Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]([NH:39]C(=O)OC(C)(C)C)[C@@H:9]([OH:38])[CH2:10][C@@H:11]([NH:25][C:26](=[O:37])[C@@H:27]([NH:32][C:33]([O:35][CH3:36])=[O:34])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:39][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]([OH:38])[CH2:10][C@@H:11]([NH:25][C:26]([C@@H:27]([NH:32][C:33](=[O:34])[O:35][CH3:36])[C:28]([CH3:31])([CH3:30])[CH3:29])=[O:37])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 108.9 %

Procedure:
A solution of the product of Example 2B (3.5 g, 5.5 mmol) in dichloromethane (40 mL) was treated with trifluoroacetic acid (20 mL), stirred at 25° C. for 1 hour, and concentrated. The concentrate was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated to afford the crude product (3.19 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:15][NH:16]C(=O)C(F)(F)F)[CH2:10][C:11]([O:13]C)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]>CO.[OH-].[Na+]>[NH2:16][CH2:15][C@@H:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([NH2:1])[CH:3]=1)[CH2:10][C:11]([OH:13])=[O:12]
Reactant: COC(=O)C[C@@H](CNC(=O)C(F)(F)F)c1ccc(Cl)c(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC[C@H](CC(=O)O)c1ccc(Cl)c(N)c1

Procedure:
Two-hundred (200) mg of methyl (3R)-3-(3-amino-4-chlorophenyl)-4-(2,2,2-trifluoroacetylamino)butanoate (65b) was dissolved in 2.5 mL of methanol and 0.2 mL of 2N sodium hydroxide, the reaction mixture was stirred at room temperature for 16 hours, the solvent was removed under reduced pressure, and the residue purified by preparative HPLC to provide 90 mg of the title compound (65c). 1H NMR (400 MHz, CD3OD): δ 7.21 (d, J=8.0 Hz, 1H), 6.83 (s, 1H), 6.65 (d, J=8.0 Hz, 1H), 3.30-3.26 (m, 2H), 3.15-3.11 (m, 1H), 2.74 (dd, J=16.4, 6.4 Hz, 1H), 2.62 (dd, J=16.4, 6.4 Hz, 1H); MS (ESI) m/z 229.0 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][C@:10]3([CH2:16][CH2:15][NH:14][C:13]3=[O:17])[N:9]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:5]=[CH:6][CH:7]=1.[F:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]Br>>[F:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28][O:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][C@:10]3([CH2:16][CH2:15][NH:14][C:13]3=[O:17])[N:9]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccccc1CBr
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2cccc(O)c2)CC[C@]12CCNC2=O
Product: CC(C)(C)OC(=O)N1[C@@H](c2cccc(OCc3ccccc3F)c2)CC[C@]12CCNC2=O
Yield: 78 %

Procedure:
The title compound (0.420 g, 78%) was prepared from 1,1-dimethylethyl (2R,5R)-2-(3-hydroxyphenyl)-6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate (D45, 410 mg, 1.23 mmol) and 2-fluorobenzyl bromide using a similar procedure to that set out earlier in Description 11.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[NH:28][C:29]([O:31]C1C=CC=CC=1)=O)[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=2)[N:9]=[CH:8][CH:7]=1.[CH:38]1([NH2:41])[CH2:40][CH2:39]1.CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[NH:28][C:29]([NH:41][CH:38]1[CH2:40][CH2:39]1)=[O:31])[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=2)[N:9]=[CH:8][CH:7]=1
Reactant: NC1CC1
Reactant: COCCOc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4)c(Cl)c3)c2cc1C(=O)OC
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)c2cc1C(=O)OC

