Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:19][O:20][C:21](=[O:30])[C:22]1[CH:27]=[C:26]([OH:28])[CH:25]=[C:24](Br)[CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:7]([C:6]1[CH:9]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[C:24]1[CH:25]=[C:26]([OH:28])[CH:27]=[C:22]([C:21]([O:20][CH3:19])=[O:30])[CH:23]=1)#[N:8]
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(C#N)c1
Reactant: COC(=O)c1cc(O)cc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(O)cc(-c2ccc(C)cc2C#N)c1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
Under an atmosphere of nitrogen, a flask was charged with 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (2.1 g, 8.2 mmol), 3-bromo-5-hydroxy-benzoic acid methyl ester (1.5 g, 6.2 mmol), potassium phosphate (2.8 g, 13 mmol), tetrakis(triphenylphosphine)palladium(0) (400 mg, 0.35 mmol), 1,4-dioxane (90 mL), and water (20 mL). The reaction mixture was stirred at 85° C. overnight. After cooling, the mixture was filtered through Celite and the filter cake was washed with EtOAc. The filtrate was concentrated and the residue was purified by silica gel column to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[C:21]([C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)([CH3:24])[CH3:23])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:32][C:33]1[CH:34]=[C:35]([CH3:41])[C:36]([CH:39]=O)=[N:37][CH:38]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH2:39][C:36]2[C:35]([CH3:41])=[CH:34][C:33]([Cl:32])=[CH:38][N:37]=2)[CH2:15][C:16]2[C:21]([C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)([CH3:24])[CH3:23])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2ncccc2C(C)(C)c2ccc(F)cc2)CC1
Reactant: Cc1cc(Cl)cnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Cl)cnc1CN(Cc1ncccc1C(C)(C)c1ccc(F)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 66 %

Procedure:
Using General Procedure B: Reaction of 4-({3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-amino)-piperidine-1-carboxylic acid tert-butyl ester in CH2Cl2 with 5-chloro-3-methyl-pyridine-2-carbaldehyde and NaBH(OAc)3 gave 4-((5-chloro-3-methyl-pyridin-2-ylmethyl)-{3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-amino)-piperidine-1-carboxylic acid tert-butyl ester 0.558 g, 66%) as a white foam. 1H NMR (CDCl3) δ 1.21 (m, 2H), 1.44 (s, 9H), 1.60 (s+m, 9H), 2.24 (s, 3H), 2.39-2.51 (m, 3H), 3.33 (s, 2H), 3.66 (s, 2H), 4.02 (br s, 2H), 6.88 (m, 4H), 7.21 (dd, 1H, J=7.5, 3.0 Hz), 7.36 (s, 1H), 7.81 (d, 1H, J=9.0 Hz), 8.21 (d, 1H, J=3.0 Hz), 8.48 (d, 1H, J=3.0 Hz). Deprotection with TFA using General Procedure F gave (5-chloro-3-methyl-pyridin-2-ylmethyl)-{3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-piperidin-4-yl-amine as a pale yellow foam. 1H NMR 1.25-1.33 (m, 2H), 1.61 (s+m, 9H), 2.22 (s, 3H), 2.34-2.49 (m, 4H), 3.03 (d, 2H, J=12.0 Hz), 3.37 (s, 2H), 3.60 (s, 2H), 6.90 (m, 4H), 7.21 (dd, 1H, J=7.5, 3.0 Hz), 7.36 (s, 1H), 7.81 (d, 1H, J=9.0 Hz), 8.21 (d, 1H, J=3.0 Hz), 8.48 (d, 1H, J=3.0 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C:14]2[S:15][CH:16]=[C:17]([C:19]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[NH:21][CH:20]=3)[N:18]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[NH4+].[OH-]>CN(C=O)C.CO.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C:14]2[S:15][CH:16]=[C:17]([C:19]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[NH:21][CH:20]=3)[N:18]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Cc1cccc([N+](=O)[O-])c1)Nc1nc(-c2c[nH]c3ncccc23)cs1
Agent: [Fe]
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1cccc(CC(=O)Nc2nc(-c3c[nH]c4ncccc34)cs2)c1
Temperature: 100 °C
Yield: 28.6 %

