Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[N:9].[C:10]1(=[O:36])[N:14]([CH2:15][CH2:16][NH:17][CH2:18][CH2:19][N:20]2[C:24](=[O:25])[C:23]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]3[C:21]2=[O:30])[C:13](=[O:31])[C:12]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:11]12.C(N(CC)CC)C>CN(C=O)C>[C:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:17]([CH2:16][CH2:15][N:14]1[C:13](=[O:31])[C:12]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:11]2[C:10]1=[O:36])[CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30])#[N:9]
Reactant: N#CCCCCCCBr
Reactant: O=C1c2ccccc2C(=O)N1CCNCCN1C(=O)c2ccccc2C1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCCCCCCN(CCN1C(=O)c2ccccc2C1=O)CCN1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Yield: 40.9 %

Procedure:
A mixture of 6-bromohexylcyanide (13.88g, 0.073 mol), bis(2-phthalimidoethyl)amine (26.52g, 0.073 mol), and triethylamine (7.37g, 0.073 mol) in DMF (120 ml) was heated at 100° C. for 20 hours. After cooling, the precipitate which had formed was removed by filtration and the filtrate was poured into ice (1000 ml). The aqueous solution was extracted with dichloromethane (3×200 ml). The combined organic extracts were washed with brine and dried over Na2SO4. Removal of the solvent under reduced pressure gave crude product which was chromatographed on silica gel (hexanes - 30% ethyl acetate/hexanes gradient elution). Impure fractions were rechromatographed to provide a total of 14.1g of (6-cyanohexyl)bis(2-phthalimidoethyl)amine (41%) as an oil. The produce was one spot on tlc. The ir spectrum was consistent with the assigned structure.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:8][C:9]=1[CH2:10][C:11](O)=[O:12])([O-])=O>C(O)(=O)C.[Fe]>[C:14]1([C:6]2[CH:5]=[C:4]3[C:9]([CH2:10][C:11](=[O:12])[NH:1]3)=[CH:8][CH:7]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1Cc2ccc(-c3ccccc3)cc2N1
Yield: 92.9 %

Procedure:
Iron chips (2.6 g) were added all at once to 4.5 g 3-nitrobiphenyl-4-acetic acid in 40 mL acetic acid. The mixture was refluxed for 2 hours, concentrated to dryness and taken up in ethyl acetate. The solids were removed by filtration and the filtrate washed twice with 1 N hydrochloric acid and brine and dried over anhydrous sodium sulfate. The filtrate was concentrated to give 3.4 g (93% yield) of 6-phenyl-2-oxindole as a light brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:11][C:12]1[C:13](F)=[CH:14][C:15]2[O:20][CH:19]([C:21]([F:24])([F:23])[F:22])[C:18]([C:25]([O:27]CC)=[O:26])=[CH:17][C:16]=2[CH:30]=1>>[Cl:11][C:12]1[C:13]([O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:14][C:15]2[O:20][CH:19]([C:21]([F:23])([F:22])[F:24])[C:18]([C:25]([OH:27])=[O:26])=[CH:17][C:16]=2[CH:30]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(O)cc1
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccc([N+](=O)[O-])cc3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 4-nitrophenol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 246.4-248.3° C. 1H NMR (acetone-d6/300 MHz) 8.34 (d, 2H, J=9.3 Hz), 7.96 (s, 1H), 7.82 (s, 1H), 7.29 (d, 2H, J=9.3 Hz), 7.02 (s, 1H), 5.90 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6/282 MHz) −79.3 (d, J=7.2 Hz). ESLRMS m/z 433 (M+NH4). ESHRMS m/z 433.0463 (M+NH4, Calc'd 433.0414). Anal. Calc'd for C17H9ClF3NO6: C, 49.12; H, 2.18; N, 3.37; Cl, 8.53. Found: C, 48.94; H, 2.05; N, 3.32; Cl, 8.72.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])(OCC)=O.Cl.[N+:24]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[OH:36])[CH2:30]CN)([O-:26])=[O:25].Cl>>[C:13]1(=[O:22])[N:12]([CH2:7][CH2:30][C:29]2[CH:33]=[CH:34][C:35]([OH:36])=[C:27]([N+:24]([O-:26])=[O:25])[CH:28]=2)[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]12
Reactant: NCCc1ccc(O)c([N+](=O)[O-])c1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1c2ccccc2C(=O)N1CCc1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.8 %

