Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O=[C:11]1[CH2:20][CH2:19][CH2:18][C:17]2[N:16]([CH2:21][CH:22]=[CH2:23])[C:15](=[O:24])[CH:14]=[CH:13][C:12]1=2.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:3]1([CH2:2][CH2:1][NH:9][CH:11]2[CH2:20][CH2:19][CH2:18][C:17]3[N:16]([CH2:21][CH:22]=[CH2:23])[C:15](=[O:24])[CH:14]=[CH:13][C:12]2=3)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NCCc1ccccc1
Reactant: C=CCn1c2c(ccc1=O)C(=O)CCC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=CCn1c2c(ccc1=O)C(NCCc1ccccc1)CCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.6 %

Procedure:
A mixture of phenethylamine (6.1 g), 5,6,7,8-tetrahydro-5-oxo-1-(2-propenyl)-2(1H)-quinolinone (10.0 g), and a catalytic amount of para-toluenesulfonic acid was heated in refluxing toluene (150 ml), with azeotropic removal of water, for 18 hrs. The solution was cooled and washed with water. The aqueous phase was extracted with dichloromethane, and the combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. Sodium borohydride (1.8 g) was added to the residue in ethyl alcohol (150 ml) and the resulting mixture was stirred at room temperature for 0.5 hr. The mixture was concentrated in vacuo, and the residue was quenched with water. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by high performance liquid chromatography (silica gel, eluted with methanol/ethyl acetate) to afford 13.6 g (89%) of product. Recrystallization from diethyl ether/petroleum ether provided the analytical sample, mp 60°-62° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH:52]=[C:51]([C:59]2[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=2)[CH:50]=1>CN(C=O)C>[N:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH:52]=[C:51]([C:59]2[CH:60]=[C:61]([NH:65][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:62]=[CH:63][CH:64]=2)[CH:50]=1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Nc1cccc(-c2cnc3ccccc3c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2cnc3ccccc3c2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 46.8 %

Procedure:
DIEA (0.013 mL, 0.075 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.014 g, 0.068 mmol) and HATU (0.028 g, 0.075 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-quinolin-3-yl-phenylamine (0.015 g, 0.068 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.013 g of product in 48% yield: LCMS (ESI) m/z 409 (MH+).
Reaction SMILES: O.[OH-].[K+].[C:4]([C:12]1[CH:13]=[C:14]([CH2:18][CH:19]([OH:26])[CH2:20][C:21]([O:23]CC)=[O:22])[CH:15]=[CH:16][CH:17]=1)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)C>[C:4]([C:12]1[CH:13]=[C:14]([CH2:18][CH:19]([OH:26])[CH2:20][C:21]([OH:23])=[O:22])[CH:15]=[CH:16][CH:17]=1)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)CC(O)Cc1cccc(C(=O)c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CC(O)Cc1cccc(C(=O)c2ccccc2)c1
Temperature: 10 °C
Yield: 96 %

Procedure:
2.7 ml of water and 1.4 ml of 12.5N potassium hydroxide were added to a solution of 2.7 g of ethyl 4-(m-benzoylphenyl)-3-hydroxy-butyrate in 27ml of ethanol and the mixture was refluxed for 11/2 hours and then evaporated to dryness. The residue was taken up in 27 ml of water and the solution was treated with activated carbon, filtered and acidified to a pH of 1 by adding 10 ml of 2N hydrochloric acid with stirring at 10°C. The mixture was extracted with methylene chloride and the organic phase was washed with water, dried over sodium sulfate, treated with activated carbon, filtered and evaporated to dryness to obtain 2.36 g of 4-(m-benzoyl-phenyl)-3-hydroxy-butyric acid in the form of a colorless amorphous solid soluble in chloroform and insoluble in water.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH:13]2[CH2:15][CH2:14]2)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:16]([NH2:19])[CH:17]=[CH2:18].C(=O)([O-])O.[Na+]>>[CH2:16]([NH:19][C:2]1[N:3]=[C:4]([NH:12][CH:13]2[CH2:15][CH2:14]2)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1)[CH:17]=[CH2:18]
Reactant: C=CCN
Reactant: Cc1csc2c(NC3CC3)nc(Cl)nc12
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NC2CC2)c2scc(C)c2n1
Yield: 84.8 %

