Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:16])([OH:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.CO>C(OCC)(=O)C.[Pd]>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]([C:11]2([OH:14])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:16])=[CH:18][CH:19]=1
Reactant: O=C(c1ccc(F)cc1)C1(O)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(c1ccc(F)cc1)C1(O)CCNCC1
Yield: 100 %

Procedure:
(0.550 g, 1.76 mmol) of (1-Benzyl-4-hydroxy-piperidin-4-yl)-(4-fluoro-phenyl)-methanone was hydrogenated in 4 mL of ethyl acetate and 2 mL of methanol using 0.065 g, (0.61 mmol) of Palladium on charcoal to yield 0.392 g of the title compound (1.76 mmol, 100% yield) as a off-white solid after filtration of the catalyst and removal of the solvent under vacuum. MS (m/e): 314.0 (M+H+).
Reaction SMILES: [C:1]([C:9]1[N:13]2[CH2:14][CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][C:12]2=[C:11]([C:25]([OH:27])=O)[N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][NH:29][C:30](=[O:37])[C@H:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[NH2:32]>>[C:1]([C:9]1[N:13]2[CH2:14][CH2:15][N:16]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:17][C:12]2=[C:11]([C:25](=[O:27])[NH:32][C@@H:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:30]([NH:29][CH3:28])=[O:37])[N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCn2c(C(=O)c3ccccc3)nc(C(=O)O)c2C1
Product: CNC(=O)[C@@H](NC(=O)c1nc(C(=O)c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CC2)C(C)(C)C

Procedure:
Intermediate 25B was synthesized in the same manner as described above for compound 22A in Example 22 except that Intermediate 25A was used in place of 3B and L-tert-Leucine methylamide was used instead of (S)-methyl 2-amino-3,3-dimethylbutanoate. LCMS (+ESI) m/z 498.3 [M+H]+
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:21][O:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][NH:26][CH2:27]2>CN(C=O)C>[CH3:21][O:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][N:26]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=1[F:16])[CH2:27]2
Reactant: COc1cccc2c1CNC2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CN(C)C=O
Product: COc1cccc2c1CN(c1c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Yield: 66.7 %

Procedure:
136 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 224 mg of 4-methoxyisoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 2 to produce 132 mg of the target compound.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17].[C:24]([O:27][CH2:28][CH3:29])(=[O:26])[CH3:25]>C1COCC1>[C:16]([Si:20]([O:26][C:24]([O:27][CH2:28][CH3:29])=[CH2:25])([CH3:23])[CH3:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(OCC)O[Si](C)(C)C(C)(C)C
Reaction time: 0.25 h

