Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)N.[CH3:6][C:7]1[CH:11]=[CH:10][S:9][C:8]=1[C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:21])[CH:19]=[O:20])=[CH:14][CH:13]=1.Cl([O-])=[O:23].[Na+].S([O-])(O)=O.[Na+]>O.C(Cl)(Cl)Cl>[CH3:6][C:7]1[CH:11]=[CH:10][S:9][C:8]=1[C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:21])[C:19]([OH:23])=[O:20])=[CH:14][CH:13]=1
Reactant: Cc1ccsc1-c1ccc(C(C)C=O)cc1
Reactant: [O-][Cl+][O-]
Agent: NS(=O)(=O)O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ccsc1-c1ccc(C(C)C(=O)O)cc1
Reaction time: 0.17 h
Yield: 89.8 %

Procedure:
In 20 ml of water was dissolved 3.2 g (0.033 mole) of sulfamic acid. To the solution was added a solution of 5.0 g (0.0217 mole) of 2-[4-(3-methyl-2-thienyl)phenyl]propionaldehyde [obtained in (1)] in 20 ml of chloroform. To the mixture, while maintaining the temperature at 0° to 10° C., was added dropwise with stirring 10 ml of an aqueous solution containing 2.6 g (0.0242 mole) of sodium chlorite (84% pure). After completion of the addition, the mixture was stirred for 10 minutes, admixed with 2.6 g (0.025 mole) of sodium hydrogensulfite, further stirred for 30 minutes, and allowed to stand, upon which the mixture separated into two layers. The organic layer was washed with 20 ml of water and extracted by the addition of 25 ml of 1 N aqueous sodium hydroxide solution. To the alkaline extract layer, which had been admixed with 20 ml of cyclohexane, was added gradually with stirring 5% hydrochloric acid to adjust the pH to 4. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and freed from the solvent by distillation under reduced pressure to obtain an oily substance which was crystallized by the addition of a small quantity of n-hexane to yield 4.8 g (90% yield) of 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid.
Reaction SMILES: CC([N:5]([C@@H:9]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:30]=[C:31]3[C:36]([CH:37]([OH:39])[CH3:38])=[CH:35][CH:34]=[CH:33][N:32]3[CH:40]=2)=[CH:25][CH:24]=1)[CH2:10][N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])[C:6](=[O:8])[O-])(C)C.Cl.O1CCOCC1.C(N(CC)C(C)C)(C)C.[Cl:57][C:58]1[CH:59]=[C:60]([CH:75]=[CH:76][C:77]=1[O:78][CH:79]([CH3:81])[CH3:80])C(OC1C(F)=C(F)C(F)=C(F)C=1F)=O>O>[Cl:57][C:58]1[CH:59]=[C:60]([CH:75]=[CH:76][C:77]=1[O:78][CH:79]([CH3:81])[CH3:80])[C:6]([NH:5][C@@H:9]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[N:30]=[C:31]3[C:36]([CH:37]([OH:39])[CH3:38])=[CH:35][CH:34]=[CH:33][N:32]3[CH:40]=2)=[CH:27][CH:28]=1)[CH2:10][N:11]1[C:12](=[O:21])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]1=[O:20])=[O:8]
Reactant: CC(O)c1cccn2cc(-c3ccc(C[C@@H](CN4C(=O)c5ccccc5C4=O)N(C(=O)[O-])C(C)(C)C)cc3)nc12
Reactant: CC(C)Oc1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1Cl
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(C(=O)N[C@@H](Cc2ccc(-c3cn4cccc(C(C)O)c4n3)cc2)CN2C(=O)c3ccccc3C2=O)cc1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99.6 %

Procedure:
A mixture of 1,1-dimethylethyl[(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]carbamate (1.79 g, 3.31 mmol) and 4 M HCl in 1,4-dioxane (20 mL, 80 mmol) was stirred at room temperature for 45 minutes. The reaction was concentrated to dryness and redissolved in DMF (30 mL). To this solution was added N,N-diisopropylethylamine (2.14 g, 16.55 mmol) and pentafluorophenyl 3-chloro-4[(1-methylethyl)oxy]benzoate (1.36 g, 3.31 mmol). The mixture was stirred overnight at room temperature, diluted with water, and extracted into ethyl acetate. The extracts were washed with water, dried (Na2SO4), and concentrated in vacuo to give the title compound (2.10 g, 100%) as a tan solid. MS (ES+) m/e 637 [M+H]+.
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:8])=[CH:3][CH:2]=1.[N+](=[CH:30][Si](C)(C)C)=[N-]>C1(C)C(CO)=CC=CC=1>[C:1]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:2]=[CH:3][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[CH2:17][CH2:18][C:19]([O:21][CH3:30])=[O:20])=[O:8])=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CON=C1C[C@@H](CCC(=O)O)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Agent: Cc1ccccc1CO
Product: CON=C1C[C@@H](CCC(=O)OC)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reaction time: 3 h
Yield: 96 %

