Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:19][C:20]([O:22][CH2:23][C:24](=[CH2:35])[CH2:25][O:26][C:27](=[O:34])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][Br:33])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[S:36]1[CH:40]=[CH:39][N:38]=[CH:37]1>>[Br-:33].[CH2:1]([NH:19][C:20]([O:22][CH2:23][C:24](=[CH2:35])[CH2:25][O:26][C:27](=[O:34])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N+:38]1[CH:39]=[CH:40][S:36][CH:37]=1)=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: c1cscn1
Reactant: C=C(COC(=O)CCCCCBr)COC(=O)NCCCCCCCCCCCCCCCCCC
Product: C=C(COC(=O)CCCCC[n+]1ccsc1)COC(=O)NCCCCCCCCCCCCCCCCCC
Product: [Br-]

Procedure:
1-Octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropane (from Preparation 9) (0.55 g) and thiazole (2.5 ml) were heated to 110° C. for 4 hours. The reaction mixture was evaporated to dryness in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH2:17](O)[CH2:18][OH:19].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:9]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[O:19][CH2:18][CH2:17][O:16]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Cc1ccccc1)c1ccc(Br)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Brc1ccc(C2(Cc3ccccc3)OCCO2)cc1
Temperature: 25 °C

Procedure:
A solution of 1-(4-bromophenyl)-2-phenylethanone (5.0 g, 18 mmol), ethylene glycol (3.0 mL, 54 mmol) and tosic acid (0.04 g, 0.2 mmol) in toluene (30 mL) was heated to reflux with a Dean-Stark trap for 15 hours. The reaction was cooled to room temperature, diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated to give crude 2-benzyl-2-(4-bromophenyl)-1,3-dioxolane as a white solid. To the crude material was added zinc cyanide (2.3 g, 20 mmol), tetrakis(triphenylphosphine)palladium (3.3 g, 2.8 mmol), DMF (20 mL) and dioxane (20 mL) and the resulting suspension was purged with nitrogen for 15 minutes prior to being heated 100° C. for 15 hours. The reaction was cooled to room temperature, poured into ether and filtered. The organic filtrate was washed with water, saturated bicarbonate, brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (1% ethyl acetate/hexane→50% ethyl acetate/hexane) gave the title compound as white solid. MS (M+H+): calculated=265.31, observed=266.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[C:11]1(=[O:18])[CH2:16][CH2:15][CH2:14][C:13](=O)[CH2:12]1.[NH2:19][C:20]1[N:24]([CH3:25])[NH:23][C:22](=[O:26])[CH:21]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[C:12]3[C:11](=[O:18])[CH2:16][CH2:15][CH2:14][C:13]=3[NH:19][C:20]3[N:24]([CH3:25])[NH:23][C:22](=[O:26])[C:21]2=3)[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: O=C1CCCC(=O)C1
Reactant: Cn1[nH]c(=O)cc1N
Product: Cn1[nH]c(=O)c2c1NC1=C(C(=O)CCC1)C2c1ccc(F)c(Br)c1
Yield: 68.8 %

Procedure:
3-Bromo-4-fluorobenzaldehyde (0.2 g, 1.0 mmol), 1,3-cyclohexanedione (0.11 g, 1.0 mmol), and 5-amino-1-methyl-1,2-dihydropyrazol-3-one (0.11 g, 1.0 mmol) were processed as described in Example I to provide 0.27 g of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 1.9 (m, 2H), 2.2 (m, 2H), 2.6 (m, 2H), 3.45 (s, 3H), 4.88 (s, 1H), 7.12 (m, 1H), 7.18 (t, 1H), 7.38 (dd, 1H), 9.53 (s, 1H), 9.72 (s, 1H); MS (ESI−) m/z 390 (M−H)−; Anal. Calcd for C11H15N3BrFO2.C2H6O: C, 52.06; H, 4.61; N, 9.85. Found: C, 51.72; H, 4.56; N, 7.98.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])=[CH:15][CH:16]=2)[O:11]1)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:23]1([S:20]([C:14]2[CH:13]=[C:12]3[C:17]([CH2:18][CH2:19][CH:10]([CH2:9][NH:7][CH3:6])[O:11]3)=[CH:16][CH:15]=2)(=[O:22])=[O:21])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CN(CC1CCc2ccc(S(=O)(=O)c3ccccc3)cc2O1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCC1CCc2ccc(S(=O)(=O)c3ccccc3)cc2O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.1 %

