Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][B:2]([OH:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[CH2:13](O)[CH2:14]CO>C1(C)C=CC=CC=1>[O:1]1[CH2:14][CH2:13][O:12][B:2]1[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: OCCCO
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(B2OCCO2)cc1
Reaction time: 6 h

Procedure:
A mixture of 4-(dihydroxyboryl)benzoic acid (30.00 g, 181 mmol) and 1,3-propanediol (15.20 g, 200 mmol) in toluene (750 mL) at 140° C. was stirred for 6 hours while collecting the water removed by azeotrope formation. The mixture was concentrated to provide the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:23](=O)[CH3:24].[BH3-]C#N.[Na+]>CO.[Cl-].[Cl-].[Zn+2]>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][N:14]([CH2:23][CH3:24])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@H](CNc2ccccc2)COC1(C)C
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CCN(C[C@@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1ccccc1
Temperature: 40 °C
Reaction time: 17 h
Yield: 77 %

Procedure:
To a stirred solution of (R)-2,2-dimethyl-4-phenylaminomethyl-oxazolidine-3-carboxylic acid tert-butyl ester (730 mg) at r.t. in methanol (20 ml) under an argon atmosphere were added acetaldehyde (0.67 ml), ZnCl2 (1.30 g) and NaBH3CN (0.45 g). The mixture was warmed to 40° C. and stirring at that temperature was continued for 17 h. The mixture was cooled to r.t., directly adsorbed on silica gel and purified by column chromatography (SiO2; gradient:cyclohexane->cyclohexane/EtOAc 4:1) to give (R)-4-[(ethyl-phenyl-amino)-methyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (614 mg, 77%) as colorless viscous oil. MS (ISP): 335.5 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:25])[C:12]3[CH:20]=[C:19]([C:21]#[C:22][CH2:23][OH:24])[S:18][C:13]=3[N:14]([CH2:16][CH3:17])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1>[Pd].C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:25])[C:12]3[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][OH:24])[S:18][C:13]=3[N:14]([CH2:16][CH3:17])[CH:15]=2)=[O:9])=[CH:26][CH:27]=1
Reactant: CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)sc21
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCCO)sc21
Yield: 57 %

Procedure:
A solution of N-(4-chlorobenzyl)-7-ethyl-2-(3-hydroxy-1-propynyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (Example No. 14) (0.197 g) in 1/1 CH2Cl2/CH3OH (50 mL) is hydrogenated over 10% Pd/C (59 mg) at 35 psi for 2 h. The reaction mixture is filtered through a Celite pad, and the filtrate is concentrated in vacuo. The resulting yellow solid is purified via column chromatography (CH2Cl2, CH2Cl2:CH3OH; 98:2, 95:5). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield 0.114 g (57%) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[Cl:24][C:25]1[C:26]([CH3:34])=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[Cl:24][C:25]1[C:26]([CH3:34])=[C:27]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([CH2:11][CH2:12][N:7]4[C@H:6]4[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:16][C@@H:5]34)[CH:10]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: Cc1c(Cl)cccc1B(O)O
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Product: Cc1c(Cl)cccc1-c1cc2c3c(c1)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N3CC2

Procedure:
The title compound was prepared by the method of Example 89 step C from tert-butyl(6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)carboxylate (189 mg, 0.5 mmol) and 3-chloro-2-methylphenylboronic acid (140 mg, 1.0 mmol) to afford after chromatographic purification the title compound (99 mg, 47%). 1H NMR (CDCl3, 300 MHz) δ 7.28–7.31 (m, 1H), 7.10 (d, 2H, J=4.4 Hz), 6.85 (s, 1H), 6.81 (s, 1H), 3.82–4.24 (m, 2H), 3.64–3.74 (m, 1H), 3.24–3.54 (m, 4H), 2.86–3.26 (m, 3H), 1.86 (s, 3H),1.84–1.89 (m, 2H), 1.48 (s, 9H) ppm. MS-ApCI: 425 [M+H+].
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Cl.Cl[CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][N:22]([CH2:30][C:31]5[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=5)[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: ClCc1cccnc1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CN(Cc3cccnc3)C2=O)CC1
Yield: 61 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), sodium hydride (2.4 equivalents) and 3-(chloromethyl)pyridine hydrochloride, to give the desired product as a light yellow foam (61%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[O:14].[OH-].[K+].Cl>O1CCCC1.O.CO>[Br:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:12]/[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[O:14])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Br)cc1C=O
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ncc(Br)cc1/C=C/C(=O)c1ccc(Cl)cc1
Reaction time: 1.5 h

