Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:13]([O:15][C:16](=[O:37])[CH2:17][O:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][N:23]1[C:28](=[O:29])[CH2:27][CH2:26][CH2:25][C@@H:24]1[CH2:30][O:31]C(OCC)C)[CH3:14]>CCO>[CH2:13]([O:15][C:16](=[O:37])[CH2:17][O:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][N:23]1[C:28](=[O:29])[CH2:27][CH2:26][CH2:25][C@@H:24]1[CH2:30][OH:31])[CH3:14]
Reactant: CCOC(=O)COC/C=C\CN1C(=O)CCC[C@@H]1COC(C)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)COC/C=C\CN1C(=O)CCC[C@@H]1CO
Reaction time: 18 h
Yield: 76.4 %

Procedure:
p-Toluenesulfonic acid hydrate (267 mg, 1.40 mmol) was added to a solution of {(Z)-4-[(R)-2-(1-ethoxyethoxymethyl)-6-oxo-piperidin-1-yl]-but-2-enyloxy}-acetic acid ethyl ester (from example 1, step 2, 477 mg, 1.33 mmol) in EtOH (6 mL). After 18 h at rt, the reaction was concentrated in vacuo and quenched with saturated aqueous NaHCO3 (20 mL). The mixture was extracted with CH2Cl2 (3×15 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2 →3% MeOH/CH2Cl2, gradient) afforded 290 mg (76%) of [(Z)-4((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-but-2-enyloxy]-acetic acid ethyl ester.
Reaction SMILES: [CH3:1]/[C:2](/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)=[CH:3]\[CH2:4][OH:5]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1]/[C:2](/[CH:6]=[CH:7]/[C:8]1[CH:9]=[CH:10][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:13]=1)=[CH:3]\[CH:4]=[O:5]
Reactant: CC(/C=C/c1ccc(C(F)(F)F)cc1)=C\CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(/C=C/c1ccc(C(F)(F)F)cc1)=C\C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
In 10 ml of methylene chloride were dissolveed 460 mg (1.90 mmol) of (2E,4E)-3-methyl-5-[4-(trifluoromethyl)phenyl]-2,4-pentadien-1-ol, and 5 g of active manganese dioxide were added to the mixture, followed by stirring of the resulting mixture at room temperature of 30 minutes. The solid was removed by filtration, and after the filtrate was concentrated, it was purified over silica gel chromatography (eluting solvent: 4% ethyl acetate-hexane) to obtain 460 mg of the title compound as an oil.
Reaction SMILES: CC1(C)[NH:6][CH:5]([P:7](=[O:10])([OH:9])[OH:8])[C:4]([CH3:12])([CH3:11])[S:3]1>O>[NH2:6][CH:5]([P:7](=[O:8])([OH:10])[OH:9])[C:4]([SH:3])([CH3:12])[CH3:11]
Reactant: CC1(C)NC(P(=O)(O)O)C(C)(C)S1
Solvent: O
Product: CC(C)(S)C(N)P(=O)(O)O
Temperature: 0 °C

Procedure:
2.0 g of DL-(2,2,5,5-tetramethyl-4-thiazolidinyl)phosphonic acid (prepared as described in Example 1) were dissolved in boiling water and the solution was concentrated by boiling off excess water until a crystalline solid began to separate. The mixture was cooled to 0° C. and the white crystals were collected. There was obtained 0.6 g of DL-(1-amino-2-mercapto-2-methylpropyl)phosphonic acid of melting point 242°-244° C. (decomposition).
Reaction SMILES: C([BH3-])#N.[Na+].C(O)(=O)C.[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[N:15]1[C:23]2[C:18](=[CH:19][C:20]([NH2:24])=[CH:21][CH:22]=2)[CH:17]=[N:16]1.C(NC1C(C)=CC(C(OC)=O)=C(C)C=1)(=O)C.[CH2:41]([N:44]1[CH:49]2[CH2:50][CH2:51][CH:45]1[CH2:46][C:47](=O)[CH2:48]2)[CH2:42][CH3:43].N>CO>[CH2:41]([N:44]1[CH:49]2[CH2:50][CH2:51][CH:45]1[CH2:46][CH:47]([NH:24][C:20]1[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=1)[N:15]([CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][O:9]1)[N:16]=[CH:17]3)[CH2:48]2)[CH2:42][CH3:43]
Reactant: Nc1ccc2c(cnn2C2CCCCO2)c1
Reactant: CCCN1C2CCC1CC(=O)C2
Agent: COC(=O)c1cc(C)c(NC(C)=O)cc1C
Agent: N
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CO
Product: CCCN1C2CCC1CC(Nc1ccc3c(cnn3C3CCCCO3)c1)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.8 %

