Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH:2](C)[C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][C:12]([F:14])=[CH:13][C:7]=2[CH:6]=1)=O.[NH:16]1[CH2:20][CH2:19][NH:18][C:17]1=[S:21].[CH2:22](O)C>C(O)(=O)C>[BrH:1].[F:14][C:12]1[CH:11]=[CH:10][C:8]2[S:9][C:5]([C:3]3([CH3:2])[CH2:22][S:21][C:17]4=[N:18][CH2:19][CH2:20][N:16]34)=[CH:6][C:7]=2[CH:13]=1
Reactant: CCO
Reactant: CC(Br)C(=O)c1cc2cc(F)ccc2s1
Reactant: S=C1NCCN1
Solvent: CC(=O)O
Product: Br
Product: CC1(c2cc3cc(F)ccc3s2)CSC2=NCCN21

Procedure:
A mixture of 2-bromo-1-(5-fluorobenzo[b]thiophen-2-yl)propan-1-one (0.2 g), 2-imidazolidinethione (0.08 g) and ethanol (6 ml) was heated under reflux for 10 minutes. Acetic acid (3 ml) was added, the mixture was heated under reflux for 24 hours, then the solvents were removed in vacuo. Ethanol (10 ml) was added then removed in vacuo, and the residue was dried in vacuo at 60° C. to give 3-(5-fluorobenzo[b]thiophen-2-yl)-3-methyl-5,6-dihydroimidazo[2,1-b]thiazole hydrobromide (0.2 g) as an off-white solid, 1H-nmr (DMSO-d6): δH 2.43 (3H, s, —CH3), 4.22-4.51 (4H, m, —CH2CH2—), 7.36-7.44 (1H, m, ArH), 7.79 (1H, s, ArH), 7.81 (1H, dd, J 9.6 Hz, 2.5 Hz, ArH), 8.13-8.19 (1H, m ArH), 9.3-9.9 (1H, br, H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH2:15][N:16]2[C:22](=[O:23])[C:21]3[C:24]([CH3:31])=[C:25]([C:28](O)=[O:29])[CH:26]=[CH:27][C:20]=3[O:19][CH2:18][CH2:17]2)=[C:13]([CH3:32])[CH:12]=[C:11]([CH3:33])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:35][NH:36]C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][N:16]2[C:22](=[O:23])[C:21]3[C:24]([CH3:31])=[C:25]([C:28]([NH:36][CH3:35])=[O:29])[CH:26]=[CH:27][C:20]=3[O:19][CH2:18][CH2:17]2)=[C:13]([CH3:32])[CH:12]=[C:11]([CH3:33])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(CN2CCOc3ccc(C(=O)O)c(C)c3C2=O)c(OCc2ccccc2)n1
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc2c(c1C)C(=O)N(Cc1c(C)cc(C)nc1OCc1ccccc1)CCO2
Temperature: 25 °C
Reaction time: 5 h
Yield: 74445.7 %

Procedure:
To a solution of 4-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-6-methyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepine-7-carboxylic acid (130f, 0.17 g, 0.38 mmol), dimethylamine hydrochloride (47 mg, 0.57 mmol) and DIPEA (0.25 g, 1.90 mmol) in DMF (10 mL) was added HATU (0.29 g, 0.76 mmol). The mixture was stirred at room temperature under N2 for 5 hours. To the reaction mixture was added H2O (30 mL). The mixture was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (4×30 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc, 1/1) to give 4-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-N,6-dimethyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepine-7-carboxamide (130 g, 0.17 g, 94.6%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([I:11])[S:10][C:3]=12.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([F:22])[CH:16]=1)([O-:14])=[O:13].C([O-])([O-])=O.[K+].[K+]>O(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)Cl>[F:22][C:17]1[CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:20]=[CH:19][C:18]=1[O:21][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([I:11])[S:10][C:3]=12
Reactant: Clc1ccnc2cc(I)sc12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Temperature: 25 °C
Yield: 74 %

