Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=[O:6])[CH3:2].[Cl:8][C:9]1[C:18]([NH2:19])=[C:17]([NH:20][CH2:21][C:22]2[O:26][N:25]=[C:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH:23]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.C(N(CC)CC)C>ClCCl>[Cl:8][C:9]1[C:18]([NH:19][C:5](=[O:6])[CH2:4][O:3][CH2:1][CH3:2])=[C:17]([NH:20][CH2:21][C:22]2[O:26][N:25]=[C:24]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[CH:23]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: CCOCC(=O)Cl
Reactant: Nc1c(Cl)nc2ccccc2c1NCc1cc(-c2ccc(F)cc2)no1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCC(=O)Nc1c(Cl)nc2ccccc2c1NCc1cc(-c2ccc(F)cc2)no1
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, ethoxyacetyl chloride (5.5 g, 45 mmol) was added dropwise to a solution of 2-chloro-N4-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}quinoline-3,4-diamine (15.00 g, 40.67 mmol) and triethylamine (8.5 mL, 61 mmol) in dichloromethane (200 mL) at 6° C. After the reaction was stirred for 30 minutes, an analysis by HPLC indicated the presence of starting material, and additional ethoxyacetyl chloride (1.01 g) was added. The stirring was continued, and over the course of five hours, a total of 13 g of ethoxyacetyl chloride was added. The work-up procedure described in Part A of Example 19 was followed to provide N-[2-chloro-4-({[3-(4-fluorophenyl)isoxazol-5-yl]methyl}amino)quinolin-3-yl]-2-ethoxyacetamide as an orange solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=[N:41][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C[CH2:51][N:52](C(C)C)C(C)C>CN(C=O)C>[O:24]=[C:22]([NH:52][CH2:51][C:39]1[CH:40]=[N:41][CH:36]=[CH:37][CH:38]=1)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:16]([NH:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:25]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)CCCCCC(=O)O
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)CCCCCC(=O)NCc1cccnc1
Reaction time: 0.17 h
Yield: 79.6 %

Procedure:
To a solution of 7-((2-((tert-butoxycarbonyl)amino)phenyl)amino)-7-oxoheptanoic acid (1.2 g, 3.42 mmol) in DMF (10 mL) were added HBTU (1.43 g, 3.76 mmol), DIEA (1.3 g, 10.3 mmol) at room temperature. The resulting mixture was stirred for 10 min, then tpyridin-3-ylmethanamine (1.43 g, 3.76 mmol) was added to the reaction solution. The reaction mixture was stirred for 12 h at room temperature. The reaction was quenched with water (100 mL). The resulting mixture was extracted by EtOAc (100 mL×2). The organic layers were combined, dried with anhydrous Na2SO4 and concentrated under reduced pressure. The resulting solid was purified by column chromatography (elute: EtOAc:MeOH=100:1) to afford desired compound (1.2 g, yield 79.7%) as an off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[C:16]([O:20]CCCO)[CH:17]=[CH:18][C:19]=3[C:11]=2[C:10]([CH3:26])([CH3:25])[CH2:9][N:8]([C:27](=[O:36])[C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30](F)[CH:29]=2)[CH:7]=1)=[O:5])[CH3:2].C(OC(C1C2NC3C=C(O)C=CC=3C=2C(C)(C)C[N:44]([C:59](=[O:67])[C:60]2C=CC(F)=CC=2)C=1)=O)C.C(N(C(C)C)CC)(C)C.BrCCCO>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[C:16]([O:20][CH2:60][C:59](=[O:67])[NH2:44])[CH:17]=[CH:18][C:19]=3[C:11]=2[C:10]([CH3:26])([CH3:25])[CH2:9][N:8]([C:27](=[O:36])[C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1cc(O)ccc21
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)c(F)c2)CC(C)(C)c2c1[nH]c1cc(OCCCO)ccc21
Agent: OCCCBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1cc(OCC(N)=O)ccc21
Temperature: 75 °C
Reaction time: 10 h