Procedure:
To a solution of 6.5 g of 5-bromo-2-methoxypyridine-3-carboxaldehyde in 30 ml of tetrahydrofuran under nitrogen was added 200 ml of methanol followed by 4.6 g of 4-chloroacetophenone. Then, a solution of 6.6 g of 85% potassium hydroxide in 15 ml of water was added. The mixture warmed, became yellow, and deposited a thick precipitate. It was then stirred mechanically for about 1.5 hours until the temperature fell back to about 25° C. It was then further cooled in an ice bath and neutralized by the addition of 20 ml of aqueous 5M hydrochloric aid in small portions. The resulting pasty mixture was poured into 400 ml of water, acidified to a pH of 1 with aqueous 1N hydrochloric acid and then filtered. The moist product was boiled with 2-propanol/ethyl acetate (3:1), cooled and filtered. The filter cake was dried under reduced pressure to give (E)-3-(5-bromo-2-methoxy-3-pyridinyl)-1-(4-chlorophenyl)-2-propen-1-one as a pale yellow solid melting at about 168.5°-171.5° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21](=[O:29])[C:22]([S:25]C(=O)C)([CH3:24])[CH3:23])=[CH:17][CH:16]=3)(=[O:13])=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1>CO.[OH-].[Na+]>[SH:25][C:22]([CH3:24])([CH3:23])[C:21]([C:18]1[CH:17]=[CH:16][C:15]([NH:14][S:11]([C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=2)(=[O:13])=[O:12])=[CH:20][CH:19]=1)=[O:29]
Reactant: CC(=O)SC(C)(C)C(=O)c1ccc(NS(=O)(=O)c2ccc3c(c2)OCCO3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(S)C(=O)c1ccc(NS(=O)(=O)c2ccc3c(c2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound of Example 14 (60 mg, 0.14 mmol) was dissolved in methanol (2 ml) before 5 M NaOH was added (150 μl). The resulting yellow solution was allowed to stir at room temperature for 30 minutes. The desired compound was isolated by prep-HPLC as a white solid. 1H-NMR (DMSO): 10.73 (s, 1H), 7.93 (d, 2H), 7.31 (m, 2H), 7.17 (d, 2H), 7.02 (d, 1H), 4.28 (q, 4H), 3.78 (s, 1H), 1.57 (s, 6H). LC-MS (ES+): 394 [MH]+ m/e.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([C:11]2[C:12]([CH3:18])=[N:13][CH:14]=[CH:15][C:16]=2[CH3:17])=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.CN(C1C=CC=CN=1)C.[Cl:28][C:29]1[CH:30]=[C:31]([S:36](Cl)(=[O:38])=[O:37])[CH:32]=[CH:33][C:34]=1[Cl:35]>N1C=CC=CC=1>[Cl:28][C:29]1[CH:30]=[C:31]([S:36]([NH:1][C:2]2[C:3]([C:9]([C:11]3[C:12]([CH3:18])=[N:13][CH:14]=[CH:15][C:16]=3[CH3:17])=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=2)(=[O:37])=[O:38])[CH:32]=[CH:33][C:34]=1[Cl:35]
Reactant: Cc1ccnc(C)c1C(=O)c1ncc(Cl)cc1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: Cc1ccnc(C)c1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 23.9 %

Procedure:
To a solution of (3-Amino-5-chloro-pyridin-2-yl)-(2,4-dimethyl-pyridin-3-yl)-methanone (43 mg, 0.16 mmol) and 10 mg of dimethylaminopyridine in 1.0 ml of pyridine was added 3,4-dichlorobenzenesulfonylchloride (70 mg, 0.28 mmol). The mixture was stirred at 80° C. for 3 hours, cooled to room temperature and concentrated. The residue was directly purified by flash column (50% ethyl acetate in hexane) or preparative HPLC (20-80% acetonitrile in water) to afford 18 mg of title compound as an off-white solid. MS: (M+H)/z =470.4.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]1([S:31][C:32]2[S:33][C:34]([C:37]([OH:39])=O)=[CH:35][N:36]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl.Cl.[NH2:42][C@@H:43]1[CH:48]2[CH2:49][CH2:50][N:45]([CH2:46][CH2:47]2)[CH2:44]1.CCN(C(C)C)C(C)C.[C:60]([OH:67])(=[O:66])/[CH:61]=[CH:62]/[C:63]([OH:65])=[O:64]>CN(C=O)C.C(Cl)Cl>[C:60]([OH:67])(=[O:66])/[CH:61]=[CH:62]/[C:63]([OH:65])=[O:64].[N:45]12[CH2:50][CH2:49][CH:48]([CH2:47][CH2:46]1)[C@@H:43]([NH:42][C:37]([C:34]1[S:33][C:32]([S:31][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[N:36][CH:35]=1)=[O:39])[CH2:44]2
Reactant: O=C(O)c1cnc(Sc2ccccc2)s1
Reactant: N[C@H]1CN2CCC1CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CN2CCC1CC2)c1cnc(Sc2ccccc2)s1
Reaction time: 8 h
Yield: 72 %

