Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1([F:16])[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C.[NH2:35][C:36]1[CH:48]=[C:47]([N:49]2[CH2:54][CH2:53][N:52]([CH3:55])[CH2:51][CH2:50]2)[CH:46]=[CH:45][C:37]=1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>ClCCl.C(OCC)(=O)C>[F:8][C:9]1([F:16])[CH2:14][CH2:13][CH:12]([NH:35][C:36]2[CH:48]=[C:47]([N:49]3[CH2:54][CH2:53][N:52]([CH3:55])[CH2:51][CH2:50]3)[CH:46]=[CH:45][C:37]=2[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:11][CH2:10]1
Reactant: O=C1CCC(F)(F)CC1
Reactant: CN1CCN(c2ccc(C(=O)OC(C)(C)C)c(N)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2ccc(C(=O)OC(C)(C)C)c(NC3CCC(F)(F)CC3)c2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 102.9 %

Procedure:
1.045 ml (13.57 mmol) of trifluoroacetic acid, 1 g (7.46 mmol) of 4,4-difluorocyclohexanone and 2.158 g (8.20 mmol) of tetramethylammonium triacetoxyborohydride are added to 1.521 g (5.22 mmol) of tert-butyl 2-amino-4-(4-methylpiperazin-1-yl)benzoate dissolved in 60 ml of dichloromethane. The reaction is left under stirring at room temperature for 24 hours. The solvent is evaporated and then the crude reaction product is redissolved in 30 ml of ethyl acetate. The solution is successively washed with 0.5 M HCl solution, 0.5 M soda solution and finally with saturated NaHCO3 solution. The organic phase is dried on sodium sulfate, filtered and concentrated to obtain 2.2 g of tert-butyl 2-(4,4-difluorocyclohexylamino)-4-(4-methylpiperazin-1-yl)benzoate in the form of a light brown gum (yield=72%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[I-:17].[Na+]>CC(C)=O>[I:17][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(C)(C)OCCCCCCBr
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)(C)OCCCCCCI
Yield: 102.6 %

Procedure:
To 76 ml of a solution of 12.16 g of ethyl 2-(6-bromohexyloxy)-2-methylpropionate in acetone, 18.52 g of sodium iodide was added, and heated to reflux for 18 hours. The reaction solution was cooled, filtered to remove insolubles and washed with acetone. The filtrate was concentrated and, after addition of water, extracted with ethyl acetate. The organic layer was washed with water and brine sequentially, dried over anhydrous magnesium sulfate and concentrated to provide 14.46 g of the objective compound as red-yellow oil.
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([O:9][C:10]([N:12]1[CH:17]=[C:16]([C:18]2([CH2:29][C:30]3[CH:35]=[C:34]([Cl:36])[N:33]=[C:32]([Cl:37])[CH:31]=3)[C:26]3[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:28])[CH2:15][CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>C(O)(=O)C>[C:5]([O:9][C:10]([N:12]1[CH:17]=[C:16]([C:18]2([CH2:29][C:30]3[CH:35]=[C:34]([Cl:36])[N:33]=[C:32]([Cl:37])[CH:31]=3)[C:26]3[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:28])[CH:15]=[CH:14][CH2:13]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1C=C(C2(Cc3cc(Cl)nc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)CCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1C=C(C2(Cc3cc(Cl)nc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C=CC1
Temperature: 60 °C

Procedure:
Sodium cyanoborohydride (0.37 g, 5.89 mmol) was added to a solution of rac-5-[6-chloro-3-(2,6-dichloro-pyridin-4-ylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.3 g, 0.589 mmol) (from Example 23 supra) in acetic acid (6 mL). The mixture was heated at 60° C. for 16 hours. After cooling, the solvent was evaporated in vacuo. To the residue was added saturated aqueous sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic layers were separated, combined, dried over Na2SO4 and concentrated. The residue was purified by chromatography (ethyl acetate-dichloromethane, 1:9, V/V) to give rac-5-[6-chloro-3-(2,6-dichloro-pyridin-4-ylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-pyridine-1-carboxylic acid tert-butyl ester as a white solid. (Yield 0.2 g, 67%). Further purification by recrystallization from dichloromethane-hexanes gave the product as a white solid. (Yield 0.075 g).