Procedure:
In a sealed tube were heated 287 g (1.2 mmol) of 2-chloro-4-cyclopropylamino-7-methylthieno[3,2-d]pyrimidine and 1.10 g (19.2 mmol) of allylamine at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate (50 ml×2). The organic layer was washed with brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 265 mg (yield: 84.9%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([O:22]CC)=[O:21])[C:11]3[CH:16]=[N:15][N:14]([CH:17]([CH3:19])[CH3:18])[C:12]=3[N:13]=2)=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([OH:22])=[O:21])[C:11]3[CH:16]=[N:15][N:14]([CH:17]([CH3:19])[CH3:18])[C:12]=3[N:13]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)nc2c1cnn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)n1ncc2c(C(=O)O)cc(-c3ccc(Cl)cc3)nc21
Reaction time: 2 h

Procedure:
The title compound was prepared in the same manner as described for intermediate 58 using ethyl 6-(4-chlorophenyl)-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (400 mg, 1.163 mmol), Ethanol (6 mL), THF (1 mL), and added sodium hydroxide (1.939 mL, 5.82 mmol) wherein the reaction time was 2 h. The final product was collected as 330 mg (90%). LCMS E-S (M+H)=315.8. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.56 (d, J=6.8 Hz, 6H), 5.26-5.47 (m, 1H), 7.62 (d, J=8.6 Hz, 2H), 8.20 (s, 1H), 8.28 (d, J=8.6 Hz, 2H), 8.38 (s, 1H), 14.03 (s, 1H).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:45])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:41][CH3:42])([C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([OH:39])([C:35]([F:38])([F:37])[F:36])[C:31]([F:34])([F:33])[F:32])=[C:24]([CH3:40])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:43])=[CH:9][C:8]=1[Cl:44]>CO.O1CCCC1>[Cl:44][C:8]1[CH:9]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:41][CH3:42])([C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([OH:39])([C:31]([F:32])([F:33])[F:34])[C:35]([F:37])([F:38])[F:36])=[C:24]([CH3:40])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:43])[CH:11]=[CH:12][C:7]=1[CH2:6][C:5]([OH:45])=[O:4]
Reactant: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(Cl)c2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)O)c(Cl)c2)c(C)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.019 mL, 0.019 mmol) was added to a solution of (3-chloro-4′-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-1-butenyl)-phenyl]-propyl}-2′-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 73-(1); 3.9 mg, 0.006 mmol) in methanol-tetrahydrofuran (1:1, 1 mL), and the mixture was stirred at 60° C. for one hour. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=8:3, saturated with water) to give the target compound as a colorless oil (2.0 mg, 53%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[C:14]([NH2:16])=[O:15].[CH3:17][N:18]([CH3:31])[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH:29]=O)=[CH:21][CH:20]=1.N1CCCCC1>CCO>[CH3:17][N:18]([CH3:31])[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][NH:1][C:2]2[NH:6][N:5]=[C:4]([NH:7][C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[C:3]=2[C:14]([NH2:16])=[O:15])=[CH:21][CH:20]=1
Reactant: NC(=O)c1c(Nc2cccnc2)n[nH]c1N
Reactant: CN(C)c1ccc(C=O)c2ccccc12
Solvent: CCO
Solvent: C1CCNCC1
Product: CN(C)c1ccc(CNc2[nH]nc(Nc3cccnc3)c2C(N)=O)c2ccccc12

Procedure:
5-amino-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide 8 (100 mg) was suspended in EtOH (3 mL) and 4-Dimethylamino-1-naphthaldehyde (1 eq.) and piperidine (I drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 5-(((4-(dimethylamino)naphthalen-1-yl)methyl)amino)-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: Cl.[N:2]1([CH2:7][CH2:8][C:9]2[CH2:18][CH2:17][C:16]3[CH:15]=[C:14]([NH:19][C:20](=[O:22])[CH3:21])[CH:13]=[CH:12][C:11]=3[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.CCN=C=NCCCN(C)C.[F:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45]C(C(O)=O)=[CH:43][CH:42]=2)=[CH:37][CH:36]=1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.CN(C)C=O>[F:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][C:21]([C:20]([NH:19][C:14]3[CH:13]=[CH:12][C:11]4[CH:10]=[C:9]([CH2:8][CH2:7][N:2]5[CH2:6][CH2:5][CH2:4][CH2:3]5)[CH2:18][CH2:17][C:16]=4[CH:15]=3)=[O:22])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)cc1
Reactant: CC(=O)Nc1ccc2c(c1)CCC(CCN1CCCC1)=C2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2c(c1)CCC(CCN1CCCC1)=C2)c1ccc(-c2ccc(F)cc2)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 52.3 %