Procedure:
A mixture of the 7-chloro-2-iodothieno[3,2-b]pyridine (23) (Ragan J. A. et al, Organic Process Research and Development 2003, 7, 676-683) (7.0 g, 23.7 mmol), 2-fluoro-4-nitrophenol (3) (11.15 g, 71.1 mmol), K2CO3 (13.08 g, 94.8 mmol) in Ph2O (30 ml) was heated at 200° C. for 3 h. The reaction mixture was cooled to room temperature, diluted with DCM and filtered; the filtrate was collected and then concentrated. The resultant solid was triturated with diethyl ether, to afford intermediate 24 (7.3 g, 74% yield), which was used directly in the next step with no additional purification. MS (m/z): 417.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:49][N:50]([CH3:60])[C:51]1[CH:52]=[C:53]([CH:57]=[CH:58][CH:59]=1)[CH:54]([OH:56])[CH3:55]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38](=[O:40])[O:56][CH:54]([C:53]2[CH:57]=[CH:58][CH:59]=[C:51]([N:50]([CH3:49])[CH3:60])[CH:52]=2)[CH3:55])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(O)c1cccc(N(C)C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)OC(C)c4cccc(N(C)C)c4)cc3)c2cc1OC
Temperature: 25 °C
Yield: 47.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (78 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (120 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-dimethylamino-α-methylbenzyl alcohol (65 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (61 mg, yield 44%).
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]2[C:13]3[CH:12]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH2:11][CH2:10][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1.IC.[C:22](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)C>[CH3:22][S:1][C:2]1[O:3][C:4]2[C:13]3[CH:12]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH2:11][CH2:10][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CC(=O)NCCC1CCc2ccc3nc(S)oc3c21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CSc1nc2ccc3c(c2o1)C(CCNC(C)=O)CC3
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.5 %

Procedure:
N-[2-(2-Mercapto-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetamide (108 mg, 0.391 mmol) was dissolved in N,N-dimethylformamide (4 mL), iodomethane (48.6 μL, 0.782 mmol) and potassium carbonate (59.4 mg, 0.430 mmol) were added, and the mixture was stirred at room temperature for 15 min. The reaction solution was diluted with diethyl ether, washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=50/50→100/0) to give the title compound (81.2 mg, yield 72%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH3:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=C.C(OCC)C>C(C(C)=O)C>[CH2:8]=[CH:9][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH:2]1[C:1](=[O:7])[O:6][C:4](=[O:5])[CH:3]=1
Reactant: C=C(C)c1ccccc1
Agent: O=C1C=CC(=O)O1
Solvent: CCOCC
Solvent: CCC(C)=O
Product: C=Cc1ccccc1
Temperature: 60 °C

Procedure:
In 200 ml of methyl ethyl ketone were dissolved 18.14 g of maleic anhydride and 21.86 g of α-methylstyrene, and to the solution was added 1.82 g of azobisisobutylnitrile (AIBN). The resulting mixture was heated at 60° C. for 7 hours under nitrogen atmosphere for performing polymerization. The reaction solution was then dropwise added to 500 ml of ethyl ether under stirring to precipitate a polymer. Thus precipitated polymer was collected by filtration and purified by repeating twice the THF dissolution-ethyl ether precipitation procedure described in Example 1. Thus purified polymer was dried under vacuum at 100° C. for 24 hours to give 17.0 g of a maleic anhydride-styrene copolymer. It was confiremed by elementary analysis that the copolymerization ratio was approximately 1:1. Mn was 11,730.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH:8]=[CH:9]/[CH2:10][CH2:11][CH2:12][CH2:13]Br.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1>C(#N)C>[Br-:1].[Br-:1].[CH2:2]([N+:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1)[CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH:8]=[CH:9]/[CH2:10][CH2:11][CH2:12][CH2:13][N+:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1
Reactant: Cc1cccnc1
Reactant: BrCCCC/C=C\C=C/CCCCBr
Solvent: CC#N
Product: Cc1ccc[n+](CCCC/C=C\C=C/CCCC[n+]2cccc(C)c2)c1
Product: [Br-]

Procedure:
cis-cis-1,12-Dibromo-dodeca-5,7-diene was added to a solution of 3-picoline (3 mmol) in acetonitrile and the solution refluxed for 24 hours. The acetonitrile was removed in vacuum and the resulting residue was partitioned between ether and water. The aqueous layer was washed extensively with ether until no picoline left in the aqueous layer. The resulting aqueous solution of the product was lyophilized to yield the pure product. (76%). 1HNMR (300 MHz, D2O, ppm) 8.50 (s, 2H), 8.44 (d, J=6.3, 2H), 8.16 (d, J=7.8, 2H), 7.74 (dd, J=7.8, J=6.3, 2H), 6.15-6.18 (m, 2H), 5.38-5.38 (m, 2H), 4.38 (t, J=5.7, 4H), 2.35 (s, 6H), 2.06 (q, J=7.5, 4H), 1.83 (p, J=7.5, 4H), 1.25 (p, J=7.5, 4H). 13CNMR, 145.99, 143.71, 141.30, 139.95, 132.19, 127.46, 124.06, 61.69, 30.27, 26.35, 25.44, 17.93.
Reaction SMILES: [CH2:1]([O:4][P:5]([O:11][CH2:12][C:13]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16])([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:2]=[CH2:3].CN(C)C=O.C(Cl)(=O)C([Cl:31])=O>ClCCl>[CH2:1]([O:4][P:5]([O:11][CH2:12][C:13]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([Cl:31])=[O:16])([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOP(=O)(OCC=C)OCc1c(C)cccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCOP(=O)(OCC=C)OCc1c(C)cccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-methylbenzoic acid (880 mg, 2.70 mmol) obtained from Example 22-(5) in dichloromethane (15 ml) was cooled to 0° C., and then N,N-dimethylformamide (15 μl) and oxalyl chloride (1.71 g, 13.5 mmol) were added thereto. After the mixture was stirred at room temperature for 30 minutes, crude 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-methylbenzoyl chloride was obtained according to a similar procedure to that described in Example 1-(12).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10]O.C1C=CC(P([N:26]=[N+:27]=[N-:28])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:26]([CH2:10][C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OCc1cc2ccccc2o1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NCc1cc2ccccc2o1
Temperature: 0 °C
Reaction time: 12.5 h

