Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH2:22]([O:24][C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[NH:32][CH:33]([CH3:35])[CH3:34])=[O:26])[CH3:23].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH2:22]([O:24][C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[N:32]([CH:33]([CH3:34])[CH3:35])[C:17](=[O:19])[CH2:16][C:11]1[NH:10][C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[S:13](=[O:14])(=[O:15])[N:12]=1)=[O:26])[CH3:23]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)C1CCCC1NC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)C1CCCC1N(C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1)C(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.1665 g, 0.5 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL). 2-Isopropylamino-cyclopentanecarboxylic acid ethyl ester (0.0996 g, 0.5 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.1003 g, 0.525 mmol). Then N-methylmorpholine (115 μL, 1.05 mmol) was added. The mixture was stirred at 25° C. for 5 h. The solution was poured into 1.0 M aqueous hydrochloric acid solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude product, 2-{isopropyl-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclopentanecarboxylic acid ethyl ester, as a yellow oil. LC-MS (ESI) calcd for C21H30N4O7S2 514.16, found 515.3 [M+H+].
Reaction SMILES: [OH:1][C:2]1[CH:17]=[C:16]([OH:18])[C:5]([C:6](=[O:15])[CH:7]=[CH:8][CH:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH2:10]2)=[C:4]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O>CN(C)C=O>[CH2:31]([O:1][C:2]1[CH:17]=[C:16]([OH:18])[C:5]([C:6](=[O:15])[CH:7]=[CH:8][CH:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH2:14]2)=[C:4]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:3]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COC(=O)COc1cc(O)cc(O)c1C(=O)C=CC1C=CC=CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1cc(OCc2ccccc2)cc(O)c1C(=O)C=CC1C=CC=CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4′,6′-dihydroxy-2′-(methoxycarbonylmethoxy)dihydrochalcone (0.6 g) in N,N-dimethylformamide (10 mL) were added potassium carbonate (0.26 g) and benzyl bromide (0.22 mL), and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration and dried under reduced pressure to give the title compound (0.53 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH3:17])[C:4]=1[NH:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].[Cl:18][CH2:19][C:20](Cl)=[O:21].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:18][CH2:19][C:20]([N:5]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:4]1[C:12]([CH2:16][CH3:17])=[CH:13][CH:14]=[CH:15][C:3]=1[CH2:1][CH3:2])=[O:21]
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)CNc1c(CC)cccc1CC
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(C(=O)CCl)c1c(CC)cccc1CC
Reaction time: 2 h

Procedure:
23.5 Grams (0.1 mol) of ethyl 2,6-diethylanilinoacetate and 11.3 g (0.1 mol) of monochloroacetic acid chloride were dissolved in 100 ml of benzene, 11.0 g of triethylamine was then added dropwise thereto with stirring maintaining the reaction temperature at 10°-20° C. and, thereafter, stirring was continued for further 2 hours at a room temperature. The reaction solution was washed with successive, 5% sodium hydroxide aqueous solution, 5% hydrochloric acid aqueous solution, and water. Then, the benzene layer was dried over anhydrous sodium sulfate. Thereafter, benzene was removed under reduced pressure to obtain the end product, ethyl N-chloroacetyl-2,6-diethylanilinoacetate. nD26 : 1.5225.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][C:25]([CH3:30])([CH3:29])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[C:25]([CH3:30])([CH3:29])[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3ccnc(Cl)n3)c2)C(C)(C)C1

