Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:19][CH2:20][CH:21]2[O:23][CH2:22]2)=[C:9]([CH:18]=1)[C:10]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:11])(=[O:3])[CH3:2].[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25]>CO>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:19][CH2:20][CH:21]([OH:23])[CH2:22][NH:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[C:9]([CH:18]=1)[C:10]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:11])(=[O:3])[CH3:2]
Reactant: COC(=O)CCC(=O)c1cc(NC(C)=O)ccc1OCC1CO1
Reactant: CC(C)(C)N
Solvent: CO
Product: COC(=O)CCC(=O)c1cc(NC(C)=O)ccc1OCC(O)CNC(C)(C)C
Yield: 33 %

Procedure:
A solution of methyl 3-[5-acetamido-2-(2,3-epoxypropoxy)benzoyl]propionate (0.52 g, 0.0016 mole), t-butylamine (20 ml) and methanol (10 ml) was heated under reflux for 16 hours. Evaporation of the reaction mixture left an oil which was dissolved in ethanol and treated with ether to give crystalline methyl 3-[5-acetamido-2-(3-t-butylamino-2-hydroxypropoxy)benzoyl]propionate (0.21 g, 33%; m.p. 127°-128°). (Found; M+, 394. C20H30N2O6 requires: M, 394).
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH3:14][Mg]Br>C1COCC1>[OH:9][CH:8]([C:6]1[N:7]=[C:2]([OH:1])[CH:3]=[C:4]([C:10]([F:13])([F:11])[F:12])[CH:5]=1)[CH3:14]
Reactant: C[Mg]Br
Reactant: O=Cc1cc(C(F)(F)F)cc(O)n1
Solvent: C1CCOC1
Product: CC(O)c1cc(C(F)(F)F)cc(O)n1
Temperature: -78 °C
Yield: 69 %

Procedure:
6-hydroxy-4-(trifluoromethyl)picolinaldehyde (2.00 g, 10.5 mmol) was dissolved in dry THF (20 mL) and cooled to −78° C. Methyl magnesium bromide (24 mmol) was added dropwise over 5 minutes. The mixture was allowed to mix for 15 minutes. The reaction was allowed to warm to room temperature and slowly quenched with saturated ammonium chloride (20 mL). The solution was then extracted with ethyl acetate (3×100 mL). The organic extracts were combined and washed with brine (1×) dried over sodium sulfate and concentrated to yield 1.50 g of desired product (70%). 1HNMR (CDCl3 400 MHz) δ6.70 (s, 1H), 6.28 (s, 1H), 4.80 (m, 1H), 3.46 (q, 1H), 1.55 (d, 3H). Mass Spec.: 208.14 (MH)+.
Reaction SMILES: [CH3:1][C:2]12[CH2:15][C:6]1([C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[N:5]1[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:4]1[S:3]2.[Br-].[Al+3].[Br-].[Br-]>ClCCl>[CH3:1][CH:2]1[CH:15]=[C:6]([C:7]([O:9][CH2:10][C:11]([Cl:12])([Cl:13])[Cl:14])=[O:8])[N:5]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C@H:4]2[S:3]1
Reactant: CC12CC1(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)Cc3ccccc3)[C@H]1S2
Agent: [Al+3]
Agent: [Br-]
Solvent: ClCCl
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
A solution of 2,2,2-trichloroethyl 2-methyl-2,3-methylene-6-(2-phenylacetamido)penam-3-carboxylate (0.92 g.) in dried dichloromethane (5 ml.) was dropwise added at -10° C. over about 5 minutes to a solution of aluminum bromide (0.8 g.) in dried dichloromethane (10 ml.) and the mixture was stirred for 2 hours at room temperature. After the reaction was completed, the reaction mixture was washed in turn with 2% hydrochloric acid, a sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution and then dried over magnesium sulfate, after which the solvent was distilled off under reduced pressure. The residual crystals were washed with ether and dried to give 2,2,2-trichloroethyl 2-methyl-7-(2-phenylacetamido)3-cephem-4-carboxylate (0.74 g.), mp 175° to 178° C. And the residue obtained by concentrating the ether washing was purified by column chromatography on silica gel to give 2,2,2-trichloroethyl 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylate (0.05 g.), mp 118° to 120° C., which is a stereoisomer at 2 position of the above obtained 2,2,2-trichloroethyl 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylate, mp 175° to 178° C., and 2,2,2-trichloroethyl 2-methyl-7-(2-phenylacetamido)-2-cephem-4-carboxylate (0.05 g.), mp 136° to 137° C. The above obtained 2,2,2-trichloroethyl 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylate, mp 118° to 120° C., was recrystallized from benzene to give crystals, mp 120° to 123° C.
Reaction SMILES: C(OC([N:8]([C:22]1[N:23]=[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]2[C:30]=1[CH3:31])[S:9]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)(=[O:11])=[O:10])=O)(C)(C)C.Cl>O1CCOCC1.CCOCC>[CH3:31][C:30]1[N:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]2=[N:23][C:22]=1[NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: COC(=O)c1ccc(S(=O)(=O)N(C(=O)OC(C)(C)C)c2nc3ccccn3c2C)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=O)c1ccc(S(=O)(=O)Nc2nc3ccccn3c2C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.4 %

