Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K].[K].[SH:3][C:4]1[S:5][C:6]([SH:9])=[N:7][N:8]=1.Cl[CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>O>[N:14]1([CH2:13][CH2:12][CH2:11][S:3][C:4]2[S:5][C:6]([S:9][CH2:11][CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:7][N:8]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: Sc1nnc(S)s1
Reactant: ClCCCN1CCOCC1
Agent: [K]
Solvent: O
Product: C(CSc1nnc(SCCCN2CCOCC2)s1)CN1CCOCC1
Reaction time: 2 h

Procedure:
A mixture of 17.0 grams (0.075 mole) of 2,5-dimercapto-1,3,4-thiadiazole dipotassium salt and 24.5 grams (0.150 mole) of 4-(3-chloropropyl)-morpholine in 170 ml of water was heated under reflux with stirring for two hours. The mixture was then cooled to between 28 and 30° C and extracted with benzene. The benzene extract was washed with a saturated sodium chloride solution and dried over anhydrous sodium carbonate. After removal of the drying agent by filtration, the solution was evaporated to dryness, leaving the 2,5-bis(3-(4-morpholinyl)propylthio)-1,3,4-thiadiazole as a pale yellow oil. The product was recrystallized from methylcyclohexane to give white crystals with a melting point of 65.5°-66° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:5][C:6]1[N:7]=[C:8]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[S:9][C:10]=1[C:11]([NH:13][O:14]C1CCCCO1)=[O:12].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:5][C:6]1[N:7]=[C:8]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[S:9][C:10]=1[C:11]([NH:13][OH:14])=[O:12]
Reactant: O=C(NOC1CCCCO1)c1sc(N2CCOCC2)nc1Cc1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NO)c1sc(N2CCOCC2)nc1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.1 %

Procedure:
To a solution of 4-(3,4-dichlorobenzyl)-2-(morpholin-4-yl)-N-(tetrahydro-2H-pyran-2-yloxy)-1,3-thiazole-5-carboxamide (153 mg, 0.324 mmol) in methylene chloride (1.50 mL) was added trifluoroacetic Acid (1.50 mL, 19.5 mmol). The reaction was stirred at rt for 12 hrs. The resulting solution was concentrated and distributed between NaHCO3(aq) saturated solution and CH2Cl2. The aqueous layer was extracted with CH2Cl2 (×2). The combined org layer was washed with water, dried, and concentrated. Purification on a silica gel column (gradient elution, 0-8% MeOH/CH2Cl2) provided 4-(3,4-dichlorobenzyl)-N-hydroxy-2-(morpholin-4-yl)-1,3-thiazole-5-carboxamide as a yellow solid (53 mg, 42.1% yield). LCMS: (AA) ES+ 388, 390, 392; 1H NMR (400 MHz, MeOD) δ 7.47-7.41 (d, J=1.8 Hz, 1H), 7.38-7.29 (d, J=8.3 Hz, 1H), 7.25-7.14 (dd, J=8.3, 1.9 Hz, 1H), 4.28-4.21 (s, 2H), 3.79-3.71 (t, J=4.9 Hz, 4H), 3.50-3.43 (t, J=4.9 Hz, 4H), 3.33-3.27 (t, J=1.6 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:20][CH2:21][F:22]>CN(C)C=O>[F:22][CH2:21][CH2:20][C:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:15])([F:16])[F:1])=[CH:14][CH:13]=1)([C:11]#[N:12])[C:9]#[N:10]
Reactant: N#CC(C#N)Cc1ccc(C(F)(F)F)cc1
Reactant: FCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCF)Cc1ccc(C(F)(F)F)cc1
Yield: 43.4 %

