Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH:18]4[CH2:19][CH2:20][CH:14]3[CH2:15][O:16][CH2:17]4)[N:10]=[C:9]([C:21]3[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:40][C:41]1[CH:49]=[CH:48][C:44]([C:45]([NH2:47])=[O:46])=[CH:43][CH:42]=1>>[N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH:14]4[CH2:20][CH2:19][CH:18]3[CH2:17][O:16][CH2:15]4)[N:10]=[C:9]([C:21]3[CH:27]=[CH:26][C:24]([NH:25][C:29]([NH:40][C:41]4[CH:49]=[CH:48][C:44]([C:45]([NH2:47])=[O:46])=[CH:43][CH:42]=4)=[O:31])=[CH:23][CH:22]=3)[N:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3C4CCC3COC4)n2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NC(=O)c1ccc(N)cc1
Product: NC(=O)c1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)nc(N4C5CCC4COC5)n3)cc2)cc1
Yield: 33.3 %

Procedure:
Following the procedure described in example 34, reaction of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline (22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and 4-aminobenzamide (25 mg, 0.18 mmol) gave the title compound as off-white solid (10.6 mg, 33% yield). MS (ESI) m/z 531.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].Cl[C:39]1[CH:44]=[N:43][CH:42]=[CH:41][N:40]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][C:39]3[CH:44]=[N:43][CH:42]=[CH:41][N:40]=3)[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: Clc1cnccn1
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Product: COc1ccc(CC2c3cc(Oc4cnccn4)c(OC)cc3CCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with 2-chloro-pyrazine
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19].O>CN(C=O)C>[CH3:17][N:18]([CH3:20])/[CH:19]=[CH:1]/[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2cccnc2c1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1ccc2cccnc2c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 56.7 %

Procedure:
A solution of 7-methyl-8-nitroquinoline (6 g, 31.9 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (4.27 ml, 31.9 mmol) in DMF (15 ml) was heated at 140° C., under nitrogen, for 16 h. After cooling to room temperature, water (15 ml) was added and the resulting precipitate was collected by filtration, washed with EtOAc and dried to give the title compound (4.4 g, 57%). The compound could not be detected by HPLCMS therefore structure was confirmed by 1H NMR.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][CH2:6][C:7]1[N:8]([CH2:44][C:45]([OH:48])([CH3:47])[CH3:46])[C:9]2[C:18]3[CH:17]=[CH:16][C:15]([C:19]([O:21]C)=[O:20])=[CH:14][C:13]=3[N:12]=[C:11]([NH:23][C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:10]=2[N:43]=1)[CH3:4]>C1COCC1.CO>[CH2:3]([O:5][CH2:6][C:7]1[N:8]([CH2:44][C:45]([OH:48])([CH3:47])[CH3:46])[C:9]2[C:18]3[CH:17]=[CH:16][C:15]([C:19]([OH:21])=[O:20])=[CH:14][C:13]=3[N:12]=[C:11]([NH:23][C:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:10]=2[N:43]=1)[CH3:4]
Reactant: CCOCc1nc2c(NC(c3ccccc3)(c3ccccc3)c3ccccc3)nc3cc(C(=O)OC)ccc3c2n1CC(C)(C)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOCc1nc2c(NC(c3ccccc3)(c3ccccc3)c3ccccc3)nc3cc(C(=O)O)ccc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 120 h
Yield: 94.6 %

Procedure:
Sodium hydroxide solution (1 N, 3.51 ml) was added to methyl 2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinoline-7-carboxylate (540 mg, 878 μmol) dissolved in THF (6.21 mL) and methanol (621 μL). The reaction mixture was stirred for 120 hours at room temperature and concentrated in vacuo. The residue was partitioned between ethyl acetate (30 mL) and cold 1M HCl solution (5 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). Organic layers were washed with water (20 mL) and brine (20 mL), combined, dried with MgSO4, and concentrated in vacuo to obtain the title compound (0.499 g, 94%) as white solid; LC-MS (UV peak area, ESI) 99%, 601.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13]CC1C=CC=CC=1)[N:9]=[C:8]1[N:21]=[C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[NH:23][C:24](=[O:25])[C:7]1=[CH:6]2.CCOCC>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[C:8]1[N:21]=[C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[NH:23][C:24](=[O:25])[C:7]1=[CH:6]2
Reactant: CCOC(=O)c1nc2nc3cc(OCc4ccccc4)c(OC)cc3cc2c(=O)[nH]1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nc2nc3cc(O)c(OC)cc3cc2c(=O)[nH]1
Yield: 6 %

