Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=CC([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][C:18]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:21]=[C:20]([OH:30])[CH:19]=2)=CC=1)C(C)C.[CH:31]([C:34]1[CH:41]=[CH:40][C:37](C=O)=[CH:36][CH:35]=1)([CH3:33])[CH3:32]>>[CH:31]([C:34]1[CH:41]=[CH:40][C:37]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][C:18]2[N:23]=[C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:21]=[C:20]([OH:30])[CH:19]=2)=[CH:36][CH:35]=1)([CH3:33])[CH3:32]
Reactant: CC(C)c1ccc(C=O)cc1
Reactant: CC(C)Cc1ccc(-c2ccccc2Cc2cc(O)nc(-c3ccccc3)n2)cc1
Product: CC(C)c1ccc(-c2ccccc2Cc2cc(O)nc(-c3ccccc3)n2)cc1

Procedure:
Compound 6 was prepared using synthesis described for the Compound 5 using 4-isopropylbenzaldehyde in procedure 5. Purification was accomplished using column chromatography to provide the title compound as a solid (mp 106-108° C.). 1H-NMR (CDCl3) δ 8.15 (m, 2H); 7.45 (m, 3H); 7.3-7.1 (m, 9H); 6.3 (s, 1H); 5.4 (s, 1H); 2.9 (m, 1H); 1.2 (d, 6H). 13C-NMR (CDCl3) δ 171.0; 165.9; 156.6; 147.5; 141.5; 138.2; 132.1; 132.0; 129.5; 129.3; 128.9; 128.5; 128.0; 126.8; 126.6; 112.4; 58.5, 33.6; 23.9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[C:14]([CH3:18])=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[C:19](N(OC)C)=[O:20])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:25][Mg]Cl.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[C:14]([CH3:18])=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[C:19](=[O:20])[CH3:25])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C[Mg]Cl
Reactant: CON(C)C(=O)c1nc2cccc(C)n2c1-c1cc(F)cc(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1nc2cccc(C)n2c1-c1cc(F)cc(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A solution of 3-(3,5-difluorophenyl)-N-methoxy-N,5-dimethylimidazo[1,2-a]pyridine-2-carboxamide (0.43 g, 1.3 mmol) in tetrahydrofuran (5.2 mL) at 0° C. was treated with 3 M methylmagnesium chloride in tetrahydrofuran (1.3 mL, 3.9 mmol) dropwise and stirred at 0° C. for 30 min. The reaction mixture was treated with additional 3 M methylmagnesium chloride in tetrahydrofuran (1.3 mL, 3.9 mmol) dropwise and stirred at 0° C. for another 30 min. The reaction mixture was quenched with 1 M hydrogen chloride (5.2 mL, 5.2 mmol), poured into saturated sodium bicarbonate (25 mL), and extracted with ethyl acetate (75 mL). The organic layer was separated, washed with brine and water, and dried with sodium sulfate, filtered, and concentrated to a crude solid. Purification by flash column chromatography gave the desired product (0.29 g, 78%). LCMS for C16H13F2N2O (M+H)+: m/z=287.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[OH:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:27]2[CH:28]=[CH:29][C:24]([OH:23])=[CH:25][CH:26]=2)=[CH:17][CH:16]=1)=[O:22]
Reactant: OB(O)c1ccc(O)cc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
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: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(-c2ccc(O)cc2)cc1
Yield: 24.7 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-hydroxybiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 4-hydroxyphenylboronic acid (0.024 g; 0.177 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 18 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.017 g (26%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-hydroxybiphenyl-4-carboxamide as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH3:16])[N:5]=[C:4]([NH2:17])[N:3]=1.Cl.[F:19][C:20]([F:29])([F:28])[C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>C(O)C.O1CCOCC1>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH3:16])=[C:8]([C:6]2[N:5]=[C:4]([NH2:17])[N:3]=[C:2]([NH:25][C:24]3[CH:26]=[CH:27][C:21]([C:20]([F:19])([F:28])[F:29])=[CH:22][CH:23]=3)[CH:7]=2)[CH:13]=1
Reactant: COc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: COc1ccc(Cl)cc1-c1cc(Nc2ccc(C(F)(F)F)cc2)nc(N)n1