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (17.34 mL, 102.14 mmol) in THF (63.4 mL) under argon, 2.9 M BuLi in hexanes (34.05 mL, 98.74 mmol) was added dropwise at 0° C. The reaction was stirred for 15 min. and subsequently cooled to −78° C. t-Butyldimethylchlorosilane (TBDMSCl) (16.94 g, 112.36 mmol) in THF (25.4 mL) was added and then a solution of anhydrous ethyl acetate (8.38 mL, 85.12 mmol) in THF (57.2 mL) was slowly added over 1 h. The mixture was stirred for an additional 10 min at −78° C. and then stirred at r.t. for 1 h. The solution was then diluted with hexanes (285.9 mL), filtered through a Celite pad, and the filtrate concentrated. Distillation under vacuum at 42-50° C. gave an orange oil (g, 2.0%). 1H NMR (400 MHz, CDCl3) δ 3.74 (q, 2H, J=7.0 Hz, CH2), 3.22 (d, 1H, J=2.0 Hz, CH2), 3.05 (d, 1H, J=2.0 Hz, CH2), 1.29 (t, 3H, J=7.1 Hz, CH3), 0.94 (s, 9H, CH3), 0.17 (s, 6H, CH3); 13C NMR (400 MHz, CDCl3) δ 160.3, 62.4, 59.6, 24.79, 17.3, 13.5, −5.4
Reaction SMILES: CC1NC(C2C=C(C=CC=2C)C(OC)=O)=C(C)N=1.[CH3:19][C:20]1[CH:29]=[C:28]([CH3:30])[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23].CC1C=CC(C(OC)=O)=CC=1B1OC(C)(C)C(C)(C)O1.[CH:60]1([C:63]2[NH:64][C:65](I)=[C:66]([CH3:68])[N:67]=2)[CH2:62][CH2:61]1.IC1NC(C)=NC=1C>>[CH:60]1([C:63]2[NH:64][C:65]([C:27]3[C:28]([CH3:30])=[CH:29][C:20]([CH3:19])=[C:21]([CH:26]=3)[C:22]([O:24][CH3:25])=[O:23])=[C:66]([CH3:68])[N:67]=2)[CH2:62][CH2:61]1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1C
Reactant: Cc1nc(C2CC2)[nH]c1I
Agent: COC(=O)c1ccc(C)c(-c2[nH]c(C)nc2C)c1
Agent: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cc1nc(C)c(I)[nH]1
Product: COC(=O)c1cc(-c2[nH]c(C3CC3)nc2C)c(C)cc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.6, except methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1) was used in place of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4) and 2-cyclopropyl-5-iodo-4-methyl-1H-imidazole (compound 160.2) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5). m/z (ES+) 285 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)([OH:3])=[O:2].[CH3:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][C:16]=1[CH:24]=O.N1CCCCC1>C(O)C>[CH3:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][C:16]=1[CH:24]=[C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([C:1]([OH:3])=[O:2])[CH:5]=2)[NH:9][C:8]1=[O:13]
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Reactant: Cc1c(C=O)[nH]c2ccccc12
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C=C2C(=O)Nc3ccc(C(=O)O)cc32)[nH]c2ccccc12
Temperature: 90 °C
Yield: 67 %

Procedure:
A mixture of 5-carboxy-2-oxindole (113 mg), 3-methylindole-2-carbaldehyde (56 mg) (prepared according to Synthetic Communications, 1986, 16, 1799) and piperidine (30 mg) in ethanol (1 mL) was heated in a sealed tube at 90° C. for overnight. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in oven for overnight to give 75 mg (58% yield) of 3-(3-methyl-1H-indol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid (piperidine salt).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH2:16][N:15]([C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])[CH2:14][C:13]([CH3:28])([CH3:27])[C:12]=3[N:11]=[C:10]([CH:29]([CH3:31])[CH3:30])[C:9]=2[CH:32]=[O:33])=[CH:4][CH:3]=1.C[Si]([C:38]#[N:39])(C)C.CO.Cl>C(Cl)Cl.[I-].[Zn+2].[I-]>[C:38]([CH:32]([OH:33])[C:9]1[C:10]([CH:29]([CH3:30])[CH3:31])=[N:11][C:12]2[C:13]([CH3:28])([CH3:27])[CH2:14][N:15]([C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:25])[CH3:26])=[O:19])[CH2:16][C:17]=2[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)#[N:39]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C=O)CN(C(=O)OCC[Si](C)(C)C)CC2(C)C
Agent: Cl
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CO
Product: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(O)C#N)CN(C(=O)OCC[Si](C)(C)C)CC2(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92 %

Procedure:
A mixture of 2-(trimethylsilyl)ethyl 4-(4-fluorophenyl)-3-formyl-2-isopropyl-8,8-dimethyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (intermediate 1) (4.28 g, 9.09 mmol), trimethylsilyl cyanide (1.46 ml, 10.91 mmol) and zinc iodide (0.145 g, 0.455 mmol) in CH2Cl2 (5 mL) was stirred at room temperature for 2.5 h. MeOH (100 mL) was added and the reaction stirred 22 h at room temperature. Additional trimethylsilyl cyanide (2 mL) was added and stirring continued at room temperature for 24 h. 1M HCl (10 mL) was added and stirring continued for 24 h. The reaction mixture was concentrated and the residue taken up in Et2O (200 mL), washed with satd NaHCO3 (50 mL), water (25 mL), brine (25 mL), dried (Na2SO4), filtered and solvent removed to give 2-(trimethylsilyl)ethyl 3-(cyano(hydroxy)methyl)-4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (4.16 g) as a tan powder contaminated with about 20% of starting material. This was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].Br[CH2:11][CH2:12][F:13].C(N(C(C)C)CC)(C)C>CCOCC>[CH2:5]([O:4][CH:3]([O:7][CH2:8][CH3:9])[CH2:2][NH:1][CH2:11][CH2:12][F:13])[CH3:6]
Reactant: FCCBr
Reactant: CCOC(CN)OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CCOC(CNCCF)OCC