Procedure:
To a solution of (7-benzenesulfonyl-chroman-2-ylmethyl)-methyl-carbamic acid tert-butyl ester (125 mg, 0.299 mmol) in DCM (25 mL) was added TFA (0.5 mL). The reaction was stirred for 4 h at RT, then concentrated in vacuo. The residue was recrystallized from acetone/hexane plus EtOAc to give (7-benzenesulfonyl-chroman-2-ylmethyl)-methyl-amine (76 mg, 80% yield) as white needles: Mp 196.2-198.2° C.
Reaction SMILES: [C:1](/[C:3](=[N:9]\O)/[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C([O-])(O)=O.[Na+].[O-]S(S([O-])=O)=O.[Na+].[Na+]>O>[NH2:9][CH:3]([C:1]#[N:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)/C(C#N)=N/O
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(N)C#N
Temperature: 35 °C
Reaction time: 2 h
Yield: 43.5 %

Procedure:
To a stirred solution of (E)-ethyl 2-cyano-2-(hydroxyimino)acetate (20 g, 0.14 mol) in water (250 mL) was added a saturated solution of NaHCO3 in water (160 mL), followed by the addition of Na2S2O4 (60 g, 0.423 mol). The reaction mixture was warmed up to 35° C. and stirred for additional 2 hr. It was then saturated with NaCl (150 g) and extracted with DCM (3×350 mL). Combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give ethyl 2-amino-2-cyanoacetate as a red oil (7.8 g, 43%) that was used at the next step without additional purification. 1H-NMR (CDCl3, 500 MHz) δ (ppm): 4.45 (s, 1H), 4.34 (q, J=7.0 Hz, 2H), 1.36 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 129 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH3:26])[CH:19]=O.Cl.[CH3:28][OH:29]>C(OCC)(=O)C>[CH3:28][O:29][CH:8]1[C:7](=[CH:19][C:18]2[CH:21]=[CH:22][C:23]([O:24][CH2:25][CH3:26])=[C:16]([O:15][CH3:14])[CH:17]=2)[CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13]
Reactant: CO
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: CCOc1ccc(C=O)cc1OC
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOc1ccc(C=C2Cc3cc(OC)ccc3C(=O)C2OC)cc1OC
Temperature: 25 °C

Procedure:
After 6-methoxy-1-tetralone 1.0 g and 3-methoxy-4-ethoxybenzaldehyde 1.27 g were added to a mixture of concentrated hydrochloric acid 60 ml and methanol 50 ml, the mixture was refluxed for 2.5 hours. The reaction mixture was cooled to room temperature, and ethyl acetate 100 ml was added. The ethyl acetate solution was washed with water 100 ml twice and saturated salt solution 100 ml twice. The ethyl acetate solution was dehydrated with magnesium sulfate, and concentrated to 20 ml at 40° C. under reduced pressure. The precipitated crystals were filtered. The crystals were dried over phosphorous pentoxide for four hours under reduced pressure to obtain the desired compound 0.89 g.
Reaction SMILES: N[C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[N+]([O-])(OCCC(C)C)=O.C(Cl)(Cl)[Cl:28].[OH-].[Na+]>CC#N>[Cl:28][C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: ClC(Cl)Cl
Reactant: CCOC(=O)c1nc(N)sc1-c1ccccc1
Agent: CC(C)CCO[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CCOC(=O)c1nc(Cl)sc1-c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of ethyl 2-amino-5-phenylthiazole-4-carboxylate in MeCN was added CuCl2 at 0° C., and the isoamyl nitrate was slowly added dropwise thereto, followed by stirring for 1 hour. To the reaction mixture was added CHCl3, followed by stirring at 0° C. for 2 hours and then at room temperature for 2 hours. The reaction mixture was neutralized by addition of a 1 M aqueous NaOH solution, and filtered through Celite. The filtrate was extracted with EtOAc, and the organic layer was washed with water and brine in this order and then dried over MgSO4. After concentration under reduced pressure, the residue obtained was purified by medium-pressure preparative liquid chromatography (silica gel YAMAZEN YFLC WPrep2XY, hexane:EtOAc) to obtain ethyl 2-chloro-5-phenylthiazole-4-carboxylate as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][CH2:18][N:19]([C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH2:20][CH:21]=2)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[H][H]>O1CCCC1.[C].[Pd]>[C:1]([O:5][C:6](=[O:28])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:17][CH2:18][N:19]([C:22](=[O:27])[C:23]([F:25])([F:26])[F:24])[CH2:20][CH2:21]2)=[CH:12][CH:11]=1)[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C2=CCN(C(=O)C(F)(F)F)CC2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C2CCN(C(=O)C(F)(F)F)CC2)cc1
Yield: 106.1 %

