Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][S:9][C:10]2[S:14][C:13]([S:15][CH2:16][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][CH:18]=3)=[N:12][N:11]=2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2].CO.O1CCCC1.[OH-].[Na+]>O>[C:1]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][S:9][C:10]2[S:14][C:13]([S:15][CH2:16][C:17]3[CH:27]=[CH:26][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)=[N:12][N:11]=2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2]
Reactant: CCCc1c(CSc2nnc(SCc3ccc(C(=O)OCC)cc3)s2)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(CSc2nnc(SCc3ccc(C(=O)O)cc3)s2)ccc(C(C)=O)c1O
Reaction time: 1 h
Yield: 27.9 %

Procedure:
A mixture of 380 mg of ethyl p-[(5-[(4-acetyl-3-hydroxy-2-propylbenzyl )thio]-1,3,4-thiadiazol-2-yl)thiomethyl]benzoate, 2 ml of methanol, 2 ml of tetrahydrofuran and 2 ml of a 1N aqueous sodium hydroxide solution was stirred at 60° to 70° C. for 1 hour. After cooling, 20 ml of water was added to the reaction mixture. The system was washed with ethyl acetate, made acidic with dil. hydrochloric acid and then, extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was recrystallized from isopropyl alcohol-water to give 100 mg of p-[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]thiomethyl]benzoic acid. The physical property of the thus obtained compound was identical with that of the compound obtained in Example 37.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][OH:12].C(N(CC)C(C)C)(C)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:12][CH2:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[I:1])(=[O:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(CO)c(I)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCc1ccc([N+](=O)[O-])cc1I
Reaction time: 2 h
Yield: 80.1 %

Procedure:
To a solution of (2-iodo-4-nitrophenyl)methanol (6.01 g, 21.5 mmol) in methylene chloride (50 mL) was added N,N-diisopropylethylamine (7.50 mL, 43.1 mmol) and methanesulfonyl chloride (1.83 mL, 23.7 mmol) at 0° C. The reaction solution was stirred at same temperature for 2 hours. The reaction was quenched with water, and aqueous layer was extracted with DCM once. The combined organic solutions were washed with brine, dried over Na2SO4, filtered and concentrated The crude product was purified by flash column chromatography to give the desired product (6.15 g, 80%). LCMS calculated for C8H91NO5S (M+H)+: m/z=358.0.
Reaction SMILES: Br[C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C:21](=[O:27])[CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[C@@H:7]([CH3:20])[C@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.[CH3:30][N:31](C=O)C>[C-]#N.[Zn+2].[C-]#N>[C:30]([C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C:21](=[O:27])[CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[C@@H:7]([CH3:20])[C@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1)#[N:31]
Reactant: CN(C)C=O
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)Nc2cc(Br)ccc2N1C(=O)CS(C)(=O)=O
Agent: [C-]#N
Agent: [Zn+2]
Product: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)Nc2cc(C#N)ccc2N1C(=O)CS(C)(=O)=O
Temperature: 110 °C
Yield: 94 %

Procedure:
A solution of tert-butyl(2S,3S)-7-bromo-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (124 mg, 253 μmol) in DMF (2.53 ml) was sparged with Ar for 10 min, then zinc cyanide (59.4 mg, 506 μmol) and tetrakis(triphenyl-phosphine)palladium(0) (29.2 mg, 25.3 μmol) were added. The mixture was sparged with Ar for an additional 5 min, then sealed and heated in the microwave at 110° C. for 20 min, then diluted with H2O and extracted with EtOAc. The combined organic layers were washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(2S,3S)-7-cyano-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (104 mg, 94%) as a white solid. MS m/z 459 (MNa)+.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1OC)[C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:7].C1(OC)C(=CC=CC=1)OC.[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)(=O)C1C=CC=CC=1>>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[O:14][CH3:15])[C:6]([C:5]1[CH:18]=[CH:19][CH:20]=[CH:3][CH:4]=1)=[O:7]
Reactant: COc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1OC
Solvent: O=C(Cl)c1ccccc1
Product: COc1ccc(C(=O)c2ccccc2)cc1OC

