Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li][CH2:2]CCC.[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]([C:19]3[N:23]([CH3:24])[C:22](C)=[N:21][CH:20]=3)[OH:18])[CH:15]=2)[N:10]=[C:9]([O:26][CH3:27])[C:8]=1[CH2:28][C:29]1[CH:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=1.[C:39]([CH:52]1[CH2:55][N:54](C(OC(C)(C)C)=O)[CH2:53]1)([CH:41]1[CH2:44]N(C(OC(C)(C)C)=O)C1)=O>C1COCC1>[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:18])([C:19]3[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=3)[C:44]3[CH:41]=[CH:39][C:52]([C:53]#[N:54])=[CH:55][CH:2]=3)[CH:15]=2)[N:10]=[C:9]([O:26][CH3:27])[C:8]=1[CH2:28][C:29]1[CH:30]=[N:31][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)C2CN(C(=O)OC(C)(C)C)C2)C1
Reactant: COc1nc2ccc(C(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccc(C#N)cc3)c3cncn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 0.7 mL, 1.75 mmol) was added dropwise by syringe to a solution of 6-bromo-4-chloro-2-methoxy-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)quinoline (0.755 g, 0.175 mmol, Intermediate 45: step d) in dry THF (9 mL) in a dry ice-acetone bath. After 1-2 minutes, a solution of 4-(1-methyl-1H-imidazole-5-carbonyl)benzonitrile (0.370 g, 1.75 mmol, Intermediate 43: step c) in dry THF (17 mL) was added dropwise. The reaction was stirred for 5 minutes, then was removed from the cold bath and allowed to warm to room temperature. The reaction was quenched with saturated aqueous ammonium chloride. The mixture was partitioned between water and dichloromethane. The separated aqueous phase was further extracted with dichloromethane. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-5% MeOH-DCM) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J=2.1 Hz, 1H), 8.08 (d, J=2.1 Hz, 1H), 7.88-7.82 (m, 4H), 7.81-7.77 (m, 1H), 7.73-7.71 (m, 1H), 7.60 (dd, J=8.7, 2.1 Hz, 1H), 7.52 (dt, J=8.5, 2.0 Hz, 2H), 7.27 (s, 1H), 6.17 (d, J=1.2 Hz, 1H), 4.37 (s, 2H), 4.03 (s, 3H), 3.32 (s, 3H); MS m/e 564.5 [M+H]+.
Reaction SMILES: [NH:1]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C@@H:2]([C:10]([O:12]CC1C=CC=CC=1)=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:30](C(OCC1C=CC=CC=1)=O)[C@@H:31]([C:33]([O:35]CC1C=CC=CC=1)=O)C.[NH:53](C(OCC1C=CC=CC=1)=O)[C@@H](C(OCC1C=CC=CC=1)=O)CCC(=O)O.N(C(OCC1C=CC=CC=1)=O)[C@H](C(OCC1C=CC=CC=1)=O)CC1C=CC=CC=1>>[NH:1]([C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])[C@@H:2]([C:10]([NH:30][CH2:31][C:33]([NH2:53])=[O:35])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)CC[C@@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: O=C(N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Product: NC(=O)CNC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1

Procedure:
Next, the extension of the use of the MEs to the coupling reaction of D-amino acids as acyl donor, Z-D-Phe-OBn (28), Z-D-Ala-OBn (29), and Z-D-Glu-OBn (30) with Z-L-Phe-OBn (1) was examined. While WT enzyme did not accept D-amino acids as acyl donors, all of the MEs were able to catalyze the coupling of D-amino acids with Z-L-Phe-OBn (1). Although the reactions of Z-D-Phe-OBn (28) in all cases were slow to give Z-D-Phe-Gly-NH2 (39) in low yield (the best was 14% by using M-n), peptide coupling of Z-D-Ala-OBn (29) or Z-D-Glu-OBn (30) with Gly-NH2 (31) proceeded without remaining substrates. It is noteworthy that using ME-k and -m in case of Z-D-Ala-OBn (29) and ME-o in case of Z-D-Glu-OBn (30) gave Z-D-Ala-Gly-NH2 (37, 86%) and Z-D-Glu-Gly-NH2 (38, 74%), respectively, in very high yields. Probably, the CMMs recognized D-amino acids in a different manner from L-amino acids, i.e., the carbobenzoxy group of α-position seems to bind the S1 pocket. On the other hand, repulsion between the phenylmethyl group of Z-D-Phe-OBn (28), which had the biggest substituent among the three kinds of substrate, and the other parts in the pocket of active site of the MEs could cause low reactivity of Z-D-Phe-OBn (28).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C@H:21]3[O:25][C:24](=[O:26])[CH2:23][C@H:22]3[CH3:27])=[CH:17][CH:16]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].[OH-:32].[Na+:33].CO>C1COCC1>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([OH:25])[CH:22]([CH3:27])[CH2:23][C:24]([O-:26])=[O:32])=[CH:17][CH:16]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].[Na+:33]
Reactant: [OH-]
Reactant: CCCc1c(OCCCOc2ccc([C@H]3OC(=O)C[C@H]3C)cc2)ccc(C(C)=O)c1O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1c(OCCCOc2ccc(C(O)C(C)CC(=O)[O-])cc2)ccc(C(C)=O)c1O