Procedure:
50 mg of the t-butyl((1S)-1-{4-[1-(trifluoroacetyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}ethyl)carbamate [154-3] was dissolved in 3 mL of tetrahydrofuran, then a catalytic amount of 10% palladiumcarbon catalyst was added thereto, and stirred at room temperature for 1 hour in a hydrogen atmosphere. The insolubles were filtered through celite, the filtrate was concentrated under reduced pressure, and 53.3 mg of t-butyl((1S)-1-{4-[1-(trifluoroacetyl)piperidin-4-yl]phenyl}ethyl)carbamate [155-1] was obtained as a white solid.
Reaction SMILES: C(N(CC)CC)C.[C:8]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Cl[C:22]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[C:23]([C:26]#[N:27])[C:24]#[N:25]>CCO>[C:26]([C:23]([C:24]#[N:25])=[C:22]([N:18]1[CH2:17][CH2:16][N:15]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:20][CH2:19]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)#[N:27]
Reactant: N#CC(C#N)=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=C(C#N)C#N)c2ccccc2)CC1
Reaction time: 16 h

Procedure:
Triethyl amine (1 ml) was added into a solution of N-Boc piperazine (1 g) and 2-(chloro(phenyl)methylene)malononitrile (1 g) in EtOH (20 ml). After 16 hours at 115° C., the reaction mixture was cooled down and some of desired product, tert-butyl 4-(2,2-dicyano-1-phenylvinyl)piperazine-1-carboxylate, precipitated out from the solution. After filteration, the mother solution was concentrated to offer a residue which was purified using silica gel chromatography to afford more tert-butyl 4-(2,2-dicyano-1-phenylvinyl)piperazine-1-carboxylate. 1H NMR (500 MHz, DMSO-d6) □7.53 (m, 5H), 3.93 (b, 2H), 3.61 (b, 2H), 3.36 (b, 2H), 3.15 (b, 2H), 1.39(s, 9H); 13C NMR(125 MHz, DMSO-d6) □170.9, 153.6, 132.6, 131.7, 129.1, 129.0, 117.4, 116.7, 79.4, 51.5, 50.33, 42.9, 27.9. MS m/z: (M+H)+ calcd for C19H23N4O2 339.18, found 339.17. Retention time 1.46 min (column A).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:11])=[C:6]([NH2:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH:12](O)=O>>[N+:1]([C:4]1[C:5]2[NH:11][CH:12]=[N:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])c1N
Reactant: O=CO
Product: O=[N+]([O-])c1cccc2nc[nH]c12

Procedure:
3-Nitro-1,2-phenylenediamine (0.065 moles, 10.2 g) was added to 200 ml formic acid and heated to reflux for 3 hours. The solution was cooled and then concentrated under vacuum. The residue was dissolved in water. The pH was adjusted to 8.3 using 5N sodium hydroxide. The intermediate was extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and concentrated to yield 7.0 g of 4-nitrobenzimidazole. (MS)
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]=1)[C:8]([OH:10])=O)[CH3:3].C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[S:33][N:32]=[C:31]([CH3:34])[N:30]=1.C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]=1)[C:8]([NH:28][C:29]1[S:33][N:32]=[C:31]([CH3:34])[N:30]=1)=[O:10])[CH3:1]
Reactant: CC(C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Reactant: Cc1nsc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nsc(NC(=O)c2cc(OCc3ccccc3)cc(OC(C)C)c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.6 %