Procedure:
7.58 g of potassium carbonate and 6.02 g of N-carboethoxyphthalimide were added to 180 ml of an aqueous solution of 6.01 g of 3-nitrotyramine hydrochloride and stirred for 15 hours at room temperature. 6N hydrochloric acid was gradually added to the reaction mixture at 0° C. so that the pH value of the mixture was adjusted to be 1 (one). The crystals thus precipitated out were removed by means of filtration and recrystallized from methanol to obtain 7.79 g (yield: 91%) of 4-[2-(phthalimido)ethyl]-2-nitrophenol as yellow crystals.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.OS(O)(=O)=O.[H][H]>C(O)C.O=[Pt]=O>[CH3:1][N:2]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3]1
Reactant: Cn1ccc2ccccc21
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CN1CCC2CCCCC21
Temperature: 100 °C
Yield: 87.6 %

Procedure:
To a solution of 100 g of 1-methylindole in absolute ethanol in a 600 mL autoclave, 5 g of PtO2 and 10 mL of H2SO4 were added. The mixture was sealed and pressurized with hydrogen to 1500 psig. The reaction mixture was heated at 100° C. overnight while stirring at about 400 rpm. The reaction mixture was pressurized again to 1500 psig and heated at 100° C. for several more hours. The reaction mixture was cooled and filtered to remove the catalyst. The filtrate was concentrated on a rotary evaporator to remove ethanol. The residue was neutralized with sodium hydroxide solution and left to stir at room temperature for about 30 minutes. The solution was transferred to a reparatory funnel and extracted with diethyl ether. The ether layer was dried over anhydrous MgSO4, filtered and concentrated at reduced pressure on a rotary evaporator to give 93.0 g of the product, 1-methyl-octahydroindole, as a yellow oil. The product was confirmed by NMR.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:11][CH2:12][CH3:13])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:18]([F:30])[CH:17]=1.Cl>O1CCCC1>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH:5]([C:4](=[O:3])[CH2:11][CH2:12][CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:17][C:18]=1[F:30])#[N:29]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)c(F)c1)C(=O)OCC
Reaction time: 0.5 h
Yield: 101.9 %

Procedure:
To a suspension (200 mL) of 60% sodium hydride (1.8 g) in tetrahydrofuran was added dropwise a solution (50 mL) of ethyl 3-oxohexanoate (10.9 g) in tetrahydrofuran at 0° C. The mixture was stirred at the same temperature for 30 min, 4′-(bromomethyl)-2′-fluorobiphenyl-2-carbonitrile (10.0 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was poured into 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow oil (12.9 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[OH:12].[C:13](O)(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>O>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:13](=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:7]2[OH:12]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: Oc1cccc2c(Cl)cccc12
Solvent: O
Product: CCCCCCCCCCCC(=O)c1ccc2c(Cl)cccc2c1O
Reaction time: 6 h

