Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([OH:18])=O)[C:8]3=[N:9]2)=[CH:4][CH:3]=1.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][NH2:24].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([NH:24][CH2:23][CH2:22][N:21]([CH3:25])[CH3:20])=[O:18])[C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: CN(C)CCN
Reactant: O=C(O)c1cccn2c(=O)c3ccc(Br)cc3nc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CN(C)CCNC(=O)c1cccn2c(=O)c3ccc(Br)cc3nc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The 3-bromo-11-oxo-11H-pyrido[2,1-b]quina-zoline-6-carboxylic acid was dissolved in dichloromethane (25 ml). To the reaction mixture was added N,N-dimethyl-ethylenediamine (1 g; 0.0023 mol), followed by the BOP reagent (1 g, 0.0023 mol). The reaction mixture was stirred at room temperature for 30 minutes, diluted with water and extracted with dichloromethane. The combined organic phases were dried, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with 10% methanol/chloroform) to provide product as a yellow solid: 0.338 g.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[CH:8][C:9]=1[Cl:10].[C:12]1(=[O:16])[O:15][CH2:14][CH2:13]1.Cl>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[Cl:10])[O:11][CH2:14][CH2:13][C:12]([OH:16])=[O:15]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: O=C1CCO1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CCOc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride 0.24 g (0.01 mol) was dissolved in 10 ml of dry DMF. After 30 min, a solution of 3,4-dichloro phenol 1.63 g (0.01 mol) dissolved in 5 ml of DMF was added in drops. The reaction mixture was heated to 100 C. After 1 hour, β-propiolactone, 0.72 g (0.628 ml, 0.01 mol) was added slowly for 5 minutes. The reaction mixture was further continued heating for 12 h. The reaction mixture was cooled to room temperature and poured over ice-cold water 10 ml was added. This diluted mixture was acidified by the addition of Con. HCl. The product was extracted twice with diethyl ether (20 ml). The ether layer was then washed with 10% Sodium bicarbonate. The aqueous layer was acidified to pH=2. The precipitated solid was filtered and dried to afford the required product 3-(3,4-dichlorophenoxy)propanoic acid (PC165).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:25]=[CH:26][C:27]=2[CH3:28])[CH2:18][CH2:17]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:23]=[C:24]([NH:29][C:30](=[O:34])[CH:31]([CH3:32])[CH3:33])[CH:25]=[CH:26][C:27]=3[CH3:28])[CH2:18][CH2:17]2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)Cc2ccc(F)cc2)CC1

Procedure:
Example 175 was prepared from (4-fluorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 12: 1H NMR (400 MHz, CDCl3) δ 7.38 (s, 1 H), 7.32 (s, 1 H), 7.28–7.16 (m, 3 H), 7.04–6.90 (m, 3 H), 6.86 (s, 1 H), 3.47 (s, 2 H), 3.27 (q, 2 H, J=6.0 Hz), 2.95 (d, 2 H, J=11.6 Hz), 2.69–2.53 (m, 1 H), 2.50–2.32 (m, 3 H), 2.19 (s, 3 H), 2.09–1.94 (m, 2 H), 1.74–1.53 (m, 6 H), 1.15 (d, 6 H, J=7.2 Hz); ESMS m/e: 454.3 (M+H)+.
Reaction SMILES: [Li][CH2:2]CCC.[Br:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][CH2:12][C:13]2=O)=[CH:9][CH:8]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][CH2:12][C:13]2=[CH2:2])=[CH:9][CH:8]=1
Reactant: [Li]CCCC
Reactant: O=C1CCc2ccc(Br)cc21
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCc2ccc(Br)cc21
Reaction time: 1 h
Yield: 62 %