Procedure:
DMF (2 drops) was added to a solution of 3-[(1-methylethyl)oxy]-5-[(phenylmethyl)oxy]benzoic acid (29.6 g, 0.103 mol) and oxalyl chloride (10.78 mL, 0.12 mol) in DCM (500 mL) The mixture was stirred at ambient temperature for 4 hours and the DCM and excess oxalyl chloride removed in vacuo. The residual acid chloride was dissolved in DCM (220 mL) and added dropwise to 5-amino-3-methyl-1,2,4-thiadiazole (12.43 g, 0.108 mol) and triethylamine (30.34 mL, 0.216 mol) in DCM (220 mL), at 0° C. The reaction was allowed to warm and stirred at ambient temperature for 72 hours. The DCM was removed in vacuo, and the residue partitioned between ethyl acetate (400 mL) and 1N hydrochloric acid (200 mL). The ethyl acetate layer was washed sequentially with saturated aqueous sodium hydrogen carbonate (200 mL) and brine (100 mL), dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silica, eluting with a gradient of 20% ethyl acetate in isohexane, to give the desired compound (33 g).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[CH:19]2[CH2:23][CH2:22][S:21][CH2:20]2)=[C:12]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:11]=1>>[ClH:9].[ClH:9].[NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][N:16]3[CH:19]3[CH2:23][CH2:22][S:21][CH2:20]3)=[C:12]([NH:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:11]=2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Clc1nc(Nc2ccccc2)c2ncn(C3CCSC3)c2n1
Product: Cl
Product: NC1CCC(Nc2nc(Nc3ccccc3)c3ncn(C4CCSC4)c3n2)CC1
Reaction time: 0.5 h
Yield: 127.9 %

Procedure:
The operation is carried out as in Stage 3 of Example 5 starting from 536 mg of trans-1,4-diaminocyclohexane and 156 mg of the product obtained in Stage 1 above, the reaction medium is taken to a temperature of approximately 140 to 145° C. for approximately 4 hours 30 minutes then left to return to ambient temperature. After purification on silica eluting with methanol/ammonium hydroxide (NH4OH) in a proportion of 98/2 salification is carried out with 1.4 N hydrochloric acid in ethanol, followed by separating, washing and drying at a temperature of approximately 50° C. In this way 145 mg of expected product is obtained in the form of pink beige crystals.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][C:32]([Cl:34])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[CH:31][C:32]([Cl:34])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(Cl)ccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2cc(Cl)ccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-5-chloro-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: C[CH:2]1[CH:7]([CH2:8]Br)[CH2:6][CH2:5][CH2:4][S:3]1(=[O:11])=[O:10].C1(O)C=CC=CC=1.[OH:19][C@@H:20]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=1)[CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]>>[O:11]=[S:3]1(=[O:10])[CH2:4][CH2:5][CH2:6][CH:7]([CH2:8][O:37][C:33]2[CH:32]=[C:31]([C@H:20]([OH:19])[CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[CH:36]=[CH:35][CH:34]=2)[CH2:2]1
Reactant: CC1C(CBr)CCCS1(=O)=O
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(O)c1
Solvent: Oc1ccccc1
Product: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(OCC2CCCS(=O)(=O)C2)c1

Procedure:
Reaction between methyl 3-(bromomethyl)tetrahydro-2H-thiopyran 1,1-dioxide and phenol (7, Intermediate I) following the method used in Example 7 gave tert-butyl ((3R)-3-(3-((1,1-dioxidotetrahydro-2H-thiopyran-3-yl)methoxy)phenyl)-3-hydroxypropyl)carbamate as a light pink semi-solid. Yield (0.43 g, 65%); 1H NMR (400 MHz, CDCl3): δ 7.24 (t, J=8.0 Hz, 1H), 6.93 (d, J=8.0 Hz, 2H), 6.77-6.75 (m, 1H), 4.86 (bs, 1H), 4.72-4.70 (m, 1H), 3.95-3.92 (m, 1H), 3.90-3.88 (m, 1H), 3.38 (s, 1H), 3.26-3.22 (m, 1H), 3.18-3.13 (m, 1H), 3.06 (d, J=4.0 Hz 1H), 2.97-2.88 (m, 2H), 2.65 (bs, 1H), 2.20-2.04 (m, 2H), 1.99-1.95 (m, 1H), 1.84-1.81 (m, 2H), 1.45 (s, 9H). MS: m/z 414.43 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: O=c1[nH]c2nccc(-c3ccc(Cl)cc3)c2c2ccccc12
Yield: 8.9 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 153 using Compound 83 (50 mg, 0.22 mmol) and 4-chlorophenylboronic acid (44 mg, 0.33 mmol) to provide 154 (6 mg, 9% yield) as a white solid. LC-MS (M+H=307, obsd.=307).
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH2:6][CH:7]=[CH:8][CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]([CH:16]([CH3:18])[CH3:17])[NH2:15])[CH:3]=[N:4]O.N.[H][H].O>CO.[Ni]>[CH:16]([CH:14]([NH2:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:2]([CH3:1])([CH3:19])[CH2:3][NH2:4])([CH3:18])[CH3:17]
Reactant: CC(C)C(N)CC=CCCC=CCC(C)(C)C=NO
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: O
Solvent: CO
Product: CC(C)C(N)CCCCCCCCC(C)(C)CN
Temperature: 100 °C
Reaction time: 5 h
Yield: 92.7 %

