Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:25])[C@@H:6]([CH3:24])[CH2:7][CH:8]([NH2:23])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:12][CH:11]=1)[CH3:3].[O:26]1[C:30](=[O:31])[CH2:29][CH2:28][C:27]1=[O:32].N1C=CC=CC=1.Cl>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:25])[C@@H:6]([CH3:24])[CH2:7][C@H:8]([NH:23][C:30](=[O:31])[CH2:29][CH2:28][C:27]([OH:32])=[O:26])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:12][CH:11]=1)[CH3:3]
Reactant: O=C1CCC(=O)O1
Reactant: CCOC(=O)[C@@H](C)CC(N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)[C@@H](C)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)CCC(=O)O
Reaction time: 2 h
Yield: 10.8 %

Procedure:
To a stirred solution of (S)-4-Amino-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester hydrochloric acid salt (200 mg, 0.52 mmol) and dihydrofuran-2,5-dione (68 mg, 0.68 mmol) in 8 ml CH2Cl2 was added pyridine (0.17 ml, 2.1 mmol) and the solution was stirred for 2 hours. The reaction mixture was acidified to pH=3 with 1M HCl. Solvent was removed under reduced pressure and the residue was purified by preparatory HPLC (DAICEL CHIRALCEL OD-H 21×250 mm column, 18 ml/min, 90% heptane 10% EtOH+0.1% TFA), collected a peak at 5.7 minutes, to give 25 mg (2S,4S)-4-(3-carboxy-propionylamino)-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester. MS m/z 446.3 (M+H), 444.3 (M−H). LC/MS (Condition A): 1.52 min.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][F:29])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.Cl>C1COCC1.CO.O>[F:29][CH2:28][CH2:27][CH2:26][CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([N:5]([CH2:4][C:3]([OH:30])=[O:2])[CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: COC(=O)CN(Cc1ccc(OC)cc1)S(=O)(=O)c1ccc(OCCCCF)cc1
Agent: Cl
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN(CC(=O)O)S(=O)(=O)c2ccc(OCCCCF)cc2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 1.04 g (2.37 mmol) of {[4-(4-fluorobutoxy)-benzenesulfonyl]-(4-methoxybenzyl)-amino}-acetic acid methyl ester in 15 ml of THF, 15 ml of MeOH and 7 ml of H2O, 0.24 g (5.7 mmol) of LiOH mono-hydrate is added in portions and the mixture is stirred for 30 min at 0–5° C. After stirring for additional 3.5 h, the reaction mixture is acidified with 1 N aqueous HCl and extracted with AcOEt. The combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure to give ([4-(4-fluoro-butoxy)-benzenesulfonyl]-(4-methoxy-benzyl)-amino)-acetic acid; NMR (CDCl3): 1.86–1.96 (m, 4H), 3.79 (s, 3H), 3.90 (s, 2H), 4.08 (t, 2H, J=5.52 Hz), 4.38 (s, 2H), 4.48 (t, 1H, J=6.04 Hz), 4.55–4.65 (m, 1H), 6.84 (d, 2H, J=8.56 Hz), 6.98 (d, 2H, J=9.08 Hz), 7.14 (d, 2H, J=8.56 Hz), 7.81 (d, 2H, J=9.08 Hz).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@@H:9]([O:10][Si](C(C)(C)C)(C)C)[CH2:8][N:7]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:6]1)=[N+:2]=[N-:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[Na+]>O1CCCC1>[N:1]([CH2:4][C@@H:5]1[C@@H:9]([OH:10])[CH2:8][N:7]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:6]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1CN=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: [N-]=[N+]=NC[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Reaction time: 1 h
Yield: 93.2 %

Procedure:
(3R,4R)-3-Azidomethyl-1-benzyloxycarbonyl-4-(tert-butyldimethylsilyl)oxypyrrolidine (3.05 g) was dissolved in tetrahydrofuran (50 mL). While this solution was cooled on an ice bath, tetrabutylammonium fluoride (lmol/L tetrahydrofuran solution, 13.3 mL) was added dropwise and the mixture was stirred for additional 1 hour. Subsequently, a saturated aqueous solution of sodium chloride 70 mL) was added and the mixture was extracted with ethyl acetate (150 mL, 100 mL). The ethyl acetate extracts were combined and the combined solvent was dried over anhydrous sodium sulfate and was concentrated under reduced pressure. The resulting residue was purified on a silica gel column (eluant=ethyl acetate) to give 2.01 g of (3R,4R)-3-azidomethyl-1-benzyloxycarbonyl-4-hydroxypyrrolidine as a milky white syrup-like product.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CC(O)=O.CN.CC(O)=O>C1COCC1.CCO>[CH3:1][NH:2]/[C:3](/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH:11]\[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CN
Solvent: CCO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)/C=C(\NC)c1ccccc1
Temperature: 25 °C
Yield: 99 %