Procedure:
2-(3-Nitro-phenyl)-N-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-yl]-acetamide (200 mg, 0.5 mmol) was taken in DMF-MeOH (5 mL) and added to sat. NH4OH (5 ml) and Fe powder (3eq, 83 mg). Then the suspension was heated overnight at 100° C. The brown colored reaction mixture was passed through a celite plug and washed with ethyl acetate. Then the reaction mixture was concentrated to dryness and taken up in ethyl acetate and extracted with water. The organic layer was dried and concentrated to give the desired product as a tan solid (50 mg, 30% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[H-].[Na+].[CH2:21](Br)[CH:22]=[CH2:23]>>[CH2:23]([N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[F:1])[C:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:8]1)[CH:22]=[CH2:21]
Reactant: C=CCBr
Reactant: COc1ccc(-c2n[nH]c3c(F)cccc23)cc1
Agent: [H-]
Agent: [Na+]
Product: C=CCn1nc(-c2ccc(OC)cc2)c2cccc(F)c21
Yield: 68.4 %

Procedure:
Prepared according to Method D step B from 7-fluoro-3-(4-methoxyphenyl)-1H-indazole (0.108 g, 0.44 mmol), sodium hydride (60% in oil, 0.018 g, 0.45 mmol) and allylbromide (0.043 mL, 0.5 mmol) to give the title compound (0.085 g) as a white solid.
Reaction SMILES: [O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:10]([NH:12][C@H:13]([C@H:28]([OH:47])[CH2:29][N:30]([S:35]([C:38]2[CH:46]=[CH:45][C:41]3[O:42][CH2:43][O:44][C:40]=3[CH:39]=2)(=[O:37])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:14][C:15]2[CH:27]=[CH:26][C:18]([O:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=O)=[CH:17][CH:16]=2)=[O:11])[CH2:2]1.[CH:48]([N:51](CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN>CN(C=O)C.CCO>[O:42]1[C:41]2[CH:45]=[CH:46][C:38]([S:35]([N:30]([CH2:31][CH:32]([CH3:33])[CH3:34])[CH2:29][C@@H:28]([OH:47])[C@@H:13]([NH:12][C:10](=[O:11])[O:9][C@@H:3]3[C@H:4]4[C@H:5]([O:6][CH2:7][CH2:8]4)[O:1][CH2:2]3)[CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:19][CH2:20][CH2:21][CH2:22][C:23]([NH:51][CH3:48])=[O:25])=[CH:26][CH:27]=3)(=[O:36])=[O:37])=[CH:39][C:40]=2[O:44][CH2:43]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCC(=O)O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCO
Solvent: CN(C)C=O
Product: CNC(=O)CCCOc1ccc(C[C@H](NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)[C@H](O)CN(CC(C)C)S(=O)(=O)c2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61.2 %