Procedure:
Using 0.23 g of (4-(trifluoromethyl)benzyl)malononitrile, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.13 g of 1-bromo-2-fluoroethane, and according to the process described in the Production Example 1, there was obtained 0.12 g of 2-(2-fluoroethyl)-2-(4-(trifluoromethyl)benzyl)malononitrile (the present compound (64)).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:26]=[CH:25][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[S:19][C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:27][CH3:28])[CH:4]=1.[OH:29][C:30]1[C:34]([CH:35]=[O:36])=[CH:33][N:32]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:31]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:35]([C:34]1[C:30]([O:29][CH2:2][C:3]2[CH:26]=[CH:25][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[S:19][C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])=[C:5]([O:27][CH3:28])[CH:4]=2)=[N:31][N:32]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=1)=[O:36]
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Reactant: CCOC(=O)c1ccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)s1
Temperature: 90 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
A mixture of ethyl 5-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}thiophene-2-carboxylate (4.63 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (2.07 g), anhydrous potassium carbonate (1.52 g) and N,N-dimethylformamide (100 mL) was stirred at 90° C. for 1 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl 5-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}thiophene-2-carboxylate as colorless crystals (5.50 g, yield 87%). Recrystallization from tetrahydrofuran-hexane gave colorless prism crystals. melting point: 156-157° C.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10](Cl)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:9])([CH3:8])[CH3:7].CN(C)C=O.[CH2:29]([N:33]1[C:37]([C:38](=[S:40])[NH2:39])=[C:36]([CH2:41][OH:42])[N:35]=[C:34]1[N:43]1[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]1)[C:30]#[C:31][CH3:32]>C(OCC)(=O)C>[Si:10]([O:42][CH2:41][C:36]1[N:35]=[C:34]([N:43]2[CH2:44][CH2:45][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:47][CH2:48]2)[N:33]([CH2:29][C:30]#[C:31][CH3:32])[C:37]=1[C:38](=[S:40])[NH2:39])([C:6]([CH3:9])([CH3:8])[CH3:7])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(CO)c1C(N)=S
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1C(N)=S
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.2 %

Procedure:
0.668 g of imidazole and 2.70 g of t-butylchlorodiphenylsilane were added to a 25 ml N,N-dimethylformamide solution of 3.221 g of t-butyl 4-[1-(2-butynyl)-4-hydroxymethyl-5-thiocarbamoyl-1H-imidazol-2-yl]piperazine-1-carboxylate, and the mixture was stirred at room temperature for 16 hours. 300 ml of ethyl acetate was added to the solution, and the organic layer was washed three times with 100 ml of water and then with 100 ml of a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 4.357 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (2:3).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:31])[CH:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])[N:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1.Cl.O>C(OCC)C.[Cl-].[Zn+2].[Cl-]>[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:31])[CH:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:29])([F:30])[CH:26]([F:27])[F:28])[N:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)n1)C(=O)c1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)n1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of zinc chloride (915 mg, 6.71 mmol) in diethyl ether (20 ml) was added sodium borohydride (508 mg, 13.4 mmol), and the mixture was-stirred at room temperature for 30 min. Insoluble material was filtered off, and a solution of ethyl 3-(4-fluorophenyl)-3-oxo-2-{[6-(1,1,2,2-tetrafluoroethoxy)pyridin-2-yl]methyl}propanoate (1.40 g, 3.35 mmol) in diethyl ether (10 ml) was added to the filtrate at 0° C. The mixture was stirred for 30 min. and 1N hydrochloric acid was added to the reaction solution to stop the reaction. Then, water (50 ml) was added and the mixture was extracted with ethyl-acetate (50 ml×2). The extract was washed with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-1:1) to give the objective substance (1.28 g, 91%).
Reaction SMILES: [BH4-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:5]=1[CH:6]=[O:7].CCCCCC.CCOCC>C(O)C>[OH:3][C:4]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:5]=1[CH2:6][OH:7]
Reactant: COc1ccc(O)c(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CCO
Product: COc1ccc(O)c(CO)c1
Yield: 69 %