Procedure:
To a solution of 3-[(2R,4EZ)-1-(biphenyl-4-ylcarbonyl)-4-(methoxyimino)pyrrolidin-2-yl]propanoic acid (Intermediate 8, 20 mg, 0.05 mmol) in toluene-methanol (1 ml, 3-1) was added (diazomethyl)trimethylsilane (0.110 ml, 2M in hexane). After 3 hours, the reaction mixture was concentrated and purified by silica gel column chromatography (ethyl acetate) to give methyl 3-[(2R,4EZ)-1-(biphenyl-4-ylcarbonyl)-4-(methoxyimino)pyrrolidin-2-yl]propanoate (20 mg). Yield: 96%. HPLC purity: 94%
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].F[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)C>[C:1]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[C:18]#[N:19])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: N#Cc1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCN(c2ccccc2C#N)CC1
Temperature: 80 °C
Reaction time: 48 h
Yield: 36.5 %

Procedure:
To a solution of 1-Boc-homopiperazine(2.18 g, 11.0 mmol) in DMSO (20 mL) was added 2-fluorobenzonitrile (1.21 g, 1.08 mL, 10 mmol) and potassium carbonate (1.52 g, 11 mmol). The mixture was stirred at 80° C. for about 48 hours. The mixture was cooled to r.t. and diluted with diethyl ether (200 mL). The solution was washed with 1N HCl (2×20 mL), H2O (3×20 mL) and brine (20 mL), dried over sodium sulfate and concentrated to a yellow oil. Purification by flash chromatography (3:1 hexanes/ethyl acetate) gave the title compound (1.1 g, 36%) as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]2[C:16]3[N:17]([N:23]=[C:24]([CH:30]([CH3:32])[CH3:31])[C:25]=3[C:26]([O:28]C)=[O:27])[C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].Cl>C1COCC1.O.CO>[CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]2[C:16]3[N:17]([N:23]=[C:24]([CH:30]([CH3:32])[CH3:31])[C:25]=3[C:26]([OH:28])=[O:27])[C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(C(C)C)nn2c(OC)ccc(-c3ccc(=O)n(Cc4ccccc4)n3)c12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(=O)n(Cc3ccccc3)n2)c2c(C(=O)O)c(C(C)C)nn12
Yield: 49.6 %

Procedure:
A solution of the compound of Example 266 (250 mg) and lithium hydroxide (140 mg) in a mixture of THF, water and methanol (6 mL, THF:water:methanol=3:2:1) was refluxed for 18 hours. Subsequently, water was added, followed by addition of 2 mol/L hydrochloric acid to adjust the pH to 4. The mixture was extracted with ethyl acetate and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was concentrated and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=98:2) to afford the title compound as a colorless powder (120 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[NH2:16][C:17]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:18]=1[O:19][C@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:16][C:17]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:18]=3[O:19][C@H:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]3)[C:7]=2[C:6]=1[CH3:15])=[O:4]
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Oc2cc(F)ccc2N)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCN(C(=O)OC(C)(C)C)C3)c2c1C
Temperature: 70 °C

Procedure:
4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (1.17 g), (S)-tert-butyl 3-(2-amino-5-fluorophenoxy)piperidine-1-carboxylate (Intermediate 1.1 g) was dissolved in dioxane (10 ml) and p-toluenesulfonic acid (61 mg) was added. The reaction was heated at 70° C. for 1.5 h. The solution was poured into sat. NaHCO3 (50 ml) and extracted with chloroform. The organic phases were passed through a phase separator and concentrated in vaco. The sample was purified by chromatography (silica gel; solvent: isohexan:EtOAc 3:1→2:1) to give the desired product.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH:11]=[CH:10][C:8](=[O:9])[NH:7][C:5]1=[O:6].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18].O>CS(C)=O>[CH2:18]([N:7]1[C:8](=[O:9])[CH:10]=[CH:11][N:4]([CH3:3])[C:5]1=[O:6])[CH2:17][CH2:16][CH2:15][CH:14]=[CH2:13]
Reactant: Cn1ccc(=O)[nH]c1=O
Reactant: C=CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCCCCn1c(=O)ccn(C)c1=O
Reaction time: 0.25 h
Yield: 71.8 %

