Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)[C@@H:10]([OH:27])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:36]([Si:40]([CH3:43])([CH3:42])Cl)([CH3:39])([CH3:38])[CH3:37].N1C=CN=C1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CO.C1COCC1.O.CCCCCC.C(OCC)(=O)C>[C:1]([NH:8][C@@H:9]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=1)[C@@H:10]([O:27][Si:40]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:43])[CH3:42])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)[C@@H](O)C[C@@H](Cc1ccc(C(F)(F)F)cc1)C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)[C@H](C[C@@H](Cc1ccc(C(F)(F)F)cc1)C(=O)O)O[Si](C)(C)C(C)(C)C

Procedure:
Analogously to Example 1 j), 1.06 g of 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-fluorophenyl)-2(R)-(p-trifluoromethylphenylmethyl)-hexanoic acid in 2.3 ml of DMF are silylated with 1.47 g of tert-butyldimethylchlorosilane and 1.18 g of imidazole. Hydrolysis of the silyl ester function with 1.76 g of potassium carbonate in 50 ml of methanol/THF/water 3:1:1 yields, after column chromatography (SiO2, hexane/ethyl acetate 2: 1), the title compound: TLC Rf (D)=0.15; 1H-NMR (200 MHz, CD3OD): 7.59 and 7.39 (2d, 8 Hz, per 2 H), 7.19 and 6.98 (2 m, per 2 H), 6.47 and 5.90 (d, approximately 9 Hz, together 1 H), 3.9-3.65 (m, 2 H), 3.15-2.8 (m, 4 H), 2.53-2.37, 2.07-1.9 and 1.6-1.4 (3 m, per 1 H), 1.37-1.22 (m, 9 H), 0.94 (s, 9 H), 0.2-0.1 (m, 6 H).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)=[CH:16][CH:15]=1.[OH-].[Na+]>CCO.C1COCC1>[Cl:29][C:24]1[CH:23]=[C:22]([CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([NH:13][C:5]3[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=3[C:3]([OH:30])=[O:2])=[CH:15][CH:16]=2)[CH:27]=[CH:26][C:25]=1[Cl:28]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Nc1ccc(CCc2ccc(Cl)c(Cl)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cc([N+](=O)[O-])ccc1Nc1ccc(CCc2ccc(Cl)c(Cl)c2)cc1
Yield: 100 %

Procedure:
A solution of 2-{4-[2-(3,4-dichloro-phenyl)-ethyl]phenylamino}-5-nitrobenzoic acid methyl ester (340 mg, 0.76 mmol) and 1N NaOH (aq.) (4.0 mL) in EtOH (4.0 mL) and THF (4.0 mL) was heated to reflux for 16 hours. The solvent was removed in vacuum. The residue was diluted with H2O and acidified with concentrated HCl to pH 1. The mixture was then extracted with methylene chloride, dried (Na2SO4), filtered and concentrated in vacuo to yield a yellow solid, 329 mg (0.76 mmol, 100%) of the desired product mp 214-217° C.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:14](=[O:15])[C:13]2[C:12]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)=[N:11][C:10]([NH:22][C@@H:23]3[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]3[NH:29]C(=O)OC(C)(C)C)=[N:9][C:8]=2[CH2:7]1.[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44]>>[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44].[NH2:29][C@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][C@H:23]1[NH:22][C:10]1[N:11]=[C:12]([C:16]2[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=2)[C:13]2[C:14](=[O:15])[NH:6][CH2:7][C:8]=2[N:9]=1
Reactant: COc1ccc(CN2Cc3nc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(-c4cnn(C)c4)c3C2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3N)nc3c2C(=O)NC3)cn1
Temperature: 70 °C
Yield: 59 %

