Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[SH:10].Br[CH2:12][C:13]1([CH3:39])[CH:17]([C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19])[N:16]2[C:26](=[O:38])[CH:27]([NH:28][C:29](=[O:37])[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@H:15]2[S:14]1>P([O-])([O-])([O-])=O.O1CCOCC1>[Cl:25][C:22]([Cl:23])([Cl:24])[CH2:21][O:20][C:18]([CH:17]1[N:16]2[C:26](=[O:38])[CH:27]([NH:28][C:29](=[O:37])[CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C@H:15]2[S:14][C:13]1([CH2:12][S:10][C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)[CH3:39])=[O:19]
Reactant: Sc1nc2ccccc2s1
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CC1(CSc2nc3ccccc3s2)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 7 h
Yield: 24 %

Procedure:
Benzothiazole-2-thiol (0.20 g) was dissolved in a mixture of pH 6.7 phosphate buffer (15 ml) and dioxane (15 ml). To this solution was added 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.54 g) and the mixture was stirred for 7 hours at room temperature. After the reaction was completed, dioxane was distilled off and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with a 2% potassium carbonate aqueous solution and then with water and thereafter dried over magnesium sulfate. The residue obtained by distilling off the solvent was purified by column chromatography on silica gel using chloroform as developing solvent to give oily 2,2,2-trichloroethyl2-(benzothiazol-2-yl)thiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.15 g) from the second fraction of fractions each of which was separated into 30 ml.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[CH:5]=[CH:6][N:7]([Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])[C:8]2=[N:9][CH:10]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 5-bromo-7-azaindole (1, 1.5 g, 7.6 mmol) in N,N-dimethylformamide (20 mL) were added sodium hydride (60% in mineral oil, 0.27 g, 11.0 mmol) and triisopropylsilyl chloride (2.6 mL, 12.0 mmol), under an atmosphere of nitrogen. The reaction was stirred for 2 hours at room temperature. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 10% ethyl acetate in hexane to give the compound (2, 1.6 g, 59%). MS (ESI) [M+H+]+=352.3.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4](O)[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].N1C=CC=CC=1.S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[Cl:21][CH:4]([CH2:3][CH2:2][Cl:1])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCCC(O)CCCl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(O)CCCCC(Cl)CCCl
Temperature: 25 °C

Procedure:
To a solution of 2.4 g (11.0 mmoles) of the methyl ester of (+)-8-chloro-6hydroxy-octanoic acid (+)-(VIII) (R=Me) and 0.04 g (0.5 mmoles) of pyridine in 8 ml toluene, 1.6 g (13.5 mmoles) of thionyl chloride in 5 ml of toluene were added slowly. The mixture was then refluxed for 1 hour. After cooling to room temperature, the reaction mixture was added to 20 ml ice water and the organic phase was separated and washed with 10 mL of water and dried over magnesium sulfate. After that, the solvent was evaporated under vacuum. The methyl ester of (-)-6,8-Dichloro-octanoic acid (-)-(III), (R=Me) was obtained in a yield of 2.0 g (81% of the theoretical yield). [α]D20 =-30.0° (c=1, benzene).
Reaction SMILES: [F:1][C:2]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1.CCCCCC>C1(C)C=CC=CC=1>[F:1][C:2]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:6][CH2:5][CH:4]=[C:3]1[SH:23]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C1(F)CCCCC1=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCOC(=O)C1(F)CCCC=C1S
Reaction time: 5 h
Yield: 18 %

Procedure:
Referring to the process described in Bulletin des Societe Chimiques Belges volume 87, page 223 (1978), 5.4 g (30 mmol) of ethyl 1-fluoro-2-oxocyclohexanecarboxylate was dissolved in 50 ml of toluene, to this was added 6.0 g (15 mmol) of Lawesson's reagent, and reaction was carried out at 100° C. for 5 hours. 100 ml of hexane was added, the precipitate was filtered out and the solvent was distilled away. The filtrate was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate=15/1) to obtain 1.1 g (yield: 18 % of ethyl 1-fluoro-2-mercapto-2-cyclohexenecarboxylate.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C(O)[C:15]1[CH:20]=[CH:19]C=[CH:17][CH:16]=1.P([O-])([O-])([O-])=O>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=1)=[O:7]
Reactant: OCc1ccccc1
Reactant: CCOC(=O)CC(=O)C(OC)OC
Agent: CN(C)c1ccncc1
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(OC)C(=O)CC(=O)OCc1ccccc1

