Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Cl[C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:15]=[C:14]([NH2:25])[N:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:17]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[N:15]=[C:14]([NH2:25])[N:13]=2)=[CH:4][CH:3]=1
Reactant: Nc1nc(Cl)cc(-c2ccc(F)cc2)n1
Reactant: OB(O)c1ccc(F)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: CN(C)C=O
Product: Nc1nc(-c2ccc(F)cc2)cc(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of compound 4-fluoro phenyl boronic acid, compound 4-chloro-6-(4-fluoro-phenyl)-pyrimidin-2-ylamine, (PPh3)4Pd and sodium carbonate in dimethylformamide was stirred for 1 hour at 25 ° C. and then for 12 hours at 80 ° C. under nitrogen atmosphere followed by purification to yield the desired compound.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[CH:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][N:39]([CH3:51])[C:40](=[O:50])[CH2:41][NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH:33]=2)=[CH:28][CH:27]=1)=O>C(Cl)(Cl)Cl.ClCCl>[OH:5][CH2:4][CH2:3][N:2]([CH2:24][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][N:39]([CH3:51])[C:40](=[O:50])[CH2:41][NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:46])[CH3:47])[CH:33]=2)=[CH:28][CH:27]=1)[CH3:1]
Reactant: CN(Cc1cccc(-c2ccc(C=O)cc2)c1)C(=O)CNC(=O)OC(C)(C)C
Reactant: CNCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(CCO)Cc1ccc(-c2cccc(CN(C)C(=O)CNC(=O)OC(C)(C)C)c2)cc1
Reaction time: 5 h
Yield: 99.6 %

Procedure:
To a mixture of 2-(methylamino)ethanol (41 mg), sodium triacetoxyborohydride (166 mg), acetic acid (9 mg), and dichloromethane (4 ml) was added tert-butyl (2-{[(4′-formylbiphenyl-3-yl)methyl](methyl)amino}-2-oxoethyl)carbamate (200 mg), followed by stirring for 5 hours. To the reaction mixture was added CHCl3-saturated aqueous sodium hydrogen carbonate solution, the organic layer was dried over Na2SO4, and then the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (3% MeOH/chloroform) to obtain tert-butyl (2-{[(4′-{[(2-hydroxyethyl)(methyl)amino]methyl}biphenyl-3-yl)methyl](methyl)amino}-2-oxoethyl)carbamate (230 mg) as a colorless oil.
Reaction SMILES: [OH:1][C:2](=[C:14]1[C:19](=[O:20])[CH2:18][C:17]([CH3:22])([CH3:21])[CH2:16][C:15]1=[O:23])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C(C)(C)C)=[O:8]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[OH:1][C:2](=[C:14]1[C:15](=[O:23])[CH2:16][C:17]([CH3:21])([CH3:22])[CH2:18][C:19]1=[O:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: CC1(C)CC(=O)C(=C(O)CCCCC(=O)OC(C)(C)C)C(=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CC(=O)C(=C(O)CCCCC(=O)O)C(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 1006.3 %

Procedure:
t-Butyl 6-hydroxy-6-(4,4-dimethyl-2,6-dioxocyclohexylidene)-hexanoate (100 mg, 0.30 mmol) was dissolved in CH2Cl2/TFA 1:1 mixture (2 ml) and stirred at room temperature for 1 h. The reaction mixture was evaporated giving 6-hydroxy-6-(4,4-dimethyl-2,6-dioxocyclohexylidene)-hexanoic acid (0.81 g, 98%)
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][N:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(OCC)(=O)C>ClCCl>[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][N:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: C1=COCCC1
Reactant: CCOC(=O)c1ccnc(CO)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccnc(COC2CCCCO2)c1
Reaction time: 8 h