Procedure:
Concentrated hydrochloric acid (2 ml) was added to N-[6-[2-(1-pyrrolidinyl)ethyl]-7,8-dihydro-2-naphthalenyl]acetamide (98.0 mg, 0.345 mmol) obtained in Reference Example 103, which was stirred at 100° C. for 16 hours. The solvent was distilled out under reduced pressure. Ethyl acetate was added to the residue, which was washed with aqueous potassium carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. WSC (62.5 mg, 0.326 mmol) was added to a dimethylformamide solution (1.5 ml) of the resulting oily substance (79.0 mg, 0.326 mmol), 4′-fluoro-[1,1′-biphenyl]-4-carboxylic acid (64.6 mg, 0.326 mmol) and DMAP (39.8 mg, 0.326 mmol) under ice-cooling, which was stirred at room temperature for 1 day. Ethyl acetate was added to the reaction mixture, which was washed with aqueous potassium carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled out under reduced pressure. The resulting residue was purified by aluminum column chromatography (development solvent; ethyl acetate), powdered with ethyl acetate-isopropyl ether (1:5), to give the titled compound (75.1 mg).
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([OH:9])[C:6]([NH:10][C:11](=[O:25])[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][N:4]=1)=O.CC([O-])=O.[Na+].Cl.[OH:32][NH2:33]>O>[OH:9][C:7]1[C:6]([NH:10][C:11](=[O:25])[CH:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:5][N:4]=[C:3]([CH:1]=[N:33][OH:32])[N:8]=1
Reactant: O=Cc1ncc(NC(=O)C(c2ccccc2)c2ccccc2)c(O)n1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(Nc1cnc(C=NO)nc1O)C(c1ccccc1)c1ccccc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of compound 3-h (1 g, 3.0 mmol), NaOAc (0.5 g, 6.0 mmol) and hydroxyamine hydrochloride (0.31 g, 4.5 mmol) in H2O (25 mL) was stirred at 100° C. for 2 h. The precipitated was isolated by filtration to afford the product, 3-2-a, as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 12.31 (s, 1H), 9.89 (s, 1H), 8.85 (s, 1H), 7.74 (s, 1H), 7.33-7.23 (m, 1H), 5.71 (s, 1H). LC-MS: (M+H)+ 349.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[S:18](Cl)(=[O:20])=[O:19]>>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:18]([C:12]2[C:13]([CH3:17])=[CH:14][CH:15]=[CH:16][C:11]=2[Cl:10])(=[O:19])=[O:20])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1Cl
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Cl
Product: Cc1cccc(Cl)c1S(=O)(=O)Nc1cc(Br)cnc1Cl

Procedure:
Prepared according to the methods described in reagent preparation 26 using 5-bromo-2-chloropyridin-3-amine and 2-chloro-6-methylbenzene-1-sulfonyl chloride in step 1. MS (EI) for C12H9BrCl2N2O2S: 393, 395, 397 (Br+Cl isotopes, MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:29])[CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=[C:11]2[CH3:28])=[CH:4][CH:3]=1.[N:30]([C:33]1[C:34]([CH3:39])=[N:35][O:36][C:37]=1[CH3:38])=[C:31]=[O:32]>>[CH3:39][C:34]1[C:33]([NH:30][C:31]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8](=[O:29])[CH2:9][N:10]3[C:14](=[O:15])[C:13]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:12]=[C:11]3[CH3:28])=[CH:6][CH:7]=2)=[O:32])=[C:37]([CH3:38])[O:36][N:35]=1
Reactant: Cc1noc(C)c1N=C=O
Reactant: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CC(=O)c1ccc(N)cc1
Product: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CC(=O)c1ccc(NC(=O)Nc2c(C)noc2C)cc1

Procedure:
Synthesis in analogy to Example 6 starting from 3-[2-(4-amino-phenyl)-2-oxo-ethyl]-2-methyl-5,5-diphenyl-3,5-dihydro-imidazol-4-one and 4-isocyanato-3,5-dimethyl-isoxazole to yield 1-(3,5-dimethyl-isoxazol-4-yl)-3-{4-[2-(2-methyl-5-oxo-4,4-diphenyl-4,5-dihydro-imidazol-1-yl)-acetyl]-phenyl}-urea. LC/MS at 254 nm; [M+H] 522; Rt 3.191 min.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20]([C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=3)=[O:21])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20]([C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=3)=[O:21])=[CH:8][N:9]2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.5 %