Procedure:
2.68 g (14.1 mmol) of ethyl 4,4-dimethoxy-3-oxo-butyrate, 3.62 ml (34.9 mmol) of benzyl alcohol and 244 mg (2.0 mmol) of 4-dimethylaminopyridine were heated under reflux in 40 ml of toluene for three nights. A phosphate buffer solution was added to the obtained reaction solution. After the extraction with ethyl acetate, the organic layer was washed with a saturated aqueous salt solution and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by the silica gel chromatography (hexane/ethyl acetate=9:1) to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.C[O-].[Na+].[CH:15](OCC)=[O:16]>>[CH:15]([CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:10]#[N:11])=[O:16]
Reactant: COc1cccc(CC#N)c1
Reactant: CCOC=O
Agent: C[O-]
Agent: [Na+]
Product: COc1cccc(C(C#N)C=O)c1

Procedure:
In a manner similar to Example 7, m-methoxyphenylacetonitrile is treated with sodium methoxide and ethyl formate to afford α-formyl-(3-methoxyphenyl)acetonitrile. Hydrogenation of this product yields 3-amino-2-(3-methoxyphenyl)-2-propenal which is condensed with dimethyl malonate to afford the product of the Example.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:7][CH:8]=2)[N:3]1[CH2:17][C:18]([OH:20])=O.[Br:21][C:22]1[C:23]([C:28]2[NH:32][N:31]=[CH:30][N:29]=2)=[C:24]([NH2:27])[S:25][CH:26]=1>>[Br:21][C:22]1[C:23]([C:28]2[NH:32][N:31]=[CH:30][N:29]=2)=[C:24]([NH:27][C:18](=[O:20])[CH2:17][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[C:6]([O:12][C:13]([F:16])([F:15])[F:14])[CH:5]=3)[CH:10]=[CH:11][C:2]2=[O:1])[S:25][CH:26]=1
Reactant: O=C(O)Cn1c(=O)ccc2ccc(OC(F)(F)F)cc21
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Product: O=C(Cn1c(=O)ccc2ccc(OC(F)(F)F)cc21)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
The title compound was prepared from 2-(2-oxo-7-(trifluoromethoxy)quinolin-1(2H)-yl)acetic acid (79 mg, 0.275 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (35 mg, 0.137 mmol) according to protocol A. Retention time (min)=6.037, method [7], MS (ESI) 514.0 (M+H); 1H NMR (300 MHz, CD3OD) δ 8.15 (s, 1H), 8.11 (d, J=9.9 Hz, 1H), 7.88 (d, J=9.1 Hz, 1H), 7.41 (s, 1H), 7.26 (m, 1H), 7.10 (s, 1H), 6.81 (d, J=9.9 Hz, 1H), 5.31 (s, 2H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10](=[O:23])[C:11]1[CH:16]=[C:15]([S:17](=[O:20])(=[O:19])[NH2:18])[CH:14]=[CH:13][C:12]=1[O:21][CH3:22])[CH3:2].[C:24](OC(=O)C)(=[O:26])[CH3:25].C(N(CC)CC)C>O>[C:24]([NH:18][S:17]([C:15]1[CH:14]=[CH:13][C:12]([O:21][CH3:22])=[C:11]([CH:16]=1)[C:10]([NH:9][CH2:8][CH:4]1[CH2:5][CH2:6][CH2:7][N:3]1[CH2:1][CH3:2])=[O:23])(=[O:19])=[O:20])(=[O:26])[CH3:25]
Reactant: CCN1CCCC1CNC(=O)c1cc(S(N)(=O)=O)ccc1OC
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCN1CCCC1CNC(=O)c1cc(S(=O)(=O)NC(C)=O)ccc1OC

Procedure:
A solution of N-(1-Ethyl-pyrrolidin-2-ylmethyl)-2-methoxy-5-sulfamoyl-benzamide, acetic anhydride and triethylamine are reacted at room temperature, diluted with water and extracted with ethyl acetate. The ethyl acetate layer is dried, filtered and concentrated under vacuum, and the residue recrystallized from ethyl acetate.
Reaction SMILES: C[N:2](/[CH:4]=[C:5]1\[C:6](=O)[C:7]2[S:11][C:10]([CH3:12])=[N:9][C:8]=2[CH2:13][CH2:14]\1)[CH3:3].[CH3:16][O:17][C:18]1[CH:30]=[CH:29][C:21]([CH2:22][N:23]2C(N)=[CH:26][CH:25]=[N:24]2)=[CH:20][CH:19]=1.FC(F)(F)C(O)=O>O>[CH3:16][O:17][C:18]1[CH:30]=[CH:29][C:21]([CH2:22][N:23]2[C:3]3[N:2]=[CH:4][C:5]4[CH2:14][CH2:13][C:8]5[N:9]=[C:10]([CH3:12])[S:11][C:7]=5[C:6]=4[C:26]=3[CH:25]=[N:24]2)=[CH:20][CH:19]=1
Reactant: Cc1nc2c(s1)C(=O)/C(=C\N(C)C)CC2
Reactant: COc1ccc(Cn2nccc2N)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cn2ncc3c4c(cnc32)CCc2nc(C)sc2-4)cc1
Temperature: 100 °C
Yield: 13.1 %