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[C:20]2[CH:21]=[CH:22][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])=[N:24][CH:25]=2)=[CH:4][CH:3]=1.[Cl:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[C:39]([CH3:46])[CH:38]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:19])[F:18])=[CH:12][C:11]=3[C:20]3[CH:21]=[CH:22][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])=[N:24][CH:25]=3)=[CH:4][CH:3]=2)=[C:39]([CH3:46])[CH:38]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2CNc2ccc(I)cc2)cn1
Reactant: Cc1cc(Cl)ccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2CNc2ccc(-c3ccc(Cl)cc3C)cc2)cn1
Temperature: 25 °C

Procedure:
Ethyl 3-(5-(2-(((4-iodophenyl)amino)methyl)-5-(trifluoromethyl)phenyl)picolinamido)propanoate (150 mg, 0.25 mmol), (4-chloro-2-methylphenyl)boronic acid (51 mg, 0.30 mmol), Pd(dppf)Cl2 (21 mg, 0.03 mmol), and K2CO3 (69 mg, 0.50 mmol) were dissolved in 1,4-dioxane (1.6 mL) and water (0.4 mL) and the resulting mixture was heated to 80° C. After 16 h the resulting mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
Reaction SMILES: C(OP([CH:9]([CH:12]([CH3:14])[CH3:13])[C:10]#[N:11])(OCC)=O)C.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:25][C:26](=[CH:28][CH2:29][CH2:30]/[C:31](=[CH:33]/[CH:34]=O)/[CH3:32])[CH3:27].O>C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[CH3:14][CH:12]([C:9](=[CH:34][CH:33]=[C:31]([CH3:32])[CH2:30][CH2:29][CH:28]=[C:26]([CH3:27])[CH3:25])[C:10]#[N:11])[CH3:13]
Reactant: CCOP(=O)(OCC)C(C#N)C(C)C
Reactant: CC(C)=CCC/C(C)=C/C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: O
Product: CC(C)=CCCC(C)=CC=C(C#N)C(C)C
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
To a solution of 2-(diethylphosphono)isovaleronitrile (6.54 g, 30 mmol) in toluene (55 ml) was added a 0.5 M solution of potassium bis(trimethylsilyl)amide in toluene (56 ml) with stirring on a cooling bath at -70° C. After 30 minutes, geranial (3.80 g, 25 mmol) was added thereto with continuous stirring at the same temperature, and then the reaction mixture was warmed up to room temperature. After addition of water to the mixture, the organic layer was extracted. The organic extract was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over MgSO4, and filtered. The filtrate was concentrated to give a residue, which was then subjected to silica gel column chromatography (solvent: n-hexane/ethyl acetate=100:1) to give 2-(1-methylethyl)-5,9-dimethyl-2,4,8-decatrienenitrile (4.87 g, 90%, 2Z:2E=22.4:1).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[S:3]([O:6][C:7]1[NH:11][N:10]=[C:9]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[CH:13]=2)[CH:8]=1)(=[O:5])=[O:4].O[CH:27]([C:29]1[CH:46]=[CH:45][C:32]([C:33]([NH:35][CH2:36][CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:34])=[CH:31][CH:30]=1)[CH3:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[CH3:23][O:22][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:9]1[CH:8]=[C:7]([O:6][S:3]([C:2]([F:1])([F:24])[F:25])(=[O:5])=[O:4])[N:11]([CH:27]([C:29]3[CH:46]=[CH:45][C:32]([C:33]([NH:35][CH2:36][CH2:37][C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])=[O:34])=[CH:31][CH:30]=3)[CH3:28])[N:10]=1)[CH:21]=[CH:20]2
Reactant: CC(O)c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1
Reactant: COc1ccc2cc(-c3cc(OS(=O)(=O)C(F)(F)F)[nH]n3)ccc2c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc2cc(-c3cc(OS(=O)(=O)C(F)(F)F)n(C(C)c4ccc(C(=O)NCCC(=O)OC(C)(C)C)cc4)n3)ccc2c1
Reaction time: 2 h
