Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:27](=[O:31])[N:28]([CH3:30])[CH3:29])[CH2:10][C:11]1[CH:26]=[CH:25][C:14]([O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.Cl.[NH2:40][OH:41].C(O)(=O)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:27](=[O:31])[N:28]([CH3:29])[CH3:30])[CH2:10][C:11]1[CH:26]=[CH:25][C:14]([O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:22])[NH:40][OH:41])=[CH:18][N:17]=2)=[CH:13][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NO
Reactant: CN(C)C(=O)C(Cc1ccc(Oc2ccc(C(=O)O)cn2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CN1CCOCC1
Product: CN(C)C(=O)C(Cc1ccc(Oc2ccc(C(=O)NO)cn2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 48.3 %

Procedure:
The acid compound 19 (1.0 g, 2.328 mmol) was dissolved in dry DMF and stirred under an atmosphere of argon. N-Methylmorpholine (1.02 mL, 9.32 mmol) was added. After 20 min, hydroxylamine hydrochloride (0.323 g, 4.66 mmol) was added and the reaction mixture was warmed up to room temperature and stirred overnight. The solvent was removed under reduced pressure and residual material was partitioned between EtOAc (50 mL) and saturated NH4Cl solution (1×30 mL). The organic layer was dried and concentrated to yield the crude material. Flash chromatography on SiO2 gel using hexanes-ethyl acetate (70-60%) mixture containing 1% acetic acid furnished the desired hydroxamic acid compound 20 (0.5 g, 98%) 1H NMR (400 MHz, DMSO-d6): 8.47 (br, 1H) 8.14 (dd, J=8.8 and 2.4 Hz, 1H), 7.29 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.8 Hz, 1H), 7.05 (m, 3H), 4.56 (m, 1H), 2.93 (s, 3H) 2.85-2.75 (m, 2H), 2.79 (s, 3H), 1.32 (s, 9H)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2].[H-].[Na+].[CH3:23][O:24][C:25](=[O:28])[CH2:26]Br>CN(C=O)C>[CH3:23][O:24][C:25](=[O:28])[CH2:26][N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][CH:8]=1)(=[O:11])=[O:12])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1
Reactant: CCOc1ccc(S(=O)(=O)Nc2ccc(C)cc2)cc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(S(=O)(=O)N(CC(=O)OC)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99.1 %

Procedure:
The crude N-aryl-benzenesulfonamide building block XIII, e.g. 4-ethoxy-N-(4-methylphenyl)benzenesulfonamide (3.087 g, 10.6 mmol), was dissolved in DMF (10 mL) and was added to a suspention of NaH (13.6 mmol, 0.593 mg of NaH 55-65% in oil) in DMF (30 mL). The mixture was stirred 45 min at room temperature. 2-Bromoacetic acid methyl ester (1.45 mL, 15.9 mmol) was added dropwise. The resulting mixture was stirred at room temperature overnight. The solvents were evaporated, affording the desired product, e.g. methyl{[(4-ethoxyphenyl)sulfonyl]-4-methylanilino}acetate (3.816 g, quantitative crude yield) as a light yellow solid, in 96.1% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[S:16][C:15]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH:21](=O)[CH2:22][CH3:23]>C(O)C.[Pt]=O>[CH2:21]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[S:16][C:15]([S:17]([NH2:20])(=[O:18])=[O:19])=[CH:14][CH:13]=2)(=[O:10])=[O:11])=[CH:5][CH:4]=1)[CH2:22][CH3:23]
Reactant: CCC=O
Reactant: NCc1ccc(S(=O)(=O)c2ccc(S(N)(=O)=O)s2)cc1
Agent: O=[Pt]
Solvent: CCO
Product: CCCNCc1ccc(S(=O)(=O)c2ccc(S(N)(=O)=O)s2)cc1
Reaction time: 2 h