Procedure:
The lactone from Example 13 (3.0 g, 7.0 mmol) was hydrolyzed with 1N NaOH (10.5 ml), methanol (1 ml) and THF (15 ml) at room temperature for 15 hours. The mixture was concentrated and the residue was Purified by chromatography on XAD-8 to provide the title compound as a foam.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[C:4]([C:10](N)=[O:11])=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1.[OH-:14].[K+].Cl>CCO>[CH3:1][N:2]([CH3:13])[C:3]1[C:4]([C:10]([OH:14])=[O:11])=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1
Reactant: [OH-]
Reactant: Cc1ccc(N(C)C)c(C(N)=O)n1
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: Cc1ccc(N(C)C)c(C(=O)O)n1
Temperature: 90 °C

Procedure:
To the title compound of Step A (91 mg, 0.5 mmol) in EtOH (1 mL) was added 4M KOH (0.5 μL). The reaction was then heated at 90° C. for 18 h. The reaction was then cooled to rt, acidified with 1N HCl (aq) to pH=3, concentrated and used without further purification in the next step.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[S:15])[CH:9]2[CH3:16])([O:3][CH2:4][CH3:5])=[O:2].[Cl:17]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:17][C:9]1([CH3:16])[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH:7]=2)[NH:11][C:10]1=[S:15]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1ccc2c(c1)C(C)C(=S)N2
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)C(C)(Cl)C(=S)N2

