Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH:35]=O)[CH2:30][CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH:48]1([O:53][C:54](=[O:61])[C@H:55]([CH2:57][CH:58]([CH3:60])[CH3:59])[NH2:56])[CH2:52][CH2:51][CH2:50][CH2:49]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCCCCCC>ClC(Cl)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:29][CH2:30][CH:31]([CH2:34][CH2:35][NH:56][C@H:55]([C:54]([O:53][CH:48]2[CH2:49][CH2:50][CH2:51][CH2:52]2)=[O:61])[CH2:57][CH:58]([CH3:59])[CH3:60])[CH2:32][CH2:33]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@H](N)C(=O)OC1CCCC1
Reactant: C=C(C)c1cc(C(=O)N2CCC(CC=O)CC2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCCCCCC
Product: C=C(C)c1cc(C(=O)N2CCC(CCN[C@@H](CC(C)C)C(=O)OC3CCCC3)CC2)c(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of Intermediate D (0.245 g, 0.5 mmol) in dichloroethane (10 mL) was added L-leucine cyclopentyl ester tosylate (0.398 g, 1.07 mmol) and sodium triacetoxyborohydride (0.417 g, 1.97 mmol). The mixture was stirred for one hour then loaded directly onto a silica gel column and eluted with 7:3 ethyl acetate:heptane to yield the desired product (0.250 g, 75% yield). LC/MS: m/z 667.25 [M+H]+
Reaction SMILES: OS(O)(=O)=O.[NH2:6][C:7]1[C:15]([Cl:16])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[Cl:17].[CH3:18]O>>[NH2:6][C:7]1[C:8]([Cl:17])=[CH:9][C:10]([C:11]([O:13][CH3:18])=[O:12])=[CH:14][C:15]=1[Cl:16]
Reactant: CO
Reactant: Nc1c(Cl)cc(C(=O)O)cc1Cl
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Cl)c(N)c(Cl)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
conc. H2SO4 (2.5 mL, 97.04 mmol) was added drop wise to a stirred solution of 4-amino-3,5-dichlorobenzoic acid (10.0 g, 48.54 mmol) in MeOH (150 mL) at 0° C. and the reaction mixture was then stirred at 80° C. for 8 h. The volatiles were evaporated; ice cold water was added to the residue and which was then extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to afford the title compound as a white solid (7.5 g, 70%): 1H NMR (300 MHz, DMSO-d6) δ 8.05 (s, 2H), 3.96 (s, 3H); ESIMS m/z 282 ([M]+); IR (KBr): 1733, 762, 514 cm−1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH2:26]([N:28]1[CH2:33][CH2:32][NH:31][C@H:30]([CH3:34])[CH2:29]1)[CH3:27].C(C1C=CC(C2C=NN(C3C=CC(C(O)=O)=CN=3)C=2O)=C(C)C=1)#N>>[CH2:26]([N:28]1[CH2:33][CH2:32][N:31]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:21])[C@H:30]([CH3:34])[CH2:29]1)[CH3:27]
Reactant: CCN1CCN[C@H](C)C1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Agent: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: CCN1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)c(F)c4C)c3O)nc2)[C@H](C)C1

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-1-ethyl-3-methylpiperazine and 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.24 (t, J=7.33 Hz, 3 H) 1.38 (d, J=7.07 Hz, 3 H) 2.33 (d, J=2.53 Hz, 3 H) 2.95-3.26 (m, 4 H) 3.34-3.55 (m, 2 H) 3.73-4.28 (m, 3 H) 7.64 (br. s., 1 H) 7.71-7.78 (m, 1 H) 7.93-8.68 (m, 4 H). ESI-MS m/z [M+H]+ 449.3.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([C:19]#[N:20])[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1.[OH-].[NH4+:29]>O1CCCC1>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]([NH:8][C:9]2[C:10]([C:11]([NH2:29])=[O:13])=[CH:14][C:15]([C:19]#[N:20])=[CH:16][C:17]=2[CH3:18])=[O:12])[N:4]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1
Reactant: [NH4+]
Reactant: Cc1cc(C#N)cc2c(=O)oc(-c3cc(Cl)nn3-c3ncccc3Cl)nc12
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc(C(N)=O)c1NC(=O)c1cc(Cl)nn1-c1ncccc1Cl
Reaction time: 0.08 h