Procedure:
A 2.5 M solution of n-BuLi in hexanes (23.6 mL, 59 mmol) was added dropwise to a 0° C. slurry of methyltriphenylphosphonium bromide (16.8 g, 47.0 mmol) in THF (200 mL). After 1 h, a solution of 6-bromo-2,3-dihydro-1H-inden-1-one (10.0 g, 47.0 mmol) in THF (50 mL) was added to the resulting solution and the reaction cold bath was removed. Upon completion, the reaction was quenched with water (40 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×40 mL). The combined organics were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to afford 6-bromo-1-methylene-2,3-dihydro-1H-indene (6.06 g, 62% yield) as a clear oil after purification by flash chromatography over silica gel (hexane eluent). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.61 (d, J=1.5 Hz, 1H), 7.32 (dd, J=8.0, 1.8 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H), 5.45 (t, J=2.5 Hz, 1H), 5.08 (t, J=2.1 Hz, 1H), 2.88-2.98 (m, 2H), 2.78-2.86 (m, 2H); MS (EI) m/z=210.1 [M+1]+.
Reaction SMILES: C([O-])(=O)C.[Na+].[Cl:6][C:7]1[CH:12]=[C:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:10]=[CH:9][C:8]=1[C:18](=[O:29])[C:19](=[CH:25]OCC)[C:20]([CH:22]1[CH2:24][CH2:23]1)=[O:21].Cl.[NH2:31]O.O>C(O)C>[Cl:6][C:7]1[CH:12]=[C:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:10]=[CH:9][C:8]=1[C:18]([C:19]1[CH:25]=[N:31][O:21][C:20]=1[CH:22]1[CH2:24][CH2:23]1)=[O:29]
Reactant: CCOC=C(C(=O)c1ccc(OS(C)(=O)=O)cc1Cl)C(=O)C1CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)Oc1ccc(C(=O)c2cnoc2C2CC2)c(Cl)c1
Reaction time: 0.75 h
Yield: 89.6 %

Procedure:
Sodium acetate (1.52 g) was added to a stirred mixture of 1-[2-chloro-4-(methylsulphonyloxy)phenyl]-3-cyclopropyl-2-ethoxymethylenepropan-1,3-dione (5.6 g) and hydroxylamine hydrochloride (1.3 g) in ethanol. The mixture was stirred for 0.75 hours. Water was added and the mixture was extracted with dichloromethane. The organic layer was washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography eluted with a mixture of ethyl acetate and dichloromethane to give 4-[2-chloro-4-(methylsulphonyloxy)benzoyl]-5-cyclopropylisoxazole (compound 1, 4.60 g) as a brown oil, NMR (CDCl3) 1.25-1.35(m,2H), 1,4-1.5 (m,2H), 2.6-2.7(m, 1H), 3.2(s, 1H), 7.3(d, 1H), 7.4(s, 1H), 7.45 (d, 1H), 8.15 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][N:9]2[CH2:29][CH2:28][C:12]3([CH2:17][C:16](=[O:18])[N:15]([CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[C:14](=[O:27])[CH2:13]3)[CH2:11][CH2:10]2)=[CH:3][CH:2]=1>C(O)(=O)C.O=[Pt]=O>[C:20]([OH:22])(=[O:21])[CH3:19].[C:20]([OH:22])(=[O:21])[CH3:19].[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][N:9]2[CH2:10][CH2:11][C:12]3([CH2:17][C:16](=[O:18])[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:14](=[O:27])[CH2:13]3)[CH2:28][CH2:29]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CN1C(=O)CC2(CCN(CCc3ccncc3)CC2)CC1=O
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: O=C(O)CN1C(=O)CC2(CCN(CCC3CCNCC3)CC2)CC1=O

Procedure:
To a solution of 0.5 g (1.25 mmol) of the compound from Example 26, Step C in 40 ml 90% acetic acid were added 100 mg PtO2. The mixture was filled into an autoclave and hydrogenated at 20 atm and room temperature for 22 h. The solvent was removed under reduced pressure, and the residue was stirred with ether. The insoluble title compound was separated and dried in vacuo.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=[CH:9][C:10](Cl)=[O:11])[CH:3]=1.[CH3:13][O:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([NH2:23])[CH:17]=1.C(N(CC)CC)C>ClCCl>[CH3:13][O:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([NH:23][C:10](=[O:11])[CH:9]=[CH:8][C:4]2[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=2)[CH:17]=1
Reactant: COC(=O)c1ccc(C)c(N)c1
Reactant: O=C(Cl)C=Cc1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C)c(NC(=O)C=Cc2cccnc2)c1
Reaction time: 0.5 h

