Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][SiH:3]([O:6][CH3:7])[O:4][CH3:5].C(O)(=O)C.[CH3:12][O:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25]>O1CCCC1>[CH3:12][O:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][Si:3]([O:6][CH3:7])([O:4][CH3:5])[O:2][CH3:1]
Reactant: CO[SiH](OC)OC
Reactant: C=CCCCCCCCCOCOC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COCOCCCCCCCCCC[Si](OC)(OC)OC
Temperature: 80 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
Under a nitrogen atmosphere, 64 g of trimethoxysilane and 0.57 g of acetic acid were dropped in a mixture of 100 g of 10-(methoxymethoxy)-1-decene and a catalytic amount of a solution of platinate chloride in tetrahydrofuran at 80° C. The reaction mixture was stirred at 80° C. for 3 hours, and distilled under reduced pressure to yield 131 g of a target compound.
Reaction SMILES: [Na].[C:2]([O:9][CH2:10][CH3:11])(=[O:8])[C:3]([O:5]CC)=O.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:14]=1[C:21](=[O:25])[CH2:22][CH2:23][CH3:24]>CCO>[CH2:23]([CH:22]([C:21](=[O:25])[C:14]1[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=1[CH3:12])[C:3](=[O:5])[C:2]([O:9][CH2:10][CH3:11])=[O:8])[CH3:24]
Reactant: CCCC(=O)c1c(C)cc(C)cc1C
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)C(CC)C(=O)c1c(C)cc(C)cc1C
Temperature: 50 °C
Yield: 53.2 %

Procedure:
Sodium (1.0 g, 42.1 mmol, spheres ) was cautiously added to 25 mL of absolute EtOH with stirring. After the sodium had dissolved, diethyl oxalate (6.0 g, 42.1 mmol) was added dropwise to the resulting solution at 0° C., followed by addition of a solution of 2',4',6'-trimethylbutyrophenone (8 g, 42.1 mmol) in 5 mL of absolute EtOH. The reaction mixture was slowly warmed to 50° C. and stirred overnight. The solvent was then evaporated. The resulting residue was washed with hexane, diluted with water, acidified with 1 N HCl, and then extracted with ether. The extracts were washed with brine, dried over Na2SO4 and concentrated to give 6.5 g of an oil which was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[O:33][C:34](=[O:38])[O:35][C:36]=1[CH3:37].CCOC(C)=O>CN(C=O)C>[CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([O:23][CH2:31][C:32]2[O:33][C:34](=[O:38])[O:35][C:36]=2[CH3:37])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: Cc1oc(=O)oc1CBr
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OCc2oc(=O)oc2C)o1
Reaction time: 14 h

Procedure:
To a stirred, room temperature solution of 5-(tetradecyloxy)furan-2-carboxylic acid (0.228 g, 0.70 mmol) in DMF (4 mL) was added potassium carbonate (0.146 g, 1.05 mmol) and 4-(bromomethyl)-5-methyl-1,3-dioxol-2-one (0.160 g, 0.84 mmol). The reaction vessel was capped and stirring was continued for 14 hrs at which time TLC ((20% EtOAc in Hexanes Rf=0.10 (SM) and 0.40 (Prod)) indicated complete consumption of the starting material. The reaction was quenched by the addition of water (5 mL), brine (5 mL) and EtOAc (30 mL). The biphasic mixture was transferred to a seperatory funnel and the organic phase was extracted 3 times with brine (3×10 mL). The organic phase was dried and concentrated to give a colourless oil. The resulting crude material was purified by flash chromatography eluting with 5-20% EtOAc in hexanes to yield a colourless syrup that solidified on standing. 1H NMR (400 MHz, DMSO-d6) δ: 7.2 (d, 1H), 5.6 (d, 1H), 5.1 (s, 2H), 4.1 (t, 2H), 2.18 (s, 3H), 1.6-1.8 (m, 2H), 1.3-1.4 (m, 2H), 1.23 (d, 6H), 1.2 (s, 20H), 0.85 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([OH:29])=O)[CH2:10]2)=[CH:5][CH:4]=1.[CH3:32][CH:33]1[CH2:38][NH:37][CH2:36][CH2:35][N:34]1[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][CH:44]=1)=[O:40]>>[CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=3)=[O:15])[C@H:11]([C:27]([N:37]3[CH2:36][CH2:35][N:34]([C:39]([O:41][CH2:42][C:43]4[CH:44]=[CH:45][C:46]([N+:49]([O-:51])=[O:50])=[CH:47][CH:48]=4)=[O:40])[CH:33]([CH3:32])[CH2:38]3)=[O:29])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CC1CNCCN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C(C)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Yield: 83.9 %

