Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([N:13]2[CH:18]([CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:17][CH2:16][C:15](=[O:25])[CH2:14]2)=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:37](O)([OH:39])[CH3:38]>C1(C)C=CC=CC=1.ClCCl>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([N:13]2[CH:18]([CH2:19][N:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)[CH2:17][CH2:16][C:15]3([O:39][CH2:37][CH2:38][O:25]3)[CH2:14]2)=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CC(O)O
Reactant: O=C1CCC(CN2CCCC2)N(C(=O)Cc2ccc(Cl)c(Cl)c2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CC2(CCC1CN1CCCC1)OCCO2
Yield: 135.3 %

Procedure:
A mixture of the product of Example 25 (0.16 g) p-toluenesulphonic acid (0.14 g) and ethanediol (0.1 g) in dry toluene (10 ml) was heated under Dean and Starke conditions for 2 hours. The cooled reaction mixture was diluted with dichloromethane (50 ml) and the organic solution was washed with aqueous sodium carbonate solution (1M; 2×15 ml). The organic solution was dried and evaporated in vacuo. The residue was purified by flash chromatography eluting with dichloromethane/methanol/ammonia (200:8:1) to give the free base of the title compound as a gum (0.12 g). A solution of the free base in dry diethyl ether (10 ml) was treated with ethereal hydrogen chloride. The resulting precipitate was washed with diethyl ether (10 ml) to give the title compound as a solid (0.10 g) m.p. 255° dec. T.l.c. SiO2 (dichloromethane/methanol/ammonia 150:8:1) Rf 0.3.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[CH2:16]1[C@@H:20]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[S:19][S:18][CH2:17]1.[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31]O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[S:18]1[CH2:17][CH2:16][C@@H:20]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:31][CH2:30][N:29]([CH3:33])[CH3:28])=[O:26])[S:19]1
Reactant: O=C(O)CCCC[C@@H]1CCSS1
Reactant: CN(C)CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN(C)CCOC(=O)CCCC[C@@H]1CCSS1
Reaction time: 18 h
Yield: 78.8 %

Procedure:
A solution of DCC (11 g, 53 mmol) in anhydrous CH2Cl2 (20 mL) was added with stirring over 10-20 minutes to a cold (0° C.) solution of R-lipoic acid (10.0 g, 48.5 mmol), N,N-dimethylethanolamine (14.5 mL, 145 mmol, 3 eq.), and DMAP (600 mg, 4.9 mmol) in anhydrous CH2Cl2 (50 mL). Following complete addition, the cold bath was removed. After 18 hours at room temperature, all volatiles were removed under reduced pressure, and the resulting residue was purified by flash column chromatography (SiO2, 2% MeOH in CH2Cl2) providing the desired product as a clear yellow oil (10.6 g, 79%). All data consistent with values reported in the literature. (See Courvoisier C. et al. 2006. Synthesis and effects of 3-methylthiopropanoyl thiolesters of lipoic acid, methional metabolite mimics. Bioorganic Chemistry 34(1):49-58.)
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=2)[N:4]([CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[N:3]=1.[Cl-].[NH4+]>C(O)C.[Fe]>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[N:4]([CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[N:3]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)c(Br)nn2CCN1CCCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1ccc2c(c1)c(Br)nn2CCN1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.3 %