Procedure:
To a stirred suspension of 4-chloro-6-(5-chloro-2-methoxy-phenyl)-pyrimidin-2-yl-amine (0.050 g, 0.185 mmol) in ethanol (7.5 ml) was added a solution of hydrogen chloride in dioxane (4.0 M, 0.03 ml) followed by 4-(trifluoromethyl)aniline (0.06 g, 0.37 mmol). The mixture was stirred under reflux for 45 minutes. After evaporation of volatiles under reduced pressure, the residue was treated with 1.0 M hydrochloric acid (10 ml) and stirred for 30 min. Filtration provided the hydrochloride salt of the title compound which was dissolved in methanol (10 ml). A solution of sodium carbonate in water (1.0 M, 1 ml) was added. After stirring for 1 hour, volatiles were evaporated under reduced pressure. The crude product was treated with water (10 ml) and stirred for 15 minutes. Filtration provided the title compound (0.053 g, 74% yield) as a white powder. 1H NMR (DMSO-d6) δ 3.90 (s, 3H, CH3), 6.44 (s, 2H, NH2), 6.81 (s, 1H, Ar), 7.19 (d, 1H, J=8.8 Hz, Ar), 7.46 (dd, 1H, J=8.8 Hz, J=2.6 Hz, Ar), 7.61 (d, 2H, J=8.5 Hz, Ar), 7.94 (d, 1H, J=2.6 Hz, Ar), 7.26 (d, 2H, J=8.5 Hz, Ar), 9.63 (s, 1H, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([OH:10])[CH3:9])=[CH:4][CH:3]=1.Cl[CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)([O:10][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]2)[CH3:9])=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1CCN(CCCl)CC1
Reactant: CC(O)(c1ccccc1)c1ccc(Cl)cc1
Product: CCOC(=O)N1CCN(CCOC(C)(c2ccccc2)c2ccc(Cl)cc2)CC1
Yield: 89 %

Procedure:
Following a procedure similar to that described in Preparation 8(a), but using 1-(4-chlorophenyl)-1-phenylethanol and 1-(2-chloroethyl)-4-(ethoxycarbonyl)piperazine, the title compound was obtained in a yield of 89%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH:16]([F:18])[F:17])[C:12]([CH3:19])=[N:11]1.Br[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O.C(OCC)C>[Br:8][C:6]1[CH:7]=[C:2]([Br:1])[C:3]([N:10]2[C:14](=[O:15])[N:13]([CH:16]([F:17])[F:18])[C:12]([CH3:19])=[N:11]2)=[CH:4][C:5]=1[O:9][CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C(C)Br
Reactant: Cc1nn(-c2cc(O)c(Br)cc2Br)c(=O)n1C(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1cc(-n2nc(C)n(C(F)F)c2=O)c(Br)cc1Br
Reaction time: 2 h
Yield: 64.6 %

Procedure:
To a stirred solution of 1.25 g (0.0031 mole) of 1-(2,4-dibromo-5-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one in 60 mL of N,N-dimethylformamide was added 0.57 g (0.0033 mole) of ethyl 2-bromopropionate. The resultant mixture was heated at 130° . for two hours, then was cooled. The solvent was evaporated from the mixture under reduced pressure, leaving a solid. This solid was dissolved in diethyl ether, and the solution was washed first with water, then with an aqueous 10% sodium hydroxide solution. The organic solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 1.0 g of ethyl 2-[2,4-dibromo-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]propionate as an oil, Compound 8.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([CH2:9][CH3:10])[CH:3]=1.C([Li])CCC.[B:16](OC)([O:19]C)[O:17]C.Cl>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([B:16]([OH:19])[OH:17])=[C:4]([CH2:9][CH3:10])[CH:3]=1
Reactant: COB(OC)OC
Reactant: CCc1cc(Br)ccc1I
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(Br)ccc1B(O)O
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
To a solution of 4-bromo-2-ethyl-1-iodobenzene (80 g, 0.25 mol) in tetrahydrofuran (800 ml) at −75° C. is added n-butyl lithium (1.6 M in hexanes, 188 ml, 0.3 mol) dropwise maintaining the temperature of the reaction mixture below −70° C. When the addition is complete the mixture is stirred at −75° C. for an additional 30 minutes and then trimethyl borate (153.7 g, 1.48 mol) is added dropwise. After the addition is complete the reaction is stirred at −75° C. for 1 hour, then allowed to come to room temperature and stirred for 2 hours, followed by cooling in an ice bath and acidification with 0.5 N aqueous hydrochloric acid. The mixture is extracted with ethyl acetate (3×500 ml) and the organic fractions are combined, washed with brine, then dried over anhydrous sodium sulphate. The mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-bromo-2-ethylphenylboronic acid (26 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30].C(N(CC)CC)C>ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:29](=[O:30])[C:28]4[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:27]=4[O:26][CH3:25])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: COc1cc(Cl)ccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Cl)ccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.7 %