Procedure:
To a mixture of (Z)-6-((dimethylamino)methylene)-2-methyl-5,6-dihydrobenzo[d]thiazol-7(4H)-one (3.5 g, 16.9 mmol) and 1-(4-methoxybenzyl)-1H-pyrazol-5-amine (3.5 g, 17.2 mmol) was added trifluoroacetic acid (2.3 mL, 29.2 mmol). The reaction mixture was heated at 100° C. for 2 hours. The reaction mixture was then poured into ice-cooled water (100 mL) and extracted with dichloromethane (3×75 mL). The combined organic extracts were dried using sodium sulfate and concentrated under reduced pressure to give a dark residue. The crude product was purified by flash column chromatography (SiO2, gradient from 100% chloroform to 2% methanol in chloroform) to a residue, which was further purified by crystallization from methanol and isopropanol to give the pure desired product (0.8 g, 19%) as a solid. 1H NMR (CDCl3, 400 MHz): δ 7.86 (s, 1H), 7.76 (s, 1H), 7.36 (d, J=8.0 Hz, 2H), 6.82 (d, J=8.0 Hz, 2H), 5.59 (s, 2H), 3.75 (s, 3H), 3.17 (t, J=6.8 Hz, 2H), 3.09 (t, J=6.8 Hz, 2H), 2.77 (s, 3H); LCMS [M+H]: 363.
Reaction SMILES: C[B-:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[N+](C)(C)C.C1(Br)C=CC=CC=1.[Mg].B(F)(F)F.CCOCC>C(OCC)C>[C:15]1([B:2]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C[B-](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[N+](C)(C)C
Agent: FB(F)F
Agent: [Mg]
Solvent: Brc1ccccc1
Solvent: CCOCC
Product: c1ccc(B(c2ccccc2)c2ccccc2)cc1

Procedure:
More specifically, in the case of the tetramethylammonium methyltriphenylborate, phenyl bromide is reacted with metallic magnesium in diethyl ether to prepare a Grignard reagent, the reagent is added dropwise to a solution containing boron trifluoride diethyl etherate dissolved in diethyl ether, the mixed solution is stirred for several hours to obtain triphenylborane, the triphenylborane obtained is added to methyllithium without passing through isolation to form lithium methyltriphenylborate, and tetramethylammonium bromide is added thereto to effect ion exchanging, as a result, tetramethylammonium methyltriphenylborate is obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH2:38]([O:37][C:34]1[CH:33]=[CH:32][C:31]([S:28]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]4)=[CH:15][CH:14]=3)[CH2:10][CH2:11]2)(=[O:30])=[O:29])=[CH:36][CH:35]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(OCCN4CCCCC4)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(OCCN4CCCCC4)cc3)CC2)cc1
Yield: 41 %

Procedure:
4-(4-Butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4- carboxylic acid was prepared starting from 4-(4-Butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid ethyl ester (5.8 g, 10 mmol) dissolved in THF:methanol 3:1 and 10N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.8 g (86%); Spongy brown solid; mp 98° C.; MS: 559.6 (M+H)+
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:33]=[CH:34][C:35]=1[N+:36]([O-])=O)[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[C:23]([N+:30]([O-])=O)[CH:22]=1)([O-])=O.O.NN>[Pd].C(O)C>[NH2:30][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[NH2:27])[O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[O:7][C:6]1[CH:33]=[CH:34][C:35]([NH2:36])=[C:4]([NH2:1])[CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2-c2ccccc2Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc(Oc2ccccc2-c2ccccc2Oc2ccc(N)c(N)c2)cc1N
Yield: 88 %