Procedure:
To a solution of 2-[3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-cyano-8-methyl-4H-3,1-benzoxazin-4-one (i.e. the cyano-benzoxazinone product of Example 3, Step F) (100 mg, 0.25 mmol) in tetrahydrofuran (5 mL) was added dropwise ammonium hydroxide (0.5 mL, 12.8 mmol) at room temperature. The reaction mixture was then stirred for five minutes, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was purified by chromatography on silica gel to afford 55 mg of the title compound, a compound of the present invention, as a white solid that decomposes in the melting apparatus above 255° C.
Reaction SMILES: [O:1]=[C:2]1[NH:21][C:5]2=[N:6][C:7]3[CH:8]=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:11][C:12]=3[CH:13]=[C:4]2[NH:3]1.[CH3:22][NH:23][CH:24]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([N:23]([CH3:22])[C:18](=[O:20])[CH2:17][CH2:16][CH2:15][O:14][C:10]2[CH:9]=[CH:8][C:7]3[N:6]=[C:5]4[NH:21][C:2](=[O:1])[NH:3][C:4]4=[CH:13][C:12]=3[CH:11]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CNC1CCCCCC1
Reactant: O=C(O)CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1
Product: CN(C(=O)CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1)C1CCCCCC1

Procedure:
This compound obtained as the hydrochloride salt, m.p. 180°-182° C., was prepared analogous to Example 15 from 4-[(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)oxy]butyric acid and N-methylcycloheptylamine.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[NH:8][C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:5]=1.Cl.C[N:15](C=O)C>C([O-])(O)=O.[Na+].O1CCOCC1.CCOCC>[ClH:3].[NH2:15][N:8]1[C:4]([Cl:3])=[CH:5][CH:6]=[C:7]1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1ccc(Cl)[nH]1
Reactant: CN(C)C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)c1ccc(Cl)n1N
Reaction time: 0.33 h
Yield: 50 %