Procedure:
To a solution of methylamine (65.03 mL of a 2M solution in THF, 130.06 mmol) and ethyl benzoylacetate (4.505 mL, 26.01 mmol) in EtOH (26 mL) was added HOAc (7.45 mL, 130.06 mmol). The mixture was then heated to reflux for 15 h. At this time, crude 1H NMR revealed only product and MeNH2—HOAc. The reaction mixture was then cooled to RT, and the solvent was removed in vacuo. The crude reaction was then extracted with 1 N HCl and DCM. The organic layer was then dried over MgSO4, and the solvent was removed in vacuo to yield 5.3 g (99%) of ethyl (2Z)-3-(methylamino)-3-phenylacrylate. The product was used as is in subsequent reactions. 1H NMR (500 MHz, CDCl3) ppm: 8.50 (br s, 1H), 7.40 (m, 3H), 7.35 (m, 2H), 4.59 (s, 1H), 4.15 (q, J=7.0 Hz, 2H), 2.77 (d, J=5.0 Hz, 3H), 2.50 (s, 3H), 1.27 (t, J=7.0 Hz, 3H).
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([C:18]1[N:22]3[CH:23]=[C:24]([C@@H:27]([N:32]4[CH2:36][CH2:35][C@H:34]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33]4)[C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:26][C:21]3=[N:20][N:19]=1)[CH:14]=[CH:13]2)(=O)C.[OH-].[Li+]>CO>[F:30][C:28]([F:29])([F:31])[C@H:27]([N:32]1[CH2:36][CH2:35][C@H:34]([NH:37][C:38](=[O:39])[O:40][C:41]([CH3:44])([CH3:42])[CH3:43])[CH2:33]1)[C:24]1[CH:25]=[CH:26][C:21]2[N:22]([C:18]([C:15]3[CH:14]=[CH:13][C:12]4[C:17](=[C:8]([O:7][CH2:6][CH2:5][OH:4])[CH:9]=[CH:10][CH:11]=4)[N:16]=3)=[N:19][N:20]=2)[CH:23]=1
Reactant: CC(=O)OCCOc1cccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc3nnc(-c4ccc5cccc(OCCO)c5n4)n3c2)C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a solution of 2-(2-(6-((R)-1-((S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl)-2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)ethyl acetate (0.47 g, 0.76 mmol) in methanol (5 mL) was added lithium hydroxide (2M; 1.9 mL, 0.76 mmol) and the mixture allowed to stir at ambient temperature for 1 hour. The reaction mixture was extracted with dichloromethane (2×30 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography on C18 (0-100% acetonitrile/water) to provide the title compound (0.40 g, 92%).
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[O:11][C:12]([CH2:15][N:16]([CH3:18])[CH3:17])=[CH:13][CH:14]=1)#[N:2].[CH3:21][NH2:22]>>[C:1]([NH:3][C:4]([NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[O:11][C:12]([CH2:15][N:16]([CH3:18])[CH3:17])=[CH:13][CH:14]=1)=[N:22][CH3:21])#[N:2]
Reactant: CSC(=NC#N)NCCSCc1ccc(CN(C)C)o1
Reactant: CN
Product: CN=C(NC#N)NCCSCc1ccc(CN(C)C)o1

Procedure:
A solution of N'-cyano-N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]carbamimidothioic acid, methyl ester (1.06 g) in ethanolic methylamine 33% (10 ml) was stirred at room temperature for 4 hr. The solution was evaporated to dryness and the oily residue crystallised from ethyl acetatelight petroleum (b.p. 80°-100°) to give the title compound m.p. 77°-80°.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH:19]([CH2:20][OH:21])[CH:18]=[C:17]([CH3:22])[CH:16]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][CH:24]=3)[O:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Cr](O)(O)(=O)=[O:33].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CC(C)=O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[CH:19]([C:20]([OH:33])=[O:21])[CH:18]=[C:17]([CH3:22])[CH:16]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH3:31])=[CH:27][CH:28]=3)[O:15]2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=[Cr](=O)(O)O
Reactant: CCOc1ccc(C2ON(S(=O)(=O)c3ccc(NC(C)=O)cc3)C(CO)C=C2C)cc1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOc1ccc(C2ON(S(=O)(=O)c3ccc(NC(C)=O)cc3)C(C(=O)O)C=C2C)cc1