Procedure:
A solution of 5-carboethoxy-3-methylthiooxindole (1.50 g, 7 mmol) and N-chlorosuccinimide (1.25 g, 9.3 mmol) in methylene chloride (150 ml) was stirred at room temperature for 24 hours. The solvent was removed in vacuo, yielding crude 3-chloro-5-carboethoxy-3-methylthiooxindole and the residue was dissolved in tetrahydrofuran and added to a vigorously stirred slurry of red mercuric oxide (1.53 g, 7 mmol) and boron trifluoride etherate (1.00 g, 7 mmol) in 100 ml of 50 percent aqueous tetrahydrofuran. After stirring at room temperature for 1 hour, the red solution was extracted with chloroform. The organic extracts were dried over anhydrous magnesium sulfate, filtered, evaporated, and the residue was chromatographed on silica gel. Elution with chloroform gave 5-carboethoxyisatin (860 mg, 56%) as a yellow solid, mp 205°-207° (recrystallized from ether), ir (KBr) 3265 (NH), 1765 (ester C=O), 1750 (C=O), and 1700 cm-1 (amide C= O); nmr (DMSO-d6) τ-1.00 (1H, b s, NH), 1.80 (d of d, 1H, J4,6 =2 Hz, J6,7 =9 Hz, H6), 1.90 (d, 1H, J4,6 =2H3, H4), 3.20 (d, 1H, J6,7 =9 Hz, H7), 5.65 (q, 2H, CO2CH2CH3), and 8.60 (t, 3H, CO2CH2CH3); mass spectrum m/e obs. 219.0534 (calc. 219.0531).
Reaction SMILES: [C:1]([C:11]1[C:12]([O:17][C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[CH:20][C:19]=2[OH:26])=[N:13][CH:14]=[CH:15][CH:16]=1)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36]Cl>CN(C)C=O>[ClH:24].[C:1]([C:11]1[C:12]([O:17][C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[CH:20][C:19]=2[O:26][CH2:36][CH2:35][N:34]([CH3:38])[CH3:33])=[N:13][CH:14]=[CH:15][CH:16]=1)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(C)CCCl
Reactant: O=C(C=Cc1ccccc1)c1cccnc1Oc1cc(Cl)c(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1cc(Cl)c(Cl)cc1Oc1ncccc1C(=O)C=Cc1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 20 ml of dimethylformamide are added 7.7 g of 3-cinnamoyl- 2-(4,5-dichloro-2-hydroxyphenoxy)pyridine and 3.3 g of potassium carbonate, and the mixture is stirred at room temperature for 30 minutes Thereto, 2.8 g of 2-dimethylaminoethyl chloride is added, and the mixture is stirred at 50° C. for 6 hours. The reaction mixture is poured into ice-water, followed by extraction with toluene After the extract is washed with water and dried over anhydrous magnesium sulfate, the solvent is distilled off. The residue is converted into its hydrochloride in isopropyl alcohol and the hydrochloride is recrystallized from isopropyl alcohol to give 3-cinnamoyl-2-[4,5-dichloro-2-(2-dimethylaminoethoxy)phenoxy]pyridine hydrochloride, m.p. 169°-171° C.
Reaction SMILES: Br.C([N:9]1[CH2:14][CH2:13][CH:12]([N:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-])=O)[C:16](=O)[CH3:17])[CH2:11][CH2:10]1)C1C=CC=CC=1.[H][H]>[C].[Pd].CO>[CH3:17][C:16]1[N:15]([CH:12]2[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:25]=1
Reactant: CC(=O)N(c1ccccc1[N+](=O)[O-])C1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Br
Solvent: CO
Product: Cc1nc2ccccc2n1C1CCNCC1
Reaction time: 8 h
Yield: 91.3 %

Procedure:
In this reference example, 14.8 g of 1-benzyl-4-[N-(2-nitrophenyl)-N-acetylamino]-piperidine hydrobromide obtained in the same manner as that of Refernce Example 4, 250 ml of methanol and 1.0 g of 5% palladium carbon are mixed and stirred at room temperature under the atmospheric pressure in the current of hydrogen for 12 hours. The resultant reaction mixture is filtered. The filtrate is mixed with 29 ml of concentrated hydrochloric acid and stirred overnight. The reaction solution is concentrated and the residue is dissolved in 50 ml of water. The solution is adjusted to pH 11.0 with 1 N aqueous sodium hydroxide. The solution is extracted with 50 ml of chloroform three times, and the extract is washed with 20 ml of a saturated aqueous sodium chloride and dried. The extract is freed from the solvent by distillation. The residue is mixed with n-hexane and stirred for crysallization. The crystals are separated by filtration, recrystallized from a mixed solvent of n-hexane and ethanol to obtain 6.7 g of 4-(2-methyl-benzimidazol-3-yl)-piperidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:17](=[O:20])(=[O:19])[NH2:18])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([OH:7])=[O:6].[CH2:21](I)[CH2:22][CH2:23][CH3:24].O>C(O)CCC>[CH2:21]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:17](=[O:20])(=[O:19])[NH2:18])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([O:7][CH2:3][CH2:2][CH2:10][CH3:9])=[O:6])[CH2:22][CH2:23][CH3:24]
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1-c1ccccc1
Reactant: CCCCI
Solvent: CCCCO
Solvent: O
Product: CCCCNc1cc(C(=O)OCCCC)cc(S(N)(=O)=O)c1-c1ccccc1