Procedure:
A solution of ethyl 7-methoxy-8-benzyloxypyrimido[4,5-b]quinolin-4(3H)one-2-carboxylate (198 mg., 0.488 mmole) in trifluoroacetic acid (4 ml.) is stirred at room temperature for 8 days. Ether (15 ml.) is added and the yellow precipitate which forms separated by filtration. It is taken up in chloroform and the solution filtered through diatomaceous earth to remove a small amount of insoluble material. The filtrate is decolorized with charcoal and concentrated under reduced pressure to small volume. The solid which forms is filtered and dried; 9 mg., 6% yield; m.p. 265°-266° C. (dec.).
Reaction SMILES: S(=O)(=O)(O)O.N[C:7]1[C:8]([C:14]([NH2:16])=[O:15])=[N:9][C:10]([F:13])=[CH:11][N:12]=1.N([O-])=[O:18].[Na+].C(=O)([O-])O.[Na+]>O>[F:13][C:10]1[N:9]=[C:8]([C:14]([NH2:16])=[O:15])[C:7]([OH:18])=[N:12][CH:11]=1
Reactant: O=N[O-]
Reactant: NC(=O)c1nc(F)cnc1N
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NC(=O)c1nc(F)cnc1O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 78.1 %

Procedure:
While keeping 285 ml of 97% sulfuric acid at 5-12° C. by cooling it with ice, 28.5 g of 3-amino-6-fluoro-2-pyrazinecarboxamide was added thereto to form a uniform solution. After adding 18.9 g of sodium nitrite to the solution at 5-12° C., the mixture thus obtained was stirred for 1.5 hours while cooling it with ice. While keeping the reaction mixture at a temperature not exceeding 10° C., the reaction mixture was dropwise added to 1.4 L of ice water, and the mixture thus formed was extracted first with one 850 mL portion and then two 200 mL portions of ethyl acetate. The organic layers thus obtained were united, 400 mL of water was added, then 160 mL of saturated aqueous solution of sodium hydrogen carbonate was added, pH was adjusted to 3.0, and the organic layer was separated. The organic layer thus obtained was washed with saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was washed with a mixture of diisopropyl ether and ethyl acetate to obtain 22.4 g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide as a solid product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH:10]2[CH2:15][CH:14]3[NH:16][CH:11]2[CH2:12][CH2:13]3)=[N:6][CH:7]=1.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH:10]2[CH2:15][CH:14]3[N:16]([C:24]([C:23]4[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=4[C:18]4[S:17][CH:21]=[CH:20][CH:19]=4)=[O:25])[CH:11]2[CH2:12][CH2:13]3)=[N:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1-c1cccs1
Reactant: Fc1ccc(OCC2CC3CCC2N3)nc1
Solvent: ClCCl
Product: O=C(c1ccccc1-c1cccs1)N1C2CCC1C(COc1ccc(F)cn1)C2
Reaction time: 18 h
Yield: 45.3 %

Procedure:
To (±)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane (35 mg, 0.2 mmol) in DCM (2.5 mL) was added TEA (25 μL, 0.2 mmol)) followed by 2-(thiophen-2-yl)benzoyl chloride (40 mg, 0.2 mmol) in DCM (2.5 mL). After 18 h, the reaction was diluted with DCM and washed with H2O. The aqueous layer was extracted DCM (1×). The combined organics were dried (Na2SO4). Purification via silica gel chromatography (50-100% EtOAc in hexanes) gave the title compound (37 mg, 57%). MS (ESI) mass calcd. for C23H21FN2O2S, 408.1; m/z found 409.1 [M+H]+.
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:7][F:8])([CH3:6])[CH2:4][OH:5].[CH2:9]([O:16][C@@H:17]([C@@H:43]1[NH:48][C@@H:47]([CH3:49])[CH:46](O)[O:45][CH2:44]1)[C@@H:18]([N:28]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:36]([N:28]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C@@H:18]([CH2:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=1)[C@@H:17]([O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@H:43]1[CH2:44][O:45][C@@H:46]([O:5][CH2:4][C:3]([CH2:7][F:8])([CH2:2][F:1])[CH3:6])[C@H:47]([CH3:49])[NH:48]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: C[C@@H]1N[C@@H]([C@H](OCc2ccccc2)[C@H](Cc2cc(F)cc(F)c2)N(Cc2ccccc2)Cc2ccccc2)COC1O
Reactant: CC(CO)(CF)CF
Product: C[C@@H]1N[C@@H]([C@H](OCc2ccccc2)[C@H](Cc2cc(F)cc(F)c2)N(Cc2ccccc2)Cc2ccccc2)CO[C@H]1OCC(C)(CF)CF
Yield: 42.1 %

