Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][CH:18]=[CH:17]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:25]([O:29][C:30](=[O:33])[CH2:31]Br)([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C.[Cl-].[Na+].O.CCCCCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH2:31][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:33])[CH:18]=[CH:17]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3[nH]ccc3c2)CC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1ccc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Reaction time: 2 h
Yield: 75.5 %

Procedure:
4-(1H-Indol-5-yl)-piperazine-1-carboxylic acid tert-butyl ester (8.50 g) was stirred in 70 mL of DMF and cooled with an ice/water bath. To this mixture sodium hydride (1.35 g of 60% dispersion in mineral oil) was added in portions. After addition was completed, the mixture was stirred for 30 minutes at 0° C. before the addition of 7.15 g of bromo-acetic acid tert-butyl ester. The reaction mixture was allowed to reach room temperature while stirring for 2 hours. At this time, brine was added to the mixture; ethyl acetate was used for extraction of the organic soluble components. The organic layer was washed with water four times, then dried with magnesium sulfate and filtered. The filtrate was concentrated in vacuo leaving a reddish oil which was dissolved in 70 mL of hexane. Upon standing for 3 days, a precipitate formed. After filtration and washing of the precipitate with pentane, the solid was dried. In this manner, 8.85 g of the desired product was obtained. H1-NMR spectroscopy indicated a spectrum consistent with 4-(1-tert-butoxycarbonylmethyl-1H-indol-5-yl)-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: C([O:5][C:6](=[O:96])[CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][NH:45][C:46]([O:48][CH2:49][CH:50]2[C:62]3[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=3[C:56]3[C:51]2=[CH:52][CH:53]=[CH:54][CH:55]=3)=[O:47])[CH:27]=[C:26]([O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][O:69][CH2:70][CH2:71][O:72][CH2:73][CH2:74][O:75][CH2:76][CH2:77][NH:78][C:79]([O:81][CH2:82][CH:83]2[C:95]3[CH:94]=[CH:93][CH:92]=[CH:91][C:90]=3[C:89]3[C:84]2=[CH:85][CH:86]=[CH:87][CH:88]=3)=[O:80])[CH:25]=1)(C)(C)C>C1(C)C=CC=CC=1>[CH:94]1[C:95]2[CH:83]([CH2:82][O:81][C:79]([NH:78][CH2:77][CH2:76][O:75][CH2:74][CH2:73][O:72][CH2:71][CH2:70][O:69][CH2:68][CH2:67][O:66][CH2:65][CH2:64][O:63][C:26]3[CH:25]=[C:24]([CH:29]=[C:28]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][NH:45][C:46]([O:48][CH2:49][CH:50]4[C:51]5[CH:52]=[CH:53][CH:54]=[CH:55][C:56]=5[C:57]5[C:62]4=[CH:61][CH:60]=[CH:59][CH:58]=5)=[O:47])[CH:27]=3)[O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][C:6]([OH:96])=[O:5])=[O:80])[C:84]3[C:89](=[CH:88][CH:87]=[CH:86][CH:85]=3)[C:90]=2[CH:91]=[CH:92][CH:93]=1
Reactant: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOc1cc(OCCOCCOCCOCCOCCNC(=O)OCC2c3ccccc3-c3ccccc32)cc(OCCOCCOCCOCCOCCNC(=O)OCC2c3ccccc3-c3ccccc32)c1
Solvent: Cc1ccccc1
Product: O=C(O)COCCOCCOCCOCCOCCOc1cc(OCCOCCOCCOCCOCCNC(=O)OCC2c3ccccc3-c3ccccc32)cc(OCCOCCOCCOCCOCCNC(=O)OCC2c3ccccc3-c3ccccc32)c1
Reaction time: 0.08 h
Yield: 77.7 %