Procedure:
3-(5,6-Oxidohexyl)-1-methyluracil was synthesized as follows: A mixture of sodium hydride (86 rag, 3.6 mmol) and 1-methyluracil (500 mg, 4 mmol) in dimethyl sulfoxide (25 ml) was stirred for 15 minutes, and then 6-bromo-1-hexene (647 mg, 4 mmol) was added. After stirring for 20 hours, the reaction mixture was poured into water (50 ml) and extracted with 20% ethanol-dichloromethane (3×50 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution (20 ml) and dried over sodium sulfate. The solvent was evaporated under vacuum to give a residue which was purified by column chromatography (silica, ethyl acetate) to give 3-(5-hexenyl)-1-methyluracil (598 mg, 72% yield).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[S:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][CH:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:6][CH:5]=1.[H-].[Na+].Br[CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24]>CN(C)C=O>[F:17][C:2]([F:16])([F:1])[S:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]([CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])([C:12]#[N:13])[C:10]#[N:11])=[CH:14][CH:15]=1
Reactant: N#CC(C#N)Cc1ccc(SC(F)(F)F)cc1
Reactant: FC(F)(F)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(SC(F)(F)F)cc1
Yield: 4.4 %

Procedure:
Using 0.50 g of (4-(trifluoromethylthio)benzyl)malononitrile, 10 ml of N,N-dimethylformamide, 0.09 g of sodium hydride (60% in oil), and 0.38 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.03 g of 2-(4-(trifluoromethylthio)benzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (13)).
Reaction SMILES: [CH:1]1([C:4]2(O)[C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[O:8][C:7]3[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=3[CH2:5]2)[CH2:3][CH2:2]1.C(O)(=O)C.[BrH:24]>O>[Br:24][CH2:3][CH2:2][CH:1]=[C:4]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[O:8][C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=2[CH2:5]1
Reactant: Br
Reactant: OC1(C2CC2)Cc2ccccc2Oc2ncccc21
Solvent: CC(=O)O
Solvent: O
Product: BrCCC=C1Cc2ccccc2Oc2ncccc21
Temperature: 60 °C

Procedure:
To a 2 L eggplant flask with a magnetic stirring bar was added 75.0 g. of 5-Cyclopropyl-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ol (0.30 mole) and 75 mL of acetic acid. The solution was cooled with water (ca. 10° C.), 120 ml of 47% aqueous hydrobromic acid was added over a period of 5 minutes. The reaction mixture was warmed to 60° C., stirred for an hour, and evaporated (aspirator vacuum, ca. 50° C.) to ca. 200 mL. The reaction mixture was poured to 1500 mL of saturated aqueous sodium bicarbonate, the mixture is extracted with two 800 mL portions of ethyl acetate, and the combined organic extracts are washed with 500 mL of saturated aqueous sodium chloride. The organic solution was dried with anhydrous magnesium sulfate, filtered, and evaporated (aspirator vacuum, ca. 30° C.). The oily residue was chromatographed on 500 g. of Silica gel 60 by eluting with 5:1-4:1 (v/v) hexane-ethyl acetate mixture. The elution was evaporated, giving the titled compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]4[NH:18][C:19]5[CH2:24][CH2:23][NH:22][CH2:21][C:20]=5[N:25]=4)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[C:5]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:4][C:3]=1[OH:31].[N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][N:40]=2)[CH:35]=[C:34]([CH:42]=O)[CH:33]=1>>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]4[NH:18][C:19]5[CH2:24][CH2:23][N:22]([CH2:42][C:34]6[CH:33]=[N:32][C:41]7[C:36]([CH:35]=6)=[CH:37][CH:38]=[CH:39][N:40]=7)[CH2:21][C:20]=5[N:25]=4)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[C:5]([CH2:26][C:27]([F:28])([F:29])[F:30])=[CH:4][C:3]=1[OH:31]
Reactant: O=Cc1cnc2ncccc2c1
Reactant: Oc1cc(CC(F)(F)F)c(-c2ccc3c(-c4nc5c([nH]4)CCNC5)n[nH]c3c2)cc1F
Product: Oc1cc(CC(F)(F)F)c(-c2ccc3c(-c4nc5c([nH]4)CCN(Cc4cnc6ncccc6c4)C5)n[nH]c3c2)cc1F