Procedure:
Methyl 4-{3-chloro-4-[(phenoxycarbonyl)amino]phenoxy}-7-(2-methoxyethoxy)-6-quinolinecarboxylate (3.2 g), cyclopropylamine (1.3 ml) and dimethylformamide (20 ml) were stirred together at 60° C. for 10 minutes. The mixture was returned to room temperature, water was added, and extraction was performed with ethyl acetate. Silica gel was added to the extract solution and the solvent was distilled off under reduced pressure. The silica gel was charged into a dry column packed with silica gel, and purification was performed by column chromatography (ethyl acetate, followed by ethyl acetate:methanol=50:1, 20:1) to obtain 2.26 g of the target substance as a white powder.
Reaction SMILES: [O:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:20]2[CH:25]=[CH:24][C:23](OS(C(F)(F)F)(=O)=O)=[C:22]([CH3:34])[CH:21]=2)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][C:10]=1[CH3:35])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].CN(C=O)C.[CH3:41][C:42]([OH:46])([C:44]#[CH:45])[CH3:43]>CCOCC>[O:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:20]2[CH:25]=[CH:24][C:23]([C:45]#[C:44][C:42]([CH3:43])([OH:46])[CH3:41])=[C:22]([CH3:34])[CH:21]=2)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][C:10]=1[CH3:35])[Si:2]([C:5]([CH3:7])([CH3:8])[CH3:6])([CH3:4])[CH3:3]
Reactant: CCC(CC)(c1ccc(O[Si](C)(C)C(C)(C)C)c(C)c1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Reactant: C#CC(C)(C)O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(C#CC(C)(C)O)c(C)c1)c1ccc(O[Si](C)(C)C(C)(C)C)c(C)c1
Temperature: 65 °C
Yield: 32.3 %

Procedure:
To an oven-dried, argon-sparged flask was added Pd[PPh3]4 (46 mg) and anhyd Cul (15 mg). To the flask under argon was added a solution of trifluoromethanesulfonic acid 4-{1-[4-(tert-butyl-dimethylsiloxy)-3-methylphenyl]-1-ethyl-propyl}-2-methylphenyl ester (0.42 g, 0.80 mmol) in anhyd DMF (2.5 mL), TEA (0.56 mL, 4.0 mmol) and 2-methyl-3-butyn-2-ol (0.12 mL, 1.2 mmol). After heating at 65° C. for 15 h, the reaction mixture was diluted with Et2O (50 mL), washed with H2O (2×30 mL) and brine, then dried (Na2SO4) and concentrated under reduced pressure. The crude material was chromatographed (silica, EtOAc/Hex, 0:100 to 10:90) to afford the title compound (0.12 g, 32%) as an orange oil. 1H-NMR (CDCl3) δ 7.26 (1.4H, d, J=8.1), 7.01 (1H, d, J=1.8), 6.94 (1H, dd, J=1.8, 8.1), 6.85 (1H, d, J=2.3), 6.80 (1H, dd, J=2.3, 8.3), 6.63 (1H, d, J=8.3), 2.36 (3H, s), 2.14 (3H, s), 2.03 (4H, q, J=7.3), 1.63 (6H, s), 1.01 (9H, s), 0.59 (6H, t, J=7.3), 0.20 (6H, s); Rf=0.10 (silica, 1:9 EtOAct/Hx).
Reaction SMILES: [N:1]1[CH:2]=[N:3][N:4]2[C:9]([NH2:10])=[CH:8][CH:7]=[CH:6][C:5]=12.N12[CH2:21][CH2:20][CH2:19][N:18]=[C:17]1[CH2:16]CCCC2.[NH:22]1[CH:26]=[CH:25][CH:24]=[N:23]1>>[N:22]1([C:2]2[N:1]=[C:5]3[CH:6]=[C:7]([C:20]4[CH:19]=[N:18][CH:17]=[CH:16][CH:21]=4)[CH:8]=[C:9]([NH2:10])[N:4]3[N:3]=2)[CH:26]=[CH:25][CH:24]=[N:23]1
Reactant: Nc1cccc2ncnn12
Reactant: C1CCC2=NCCCN2CC1
Reactant: c1cn[nH]c1
Product: Nc1cc(-c2cccnc2)cc2nc(-n3cccn3)nn12

Procedure:
The title compound, MS m/e (%):277 (M+,100), was prepared in accordance with the method of example 339b) from 2-methanesulfinyl-7-pyridin-3-yl—([1,2,4]triazolo[1,5-a]pyridin-5-ylamine and 1,8-diazabicyclo[5.4.0]undec-7-en in pyrazole at 75° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:11]([N:19]=[C:20]=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCOCC>[NH2:6][C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[NH:1][C:20](=[S:21])[NH:19][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5]
Reactant: NC(=O)c1ccccc1N
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CCOCC
Product: NC(=O)c1ccccc1NC(=S)NC(=O)c1ccccc1
Reaction time: 48 h
Yield: 95 %