Procedure:
A solution of 3-amino-4-phenyl-5-sulfamylbenzoic acid (1.46 g) and n-butyl iodide (1.5 ml) in n-butanol (20 ml) is refluxed for 3-4 days under such conditions, that the water formed during the reaction is separated. After 12, 24, 36 and 48 hours, additional amounts of n-butyl iodide (each time 0.75 ml) are added. The resulting solution is evaporated in vacuo, and the obtained crude n-butyl 3-n-butylamino-4-phenyl-5-sulfamylbenzoate is saponified by heating with 2 N sodium hydroxide (20 ml) for 30 minutes. After cooling, the resulting solution is acidified with 4 N hydrochloric acid (12 ml) to precipitate 3-n-butylamino-4-phenyl-5-sulfamylbenzoic acid, which is collected by filtration, washed with water and dried. After recrystallization from aqueous ethanol, the acid is obtained with a melting point of 134°-136° C.
Reaction SMILES: [CH3:1][CH:2]1[C@H:6]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:5][CH2:4][NH:3]1.[CH2:15]([O:22][C:23]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:10]([O:9][C:8](=[O:14])[NH:7][C@@H:6]1[CH2:5][CH2:4][N:3]([C:27](=[O:28])[CH2:26][NH:25][C:23]([O:22][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:24])[C@@H:2]1[CH3:1])([CH3:13])([CH3:12])[CH3:11].[C:10]([O:9][C:8](=[O:14])[NH:7][C@@H:6]1[CH2:5][CH2:4][N:3]([C:27](=[O:29])[CH2:26][NH:25][C:23]([O:22][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:24])[C@H:2]1[CH3:1])([CH3:13])([CH3:11])[CH3:12]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CC1NCC[C@H]1NC(=O)OC(C)(C)C
Product: C[C@@H]1[C@H](NC(=O)OC(C)(C)C)CCN1C(=O)CNC(=O)OCc1ccccc1
Product: C[C@H]1[C@H](NC(=O)OC(C)(C)C)CCN1C(=O)CNC(=O)OCc1ccccc1

Procedure:
[(2R,3R)-1-(2-Benzyloxycarbonylamino-acetyl)-2-methyl-pyrrolidin-3-yl]-carbamic acid tert-butyl ester and [(2S,3R)-1-(2-benzyloxycarbonylamino-acetyl)-2-methyl-pyrrolidin-3-yl]-carbamic acid tert-butyl ester were synthesized from tert-butyl (3R)-2-methylpyrrolidin-3-ylcarbamate and 2-(benzyloxycarbonylamino)acetic acid using general procedure G. RP-HPLC (Table 1, Method d) Rt 5.57 min. (trans) and 5.53 min. (cis); m/z: (M+H)+ 392.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:20]([CH:22]1[O:24][CH2:23]1)Cl>CC(C)=O>[O:24]1[CH2:23][CH:22]1[CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: ClCC1CO1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CCc1ccc(OCC2CO2)cc1

Procedure:
A mixture of 228 gm (1.27 mole) of methyl 3-(4-hydroxyphenyl)propionate, 263 gm (1.90 mole) of K2CO3 and 298 mL (3.80 mole) of epichlorohydrin in 2 liters of acetone was stirred and heated to reflux for 20 hours. The reaction medium was then filtered and evaporated under reduced pressure. The resulting oil was taken up in 1 liter of toluene andwashed consecutively with 500 mL water, 2×500 mL 1N NaOH and 2×500 mL water. The toluene phase was then dried over MgSO4 andevaporated under reduced pressure to provide a clear oil which was further purified by vacuum distillation. The final yield of purified oil was 131.2gm (44%): bp 156° (p=0.4 mm Hg). The NMR and IR spectra of the product were consistent with the assigned structure and the elemental analysis was consistent with the formula C13H16O4.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:50][CH:51]([CH3:53])[CH3:52])[CH2:14][C@@H:15]([OH:49])[C@@H:16]([NH:37][C:38](=[O:48])[O:39][C@@H:40]3[C@H:47]4[C@H:43]([O:44][CH2:45][CH2:46]4)[O:42][CH2:41]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][Si](C(C)(C)C)(C)C)=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.C(O)(=O)C>O1CCCC1.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:50][CH:51]([CH3:53])[CH3:52])[CH2:14][C@@H:15]([OH:49])[C@@H:16]([NH:37][C:38](=[O:48])[O:39][C@@H:40]3[C@H:47]4[C@H:43]([O:44][CH2:45][CH2:46]4)[O:42][CH2:41]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCCO[Si](C)(C)C(C)(C)C)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCCO)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.2 %

