Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:21]2=[CH:22][CH:23]=[N:24][CH:25]=[C:20]2[C:5]2[C:6]([OH:19])=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1.[ClH:27].[N:28]1([CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])[CH2:32][CH2:31][CH2:30][CH2:29]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:27].[CH3:26][C:2]1([CH3:1])[C:21]2=[CH:22][CH:23]=[N:24][CH:25]=[C:20]2[C:5]2[C:6]([O:19][C:36](=[O:37])[CH2:35][CH2:34][CH2:33][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: O=C(O)CCCN1CCCC1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCCC2)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
5,5-Dimethyl-8-(3-methyl-2-octyl)-10-[4-(pyrrolidino)butyryloxy]-5H-[1]benzopyrano[3,4-d]pyridine hydrochloride is prepared according to the method of Example 29 by reacting equimolar quantities of 5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-5H-[1]benzopyrano[3,4-d]pyridine and γ-pyrrolidinobutyric acid hydrochloride in the presence of dicyclohexyl carbodiimide.
Reaction SMILES: [F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][OH:4].[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[S:19](Cl)(=[O:21])=[O:20].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.O>[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[S:19]([O:4][CH2:3][C:2]([F:8])([F:1])[CH:5]([F:7])[F:6])(=[O:20])=[O:21]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: OCC(F)(F)C(F)F
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: O=S(=O)(OCC(F)(F)C(F)F)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.2 %

Procedure:
A mixture of 52.8 parts of 2,2,3,3-tetrafluoro-1-propanol, 117.8 parts of 2-naphthalenesulfonyl chloride, 294 parts of pyridine and 2.0 parts of N,N-dimethyl-4-pyridinamine was stirred for 48 hours at room temperature. The reaction mixture was diluted with water and the whole was left to crystallize. The product was filtered off, washed with water and recrystallized from 2-propanol, yielding 98.2 parts (76.2%) of 2,2,3,3-tetrafluoropropyl 2-naphthalenesulfonate; mp. 89.6° C. (interm. 27).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([CH3:24])=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[F:23])[CH:13]=2)[NH:8][N:7]=1)=[O:5])C.[Li+].[OH-].Cl>C1COCC1.O>[F:23][C:16]1[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=1[C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[CH3:24])[NH:8][N:7]=[C:6]2[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1n[nH]c2cc(C)c(-c3ccc(OC)cc3F)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2cc3c(C(=O)O)n[nH]c3cc2C)c(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.8 %

Procedure:
To a solution of 5-(2-fluoro-4-methoxyphenyl)-6-methyl-1H-indazole-3-carboxylic acid ethyl ester (292 mg, 0.89 mmol) in THF (4 mL) was added a solution of LiOH (298.0 mg, 12.25 mmol) in water (2 mL). The reaction mixture was heated to reflux for 9 hours, and stirred at room temperature for an additional 48 hours. 1N HCl solution was added to acidify the solution to pH 2. White solid formed, which was collected with filtration and dried in a vacuum oven at 50° C. for 4 hours to give the title compound (240 mg, 90% yield) as a solid. MS (ES+) 301.2 (M+H)+. 1H NMR (500 MHz, CD3OD) δ 7.92 (s, 1H), 7.51 (s, 1H), 7.22 (dd, J=8.70, 8.70 Hz, 1H), 6.87 (dd, J=8.42, 2.56 Hz, 1H), 6.81 (dd, J=11.59, 2.56 Hz, 1H), 3.88 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: C(O[CH:4]=[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]3[N:16]=[CH:15][S:14][C:12]3=2)[NH:7][C:6]1=[O:17])C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(O)C>[O:17]=[C:6]1[C:5](=[CH:4][NH:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]3[N:16]=[CH:15][S:14][C:12]3=2)[NH:7]1
Reactant: Nc1ccc(S(=O)(=O)NCc2ccncc2)cc1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Solvent: CCO
Product: O=C1Nc2ccc3ncsc3c2C1=CNc1ccc(S(=O)(=O)NCc2ccncc2)cc1
Temperature: 78 °C
Yield: 22.4 %

