Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:6]=[CH:5][C:4]([C@@:7]23[CH2:27][N:20]([C@H:21]([C:23]([O:25]C)=[O:24])[CH2:22]2)[C:19](=[O:28])[C@@H:18]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=[CH:10][CH2:9][S:8]3)=[CH:3][CH:2]=1.O.[OH-].[Li+]>C1COCC1.CO.O>[C:1]1([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:6]=[CH:5][C:4]([C@@:7]23[CH2:27][N:20]([C@H:21]([C:23]([OH:25])=[O:24])[CH2:22]2)[C:19](=[O:28])[C@@H:18]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:31])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=[CH:10][CH2:9][S:8]3)=[CH:3][CH:2]=1
Reactant: COC(=O)[C@@H]1C[C@@]2(c3ccc(-c4ccccc4)cc3)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CCCCCCC=CCS2
Agent: CC(C)(C)OC(=O)N[C@H]1CCCCCC/C=C/CS[C@@]2(c3ccc(-c4ccccc4)cc3)C[C@@H](C(=O)O)N(C2)C1=O
Agent: COC(=O)[C@@H]1C[C@@]2(c3ccc(-c4ccccc4)cc3)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CCCCCC/C=C/CS2
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCCCCC=CCS[C@@]2(c3ccc(-c4ccccc4)cc3)C[C@@H](C(=O)O)N(C2)C1=O
Reaction time: 5 h

Procedure:
To a solution of (3S,14R,16S,E)-methyl 14-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)-2-oxo-13-thia-1-azabicyclo[12.2.1]heptadec-10-ene-16-carboxylate (82 mg, 0.138 mmol) in THF (1 mL) and MeOH (1.000 mL) was added pre-made solution of lithium hydroxide hydrate (17.41 mg, 0.415 mmol) in Water (1 mL). The resulting cloudy solution was stirred at room for 5 h. Quenched with 5% citric acid, extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, evaporated, to afford the desired product (3S,14R,16S,E)-14-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)-2-oxo-13-thia-1-azabicyclo[12.2.1]heptadec-10-ene-16-carboxylic acid (80 mg, 0.124 mmol, 90% yield) as a tan foam. LC-MS (retention time: 3.43 min, method C), MS m/z 579 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Li]CCCC.C(O[B:24]1[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]1)(C)C>C1COCC1.[NH4+].[Cl-]>[CH3:14][N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([B:24]3[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]3)=[CH:3][CH:4]=2)[CH2:9][CH2:10]1
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled (−78° C.) solution of 1-(4-Bromo-phenyl)-4-methyl-piperazine (8.05 g, 31.54 mmol, CAS 130307-08-3) in dry THF (500 ml) are added dropwise 28 ml of a solution of n-BuLi (2.5M in hexanes, 69 mmol). After 1 h, of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13.1 ml, 63.1 mmol) in solution in dry THF (20 ml) are introduced. After complete addition, the reaction mixture is allowed to slowly warm up to RT. The reaction mixture is then diluted with 200 ml of a saturated solution of NH4Cl and most of the THF is removed by evaporation. The residue is diluted with EtOAc and the phases are separated. The aqueous phase is re-extracted three times with EtOAc and the combined organic extracts are washed twice with de-ionized water, once with saturated brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by chromatography (silicagel, CH2Cl2/EtOH 9:1) to afford the title compound as a colorless solid, Rt=0.851 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 303 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([CH3:10])=[CH2:9])[CH:3]=1.[Cl:11]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl>CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([CH2:10][Cl:11])=[CH2:9])[CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: C=C(C)c1cc(Cl)ccn1
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(CCl)c1cc(Cl)ccn1
Temperature: 25 °C
Yield: 17.1 %

Procedure:
A mixture of 4.3 g of 4-chloro-2-isopropenylpyridine, 3.8 g of N-chlorosuccinimide and 10 ml of carbon tetrachloride was stirred in an oil bath at 150° to 160° C. for hour. After the reaction mixture was cooled to room temperature, n-hexane was added thereto to remove the insoluble matter through filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluted with n-hexane-ethyl acetate 20:1) to obtain 0.90 g of the objective compound.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:4]([N:9]2[CH2:15][CH2:14][C:13]3[C:16](O)=[N:17][CH:18]=[N:19][C:12]=3[CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.O=P(Cl)(Cl)[Cl:25]>CC#N.CCOC(C)=O>[Cl:25][C:16]1[C:13]2[CH2:14][CH2:15][N:9]([C:4]3[C:3]([C:2]([F:22])([F:21])[F:1])=[CH:8][CH:7]=[CH:6][N:5]=3)[CH2:10][CH2:11][C:12]=2[N:19]=[CH:18][N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2c1CCN(c1ncccc1C(F)(F)F)CC2
Solvent: CCOC(C)=O
Solvent: CC#N
Product: FC(F)(F)c1cccnc1N1CCc2ncnc(Cl)c2CC1
Temperature: 90 °C
Yield: 33 %