Procedure:
3,4-Dimethoxybenzophenone was prepared analogously to 3,4,3',4'-tetramethoxybenzophenone using veratrole (2 mL, 15 mmol), aluminum chloride (2.2 g, 16.5 mmol) and benzoyl chloride (1.8 mL, 15.5 mmol). The crude mixture was purified by flash column chromatography (silica gel, 3% ethyl acetate/methylene chloride) to yield 3.44 g (93%) of the product as a white solid: mp 99-100° C.; 1H NMR (CDCl3) δ 7.82-7.30 (m, 7 H), 6.95-6.85 (m, 1 H), 3.96 (s, 3 H), 3.94 (s, 3 H); 13C NMR (CDCl3) δ 195.5, 153.0, 149.0, 138.2, 131.8, 130.2, 129.6, 128.1, 125.4, 112.1, 109.7, 56.0, 56.0; Anal. Calcd for C15H14O3. Theoretical: C, 74.36; H, 5.82. Found: C, 74.21; H, 6.01.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:9]([CH2:20][CH2:21]/[CH:22]=[CH:23]/[N+:24]([O-:26])=[O:25])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]1[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O.O.C(=O)(O)[O-].[Na+]>O1CCOCC1.C(Cl)Cl.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:9]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:20][CH2:21][C@@H:22]([C:39]1[CH:38]=[CH:37][CH:36]=[C:35]([F:34])[C:40]=1[F:41])[CH2:23][N+:24]([O-:26])=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccc(F)c1F
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CC/C=C/[N+](=O)[O-])C(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CC[C@H](C[N+](=O)[O-])c1cccc(F)c1F)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 87.4 %

Procedure:
A solution of benzyl (2R,5E)-2-[bis(tert-butoxycarbonyl)amino]-6-nitrohex-5-enoate (34.0 g, 73.2 mmol), 2,3-difluorophenylboronic acid (28.9 g, 183.0 mmol) and water (4.62 mL, 256.2 mmol) in dioxane (240 mL) was degassed with argon for 15 min. To this solution was added sodium bicarbonate (3.08 g, 36.6 mmol), (S)-BINAP (1.28 g, 2.05 mmol) and acetylacetanotobis(ethylene)rhodium(I) (0.472 g, 1.83 mmol). The mixture was stirred at RT for 2 min then heated to 35° C. After 4 h, 255 mg of (S)-BINAP and 94 mg of acetylacetanotobis(ethylene)rhodium(I) were added. After an additional 2 h the reaction was diluted with DCM/NaHCO3, the layers separated and the aqueous phase was backwashed with another portion of DCM. The combined organics were dried over magnesium sulfate, filtered and concentrated to give a residue that was purified by silica gel chromatography (5%→60% ethyl acetate/hexanes) to give the title compound (37.0 g, 87%) contaminated with ˜5% 5R isomer. MS 379.1 (M+1-2Boc).
Reaction SMILES: N[C:2]1C(C(OC)=[O:11])=NC(I)=C(N)N=1.[C-]#N.[Na+].O.[NH2:18][C:19]1[C:20]([C:28]([OH:30])=[O:29])=[N:21][C:22]([C:26]#[N:27])=[C:23]([NH2:25])[N:24]=1.[NH2:31][C:32]1[C:33]([C:41]([OH:43])=[O:42])=[N:34][C:35]([C:39]#[N:40])=[C:36]([NH2:38])[N:37]=1>CN(C)P(N(C)C)(N(C)C)=O>[OH2:11].[NH2:18][C:19]1[C:20]([C:28]([O:30][CH3:2])=[O:29])=[N:21][C:22]([C:26]#[N:27])=[C:23]([NH2:25])[N:24]=1.[CH3:2][O:42][C:41]([C:33]1[C:32]([NH2:31])=[N:37][C:36]([NH2:38])=[C:35]([C:39]#[N:40])[N:34]=1)=[O:43]
Reactant: COC(=O)c1nc(I)c(N)nc1N
Reactant: N#Cc1nc(C(=O)O)c(N)nc1N
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: COC(=O)c1nc(C#N)c(N)nc1N
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Methyl 3,5-diamino-6-iodo-2-pyrazinoate (370 mg., 0.0012 mole), cuprous cyanide (215 mg., 0.0024 mole) and hexamethylphosphoramide (10 ml.) are combined and heated at 100° C. for 15 minutes. After cooling to 25° C. the reaction mixture is added to aqueous sodium cyanide solution, stirred at 25° C. for 1 hour and extracted with CHCl3. The CHCl3 layer was washed with dilute NaCN solution, then with H2O, and dried (MgSO4). After evaporation of the CHCl3, the residual oil was treated with hexane to give 75 mg. of methyl, 3,5-diamino-6-cyano-2-pyrazinoate hemihydrate melting at 284°-5° C.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[NH:6][C:4](=[O:5])[C:3]=1Br.C(=O)([O-])O.[Na+].[C:15]1([SH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[C:15]1([S:21][C:3]2[C:4](=[O:5])[NH:6][C:7](=[O:8])[C:2]=2[S:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Sc1ccccc1
Reactant: O=C1NC(=O)C(Br)=C1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=C1NC(=O)C(Sc2ccccc2)=C1Sc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.6 %

