Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[SH:29][CH2:30][C@@H:31]([CH3:42])[C:32]([N:34]1[C@H:38]([C:39]([OH:41])=[O:40])[CH2:37][S:36][CH2:35]1)=[O:33]>O1CCCC1.O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([S:29][CH2:30][C@@H:31]([CH3:42])[C:32]([N:34]2[C@H:38]([C:39]([OH:41])=[O:40])[CH2:37][S:36][CH2:35]2)=[O:33])=[O:11])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: C[C@H](CS)C(=O)N1CSC[C@H]1C(=O)O
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(C(=O)SC[C@@H](C)C(=O)N2CSC[C@H]2C(=O)O)cc1
Temperature: -5 °C

Procedure:
1.8 g of 4-acetylaminobenzoic acid is dissolved in 20 ml of dry tetrahydrofuran. To this solution, 1.4 ml of triethylamine is added. To this mixture, 1.3 ml of isobutyl chloroformate is added dropwise with stirring at -5° C. After ten minutes, to this solution, 20 ml of aqueous solution of 2.4 g of (4R)-3-[(2S)-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid and 1.4 ml of triethylamine is added, and the mixture is stirred at room temperature for 30 min. To this reaction solution, 40 ml of water is added, and the obtained mixture is washed with ethyl acetate. The aqueous layer is acidified with conc. hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give oil, yield 4.1 g. The oil is purified by silica gel column chromatography to give the titled compound, yield 3.6 g (90%), mp. 206°-207° C. (methanol), [α]D27 -152.5° (c=1.0, methanol).
Reaction SMILES: CN(C=O)C.[N+:6]([C:9]1[CH:10]=[CH:11][C:12]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])=[C:13]([CH:19]=1)[O:14][CH2:15][CH:16]1[CH2:18][O:17]1)([O-:8])=[O:7]>CCOC(C)=O>[N+:6]([C:9]1[CH:10]=[CH:11][C:12]([C:20]([F:26])([F:25])[C:21]([F:22])([F:23])[F:24])=[C:13]([CH:19]=1)[O:14][CH2:15][C@@H:16]1[CH2:18][O:17]1)([O-:8])=[O:7]
Reactant: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(OCC2CO2)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(OC[C@@H]2CO2)c1
Reaction time: 4 h

Procedure:
Combined 5-nitro-2-pentafluoromethylphenol (2.69 g), DMF (25 ml) K2CO3 (3.03 g) and (S) toluene-4-sulfonic acid oxiranyl-methyl ester (2.27 g) and stirred the mixture at 90° C. After about 4 hours, the mix was cooled, diluted with EtOAc, washed with H2O, 1N NaOH (2×), 1N HCl and then with brine. Dried over Na2SO4, filtered and concentrated in vacuo. Purified the crude on silica gel column with 5% EtOAc/hexane and drying under high vacuum provided the (S)-2-(5-nitro-2-pentafluoroethyl-phenoxymethyl)-oxirane.
Reaction SMILES: [CH:1]12[CH2:6][CH:4]([CH2:5]1)[CH2:3][N:2]2[C:7]1[N:12]=[C:11]([C:13]2[CH:14]=[C:15]([C:20]([F:23])([F:22])[F:21])[C:16]([NH2:19])=[N:17][CH:18]=2)[CH:10]=[C:9]([N:24]2[CH2:29][C@@H:28]3[CH2:30][C@H:25]2[CH2:26][NH:27]3)[N:8]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32].C(N(C(C)C)C(C)C)C>CS(C)=O>[NH2:19][C:16]1[N:17]=[CH:18][C:13]([C:11]2[N:12]=[C:7]([N:2]3[CH2:3][CH:4]4[CH2:5][CH:1]3[CH2:6]4)[N:8]=[C:9]([N:24]3[CH2:29][C@@H:28]4[CH2:30][C@H:25]3[CH2:26][N:27]4[C:31](=[O:33])[CH3:32])[CH:10]=2)=[CH:14][C:15]=1[C:20]([F:23])([F:22])[F:21]
Reactant: Nc1ncc(-c2cc(N3C[C@@H]4C[C@H]3CN4)nc(N3CC4CC3C4)n2)cc1C(F)(F)F
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(=O)N1C[C@@H]2C[C@H]1CN2c1cc(-c2cnc(N)c(C(F)(F)F)c2)nc(N2CC3CC2C3)n1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 45.8 %