Procedure:
To a suspension of sodium borohydride (2.50 g, 65.8 mmol) in ethanol (100 mL) at 5° C. was added a solution of 2-hydroxy-5-methoxybenzaldehyde (10.00 g, 65.8 mmol) in ethanol (35 mL) dropwise. Upon completion of the addition the reaction mixture was allowed to stir for ten minutes then quenched by the dropwise addition of 10% aqueous acetic acid (75 mL). The ethanol was removed by concentration in vacuo and the resulting mixture poured into water (250 mL) and extracted with ethylacetate (3×100 mL). The combined extracts were washed sequentially with saturated sodium bicarbonate (50 mL), and brine (3×100 mL). The organic extract was dried (Na2SO4) and concentrated to afford a crude product (8.75 g). Trituration with hexane:ether (3:2, 25 mL) afforded 2-hydroxy-5-methoxybenzyl alcohol (7.00 g, 70%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:35]=[CH:34][C:8]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH2:20][C:21]3[CH:22]=[N:23][C:24]([O:32]C)=[C:25]([C:27]4[O:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=3)=[N:12][N:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(C1C=CC(NC2C3C(=CC=CC=3)C(CC3C=NC(OC)=C(Br)C=3)=NN=2)=CC=1)(C)(C)C.C([Sn](CCCC)(CCCC)C1OC=CC=1)CCC>CCOC(C)=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH2:20][C:21]3[CH:22]=[N:23][C:24]([OH:32])=[C:25]([C:27]4[O:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=3)=[N:12][N:11]=2)=[CH:34][CH:35]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ncc(Cc2nnc(Nc3ccc(C(C)(C)C)cc3)c3ccccc23)cc1-c1ccco1
Agent: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: COc1ncc(Cc2nnc(Nc3ccc(C(C)(C)C)cc3)c3ccccc23)cc1Br
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(Nc2nnc(Cc3cnc(O)c(-c4ccco4)c3)c3ccccc23)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
1-(4-tert-Butyl-anilino)4[5-(furan-2-yl)-6-methoxy-(pyridin-3-yl)-methyl]phthalazine: To a solution of 366 mg (0.76 mMol) 1-(4-tert-butyl-anilino)-4-[5-bromo-6-methoxy-(pyridin-3-yl)-methyl]phthalazine (Ex. 17: a) In 7 ml degassed DMF under a N2-atmoshere are added 174 mg (0.15 mMol) of Pd[P(C8H5)3]4 and 0.6 ml (1.9 mMol) of 2-tributylstannyl-furan (Aldrich). After 4 h stirring at 100° C., the reaction mixture is diluted with EtOAc and washed with NaHCO3 solution. The aqueous layers are extracted twice with EtOAc, the organic phases washed with water, brine, dried (Na2SO4) and concentrated in vacuuo. Column chromatography (SiO2; CH2Cl2/Et2O 7:3) and cristalization from DIPE yields the title compound. mp: 180-182° C.; ES-MS: (M+H)+=465; HPLC(Grad20-100) tRet=15.0.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][C:2]1=[N:10][CH2:11][CH2:12][C:13]([O:15]CC)=[O:14].[OH-].[Na+]>C(O)C.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][C:2]1=[N:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)CCN=c1sc2ccccc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCN=c1sc2ccccc2s1
Yield: 70.8 %

Procedure:
A solution of 3-[(1,3-benzodithiol-2ylidene)amino]-propanoic acid, ethyl ester (3.0g, prepared as described in Example 2) and sodium hydroxide (499 mg) in 120 ml of absolute ethanol is stirred at room temperature for 120 hours. The reaction mixture is concentrated in vacuo, and the resultant solid residue is washed with diethyl ether to remove unreacted starting material. The crude reaction product is dissolved in 50 ml of water, filtered through Celite, and the aqueous solution is then treated with 10% hydrochloric acid until the pH is 5. The resultant precipitate is collected by filtration and dried in vacuo at 60° C overnight. Recrystallization of the dried product from n-pentyl alcohol yields 1.9g of the title compound, melting point 203-204° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:17][C@@H:18]([CH3:22])[C:19]([OH:21])=[O:20]>CCO.O>[N+:8]([C:7]1[C:2]([NH:17][C@H:18]([CH3:22])[C:19]([OH:21])=[O:20])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: C[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C[C@@H](Nc1ncccc1[N+](=O)[O-])C(=O)O
Temperature: 0 °C
Yield: 69.2 %