Procedure:
To a test tube (20 mm by 150 mm) was added a magnetic stir bar, 8-[ethoxymethylidene]-6H-[1,3]thiazolo[5,4-e]indol-7-one (0.123 gram, 0.5 mmol), 4-amino-N-(4-pyridinylmethyl)benzenesulfonamide (0.132 gram, 0.5 mmol) and 95% ethanol (5 milliliters). The reaction mixture was sealed with a rubber septum (14/22) and vented with a 3-inch 18-gauge hypodermic needle. The reaction vessel was placed in an oil bath at room temperature with stirring, and the temperature of the oil bath was then raised to 78° C. and maintained at that temperature for approximately 24 hours. The reaction vessel was removed from the oil bath and allowed to cool until warm to the touch. The resulting precipitate was collected by suction filtration. The solid was washed with excess 95% ethanol and collected by suction filtration. The resultant solid was dried under vacuum for two hours at 40° C. The solid was allowed to cool to yield 52 mg (11%) of the title compound. MS (M+H)=464.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH:25]1[CH2:31][CH2:30][CH2:29][C@@H:26]1[CH2:27][OH:28]>>[OH:28][CH2:27][C@H:26]1[CH2:29][CH2:30][CH2:31][N:25]1[C:3]([C:4]1[CH:5]=[N:6][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[CH:8][CH:9]=1)=[O:24]
Reactant: OC[C@H]1CCCN1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCC[C@@H]2CO)cn1
Yield: 96 %

Procedure:
As described for example 223, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (120 mg, 0.37 mmol) was converted, using D-prolinol instead of L-prolinol, to the title compound (139 mg, 96%) which was obtained as a colourless oil. MS: m/e=394.1 [M+H]′.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([CH2:14][CH3:15])=[CH:12][CH:11]=[C:10]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])(=[O:19])=[O:18])[C:5]=1[C:6]([O:8]C)=[O:7])[CH3:2].O.[OH-].[Li+].Cl>O1CCOCC1.O>[CH2:1]([O:3][C:4]1[C:13]([CH2:14][CH3:15])=[CH:12][CH:11]=[C:10]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])(=[O:18])=[O:19])[C:5]=1[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOc1c(CC)ccc(NS(=O)(=O)c2ccccc2F)c1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCOc1c(CC)ccc(NS(=O)(=O)c2ccccc2F)c1C(=O)O
Yield: 94.8 %

Procedure:
Two reactions were run simultaneously. For each reaction, a solution of Example 385H (0.26 g, 0.68 mmol) and lithium hydroxide hydrate (0.275 g, 6.5 mmol) in dioxane (3 mL) and water (1.5 mL) was heated to 160° C. for 15 minutes. The combined reaction mixture was acidified to pH 2.0 with 1 N HCl and extracted with ethyl acetate. The extract was dried (MgSO4), filtered, and concentrated to provide the desired product, 0.475 g, 94.8% yield. 1H NMR (DMSO-d6) δ 1.10 (t, 3H) 1.22 (t, 3H), 2.54 (q, 2H), 3.80 (q, 2H), 6.80 (d, 1H), 7.20 (d, 1H), 7.30 (t, 1H), 7.40 (dd, 1H), 7.65-7.75 (m, 2H), 9.90 (s, 1H), 13.25 (br s, 1H); MS (ESI(−)) m/e 366 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:8])[C:6]=1[NH2:7].C([O-])([O-])=O.[K+].[K+].O.[C:16]([O:19][CH2:20][C:21](Cl)=[O:22])(=[O:18])[CH3:17]>C(Cl)Cl>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:8])[C:6]=1[NH:7][C:21](=[O:22])[CH2:20][O:19][C:16](=[O:18])[CH3:17]
Reactant: Cc1csc(C)c1N
Reactant: CC(=O)OCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCC(=O)Nc1c(C)csc1C