Procedure:
To compound 1-F (0.188 g, 0.422 mmol) was added 4N HCl in dioxane (6 mL) and the reaction mixture was stirred at room temperature for 18 h. The reaction was diluted with ether, filtered, and the solid washed with ether and dried in vacuo to afford compound 1-G as a white solid (0.104 g, 65%). 1H-NMR (CD3OD): δ 8.53-8.55 (d, 1H), 8.21-8.23 (d, 2H), 7.99-8.03 (m, 1H), 7.84-7.86 (d, 2H), 7.51-7.55 (m, 1H), 3.97 (s, 3H), 2.07 (s, 9H); MS: m/z 346.0 (MH+).
Reaction SMILES: Cl.[CH2:2]([C:7]1[S:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:3][CH2:4][CH2:5][CH3:6].FC(F)(F)S(O)(=O)=O.[N+:24]([O-])([OH:26])=[O:25].O>C(Cl)Cl>[CH2:2]([C:7]1[S:8][C:9]2[CH:15]=[C:14]([N+:24]([O-:26])=[O:25])[CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CCCCCc1nc2ccccc2s1
Agent: Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCCCCc1nc2ccc([N+](=O)[O-])cc2s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Pentylbenzothiazole hydrochloride (20.5 g, 0.084 mol) is added, at 0° C., to trifluoromethanesulfonic acid (44.6 ml 0.504 mol) and 100% nitric acid (10.6 ml, 0.215 mol) in methylene chloride (270 ml), and the mixture is stirred at 0° C. for 1.5 hours and at room temperature for one hour. Water (150 ml) is added dropwise and the phases are separated. The organic phase is washed with 0.5M NaHCO3 and with water. The resulting solution is dried, filtered and concentrated. The solid obtained is recrystallized from petroleum ether. Yield: 10.6 g (50%); Rf (8/2 petroleum ether/ethyl acetate): 0.71; 1H-NMR (d6-DMSO) 9.05 (d, 1H); 8.25 (dd, 1H); 8.15 (d, 1H); 3.13 (t, 2H); 1.28-1.36 (m, 4H); 0.85 (t, 3H).
Reaction SMILES: [N:1](OC)=[O:2].[F:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[S:13][C:14]1[CH:24]=[C:23]([C:25](=[O:28])[CH2:26][CH3:27])[CH:22]=[CH:21][C:15]=1[NH:16][S:17]([CH3:20])(=[O:19])=[O:18]>O1CCCC1.Cl.CCOCC>[F:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[S:13][C:14]1[CH:24]=[C:23]([C:25](=[O:28])[C:26](=[N:1][OH:2])[CH3:27])[CH:22]=[CH:21][C:15]=1[NH:16][S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: CCC(=O)c1ccc(NS(C)(=O)=O)c(Sc2ccc(F)cc2F)c1
Reactant: CON=O
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=NO)C(=O)c1ccc(NS(C)(=O)=O)c(Sc2ccc(F)cc2F)c1
Temperature: 3 °C
Reaction time: 5 h
Yield: 91.3 %