Procedure:
To prepare 3-(3,4-difluoro-benzoyl)-1,1-dimethyl-8-(3-hydroxy-propoxy)-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester, a mixture of 3-(4-fluorobenzoyl)-8-hydroxy-1,1-dimethyl-1,2,3,6-tetrahydroazepino[4,5-b]-indole-5-carboxylic acid ethyl ester (46 mg, 0.11 mmol), diisopropylethylamine (0.5 mL), and 3-bromo-1-propanol (1.4 mL) in dry acetonitrile (1 mL) was stirred at 75° C. for 10 hours. The solvent was removed in vacuo, and the residue was purified by preparative reverse-phase HPLC, which was then acylated in the manner described in Example 2A. 1HNMR (CDCl3): δ 10.51 (1H, s), 7.86 (1H, s), 7.82 (1H, d), 7.66-7.59 (2H, m), 7.15-7.09 (2H, m), 6.87 (1H, d), 6.74 (1H, m), 4.27-4.15 (4H, m), 4.09 (2H, brs), 3.90 (2H, m), 2.11-2.05 (2H, m), 1.60 (6H, s), 1.26-1.21 (3H, m). MS (ES): 481 (MH+).
Reaction SMILES: [CH2:1]=O.[CH:3]([NH:6][CH:7]([CH3:27])[CH2:8][C:9]1[C:10](=[O:26])[NH:11][CH2:12][CH2:13][CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:25])[CH:20]=3)[C:15]=12)([CH3:5])[CH3:4].[CH:28]([OH:30])=O>>[CH:3]([N:6]([CH:7]([CH3:27])[CH2:8][C:9]1[C:10](=[O:26])[N:11]([CH2:28][OH:30])[CH2:12][CH2:13][CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:25])[CH:20]=3)[C:15]=12)[CH3:1])([CH3:4])[CH3:5]
Reactant: C=O
Reactant: COc1ccc2c(c1)CCC1CCNC(=O)C(CC(C)NC(C)C)=C21
Reactant: O=CO
Product: COc1ccc2c(c1)CCC1CCN(CO)C(=O)C(CC(C)N(C)C(C)C)=C21

Procedure:
24.4 ml of 37 percent aqueous formaldehyde are added to the stirred suspension of 10.3 g of slow moving 1-(2-isopropylaminopropyl)-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one (Example 1) in 15.7 ml of formic acid. The mixture is refluxed for 8 hours, evaporated and the residue suspended in water. The mixture is basified to pH=10-11 with 3 N aqueous sodium hydroxide and extracted with chloroform. The extract is dried, evaporated, and the residue crystallized from diethyl ether, to give the 1-[2-(N-isopropyl-N-methylamino)-propyl]-3-hydroxymethyl-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one melting at 158°-161°, (R,R-isomer).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[C:15]1([C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:22][CH:23]=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[ClH:31]>O1CCCC1.C(OCC)C.C(O)C>[ClH:31].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:23]3[N:26]4[C:25]([CH:30]=[CH:29][CH:28]=[CH:27]4)=[C:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:22]=3)[CH2:9][CH2:8]2)=[CH:13][CH:14]=1
Reactant: Cc1ccc(CN2CCNCC2)cc1
Reactant: O=CC=C(c1ccccc1)c1ccccn1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(CN2CCN(c3cc(-c4ccccc4)c4ccccn34)CC2)cc1
Temperature: 66 °C
Reaction time: 8 h