Procedure:
A mixture of 3-bromo-5-nitro-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazole (1.9 g, 5.6 mmol), iron powder (3.1 g, 56 mmol), and ammonium chloride (0.15 g, 2.8 mmol) in 80% ethanol was heated to reflux for 3 hours, cooled to room temperature and concentrated under reduced pressure. The residue was taken up and stirred in triethylamine/ethyl acetate (1/4, 20 mL) for 15 minutes, filtered through a plug of silica gel, which was rinsed with triethylamine/ethyl acetate (1/4), and the filtrate concentrated under reduced pressure to provide the title compound (1.2 g, 70%). 1H NMR (300 MHz, DMSO-d6) ppm 1.62 (m, 4H), 2.44 (m, 4H), 2.81 (t, 2H, J=6.44), 4.36 (t, J=6.44, 2H), 5.05 (s, 2H), 6.52 (m, 1H), 6.88 (m, 1H), 7.42 (m, 1H); MS (DCI/NH3) m/z 309 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][O:11][CH2:12][C:13]#[CH:14])=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].[I:17]I>CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:10][O:11][CH2:12][C:13]#[C:14][I:17])=[CH:7][CH:8]=1)#[N:2]
Reactant: C#CCOCOc1ccc(C#N)cc1
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc(OCOCC#CI)cc1
Reaction time: 3 h
Yield: 80.5 %

Procedure:
1 -Cyano-4-[(2-propynyloxy)methoxy]benzene (Intermediate II-i) (9.4 g, 0.05 mol) prepared in the above example 4 and 48% w/v aqueous sodium hydroxide solution (11.3 g) were added to methanol (75 g). Iodine (14.0 g, 0.055 mol) was then added to the solution in several portions while maintaining the inner temperature below 10° C. The reaction mixture was stirred for further 3 hours and the solvent was then evaporated off. The residue was extracted with toluene (10 ml) and the toluene layer was washed with distilled water. Toluene was then evaporated off to obtain a crude reaction product (15.3 g). The crude reaction product (15.3 g) was recrystallized from hexane (50 ml) to obtain the desired 1-cyano-4-[[(3-iodo-2-propynyl)oxy]methoxy]benzene (Derivative III-i)(12.6 g, 94% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C:3]1[C:8]([NH:9][C:10](=[O:35])[C:11]2[CH:16]=[C:15]([CH2:17][C:18]3[C:19](=[O:30])[C:20]([O:28][CH3:29])=[C:21]([O:26][CH3:27])[C:22](=[O:25])[C:23]=3[CH3:24])[CH:14]=[CH:13][C:12]=2[O:31]C(=O)C)=[CH:7][CH:6]=[CH:5][N:4]=1.C(=O)([O-])O.[Na+]>CO.O>[CH3:36][N:2]([CH3:1])[C:3]1[C:8]([NH:9][C:10](=[O:35])[C:11]2[CH:16]=[C:15]([CH2:17][C:18]3[C:19](=[O:30])[C:20]([O:28][CH3:29])=[C:21]([O:26][CH3:27])[C:22](=[O:25])[C:23]=3[CH3:24])[CH:14]=[CH:13][C:12]=2[OH:31])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cccnc3N(C)C)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3cccnc3N(C)C)c2)=C(C)C1=O
Yield: 99.7 %

Procedure:
N-(2-Dimethylaminopyridin-3-yl)-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide (0.074 g, 0.0933 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (ethyl acetate:hexane=1:1) to obtain the titled compound (0.042 g, 0.0930 mmol, 99%).
Reaction SMILES: ClC1N=C2C(C=[CH:7][C:8]([N:12]3[CH:20](OC(OC4C=CC=CC=4)=O)[C:19]4[C:14](=CC=[CH:17][CH:18]=4)[C:13]3=O)=N2)=CC=1.C(#[N:34])C>>[CH2:20]([N:12]1[CH2:8][CH2:7][NH:34][CH2:14][CH2:13]1)[CH2:19][CH2:18][CH3:17]
Reactant: O=C(Oc1ccccc1)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Reactant: CC#N
Product: CCCCN1CCNCC1