Procedure:
To a solution of 1.64 g of ethyl 2-(hydroxymethyl)isonicotinate in 32.8 ml of dichloromethane were added 1.24 ml of dihydropyrane and 2.32 g of pyridinium p-toluenesulfonate, followed by stirring overnight. Ethyl acetate was added thereto, followed by washing with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 2.4 g of ethyl 2-[(tetrahydro-2H-pyran-2-yloxy)methyl]isonicotinate.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH:9]=[C:8]([Cl:12])[NH:7][C:6]1=[O:13])[CH2:2][CH2:3][CH3:4].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[N:32]([C:33]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:31]=[N:30][N:29]=2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([N:5]1[C:10](=[O:11])[CH:9]=[C:8]([Cl:12])[N:7]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:31]=[N:30][N:29]=3)=[CH:20][CH:21]=2)[C:6]1=[O:13])[CH2:2][CH2:3][CH3:4]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCn1c(=O)cc(Cl)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 58.8 %

Procedure:
A mixture of 3-butyl-6-chloropyrimidine-2,4(1H,3H)-dione (1 g), 4-bromomethyl-2'-(N-trityltetrazol-5-yl)biphenyl (3.02 g) and potassium carbonate (0.82 g) in DMF (50 ml) was stirred at 60° C. for 4 hours. The reaction mixture was concentrated to dryness in vacuo and then the residue was dissolved in methylene chloride. The insoluble material was removed from the reaction mixture by filtration and the filtrate was concentrated to dryness. The resulting residue was purified by column chromatography on silica gel and recrystallized from ethyl acetate-hexane to give colorless prisms (1.97 g, 59%).
Reaction SMILES: [CH2:1]1[O:23][C:4]2([CH2:9][CH2:8][C:7](O)([C:10]3[C:19]4[O:18][CH2:17][CH2:16][O:15][C:14]=4[C:13]([O:20][CH3:21])=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[O:3][CH2:2]1.C[Si]([C:28]#[N:29])(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]1[O:23][C:4]2([CH2:9][CH2:8][C:7]([C:28]#[N:29])([C:10]3[C:19]4[O:18][CH2:17][CH2:16][O:15][C:14]=4[C:13]([O:20][CH3:21])=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[O:3][CH2:2]1
Reactant: C[Si](C)(C)C#N
Reactant: COc1ccc(C2(O)CCC3(CC2)OCCO3)c2c1OCCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C2(C#N)CCC3(CC2)OCCO3)c2c1OCCO2
Reaction time: 0.17 h
Yield: 60.4 %

Procedure:
To a solution of Compound 2a (0.49 g, 1.5 mmol) obtained in Step A in dichloromethane (4.9 mL), trimethylsilyl cyanide (0.26 mL, 1.9 mmol) was added at −78° C., then boron trifluoride-ethyl ether complex (0.20 mL, 1.6 mmol) was added dropwise, and the mixture was stirred for 10 minutes, followed by stirring at room temperature for 10 minutes. A saturated aqueous solution of sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluted with hexane/ethyl acetate=2/1) to give Compound 2 (0.30 g, 61%)as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([N+:19]([O-])=O)=[N:15][CH:16]=[CH:17][CH:18]=1)[CH3:11].Cl>C(O)C.[Fe]>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1)[CH3:11]
Reactant: CC(Oc1cccnc1[N+](=O)[O-])c1c(Cl)ccc(F)c1Cl
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: CC(Oc1cccnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 94 %