Procedure:
To a stirred solution of 2-(4-acetamidobenzenesulphonyl)-3,6-dihydro-6-(4-ethoxyphenyl)-3-hydroxymethyl-5-methyl-2H-1,2-oxazine (1.02 g, 2.28 mmol) in acetone (20 ml) at 10° C. was added a solution of aaueous chromic acid (8M, 1.2 ml) dropwise. Stirred at room temperature for 2.5 h with addition of aqueous chromic acid (8M, 1.2 ml and 0.4ml) at intervals. Aqueous sodium metabisulphite was then added to terminate the reaction and the mixture concentrated in vacuo. The concentrate was diluted with water and extracted twice with ethyl acetate. The combined extracts was washed with water and brine, dried over magnesium sulphate, filtered and evaporated to a foam. 2-(4-Acetamidobenzenesulphonyl)-3-carboxy-3,6-dihydro-6-(4-ethoxyphenyl)-5-methyl-2H-1,2-oxazine crystallised as a white power from chloroform. 1H NMR (CDCl3)δ 1.40(3H, t) 1.48(3H, s), 2.15(2H, s), 4.01(2H, q), 4.97(1H, d), 5.29(1H, s), 5.85(1H, d), 6.75(2H, d), 7.19(2H, d), 7.68(2H, d), 7.22(2H, d).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3].[C:18](N1C=CN=C1)(N1C=CN=C1)=[S:19]>CN(C)C=O>[N:17]([C:14]1[CH:13]=[CH:12][C:11]([N:8]2[CH2:9][CH2:10][N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][CH2:7]2)=[CH:16][CH:15]=1)=[C:18]=[S:19]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CC(C)CN1CCN(c2ccc(N)cc2)CC1
Solvent: CN(C)C=O
Product: CC(C)CN1CCN(c2ccc(N=C=S)cc2)CC1
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 87 %

Procedure:
A solution of 4-[4-(isobutyl)-1-piperazinyl]benzenamine (7.8 g, 33.4 mmol) (from Step B above) in N,N-dimethylformamide (75 mL) was added dropwise over 20 min to a cooled (−15° C.) solution of thiocarbonyldiimidazole (5.97 g, 33.5 mmol) (Aldrich) in N,N-dimethylformamide (25 mL). After the addition was complete, the mixture was stirred at −15° C. for 20 min, the cooling bath was removed and the solution was stirred for 1 h. Ice-water (700 ml) was added and the mixture was stirred for 30 min. The solid was filtered off and washed with water and dried under vacuum to give 1-(4-Isothiocyanatophenyl)-4-(1-isobutyl)piperazine (8 g, 87%)
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]([F:22])([F:21])[O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:18][C:17]1[CH:19]=[CH:20][C:14]([O:13][C:12]([F:11])([F:21])[F:22])=[CH:15][CH:16]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: Clc1nc2ccccc2[nH]1
Product: FC(F)(F)Oc1ccc(Nc2nc3ccccc3[nH]2)cc1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 4-(trifluoromethoxy)aniline by Procedure A. The product was isolated by filtration to give the title compound as a hydrochloride salt (white solid, mp 250-251° C.). MS(ES+) m/z 294 ([M+1]+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[C:6]([CH3:12])=[N:7]2.[CH3:22][O:23][CH2:24][C:25](Cl)=[O:26]>O1CCCC1>[O:20]=[C:14]1[CH:13]([N:5]2[C:4](=[O:21])[C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[NH:1][C:25](=[O:26])[CH2:24][O:23][CH3:22])[N:7]=[C:6]2[CH3:12])[CH2:18][CH2:17][C:16](=[O:19])[NH:15]1
Reactant: Cc1nc2cccc(N)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: COCC(=O)Cl
Solvent: C1CCOC1
Product: COCC(=O)Nc1cccc2nc(C)n(C3CCC(=O)NC3=O)c(=O)c12
Temperature: 80 °C
Yield: 35.1 %