Procedure:
Methyl nitrite [prepared from sodium nitrite (1.4 g), methanol (0.9 ml) and sulfuric acid (0.7 ml) in water (2.3 ml)] was introduced into an ice-cooled mixture of 2'-(2,4-difluorophenylthio)-4'-propionylmethanesulfonanilide (2.54 g) in tetrahydrofuran (10 ml) and 12% hydrogen chloride in ether (10 ml). The mixture was stirred for 5 hours at 3° C. and evaporated. The residual solid was recrystallized from ethanol to give colorless crystals of 2'-(2,4-difluorophenylthio)-4'[2-(hydroxyimino)-1-oxopropyl]methanesulfonanilide (2.5 g).
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][C:7]1([C:12]2([CH:15]=O)[CH2:14][CH2:13]2)[O:11][CH2:10][CH2:9][O:8]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)C>[CH:15]([C:12]1([C:7]2([CH3:6])[O:8][CH2:9][CH2:10][O:11]2)[CH2:13][CH2:14]1)=[CH2:1]
Reactant: [Li]CCCC
Reactant: CC1(C2(C=O)CC2)OCCO1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Product: C=CC1(C2(C)OCCO2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
44.6 g of methyltriphenylphosphonium bromide in 700 ml of diethyl ether is introduced, and 50 ml of n-butyllithium solution (2.5 M in hexane) is added in drops at 0° C. under nitrogen. It is stirred for 1 more hour at room temperature and then 9.5 g of 7 in 10 ml of diethyl ether is added. After 1 hour, the reaction solution is quenched with sodium chloride solution, extracted with ethyl acetate, washed with sodium chloride solution, dried on sodium sulfate, and the solvent is removed. The residue is chromatographed on silica gel with ethyl acetate/hexane, whereby 5.4 g of title compound 8 is obtained as a colorless oil.
Reaction SMILES: O[CH2:2][CH2:3][C@H:4]1[C:13]([CH3:15])([CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:16])[CH:11]=2)[C:6]([CH3:18])([CH3:17])[CH2:5]1.N1C=CC=CC=1.S(Cl)([Cl:27])=O>C1(C)C=CC=CC=1>[Cl:27][CH2:2][CH2:3][C@H:4]1[C:13]([CH3:15])([CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:16])[CH:11]=2)[C:6]([CH3:18])([CH3:17])[CH2:5]1
Reactant: Cc1ccc2c(c1)C(C)(C)[C@H](CCO)CC2(C)C
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc2c(c1)C(C)(C)[C@H](CCCl)CC2(C)C
Temperature: 0 °C
Yield: 61.3 %

Procedure:
(S)-3-(2-Hydroxyethyl)-1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene ([α]546 -8.1° (C=0.62 in ethanol)) (70.5 g; 0.287 mol) was dissolved in toluene (700 g), and pyridine (25.0 g; 0.316 mol) was added thereto. The resulting mixture was cooled to 0° C., and thionyl chloride (41.0 g; 0.345 mol) was added dropwise thereto. After the addition was completed, the resultant mixture was heated at 60° C. for 5 hours. The reaction mixture was cooled, washed with dilute hydrochloric acid, saturated sodium carbonate solution and saturated sodium chloride solution in order, dried over anhydrous sodium sulfate and concentrated to give (S)-3-(2-chloroethyl)-1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene (46.5 g; 0.176 mol; 61%). B.P., 106°-107° C./0.13 mmHg. [α]546 -33.4° (C=1.2 in ethanol).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]([F:17])([F:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15].Cl[CH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][C@H:24]([NH:29][S:30]([CH:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])[CH2:23]2>CN(C=O)C>[F:7][C:8]([F:16])([F:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][C@H:24]([NH:29][S:30]([CH:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])[CH2:23]2
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(CCl)cc2C1
Reactant: Oc1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(COc3ccccc3C(F)(F)F)cc2C1
Temperature: 120 °C
Yield: 27.8 %