Procedure:
To Compound 52 (106 mg, 0.079 mmol), 5% hydrated trifluoroacetic acid (0.54 ml) was added at room temperature, and this was followed by stirring for 5 minutes. Toluene (about 1 ml) was added; after concentration under reduced pressure, the concentrate was purified by silica gel column chromatography (Yamazen YFLC Gel, eluent; chloroform solution containing 2% methanol-chloroform solution containing 3% methanol-chloroform solution containing 5% methanol) to yield Compound 53 (light-yellow oil 79 mg, 78%).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:39]=[C:40]([Cl:42])[CH:41]=1)[CH2:23][N:24]1[C:32]2[C:27](=[N:28][C:29](Cl)=[CH:30][CH:31]=2)[CH:26]=[C:25]1[C:34]1[O:35][CH:36]=[N:37][N:38]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:43]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:39]=[C:40]([Cl:42])[CH:41]=1)[CH2:23][N:24]1[C:32]2[C:27](=[N:28][C:29]([N:43]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[NH:44][C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])=[CH:30][CH:31]=2)[CH:26]=[C:25]1[C:34]1[O:35][CH:36]=[N:37][N:38]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](OCc1cc(Cl)cc(Cn2c(-c3nnco3)cc3nc(Cl)ccc32)c1)(c1ccccc1)c1ccccc1
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(-c3nnco3)n2Cc2cc(Cl)cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)n1
Temperature: 110 °C
Reaction time: 5 h

Procedure:
A degassed mixture of 1-[3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-chlorobenzyl]-5-chloro-2-(1,3,4-oxadiazol-2-yl)-1H-pyrrolo[3,2-b]pyridine (0.500 g, 0.815 mmol, from Step 2), di-tert-butyl hydrazine-1,2-dicarboxylate (0.21 g, 0.90 mmol, Aldrich), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.076 g, 0.096 mmol, Aldrich) and Cs2CO3 (0.29 g, 0.90 mmol) in toluene (7 mL) was heated at 110° C. for 4 h. Additional di-tert-butyl hydrazine-1,2-dicarboxylate (0.1 g, 0.43 mmol), Cs2CO3 (0.15 g, 0.46 mmol), and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.050 g, 0.063 mmol) were added and heating was continued for 5 h. Upon cooling, the reaction mixture was diluted with water and extracted with three portions of EtOAc. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-50% EtOAc in hexanes was used to purify product. Yield: (0.26 g, 39%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9][CH:8]=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:27])(=O)=O)=CC=1>CCCCCC.O1CCCC1>[F:27][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9][CH:8]=1
Reactant: Brc1cncc2ccccc12
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Fc1cncc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
A solution of n-butyllithium in n-hexane (1.58 M, 60.1 ml, Kanto Chemicals) was added with tetrahydrofuran (345 ml), and the mixture was sufficiently cooled on a dry ice-acetone bath. The mixture was added dropwise with a solution of 4-bromoisoquinoline (9.0 g, Tokyo Kasei Kogyo) in tetrahydrofuran (65 ml) over 1 hour so that the temperature of the reaction mixture should not exceed −65° C. The mixture was stirred at the same temperature for 30 minutes, and then added dropwise with a solution of N-fluorobenzenesulfonimide (30 g, Tokyo Kasei Kogyo) in tetrahydrofuran (100 ml) over 1 hour so that the temperature of the reaction mixture should not exceed −65° C. Subsequently, the mixture was stirred at the same temperature for 1 hour, then the cooling bath was removed, and the mixture was gradually warmed to room temperature. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate (300 ml) and ethyl acetate (300 ml), and stirred at room temperature for 12 hours. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate 3 times (200 ml for each time). The combined organic layer was washed with saturated brine (500 ml), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was added with chloroform (250 ml), and the insoluble solids were removed by filtration. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (n-hexane:ethyl acetate=5:1) to obtain the title compound (3.6 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.[C:26]([S:34][CH2:35][C@@H:36]([CH3:40])[C:37](O)=[O:38])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[C:26]([S:34][CH2:35][C@@H:36]([CH3:40])[C:37]([O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:38])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C[C@H](CSC(=O)c1ccccc1)C(=O)O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C[C@H](CSC(=O)c1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
4-Nitrophenol (10.2 g) and dicyclohexylcarbodiimide (15.2 g) are added successively to a solution of (2S)-3-(benzoylthio)-2-methylpropionic acid (15 g) in methylene chloride (100 ml) under ice-cooling. The mixture is stirred under ice-cooling for 30 minutes and at room temperature for 4.5 hours. The resulting precipitate is filtered out, and the filtrate is concentrated under reduced pressure. The obtained oily residue is purified by silica gel column chromatography to give 26.01 g (quantitatively) of the titled compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([O:16][CH3:17])[C:7](=[CH:9][CH:10]=[C:11]([CH:15]=1)[CH2:12][CH:13]=[CH2:14])[OH:8].C(N(CC)CC)C.O>ClCCl.C(OCC)(=O)C>[CH3:1][S:2]([O:8][C:7]1[CH:9]=[CH:10][C:11]([CH2:12][CH:13]=[CH2:14])=[CH:15][C:6]=1[O:16][CH3:17])(=[O:4])=[O:3]
Reactant: C=CCc1ccc(O)c(OC)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCc1ccc(OS(C)(=O)=O)c(OC)c1
Temperature: -20 °C
Reaction time: 3 h
Yield: 108.9 %