Procedure:
To a solution of (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-1-[4-(4-{[tert-butyl(dimethyl)silyl]oxy}butoxy)benzyl]-2-hydroxypropylcarbamate (0.38 g, 0.48 mmol) in tetrahydrofuran (5 mL) at 0° C. was added a 1:1 mixture of 1M tetra-n-butyl ammonium fluoride/tetrahydrofuran and acetic acid (1.2 mL) and the mixture was stirred at ambient temperature for 18 h. The mixture was diluted with ethyl acetate and washed with water (4×), dried (sodium sulfate) and evaporated. The resulting solid was triturated with diethyl ether and filtered to afford the title compound as a white solid (0.24 g). 1H NMR (DMSO-d6): δ 0.78 (3H, d), 0.82 (3H, d), 1.2 (1H ,dd), 1.38 (1H, quintuplet), 1.5 (2H, quintuplet), 1.65 (2H, quintuplet), 1.9-2.0 (1H, m), 2.18 (1H, t), 2.7-2.8 (3H, m), 2.9 (1H, d), 2.97 (1H, dd), 3.20-3.25 (1H, m), 3.38 (2H, t), 3.4-3.5 (1H, m), 3.52-3.62 (3H, m), 3.7 (1H, t), 3.8 (1H, dd), 3.93 (2H, t), 4.2 (1H, br s), 4.8 (1H, dt), 5.0 (1H, d), 5.5 (1H, d), 6.18 (2H, s), 6.78 (2H, d), 7.0-7.1 (3H, m), 7.2 (1H, d), 7.26 (1H, s), 7.3 (1H, d); MS: 665 (MH+)
Reaction SMILES: Cl.[Cl:2][C:3]1[C:10]([N+:11]([O-])=O)=[CH:9][C:8]([N+:14]([O-])=O)=[CH:7][C:4]=1[C:5]#[N:6].[OH-].[Na+]>>[Cl:2][C:3]1[C:10]([NH2:11])=[CH:9][C:8]([NH2:14])=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: N#Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1cc(N)cc(N)c1Cl
Temperature: 25 °C

Procedure:
To a solution of 194 gm. (0.86 mole) of stannous chloride dihydrate in 475 ml. of concentrated hydrochloric acid is added 27.5 gm. (0.12 mole) of 2-chloro-3,5-dinitrobenzonitrile. The temperature rises to 84° and a solution occurs. The mixture is allowed to cool to room temperature, placed in an ice-bath, cooled to 0° and a cold 50% sodium hydoxide solution is added, with cooling, until the mixture is strongly basic. The gelatinous precipitate is removed by filtration. The precipitate is washed thoroughly (4 times) with portions of ethyl acetate. The combined ethyl acetate washes are used to extract the aqueous filtrate. The combined ethyl acetate extracts are dried over anhydrous MgSO4 and the solvent removed by distillation. The residue is recrystallized from ethanol. There is obtained 11.30 gm. (56%) of colorless needles melting at 181-82°.
Reaction SMILES: [CH:1]1([C@@H:7]([NH:9][CH2:10][C:11]([CH3:14])([CH3:13])O)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=S(Cl)[Cl:17].[CH3:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[N:29]=[C:30]=[S:31]>>[ClH:17].[CH3:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[N:29]=[C:30]1[N:9]([C@H:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH3:8])[CH2:10][C:11]([CH3:14])([CH3:13])[S:31]1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: C[C@H](NCC(C)(C)O)C1CCCCC1
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SC(C)(C)CN1[C@@H](C)C1CCCCC1
Product: Cl

Procedure:
(1S)-1-Cyclohexyl-1-ethylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N-((1S)-1-cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2-hydroxyethyl)amine. N-((1S)-1-Cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2-hydroxyethyl)amine was reacted with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2f to afford 2-(2-methyl-4-nitrophenylimino)-3-((1S)-1-cyclohexyl-1-ethyl)-5,5-dimethyl-1,3-thiazolidine HCl salt.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:10]([CH2:11][C:12]([OH:14])=[O:13])[N:9]=[N:8][N:7]=2)=[CH:2]1.[CH2:15](O)[CH2:16][CH2:17][CH2:18][CH2:19][OH:20].C1(N=C=NC2CCCCC2)CCCCC1.C(O)(=O)C>CN(C)C=O>[OH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:13][C:12](=[O:14])[CH2:11][N:10]1[C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[N:7][N:8]=[N:9]1
Reactant: OCCCCCO
Reactant: O=C(O)Cn1nnnc1-c1ccsc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C(Cn1nnnc1-c1ccsc1)OCCCCCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.5 %