Procedure:
A mixture of potassium carbonate (0.174 mmol, 24.01 mg), 2-(trifluoromethyl)phenol (0.087 mmol, 14.08 mg), and (S)-N-(5-(chloromethyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (0.087 mmol, 25 mg) in DMF (2 mL) was heated at 120° C. for 900 s in a Smith Synthesiser microwave. The reaction mixture was concentrated to dryness before DCM (2 mL) and H2O (2 mL) was added and the reaction mixture filtered through a hydrophobic frit washing with further DCM (2 mL). The DCM layer was concentrated to dryness and purified by preparative HPLC to furnish the desired product (10.0 mg, 27.8%). MS (ESI): m/z [M−H]− 412.2
Reaction SMILES: C([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[CH3:12])C.[OH:16][C@@H:17]1[CH2:21][CH2:20][N:19]([CH2:22]CC(N(OC)C)=O)[CH2:18]1>>[F:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]2[C:6]=1[CH:12]=[C:14]([CH2:15][CH2:22][N:19]1[CH2:20][CH2:21][C@@H:17]([OH:16])[CH2:18]1)[NH:3][C:4]2=[O:13]
Reactant: CCN(CC)C(=O)c1cccc(F)c1C
Reactant: CON(C)C(=O)CCN1CC[C@@H](O)C1
Product: O=c1[nH]c(CCN2CC[C@@H](O)C2)cc2c(F)cccc12
Yield: 26 %

Procedure:
In the same manner as in Example 16b and using N,N-diethyl-3-fluoro-2-methylbenzamide (3.46 g) and (R)-3-(3-hydroxypyrrolidin-1-yl)-N-methoxy-N-methylpropanamide (3.36 g), (R)-5-fluoro-3-[2-(3-hydroxypyrrolidin-1-yl)ethyl]-2H-isoquinolin-1-one (1.19 g) was obtained.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C@@:19]([CH3:25])([CH:22]([CH3:24])[CH3:23])[CH2:20][OH:21]>>[OH:21][CH2:20][C@:19]([NH:18][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([CH3:25])[CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)[C@](C)(N)CO
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Product: CC(C)[C@@](C)(CO)NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 15, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g; 100 mg, 0.42 mmol) and (2S)-2-amino-2,3-dimethyl-1-butanol (CAN 956102-64-0, 107.06 mg, 0.64 mmol) as starting materials, and isolated (25 mg, 16.04%) as off white sticky solid, LC-MS (UV peak area, ESI) 90.02%, 334.4 (M+H).
Reaction SMILES: [CH:1]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.OS(O)(=O)=O.[CH3:16]O>>[CH:1]1([C:8]([O:10][CH3:16])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CO
Reactant: O=C(O)C1CCCCCC1
Agent: O=S(=O)(O)O
Product: COC(=O)C1CCCCCC1

Procedure:
To a solution of 25.0 g cycloheptanecarboxylic acid in methanol (300 mL) was added concentrated H2SO4 (0.5 g) and the mixture was stirred at reflux overnight. The reaction mixture was concentrated under vacuum and the residue was diluted with ethyl ether (500 mL). The mixture was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:22]I>CN(C=O)C>[CH3:22][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:18][CH:17]=1
Reactant: Oc1ccc(C2(c3ccccc3)CCCCC2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C2(c3ccccc3)CCCCC2)cc1
Reaction time: 2 h

Procedure:
4-(1-phenylcyclohexyl)phenol (20 mg, 0.08 mmol) was dissolved in DMF (2 mL). A suspension of NaH in oil (60%, 5 mg, 0.125 mmol) was added. After stirring for 5 minutes methyl iodide (0.05 mL; 0.8 mmol) was added. The reaction mixture was stirred for 2 h. (tlc indicated full conversion of the starting material) then quenched with water (10 mL). Dichloromethane (10 mL) was added. The mixture was shaken and the organic phase separated off, dried (Na2SO4) and concentrated to syrup. The title product was afforded after work-up by flash-chromatography (eluent dichloromethane). Yield: 20 mg, quantitatively. LC-MS purity (UV/MS): 100/-, Rt 6.48 min. 1H NMR data were in accordance with the data written above.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.[CH:26]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([NH:31][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:11])[CH:7]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Reactant: NC1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)NC2CCCC2)c1
Reaction time: 16 h
Yield: 6.3 %