Procedure:
To a suspension of 3-pyridin-3-ylacryloyl chloride hydrochloride (5.1 g) in anhydrous dichloromethane (100 ml), a solution of 3-amino-4-methyl benzoic acid methyl ester (2.75 g) and triethylamine (2.3 ml) in dichloromethane (50 ml) was added dropwise slowly in an ice-bath with the temperature no more than 5° C. After addition, the reaction was carried out for 30 min in an ice-bath, and to then at room temperature for 3 h. The completion of reaction was indicated by TLC. The reaction mixture was concentrated and dissolved into 150 ml of sodium hydroxide solution (10%). The reaction mixture was extracted with EtOAc (30 ml*3). The organic layer was dried over anhydrous MgSO4, and filtered. Most EtOAc was removed by evaporation under reduced pressure. The is residue was cooled in refrigerator. Crystallization and filtration provided a light yellow crystal.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.Cl[C:18]1[CH:23]=[N:22][CH:21]=[CH:20][N:19]=1>CS(C)=O>[N:19]1[CH:20]=[CH:21][N:22]=[CH:23][C:18]=1[O:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: Clc1cnccn1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cnccn2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59 %

Procedure:
To a slurry of sodium hydride (about 60% oil suspension, 114 mg) in dimethyl sulfoxide (5 ml) was added dropwise tert-butyl 4-hydroxy-1-piperidinecarboxylate (576 mg). Considerable foaming occurred and the solution turned pale orange. To this solution was added chloropyrazine (377 mg) and the mixture was stirred at room temperature for 12 hours. The resulting mixture was partitioned between saturated aqueous sodium hydrogencarbonate solution and ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residual solid was triturated with a mixture of ethyl acetate and n-hexane to give the title compound (472 mg) as white crystals.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:25]=[CH:24][CH:23]=4)=[N:14]3)=[C:9]([F:33])[CH:8]=2)[CH2:3][CH2:2]1.C1COCC1>[Pd].CO>[F:33][C:9]1[CH:8]=[C:7]([CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH:12]=[CH:11][C:10]=1[N:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]2[N:26]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:25]=[CH:24][CH:23]=2)=[N:14]1
Reactant: COc1cn(-c2ccc(C3=CCOCC3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cn(-c2ccc(C3CCOCC3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reaction time: 2 h
Yield: 84.6 %

Procedure:
A mixture of 1-[4-(3,6-dihydro-2H-pyran-4-yl)-2-fluorophenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (300 mg, 0.675 mmol), 10% Pd—C (50% wet, 300 mg), THF (30 mL), and MeOH (30 mL) was hydrogenated for 2 h at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from MeOH/H2O to give the title compound (255 mg, 85% yield) as a white solid: mp 187-189° C.; NMR (300 MHz, CDCl3): δ ppm 1.57-1.83 (4H, m), 2.72-2.82 (1H, m), 3.45-3.58 (2H, m), 3.90 (3H, s), 4.09 (2H, td, J=3.0, 11.3 Hz), 6.35 (1H, t, J=8.3 Hz), 6.86 (1H, dd, J=1.5, 8.3 Hz), 7.03 (1H, dd, J=1.9, 12.8 Hz), 7.28 (1H, d, J=1.9 Hz), 7.35-7.46 (5H, m), 7.78 (1H, d, J=1.9 Hz), 7.79 (1H, d, J=2.6 Hz). LC-MS (ESI) m/z 447 [M+H]+. Anal. Calcd for C25H23FN4O3: C, 67.25; H, 5.19; N, 12.55. Found: C, 67.13 H, 5.13; N, 12.57.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C@@H:7]([NH:16][C:17]([O:19][CH2:20][CH:21]1[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41]O)[CH:36]=1>>[C:1]([O:5][C:6](=[O:34])[C@@H:7]([NH:16][C:17]([O:19][CH2:20][CH:21]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=2[C:28]2[C:33]1=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:18])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:41][C:37]2[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=2)=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OCc1cccnc1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCc2cccnc2)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
In a manner similar to that described in Example H, the product from Example G ((S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(4-hydroxyphenyl)-propionic acid tert-butyl ester) (4.39 g, 9.50 mmol) and 3-pyridylcarbinol (0.92 mL, 9.50 mmol) were converted to the title compound.
Reaction SMILES: [CH2:1]([C@@H:5]([C:11]([OH:13])=[O:12])[C@H:6]([OH:10])[C:7]([OH:9])=[O:8])[CH2:2][CH2:3][CH3:4].[C:14]1([CH3:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)C[C:22]2=[O:23]>COC(OC)(OC)C1C=CC=CC=1.C(OCC)(=O)C>[CH3:22][O:23][C:20]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:8][C:7](=[O:9])[CH:6]([CH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:11]([OH:13])=[O:12])[O:10]1
Reactant: CCCC[C@@H](C(=O)O)[C@H](O)C(=O)O
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: Cc1ccccc1
Agent: COC(OC)(OC)c1ccccc1
Solvent: CCOC(C)=O
Product: CCCCC(C(=O)O)C1OC(OC)(c2ccccc2)OC1=O
Temperature: 110 °C