Procedure:
As described for Example 9, a mixture of 0.377 g (1 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.295 g of 2-methoxy-4-chlorobenzoyl chloride, and 0.15 g of triethylamine in 10 ml of dichloromethane is stirred at room temperature for 3 hours. An additional 0.148 g of 2-methoxy-4-chlorobenzoyl chloride and 75 mg of triethylamine is added and the mixture stirred overnight. The solution is worked-up as for Example 9 to give 0.38 g of product (crystallized from dichloromethane-hexane) m.p. 237°-239° C.
Reaction SMILES: [H-].[Na+].[C:3]([C:8]1[CH:22]=[CH:21][C:11]([CH2:12]P(=O)(OCC)OCC)=[CH:10][CH:9]=1)([O:5][CH2:6][CH3:7])=[O:4].[CH:23]([C:25]1[C:34]([O:35][CH2:36][CH2:37][CH3:38])=[CH:33][C:32]2[C:31]([CH3:40])([CH3:39])[CH2:30][CH2:29][C:28]([CH3:42])([CH3:41])[C:27]=2[CH:26]=1)=O.Cl>O1CCCC1.CS(C)=O>[CH3:39][C:31]1([CH3:40])[CH2:30][CH2:29][C:28]([CH3:41])([CH3:42])[C:27]2[CH:26]=[C:25](/[CH:23]=[CH:12]/[C:11]3[CH:10]=[CH:9][C:8]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:22][CH:21]=3)[C:34]([O:35][CH2:36][CH2:37][CH3:38])=[CH:33][C:32]1=2
Reactant: CCCOc1cc2c(cc1C=O)C(C)(C)CCC2(C)C
Reactant: CCOC(=O)c1ccc(CP(=O)(OCC)OCC)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCCOc1cc2c(cc1/C=C/c1ccc(C(=O)OCC)cc1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
1.3 g of sodium hydride, 50% in mineral oil, were suspended in 20 ml of abs. dimethyl sulphoxide (DMSO) and treated dropwise at 15° C. with a solution of 8.6 g of diethyl (4-carbethoxybenzyl)-phosphonate in 25 ml of abs. DMSO. The mixture was stirred at room temperature for 1 hour and then a solution of 3.3 g of the above aldehyde in 25 ml of abs. DMSO and 10 ml of tetrahydrofuran was added dropwise thereto. After stirring at 40° C. for 2 hours the mixture was poured into ice-water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. After drying the organic phase with sodium sulphate and evaporation of the solvent the crude product was filtered over a silica gel column (eluent hexane/5% methyl tert.butyl ether). After recrystallization from hexane/ethyl acetate there were obtained 4.4 g of ethyl (E)-4-[2-(5,5,8,8-tetra-methyl-3 -propoxy-5,6,7,8 -tetrahydro-naphthalen-2-yl)vinyl]benzoate in the form of white crystals, melting point 97°-100° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[C:8](=[O:9])O[C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>CO>[CH2:22]([N:29]1[C:6]([C:13]([OH:15])=[O:14])=[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]2[C:10](=[CH:11][CH:12]=[C:2]([F:1])[CH:3]=2)[C:8]1=[O:9])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1oc(=O)c2ccc(F)cc2c1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)c1c(-c2ccccc2)c2cc(F)ccc2c(=O)n1Cc1ccccc1
Temperature: 50 °C
Reaction time: 36 h
Yield: 76.1 %