Procedure:
tert-Butyl (1S,2R)-2-(6-(2,4-dimethoxybenzyl)-4-(1-methyl-1H-pyrazol-4-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-ylamino)cyclohexylcarbamate (0.0625 g, 0.108 mmol) was dissolved in TFA (2 mL) and heated at 70° C. for 1 h. The solvent was removed under reduced pressure and the resulting residue was dispersed in DMSO/MeOH (1/1) solution. A pale purple precipitate was formed and was separated by filtration. The filtrate, which contained the product, was purified via reverse phase preparative HPLC. Lyophilized fractions gave a TFA salt of the title compound as a white solid (21 mg, 59%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.28-1.52 (m, 2H) 1.51-1.94 (m, 6H) 3.93 (s, 3H) 4.14-4.30 (m, 2H) 4.29-4.58 (m, 1H) 7.51 (d, J=6.83 Hz, 1H) 7.71 (br s, 2H) 8.29 (s, 1H) 8.34-8.69 (m, 1H) 9.11 (d, J=17.09 Hz, 1H). [M+H] calc'd for C16H21N7O, 328. found, 328.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([NH:14][NH2:15])=[N:12][N:11]([CH2:16][C:17]3[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[C:10](=[O:28])[C:9]=2[C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[Cl:44][CH2:45][C:46](Cl)=[O:47]>C1COCC1.CCOC(C)=O>[Cl:44][CH2:45][C:46]([NH:15][NH:14][C:13]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:9]([C:29]2[CH:30]=[CH:31][C:32]([C:33]#[N:34])=[CH:35][CH:36]=2)[C:10](=[O:28])[N:11]([CH2:16][C:17]2[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=2)[N:12]=1)=[O:47]
Reactant: O=C(Cl)CCl
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc(NN)c(-c2ccc(Cl)cc2)c(-c2ccc(C#N)cc2)c1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1nc(C(F)(F)F)ccc1Cn1nc(NNC(=O)CCl)c(-c2ccc(Cl)cc2)c(-c2ccc(C#N)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
To a solution of 4-(5-(4-chlorophenyl)-6-hydrazinyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-oxo-2,3-dihydropyridazin-4-yl)benzonitrile (500 mg, 0.977 mmol) in THF (7 ml), Et3N (197 mg, 1.953 mmol) was added chloroacetyl chloride (110 mg, 0.977 mmol). The reaction was stirred at room temperature for 30 min. The reaction mixture was diluted with EtOAc (50 ml) and the resulting solution was washed with water (2×20 ml) and saturated NaCl (20 ml). The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified using an ISCO automated chromatography system (12 g silica gel, 20-40% EtOAc/CH2Cl2) to give the product 2-chloro-N′-(4-(4-chlorophenyl)-5-(4-cyanophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-1,6-dihydropyridazin-3-yl)acetohydrazide as a light yellow solid (410 mg, 72% yield). HPLC retention time 2.920 min (Method A); LCMS (M+H)=587.0.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[CH2:16]([C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1)[CH2:17][CH2:18][CH3:19]>ClCCl>[CH2:16]([C:20]1[CH:21]=[CH:22][C:23]([C:24]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])=[O:25])=[CH:27][CH:28]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCc1ccc(C(=O)Cl)cc1
Reactant: NCCCCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1ccc(C(=O)NCCCCCCO)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.4 %

Procedure:
To a stirred solution of 23.5 g of 6-amino-1-hexanol and 30 g of triethylamine in 200 ml of dichloromethane, cooled in an ice bath, was added dropwise a solution of 43.3 g of p-butylbenzoyl chloride in 100 ml of dichloromethane. The mixture was allowed to stir at room temperature for 16 hours. Then the mixture was washed in succession with water, saturated sodium carbonate, water, and finally brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was triturated, filtered, and rinsed with cold hexane and gave 47.5 g of the desired product in 61% yield as a beige solid, m.p. 80°-81° C.
Reaction SMILES: [CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]4[O:22][CH:6]5[C:7]([CH:9]=[CH:10][C@:11]2([OH:23])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8]>O>[CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]4[O:22][C@H:6]5[C:7]([CH2:9][CH2:10][C@:11]2([OH:23])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8]
Reactant: COc1ccc2c3c1OC1C(=O)C=C[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Solvent: O
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314