Procedure:
To 12.7 g (0.1 mol) of 2,4-dimethyl-3-aminothiophene, 13.8 g (0.1 mol) of K2CO3, 20 ml of water and 150 ml of methylene chloride are added dropwise at ambient temperature 15 g (0.11 mol) of acetoxyacetyl chloride.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][C:11]=1[F:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][N:21]1[C:30]2[NH:29][C:28]3[CH:31]=[C:32]([CH3:35])[CH:33]=[CH:34][C:27]=3[NH:26][CH2:25][C:24]=2[CH:23]=[N:22]1.CCN(C(C)C)C(C)C>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:26]2[CH2:25][C:24]3[CH:23]=[N:22][N:21]([CH3:20])[C:30]=3[NH:29][C:28]3[CH:31]=[C:32]([CH3:35])[CH:33]=[CH:34][C:27]2=3)=[O:16])=[CH:12][C:11]=1[F:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1F
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)c1ccc(CNC(=O)OC(C)(C)C)c(F)c1
Yield: 59 %

Procedure:
A mixture of 4-(tert-butoxycarbonylamino-methyl)-3-fluoro-benzoic acid from Example E3 (1.38 g, 5.1 mmol) and 3,6-dimethyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E2 (11.0 g, 4.7 mmol) in di-chloromethane (20 ml) at room temperature was treated with DIEA (2.44 ml, 14.0 mmol), DMAP (627 mg, 5.1 mmol) and WSCD (1.16 g, 6.1 mmol). The solution was heated at re-flux for 2 days then washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel through an isolute (eluant; EtOAc) to yield the title compound (1.29 g, 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[S:13][CH:12]3[N:9]([CH2:10][CH2:11]3)[C:8]=2[C:14]([O:16]CC2C=CC([N+]([O-])=O)=CC=2)=[O:15])=[CH:4][CH:3]=1.C(=O)(O)[O-:30].[Na+:33]>O1CCOCC1.O.[Pd]>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[S:13][CH:12]3[N:9]([C:10](=[O:30])[CH2:11]3)[C:8]=2[C:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.[Na+:33]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)C1=C(Oc2ccc(Cl)cc2)SC2CCN12
Reactant: O=C([O-])O
Agent: [Pd]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C([O-])C1=C(Oc2ccc(Cl)cc2)SC2CC(=O)N12

Procedure:
A mixture of a solution of 500 mg of 4-nitrobenzyl 3-(4-chlorophenoxy)-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate in dioxan and 97 mg of sodium bicarbonate in water, and 10% palladium/charcoal was hydrogenated at 50 psi at 25° for 60 minutes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:3]=1.CC(C)([O-])C.[K+].[C:24]([O:28][C:29]([N:31]1[CH2:35][C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH2:33][C@H:32]1[CH2:44][CH2:45]Cl)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(OCC)(=O)C>CN(C)C(=O)C>[C:24]([O:28][C:29]([N:31]1[CH2:35][C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH2:33][C@H:32]1[CH2:44][CH2:45][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: Oc1ccc(F)cc1CCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCOc1ccc(F)cc1CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
248 mg of 4-fluoro-2-[2-(4-fluorophenyl)ethyl]phenol (prepared as described in Preparation 6) were dissolved in 10 ml of N,N-dimethylacetamide, and then 125 mg of potassium t-butoxide and 405 mg of (2S,4R)-1-t-butoxycarbonyl-4-t-butyldimethylsilyloxy-2-(2-chloroethyl)pyrrolidine were added to the resulting solution, whilst ice-cooling. The resulting mixture was then stirred at room temperature for 3 hours, after which 150 ml of ethyl acetate were added to the reaction mixture. The reaction mixture was then washed with water and with a saturated aqueous solution of sodium chloride, in that order. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and then concentrated by evaporation under reduced pressure. The resulting oily substance was purified by silica gel column chromatography, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 433 mg (yield 73%) of the title compound as a colorless oily substance.
Reaction SMILES: C(C1C=CC(C[S:8][C:9]2[CH:10]=[C:11]([O:19][CH2:20][O:21][CH3:22])[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=2)=CC=1)C.Cl[CH2:26][C:27]1[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1>>[CH3:22][O:21][CH2:20][O:19][C:11]1[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=[C:9]([S:8][CH2:26][C:27]2[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[CH:10]=1
Reactant: COc1ccc(CCl)cn1
Reactant: CCc1ccc(CSc2cc(OCOC)c(=O)n(COC)c2)cc1
Product: COCOc1cc(SCc2ccc(OC)nc2)cn(COC)c1=O