Procedure:
5-[4-aminomethylphenylsulfonyl]thiophene-2-sulfonamide (1.9 g, 5.15 mmol) and propionaldehyde (0.314 g, 5.40 mmol) were dissolved in ethanol (75 ml). Platinum oxide (300 mg) was added and the mixture was hydrogenated in a Parr apparatus at about 65 psi (96 Nm-2) for about 2 hours. The mixture was filtered through a filter aid and evaporated to dryness. The residual oil was chromatographed (50 mm×5 in, 230-400 mesh silica gel; chloroform methanol, 9 to 1 respectively) and the appropriate fractions were combined and treated with methanolic HCl. Evaporation of the solvent left a white solid which after drying for 2 hours under high vacuum at room temperature, had m.p. 151°-153° C. Anal Calc'd. for: C14H18N2O4S3.HCl: C, 40.91; H, 4.65; N, 6.82. Found: C, 40.72; H, 4.60; N, 6.89.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[CH:17][C:18]=3[O:20][CH2:21][C@H:22]3[CH2:26][CH2:25][CH2:24][NH:23]3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[C:29](O)(=[O:32])[CH2:30][OH:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:27][CH3:28])=[CH:17][C:18]=2[O:20][CH2:21][C@H:22]2[CH2:26][CH2:25][CH2:24][N:23]2[C:30](=[O:31])[CH2:29][OH:32])[N:13]=[CH:12][N:11]=1
Reactant: O=C(O)CO
Reactant: COc1cc(OC[C@H]2CCCN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Product: COc1cc(OC[C@H]2CCCN2C(=O)CO)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Yield: 47 %

Procedure:
The procedure described in Example 1 was repeated using N-(3-chloro-4-fluorophenyl)-7-methoxy-5-[(2R)-pyrrolidin-2-ylmethoxy]-quinazolin-4-amine (90 mg) and glycolic acid (19 mg) to give the title compound in 47% yield; NMR Spectrum (DMSO-d6) 9.90 (s, 1H), 8.42 (s, 1H), 8.15 (dd, 1H), 7.70-7.60 (m, 1H), 7.40 (t, 1H), 6.90 (d, 1H), 6.78 (d, 1H), 4.65-4.53 (m, 2H), 4.42-4.37 (m, 1M), 4.20-4.11 (m, 1H), 4.03 (d, 1H), 3.90 (s, 3H), 3.45-3.35 (m, 3H), 2.10-1.82 (m, 41); Mass spectrum MH+ 461.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=2)[NH:13][N:12]=1.[H-].[Na+].[CH:23]1(Br)[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([N:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:11]([C:4]3[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=3[O:2][CH3:1])=[N:12]2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: BrC1CCCC1
Reactant: COc1ccc(-c2n[nH]c3c(F)cccc23)c(OC)c1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)c(OC)c1
Yield: 125 %

Procedure:
Prepared according to Method D step B from 3-(2,4-dimethoxyphenyl)-7-fluoro-1H-indazole (0.150 g, 0.55 mmol), sodium hydride (60% in oil, 0.058 g, 0.66 mmol) and cyclopentyl bromide (0.214 mL, 2.0 mmol) to give the title compound (0.234 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:28]1[CH2:30][C@H:29]1[CH2:31]O.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:31][C@@H:29]2[CH2:30][O:28]2)=[CH:6][N:7]=1
Reactant: OC[C@@H]1CO1
Reactant: Oc1ccc(Cl)nc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc(OC[C@@H]2CO2)cn1
Temperature: 0 °C
Reaction time: 30 h
Yield: 59.5 %