Procedure:
To a stirred mixture of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (0.11 g, 0.35 mmol) in tetrahydrofuran (4 mL), was added methoxyacetyl chloride (0.06 mL, 0.70 mmol) and heated at 80° C. for one hour. The mixture was quenched with a few drops of methanol. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-yl]-2-methoxy-acetamide (44 mg, 35% yield) as a white solid; HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 6.77 min (96.3%); mp, 282-284° C.; 1HNMR (DMSO-d6) δ 2.20-2.22 (m, 1H, CHH), 2.60-2.85 (m, 6H, CHCH2, CH3), 3.40 (s, 3H, ° CH3), 4.04 (s, 2H, ° CH2), 5.30 (dd, J=6, 11 Hz, 1H, CH), 7.30-8.64 (m, 3H, Ar), 11.09 (s, 1H, NH), 12.31 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.77, 23.31, 30.62, 56.71, 59.04, 71.88, 107.95, 115.39, 120.94, 135.51, 138.89, 147.90, 154.84, 162.69, 169.12, 169.34, 172.64. LCMS MH=359; Anal Calcd For C17H18N4O5+0.7H2O: C, 55.04; H, 5.27; N, 15.10. Found: C, 54.75; H, 5.32; N, 14.91.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:21]=[CH:22][C:23]([N:26]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:27]([C:29]4([C:32]([NH2:34])=[O:33])[CH2:31][CH2:30]4)=[O:28])=[N:24][CH:25]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:21]=[CH:22][C:23]([N:26]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:27]([C:29]4([C:32]([NH2:34])=[O:33])[CH2:31][CH2:30]4)=[O:28])=[N:24][CH:25]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1
Reactant: NC(=O)C1(C(=O)N(c2ccccc2)c2ccc(Oc3ccnc4cc(OCc5ccccc5)ccc34)cn2)CC1
Agent: [Pd]
Solvent: CO
Product: NC(=O)C1(C(=O)N(c2ccccc2)c2ccc(Oc3ccnc4cc(O)ccc34)cn2)CC1
Yield: 89.9 %

Procedure:
A solution of N-(5-(7-(benzyloxy)quinolin-4-yloxy)pyridin-2-yl)-N-phenylcyclopropane-1,1-dicarboxamide (1.22 g, 2.3 mmol) and Pd/C (1.2 g) in methanol (30 mL) under H2 was stirred at room temperature for 2 hrs, then the reaction mixture was filtered and washed with methanol (10 mL×3). The combined solvent was concentrated in vacuo to give N-(5-(7-hydroxyquinolin-4-yloxy)pyridin-2-yl)-N-phenyl-cyclopropane-1,1-dicarboxamide as a white solid (910.8 mg, 90%).
Reaction SMILES: [C:1]([NH:11][CH:12]([CH2:15][OH:16])[CH2:13][OH:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]([NH:11][C@H:12]([CH:13]=[O:14])[CH2:15][OH:16])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(NC(CO)CO)OCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C[C@H](CO)NC(=O)OCc1ccccc1
Reaction time: 2.5 h

Procedure:
Compound (19) was prepared as described for compound (9). To a solution of 80 mmol of Cbz-O-Bn serinol (18) in 200 mL of dry dichloromethane, kept at room temperature under nitrogen, was added 88 mmol of Dess-Martin periodinane, and the reaction stirred for 2.5 hours, and then quenched by addition of 400 mL of 10% aqueous sodium thiosulfate solution. The layers were separated, and the organic layer concentrated, diluted with 300 mL of ethyl ether, and washed three times with a saturated aqueous bicarbonate solution containing 10% sodium thiosulfate, dried over magnesium sulfate, and concentrated. Compound (19) was obtained in 99% crude yield, and used without further purification. 1H NMR δ (CDCl3) 3.69-3.78 (dd, 1H, CH2O), 3.99-4.06 (dd, 1H, CH2O), 4.37-4.46 (m, 1H, CHN), 4.47-4.52 (d, 2H, CH2O), 5.14 (s, 2H, CH2O), 5.65-5.75 (br. d, 1H, NH), 7.14-7.48 (a series of m, 9H, Ph), 7.98-8.08 (dd, 1H, Ph), 9.63 (s, 1H, CHO).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:34](=[O:35])[N:6]2[C:7]([C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])=[C:8](OP(OC3C=CC=CC=3)(OC3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@@H:5]12)[CH3:3].[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([SH:47])[CH2:44][C@H:43]1[CH2:48][CH:49]1[CH2:53][N:52]([C:54]([O:56][CH2:57][CH:58]=[CH2:59])=[O:55])[C@H:51]([C:60](=[O:64])[N:61]([CH3:63])[CH3:62])[CH2:50]1)=[O:41])[CH:37]=[CH2:38].C(N(CC)C(C)C)(C)C>>[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([S:47][C:8]2[C@H:9]([CH3:10])[C@@H:5]3[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:34](=[O:35])[N:6]3[C:7]=2[C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])[CH2:44][C@H:43]1[CH2:48][CH:49]1[CH2:53][N:52]([C:54]([O:56][CH2:57][CH:58]=[CH2:59])=[O:55])[C@H:51]([C:60](=[O:64])[N:61]([CH3:62])[CH3:63])[CH2:50]1)=[O:41])[CH:37]=[CH2:38]
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1CC1C[C@@H](C(=O)N(C)C)N(C(=O)OCC=C)C1
Reactant: C=CCOC(=O)C1=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@H]2[C@@H]([C@@H](C)O)C(=O)N12
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CC3C[C@@H](C(=O)N(C)C)N(C(=O)OCC=C)C3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 44.5 %