Procedure:
A mixture of sodium hydride (60%, 1.01 g, 25 mmol) and methyl 5-chloro-1H-pyrrole-2-carboxylate (J. Chem. Soc. 1965, 459–470, 2.96 g, 19.6 mmol) in DMF (40 mL) at 0° C. was stirred for 20 min, then was added 2,4-dinitrophenolamine (Tetrahedron Lett. 1968, 16, 1909–1910 and J. Heterocyclic Chem. 1967, 413, 3.90 g, 19.6 mmol) and the reaction mixture was stirred at 0° C. to rt overnight. The reaction mixture was diluted with saturated NaHCO3 solution and the product was extracted with EtOAc (3×100 mL). The EtOAc solution was washed with saturated NaHCO3 solution (4×60 mL), 10% LiCl solution (80 mL), brine (80 mL), dried over MgSO4 and concentrated in vacuo to give the crude product as a brown oil. The crude product was treated with 4 N HCl in dioxane in Et2O. The precipitated solid was collected, washed with Et2O and dried in vacuo to obtain the title compound (1.91 g, 50%): 1H NMR (DMSO-d6) δ 6.76 (d, 1H, J=4.4 Hz), 6.11 (d, 1H, J=4.4 Hz), 4.23 (q, 2H, J=6.02 Hz), 1.28 (t, 3H, J=6.02 Hz); 13C NMR (DMSO-d6) δ 159.9, 122.9, 120.3, 114.0, 104.6, 59.8, 14.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)[N:17]=2)[CH:13]=[CH:12][S:11]3)=[CH:4][C:3]=1[O:36][CH3:37].[ClH:38]>O1CCOCC1.CCOCC>[ClH:38].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]4[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]4)[N:17]=2)[CH:13]=[CH:12][S:11]3)=[CH:4][C:3]=1[O:36][CH3:37]
Reactant: COc1cc(-c2nc3sccn3c2-c2ccnc(NC3CCN(C(=O)OC(C)(C)C)CC3)n2)ccc1F
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1cc(-c2nc3sccn3c2-c2ccnc(NC3CCNCC3)n2)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
The tert-butyl 4-({4-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)piperidine-1-carboxylate (0.713 g, 1.36 mmol) was dissolved in 15 ml of dioxane and treated with 7.5 ml of anhydrous 4N HCl in dioxane at room temperature (RT). The reaction mixture was stirred at room temperature for two hours. The mixture was then diluted with 25 ml of ether and stirred until product separated as a solid. Solid product was filtered and washed with ether. The solid was dissolved in MeOH (20 ml) and concentrated to dryness twice. The product was dried at high vacuum to yield 0.652g of yellow solid (bis HCl salt) (96%). 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 9.32 (br. s, 1H), 8.10 (d, J=4.7 Hz, 1H), 7.61 (d, J=4.3 Hz, 1H), 7.39 (dd, J=8.2, 2.0 Hz, 1H), 7.33 (dd, J=11.3, 8.2 Hz, 1H), 7.19 (ddd, J=8.2, 4.3, 2.0 Hz, 1H), 6.56 (d, J=6.7 Hz, 1H), 4.30-4.20 (m, 1H), 3.86 (s, 3H), 3.40-3.32 (m, 2H), 3.12-2.96 (m, 2H), 2.22-2.12 (m, 2H), 1.99-1.86(m, 2H). LCMS: 425 [M+H].
Reaction SMILES: C(N=C=NC(C)C)(C)C.[OH:10][C:11]1[C:12]([C:17]([OH:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=1.[F:20][C:21]1[C:26](O)=[C:25]([F:28])[C:24]([F:29])=[C:23]([F:30])[C:22]=1[F:31]>C(Cl)Cl.O>[OH:10][C:11]1[C:12]([C:17]([O:19][C:26]2[C:25]([F:28])=[C:24]([F:29])[C:23]([F:30])=[C:22]([F:31])[C:21]=2[F:20])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C(O)c1ncccc1O
Agent: CC(C)N=C=NC(C)C
Solvent: O
Solvent: ClCCl
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ncccc1O
Reaction time: 12 h

