Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:4]1[C@@:9]([CH2:20][F:21])([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[F:19])[N:8]=[C:7]([N:22]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:6]([CH3:38])([CH3:37])[S:5]1(=[O:40])=[O:39])[CH:2]=[CH2:3].C(=O)(O)[O-:42].[Na+].O=O.[BH4-].[Na+]>C(Cl)Cl.CO>[C:25]([O:24][C:23]([N:22]([C:7]1[C:6]([CH3:38])([CH3:37])[S:5](=[O:39])(=[O:40])[CH:4]([CH2:1][CH2:2][CH2:3][OH:42])[C@@:9]([CH2:20][F:21])([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[F:19])[N:8]=1)[C:30](=[O:31])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:29])([CH3:28])([CH3:27])[CH3:26]
Reactant: O=C([O-])O
Reactant: C=CCC1[C@@](CF)(c2cc([N+](=O)[O-])ccc2F)N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(C)(C)S1(=O)=O
Agent: O=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@](CF)(c2cc([N+](=O)[O-])ccc2F)C(CCCO)S(=O)(=O)C1(C)C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl N-[(3S)-2-allyl-3-(fluoromethyl)-3-(2-fluoro-5-nitro-phenyl)-6,6-dimethyl-1,1-dioxo-2H-1,4-thiazin-5-yl]-N-tert-butoxycarbonyl-carbamate (1.95 g, 3.33 mmol) in DCM (60 mL) and MeOH (20 mL) was added sodium bicarbonate (0.56 g, 6.65 mmol). The reaction mixture was cooled to −78° C. and ozonolized for about 15 min or until analysis showed no starting material present. A stream of oxygen was passed through the solution for 5 min, and then solid sodium borohydride (252 mg, 6.65 mmol) was added to the mixture. The flask was removed from the bath and allowed to reach RT and stirred for 1 h. The reaction was quenched with satd. aqueous NH4Cl, diluted with water to dissolve solids, and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give tert-butyl N-tert-butoxycarbonyl-N-[(3S)-3-(fluoromethyl)-3-(2-fluoro-5-nitro-phenyl)-2-(3-hydroxypropyl)-6,6-dimethyl-1,1-dioxo-2H-1,4-thiazin-5-yl]carbamate which was taken to next step without further purification. LC/MS (ESI+) m/z=614 (M+Na).
Reaction SMILES: [Mg].Br[C:3]1[CH:12]=[CH:11][C:10]2[C:9]([CH3:14])([CH3:13])[CH2:8][CH2:7][C:6]([CH3:16])([CH3:15])[C:5]=2[CH:4]=1.BrCCBr.[CH2:21]([O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1Br)[CH3:22]>C1COCC1.C(OCC)C.C(OC(=O)C)C.[Cl-].[Cl-].[Zn+2]>[CH3:13][C:9]1([CH3:14])[CH2:8][CH2:7][C:6]([CH3:16])([CH3:15])[C:5]2[CH:4]=[C:3]([C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:24]([O:23][CH2:21][CH3:22])=[O:32])[CH:12]=[CH:11][C:10]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(Br)ccc21
Reactant: CCOC(=O)c1ccccc1Br
Agent: [Cl-]
Agent: [Mg]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CCOC(=O)c1ccccc1-c1ccc2c(c1)C(C)(C)CCC2(C)C
Reaction time: 0.25 h

