) containing 10% palladium on carbon (150 mgs.) was refluxed for 7 hours. The mixture was flash evaporated to dryness and the residue extracted with boiling ethanol. The combined extracts were filtered and concentrated by boiling to give flocculent colorless needles of ethyl 9-methoxy-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate: 420 mgs. (81% yield), m.p. 211.5°-212°. An additional recrystallization from ethanol raised the m.p. to 217°-218°.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:6])[CH2:3][CH2:2]1.Cl>[OH-].[Na+]>[CH:1]1([N:4]2[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][CH3:17])=[N:8][NH:7][C:5]2=[O:6])[CH2:3][CH2:2]1
Reactant: COc1ccccc1C(=O)NNC(=O)NC1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccccc1-c1n[nH]c(=O)n1C1CC1

Procedure:
700 mg (2.81 mmol) of N-cyclopropyl-2-(2-methoxybenzoyl)-hydrazinecarboxamide from Example 14A are heated under reflux overnight in 10 ml 3 N aqueous sodium hydroxide. After cooling, it is acidified to pH 5-6 with dilute hydrochloric acid, and the mixture is concentrated and the residue purified by preparative HPLC [Method 12]. 240 mg (37% of theory) of the target compound are thus obtained.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([OH:15])=O)=[CH:4][N:3]=1.[CH2:16]1[C:19]2([CH2:22][NH:21][CH2:20]2)[CH2:18][O:17]1>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([N:21]2[CH2:22][C:19]3([CH2:16][O:17][CH2:18]3)[CH2:20]2)=[O:15])=[CH:4][N:3]=1
Reactant: Cc1cccc2c(Cl)ncc(C(=O)O)c12
Reactant: C1NCC12COC2
Product: Cc1cccc2c(Cl)ncc(C(=O)N3CC4(COC4)C3)c12

Procedure:
The title compound was prepared by using 1-chloro-5-methylisoquinolin-4-carboxylic acid (Intermediate-10) and 2-oxa-6-azaspiro[3.3]heptane by following the similar procedure as described for intermediate-11a.