Procedure:
To a stirred solution of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (360 mg, 1 mmol) and cyclopentylamine (0.6 mL, 6 mmol) in 10 mL of DMF was added PyBOP (780 mg, 1.5 mmol) and TEA (0.5 mL, 3.56 mmol). The reaction mixture was stirred for 16 hours. After water was added, the reaction mixture was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated. The crude residue was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the desired product as a white powder (27 mg, yield 6%). MS calcd for (C20H24BN3O5S): 429.2. MS found (ESI negative): (M−H)−=428.2. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.89 (s, 1H), 9.17 (bs, 1H), 8.02 (d, J=7.2 Hz, 1H), 7.44 (m, 2H), 7.22 (d, J=8 Hz, 1H), 7.11 (d, J=8 Hz, 1H), 6.46 (s, 1H), 6.35 (d, J=8 Hz, 1H), 5.94 (bs, 2H), 4.87 (s, 2H), 4.02 (q, J=6.4 Hz, 1H), 3.77 (s, 2H), 1.81 (m, 2H), 1.64 (m, 2H), 1.51 (m, 2H), 1.39 (m, 2H).
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+](C)C.[C:10]([O:14][C:15]([N:17]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>C(Cl)Cl>[C:10]([O:14][C:15]([N:17]1[CH2:23][CH2:22][C:21]([O:24][CH3:6])=[N:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)CC1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC1=NCCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
Trimethyloxonium tetrafluoroborate (Meerwein's salt) (141 mg, 0.94 mmol) was added in one portion to a solution of 1-(tert-butoxycarbonyl)hexahydro-(5H)-1,4-diazepin-5-one (200 mg, 0.94 mmol) in 2.0 mL of anhydrous methylene chloride. The mixture was stirred overnight at room temperature. The reaction mixture was partitioned between 10 mL of saturated aqueous sodium bicarbonate and 20 mL of ethyl acetate. The organic layer was separated and the aqueous layer was extracted with 3×10 mL of ethyl acetate. The combined ethyl acetate layers were washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the organic solution was concentrated in vacuo to give 180 mg (85%) of 1-(tert-butoxycarbonyl)-2,3,6,7-tetrahydro-5-methoxy-(1H)-1,4-diazepine as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:3]=1[C:4]([NH:6][C:7]([N:9]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[C:20]([O:28][CH3:29])[CH:19]=1)[NH:10]C(OC(C)(C)C)=O)=[O:8])=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:3]=1[C:4]1[NH:6][C:7](=[O:8])[N:9]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[C:20]([O:28][CH3:29])[CH:19]=2)[N:10]=1
Reactant: COC(=O)c1ccc(N(NC(=O)OC(C)(C)C)C(=O)NC(=O)c2c(Cl)cccc2Cl)cc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)cc1OC
Yield: 103.8 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-9 by using tert-butyl 2-((2,6-dichlorobenzoyl)carbamoyl)-2-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate (1.5 g, 2.2 mmol), DCM (50 mL) and trifluoro acetic acid (5.0 mL) to afford 0.900 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.78 (s, 3H), 3.84 (s, 3H), 7.62-7.30 (m, 5H), 7.82 (d, J=8.7 Hz, 1H), 12.76 (br s, 1H); MS (m/z): 393.85 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[Br:16]C1C=C(CC(OCC)=O)C=CC=1>>[Br:16][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:2]=1
Reactant: CCOC(=O)Cc1cccc(Br)c1
Reactant: CCOC(=O)CCCc1ccc(Br)cc1
Product: CCOC(=O)CCCc1cccc(Br)c1