Procedure:
A solution of 3.1 ml (21.5 mmol) of 1-amino-2,2-diethoxyethane, 3.0 g (23.6 mmol) of 1-bromo-2-fluoroethane and 5.56 g (43 mmol) of diisopropylethylamine was heated at 100° C. in a closed vessel for 6 hours. The reaction mixture was diluted with ether and washed with 1N NaOH and water. The organic phase was dried (MgSO4) and concentrated in vacuo. The residue was distilled in vacuo. 1.3 g of substance were obtained as a clear liquid.
Reaction SMILES: [O:1]=[C:2]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH2:13](O)[CH2:14][OH:15].C[Si](Cl)(C)C>C(Cl)Cl>[O:1]1[CH2:13][CH2:14][O:15][C:2]1([CH2:3][C:4]([O:6][CH3:7])=[O:5])[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: OCCO
Reactant: COC(=O)CC(=O)CC(=O)OC
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Product: COC(=O)CC1(CC(=O)OC)OCCO1
Temperature: 50 °C
Reaction time: 72 h
Yield: 50 %

Procedure:
To a solution of 4.2 g (24 mmol) of dimethyl 3-oxopentanedioate and 2.7 ml (48 mmol) of ethylene glycol in 50 mL of methylene chloride was added 12 mL (96 mmol) of TMSCl at room temperature. The reaction mixture was stirred at 50° C. for 3 days. The reaction was quenched with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with ether. The combined organic layers were washed with brine, dried over Na2SO4, evaporated under reduced pressure. Chromatography on silica gel gave the desired product, dimethyl 2,2′-(1,3-dioxolane-2,2-diyl)diacetate (2.6 g, 12 mmol, yield: 50%): MS (m/e): 219 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=[O:22])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)=[C:4]([Cl:23])[N:3]=1.[CH3:24]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].CI>O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH3:24])[C:7](=[O:22])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)=[C:4]([Cl:23])[N:3]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(Cn2c(=O)[nH]c3c(Cl)nc(N)nc32)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COc1ccc(Cn2c(=O)n(C)c3c(Cl)nc(N)nc32)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
A mixture of 2-amino-6-chloro-9-[(3,4-dimethoxyphenyl)methyl]-7H-purin-8-one (8.8 g, 26.21 mmol), DMF (90 ml), potassium carbonate (5.4 g, 39.31 mmol) and methyl iodide (1.96 ml, 31.45 mmol) stirred at 25° C. for 3 hours. Reaction mixture was cooled to 0° C. Water was added and solid obtained was filtered off to obtain 2-amino-6-chloro-9-[(3,4-dimethoxyphenyl)methyl]-7-methyl-purin-8-one (9.0 g, 98%).
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[C:4](=[O:6])[CH3:5])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[C:17]([CH2:19][C@@H:20]([OH:27])[CH2:21][C:22](OCC)=[O:23])#[N:18].Cl>O1CCCC1.O1CCCC1.CCCCCCC>[C:17]([CH2:19][C@@H:20]([OH:27])[CH2:21][C:22](=[O:23])[CH2:5][C:4]([N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])=[O:6])#[N:18]
Reactant: CCN(CC)C(C)=O
Reactant: CCOC(=O)C[C@H](O)CC#N
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)CC(=O)C[C@H](O)CC#N
Reaction time: 0.5 h