Procedure:
To magnesium (180 mgs, 7.5 mmols) in THF (3 ml) was added a solution of 2-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (200 mgs) in THF (5 ml) followed by 1,2-dibromoethane (94 mgs, 0.5 mmol). The mixture was stirred for 15 mins, then another portion of 2-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (1.14 g, 5 mmols) in THF (10 ml) was added. The mixture was stirred for 15 mins at room temperature, and refluxed for 1 h. ZnCl2 (680 mgs, 5 mmols) was added, stirred for 40 mins, and to the white precipitate. ethyl-2-bromobenzoate (1.09 g) in THF (5 ml) was added, immediately followed by addition of Ni(PPh2CH2CH2)Cl2 (26 mgs, 0.05 mmols). The mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with diethyl ether:ethylacetate (1:1, a total of 180 ml), the organic phase was washed with water (10 ml), brine (10 ml) NaHCO3 (10 ml) and brine (10 ml), dried (MgSO4) and the solvent was removed under reduced pressure. Silicagel chromatography (5% ethyl acetate in hexane) followed by HPLC purification of the crude material gave the title compound as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][CH:5]1[N:8]([CH2:9][C:10](=[O:19])[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7](=[O:20])[CH2:6]1.C1C=C(Cl)C=C(C(OO)=[O:29])C=1>>[OH:1][CH2:2][CH2:3][S:4]([CH:5]1[N:8]([CH2:9][C:10](=[O:19])[CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:7](=[O:20])[CH2:6]1)=[O:29]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(CCc1ccccc1)CN1C(=O)CC1SCCO
Product: O=C(CCc1ccccc1)CN1C(=O)CC1S(=O)CCO
Yield: 20 %

Procedure:
Treatment of 4-(2-hydroxyethylthio)-N-(4-phenyl-2-oxobutyl)azetidin-2-one with mCPBA as described for Example 17 gave the title compound by crystallisation: white crystals, m.p. 104-5° C., 20% yield
Reaction SMILES: [Na].O=[C:3]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:15][C:16]1[C:25]2[NH:24]C(=O)[O:22][C:21](=O)[C:20]=2[CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O>[Cl:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:21]2[OH:22]
Reactant: O=c1[nH]c2c(Cl)cccc2c(=O)o1
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nc2c(Cl)cccc2c(O)c1C(=O)OCC
Temperature: 130 °C
Yield: 43.8 %

Procedure:
To a stirred mixture of diethyl oxosuccinate sodium salt (2.31 g, 11.0 mM) in dimethylformamide (20 mL) under a nitrogen atmosphere was added 8-chloro-2H-3,1-benzoxazine-2,4(1H)-dione (2.17 g, 11.0 mM). The resulting mixture was heated slowly to 130° C. and maintained at this temperature for 2.5 hr. After cooling, the reaction mixture was poured into water and the resulting mixture was then extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried (MgSO4), filtered and concentrated to obtain an oily solid (1.55 g). This material was chromatographed (eluant: CH2C12 /CH3OH; 98/2) over silica gel to provide the title compound as an oil which slowly crystallized to a tan solid (0.700 g, 19.7%). A 0.150 g portion of this material was recrystallized from toluene/hexane to provide an analytical sample (0.050 g) of the title compound as a tan solid, mp 98°-99° C.; MS(CI): 324 (M+H).
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.Br[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C>C(O)CCC>[CH2:17]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10][CH:11]1[CH2:12][CH2:13][N:14]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH2:15][CH2:16]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Brc1ccncc1
Reactant: c1ccc(CN(CCC2CCNCC2)Cc2ccccc2)cc1
Agent: Br
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(CN(CCC2CCN(c3ccncc3)CC2)Cc2ccccc2)cc1
Yield: 53 %

Procedure:
N,N-Dibenzyl-2-(piperidin-4-yl)ethanamine (2.4 g, 7.79 mmol, 1 eq) and 4-bromopyridine HBr (1.97 g, 10.12 mmol, 1.3 eq) were dissolved in n-butanol (30 ml) and DIPEA (3.3 ml, 19.47 mmol, 2.5 eq) and the mixture was refluxed for 48 h. After monitoring by thin-layer chromatography, the reaction solution was concentrated under reduced pressure and the residue was taken up in dichloromethane (100 ml), washed with water and sat. NaCl solution (in each case 50 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by column chromatography (silica gel, 3.5% MeOH in dichloromethane), a white solid was obtained. Yield: 53% (1.6 g, 4.15 mmol).
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][CH2:6][CH2:5]2)[CH2:3][C:2]1([C:14]([O:16]C(C)C)=[O:15])[C:8]([O:10]C(C)C)=[O:9].[OH-].[Na+]>CO>[CH2:1]1[C:4]2([CH2:5][CH2:6][CH2:7]2)[CH2:3][C:2]1([C:14]([OH:16])=[O:15])[C:8]([OH:10])=[O:9]
Reactant: CC(C)OC(=O)C1(C(=O)OC(C)C)CC2(CCC2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1(C(=O)O)CC2(CCC2)C1
Temperature: 50 °C
Yield: 88.8 %