Procedure:
A solution of 35 mg (0.052 mmol) of 4-(4-{(2S,3R)-2-({[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl}amino)-4-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-3-hydroxybutyl}phenoxy)butanoic acid and 27 μL (0.16 mmol) of N,N-diisopropylethylamine in 1 mL of anhydrous DMF was treated with 49 mg (0.13 mmol) of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU). The resulting solution was stirred at RT for 15 minutes and was then treated with 0.5 mL of 8M MeNH2 in EtOH. After 18 hours TLC indicated the reaction to be complete. The solution was concentrated to dryness at reduced pressure and the residue subjected to flash chromatography (SiO2, 95:5 CH2Cl2/MeOH) to afford 22 mg (61%) of the desired compound as a white powder. 1H NMR (CDCl3): 7.37 (d, 1H), 7.22 (s, 1H), 7.13 (d, 2H), 6.92 (d, 1H), 6.82 (d, 2H), 6.13 (s, 2H), 5.67 (m, 2H), 5.05 (m, 2H), 4.00 (m, 3H), 3.88 (m, 3H), 3.72 (m, 2H), 3.24-2.71 (m, 11H), 2.40 (t, 2H), 2.16 (m, 2H), 1.88 (m, 1H), 1.67 (m, 1H), 1.53 (m, 1H), 0.94 (m, 6H). MS(ESI): 692(M+H).
Reaction SMILES: I[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([OH:17])[CH3:16])[N:8]=2)=[CH:5][N:4]([CH:18]([CH3:20])[CH3:19])[N:3]=1.[NH:21]1[C:25]2=[N:26][CH:27]=[C:28](B(O)O)[CH:29]=[C:24]2[CH:23]=[CH:22]1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:18]([N:4]1[CH:5]=[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([OH:17])[CH3:16])[N:8]=2)[C:2]([C:28]2[CH:29]=[C:24]3[CH:23]=[CH:22][NH:21][C:25]3=[N:26][CH:27]=2)=[N:3]1)([CH3:20])[CH3:19]
Reactant: OB(O)c1cnc2[nH]ccc2c1
Reactant: CC(C)n1cc(-c2ccnc(NC[C@H](C)O)n2)c(I)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)n1cc(-c2ccnc(NC[C@H](C)O)n2)c(-c2cnc3[nH]ccc3c2)n1
Reaction time: 8 h
Yield: 86.1 %

Procedure:
To a solution of (2S)-1-(4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol B-1-3 (0.312 g, 0.8 mmol) in toluene (15 mL) and EtOH (5 mL) were added 1H-pyrrolo[2,3-b]pyridin-5-ylboronic acid (0.40 g, 1.6 mmol) and 2 N aq. Na2CO3 (1.24 mL), and the resulting mixture was degassed under N2 for 2 minutes. Then Pd(PPh3)4 (0.23 g, 0.2 mmol) was added and the mixture was degassed again. The resulting mixture was heated to reflux and stirred overnight. The organic layer was separated and concentrated, the residue was purified via prep HPLC to afford (2S)-1-(4-(1-isopropyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (B-1) (0.260 g, 66.19%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O/C=C/C(Cl)=O)C.OC1C=C[C:24]2[C:19](=[CH:20][CH:21]=CC=2)N=1.[Cl-].C(=O)/C=C/C>P(Cl)(Cl)(Cl)=O>[CH3:21][C:20]1[CH:19]=[CH:24][C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:1]=1
Reactant: Nc1ccccc1
Reactant: Oc1ccc2ccccc2n1
Agent: C/C=C/C=O
Agent: CCO/C=C/C(=O)Cl
Agent: [Cl-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc2ccccc2n1