Procedure:
Employing the same general multistep preparation as for ethyl 4-(4-bromophenyl)butanoate (Compound C), 60 g (246 mmol) of ethyl (3-bromophenyl)acetate (Compound B) was converted into the title compound (oil) using 255 ml (255 mmol) of diisobutylaluminum hydride (DIBAL-H, 1M in hexane), 85.8 g (250 mmol) of (carbethoxymethylene) triphenylphosphorane and 1.7 g of 10% Pd/C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH2:11]Cl)[O:10][C:6]=2[CH:5]=[C:4]([Cl:13])[CH:3]=1.[OH:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:24][C:25]1([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:30][O:29][C:28]([CH3:32])([CH3:31])[O:27][CH2:26]1)[CH2:19][CH2:18]2.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)C>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH2:11][O:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:24][C:25]3([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:30][O:29][C:28]([CH3:32])([CH3:31])[O:27][CH2:26]3)[CH2:19][CH2:18]4)[O:10][C:6]=2[CH:5]=[C:4]([Cl:13])[CH:3]=1
Reactant: ClCc1cc2c(Cl)cc(Cl)cc2o1
Reactant: CC(C)(C)OC(=O)NC1(CN2CCc3cc(O)ccc32)COC(C)(C)OC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(CN2CCc3cc(OCc4cc5c(Cl)cc(Cl)cc5o4)ccc32)COC(C)(C)OC1
Yield: 41.2 %

Procedure:
A mixture of the product of Step F (0.05 g; 0.21 mmol) and the product of Step C (0.08 g; 0.21 mmol) and Cs2CO3 (0.07 g; 0.21 mmol) in anhydrous DMF (1 ml) was stirred overnight at room temperature under N2. This was diluted to 10 ml with diethyl ether, washed with H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO2; hexane/EtOAc 7:3), to give the title compound (0.05 g; 41%) as a brownish syrup. 1H-NMR (CDCl3) 1.44 (m, 15H); 2.95 (tr, 2H, J=8.5 Hz); 3.41 (tr, 2H, J=8.5 Hz); 3.45 (5, 2H); 3.87-4.01 (m, 4H); 4.69 (broad s, 1H); 5.03 (s, 2H); 6.49 (d, 1H, J=8.5 Hz); 6.69 (dd, 1H, J=2.5, 8.5 Hz); 6.79 (s, 2H); 7.23 (s, 1H, J=2.5 Hz); 7.39 (s, 1H).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:24]=[CH:23][S:22][CH:21]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:3]1.[CH2:32]([O:35][C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[CH:39][C:40]([CH2:46]Cl)=[CH:41][CH:42]=2)[CH:37]=1)[CH:33]=[CH2:34]>>[CH2:32]([O:35][C:36]1[CH:37]=[C:38]2[C:43]([CH:42]=[CH:41][C:40]([CH2:46][O:1][CH:2]3[CH:7]([C:8]4[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]5[CH:24]=[CH:23][S:22][CH:21]=5)=[CH:12][CH:13]=4)[CH2:6][CH2:5][N:4]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:3]3)=[CH:39]2)=[CH:44][CH:45]=1)[CH:33]=[CH2:34]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccsc3)cc2)C(O)C1
Reactant: C=CCOc1ccc2ccc(CCl)cc2c1
Product: C=CCOc1ccc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccsc4)cc3)cc2c1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-[3-(thiophen-3-ylmethoxy)-propoxy]-phenyl]-piperidine-1-carboxylate with 2-allyloxy-7-chloromethyl-naphthalene there was obtained tert-butyl (3RS,4RS)-3-(7-allyloxy-naphthalen-2-ylmethoxy)-4-{4-[3-(thiophen-3-ylmethoxy)-propoxy]-phenyl}-piperidine-1-carboxylate, from which after cleavage of the allyl group by means of bis-(triphenylphosphine)-palladium(II) diacetate analogously to Example 152(e) there was obtained tert-butyl (3RS,4RS)-3-(7-hydroxy-naphthalen-2-ylmethoxy)-4-{4-[3-(thiophen-3-yl-methoxy)-propoxy]-phenyl}-piperidine-1-carboxylate as a yellowish, viscous oil; MS: 604 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9].[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:10]1([S:16][CH2:2][CH2:3][CH:4]2[CH2:8][CH2:7][CH2:6][N:5]2[CH3:9])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN1CCCC1CCCl
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCCC1CCSc1ccccc1
Yield: 10012.5 %

Procedure:
2-(2-Chloroethyl)-1-methylpyrrolidine (1.30 g, 0.08 mmole), thiophenol (1.00 g, 9.08 mmole), potassium carbonate (12.56 g, 90.8 mmole) and DMF (18 mL) were combined, yielding 1.77 g (8.01 mmole, 89%) of the desired compound.