Procedure:
Following the procedure of Example 15 but starting with 2-(7-chloro-1,8-naphthyridin-2-yl)-3-phenoxycarbonyloxy-isoindolin-1-one (5.1 g.) and 1-t.-butylpiperazine (5 g.) in acetonitrile (31 cc.), 2-(7-chloro-1,8-naphthyridin-2-yl)-3-(4-t.-butylpiperazin-1-yl)carbonyloxy-isoindolin-1-one (3.3 g.), melting at 240° C., is obtained.
Reaction SMILES: [C:1]([S:5]([CH2:8][C@@H:9]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:10]([NH:12][C@@H:13]([CH2:32][C:33]1[N:34]=[CH:35][NH:36][CH:37]=1)[C:14]([NH:16][C@@H:17]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C@@H:18]([OH:24])[C@H:19]([CH:21]1[CH2:23][CH2:22]1)[OH:20])=[O:15])=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].Br[CH2:46][C:47](=[CH2:53])[C:48]([O:50][CH2:51][CH3:52])=[O:49].C(N(CC)CC)C>C(Cl)Cl>[C:1]([S:5]([CH2:8][C@@H:9]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:10]([NH:12][C@H:13]([C:14](=[O:15])[NH:16][C@@H:17]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C@@H:18]([OH:24])[C@H:19]([CH:21]1[CH2:22][CH2:23]1)[OH:20])[CH2:32][C:33]1[N:34]=[CH:35][N:36]([CH2:53][C:47](=[CH2:46])[C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH:37]=1)=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reactant: C=C(CBr)C(=O)OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(Cn1cnc(C[C@H](NC(=O)[C@H](Cc2ccccc2)CS(=O)(=O)C(C)(C)C)C(=O)N[C@@H](CC2CCCCC2)[C@@H](O)[C@@H](O)C2CC2)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 100 mg (0.16 mmol) of (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]imidazole-4-propionamide, 46 mg (0.24 mmol) of ethyl 2-(bromomethyl)acrylate and 0.044 ml (0.32 mmol) of triethylamine in 3 ml of methylene chloride is stirred at room temperature under argon for 24 hours. Subsequently, the reaction mixture is evaporated and, for purification, the residue is chromatographed on 30 g of silica gel using a 14:1:0.1 mixture of methylene chloride, methanol and ammonia as the eluent. There are obtained mg of ethyl 4-[(S)-2-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-2-[[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamoyl]ethyl]-α-methyleneimidazole-1-propionate as an amorphous solid; MS: 743 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2=[N:6][O:7][N:8]=[C:4]2[CH:3]=1.[CH2:11](O)[CH3:12]>>[CH:11]([C:2]1[CH:10]=[CH:9][C:5]2=[N:6][O:7][N:8]=[C:4]2[CH:3]=1)=[CH2:12]
Reactant: Brc1ccc2nonc2c1
Reactant: CCO
Product: C=Cc1ccc2nonc2c1

Procedure:
5-Bromo-2,1,3-benzoxadiazole (5.5 g, 27.6 mmol)), potassium vinylfluoroborate (7.40 g, 55.3 mmol), and PdCl2(dppf)-CH2Cl2Adduct (1.088 g, 1.332 mmol) were suspended in ethanol (75 ml) then added TEA (7.70 ml, 55.3 mmol). The reaction mixture was then degassed and heated to reflux for 3 hrs. The reaction was diluted with ethyl acetate and washed with brine. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. The residue was purified through a 330 g ISCO Redi-Sep silica gel plug and eluted with 20% ETOAc/hexane to yield 5-ethenyl-2,1,3-benzoxadiazole.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][CH:15]=[C:14]2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:27]=[C:28]([OH:35])[CH:29]=[CH:30][C:31]=1[N+:32]([O-:34])=[O:33].C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[CH2:1]([O:8][C:9](=[O:24])[NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][CH:15]=[C:14]2[O:35][C:28]1[CH:29]=[CH:30][C:31]([N+:32]([O-:34])=[O:33])=[C:26]([F:25])[CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: COc1cc2nccc(Cl)c2cc1NC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1cc2nccc(Oc3ccc([N+](=O)[O-])c(F)c3)c2cc1NC(=O)OCc1ccccc1
Temperature: 130 °C
Reaction time: 6 h
Yield: 8.8 %