Procedure:
Aniline 22 may be acylated with (E)-3-ethoxyacryloyl chloride and treatment of the resulting amide with sulfuric acid leads to hydroxyquinoline 29, which can be converted to the corresponding chloride 30 by heating in phosphorus oxychloride. Condensation of aniline 24 with crotonaldehyde in the presence of acid and an oxidant affords the 2-methylquinoline 31. The use of other aldehydes under similar conditions can lead to alternatively substituted quinolines. Oxidation of quinoline 31 with selenium dioxide can provide either aldehyde 32 or carboxylic acid 33, depending on the amount of oxidant used and the duration of the reaction. Reduction of aldehyde 32 with sodium borohydride provides the corresponding alcohol, and treatment of this with thionyl chloride may be used to give the chloride 34. Intermediates such as 30, 32, 33 and 34 may be converted to compounds of the present invention using a variety of known methodology. While the methodology shown in scheme 6 is exemplified using aniline 22, it is understood that it may be applied to a variety of aniline substrates, such as those described herein, in order to provide various quinoline intermediates.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH2:15][OH:16])[NH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](Cl)(=[O:20])[CH3:19]>N1C=CC=CC=1>[C:18]([O:16][CH2:15][C:12]1[NH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10](=[O:17])[CH:11]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: O=c1cc(CO)[nH]cc1OCc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OCc1cc(=O)c(OCc2ccccc2)c[nH]1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To a solution of 10 g of 5-(benzyloxy)-2-(hydroxymethyl)pyridin-4(1H)-one in 58 mL of pyridine, 4.6 mL of acetyl chloride was added under cooling with ice, and the mixture was stirred at 60 to 70° C. for 3 hours. The solvent was distilled off under reduced pressure, water was added thereto, and the mixture was stirred under cooling with ice. The solid was filtered off, chloroform was added thereto and the resultant was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. Thereto was added diethyl ether and the solid was filtered off to obtain 9.2 g of (5-(benzyloxy)-4-oxo-1,4-dihydropyridin-2-yl)methyl acetate as a light brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[N:7]=[C:6]2[C:22](O)=[O:23].Cl.[F:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[CH2:33][NH:32][CH2:31][CH2:30]2>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[N:7]=[C:6]2[C:22]([N:32]1[CH2:31][CH2:30][C:29]2[C:34](=[CH:35][CH:36]=[C:27]([F:26])[CH:28]=2)[CH2:33]1)=[O:23]
Reactant: COc1cc2nc(-c3ccc(F)cc3)nc(C(=O)O)c2cc1OC
Reactant: Fc1ccc2c(c1)CCNC2
Agent: Cl
Product: COc1cc2nc(-c3ccc(F)cc3)nc(C(=O)N3CCc4cc(F)ccc4C3)c2cc1OC
Yield: 17.9 %

Procedure:
Reaction of 6,7-dimethoxy-2-(4-fluorophenyl)quinazoline-4-carboxylic acid with 6-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 114 (17.9% yield). 1H NMR (400 MHz, DMSO-d6) δ 2.84 and 3.09 (2t, 2H), 3.50-4.06 (m, 8H), 4.47 and 4.98 (2s, 2H), 6.94-7.43 (m, 5H), 7.52-7.55 (2s, 1H), 7.59-7.65 (m, 1H), 8.13-8.21 (m, 1H), 8.30-8.35 (m, 1H); 19F (376 MHz, DMSO-d6) δ −113.0, −116.1, −116.3; MS (ESI) m/z 462 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([CH:21]3[CH2:23][CH2:22]3)([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]=[C:15]=3)O)[C:6]3[CH2:24][CH2:25][N:26]([CH3:28])[CH2:27][C:5]=3[C:4]=2[CH:3]=1.S(=O)(=O)(O)[OH:30]>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11]/[C:12](/[C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:21]/[CH2:22][CH2:23][OH:30])[C:6]3[CH2:24][CH2:25][N:26]([CH3:28])[CH2:27][C:5]=3[C:4]=2[CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(O)(C2=C=C=C(F)C=C2)C2CC2)C1
Solvent: O
Product: CN1CCc2c(c3cc(Cl)ccc3n2C/C(=C/CCO)c2ccc(F)cc2)C1
Temperature: 110 °C

Procedure:
2-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-cyclopropyl-1-(4-fluorocyclohexa-1,2,3,5-tetraenyl)ethanol (1 g, 25 mmol) was dissolved in 10 mL 25% sulfuric acid and and heated at 110° C. for 4 h. The reaction mixture was cooled to RT, diluted with water and the resultant solid was filtered, washed with water, and diethylether. The solid was purified by reverse phase HPLC, and separated from the regioisomeric Compound No. 348. 1H NMR (CD3OD, HCl salt) δ (ppm): 7.48 (d, 1H), 7.40 (m, 1H), 7.15 (m, 1H), 7.0 (m, 4H), 5.60 (m, 1H), 5.0 (m, 2H), 4.80 (m, 2H), 4.60 (m, 1H), 4.30 (m, 1H), 3.80 (m, 1H), 3.42 (m, 2H), 3.05 (s, 3H), 3.0 (m, 1H), 2.10 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH2:15][CH:14]([CH3:16])[O:13][N:12]=2)=[C:9]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[OH:28][C:29]1[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:1][C:2]1[C:10]([C:11]2[CH2:15][CH:14]([CH3:16])[O:13][N:12]=2)=[C:9]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:8]=[CH:7][C:3]=1[C:4]([C:30]1[CH:31]=[N:32][N:33]([CH3:34])[C:29]=1[OH:28])=[O:5]
Reactant: CC1CC(c2c(S(C)(=O)=O)ccc(C(=O)Cl)c2Cl)=NO1
Reactant: Cn1nccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC1CC(c2c(S(C)(=O)=O)ccc(C(=O)c3cnn(C)c3O)c2Cl)=NO1
Reaction time: 12 h
Yield: 33.5 %