Procedure:
To a solution of 5-(2-(2-azabicyclo[2.1.1]hexan-2-yl)-6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidin-4-yl)-3-(trifluoromethyl)pyridin-2-amine (80 mg, 0.22 mmol) in DMSO (2 mL) was added acetic anhydride (46 mg, 0.44 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.1 mL). The mixture was stirred at room temperature for 25 min. The mixture was concentrated in vacuum and the residue was purified by Prep-HPLC (BASE) to provide 1-((1S,4S)-5-(6-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-2-(2-azabicyclo[2.1.1]hexan-2-yl)pyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethanone (46.34 mg, 40.0% yield). LCMS (ESI): [MH]+=459.9; 1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.36 (s, 1H), 6.79 (s, 2H), 6.53-6.21 (m, 1H), 5.10-4.89 (m, 1H), 4.80-4.78 (m, 1H), 4.74-4.63 (m, 1H), 3.55-3.51 (m, 1H), 3.44-3.35 (m, 2H), 3.23-2.84 (m, 4H), 2.82 (s, 1H), 2.00 (s, 1H), 1.91 (s, 3H), 1.83-1.81 (m, 2H), 1.29 (d, J=2.0 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17]>CC(C)=O>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1)=[O:17]
Reactant: O=C(Cl)CCCCCBr
Reactant: Cc1cc(N)ccc1O
Solvent: CC(C)=O
Product: Cc1cc(NC(=O)CCCCCBr)ccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 25 g (0.20 mol) of 4-amino-2-methylphenol in about 450 mL of acetone was stirred at room temperature and 20.6 g (0.09 mol) of 6-bromohexanoyl chloride was dripped in over 20 minutes. The reaction was stirred at room temperature for 3 hours then ice-cooled and filtered. The filtrate was stripped in vacuo to a residual oil which was triturated once in 225 mL of 1N HCl and then several times in cold water. The resulting gum was dissolved in absolute ethanol and 28 g of product (95%) were crystallized out by the addition of water, mp 111°-112° C. The product, which contained a small amount of 4-amino-2-methylphenol, was used as is in the following reaction.
Reaction SMILES: NC([NH:4][CH2:5][CH2:6][CH2:7][CH:8]([NH:12][CH:13]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:14]([OH:16])=[O:15])[C:9]([OH:11])=[O:10])=N>[OH-].[Na+]>[CH2:6]([CH2:5][NH2:4])[CH2:7][CH:8]([NH:12][CH:13]([C:14]([OH:16])=[O:15])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:9]([OH:11])=[O:10]
Reactant: N=C(N)NCCCC(NC(CCC(=O)O)C(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: NCCCC(NC(CCC(=O)O)C(=O)O)C(=O)O
Temperature: 100 °C

Procedure:
2 grams of nopaline were dissolved in 35 ml of 1M NaOH and the solution was heated at 100° C. for 12 hours. The reaction mixture was evaporated to dryness to remove ammonia and the crude solid material was dissolved in 25 ml of water. The pH was adjusted to 0.8 to 1.0 and the pH-adjusted solution was chromatographed on a strong cationic exchange column (H+ form). After washing with two column volumes of water, the column was eluted with 10% aqueous ammonia. The eluate containing the nopalinic acid was evaporated to dryness, dissolved in 15 ml of water, adjusted to pH 3.2-3.5 with 1M HCl, and recrystallized by adding approximately 1.5 volumes of ethanol (or acetone). The crystals were recrystallized from aqueous acetone. The characteristics of the compound were as follows:
Reaction SMILES: [CH2:1]=[CH:2][C:3]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])([CH3:5])O.C[Si](C)(C)[Cl:14]>[Bi+]=O>[Cl:14][CH2:1][CH:2]=[C:3]([CH3:5])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10]
Reactant: C[Si](C)(C)Cl
Reactant: C=CC(C)(O)CCC=C(C)C
Agent: O=[Bi+]
Product: CC(C)=CCCC(C)=CCCl
Temperature: 60 °C
Yield: 83.2 %