Procedure:
At 20-25° C. 13 g of N,N′-diisopropylcarbodiimide (DIC) were added dropwise to a solution of 14 g of 3-hydroxypyridine-2-carboxylic acid and 18.5 g of pentafluorophenol in 700 ml of CH2Cl2. After the reaction had ended (about 40 min), the solution was allowed to stand at 20-25° C. for about 12 hours. The solvent was removed, and the residue formed was then taken up in water and the solution was extracted with CH2Cl2. The organic phase gave, after drying and removal of the solvent, 29 g of the title compound.
Reaction SMILES: Br[C:2]1[C:3](=[O:28])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[CH3:55][O:56][C:57]1[N:62]=[CH:61][C:60](B(O)O)=[CH:59][CH:58]=1>>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[CH:7][CH:8]=2)[C:3](=[O:28])[C:2]=1[C:60]1[CH:61]=[N:62][C:57]([O:56][CH3:55])=[CH:58][CH:59]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: O=C1C(Br)=C(c2ccc(F)cc2F)c2ccc(OCCN3CCOCC3)cc21
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: COc1ccc(C2=C(c3ccc(F)cc3F)c3ccc(OCCN4CCOCC4)cc3C2=O)cn1
Yield: 81 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(2,4-difluorophenyl)-6-{2-(morpholin-4-yl)ethoxy}-1H-inden-1-one obtained in Step 1 of Example 124 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one and 6-methoxy-3-pyridinylboronic acid instead of 3-pyridinylboronic acid to obtain the title compound (81%).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([S:7]([O-:9])=[O:8])=[CH:3][CH:2]=1.[Na+].[CH2:12](N(CC)CC)C.O>CP(OC)(=O)OC>[C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([S:7]([CH3:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CCN(CC)CC
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: COP(C)(=O)OC
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(C)(=O)=O)cc1
Temperature: 171 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
A suspension of 22.7 g of sodium p-toluenesulphinate in 50 ml of dimethyl methanephosphonate is treated with 12.6 g of triethylamine and the mixture is heated in the course of 45 minutes to 167° C. The temperature is raised further to 171° C. and kept thereat for a further 30 minutes. The cooled solution is poured into 700 ml of water and stired for 1 hour. The precipitated crystalline product is collected by filtration and washed with 350 ml of water. The residue is dried at 25 torr and 50° C., affording 17.2 g (80.9% of theory) of p-tolylmethylsulphone of the formula ##STR14## with a melting point of 85°-96° C. and a purity of 95.8%.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:23]O)[CH:19]=[CH:20][C:21]=1[Cl:22]>>[Cl:15][C:16]1[CH:17]=[C:18]([CH2:23][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccc(Cl)c(Cl)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Cl)c(Cl)c2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (3,4-dichlorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.12 (2H, s), 5.66 (1H, d, J=1.6 Hz), 7.20 (1H, d, J=2.0 Hz), 7.35 (1H, dd, J=1.2, 5.2 Hz), 7.40 (1H, d, J=8.0 Hz), 7.52 (2H, m), 7.98 (1H, s), 8.64 (1H, d, J=4.8 Hz). [M+H] Calc'd for C16H10C12N4O, 345. Found, 345.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].CO[CH:14]1[CH2:18][CH2:17][CH:16](OC)O1>C(O)(=O)C.O>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[N:4]1[CH:14]=[CH:18][CH:17]=[CH:16]1
Reactant: COC1CCC(OC)O1
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(-n2cccc2)c(Cl)c1
Temperature: 25 °C
Yield: 84.2 %

Procedure:
A stirred mixture of 20.0 g (0.12 mole) of 2-chloro-4-nitroaniline and 17.9 g (0.14 mole) of 2,5-dimethoxytetrahydrofuran in 30 ml of glacial acetic acid was heated at reflux for three hours. The mixture was cooled to room temperature, diluted with water, and extracted with diethyl ether. The extract was washed with a saturated aqueous potassium carbonate solution then dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure to leave a solid. The solid was purified by recrystallization from methylcyclohexane to yield 22.5 g of 1-(2-chloro-4-nitrophenyl)pyrrole (mp 54°-55° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[F:23].[CH3:24][N:25]1[C:29]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[C:28]([C:36](O)=[O:37])[C:27](=[O:39])[N:26]1[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:36]([C:28]2[C:27](=[O:39])[N:26]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:25]([CH3:24])[C:29]=2[C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[O:37])=[CH:18][C:17]=1[F:23]
Reactant: Cn1c(-c2ccncc2)c(C(=O)O)c(=O)n1-c1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4c(-c5ccncc5)n(C)n(-c5ccccc5)c4=O)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.7 %