Procedure:
3.1 ml (40 mmol) of methanesulfonyl chloride are added to a solution of 6 g (36 mmol) of eugenol and 5.5 ml (43 mmol) of triethylamine in 100 ml of dichloromethane, cooled beforehand to −20° C. After stirring at room temperature for 3 hours, the reaction medium is treated with water and ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated. 9.5 g (100%) of 4-allyl-2-methoxyphenyl methanesulfonate are obtained.
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]1(=O)[O:13][C:11](=O)[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12.[N:19]1C=CC=[CH:21][CH:20]=1>>[O:13]1[CH2:11][CH2:10][C:14]2[CH:15]=[CH:16][CH:17]=[C:9]([CH2:21][C:20]#[N:19])[C:8]1=2
Reactant: c1ccncc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: N#CCc1cccc2c1OCC2

Procedure:
A mixture of the oil, toluene (60 ml), pyridine (2.2 ml) and phthalic anhydride (4 g) was heated at 90°-95° C. for 4 hours. The resulting solution was cooled, washed with 10% aqueous potassium carbonate solution, then with dilute hydrochloric acid. The solution was then dried over sodium sulphate and the solvent removed in vacuo to yield an oil. The oil was distilled, (b.p. 120° C./1 mbar) to give 2,3-dihydrobenzo[b]furan-7-ylacetonitrile which rapidly solidified (16.97 g).
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N:19]1([C:24]2[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[NH:29][C:28]([C:27]3[CH:26]=[CH:25][C:24]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:31][CH:30]=3)=[N:2][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(OC)cc1
Reactant: NCc1ccc(N2CCCC2)cc1
Product: CCOC(=O)c1nc(-c2ccc(N3CCCC3)cc2)[nH]c1-c1ccc(OC)cc1

Procedure:
Ethyl 2-hydroxyimino-3-(4-methoxyphenyl)-3-oxopropionate, 4-(1-pyrrolidinyl)benzylamine is reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(4-methoxyphenyl)-2-(4-(1-pyrrolidinyl)phenyl)imidazole-4-carboxylate. Ethyl 5-(4-methoxyphenyl)-2-(4-(1-pyrrolidinyl)-phenyl)imidazole-4-carboxylate is reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 5-(4-methoxyphenyl)-2-(4-(1-pyrrolidinyl)phenyl)imidazole-4-carboxylic acid. 5-(4-Methoxyphenyl)-2-(4-(1-pyrrolidinyl)phenyl)imidazole-4-carboxylicacid isreactedandtreatedinthesamemanneras in Example 1 to give 5-(4-methoxyphenyl)-2-(4-(1-pyrrolidinyl)phenyl)-N-(2-thiazolyl)imidazole-4-carboxamide.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C@@H:20]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@H:19]([OH:30])[CH2:18][CH2:17]2.C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C@@H:20]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@H:19]([O:30][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[CH2:18][CH2:17]2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc2c(c1)CC[C@@H](O)[C@@H]2c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CC[C@@H](OS(=O)(=O)c1ccc(C)cc1)[C@@H]2c1ccccc1
Yield: 108.1 %

Procedure:
A solution of para-toluenesulfonyl chloride (1.8 g, 9.43 mmol) in dichloromethane (10 mL) was added to a solution of trans-6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-ol 29 (2.0 g, 7.86 mmol), N,N-diisopropylethylamine (4.8 mL, 27.5 mmol) and 4-dimethylaminopyridine (1.15 g, 9.43 mmol) in dichloromethane (40 mL) at 0C. The resultant solution was stirred at ambient temperature for 16 h. The solution was washed successively with 1 N aqueous sodium hydroxide (×2) and a saturated aqueous solution of sodium chloride, then dried over sodium sulfate. The solvent was evaporated in vacuo to give crude trans-6-methoxy-1-phenyl-2-(4-methylbenzenesulfonyl)oxy-1,2,3,4-tetrahydronaphthalene 30 (3.47 g), as a pale yellow solid which was used without further purification in the subsequent step. 1H NMR(CDCl3) δ1.90-2.04 (m, 1H), 2.14-2.24 (m, 1H), 2.42 (s, 3H), 2.83-3.07 (m, 2H), 3.77 (s, 3H), 4.16 (d, 1H), 4.80-4.87 (m, 1H), 6.60-6.67 (m, 3H), 6.82-6.90 (m, 2H), 7.13-7.23 (m, 5H), 7.58 (d, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][OH:11].[C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH:13]=[CH2:14].[Na].Cl>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:14][CH2:13][C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: COCCOCCOCCO
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Product: COCCOCCOCCOCCC(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
Triethylene glycol monomethyl ether (1.0 g, 6.1 mmol) and tert-butyl acrylate (390 mg, 3.05 mmol) were dissolved in dry THF and sodium metal (0.7 mg, 0.03 mmol) was added at room temperature. The mixture was stirred for 4 hours and 1 M HCl was added to quench the reaction. The mixture was extracted twice with dichloromethane, and the organic phase was dried over MgSO4 and concentrated in vacuo to provide an oil, which was purified by silica chromatography using ethyl acetate as eluent. The product was an oil, 773 mg (44%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][C@H:16]2[F:28])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:29]>O1CCOCC1>[ClH:29].[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:20][CH2:19][NH:18][CH2:17][C@H:16]2[F:28])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(OCc3ccccc3)cc2)[C@H](F)C1
Agent: Cl
Solvent: C1COCCO1
Product: F[C@@H]1CNCC[C@H]1c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of (3S,4S)-t-butyl 4-(4-(benzyloxy)phenyl)-3-fluoropiperidine-1-carboxylate (0.12 g, 0.31 mmol, E-1 from step E) in 1,4-dioxane (3 mL) was added a 4 M HCl in dioxane solution (2 mL, 8 mmol) and the reaction mixture was stirred at rt overnight. The mixture was concentrated in vacuo and the solid was triturated with ethyl acetate and dried to afford E-1a (3S,4S)-4-(4-(benzyloxy)phenyl)-3-fluoropiperidine hydrochloride (0.09 g, 88% yield) as an off-white solid. LCMS (method P) RT 0.95 min, m/z 286 (M+H+; 400 MHz, DMSO-d6: δ 1.94-1.96 (m, 2H), 2.97-3.04 (m, 3H), 3.38-3.62 (m, 2H), 4.84-4.95 (m, 1H), 5.10 (s, 2H), 7.00-7.03 (m, 2H), 7.17-7.20 (m, 2H), 7.31-7.46 (m, 5H), 9.30 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:22](O)[CH2:23][OH:24].O>C1C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:24][CH2:23][CH2:22][O:7]2)=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: O=Cc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Brc1ccc(C2OCCO2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Bromobenzaldehyde (3 g, 0.0162 mol) in benzene (60 mL) was treated with p-toluenesulfonic acid monohydrate (0.15 g, 0.79 mmol) and ethylene glycol (5 mL, 0.0896 mol). The reaction was refluxed under nitrogen with azeotropic removal of water. After 3 hours, the reaction was cooled to room temperature and diluted with an equal volume of ethyl acetate. This solution was washed twice with aqueous bicarbonate, dried over magnesium sulfate and concentrated under reduced pressure. A colorless oil was recovered. Yield=2.83 g (92%). TLC (5% ethyl acetate in hexanes) showed clean product, Rf=0.17.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][O:10][CH:11]2[CH2:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]2)[CH:5]=[CH:6][C:7]=1[F:8].C(OCC)C>CO>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][O:10][CH:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCCC(OCc2ccc(F)c(F)c2)C1
Solvent: CO
Solvent: CCOCC
Product: Fc1ccc(COC2CCCNC2)cc1F
Temperature: 2.5 °C
Yield: 76 %

Procedure:
1,1-dimethylethyl 3-{[(3,4-difluorophenyl)methyl]oxy}piperidine-1-carboxylate (Preparation 145, 3.38 g, 10.3 mmol) was dissolved in methanol (100 ml) and cooled 5 to 0° C., hydrogen chloride gas was bubbled into the reaction mixture for 3-5 min. The reaction mixture was concentrated in vacuo to give an oil, upon tituration with diethyl ether a white solid formed. The solid was separated by filtration to give the title compound (1.78 g, 65%) as the hydrochloride salt.
Reaction SMILES: NC1SC=C(C(=NOCC2C=CC(Cl)=CC=2)C(N[C@@H:11]2[C:26](=[O:27])[N:13]3[C:14](C(O)=O)=[C:15]([CH2:18]OC(=O)C)[CH2:16][S:17][C@H:12]23)=O)N=1.CN([Si](C)(C)C)C(C(F)(F)F)=O.[Si]([I:54])(C)(C)C.C1COCC1>C(Cl)Cl>[I:54][CH2:18][C:15]1[CH2:16][S:17][C@@H:12]2[CH2:11][C:26](=[O:27])[N:13]2[CH:14]=1
Reactant: C[Si](C)(C)I
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NOCc3ccc(Cl)cc3)c3csc(N)n3)[C@H]2SC1
Agent: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1C[C@H]2SCC(CI)=CN12
Temperature: 40 °C