Procedure:
A solution of 1-(4-methylbenzyl)piperazine (14 g) in tetrahydrofuran (30 cc) is added in the course of 15 minutes at a temperature in the region of 20° C. to a stirred solution of 3-phenyl-3-(2-pyridyl)propenal (5.4 g) in tetrahydrofuran (150 cc), and the mixture is left with stirring for 8 hours at a temperature in the region of 66° C. After the solution is cooled to a temperature in the region of 20° C., the reaction mixture is evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in ethyl ether (50 cc) and the solution obtained poured onto silica (400 g) contained in a column 4.7 cm in diameter. Elution is performed with a mixture (300 cc) of ethyl ether and petroleum ether (40°-65° C.) (80:20 by volume) and the corresponding eluate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The oil obtained is dissolved in boiling ethyl ether (200 cc). A boiling 2.5N solution (3 cc) of hydrochloric acid in ethyl alcohol is added. After the mixture is cooled to a temperature in the region of 20° C, the precipitate formed is separated by filtration and then recrystallized in boiling ethyl alcohol (400 cc). 3-[4-(4-Methylbenzyl)-1-piperazinyl]-1-phenylindolizine hydrochloride (3.1 g), m.p. 210° C. with decomposition, is thereby obtained.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[I-].[CH:20]1([N:26]([CH3:35])[C:27](N2C=C[N+](C)=C2)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(OCC)(=O)C.CCCCCCC>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:27](=[O:28])[N:26]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH3:35])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CN(C(=O)n1cc[n+](C)c1)C1CCCCC1
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CN(C(=O)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C1CCCCC1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 3-(cyclohexyl-methyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide. The crude product was subjected to flash chromatography (ethyl acetate/heptane, 1:5) (80%, white crystals). HPLC-MS m/z=395.2 (M+1), Rt: 5.7 min.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[BH4-].[Na+]>CO.C(OCC)(=O)C>[N:1]([CH2:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCc1ccc(CO)cc1
Reaction time: 1 h
Yield: 96.8 %

Procedure:
Azide 4 (2.0 g, 12.4 mmol) was dissolved in MeOH (50 ml) and cooled to 0° C. before NaBH4 was added slowly and the reaction mixture was stirred for 1 hour, after which the solvent was evaporated. The residue obtained was dissolved in ethyl acetate (50 ml) and water (50 ml), the phases were separated and the organic phase was washed with water (100 ml), dried over Na2SO4, and evaporated to yield 5 as a clear oil (1.96 g, 12.0 mmol, 97%). Rf=0.45 (DCM); νmax=cm−1; 1H NMR (300 MHz, CDCl3) δ=7.40 (d, 3J(H,H) 8.2 Hz, 2H, ArCH α to CH2OH), 7.33 (d, 3J(H,H)=8.2 Hz, 2H, ArCH α to CH2N3), 4.71 (s, 2H, CH2OH), 4.34 (s, 2H, CH2N3), 1.80 (bs, 1H, OH); 13C NMR (75 MHz, CDCl3) δ=141.0 (ArCCH2OH), 134.7 (ArCCH2N3), 128.5 (ArCH α to CH2N3), 127.4 (ArCH α to CH2OH), 64.9 (CH2OH), 54.5 (CH2N3).
Reaction SMILES: [CH3:1][CH:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[CH3:13][C:14]([CH3:18])=[CH:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][CH:2]1[N:11]([CH2:16][CH:15]=[C:14]([CH3:18])[CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12]
Reactant: CC1Nc2ccccc2NC1=O
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)=CCN1c2ccccc2NC(=O)C1C
Temperature: 25 °C
Yield: 83.9 %

Procedure:
(3RS)-3-Methyl-3,4-dihydroquinoxalin-2(1H)-one (4.86 g, 0.03 mol) dissolved in 50 ml of N,N-dimethylformamide, was alkylated with 4.2 ml (0.033 mol) of 3-methyl-2-buten-1-yl bromide (90%) in the presence of 4.60 g (0.033 mol) of pulverulent potassium carbonate. The reaction mixture was stirred at room temperature until reaction of the educt was complete. The solvent was then stripped off in vacuo, the residue was taken up in ethyl acetate and water, the phases were separated, the aqueous phase was extracted twice with ethyl acetate, and the combined organic extracts were washed twice with water. Drying over sodium sulfate, concentration in vacuo and crystallization from pentane gave 5.80 g (84%) of white crystalline product of melting point 92-93° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([CH3:12])[C:8]2=O)=[CH:4][CH:3]=1.C([CH2:15][C:16]([OH:18])=[O:17])#N.C(O)(=O)C.C([O-])(=O)C.[NH4+]>C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[CH2:6][C:7]([CH3:12])=[C:8]2[CH2:15][C:16]([OH:18])=[O:17]
Reactant: N#CCC(=O)O
Reactant: CC1Cc2ccc(F)cc2C1=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=C(CC(=O)O)c2cc(F)ccc2C1