Procedure:
Intermediate 1 was coupled with 3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 417.
Reaction SMILES: [CH:1]1[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=2[CH:4]=[C:3]2[C:12]([O:14][C:15](=[O:16])[C:2]=12)=[O:13])=[O:8].[CH:17]([N:20](C(C)C)CC)(C)C.[O:26]([C:33]1[CH:34]=[C:35]([CH:48]=[CH:49][CH:50]=1)[CH2:36][NH:37][C@@H:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:41][CH2:40][CH2:39]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CN>C1COCC1>[CH3:17][NH:20][C:7]([C:6]1[CH:1]=[C:2]([C:15]([N:37]([CH2:36][C:35]2[CH:48]=[CH:49][CH:50]=[C:33]([O:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:34]=2)[C@@H:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH2:41][CH2:40][CH2:39]2)=[O:16])[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]=1[C:10]([OH:9])=[O:11])=[O:8]
Reactant: c1ccc(Oc2cccc(CN[C@H]3CCCc4ccccc43)c2)cc1
Reactant: O=c1oc(=O)c2cc3c(=O)oc(=O)c3cc12
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)c1cc(C(=O)N(Cc2cccc(Oc3ccccc3)c2)[C@H]2CCCc3ccccc32)c(C(=O)O)cc1C(=O)O
Temperature: 25 °C
Yield: 12.3 %

Procedure:
1,2,4,5-Benzenetetracarboxylic dianhydride (1.1 g, 5 mmol) in THF (25 mL) was treated with diisopropylethyl amine (1.6 mL, 9.2 mmol) dropwise at −78° C. and then treated with N-(3-phenoxybenzyl)-N-[(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]amine (9 mL, 4.5 mmol, 0.5M solution in ClCH2CH2Cl) dropwise. After allowing the reaction mixture to gradually warm to room temperature overnight, the mixture was recooled to −78° C. and treated with methylamine (2.5 mL, 5 mmol, 2M in MeOH) dropwise. The reaction mixture was again allowed to slowly warm to room temperature. The organics were removed under reduced pressure and the residue was dissolved in ethyl acetate (25 mL). The ethyl acetate solution was washed with 1N HCl (2×5 mL), brine (5 mL), dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatographed (silica gel, 5:95 MeOH:CH2Cl2 to 1:9 MeOH:CH2Cl2) to provide a solid. The solid was further purified by RP-HPLC to provide the title compound as an off-white solid (319 mg, 12%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12].[CH3:15][S:16]([OH:19])(=[O:18])=[O:17]>[Pd].C(O)C.O>[CH3:15][S:16]([OH:19])(=[O:18])=[O:17].[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:12])=[O:13]
Reactant: Nc1ccc([N+](=O)[O-])cc1S(N)(=O)=O
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: O
Solvent: CCO
Product: Nc1ccc(N)c(S(N)(=O)=O)c1
Temperature: 55 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
2-Amino-5-nitrobenzenesulfonamide (prepared as described in Example 1b, 100.00 g, 0.460 mol) and 5% palladium on carbon (wet, 5.00 g) were suspended in ethanol (2 L) and water (100 mL). Methanesulfonic acid (33 mL, 0.51 mol) was added, and the resulting mixture was heated to 55° C. and stirred under atmospheric hydrogen for 8 h. The mixture was filtered and the filtrate was concentrated in vacuo to a volume of about 450 mL. To the concentrate was added acetonitrile (1 L) and resulting mixture was stirred at 25° C. overnight. The suspension was filtered to afford the desired product, 2,5-diamino-benzenesulfonamide methanesulfonate (122.36 g, 0.432 mol, 93.8%) as a purple solid.
Reaction SMILES: C(O[C:4](=[O:35])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([NH:17][C:18]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)=[O:19])=[CH:15][C:14]([C:31]([CH3:34])([CH3:33])[CH3:32])=[N:13]2)=[CH:8][CH:7]=1)C.[NH3:36].CO>CO>[C:31]([C:14]1[CH:15]=[C:16]([NH:17][C:18]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)=[O:19])[N:12]([C:9]2[CH:8]=[CH:7][C:6]([CH2:5][C:4]([NH2:36])=[O:35])=[CH:11][CH:10]=2)[N:13]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: N
Reactant: CCOC(=O)Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2cccc3ccccc23)cc1
Solvent: CO
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc3ccccc23)n(-c2ccc(CC(N)=O)cc2)n1
Reaction time: 8 h
Yield: 31 %