Procedure:
In a 250 mL round-bottomed flask, 6-chloropyridin-3-ol (2.116 g, 16.3 mmol), triphenylphosphine (5.14 g, 19.6 mmol) and (R)-oxiran-2-ylmethanol (1.21 g, 1.08 ml, 16.3 mmol) were combined with THF (75.0 ml) to give a colorless solution. Cooled to 0° C. DEAD (3.41 g, 3.1 ml, 19.6 mmol) was added. The reaction mixture was allowed to come to 25° C. and stirred for 30 h. The reaction mixture was concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 80 g, 5% to 25% EtOAc in hexanes) followed by flash chromatography (silica gel, 40 g, 0.5% to 1% MeOH in DCM) to afford the desired product (1.8 g, 59%) as a white solid. (M+H)+=186 m/e.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([O:12][CH3:13])([O:10][CH3:11])[CH3:9])[CH:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[C:3]=1[O:18][CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[NH:68]1[CH2:73][CH2:72][O:71][CH2:70][CH2:69]1>O1CCOCC1>[CH3:11][O:10][C:8]([C:6]1[CH:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[C:3]([O:18][CH3:19])=[C:2]([N:68]2[CH2:73][CH2:72][O:71][CH2:70][CH2:69]2)[CH:7]=1)([O:12][CH3:13])[CH3:9]
Reactant: C1COCCN1
Reactant: COc1c(Br)cc(C(C)(OC)OC)cc1C(F)(F)F
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COc1c(N2CCOCC2)cc(C(C)(OC)OC)cc1C(F)(F)F
Temperature: 90 °C
Reaction time: 8 h

Procedure:
1-Bromo-5-(1,1-dimethoxyethyl)-2-methoxy-3-trifluoromethylbenzene (03.004; 700 mg) was initially charged in dioxane (7 ml) and admixed successively with Pd(II) acetate (46 mg), cesium carbonate (2 g), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (118 mg) and morpholine (0.27 ml). Thereafter, the reaction mixture was heated to 90° C. for 7 h and then left to stand overnight. Subsequently, it was filtered and the filtrate was concentrated by rotary evaporation. The residue was purified using silica gel (50 g cartridge, n-heptane/EA gradient). 433 mg of the title compound were obtained.
Reaction SMILES: [OH-].[K+].[C:3]([C:7]1[CH:8]=[C:9]([CH3:12])[CH2:10][CH:11]=1)([CH3:6])([CH3:5])[CH3:4].[Cl:13][C:14]1[CH:28]=[CH:27][C:17]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=O)=[CH:16][CH:15]=1.Cl>C(OCC)C.C(COC)OC>[C:3]([C:7]1[CH:8]=[C:9]([CH3:12])[C:10](=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[C:17]2[CH:27]=[CH:28][C:14]([Cl:13])=[CH:15][CH:16]=2)[CH:11]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: CC1=CC(C(C)(C)C)=CC1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: COCCOC
Product: CC1=CC(C(C)(C)C)=CC1=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
In a 200 ml three-necked flask equipped with a magnetic stirrer chip and three-way cock thoroughly purged with nitrogen, 0.65 g of powdery potassium hydroxide (13.0 mmol) and 70 ml of dehydrated dimethoxy ethane were added in a nitrogen atmosphere. To the suspension, 1.24 g of 3-tert-butyl-1-methyl-cyclopentadiene (9.11 mmol) was added dropwise at room temperature and then 2.40 g of 4,4′-dichloro-benzophenone (9.58 mmol) was added and stirred under reflux for 3 days. To a 30 ml of a hydrochloric acid aqueous solution (1N) set in an ice bath, the reaction mixture was gradually added dropwise and stirred for some time. Diethyl ether was added to the mixed solution to separate an organic phase. The organic phase was washed with a saturated sodium bicarbonate aqueous solution, water and saturated brine. The organic phase was dried with anhydrous magnesium sulfate, thereafter the drying agent was filtered off and the solvent was distilled off from the filtrate under reduced pressure to give a reddish-orange solid. The solid was purified with a column chromatography using 110 g of silica gel (developing solvent: n-hexane) and the developing solvent was distilled off under reduced pressure, and thereby the aimed compound was obtained in an amount of 2.79 g (7.56 mmol) as a red solid (yield: 83%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][S:25](=[O:28])[CH2:24][CH2:23]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH:13]([CH3:21])[CH2:14][CH2:15][CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[C:6]=2[N:7]=1.[OH:29][CH2:30][CH2:31][NH2:32]>>[OH:29][CH2:30][CH2:31][NH:32][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][S:25](=[O:28])[CH2:24][CH2:23]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH:13]([CH3:21])[CH2:14][CH2:15][CH2:16][C:17]([OH:20])([CH3:18])[CH3:19])[C:6]=2[N:7]=1
Reactant: NCCO
Reactant: CC(CCCC(C)(C)O)Nc1ncnc2c(N3CCS(=O)CC3)nc(Cl)nc12
Product: CC(CCCC(C)(C)O)Nc1ncnc2c(N3CCS(=O)CC3)nc(NCCO)nc12