Procedure:
A mixture of 6-fluoro-2-methylindanone (18.4 g, 0.112 mol), cyanoacetic acid (10.5 g, 0.123 mol), acetic acid (6.6 g), and ammonium acetate (1.7 g) in dry toluene (15.5 ml) is refluxed for 21 hours, as the liberated water is collected in a Dean Stark trap. The mixture is evaporated to dryness, and the residue is dissolved in hot ethanol (60 ml) and 2.2 N aqueous potassium hydroxide solution (14 ml). 85% KOH (22 g) in water (150 ml) is added, and the mixture is refluxed for 13 hours under nitrogen. The ethanol is removed in vacuo, and water (500 ml) is added. The aqueous solution is washed well with ether and is boiled with charcoal, and is filtered. The aqueous filtrate is acidified to pH 2 with 50% cold hydrochloric acid. The precipitate yields the title compound, 5-fluoro-2-methylinden-3-yl acetic acid (m.p. 164-166° C.).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[N:10][N:11]=[C:12]3[C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH:25]=2)[C:22]([OH:24])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:58][C:59]1([CH3:66])[O:63][CH:62]([CH2:64][NH2:65])[CH2:61][O:60]1>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:58][C:59]1([CH3:66])[O:63][CH:62]([CH2:64][NH:65][C:22](=[O:24])[C:21]2[CH:25]=[C:17]([C:12]3[C:13]4[C:8](=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH:16]=[CH:15][CH:14]=4)[C:9]([NH:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[N:10][N:11]=3)[CH:18]=[N:19][CH:20]=2)[CH2:61][O:60]1
Reactant: O=C(O)c1cncc(-c2nnc(NCc3ccccn3)c3c(-c4ccccc4)cccc23)c1
Reactant: CC1(C)OCC(CN)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC1(C)OCC(CNC(=O)c2cncc(-c3nnc(NCc4ccccn4)c4c(-c5ccccc5)cccc34)c2)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.9 %

Procedure:
To a solution of 5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)phthalazin-1-yl)nicotinic acid (0.200 g, 0.461 mmol) in DMF (5 mL) was added HATU (0.526 g, 1.38 mmol) at ambient temperature. DMAP (0.169 g, 1.38 mmol) was added followed by (2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (0.0610 g, 0.461 mmol, commercial) and the contents were stirred at ambient temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water. The reaction mixture was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by combiflash (REDISEP®, silica gel, 12 g, 50% EtOAc/hexanes) to obtain N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-5-(5-phenyl-4-((pyridin-2-ylmethyl)amino) phthalazin-1-yl)nicotinamide (0.0300 g, 11.9%) as an off-white solid. LCMS (Condition 7): retention time 1.76 min, [M+1]=547.2. HPLC (Condition 24): retention time 7.68 min, Purity 96.10%. 1H NMR (400 MHz, DMSO-d6) δ 1.27 (s, 3H), 1.36 (s, 3 H), 3.31-3.51 (m, 2 H), 3.74 (dd, J=5.6 Hz, J=8.4 Hz, 1 H), 4.03 (dd, J=6.0 Hz, J=8.4 Hz, 1 H), 4.26 (m, 1 H), 4.66 (d, J=4.0 Hz, 2 H), 6.33 (dd, J=4.0 Hz, J=4.4 Hz, 1 H), 7.22 (dd, J=5.2 Hz, J=6.4 Hz, 1 H), 7.29 (d, J=6.8 Hz, 1 H), 7.50-7.59 (m, 5 H), 7.69-7.73 (m, 2 H), 7.84 (dd, J=1.6 Hz, J=8.0 Hz, 1 H), 7.93 (dd, J=7.2 Hz, J=8.0 Hz, 1 H), 8.23 (d, J=4.8 Hz, 1 H), 8.51 (t, J=2.0 Hz, 1 H), 8.94 (dd, J=5.6 Hz, J=6.0 Hz, 1 H), 9.0 (d, J=2.0 Hz, 1H), 9.16 (d, J=2.0 Hz, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8](CCCCCCCCCCCCCCC)[C:4]=1[C:5](Cl)=[O:6].[NH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([C:36]([F:39])([F:38])[F:37])[CH:29]=1.C(N(CC)CC)C>ClCCl>[C:32]([C:31]1[CH:34]=[CH:35][C:28]([NH:27][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])=[CH:29][C:30]=1[C:36]([F:37])([F:38])[F:39])#[N:33]
Reactant: CCCCCCCCCCCCCCCc1cccc(OC)c1C(=O)Cl
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1