Procedure:
To a solution of {4-[3-t-butyl-5-(3-naphthalen-1-yl-ureido)pyrazol-1-yl]phenyl}acetic acid ethyl ester (150 mg, 0.32 mmol, intermediate in Example 559) in MeOH (2 mL) was added NH3/MeOH (10 mL) at RT. The mixture was stirred at that temperature overnight. After removal of the solvent, the crude product was purified by preparative HPLC to afford 2-{4-[3-t-butyl-5-(3-naphthalen-1-ylureido)pyrazol-1-yl]phenyl}acetamide (48 mg, 31% yield). 1H NMR (300 MHz, CD3OD): δ 7.87 (m, 2H), 7.76 (d, J=5.4 Hz, 1H), 7.68 (d, J=6.0 Hz, 1H), 7.53-7.42 (m, 7H), 6.57 (s, 1H), 3.64 (s, 2H), 1.36 (s, 9H); MS (ESI) m/z: 442 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([C:16]3[CH:31]=[CH:30][C:19]([C:20]([NH:22][CH2:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:21])=[CH:18][N:17]=3)[C:13]=2[O:14]C)[CH:6]=[CH:5][N:4]=1.[Cl-].[Li+].CC(N(C)C)=O>CS(C)=O>[CH3:1][N:2]([CH3:32])[C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([C:16]3[CH:31]=[CH:30][C:19]([C:20]([NH:22][CH2:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:21])=[CH:18][N:17]=3)[C:13]=2[OH:14])[CH:6]=[CH:5][N:4]=1
Reactant: COc1c(-c2ccnc(N(C)C)c2)cnn1-c1ccc(C(=O)NCC2CCOCC2)cn1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(=O)N(C)C
Solvent: CS(C)=O
Product: CN(C)c1cc(-c2cnn(-c3ccc(C(=O)NCC4CCOCC4)cn3)c2O)ccn1
Temperature: 60 °C
Yield: 49.3 %

Procedure:
Combined 6-(4-(2-(dimethylamino)pyridin-4-yl)-5-methoxy-1H-pyrazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide from the above reaction and lithium chloride (42.7 mg, 1.008 mmol) and DMA (1 mL) and heated at 60° C. for 20 h. The reaction mixture was diluted with 0.2 mL DMSO and purified by prep HPLC (ammonium hydroxide conditions) to give the title compound (42 mg, 49.3% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.28 (m, 2 H) 1.56-1.67 (m, 2 H) 1.81 (ddt, J=14.9, 7.5, 3.8, 3.8 Hz, 1 H) 3.05 (s, 6 H) 3.17 (t, J=6.4 Hz, 2 H) 3.28 (td, J=11.6, 1.8 Hz, 2 H) 3.86 (dd, J=11.4, 2.5 Hz, 2 H) 7.07 (d, J=4.5 Hz, 1 H) 7.35 (br. s., 1 H) 7.67 (d, J=6.1 Hz, 1 H) 7.90 (s, 1 H) 8.10-8.19 (m, 1 H) 8.47-8.59 (m, 2 H) 8.80 (d, J=2.0 Hz, 1 H). MS m/z 423 [M+H]+.
Reaction SMILES: [C:1]([Si:5]([CH3:35])([CH3:34])[O:6][CH:7]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:21]2[S:25][C:24]([CH2:26][OH:27])=[C:23]([CH3:28])[CH:22]=2)([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:12][C:11]=1[CH3:29])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:39][C:40]([O:42][CH3:43])=[O:41]>C1COCC1>[CH3:43][O:42][C:40](=[O:41])[CH2:39][O:27][CH2:26][C:24]1[S:25][C:21]([C:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:35])[CH3:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[C:11]([CH3:29])[CH:12]=2)([CH2:17][CH3:18])[CH2:19][CH3:20])=[CH:22][C:23]=1[CH3:28]
Reactant: CCC(CC)(c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1cc(C)c(CO)s1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1cc(C)c(COCC(=O)OC)s1
Temperature: 25 °C
Yield: 30.8 %