Procedure:
To a stirred -10° C. solution of N,N-diethylacetamide (prepared from N,N-diethylamine and acetyl chloride by refluxing for 2 hours in toluene) (28.75 g, 0.25 mol) in tetrahydrofuran (0.25 L) is slowly added a solution of lithium diisopropylamide in tetrahydrofuran-heptane (0.125 L of 2M) while maintaining the temperature between -10° C. to -5° C., and the mixture is stirred at -20° C. to 0° C. for 30 minutes. (R)-4-cyano-3-hydroxybutyric acid, ethyl ester (Brower, supra) (10 g, 0.06 mol) as a solution in 200 mL of tetrahydrofuran is added to the previously prepared mixture. The reaction mixture is stirred for 30 minutes at -5° C. to -20° C., and transferred to a 2.2N aqueous hydrochloric acid solution (0.25 L). The aqueous layer is extracted with 300 mL of ethyl acetate, the aqueous layer is separated and reextracted with 50 mL of ethyl acetate, the extracts are combined and concentrated in vacuo to afford crude (R)-6-cyano-N,N-diethyl-5-hydroxy-3-oxohexanamide as an oil; Molecular weight: 226. GC/MS m/e 226, 157, 140, 114, 72, 58, 32.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:16]=1)[CH2:7][NH:8][C:9](=[O:15])[CH:10]([O:13][CH3:14])[O:11][CH3:12].[F:18][C:19]([F:30])([F:29])[O:20]C1C=C(C=CC=1)CN.COC(OC)C(OC)=O>>[CH3:12][O:11][CH:10]([O:13][CH3:14])[C:9]([NH:8][CH2:7][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([O:20][C:19]([F:30])([F:29])[F:18])[CH:16]=1)=[O:15]
Reactant: COC(OC)C(=O)NCc1cc(Cl)ccc1F
Reactant: NCc1cccc(OC(F)(F)F)c1
Agent: COC(=O)C(OC)OC
Product: COC(OC)C(=O)NCc1cccc(OC(F)(F)F)c1

Procedure:
By following the procedure for the preparation of N-(5-chloro-2-fluorobenzyl)-2,2-dimethoxyacetamide, the title compound was prepared from 3-(trifluoromethoxy)benzylamine (4.0 g, 21 mmol) and methyl dimethoxyacetate (2.8 g, 21 mmol). 1H NMR (CDCl3, 300 MHz): δ=3.40 (s, 6H), 4.44 (d, J=4.2 Hz, 2H), 4.75 (s, 1H), 6.95 (bs, 1H), 7.11 (s, 2H), 7.20 (d, J=2.4 Hz, 1H), 7.35-7.40 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]2[C:11]3[C:12](I)=[N:13][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([OH:16])[C:10]=3[O:9][N:8]=2)=[CH:4][CH:3]=1.[C:23]([Cu])#[N:24].[OH-].[NH4+].Cl>CCOC(C)=O.CN1CCCC1=O>[Br:1][C:2]1[O:6][C:5]([C:7]2[C:11]3[C:12]([C:23]#[N:24])=[N:13][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([OH:16])[C:10]=3[O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc(I)c2c(-c3ccc(Br)o3)noc2c1O
Reactant: N#C[Cu]
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(C#N)c2c(-c3ccc(Br)o3)noc2c1O
Temperature: 110 °C
Yield: 34.3 %