Procedure:
2-Methoxy-6-pentadecyl-benzoyl chloride was condensed with 4-Amino-2-trifluoromethyl benzonitrile in dichloromethane in presence of triethylamine as acid scavenger to yield N-(4-Cyano-3-trifluoromethyl-phenyl)-2-methoxy-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([N:12]2[CH2:16][C@@H:15]3[CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][C@@H:14]3[CH2:13]2)[CH:9]=[N:10][CH:11]=1)=[O:5])C.[OH-].[Na+]>C(O)C.O.C(OCC)(=O)C>[C:23]([O:22][C:20]([N:18]1[CH2:19][C@H:14]2[CH2:13][N:12]([C:8]3[CH:9]=[N:10][CH:11]=[C:6]([CH:7]=3)[C:4]([OH:5])=[O:3])[CH2:16][C@H:15]2[CH2:17]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CCOC(=O)c1cncc(N2C[C@H]3CN(C(=O)OC(C)(C)C)C[C@H]3C2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
The product from Example 33A (3.20 g, 8.90 mmol) was dissolved in a solvent mixture of ethanol (40 mL) and water (20 mL). Sodium hydroxide (2.0 M, 13 mL) was added, and the reaction mixture was stirred at ambient temperature for 1 hour. The mixture was then diluted with ethyl acetate (100 mL) and partitioned between ethyl acetate (250 mL) and water (30 mL). The aqueous layer was acidified to pH 4 and repartitioned between dichloromethane (200 mL) and water (250 mL). The organic layer was dried (Na2SO4) and concentrated under vacuum to afford the title compound (3.0 g, 102%). 1H NMR (400 MHz, CD3OD) δ ppm 1.45 (s, 9H), 3.06-3.14 (br s, 2H), 3.27-3.34 (m, 4H), 3.61 (dd, J=10.0, 7.5 Hz, 2H), 3.64-3.71 (m, 2H), 7.57 (dd, J=2.8, 1.8 Hz, 1H), 8.04 (d, J=1.5 Hz, 1H), 8.39 (s, 1H). MS (APCI) m/z 334 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:22])=[O:21])=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]=2)=[C:4]([O:35][CH3:36])[CH:3]=1.[S:37]1[CH:41]=[N:40][N:39]=[C:38]1[NH2:42].C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C>CCOC(C)=O.Cl>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([NH:42][C:38]4[S:37][CH:41]=[N:40][N:39]=4)(=[O:21])=[O:22])=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]=2)=[C:4]([O:35][CH3:36])[CH:3]=1
Reactant: COc1cc(Cl)c(C#N)cc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: Nc1nncs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(Cl)c(C#N)cc1-c1nccc2cc(S(=O)(=O)Nc3nncs3)ccc12
Reaction time: 2 h
Yield: 53.7 %