Procedure:
A stirred mixture of 2,2'-bis(3,4-dinitrophenoxy)biphenyl (22.0 g, 0.0425 mole) and 10 weight percent palladium on charcoal (2.2 g) in absolute ethanol (500 ml) was heated to reflux under nitrogen, and a solution of hydrazine hydrate (43 ml) in ethanol (100 ml) was added dropwise over a period of 40 minutes. The reaction mixture was heated at reflux for 17 hours, chilled in an ice bath, and suction filtered through Celite filter aid into one liter of stirred, cold, concentrated hydrochloric acid. The resulting precipitate of hydrazine hydrochloride and desired tetraamine hydrochloride was collected, partially dried and dissolved in water (1 liter). Concentrated ammonium hydroxide solution (300 ml) was added and the resulting precipitate collected and vacuum dried to produce 14.9 g (88 percent) of 2,2'-bis(3,4-diaminophenoxy)biphenyl). A portion of the product was recrystallized from ethanol-water to provide an analytical sample (melting point 172°-174°C).
Reaction SMILES: S1C=CC=C1CC(O)=O.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH2:32][N:33]=[C:34]=[O:35].[F:36][C:37]1[C:38](=[O:44])[NH:39][C:40](=[O:43])[NH:41][CH:42]=1>C1C=CC=CC=1.C(N(CC)CC)C>[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH2:32][NH:33][C:34]([N:41]1[CH:42]=[C:37]([F:36])[C:38](=[O:44])[NH:39][C:40]1=[O:43])=[O:35]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: O=C=NCc1cccs1
Agent: O=C(O)Cc1cccs1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NCc1cccs1)n1cc(F)c(=O)[nH]c1=O