Procedure:
Ethyl 3-(5-bromofuran-2-yl)-7-hydroxy-4-iodoisoxazolo[4,5-c]pyridine-6-carboxylate (155 mg, 0.324 mmol) and CuCN (87 mg, 0.971 mmol) were added to 2.2 mL of N-methyl-2-pyrrolidone. The resulting suspension was heated in an oil bath (T=110° C.) for 1 h. The reaction mixture was cooled slightly and poured into a vigorously stirring mixture of ammonium hydroxide (5 mL, 15% aqueous solution) and EtOAc (50 mL). The mixture was acidified with concentrated hydrochloric acid to pH 3 and extracted with EtOAc. The combined organic layer was dried over MgSO4 and concentrated, and the residue was purified flash chromatography (0-100% EtOAc/hexanes) to afford 42 mg of the title compound. MS: (+) m/z 378.29, 380.26 (M+1, 79Br/81Br).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])[CH2:11][CH2:10]1.C(N(CC)CC)C.[O:30]1C[CH2:33][CH2:32][CH2:31]1.C(Cl)(=O)C=C>CCOCC>[C:31]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])[CH2:13][CH2:14]1)(=[O:30])[CH:32]=[CH2:33]
Reactant: C1CCOC1
Reactant: OCCCCCCC[C@H]1CC[C@H](c2cccc(F)c2F)CC1
Agent: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=CC(=O)OCCCCCCC[C@H]1CC[C@H](c2cccc(F)c2F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
First, 3.5 g of 1-[trans-4-(7-hydroxyheptyl)cyclohexyl]-2,3-difluorobenzene, 1.3 g of triethylamine, and 45 ml of dry tetrahydrofuran were placed in a 100 ml flask. Then, 1.1 g of acryloyl chloride was added dropwise to the reaction mixture under ice water cooling. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. Ether was added to the reaction mixture. An ether layer was washed with water and dried over anhydrous sodium sulfate. A solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: benzene/hexane=3/7 to 4/6) and recrystallized from hexane to obtain 2.23 g of 1-[trans-4-(7-propenoyloxyheptyl)cyclohexyl]-2,3-difluorobenzene (Y: 54%). The compound thus obtained had a purity of 99.6% by GC, 99.5% by HPLC, and of 1 spot by TLC. Furthermore, the compound had an m.p. of 34.0° C. to 35.3° C.
Reaction SMILES: C(O[CH:5]1[CH2:10][CH2:9][CH:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][O:6]1)(=O)C.[CH3:19][O:20][C:21]([O:25][Si](C)(C)C)=[C:22]([CH3:24])[CH3:23].B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:12]([O:11][CH:8]1[CH2:7][O:6][CH:5]([C:22]([CH3:24])([CH3:23])[C:21]([O:20][CH3:19])=[O:25])[CH2:10][CH2:9]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Reactant: CC(=O)OC1CCC(OCc2ccccc2)CO1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C(C)(C)C1CCC(OCc2ccccc2)CO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.1 %