Procedure:
To a solution of 7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ol (185 mg, 0.60 mmol) in CH3CN (2 mL) was added POCl3 (0.11 mL, 1.19 mmol). The reaction mixture was heated at 90° C. for 2 h. The mixture was cooled to rt, diluted with EtOAc, and quenched slowly with saturated (satd.) aq. NaHCO3. The combined organic layers were dried (Na2SO4) and concentrated. The crude residue was purified (FCC) to give the title compound (65 mg, 33%).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][C:6]([Br:38])=[C:7]([C:9](=[N:35][O:36][CH3:37])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:20]([O:22]CC4C=CC([N+]([O-])=O)=CC=4)=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].O1CCCC1.CO>[Pd].C(O)(=O)C>[CH:1]([NH:3][C:4]1[S:5][C:6]([Br:38])=[C:7]([C:9](=[N:35][O:36][CH3:37])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1nc(NC=O)sc1Br
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1nc(NC=O)sc1Br
Yield: 38.5 %

Procedure:
4-Nitrobenzyl 7-[2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 2.65 g.) was add to a mixture of tetrahydrofuran (110 ml.) and methanol (80 ml.). To the solution was added a suspension of 10% palladium on carbon (1.5 g.) in acetic acid (10 ml.) and the mixture was subjected to catalytic hydrolysis at room temperature under ordinal pressure. The reaction mixture was filtered and washed with tetrahydrofuran. The filtrate and washings were combined and evaporated in vacuo. Ethyl acetate was added to the residue, adjusted to pH 7.5 with saturated aqueous sodium bicarbonate and filtered. The aqueous layer was separated and washed with ethyl acetate. 100 ml. of 20% Isopropyl alcohol in ethyl acetate was added to the aqueous solution and adjusted to pH 2.0 with 6N-hydrochloric acid. The mixture was saturated with sodium chloride and the organic layer was separated. The remaining aqueous layer was extracted with a mixture (100 ml. and 50 ml.) of ethyl acetate and isopropyl alcohol (4:1). The organic layer and the extracts were combined, washed with a small amount of saturated aqueous sodium chloride, dried over magnesium sulfate, treated with activated charcoal and then evaporated in vacuo. The residue was pulverized with diisopropyl ether and the precipitates were collected by filtration, washed with diisopropyl ether and dried to give 7-[2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.8 g.).
Reaction SMILES: C([O:3][C:4](=[O:28])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[C:19]([CH2:21][N:22]([CH:24]3[CH2:26][CH2:25]3)[CH3:23])[CH:18]=[CH:17][C:16]=2[CH3:27])=[CH:9][CH:8]=1)C.[OH-].[K+].Cl>C(O)C.O1CCCC1>[CH:24]1([N:22]([CH2:21][C:19]2[CH:18]=[CH:17][C:16]([CH3:27])=[C:15]([C:14]#[C:13][C:10]3[CH:9]=[CH:8][C:7](/[CH:6]=[CH:5]/[C:4]([OH:28])=[O:3])=[CH:12][CH:11]=3)[CH:20]=2)[CH3:23])[CH2:25][CH2:26]1
Reactant: CCOC(=O)/C=C/c1ccc(C#Cc2cc(CN(C)C3CC3)ccc2C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(CN(C)C2CC2)cc1C#Cc1ccc(/C=C/C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
A solution of (E)-3-(4-{5-[(cyclopropyl-methyl-amino)-methyl]-2-methyl-phenylethynyl}-phenyl)-acrylic acid ethyl ester (Intermediate 100, 0.14 g, 0.37 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with a 3M solution of potassium hydroxide (1 mL, 3 mmol) and the resulting reaction mixture was stirred at ambient temperature overnight. The reaction mixture was neutralized with 5% aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue that was subjected to flash column chromatography over silica gel (230-400 mesh) using 5% methanol in ethyl acetate as the eluent to afford the title product as an amorphous solid (0.071 g, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[NH2:51][CH2:52][CH2:53][CH2:54][OH:55]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:31][CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([NH:51][CH2:52][CH2:53][CH2:54][OH:55])=[O:27])=[CH:29][CH:30]=3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3ccc(C(=O)O)cc3)n2)cc1Cl
Reactant: NCCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3ccc(C(=O)NCCCO)cc3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 29.8 %