Procedure:
To a mixture of 170 g linalool and 20 mg bismuth(III)-oxide heated to 60° C., 130.5 g trimethylchlorosilane were dropped in. Then the mixture was cooled to room temperature and the organic layer was separated. The resulting oil was purified by distillation to yield 158.35 g of a colorless oil.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][N:15]2[C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([O:28][CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])[C:22]=3[C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][C:20]=3[C:37](=[O:39])[NH2:38])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[O:1]([C:8]1[CH:9]=[C:10]([CH2:14][N:15]2[C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([O:28][CH2:29][C:30]([OH:32])=[O:31])[C:22]=3[C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][C:20]=3[C:37](=[O:39])[NH2:38])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(Oc2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cccc2c1c1c(OCC(=O)O)cccc1n2Cc1cccc(Oc2ccccc2)c1
Yield: 112 %

Procedure:
A solution of the {9-[(3-phenoxyphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, tert-butyl ester (30.0 mg, 0.063 mM) in 2 mL of trifluoroacetic acid was stirred at room temperature for 6 hours. The solvent was removed in vacuo. The residue was dried in vacuo to afford 30.0 mg (100%) of the {9-[(3-phenoxyphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid as a white powder. 1H NMR (DMSO-d6) δ13.0 (br s, 1H), 7.75 (s, 1H), 7.6 (d, 1H, J=8 Hz), 7.5-6.8 (m, 14H), 6.6 (d, 1H, J=8 Hz), 5.7 (s, 2H), and 4.8 (s, 2H). IR (KBr, cm−1) 3450, 3400, 1740, 1651, 1592, 1585, 1487, 1457, 1441, 1329, 1250, and 1158. MS (ES) m/e 465, 467.
Reaction SMILES: [Br:1][C:2]1[C:11]([CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:18][CH3:19])[CH:8]=2)[C:3]=1[OH:20].[CH3:21][O:22][CH2:23]Cl.C(N(C(C)C)CC)(C)C>C1COCC1>[Br:1][C:2]1[C:11]([CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:18][CH3:19])[CH:8]=2)[C:3]=1[O:20][CH2:21][O:22][CH3:23]
Reactant: COc1ccc2c(O)c(Br)c(CCC(F)(F)F)cc2c1
Reactant: COCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1c(Br)c(CCC(F)(F)F)cc2cc(OC)ccc12
Yield: 80 %

Procedure:
2-Bromo-6-(methyloxy)-3-(3,3,3-trifluoropropyl)-1-naphthalenol (122) (0.47 g, 1.35 mmol) was treated with chloromethyl methyl ether in the presence of diisopropylethylamine in THF to give 0.42 g (80%) of the title compound (123) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 2.40-2.55 (m, 2H), 3.10-3.20 (m, 2H), 3.72 (s, 3H), 3.91 (s, 3H), 5.23 (s, 2H), 7.04 (d, J=2.6 Hz, 1H), 7.16 (dd, J1=9.3 Hz, J2=2.5 Hz, 1H), 7.43 (s, 1H), 8.03 (d, J=9.3 Hz, 1H).
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[Al+3].[CH3:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([CH3:15])[CH:14]=1)[C:9](Cl)=[O:10]>ClC1C=CC=CC=1>[CH3:5][C:6]1[CH:7]=[C:8]([C:9](=[O:10])[C:6]2[CH:7]=[CH:8][C:12]([Cl:1])=[CH:13][CH:14]=2)[CH:12]=[C:13]([CH3:15])[CH:14]=1
Reactant: [Cl-]
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Agent: [Al+3]
Solvent: Clc1ccccc1
Product: Cc1cc(C)cc(C(=O)c2ccc(Cl)cc2)c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 172.3 %