Procedure:
React 2,2-di-(fluoromethyl)propanol (2.172 g, 17.5 mmol) with (3S,5R)-5-[(1S,2S)-1-benzyloxy-2-dibenzylamino-3-(3,5-difluorophenyl)-propyl]-3-methylmorpholin-2-ol (2.004 g, 3.5 mmol) essentially as described in Preparation 307 to provide 1.0 g of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1N(C2C=CC=CC=2)[C:7]2[C:12]([C:13](=[O:25])[C:14]=1[CH2:15][C:16]1[CH:17]=[N:18][C:19]([C:22](O)=[O:23])=[CH:20][CH:21]=1)=[CH:11][CH:10]=[C:9]([CH3:26])[N:8]=2)=[O:4].F[P-](F)(F)(F)(F)F.[N:40]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2N=N1.[CH2:60]([NH2:62])[CH3:61].CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:40]([C:44]2[CH:43]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:7]2[C:12]([C:13](=[O:25])[C:14]=1[CH2:15][C:16]1[CH:17]=[N:18][C:19]([C:22](=[O:23])[NH:62][CH2:60][CH3:61])=[CH:20][CH:21]=1)=[CH:11][CH:10]=[C:9]([CH3:26])[N:8]=2)=[O:4]
Reactant: CCN
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: COC(=O)c1c(Cc2ccc(C(=O)O)nc2)c(=O)c2ccc(C)nc2n1-c1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNC(=O)c1ccc(Cc2c(C(=O)OC)n(-c3ccccc3)c3nc(C)ccc3c2=O)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(6-carboxy-pyridin-3-ylmethyl)-7-methyl-4-oxo-1-phenyl-1,4-dihydro[1,8]-naphthyridine-2-carboxylic acid methyl ester (0.11 g) in DCM was added BOP (0.14 g), followed by ethylamine (0.016 g) and Hunig's Base (0.06 mL), and the mixture stirred at RT overnight. The product was taken up in EtOAc and H2O, washed with NaHCO3 (aq), and dried over MgSO4, then filtered, concentrated, and purified by prep TLC using 100% EtOAc, to provide 3-(6-ethylcarbamoyl-pyridin-3-ylmethyl)-7-methyl-4-oxo-1-phenyl-1,4-dihydro[1,8]-naphthyridine-2-carboxylic acid methyl ester (compound 101) as an off-white solid. M+H=457.
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH3:31])[C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:19])[CH:16]=3)[N:11]([CH2:20][CH2:21][O:22]CC3C=CC=CC=3)[C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]>CO>[CH2:30]([N:3]([CH2:1][CH3:2])[C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:19])[CH:16]=3)[N:11]([CH2:20][CH2:21][OH:22])[C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:31]
Reactant: CCN(CC)C(=O)C1CCCc2c1c1cc(F)ccc1n2CCOCc1ccccc1
Solvent: CO
Product: CCN(CC)C(=O)C1CCCc2c1c1cc(F)ccc1n2CCO
Reaction time: 24 h
Yield: 98.8 %