Procedure:
4-{3-[2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoic acid (prepared in example 45, 40 mg, 0.08 mmol) was suspended in methylene chloride (1 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (38 μL, 0.08 mmol) was added and the reaction stirred at 25° C. for 20 min. The solution was chilled to 0° C. and 2,6-lutidine (18 μL, 0.15 mmol) was added. The reaction continued to stir at 0° C. for 20 min. 3-Amino-propan-1-ol (7 μL, 0.09 mmol) was added, the ice bath was removed and the reaction continued to stir at 25° C. for 16 h. The reaction was diluted with methylene chloride (10 mL), washed with water (2×4 mL), saturated aqueous brine solution (1×4 mL), dried over magnesium sulfate and concentrated in vacuo to a beige foam. Purification by reverse phase preparative HPLC (Column: Thomson C18 ODSA, 5 micron, 50×21.2 mm ID; 30% acetonitrile/water to 100% acetonitrile/water; 30 mL/min flow rate for 15 min run) followed by preparative thin layer chromatography (Merck Silica gel 60 F254, 500 μm, 20×20 cm; 100% ethyl acetate) afforded 4-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-N-(3-hydroxy-propyl)-benzamide (14 mg, 32%) as a white waxy solid: ESI-LRMS m/e calcd for C29H35ClN4O5S [M+] 586.2, found 587.29 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.08-1.22 (m, 2H, CH2), 1.43-1.93 (m, 10H, 5×CH2), 2.15-2.31 (m, 1H, CH), 3.26 (s, 3H, SO2CH3), 3.57-3.67 (m, 3H, CH2 and CH), 3.73 (t, J=5.5 Hz, 2H, CH2), 5.18 (s, 2H, NCH2), 6.74 (d, J=2.3 Hz, 1H, Ar), 6.82 (brm, 1H, NH), 7.12 (d, Jo=8.1 Hz, 2H, Ar), 7.36 (d, J=2.3 Hz, 1H, Ar), 7.43 (dd, Jo=8.1, Jm=1.6 Hz. 1H, Ar), 7.59 (d, Jm=1.6 Hz, 1H, Ar), 7.67 (d, Jo=8.1 Hz, 2H, Ar), 8.04 (d, Jo=8.1 Hz, 1H, Ar), 8.32 (s, 1H, NH).
Reaction SMILES: ClC1C=NC=C(Cl)C=1CO.[Cl:11][C:12]1[C:13]([CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)=[C:14]([CH:18]=[O:19])[CH:15]=[N:16][CH:17]=1>>[Cl:11][C:12]1[C:13]([CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)=[C:14]([CH2:18][OH:19])[CH:15]=[N:16][CH:17]=1
Reactant: O=Cc1cncc(Cl)c1COC1CCCCO1
Agent: OCc1c(Cl)cncc1Cl
Product: OCc1cncc(Cl)c1COC1CCCCO1

Procedure:
Reduction of the aldehyde group in 5-chloro-4-(tetrahydro-pyran-2-yloxymethyl)-pyridine-3-carbaldehyde according to the synthesis of (3,5-dichloro-pyridin-4-yl)-methanol yielded the title compound. MS (m/z): 258.2 [M+H+].
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([C:10]2[N:15]=[C:14]([O:16][C@@H:17]([C@H:19]3[CH2:23][N:22]([C@@H](C4C=CC(OC)=CC=4)C)[C:21](=[O:34])[CH2:20]3)[CH3:18])[C:13]3[N:35]([CH:38]([F:40])[F:39])[CH:36]=[N:37][C:12]=3[CH:11]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]>C(O)(C(F)(F)F)=O>[C:1]([N:5]1[CH:9]=[C:8]([C:10]2[N:15]=[C:14]([O:16][C@@H:17]([C@H:19]3[CH2:23][NH:22][C:21](=[O:34])[CH2:20]3)[CH3:18])[C:13]3[N:35]([CH:38]([F:40])[F:39])[CH:36]=[N:37][C:12]=3[CH:11]=2)[CH:7]=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(-c4cnn(C(C)(C)C)c4)cc4ncn(C(F)F)c34)CC2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](Oc1nc(-c2cnn(C(C)(C)C)c2)cc2ncn(C(F)F)c12)[C@H]1CNC(=O)C1
Temperature: 60 °C
Reaction time: 15 h