Procedure:
A solution of methyl 4-((7-chloro-4-oxo-1-phenyl-1,4-dihydroquinolin-3-yl)methylcarbamoyl)benzoate (128 mg, 0.286 mmol) in tetrahydrofuran (2.3 mL) at 25° C. was treated with a solution of lithium hydroxide monohydrate (24.0 mg, 0.573 mmol) in water (573 μL). The reaction was stirred at 25° C. for 24 hr. At this time, LC/MS indicated complete conversion to the desired acid. The reaction was diluted with water (30 mL) and was extracted with methylene chloride (1×50 mL). The aqueous layer was then acidified with a 1N aqueous hydrochloric acid solution, and then extracted with 90:10 methylene chloride-methanol (3×40 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to give the intermediate 4-((7-chloro-4-oxo-1-phenyl-1,4-dihydroquinolin-3-yl)methylcarbamoyl)benzoic acid (55.1 mg, 44%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:7][C:6]=2[CH:16]=1.C1C(=O)N([Br:24])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:24][CH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:7][C:6]=2[CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2oc(-c3ccccc3)nc2c1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2oc(-c3ccccc3)nc2c1
Yield: 70.6 %

Procedure:
5-methyl-2-phenylbenzoxazole 55 (1.23 g, 5.8 mmol) and NBS (1.17 g, 6.5 mmol) were dissolved in carbon tetrachloride (20 ml). The mixture was evacuated and flushed with argon. AIBN (ca. 5 mg) was added and the mixture heated at reflux and irradiated with a sun lamp for 3 hrs. The solvent was evaporated under reduced pressure and the residue purified by chromatography to yield 1.18 g of 5-bromomethyl-2-phenylbenzoxazole 56.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]#[CH:15])[CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-])=O.[Sn](Cl)Cl>C(OCC)(=O)C.C(O)C>[CH2:13]([N:10]1[CH2:11][CH2:12][C:6]2[CH:5]=[C:4]([NH2:1])[CH:17]=[CH:16][C:7]=2[CH2:8][CH2:9]1)[C:14]#[CH:15]
Reactant: C#CCN1CCc2ccc([N+](=O)[O-])cc2CC1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: C#CCN1CCc2ccc(N)cc2CC1
Temperature: 25 °C
Yield: 95 %

Procedure:
7-Nitro-3-prop-2-ynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (589 mg, 2.56 mmol) was dissolved in ethyl acetate (80 mL) and ethanol (30 mL). Tin (II) chloride dehydrate (2.88 g, 12.80 mmol, 5.0 eq) was added and the reaction was heated at reflux for 18 hours. The reaction was allowed to cool to room temperature and was then concentrated under reduced pressure. The residue was taken up in EtOAc (100 mL) and washed with 10% aqueous KF (70 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure to obtain 3-prop-2-ynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine as a yellow solid (487 mg, 95%). An analytical sample was purified by prep-HPLC using a gradient of 0-30% acetonitrile/water. LCMS (m/e) 201 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 6.91 (d, 1H, J=7.7 Hz), 6.52-6.46 (m, 2H), 3.43 (d, 2H, J=2.3 Hz), 2.91-2.82 (m, 4H), 2.78-2.64 (m, 4H), 2.24-2.19 (m, 1H).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C@@H:9]2[N:12]([C:13](=[O:15])[CH3:14])[C:11](=[O:16])[C@H:10]2[CH2:17][CH2:18][CH2:19][NH:20][C:21]([NH:33]C(OCC2C=CC=CC=2)=O)=[N:22]C(OCC2C=CC=CC=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:44]>[Pd].CO.C(OCC)(=O)C>[ClH:44].[C:1]1([CH2:7][CH2:8][C@@H:9]2[N:12]([C:13](=[O:15])[CH3:14])[C:11](=[O:16])[C@H:10]2[CH2:17][CH2:18][CH2:19][NH:20][C:21]([NH2:33])=[NH:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)N1C(=O)[C@@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C=Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)N1C(=O)[C@@H](CCCNC(=N)N)[C@@H]1CCc1ccccc1
Yield: 76 %

Procedure:
A methanol/ethyl acetate (3 ml/1mL) solution of compound 27 (470 mg, 0.82 mmol) and 1N HCl (0.9 mL), containing 10% palladium on carbon, was stirred under a hydrogen atmosphere until TLC indicated the disappearance of the starting material (about 30 min). The suspension was filtered through a pad of Celite, and the filtrate was concentrated to afford 220 mg (76%) of the title product.
Reaction SMILES: C([O:5][C:6](=[O:38])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15](=O)[NH:16][C:17]2[CH:18]=[C:19]([C:30]3[CH:35]=[CH:34][N:33]=[CH:32][C:31]=3[F:36])[C:20]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[N:21][C:22]=2[NH2:23])=[CH:9][CH:8]=1)(C)(C)C>C(O)(=O)C>[F:36][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][C:30]=1[C:19]1[CH:18]=[C:17]2[N:16]=[C:15]([CH2:14][CH2:13][C:10]3[CH:9]=[CH:8][C:7]([C:6]([OH:5])=[O:38])=[CH:12][CH:11]=3)[NH:23][C:22]2=[N:21][C:20]=1[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CCC(=O)Nc2cc(-c3ccncc3F)c(-c3cccnc3)nc2N)cc1
Solvent: CC(=O)O
Product: O=C(O)c1ccc(CCc2nc3cc(-c4ccncc4F)c(-c4cccnc4)nc3[nH]2)cc1
Yield: 69.2 %