Yield: 30.8 %

Procedure:
3-(6-Methoxy-2-naphthyl)-1H-pyrazol-5-yl trifluoromethanesulfonate (1.36 g, 3.65 mmol), tert-butyl N-[4-(1-hydroxyethyl)benzoyl]-β-alaninate (1.2 g, 4.02 mmol), and triphenylphosphine (1.44 g, 5.48 mmol) were suspended in DCM (25 ml). Diisopropyl azodicarboxylate (0.87 ml, 4.38 mmol) was added slowly. The mixture was stirred for 2 hr and then concentrated to ˜10 ml. This residue was chromatographed (SiO2, 25-30% ethyl acetate gradient) to give 0.727 g of tert-butyl N-{4-[1-(3-(6-methoxy-2-naphthyl)-5-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrazol-1-yl)ethyl]benzoyl}-β-alaninate, NMR (500 MHz, CDCl3) δ: 1.45 (s, 9H); 2.01 (d, J=7.1 Hz, 3H); 2.53 (t, J=5.9 Hz, 2H); 3.67 (q, J=5.9 Hz, 2H); 3.94 (s, 3H); 5.56 (q, J=7.1 Hz, 1H); 6.54 (s, 1H); 6.78 (br, 1H); 7.16 (br, 1H); 7.17 (dd, J=2.6 Hz, 9 Hz, 1H); 7.41 (d, J=8.4 Hz, 2H); 7.74 (d, J=8.4 Hz, 2H); 7.78 (d, J=8.4 Hz, 1H); 7.79 (d, J=8.5 Hz, 1H); 7.93 (dd, J=1.8 Hz, 8.5 Hz, 1H); 8.14 (d, J=1.6 Hz, 1H). MS C31H32F3N3O7S Cald: 647.19; Obsd (M+Na): 670.02 and 1.165 g of tert-butyl N-{4-[1-(5-(6-methoxy-2-naphthyl)-3-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrazol-1-yl)ethyl]benzoyl}-β-alaninate. NMR (500 MHz, CDCl3) δ: 1.46 (s, 9H); 1.85 (d, J=7.1 Hz, 3H); 2.55 (t, J=5.8 Hz, 2H); 3.68 (q, J=5.8 Hz, 2H); 3.95 (s, 3H): 5.52 (q, J=7.1 Hz, 1H); 6.23 (s, 1H); 6.85 (br, 1H); 7.16 (d, J=2.6 Hz, 1H); 7.21 (dd, J=2.6 Hz, 8.7 Hz, 1H); 7.22 (d, J=8.4 Hz, 2H); 7.24 (dd, J=1.5 Hz, 8.4 Hz, 1H); 7.62 (d, J=1.5 Hz, 1H); 7.67 (d, J=8.7 Hz, 1H); 7.71 (d, J=8.3 Hz, 2H); 7.76 (d, J=8.4 Hz, 1H). MS C31H32F3N3O7S Cald: 647.19; Obsd (M+Na): 670.20.
Reaction SMILES: CO.[OH-].[K+].O.C([O:25][CH2:26]/[CH:27]=[C:28](/[CH2:30][CH2:31]/[CH:32]=[C:33](\[CH3:45])/[CH2:34][CH2:35]/[CH:36]=[C:37](/[CH2:39][CH2:40][CH:41]=[C:42]([CH3:44])[CH3:43])\[CH3:38])\[CH3:29])(=O)CCCCCCCCCCCCCCCCC>CCCCCC>[CH2:35]([CH2:34][C:33](=[CH:32][CH2:31][CH2:30]/[C:28](=[CH:27]/[CH2:26][OH:25])/[CH3:29])[CH3:45])/[CH:36]=[C:37](/[CH2:39][CH2:40][CH:41]=[C:42]([CH3:44])[CH3:43])\[CH3:38]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CCC=C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Solvent: CO
Product: CC(C)=CCC/C(C)=C/CCC(C)=CCC/C(C)=C/CO
Temperature: 50 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
250 g of methanol, 4.7 g of potassium hydroxide and 10 g of water were added to 23.0 g of geranylgeranyl stearate (containing 22.08 g of geranylgeranyl stearate and 0.37 g of geranylneryl stearate) obtained as a cake in Example 2. The reaction mixture was stirred at 50° C. for 1 hour and cooled down to room temperature, to which 130 g of hexane was added. The resulting organic phase was separated, and the aqueous phase (lower phase) was washed twice with 120 g of hexane. Thereafter, the hexane washings were combined to the organic phase, followed by washing twice with 100 g of a 50% aqueous methanol. The resultant organic phase was concentrated under reduced pressure to give 12 g of crude geranylgeraniol. This crude product was subjected to simple distillation (137° C., 0.3 mmHg) to give 8.2 g of a main fraction. The results of the analysis of the obtained fraction with gas chromatography revealed that it contained geranylgeraniol with a purity of 98.1% and geranylnerol with a purity of 1.2%.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[F:24][C:25]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:26]=1[C:27](O)=[O:28]>>[F:24][C:25]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:26]=1[C:27]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:28]
Reactant: Cc1ccc(F)c(C(=O)O)c1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cc(C)ccc2F)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2-Fluoro-5-methyl-benzoic acid.