Procedure:
To a solution of (2S,3R)-3-(n-butyl)-2-hydroxysuccinic acid F-4 (300 mg, 1.58 mmol) and powdered molecular sieves (1 g) in trimethyl orthobenzoate (5 mL) and toluene (5 ml) was added 10-Camphorsulfonic acid (20 mg) and the reaction was heated at 110° C. under vacuum (20 torr) for 5 h. The solution was diluted with ethyl acetate, filtered through Celite and washed with brine, dried (Na2SO4) and then purified by silica gel chromatography to afford 1.2 mmol 2-(2-methoxy-2-phenyl-4-oxo-1,3-dioxolan-5-yl)hexanoic acid I-1 (40%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]#[N:13])=[C:7]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:6][CH2:5]2.[Mg].O1CCCC1.Cl>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]#[N:13])[CH:7]([C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)[CH2:6][CH2:5]2
Reactant: N#CC1=C(c2ccc(F)cc2)CCc2cc(Br)ccc21
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CO
Product: N#CC1c2ccc(Br)cc2CCC1c1ccc(F)cc1
Reaction time: 1.5 h

Procedure:
A mixture of 6-bromo-2-(4-fluorophenyl)-3,4-dihydronaphthalene-1-carbonitrile (8 g), magnesium (3 g), tetrahydrofuran (300 ml) and methanol (300 ml) was stirred at 0° under an atmosphere of argon for 1.5 h. The reaction mixture was then poured into 2N hydrochloric acid (300 ml), and the organic solvents were evaporated under reduced pressure. The residue was extracted with ethyl acetate (300 ml), the extract was dried and evaporated to dryness and the residue was triturated with diethyl ether to give 6-bromo-2-(4-fluorophenyl)-1,2,3,4-tetrahydronaphthalene-1-carbonitrile as a white solid, m.p. 146°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:14][C:13](=[O:15])[C:12]([C:16]#N)=[CH:11][C:10]=1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1.C[Mg+].[Br-].[CH:28]([Mg]Br)=[CH:29][CH3:30].C1C[O:36]CC1>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:10]2[CH:11]=[C:12]3[C:16](=[O:36])[CH2:28][CH:29]([CH3:30])[O:15][C:13]3=[N:14][C:9]=2[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[CH:23][CH:22]=1
Reactant: C1CCOC1
Reactant: CC=C[Mg]Br
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)[nH]c1=O
Agent: C[Mg+]
Agent: [Br-]
Product: CC1CC(=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Temperature: 50 °C
Reaction time: 0.05 h