Procedure:
To a solution of 9-(2-benzyloxy-ethyl)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (36) (600 mg, 1.4 mmol) in methanol (40 mL) was added a slurry of Pd/C_(100 mg) in methanol (5 mL). The mixture was placed on the Parr hydrogenator and shaken for 24 h under a hydrogen atmosphere. The reaction was filtered through a pad of celite, washed with methanol and concentrated in vacuo to afford 460 mg (80%) of 6-fluoro-9-(2-hydroxy-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (37) as a yellow oil which was used in the next step without purification. The structure was confirmed by 1H NMR (300 MHz, MeOD-d3) δH 1.18 (3H, t, J=9 Hz, N(CH2CH3)2), 1.35 (3H, t, J=9 Hz, N(CH2CH3)2), 1.80-2.20 (4H, m, 2- and 3-CH2), 2.69-3.88 (2H, m, 1-CH2), 3.40-3.86 (6H, m, N(CH2CH3)2 and NCH2CH2OH), 4.03-4.22 (3H, m, NCH2CH2OH and 4-CH), 6.75-6.95 (2H, m, NCCHCHCFCH), and 7.05-7.15 (1H, m, NCCHCHCFCH.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=CC=CC=2)[CH:3]=[CH:2]1.C([N:17]1[C:29]2[C:28]([OH:30])=[C:27]3[N:31](C(OC(C)(C)C)=O)[C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Cl:46])[CH:22]=2)(OC(C)(C)C)=O.O[C@H]1CCN(C(OC(C)(C)C)=O)C1>>[Cl:38][C:35]1[CH:36]=[C:37]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:27]1[C:28]([O:30][C@H:3]3[CH2:4][CH2:9][NH:1][CH2:2]3)=[C:29]3[NH:17][C:18]4[CH:19]=[CH:20][C:21]([Cl:46])=[CH:22][C:23]=4[C:24]3=[CH:25][C:26]2=1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Cl)cc2c2cc3c4cc(Cl)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Reactant: c1ccc2[nH]ccc2c1
Agent: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Product: Clc1ccc2[nH]c3c(O[C@H]4CCNC4)c4[nH]c5ccc(Cl)cc5c4cc3c2c1

Procedure:
The title compound was prepared in a manner analogous to Example 28 except the starting indole is 5,7-diBOC-2,10-dichloro-6-hydroxyindolo[2,3-b]carbazole and the reagent is (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate. 1H-NMR (400 MHz, CDCl3) δ ppm 9.27 (br s, 2H), 8.35 (s, 1H), 8.07 (s, 2H), 7.38-7.30 (m, 4H), 5.09 (t, J=4.0 Hz, 1H), 3.55-3.46 (m, 2H), 3.29 (d, J=12.0 Hz, 1H), 3.15 (td, J=10.0, 4.8 Hz, 1H), 2.83 (dd, J=11.6, 3.6 Hz, 1H), 2.38-2.28 (m, 1H), 2.21-2.10 (m, 1H); MS (ESI) m/z 408.2 (M−H)−; MS (ESI) m/z 410.1 (M+H)+
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:25](=[O:26])[C:14]3[CH:15]=[N:16][C:17]4[C:18]([O:23][CH3:24])=[CH:19][CH:20]=[CH:21][C:22]=4[C:13]=3[N:12]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:11]2=[O:33])[CH:7]=[CH:8][CH:9]=1.[C:34]1([S:40](Cl)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[C:34]1([S:40]([N:30]2[CH2:31][CH2:32][CH:27]([N:12]3[C:13]4[C:22]5[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH3:24])[C:17]=5[N:16]=[CH:15][C:14]=4[C:25](=[O:26])[N:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=4)[C:11]3=[O:33])[CH2:28][CH2:29]2)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n(C3CCNCC3)c12
Agent: Cl
Product: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n(C3CCN(S(=O)(=O)c4ccccc4)CC3)c12