Procedure:
To a suspension of 200 mg (0.35 mmole) of 7β-[2-(2-aminothiazol-4-yl)-2-(4-chlorobenzyloxyimino)acetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid in 5 ml of methylene chloride was added 0.5 ml of MSTFA and the suspension was stirred at 40° C. until solution occurred. The solution was cooled to room temperature and 0.13 ml (0.87 mmole) of TMSI was added. The reaction stirred at room temperature for 30 minutes and evaporated to an oil. The oil was dissolved in 3 ml of acetonitrile and 0.12 ml (1.5 mmole) of THF was added. The mixture was then stirred at room temperature for 5 minutes to destroy excess TMSI and provide in solution the corresponding 3-iodomethyl-3-cephem derivative.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=4)=[O:2])([CH2:11][CH2:10]2)[CH2:9][CH2:8]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: Cc1ccc(N)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: Cc1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 22.3 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and p-toluidine (36.0 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(4-methylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (14.2 mg).
Reaction SMILES: [CH:1]1([C:4]2(O)[C:12]3[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[CH3:15][S:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:26]=1[NH:25][CH:24]=[CH:23]2.FC(F)(F)C(O)=O.[Cl-].[NH4+]>ClCCl>[CH:1]1([C:4]2([C:23]3[C:22]4[C:26](=[C:18]([CH2:17][S:16][CH3:15])[CH:19]=[CH:20][CH:21]=4)[NH:25][CH:24]=3)[C:12]3[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: OC1(C2CC2)CCc2cc(F)ccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cccc2c(C3(C4CC4)CCc4cc(F)ccc43)c[nH]c12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
200 mg (0.78 mmol) of the compound from Example 76A with a purity of 75% and 152 mg (0.86 mmol) of the compound from Example 8A were introduced into 3.8 ml of dichloromethane at 0° C., 0.07 ml (0.94 mmol) of trifluoroacetic acid was added, and the mixture was stirred at 0° C. for 4 h. It was diluted with dichloromethane and added to saturated aqueous ammonium chloride solution, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 175 mg (64% of theory) of the title compound.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[CH:12]=2)[N:7]([CH2:15][CH2:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[CH:6]=1.[C:24](O)(C(F)(F)F)=O.C=O>C(#N)C>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[CH:12]=3)[N:7]([CH2:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[C:6]=2[CH2:24]1
Reactant: CNCCc1cn(CCc2ccc(C)nc2)c2ccc(C)cc12
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Solvent: CC#N
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CN(C)CC1
Temperature: 25 °C

Procedure:
N-methyl-2-(5-methyl-1-(2-(6-methylpyridin-3-yl)ethyl)-1H-indol-3-yl)ethanamine (150 mg) was dissolved in acetonitrile (4 mL) containing 5% TFA and the reaction mixture was refluxed. 37% aqueous formaldehyde (0.04 mL) was added and the reaction mixture was refluxed for additional 1.5 h, cooled to 25° C., concentrated under reduced pressure and partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was dried over sodium sulfate, evaporated under reduced pressure and the residue was purified by silica gel chromatography (eluent Methanol: aqueous NH3, 95:5) to obtain 2,3,4,9-tetrahydro-2,6-dimethyl-9-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[3,4-b]indole. The free base was converted into its dihydrochloride salt by treatment of dioxane-HCl. 1H NMR (DMSO): 11.7 (bs, 1H), 8.6 (s, 1H), 8.3 (d, 1H), 7.7 (d, 1H), 7.3 (d, 1H), 7.25 (s, 1H), 6.9 (d, 1H), 4.8 (m, 1H), 4.4 (m, 1H), 4.35 (t, 2H), 3.7 (bs, 1H), 3.55 (s, 3H), 3.5 (m, 1H), 3.4 (bs, 1H), 3.1 (t, 2H), 3.05 (bs, 1H), 2.65 (s, 3H), 2.35 (s, 3H).