Procedure:
Prepared as described for 5-[(4-ethylbenzyl)sulfanyl]-3-(methoxymethoxy)-1-(methoxymethyl)pyridin-2(1H)-one (Intermediate 17) but using 3-chloromethyl-6-methoxypyridine instead of 1-(chloromethyl)-4-ethylbenzene.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH3:32])[CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29]([OH:31])=O)[CH2:24]2)[O:12]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.[F:67][C:68]([F:79])([F:78])[O:69][C:70]1[CH:71]=[C:72]([NH2:77])[C:73]([NH2:76])=[CH:74][CH:75]=1>C(Cl)Cl>[NH2:77][C:72]1[CH:71]=[C:70]([O:69][C:68]([F:67])([F:78])[F:79])[CH:75]=[CH:74][C:73]=1[NH:76][C:29](=[O:31])[CH2:28][CH2:27][CH:25]1[CH2:26][CH:23]([N:22]([CH2:21][C@@H:13]2[C@@H:14]3[C@@H:15]([O:16][C:17]([CH3:20])([CH3:19])[O:18]3)[C@H:11]([N:6]3[CH:5]=[N:4][C:3]4[C:7]3=[N:8][CH:9]=[N:10][C:2]=4[NH2:1])[O:12]2)[CH3:32])[CH2:24]1
Reactant: Nc1ccc(OC(F)(F)F)cc1N
Reactant: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)Nc2ccc(OC(F)(F)F)cc2N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
To a solution of 3-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)propanoic acid (1.2 g, 2.91 mmol), HATU (2.17 g, 5.83 mmol) and HOAT (0.91 g, 5.83 mmol) in DCM (17 mL) were added 4-(trifluoromethoxy)benzene-1,2-diamine (1.1 g, 5.83 mmol) and TEA (2.05 mL, 14.56 mmol). The mixture was stirred at rt overnight. The mixture was diluted with DCM (50 mL) and washed with water (15 mL×3) and brine (30 mL). The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by Combi-Flash (40 g silica gel, start EA:DCM MeOH=10:10:0 to 10:10:8 by gradient, 40 mL/min, 50 min, 2.0 L total solvent volume) to afford the desired compound (1.0 g, yield: 60%) as a yellow solid. 1H NMR (500 MHz, MeOD): δH 8.29 (s, 1H), 8.25-8.24 (m, 1H), 7.20-7.13 (m, 1H), 6.95-6.85 (m, 0.4H), 6.73 (brs, 0.8H), 6.54 (d, J=7.5 Hz, 0.8H), 6.22 (d, J=2.0 Hz, 1H), 5.60-5.55 (m, 1H), 5.03-5.00 (m, 1H), 4.40-4.35 (m, 1H), 3.40-3.35 (m, 0.3H), 3.00-2.92 (m, 0.7H), 2.70-2.47 (m, 3H), 2.36-2.28 (m, 2H), 2.20-1.80 (m, 6H), 1.76-1.66 (m, 2H), 1.60 (s, 3H), 1.40 (s, 3H), 1.26-1.16 (m, 1H) ppm; ESI-MS (m/z): 621.3 [M+1]+.
Reaction SMILES: [CH:1]1([NH:4][NH2:5])[CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[N:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:16](=[O:27])[C:15](O)=[C:14]2[C:29](=O)[CH2:30][O:31][CH3:32])=[CH:9][CH:8]=1>CCO.C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[C:14]3[C:29]([CH2:30][O:31][CH3:32])=[N:5][N:4]([CH:1]4[CH2:3][CH2:2]4)[C:15]=3[C:16](=[O:27])[N:17]2[CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)=[CH:9][CH:8]=1
Reactant: NNC1CC1
Reactant: COCC(=O)C1=C(O)C(=O)N(Cc2ccc(OC)cc2)C1c1ccc(Cl)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COCc1nn(C2CC2)c2c1C(c1ccc(Cl)cc1)N(Cc1ccc(OC)cc1)C2=O
Temperature: 115 °C
Reaction time: 16 h
Yield: 48.2 %