Procedure:
To a solution of 5-(benzyloxy)tetrahydro-2H-pyran-2-yl acetate (281 mg, 1.123 mmol) and ((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (783 mg, 4.49 mmol) in DCM (5 mL) at −78° C. was added BF3.OEt2 (0.228 mL, 1.796 mmol). The reaction mixture was gradually allowed to warm to rt and stirred at rt for 18 h. The reaction mixture was quenched with sat. NaHCO3 (5 mL) and diluted with DCM (20 mL). The organic layer was separated, washed with water, brine, dried (MgSO4) and concentrated. The crude product was purified by silica gel FCC (10-20% EtOAc in hexanes) to afford methyl 2-(5-(benzyloxy)tetrahydro-2H-pyran-2-yl)-2-methylpropanoate as a colorless oil (253 mg). To a solution of methyl 2-(5-(benzyloxy)tetrahydro-2H-pyran-2-yl)-2-methylpropanoate (250 mg) in MeOH (20 mL) was added 10% Pd—C (59.7 mg) and the reaction mixture was hydrogenated at 40 psi overnight. The suspension was filtered and the filtrate was evaporated to dryness to afford methyl 2-(5-hydroxytetrahydro-2H-pyran-2-yl)-2-methylpropanoate as a clear oil (188 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@@H:11]([OH:14])[C@H:10]([CH2:15][O:16][C:17]2[N:18]=[N:19][C:20]([CH2:36][CH2:37][CH2:38][CH3:39])=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:25][CH:24]=3)[CH:22]=2)[CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[CH2:36]([C:20]1[N:19]=[N:18][C:17]([O:16][CH2:15][C@H:10]2[C@H:11]([OH:14])[CH2:12][CH2:13][NH:8][CH2:9]2)=[CH:22][C:21]=1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:25][CH:24]=1)[CH2:37][CH2:38][CH3:39]
Reactant: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@H]2O)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCCc1nnc(OC[C@@H]2CNCC[C@H]2O)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (±)-trans-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.157 mmol, 0.85 g; Example 46) in DCM (1 mL) was added 4 N HCl in dioxane (4 mL) and continued stirring for 30 min at room temperature. The volatiles were removed under reduced pressure. The residue was washed with anhydrous ether and the solid was dried under high vacuum to provide (±)-trans-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-piperidin-4-ol.
Reaction SMILES: C1(C2OC(C(F)(F)F)=C(C(NC3C=CC(C4C=CC(C([C@@H]5CCC[C@H]5C(O)=O)=O)=CC=4)=CC=3)=O)N=2)C=CC=CC=1.[C:41]1([C:47]2[O:48][C:49]([C:78]([F:81])([F:80])[F:79])=[C:50]([C:52]([NH:54][C:55]3[CH:60]=[CH:59][C:58]([C:61]4[CH:66]=[CH:65][C:64]([C:67]([CH:69]5[CH2:74][CH2:73][CH2:72][CH2:71][CH:70]5[C:75]([OH:77])=[O:76])=[O:68])=[CH:63][CH:62]=4)=[CH:57][CH:56]=3)=[O:53])[N:51]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C1(C2OC(C(F)(F)F)=C(C(O)=O)N=2)C=CC=CC=1.NC1C=CC(C2C=CC(C([C@@H]3CCCC[C@H]3C(O)=O)=O)=CC=2)=CC=1>>[C:41]1([C:47]2[O:48][C:49]([C:78]([F:80])([F:81])[F:79])=[C:50]([C:52]([NH:54][C:55]3[CH:56]=[CH:57][C:58]([C:61]4[CH:66]=[CH:65][C:64]([C:67]([C@H:69]5[CH2:74][CH2:73][CH2:72][CH2:71][C@@H:70]5[C:75]([OH:77])=[O:76])=[O:68])=[CH:63][CH:62]=4)=[CH:59][CH:60]=3)=[O:53])[N:51]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(Nc1ccc(-c2ccc(C(=O)C3CCCCC3C(=O)O)cc2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: Nc1ccc(-c2ccc(C(=O)[C@@H]3CCCC[C@H]3C(=O)O)cc2)cc1
Agent: O=C(Nc1ccc(-c2ccc(C(=O)[C@@H]3CCC[C@H]3C(=O)O)cc2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: O=C(Nc1ccc(-c2ccc(C(=O)[C@H]3CCCC[C@@H]3C(=O)O)cc2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a method similar to that used for the preparation of racemic trans-2-{4′-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carbonyl}-cyclopentanecarboxylic acid above, racemic 2-{4′-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carbonyl}-cyclohexanecarboxylic acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and racemic trans-2-(4′-amino-biphenyl-4-carbonyl)-cyclohexanecarboxylic acid. The racemic product obtained was separated by chiral SFC to afford (1S,2S)-2-{4′-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carbonyl}-cyclohexanecarboxylic acid (or enantiomer). [α]D: −23° in DMSO. LCMS calcd for C31H25F3N2O5 (m/e) 562, obsd 563 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:13][C:14]3[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=3)=[O:12])=[CH:8][C:7]=2[CH:27]=1)#[N:2].[SH2:28]>N1C=CC=CC=1.C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:13][C:14]3[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=3)=[O:12])=[CH:8][C:7]=2[CH:27]=1)(=[S:28])[NH2:2]
Reactant: S
Reactant: CCOC(=O)COc1ccc(NC(=O)c2cc3cc(C#N)ccc3o2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)COc1ccc(NC(=O)c2cc3cc(C(N)=S)ccc3o2)cc1
Reaction time: 16 h

Procedure:
Ethyl 4-[(5-cyano-2-benzofuranyl)carbonylamino]phenoxyacetate (1.49 g, 4.09 mmol) was dissolved in a mixed solvent of pyridine (50 ml) and triethylamine (5 ml). A hydrogen sulfide gas was blown in for 10 minutes at room temperature and the mixture was stirred for 16 hours. Low boiling matters were distilled away from the reaction mixture under reduced pressure to give ethyl 4-[(5-thiocarbamoyl-2-benzofuranyl)carbonylamino]phenoxyacetate as a yellow solid. Acetone (100 ml) and iodomethane (10 ml) were added to this solid, and the mixture was refluxed under heating for 2 hours. The reaction mixture was heated to room temperature. The resulting precipitate was collected by filtration to give ethyl 4-[[5-[(1-methylthio)iminomethyl]-2-benzofuranyl]carbonylamino]phenoxyacetate as a yellow solid. To this solid was added ethanol (50 ml) and benzylamine (0.5 ml, 4.6 mmol), and the mixture was refluxed under heating for 2 hours. The reaction mixture was concentrated to about 10 ml under reduced pressure, and diethyl ether (40 ml) was added. The resulting precipitate was collected by filtration to give 1.970 g of hydriodide of compound (1) as a yellow solid (69% in three steps).