Procedure:
A solution of diisopropyl spiro[3.3]heptane-2,2-dicarboxylate (2.85 g, 10.62 mmol) in MeOH (20 mL) was treated with 2N NaOH (31.9 mL, 63.7 mmol) and heated at 50° C. overnight. The organics were removed under reduced pressure, the aqueous residue acidified with 3M HCl, cooled to 5° C. and the solid collected via filtration. The filtrate was extracted with DCM (2×), then EtOAc (2×) and the combined organics were dried over Na2SO4, concentrated to dryness and combined with the first solid to afford spiro[3.3]heptane-2,2-dicarboxylic acid (1.737 g, 89%). 1H NMR (400 MHz, DMSO-d6): δ 12.58 (s, 2H), 2.39 (s, 4H), 1.91 (t, J=7.5 Hz, 4H), 1.71 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH:10]([OH:12])[CH3:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(OC=C)(=O)CCCCCCCCCCC>>[CH3:1][CH:2]([C@@H:10]([OH:12])[CH3:11])[C:3]([O:5][C:6]([CH3:8])([CH3:7])[CH3:9])=[O:4]
Reactant: CC(O)C(C)C(=O)OC(C)(C)C
Agent: C=COC(=O)CCCCCCCCCCC
Product: CC(C(=O)OC(C)(C)C)[C@H](C)O
Temperature: 35 °C
Reaction time: 168 h
Yield: 43.3 %

Procedure:
A mixture of a racemate, t-butyl 2-methyl-3hydroxybutanoate 30 g, vinyl laurate 40 g, and Lipase P (Amano Pharmaceutical Co., Ltd.) 8.0 g was stirred at 35° C. for 7 days. After stopping the reaction, the enzyme was removed by filtration and washed with n-heptane on a filter paper. n-Heptane was distilled off from the filtrate and the residue was subjected to a vacuum distillation to give 13 g of t-butyl (3S)-2-methyl-3-hydroxybutanoate of the following formula, ##STR25## and 23 g of t-butyl (3R)-2-methyl-3-dodecanoyloxy butanoate of the following formula, ##STR26##
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:23]=[C:24]1[O:28][C:26](=[O:27])[CH2:25]1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:26]([O:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:27])[CH2:25][C:24]([CH3:23])=[O:28]
Reactant: C=C1CC(=O)O1
Reactant: OCC(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)OCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
500 mg (2.52 mmol) of 2,2-diphenylethanol was dissolved in 10 ml of toluene. 382 mg (3.78 mmol) of triethylamine was added to the obtained solution, and they were stirred at room temperature for 1 hour. 386 mg (3.03 mmol) of diketene was added to the obtained mixture under cooling with ice, and then they were stirred under heating at 100° C. for 2 hours. After the addition of saturated aqueous sodium hydrogencarbonate solution followed by the extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the unpurified title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=1.C(N(CC)CC)C.[C:26]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:3]=[C:2]([N:35]3[CH2:36][CH2:37][N:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:33][CH2:34]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CP(C)(=O)c1ccc(Nc2ncnc(Cl)n2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CP(C)(=O)c1ccc(Nc2ncnc(N3CCN(c4ccccc4)CC3)n2)cc1

