Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH2:9](Br)[CH2:10][CH2:11][CH3:12]>>[CH2:9]([O:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][CH:8]=1)[CH2:10][CH2:11][CH3:12]
Reactant: Oc1cccc(O)c1
Reactant: CCCCBr
Product: CCCCOc1cccc(O)c1
Yield: 39 %

Procedure:
Prepared according to the method described in Example A above from resorcinol (55 g; 0.5 mol) and n-butylbromide (75.4 g; 0.55 mol) to yield 32.4 g (39%) of the title compound as an oil (92% purity). bp 148° C. (12 mm Hg) MW=166 (GC-MS)
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=2)[CH:6]=1.C([O-])=O.[Na+].C(O)=O>CO.[Pd]>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:8]=[C:9]([NH2:13])[CH:10]=[CH:11][CH:12]=2)[CH:6]=1
Reactant: Cc1cn(-c2cccc([N+](=O)[O-])c2)cn1
Agent: [Pd]
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: CO
Product: Cc1cn(-c2cccc(N)c2)cn1
Reaction time: 18 h
Yield: 82.8 %

Procedure:
A mixture of 14.6 g of 4-methyl-1-(3-nitrophenyl)-1H-imidazole, 766 mg of palladium black, 19.6 g of sodium formate, 12.8 ml of formic acid in 300 ml of methyl alcohol is stirred for 18 hours under a hydrogen atmosphere. The mixture is filtered through diatomaceous earth and the filtrate evaporated to a residue. The residue is partitioned between saturated potassium bicarbonate and chloroform. The organic layer is dried and evaporated to a residue which is dissolved in a minimum of chloroform and passed through a pad of hydrous magnesium silicate. The filtrate is evaporated to a residue which is stirred with ether and the resulting solid filtered and air dried to give 10.3 g of the desired product as a solid, m.p. 117°-119° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.[CH:40]1([CH2:46][NH2:47])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1.O>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][C:14]([NH:20][C:21](=[O:22])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])([C:17]([NH:47][CH2:46][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[O:19])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(C(=O)OCc2ccccc2)CC1
Reactant: NCC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(C(=O)NCC2CCCCC2)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-benzyloxycarbonyl-4-(t-butoxycarbonylamino)piperidin-4-carboxylic acid (297 mg) in dimethylformamide (2.5 mL) were added 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (226 mg), 4-N,N-dimethylaminopiperidine (144 mg) and cyclohexylmethylamine (0.15 mL) and the solution was stirred at room temperature overnight. Water was added to the reaction mixture, which was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (ethyl acetate:methanol=40:1-10:1) to give the title compound having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[C:9]([NH2:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:11])[CH:3]=1.[CH:12](O)=O>>[CH3:11][C:4]1[C:5]([C:6]#[N:7])=[CH:8][C:9]2[NH:10][CH:12]=[N:1][C:2]=2[CH:3]=1
Reactant: O=CO
Reactant: Cc1cc(N)c(N)cc1C#N
Product: Cc1cc2nc[nH]c2cc1C#N

Procedure:
A reaction mixture of 4,5-diamino-2-methylbenzonitrile (20 mg) and formic acid (6 ml) was refluxed for 3 hours. The reaction solution was cooled and concentrated. To the residue was added a 1M aqueous NaOH solution, and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated to obtain 5-methyl-1H-benzimidazole-6-carbonitrile as colorless powders.
Reaction SMILES: CN1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14][CH2:15][C:16]3[CH:17]=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[O:25]1CCC(=O)CC1.CN1CCC(=O)CC1>>[CH3:13][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:14][CH2:15][C:16]3[CH:17]=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=3)[C:5]3[CH2:23][CH2:24][O:25][CH2:3][C:4]=3[C:12]=2[CH:11]=1
Reactant: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(C)C1
Reactant: O=C1CCOCC1
Agent: CN1CCC(=O)CC1
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCOC1