Procedure:
Cyclopropylhydrazine (2.71 g) (Step 17.2) was added to a solution of 5-(4-chlorophenyl)-3-hydroxy-4-(2-methoxyacetyl)-1-(4-methoxybenzyl)-1H-pyrrol-2(5H)-one (5 g, 12.4 mmol) (Step 130.2) in a mixture of EtOH and toluene (60 mL, 1:1, v/v). The reaction mixture was stirred 16 h at 115° C., concentrated, quenched with a saturated aq. NaHCO3 solution, and extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The crude material was purified by silica gel column chromatography (hexane/EtOAc 20-50%) to afford the title compound (2.62 g) as a yellow solid. tR: 1.24 min (LC-MS 2); ESI-MS: 438.1 [M+H]+ (LC-MS 2); Rf=0.50 (hexane/EtOAc 1:1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][O:13][C:14]2[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:17]=[CH:16][C:15]=2[CH3:23])=[C:4]([CH3:24])[N:3]=1.[CH:25]([C:28]1[CH:36]=[CH:35][C:34]2[NH:33][N:32]=[CH:31][C:30]=2[C:29]=1B(O)O)([CH3:27])[CH3:26].C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:25]([C:28]1[C:29]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][O:13][C:14]3[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:17]=[CH:16][C:15]=3[CH3:23])=[C:4]([CH3:24])[N:3]=2)=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][N:32]=[CH:31]2)([CH3:27])[CH3:26]
Reactant: Cc1ccc(C(C)C)cc1OCc1c(C)nc(Cl)c2ccccc12
Reactant: CC(C)c1ccc2[nH]ncc2c1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(C(C)C)cc1OCc1c(C)nc(-c2c(C(C)C)ccc3[nH]ncc23)c2ccccc12
Temperature: 100 °C
Yield: 44.1 %