Procedure:
The ratio of acid:14-hydroxycodeinone may be in the range of about 1:2.0 g/g to about 1:2.5 g/g, such as about 1:2.15 g/g. The ratio of 14-hydroxycodeinone:water may be in the range of about 1:0.005 to about 1:10, such as about 1:0.01 to about 1:3.13 g/g. The quantities of water and/or acid are not particularly limiting provided there is enough water and/or acid to substantially dissolve the 14-hydroxycodeinone. In this regard, the inventors have found that minimal water may be added to reaction mixture and the hydrogenation of 14-hydroxycodeinone has been successfully performed to produce oxycodone acid adduct having a low level of 6α-oxycodol when the quantity of water added corresponded only to amount which would have been present in the water-wet catalyst. The quantity of water present in the catalyst and/or 14-hydroxycodeinone (which may also be used wet) may be taken into account when calculating the total quantity of water to be used.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([CH:8]([C:10]1[N:11]=[CH:12][NH:13][CH:14]=1)[CH3:9])[C:5]([OH:7])=[O:6].[CH3:15]O>>[NH2:3][CH:4]([CH:8]([C:10]1[N:11]=[CH:12][NH:13][CH:14]=1)[CH3:9])[C:5]([O:7][CH3:15])=[O:6]
Reactant: CC(c1c[nH]cn1)C(N)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)C(N)C(C)c1c[nH]cn1

Procedure:
9.40 g (38.9 mmol) of 2-amino-3-(1H-imidazol-4-yl)butyric acid dihydrochloride are solved in 100 ml methanol. Dry HCl-gas is bubbled through the solution while heating under reflux for 4 hours. After cooling the excess hydrochloric acid is removed by evaporation in vacuo. Yield: 9.8 g (98%) methyl 2-amino-3-(1H-imidazol-4-yl)butyrate hydrochloride as an amorphous solid.
Reaction SMILES: [OH:1][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:30][CH2:31][CH2:32]O.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:30][CH2:31][CH2:32][O:1][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc2nc[nH]c12
Reactant: OCCCl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClCCOc1cccc2nc[nH]c12
Temperature: 23 °C
Reaction time: 48 h
Yield: 45.5 %

Procedure:
To a solution of 4-hydroxybenzimidazole (3.1 g, 32.4 mmol), triphenylphosphine (12.75 g, 48.6 mmol) and 2-chloroethanol (5.2 g, 64.8 mmol) in tetrahydrofuran (75 mL) at 0-5° C. was added over 30 min a solution of diethyl azodicarboxylate (8.5 g, 48.7 mmol) in tetrahydrofuran (75 mL). The mixture was warmed to 23° C. and stirred for 48 hr. The solvent was removed under vacuum to give a dark brown oil. Purification by chromatography (silica gel, ethyl acetate-1% 2M NH3 in methanol) afforded 2.9 g (63.8%) of a solid residue that was crystallized from ethyl acetate to give the title compound as a white solid, mp 153-154° C.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>C(Cl)Cl>[C:12]([Si:9]([CH3:11])([CH3:10])[O:7][C:6]1[CH:1]=[C:2]([CH3:8])[CH:3]=[CH:4][CH:5]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cccc(O)c1
Solvent: ClCCl
Product: Cc1cccc(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
To a solution of m-cresol(1 mL, 9.6 mmol) in CH2Cl2 (10 mL) was added tert-butyldimethylsilyl chloride (1.5 g, 10 mmol), triethyl aimine (3 ml, 20 mmol. The reaction was stirred at room temperature overnight. It was filtered and filtrate was concentrated and purified by column chromatography on ISCO (40 g) with 10% ethyl acetate in hexanes to yield tert-butyldimethyl(m-tolyloxy)silane as a colorless oil (1.31 g, 62%). HPLC retention time (Method C)=3.22 min. LC/MS (ESD (M+H)+=223.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][C:6]([CH3:16])=[C:7]([C:9](=[N:13][O:14][CH3:15])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.[NH2:22][CH:23]1[C:40](=[O:41])[N:25]2[C:26]([C:37]([OH:39])=[O:38])=[C:27]([CH2:30][S:31][C:32]3[S:33][CH:34]=[N:35][N:36]=3)[CH2:28][S:29][C@H:24]12.C[Si](CC(N)=O)(C)C>C(OCC)(=O)C.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][C:6]([CH3:16])=[C:7]([C:9](=[N:13][O:14][CH3:15])[C:10]([NH:22][CH:23]2[C:40](=[O:41])[N:25]3[C:26]([C:37]([OH:39])=[O:38])=[C:27]([CH2:30][S:31][C:32]4[S:33][CH:34]=[N:35][N:36]=4)[CH2:28][S:29][C@H:24]23)=[O:12])[N:8]=1)=[O:2]
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Reactant: CON=C(C(=O)O)c1nc(NC=O)sc1C
Agent: C[Si](C)(C)CC(N)=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1nc(NC=O)sc1C
Reaction time: 1.5 h
Yield: 105.8 %

Procedure:
A solution of 2-(2-formamido-5-methylthiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 1.2 g.), dimethylformamide (0.46 ml.) and phosphoryl chloride (0.54 ml.) in dry ethyl acetate (12 ml.) was added to a solution of 7-amino-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (2.12 g.) and trimethylsilylacetamide (6.7 g.) in dry ethyl acetate (20 ml.) at -10° to -20° C. and stirred at the same temperature for 1.5 hrs. The reaction mixture was washed with water and adjusted to pH 8 with an aqueous solution of sodium bicarbonate. The aqueous layer was separated and adjusted to pH 2 with hydrochloric acid. The precipitates were collected by filtration and dried to give 7-[2-(2-formamido-5-methylthiazol-4-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer, 2.9 g.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([OH:20])=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:22][O:23][C:24]1[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([N:28]3[CH2:27][CH2:26][C:25]4[C:30](=[CH:31][CH:32]=[C:33]([O:34][CH3:35])[C:24]=4[O:23][CH3:22])[CH2:29]3)=[O:20])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Reactant: COc1ccc2c(c1OC)CCNC2
Agent: Cl
Product: COc1ccc2c(c1OC)CCN(C(=O)c1nc(-c3ccc(C)cc3)nc3ccccc13)C2
Yield: 17 %

Procedure:
Reaction of 2-(4-methylphenyl)quinazoline-4-carboxylic acid with 5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 14 (17% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.41 (s, 3H), 2.73 and 2.98 (2t, 2H), 3.48 and 4.03 (2t, 2H), 3.69 and 3.75 (2s, 3H), 3.76 and 3.82 (2s, 3H), 4.41 and 4.93 (2s, 2H), 6.62 and 7.01 (2d, 1H), 6.80 and 7.08 (2d, 1H), 7.37-7.41 (m, 2H), 7.67-7.77 (m, 1H), 7.86-7.98 (2d, 1H), 8.04-8.16 (m, 2H), 8.40-8.43 (m, 2H); MS (ESI) m/z 440 ([M+H]+).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14]([OH:16])=[O:15])=[CH:7][CH:8]=2)[NH:3]1.[O:20]=[C:21]1[C:26]2=[CH:27][NH:28][C:29]([CH:30]=O)=[C:25]2[CH2:24][CH2:23][O:22]1>>[O:1]=[C:2]1[C:10](=[CH:30][C:29]2[NH:28][CH:27]=[C:26]3[C:21](=[O:20])[O:22][CH2:23][CH2:24][C:25]=23)[C:9]2[C:4](=[CH:5][C:6]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14]([OH:16])=[O:15])=[CH:7][CH:8]=2)[NH:3]1
Reactant: O=C1Cc2ccc(-c3cccc(C(=O)O)c3)cc2N1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Product: O=C1Nc2cc(-c3cccc(C(=O)O)c3)ccc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
3-(2-Oxo-2,3-dihydro-1H-indol-6-yl)-benzoic acid was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [CH2:1]1[C:11]2[C:5]([C:6]([C:16](O)=[O:17])=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=[CH:9][CH:10]=2)=[CH:4][CH:3]=[CH:2]1.[NH2:19][C@H:20]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:21]1>>[F:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][CH2:25][N:22]2[CH2:23][CH2:24][C@H:20]([NH:19][C:16]([C:6]3[C:5]4=[CH:4][CH:3]=[CH:2][CH2:1][C:11]4=[CH:10][CH:9]=[C:8]4[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=34)=[O:17])[CH2:21]2)=[CH:32][CH:31]=1
Reactant: O=C(O)C1=c2ccccc2=CC=C2CC=CC=C21
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Product: O=C(N[C@H]1CCN(CCc2ccc(F)cc2)C1)C1=c2ccccc2=CC=C2CC=CC=C21

Procedure:
Dibenzo[a,d]cycloheptene-5-carboxylic acid and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine were reacted under the same conditions as in Example 23 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)dibenzo[a,d]cycloheptene-5-carboxamide, melting point 127-128° C.
Reaction SMILES: Br[C:2]([F:17])([F:16])[CH2:3][CH:4]1[CH2:8][N:7]([CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[C:6](=[O:15])[CH2:5]1.N12CCCC=C1CCCCN2>C(Cl)(Cl)Cl>[F:17][C:2]([F:16])=[CH:3][CH:4]1[CH2:8][N:7]([CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[C:6](=[O:15])[CH2:5]1
Reactant: O=C1CC(CC(F)(F)Br)CN1Cn1ccnc1
Agent: C1=C2CCCCNN2CCC1
Solvent: ClC(Cl)Cl
Product: O=C1CC(C=C(F)F)CN1Cn1ccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
In a 50 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, 4-(2-bromo-2,2-difluoro-ethyl)-1-(1H-imidazol-1-ylmethyl)-pyrrolidin-2-one 17 (0.16 g, 0.52 mmol) and diazabicyclo [5.4.0]undec-7-ene (0.1 ml, 0.62 mmol) in CHCl3 (0.5 ml) are stirred overnight at room temperature. The reaction mixture is filtered, evaporated in vacuo, diluted with CH2Cl2 and the organic layer is washed with water, dried over MgSO4, filtered and evaporated in vacuo. The residue is purified by chromatography on silicagel (CH2Cl2/EtOH/NH4OH: 93.5/06/0.5 (v/v/v)) to afford 4-(2,2-difluorovinyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one 18 (0.092 g, 80%) which is crystallized as a maleic salt in THF.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH2:4][CH2:3][CH2:2][NH:1]2)=[CH:6][CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: Oc1ccc2c(c1)NCCC2
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: c1ccc(Oc2ccc3c(c2)NCCC3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 6.6 %

Procedure:
To a solution of 0.15 g (1.01 mmol) 1,2,3,4-tetrahydro-quinolin-7-ol in 10 ml dichloromethane were added 0.19 g (1.56 mmol) phenylboronic acid, 0.27 g (1.49 mmol) copper(II) acetate, a spatula end of 4 Å molecular sieves and 0.64 ml (5.03 mmol) triethylamine. The reaction mixture was stirred at room temperature for 72 hours and then filtered through celite, washing with dichloromethane. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, ethyl acetate/heptane gradient) to afford 15 mg (7%) of the title compound as a light yellow oil. MS (ISP): 226.3 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][NH:19][CH:20]2[C:25]([F:28])([F:27])[F:26]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:18][CH2:17][C:16]4[C:21](=[CH:22][CH:23]=[CH:24][C:15]=4[F:14])[CH:20]3[C:25]([F:26])([F:27])[F:28])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: Fc1cccc2c1CCNC2C(F)(F)F
Product: O=C(c1cc2ncc(Cl)cn2n1)N1CCc2c(F)cccc2C1C(F)(F)F

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-fluoro-1-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.CCN=C=NCCCN(C)C.Cl.C[O:27][C:28](=[O:79])[C@@H:29]([NH:46][C:47]([C@@H:49]1[CH2:58][C:57]2[CH:56]=[C:55]3[O:59][CH2:60][C@H:61]([C:63]4[CH:68]=[CH:67][C:66]([O:69][CH2:70][C:71]5[CH:76]=[CH:75][C:74]([Cl:77])=[C:73]([Cl:78])[CH:72]=5)=[CH:65][CH:64]=4)[O:62][C:54]3=[CH:53][C:52]=2[CH2:51][NH:50]1)=[O:48])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[C:39]=2[CH3:45])=[CH:33][CH:32]=1>C(Cl)Cl>[Cl:78][C:73]1[CH:72]=[C:71]([CH:76]=[CH:75][C:74]=1[Cl:77])[CH2:70][O:69][C:66]1[CH:67]=[CH:68][C:63]([C@H:61]2[CH2:60][O:59][C:55]3=[CH:56][C:57]4[CH2:58][C@@H:49]([C:47]([NH:46][C@@H:29]([CH2:30][C:31]5[CH:36]=[CH:35][C:34]([O:37][C:38]6[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[C:39]=6[CH3:45])=[CH:33][CH:32]=5)[C:28]([OH:79])=[O:27])=[O:48])[N:50]([C:6](=[O:8])[C:5]5[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=5)[CH2:51][C:52]=4[CH:53]=[C:54]3[O:62]2)=[CH:64][CH:65]=1
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: COc1ccc(C(=O)O)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(C(=O)N2Cc3cc4c(cc3C[C@H]2C(=O)N[C@@H](Cc2ccc(Oc3ccnc(C)c3C)cc2)C(=O)O)OC[C@H](c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)O4)cc1OC
Reaction time: 16 h

Procedure:
3,4-Dimethoxybenzoic acid (1 eq.) was stirred in dry DCM with 0.5 eq EDCl at RT for 1 h. (S)-2-({(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester in dry DCM (10 eq benzoic acid relative to amine) was added and the resulting mixture stirred 16 h, then directly purified by flash chromatography. The resulting compound was hydrolyzed according to General Procedure B to give the title compound (5 mg). LCMS (m/z) 919.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:24][CH2:25][CH2:26]OS(C1C=CC(C)=CC=1)(=O)=O>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:26][CH2:25][F:24])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: Oc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: FCCOc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 44.5 h
Yield: 66.5 %

Procedure:
578 mg (corresponding to 2.0 mmol) of 6-bromo-2-(4′-hydroxyphenyl)imidazo[1,2-a]pyridine that was sufficiently dried to remove moisture was dissolved in 20 mL of N,N-dimethylformamide, and 830 mg (corresponding to 6.0 mmol) of potassium carbonate was added thereto. The mixture was supplemented with 510 μL (corresponding to 3.0 mmol) of 2-fluoroethyl-p-toluenesulfonate, and then the solution was stirred at room temperature for 44.5 hours. After the completion of the reaction, the reaction solution was poured into water and extracted three times with chloroform. The combined chloroform layer was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was purified by flash silica gel column chromatography (elution solvent: chloroform/methanol=100/1), by recycle preparative HPLC (HPLC apparatus: LC-908 (under trade name; manufactured by Japan Analytical Industry Co., Ltd.); column: two JAIGEL 2H (under trade name; manufactured by Japan Analytical Industry Co., Ltd.) connected together; mobile phase: chloroform), and further by preparative TLC (elution solvent: chloroform/methanol=50:1) to obtain 446 mg (corresponding to 1.33 mmol) of 6-bromo-2-[4′-(2″-fluoroethoxy)phenyl]imidazo[1,2-a]pyridine (FIG. 1-6, Step 3).
Reaction SMILES: CC1(C)S[C@@H]2[C@H](N[C:11]([CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:12])C(=O)N2[C@H]1C(O)=O.C(O)([OH:28])CCC>>[C:14]1([CH2:13][C:11]([OH:12])=[O:28])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Reactant: CCCC(O)O
Product: O=C(O)Cc1ccccc1

Procedure:
A solution of 40 mM of 6 APA and 200 mM of phenylacetic acid in 50% butanediol/50% acetate 50 mM is prepared at a pH of 6.5. The column is thermostatized at 4° C. The rest of the conditions are as in example 1. In these conditions, the degree of conversion of 6 APA to penicillin G is higher than 85%.