Procedure:
4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorobenzenamine (628.9 mg, 2.001 mmol) and 1-methyl-3-oxo-2-phenyl-5-(pyridin-4-yl)-2,3-dihydro-1H-pyrazole-4-carboxylic acid (520 mg, 1.76 mmol) (1.679 g of a ˜30% by weight solution of acid in DMF) was dissolved in DCM (20 ml) and HATU (1.042 g, 2.740 mmol) was added. The reaction was stirred under nitrogen at room temperature overnight, and then filtered. The filtered solid was washed with dichloromethane, and the filtrate was concentrated and purified on silica gel (DCM→50:1→25:1→10:1 DCM/MeOH). The fractions with product were collected, concentrated, and purified on silica gel (30:1→20:1→10:1 DCM/MeOH). Fractions with product collected, concentrated, and purified again on silica gel (25:1→20:1 DCM/MeOH). Fractions with pure product collected and concentrated to give desired N-(4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl)-1-methyl-3-oxo-2-phenyl-5-(pyridin-4-yl)-2,3-dihydro-1H-pyrazole-4-carboxamide (225.9 mg, 0.382 mmol, 22% yield). MS (ESI pos. ion) m/z: 592 (MH+). Calc'd exact mass for C33H26FN5O5: 591. 1H NMR (400 MHz, CDCl3): 10.96 (s, 1H), 8.88 (d, J=4.0 Hz, 2H), 8.48 (d, J=6.0 Hz, 1H), 7.83 (d, J=12 Hz, 1H), 7.65-7.47 (m, 8H), 7.41 (s, 1H), 7.30 (d, J=10.0 Hz, 1H), 7.16 (t, J=8.0 Hz, 1H), 6.40 (d, J=5.2 Hz, 1H), 4.05 (s, 6H), 3.20 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:12])=[N:4][C:5](Cl)=[CH:6][C:7]=1[CH2:8][CH2:9][CH3:10].[H][H]>CO.O.[Pd]>[NH2:1][C:2]1[C:3]([Cl:12])=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH3:10]
Reactant: [H][H]
Reactant: CCCc1cc(Cl)nc(Cl)c1N
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CCCc1ccnc(Cl)c1N

Procedure:
In a 1 liter stirred autoclave 150.0 g of 3-amino-2,6-dichloro-4-n-propylpyridine and 5.0 g of 10% palladium/carbon are suspended in a mixture of 450.0 ml of methanol and 150.0 ml of water and hydrogenated under 3 bars of hydrogen at 50°-70° C. until the uptake of gas has ceased.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[NH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1.[CH2:17]([O:19][CH:20]([O:24][CH2:25][CH3:26])[CH2:21][CH2:22]Cl)[CH3:18]>>[CH2:17]([O:19][CH:20]([O:24][CH2:25][CH3:26])[CH2:21][CH2:22][N:9]1[C:8](=[O:12])[CH2:7][C:6]2[CH:13]=[C:14]([O:15][CH3:16])[C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH:11]=[CH:10]1)[CH3:18]
Reactant: COc1cc2c(cc1OC)CC(=O)NC=C2
Reactant: CCOC(CCCl)OCC
Product: CCOC(CCN1C=Cc2cc(OC)c(OC)cc2CC1=O)OCC

Procedure:
This is prepared analogously to Example H (a) by reacting 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one with 3-chloro-propionaldehyde diethyl acetal.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].C(N(CC)C(C)C)(C)C.[F:17][C:18]([F:46])([F:45])[C:19]1[CH:20]=[C:21]([CH:42]=[CH:43][CH:44]=1)[CH2:22][NH:23][C:24](=[O:41])[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]2[CH:36]=[C:35](F)[CH:34]=[CH:33][C:32]=2[N+:38]([O-:40])=[O:39])[CH:26]=1>CN(C)C=O.O>[F:17][C:18]([F:45])([F:46])[C:19]1[CH:20]=[C:21]([CH:42]=[CH:43][CH:44]=1)[CH2:22][NH:23][C:24](=[O:41])[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]2[CH:36]=[C:35]([N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])[CH:34]=[CH:33][C:32]=2[N+:38]([O-:40])=[O:39])[CH:26]=1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(F)ccc2[N+](=O)[O-])c1
Reactant: CCCNCCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCN(CCC)c1ccc([N+](=O)[O-])c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reaction time: 8 h