Procedure:
3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-nitropyridine (56.7 g, 171 mmol) was dissolved in ethanol (354 mL), 2N HCl (35.4 mL) was added, and iron powder (67.0 g, 1196 mmol) was added portionwise under the cooling of ice bath. After 15 min, it was warmed to 85° C. After 1 h, the reaction liquid was cooled to room temperature, to which was added diatomaceous earth (85 g). After stirring for 15 min, the reaction liquid was sucking filtered using diatomaceous earth. The filtrate was evaporated to dryness under reduced pressure to yield the target product as light yellow solid powder (48.2 g, 160 mmol; yield=94%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22](=O)([O-])[O-].[K+].[K+].IC.C(OCC)(=O)C.CCCCCCC>CN(C=O)C>[CH3:22][N:10]1[CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[C:9]1[CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NCCc1nc(-c2ccccc2)c[nH]1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccccc2)nc1CCNC(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
A suspension of tert-butyl 2-(4-phenyl-1H-imidazol-2-yl)ethylcarbamate (1.071 g, 3.73 mmol) and potassium carbonate (1.13 g, 8.2 mmol) in DMF (10 mL) was stirred at 20° C. for 30 min. Then the reaction mixture was cooled to 0-5° C. and iodomethane (280 μl, 4.47 mmol) was added and the resulting mixture was stirred for 30 min. After removal of the ice bath the reaction mixture was stirred at 20° C. for 6 h, poured into water (10 mL) and extracted with dichloromethane (2×20 mL). The organic layers were combined, dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (using silica gel amine phase and an ethyl acetate/heptane gradient) to give the product as light yellow solid (835 mg, 2.77 mmol, 74.3%).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([OH:18])=[CH:4][C:3]=1[O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.O1CCOCC1.[F-:36].[K+]>O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([OH:18])=[CH:4][C:3]=1[O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([F:36])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Nc1c(Oc2ccc(S(=O)(=O)Cl)cc2)cc(O)c2c1C(=O)c1ccccc1C2=O
Reactant: [F-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1c(Oc2ccc(S(=O)(=O)F)cc2)cc(O)c2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C

Procedure:
To a mixture of 1-amino-4-hydroxy-2-(4-chlorosulphonylphenoxy)anthraquinone (2 parts) and 1,4-dioxane (25 parts), stirring at ambient temperature, was added a solution of potassium fluoride (0.6 parts) in water (5 parts). The mixture was heated to 60° C. and stirred at this temperature for 20 minutes. After cooling to 0°-5° C., the product was isolated by filtration, washed with water and dried at 50° C. to yield: 1-amino-4-hydroxy-2-(4-fluorosulphonylphenoxy)anthraquinone (1.6 parts). λmax=515.0 nm (CH2Cl2).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[C:20]([C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1)=[O:21]>C1COCC1>[O:31]=[C:27]1[CH2:26][C:25]2[C:29](=[CH:30][C:22]([C:20]([C:19]3[CH:18]=[C:17]([NH:16][C:9]([C:8]4[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[CH:6][CH:7]=4)=[O:11])[CH:34]=[CH:33][CH:32]=3)=[O:21])=[CH:23][CH:24]=2)[NH:28]1
Reactant: CC(C)n1nccc1C(=O)O
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)n1nccc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Temperature: 79 °C
Reaction time: 3 h
Yield: 81.6 %

Procedure:
A dry flask was charged with 2-Isopropyl-2H-pyrazole-3-carboxylic acid (0.159 g, 1.03 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 3 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (10 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.260 g, 1.03 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and filtered. The solid residue was washed with 0° C. THF and collected to afford the 2-Isopropyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.328 g, 0.84 mmol, 82%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]#[N:21])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:30]>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10]([F:30])=[O:11])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]#[N:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C#N)C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C#N)C(=O)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(S)-2-tert-Butoxycarbonylamino-3-(2-cyano-phenyl)-propionic acid (2.5 g, 8.6 mmol) and pyridine (0.68 g, 8.6 mmol) were dissolved in dichloromethane (50 mL) at 0° C. Cyanuric fluoride (1.74 mL, 12.9 mmol) was added dropwise. The mixture was stirred at 0° C. for 1 hour and then ice-water was added. The mixture was extracted with dichloromethane (2×). The organic extracts were washed with water, brine, and dried over sodium sulfate. Evaporation of the solvents gave crude [(S)-2-(2-cyano-phenyl)-1-fluorocarbonyl-ethyl]-carbamic acid tert-butyl ester as a yellow solid which was used without further purification in the next step (2.4 g).
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([N+:16]([O-])=O)=[CH:7][C:6]=2[N:5]([C:19]([C:21]2[NH:22][C:23]3[C:28]([CH:29]=2)=[CH:27][C:26]([N+:30]([O-])=O)=[CH:25][CH:24]=3)=[O:20])[CH2:4]1>C1COCC1.O=[Pt]=O>[NH2:16][C:8]1[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[C:11]2[CH:3]([CH2:2][Cl:1])[CH2:4][N:5]([C:19]([C:21]3[NH:22][C:23]4[C:28]([CH:29]=3)=[CH:27][C:26]([NH2:30])=[CH:25][CH:24]=4)=[O:20])[C:6]=2[CH:7]=1
Reactant: O=C(c1cc2cc([N+](=O)[O-])ccc2[nH]1)N1CC(CCl)c2c1cc([N+](=O)[O-])c1ccccc21
Agent: O=[Pt]=O
Solvent: C1CCOC1
Product: Nc1ccc2[nH]c(C(=O)N3CC(CCl)c4c3cc(N)c3ccccc43)cc2c1
Yield: 91.6 %