Procedure:
Following a procedure similar to that described in Preparation 1(i), but using 3.06 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid, 1.34 g of N,N'-carbonyldiimidazole and 2.30 g of 2-methyl-1-(4-nitrobenzyloxycarbonyl)piperazine, 4.07 g of the title compound were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([NH2:22])[CH2:13][C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]([N:26]1[CH:30]=[C:29]([CH2:31][CH2:32]OS(C)(=O)=O)[CH:28]=[N:27]1)([CH3:25])[CH3:24]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([NH:22][CH2:32][CH2:31][C:29]3[CH:28]=[N:27][N:26]([CH:23]([CH3:25])[CH3:24])[CH:30]=3)[CH2:13][C:12]2=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)n1cc(CCOS(C)(=O)=O)cn1
Reactant: NC1CCc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Product: CC(C)n1cc(CCNC2CCc3[nH]c4ccc(OCc5ccccc5)cc4c3C2)cn1
Yield: 63.4 %

Procedure:
Beginning with 0.698 gm (2.39 mMol) 6-benzyloxy-3-amino-1,2,3,4-tetrahydro-9H-carbazole and 0.787 gm (3.39 mMol) 2-(1-isopropyl-1H-pyrazol-4-yl)-1-mesyloxyethane, 0.649 gm (63.4%) of the desired compound were prepared by the procedure described in detail in EXAMPLE B-72.
Reaction SMILES: CC([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Se:15][CH3:16])(=[O:8])=[O:7])(C)C>FC(F)(F)C(O)=O>[CH3:16][Se:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[S:6]([NH2:5])(=[O:8])=[O:7]
Reactant: C[Se]c1ccccc1S(=O)(=O)NC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: C[Se]c1ccccc1S(N)(=O)=O
Yield: 81712.1 %

Procedure:
Under nitrogen a solution of N-(1,1-dimethylethyl)-2-(methylselenyl)benzenesulfonamide (34.5 g, 0.113 mmol) in trifluoroacetic acid (100 mL) was stirred at room temperature overnight. The solvent was then rotary evaporated to leave an amber solid. This was again treated with trifluoroacetic acid (100 mL) at room temperature overnight. The mixture was concentrated in vacuo, then poured into ice-water. The solid was collected, rinsed with ice-water, and dried in vacuo. The crude product was recrystallized from hot benzene (5 mL/g), collected at room temperature, rinsed with benzene and hexanes, and dried. The 2-(methylselenyl)benzenesulfonamide (23.1 g) obtained melted at 119°-121° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].Cl[CH:11]([CH3:15])[C:12]([OH:14])=[O:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH:11]([C:12]([OH:14])=[O:13])[CH3:15])[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: CC(Cl)C(=O)O
Product: CC(Nc1cc(Cl)cc(Cl)c1)C(=O)O

Procedure:
Using the procedure set forth in U.S. Pat. No. 3,598,859 (or Example A above), N-(3,5-dichlorophenyl)-D,L-alanine was prepared using 3,5-dichloroaniline (Aldrich) and 2-chloropropionic acid (Aldrich).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].CCN(CC)CC.[O:19](S(C(F)(F)F)(=O)=O)[S:20]([C:23]([F:26])([F:25])[F:24])(=O)=[O:21]>C(Cl)Cl>[F:24][C:23]([F:26])([F:25])[S:20]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11])(=[O:21])=[O:19]
Reactant: COc1cc(C=O)ccc1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C=O)ccc1OS(=O)(=O)C(F)(F)F
Reaction time: 1 h
Yield: 91 %

Procedure:
To a mixture of 4-hydroxy-3-methoxybenzaldehyde (10.0 g, 65.7 mmol) and Et3N (13.0 g, 128.7 mmol) in anhydrous DCM (100 mL) was added Tf2O (28.0 g, 99.2 mmol) dropwise at room temperature and the reaction was stirred for 1 hour. The resulting mixture was quenched with water (100 mL) followed by a standard aqueous/EtOAc workup. The residue was purified by silica gel column chromatography (PE:EtOAc=20:1) to give the product as a colorless oil (17.0 g, yield 91%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][NH:12][C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[C:17]1[CH:18]=[N:19][CH:20]=[C:21]([Cl:24])[C:22]=1[CH3:23].N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:17]4[CH:18]=[N:19][CH:20]=[C:21]([Cl:24])[C:22]=4[CH3:23])[C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Cc1c(Cl)cncc1Br
Reactant: O=C1NCCN1c1ccc2ncsc2c1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1c(Cl)cncc1N1CCN(c2ccc3ncsc3c2)C1=O
Yield: 33.1 %

Procedure:
Using the same reaction conditions as in Example 14, 1-benzothiazol-6-yl-imidazolidin-2-one (I-84b: 100 mg, 0.456 mmol) was reacted with 3-bromo-5-chloro-4-methyl-pyridine (94 mg, 0.456 mmol), 1,4-dioxane (5 mL), copper iodide (8.68 mg, 0.0456 mmol), trans-1,2-diamino cyclohexane (15.66 mg, 0.1368 mmol) and potassium phosphate (290.38 mg, 1.368 mmol) to afford the crude product. Purification by preparative HPLC afforded 52 mg of the product (34.21% yield).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH2:13]O)[N:10]=[C:9]2[S:15][CH3:16])=[CH:4][CH:3]=1.C1(P([N:31]=[N+:32]=[N-:33])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1.O>O1CCOCC1.CCOC(C)=O>[N:31]([CH2:13][C:11]1[N:10]=[C:9]([S:15][CH3:16])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)[CH:12]=1)=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CSc1nc(CO)cn1-c1ccc(I)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: CSc1nc(CN=[N+]=[N-])cn1-c1ccc(I)cc1
Temperature: 110 °C
Yield: 89 %

Procedure:
To a solution of (1-(4-iodophenyl)-2-(methylthio)-1H-imidazol-4-yl)methanol (0.41 g, 1.18 mmol) in anhydrous dioxane (10 mL), diphenylphosphoryl azide (0.80 mL, 3.71 mmol) and DBU (0.600 mL, 4.02 mmol) were added. The mixture in a sealed tube was heated at 110° C. for 3 h. After being cooled down, H2O and EtOAc were added. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel column, eluted with EtOAc in hexane (0-20% EtOAc) to give 4-(azidomethyl)-1-(4-iodophenyl)-2-(methylthio)-1H-imidazole (0.39 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:33])[CH2:14][C:15]([S:29]C(=O)C)([C:20]2[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[C:22]([Cl:28])[CH:21]=2)[C:16]([F:19])([F:18])[F:17])=[CH:9][C:8]=1[CH3:34])([CH3:4])([CH3:3])[CH3:2]>NC1C=CC=CC=1>[C:1]([O:5][C:6](=[O:35])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:33])[CH2:14][C:15]([SH:29])([C:20]2[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[C:22]([Cl:28])[CH:21]=2)[C:16]([F:17])([F:18])[F:19])=[CH:9][C:8]=1[CH3:34])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)SC(CC(=O)c1ccc(C(=O)OC(C)(C)C)c(C)c1)(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Solvent: Nc1ccccc1
Product: Cc1cc(C(=O)CC(S)(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Yield: 77.1 %

Procedure:
A solution of 4-[3-Acetylsulfanyl-4,4,4-trifluoro-3-(3,4,5-trichloro-phenyl)-butyryl]-2-methyl-benzoic acid tert-butyl ester (1.33 g) in aniline (13 mL) was stirred at room temperature for 3 hours. The mixture was quenched with a solution of hydrochloric acid (1N), extracted with ethyl acetate and washed with brine. The collected organic phases were dried over magnesium sulfate, filtered and the filtrate was evaporated under vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane/dichloromethane) to give 2-Methyl-4-[4,4,4-trifluoro-3-mercapto-3-(3,4,5-trichloro-phenyl)-butyryl]-benzoic acid tert-butyl ester (950 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:20]3[CH:35]=[CH:34][C:23]([O:24][CH2:25][C@@H:26]([N:28]4[CH2:32][CH2:31][C@@H:30]([CH3:33])[CH2:29]4)[CH3:27])=[CH:22][CH:21]=3)=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH2:9]2)=[CH:5][CH:4]=1.C(OCC)(=O)C>[Pd].C(O)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6](=[CH:5][CH:4]=1)[CH:7]([C:20]1[CH:21]=[CH:22][C:23]([O:24][CH2:25][C@@H:26]([N:28]3[CH2:32][CH2:31][C@@H:30]([CH3:33])[CH2:29]3)[CH3:27])=[CH:34][CH:35]=1)[CH:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:9]2
Reactant: COc1ccc(C2=C(c3ccc(OC[C@H](C)N4CC[C@@H](C)C4)cc3)c3ccc(OC)cc3C2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(C2Cc3cc(OC)ccc3C2c2ccc(OC[C@H](C)N3CC[C@@H](C)C3)cc2)cc1
Reaction time: 25 h
Yield: 85.6 %

Procedure:
A mixture of (R)-1-((S)-1-(4-(6-methoxy-2-(4-methoxyphenyl)-1H-inden-3-yl)phenoxy)propan-2-yl)-3-methylpyrrolidine (400 mg, 0.85 mmol), 10% Pd/C (350 mg, 0.33 mmol), ethyl acetate (8 mL), and ethanol (8 mL) was shaken at 65 psi of H2 for 25 h. The sides of the reaction vessel were rinsed (4 mL, 1:1 EtOAc/EtOH), and the mixture was shaken at 65 psi of H2 for an additional 22.5 h. The reaction was filtered through Celite. The Celite was washed (200 mL, 1:1 EtOAc/EtOH), and the filtrate was concentrated and purified by silica gel chromatography (1:0→17:3; dichloromethane:methanol) to give 343 mg of (3R)-1-((2S)-1-(4-(5-methoxy-2-(4-methoxyphenyl)-2,3-dihydro-1H-inden-1-yl)phenoxy)propan-2-yl)-3-methylpyrrolidine: 1H NMR (400 MHz, DMSO-d6): δ 6.99 (d, 1H), 6.92 (d, 1H), 6.80 (d, 2H), 6.74 (dd, 1H), 6.66-6.57 (m, 4H), 6.50 (d, 2H), 4.51 (d, 1H), 3.96-3.87 (m, 2H), 3.77 (s, 3H), 3.63 (s, 3H), 3.70-3.60 (br, 1H), 3.26 (dd, 1H), 3.12 (dd, 1H), 2.81 (br, 1H), 2.70-2.50 (br, 3H), 2.07 (br, 2H), 1.88 (br, 1H), 1.24 (br, 1H), 1.07 (br d, 3H), 0.96 (d, 3H); LCMS: 472.8 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]2[C:4]=1[C@@:5]1([CH3:26])[C@H:10]([CH2:11]2)[C@@:9]2([CH3:25])[CH2:18][CH2:19][C@H:20]([OH:24])[C:21]([CH3:23])([CH3:22])[C@@H:8]2[CH2:7][CH2:6]1.N1C=CC=CC=1.CN(C1C=CC=CN=1)C.[CH3:42][O:43][C@:44]([C:54]([F:57])([F:56])[F:55])([C:51](Cl)=[O:52])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(Cl)Cl>[F:55][C:54]([F:56])([F:57])[C@:44]([O:43][CH3:42])([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:51]([O:24][C@H:20]1[CH2:19][CH2:18][C@:9]2([CH3:25])[C@@H:10]3[C@@:5]([CH3:26])([CH2:6][CH2:7][C@H:8]2[C:21]1([CH3:22])[CH3:23])[C:4]1[C:12](=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=1[O:2][CH3:1])[CH2:11]3)=[O:52]
Reactant: CO[C@](C(=O)Cl)(c1ccccc1)C(F)(F)F
Reactant: COc1cc2c(c(OC)c1)[C@]1(C)CC[C@H]3C(C)(C)[C@@H](O)CC[C@]3(C)[C@H]1C2
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc2c(c(OC)c1)[C@]1(C)CC[C@H]3C(C)(C)[C@@H](OC(=O)[C@@](OC)(c4ccccc4)C(F)(F)F)CC[C@]3(C)[C@H]1C2
Temperature: 25 °C

Procedure:
Alcohol 5b (219 mg, 0.610 mmol) was dissolved in 4 mL of methylene chloride (DCM). To this mixture was added pyridine (0.074 mL, 0.92 mmol) and dimethylaminopyridine (DMAP) (7.4 mg, 0.061 mmol), and the mixture was taken to 0° C. To this mixture was added (R)-(−)-MTPA-Cl (170 mg, 0.671 mmol), and the mixture was allowed to warm to room temperature overnight. The reaction was quenched with saturated aqueous NH4Cl (50 mL), and the aqueous layer was extracted 3 times with methylene chloride (3×50 mL). The organic extracts were combined and dried with MgSO4 and concentrated. A 1H NMR (400 MHz) spectrum of the crude mixture showed the absence of diastereomers, meaning that alcohol 5b was enantiomerically pure after crystallization. The product mixture was then purified using flash chromatography (hexanes:ethyl acetate 12:1) to give 10b quantitatively. 1H NMR (400 MHz, CDCl3) δ 7.54 (m, 2H), 7.41 (m, 3H), 6.40 (d, J=1.8 Hz, 1H), 6.26 (d, J=1.9 Hz, 1H), 4.72 (dd, J=12, 4.9 Hz, 1H), 3.77 (s, 3H), 3.75 (s, 3H), 3.54 (s, 3H), 2.62 (m, 1H), 2.51 (dd, J=14, 6.2 Hz, 1H), 2.46 (dd, J=8.4, 2.9 Hz, 1H), 1.85-1.76 (m, 1H), 1.74-1.67 (m, 3H), 1.65-1.57 (m, 3H), 1.23 (td, J=13, 4.2 Hz, 1H), 1.07 (s, 3H), 1.04 (s, 3H), 1.04 (m, 1H), 0.92 (s, 3H), 0.87 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.3, 159.5, 155.8, 144.7, 133.2, 132.3, 129.5, 128.3 (2C), 127.6 (2C), 124.9, 122.0, 101.9, 96.9, 84.5, 64.2, 56.2, 55.4, 55.3, 55.1, 46.1, 38.1, 38.0, 37.9, 36.5, 29.5, 28.1, 23.0, 20.3, 19.0, 16.2, 16.1. ESIMS [M+Na]+ calcd for C33H41O5F3Na 597.2804, found 597.2814. [α]24D=−31.76°.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8](O)=[O:9])[S:5][C:4]2[S:11][CH:12]=[CH:13][C:3]1=2.[C:14](N1C=CN=C1)([N:16]1C=CN=[CH:17]1)=O>O1CCCC1>[CH3:14][N:16]([CH3:17])[C:8]([C:6]1[S:5][C:4]2[S:11][CH:12]=[CH:13][C:3]=2[C:2](=[O:1])[CH:7]=1)=[O:9]
Reactant: O=C(O)c1cc(=O)c2ccsc2s1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc(=O)c2ccsc2s1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
Under a nitrogen atmosphere, to a stirred solution of 4-oxo-4H-thieno[2,3-b]thiopyran-6-carboxylic acid (10.7 g, 0.05 mol) in tetrahydrofuran (50 ml) was added carbonyldiimidazole (8.9 g, 0.055 mol). The mixture was stirred at ambient temperature for 3/4 hour. Anhydrous dimethylamine was bubbled into the thick suspension at 0° C. until an excess was present. The resulting solution was stirred at 0° C. for 3/4 hour and the solvent was removed in vacuo. The residual oil was diluted with H2O (50 ml) and the solid which separated was filtered and dried to give 7.14 g of product, m.p. 126.5°-128 of 97% purity by HPLC. The aqueous filtrate was concentrated in vacuo and the residual gum was chromatographed on silica gel (200 g) using 10% methanol in chloroform. An additional 3.15 g of impure product was recovered. Yield was about 80%.
Reaction SMILES: [C:1]([C@@H:4]([CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[C@@H:5]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:6]([NH:8][N:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:10]([CH3:13])(=[O:12])=[O:11])=[O:7])([OH:3])=[O:2].C1([C@H](C(=O)NOC2CCCCO2)[C@@H](CC(C)C)C(NN(CC(C)C)S(C)(=O)=O)=O)CCCC1>>[C:1]([C@@H:4]([CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26]1)[C@@H:5]([CH:18]=[C:19]([CH3:21])[CH3:20])[C:6]([NH:8][N:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:10]([CH3:13])(=[O:11])=[O:12])=[O:7])([OH:3])=[O:2]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)S(C)(=O)=O)[C@@H](C(=O)O)C1CCCC1
Agent: CC(C)C[C@@H](C(=O)NN(CC(C)C)S(C)(=O)=O)[C@@H](C(=O)NOC1CCCCO1)C1CCCC1
Product: CC(C)=C[C@@H](C(=O)NN(CC(C)C)S(C)(=O)=O)[C@@H](C(=O)O)C1CCCC1