Procedure:
This compound was prepared analogous to Example 2 from 2-chloro-8-(5-hydroxy-1,5-dimethylhexyl-amino)-4-(1-oxido-thiomorpholino)-pyrimido[5,4-d]pyrimidine (resin) and 2-hydroxyethyl-amine. Resin.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:19]=[CH:18][C:7]2[NH:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[CH:5]=1.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[S:31](Cl)(=[O:33])=[O:32].O>CN(C=O)C>[Cl:3][C:4]1[CH:19]=[CH:18][C:7]2[N:8]([S:31]([C:23]3[CH:24]=[CH:25][C:26]([N+:28]([O-:30])=[O:29])=[CH:27][C:22]=3[O:21][CH3:20])(=[O:32])=[O:33])[C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[CH:5]=1
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Reactant: O=c1[nH]c2ccc(Cl)cc2n1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)n1c(=O)n(-c2ccccc2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.15 g of sodium hydride as an 80% dispersion in oil was added in portions, with stirring, to a solution of 1.223 g of 5-chloro-1,3-dihydro-3-phenyl-2H-benzimidazol-2-one in 12 ml of DMF at room temperature; 1.384 g of 2-methoxy-4-nitrobenzenesulfonyl chloride were then introduced and the reaction medium was stirred at room temperature for 24 hours. The solvent was then evaporated off under vacuum and the residue obtained was taken up with water. It was then extracted with DCM, washed with water and then dried over sodium sulfate and the solvent was evaporated off to dryness. The residue obtained was chromatographed on silica using a DCM/AcOEt mixture (92/8; v/v) as the eluent to give the expected product in the form of a yellow product, which crystallized from absolute EtOH. m=1.870 g. M.p.>250° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][OH:12].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[OH:12][CH2:11][CH2:10][S:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: OCCBr
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCSc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72 %