Procedure:
To a stirred mixture of 13.6 g of 2-aminobenzamide and 200 ml of ether was added dropwise, a solution of 16.3 g of benzoyl isothiocyanate in 100 ml of ether over 30 minutes. After standing 48 hours the solid was collected, giving 28.4 g of N-[[[2-(aminocarbonyl)phenyl]amino]thioxomethyl]benzamide.
Reaction SMILES: [C:1]([BH3-])#N.[Na+].[OH:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[CH3:17].O>O1CCCC1.C(O)=O>[CH3:1][N:15]1[C:16]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][OH:5])[C:12]([CH3:17])=[CH:13][CH2:14]1
Reactant: Cc1ccnc2c(CO)cccc12
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=CO
Solvent: O
Product: CC1=CCN(C)c2c(CO)cccc21
Yield: 23.5 %

Procedure:
Sodium cyanoborohydride (7.9 g) was dissolved in tetrahydrofuran (50 ml). After adding and dissolving 8-hydroxymethyl-4-methylquinoline (3.5 g) in the solution, formic acid (50 ml) was added dropwise thereto with stirring under ice-cooling in nitrogen stream. The mixture was stirred for 5 hours at room temperature. After completion of the reaction, water was added to the reaction mixture and the mixture was concentrated under reduced pressure. The resulting residue was adjusted to alkalinic with a sodium hydroxide aqueous solution and extracted with chloroform. After drying the extract over anhydrous magnesium sulfate, chloroform was distilled off. The resulting residue was purified by silica gel column chromatography [eluent: dichloromethane-methanol(200:1)], then 1,4-dimethyl-8-hydroxymethyl-1,2-dihydroquinoline (0.9 g) was obtained.
Reaction SMILES: ClC1C=CC(O)=CC=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[C:17]([CH2:19][CH2:20][NH:21][C:22](=[O:27])[C:23](Br)([CH3:25])[CH3:24])#[N:18]>>[C:17]([CH2:19][CH2:20][NH:21][C:22](=[O:27])[C:23]([O:16][C:13]1[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=1)([CH3:25])[CH3:24])#[N:18]
Reactant: CC(C)(Br)C(=O)NCCC#N
Reactant: Oc1ccc(F)cc1
Agent: Oc1ccc(Cl)cc1
Product: CC(C)(Oc1ccc(F)cc1)C(=O)NCCC#N

Procedure:
The procedure of Example 1 was repeated except that the p-chlorophenol was replaced by p-fluorophenol, which after the dodium treatment was reacted with N-Cyanoethyl α -bromo-isobutyramide.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[Mn]([O-])(=O)(=O)=[O:13].[K+].[OH2:18]>C(O)(=O)C>[CH3:1][S:2]([C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2)(=[O:13])=[O:18]
Reactant: CSc1nc2cccnc2s1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O
Agent: [K+]
Solvent: CC(=O)O
Product: CS(=O)(=O)c1nc2cccnc2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.1 %