Procedure:
Sodium cyanoborohydride (484 mg, 7.70 mmol) and then acetic acid (440 μl, 7.68 mmol) were added to a solution of the 1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-amine (335 mg, 1.54 mmol) obtained in Example 317, (e) and 8-propyl-8-azabicyclo[3.2.1]octan-3-one (300 mg, 1.85 mmol) in methanol (6 ml), and the resulting mixture was stirred at room temperature for 1 day. Aqueous ammonia was added thereto, followed by extraction with ethyl acetate. The extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a silica gel column chromatography (chloroform/methanol/triethylamine=100/1/5) to obtain N-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-amine (413 mg, 73%).
Reaction SMILES: C[O:2][C:3](=[O:31])[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][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)=[CH:16][CH:15]=1.[OH-].[Na+]>CCO.C1COCC1>[Cl:30][C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][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:31])=[O:2])=[CH:19][CH:18]=2)[CH:28]=[CH:27][C:26]=1[Cl:29]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Nc1ccc(CCCc2ccc(Cl)c(Cl)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cc([N+](=O)[O-])ccc1Nc1ccc(CCCc2ccc(Cl)c(Cl)c2)cc1
Yield: 100.9 %

Procedure:
The title compound was 2-{4-[3-(3,4-dichlorophenyl)-propyl]phenylamino}-5-nitrobenzoic acid methyl ester (0.50 g, 1.09 mmol), 2N NaOH (5.0 mL) in EtOH (2 mL) and THF (4 mL) using the procedure described in Example 2. This procedure yielded an orange solid, 0.49 g (1.10 mmol, 100%) of the desired product. mp 153-155° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:13](Br)[C:14]#[CH:15]>C(#N)C>[CH2:15]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[C:14]#[CH:13]
Reactant: C1COCCN1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCN1CCOCC1

Procedure:
To a mixture of morpholine (0.78 mL, 8.98 mmol) and potassium carbonate (3.7 g, 26.9 mmol) in acetonitrile (10 mL) was added propargyl bromide (1.0 mL, 8.98 mmol) and the mixture was heated to about 80 C overnight. The reaction was quenched by addition of water and the mixture was extracted with diethyl ether. The combined organic extracts were washed with water, dried (Na2SO4), filtered and concentrated under vacuum to provide Example 639. 1H NMR (300 MHz, CD3OD) δ 2.57 (m, 4H) 2.68 (t, J=2.4 Hz, 1H) 3.29 (s, 2H) 3.70 (m, 4H).
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH2:18][C:19]#[C:20][CH3:21].C([CH2:25][C:26]([NH:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31]([OH:33])=[O:32])=[O:27])(O)=O.CC(O)=O>C1(C)C=CC=CC=1>[CH2:18]([O:17][C:10]1[CH:11]=[C:12](/[CH:13]=[CH:25]/[C:26]([NH:28][C:29]2[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=2[C:31]([OH:33])=[O:32])=[O:27])[CH:15]=[CH:16][C:9]=1[O:8][CH3:7])[C:19]#[C:20][CH3:21]
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Reactant: CC#CCOc1cc(C=O)ccc1OC
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CC#CCOc1cc(/C=C/C(=O)Nc2ccccc2C(=O)O)ccc1OC
Yield: 69.3 %

Procedure:
Piperidine (0.35 mL, 3.5 mmol) was added to a suspension of 4-methoxy-3-(but-2-ynyl)oxybenzaldehyde (0.72 g, 3.5 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.72 g, 3.2 mmol) in toluene (10 mL) and treated according to Procedure 2, acidifying with 20% AcOH. (E)-2-{[3-(3-(But-2-ynyloxy)-4-methoxyphenyl)-1-oxo-2-propenyl]amino}benzoic acid (0.81 g, 69%) was obtained as a yellow crystalline solid; mp 170-171° C.; δH (400 MHz, DMSO-d6) 1.82 (t, J=2.0 Hz, 3H, CH3), 3.80 (s, 3H, OCH3), 4.80 (d, J=2.0 Hz, 2H, OCH2), 6.74 (d, J=15.6 Hz, 1H, CH═CHCO), 7.00 (d, 8.4 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.27 (d, J5′,6′=8.4 Hz, 1H, H6′), 7.40 (s, 1H, H2′), 7.54 (d, J=15.6 Hz, 1H, CH═CHCO), 7.61 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.61 (d, J5,6=8.0 Hz, 1H, H6), 11.31 (s, 1H, NH), 13.57 (br s, 1H, CO2H); δC (100 MHz DMSO-d6) 3.2, 55.6, 56.5, 74.7, 83.7, 111.9, 112.3, 116.6, 120.0, 120.3, 122.7, 123.2, 127.1, 131.2, 134.1, 141.1, 141.6, 146.9, 151.0, 164.1, 169.5; HRMS (ESI) calculated for C21H19NO5 [M+Na]+ 388.1155. found 388.12158; vmax 749, 1261, 1512, 1584, 1659, 2917, 3239, 3520 cm−1.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39]([OH:41])=O)=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]4[N:25]([CH2:26][CH3:27])[N:24]=[CH:23][C:22]=4[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:18][C:17]4[CH:33]=[C:34]([O:37][CH3:38])[CH:35]=[CH:36][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:42][CH:43]([S:45]([NH2:48])(=[O:47])=[O:46])[CH3:44].C(Cl)CCl>CN(C1C=CN=CC=1)C.ClCCl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39](=[O:41])[NH:48][S:45]([CH:43]([CH3:44])[CH3:42])(=[O:47])=[O:46])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]4[N:25]([CH2:26][CH3:27])[N:24]=[CH:23][C:22]=4[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:18][C:17]4[CH:33]=[C:34]([O:37][CH3:38])[CH:35]=[CH:36][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)S(N)(=O)=O
Reactant: CCOC(=O)c1cnn(CC)c1C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)c1cnn(CC)c1C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)C(C)C)cc3n2C1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
In a 100 ml round bottom flask dissolve 13-cyclohexyl-6-(4-(ethoxycarbonyl)-1-ethyl-1H-pyrazol-5-yl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (950 mg, 1.680 mmol), propane-2-sulfonamide (652 mg, 5.29 mmol) and DMAP (655 mg, 5.36 mmol) in dichloromethane (16.8 mL). To the reaction add EDC (508 mg, 2.65 mmol). Place the reaction under a nitrogen atmosphere and stir a room temperature for 64 hours.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[C:10]([S:12][CH3:13])[N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].C(N(CC)CC)C>O1CCOCC1>[CH3:14][C:15]1[CH:16]=[C:17]([NH:18][C:2]2[C:3]3[N:11]=[C:10]([S:12][CH3:13])[N:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cccc(N)c1
Reactant: CSc1ncc2ncnc(Cl)c2n1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CSc1ncc2ncnc(Nc3cccc(C)c3)c2n1

Procedure:
4.9 g of 4-chloro-6-methylthio-pyrimido[5,4-d]pyrimidine, 2.0 g of 3-methylaniline, 2.4 ml of triethylamine and 100 ml of dioxane are heated at 100° C. for 3 hours. After cooling, the reaction mixture is concentrated and partitioned between water and methylene chloride. The organic phase is separated off, dried and concentrated and the residue is purified by chromatography over a silica gel column (petroleum ether/ethyl acetate=2:1). The solid is triturated with diethyl ether, filtered off with suction and dried.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[CH2:15][OH:16])=O)(C)(C)C>O1CCOCC1>[ClH:1].[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[CH2:15][OH:16]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1CO
Agent: Cl
Solvent: C1COCCO1
Product: OC[C@H]1CCCCN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 4M HCl solution in dioxane (30 mL) was added to (R)-2-Hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (4.65 g, 21.6 mmol). The mixture was stirred at rt for 3 h. The solvent was removed in vacuo to yield the title product as a hydrochloride salt (3.47 g).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13][NH:14][C:15]3[CH:55]=[CH:54][C:18]([C:19]([NH:21][C@H:22]([C:47]([O:49]C(C)(C)C)=[O:48])[CH2:23][CH2:24][C:25](=[O:46])[NH:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][NH:38]C(=O)OC(C)(C)C)=[O:20])=[CH:17][CH:16]=3)[N:8]=2)[N:3]=1>Cl>[NH2:38][CH2:37][CH2:36][O:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][NH:26][C:25](=[O:46])[CH2:24][CH2:23][C@H:22]([NH:21][C:19](=[O:20])[C:18]1[CH:54]=[CH:55][C:15]([NH:14][CH2:13][C:7]2[N:8]=[C:9]3[C:4](=[N:5][CH:6]=2)[N:3]=[C:2]([NH2:1])[N:11]=[C:10]3[OH:12])=[CH:16][CH:17]=1)[C:47]([OH:49])=[O:48]
Reactant: CC(C)(C)OC(=O)NCCOCCOCCOCCNC(=O)CC[C@H](NC(=O)c1ccc(NCc2cnc3nc(N)nc(O)c3n2)cc1)C(=O)OC(C)(C)C
Agent: Cl
Product: NCCOCCOCCOCCNC(=O)CC[C@H](NC(=O)c1ccc(NCc2cnc3nc(N)nc(O)c3n2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.7 %

Procedure:
To (S)-tert-butyl 21-(4-((2-amino-4-hydroxypteridin-6-yl)methylamino)benzamido)-2,2-dimethyl-4,18-dioxo-3,8,11,14-tetraoxa-5,17-diazadocosan-22-oate (425 mg, 0.551 mmol) aqueous 6 M hydrochloric acid (10 mL) was added. The reaction was stirred at ambient temperature for 16 hours. After this time, the reaction was not complete. The reaction was concentrated under reduced pressure and dissolved in N,N-dimethylformamide (5 mL). To the resulting mixture TFA (7 mL) was added and reaction mixture stirred at ambient temperature for 16 hours. After this time, the reaction was diluted with 6 M aqueous hydrochloric acid (50 mL) and filtered through diatomaceous earth. The filter cake was rinsed with methanol (40 mL), and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by semi-preparative HPLC (100:0 to 3:7 H2O/CH3CN with 0.05% TFA over 25 min). Further purification by semi-preparative HPLC (100:0 to 3:7 H2O/CH3CN with 0.05% TFA over 25 min) was required to obtain pure (S)-1-amino-16-(4-((2-amino-4-hydroxypteridin-6-yl)methylamino)benzamido)-13-oxo-3,6,9-trioxa-12-azaheptadecan-17-oic acid (121 mg, 36%) as a yellow solid that was obtained via lyophilization: 1H NMR (300 MHz, DMSO-d6) δ 10.88 (vbs, 1H), 8.65 (s, 1H), 8.20 (d, J=6.6 Hz, 1H), 7.95-7.89 (m, 1H), 7.78 (bs, 2H), 7.65 (d, J=8.7 Hz, 2H), 7.00-6.90 (m, 2H), 6.64 (d, J=8.7 Hz, 2H), 4.49 (s, 2H), 4.31-4.28 (m, 1H), 3.78-3.45 (m, 12H), 3.43-3.35 (m, 2H), 3.28-3.20 (m, 2H), 3.02-2.98 (m, 2H), 2.23-2.17 (m, 2H), 2.12-2.00 (m, 1H), 1.99-1.87 (m, 1H); ESI MS m/z=614 [M−H]−.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[CH:45]=[CH:44][C:11]([CH2:12][CH:13](/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:35][CH2:36][CH2:37][N:38]2[CH2:42][CH2:41][O:40][C:39]2=[O:43])[CH2:14][CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)=[O:7].Cl>C1COCC1.O>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH:13](/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:35][CH2:36][CH2:37][N:38]2[CH2:42][CH2:41][O:40][C:39]2=[O:43])[CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=2)=[CH:44][CH:45]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCN2CCOC2=O)Cc2ccc(C(=O)OC)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CCC(/C=C/c2ccccc2OCCCN2CCOC2=O)Cc2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
81.5 mg (1.94 mmol) of lithium hydroxide monohydrate are added to a solution of 370 mg (0.647 mmol) of methyl 4-[(4E)-3-[4-(methoxycarbonyl)benzyl]-5-{2-[3-(2-oxo-1,3-oxazolidin-3-yl)-propoxy]phenyl}pent-4-en-1-yl]benzoate (Example 26A) in 2 ml of THF and 2 ml of water, and the mixture is stirred at room temperature for 18 h. The mixture is then adjusted to pH 2 using 1 M hydrochloric acid and extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate. After filtration, the solvent is removed to dryness and the crude product is purified by preparative HPLC. This gives 114 mg (0.210 mmol, 32.4% of theory) of the title compound as a colorless solid.
Reaction SMILES: O1C=CC(=O)C=C1.[Cl-].[Cl-].[Cl-].[Al+3].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl[C:20]([CH3:28])([CH2:22][CH2:23][C:24](Cl)([CH3:26])[CH3:25])[CH3:21]>ClCCl>[CH3:21][C:20]1([CH3:28])[CH2:22][CH2:23][C:24]([CH3:26])([CH3:25])[C:16]2[CH:17]=[C:12]([OH:18])[CH:13]=[CH:14][C:15]1=2
Reactant: Oc1ccccc1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: O=c1ccocc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(O)ccc21
Reaction time: 2 h

Procedure:
The title compound was synthesized in a manner similar to that of compound 101b except 3,4,5,6,7,8-hexahydro-2,2,5,5,8,8-hexamethylnaphtho(2,3-b)-1,2-pyran-4-one (structure 1) was employed as the starting ketone. The synthesis of the pyran-4-one is detailed here. Aluminum trichloride (25 g, 0.18M) was added in portions to a solution of phenol (49.5 g, 0.52M) and 2,5-dichloro-2,5-dimethylhexane (101.0 g, 0.55M) in dichloromethane (700 ml). The reaction mixture was allowed to stir at 25°-40° C. for 2 h, then the dark red mixture was poured onto ice. Aqueous work up (EtOAc extraction) gave 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-ol as a white solid, which was recrystallized from hexane to give colorless needles (84.8 g, 0.42 moles, 80%): 1H NMR (400 MHz, CDCl3) δ 7.17 (d, 1H), 6.78 (d, 1H), 6.62 (dd, 1H), 4.55 (s, 1H), 1.65 (s, 4H), 1.25 (s, 12H). The hydroxynaphthalene (19.1g, 93.6 mmol) was treated dropwise with acetyl chloride (7.7 g, 98.2 mmol) in 1,2-dichloroethane (250ml) at 0° C. After completion of the addition, aluminum chloride (10 g, 75.2 mmol) was added in portions over 5 min. The mixture was refluxed for 10 h, then stirred at 25° C. for 8 h. GLC analysis indicated the desired keto-phenol was present in 98.6% purity. The reaction mixture was poured onto ice and aqueous work up (EtOAc extract) gave a brown-black solid, which was dissolved in hot methanol, filtered, and concentrated to give a brown viscous semi-solid. Flash chromatography (15% EtOAc/hexane) gave 1-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)ethanone as a light yellow solid. Recrystallization from hexane afforded white crystals (15.2 g, 61.8 mmol, 66%): 1H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H,), 6.9 (s, 1H), 2.61 (s, 3H), 1.67 (s, 4H), 1.29 (s, 6H), 1.27 (s, 6H).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.[NH2:28][CH:29]1[C:56](=[O:57])[N:31]2[C:32]([C:53]([OH:55])=[O:54])=[C:33]([CH2:36][S:37][C:38]3[N:42]([CH2:43][CH2:44][NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[N:41]=[N:40][N:39]=3)[CH2:34][S:35][C@H:30]12.Cl>O1CCCC1.CC(C)=O.C(OCC)(=O)C.C(N(CC)CC)C.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]([NH:28][CH:29]2[C:56](=[O:57])[N:31]3[C:32]([C:53]([OH:55])=[O:54])=[C:33]([CH2:36][S:37][C:38]4[N:42]([CH2:43][CH2:44][NH:45][C:46]([O:48][C:49]([CH3:51])([CH3:52])[CH3:50])=[O:47])[N:41]=[N:40][N:39]=4)[CH2:34][S:35][C@H:30]23)=[O:12])[N:8]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)NCCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)O)c1csc(NC=O)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCNC(=O)OC(C)(C)C)CS[C@H]12)c1csc(NC=O)n1
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetic acid (syn isomer, 1.62 g.) was added to a solution of N,N-dimethylformamide (432 mg.) and phosphoryl chloride (905 mg.) in tetrahydrofuran (16 ml.) and treated in a similar manner to that of Example 6-(1). The solution was added to a solution of 7-amino-3-[1-(2-tert-butoxycarbonylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (3.0 g.) and triethylamine in 50% aqueous acetone (30 ml.) at -5° to -3° C. and pH 7 to 7.5 and stirred for 30 minutes. Ethyl acetate was added to the resultant solution and adjusted to pH 2.0 with 10% hydrochloric acid. After removing the insoluble substance by filtration, water and ethyl acetate were added to the filtrate. The ethyl acetate layer was separated and washed with saturated sodium chloride solution. The solution was dried over magnesium sulfate and concentrated in vacuo. The residue was pulverized with diethyl ether and the precipitates were collected by filtration to give 7-[2-(2-formamidothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-[1-(2-tert-butoxycarbonylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 2.93 g.).
Reaction SMILES: C(N(CC)CC)C.[SH:8][CH2:9][C:10]([NH2:12])=[O:11].[CH2:13](Br)[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O>C(O)C>[C:16]1([C:14]2[NH:12][C:10](=[O:11])[CH2:9][S:8][CH:13]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC(=O)CS
Reactant: O=C(CBr)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1CSC=C(c2ccccc2)N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Triethylamine (4.55 g) is added to a solution of 2-mercaptoacetamide (8.00 g, Reference compound No. 40-1) in ethanol (70 ml), then phenacyl bromide (17.5 g) is added to the mixture, and the whole is stirred for four hours. The reaction mixture is concentrated under reduced pressure, water and 0.1 N hydrochloric acid are added to the resulting residue, and the whole is extracted with ethyl acetate. The extract is washed with saturated brine and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure. The resulting residue is suspended in ethanol (200 ml), p-toluenesulfonic acid monohydrate (catalytic amount) is added to the suspension, and the mixture is refluxed for five days. The reaction mixture is cooled to room temperature to precipitate crystals. The crystals are filtered off and washed with ethanol to give the titled reference compound (11.6 g).
Reaction SMILES: [CH3:1]I.[CH3:3][N:4]1[C:8]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[N:7][NH:6][C:5]1=[S:14].[OH-].[Na+]>C(O)C>[S:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:8]1[N:4]([CH3:3])[C:5]([S:14][CH3:1])=[N:6][N:7]=1
Reactant: CI
Reactant: Cn1c(-c2cccs2)n[nH]c1=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1nnc(-c2cccs2)n1C
Reaction time: 14 h

Procedure:
A solution of methyl iodide (6.3 ml, 1.0×10-1 mole) in ethanol (32 ml) was added dropwise to a stirred, room temperature solution of 2,4-dihydro-4-methyl-5-(2-thienyl)-3H-1,2,4-triazole-3-thione (12.5 g, 6.34×10-2 mole) and 1 molar aqueous NaOH (142 ml, 1.42×10-1 mole). After being stirred for about 14 hours the reaction was extracted four times with EtOAc. The EtOAc extracts were combined, washed with saturated aqueous NaCl, and dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure giving a tacky yellow solid which was purified by flash chromatography (EtOAc). Crystallization from EtOAc gave colorless crystals: 10.5 g (78%), mp 83°-85° C.
Reaction SMILES: CO[C:3]([C@H:5]1[CH2:9][C@H:8]([OH:10])[C@@H:7]([NH:11][C:12]([C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:13])[CH2:6]1)=[O:4].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]2=[O:33])=[CH:23][CH:22]=1>>[OH:10][C@H:8]1[CH2:9][C@H:5]([C:3](=[O:4])[NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]3=[O:33])=[CH:23][CH:22]=2)[CH2:6][C@@H:7]1[NH:11][C:12]([C:14]1[S:15][C:16]([Cl:19])=[CH:17][CH:18]=1)=[O:13]
Reactant: Nc1ccc(-n2ccccc2=O)cc1
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](O)C1
Product: O=C(N[C@H]1C[C@@H](C(=O)Nc2ccc(-n3ccccc3=O)cc2)C[C@@H]1O)c1ccc(Cl)s1

Procedure:
In analogy to example 1C, (1R,3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-hydroxy-cyclopentanecarboxylic acid methyl ester (example 1B) was reacted with 1-(4-amino-phenyl)-1H-pyridin-2-one (CAS 13143-47-0) to give 5-chloro-thiophene-2-carboxylic acid {(1S,2S,4R)-2-hydroxy-4-[4-(2-oxo-2H-pyridin-1-yl)-phenyl-carbamoyl]-cyclopentyl}-amide. Orange solid. MS: 458.3 ([M+H]+).