Procedure:
(FIG. 2) (a) (4-(2-hydroxyethylsulfanyl) phenol) was synthesized by a modified literature procedure (pl add ref). 4-hydroxythiophenol (mercaptophenol) (6.00 g, 47.61 mmole), 2-bromoethanol (5.90 g, 47.6 mmol) and K2CO3 (6.6 g, 47.48 mmol) was stirred in dimethylformamide (DMF, 50 ml) at −5° C. for 30 minutes. The reaction mixture was then stirred for 12 hours at room temperature. The reaction mixture was poured in ice water (300 ml) and extracted with dichloromethane (DCM) (3×50 ml). The organic part was dried by MgSO4 and then solvent was removed under a rotary evaporator. The crude product was purified on silica gel column by using a chloroform/methanol (94:6) solvent mixture. Yield: 72%. 1H NMR (CDCl3): δ, 8.01 (s, OH, 1H), 7.33 (d, 2H, J=8.7 Hz), 6.78 (d, 2H, J=8.7 Hz), 4.52 (s, OH, 1H), 3.67 (t, 2H, J=6 Hz), 2.99 (t, 2H, J=5.7).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15]2[N:20]=[C:19]([N:21]3[CH2:37][CH2:36][C:24]4([CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)[CH2:23][CH2:22]3)[C:18]([C:38]#[N:39])=[CH:17][N:16]=2)[CH:9]=1>C(Cl)Cl>[C:8]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15]2[N:20]=[C:19]([N:21]3[CH2:22][CH2:23][C:24]4([CH2:28][NH:27][CH2:26][CH2:25]4)[CH2:36][CH2:37]3)[C:18]([C:38]#[N:39])=[CH:17][N:16]=2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(c3nc(Nc4cccc(-c5ccccc5)c4)ncc3C#N)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cnc(Nc2cccc(-c3ccccc3)c2)nc1N1CCC2(CCNC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (1 mL) was added to a solution of the tert-butyl 8-[2-(biphenyl-3-ylamino)-5-cyanopyrimidin-4-yl]-2,8-diazaspiro[4.5]decane-2-carboxylate (24 mg, 0.047 mmol) in CH2Cl2 (1 mL) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to afford 2-(biphenyl-3-ylamino)-4-(2,8-diazaspiro[4.5]dec-8-yl)pyrimidine-5-carbonitrile as a white solid. MS ESI calcd. for C25H27N6 [M+H]+ 411, found 411. 1H NMR (400 MHz, DMSO) δ 10.25 (s, 1H), 9.08 (s, 1H), 8.72 (s, 1H), 8.32 (s, 1H), 7.87 (d, 7.9 Hz, 2H), 7.85 (s, 1H), 7.74 (t, J=7.6 Hz, 2H), 7.69-7.59 (m, 2H), 7.57 (d, J=7.8 Hz, 1H), 4.31-4.14 (m, 2H), 4.14-4.04 (m, 2H), 3.65-3.43 (m, 2H), 3.32 (t, J=5.6 Hz, 2H), 2.13 (t, J=7.4 Hz, 2H), 1.94-1.92 (br m, 4H).
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31](I)[CH:30]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.C(N(CC)CC)C.[CH:44]1([SH:49])[CH2:48][CH2:47][CH2:46][CH2:45]1.O>CN1CCCC1=O.[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[Fe+2].[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH:44]1([S:49][C:31]2[CH:30]=[C:29]([CH2:28][CH2:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:14]3[CH2:13][C@@H:12]([C:10]4[CH:9]=[CH:8][C:6]5[O:7][C:2]([CH3:1])([CH3:36])[O:3][CH2:4][C:5]=5[CH:11]=4)[O:16][C:15]3=[O:17])[CH:34]=[CH:33][CH:32]=2)[CH2:48][CH2:47][CH2:46][CH2:45]1
Reactant: SC1CCCC1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCCCc4cccc(I)c4)C(=O)O3)ccc2O1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN1CCCC1=O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCCCc4cccc(SC5CCCC5)c4)C(=O)O3)ccc2O1
Temperature: 60 °C

Procedure:
A stirred solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-{6-[4-(3-iodophenyl)butoxy]hexyl}-1,3-oxazolidin-2-one (1.8 g), 1,1 bis(diphenylphosphino) ferrocene (86 mg) and tris(dibenzylideneacetone) di palladium (180 mg) was stirred at room temperature in 1-methyl-2-pyrrolidinone (10 ml) and triethylamine (2 ml) for 10 min under nitrogen. Cyclopentyl mercaptan (0.63 ml) was added and the mixture was heated at 60° C. for 1 h. The mixture was cooled, poured into water and extracted into dichloromethane. The extracts were dried (Na2SO4) and evaporated. The residual oil was purified on a biotage cartridge (90 g) using ether-hexane (3:2) as eluent changing to ether. The appropriate fractions were evaporated to give the title compound (1.07 g).
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:14])[NH:6][C:7]1[O:11][N:10]=[C:9]([CH3:12])[C:8]=1[CH3:13].[S:17]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[C:24]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH:25]=[CH:26][CH:27]=2)=[CH:18]1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:12][C:9]1[C:8]([CH3:13])=[C:7]([NH:6][C:5]([N:31]2[CH2:32][CH2:33][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([C:19]4[CH:20]=[CH:21][S:17][CH:18]=4)[CH:23]=3)[CH2:29][CH2:30]2)=[O:14])[O:11][N:10]=1
Reactant: c1cc(-c2ccsc2)cc(N2CCNCC2)c1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: Cc1noc(NC(=O)N2CCN(c3cccc(-c4ccsc4)c3)CC2)c1C
Yield: 19.6 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl(3,4-dimethylisoxazol-5-yl)carbamate (129 mg, 0.450 mmol), 1-[3-(3-thienyl)phenyl]piperazine (100 mg, 0.409 mmol) and diisopropylethylamine (0.143 ml, 0.818 mmol) in dimethylsulfoxide (1.5 ml) was stirred at 70° C. for 15 hours. Water was poured into the reaction solution, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduce pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:7), and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the titled compound 30.7 mg (19.6%) as solid product.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].S(=O)(=O)(O)O.[CH3:13][O:14][C:15]([C:17]1([F:23])CC[CH2:19][CH:18]1O)=[O:16]>>[CH3:13][O:14][C:15]([C:17]1([F:23])[CH2:18][CH2:19][CH2:6][CH:5]1[O:4][C:1](=[O:3])[CH3:2])=[O:16]
Reactant: COC(=O)C1(F)CCCC1O
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: COC(=O)C1(F)CCCC1OC(C)=O
Temperature: 0 °C
Reaction time: 5 h
Yield: 73.5 %