Procedure:
The title compound was prepared from 2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-5-(2,2,2-trifluoro-ethyl)-phenol (100 mg, 0.21 mmol) and [1,8]naphthyridine-3-carbaldehyde (146.1 mg, 0.92 mmol) using the method of Example 51. The crude material was purified initially over silica and finally by Prep TLC (Mobile Phase: 10% MeOH-DCM) to afford the title compound as an off white solid in 9.0% yield, 22 mg.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.C([Li])CCC.[CH3:15][CH:16]1[CH2:20][CH2:19][CH2:18][C:17]1=O.Cl>CCCCCC.C(OCC)C>[CH3:15][C:16]1[CH2:20][CH:19]=[C:18]([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[CH:3]=2)[CH:17]=1
Reactant: CC1CCCC1=O
Reactant: Cc1cc(C)cc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1=CC(c2cc(C)cc(C)c2)=CC1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
1-Bromo-3,5-dimethylbenzene (13.6 g, 73.6 mmol) was dissolved in a mixed solution of hexane (150 mL) and diethyl ether (20 mL) and added dropwise at 0° C. with a solution (46.6 mL, 1.58M) of n-butyllithium in hexane. The solution was immediately warmed to room temperature, stirred night and day and added dropwise at −78° C. to a solution of 3-methyl-2-cyclopentanone (7.3 mL, 74 mmol) in diethyl ether (100 mL). The resultant solution was warmed to room temperature immediately after dropwise addition and stirred for 2 hours. After termination of the reaction, the reaction solution was added with dilute hydrochloric acid, stirred at room temperature for 30 minutes and then subjected to layer separation. The organic layer was dried with magnesium sulfate and then had the solvent distilled off under reduced pressure. The crude product was distilled under reduced pressure (125 to 127° C./0.5 mmHg) to obtain 1-methyl-3-(3,5-dimethyl-phenyl)-cyclopentadiene (6.2 g, yield: 46%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:19])=[C:7]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([Cl:18])[CH:17]=2)[C:13]#[N:14])[CH:8]=1.[CH3:20][C:21]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(#N)C.CCOC(C)=O.CN(C=O)C>[Cl:19][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:21]=2[CH3:20])=[CH:8][C:7]=1[O:9][C:10]1[CH:11]=[C:12]([C:13]#[N:14])[CH:15]=[C:16]([Cl:18])[CH:17]=1
Reactant: N#Cc1cc(Cl)cc(Oc2cc(CN)ccc2Cl)c1
Reactant: COc1ccc(C(=O)O)c(C)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2)c(C)c1
Yield: 45.3 %

Procedure:
3-{[5-(Aminomethyl)-2-chlorophenyl]oxy}-5-chlorobenzonitrile (0.15 g, 0.51 mmol), 2-methyl-4-(methyloxy)benzoic acid (0.6 g, 0.25 mmol), HATU (0.21 g, 0.56 mmol) and DIPEA (0.11 mL, 0.60 mmol) were dissolved in acetonitrile (3 mL) and DMF (1 mL) then stirred overnight. EtOAc (25 mL) and saturated NaHCO3 (10 mL) were added. The layers were separated and the aqueous layer was extracted with EtOAc (2×10 mL). The organic extracts were combined, dried over Na2SO4, filtered and evaporated. Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.05 g, 19%) as a white solid. 1H NMR (400 MHz, DMSO-d5): δ ppm 8.63 (s, 1H), 7.82 (d, 1H), 7.59 (d, 1H), 7.46 (dd, 1H), 7.39 (d, 1H), 7.26 (t, 2H), 7.16 (d, 1H), 6.73-6.78 (m, 2H), 4.38 (d, 2H), 3.73 (s, 3H), 2.25 (s, 3H). MS: m/z 441.0 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5](=O)[CH2:6][C:7](=[O:17])/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[CH3:2].C([O-])(=O)C.[NH4+:24]>CCO>[CH2:1]([O:3][C:4](=[O:19])/[C:5](/[NH2:24])=[CH:6]/[C:7](=[O:17])/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[CH3:2]
Reactant: [NH4+]
Reactant: CCOC(=O)C(=O)CC(=O)/C=C/c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Solvent: CCO
Product: CCOC(=O)/C(N)=C/C(=O)/C=C/c1ccc(Cl)cc1
Yield: 59.2 %