Procedure:
T a 0° C. solution of 5-(1-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophen-2-yl-methanol (0.96 g, 1.85 mmol) in THF (10 mL) is added 60% NaH (81 mg, 2.0 mmol) and stirred for 20 m. The mixture is added methyl bromoacetate (0.21 mL, 2.22 mmol)warmed to RT, and stirred overnight. The reaction is quenched with satd NH4Cl (10 mL), diluted with H2O (10 mL), and extracted with EtOAc (2×20 mL). The combined organic layers is MgSO4 dried and concentrated. The resulting residue is chromatographed to give the title compound (0.33 g, 0.57 mmol, 31%). 1H NMR (CDC3), δ 0.06 (s, 3H), 0.12 (s, 3H), 0.70 (t, J=7.3 Hz, 6H), 0.91 (s, 9H), 0.97 (s, 9H), 2.01-2.10 (m, 4H), 2.19 (s, 3H), 2.20 (s, 3H), 3.67 (dd, J=5.8, 3.4 Hz, I H), 3.76 (s, 3H), 3.85 (dd, J=9.8, 5.8 Hz, 1H), 3.98 (dd, J=9.8, 3.4 Hz, 1H), 4.09 (s, 2H), 4.64 (s, 2H), 6.53 (s, 1H), 6.67 (d, J=8.3 Hz, I H), 7.00-7.06 (m, 2H). LC/MS (m/z): calcd for C 10 33H58NO5SSi (M+NH4)+: 608.9; found: 608.3.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:33](Cl)[C:34]1[CH:42]=[CH:41][C:40]2[O:39][CH2:38][O:37][C:36]=2[CH:35]=1.C1C[O:47]CC1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[C:33](=[O:47])[C:34]2[CH:42]=[CH:41][C:40]3[O:39][CH2:38][O:37][C:36]=3[CH:35]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: COC(=O)c1ccc(OCCCNc2ccc(C(C)(C)C)cc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OCCCN(C(=O)c2ccc3c(c2)OCO3)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl 4-[3-[N-(4-tert-butylphenyl)amino]propoxy]benzoate (1.80 g) and triethylamine (3.65 ml) were dissolved in THF (40 ml), and cooled with ice, and piperonyl chloride (1.46 g) was added thereto, and the mixture was stirred at room temperature for 16 hours. After the reaction solution was concentrated under reduced pressure, water and ethyl acetate were added thereto and the mixture was separated into layers. The organic layer was washed with water 3 times, and dried under reduced water. The resulting residue was subjected to column chromatography on silica gel and eluted with chloroform to give the desired product (2.01 g).
Reaction SMILES: S(C)C.CC(CC)=C.[CH2:9]([C:12]1([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])[CH2:14][CH2:13]1)[CH:10]=[CH2:11].[OH2:35]>C1COCC1>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[CH2:19][N:15]1[CH2:14][CH2:13][C:12]([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)([CH2:9][CH2:10][CH2:11][OH:35])[O:17][C:16]1=[O:18]
Reactant: C=CCC1(c2ccc(F)cc2)CCN(Cc2ccc(Cl)cc2Cl)C(=O)O1
Reactant: O
Solvent: C=C(C)CC
Solvent: CSC
Solvent: C1CCOC1
Product: O=C1OC(CCCO)(c2ccc(F)cc2)CCN1Cc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
A stirred solution of BH3.Me2S (0.7 mL, 7.0 mmol) in dry THF (7 mL) was cooled in an ice bath and 2 M 2-methylbutene in THF (7 mL, 14 mmol) was added dropwise over 3 min. The mixture was stirred in the ice bath for 1.5 h. An aliquot of this solution (0.25 mL, 0.12 mmol) was added to an ice-cold solution of 6-allyl-3-(2,4-dichlorobenzyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (3.2 mg, 8.0 μmol) in dry THF (0.5 mL). The mixture was stirred overnight at rt. Water (2 mL) was added and the mixture was stirred for 3 h. Solid NaBO3.H2O (10 mg) was added. The mixture was stirred overnight, applied to a 10-mL ChemElut cartridge and eluted with CH2Cl2 (20 mL). The eluate was concentrated and the residue was purified by prep HPLC to afford 3-(2,4-dichlorobenzyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (1.3 mg, 39%). LC-MS Method 1 tR=1.78 min, m/z=368; 1H NMR (CDCl3) 1.37 (m, 1H), 1.66 (m, 1H), 1.99 (m, 2H), 2.30 (m, 2H), 2.92 (m, 1H), 3.10 (m, 1H), 3.58 (t, 2H), 4.50 (d, 1H), 4.63 (d, 1H), 6.90-7.35 (7H).
Reaction SMILES: [C:1]([C:3]1[NH:7][C:6]([CH2:8][CH2:9][CH3:10])=[N:5][C:4]=1[C:11]([OH:15])([CH3:14])[CH2:12][CH3:13])#[N:2].[H-].[Na+].[C:18]([N:37]1[C:41]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:48]2[CH:55]=[CH:54][C:51]([CH2:52]Br)=[CH:50][CH:49]=2)=[N:40][N:39]=[N:38]1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:1]([C:3]1[N:7]([CH2:52][C:51]2[CH:50]=[CH:49][C:48]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[C:41]3[N:37]([C:18]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:38]=[N:39][N:40]=3)=[CH:55][CH:54]=2)[C:6]([CH2:8][CH2:9][CH3:10])=[N:5][C:4]=1[C:11]([OH:15])([CH3:14])[CH2:12][CH3:13])#[N:2]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1nc(C(C)(O)CC)c(C#N)[nH]1
Agent: [H-]
Agent: [Na+]
Product: CCCc1nc(C(C)(O)CC)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 77.4 %