Procedure:
To a stirring solution of 1.00 g (6.77 mmol) of benzofuran-2-ylmethanol in 10 mL of toluene at r.t. was added 1.7 mL (7.89 mmol) of DPPA. The solution was cooled to 0° C. and 1.2 ml (8.02 mmol) of DBU was added. The ice bath was removed, and the mixture was stirred with warming to r.t. After 12.5 h, 1N HCl was added to a pH=4, and the aqueous layer was extracted with EtOAc. The pH of the aqueous layer was then adjusted to pH=6 with saturated NaHCO3 solution, and the aqueous layer was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (5% EtOAc/hexanes) provided 2-(azidomethyl)benzofuran as a pale yellow oil in quantitative yield.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2(C)[CH2:27][O:26]2)=[CH:21][CH:20]=1.O.[CH2:30]1COCC1>CN(C=O)C.C(OCC)(=O)C>[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH:25]([N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)[CH:27]([OH:26])[CH3:30])=[CH:23][CH:24]=1
Reactant: CC1(c2ccc(F)cc2)CO1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2C(c2ccc(F)cc2)C(C)O)CCN(C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of compound 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (2.6 g, 13.1 mmol, 1 equiv.) and NaH (55%, 750 mg, 17.2 mmol, 1.3 equiv.) in 60 ml of THF was heated to 120 deg C. for 1 h. It was then cooled to RT and compound 2-(4-fluorophenyl)-2-methyloxirane (4 g, 26 mmol, 2 equiv.) in 25 ml of DMF was added dropwise for 5 mins at RT followed by heating at 120 deg C. for 2 h. It was cooled to RT and 10 ml of water was added followed by dilution with 800 ml of ethyl acetate, which was first washed with water (150 ml×3) and then brine, dried over sodium sulphate and concentrated under vacuum. Column purified over 230-400 Silica gel (flash) using 15% methanol in ethyl acetate as eluent, Yield: 3 g (66%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:12])[CH3:11])=[C:6]([C:13]#[N:14])[CH:5]=1.Cl[CH2:17]Cl.C[O:20][S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22]>C(OCC)C>[F:25][C:24]([F:27])([F:26])[S:21]([O-:23])(=[O:22])=[O:20].[C:13]([C:6]1[CH:5]=[C:4]([C:3]([O:2][CH3:1])=[O:15])[CH:9]=[CH:8][C:7]=1[N+:10]([CH3:17])([CH3:11])[CH3:12])#[N:14]
Reactant: ClCCl
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: COC(=O)c1ccc(N(C)C)c(C#N)c1
Solvent: CCOCC
Product: COC(=O)c1ccc([N+](C)(C)C)c(C#N)c1
Product: O=S(=O)([O-])C(F)(F)F
Yield: 69 %