Procedure:
8-Methyl-5-[2-(6-methyl-pyridin-3-yl)-ethyl]-1,3,4,5-tetrahydro-pyrano[4,3-b]indole is prepared in an analagous manner to Dimebon, except that tetrahydro-pyran-4-one is used in the final step in place of 1-methyl-piperidin-4-one.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:10][C:11]([NH:13]C(=O)C2C=CC=CC=2)=[S:12])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO>[CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:10][C:11]([NH2:13])=[S:12])[CH2:2][CH2:3]1
Reactant: O=C(NC(=S)Nc1ccccc1C1CC1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=S)Nc1ccccc1C1CC1
Temperature: 65 °C
Reaction time: 3 h
Yield: 56.7 %

Procedure:
To N-((2-cyclopropylphenyl)carbamothioyl)benzamide (1.210 g, 4.08 mmol) in MeOH (10 mL) was added 2 N NaOH (4.1 mL, 8.17 mmol) and stirred at 65° C. for 3 hours. The reaction was cooled, neutralized with 2 N HCl, and half of the reaction volume was evaporated under a stream of nitrogen. A yellow precipitate formed that was filtered, rinsed with water and dried in the vacuum oven to give 1-(2-cyclopropylphenyl)thiourea as a yellow solid (444.5 mg, 56%): mp 152-154° C.; 1H NMR (400 MHz, CDCl3) δ 7.75 (s, 1H), 7.31-7.27 (m, 1H), 7.26-7.22 (m, 2H), 7.00 (d, J=7.4 Hz, 1H), 5.95 (s, 2H), 1.99 (tt, J=8.4, 5.3 Hz, 1H), 1.06 (ddd, J=8.4, 6.3, 4.5 Hz, 2H), 0.69 (dt, J=6.4, 4.6 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 182.10, 140.33, 135.18, 128.81, 126.96, 126.45, 126.04, 10.95, 8.39; ESIMS m/z 193 ([M+H]+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1.[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C(#N)C>[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=S)c1cnc(C)nc1Cl
Reactant: Nc1ccc(F)cc1
Solvent: CC#N
Product: CCOC(=S)c1cnc(C)nc1Nc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 76.6 %

Procedure:
To a solution of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (Aldrich, 24 g, 103 mmol) in 250 mL of acetonitrile at room temperature was added 4-fluoroaniline (22.75 g, 205 mmol). After stirring for two days, the mixture was heated at 60° C. for four hours. The resulting solid was filtered and washed with EtOAc. The filtrate was concentrated, diluted in EtOAc (300 L), washed with brine, dried (MgSO4), filtered and concentrated to provide a crude product. The crude product was stirred with hexanes (400 mL) and then filtered to give 23 g of the ethyl 4-(4-fluorophenyl)amino-2-methylthiopyrimidine-5-carboxylate as a white solid.
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH:4]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:10][CH:9]=1)[C:5]([OH:7])=[O:6].[H][H]>[Pt]=O.C(O)C>[OH:1][CH2:2][CH2:3][CH:4]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:10][CH:9]=1)[C:5]([OH:7])=[O:6]
Reactant: [H][H]
Reactant: O=CCC(C(=O)O)c1ccc(-c2ccccc2Cl)cc1
Agent: O=[Pt]
Solvent: CCO
Product: O=C(O)C(CCO)c1ccc(-c2ccccc2Cl)cc1

Procedure:
To a suspension of γ-keto-(2'-chloro-4-biphenylyl)butyric acid 8.64 g. (0.031 mole) in 300 ml. of 90% ethanol is added 1 ml. of 0.1M ferrous sulfate solution followed by 0.5 g. of platinum oxide catalyst. The mixture is shaken with hydrogen for 31/2 hours. The catalyst is filtered off. The filtrate is distilled under reduced pressure to yield γ-hydroxy(2'-chloro-4-biphenylyl)butyric acid.
Reaction SMILES: [K+].[NH:2]1[CH2:6][C@H:5]([S:7][C:8]2[C@H:9]([CH3:22])[C@@H:10]3[C@@H:17]([C@H:18]([OH:20])[CH3:19])[C:16](=[O:21])[N:11]3[C:12]=2[C:13]([O-:15])=[O:14])[CH2:4][C:3]1=[S:23].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[C:35]([O:40][CH2:41]I)(=[O:39])[CH:36]([CH3:38])[CH3:37]>C(OCC)(=O)C>[C:35]([O:40][CH2:41][O:14][C:13]([C:12]1[N:11]2[C:16](=[O:21])[C@H:17]([C@H:18]([OH:20])[CH3:19])[C@H:10]2[C@@H:9]([CH3:22])[C:8]=1[S:7][C@H:5]1[CH2:6][NH:2][C:3](=[S:23])[CH2:4]1)=[O:15])(=[O:39])[CH:36]([CH3:38])[CH3:37]
Reactant: CC(C)C(=O)OCI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S[C@H]3CNC(=S)C3)[C@H](C)[C@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C(=O)OCOC(=O)C1=C(S[C@H]2CNC(=S)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reaction time: 0.5 h
Yield: 30.3 %