Procedure:
At room temperature, initially 4.00 g (12 mmol) of 2-chloro-3-(5-methyl-4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoyl chloride in 50 ml of dioxane and then 1.20 g (12.2 mmol) of triethylamine in 30 ml of dioxane were added dropwise to a solution of 1.20 g (12 mmol) of 5-hydroxy-1-methylpyrazole in 30 ml of dioxane. The reaction mixture was stirred for 12 hours and then filtered through silica gel and the filtrate was admixed with 0.50 g (3.6 mmol) of potassium carbonate and heated under reflux for 12 hours. After a further 12 hours of stirring at room temperature, a spatula tipful of potassium carbonate was added, and the mixture was once again heated under reflux. After cooling, the solvent was distilled off under reduced pressure, the residue was taken up in water and washed with ethyl acetate, the pH was adjusted to 1-2 using 10% strength hydrochloric acid and the mixture was extracted repeatedly with ethyl acetate. The combined organic phases were washed with water and dried and the solvent was removed. The residue was digested in cold ethyl acetate. 1.60 g (34% of theory) of 4-[2-chloro-3-(5-methyl-4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoyl]-5-hydroxy-1-methyl-1H-pyrazole were obtained.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=1>O1CCCC1>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[N:16][CH:17]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])cn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
Diethyl malonate (74 g) was added to a stirred suspension of sodium hydride (60% dispersion in oil; 18 g) in dry tetrahydrofuran under an inert atmosphere. The resulting suspension was stirred at reflux for one hour. The mixture was cooled to 60° C. and a solution of 2-chloro-5-nitropyridine (50 g) in dry tetrahydrofuran was added. The resulting red solution was stirred at reflux for 3 hours then allowed to stand at room temperature overnight. The volume of solvent was reduced by evaporation, water was added to the residue and the mixture was acidified to pH 1 with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate, washed with water, dried (anhydrous magnesium sulphate), filtered and evaporated. The crude product was triturated in a mixture of cyclohexane and diethyl ether to yield diethyl 2-(5-nitropyridin-2-yl)malonate (56.5 g) as a yellow solid, m.p. 91.5°-93.5° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH2:14][CH2:13][CH2:12][C:11]([CH3:16])([CH3:15])[C:10]=1/[CH:17]=[CH:18]/[C:19](/[CH3:28])=[CH:20]/[CH:21]=[CH:22]/[C:23](/[CH3:27])=[CH:24]/[CH2:25][OH:26].CCCCCC.C(OCC)C>ClCCl>[CH3:8][C:9]1[CH2:14][CH2:13][CH2:12][C:11]([CH3:15])([CH3:16])[C:10]=1/[CH:17]=[CH:18]/[C:19](/[CH3:28])=[CH:20]/[CH:21]=[CH:22]/[C:23](/[CH3:27])=[CH:24]/[CH:25]=[O:26]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/CO)C(C)(C)CCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCCCCC
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=O)C(C)(C)CCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 152.3 %