Procedure:
A mixture of 6-fluoro-4-phenylisocoumarin-3-carboxylic acid (300 mg), benzylamine (230 mg), triethylamine (0.3 ml) and methanol (3 ml) was stirred at 50° C. for 36 hrs. The reaction mixture was concentrated, 1N-hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 4N-Hydrochloric acid-ethyl acetate solution (3 ml) was added to the residue at room temperature, and the mixture was stirred for 12 hrs. The reaction mixture was concentrated under reduced pressure and the obtained crystals were washed with (diisopropyl ether) to give the title compound, 2-benzyl-6-fluoro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (300 mg).
Reaction SMILES: [OH:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].Br[CH2:14][CH2:15][Cl:16].C(N(CC)CC)C>CN(C=O)C>[Cl:16][CH2:15][CH2:14][O:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12]
Reactant: ClCCBr
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1OCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A 1 L round-bottomed flask was charged 2-hydroxyisoindoline-1,3-dione (16.6 g, 98.71 mmol), followed by DMF (100 mL), then 1-bromo-2-chloroethane (25.2 mL, 296.1 mmol), and then triethylamine (42.1 mL, 296.1 mmol). After stirring at ambient temperature overnight, the reaction mixture was filtered (GF/F) and rinsed with DMF. The filtrate (250 mL) was poured into ice-water (2 L) while stirring, and the resulting precipitate was filtered, rinsed with water, and dried, yielding the crude product as a white solid (21 g). The crude product was triturated with heptane (3×400 mL), filtered and air-dried, giving the product as white solid (17.6 g, 79%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:18]=[C:17]([OH:28])[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:30][CH:31]([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:18]=[C:17]([O:28][CH2:30][CH:31]([CH3:33])[CH3:32])[CH:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CBr
Reactant: COc1ccc(-n2nc(O)cc2-c2ccc(OCc3ccccc3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2nc(OCC(C)C)cc2-c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A suspension of 5-[4-(benzyloxy)phenyl]-3-hydroxy-1-(4-methoxyphenyl)-1H-pyrazole (1.5 g), 1-bromo-2-methylpropane (2.76 g) and anhydrous potassium carbonate (1.67 g) in DMF (10 ml) was added stirred at 100° C. for 1 hour. The mixture was poured into ice water and extracted with AcOEt. The organic layer was washed with H2O, saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated invacuo. The residue was purified by silica gel column chromatography eluted with AcOEt/n-hexane=30% to give 5-[4-(benzyloxy)phenyl]-3-isobutoxy-1-(4-methoxyphenyl)-1H-pyrazole (1.64 g) as a solid.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[C:6]1=[O:16])[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH2:19](I)[CH:20]=[CH2:21]>CN(C)C=O>[CH2:21]([C:5]1([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[C:6]1=[O:16])[CH:20]=[CH2:19]
Reactant: C=CCI
Reactant: CCCCC1Cc2cc(OC)ccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC1(CCCC)Cc2cc(OC)ccc2C1=O
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A solution of 2-butyl-5-methoxy-1-indanone (500 mg, 2.3 mmol) in anhydrous N,N-dimethylformamide (DMF, 5 mL) was added to a suspension of sodium hydride (100 mg of a 60% dispersion in mineral oil, 2.5 mmol) in DMF (5 mL). The mixture was diluted with more DMF (2 mL, used to rinse in the indanone solution), placed under a nitrogen atmosphere, and stirred at room temperature for 25 minutes. Allyl iodide (0.32 mL, 3.5 mmol) was then added over 5 minutes, during which time the mixture clarified. After stirring at room temperature for an additional 15.5 hours, the mixture was partitioned between EtOAc (200 mL) and water (150 mL) containing brine. The aqueous phase was extracted with EtOAc (2×100 mL). The combined EtOAc solution was washed with brine, dried over MgSO4, filtered, and concentrated under vacuum to afford an oil. The crude product was purified by Biotage™ (Charlottesville, Va.) flash chromatography on a 40S (4.0×7.0 cm) silica gel column, eluting with 49:1 hexanes-EtOAc. The product-containing fractions were evaporated under vacuum to afford 2-allyl-2-butyl-5-methoxy-1-indanone as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][N:3]=1.C(O[CH:15]=[C:16]([C:22]#[N:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C.CCCCCC>C1(C)C=CC=CC=1>[C:22]([C:16](=[CH:15][NH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][N:3]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:23]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: Nc1nccc2c1CCCC2
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCOC(=O)C(C#N)=CNc1nccc2c1CCCC2
Temperature: 105 °C
Yield: 75.6 %

Procedure:
A solution of 1-amino-5,6,7,8-tetrahydroisoquinoline [2.96 g., 0.02 mole; E. Ochiai and Y. Kawazoe, Pharm. Bull. (Tokyo), 5, 606 (1957)] and ethyl ethoxymethylenecyanoacetate (3.38 g., 0.02 mole) in toluene (8 ml.) was heated by means of an oil bath maintained at 105° C. for 15 minutes. The cooled solution was poured into Skellysolve B (175 ml.) with good stirring. The mixture was triturated and cooled with an ice bath. The mixture was filtered and the collected gummy solid recrystallized from cyclohexane to give the title compound (4.1 g., 75%), m.p. 116°-120° C. The product was recrystallized from cyclohexane to give analytical material, m.p. 121°-123° C.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]([C:5](F)=[O:6])[C:3]=1[C:14](F)=[O:15].FC1(F)C2C(=C(F)C(F)=C(F)C=2F)C(=O)[O:19]1.C(=O)([O-])[O-].[Na+].[Na+]>>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]2[C:5](=[O:19])[O:6][C:14](=[O:15])[C:3]=12
Reactant: O=C1OC(F)(F)c2c(F)c(F)c(F)c(F)c21
Reactant: O=C(F)c1c(F)c(F)c(F)c(F)c1C(=O)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Yield: 83.2 %