Procedure:
To a mixture of (1R, 5S, 6S)-2-[(4R)-pyrrolidine-2- thion-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2- em-3-carboxylic acid potassium salt (0.34 g), N,N-dimethylformamide (3 ml) and potassium carbonate (0.12 g) is added dropwise isobutyryloxymethyl iodide (0.27 g) under ice cooling. After stirring the mixture at the same temperature for 30 minutes, ethyl acetate (10 ml) is added to the reaction mixture, and the mixture is washed with water, and the organic layer is dried and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel flash column chromatography (eluent, chloroform: ethanol=20:1), followed by crystallization from isopropyl ether and ethyl acetate to give (1R, 5S, 6S)-2-[(4R)-pyrrolidine-2-thion-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid isobutyryloxymethyl ester (0.12 g) as colorless needles.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([N:23]([CH:25]([CH3:27])[CH3:26])[CH3:24])[CH2:19][C@@H:18]2[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:13]1=[O:33])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([N:23]([CH:25]([CH3:27])[CH3:26])[CH3:24])[CH2:19][C@@H:18]2[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:13]1=[O:33]
Reactant: CCOC(=O)[C@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)[C@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Yield: 100.6 %

Procedure:
A solution of (1S,2S,5R)-ethyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(isopropyl(methyl)amino)-cyclohexanecarboxylate (530 mg, 1.1 mmol) in methanol was treated with 150 mg of 10% Pd/C and hydrogenated at 55 psi of H2 in a Parr shaker overnight. The catalyst was filtered and the filtrate concentrated in vacuo to give 360 mg of (1S,2S,5R)-ethyl 2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(isopropyl(methyl)amino)cyclohexanecarboxylate. This was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27]C)=[O:26])=[CH:19][CH:18]=3)[CH:10]=2)=[C:4]([CH3:29])[CH:3]=1.[OH-].[Na+]>CO.O1CCCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH3:29])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:21][CH:22]=3)[CH:10]=2)=[C:6]([CH3:8])[CH:7]=1
Reactant: COC(=O)CCc1ccc(OCc2cccc(-c3c(C)cc(O)cc3C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(O)cc(C)c1-c1cccc(COc2ccc(CCC(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
To a solution of methyl 3-[4-[(4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methoxy]phenyl]propanoate (0.18 g, 0.46 mmol) in methanol (2 mL) and tetrahydrofuran (4 mL) was added 1 N aqueous sodium hydroxide solution (0.91 mL) and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated and the residue was diluted with ethyl acetate, washed with 1 N hydrochloric acid and saturated brine, dried and concentrated under reduced pressure. The residue was crystallized from hexane/ethyl acetate=4/1 to give the title compound (0.13 g, yield 74%) as colorless crystals.
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[C:14]([O:16][CH3:17])=[O:15])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>CN(C=O)C>[N:22]1([C:2]2[CH:19]=[CH:18][C:5]([C:6]([C:8]3[CH:13]=[CH:12][N:11]=[CH:10][C:9]=3[C:14]([O:16][CH3:17])=[O:15])=[O:7])=[CH:4][CH:3]=2)[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: COC(=O)c1cnccc1C(=O)c1ccc(F)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cnccc1C(=O)c1ccc(-n2ccnc2)cc1