Procedure:
A solution of the preceding dinitro compound 14b (170 mg, 0.38 mmol) in THF (120 mL) was hydrogenated over PtO2 at 50 psi for 2 h. After removal of the catalyst, the solution was concentrated to a small volume under reduced pressure below 25° C. and diluted with iPr2O to give 15b (136 mg, 92%), mp >300° C. 1H NMR [(CD3)2SO] δ 11.23 (d, J=1.4 Hz, 1 H, NH), 8.07 (d, J=8.4 Hz, 1 H, H-6), 7.75 (d, J=8.2 Hz, 1 H, H-9), 7.70 (s, 1 H, H-4), 7.45 (t, J=7.5 Hz, 1 H, H-8), 7.27 (t, J=7.7 Hz, 1 H, H-7), 7.21 (d, J=8.6 Hz, 1 H, H-7'), 6.88 (d, J=1.8 Hz, 1 H, H-3'), 6.76 (d, J=1.8 Hz, 1 H, H-4'), 6.68 (dd, J=8.6, 2.1 Hz, 1 H, H-6'), 5.96 (s, 2 H, dihydroindole NH2), 4.70 (dd, J=10.9, 8.9 Hz, 1 H, H-2), 4.64 (br, s, 2 H, indole NH2), 4.49 (dd, J=11.0, 1.6 Hz, 1 H, H-2), 4.15-4.07 (m, 1 H, H-1), 3.97 (dd, J=11.0, 3.0 Hz, 1 H, CHHCl), 3.74 (dd, J=11.0, 8.0 Hz, 1 H, CHHCl).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]1[O:13][C:12]([C:14](=[O:16])[CH3:15])=[CH:11][CH:10]=1>CO>[OH:7][CH2:8][C:9]1[O:13][C:12]([C:14](=[O:16])[CH3:15])=[CH:11][CH:10]=1
Reactant: CC(=O)c1ccc(COC2CCCCO2)o1
Solvent: CO
Product: CC(=O)c1ccc(CO)o1
Temperature: 35 °C
Reaction time: 1 h

Procedure:
Crude 1-[5-(tetrahydro-pyran-2-yloxymethyl)-furan-2-yl]-ethanone (89 g, 0.40 mol) was dissolved in MeOH (500 mL) and treated with Amberlyst 15 (15 g) at rt. The reaction mixture was stirred at 35° C. for 1 h, cooled to rt and filtered over celite. Et3N (1 mL) was added and the mixture was evaporated to dryness. The residue was stripped with methylcyclohexane and 1-(5-hydroxymethyl-furan-2-yl)ethanone was obtained as a yellow oil that solidified on standing.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:50]=[CH:49][C:9]2[N:10]([CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23]3[C:28]([C:29]5[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=5)=[CH:27][CH:26]=[C:25]([C:36]([N:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)=[O:37])[CH:24]=3)[CH:17]=[CH:16]4)=[N:12][C:8]=2[CH:7]=1)=[O:5])C.Cl>C1COCC1.CO.[OH-].[Na+]>[CH:43]1([N:10]2[C:9]3[CH:49]=[CH:50][C:6]([C:4]([OH:5])=[O:3])=[CH:7][C:8]=3[N:12]=[C:11]2[C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]([C:23]2[C:28]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)=[CH:27][CH:26]=[C:25]([C:36]([N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)=[O:37])[CH:24]=2)[CH:17]=[CH:16]3)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4-c4ccc(F)cc4)ccc3c1)n2C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4-c4ccc(F)cc4)ccc3c1)n2C1CCCCC1
Temperature: 50 °C
Yield: 34.4 %