Procedure:
(R)-4-((R)-1-(6-(1-tert-butyl-1H-pyrazol-4-yl)-3-(difluoromethyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 2.34 (max. 0.107 mmol) was dissolved in TFA (2 mL) and heated to 60° C. with stirring. After 15 h, the red solution was concentrated in vacuo and diluted with EtOAc (20 mL) and 1:1 saturated aqueous NaHCO3: brine (20 mL). The phases were separated and the aqueous phase was extracted with EtOAc (20 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated onto silica gel. Purification by silica gel chromatography (40% to 100% acetone in hexanes) provided (R)-4-((R)-1-(6-(1-tert-butyl-1H-pyrazol-4-yl)-3-(difluoromethyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3.03.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([O:11][CH2:12][C:13]2[C:14]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[N:15][O:16][CH:17]=2)=[CH:7][N:6]=1)=[O:4].O.[OH-].[Li+].Cl>C1COCC1.O.CO>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:14]2[C:13]([CH2:12][O:11][C:8]3[N:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=3)=[CH:17][O:16][N:15]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1cnc(OCc2conc2-c2ccc(Cl)cc2)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cnc(OCc2conc2-c2ccc(Cl)cc2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.6 %

Procedure:
To a solution of 5-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-pyrazine-2-carboxylic acid methyl ester (1.0 g, 2.89 mmol) in THF (6.3 mL), water (6.3 mL) and methanol (1.75 mL) was added lithium hydroxide monohydrate (141.4 mg, 5.78 mmol) and the resulting mixture stirred at room temperature for 2 h and then acidified with HCl (4 N) and extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated to afford the title product (360 mg, 38%) which was obtained as white solid. MS: m/e=330.0 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](C(O)=O)=[CH:8]2.C[N:17](C=O)C.C(Cl)(=O)C(Cl)=O.[N-]=[N+]=[N-].[Na+].[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([NH2:17])=[CH:8]2
Reactant: COc1cccc2cc(C(=O)O)ccc12
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Product: COc1cccc2cc(N)ccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61 %

Procedure:
5-Methoxy-2-naphthoic acid (3.17 g, 15.7 mmol), CH2CO2 (38 mL) and DMF (3.04 mL, 39.2 mmol) were combined in a 50-mL flask under a N2 atmosphere. Oxalyl chloride (2.73 mL, 31.3 mmol) was added dropwise over 30 minutes at 20 to 23° C. The resulting yellow solution was stirred at room temperature for 15 minutes. The solution was then concentrated in vacuo to 6.48 g of yellow solid which was slightly wet with DMF. The solid was dissolved in CH3CN (157 mL) and added dropwise over 35 minutes to a solution of sodium azide (2.55 g, 39.2 mmol) in 24 mL of water, and rinsed in with an additional 25 mL of CH3CN. Analysis of the resulting yellow mixture by HPLC after 5 minutes showed 15% acyl chloride remaining. Water (15 mL) was added to give an orange mixture and to promote acyl azide formation. The mixture was heated at reflux for 1 hour and 40 minutes. The mixture was cooled to room temperature. Sodium hydroxide (50 mL, 2N solution) was added and the resulting yellow mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo to 102.0 g of brown gum plus liquid. The mixture was extracted with 50 mL of CH2Cl2. The CH2Cl2 layer was dried over Na2SO4, filtered and concentrated in vacuo to provide 1.83 g of the intermediate title compound as a brown oil (HPLC: 91%, 61% yield).
Reaction SMILES: [CH3:1][C:2]([C@H:4]1[N:7]([CH:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:6](=[O:27])[C@@H:5]1[C@H:28]([O:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH3:29])=[CH2:3].[Cl:41]Cl.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C.C(Cl)(Cl)(Cl)Cl>[Cl:41][CH2:3][C:2]([C@H:4]1[N:7]([CH:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:6](=[O:27])[C@@H:5]1[C@H:28]([O:30][C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])[CH3:29])=[CH2:1]
Reactant: ClCl
Reactant: C=C(C)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(CCl)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Reaction time: 0.25 h