Procedure:
A solution of 4-(4-fluorobenzoyl)-3-carbomethoxypyridine (2.05 g, 7.91 mmol) in 20 mL of DMF is added dropwise to NaH (0.37 g, 9.10 mmol) and imidazole (0.54 g, 7.91 mmol) in 35 mL of DMF. Using the same reaction conditions and workup as those used in Example 13, leads to the recovery of crude product. Chromatographic purification on silica gel (using EtOAc-MeOH, 95:5 as the eluent) gives pure 4-[4-(1H-imidazol-1-yl)benzoyl]-3-carbomethoxypyridine. M.P. 135°-137° C.
Reaction SMILES: [NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([O:12]C)=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[O-]CC.[Na+]>C(O)C>[N:1]1[C:2]2[C:7](=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:8]=[CH:9][C:10]=1[OH:12]
Reactant: COC(=O)/C=C/c1cccnc1N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Oc1ccc2cccnc2n1
Reaction time: 0.17 h
Yield: 97.6 %

Procedure:
(E)-Methyl 3-(2-aminopyridin-3-yl)acrylate (3.50 g, 19.64 mmol) was dissolved in ethanol (80 mL) and treated with sodium ethoxide (21 wt. % solution in denatured ethanol, ml, 26.8 mmol). The solution was heated at reflux for 2 hours then evaporated to dryness under reduced pressure. Saturated ammonium chloride (100 mL) and water (100 mL) were added to the crude and it was stirred for 10 minutes. The solid product was filtered off and dried by toluene azeotrope to give 1,8-naphthyridin-2-ol (2.80 g, 19.16 mmol, 83% yield) as a white powder.
Reaction SMILES: ClC(OCC(C)C)=O.[CH2:9]([O:16][C:17]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([OH:23])=O)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN1CCOCC1.[CH3:34][C:35]1[C:40]([C:41]([OH:43])=[O:42])=[C:39]([NH:44][C:45](=[O:51])[C@H:46]([CH:48]([CH3:50])[CH3:49])[NH2:47])[CH:38]=[CH:37][CH:36]=1.Cl>C(OCC)(=O)C.CN(C)C=O.O1CCCC1>[CH2:9]([O:16][C:17]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([NH:47][C@H:46]([C:45]([NH:44][C:39]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:34])[C:40]=1[C:41]([OH:43])=[O:42])=[O:51])[CH:48]([CH3:50])[CH3:49])=[O:23])=[O:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cccc(NC(=O)[C@@H](N)C(C)C)c1C(=O)O
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cccc(NC(=O)[C@@H](NC(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)C(C)C)c1C(=O)O
Reaction time: 0.15 h
Yield: 73.9 %

Procedure:
Isobutyl chloroformate (0.1 ml) was added dropwise to a tetrahydrofuran solution (2.5 ml) containing N-benzyloxycarbonyl-L-proline (229 mg) and N-methylmorpholine (0.1 ml) at -12° C. to -18° C., and the mixture was stirred at this temperature for nine minutes. An N,N-dimethylformamide solution (1.5 ml) containing 6-methyl-2-(L-valylamino)benzoic acid (142 mg) and N-methylmorpholine (0.075 ml) was added dropwise to the above solution at -15° C., and the resultant solution was stirred at this temperature for 20 minutes and then at room temperature for 45 minutes. Thereafter, 1N hydrochloric acid was added to stop the reaction, and extraction was performed using ethyl acetate. The organic layer was successively washed with 1N hydrochloric acid and brine, dried over sodium sulfate, and concentrated. The residue was purified by flash column chromatography using silica gel to obtain 202 mg of 2-(N-benzyloxycarbonyl-L-prolyl-L-valyl)amino-6-methylbenzoic acid.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](Cl)=[O:5].[Br:9][C:10]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[C:13]([NH2:14])=[C:12]([Cl:21])[CH:11]=1.O>C(#N)C>[Br:9][C:10]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[C:13]([NH:14][C:4](=[O:5])[CH2:3][C:2]([CH3:8])([CH3:7])[CH3:1])=[C:12]([Cl:21])[CH:11]=1
Reactant: Nc1c(Cl)cc(Br)cc1C(F)(F)F
Reactant: CC(C)(C)CC(=O)Cl
Solvent: O
Solvent: CC#N
Product: CC(C)(C)CC(=O)Nc1c(Cl)cc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.9 %