Procedure:
To the product of Example 1 Step B (7.0 g, 18.6 mmol in THF (90 mL) was added MeMgBr (1.4 M in toluene/THF, 14 mL, 19.6 mmol). After stirring for 3 min, prop-1-enylmagnesium bromide (0.5 M in THF, 55.9 mL, 28 mmol) was added and the temperature was increased to 50° C. The reaction was quenched with 2 M HCl after 30 min and diluted with EtOAc. The solution was washed with brine, and concentrated The residue was purified by flash chromatography on silica gel gradient eluted with 0-35% EtOAc in hexane to afford the title compound. (LC-2) HPLC/MS: 418.2 (M+1), 420.2 (M+3); Rt=4.08 min.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[O:7][N:6]=1)([CH3:4])[CH3:3].[NH2:20][C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=1.CN(C1C=CC=CN=1)C>C1COCC1>[F:1][C:2]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=2)=[O:19])[O:7][N:6]=1)([CH3:3])[CH3:4]
Reactant: Nc1cccc(O)c1
Reactant: CC(C)(F)c1cc(NC(=O)Oc2ccccc2)on1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: CC(C)(F)c1cc(NC(=O)Nc2cccc(O)c2)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To THF (10 mL) was added phenyl 3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate from the previous step (500 mg, 1.9 mmol), 3-aminophenol (207 mg, 1.9 mmol) and dimethylaminopyridine (60 mg, 0.5 mmol) and the mixture stirred overnight at room temperature. The mixture was concentrated in vacuo and purified by chromatography on silica gel (10-50% EtOAc/hexanes) to afford 1-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)-3-(3-hydroxyphenyl)urea (390 mg, 1.4 mmol, 74%). LC-MS (ESI) m/z 280 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([O:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:34]=[CH:33][C:25]([C:26]([O:28]C(C)(C)C)=[O:27])=[C:24]([NH:35][C:36]([C:38]3[CH:39]=[N:40][CH:41]=[C:42]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH:43]=3)=[O:37])[CH:23]=2)[CH:19]=[CH:20][CH:21]=1)=O)(C)(C)C>>[OH:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:34]=[CH:33][C:25]([C:26]([OH:28])=[O:27])=[C:24]([NH:35][C:36]([C:38]3[CH:39]=[N:40][CH:41]=[C:42]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH:43]=3)=[O:37])[CH:23]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)Oc1cccc(-c2ccc(C(=O)OC(C)(C)C)c(NC(=O)c3cncc(-c4ccccc4)c3)c2)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2cccc(O)c2)ccc1C(=O)O)c1cncc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Trifluoroacetic acid (4.0 mL) was added to the obtained tert-butyl 4-(3-(tert-butoxycarbonyl)oxyphenyl)-2-(5-phenylpyridine-3-carboxamido)benzoate, followed by stirring at room temperature for 1 hour and 15 minutes. The solvent was evaporated under reduced pressure, and diisopropyl ether was added to the obtained residue. The solid substance was collected by filtration to obtain 70 mg of 4-(3-hydroxyphenyl)-2-(5-phenylpyridine-3-carboxamido)benzoic acid as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([C:22]2[NH:26][C:25](=[O:27])[O:24][N:23]=2)[CH:8]=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[O:11]COCCOC)([CH3:4])[CH3:3]>ClCCl.[Br-].[Zn+2].[Br-]>[CH3:21][C:18]([C:9]1[CH:8]=[C:7]([C:22]2[NH:26][C:25](=[O:27])[O:24][N:23]=2)[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:19])[CH3:20]
Reactant: COCCOCOc1c(C(C)(C)C)cc(-c2noc(=O)[nH]2)cc1C(C)(C)C
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC(C)(C)c1cc(-c2noc(=O)[nH]2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1.9 g (0.005 mole) of 3-[3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]phenyl]-1,2,4-oxadiazol-5(4H)-one and 5.7 g (0.025 mole) of zinc bromide in dichloromethane (10 ml) is stirred vigorously at room temperature for three hours. The dichloromethane is then carefully decanted and the white solid is washed with additional dichloromethane (2×50 ml). The combined organic layers are washed with 10% sodium bicarbonate (2×50 ml), saturated sodium chloride (2×50 ml) and dried (anhydrous magnesium sulfate). Concentration leaves a solid which is recrystallized from ethyl acetate and hexane giving 0.7 g (48%) of 3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,2,4-oxadiazol-5(4H)-one, mp 189°-191° C.
Reaction SMILES: [CH:1]([C:3]1[C:9](=[O:10])[C:8]([OH:11])=[CH:7][C:6]([CH:12]([CH3:14])[CH3:13])=[CH:5][CH:4]=1)=[O:2].C[Li].[CH3:17]COCC>O1CCCC1>[OH:2][CH:1]([C:3]1[C:9](=[O:10])[C:8]([OH:11])=[CH:7][C:6]([CH:12]([CH3:14])[CH3:13])=[CH:5][CH:4]=1)[CH3:17]
Reactant: CCOCC
Reactant: CC(C)c1ccc(C=O)c(=O)c(O)c1
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(C)c1ccc(C(C)O)c(=O)c(O)c1
Temperature: -78 °C