Procedure:
HATU (0.493 g, 1.30 mmol, 1 eq) is added to a solution of 2-phenylsulfanyl-thiazole-5-carboxylic acid (0.307 g, 1.30 mmol, 1 eq), (R)-(+)-3-aminoquinuclidine dihydrochloride (0.258 g, 1.30 mmol, 1 eq), and DIEA (0.677 mL, 3.89 mmol, 3 eq) in DMF (9.8 mL), the flask containing which was in an ice bath. The reaction is stirred overnight. CH2Cl2 is added, and the mixture is washed with water three times. The organic layer is dried over MgSO4, and the solvent removed in vacuo. The product is purified using a Biotage Flash 40M column (1% NH4OH/9% MeOH/90%CH2Cl2), affording a clear oil. The fumaric acid salt of the product is made, and recrystallized from MeOH and ether to give the product as a white crystalline solid (0.408 g, 72%). MS (ESI) for C17H19N3OS2 m/z 346.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:3]=1[CH2:4][O:5][CH:6]([CH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29])[CH:16]=[CH:15]2)[C:7]([O:9]C)=[O:8].[OH-].[Na+].OS([O-])(=O)=O.[K+]>C(#N)C.O>[Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:3]=1[CH2:4][O:5][CH:6]([CH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29])[CH:16]=[CH:15]2)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)C(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)OCc1c(Cl)cccc1Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(O)C(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)OCc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
A solution of methyl 2-[(2,6-dichlorobenzyl)oxy]-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoate 56 (0.123 g) and 1 N NaOH (0.236 ml) in a mixture of acetonitrile/water (3 ml/0.14 ml) is stirred for 3 h at room temperature. After addition of a 10% KHSO4 solution (3 ml), the mixture is concentrated. The aqueous phase is extracted with AcOEt (3×10 ml). The organic phases are washed with brine, dried over MgSO4 and evaporated under vacuum. The residue is washed with CH2Cl2 and 2-[(2,6-dichlorobenzyl)oxy]-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoic acid 91 is obtained as a white powder.
Reaction SMILES: Br[C:2]1[N:3]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[CH:29]([C:31]1[S:32][CH:33]=[CH:34][C:35]=1B(O)O)=[O:30].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:25]([O:24][C:22](=[O:23])[CH2:21][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2)[C:10]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:2]1[C:35]1[CH:34]=[CH:33][S:32][C:31]=1[CH:29]=[O:30])([CH3:28])([CH3:27])[CH3:26]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CC(=O)OC(C)(C)C)c2c1
Reactant: O=Cc1sccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccsc3C=O)n(CC(=O)OC(C)(C)C)c2c1