Procedure:
2-Chloro-3-nitropyridine (500 mg, 3.15 mmol) was dissolved in EtOH (12.5 ml), added potassium carbonate (435 mg, 3.15 mmol) and to this mixture (S)-2-aminopropanoic acid (561 mg, 6.3 mmol) in 2.5 ml water was added and refluxed for overnight. Reaction mixture cooled to 0° C. to obtain the solid. Then EtOH was removed on rotavapour and acidified with 2N HCl and solid filtered and dried on vacuum to obtain the title compound (460 mg) as an yellow solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[O:18][CH3:19])=[O:6].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:48]1[CH:49]=[C:50]2[C:55](=[CH:56][CH:57]=1)[C:54]([N:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1)=[N:53][N:52]=[CH:51]2.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].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.C(O)C>[CH3:19][O:18][C:9]1[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]=1[NH:7][C:5](=[O:6])[C:4]1[CH:20]=[CH:21][C:22]([CH3:23])=[C:2]([C:48]2[CH:49]=[C:50]3[C:55](=[CH:56][CH:57]=2)[C:54]([N:58]2[CH2:59][CH2:60][O:61][CH2:62][CH2:63]2)=[N:53][N:52]=[CH:51]3)[CH:3]=1
Reactant: Brc1ccc2c(N3CCOCC3)nncc2c1
Reactant: COc1ccc(C(F)(F)F)cc1NC(=O)c1ccc(C)c(I)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(C(F)(F)F)cc1NC(=O)c1ccc(C)c(-c2ccc3c(N4CCOCC4)nncc3c2)c1
Temperature: 160 °C

Procedure:
3-Iodo-N-(2-methoxy-5-(trifluoromethyl)phenyl)-4-methylbenzamide (205 mg, 471 μmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (34 mg, 47 μmol), bis(pinacolato)diboron (179 mg, 707 μmol), and potassium acetate (118 μL, 1884 μmol) were dissolved/suspended in DMF (2.4 mL) and heated in the microwave at 160° C. for 10 min. The reaction mixture was transferred to another vial containing 6-bromo-1-morpholinophthalazine (125 mg, 424 μmol), tetrakis(triphenylphosphine)palladium(0) (54 mg, 47 μmol), potassium carbonate-2 M in water (942 μL, 1884 μmol), and ethanol (2.4 mL), and heated in a microwave at 160° C. for 10 min. The reaction mixture was diluted with 50 mL of ethyl acetate, added to a separation funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed 3 times with 50 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated in vacuo to give a crude product, which was purified by chromatography to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:28]3[CH:29]=[C:30]([CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])[CH:31]=[CH:32][CH:33]=3)=[C:7]([CH2:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])=[O:15])[C:8](=[O:12])[O:9]2)=[CH:4][C:3]=1[CH3:40].N.[Cl-].[Ca+2:43].[Cl-]>CC(C)=O.O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:28]3[CH:29]=[C:30]([CH2:34][CH2:35][CH2:36][C:37]([O-:39])=[O:38])[CH:31]=[CH:32][CH:33]=3)=[C:7]([CH2:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[C:24]([F:25])([F:27])[F:26])=[O:15])[C:8](=[O:12])[O:9]2)=[CH:4][C:3]=1[CH3:40].[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:28]3[CH:29]=[C:30]([CH2:34][CH2:35][CH2:36][C:37]([O-:39])=[O:38])[CH:31]=[CH:32][CH:33]=3)=[C:7]([CH2:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[C:24]([F:25])([F:27])[F:26])=[O:15])[C:8](=[O:12])[O:9]2)=[CH:4][C:3]=1[CH3:40].[Ca+2:43]
Reactant: Cc1cc2c(-c3cccc(CCCC(=O)O)c3)c(CC(=O)Nc3ccc(F)cc3C(F)(F)F)c(=O)oc2cc1Cl
Agent: N
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc2c(-c3cccc(CCCC(=O)[O-])c3)c(CC(=O)Nc3ccc(F)cc3C(F)(F)F)c(=O)oc2cc1Cl
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-{3-[7-chloro-3-(2-{[4-fluoro-2-(trifluoromethyl)phenyl]amino}-2-oxoethyl)-6-methyl-2-oxo-2H-chromen-4-yl]phenyl}butanoic acid obtained in Reference Example 9 (26.7 g, 0.0463 mol) in acetone (534 ml) was added 25% aqueous ammonia (4 ml) at 50° C., and the mixture was stirred at the same temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in a mixture of acetonitrile (534 ml) and water (107 ml). The reaction mixture was heated to 70° C., and a solution of calcium chloride (3.14 g, 0.0255 mol) in water (107 ml) was slowly added dropwise thereto. The reaction mixture was stirred at 70° C. for 3.5 hours, water (214 ml) was added thereto and the mixture was further stirred at 70° C. for 1 hour and at room temperature for 12 hours. Crystals obtained were collected by filtration, washed with water (100 ml) and dried at 50° C. under reduced pressure to obtain the title compound (26.67 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]#[N:5].C(N(CC)CC)C.FC(F)(F)S(O[Si:19]([CH3:22])([CH3:21])[CH3:20])(=O)=O>C1(C)C=CC=CC=1>[CH3:20][Si:19]([N:5]([Si:19]([CH3:22])([CH3:21])[CH3:20])[CH2:4][CH2:3][C:2]#[N:1])([CH3:22])[CH3:21]
Reactant: N#CCCN
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)N(CCC#N)[Si](C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.9 %