Procedure:
100 ml chlorobenzene and 14.7 g aluminium trichloride are added in a 250 ml three-neck flask, and then 16.8 g 3,5-dimethyl benzoyl chloride is dropped into the solution at room temperature. Maintaining the temperature at 70° C., react with stirring for 16 h. The reaction solution is acidolyzed and washed with water, and then is distilled to remove chlorobenzene, obtaining 21 g residue, the yield is 86%. The residue is recrystallized with ethanol to obtain a purified white crystal, and the melting point is 72-73° C. 1H-NMR data (solvent CDCl3): δ2.371 ppm, s, 6H, δ7.230 ppm, s, 1H, δ7.363 ppm, s, 2H; δ7.438, 7.466 ppm, d, 2H, δ7.729, 7.757 ppm, d, 2H.
Reaction SMILES: [C:1]([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][CH2:18][CH2:19][CH3:20])#[N:2].N[C:22]1[C:27]([OH:28])=[CH:26][CH:25]=[CH:24][N:23]=1>>[O:28]1[C:27]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[N:2]=[C:1]1[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][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCCCCCCCC#N
Reactant: Nc1ncccc1O
Product: CCCCCCCCCCCCCCCCCCc1nc2ncccc2o1
Yield: 30 %

Procedure:
This material was prepared in 30% yield from 1-cyanooctadecane (Mangold, H. K., et al., (1976) Chem. Phys. Lipids 17, 176-181) and 2-amino-3-hydroxypyridine using Method C3: mp 84-85° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:9].[OH:16][C:17]1[C:22]2[N:23]=[C:24]([NH:26][C:27](=[O:29])[CH3:28])[S:25][C:21]=2[CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:11]([NH:10][C:8](=[O:9])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:16][C:17]1[C:22]2[N:23]=[C:24]([NH:26][C:27](=[O:29])[CH3:28])[S:25][C:21]=2[CH:20]=[CH:19][CH:18]=1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CC(=O)Nc1nc2c(O)cccc2s1
Reactant: CCCCCNC(=O)NCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCNC(=O)NCCCCCOc1cccc2sc(NC(C)=O)nc12
Temperature: 60 °C
Reaction time: 6 h
Yield: 40.6 %

Procedure:
A mixture of 1-(5-bromopentyl)-3-n-pentylurea (100 mg, 0.37 mmol), commercial N-(4-hydroxybenzo[d]thiazol-2-yl)acetamide (100 mg, 0.48 mmol), and K2CO3 (67 mg, 0.48 mmol) in DMF (5 mL) was heated at 60° C. After 6 h, the reaction mixture was cooled to rt, diluted with water (25 mL), and extracted into EtOAc (3×10 mL). The combined organic extracts were washed with water (2×5 mL), brine (10 mL), dried (Na2SO4) and concentrated in vacuo. The residue thus obtained was purified by silica gel column chromatography to give 31 (61 mg, 40%), mp 61.6-61.8° C. TLC: EtOAc/hexane (3:2), Rf˜0.40; 1H NMR (300 MHz) δ 7.39 (dd, J=0.9, 7.3 Hz, 1H), 7.20 (dd, J=7.8, 7.3 Hz, 1H), 6.86 (dd, J=0.9, 7.8 Hz, 1H), 4.42 (br s, —NH, 2H), 4.17 (t, J=5.4 Hz, 2H), 3.19-3.30 (m, 4H), 2.33 (s, 3H), 1.82-1.98 (m, 2H), 1.64-1.80 (m, 4H), 1.42-1.60 (m, 2H), 1.24-1.40 (m, 4H), 0.88 (t, J=7.3 Hz, 3H); 13C NMR (75 MHz) δ 170.16, 159.91, 158.94, 151.37, 139.10, 133.67, 124.40, 113.94, 108.68, 68.21, 40.64, 39.98, 30.27, 29.30, 28.33, 26.54, 23.25, 22.64, 22.33, 14.26. HRMS (ESI-neg) calcd for C20H29N4O3S [M−1]− 405.1960. found 405.1938.
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8]([NH2:11])=[N:7][C:6]=2[CH:5]=[C:4]([I:12])[CH:3]=1.[CH2:13]([N:15]=[C:16]=[O:17])[CH3:14].CCOCC.CCCCC>O1CCOCC1>[Br:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C:16]([NH:15][CH2:13][CH3:14])=[O:17])=[N:7][C:6]=2[CH:5]=[C:4]([I:12])[CH:3]=1
Reactant: CCN=C=O
Reactant: Nc1nc2cc(I)cc(Br)c2s1
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CCCCC
Product: CCNC(=O)Nc1nc2cc(I)cc(Br)c2s1
Temperature: 80 °C
Reaction time: 0.58 h
Yield: 88.5 %