Procedure:
Methyl 2-bromo-1-(2-tert-butoxy-2-oxoethyl)-3-cyclohexyl-1H-indole-6-carboxylate (prepared as described in Example 1, Step 1) and (2-formyl-3-thienyl) boronic acid (1.5 eq) were dissolved in dioxane (0.07 M) and 2M aqueous Na2CO3 (6 eq) was added. The solution was degassed by bubbling argon, Pd(PPh3)2Cl2 (0.2 eq) was added, and the reaction mixture was refluxed for 45 min; after cooling EtOAc was added and the solution washed with water and brine, dried over Na2SO4 and concentrated. The title compound was isolated by chromatography (PE/EtOAc 9:1). Yield (84%); MS (ES+) m/z 504 (M+Na)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]2[C:21](=[O:28])[NH:22][NH:23][C:24]=2[CH:25]([CH3:27])[CH3:26])=[C:15]([CH3:29])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][C:31]([O:33][CH2:34][C@H:35]1[O:40][C@H:39](Br)[C@H:38]([O:42][C:43]([CH3:45])=[O:44])[C@@H:37]([O:46][C:47]([CH3:49])=[O:48])[C@H:36]1[O:50][C:51]([CH3:53])=[O:52])=[O:32].CC(OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O)=O>>[C:43]([O:42][C@@H:38]1[C@@H:37]([O:46][C:47](=[O:48])[CH3:49])[C@@H:36]([O:50][C:51](=[O:52])[CH3:53])[C@@H:35]([CH2:34][O:33][C:31](=[O:32])[CH3:30])[O:40][C@H:39]1[O:28][C:21]1[C:20]([CH2:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:14][C:15]=2[CH3:29])=[C:24]([CH:25]([CH3:27])[CH3:26])[NH:23][N:22]=1)(=[O:44])[CH3:45]
Reactant: Cc1cc(OCCCOCc2ccccc2)ccc1Cc1c(C(C)C)[nH][nH]c1=O
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCOCc3ccccc3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 17 using 4-{[4-(3-benzyloxypropoxy)-2-methylphenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and acetobromo-α-D-galactose instead of 4-{[4-(3-benzyloxypropoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and acetobromo-α-D-glucose, respectively.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[F:13].CCCC.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH:30]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:32]=2)[CH2:29][C:28]([C:46]([F:52])([F:51])[C:47]([F:50])([F:49])[F:48])=[N:27]1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[F:13][C:3]1[CH:4]=[C:5]([S:9]([CH3:12])(=[O:11])=[O:10])[C:6]([F:8])=[CH:7][C:2]=1[C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([CH:30]2[N:26]([C:20]3[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=3[F:18])[N:27]=[C:28]([C:46]([F:52])([F:51])[C:47]([F:48])([F:50])[F:49])[CH2:29]2)[CH:32]=1
Reactant: CS(=O)(=O)c1cc(F)c(Br)cc1F
Reactant: CC1(C)OB(c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCC
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1cc(F)c(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)cc1F
Temperature: 88 °C
Reaction time: 2 h
Yield: 25.2 %

Procedure:
To 1-bromo-2,5-difluoro-4-(methylsulfonyl)benzene (19.0 mg, 0.07 mmol), were added 1,2-dimethylethane (1.5 mL) and Pd(PPh3)4 (8.1 mg, cat.). To the reaction mixture, were added 1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4,5-dihydro-1H-pyrazole (35 mg, 0.07 mmol) prepared in Step 1, ethanol (350.0 uL), and a 2N sodium carbonate solution (350.0 uL). The reaction mixture was stirred at 88° C. for 2 hours. Distilled water was added to the reaction mixture, which was then extracted with diethyl ether two times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to give 10.0 mg of the titled compound as a pale yellow liquid.
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[C:15]([Br:17])[C:14]([CH3:18])=[CH:13][C:12]=3[OH:19])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:1]12([C:11]3[C:12]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:13][C:14]([CH3:18])=[C:15]([Br:17])[CH:16]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: Cc1cc(O)c(C23CC4CC(CC(C4)C2)C3)cc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(OCc2ccccc2)c(C23CC4CC(CC(C4)C2)C3)cc1Br
Yield: 91.8 %

Procedure:
To a solution of 2-(1-adamantyl)-4-bromo-5-methylphenol (6.53 g, 20.34 mmol) in acetone (65 mL) was added benzyl bromide (3.48 g, 20.34 mmol) followed by K2CO3 (3.51 g, 25.43 mmol). The mixture was stirred and heated at reflux for 24 h under argon. Acetone was removed at reduced pressure, and then 2 N HCl (80 mL) was added. The mixture was extracted with EtOAc (300 mL), and the organic layer was washed with H2O and brine and dried. After removal of solvent, the residue was purified by chromatography on a silica gel using hexane to give 7.68 g (80%) of 5-(1-adamantyl)-4-benzyloxy-2-methylphenyl bromide as a white solid, mp 138-139° C. IR 2903, 2848, 1163 cm−1; 1H NMR (CDCl3) δ 1.71 (bs, 614, AdCH2), 2.02 (bs, 3H, AdCH), 2.08 (bs, 6H, AdCH2), 2.33 (s, 3H, CH3), 5.07 (s, 2H, C6H5CH2), 6.80 (s, 1H, 3-ArH), 7.33 (s, 1H, 6-ArH), 7.3-7.5 ppm (m, 5H, C6H5).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].O=[C:15]1[CH2:23][CH:22]2[CH:17]3[CH2:18][CH:19]4[CH:21]2[CH:20]4[CH:16]13.O>O1CCCC1.CS(C)=O>[C:3]([CH:5]=[C:15]1[CH2:23][CH:22]2[CH:17]3[CH2:18][CH:19]4[CH:21]2[CH:20]4[CH:16]13)#[N:4]
Reactant: O=C1CC2C3CC4C2C4C13
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: O
Product: N#CC=C1CC2C3CC4C2C4C13
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (2.4 g. washed free of oil) was treated with dimethyl sulphoxide (100 ml.) and warmed under nitrogen to 75°-80° C. for 35 minutes. The mixture was cooled to ambient temperature and a solution of diethyl cyanomethylphosphonate (17.7 g.) in dry tetrahydrofuran (100 ml.) added dropwise. The mixture was stirred for 30 minutes. A solution of the above ketone (13.4 g.) in a mixture of dimethyl sulphoxide (100 ml.) and tetrahydrofuran (100 ml.) was then added dropwise and stirred for 16 hours at room temperature. The product was poured into water (1000 ml.) and the mixture extracted with ether (5×100 ml.). The combined extracts were washed with saturated brine, dried over potassium carbonate, filtered and evaporated. Distilled in vacuo gave 8-cyanomethylenetetracyclo-[4,3,0,02,4,03,7 ]nonane, b.p. 138°-140° C./18 mm.
Reaction SMILES: [NH2:1][CH:2]([CH3:22])[CH:3]([CH2:11][C:12]1[O:13][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:16]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[CH:33]=O.[BH4-].[Na+].C(OCC)(=O)C>CO.O>[CH2:20]([O:19][C:17]([C:14]1[O:13][C:12]([CH2:11][CH:3]([CH:2]([NH:1][CH2:33][C:24]2[CH:25]=[CH:26][C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:23]=2)[CH3:22])[C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5])=[CH:16][CH:15]=1)=[O:18])[CH3:21]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CCOC(=O)c1ccc(CC(C(=O)OC(C)(C)C)C(C)N)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)c1ccc(CC(C(=O)OC(C)(C)C)C(C)NCc2ccc3ccccc3c2)o1
Temperature: 0 °C
Yield: 76.5 %