Procedure:
About 5.04 g of 3-aminopropionitrile, 16.01 g of triethylamine, and 10 ml of toluene were mixed in a round-bottom reaction flask cooled with an ice bath. To this mixture was added, in a dropwise fashion, a solution of 35.16 g of trimethylsilyl trifluoromethanesulfonate in 50 ml of toluene. The resulting mixture was stirred at room temperature for 2 days to give a biphasic mixture. The top layer was transferred to another flask, and the bottom layer was extracted with 50 ml of toluene. The combined toluene solution was evaporated under vacuum. The residue was extracted with 100 ml of hexane, and the hexane layer was evaporated under vacuum, yielding 3-[bis(trimethylsilyl)amino]propionitrile (3-BTMSAPN) as a white solid (13.86 g, 90% yield). The 1H NMR data (C6D6, 25° C., referenced to tetramethylsilane) of the product are listed as follows: δ 2.65 (triplet, 2H, CH2 protons), 1.59 (triplet, 2H, CH2 protons), −0.05 (singlet, 18H, Si—CH3 protons). From the 1H NMR data, the structure of the product was determined to be as follows:
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])=[CH:11][C:10]=2[CH:22]=1)=[O:5].[CH2:24]([CH:26]([CH2:30][CH3:31])[CH2:27][Mg]Br)[CH3:25]>>[CH2:24]([CH:26]([CH2:30][CH3:31])[CH2:27][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])=[CH:11][C:10]=2[CH:22]=1)=[O:5])[CH3:25]
Reactant: CCC(CC)C[Mg]Br
Reactant: CON(C)C(=O)c1ccc2oc(CCN3CCC[C@H]3C)cc2c1
Product: CCC(CC)CC(=O)c1ccc2oc(CCN3CCC[C@H]3C)cc2c1

Procedure:
The product from Example 71E and 2-ethylbutylmagnesium bromide were processed as described in Example 71F to provide the title compound. 1HNMR (300 MHz, CD3OD) δ 0.9 (m, 6H), 1.23 (m, 1H), 1.20 (m, 6H), 1.75 (m, 1H), 2.1 (m, 2H), 2.35 (m, 1H), 3.05 (m, 1H), 3.2-3.5 (m, 7H), 3.55 (m, 1H), 3.8 (m, 1H), 6.85 (s, 1H), 7.55 (d, 1H) 7.95 (dd, 1H), 8.24 (d, 1H); MS (ESI) m/z 342 (M+H)+.
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: CC(C)c1ccc2[nH]ncc2c1B(O)O
Reactant: Cc1ccc(C(C)C)cc1OCc1c(C)nc(Cl)c2ccccc12
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[C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.C(O)[C:12]1[CH:17]=[CH:16]C=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:2]([O:7][C:6](=[O:8])[CH2:5][C:4]([OH:3])=[O:9])[C:10]1[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=1
Reactant: OCc1ccccc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(O)CC(=O)OCc1ccccc1
Yield: 33.8 %

Procedure:
A solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (25 g, 174 mmol) and benzyl alcohol (36 mL, 347 mmol) in toluene (100 mL) was heated at 106° C. for 24 h. The solution was poured into 5% Na2CO3 (aqueous), the organic layer was separated, and the aqueous layer was washed with ether (3×). The aqueous layer was then acidified with 1N HCl and extracted with ethyl acetate (2×). The combined ethyl acetate extracts were dried over anhydrous MgSO4, filtered and evaporated at reduced pressure to give malonic acid monobenzyl ester (11.42 g, 34%).