Procedure:
To dibromomaleimide (80.0 mg, 0.3 mmol) and sodium hydrogencarbonate (130.2 mg, 1.6 mmol) in methanol (6 ml) was slowly added benzenethiol (66.6 μl, 0.7 mmol) in methanol (1 ml). The reaction was stirred for 15 min at RT. The solvent was removed in vacuo and the residual material was purified by flash chromatography on silica gel (petroleum ether: ethyl acetate, gradient elution from 9:1 to 7:3) to afford the desired product as bright yellow crystals (73 mg, 75%). λmax (50 mM sodium phosphate, pH 6.2, 40% MeCN, 2.5% DMF)/412 nm (ε/dm3 mol−1 cm−1 2245); 1H NMR (500 MHz, MeOD): δ=7.27-7.22 (m, 6H, Ar—H), 7.16-7.14 (m, 4H, Ar—H); 13C NMR (125 MHz, MeOD): δ=169.3 (C), 137.6 (C), 135.4 (C), 132.4 (CH), 130.1 (CH), 129.1 (CH); IR (solid, cm−1): 3285 (m), 3059 (w), 2924 (w), 1774 (m), 1715 (s); MS (CI) m/z, (%): 314 (M+H, 100), 206 (13), 111 (12); Mass calc. for C16H11O2NS2[H]: 314.0231. Found: 314.0309; m.p. 102-104° C. (Literature: 123-126° C.).
Reaction SMILES: C(O)/C=C\CO.[C:7]([O:11][C:12]([NH:14][CH2:15][C:16]#[C:17][CH2:18][OH:19])=[O:13])([CH3:10])([CH3:9])[CH3:8]>>[C:7]([O:11][C:12]([NH:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][OH:19])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)NCC#CCO
Agent: OC/C=C\CO
Product: CC(C)(C)OC(=O)NC/C=C\CO
Yield: 30 %

Procedure:
The title compound was synthesized from cis-2-butene-1,4-diol in an overall yield of 30% according to the procedure used for 4-tert-butoxycarbonylamino-2-butyn-1-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[C:8]([C@@H:18]([NH:23][C:24]1[C:25]3[N:33]=[CH:32][CH:31]=[CH:30][C:26]=3[N:27]=[CH:28][N:29]=1)[C:19]([F:22])([F:21])[F:20])=[CH:7]2.[H-].[Na+].[CH3:36]I.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[C:8]([C@@H:18]([N:23]([C:24]1[C:25]3[N:33]=[CH:32][CH:31]=[CH:30][C:26]=3[N:27]=[CH:28][N:29]=1)[CH3:36])[C:19]([F:22])([F:21])[F:20])=[CH:7]2
Reactant: CI
Reactant: FC(F)(F)[C@H](Nc1ncnc2cccnc12)c1cc2cccc(Cl)c2nc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1ncnc2cccnc12)[C@H](c1cc2cccc(Cl)c2nc1-c1cccnc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 16.9 %