Procedure:
A solution of 4-[2-(6′-Amino-3″-fluoro-[3,2′;3′,4″]terpyridin-5′-ylcarbamoyl)-ethyl]-benzoic acid tert-butyl ester (0.135 g, 0.263 mmol) in acetic acid (2 mL) was heated in a sealed tube at 118° C. for 16 h. The solvent was evaporated and ethyl acetate was added. The solid formed was filtered and washed with 4% sodium bicarbonate aqueous solution, water and dried to give the title compound (0.08 g, 69% of yield).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4](Cl)=[C:5]2[C:9]([N:10]=1)=[N:8][CH:7]=[N:6]2.[NH3:12]>C(O)(C)C>[Cl:1][C:2]1[NH:3][C:4]([NH2:12])=[C:5]2[C:9]([N:10]=1)=[N:8][CH:7]=[N:6]2
Reactant: Clc1nc2ncnc-2c(Cl)[nH]1
Reactant: N
Solvent: CC(C)O
Product: Nc1[nH]c(Cl)nc2ncnc1-2
Temperature: 120 °C

Procedure:
A mixture of 2,6-dichloro-1H-purine (5 g) and ammonia solution (79.2 mL, 2M in (isopropanol) was stirred and heated at 120° C. in an autoclave overnight. The reaction was cooled and concentrated in vacuo to give the title compound as an off-white solid in quantitative yield.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH3:9])[NH:4][N:3]=1.[ClH:10].[C:11](=[NH:16])(OCC)[CH3:12]>C(#N)C>[ClH:10].[CH2:7]([C:5]1[NH:4][N:3]=[C:2]([NH:1][C:11](=[NH:16])[CH3:12])[CH:6]=1)[CH2:8][CH3:9]
Reactant: CCCc1cc(N)n[nH]1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CC#N
Product: CCCc1cc(NC(C)=N)n[nH]1
Reaction time: 1 h

Procedure:
A 11.5 g portion of 3-amino-5-propyl-1H-pyrazole was dissolved in 60 ml of acetonitrile, and 12.8 g of ethyl acetimidate hydrochloride was added to the above solution with cooling on an ice bath. The resulting mixture was stirred for 1 hour at the same temperature and then overnight at room temperature.
Reaction SMILES: Br[C:2]1[CH:18]=[C:17]([CH3:19])[C:5]([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])=[C:4]([CH3:20])[CH:3]=1.[Li]CCCC.[CH3:26][S:27]SC>C1COCC1>[CH3:19][C:17]1[CH:18]=[C:2]([S:27][CH3:26])[CH:3]=[C:4]([CH3:20])[C:5]=1[O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9]
Reactant: CSSC
Reactant: Cc1cc(Br)cc(C)c1O[Si](C(C)C)(C(C)C)C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1cc(C)c(O[Si](C(C)C)(C(C)C)C(C)C)c(C)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
To a stirring solution of (4-bromo-2,6-dimethylphenoxy)-triisopropylsilane (0.5 g, 1.4 mmol) in THF (15 mL) at −78° C. was added n-BuLi (2.5 M in hexanes, 0.56 mL), the reaction mixture was stirred at −78° C. for 1 hr, then dimethyldisulfide (0.16 mL, 1.82 mmol) was added at −78° C. The reaction mixture was stirred at room temperature for 1 h and quenched with saturated NH4Cl and diluted with diethyl ether. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude (2,6-dimethyl-4-methylsulfanylphenoxy)triisopropyl-silane as an oil (0.46 g, 100%): 1H NMR (300 MHz, DMSO-d6): δ 6.92 (s, 2 H), 2.41 (s, 3 H), 2.20 (s, 6 H), 1.29 (m, 3 H), 1.10 (d, J=7.2 Hz, 18 H). TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (2:98); Rf=0.57.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Cl[CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1>>[N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[CH2:13][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: ClCc1ccc2ccccc2n1
Product: COC(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Yield: 88 %

Procedure:
The title compound was prepared from methyl 4-hydroxybenzoate and 2-chloromethylquinoline using methods as described in the literature for similar compounds (Musser et al., 1990) in 88% yield.