Procedure:
To a stirred solution of 7-bromo-5-iodobenzothiazol-2-amine (250 g, 0.70 mol) in 1,4-dioxane at rt was added ethylisocyanate (278 mL, 3.52 mol). The resulting reaction mixture was heated to 80° C. for 10-12 h under N2 atmosphere. After reaction completion (by TLC), the solvent was evaporated then n-hexane added and the evaporation procedure repeated. The resulting residue was stirred in hot water (2 L) at 60-65° C. for 30-40 min then filtered. The residue thus obtained was treated with a mixture of Et2O and n-pentane and filtered to obtain the desired product (264 g, 88%). 1H NMR (DMSO-d6): δ 1.08 (t, J=7.20 Hz, 3H), 3.20 (q, J=6.80, 2H), 6.73 (br s, 1H), 7.72 (s, 1H), 7.96 (s, 1H) and 11.07 (br s, 1H). MS: 426.0 [M+H]+.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH2:13]([N:20]1[CH2:25][CH2:24][CH2:23][C:22]([CH:27]=[C:28]([Sn:31]([CH2:40][CH2:41][CH2:42][CH3:43])([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH2:34][CH3:35])[CH2:29][OH:30])(O)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:13]([N:20]1[CH2:25][CH2:24][CH2:23][C:22]2([O:30][CH2:29][C:28]([Sn:31]([CH2:40][CH2:41][CH2:42][CH3:43])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:36][CH2:37][CH2:38][CH3:39])=[CH:27]2)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C(=CC1(O)CCCN(Cc2ccccc2)C1)CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)C1=CC2(CCCN(Cc3ccccc3)C2)OC1
Reaction time: 0.75 h
Yield: 59.3 %

Procedure:
Diethyl azodicaboxylate (3.1 ml, 19.7 mmol) was added dropwise to a solution of 1-benzyl-3-(3-hydroxy-2-tributylstannyl-1-propen-1-yl)piperidin-3-ol (Desc. 2; 8.72 g, 16.26 mmol) and triphenylphosphine (5.12 g, 19.5 mmol) in tetrahydrofuran (100 ml) at -5° C. The cooling bath was removed and the reaction mixture stirred for 45 minutes. The solvent was evaporated, the residue dissolved in acetonitrile (300 ml) and extracted with hexane (3×150 ml). The combined hexane extracts were evaporated and the residue chromatographed on silica, eluting with ethyl acetate/hexane (1:9 then 1:4), to afford the title compound as a colourless oil (5.00 g, 59%); δH (250 MHz, CDCl3) 0.87-0.96 (15 H, m), 1.25-1.35 (6H, m), 1.45-1.60 (11H, m), 1.79 (1H, m), 2.29-2.48 (4H, m), 3.48 (1H, d, J 13.3Hz, NCHZCHBPh), 3.59 (1H, d, J 13.3Hz, NCHACHBPh), 4.67 (2H, m, 2-CH2), 6.03 (1H, br s, 4-CH=), 7.22-7.30 (5H, m ArH).
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]([N:7]([CH2:29][CH:30]([CH3:32])[CH3:31])[C@H:8]1[CH2:13][C@@H:12]([C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])[CH2:11][N:10]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:9]1)=[O:6])C.[OH-].[Na+].Cl>C(O)C>[C:25]([O:24][C:22]([N:10]1[CH2:11][C@H:12]([C:14]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[O:15])[CH2:13][C@H:8]([N:7]([C:5](=[O:6])[C:4]([OH:33])=[O:3])[CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:9]1)=[O:23])([CH3:27])([CH3:28])[CH3:26]
Reactant: CCOC(=O)C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CN(C(=O)C(=O)O)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 106.4 %