Procedure:
490 g (1.84 mols) of 2,2-dimethyl-11-isopropyl-11-amino-undeca-4,8-dienal-oxime is dissolved in 2.4 liters of methanol, and the solution is transferred, together with about 200 g of liquid ammonia, with the addition of 150 g of Raney nickel, to a 6.3-liter steel autoclave. Hydrogen is subsequently injected up to a pressure of 100 bars, and the temperature is raised to 100° C. with stirring. Hydrogenation is performed for about 5 hours under these conditions; the mixture is then cooled, and the ammonia and excess hydrogen are released. Subsequent distillation under high vacuum yields 436 g (1.705 mols) of 1-isopropyl-10,10-dimethyl-1,11-diaminoundecane in the form of colourless liquid clear as water; yield 92.6% of theory; b.p. 87° C./4 Pa; nD20 =1.4619.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH:11]([CH2:17][C:18](=O)C)C(OCC)=O)=[CH:5][CH:4]=1.[OH-:22].[K+]>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH2:10][CH2:11][C:17](=[O:22])[CH:18]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(CC(C)=O)CC(=O)c1ccc(OC)cc1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: COc1ccc(C2=CC(=O)CC2)cc1
Yield: 64.4 %

Procedure:
To ethyl 2-[2-(4-methoxyphenyl)-2-oxoethyl]-4-oxopentanoate (26.2 g) there was added 1000 ml of 1% aqueous potassium hydroxide solution, and the mixture was refluxed for an hour. Next, potassium hydroxide was added so that the aqueous potassium hydroxide solution reached a concentration of 10% (adding a solution of 146 g of potassium hydroxide in 200 ml of water), and the mixture was further refluxed for 2 hours. After allowing the reaction solution to cool, extraction was performed with ethyl acetate and water washing was then followed by drying with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to produce crude crystals which were then washed with diethyl ether to give 11.4 g of 3-(4-methoxyphenyl)-2-cyclopenten-1-one (64.4% yield).
Reaction SMILES: [OH:1][CH:2]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1>>[F:31][C:32]1[CH:37]=[CH:36][C:35]([O:1][CH:2]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[CH:34][CH:33]=1
Reactant: COc1ccc(C(O)CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1
Reactant: Oc1ccc(F)cc1
Product: COc1ccc(C(CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)Oc2ccc(F)cc2)cc1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-hydroxy-3-(4-methoxyphenyl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-fluorophenol: ESMS m/e: 505.5 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([CH2:11][NH:12][C:13]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)=[O:14])[N:10]=2)[CH2:3]1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[CH3:20][S:21]([O:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([CH2:11][NH:12][C:13]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)=[O:14])[N:10]=2)[CH2:3]1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NCc1csc(N2CC(O)C2)n1)c1cccs1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(c2nc(CNC(=O)c3cccs3)cs2)C1
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of 3-hydroxy-1-[4-(thiophene-2-carbonyl-amino)methyl-1,3-thiazol-2-yl]azetidine (571 mg, 1.93 mmol) (obtained as described in Reference Example 66(2)) in methylene chloride (28 ml) were added methanesulfonyl chloride (0.18 ml, 2.32 mmol) and triethylamine (0.33 ml, 2.32 mmol) in an ice bath and the mixture was stirred for 1 hour. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (1:1) as the eluant to afford 3-methanesulfonyloxy-1-[4-(thiophene-2-carbonyl-amino)methyl-1,3-thiazol-2-yl]azetidine (490 mg, yield 91%) as a pale yellow solid.