Procedure:
500 mg of tert-butyl (2RS,3RS)-3-amino-2-{5-(ethoxycarbonyl)-2-furylmethyl}butanoate in 15 ml of methanol was stirred together with 251 mg of 2-naphthaldehyde at 50° C. for 2 hours under heating. The reaction solution was cooled to 0° C. and stirred with 61 mg of sodium borohydride at the same temperature for 15 minutes. Ethyl acetate and water were added to the reaction solution for extraction, and the organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [hexane/ethyl acetate=6/1] to give 555 mg of the title compound as a colorless oily substance.
Reaction SMILES: CC1C=C(N2CCN(CC3C=CC(C(F)(F)F)=CC=3)C2=O)SC=1C(O)=O.[CH2:27]([NH:34][C:35]([C:37]1[S:41][C:40]([N:42]2[CH2:46][CH2:45][N:44]([CH2:47][C:48]([OH:50])=O)[C:43]2=[O:51])=[N:39][C:38]=1[CH3:52])=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[F:53][C:54]1[CH:61]=[CH:60][C:57]([CH2:58][NH2:59])=[CH:56][CH:55]=1>>[CH2:27]([NH:34][C:35]([C:37]1[S:41][C:40]([N:42]2[CH2:46][CH2:45][N:44]([CH2:47][C:48]([NH:59][CH2:58][C:57]3[CH:60]=[CH:61][C:54]([F:53])=[CH:55][CH:56]=3)=[O:50])[C:43]2=[O:51])=[N:39][C:38]=1[CH3:52])=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1nc(N2CCN(CC(=O)O)C2=O)sc1C(=O)NCc1ccccc1
Reactant: NCc1ccc(F)cc1
Agent: Cc1cc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(CC(=O)NCc3ccc(F)cc3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 75 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace 3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 2-(3-(5-(benzylcarbamoyl)-4-methylthiazol-2-yl)-2-oxoimidazolidin-1-yl)acetic acid to react with 4-fluorobenzylamine, the title compound was obtained as a colorless solid in 75% yield: mp 232-234° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.64 (t, J=5.9 Hz, 1H), 8.52 (t, J=5.9 Hz, 1H), 7.37-7.12 (m, 9H), 4.38 (d, J=5.9 Hz, 2H), 4.29 (d, J=5.9 Hz, 2H), 4.05-3.98 (m, 2H), 3.93 (s, 2H), 3.65-3.57 (m, 2H), 2.48 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 167.4, 161.7, 161.1 (d, JC-F=242.0 Hz), 157.3, 155.4, 150.8, 139.6, 135.3 (d, JC-F=2.9 Hz), 129.1 (d, JC-F=8.1 Hz), 128.2, 127.2, 126.6, 117.8, 115.0 (d, JC-F=21.3 Hz), 46.2, 42.8, 42.5, 42.0, 41.3, 17.0; MS (ES+) m/z 482.1 (M+1).