Procedure:
1-(1-Benzenesulfonyl-piperidin-4-yl)-3-(3-chloro-phenyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (51 mg) was prepared according to general procedure H from 3-(3-chloro-phenyl)-7-methoxy-1-piperidin-4-yl-1H-pyrimido[5,4-c]quinoline-2,4-dione.dihydrochloride (50 mg, 0.1 mmol) and benzenesulfonyl chloride. LCMS: m/z 577 [M+1]+.
Reaction SMILES: C(O)C.[CH2:4]([O:6][C:7](=[O:11])[CH2:8][C:9]#[N:10])[CH3:5].[OH-:12].[Na+].Cl.[NH2:15]O>O>[CH2:4]([O:6][C:7](=[O:11])[CH2:8][C:9](=[NH:15])[NH:10][OH:12])[CH3:5]
Reactant: CCOC(=O)CC#N
Reactant: [OH-]
Reactant: NO
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC(=N)NO
Temperature: 50 °C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
To a ethanol solution (40 ml) of cyano-acetic acid ethyl ester (9.9 g, 0.1 mol), the mixture solution of sodium hydroxide (4 g, 0.1 mol) in water (40 ml) and 5 M hydroxylamine hydrochloride (20 ml) was added and the reaction mixture was stirred at 50° C. overnight. After being concentrated, the reaction mixture was diluted with water and extrated with ethyl acetate. The organic layer was dried, concentrated again. The residue was purified by column chromatography with 30˜70% ethyl acetate in hexanes to give 3.32 g (22.7%) of (N-Hydroxycarbamimidoyl)-acetic acid ethyl ester as white solid. 1H-NMR(CDCl3) d(ppm): 5.04 (ws, 2H), 4.20 (q, 2H), 3.19 (s, 2H) and 1.30 (t, 3H). Step 2: [5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-acetic acid ethyl ester: To a dichloromethane solution (10 ml) of (N-hydroxycarbamimidoyl)-acetic acid ethyl ester (1.46 g, 10 mmol) and triethylamine, 3-chlorobenzoyl chloride (1.75 g, 10 mmol) was added slowly at 5° C. and the reaction mixture was stirred for 10 min. DMF (8 ml) was added to the reaction mixture was heated to 135° C. for 2 h. Standard work-up, the product was passed column with dichloromethane to give 1.2 g (45%) of [5-(3-chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-acetic acid ethyl ester as pale-yellow oil. 1H-NMR(CDCl3) d(ppm): 8.168 (s, 1H), 8.04 (d, 1H), 7.59 (d, 1H), 7.49 (t, 1H), 4.26 (q, 2H), 3.91 (s, 2H) and 1.31 (t, 3H). Step 3: [5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-acetic acid hydrazide: 5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-acetic acid ethyl ester (0.64 g, 2.4 mmol) was mixed with 37% hydrazine (1.6 ml) in ethabol (10 ml) at 80° C. for 4 h. The reaction mixture was concentrated and diluted with water. The precipitate was filtered, washed with water to give 0.51 g (83.3%) of [5-(3-chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-acetic acid hydrazide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C@@H:8]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1)[CH2:9][CH2:10][C:11]([NH:13][NH:14][C:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[N:22][CH:21]=[CH:20]2)=O)=[O:12])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.CCN(C(C)C)C(C)C>C1COCC1>[CH:23]1[C:24]2[C:19](=[CH:18][C:17]([C:15]3[O:12][C:11]([CH2:10][CH2:9][C@@H:8]([NH:7][C:6](=[O:38])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:27][C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:30][CH:29]=4)=[N:13][N:14]=3)=[CH:26][CH:25]=2)[CH:20]=[CH:21][N:22]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CCC(=O)NNC(=O)c1ccc2cnccc2c1)Cc1ccc(C(F)(F)F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@H](CCc1nnc(-c2ccc3cnccc3c2)o1)Cc1ccc(C(F)(F)F)cc1
Yield: 78 %

Procedure:
tert-Butyl((1R)-4-(2-(6-isoquinolinylcarbonyl)hydrazino)-4-oxo-1-(4-(trifluoromethyl)benzyl)butyl)carbamate (0.080 g, 0.15 mmol) and triphenylphosphine (0.070 mL, 0.30 mmol), and 0.5 mL CCl4 were heated under nitrogen in 10 mL THF at 50° C. for 20 hours. 0.2 mL DIEA was added, and the reaction mixture was heated at reflux 4 hours. The reaction mixture was filtered and the solid was washed with THF. The filtrate was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate (3×). The solvent was evaporated, and the residue was purified by chromatography on silica gel (60% EtOAc in hexane) to provide the product as a white solid (0.06 g, 78%). LCMS (API-ES) m/z: 513 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.CN(C)C(=O)C.[CH2:16]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36](Cl)=[S:37])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1C=CC=CC=1>[O:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][C:36](=[S:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:5][CH2:6]1
Reactant: NCCN1CCOCC1
Reactant: CCCCCCCCCCCCCCCCCCCCC(=S)Cl
Solvent: c1ccccc1
Solvent: CC(=O)N(C)C
Product: CCCCCCCCCCCCCCCCCCCCC(=S)NCCN1CCOCC1