Procedure:
A mixture of 16.6 parts of 5-chloro-1-naphthalenol [Erdmann and Kirchoff, Liebig's Ann., 247, 372 (1888)] 19.2 parts of dodecanoic acid and 132 parts of boron trifluoride ether complex (48% BF3) was stirred under nitrogen on a steam bath for 6 hours. Water (114 parts) was added and ether distilled off by further heating. The resulting mixture was cooled in ice and a tan solid was filtered and recrystallized from ethanol to give 18 parts of yellow 1-(5-chloro-1-hydroxynaphthalen-2-yl)-1-dodecanone, m.p. 86°-87° C.
Reaction SMILES: Br[C:2]1[N:11]([CH3:12])[C:10](=[O:13])[C:9]([OH:14])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=1)[C:7]2=[O:15].[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O1CCOCC1>[Cl:24][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[F:23])[CH2:16][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[C:9]([OH:14])[C:10](=[O:13])[N:11]([CH3:12])[C:2]=2[C:27]2[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=2)[C:7]1=[O:15]
Reactant: OB(O)c1cccnc1
Reactant: Cn1c(Br)c2c(c(O)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
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: C1COCCO1
Product: Cn1c(-c2cccnc2)c2c(c(O)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Temperature: 100 °C

Procedure:
A mixture of 5-bromo-2-(3-chloro-4-fluorobenzyl)-8-hydroxy-6-methyl-2,3,4,6-tetrahydro-2,6-naphthyridine-1,7-dione (35 mg, 0.08 mmol; Example 80), tetrakis(triphenylphosphine)palladium(0) (5 mg), pyridine-3-boronic acid (15 mg, 0.13 mmol), aq sodium carbonate (2 M, 0.5 mL), and dioxane (1.5 mL) was heated in a microwave oven at 100° C. for 15 minutes. The product mixture was concentrated under vacuum, and the residue was partitioned between water and dichloromethane. The organic extract was separated, concentrated under vacuum. The residue was subjected to preparative reverse phase HPLC purification. Collection and lyophilization of appropriate fractions provide the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@:20]([CH3:28])([C:24]([O:26]C)=[O:25])[CH2:19]4)[C:14]([F:29])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.O.[Li+].[OH-]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@:20]([CH3:28])([C:24]([OH:26])=[O:25])[CH2:19]4)[C:14]([F:29])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COC(=O)[C@]1(C)CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@@]1(C(=O)O)CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (1R,3S)-methyl 3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-methylcyclohexanecarboxylate, 52j, (0.035 g, 0.083 mmol) dissolved in MeOH (5 mL) and water (1 mL) was added LiOH (0.004 g, 0.168 mmol). The reaction was allowed to stir for 2 days at room temperature and then concentrated to dryness. The residue was washed with ethanol. The combined ethanol washings were concentrated in vacuo, yielding 30 mg of desired product as an off white solid.
Reaction SMILES: [Cl:1][C:2]([O:4][C:5](Cl)(Cl)Cl)=[O:3].[C:9]([C:17]1[CH:18]=[CH:19][C:20]([N+:27]([O-:29])=[O:28])=[C:21]([CH:23](C)[CH2:24]O)[CH:22]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>O1CCCC1>[C:9]([C:17]1[CH:18]=[CH:19][C:20]([N+:27]([O-:29])=[O:28])=[C:21]([CH:23]([CH3:24])[CH2:5][O:4][C:2]([Cl:1])=[O:3])[CH:22]=1)(=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(CO)c1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(COC(=O)Cl)c1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of trichloromethyl chloroformate (15.83 g, 80 mmol, 0.8 equivalents) in dry tetrahydrofuran (150 mL), which has been pre-cooled to 0° C., was added over a period of approximately 2 hours a solution of 2-(5-benzoyl-2-nitrophenyl)-1-propanol (4f) (28.53 g, 100 mmol) and triethylamine (10.12 g, 100 mmol) in tetrahydrofuran (250 mL) with continued cooling. After stirring for 1 hour at ambient temperature the resulting suspension was filtered, the filter cake was washed with a little tetrahydrofuran, and the combined organic phases were concentrated in vacuo to give 19f as yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH2:7])[CH:4]=[N:3]1.O=[C:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:15]([O-])=[O:16]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][N:2]1[C:6]2[C:5](=[N:7][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:15]=2[OH:16])[CH:4]=[N:3]1
Reactant: O=C([O-])C1CCCCC1=O
Reactant: Cn1cc(N)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1ncc2nc3c(c(O)c21)CCCC3
Temperature: 25 °C
Yield: 45.4 %