Procedure:
(4-Chloro-7-methoxyquinolin-6-yl)carbamic acid benzyl ester (1.58 g) was added to 1-methyl-2-pyrrolidone (5 ml), and then 3-fluoro-4-nitrophenol (0.87 g) and N,N-diisopropylethylamine (1.2 ml) were added and the mixture was heated and stirred at 130° C. for 6 hours. The reaction solution was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The organic layer was concentrated and the obtained residue was subjected to NH silica gel column chromatography for elution with a solvent (ethyl acetate) to obtain the title compound (188 mg) as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.[Cu]I>[N:11]1([C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=2)[C:5]([OH:7])=[O:6])[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: c1c[nH]cn1
Reactant: O=C(O)c1ccnc(Br)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=C(O)c1ccnc(-n2ccnc2)c1
Temperature: 125 °C
Reaction time: 18 h
Yield: 108 %

Procedure:
To a solution of 2-bromoisonicotinic acid (1.87 g, 9.26 mmol), 1H-imidazole (573 mg, 8.42 mmol) and Cs2CO3 (6.03 g, 18.5 mmol) in DMSO (18.6 mL), was added CuI (176 mg, 0.926 mmol). The mixture was heated to 125° C., stirred for 18 hours, cooled to room temperature, filtered and purified by preparative HPLC (10-90% acetonitrile in water) to give the title compound as a light pink solid (1.72 g, 98%). MS 190 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:14][O:15][C@H:16]1[C@@H:21]([NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20][CH2:19][NH:18][CH2:17]1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[CH2:25]([O:24][C:23]([NH:22][C@H:21]1[CH2:20][CH2:19][N:18]([C:2]2[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:17][C@H:16]1[O:15][CH3:14])=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CO[C@@H]1CNCC[C@@H]1NC(=O)OCc1ccccc1
Reactant: COC(=O)c1cc(Br)cc(OC)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COC(=O)c1cc(OC)cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)c1
Yield: 27.5 %

Procedure:
The same operation as in Example (42a) was performed using methyl 3-bromo-5-methoxybenzoate obtained in Example (257a) (371 mg, 1.51 mmol), benzyl cis(±)-(3-methoxypiperidin-4-yl)-carbamate obtained in Example (40b) (400 mg, 1.51 mmol), palladium acetate (34 mg, 0.15 mmol), (±)-BINAP (188 mg, 0.30 mmol), cesium carbonate (1.08 g, 3.33 mmol), 1,4-dioxane (15 mL) and DMF (4.5 mL), to obtain 178 mg of the title compound as a yellow oily substance (27%).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:14][C:15]([F:29])([F:28])[C:16]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:17]=1[CH:18]=O>>[F:14][C:15]([F:28])([F:29])[C:16]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][C:17]=1[CH2:18][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: O=Cc1cc(C(F)(F)F)ccc1C(F)(F)F
Product: O=c1cc(N2CCN(Cc3cc(C(F)(F)F)ccc3C(F)(F)F)CC2)nc[nH]1

Procedure:
6-[4-(2,5-Bis-trifluoromethyl-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 2,5-bis(trifluoromethyl)benzaldehyde. Mass spectrum (ES) MH+=407.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[S:10])[NH2:9])[CH:5]=[C:4]([Cl:11])[N:3]=1.Br[CH2:13][C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16].N1C=CC=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[S:10][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:9]=2)[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)c1cc(Cl)nc(Cl)c1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CCOC(=O)c1csc(-c2cc(Cl)nc(Cl)c2)n1
Temperature: 25 °C