Procedure:
Using the procedure of Example 4, (E)-6-(4-chlorophenyl)-2,4-dioxo-hex-5-enoic acid ethyl ester (4; 79.5 g, 0.284 mol) and ammonium acetate (43.78 g, 0.568 mol) were allowed to react in EtOH (795 mL) to provide (2Z,5E)-2-amino-6-(4-chlorophenyl)-4-oxo-hexa-2,5-dienoic acid ethyl ester (8; 47 g, 86%) as a yellow solid: mp 105-107° C.; 1H NMR (400 MHz, CDCl3) δ 9.40 (br s, 1H), 7.52 (d, J=15.9 Hz, 1H), 7.50-7.47 (m, 2H), 7.38-7.32 (m, 2H), 6.78 (d, J=15.9 Hz, 1H), 6.14 (s, 1H), 6.01 (s, 1H), 4.37 (q, J=7.1 Hz, 2H), 1.39 (t, J=7.1 Hz, 3H); HRMS-ESI (m/z): calcd for C14H14ClNO3, 279.067. found, 279.066.
Reaction SMILES: CSC.B(F)(F)F.C[N:9]([C:14](=[O:36])[C:15]1[CH:20]=[C:19]([Cl:21])[C:18]([O:22][C:23]2[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[C:26]([O:32]C)=[C:25]([F:34])[CH:24]=2)=[C:17]([Cl:35])[CH:16]=1)[CH2:10][C:11]([OH:13])=[O:12].ClCCl>O>[Cl:21][C:19]1[CH:20]=[C:15]([CH:16]=[C:17]([Cl:35])[C:18]=1[O:22][C:23]1[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[C:26]([OH:32])=[C:25]([F:34])[CH:24]=1)[C:14]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:36]
Reactant: COc1c(F)cc(Oc2c(Cl)cc(C(=O)N(C)CC(=O)O)cc2Cl)cc1C(C)C
Agent: FB(F)F
Solvent: CSC
Solvent: O
Solvent: ClCCl
Product: CC(C)c1cc(Oc2c(Cl)cc(C(=O)NCC(=O)O)cc2Cl)cc(F)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 10.9 %