Procedure:
A solution of 1-methyl-1H-pyrazol-4-amine ((J. Catalan et al., J. Heterocycl. Chem., 1985, 22, 997), 200 mg, 2.06 mmol), 2-oxocyclohexanecarboxylate (351 mg, 2.06 mmol), and p-toluenesulfonic acid monohydrate (10 mg, 0.05 mmol) in toluene (20 ml) was stirred at 120° C. for 2.5 h. After cooling to room temperature, the solvent was removed in vacuo. Diphenyl ether (5 ml) was added to the residue (ca. 300 mg) and the resulting mixture was heated at 240° C. for 40 min. After cooling to room temperature, hexane (2 ml) was added. The precipitate was collected by filtration and washed with dichloromethane to give 190 mg (46%) of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14]CC)=[O:13])[N:6]2[CH3:11].O[Li].O.OS([O-])(=O)=O.[K+]>C1COCC1.O>[OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[N:6]2[CH3:11]
Reactant: CCOC(=O)c1cc2c(O)cccc2n1C
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(C(=O)O)cc2c(O)cccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.8 %

Procedure:
To a solution of ethyl 4-hydroxy-1-methyl-1H-indole-2-carboxylate (0.20 g) in THF (20 mL) was added LiOH.H2O (0.1 g) in water (20 mL) and the resulting two phase solution was stirred at room temperature under nitrogen for 4 h. The reaction mixture was acidified with KHSO4 and the product was extracted into EtOAc, washed with brine, dried over MgSO4, and concentrated. The residue was chromatographed over silica gel with a mixture of EtOAc and hexane to give 0.12 g of the title compound. MS ES (M++H)=192.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]1[CH:18]=[C:19]([CH2:24][CH2:25][OH:26])[CH:20]=[CH:21][C:22]=1[F:23].Cl.C1C[O:31][CH2:30]C1>C(OCC)(=O)C.CN(C=O)C>[F:23][C:22]1[C:17]([F:16])=[CH:18][C:19]([CH2:24][CH2:25][OH:26])=[CH:20][C:21]=1[CH:30]=[O:31]
Reactant: OCCc1ccc(F)c(F)c1
Reactant: C1CCOC1
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1cc(CCO)cc(F)c1F
Temperature: -70 °C
Reaction time: 6 h

Procedure:
2,2,6,6-Tetramethylpiperidine (6.15 mL) was added to a solution of n-butyllithium in hexanes (1.6M, 22.8 mL) at −70° C. A solution of 2-(3,4-difluorophenyl)ethanol (example 32, step a) (1.92 g) in THF (25 mL) was added dropwise. THF (25 mL) was added and the mixture stirred at −70° C. for 6 h. DMF (4.7 mL) was then added and the mixture stirred for 1 h at −70° C. The mixture was then allowed to warm to RT and stirred for 70 h. Aqueous HCl solution (2M, 10 mL) was added followed by ethyl acetate (20 mL) and the layers separated. The aqueous phase was extracted with ethyl acetate (2×20 mL). The combined organic solutions were washed with brine (20 mL), dried over magnesium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with 4:1 to 2:1 isohexane:diethyl ether gradient. The fractions containing product were combined and evaporated in vacuo to give the subtitled compound as a yellow oil. Yield 1.9 g.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH2:12][CH3:13])[CH:3]=1.[C:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:12]([O:11][C:4]1[CH:3]=[C:2]([N:20]2[CH2:21][CH2:22][N:17]([C:14](=[O:16])[CH3:15])[CH2:18][CH2:19]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])[CH3:13]
Reactant: CCOc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(N2CCN(C(C)=O)CC2)ccc1[N+](=O)[O-]