Procedure:
Following a procedure a similar to that described in Example 18(a), but using 380 mg of 5-cyano-4-(1-hydroxy-1-methylpropyl)-2-propylimidazole (prepared as described in Preparation 20), 88 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) and 1.07 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide, 0.97 g of the title compound were obtained as an amorphous solid.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH:13]1[F:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:26][S:27]([O:18][CH:15]1[CH2:16][CH2:17][CH:12]([O:11][CH2:10][CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:13]([F:19])[CH2:14]1)(=[O:29])=[O:28]
Reactant: CC(C)(C)[Si](C)(C)OC(COC1CCC(O)CC1F)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OC(COC1CCC(OS(C)(=O)=O)CC1F)c1ccccc1
Reaction time: 0.02 h
Yield: 95.5 %

Procedure:
To a solution of 4-(2-{[tert-Butyl(dimethyl)silyl]oxy}-2-phenylethoxy)-3-fluorocyclohexanol (8.46 g, 22.9 mmol) in dichloromethane (100 mL) at 0° C. was added methanesulfonyl chloride (2.49 mL, 32.1 mmol) and diisopropylethylamine (11.1 mL, 64.1 mmol). The reaction mixture was stirred for 1 min, diluted with dichloromethane and washed with 5% potassium bisulfate. The layers were separated and the aqueous extracted with dichloromethane (3×). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated. Purification by flash column chromatography (hexane: ethyl acetate 70:30) gave 4-(2-{[tert-Butyl(dimethyl)silyl]oxy}-2-phenylethoxy)-3-fluorocyclohexyl methanesulfonate (9.77 g, 100% yield) as a clear oil.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([OH:16])=O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:31][C:32]1[CH:33]=[C:34]([CH:39]([N:43]2[CH2:48][CH2:47][C:46]([OH:55])([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH2:45][CH2:44]2)[CH2:40][NH:41][CH3:42])[CH:35]=[CH:36][C:37]=1[Cl:38]>O1CCCC1>[ClH:31].[Cl:31][C:32]1[CH:33]=[C:34]([CH:39]([N:43]2[CH2:44][CH2:45][C:46]([OH:55])([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[CH2:47][CH2:48]2)[CH2:40][N:41]([CH3:42])[C:14](=[O:16])[CH2:13][C:5]2[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=[C:3]([C:2]([F:17])([F:18])[F:1])[CH:4]=2)[CH:35]=[CH:36][C:37]=1[Cl:38]
Reactant: O=C(O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNCC(c1ccc(Cl)c(Cl)c1)N1CCC(O)(c2ccccc2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(CC(c1ccc(Cl)c(Cl)c1)N1CCC(O)(c2ccccc2)CC1)C(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: Cl
Temperature: 23 °C
Reaction time: 18 h
Yield: 48 %