Procedure:
(3S,4S)-4-(1-Methylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (200 g) was dissolved in ethyl acetate (3 liters), and a solution of chlorine in carbon tetrachloride (3.85%, 870 g) was added dropwise thereto at room temperature over a period of 15 minutes, followed by stirring for 1 hour. Water (1 liter) and then 10% aqueous sodium thiosulfate (50 ml) were poured into the reaction mixture, which was stirred for 0.5 hour and allowed to stand. The organic layer was washed successively with saturated sodium bicarbonate and brine and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave (3S,4S)-4-(1-chloromethylethenyl)- 3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone. m.p., 84°-85° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].S(=O)(=O)(O)O.[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([O:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(C)ccc1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C)ccc1OC(C)=O
Temperature: 0 °C
Reaction time: 72 h

Procedure:
A solution of the product from step (i) (5.87 g) in acetic anhydride (4.32 g) was treated with concentrated sulphuric acid (0.5 ml) and stirred for 72 hours. The mixture was poured into ice-water and extracted with diethyl ether. The extract was washed with water and saturated aqueous sodium bicarbonate, dried (MgSO4) and evaporated. Yield 5.5 g.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10]Cl.[I-:18].[Na+]>CC(=O)CC>[Cl:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][I:18]
Reactant: [I-]
Reactant: COc1ccc(OCCOCCCl)c(Cl)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1ccc(OCCOCCI)c(Cl)c1

Procedure:
2-[2-(2-Chloro-4-methoxyphenoxy)ethoxy]ethyl iodide was prepared from 24.7 g. of the corresponding chloride of part (a) by three hours reflux with 13.5 g. of sodium iodide in 200 ml. of 2-butanone. The crude product was used directly in part (c) below.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:17])[CH:9]([NH2:16])[CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.Cl.[CH2:19]([O:21][C:22]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:23]=1[C:24](=N)OCC)[CH3:20].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[NH:17][C:24]([C:23]3[CH:29]=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:22]=3[O:21][CH2:19][CH3:20])=[N:16][CH:9]2[CH2:10][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)=[CH:6][CH:7]=1
Reactant: NC(CC1CCCC1)C(N)c1ccc(Cl)cc1
Reactant: CCOC(=N)c1ccc(OC)cc1OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1
Yield: 62.7 %

Procedure:
To a solution of 1-(4-chloro-phenyl)-3-cyclopentyl-propane-1,2-diamine (170 mg, 0.672 mmol) and ethyl 2-ethoxy-4-methoxy-benzimidate hydrochloride (210 mg, 0.806 mmol) in ethanol (10 mL) was added triethylamine (82 μL, 0.806 mmol). The reaction mixture was heated at gentle reflux for 6 h. The solvent was removed and the residue was partitioned between water and methylene chloride. The product was extracted with methylene chloride (2×20 mL). The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (Biotage system, KP-Sil™ 32–63 μm, 60 Å silica gel) eluting with ethyl acetate then 5–10% methanol in ethyl acetate to give 5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole (174 mg, 63%, 4.5:1.0 ratio of cis:trans) as a white foam. HR-MS (ES, m/z) observed 413.1993, calculated for C24H30N2O2Cl [(M+H)+] 413.1991.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][CH2:24][C@@H:25]([N:27]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[C:46]2[N:50]([C:51]([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[N:49]=[N:48][N:47]=2)=[CH:36][CH:35]=1)[C:28](=[O:32])[CH2:29][CH2:30][CH3:31])[CH3:26].O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH3:26][C@H:25]([N:27]([CH2:33][C:34]1[CH:35]=[CH:36][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[C:46]2[N:50]([C:51]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)([C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=3)[C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=3)[N:49]=[N:48][N:47]=2)=[CH:38][CH:39]=1)[C:28](=[O:32])[CH2:29][CH2:30][CH3:31])[CH:24]=[O:23]
Reactant: CCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)[C@@H](C)CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)[C@@H](C)C=O
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
Dess-Martin periodinane (971 mg, 2.3 mmol) was added to a solution of intermediate (5b) (474 mg, 0.8 mmol) in DCM (20 mL) at room temperature. After 30 minutes, water (20 mL) and saturated aqueous sodium thiosulfate (20 mL) was added. The mixture was extracted with DCM (3×30 mL), washed with saturated aqueous NaCl (20 mL), dried over MgSO4, and concentrated in vacuo. Silica gel chromatography gave intermediate (5c) as a white solid (411 mg).