Procedure:
To a stirred, room temperature solution of 2-(methylthio)thiazolo[5,4-b]pyridine (182 mg, 1.0 mmol) in acetic acid (10 mL) was added a solution of potassium permanganate (47.3 mg, 0.3 mmol) in water (6 mL) dropwise. The reaction mixture was stirred at room temperature for 16 h. LCMS showed incomplete conversion. Additional KMnO4 (158 mg) was mixed in and stirred for another 5 h. LCMS showed complete conversion. The reaction mixture was quenched with aqueous sodium sulfite. The resulting mixture was vigorously stirred at room temperature overnight. The resulting solution was partitioned between EtOAc and saturated Na2CO3. The aqueous layer was extracted with ethyl acetate, dried (Na2SO4), and concentrated. To the residue was added aq. Na2CO3 until the pH reaches 7. The precipitate formed was collected by filtration, dried to give 2-(methylsulfonyl)thiazolo[5,4-b]pyridine (43 mg, 0.201 mmol, 20.10% yield) as a tan solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.42 (s, 3 H) 7.62 (dd, J=8.40, 4.60 Hz, 1 H) 8.47 (dd, J=8.33, 1.46 Hz, 1 H) 8.75-8.84 (m, 1H). EST (M+1) 214.9.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:29][NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]2[C:22](=[O:23])[N:21]3[CH:24]=[CH:25][CH:26]=[CH:27][C:20]3=[N:19][C:18]=2[CH3:28])[CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].C(O)CO>O>[CH3:28][C:18]1[N:19]=[C:20]2[CH:27]=[CH:26][CH:25]=[CH:24][N:21]2[C:22](=[O:23])[C:17]=1[CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][N:9]([C:8]2[C:3]3[C:4](=[CH:5][CH:6]=[CH:7][CH:2]=3)[N:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:29]=2)[CH2:10][CH2:11]1
Reactant: Cc1nc2ccccn2c(=O)c1CCN1CCN(C(=NNc2ccccc2)c2ccccc2F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: O
Product: Cc1nc2ccccn2c(=O)c1CCN1CCN(c2nn(-c3ccccc3)c3ccccc23)CC1
Reaction time: 8 h
Yield: 25.5 %

Procedure:
A mixture of 2.5 parts of 3-[2-[4-[(2-fluorophenyl)(2-phenylhydrazono)methyl]-1-piperazinyl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 1 part of potassium carbonate and 27.8 parts of 1,2-ethanediol was stirred overnight at reflux temperature. The reaction mixture was cooled and then poured into water. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in 2-propanol. The salt was filtered off and dried, yielding 0.7 parts (25.5%) of 2-methyl-3-[2-[4-(1-phenyl-1H-indazol-3-yl)-1-piperazinyl]ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 260.0° C. (decomp.) (compound 4).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:37])=[C:4]([C:33]([F:36])=[CH:34][CH:35]=1)[O:5][C:6]1[CH2:10][N:9]([C@@H:11]([CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:12]([NH:14][C:15]2[CH:19]=[CH:18][N:17]([CH2:20]C(O)(C)C)[N:16]=2)=[O:13])[C:8](=[O:32])[CH:7]=1.CN1C=CC(N)=N1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([F:37])=[C:4]([C:33]([F:36])=[CH:34][CH:35]=1)[O:5][C:6]1[CH2:10][N:9]([C@@H:11]([CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:12]([NH:14][C:15]2[CH:19]=[CH:18][N:17]([CH3:20])[N:16]=2)=[O:13])[C:8](=[O:32])[CH:7]=1
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3c(F)ccc(Cl)c3F)=CC2=O)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cn1ccc(N)n1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3c(F)ccc(Cl)c3F)=CC2=O)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (S)-2-[4-(3-chloro-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid (prepared as in Example 72, 160 mg, 0.40 mmol) in N,N-dimethylformamide (3 mL) was treated with 1-methyl-1H-pyrazol-3-ylamine (50 mg, 0.51 mmol), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (450 mg, 1.01 mmol) and N,N-diisopropylethylamine (130 mg, 1.01 mmol). The reaction mixture was stirred for 4 h at 25° C., under nitrogen. The reaction mixture was diluted with ethyl acetate, washed with saturated ammonium chloride, water, a saturated sodium chloride solution and dried over sodium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 20% to 90% ethyl acetate/hexanes) to afford (S)-2-[4-(3-chloro-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-(1-methyl-1H-pyrazol-3-yl)-propionamide as a waxy material. This material was dissolved in dichloromethane (4 mL) and treated with hydrogen chloride in diethyl ether (1 M, 4 mL). Solvents were evaporated and the residue was triturated with diethyl ether. The resulting mixture was filtered to give (S)-2-[4-(3-chloro-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-(1-methyl-1H-pyrazol-3-yl)-propionamide hydrochloride (75 mg, 36%) as a tan solid: LR-ES-MS m/z calculated for C23H25ClF2N4O3 [M]+ 478, observed 479 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.65-1.30 (m, 6H) 1.42-1.83 (m, 7H) 3.71 (s, 3H) 4.27 (d, J=18.7 Hz, 1H) 4.61 (d, J=18.7 Hz, 1H) 4.87 (dd, J=10.3, 5.1 Hz, 1H) 5.22 (s, 1H) 6.38 (d, J=2.1 Hz, 1H) 7.43 (td, J=9.0, 1.7 Hz, 1H) 7.53 (d, J=2.1 Hz, 1H) 7.66 (td, J=9.0, 5.4 Hz, 1H) 10.72 (s, 1H).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].BrC1C=CC(S([O:17][C@@H:18]2[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:20]([C:30]([O:32][CH3:33])=[O:31])[CH2:19]2)(=O)=O)=CC=1.[Br:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][C:44]=1[O:45][CH3:46])[NH:41][C:40](=[O:47])[CH:39]=[C:38]2O>CN1C(=O)CCC1>[Br:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][C:44]=1[O:45][CH3:46])[NH:41][C:40](=[O:47])[CH:39]=[C:38]2[O:17][C@H:18]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[C@H:20]([C:30]([O:32][CH3:33])=[O:31])[CH2:19]1
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Reactant: COc1cc2[nH]c(=O)cc(O)c2cc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COC(=O)[C@@H]1C[C@@H](Oc2cc(=O)[nH]c3cc(OC)c(Br)cc23)CN1C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 6.5 h
Yield: 52.8 %