Procedure:
A stirred solution of Example 1 (92 mg, 0.197 mmol) in DMF (10 mL) was cooled to 0° C. NaH (60%; 9 mg, 0.217 mmol) was added and the mixture was stirred at 0° C. for 5 minutes. Methyl iodide (30 mg, 0.207 mmol) was added and the mixture was stirred at r.t. for 16 h. Water (0.5 mL) was added and the mixture was evaporated in vacuo. The residue was partitioned between DCM and water. The aqueous phase was extracted with further DCM, the combined organic fractions were washed with brine and dried Na2SO4), then the solvent was evaporated in vacuo. The residue was purified twice by column chromatography (SiO2, 0-35% MeOH in EtOAc) to give the title compound (16 mg, 17%) as an off-white solid. δH (DMSO-d6) 9.00 (d, J 1.7 Hz, 1H), 8.77 (dd, J 4.8, 1.6 Hz, 1H), 8.73-8.70 (m, 2H), 8.27 (dt, J 7.8, 1.8 Hz, 1H), 8.11 (dd, J 8.3, 1.2 Hz, 1H), 8.01 (s, 1H), 7.98 (dd, J 7.5, 1.2 Hz, 1H), 7.85 (dd, J 8.5, 1.2 Hz, 1H), 7.71 (dd, J 8.5, 4.4 Hz, 1H), 7.66-7.56 (m, 2H), 5.93 (q, J 7.7 Hz, 1H), 3.53 (s, 3H). LCMS (ES+) 481 (M+H)+, RT 2.31 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:23])=[C:5]([N:9]=C(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=[N:7][CH:8]=1.Cl.C1COCC1.[OH-].[Na+]>>[CH3:1][O:2][C:3]1[C:4]([CH3:23])=[C:5]([NH2:9])[CH:6]=[N:7][CH:8]=1
Reactant: COc1cncc(N=C(c2ccccc2)c2ccccc2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cncc(N)c1C
Temperature: 55 °C

Procedure:
To 5-methoxy-4-methyl-N-(diphenylmethylene)pyridine-3-amine (0.7g) in a single neck round bottle flask, was added 14 ml of 1N HCl/THF (1:1) and the resulting mixture heated at 55° C. for 1 h. The reaction was basified with 1N NaOH to pH9, extracted with DCM, dried over Na2SO4, and concentrated to dryness under vacuum affording 5-methoxy-4-methyl-pyridin-3-ylamine. MS (ESI+) for m/z 139 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]3[CH2:20][CH2:21][O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:18]=3[N:17]=[C:16]([NH2:29])[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:11]1([C:14]2[C:19]3[CH2:20][CH2:21][O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:18]=3[N:17]=[C:16]([NH2:29])[N:15]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(N)nc3c2CCOc2ccccc2-3)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc2c(c(N3CCNCC3)n1)CCOc1ccccc1-2
Temperature: 60 °C

Procedure:
A solution of Example 30A (38 mg, 0.096 mmol) in CH2Cl2 (1 mL) was treated with TFA (2 mL), heated at 60° C. for 2 minutes, cooled, concentrated under reduced pressure and chromatographed on silica gel eluting with a gradient of 2, 3.5, 5 and 10% (9:1 MeOH: saturated aqueous NH4OH) in CH2Cl2 to provide the title compound. 1H NMR (CDCl3) δ 2.72 (t, J=5.93 Hz, 2H), 2.91-3.09 (m, 4H), 3.26-3.46 (m, 4H), 4.54 (t, J=5.93 Hz, 2H), 4.79 (s, 2H), 7.09 (dd, J=7.97, 1.19 Hz, 1H), 7.17-7.26 (m, 1H), 7.34-7.41 (m, 1H), 7.89 (dd, J=7.63, 1.86 Hz, 1H); MS (M+H)+ m/z 298.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][CH:5]([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH2:4][O:3]1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[O:6][CH:5]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=2)(=[O:21])=[O:20])[CH2:4][O:3]1
Reactant: CC1(C)OCC(CCCCO)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCCC2COC(C)(C)O2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred, ice-cold solution of 6.97 g. of 2,2-dimethyl-4-(4-hydroxybutyl)-1,3-dioxolane [Chem. Abstr., 67, 32617f (1967)] in 40 ml. of pyridine is added 9.2 g. of p-toluenesulfonyl chloride. The mixture is kept at 0°-5° C. overnight, diluted with ice water, and extracted with ether. The extract is washed successively with water, sodium bicarbonate, water, and brine. The extract is dried over magnesium sulfate and concentrated to give a syrup; pmr (CDCl3) δ 2.50 (singlet).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH:16]=O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:18][NH2:19]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:16][NH:19][CH3:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CN
Reactant: O=CC1(c2ccc3c(c2)OCO3)CCCCC1
Product: CNCC1(c2ccc3c(c2)OCO3)CCCCC1
Yield: 88.1 %