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine (prepared as in Example 92: 0.12 mmol) in 2 mL of ethanol is added 50 L of triethylamine and 1-Phenylpiperazine (19 mg, 0.12 mmol). The mixture is microwaved at 120 degrees until formation of the desired compound. The reaction mixture is filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([O:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18]Br)=[O:13])([CH3:10])([CH3:9])[CH3:8].[C:20]1([CH3:45])[CH:25]=[CH:24][C:23]([S:26]([N:29]2[CH:33]=[C:32]([CH:34]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:31]=[CH:30]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1>CN(C=O)C>[C:7]([O:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][C:34]([C:32]1[N:31]=[CH:30][N:29]([S:26]([C:23]2[CH:22]=[CH:21][C:20]([CH3:45])=[CH:25][CH:24]=2)(=[O:27])=[O:28])[CH:33]=1)([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CCOC(=O)C(C(=O)OCC)c1cn(S(=O)(=O)c2ccc(C)cc2)cn1
Reactant: CC(C)(C)OC(=O)NCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCCCNC(=O)OC(C)(C)C)(C(=O)OCC)c1cn(S(=O)(=O)c2ccc(C)cc2)cn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
13.7 g (42.0 mmol) of cesium carbonate and 3.24 g (11.56 mmol) of 4-(t-butyloxycarbonylamino)butyl bromide were added to a solution of 4.0 g (10.51 mmol) of diethyl 2-[1-(toluene-4-sulfonyl)-1H-imidazol-4-yl]malonate in 67 ml of DMF, and the mixture was stirred at 60° C. for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was taken up in ethyl acetate and washed with water. The organic phase was dried over Na2SO4, filtered and concentrated. Chromatography on silica gel (heptane/ethyl acetate 1:1) gave the title compound (4.21 g, 73%). LC/MS: Rt=2.08 min, [M+H]+=552, (method A).
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C@@:7]([C:16]([F:19])([F:18])[F:17])([OH:15])[C:6]=2[CH:5]=[C:4]([OH:20])[CH:3]=1.C1(C)C=CC(S(O[CH2:31][CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C@@:7]([C:16]([F:18])([F:19])[F:17])([OH:15])[C:6]=2[CH:5]=[C:4]([O:20][CH2:31][CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Reactant: Oc1cc(Cl)c2c(c1)[C@@](O)(C(F)(F)F)c1ccccc1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)CCOc1cc(Cl)c2c(c1)[C@@](O)(C(F)(F)F)c1ccccc1-2
Temperature: 70 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
Under a nitrogen atmosphere, (9R)-4-chloro-9-(trifluoromethyl)-9H-fluorene-2,9-diol (55.5 g) was dissolved in N,N-dimethylformamide (550 ml), 3-hydroxy-3-methylbutyl toluene-4-sulfonate (49.6 g) and potassium carbonate (39.5 g) were added, and the mixture was stirred at an oil bath temperature of 70° C. overnight. To the reaction mixture was added a solution of 3-hydroxy-3-methylbutyl toluene-4-sulfonate (4.0 g) in N,N-dimethylformamide (5 ml), and the mixture was further stirred at the same temperature for 9.5 hr. The reaction mixture was ice-cooled, water (800 ml) was added, and the mixture was extracted with ethyl acetate (900 ml). The obtained organic layer was washed with water (500 ml, 3 times) and saturated brine (500 ml). The obtained organic layer was dried over anhydrous sodium sulfate, the insoluble material was filtered off, and the solvent in the filtrate was evaporated. The obtained residue was purified by silica gel column chromatography (a mixture of hexane and ethyl acetate was used as an elution solvent, first eluted with a mixture of (hexane:ethyl acetate) at a mixing ratio 3:1, and then with the mixture at a mixing ratio 2:1, and further with the mixture at a mixing ratio 3:2) to give the title compound (49.5 g).
Reaction SMILES: [CH2:1]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]([CH3:26])[C:23]([OH:25])=[O:24])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[OH:27][CH2:28][CH:29]([CH2:31]O)[OH:30].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH2:1]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]([CH3:26])[C:23]([O:25][CH2:31][CH:29]([OH:30])[CH2:28][OH:27])=[O:24])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: OCC(O)CO
Reactant: CCCCCCCCCC=CCCCNc1ccccc1C(C)C(=O)O
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCCCCCCCC=CCCCNc1ccccc1C(C)C(=O)OCC(O)CO
Reaction time: 120 h