Procedure:
To a solution of tert-butyl (3S,5R)-3-{[ethoxy(oxo)acetyl](2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (10.3 g) in ethanol (40 ml) was added 2M aqueous sodium hydroxide solution (22 ml), and the mixture was stirred at room temperature for 6 hr. The reaction mixture was adjusted to pH 7 with 1M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (10.3 g).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][C:3]=1[O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1.C([Li])CCC.[CH:29](=[O:31])[CH3:30].O>O1CCCC1.CCCCCC>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([CH:29]([OH:31])[CH3:30])[C:3]=1[O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1
Reactant: CC(C)(C)C(=O)Nc1cc(OC2CCCCO2)c(F)c(F)c1F
Reactant: CC=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(O)c1c(NC(=O)C(C)(C)C)c(F)c(F)c(F)c1OC1CCCCO1
Temperature: -35 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
3.60 g (10.9 mmol) of the above 2,3,4-trifluoro-5-pivaloylamino-O-tetrahydropyranylphenol was dissolved in 50 mL of tetrahydrofuran, 14 mL of a 1.6 M solution of n-butyl lithium in n-hexane was added dropwise to the solution at an internal temperature of -60° C. or below, the mixture was warmed to -35° C. and cooled again to -60° C. or below. About 2 mL of acetaldehyde was added thereto in a gaseous condition and the mixture was stirred for 20 minutes. Water was added to the reaction solution, the mixture was warmed to room temperature and extracted once with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1-3:1) to give 2.45 g of a mixture of diastereomers of 2,3,4-trifluoro-6-(1-hydroxyethyl)-5-pivaloylamino-O-tetrahydropyranylphenol (yield: 60%).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[NH:5][C:6]([CH3:37])=[C:7]([C:33]([O:35][CH3:36])=[O:34])[CH:8]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=2)[C:9]=1[C:10]([O:12][CH2:13][C:14]([CH3:23])([CH3:22])[CH2:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:11].C(N(CC)CC)C.[O:45]1[CH:49]=[CH:48][CH:47]=[C:46]1[C:50]([Cl:52])=[O:51].Cl>O1CCCC1.C(OCC)C.C(O)C>[ClH:52].[CH3:3][C:4]1[NH:5][C:6]([CH3:37])=[C:7]([C:33]([O:35][CH3:36])=[O:34])[CH:8]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=2)[C:9]=1[C:10]([O:12][CH2:13][C:14]([CH3:22])([CH3:23])[CH2:15][N:16]1[CH2:17][CH2:18][N:19]([C:50]([C:46]2[O:45][CH:49]=[CH:48][CH:47]=2)=[O:51])[CH2:20][CH2:21]1)=[O:11]
Reactant: O=C(Cl)c1ccco1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)(C)CN2CCNCC2)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)(C)CN2CCN(C(=O)c3ccco3)CC2)C1c1cccc([N+](=O)[O-])c1
Reaction time: 0.17 h
Yield: 52 %