Procedure:
In an analogous manner to that described in Example 2, part (v), starting from 0.91 g of a mixture of 2(R)-[(S)-(carboxy)(cyclopentyl)methyl]-2′-isobutyl-2′-(methanesulphonyl)-4-methylvalerohydrazide and 2(R)-[(S)-(carboxy)(cyclopentyl)methyl]-2′-isobutyl-2′-(methanesulphonyl)-4-methyl-3-pentenohydrazide there was obtained 0.357 g of a mixture of 2(R)-[(S)-(cyclopentyl)[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]methyl]-2′-isobutyl-2′-(methanesulphonyl)-4-methylvalerohydrazide and 2(R)-[(S)-(cyclopentyl)[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]methyl]-2′-isobutyl-2′-2′-(methanesulphonyl)-4-methyl-3-pentenohydrazide in the form of a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([O:12][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-2-methylpropionic acid (4.06 g) in N,N-dimethylformamide (40 mL) were added potassium carbonate (4.15 g) and benzyl bromide (2.85 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethylacetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue (solid) was treated with n-hexane and collected by filtration. The crystals were dried under reduced pressure to give benzyl 2-(tert-butoxycarbonylamino)-2-methylpropionate (4.44 g). To the obtained benzyl 2-(tert-butoxycarbonylamino)-2-methylpropionate (4.44 g) was added 4 mol/L hydrochloric acid (1,4-dioxane solution, 15 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with diethyl ether, and the mixture was stirred for 1 hour. The insoluble material was collected by filtration, washed with diethyl ether and dried under reduced pressure to give the title compound (3.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].[OH-].[Na+].Cl.[NH:19]1[CH2:24][CH2:23][C:22](O)([OH:25])[CH2:21][CH2:20]1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:19]2[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]2)=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13]
Reactant: OC1(O)CCNCC1
Reactant: COc1ccc(C(=O)Cl)cc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)N2CCC(=O)CC2)cc1C(F)(F)F
Yield: 91.7 %

Procedure:
A solution of 4-methoxy-3-(trifluoromethyl)benzoyl chloride (4.00 g, 16.8 mmol) in toluene (16 mL) and a solution of NaOH (3.8 mL of 4.0 M, 15 mmol) were contemporaneously added drop-wise to a solution of piperidine-4,4-diol hydrochloride (2.30 g, 15.2 mmol) in NaOH (7.6 mL of 2.0 M, 15 mmol) at 25° C. The mixture was stirred for 90 min before the toluene was removed in vacuo. The alkaline phase was extracted with dichloromethane (3 times). The organics were combined, washed with brine, dried over Na2SO4, and concentrated in vacuo to provide 1-(4-methoxy-3-(trifluoromethyl)benzoyl)piperidin-4-one (4.2 g, 91%). ESI-MS m/z calc. 301.3, found 302.2 (M+1)+. Retention time: 0.95 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J=1.9 Hz, 1H), 7.70 (dd, J=8.6, 2.1 Hz, 1H), 7.09 (d, J=8.6 Hz, 1H), 3.98 (s, 3H), 3.94 (s, 4H), 2.55 (s, 4H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][C:10](=[O:13])[NH:11][CH2:12][C:6]=2[CH:5]=1.[CH3:16]I>CN(C)C=O>[CH3:16][N:11]1[C:10](=[O:13])[CH2:9][CH2:8][C:7]2[CH:14]=[CH:15][C:4]([CH3:3])=[CH:5][C:6]=2[CH2:12]1
Reactant: CI
Reactant: Cc1ccc2c(c1)CNC(=O)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)CN(C)C(=O)CC2
Temperature: 80 °C
Yield: 55 %

Procedure:
0.023 moles of sodium hydride is added slowly, while stirring, to a solution of 2.0 g. (0.011 moles) of 8-methyl-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one in 60 ml. of dimethylformamide, followed by heating at 80° C. for 80 minutes. The reaction mixture is cooled in an ice bath and 6.5 g. (0.046 moles) of methyl iodide added dropwise, the rate of addition being regulated so as to maintain the temperature of the reaction mixture at about 10° C. When the addition is complete, the temperature is raised slowly to 60° C. and then maintained at this level for 3 hours. The reaction mixture is evaporated to dryness in vacuo and the solid residue is extracted with chloroform. The organic solution is washed twice with water, dried over anhydrous sodium sulfate, filtered and then evaporated to dried over anhydrous sodium sulfate, filtered and then evaporated to dryness in vacuo. The solid residue is taken up in diisopropyl ether, filtered over active carbon and recrystallized from diisopropyl ether. 2,8-Dimethyl-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one is obtained in a yield of 55% of theory. M.P. 75°-76° C.