Procedure:
The title compound was prepared from 1-(benzo[d][1,3]dioxol-5-yl)cyclohexanecarbaldehyde (232 mg, 1.0 mmol) and methylamine (2.0 M in THF, 3 ml, 6.0 mmol) according to General Procedure H2.The crude product was purified by silica gel column chromatography (SiO2, MeOH/CH2Cl2, MeOH from 0% to 20%) to give 1-(1-(benzo[d][1,3]dioxol-5-yl)cyclohexyl)-N-methylmethanamine (218 mg, 88%). 1H NMR (CDCl3): δ 1.26-1.52 (m 4H), 1.54-1.61 (m, 2H), 1.66-1.73 (m, 2H), 2.03-2.12 (m, 2H), 2.28 (s, 3H), 2.60 (s, 2H), 5.90 (s, 2H), 6.75-6.86 (m, 2H), 6.90 (s, 1H). 13C NMR (CDCl3) δ 22.3, 26.7, 35.2, 37.4, 42.3, 64.8, 101.0, 107.6, 108.2, 120.3, 139.4, 145.6, 148.1.ESI MS m/z 248.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([OH:13])[CH:4]=1)[CH3:2].[Br:14]Br.O>C(O)(=O)C>[Br:14][C:12]1[C:3]([CH2:1][CH3:2])=[CH:4][C:5]([OH:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: BrBr
Reactant: CCc1ccc(C(=O)OC)c(O)c1
Solvent: CC(=O)O
Solvent: O
Product: CCc1cc(O)c(C(=O)OC)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.5 %

Procedure:
To a solution of methyl 4-ethyl-2-hydroxybenzoate (1.43 g) in acetic acid (15.0 mL) was added bromine (1.40 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hr under argon atmosphere. To the reaction mixture was added water, the resulting solid was collected by filtration, and dried under reduced pressure to give the title compound (2.21 g) as a mixture with methyl 3,5-dibromo-4-ethyl-2-hydroxybenzoate (2:1). This compound was used in the next step without an additional purification.
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:23]=[CH:22][C:7]([C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[C:17]([O:19]CC)=[O:18])=[O:9])=[CH:6][CH:5]=1.C(O)C.[OH-].[Na+].O>CCCCCCC.C1(C)C=CC=CC=1>[F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[C:17]([OH:19])=[O:18])=[O:9])=[CH:22][CH:23]=1
Reactant: CCOC(=O)[C@H]1CCCC[C@H]1NC(=O)c1ccc(OC(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCC
Solvent: CCO
Solvent: O
Product: O=C(N[C@@H]1CCCC[C@@H]1C(=O)O)c1ccc(OC(F)F)cc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
In a 100 ml three-mouthed flask were charged crude (1S,2R)-ethyl 2-{4-(difluoromethoxy)benzoyl}aminocyclohexane-1-carboxylate (14 g, 41.0 mmol), and ethanol (42 ml), and the mixture was heated to 40° C. 5N Aqueous sodium hydroxide solution (9 ml, 45 mmol) was added, and the mixture was stirred at 40° C. for 2 hr 30 min. After cooling to 25° C., water (89 ml), toluene (28 ml) and heptane (28 ml) were added. The mixture was stirred and the aqueous layer was obtained. The aqueous layer was washed with a mixture of toluene (28 ml) and heptane (28 ml). To the aqueous layer was added acetonitrile (14 ml), and 6N hydrochloric acid and water (47 ml) were added to give crystals. The resulting crystals were collected by filtration, washed with water (70 ml) and then dried to give the title compound as a crude product. Recrystallization from an acetonitrile (80 ml)-water (120 ml) system gave the title compound as pale-gray crystals. yield 8.3 g. (diastereomeric excess>99.9% de) (enantiomeric excess>99.9% ee)
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH2:43][CH2:44][OH:45])[CH:40]=[CH:41][CH:42]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:45][CH2:44][CH2:43][C:39]3[CH:40]=[CH:41][CH:42]=[C:37]([O:36][CH3:35])[CH:38]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH2:23]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(O)cc2)c1N1CCC(C)(C)CC1
Reactant: COc1cccc(CCO)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc(CCOc2ccc(-c3c(C)nc(C)c([C@H](OC(C)(C)C)C(=O)O)c3N3CCC(C)(C)CC3)cc2)c1
Reaction time: 18 h
Yield: 48.8 %