Procedure:
0.73 g of 3-(1-piperazinyl)-2,2-dimethylpropyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate dihydrochloride was dissolved in 5 ml of tetrahydrofuran, and 0.6 ml of triethylamine and 0.13 ml of 2-furoyl chloride were added; the mixture was then stirred for 10 minutes while cooling with ice. After evaporating the solvent, the residue was purified by the chromatography method [20 g silica gel, n-hexane:ethyl acetate (2:5)] to give 0.4 g of an oily substance. This oily substance was dissolved in diethyl ether; a slightly excessive amount of a solution of hydrogen chloride in ethanol was added; the solid which separated was collected by filtration to give 0.42 g of the subject compound (yield: 52%). The IR and NMR data of the compound thus obtained are as follows: ##STR12##
Reaction SMILES: [Na].Cl.[C:3]([NH2:9])(=[NH:8])[CH2:4][CH2:5][CH2:6][CH3:7].[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]=[C:25]=[O:26])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CC(C)=O>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:25]([NH:8][C:3](=[NH:9])[CH2:4][CH2:5][CH2:6][CH3:7])=[O:26])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C=Nc1ccccc1OCc1ccccc1
Reactant: CCCCC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CCCCC(=N)NC(=O)Nc1ccccc1OCc1ccccc1

Procedure:
Following a procedure similar to that described in Example 1 but using 2.9 g. sodium in 300 ml. dry acetone, 17.7 g. valeramidine hydrochloride, and 29.3 g. 2-(benzyloxy)phenyl isocyanate in 200 ml. dry acetone, there was obtained after recrystallization from isopropyl alcohol 33.9 g. of the hydrochloride of 1-[2-(benzyloxy)phenyl]-3-(pentanimidoyl)urea; m.p. 145°-147°C.
Reaction SMILES: F[C:2]1[C:7](F)=[CH:6][CH:5]=C[C:3]=1[CH2:9][S:10]([C:13]1[N:22]=[C:21]([NH:23][C@H:24]([CH3:27])[CH2:25][OH:26])[C:20]2[N:19]=[CH:18][C:17](=[O:28])[NH:16][C:15]=2[N:14]=1)(=O)=O.CC1[O:34]C(CS)=CC=1>>[OH:26][CH2:25][C@H:24]([NH:23][C:21]1[C:20]2[N:19]=[CH:18][C:17](=[O:28])[NH:16][C:15]=2[N:14]=[C:13]([S:10][CH2:9][C:3]2[O:34][C:6]([CH3:5])=[CH:7][CH:2]=2)[N:22]=1)[CH3:27]
Reactant: Cc1ccc(CS)o1
Reactant: C[C@H](CO)Nc1nc(S(=O)(=O)Cc2cccc(F)c2F)nc2[nH]c(=O)cnc12
Product: Cc1ccc(CSc2nc(N[C@H](C)CO)c3ncc(=O)[nH]c3n2)o1
Yield: 34.3 %

Procedure:
The titled compound (0.058 g) was prepared by the method of Example 13, step (c) using the product from Example 13, step (a) (0.20 g) and 5-methyl-2-furanylmethylmercaptan (0.15 g of 80% pure).
Reaction SMILES: [CH2:1]([N:5]([CH2:11][CH2:12][CH2:13][CH3:14])[C:6](=[O:10])[O:7][CH2:8]Cl)[CH2:2][CH2:3][CH3:4].[OH:15][C@@H:16]([C@H:18]1[C:38](=[O:39])[N:20]2[C:21]([C:35]([O-:37])=[O:36])=[C:22]([S:25]/[CH:26]=[CH:27]\[C:28]3[S:32][CH:31]=[N:30][C:29]=3[CH2:33][OH:34])[C@H:23]([CH3:24])[C@H:19]12)[CH3:17].[Na+]>>[OH:15][C@@H:16]([C@H:18]1[C:38](=[O:39])[N:20]2[C:21]([C:35]([O:37][CH2:8][O:7][C:6]([N:5]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:1][CH2:2][CH2:3][CH3:4])=[O:10])=[O:36])=[C:22]([S:25]/[CH:26]=[CH:27]\[C:28]3[S:32][CH:31]=[N:30][C:29]=3[CH2:33][OH:34])[C@H:23]([CH3:24])[C@H:19]12)[CH3:17]
Reactant: CCCCN(CCCC)C(=O)OCCl
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: CCCCN(CCCC)C(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 67.3 %

Procedure:
In the same manner as in step b) in Example 125, 220 mg of the title compound was prepared from 154 mg of chloromethyl N,N-di-n-butylcarbamate and 233 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate.