Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH2:17]Cl)[C:11]=2[OH:19])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[C:20](=[O:23])([O-])[O-:21].[Na+].[Na+]>O1CCCC1>[N:1]1[N:2]([C:10]2[C:11]([OH:19])=[C:12]([CH:13]=[C:14]([CH3:16])[CH:15]=2)[CH2:17][O:21][C:20](=[O:23])[CH2:11][CH:12]([CH3:17])[CH3:13])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Cc1cc(CCl)c(O)c(-n2nc3ccccc3n2)c1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(COC(=O)CC(C)C)c(O)c(-n2nc3ccccc3n2)c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 205.4 %

Procedure:
2-(2H-Benzotriazol-2-yl)-6-chloromethyl-4-methyl-phenol (10.0 g, 33 mmol) is suspended in a mixture of 2-isovaleric acid (8.4 g, 82 mmol) and tetrahydrofuran (75 g) and stirred at 70° C. for 30 minutes. Sodium carbonate (10.5 g, 99 mmol) is added. The reaction mixture is stirred at 60° C. for 15 minutes and evaporated to dryness. The residue is dissolved in ethyl acetate and extracted with an aqueous potassium carbonate solution (10%) and brine. The organic layer is dried over sodium sulphate, filtered and evaporated to dryness. The crude product is purified by column chromatography (ethyl acetate/heptane 1:12) to yield 11.5 g of 3-Methyl-butyric acid 3-(2H-benzotriazol-2-yl)-2-hydroxy-5-methyl-benzyl ester.
Reaction SMILES: [CH2:1]([CH:8]1[C:12]2[CH:13]=[C:14]([C:17]([O:19]CC)=O)[CH:15]=[CH:16][C:11]=2[O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22](C1C2C=C(CO)C=CC=2OC1)C1C=CC=CC=1>>[C:7]1([CH2:2][CH2:1][CH:8]2[C:12]3[CH:13]=[C:14]([CH2:17][OH:19])[CH:15]=[CH:16][C:11]=3[O:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:22]=1
Reactant: OCc1ccc2c(c1)C(Cc1ccccc1)CO2
Reactant: CCOC(=O)c1ccc2c(c1)C(Cc1ccccc1)CO2
Product: OCc1ccc2c(c1)C(CCc1ccccc1)CO2

Procedure:
Analogously, starting from ethyl 3-benzyl-2,3-dihydro-1-benzofuran-5-carboxylate the 3-benzyl-2,3-dihydro-1-benzofuran-5-yl-methanol was obtained in 62% yield.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:13]=1F>>[Br:11][C:12]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:13]=1[O:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1ccc(Br)cc1Br
Reactant: Nc1ncccc1O
Agent: [H-]
Agent: [Na+]
Product: Nc1ncccc1Oc1ccc(Br)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
An nitrogen-purged 22 L 5-necked flask was charged with DMF (9 L) followed by slow addition of 2-aminopyridin-3-ol (250.0 g, 2270 mmol) and stirred with mechanical overhead agitator at ambient temperature for 30 minutes to dissolve material. 60% Sodium hydride (87.17 g, 2180 mmol) was added in portions with vigorous stirring and a nitrogen sweep of the reaction vessel. The pot temperature rose from 16° C. to 25° C. during the NaH addition. After the addition was complete, the reaction was stirred at ambient temperature for 60 minutes to ensure all NaH was consumed. 2,4-Dibromo-1-fluorobenzene (225.3 mL, 1816 mmol) was added and heated to 110° C. under nitrogen for 24 hours. The reaction was cooled to 60° C. and transferred to a 20 L flask and the majority of the DMF removed. The resultant sludge was diluted with 1N NaOH (8 L) and EtOAc (8 L) and the mixture was passed through a plug of celite and washed with EtOAc. The layers were separated and the aqueous was extracted with EtOAc (4 L). The combined organic layers were washed with 1 N NaOH (4 L) and 50% saturated brine (4 L), water (2 L) and concentrated until solids started to form. Hexanes (4 L) were added slowly and the mixture was concentrated to around 2 L volume. Hexanes (4 L) were added and the mixture was stirred for 1 hour to allow to cool to ambient temperature. The resulting slurry was filtered, dried on the filter and then dried under high vacuum overnight to afford 3-(2,4-dibromophenoxy)pyridin-2-amine (277.3 g, 44.4% yield).
Reaction SMILES: [O:1]=[C:2]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[CH:3]=[CH:4][Sn](CCCC)(CCCC)CCCC.[NH2:25][C:26]1[N:31]=[C:30]([NH2:32])[C:29](I)=[C:28]([CH3:34])[N:27]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN(C)C=O>[NH2:25][C:26]1[N:31]=[C:30]([NH2:32])[C:29]([CH:4]=[CH:3][C:2]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[O:1])=[C:28]([CH3:34])[N:27]=1
Reactant: Cc1nc(N)nc(N)c1I
Reactant: CCCC[Sn](C=CC(=O)c1ccc(Cl)cc1)(CCCC)CCCC
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CN(C)C=O
Product: Cc1nc(N)nc(N)c1C=CC(=O)c1ccc(Cl)cc1

Procedure:
This compound is prepared in a manner analogous to that of Step E of Example 4, using 2.9 grams of (0.0064 mole) of 1-oxo-1-(4-chlorophenyl)-3-tributylstannyl-2-propene, 1.2 grams (0.0048 mole) of 2,4-diamino-5-iodo-6-methylpyrimidine (prepared in Step B of Example 3), 0.04 gram of tri-2-furylphosphine and 0.04 gram (catalyst) of tris(dibenzylidineacetone)dipalladium(0) in 30 mL of N,N-dimethylformamide, yielding 2,4-diamino-6-methyl-5-[3-(4-chlorophenyl)-3-oxo-1-propenyl]pyrimidine.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:31](OC)=[O:32])=[C:12]2[C:16]=1[N:15]=[C:14]1[N:17]([C:21]3[C:26]([Cl:27])=[CH:25][C:24]([O:28][CH3:29])=[CH:23][C:22]=3[Cl:30])[CH2:18][CH2:19][CH2:20][N:13]21.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O1CCCC1.C(#N)C.C(=O)(O)[O-].[Na+].C(OCC)(=O)C.CS(C)=O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH:31]=[O:32])=[C:12]2[C:16]=1[N:15]=[C:14]1[N:17]([C:21]3[C:22]([Cl:30])=[CH:23][C:24]([O:28][CH3:29])=[CH:25][C:26]=3[Cl:27])[CH2:18][CH2:19][CH2:20][N:13]21
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(OC)cc1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(Cl)c(N2CCCn3c2nc2c(Cl)ccc(C=O)c23)c(Cl)c1
Yield: 88.8 %

Procedure:
To a suspension of lithium aluminum hydride (45.7 mg, 1.20 mmol) in tetrahydrofuran (4 mL) was added a solution of methyl 9-chloro-1-(2,6-dichloro-4-methoxyphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (177 mg, 0.401 mmol) in tetrahydrofuran (4 mL) at 0° C., and the resultant mixture was stirred at 0° C. for 5 min. After sodium sulfate decahydrate (450 mg) was added at 0° C., the resultant mixture was filtered and concentrated in vacuo to give a crude solid. To a solution of the crude solid in acetonitrile (4 mL) and dimethylsulfoxide (0.8 mL) was added Dess-Martin reagent (204 mg, 0.481 mmol) at room temperature, and the resultant mixture was stirred at room temperature for 20 min, diluted with aqueous sodium bicarbonate and ethyl acetate, filtered and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (146 mg, 0.356 mmol, 89%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.N1C=CN=C1.[CH:14]([Si:17]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])Cl)([CH3:16])[CH3:15]>ClCCl>[CH3:15][CH:14]([Si:17]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)[CH3:16]
Reactant: Nc1ccc(O)cc1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)[Si](Oc1ccc(N)cc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of 4-aminophenol (20 g, 183 mmol) in dichloromethane (300 ml) was added 1H-imidazole (16.2 g, 240 mmol, 1.3 eq.). Triisopropyl chlorosilane (53.1 g, 275 mmol, 1.5 eq.) was added dropwise with stirring for 2 hours at room temperature. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give a residue, which was purified by silica gel column chromatography using 25% ethyl acetate in petroleum ether to afford 4-[[tris(propan-2-yl)silyl]oxy]aniline as brown oil (34 g, 70%); (ES, m/z): [M+H]+ 266; 1H NMR (300 MHz, CDCl3): δ 6.66-6.72 (m, 2H), 6.55-6.59 (m, 2H), 3.23 (s, 2H), 1.20-1.30 (m, 3H), 1.13 (s, 18H).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[I:14]I.OS(O)(=O)=O.[OH-].[Na+]>C(O)C.CCOC(C)=O.CCCCCC>[I:14][C:3]1[CH:2]=[CH:1][C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: II
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: Ic1ccc2[nH]c3ccccc3c2c1
Temperature: 65 °C
Yield: 140.1 %

Procedure:
To an ethanol solution (500 mL) of carbazole (2.50 g, 15.0 mmol), NaIO4 (0.80 g, 3.75 mmol) and I2 (1.89 g, 7.45 mmol) were sequentially added, and then an ethanol solution (100 mL) of H2SO4 (1.60 mL, 30.0 mmol) was added. The reaction solution was refluxed for one hour at 65° C. The loss of raw materials was confirmed by TLC (HexH:AcOEt=4:1), and an ethanol solution (100 mL) of NaOH (1.4 g) was added thereto to neutralize the system. Ethanol was removed, and then the reaction solution was extracted two times with chloroform. The extract was washed two times with water. The organic phase was dried over Na2SO4, and the solvent was removed. The residue was purified by column chromatography (HexH:AcOEt=4:1), and thus compound 1 (3.06 g, 70%) was obtained as a white powder. Thus, 3,6-diiodocarbazole (0.47 g, 7.5%) was obtained as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2.OC1C=C2C(=CC=1)N([CH2:21][C:22]1([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24][CH2:23]1)CC2>>[OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[CH2:21][C:22]1([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:27][O:26][C:25]([CH3:28])([CH3:29])[O:24][CH2:23]1
Reactant: Oc1cccc2c1CCN2
Reactant: CC(C)(C)OC(=O)NC1(CN2CCc3cc(O)ccc32)COC(C)(C)OC1
Product: CC(C)(C)OC(=O)NC1(CN2CCc3c(O)cccc32)COC(C)(C)OC1
Yield: 74 %

Procedure:
When the product of Step A was substituted for tert-butyl 5-((5-hydroxyindolin-1-yl)methyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 8, Step G, the identical process afforded the title compound in 74% yield, as a creamy solid. 1H-NMR (CDCl3) 1.4-1.65 (m, 15H+H2O); 2.94 (tr, 2H, J=8.4 Hz); 3.5 (tr, 2H, J=8.4 Hz); 3.52 (s, 2H); 3.8-3.99 (m, 4H); 4.64 (broad s, 1H); 4.7 (broad s, 1H); 6.15-6.23 (m, 2H); 6.93 (tr, 1H, J=7.96 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][C@@H:12]([O:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[C:26](=[O:35])[NH:27][C:28]4[C:33]([CH:34]=3)=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.C(N(C(C)C)CC)(C)C.[N:45]1[CH:50]=[CH:49][C:48]([N:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)=[CH:47][CH:46]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C=O.ClCCl>[O:35]=[C:26]1[C:25]([CH:22]2[CH2:21][CH2:20][N:19]([C:17]([O:16][C@H:12]([CH2:11][C:4]3[CH:5]=[C:6]4[C:10](=[C:2]([CH3:1])[CH:3]=3)[NH:9][N:8]=[CH:7]4)[C:13](=[O:14])[N:54]3[CH2:55][CH2:56][N:51]([C:48]4[CH:49]=[CH:50][N:45]=[CH:46][CH:47]=4)[CH2:52][CH2:53]3)=[O:18])[CH2:24][CH2:23]2)=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27]1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)O)cc2cn[nH]c12
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)N2CCN(c3ccncc3)CC2)cc2cn[nH]c12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-3-(7-methyl-1H-indazol-5-yl)-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carbonyloxy)propanoic acid (50 mg, 0.11 mmol), diisopropylethylamine (37 μL, 0.21 mmol), and 1-(4-pyridyl)piperazine (34.4 mg, 2.0 equiv) in dimethylformamide (0.50 mL) and dichloromethane (0.50 mL) at 0° C. was added PyBOP® (57.6 mg, 0.11 mmol). The reaction was stirred at 0° C. for 4 h, was concentrated, and purified by column chromatography (95:5:1 to 90:10:1 dichloromethane/methanol/triethylamine). The resulting residue was dissolved in 5% methanol/dichloromethane and passed through a basic alumina column to give 53.8 mg (80%) as a white powder. 1H-NMR (CD3OD, 500 MHz) δ 1.25-2.00 (m, 4H), 2.51 (s, 3H), 2.67 (bs, 1H), 2.80-3.31 (m, 7H), 3.35-3.83 (m, 5H), 4.05-4.49 (m, 2H), 5.52 (dd, J=7.6, 7.3, 1H), 6.64 (bs, 2H), 7.12 (s, 11H), 7.22 (dd, J=7.0, 7.0, 1H), 7.32 (d, J=8.2, 1H), 7.47 (m, 1H), 7.52 (m, 1.5H), 7.62 (d, J=7.0, 11H), 7.69 (bs, 0.5H), 7.99 (s, 1H), 8.10 (m, 2H). Mass spec.: 620.28 (MH)+.
Reaction SMILES: C([N:3]1[C@H:11]2[C@@:6]([CH3:20])([C:7]([CH3:19])([CH3:18])[C:8]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:9]=3[CH2:10]2)[CH2:5][CH2:4]1)=O.Cl>C(O)CC.O>[CH3:17][O:16][C:12]1[C:9]2[CH2:10][C@@H:11]3[C@:6]([CH3:20])([CH2:5][CH2:4][NH:3]3)[C:7]([CH3:19])([CH3:18])[C:8]=2[CH:15]=[CH:14][CH:13]=1
Reactant: COc1cccc2c1C[C@H]1N(C=O)CC[C@]1(C)C2(C)C
Agent: Cl
Solvent: O
Solvent: CCCO
Product: COc1cccc2c1C[C@H]1NCC[C@]1(C)C2(C)C
Yield: 100.1 %

Procedure:
9.6 g (35 mmol) of trans-1-formyl-8-methoxy-3a,4,4-trimethyl-2,3,3a,4,9,9a-hexahydro-1H-benz[f]indole (5) are dissolved in 75 mL of n-propanol and mixed with 25 mL of conc. hydrochloric acid and 15 mL of water. The mixture is refluxed for 12 h, the alcohol is eliminated in vacuo and diluted with 800 mL of water. The mixture is extracted once with 150 mL of ethyl acetate (discarded), the aqueous phase is made alkaline with sodium hydroxide and extracted three times with 200 mL ethyl acetate. The combined organic phases are dried over MgSO4 and the solvent is eliminated in vacuo. 8.6 g (100%) of trans-8-methoxy-3a,4,4-trimethyl-2,3,3a,4,9,9a-hexahydro-1H-benz[f]indole (6) are obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([C:12]([N+]([O-])=O)=[N:13][O:14][CH3:15])[CH2:9][N+:8]([O-:19])=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:6]=2[CH:27]=1.C(O)C.[BH4-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH:10]([CH:12]=[N:13][O:14][CH3:15])[CH2:9][N+:8]([O-:19])=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:6]=2[CH:27]=1
Reactant: CON=C(C1=Nc2ccc(Cl)cc2C(c2ccccc2F)=[N+]([O-])C1)[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CON=CC1C[N+]([O-])=C(c2ccccc2F)c2cc(Cl)ccc2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.5 g of 7-chloro-5-(2-fluorophenyl)-N-methoxy-α-nitro-3H-1,4-benzodiazepine-2-methanimine 4-oxide, 10 ml of ethanol, 5 ml of tetrahydrofuran and 0.4 g of sodium borohydride was stirred at ambient temperature for 1 hr. After partitioning between methylene chloride and aqueous sodium bicarbonate solution, the organic phase was dried and evaporated. Chromatography of the residue over 7 g of silica gel yielded 7-chloro-5-(2-fluorophenyl)-2,3-dihydro-N-methoxy-1H-1,4-benzodiazepine-2-methanimine 4-oxide as light yellow resin.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH:14]([NH:16][C:17]1[S:18][CH:19]=[C:20]([C:22](=[N:60][O:61][CH3:62])[C:23]([NH:25][CH:26]2[C:58](=[O:59])[N:28]3[C:29]([C:34]([O:36][CH:37]([CH2:48][O:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:38][O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:35])=[CH:30][CH2:31][S:32](=O)[C@H:27]23)=[O:24])[N:21]=1)=[O:15].[I-].[Na+]>CC(C)=O>[CH:14]([NH:16][C:17]1[S:18][CH:19]=[C:20]([C:22](=[N:60][O:61][CH3:62])[C:23]([NH:25][CH:26]2[C:58](=[O:59])[N:28]3[C:29]([C:34]([O:36][CH:37]([CH2:38][O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:48][O:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])=[O:35])=[CH:30][CH2:31][S:32][C@H:27]23)=[O:24])[N:21]=1)=[O:15]
Reactant: CCCCCCCCOCC(COCCCCCCCC)OC(=O)C1=CCS(=O)[C@@H]2C(NC(=O)C(=NOC)c3csc(NC=O)n3)C(=O)N12
Agent: [I-]
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC(C)=O
Product: CCCCCCCCOCC(COCCCCCCCC)OC(=O)C1=CCS[C@@H]2C(NC(=O)C(=NOC)c3csc(NC=O)n3)C(=O)N12
Temperature: 0 °C
Reaction time: 2 h
Yield: 68.6 %

Procedure:
2,2,2-Trifluoroacetic anhydride (2.12 g) was dropwise added to a stirred solution of 2-n-octyloxy-1-n-octyloxymethylethyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate-1-oxide (syn isomer, 2.34 g) and sodium iodide (1.56 g) in dry acetone (40 ml) at 0° to 5° C. over 45 minutes, and stirred at 0° to 5° C. for 2 hours. The resultant mixture was poured into ice water (200 ml), and then extracted with ethyl acetate (110 ml). The extract was washed with an aqueous solution of sodium thiosulfate, an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in turn, and then dried over anhydrous magnesium sulfate. After evaporating the solution in vacuo, the residue was subjected to column chromatography, on silica gel (100 g) with a mixture of chloroform and methanol (20:1). The eluate was evaporated in vacuo to give powder (1.57 g) of 2-n-octyloxy-1-n-octyloxymethylethyl 7-[2-(2-formamidothiazol-4 -yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 1.57 g).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[N:11]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:12](=[O:34])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([C:26]1[S:27][CH:28]=[C:29]([C:31]([OH:33])=[O:32])[N:30]=1)=[CH:15][CH:14]=2)=O)(C)(C)C.[ClH:39]>C(OCC)(=O)C>[ClH:39].[NH2:8][CH2:9][C:10]1[N:11]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:12](=[O:34])[C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[CH:17][C:16]([C:26]1[S:27][CH:28]=[C:29]([C:31]([OH:33])=[O:32])[N:30]=1)=[CH:15][CH:14]=2
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(-c3nc(C(=O)O)cs3)ccc2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)Cn1c(CN)c(-c2ccccc2)c2cc(-c3nc(C(=O)O)cs3)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
2-[3-[[(Tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylic acid (0.16 g, 0.3 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (5 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was crystallized from ethyl acetate to give 2-[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylic acid hydrochloride (0.13 g, 92.9%) as crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[O:16]([NH2:18])[CH3:17].C(=O)(O)[O-].[Na+]>CCO>[CH3:17][O:16][N:18]=[C:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=2)[CH2:8][CH2:9][CH2:10]1
Reactant: CON
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CON=C1CCCc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Yield: 95.5 %

Procedure:
7-Nitro-tetralone (1.00 g, 5.23 mmol) was suspended in EtOH (10 mL), cooled by an ice water bath and treated with methoxylamine hydrochloride (0.52 g, 6.23 mmol) and sodium bicarbonate (0.57 g, 6.78 mmol). The mixture was stirred at room temperature for 1 h before ice water (50 mL) was added. A precipitate formed which was filtered off to give a white solid (1.10 g, 95% yield). This solid contained two geometric isomers in a ratio of 7:1. It was dissolved in CHCl4/CHCl3 and flash chromatographed over silica gel (50 g) eluting with EtOAc/hexane (1:20) to afford the major isomer as a white solid. It was recrystallized from hot EtOAc to give colorless crystals (556 mg): mp 128-131° C.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[NH:2]1.[CH:12]1([N:15]2[C:23]3[C:18](=[CH:19][C:20]([C:24](OC)=O)=[CH:21][CH:22]=3)[CH:17]=[N:16]2)[CH2:14][CH2:13]1>>[CH:12]1([N:15]2[C:23]3[C:18](=[CH:19][C:20]([CH2:24][N:2]4[C:3](=[O:10])[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[C:1]4=[O:11])=[CH:21][CH:22]=3)[CH:17]=[N:16]2)[CH2:14][CH2:13]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COC(=O)c1ccc2c(cnn2C2CC2)c1
Product: O=C1c2ccccc2C(=O)N1Cc1ccc2c(cnn2C2CC2)c1

Procedure:
The titled compound was prepared according to the procedure described in step-3 of Example 13 from isoindoline-1,3-dione and (1-cyclopropyl-1H-indazol-5-yl)methanol (step-2 of Example 28).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[C:13]=1[CH2:20][C:21]([O:23][CH3:24])=[O:22].[C:25](Cl)(=[O:27])[CH3:26].O>O1CCCC1>[C:25]([CH:20]([C:13]1[C:12]([F:11])=[CH:17][C:16]([F:18])=[CH:15][C:14]=1[F:19])[C:21]([O:23][CH3:24])=[O:22])(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: COC(=O)Cc1c(F)cc(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(C(C)=O)c1c(F)cc(F)cc1F
Temperature: -65 °C
Reaction time: 0.5 h

Procedure:
To a commercially obtained tetrahydrofuran solution of lithium bis(trimethyl-silyl)amide (1.0 M, 21.0 mL) stirred under a nitrogen atmosphere and cooled to an internal temperature of −65° C., was added dropwise over 30 minutes a solution of methyl 2,4,6-trifluorobenzeneacetate (i.e. the product of Step A) (2.04 g, 10.0 mmol) dissolved in dry tetrahydrofuran (10 mL). The reaction mixture was stirred for an additional 30 minutes, and then while maintaining the −65° C. temperature, a solution of freshly distilled acetyl chloride (0.80 mL, 11 mmol) in dry tetrahydrofuran (3 mL) was added dropwise. The reaction mixture was allowed to warm slowly to ambient temperature, and then water (30 mL) was added. The resultant mixture was extracted with ethyl acetate (60 mL). The aqueous phase was acidified with 1 N hydrochloric acid and extracted with ethyl acetate (60 mL). Only the first ethyl acetate extract was retained, because thin layer chromatographic analysis showed the second extract to contain apparent polar impurities besides additional desired product. The first ethyl acetate extract was further sequentially washed with 1 N hydrochloric acid, water and brine, dried (MgSO4), and concentrated to provide the title compound as a clear oil (1.86 g).
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[C:21]3[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=3[S:19](=[O:28])(=[O:27])[NH:18]2)=[C:9]1[CH3:29])(C)(C)C.Cl[CH2:32][C:33]1[C:34]([CH3:39])=[N:35][O:36][C:37]=1[CH3:38]>>[CH3:39][C:34]1[C:33]([CH2:32][N:18]2[CH:17]([C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=4)[N:8]([CH2:7][C:6]([OH:5])=[O:30])[C:9]=3[CH3:29])[C:21]3[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=3[S:19]2(=[O:28])=[O:27])=[C:37]([CH3:38])[O:36][N:35]=1
Reactant: Cc1c(C2NS(=O)(=O)c3cc(F)ccc32)c2ccccc2n1CC(=O)OC(C)(C)C
Reactant: Cc1noc(C)c1CCl
Product: Cc1noc(C)c1CN1C(c2c(C)n(CC(=O)O)c3ccccc23)c2ccc(F)cc2S1(=O)=O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 13, step e) and chloromethyl-3,5-dimethyl-isoxazole. 1H NMR (DMSO-d6) δ 13.1 (bs, 1H), 7-99 (dd, J=2.4, 7.5 Hz, 1H), 7.47 (dt, J=2.1, 8.8 Hz, 1H), 7.14-6.74 (m, 4H), 5.93 (s, 1H), 5.01 (s, 2H), 4.02 (d, J=15 Hz, 1H), 3.98 (d, 1H, J=15 Hz, 1H), 2.40 (s, 3H), 2.04 (s, 3H), 1.71 (s, 3H); MS: ESI (negative): 482 (M−H).