Procedure:
A solution of 197 mg (0.30 mmol) Compound 549a in 3.75 mL THF, 3 mL MeOH and 0.75 mL 2 N NaOH was stirred at room temperature overnight and then heated at 50° C. for 1.5 h. After the addition of 1.5 mL 1 M HCl, the solution was evaporated to dryness and the residue was purified on HPLC to yield 66 mg yellow solid.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[N:5][NH:6][CH:7]=1.N1C2C(=CC=CC=2O)C=CC=1.C(=O)([O-])[O-].[K+].[K+].Br[C:28]1[CH:33]=[CH:32][C:31]([CH:34]=[C:35]([C:40]2[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=2)[CH2:36][CH:37]([CH3:39])[CH3:38])=[CH:30][CH:29]=1>CS(C)=O.[Cu]I>[CH3:38][CH:37]([CH3:39])[CH2:36][C:35]([C:40]1[CH:41]=[CH:42][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:48][CH:49]=1)=[CH:34][C:31]1[CH:32]=[CH:33][C:28]([N:5]2[CH:4]=[C:3]([C:2]([F:9])([F:8])[F:1])[CH:7]=[N:6]2)=[CH:29][CH:30]=1
Reactant: FC(F)(F)c1cn[nH]c1
Reactant: COC(=O)c1ccc(C(=Cc2ccc(Br)cc2)CC(C)C)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: COC(=O)c1ccc(C(=Cc2ccc(-n3cc(C(F)(F)F)cn3)cc2)CC(C)C)cc1
Temperature: 90 °C
Yield: 9.5 %

Procedure:
An oven-dried and nitrogen-cooled vial was charged with 4-trifluoromethyl pyrazole (77.0 mg, 0.56 mmol), quinolin-8-ol (10 mg, 0.07 mmol), copper (I) iodide (14 mg, 0.073 mmol), and potassium carbonate (140 mg, 1.0 mmol). A solution of methyl 4-(1-(4-bromophenyl)-4-methylpent-1-en-2-yl)benzoate (182.7 mg, 0.489 mmol) in dimethylsulfoxide (2.5 mL) was then added. The vial was capped and evacuated and back-filled with nitrogen four times. The reaction was then heated to 90° C. for 18 hours. The reaction was cooled to room temperature and partitioned between saturated ammonium chloride and ethyl acetate. The aqueous layer was extracted again with ethyl acetate, and the combined organics were dried over magnesium sulfate, filtered, and concentrated. Column chromatography (0-10% ethyl acetate in heptane) provided methyl 4-(4-methyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pent-1-en-2-yl)benzoate (19.8 mg, 9.5%) as an approximate 1:1 mixture of E/Z isomers. 1H NMR (400 MHz, CDCl3, δ): 8.20 (s, 1H), 8.06 (s, 1H), 8.05-8.01 (m, 2H), 7.98-7.93 (m, 2H), 7.91 (s, 1H), 7.83 (s, 1H), 7.71-7.66 (m, 2H), 7.53-7.49 (m, 2H), 7.46-7.42 (m, 2H), 7.41-7.36 (m, 2H), 7.24-7.20 (m, 2H), 7.01-6.96 (m, 2H), 6.78 (s, 1H), 6.49 (s, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 2.62 (d, J=7.2 Hz, 2H), 2.41 (dd, J=7.2, 1.0 Hz, 2H), 1.70-1.48 (m, 2H), 0.90 (d, J=6.6 Hz, 6H), 0.80 (d, J=6.6 Hz, 6H). MS (M+1): 429.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][C@H:9]1[C:15](O)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.O1CCCC1>O1CCCC1>[OH:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@H:9]([CH2:15][OH:16])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C[C@H]1C(=O)O
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)C[C@H]1CO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (S)-1-(tert-butoxycarbonyl)-4-oxopiperidine-2-carboxylic acid (5 g, 20.55 mmol) in tetrahydrofuran (100 mL) under nitrogen was cooled in an ice bath. 1N Borane-tetrahydrofuran in tetrahydrofuran (61.7 mL, 61.7 mmol) was added dropwise over 25 minutes and the mixture was stirred at room temperature for 3 hours, cooled to 0° C. and quenched with 10 mL water. Potassium carbonate (5 g) was added and the mixture was stirred overnight at room temperature, and partitioned between water and ether (three times). The ether extracts were dried over sodium sulfate, filtered, concentrated onto silica gel, and purified by flash chromatography (gradient of 0-100% ethyl acetate-heptanes) to give the title compound as a mixture of diastereomers. MS (ESI+) m/z 231.9 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1.C(O)=O.[ClH:37]>C(O)C>[ClH:37].[ClH:37].[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][N:31]1[CH2:30][CH2:29][N:28]([CH:20]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:17]2[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=2)[CH2:33][CH2:32]1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: COc1ccc(C=O)c(OC)c1
Agent: Cl
Solvent: CCO
Solvent: O=CO
Product: COc1ccc(CN2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c(OC)c1
Temperature: 25 °C
Yield: 25 %