Procedure:
To a solution of 1 g (4.76 mM) of [5-(3-thienyl)tetrazol-1-yl]acetic acid and 590 mg (5.71 mM) of 1,5-pentanediol in 10 ml of N,N-dimethylformamide was added 1.08 g (5.23 mM) of dicyclohexylcarbodiimide at room temperature. After the mixture was stirred at room temperature for 30 min, a small amount of acetic acid was added to the mixture and then was stirred for 30 min. The mixture was poured into ice-water. The precipitated crystal was filtered off and washed with water. The filtrate was extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (eluent: chloroform/ethyl alcohol=60/0) for separation and purification, to give 670 mg (yield 47.5%) of [5-(3-thienyl)tetrazol-1-yl]acetic acid 5-hydroxypentyl ester.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1)(=[O:4])[CH2:2][CH3:3].[BrH:17].C(O)(=O)C.Br.[NH+]1C=CC=CC=1.O>C(O)(=O)C>[Br:17][CH:2]([CH3:3])[C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1)=[O:4]
Reactant: Br
Reactant: CCC(=O)c1ccc2c(c1)NC(=O)C(C)O2
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(=O)O
Product: CC(Br)C(=O)c1ccc2c(c1)NC(=O)C(C)O2
Reaction time: 2 h

Procedure:
To a solution of 6-propionyl-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (3.4 g) and 30% hydrogen bromide-acetic acid (10 ml) in acetic acid (50 ml) was added pyridinium hydrobromide perbromide (5.12 g) at ambient temperature and the mixture was stirred for 2 hours at the same temperature. The reaction mixture was poured into water. The resultant precipitate was collected by filtration and dissolved in a mixture of ethyl acetate and tetrahydrofuran. The organic solution was washed with a saturated aqueous solution of sodium bicarbonate and brine. The solvent was dried over magnesium sulfate and removed in vacuo to afford a crystalline residue, which was washed with diisopropyl ether to give 6-(2-bromopropionyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (3.8 g).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]=1[O:13][CH3:14])[C:7]([OH:9])=O)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[CH2:29]([C:36]1[O:37][C:38]([CH3:42])=[C:39]([CH3:41])[CH:40]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl.CN(C)C=O>[CH2:29]([C:36]1[O:37][C:38]([CH3:42])=[C:39]([CH3:41])[C:40]=1[C:7]([C:6]1[CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]([O:13][CH3:14])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)=[O:9])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Cc1cc(Cc2ccccc2)oc1C
Reactant: COc1c(C(C)C)cc(C(=O)O)cc1C(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1c(C(C)C)cc(C(=O)c2c(Cc3ccccc3)oc(C)c2C)cc1C(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
At ambient temperature, to a stirred suspension containing 3,5-diisopropyl-p-anisic acid (1.95 g, 8.23 mmol, RN-117439-59-5) and oxalyl chloride (0.8 mL, 9.20 mmol) in CH2Cl2 (22.5 mL) was added N,N-dimethylformamide (2 drops). After 2 h, the reaction was cooled to -78° C. To the reaction was added tin (IV) chloride (1.05 mL) followed by a solution of 2-benzyl-4,5-dimethylfuran (1.8 g, 9.68 mmol) in CH2Cl2 (10.0 mL). After the additions were complete, the reaction was allowed to warm to ambient temperature and stirred for 24 h. The reaction was quenched into crushed ice (100 g), diluted with sat. aq. KH2PO4 (100 mL) and extracted with ether. The combined ethereal extracts were washed with sat aq. NaHCO3 (2×60 mL), with brine (1×60 mL), dried (Na2SO4) and concentrated. The crude product was purified on Biotage KP-Sil eluting with 1% EtOAc/pet. ether to give 2.07 g, (62%) of the title compound as an oil; 1H NMR (DMSO-d6) δ 1.17 (d, 12 H), 1.81 (s, 3 H), 2.19 (s, 3 H), 3.29 (septet, 2 H), 3.74 (s, 3 H), 3.84 (s, 2 H), 7.01-7.03 (m, 2 H), 7.16-7.25 (m, 3 H), 7.47 (s, 2 H). mass spectrum (EI), m/z 404 (M+). Anal. Calcd. for C27H32O3.0.6H2O: C, 78.07; H, 8.06; N, 0.00. Found: C, 78.04; H, 7.93; N, -0.02.