Procedure:
Cs2CO3 (8.42 g, 25.8 mmol) was added to a solution of 1-tert-butyl 2-methyl (2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate (4 g, 8.61 mmol) and the product from step 1 (3.49 g, 12.92 mmol) in NMP (86 ml) under nitrogen. The mixture was then heated to 60° C. After 6.5 h, the reaction was extracted with water and EtOAc. The organic layer was extracted with water and brine and dried over MgSO4. The solvent was then removed in vacuo. The crude product (6.5 g) was purified on silica (gradient elution, 0-100% EtOAc/hexanes, and then 0-5% MeOH/DCM) to yield 2.26 g (53%) of the title compound. LRMS ESI+ ((M-Boc)+H)+ 397.3/399.3.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([O:12][CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7]1.[C:26]12[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=1)[NH:31]C(=O)O[C:27]2=[O:28]>>[NH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:26]=1[C:27]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([O:12][CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)=[O:28]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Product: Nc1ccccc1C(=O)NCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Yield: 100 %

Procedure:
Using the method similar to that in Reference Example 1 and using 1-(4-aminobutyl)-4-diphenylmethoxypiperidine instead of 4-methoxybenzylamine and starting from isatoic anhydride (3.18 g), the title compound (9.14 g, about 100%) was synthesized. Recrystallization from ethyl acetate-isopropyl ether yielded a colorless crystal, melting point 74.0 to 75.0° C.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:14]=[CH:13][C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:15][O:16][C:17](=[O:25])/[C:18](/[N+:23]#[C-:24])=[CH:19]/N(C)C.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:15][O:16][C:17]([C:18]1[N:23]=[CH:24][N:12]([CH2:11][C:10]2[CH:13]=[CH:14][C:7]([CH2:6][N:1]3[CH:5]=[CH:4][CH:3]=[N:2]3)=[CH:8][CH:9]=2)[CH:19]=1)=[O:25]
Reactant: [C-]#[N+]/C(=C\N(C)C)C(=O)OC
Reactant: NCc1ccc(Cn2cccn2)cc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cn(Cc2ccc(Cn3cccn3)cc2)cn1
Temperature: 120 °C

Procedure:
A mixture of 4-Pyrazol-1-ylmethyl-benzylamine (550 mg, 2.5 mmol), (Z)-methyl-3-(dimethylamino)-2-isocyanoacrylate (380 mg, 2.5 mmol) and DIPEA (1.3 mL, 7.4 mmol) in 20 mL nBuOH was heated to 120° C. for 16 h. The mixture was concentrated in vacuo and the crude product was used in the next step without further purification. LCMS (method A) RtA=1.210 min; [M+H]+=297.0.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].F[C:12]1[C:21]([F:22])=[CH:20][C:19]2[C:23](=[O:31])[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:25][N:17]3[C:18]=2[C:13]=1[CH2:14][CH2:15][N:16]3[CH3:32]>CN(C)C=O>[F:22][C:21]1[C:12]([CH:5]([C:3]#[N:4])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:13]2[C:18]3=[C:19]([C:23](=[O:31])[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:25][N:17]3[N:16]([CH3:32])[CH2:15][CH2:14]2)[CH:20]=1
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)CCN2C
Reactant: CCOC(=O)CC#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c3c(c(C(C#N)C(=O)OCC)c(F)cc3c1=O)CCN2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.1 %