Procedure:
Boron trifluoride dimethyl sulfide (2.0 mL) was added at room temperature to a stirred solution of methyl-N-[3,5-dichloro-4-(3-fluoro-5-isopropyl-4-methoxyphenoxy)benzoyl]glycine (50 mg, 0.11 mmol) and dichloromethane (8 mL). The reaction mixture was stirred at room temperature for 24 hours, poured out in water and extracted with ethyl acetate. The combined organic phases were washed with water, concentrated and the resulting residue purified on column (HPLC, ACE-C8, acetonitrile/0.05% formic acid in water, gradient elution from 5/95 to 60/40) to give 5 mg (20%) of N-[3,5-dichloro-4-(3-fluoro-4-hydroxy-5-isopropylphenoxy)benzoyl]glycine. LC-MS (ES−1): m/z 414.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:17][C:18]2[C:23]([C:24]([CH3:32])([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[O:33]([C:40](NO)=[O:41])C1C=CC=CC=1>C1COCC1>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:17][C:18]2[C:23]([C:24]([CH3:32])([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH3:25])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:11]2[CH2:12][CH2:13][N:14]([C:40]([OH:41])=[O:33])[CH2:15][CH2:16]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(CN(Cc2ncccc2C(C)(C)c2ccccc2)C2CCNCC2)c(C)c1
Reactant: O=C(NO)Oc1ccccc1
Solvent: C1CCOC1
Product: Cc1cnc(CN(Cc2ncccc2C(C)(C)c2ccccc2)C2CCN(C(=O)O)CC2)c(C)c1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
A stirred solution of (3,5-dimethyl-pyridin-2-ylmethyl)-[3-(1-methyl-1-phenyl-ethyl)-pyridin-2-ylmethyl]-piperidin-4-yl-amine (1.20 g, 2.8 mmol) and N-(phenoxycarbonyl)-hydroxylamine (515 mg, 3.4 mmol) in THF (28 mL) was heated at reflux for 16 hours. The mixture was cooled to room temperature, concentrated, and purified on a silica gel column (40 g, eluted with 5% NH4OH/10% MeOH/CH3CN) to afford COMPOUND 350 (1.12 g, 82%), as a white solid. 1H NMR (CDCl3) δ 1.10-1.26 (m, 2H), 1.51 (d, 2H, J=11.5 Hz), 1.62 (s, 6H), 2.23 (s, 3H), 2.25 (s, 3H), 2.48 (t, 3H, J=11.5), 3.41 (s, 2H), 3.60 (s, 2H), 3.86 (d, 2H, J=12.0 Hz), 7.03 (d, 2H, J=7.5 Hz), 7.12-7.25 (m, 5H), 7.87 (d, 1H, J=8.0 Hz), 8.10 (s, 1H), 8.50 (d, 1H, J=3.5 Hz); 13C NMR (CDCl3) δ 18.31, 18.76, 27.73(2), 31.23 (2), 42.86, 43.94(2), 54.18, 54.78, 58.20, 121.96, 126.15(2), 126.42, 128.93(2), 131.98, 133.14, 134.44, 139.45, 143.75, 146.51, 146.89, 149.75, 161.05; ES-MS m/z 488 (M+H). Anal. Calcd. For C29H37N5O2.0.6H2O: C, 69.88; H, 7.72; N, 14.05. Found: C, 69.51; H, 7.55; N, 14.12.
Reaction SMILES: CCN=C=NCCCN(C)C.[CH2:12]([N:14]1[C:18]([C:19]2[CH:20]=[C:21]([C:32](O)=[O:33])[CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)[CH:24]=2)=[N:17][N:16]=[N:15]1)[CH3:13].C1C=CC2N(O)N=NC=2C=1.CN1C(=O)CCC1.[CH3:52][O:53][CH2:54][CH:55]([NH2:57])[CH3:56]>C(Cl)Cl>[CH3:52][O:53][CH2:54][CH:55]([NH:57][C:32]([C:21]1[CH:22]=[C:23]([C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)[CH:24]=[C:19]([C:18]2[N:14]([CH2:12][CH3:13])[N:15]=[N:16][N:17]=2)[CH:20]=1)=[O:33])[CH3:56]
Reactant: COCC(C)N
Reactant: CCn1nnnc1-c1cc(C(=O)O)cc(-c2ccc(C)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CCn1nnnc1-c1cc(C(=O)NC(C)COC)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
EDCI (54.0 mg, 0.282 mmol) was added in one portion to a solution of 5-(1-ethyl-1H-tetrazol-5-yl)-4′-methyl-biphenyl-3-carboxylic acid (70.0 mg, 0.229 mmol), HOBt (40.0 mg, 0.296 mmol) and NMP (101.5 mg, 1.000 mmol) in CH2Cl2 (5 mL) at 0° C. After the reaction stirred at the same temperature for 1 hour, 2-methoxy-1-methyl-ethylamine (64.3 mg, 0.72 mmol) was added. The mixture was allowed to warm to room temperature and was stirred overnight. Solvent was removed under reduced pressure and the residue was purified by column chromatography to afford 5-(1-ethyl-1H-tetrazol-5-yl)-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide as white solid (40 mg, 46%). MS (M+H)=380.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:24])[CH:10]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)C(OCC)=O)=[C:5]([CH3:25])[CH:4]=1)#[N:2]>CS(C)=O.[Cl-].[Na+].O>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[CH3:25])=[O:24])=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(C(=O)c1ccc(C#N)cc1C)c1ccc(OC)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CC(=O)c2ccc(C#N)cc2C)cc1
Temperature: 150 °C
Yield: 60.4 %

Procedure:
To a mixture of ethyl 3-(4-cyano-2-methylphenyl)-2-(4-methoxyphenyl)-3-oxopropanoate (9F) (40 g, 0.1186 mol) in dimethyl sulfoxide (75 mL) was added catalytic amount of brine (2.5 mL), and the reaction mixture was heated at 150° C. for 2.5 h. When TLC showed the starting material was consumed, the reaction mixture was cooled down to room temperature, and partitioned between water (150 mL) and ethyl acetate (150 mL). The aqueous layer was extracted with ethyl acetate (100 mL×2). The combined organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate (15 g), evaporated, and purified by chromatography on silica gel (petroleum ether/ethyl acetate=25:1) to give 4-(2-(4-methoxyphenyl)acetyl)-3-methylbenzonitrile (9G) (19 g, yield 60.4%).