Procedure:
2,6-Dichloropyridine-4-thiocarboxamide (1.0 g, 4.83 mmol) was dissolved in dry 1,4-dioxane followed by adding ethyl bromopyruvate (0.9 mL, 7.24 mmol) and pyridine (0.4 mL, 4.83 mmol). The resulting mixture was heated to reflux under N2 for 5 h. After cooling to RT, solvent was removed. The residue was extracted with CHCl3. The organic layer was washed with H2O and brine, dried over MgSO4, and concentrated to give a brownish solid. This crude was purified by chromatography on silica gel. Elution with hexane:acetone (90:10) gave a title compound as yellow solid. MS m/z: 303 (M+H). Calc'd. for C11H8Cl2N2O2S-303.16.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH:18]=[O:19])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH3:22])[CH3:21])[S:14]2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si]([C:27]([F:30])([F:29])[F:28])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH:18]([OH:19])[C:27]([F:30])([F:29])[F:28])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH3:22])[CH3:21])[S:14]2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C1=N[C@@H]2C[C@H](OCc3ccccc3)[C@@H](C=O)O[C@@H]2S1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: CN(C)C1=N[C@@H]2C[C@H](OCc3ccccc3)[C@@H](C(O)C(F)(F)F)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.6 %

Procedure:
To a solution of (3aR,5S,6S,7aR)-6-(benzyloxy)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-5-carbaldehyde (0.650 g) in anhydrous THF (15 mL) at room temperature was TMSCF3 (0.750 mL, 5.08 mmol) followed by TBAF (1.0 M in THF, 0.10 mL, 0.10 mmol). The reaction was stirred at room temperature for 2 h. Another 2.50 mL of TBAF (1.0 M in THF) was added and the mixture was stirred at room temperature for 18 h. The solution was diluted with saturated aqueous NaHCO3 (30 mL), extracted with EtOAc (2×20 mL). The combined extract was dried over anhydrous Na2SO4. The solvents were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with 1%-3% 2 M NH3 MeOH solution in DCM to give 1-((3aR,5R,6S,7aR)-6-(benzyloxy)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)-2,2,2-trifluoroethanol (0.274 g, 35%) as a pale yellow foam. MS m/z 391.1 (M+1, 100%). An estimation ratio of the two diastereomers was 70:30 based on its 1H NMR (400 MHz, CDCl3) spectrum.
Reaction SMILES: [O:1]=[C:2]1[O:6][CH2:5][C:4]([C:7]([O-:9])=[O:8])=[CH:3]1.[Na+].[H][H]>O.[Pd]>[O:1]=[C:2]1[O:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3]1
Reactant: [H][H]
Reactant: O=C1C=C(C(=O)[O-])CO1
Agent: [Pd]
Agent: [Na+]
Solvent: O
Product: O=C1CC(C(=O)O)CO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.8 %

Procedure:
To a solution of sodium 5-oxo-2,5-dihydrofuran-3-carboxylate (150 mg) in water (3 ml) was added 10 wt % palladium on carbon (30 mg), and the mixture was stirred for 18 hours at room temperature under one atm. of hydrogen. Under nitrogen atmosphere, an appropriate amount of amberlite IR-120 was added to the reaction solution, the mixture was stirred at room temperature for 10 minutes, and then filtered through Celite. The filtrate was concentrated under reduced pressure, ethyl acetate was added to the resulting residue, the mixture was dried over sodium sulfate, and then again concentrated under reduced pressure to give the titled compound (83 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:7][CH:6]=[CH:5][CH2:4][O:3]1.ClC1C=C(C=CC=1)C(OO)=[O:14]>ClCCl>[CH3:1][C:2]1([CH3:8])[CH2:7][CH:6]2[CH:5]([O:14]2)[CH2:4][O:3]1
Reactant: CC1(C)CC=CCO1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(C)CC2OC2CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.4 %