Procedure:
The compound obtained in Step 1 above (300 mg), N-acetylpiperazine (300 mg), and potassium carbonate (500 mg) were dissolved in dimethylformamide (3 mL) and reacted at 80° C. overnight. The dimethylformamide of the reaction mixture was removed under reduced pressure, and added with water to form a solid. The solid was filtered to obtain a target compound as a yellow solid.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:19])[CH:6]([O:17][CH3:18])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([O:15][CH3:16])[CH:9]=1>C1COCC1>[OH:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][CH:6]([O:17][CH3:18])[C:5]([OH:19])=[O:4])=[CH:9][C:10]=1[O:15][CH3:16]
Reactant: COC(=O)C(Cc1ccc(O)c(OC)c1)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(CC(OC)C(=O)O)ccc1O
Reaction time: 8 h
Yield: 69.1 %

Procedure:
A 1N aqueous lithium hydroxide solution was added to a solution of 3-(4-hydroxy-3-methoxy-phenyl)-2-methoxy-propionic acid methyl ester (280 mg, 1.17 mmol) in THF at room temperature, and the reaction mixture stirred overnight. The aqueous phase was extracted with ethyl acetate (20 mL), acidified to pH 2, and extracted with ethyl acetate (3×15 mL). The later organic layers were combined and washed with water (15 mL) and brine (10 mL), dried (MgSO4), filtered, and concentrated under vacuum to produce 3-(4-hydroxy-3-methoxy-phenyl)-2-methoxy-propionic acid as an oil (183 mg, 74%). 1H-NMR (250.13 MHz, CDCl3): δ 6.83 (1H, d, J=7.8), 6.74 (1H, s), 6.72 (1H, d, J=7.8), 3.99 (1H dd, J=7.8, 4.0), 3.85 (s, 3H), 3.40 (s, 3H), 3.09 (1H, dd, J=14.2, 4.0), 2.91 (1H dd, J=14.2, 7.8).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[F:14].[O:15]1CCC[CH2:16]1.[Li]CCCC>CN(C)C=O>[F:14][C:3]1[C:4]([C:10]([F:13])([F:12])[F:11])=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[CH:16]=[O:15]
Reactant: COc1ccc(Br)c(F)c1C(F)(F)F
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: COc1ccc(C=O)c(F)c1C(F)(F)F
Temperature: -78 °C

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1-bromo-2-fluoro-4-methoxy-3-(trifluoromethyl)benzene (380 mg, 1.39 mmol, 1.00 equiv), tetrahydrofuran (5.0 mL). This was followed by the addition of n-BuLi (2.5M) (0.62 mL, 1.10 equiv) dropwise with stirring at −78° C. The mixture was stirred for 1 h at −78° C. To this was added N,N-dimethylformamide (1.0 mL) and the resulting solution was stirred for 30 min at −78° C. in a liquid nitrogen bath. The reaction progress was monitored by GCMS. The reaction was then quenched by the addition of 2 mL of water. The resulting solution was extracted with 3×10 mL of ethyl acetate and the organic layers combined and dried in an oven under reduced pressure. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4). This resulted in 0.140 g (45%) of 2-fluoro-4-methoxy-3-(trifluoromethyl)benzaldehyde as a light yellow solid. Mass spectrum (GC, m/z): Calcd. for C9H6F4O2, 222.0 (M). found 222.0.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])=[N:8][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:10][CH:11]=1)=[O:5])C.[OH-].[Na+].Cl>C(O)C.O>[N:15]1[CH:16]=[CH:17][C:12]([C:9]2[N:8]=[C:7]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:6]([C:4]([OH:5])=[O:3])=[CH:11][N:10]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1cnc(-c2ccncc2)nc1Oc1ccccc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccccc1Oc1nc(-c2ccncc2)ncc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a solution of 0.70 g (2.08 mmol) 2-pyridin-4-yl-4-o-tolyloxy-pyrimidine-5-carboxylic acid ethyl ester in 20 ml ethanol a solution of 0.12 g (3.12 mmol) sodiumhydroxide in 10 ml water was added and the resulting mixture was stirred 2 h at RT. The pH of the solution was adjusted to 3 with 25% HCl. The mixture was extracted twice with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered and evaporated. The resulting solid was triturated twice with 10 ml ethanol, filtered off and dried to give 0.60 g (94%) 2-pyridin-4-yl-4-o-tolyloxy-pyrimidine-5-carboxylic acid as a colorless solid, MS (EI): 307.1 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:18]=[CH:17][CH:16]=[N:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:26])C(=O)C1.C1COCC1>C(Cl)Cl>[Br:26][C:17]1[CH:16]=[N:15][N:14]([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[CH:18]=1
Reactant: Cc1ccc(-c2ccc(-n3cccn3)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(-n3cc(Br)cn3)cc2)cc1
Yield: 87.1 %