Procedure:
To a stirred solution of 6.16 g (30.2 mmol) 2c and 110 ml dichloromethane were added 50.0 g (302 mmol) methyltriflate (Aldrich) drop wisely. The reaction mixture was stirred over night and diethylether was added. After evaporation of one third of the solvent volume the desired compound precipitates and the rest of the solvent was decanted. The solid was washed extensively (ten times) with large amounts of diethylether. The solid was dried by use of oil pump vacuum and purified by (C-18) RP-column chromatography (acetonitril/water-gradient 1:99 to 80:20). The desired compound 2d was obtained in 69% yield (20.8 mmol, 7.68 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:10](=[O:20])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1.[CH3:21][O:22][CH2:23][CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:21][O:22][CH2:23][CH2:24][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:10](=[O:20])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1
Reactant: COCCO
Reactant: Cc1cccc(C=CC(=O)c2c(O)cc(C)oc2=O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCOc1cc(C)oc(=O)c1C(=O)C=Cc1cccc(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 0.81 g of 4-hydroxy-3-[3-(3-methylphenyl)-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one, 10 ml of tetrahydrofuran, 0.25 ml of 2-methoxyethanol, and 0.87 g of triphenylphosphine was added dropwise a solution of 0.57 g of diethyl azodicarboxylate in 6 ml of tetrahydrofuran, and this was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography to obtain 389 mg of 4-(2-methoxyethoxy)-3-[3-(3-methylphenyl)-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one [Compound No. (2a-24)] as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:35])([CH2:29][N:30]1[CH:34]=[N:33][CH:32]=[N:31]1)[C@H:10]([N:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[N:26][N:25]=[N:24]3)=[CH:19][CH:18]=2)[C:13]1=[O:28])[CH3:11].[C:36]([O:40][CH2:41][Cl:42])(=[O:39])[CH2:37][CH3:38]>C(#N)C>[Cl-:42].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:35])([C@H:10]([N:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[N:26][N:25]=[N:24]3)=[CH:19][CH:18]=2)[C:13]1=[O:28])[CH3:11])[CH2:29][NH+:30]1[CH2:34][N:33]([CH2:41][O:40][C:36](=[O:39])[CH2:37][CH3:38])[CH:32]=[N:31]1
Reactant: C[C@@H](N1CCN(c2ccc(-n3cnnn3)cc2)C1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CCC(=O)OCCl
Solvent: CC#N
Product: CCC(=O)OCN1C=N[NH+](C[C@](O)(c2ccc(F)cc2F)[C@@H](C)N2CCN(c3ccc(-n4cnnn4)cc3)C2=O)C1
Product: [Cl-]
Temperature: 100 °C
Reaction time: 10 h
Yield: 4 %

Procedure:
To a mixture of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-tetrazol-1-yl)phenyl]-2-imidazolidinone (0.80 g) and chloromethyl propanate (4.07 g) was added acetonitrile (1.6 ml), and the mixture was stirred for 10 hours at 100° C. under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and to the residue was added diisopropyl ether (8 ml). The resulting powder was collected by filtration. The powder was subjected to silica gel flush chromatography (eluent: ethyl acetate→acetone→acetone/ethanol=9/1→5/1), and the fraction containing the desired compound was concentrated under reduced pressure. The residue was subjected to ODS column chromatography (eluent: methanol/water=3/2). The eluate was concentrated in vacuo, and the residue was dissolved in water (10 ml). The solution was lyophilized to give 1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl]-1-imidazolidinyl]butyl]-4-propanoyloxymethyl-1H-1,2,4-triazolium chloride (Compound 14, 0.04 g) as a white powder.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([CH:23]2[C:31](=[O:32])[CH:30]3[CH:25]([CH:26]4[O:33][CH:29]3[CH:28]=[CH:27]4)[C:24]2=[O:34])=[C:18]([CH3:35])[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:36][C:37]([CH3:42])([CH3:41])[C:38](Cl)=[O:39]>ClCCl>[CH3:36][C:37]([CH3:42])([CH3:41])[C:38]([O:32][C:31]1[CH:30]2[CH:25]([C:24](=[O:34])[C:23]=1[C:19]1[C:18]([CH3:35])=[CH:17][C:16]([O:15][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:21][C:20]=1[CH3:22])[CH:26]1[O:33][CH:29]2[CH:28]=[CH:27]1)=[O:39]
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1C1C(=O)C2C3C=CC(O3)C2C1=O
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(OCc2ccccc2)cc(C)c1C1=C(OC(=O)C(C)(C)C)C2C3C=CC(O3)C2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (5 ml, 35.9 mmol) is added, dropwise, to a solution of 4-(4-benzyloxy-2,6-dimethylphenyl)-10-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (5.0 g, 13.4 mmol) and trimethylacetyl chloride (5 ml, 40.6 mmol) in dry dichloromethane (75 ml). The mixture is stirred for 2 hours at room temperature, then silica gel is added and the solvent is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give rac-(1R,2S,6R,7S)-4-(4-benzyloxy-2,6-dimethylphenyl)-5-oxo-10-oxatricyclo[5.2.1.02,6]deca-3,8-dien-3-yl 2,2-dimethylpropionate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:23]=3[CH2:22][C:21](=[O:24])[CH2:20][CH2:19]4)=[N:10][CH:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C1C=CC(C2OC(NC3C=CC=C4C=3CC(=O)CC4)=NC=2)=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:23]=3[CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]4)=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCc2cccc(Nc3ncc(-c4ccc(Br)cc4)o3)c2C1
Agent: O=C1CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Product: OC1CCc2cccc(Nc3ncc(-c4ccc(Br)cc4)o3)c2C1