Procedure:
Retinol anhydride (1.00 g, 0.0017 mol) and triethylamine (0.31 g, 0.0021 mol) were added to retinol (0.60 g, 0.0021 mol) dissolved in anhydrous dichloromethane (30 ml) at 0° C. The reaction solution was slowly warmed to room temperature and stirred for 5 hours under nitrogen atmosphere and under the condition for light and moisture to be intercepted. The reaction solution was filtered and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (silica gel 60 for cc part, Merk Co., mesh size 270–400, hexane/diethylether=9/1, v/v) to give 0.91 g (Yield 92%) of the pale yellow title compound. 1H NMR data of this compound were the same as those in Example 1.
Reaction SMILES: [C:1]1([S:7][C:8]2([CH2:12][C:13]([OH:15])=O)[CH2:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)Cl>C1C=CC=CC=1>[O:15]=[C:13]1[C:6]2[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=2[S:7][C:8]2([CH2:9][CH2:10][CH2:11]2)[CH2:12]1
Reactant: O=C(O)CC1(Sc2ccccc2)CCC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: O=C1CC2(CCC2)Sc2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 1-Phenylthiocyclobutane-1-acetic acid (10 mmol) in benzene was treated with excess of PCl5 at room temperature for 15 h. The reaction mixture was concentrated under vacuum and the residue was again dissolved in benzene. AlCl3 was then added to the solution and it was stirred for 24 h at room temperature. The reaction mixture was diluted with excess of ethyl acetate and washed with water and brine. Organic layer was then separated, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography to afford the desired compound as oil.
Reaction SMILES: O(P(O[C:18]1[CH2:19][C@@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[O:42]=[C:43]1[NH:47][C:46](=[O:48])[CH:45]([C@@H:49]2[CH2:53][C@H:52]([S:54]CC3C=CC(OC)=CC=3)[CH2:51][N:50]2[C:64]([O:66][CH2:67][C:68]2[CH:73]=[CH:72][C:71]([N+:74]([O-:76])=[O:75])=[CH:70][CH:69]=2)=[O:65])[NH:44]1>>[O:42]=[C:43]1[NH:47][C:46](=[O:48])[CH:45]([C@@H:49]2[CH2:53][C@H:52]([S:54][C:18]3[CH2:19][C@@H:20]4[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]4[C:22]=3[C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])[CH2:51][N:50]2[C:64]([O:66][CH2:67][C:68]2[CH:73]=[CH:72][C:71]([N+:74]([O-:76])=[O:75])=[CH:70][CH:69]=2)=[O:65])[NH:44]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)C[C@H]12
Reactant: COc1ccc(CS[C@H]2C[C@@H](C3NC(=O)NC3=O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4NC(=O)NC4=O)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)C[C@H]12
Yield: 17.6 %

Procedure:
The same procedure as in Example 1-1 was carried out by using p-nitrobenzyl (5R,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylate (150 mg, 0.258 mmol) and (2S,4S)-2-(2,4-dioxoimidazolidin-5-yl)-4-(p-methoxybenzylthio)-N-(p-nitrobenzyloxycarbonyl)pyrrolidine (120 mg, 0.240 mmol, compound of Reference Example 28) to obtain p-nitrobenzyl (5R,6S)-2-[(2S,4S)-2-(2,4-dioxoimidazolidin-5-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylate (30 mg, yield: 18%).
Reaction SMILES: BrN1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:14]([CH3:23])=[C:13]2[C:24]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1.[CH3:35][S-:36].[Na+]>CN(C=O)C>[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:14]([CH2:23][S:36][CH3:35])=[C:13]2[C:24]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1
Reactant: C[S-]
Reactant: Cc1c(-c2ccnc3cc(Cl)ccc23)c2cc(Cl)ccc2n1CC(=O)O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCc1c(-c2ccnc3cc(Cl)ccc23)c2cc(Cl)ccc2n1CC(=O)O
Reaction time: 0.17 h

Procedure:
1-Bromo-2,5-pyrrolidinedione (0.11 g) was added to a solution of the product from Example 27 step b) (0.2 g) in DMF (2 ml), and the solution stirred for 10 min. Sodium thiomethoxide (43 mg) was then added and the mixture stirred for a further 3 hours. The solvents were evaporated in vacuo and the residue purified by reverse phase HPLC. The residue was triturated with ether to give a solid, which was filtered and dried to yield the title compound as a white solid (40 mg).