Procedure:
2,4-Dimethoxybenzaldehyde (6.7 g; 40.3 millimoles) and 11.5 g (39.9 millimoles) of bis(4-fluorophenyl)methylpiperazine were melted in an oil bath at 100° C., and 2.0 ml (53.0 millimoles) of formic acid was added dropwise. The mixture was stirred under heat for 30 minutes, and allowed to cool to room temperature. A mixture of 8 ml of conc. hydrochloric acid and 80 ml of ethanol was added, and the precipitated crystals were collected by filtration. Recrystallization of the crystals from ethanol gave 5.1 g (yield 25.0%) of 1-(2,4-dimethoxybenzyl)-4-[bis(4-fluorophenyl)methyl]piperazine dihydrochloride as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][CH:19]1[CH2:25][CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[NH:21][C:20]1=[O:30]>>[C:1]([O:5][C:6]([NH:8][C:9]1([C:15]([NH:18][CH:19]2[CH2:25][CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=3[NH:21][C:20]2=[O:30])=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCCCC1
Reactant: NC1CCc2ccccc2NC1=O
Product: CC(C)(C)OC(=O)NC1(C(=O)NC2CCc3ccccc3NC2=O)CCCCC1

Procedure:
Prepared from 1-(t-butoxycarbonylamino)cyclohexanecarboxylic acid and 3-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (Example 1, Step A) by the procedure described in Example 25, Step A. 1H NMR (200 MHz, CDCl3): 1.1-2.2 (m,19H), 2.00 (m,2H), 2.50 (m,2H), 4.55 (m,1H), 6.9-7.2 (m,4H). FAB-MS: calculated for C22H31N3O4 401; found 402 (M+H,40%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:11]1[O:12][CH:13]=[CH:14][CH:15]=1)=[CH2:10])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([C:11]1[O:12][CH:13]=[CH:14][CH:15]=1)[CH3:10])[CH3:2]
Reactant: C=C(c1ccco1)c1ccccc1CC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCc1ccccc1C(C)c1ccco1
Yield: 87.6 %

Procedure:
A solution of 1-(2-ethylphenyl)-1-(2-furyl)ethylene (27 g.) in ethanol (150 ml.) in the presence of 10% palladium on charcoal (0.5 g.) was treated with hydrogen at room temperature for 3 hours. The mixture was filtered and evaporated to give a clear oil which was distilled to give (±) 2-[1-(2-ethylphenyl)ethyl]-furan (23.9 g.), b.p. 130°-150° C./20 mm.Hg, in the form of a yellow oil.