Reaction SMILES: C(C1C=CC=CC=1C(C1C=CC(C)=CC=1)=O)#N.[CH3:18][C:19]1[CH:37]=[CH:36][C:22]([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[NH:35][N:34]=[N:33][N:32]=2)=[O:24])=[CH:21][CH:20]=1.[C:38]1([C:44](Cl)([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[C:38]1([C:44]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[N:32]2[C:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[C:23](=[O:24])[C:22]3[CH:21]=[CH:20][C:19]([CH3:18])=[CH:37][CH:36]=3)=[N:35][N:34]=[N:33]2)[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: Cc1ccc(C(=O)c2ccccc2-c2nnn[nH]2)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(C(=O)c2ccccc2C#N)cc1
Product: Cc1ccc(C(=O)c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
2-Cyano-4'-methylbenzophenone, prepared as described by G. W. Ebert and R. D. Rieke in J. Organic Chem., 49, 5280-2 (1984), is converted to 5-[2-(4-methylbenzoyl)phenyl]tetrazole by the procedures described in Step 1 of Example 39. Reaction with triphenylmethyl chloride gives N-triphenylmethyl-5-[2-(4-methylbenzoyl)phenyl]tetrazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[N:13]=[C:14]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[O:15][C:16]=1[CH3:17])[CH:5]=[O:6].C(O)C.[BH4-].[Na+].O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[N:13]=[C:14]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[O:15][C:16]=1[CH3:17]
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(C=O)cc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccco2)nc1COc1ccc(CO)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
To a solution of 3-bromo-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzaldehyde (4.93 g) in tetrahydrofuran (100 mL)-ethanol (50 mL) was gradually added sodium borohydride (0.51 g) at 0° C. After stirring at room temperature for 2 hrs, water was added to the reaction mixture and the precipitated crystals were collected by filtration to give (3-bromo-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}phenyl)methanol as colorless crystals (4.40 g, yield 89%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 141-142° C.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:17])[C:13]([NH:15][CH3:16])=[O:14].[BH4-].[Na+].Cl>CO>[CH3:1][C:2]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([OH:17])[C:13]([NH:15][CH3:16])=[O:14]
Reactant: CNC(=O)C(=O)c1ccccc1COc1cc(C)ccc1C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNC(=O)C(O)c1ccccc1COc1cc(C)ccc1C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
2-[2-(2,5-Dimethylphenoxymethyl)phenyl]-N-methyl-2-oxoacetamide (0.93 g, 3.1 mmol) was dissolved in methanol (10 ml). Sodium borohydride (0.06 g, 1.6 mmol) was added slowly under ice-cooling. After stirring for 30 minutes, the mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated to give an oil. The oil was purified by column chromatography on silica gel (eluting with n-hexane - ethyl acetate) to give the desired compound 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-hydroxy-N-methylacetamide (0.85 g, 91%) as white crystals.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH3:12][C:13]1[CH:17]=[C:16]([CH3:18])[O:15][N:14]=1.Cl.C1C[O:23][CH2:22][CH2:21]1>CC(N(C)C)=O>[CH2:18]([C:16]1[O:15][N:14]=[C:13]([CH3:12])[CH:17]=1)[C:22]([CH3:21])=[O:23]
Reactant: Cc1cc(C)on1
Reactant: C1CCOC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(=O)N(C)C
Solvent: CCCCCC
Product: CC(=O)Cc1cc(C)no1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Into a 2 L flask filled with nitrogen were placed 1000 ml of anhydrous THF and 500 ml of a 1.6M n-hexane solution of n-butyl lithium. The flask was placed in a dry ice-acetone bath to set the inside temperature to −70° C., and 68.0 g of 3,5-dimethylisoxazole was slowly dropped in the flask. After the resulting solution was stirred for 30 minutes at the same temperature, a solution of 120.0 g of dimethylacetamide in 300 ml of THF was slowly dropped. After the completion of the dropping, the solution was further stirred for an hour at −60° C. to −65° C. The reaction solution was poured into 1 L of ice water acidified with hydrochloric acid. The organic layer was separated. The aqueous layer was further extracted with ethyl acetate. The obtained organic layers were combined and concentrated under reduced pressure. The obtained concentrate was dissolved in 500 ml of ethyl acetate, washed with water and then with saturated salt water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by distillation under reduced pressure to give 68.5 g of the title compound as a colorless liquid. Boiling point: 85° C./1.0 mmHg.