Procedure:
To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (20 mg, 0.043 mmol), 2-(3-methoxyphenyl)ethanol (32.5 mg, 0.213 mmol) and Ph3P-resin (55.8 mg, 0.213 mmol) in THF (2 mL) was added DEAD (0.014 mL, 0.085 mmol) at rt. After 18 h, mixture was filtered to remove polymer, concentrated and treated with 1N NaOH (0.854 mL, 0.854 mmol) in MeOH (1 mL) at 75° C. for 16 h. Mixture was then cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-(3-methoxyphenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetic acid (11.9 mg, 0.021 mmol, 48.5% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.26-7.18 (m, 2H), 7.07-6.98 (m, 3H), 6.94-6.87 (m, 2H), 6.82-6.78 (m, 1H), 5.81 (s, 1H), 4.31-4.17 (m, 2H), 3.31 (br. s., 2H), 3.04 (t, J=6.8 Hz, 2H), 2.86-2.76 (m, 1H), 2.43 (s, 3H), 2.16 (br. s., 1H), 2.05 (s, 3H), 1.98-1.92 (m, 1H), 1.50 (br. s., 1H), 1.36-1.23 (m, 1H), 1.17 (d, J=11.7 Hz, 1H), 1.12 (s, 9H), 1.02 (d, J=14.7 Hz, 1H), 0.85 (s, 3H), 0.61 (s, 3H). 2H of piperidine were not resolved. LCMS (M+H)=575.5.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH2:15][N:16]=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH:26]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH:38]=[N:39][NH2:40])[CH:33]=2)[CH2:27][C:28]([O:30]C)=[O:29])=[CH:20][CH:19]=1.[ClH:41]>>[ClH:41].[ClH:41].[NH2:15][N:16]=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH:26]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH:38]=[N:39][NH2:40])[CH:33]=2)[CH2:27][C:28]([OH:30])=[O:29])=[CH:20][CH:19]=1
Reactant: COC(=O)CC(CCc1ccc(C=NN)cc1)c1cccc(C=NN)c1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: NN=Cc1ccc(CCC(CC(=O)O)c2cccc(C=NN)c2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 66 %

Procedure:
Methyl 4-(aminoiminomethyl)-beta-[3-(aminoiminomethyl) phenyl]benzene pentanoate bis(trifluoroacetate) (0.030 gm, 0.08 mmol) was dissolved in 0.5 mL of 6 N HCl under N2 and stirred at room temperature for 48 hrs. The solution was concentrated to give the title compound as a white solid 0.018 gm (66%). Mp >200° C. (dec); MS: (M+H)+ 339; 1H NMR (DMSO-d6): 2.0 (m, 2H), 2.5 (m, 2H), 2.7 (dd, 1H), 2.85 (dd, 1H), 3.15(m, 1H), 7.40 (d, 2H), 7.55 (m, 2H), 7.75 (m, 4H), 9.1 (d, 4H), 9.25 (d, 4H).
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:12][C@@H:13]1[CH2:18][CH2:17][C@H:16](O)[CH2:15][CH2:14]1>>[CH3:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([O:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:15][CH2:14]1
Reactant: C[C@H]1CC[C@@H](O)CC1
Reactant: CCOC(=O)/C(=N\O)C(C)=O
Product: CCOC(=O)/C(=N\O[C@H]1CC[C@H](C)CC1)C(C)=O

Procedure:
Ethyl (Z)-2-(hydroxyimino)-3-oxobutyrate (3.0 g) was reacted with cis-4-methylcyclohexanol as described in Example 4a, Method 3, to give the title compound as a colourless liquid (1.2 g, 25%), νmax (film) 2950, 1745, 1695 cm-1, δH (CDCl3) 0.91 (3H, d), 1.02 (2H, m), 1.32 (3H, t), 1.41 (3H, m), 1.78 (2H, m), 2.10 (2H, m), 2.39 (3H, s), 4.20 (1H, m), 4.34 (2H, q); δC (CDCl3) 14.1, 21.7, 25.1, 31.2 (2C), 31.7, 32.9 (2C), 61.8, 85.2, 149.9, 161.5, 193.0.