Procedure:
168 mg (4.2 mmol) of 60% sodium hydride was added to 20 ml of N,N-dimethylformamide, and while cooling on ice, 452 mg (4 mmol) of ethyl cyanoacetate was dropped to the solution. The solution was stirred for 1 hour at room temperature. 612 mg (2 mmol) of ethyl 4,5-difluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylate was added to the solution, and the solution was stirred overnight at room temperature. The solution was heated at 70° C. for 2 hours, and the solvent was removed by distillation. 80 ml of chloroform and 20 ml of water were added to the residue, and the solution was acidified with citric acid. The organic layer was separated and after drying over magnesium sulfate, the solvent was removed by distillation. The residue was purified by column chromatography (silica gel 20 g, eluent solvent; ethyl acetate) to obtain 450 mg of the subject compound (161).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9]([NH2:12])(=[O:11])=[O:10])[S:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:31])[CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:25]1([CH:24]=[CH:23][C:22]([O:1][C:2]2[CH:14]=[CH:13][C:5]3[N:6]=[C:7]([S:9](=[O:11])(=[O:10])[NH2:12])[S:8][C:4]=3[CH:3]=2)=[O:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: NS(=O)(=O)c1nc2ccc(O)cc2s1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1nc2ccc(OC(=O)C=Cc3ccccc3)cc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 6-hydroxy-2-benzothiazolesulfonamide (2.3 g., 0.01 mole), 4-dimethylaminopyridine (100 mg., catalyst) and triethylamine (1.4 ml., 0.01 mole) in dimethylformamide (20 ml.) is added cinnamoyl chloride (1.7 g., 0.01 mole). The reaction mixture is stirred at 25° C. for 2 hours and then poured into ice water and excess hydrochloric acid to give 3.5 g. of 2-sulfamoyl-6-benzothiazolyl 3-phenyl-2-propenoate which melts at 235°-235° C. after recrystallization from ethyl acetatehexane.
Reaction SMILES: [Br-].[C:2]1(C([PH3+])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1COCC1.C([Li])CCC.[CH3:32][CH:33]([CH2:40][CH2:41][CH2:42][CH:43]([CH3:50])[CH2:44][CH2:45][CH2:46][CH:47]([CH3:49])[CH3:48])[CH2:34][CH2:35][CH2:36][C:37](=O)[CH3:38]>O>[CH3:48][C:47]([CH2:46][CH2:45][CH2:44][CH:43]([CH3:50])[CH2:42][CH2:41][CH2:40][CH:33]([CH3:32])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:2])[CH3:38])=[CH2:49]
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)CCCC(C)CCCC(C)CCCC(C)C
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)CCCC(C)CCCC(C)CCCC(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A flask, equipped with a mechanical stirrer and placed under argon, was charged with 1.80 mol (642.6 g) of triphenylmethylphosphonium bromide and 2 L of THF. To this suspension 1.88 mol (1.175 L) of a solution of butyllithium (1.6 mol/L in hexane) were added dropwise during 3 hours at 0° C. The resulting mixture was stirred at 0° C. for an additional hour. Then 1.50 mol (402.7 g) of 6,10,14-trimethyl-2-pentadecanone were added dropwise at 0° C. during 1 hour and the mixture was allowed to warm up to 22 to 23° C. After 2 hours, 150 mL of water were added dropwise and the resulting white suspension was filtered off over decalite. The filtrate was washed thrice with 300 mL of water and dried over Na2SO4. After filtration and evaporation of the solvent in vacuo, the mixture was filtered off over decalite to remove white cristals and the filtrate was evaporated in vacuo. The resulting crude oil was purified by distillation under vacuum (145° C., 0.2 mbar) to give 1.20 mol (319.2 g) of 2,6,10,14-tetramethylpentadecene as a colorless oil (yield: 80% based on 6,10,14-trimethyl-2-pentadecanone; purity: 96.2%-GC area).