Procedure:
3,3-dimethylbutanoyl chloride (1.08 g, 8.0 mmol) was added to a solution of 4-bromo-2-chloro-6-(trifluoromethyl)aniline (2.0 g, 7.3 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature overnight. Water was added to the mixture and then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. Purification by column chromatography (100% DCM) afforded the title compound as a powder (1.22 g, 65%) over the two steps,
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:27]2[CH:28]=[CH:29][C:30]([Cl:42])=[C:31]3[C:35]=2[N:34]([CH3:36])[N:33]=[C:32]3[NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:5]([C@@H:9]([NH:19][C:20](=[O:26])OC(C)(C)C)[CH2:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)=[N:6][C:7]=1[Cl:8].[F:43][C:44]1([F:61])[C:48]2[N:49]([CH2:56]C(O)=O)[N:50]=[C:51]([C:52]([F:55])([F:54])[F:53])[C:47]=2[C@H:46]2[CH2:60][C@@H:45]12.FC(F)C1C2[C@H]3C[C@H]3C(F)(F)C=2N(CC(O)=O)N=1>>[NH2:1][C:2]1[CH:3]=[C:4]([C:27]2[CH:28]=[CH:29][C:30]([Cl:42])=[C:31]3[C:35]=2[N:34]([CH3:36])[N:33]=[C:32]3[NH:37][S:38]([CH3:41])(=[O:39])=[O:40])[C:5]([C@@H:9]([NH:19][C:20](=[O:26])[CH2:56][N:49]2[C:48]3[C:44]([F:43])([F:61])[C@@H:45]4[CH2:60][C@@H:46]4[C:47]=3[C:51]([C:52]([F:53])([F:54])[F:55])=[N:50]2)[CH2:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)=[N:6][C:7]=1[Cl:8]
Reactant: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3cc(N)c(Cl)nc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)OC(C)(C)C)c21
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1C(F)(F)[C@@H]1C[C@H]21
Agent: O=C(O)Cn1nc(C(F)F)c2c1C(F)(F)[C@@H]1C[C@H]21
Product: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3cc(N)c(Cl)nc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)Cn3nc(C(F)(F)F)c4c3C(F)(F)[C@@H]3C[C@H]43)c21

Procedure:
Compound 54 was prepared from compound 53A according to the method presented for the synthesis of Example 49 substituting 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid for 2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid to provide 13 mg of title compound: 1H NMR (400 MHz, Methanol-d4) δ 7.12-6.94 (m, 2H), 6.81-6.60 (m, 1H), 6.55-6.35 (m, 2H), 6.25 (d, 1H), 5.01-4.90 (m, 1H), 4.76 (t, 2H), 3.41 (s, 2H), 3.24 (d, 3H), 3.15-2.88 (m, 3H), 2.48 (q, 2H), 1.47-1.38 (m, 1H), 1.16-1.04 (m, 1H). MS (m/z) 805 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH:8]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:7].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([O:38][CH3:39])[CH:37]=1)[CH:33]=O>C1C=CC=CC=1>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:33]=[CH:8][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][OH:1])[CH:35]=[C:36]([O:38][CH3:39])[CH:37]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)CCCCO
Solvent: c1ccccc1
Product: COc1cc(C=CC(=O)CCCCO)cc(OC)c1
Temperature: 25 °C