Procedure:
A solution of 3,5-bis(trifluoromethyl)phenylacetic acid (1.61 g) and 1,1'-carbonyldiimidazole (1.01 g) in tetrahydrofuran (15 mL) was stirred at reflux for 0.5 hours. The reaction was cooled to 23° C. and treated with a solution of N-[2-(3,4-dichlorophenyl)-2-(4-hydroxy-4-phenylpiperdino)ethyl]methylamine (2.24 g) in tetrahydrofuran (70 mL). The reaction was stirred at 23° C. for 18 hours. The reaction was evaporated to an oil, and the oil was partitioned between diethylether and 1N hydrochloric acid (100 mL). The organic layer was treated with ethereal hydrochloric acid to produce the title compound as a white solid (950 mg); mp 230° C.; MS: m/z=633(M+1); NMR: 1.73 (m,2), 2.42 (m, 1), 2.75 (m, 1), 3.01 (s,4), 3.86 (m,4,), 4.43 (m, 1), 4.85 (m, 1), 5.34 (m, 1), 7.34 (m, 5), 7.73 (s 2), 7.87 (m,5), 8.06 (s,1), 11.36 (broad s,1). Analysis Calculated: C, 53.79; H, 4.36; N, 4.18; Found: C, 54.06; H, 4.48; N, 4.23.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])C.O.[OH-].[Li+]>C1COCC1.CO.O>[CH2:11]([C:6]1([C:4]([OH:5])=[O:3])[CH2:10][CH2:9][CH2:8][CH2:7]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)C1(Cc2ccccc2)CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1(Cc2ccccc2)CCCC1
Temperature: 40 °C
Reaction time: 72 h
Yield: 97.9 %

Procedure:
A solution of 1-benzylcyclopentane carboxylic acid ethyl ester (0.40 g, 1.7 mmol) in 10 mL of THF and 5 mL of methanol was treated with a solution of 200 mg of lithium hydroxide hydrate in 5 mL of water and the mixture was stirred for 3 days at room temperature and at 40° C. for 3 days. The mixture was diluted with water, washed with ether and acidified with excess 6 N HCl. The aqueous layer was extracted with ether and the combined extracts were washed with water and brine and were dried (MgSO4). Evaporation gave 0.34 g (96%) of 1-benzylcyclopentane carboxylic acid as a thick yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:13]([NH:15][C:16]2[O:17][C:18]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)=[N:19][N:20]=2)=[O:14])[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.[CH2:26]([C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=2)=[CH:30][CH:29]=1)[CH3:27]>>[CH2:26]([C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([C:13]([NH:15][C:16]4[O:17][C:18]([C:21]5[O:22][CH:23]=[CH:24][CH:25]=5)=[N:19][N:20]=4)=[O:14])[CH:3]=3)=[CH:36][CH:35]=2)=[CH:30][CH:29]=1)[CH3:27]
Reactant: O=C(Nc1nnc(-c2ccco2)o1)c1cc(Br)cc(OC(F)(F)F)c1
Reactant: CCc1ccc(-c2ccc(B(O)O)cc2)cc1
Product: CCc1ccc(-c2ccc(-c3cc(OC(F)(F)F)cc(C(=O)Nc4nnc(-c5ccco5)o4)c3)cc2)cc1

Procedure:
The title compound was synthesized in accordance with the synthesis method of compound Ia-50, using 3-bromo-N-[5-(2-furyl)-1,3,4-oxadiazol-2-yl]-5-trifluoromethoxybenzenecarboxamide prepared in Reference Example 40 instead of compound Ia-50 and using commercially available 4′-ethyl-4-biphenylboronic acid instead of 1-methyl-5-indoleboronic acid pinacol ester.