Procedure:
2.6 Grams of N-(2-aminoethyl)morpholine and 30 ml of N,N-dimethylacetamide were charged in a flask equipped with a stirrer, a condenser and a calcium chloride drying tube and stirred with ice cooling. To the resulting solution was slowly added dropwise 7.5 g of 11-decylthioundecanoic acid chloride. After completion of the addition, the temperature of the solution was returned to room temperature, followed by further stirring for 2 hours. The reaction mixture was diluted with 300 ml of benzene, and washed with 5% aqueous sodium bicarbonate solution, pure water and saturated aqueous sodium chloride solution in succession. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain a crystal. The crystal was recrystallized from n-hexane to obtain 7.3 g of the desired product. m.p. 80° C.
Reaction SMILES: [C:1]([O:6][CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:5])[C@H:2]([CH3:4])O.S(Cl)([Cl:23])(=O)=O>CN(C)C=O>[Cl:23][C@H:2]([CH3:4])[C:1]([O:6][CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: C[C@H](O)C(=O)OC(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: CN(C)C=O
Product: C[C@@H](Cl)C(=O)OC(c1ccccc1)c1ccccc1
Temperature: -40 °C

Procedure:
In 11 ml of dimethylformamide was dissolved 2.16 g of benzhydryl L-lactate. After cooling the solution to -40° C., 0.8 ml of sulfuryl chloride was added thereto followed by stirring for an hour. Thereafter the reaction solution was extracted with ethyl acetate and a sodium bicarbonate aqueous solution. The organic phase was washed with water, dried and then concentrated to dryness to give 1.8 g of benzhydryl (2R)-2-chloropropionate. This ester was reacted with 3.1 g of allyl (Z)-2-hydroxyimino-2-(2-tritylaminothiazol-4-yl)acetate prepared in a manner similar to the description of Published Unexamined Japanese Patent Application No. 149289/80 in 16 ml of dimethylsulfoxide overnight at room temperature in the presence of 1.8 g of potassium carbonate. The reaction solution was partitioned with ice water and ethyl acetate. The organic phase was washed with water, dried and concentrated. The residue was dissolved in 30 ml of methylene chloride. To the solution were added 182 mg of triphenylphosphine and 34 mg of tetrakistriphenylphosphine palladium. The mixture was stirred at room temperature for 30 minutes. Then, a solution of 1.26 g of potassium 2-ethylhexanoate in ethyl acetate. After stirring at room temperature for 2 hours, 45 ml of isopropyl ether was added and the mixture was allowed to stand overnight at 0° C. The obtained precipitates were partitioned in ethyl acetate-acidic water (pH 2.8). The organic phase was washed with water, dried and concentrated to give 2.13 g of 2-(2-tritylamino-thiazol-4-yl)-2-{(1S)-1-diphenylmethoxycarbonylethoxyimino}acetic acid.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[C:5]([C:18]([O:20]C)=[O:19])=[N:6][CH:7]=[C:8]([O:10][CH2:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[CH:9]=1.Cl.O1CCOCC1>C1COCC1>[F:3][C:4]1[C:5]([C:18]([OH:20])=[O:19])=[N:6][CH:7]=[C:8]([O:10][CH2:11][C:12]([F:16])([F:17])[CH:13]([F:15])[F:14])[CH:9]=1
Reactant: COC(=O)c1ncc(OCC(F)(F)C(F)F)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C(O)c1ncc(OCC(F)(F)C(F)F)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 116.4 %

Procedure:
Sodium hydroxide (2 M in water, 2 mL, 4.0 mmol) is added to a solution of methyl 3-fluoro-5-(2,2,3,3-tetrafluoropropoxyl)pyridine-2-carboxylate (430 mg, 0.1.51 mmol) in THF (15 mL). The reaction is stirred at room temperature for 18 hours. The reaction is quenched by the addition of 4 M HCl in dioxane (1.25 mL, 5 mmol) and the solution concentrated to give the crude title compound (476 mg, 99%). ES/MS (m/e): 222.0 (M+1).