Procedure:
10 parts of the phosphonium salt produced in Example 16 was dissolved in water containing an amount of potassium carbonate in excess of that necessary to deprotonate the phosphonium chloride. After extracting this solution with methylene chloride, the organic phase was dried over sodium sulfate. After separation of the drying agent, the methylene chloride was removed at room temperature and under a stream of nitrogen, leaving (5-hydroxypentanoylmethylene)-triphenylphosphorane. 7.04 parts of this phosphorane and 3.11 parts of 3,5-dimethoxybenzaldehyde were dissolved in about 135 parts of benzene, and the solution was maintained under a nitrogen atmosphere and refluxed for 3 days. After the reaction mixture was cooled to room temperature, the benzene was removed at room temperature under a nitrogen stream, leaving a product mixture. This mixture was separated chromatographically on a silica column using as the elution solvent a mixture of 30 percent by volume of ethyl acetate in benzene, to yield 1-(3,5-dimethoxyphenyl)-7-hydroxy-1-hepten-3-one which, after recrystallization from a mixture of benzene and cyclohexane, melted at about 78°-80° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]1[S:40][C:39]([CH2:41][CH2:42][OH:43])=[CH:38][CH:37]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:43][CH2:42][CH2:41][C:39]3[S:40][C:36]([CH3:35])=[CH:37][CH:38]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH2:23]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(O)cc2)c1N1CCC(C)(C)CC1
Reactant: Cc1ccc(CCO)s1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(CCOc2ccc(-c3c(C)nc(C)c([C@H](OC(C)(C)C)C(=O)O)c3N3CCC(C)(C)CC3)cc2)s1
Reaction time: 18 h
Yield: 21.5 %

Procedure:
To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (50 mg, 0.107 mmol), 2-(5-methylthiophen-2-yl)ethanol (76 mg, 0.533 mmol) and Ph3P (139 mg, 0.533 mmol) in THF (2 mL) was added DIAD (0.104 mL, 0.533 mmol) at rt. After 18 h, mixture was filtered to remove polymer, concentrated and treated with 1N NaOH (0.854 mL, 0.854 mmol) in MeOH (1 mL) at 75° C. for 16 h. Mixture was then cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(4-(2-(5-methylthiophen-2-yl)ethoxy)phenyl)pyridin-3-yl)acetic acid (13 mg, 0.023 mmol, 21.57% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.20 (d, J=8.8 Hz, 1H), 7.10-6.91 (m, 4H), 6.73 (d, J=3.3 Hz, 1H), 6.63 (br. s., 1H), 5.82 (s, 1H), 4.29-4.07 (m, 3H), 3.26 (br. s., 1H), 3.17 (t, J=6.1 Hz, 1H), 2.43 (s, 3H), 2.38 (s, 3H), 2.15 (br. s., 1H), 2.05 (s, 3H), 1.28 (br. s., 2H), 1.17 (d, J=16.5 Hz, 1H), 1.11 (s, 9H), 1.07-0.94 (m, 2H), 0.83 (br. s., 3H), 0.60 (br. s., 3H). LCMS (M+H)=565.3.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:19][C:20]1[C:21]([C:26]2[N:30]([CH2:31][C:32]([F:35])([F:34])[F:33])[N:29]=[CH:28][CH:27]=2)=[N:22][CH:23]=[CH:24][CH:25]=1>CN(C=O)C>[OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:19][C:20]2[C:21]([C:26]3[N:30]([CH2:31][C:32]([F:35])([F:33])[F:34])[N:29]=[CH:28][CH:27]=3)=[N:22][CH:23]=[CH:24][CH:25]=2)[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(O)cccc1O
Reactant: FC(F)(F)Cn1nccc1-c1ncccc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1c(O)cccc1OCc1cccnc1-c1ccnn1CC(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2,6-dihydroxybenzaldehyde (438 mg, 11.47 mmol, 2 eq.) and K2CO3 (2.4 g, 17.22 mmol, 3 eq.) in DMF (150 mL) was stirred at rt for 10 min. To this mixture was added 3-(chloromethyl)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridine hydrochloride (498 mg, 1.59 mmol, 1 eq.) at rt. The mixture was heated at 50° C. for 2 h, filtered, concentrated and purified on silica gel using a mixture of EtOAc and hexanes as eluent to 2-hydroxy-6-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde (338.4 mg, 56%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 11.99 (s, 1H), 10.41 (s, 1H), 8.76 (dd, J=4.7, 1.6 Hz, 1H), 8.01 (dd, J=7.9, 1.4 Hz, 1H), 7.69 (d, J=1.9 Hz, 1H), 7.49-7.39 (m, 2H), 6.61 (d, J=8.5 Hz, 1H), 6.53 (d, J=1.9 Hz, 1H), 6.32 (d, J=8.3 Hz, 1H), 5.30 (q, J=8.6 Hz, 2H), 5.17 (s, 2H). LRMS (M+H+) m/z 378.1