Procedure:
Into a 10-mL vial, was placed a solution of dipropylamine (216.9 mg, 2.15 mmol, 3.00 equiv) in N,N-dimethylformamide (3 mL), N,N-diisopropylethylamine (277 mg, 2.15 mmol, 3.00 equiv), and a solution of N-(3-(trifluoromethyl)benzyl)-2-(5-fluoro-2-nitrophenyl)isonicotinamide 14d (300 mg, 0.72 mmol, 1.00 equiv) in N,N-dimethylformamide (2 mL). The resulting solution was stirred for 8 h at 90° C. to 100° C. in an oil bath. The resulting solution was diluted with 50 mL of water. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×70 mL of brine, dried over sodium sulfate, and concentrated under vacuum. The crude product was obtained as 400 mg of a yellow to green oil.
Reaction SMILES: C([O:3][C:4](=[O:16])[CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)[N:6]([CH3:8])[CH3:7])C.[OH-].[K+].O.Cl>CN(C=O)C>[Br:15][C:11]1[CH:10]=[C:9]([CH:5]([N:6]([CH3:8])[CH3:7])[C:4]([OH:16])=[O:3])[CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(c1cccc(Br)c1)N(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(C(=O)O)c1cccc(Br)c1
Yield: 93.6 %

Procedure:
To a solution of (3-bromo-phenyl)-dimethylamino-acetic acid ethyl ester (350 mg, 1.2 mmol) in DMF was added potassium hydroxide (4 mL, 50% in water) and water (50 mL). The resulting mixture was refluxed for 25 hours. The mixture was neutralized to pH 7 with concentrated hydrochloric acid and extracted with ethyl acetate (50 mL×4). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to afford (3-Bromo-phenyl)-dimethylamino-acetic acid (290 mg, 94%). MS: m/z 258 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([N:15]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:14])[CH:3]=1.[C:52]([CH2:54][CH2:55][S:56]([C:59]1[CH:64]=[CH:63][C:62]([S:65](Cl)(=[O:67])=[O:66])=[CH:61][CH:60]=1)(=[O:58])=[O:57])#[N:53]>N1C=CC=CC=1>[C:52]([CH2:54][CH2:55][S:56]([C:59]1[CH:64]=[CH:63][C:62]([S:65]([NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([OH:12])=[C:4]([C:13]([N:15]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:14])[CH:3]=2)(=[O:66])=[O:67])=[CH:61][CH:60]=1)(=[O:58])=[O:57])#[N:53]
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1cc(N)c2ccccc2c1O
Reactant: N#CCCS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1cc(NS(=O)(=O)c2ccc(S(=O)(=O)CCC#N)cc2)c2ccccc2c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
A solution of 4-amino-1-hydroxy-N,N-dioctadecyl-2-naphthamide (U.S. Pat. No. 4,135,929) (0.03 mol) in 450 ml of degassed pyridine was cooled to 5° to 10° C. and 8.8 g (0.03 mol) of 4-(2-cyanoethylsulfonyl)benzenesulfonyl chloride was added scoopwise at 0° to 5° C. The mixture was stirred for one hour at this temperature and was warmed to 20° to 25° C. and held for one hour. The reaction mixture was drowned in 2 liters of ice and water, filtered, reslurried in water and dried. The product was recrystallized from hexane to give 18 g (62 percent) of a tan solid, melting point 85° to 86° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O>[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10]
Reactant: Cc1cc(C)c(O)c(Br)c1
Reactant: OB(O)c1ccco1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(C)c(O)c(-c2ccco2)c1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 49.3 %

Procedure:
2-Bromo-4,6-dimethylphenol (500 mg, 2.49 mmol), furan-2-ylboronic acid (88 mg, 2.99 mmol), sodium carbonate (791 mg, 7.47 mmol) and Pd2(dppf)2Cl2 (406 mg, 0.49 mmol) were dissolved in dimethoxyethane/water 6 mL/3 mL, followed by stirring in microwave at 120° C. for 20 minutes. After the completion of the reaction, the reaction mixture was filtered using Celite. The filtrate was added with water, and extracted with ethyl acetate. The obtained organic layer was dried over magnesium sulfate, and purified by column chromatography (ethyl acetate:hexane=1:3) to obtain 2-(furan-2-yl)-4,6-dimethylphenol (231 mg, 45%).