Procedure:
0.32 g (3 mmol) of acetic anhydride and a catalytic amount of concentrated sulfuric acid were added at room temperature to 0.5 g (3 mmol) of 1-fluoro-2-hydroxycyclopentanecarboxylic acid methyl ester in cis form (compound number 2a) synthesized in Example 1, and the mixture was stirred for 5 hours. The reaction solution was poured into ice water and extracted with ethyl acetate, and the extract was successively washed with saturated saline, a saturated aqueous sodium bicarbonate solution and saturated saline. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled away to obtain 0.45 g (yield: 72%) of the objective 2-acetoxy-1-fluoro-1-cyclopentanecarboxylic acid methyl ester in cis form (compound number 3a).
Reaction SMILES: [CH2:1]([C@@:4]1([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20](=[O:26])[N:21]([CH3:25])[CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].C(BC(C(C)C)C)(C(C)C)C.C1C[O:48]CC1>>[F:33][C:30]1[CH:31]=[CH:32][C:27]([C@:4]2([CH2:1][CH2:2][CH2:3][OH:48])[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]3[CH:14]=[CH:15][C:16]([C:19]4[C:20](=[O:26])[N:21]([CH3:25])[CH:22]=[CH:23][CH:24]=4)=[CH:17][CH:18]=3)[CH3:12])[CH2:6][CH2:5]2)=[CH:28][CH:29]=1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3cccn(C)c3=O)cc2)C(=O)O1
Reactant: C1CCOC1
Agent: CC(C)C(C)BC(C)C(C)C
Product: C[C@@H](c1ccc(-c2cccn(C)c2=O)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30 %

Procedure:
A solution of (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (13.3 mg, 0.030 mmol) in dry THF (1.5 mL) was cooled to 0° C. Disiamyl borane (0.5M in THF, 500 μL, excess) was added. After 10 min, the mixture was warmed to rt and stirred for 1 h. The mixture was cooled to 0° C. again, quenched with water (1 mL) and NaBO3 (10 mg). The mixture was concentrated and purified by prep HPLC to afford (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (4.2 mg, 30% yield). LC-MS Method 1 tR=1.33 min, m/z=487(M+1); 1H NMR (CD3Cl) δ 7.47(dd, 1H), 7.38 (m, 3H), 7.24 (m, 2H), 7.07 (t, 2H), 6.96 (d, 2H), 6.39 (t, 1H), 5.65 (m, 1H), 4.26 (t, 1H), 3.66 (s, 3H), 2.91 (m, 1H), 2.40-2.14 (m, 3H), 1.54 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][NH:42][C@@H:41]([CH2:45][CH3:46])[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=3[C:28]([F:29])([F:31])[F:30])[N:8]=[CH:9]4)[C:18](=[O:25])[N:19]=2)[CH:41]([CH2:45][CH3:46])[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CCC1CN(C(=O)OC(C)(C)C)CCN1C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-3-ethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and (3S)-3-Ethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.