Procedure:
A solution of 11.8 g. of 2-(4-tetradecenylamino)phenylpropionic acid, 1.00 g. of glycerol, and 5.35 ml. of boron trifluoride etherate in 200 ml. of toluene is stirred under reflux for 48 hours. The solution is treated with an additional 5.35 ml. of boron trifluoride etherate and refluxing is continued for 120 hours. Dilution with water and methylene chloride followed by filtration affords the product as a white solid.
Reaction SMILES: [NH:1]([C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C@@H:2]([C:4]([NH:6][CH2:7][C:8]([NH:10][C@H:11]([C:19]([O:21]CC)=O)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:9])=[O:5])[CH3:3].O.[NH2:35][NH2:36].C(OCC)C>CO>[NH:1]([C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C@@H:2]([C:4]([NH:6][CH2:7][C:8]([NH:10][C@H:11]([C:19]([NH:35][NH2:36])=[O:21])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:9])=[O:5])[CH3:3]
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](C)NC(=O)OCc1ccccc1
Reactant: NN
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: C[C@@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NN
Reaction time: 48 h

Procedure:
In 50 ml of MeOH is dissolved 3.3 g of Z-(D)-Ala-Gly-Phe-OEt and after 1 mlof hydrazine hydrate is added, the solution is allowed to stand at room temperature for 2 days. It is then treated with diethyl ether, collected by filtration and recrystallized from ethanol. 3.0 g (94%); m.p. 196°-197° C; Rf1 =0.34; [α]D27 +2.4°(c=0.37, DMF).
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][CH3:11])[CH2:5][CH2:6][CH2:7][CH2:8]O)[CH3:2].CS([Cl:16])(=O)=O.N1C=CC=CC=1>CN(C)C=O>[Cl:16][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([O:3][CH2:1][CH3:2])[CH2:10][CH3:11]
Reactant: CCOC(CC)CCCCO
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCOC(CC)CCCCCl

Procedure:
As shown in Reaction 4, Compound III may be reacted with lithium aluminum hydride (LAH) in tetrahydrofuran (THF) to produce 5-ethoxyheptanol (Compound IV). Compound IV may be produced at a yield of from approximately 90% to approximately 99%. The reaction may be conducted at a temperature of from approximately −50° C. to approximately room temperature (from approximately 20° C. to approximately 25° C.). To control the reaction, in some embodiments, the reaction is conducted at room temperature. As shown in Reaction 5, Compound IV may be reacted with methanesulfonyl chloride (MSCl) and pyridine in dimethylformamide (DMF) to produce 1-chloro-5-ethoxyheptane (Compound V) at a yield of from approximately 75% to approximately 95%.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([C:19]2[CH:23]=[CH:22][N:21](COCC[Si](C)(C)C)[N:20]=2)=[C:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8](=[O:18])[C:7]=12.Cl>CO>[CH3:1][S:2][C:3]1[S:4][C:5]([C:19]2[CH:23]=[CH:22][NH:21][N:20]=2)=[C:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:8](=[O:18])[C:7]=12
Reactant: CSc1sc(-c2ccn(COCC[Si](C)(C)C)n2)c2c1C(=O)N(c1ccccc1)CC2
Agent: Cl
Solvent: CO
Product: CSc1sc(-c2cc[nH]n2)c2c1C(=O)N(c1ccccc1)CC2
Temperature: 80 °C