Procedure:
The same procedure as in Example 8-1 was carried out by using allyl (IR,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-diphenoxyphosphoryloxy-1-carbapen-2-em-3-carboxylate (129 mg, 0.26 mmol), (2R,4S)-N-allyloxycarbonyl-2-[(2S)-N-allyloxycarbonyl-2-(dimethylcarbamoyl)pyrrolidin-4-ylmethyl]-4-mercaptopyrrolidine (110 mg, 0.26 mmol) and N,N-diisopropylethylamine (45 μl, 0.26 mmol) to obtain allyl (1R,5S,6S)-2-[(2R,4S)-N-allyloxycarbonyl-2-[(2S)-N-allyloxycarbonyl-2-(dimethylcarbamoyl)pyrrolidin-4-ylmethyl]pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (78 mg, yield: 45%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([CH2:13][C@H:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][OH:16])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:27]([CH3:29])=[CH2:28].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[C:21]([O:20][C:18]([N:17]1[C@@H:14]([CH2:13][C:10]2([CH2:9][O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:11][CH2:12]2)[CH2:15][O:16][C:27]1([CH3:29])[CH3:28])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: C=C(C)OC
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC1(COCc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H](CC2(COCc3ccccc3)CC2)COC1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 31.4 g of 1-benzyloxymethyl-1-[2(S)-tert-butoxycarbonylamino-3-hydroxy-propan-1-yl]cyclopropane, 80 ml of 2-methoxypropene and 0.5 g of p-toluenesulfonic acid hydrate in 170 ml of methylene chloride is stirred at room temperature for 16 h. The mixture is concentrated and the residue is purified by means of FC over 900 g of silica gel (mobile phase G): Rf (G)=0.23.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([Cl:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:15])=O>>[Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([Cl:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(Cl)ccc(C(=O)O)c1Cl
Product: Cc1c(Cl)ccc(C(=O)Cl)c1Cl
Temperature: 25 °C

Procedure:
A 500 ml. three-necked flat-bottomed flask equipped with a reflux condenser, a thermometer and a Teflon agitator inside was charged with 205 g (1.0 mole) of 2,4-dichloro-3-methylbenzoic acid and 300 g (2.5 moles) of thionyl chloride. With stirring, they were reacted at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, and the excess of thionyl chloride was distilled off by a rotary evaporator. The residue was dried under reduced pressure to give crude 2,4-dichloro-3-methylbenzoyl chloride as yellow crystals containing a small amount of a yellowish brown liquid. This product was distilled under reduced pressure to recover a fraction having a boiling point of 125° to 128° C. at 6 mmHg which was the desired product having a high purity. The amount of 2,4-dichloro-3-methylbenzoyl chloride obtained was 176.2 g (yield 79 mole%). The product had a melting point of 43.2° to 47.2° C. The structure of the 2,4-dichloro-3-methylbenzoyl chloride was determined by infrared absorption spectroscopy, mass spectroscopy, NMR spectroscopy and elemental analysis.
Reaction SMILES: C([N:5]1[C:9](=[O:10])[CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH2:20][C@@H:19]([NH:22]C(=O)OC(C)(C)C)[CH2:18]3)=[C:13]([CH:30]=[O:31])[CH:12]=2)[S:6]1(=[O:33])=[O:32])(C)(C)C.C([SiH](C(C)C)C(C)C)(C)C>C(O)(C(F)(F)F)=O>[NH2:22][C@@H:19]1[CH2:20][CH2:21][N:17]([C:14]2[CH:15]=[CH:16][C:11]([C:7]3[S:6](=[O:33])(=[O:32])[NH:5][C:9](=[O:10])[CH:8]=3)=[CH:12][C:13]=2[CH:30]=[O:31])[CH2:18]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(C3=CC(=O)N(C(C)(C)C)S3(=O)=O)cc2C=O)C1
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CCN(c2ccc(C3=CC(=O)NS3(=O)=O)cc2C=O)C1
Temperature: 130 °C
Yield: 23.9 %