Procedure:
To a solution of 2,2-dimethyl-3,6-dihydro-2H-pyran (4.0 g, 36 mmol) in dichloromethane (20 mL) was added 3-chloroperoxybenzoic acid (18.4 g, 107 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was then diluted with dichloromethane, and washed with saturated aqueous sodium sulfite and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (5.0 g, crude) as a yellow oil, which was directly used in the next step without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[OH:28][C:29]1([C:33](O)=[O:34])[CH2:32][CH2:31][CH2:30]1>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:23])([CH3:24])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:33]([C:29]3([OH:28])[CH2:32][CH2:31][CH2:30]3)=[O:34])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1NC(=O)OC(C)(C)C
Reactant: O=C(O)C1(O)CCC1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC(=O)C3(O)CCC3)ccc2F)N=C1N

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate F) and 1-hydroxy-cyclobutanecarboxylic acid followed by deprotection of the intermediate yielded the title compound as a colorless amorphous solid. MS (ESI): m/z=377.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)=[O:3].I[C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[O:24][CH2:23][CH2:22][O:21]2)=[C:16]([C:25]([F:28])([F:27])[F:26])[CH:15]=1>C1(C)C=CC=CC=1.CCO>[O:21]1[CH2:22][CH2:23][O:24][CH:20]1[C:17]1[CH:18]=[CH:19][C:14]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:2]([NH2:1])=[O:3])[CH:5]=2)=[CH:15][C:16]=1[C:25]([F:26])([F:27])[F:28]
Reactant: NC(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)c1cc(I)ccc1C1OCCO1
Solvent: Cc1ccccc1
Solvent: CCO
Product: NC(=O)c1cccc(-c2ccc(C3OCCO3)c(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared from 3-(aminocarbonyl)phenyl boronic acid and 2-[4-iodo-2-(trifluoromethyl)phenyl]-1,3-dioxolane (I-IX-7) according to the procedure described for IX-10, using PhMe/EtOH (4:1) as organic cosolvents. Colorless solid. LC/MS (method A) 2.38 min; m/z 338 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[N+:16]([O-])=O>C(O)C.O1CCCC1.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[NH2:16]
Reactant: COc1ccnc(-c2ccc(F)c([N+](=O)[O-])c2)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccnc(-c2ccc(F)c(N)c2)c1
Yield: 100.1 %

Procedure:
A suspension of 2-fluoro-5-(4-methoxypyridin-2-yl)nitrobenzene (0.2 g) in ethanol (4 ml) and tetrahydrofuran (3 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 60 mg) under a hydrogen atmosphere for 5 hours. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give 2-fluoro-5-(4-methoxypyridin-2-yl)aniline (176 mg).
Reaction SMILES: C([O:3][C:4](=[O:37])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Li+].C(O)C.Cl>O>[F:36][C:33]1[CH:32]=[CH:31][C:30]([C:27]2[CH:26]=[CH:25][C:24]([C:20]3[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]4[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:37])=[O:3])=[CH:14][CH:13]=4)[N:19]=3)=[CH:29][CH:28]=2)=[CH:35][CH:34]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccc(F)cc4)cc3)oc2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3ccc(F)cc3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1

Procedure:
To a 20 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4′-fluorobiphenyl-4-yl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (0.268 mmoles), lithium hydroxide (0.535 mmoles, 0.268 mL of a 2N solution), and ethanol (5 mL). This solution was heated to reflux for 2 h. Distilled water was added to the mixture and the pH was adjusted to 3 using a 1N HCl solution. The organic layer was extracted with ethyl acetate, washed with brine, and concentrated in-vacuo. This crude oil was resolvated in pure ethyl acetate and filtered over a pad of Celite. The filtrate was concentrated in-vacuo, and the crude oil was crystallized using acetonitrile. The crystals were collected and dried in-vacuo affording 2-(4-{2-[2-(4′-fluorobiphenyl-4-yl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid. 1H NMR (400 MHz, CDCl3) 8.02 (2H, m), 7.64 (4H, m), 7.59 (2H, m), 7.13 (2H, m), 6.89 (2H, d), 6.78 (2H, d), 4.16 (2H, t), 3.00 (2H, t) 2.39 (3H, s), 1.53 (6H, s).