Procedure:
To a solution of 3-(methylsulfanyl)-5-phenyl-1-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl)-6,7-dihydrothieno[3,4-c]pyridin-4(5H)-one (45 mg, 0.095 mmol) in MeOH (25 μL) at rt was added 4M HCl in MeOH (25 μL, 0.095 mmol). The solution was heated at 80° C. for 1 h. The resulting mixture was concentrated and purified by Gilson reverse phase chromatography to afford the title compound as a mixture of amide rotamers. 1H NMR (400 MHz, ppm, CDCl3) δ 7.62 (d, J=2.4 Hz, 1 H); 7.45-7.30 (m, 4 H); 7.28-7.22 (m, 1 H); 6.42 (d, J=2.4 Hz, 1 H); 3.96 (t, J=6.3 Hz, 2 H); 3.23 (t, J=6.3 Hz, 3 H); 2.62 (s, 3 H). HRMS (ES+) m/z 342.0728 [(M+H)+; calcd for C17H15N3OS2: 342.0729].
Reaction SMILES: [Br:1][C:2]1[C:11]([CH2:12]O)=[C:10]2[C:5]([NH:6][C:7]([CH3:17])([CH3:16])[C:8](=[O:15])[N:9]2[CH3:14])=[CH:4][CH:3]=1.C(N(CC)CC)C.CS([Cl:29])(=O)=O.C(OCC)(=O)C>ClCCl.O>[Br:1][C:2]1[C:11]([CH2:12][Cl:29])=[C:10]2[C:5]([NH:6][C:7]([CH3:17])([CH3:16])[C:8](=[O:15])[N:9]2[CH3:14])=[CH:4][CH:3]=1
Reactant: CN1C(=O)C(C)(C)Nc2ccc(Br)c(CO)c21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CN1C(=O)C(C)(C)Nc2ccc(Br)c(CCl)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
7-Bromo-8-hydroxymethyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 6, 37.5 mg, 0.125 mmol 1) was dissolved in anhydrous dichloromethane (1 mL), and triethylamine (20.9 μL, 0.150 mmol) and methanesulfonyl chloride (10.7 μL, 0.138 mmol) were added thereto successively. The reaction mixture was stirred at room temperature overnight. Ethyl acetate (10 mL) and water (10 mL) were added to the reaction mixture and partitioned. The organic layer was washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (28.7 mg) as an orange amorphous product. (Yield 72%)
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][CH2:4][S:5][C:6]1[C:7]2[CH:20]=[C:19]([S:21][CH3:22])[CH:18]=[CH:17][C:8]=2[O:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[C:30]1([O:36][C:37](Cl)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[CH3:1][N:2]([CH2:3][CH2:4][S:5][C:6]1[C:7]2[CH:20]=[C:19]([S:21][CH3:22])[CH:18]=[CH:17][C:8]=2[O:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[CH:12]=1)[C:37]([O:36][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:38]
Reactant: CSc1ccc2c(c1)C(SCCN(C)C)=Cc1ccccc1O2
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CSc1ccc2c(c1)C(SCCN(C)C(=O)Oc1ccccc1)=Cc1ccccc1O2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirring solution of 11.3 g of 11-[β-(dimethylamino)ethylthio]-2-(methylthio)dibenz[b,f]oxepin, free base of Example 21, and 10.0 g of potassium carbonate in 50 ml of methylene chloride is added dropwise a solution of 5.7 g of phenylchloroformate in 50 ml of methylene chloride. After total addition the reaction mixture is stirred at ambient temperature for 24 hours and then evaporated to dryness. The residue is triturated with ether and the ethereal solution is sequentially washed successively with a 10% sodium hydroxide solution and water, dried and filtered and the filtrate evaporated to dryness leaving a yellow oil. The oil is chromatographed through a silica gel column with a methylene chloride eluant to obtain the purified orange oil of 11-[β-(N-methyl-N-phenoxycarbonylamino)ethylthio]-2-(methylthio)-dibenz[b,f]oxepin.
Reaction SMILES: [OH:1][C@H:2]1[CH2:16][CH:15]=[C:14]2[C@:4]([CH3:17])([CH2:5][C:6]3[C:7](=[CH:13]2)[O:8][C:9](=[O:12])[C:10]=3[CH3:11])[C@H:3]1[CH3:18].[C:19]1([C:24](Cl)=[O:25])[S:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([C:24]([O:1][C@H:2]2[CH2:16][CH:15]=[C:14]3[C@:4]([CH3:17])([CH2:5][C:6]4[C:7](=[CH:13]3)[O:8][C:9](=[O:12])[C:10]=4[CH3:11])[C@H:3]2[CH3:18])=[O:25])[S:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1cccs1
Reactant: CC1=C2C[C@@]3(C)C(=CC[C@H](O)[C@@H]3C)C=C2OC1=O
Product: CC1=C2C[C@@]3(C)C(=CC[C@H](OC(=O)c4cccs4)[C@@H]3C)C=C2OC1=O

Procedure:
The title compound was prepared in the same manner as in Example B2, except that the compound prepared in Example B1 was reacted with 2-thenoyl chloride.