Procedure:
Into a 500 ml glass reactor equipped with a reflux condenser and a stirrer, a 100 g (0.413 mol) of a mixture (1:1) of the 3,4,5,6-tetrafluorophthaloyldifluoride and the 3,3,4,5,6,7-hexafluoro-1-[3H]-isobenzofuranone of Example 2, and 43.8 g (0.413 mol) of sodium carbonate were charged, and the mixture was reacted at 130° C. for 5 hours with vigorous stirring. Then, the reaction mixture was subjected to distillation to obtain 75.6 g of tetrafluorophthalic anhydride. The yield was 83.2%.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19](O)=[O:20])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:22][CH2:23][CH:24]1[CH2:29][NH:28][CH2:27][CH2:26][NH:25]1.[ClH:30].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>ClCCl>[ClH:30].[CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]([N:28]3[CH2:27][CH2:26][NH:25][CH:24]([CH2:23][F:22])[CH2:29]3)=[O:20])=[CH:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cccc2c(C(=O)O)cn(CC3CCCCC3)c12
Reactant: FCC1CNCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cccc2c(C(=O)N3CCNC(CF)C3)cn(CC3CCCCC3)c12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(cyclohexyl)methyl-7-methoxy-indole-3-carboxylic acid (0.59 g, 2.04 mmol, prepared following the method in Example 1) and 2-(fluoromethyl) piperazine (0.37 g, 3.15 mmol) in dichloromethane (15 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.47 g, 2.45 mmol) and 1-hydroxy benzotriazole (0.07 g, 0.51 mmol). The mixture was stirred at room temperature for 18 h and evaporated. The residue was purified by flash chromatography eluting with 0-10% (v/v) methanol in dichloromethane to afford the title compound (free base) as a colourless oil (0.47 g). The free base (0.05 g) was dissolved in diethyl ether (3 ml) and treated dropwise with 2 M hydrochloric acid in diethyl ether (1 ml). The resulting precipitate was collected by filtration, washed with diethyl ether (10 ml) and dried under reduced pressure to afford the title compound (1:1 hydrochloric acid salt) as a colourless solid (0.05 g, 0.12 mmol). 1H NMR (400 MHz, CD3OD) δH 0.98-1.27 (5H, m), 1.57 (2H, br d, J 12.9), 1.63-1.90 (4H, m), 3.21-3.53 (4H, m), 3.68-3.79 (1H, m) 3.95 (3H, s), 4.26 (2H, d, J 7.1), 4.43-4.82 (4H, m), 6.77 (1H, d, J 7.7), 7.11 (1H, t, J 7.5), 7.27 (1H, d, J 8.0), 7.57 (1H, s); EIMS: m/z 270.2 [Fragment+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:17]=2)[C:15]#[N:16])=[CH:5][CH:4]=1.[CH2:18]([C:20]1[C:21]([OH:30])=[C:22]([C:27](=[O:29])[CH3:28])[CH:23]=[CH:24][C:25]=1O)[CH3:19]>>[C:27]([C:22]1[CH:23]=[CH:24][C:25]([O:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([S:9][C:10]3[CH:11]=[N:12][CH:13]=[C:14]([CH:17]=3)[C:15]#[N:16])=[CH:7][CH:8]=2)=[C:20]([CH2:18][CH3:19])[C:21]=1[OH:30])(=[O:29])[CH3:28]
Reactant: CCc1c(O)ccc(C(C)=O)c1O
Reactant: N#Cc1cncc(Sc2ccc(CO)cc2)c1
Product: CCc1c(OCc2ccc(Sc3cncc(C#N)c3)cc2)ccc(C(C)=O)c1O
Yield: 37.5 %

Procedure:
Using the method of Preparation 160 using 5-(4-(hydroxymethyl)phenylthio) nicotinonitrile (1.20 g, 4.95 mmol) and 1-(3-ethyl-2,4-dihydroxyphenyl)ethanone (937 mg, 5.20 mmol) affords the title compound (750 mg, 37%): 1H NMR (CDCl3) δ 1.15 (t, J=7.64 Hz, 3H), 2.57 (s, 3H), 2.76 (q, J=7.6 Hz, 2H), 5.22 (s, 2H), 6.47 (d, J=9.0 Hz, 1H), 7.49 (d, J=8.2 Hz, 2H),), 7.52 (d, J=8.2 Hz, 2H), 7.60 (d, J=9.0 Hz, 1H), 7.63 (dd, J=2.0, 2.3 Hz, 1H), 8.64 (t, J=2.0 Hz, 2H), 12.75 (s, 1H).