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])(=[O:13])=[O:12])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:31][CH2:32][O:33][CH3:34].C(OCC)(=O)C>CN(C=O)C.O>[O:23]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]([CH2:31][CH2:32][O:33][CH3:34])[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])(=[O:12])=[O:13])[CH2:4][CH2:3]1
Reactant: COCCBr
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCN1CCS(=O)(=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCN(CCN1CCS(=O)(=O)CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.8 %

Procedure:
N-(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)-2-nitrobenzenesulfonamide (0.400 g, 1.10 mmol) was combined with cesium carbonate (0.538 g, 1.65 mmol) in DMF (5 mL). The slurry was stirred at rt for 30 min, then to it was added 1-bromo-2-methoxyethane (0.306 g, 2.20 mmol). The resulting mixture was stirred at rt for 72 h. LCMS indicated incomplete conversion, so additional 1-bromo-2-methoxyethane (0.306 g, 2.20 mmol) and cesium carbonate (0.538 g, 1.65 mmol) were added and the mixture was heated to 70° C. for 1 h. Dilution with ethyl acetate (60 mL) and water (40 mL) followed by shaking gave a separation of phases. The organic phase was isolated, washed with water (2×30 mL) and brine (25 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to a residue. Purification by silica gel chromatography (gradient 100% DCM to 60:1 DCM:MeOH) gave the title compound as a yellow oil (0.486 g, 105% yield). LCMS: m/z 422 (M+H+), retention time 1.35 min (method 11). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 2.72 (t, J=6.41 Hz, 2H) 3.01 (s, 8H) 3.21 (s, 3H) 3.39-3.52 (m, 6H) 7.62-7.66 (m, 1H) 7.66-7.74 (m, J=7.48, 7.32, 7.32, 7.32, 1.68 Hz, 2H) 8.01 (dd, J=7.78, 1.68 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH2:23])=[CH:17][C:16]=1[C:24]([F:27])([F:26])[F:25].C(=O)([O-])[O-].[K+].[K+].[BH4-].[Na+].Cl>CO>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:23][CH2:22][CH2:21][C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[C:16]([C:24]([F:27])([F:25])[F:26])[CH:17]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
1.54 ml of 4-tert-butylbenzaldehyde (9.23 mmol), 1.6 g of 2-(4-chloro-3-trifluoromethyl -phenyl)-ethylamine hydrochloride (6.15 mmol) and 850 mg of potassium carbonate (6.15 mmol) were suspended in 18 ml methanol at rt, and after stirring for 30 min at rt, were refluxed for 2 h. After cooling down to rt, 349 mg (9.23 mmol) of sodium borohydride were added and after stirring for 5 min at rt, the reaction mixture was refluxed for 2.5 h. After cooling down to rt, the reaction mixture was treated with 1.2 ml 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:2) to give 2.01 g light yellow oil (88%). MS (ISP) 370.2 (M+H)+.
Reaction SMILES: C[Si](Cl)(C)C.Br[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[OH:15][C@@H:16]1[CH2:21][O:20][C:18](=[O:19])[CH2:17]1.[OH-].[Na+]>O1CCCC1.O.[Zn]>[C:11]([O:10][C:8](=[O:9])[CH2:7][C:18](=[O:19])[CH2:17][C@H:16]([OH:15])[CH2:21][OH:20])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1C[C@H](O)CO1
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)C[C@H](O)CO
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 116.1 %

Procedure:
To a suspension of 9.82 g (150 mmol) of zinc dust in 40 mL of tetrahydrofuran was added 1.9 mL (15 mmol) of trimethylsilyl chloride at room temperature, and the mixture was stirred for 30 minutes. To this mixture were added 2.4 mL (10.5 mmol) of tert-butyl α-bromoacetate and 4.27 g (42 mmol) of (S)-β-hydroxy-γ-butyrolactone, and the temperature was increased to 65° C. At the same temperature, 15.3 mL (94.5 mmol) of tert-butyl α-bromoacetate was further added gradually over 30 minutes. After completion of addition, the mixture was further stirred at 65° C. for 30 minutes, at the end of which time the reaction mixture was cooled to room temperature and diluted with 50 mL of water. The reaction mixture was then adjusted to pH 6.8 with 20% aqueous NaOH solution and the precipitated solid was filtered off. The filtrate was extracted with 3 portions of ethyl acetate, 100 mL each, and the organic layers were combined and dehydrated over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure to give a yellow oil. This residue was purified by silica gel column chromatography (Kieselgel 60, product of Merck; hexane:acetone=5:1) to give 2.66 g of (5S)-5,6-dihydroxy-3-oxohexanoic tert-butyl ester (yellow oil). Yield 29%.