Procedure:
22-C (63 mg, 0.13 mmol) in TFA (0.65 mL) was treated with triisopropylsilane (0.8 μL, 0.004 mmol). The solution was sealed in a microwave tube and heated to 130° C. for 15 min. The solution was concentrated in vacuo. The residue was purified by reverse phase HPLC to afford a yellow solid (10 mg, 17%). 1H NMR (500 MHz, CD3OD): δ 10.04 (s, 1H), 8.31 (d, J=2.44 Hz, 1H), 7.97 (dd,J=11.2, 2.4 Hz, 1H), 7.14 (d, J=9.27 Hz, 1H), 4.05 (m, 1H), 3.80–3.75 (m, 2H), 3.65–3.47 (m, 2H), 2.52 (m, 1H), 2.22 (m, 1H); LCMS found for C14H15N3O4S (M+H)+: m/z=322.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH2:4][F:5].[C:7]([NH:10][C:11]([NH2:13])=[S:12])(=[O:9])[CH3:8]>CCO>[F:5][CH2:4][C:3]1[N:13]=[C:11]([NH:10][C:7](=[O:9])[CH3:8])[S:12][CH:2]=1
Reactant: O=C(CF)CCl
Reactant: CC(=O)NC(N)=S
Solvent: CCO
Product: CC(=O)Nc1nc(CF)cs1
Reaction time: 1.5 h
Yield: 8 %

Procedure:
A mixture of 1-chloro-3-fluoro-propan-2-one (Step 38.3) (1.14 g, 10.3 mmol) and N-acetyl-2-thiourea (1.22 g, 10.3 mmol) in EtOH (10 mL) is stirred for 1.5 h at reflux, allowed to cool and concentrated. The residue is dissolved in DCM/H2O and extracted with DCM. The organic phase is dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (Hex/EtOAc, 1:1) to afford 0.143 g of the title compound: ESI-MS: 173.1 [M−H]−; tR=1.98 min (System 1); TLC: Rf=0.21 (Hex/EtOAc, 1:1).
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([C:13]#[N:14])=[N:7][C:8]([CH2:11][CH3:12])=[CH:9][CH:10]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[CH2:11]([C:8]1[N:7]=[C:6]2[C:13]([NH2:14])=[N:1][CH2:4][C:5]2=[CH:10][CH:9]=1)[CH3:12]
Reactant: CCc1ccc(CN=[N+]=[N-])c(C#N)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc2c(n1)C(N)=NC2
Yield: 89.3 %

Procedure:
After dissolving 3-(azidomethyl)-6-ethyl-2-pyridinecarbonitrile (1.0 g, 5.34 mmol) in tetrahydrofuran (16 ml)-water (0.8 ml), triphenylphosphine (2.1 g, 8.01 mmol) was added while stirring on ice, and the mixture was further stirred at room temperature for 2.0 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (solvent: ethyl acetate, ethyl acetate:methanol=4:1, ethyl acetate:methanol:aqueous ammonia=2:1:0.1 in this order). The title compound (0.769 g) was obtained as a light green substance. (89.3% yield)
Reaction SMILES: C([NH:4][C:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([CH2:11][O:12]C(=O)C)[CH2:6][O:7]C(=O)C)(=O)C.[OH-].[Na+].[ClH:32]>CO>[ClH:32].[NH2:4][C:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([CH2:6][OH:7])[CH2:11][OH:12]
Reactant: CCCCCCCCCCCCCCC(COC(C)=O)(COC(C)=O)NC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCC(N)(CO)CO

Procedure:
2-Acetamido-1,3-diacetoxy-2-tetradecylpropane (1.25 g) was dissolved in 100 ml of methanol and 19.4 ml of a 1N aqueous sodium hydroxide solution was added thereto. The mixture was refluxed under heating for 6 hours. The mixture was neutralized with a 1N aqueous hydrochloric acid solution and concentrated under reduced pressure. The concentrate was washed with water and ethyl acetate:hexane =1:1 in order to give 791 mg of 2-amino-2-tetradecyl-l,3-propanediol hydrochloride.