Procedure:
7-formyl-4-isopropyl-2-hydroxy-2,4,6-cycloheptatrien-1-one (2.00 g, 10 mmol) was dissolved in tetrahydrofuran (20 ml) and cooled to -78° C. in a dry ice/acetone bath. A solution of methyllithium the ether (1.4M, 15 ml) was added dropwise to the solution, then dry ice/acetone bath was removed and stirring was continued until the insolubles were dissolved. An aqueous saturated ammonium chloride was added to the reaction mixture and extracted with methylene chloride. The methylene chloride layer was washed with water, dried over anhydrous sodium sulfate and solvent was distilled off to give 2.18 g of 7-(α-hydroxyethyl)-4-isopropyl-2-hydroxy-2,4,6-cycloheptatrien-1-one as a reddish brown oil (yield: quantitative).
Reaction SMILES: [ClH:1].[O:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([N:14]3[CH2:19][CH:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)[CH2:17][CH:16]([NH:30]C(=O)OC(C)(C)C)[CH2:15]3)=[O:13])[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1>O1CCOCC1>[ClH:1].[NH2:30][CH:16]1[CH2:17][CH:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:22][CH:21]=2)[CH2:19][N:14]([C:12]([N:9]2[CH2:8][CH2:7][C:6]3([O:2][CH2:3][CH2:4][O:5]3)[CH2:11][CH2:10]2)=[O:13])[CH2:15]1
Reactant: CC(C)(C)OC(=O)NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC3(CC2)OCCO3)C1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC3(CC2)OCCO3)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
37 ml of a 4 N solution of hydrochloric acid in dioxane were added to the carbamate from Example 61A (5.30 g, 7.33 mmol), and the mixture was then stirred at RT for 1 h. Another 37 ml of a 4 N hydrochloric acid solution in dioxane were added, and the mixture was stirred at 60° C. for 3 h. The reaction solution was concentrated under reduced pressure and the residue was taken up in 1 N aqueous hydrogen chloride solution. After washing of the aqueous phase with diethyl ether, the aqueous phase was concentrated under reduced pressure. The crude product obtained in this manner was used further without further purification. Yield: 3.20 g (92% of theory)
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[C:20]([F:22])[C:19]([O:23]CC4C=CC=CC=4)=[CH:18][C:17]=3[O:31]CC3C=CC=CC=3)[CH2:12][CH2:11]2)=[O:9])C=CC=C[CH:2]=1.CO>C(OCC)(=O)C.[Pd]>[C:16]1([C@@H:1]([NH:7][C:8]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]3[CH:21]=[C:20]([F:22])[C:19]([OH:23])=[CH:18][C:17]=3[OH:31])[CH2:14][CH2:15]2)=[O:9])[CH3:2])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Nc1ccccc1)N1CCC(c2cc(F)c(OCc3ccccc3)cc2OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@H](NC(=O)N1CCC(c2cc(F)c(O)cc2O)CC1)c1ccccc1
Yield: 144.7 %

Procedure:
A mixture of 174 mg (0.32 mmol, 1 eq) of 4-(2,4-bis(benzyloxy)-5-fluorophenyl)piperidine-1-carboxylic acid phenylamide in 1 ml of ethyl acetate and of 2 ml of methanol in the presence of 51 mg (30% by mass) of palladium-on-charcoal at 10% is stirred at ambient temperature under atmospheric hydrogen pressure for 8 hours. The reaction medium is filtered through filter paper and the filtrate is evaporated off. The residue is chromatographed on silica gel, elution being carried out with 30/70 heptane/ethyl acetate. 83 mg of 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid ((S)-1-phenylethyl)amide are obtained. Yield=72%.