Procedure:
A vial was charged with perfluorophenyl 1-(4-chloro-5-cyano-2-methoxyphenyl)isoquinoline-6-sulfonate (INTERMEDIATE VVVV, 145.2 mg, 0.268 mmol). 1,3,4-thiadiazol-2-amine (32.6 mg, 0.322 mmol), and cesium carbonate (262 mg, 0.805 mmol). Acetonitrile (1342 μl) was added, and the mixture was stirred for 2 h. The mixture was diluted with EtOAc and 0.5 N aq. HCl. The layers were separated, and the aq. layer was extracted with 10% MeOH/EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was concentrated from MeOH, then the mixture was filtered through a membrane filter. The collected solid was washed with MeOH (3×), dried under a stream of N2 (g), then dried under vacuum to give 1-(4-chloro-5-cyano-2-methoxyphenyl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide (65.89 mg, 0.144 mmol, 53.6% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=14.51 (br. s., 1H), 8.80 (s, 1H), 8.70 (d, J=5.7 Hz, 1H), 8.58 (d, J=1.6 Hz, 1H), 8.16 (d, J=5.7 Hz, 1H), 7.98 (s, 1H), 7.89-7.82 (m, 1H), 7.80-7.72 (m, 1H), 7.65 (s, 1H), 3.78 (s, 3H). m/z (ESI) 458.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([NH2:14])[CH:10]=2)=[CH:5][CH:4]=1.[Cl:17][C:18]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:19]=1[C:20]([N:22]=[C:23]=[O:24])=[O:21].[N-]=C=O>CO>[Cl:17][C:18]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:19]=1[C:20]([NH:22][C:23]([NH:14][C:11]1[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=2)[O:13][N:12]=1)=[O:24])=[O:21]
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Reactant: Nc1cc(-c2ccc(C(F)(F)F)cc2)on1
Agent: [N-]=C=O
Solvent: CO
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1cc(-c2ccc(C(F)(F)F)cc2)on1

Procedure:
5-(4-(Trifluoromethyl)phenyl)-3-aminoisoxazole (500 grams) in 6 l. 1,2-dichloromethane was reacted in a reaction vessel with 2,6-dichlorobenzoyl isocyanate (567 grams). The isocyanate was added in rapid dropwise fashion over one hour keeping the temperature between 20°-40° C. The reaction mixture was allowed to react at 40° C. for three hours and was then stripped and slurried in 1 l. methanol. A white solid product formed which was filtered, dried in an air dryer, and then identified by NMR analysis as the desired compound, yield, 881 grams, m.p.=227°-230° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)=[CH:4][CH:3]=1>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:8][CH2:9][C:10]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[C:6]=2[CH:7]=1
Reactant: O=C(O)c1cccc(F)c1CCc1ccc(Br)cc1
Solvent: O
Product: O=C1c2cc(Br)ccc2CCc2c(F)cccc21
Temperature: 170 °C
Reaction time: 3 h

Procedure:
To 25.8 g (80 mmol) of 2-[2-(4-bromophenyl)ethyl]-3-fluorobenzoic acid was added 550 g of polyphosphoric acid, and the mixture was stirred at 170° C. for 3 hours. After cooling the mixture to 80° C. by allowing to stand, water was added to the mixture and the resulting mixture was cooled to room temperature under stirring by allowing to stand.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[O:15]([CH2:22][CH2:23][NH2:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[O:15]([CH2:22][CH2:23][NH:24][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCOc1ccccc1
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Product: O=[N+]([O-])c1cnc2cccnc2c1NCCOc1ccccc1
Yield: 88.6 %

Procedure:
Using the general method of Example 76, 4-chloro-3-nitro[1,5]naphthyridine (5.0 g, 24 mmol) was reacted with 2-phenoxyethylamine (3.5 mL, 27 mmol) to provide 6.6 g of N4-(2-phenoxyethyl)-3-nitro[1,5]naphthyridin-4-amine as a yellow solid, m.p. 107-108° C. Analysis: Calculated for C16H14N4O3: %C, 61.93; %H, 4.55; %N, 18.05; Found: %C, 61.99; %H, 4.58; %N, 18.42. 1H NMR (300 MHz, DMSO): δ 10.25 (broad s, 1H), 9.39 (broad s, 1H), 8.81 (dd, J=4.1, 1.7 Hz, 1H), 8.25 (dd, J=8.5, 1.7 Hz, 1H), 7.67 (dd, J=8.5, 4.1 Hz, 1H), 7.34-7.26 (m, 2H), 7.01-6.96 (m, 3H), 4.89 (broad s, 2H), 4.35 (t, J=5.1 Hz, 2H); MS (EI): m/e 310.1065 (310.1065 calc'd for C16H14N4O3).