Procedure:
The reaction of 2-thienylacetic acid and diphenylphosphoryl azide in a solution of triethyl amine and benzene provided a solution comprising 2-thienylmethyl isocyanate, which was reacted with 5-fluorouracil to provide 1-[N-(2-thienylmethyl)carbamoyl]-5-fluorouracil substantially in the similar method to that of Example 13.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.CCN(CC)CC.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)(=[O:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(COS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
Di-t-butyl dicarbonate (595.14 g, 2.73 mol, 1.05 eq) was slowly added to a solution of piperidin-3-ylmethanol (300.0 g, 2.60 mol, 1 eq), sodium hydroxide (124.8 g, 3.12 mol, 1.2 eq), DCM (1.5 L) and water (800 mL) while maintaining the internal temperature below 10° C. with an ice-water bath. The reaction was warmed to room temperature and stirred for 24 h. The mixture was filtered and sodium bisulfate was added until the solution was acidic (pH 3). The phases were separated, and the organic phase was washed with water (600 mL) and brine (600 mL). The solution was dried over sodium sulfate, and the solvent removed under vacuum to afford t-butyl 3-(hydroxymethyl)piperidine-1-carboxylate as a colorless oil. Crude t-butyl 3-(hydroxymethyl)piperidine-1-carboxylate was dissolved in DCM (1.5 L), Et3N (315.71 g, 3.12 mol, 1.2 eq) was added, and the reaction vessel was flushed with nitrogen. The reaction mixture was cooled to below 0° C. in a dry ice/isopropyl alcohol bath and methanesulfonyl chloride (357.4 g, 3.12 mol, 1.2 eq) was slowly added. After the addition was complete, the reaction was warmed to ambient temperature and stirred for 24 h. The reaction mixture was filtered, washed with water (500 mL) and saturated sodium bicarbonate (500 mL), and dried over sodium sulfate. The solvent was removed under vacuum, and the yellow oil was added to hexane (2.5 L) and stirred for 3 h. The precipitate was filtered and washed with hexane (700 mL) to afford title compound as a white solid (609.11 g, 2.08 mol, 80%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][C@@H:12]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[C:27](=[O:36])[NH:28][C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:22][CH2:21]2)=[O:19])[C:13](OC)=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[NH2:37][C@H:38]([C:51](=[O:64])[N:52]1[CH2:57][CH2:56][N:55]([C:58]2[CH:63]=[CH:62][N:61]=[CH:60][CH:59]=2)[CH2:54][CH2:53]1)[CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][C@@H:12]([NH:17][C:18]([N:20]2[CH2:21][CH2:22][CH:23]([C:26]3[C:27](=[O:36])[NH:28][C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:24][CH2:25]2)=[O:19])[C:13]([NH:37][C@H:38]([C:51](=[O:64])[N:52]2[CH2:57][CH2:56][N:55]([C:58]3[CH:59]=[CH:60][N:61]=[CH:62][CH:63]=3)[CH2:54][CH2:53]2)[CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44](=[O:50])[O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2
Reactant: COC(=O)[C@@H](Cc1cc(C)c2[nH]ncc2c1)NC(=O)N1CCC(c2cc3ccccc3[nH]c2=O)CC1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)N1CCN(c2ccncc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C[C@@H](NC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N2CCN(c3ccncc3)CC2)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of (R)-methyl 3-(7-methyl-1H-indazol-5-yl)-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamido)propanoate (95 mg, 0.2 mmol) in DMF (2.0 mL) was added (S)-tert-butyl 5-amino-6-oxo-6-(4-(pyridin-4-yl)piperazin-1-yl)hexylcarbamate (78 mg, 0.2 mmol) followed by 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (71 mg, 0.22 mmol) and triethylamine (1 mL). After stirring at room temperature for 2 h, the solvent was removed and the crude product was purified by flash chromatography using 7% methanol in dichloromethane containing 2% ammonium hydroxide (ammonia content 28-30%) to give tert-butyl (S)-5-((R)-3-(7-methyl-1H-indazol-5-yl)-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamido)propanamido)-6-oxo-6-(4-(pyridin-4-yl)piperazin-1-yl)hexylcarbamate in 87% yield as white solid. 1H-NMR (CD3OD) δ 8.11-8.10 (m, 2H), 7.97 (s, 1H), 7.61 (d, J=7.5 Hz, 1H), 7.50-7.44 (m, 3H), 7.32-7.30 (d, J=7.5 Hz, 2H), 7.23-7.20 (m, 1H), 7.13 (s, 1H), 6.77 (d, J=6.5 Hz, 1H), 4.83-4.81 (m, 1H), 4.67-4.65 (m, 1H), 4.14-4.08 (m, 2H), 3.82-3.78 (m, 2H), 3.69-3.62 (m, 1H), 3.60-3.53 (m, 1H), 3.48-2.80 (m, 10H), 2.52 (s, 3H), 1.84-1.78 (m, 2H), 1.69-1.61 (m, 1H), 1.40 (s, 9H), 1.49-1.11 (m, 8H); MS (ESI) 847 (M+H) ; Rf=2.34.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[C:7]1(=O)[O:12][C:10](=[O:11])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12.C(OCC)(=O)C>CCCCCC>[C:7]1(=[O:12])[N:1]([CH2:2][CH2:3][C:4]([OH:6])=[O:5])[C:10](=[O:11])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCC(=O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(O)CCN1C(=O)c2ccccc2C1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
A mixture of β-alanine (89 g) and phthalic anhydride (148 g) was heated at 180° C. to 190° C. for 30 min. The mixture was cooled to 60° C. and ethyl acetate (500 ml) was added, and the mixture was stirred at 0° C. for 1 hr. n-Hexane is added to the reaction mixture and the reactant crystals were collected filteration to afford 219.5 g of 3-phthalimidopropionic acid in colorless crystals.
Reaction SMILES: [CH3:1][S:2]([NH:5][C@H:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=O)(=[O:4])=[O:3].Cl.[CH2:18]([O:25][C:26](=[O:32])[C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][C:26]([C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[C:7](=[O:9])[C@H:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:32])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: Cl
Product: CS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Yield: 76.5 %

Procedure:
reaction of 0.65 g of 2-(R)-methanesulfonylamino-3-phenyl-propionic acid and 0.66 g of (L)-proline benzyl ester hydrochloride using the procedure described for example xib yielded 0.88 g (75%) of the title compound as a yellow oil. (+)-APCI-MS: 431 (MH+).
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2C=[C:11]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:12]([F:14])=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1.CC1(C)S[C@@H]2[C@H](N)C(=O)[N:27]2[C@H]1C(O)=O>>[CH3:1][CH2:2][N:3]1[C:9]2[N:27]=[C:11]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:12]([F:14])=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)nc21
Yield: 25 %

Procedure:
The tetrabutyl ammonium salt of enoxacin [J. Med. Chem., 27, 292 (1984)] was prepared and converted into the corresponding dimethylacetal, using the procedure described for the corresponding norfloxacin analog in Example 15 (but done on a 0.112 mmol scale). This was coupled to 6-aminopenicillanic acid (24. 2 mg, 0.112 mmol) by following the procedure as described for the preparation of the product in Example 33. The product, which was very unstable, was purified by preparative liquid chromatography (C-18 reverse phase, 0-100% aqueous acetonitrile gradient) to give an amorphous, pale yellow powder after lyophilization (16.4 mg, 25% yield).