Procedure:
A solution of 1-chloro-4-chloromethyl-3-methyl-isoquinoline (150 mg, 0.66 mmol) is added to a mixture of carvacrol (199 mg, 1.33 mmol) and CsCO3 (645 mg, 1.98 mmol) in DMF (8 ml). After stirring overnight at room temperature, water is added and the mixture is extracted with ether. The combined extracts are washed with saturated brine, dried over Na2SO4, and concentrated in vacuo. The residue is chromatographed on silica gel to give 220 mg of 1-chloro-4-(5-isopropyl-2-methyl-phenoxymethyl)-3-methyl-isoquinoline. A mixture of 1-chloro-4-(5-isopropyl-2-methyl-phenoxymethyl)-3-methyl-isoquinoline (220 mg, 0.65 mmol), 5-isopropylindazole-4-boronic acid (173 mg, 0.85 mmol), Pd(PPh3)4 (38 mg, 0.033 mmol), and Na2CO3 (1.3 ml of 2M in H2O) in dioxane (8 ml) The mixture is heated for 18 h at 100° C. After cooling to room temperature, water is added and the resulting mixture is extracted with EtOAc. The combined extracts are dried over Na2SO4 and concentrated in vacuo. The residue is chromatographed on silica gel to give 133 mg of 1-(5-isopropyl-1H-indazol-4-yl)-4-(5-isopropyl-2-methyl-phenoxymethyl)-3-methyl-isoquinoline
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.Cl[C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][N:29]=1.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[C:32]([C:31]1[CH:34]=[CH:35][C:28]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:26])[S:12][CH:13]=2)=[N:29][CH:30]=1)#[N:33]
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Reactant: N#Cc1ccc(Cl)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A compound obtained using 2-({4-[2-(heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 and 6-chloronicotinonitrile as starting materials and by an operation similar to that of Example 303-3 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=50:1) to give the title compound.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[C:24]1([CH2:30][CH2:31][C:32](Cl)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:32](=[O:33])[CH2:31][CH2:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(NC(=O)CCc3ccccc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 3-phenylpropionyl chloride (11 mg) and N,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) was performed according to the method described in example 6.
Reaction SMILES: [CH2:1]([C:9]1[C:14]([CH:15]=[CH:16][C:17]([O:19]C)=[O:18])=[CH:13][CH:12]=[C:11]([C:21]([F:24])([F:23])[F:22])[N:10]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Li+].[OH-]>C1COCC1.O>[CH2:1]([C:9]1[C:14]([CH:15]=[CH:16][C:17]([OH:19])=[O:18])=[CH:13][CH:12]=[C:11]([C:21]([F:23])([F:22])[F:24])[N:10]=1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C=Cc1ccc(C(F)(F)F)nc1CCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C=Cc1ccc(C(F)(F)F)nc1CCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a suspension of compound 3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid, methyl ester (1.46 g, 4.35 mmol) in THF (3 ml) was added a solution of 1 N-LiOH (6.0 ml), and the mixture was stirred for 3 hours at room temperature. The resulting residue was dissolved in H2O and then washed with EtOAc, acidified with 1N HCl to pH 1˜2. The solution was extracted three times with methylene chloride and then dried over anhyd. MgSO4 and concentrated in vacuo to give 3-(2-phenethyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (1.37 g, 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][OH:7].C1C(=O)N([Br:18])C(=O)C1>C(#N)C>[Br:18][C:8]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:6][OH:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(CO)c1
Solvent: CC#N
Product: COc1ccc(Br)c(CO)c1

Procedure:
The title compound was prepared by reacting 3-methoxybenzyl alcohol (13.82 g, 0.1 mol) and NBS (19.58 g, 0.11 mol) in acetonitrile (250 mL) at room temperature for 3 hr. The solvent was removed and the resulting mass slurried in dichloromethane (250 mL) and filtered to remove the insoluble succinimide side product. The crude material was purified by chromatography (20% EtOAc-hexanes) to provide a white solid (17.69 g, 81%), mp 57–58° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:8]([CH2:17][CH2:18][NH2:19])[C:7]=2[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[C:27](Cl)(=[O:29])[CH3:28]>O.ClCCl>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:8]([CH2:17][CH2:18][NH:19][C:27](=[O:29])[CH3:28])[C:7]=2[CH:20]=1
Reactant: CC(=O)Cl
Reactant: NCCc1c(-c2ccccc2)sc2ccc(Cl)cc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)NCCc1c(-c2ccccc2)sc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound obtained in Step E is dissolved in a mixture of water/dichloromethane (2/3); 2 eq. of potassium carbonate are then added and 2 eq. acetyl chloride are added dropwise. After stirring for 2 hours at ambient temperature, the 2 phases are separated; the organic phase is washed with 1M HCl and then with water, until the washing waters are neutral, and is then dried over MgSO4 and evaporated. The residue obtained is purified by chromatography on silica gel.