Procedure:
Prepared from INT-85: To a stirring solution of 1-(4′-methyl-[1,1′-biphenyl]-4-yl)-1H-pyrazole (309 mg, 1.319 mmol) INT-85 in DCM (4 mL) was added NBS (258 mg, 1.45 mmol). After stirring at room temperature for 1 h additional THF (4 mL) was added and stirring continued. After 18 h the reaction mixture was concentrated in vacuo and slurried in MeCN (4 mL). The solid was collected by filtration and washed with MeCN (2×2 mL) to provide 360 mg (87%) of 4-bromo-1-(4′-methyl-[1,1′-biphenyl]-4-yl)-1H-pyrazole INT-86. LCMS-ESI (m/z) calculated for C16H13BrN2: 312; found 313 [M+H]+, tR=3.07 min (Method 5).
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][O:8][CH:9]1[CH2:12][NH:11][CH2:10]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[CH2:44]([O:46][C:47](=[O:65])[CH2:48][N:49]1[CH2:54][C:53]2[CH:55]=[C:56](/[CH:59]=[CH:60]/[C:61](O)=[O:62])[CH:57]=[N:58][C:52]=2[NH:51][C:50]1=[O:64])[CH3:45]>CN(C)C=O>[O:64]=[C:50]1[NH:51][C:52]2[N:58]=[CH:57][C:56](/[CH:59]=[CH:60]/[C:61](=[O:62])[N:11]3[CH2:12][CH:9]([O:8][CH2:7][C:3]4[S:2][CH:6]=[CH:5][CH:4]=4)[CH2:10]3)=[CH:55][C:53]=2[CH2:54][N:49]1[CH2:48][C:47]([O:46][CH2:44][CH3:45])=[O:65]
Reactant: CCOC(=O)CN1Cc2cc(/C=C/C(=O)O)cnc2NC1=O
Reactant: c1csc(COC2CNC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CN1Cc2cc(/C=C/C(=O)N3CC(OCc4cccs4)C3)cnc2NC1=O
Reaction time: 48 h

Procedure:
3-(Thiophen-2-ylmethoxy)-azetidine hydrochloride (243 mg, 1.18 mmol), EDCI (227 mg, 1.18 mmol), HOBt (160 mg, 0.6 mmol) and diisopropylethylamine (340 μL, 1.97 mmol) were successively added to a solution of (E)-3-(3-(2-ethoxy-2-oxoethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-6-yl)acrylic acid hydrochloride (270 mg, 0.79 mmol) in dimethylformamide (15 mL) at room temperature. The reaction mixture was stirred for 2 days then partitioned between ethyl acetate (30 mL) and water (40 mL). The aqueous layer was separated and successively extracted with ethyl acetate (2×30 mL) and dichloromethane (2×30 mL). The combined organic phases were washed with a saturated solution of sodium chloride (3×40 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel using dichloromethane/methanol (10:0 to 98:2) as eluent. The title product was obtained as an off-white solid (215 mg, 60%).