Procedure:
The title compound was prepared using the procedure as described in Example 2, substituting the product of Example 8C for the product of Example 1I. 1H NMR (DMSO-d6) 69.17 (s, 1H), 7.43-7.57 (m, 6H), 7.10 (t, 1H, J=7.3 Hz), 6.81 (d, 1H, J=6.8 Hz), 4.80 (d, 1H, J=3.9 Hz), 3.90 (m, 1H), 2.68-2.96 (m, 4H), 1.82 (m, 1H), 1.60 (m, 1H); MS (ESI+) m/z 385/387 (M+H, 79Br/81Br).
Reaction SMILES: C([Si]([O:8]/[C:9](/[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)=[CH:10]\[CH3:11])(C)C)(C)(C)C.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:43]C)C=C4)N(CC2)C1.CS(N)(=O)=O>C(O)(C)(C)C.O>[OH:43][C@H:10]([CH3:11])[C:9]([C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)=[O:8]
Reactant: C/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc2ccccc12
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: CS(N)(=O)=O
Solvent: CC(C)(C)O
Solvent: O
Product: C[C@@H](O)C(=O)c1cccc2ccccc12
Yield: 38.3 %

Procedure:
Compound 10h was synthesized by a procedure similar to that described for (R)-10a using (Z)-tert-butyl(1-(naphthalen-1-yl)prop-1-enyloxy)dimethylsilane, (9h, 4.58 g, 0.015 mol), AD-mix-β (21.4 g), and CH3SO2NH2 (1.5 g, 0.0158 mol) in tert-butyl alcohol-water (60 mL:60 mL). The reaction was quenched with sodium sulfite (15.3 g). After purification by column chromatography on silica gel, 1.15 g (38%) of the title product was isolated plus 2.1 g of starting olefin was recovered, raising the effective yield to 70%: [α]20D +140.2° (c 3.2, CHCl3); 1H NMR (CDCl3) δ 8.51-8.46 (m, 1H), 8.04 (d, 1H, J=8.3 Hz), 7.93-7.87 (m, 1H), 7.80-7.75 (m, 1H), 7.66-7.48 (m, 3H), 5.30-5.17 (m, 1H), 3.96 (d, 111, J=5.8 Hz), 1.36 (d, 3H, J=7.1 Hz); 13C NMR (CDCl3) δ 205.7, 134.1, 133.5, 132.5, 130.7, 128.7, 128.4, 127.7, 126.9, 125.5, 124.4, 71.2, 21.3; LCMS (ESI) m/z 201.2 [(M+H)+, M=C13H12O2].
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].[CH3:23][N:24]1[C:28]([CH2:29][NH2:30])=[CH:27][N:26]=[CH:25]1>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH:18][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:30][CH2:29][C:28]3[N:24]([CH3:23])[CH:25]=[N:26][CH:27]=3)[CH:8]=2)[N:3]=1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: Cn1cncc1CN
Reactant: COc1ccccc1CN
Product: COc1ccccc1CNc1ccc2cc(NCc3cncn3C)ccc2n1

Procedure:
The title compound, MS: m/e=374.1 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-methoxybenzylamine and (1-methyl-1H-imidazol-5-yl)methylamine.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:25])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14](=[O:24])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)[CH:7]=1.CO.O1CCCC1>O>[C:22]([C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:14]([CH2:13][O:12][C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[C:5]([OH:25])=[O:4])=[O:24])=[CH:21][CH:20]=1)#[N:23]
Reactant: COC(=O)c1cccc(OCC(=O)Nc2ccc(C#N)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1ccc(NC(=O)COc2cccc(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 60.8 %

Procedure:
Add lithium hydroxide (0.10 g, 4.18 mmol) to a suspension of 3-[(4-cyano-phenylcarbamoyl)-methoxy]-benzoic acid methyl ester (0.50 g, 1.61 mmol) in a 1:1:1 mixture of water: MeOH: tetrahydrofuran. Stir the mixture at room temperature for 36 h then dilute with water and wash with EtOAc. Adjust the pH of the aqueous phase by the addition of a 1 N solution of hydrochloric acid. Extract the mixture with EtOAc and dry the combined organic phase over anhydrous sodium sulfate. Concentrate under reduced pressure to provide 0.290 g of 3-[(4-cyano-phenylcarbamoyl)-methoxy]-benzoic acid as a solid.