Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[S:25]1[C:29]([C:30]([OH:32])=O)=[CH:28][C:27]2[CH:33]=[CH:34][CH:35]=[CH:36][C:26]1=2.[Si:37]([O:44][CH2:45][CH2:46][C:47]1[C:48]([F:65])=[C:49]([CH:62]=[CH:63][CH:64]=1)[CH2:50][N:51]1[CH2:61][CH2:60][C:54]2([O:59][CH2:58][CH2:57][NH:56][CH2:55]2)[CH2:53][CH2:52]1)([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38].C(N(CC)CC)C>CN(C=O)C>[S:25]1[C:29]([C:30]([N:56]2[CH2:55][C:54]3([CH2:53][CH2:52][N:51]([CH2:50][C:49]4[CH:62]=[CH:63][CH:64]=[C:47]([CH2:46][CH2:45][O:44][Si:37]([C:40]([CH3:42])([CH3:41])[CH3:43])([CH3:38])[CH3:39])[C:48]=4[F:65])[CH2:61][CH2:60]3)[O:59][CH2:58][CH2:57]2)=[O:32])=[CH:28][C:27]2[CH:33]=[CH:34][CH:35]=[CH:36][C:26]1=2
Reactant: O=C(O)c1cc2ccccc2s1
Reactant: CC(C)(C)[Si](C)(C)OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCc1cccc(CN2CCC3(CC2)CN(C(=O)c2cc4ccccc4s2)CCO3)c1F
Reaction time: 1 h

Procedure:
2-(3H-[1,2,3]Triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.378 g) was added to a stirred solution of benzo[b]thiophene-2-carboxylic acid (0.186 g), 9-(3-(2-(tert-butyldimethylsilyloxy)ethyl)-2-fluorobenzyl)-1-oxa-4,9-diazaspiro[5.5]undecane (example 78, step d) (0.40 g), and triethylamine (0.383 g) in DMF (4 mL). After 1 h, the reaction mixture was partitioned between water and ethyl acetate. The ethyl acetate layer was washed twice with water and once with brine, dried over magnesium sulphate, filtered and evaporated in vacuo. Purification by silica gel chromatography eluting with 7:1:0.5, isohexane:ethyl acetate:triethylamine gave the subtitled compound as a gum. Yield 0.38 g.
Reaction SMILES: C(CO[C:5](=[O:31])[C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][N:7]=1)#N.[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33]>O>[CH2:32]([N:34]([CH2:35][CH3:36])[C:5](=[O:31])[C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:8][N:7]=1)[CH3:33]
Reactant: N#CCOC(=O)c1ccc(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCNCC
Solvent: O
Product: CCN(CC)C(=O)c1ccc(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
Heat at reflux for 6 hours a mixture of 0.1 mole of cyanomethyl-5-(triphenylmethyl)-picolinate and 0.5 moles of diethylamine. Cool the reaction mixture, pour into water and extract with chloroform. Dry the chloroform layer over anhydrous sodium sulfate and evaporate to obtain thereby the product of this example.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH2:7][C:8]([OH:10])=O)[O:4][N:3]=1.[NH2:11][CH:12]1[C:30](=[O:31])[N:14]2[C:15]([C:27]([OH:29])=[O:28])=[C:16]([CH:19]([C:21]3[S:22][C:23]([CH3:26])=[N:24][N:25]=3)[SH:20])[CH2:17][S:18][C@H:13]12>C(#N)C>[CH3:1][C:2]1[N:6]=[C:5]([CH2:7][C:8]([NH:11][CH:12]2[C:30](=[O:31])[N:14]3[C:15]([C:27]([OH:29])=[O:28])=[C:16]([CH:19]([C:21]4[S:22][C:23]([CH3:26])=[N:24][N:25]=4)[SH:20])[CH2:17][S:18][C@H:13]23)=[O:10])[O:4][N:3]=1
Reactant: Cc1noc(CC(=O)O)n1
Reactant: Cc1nnc(C(S)C2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Solvent: CC#N
Product: Cc1noc(CC(=O)NC2C(=O)N3C(C(=O)O)=C(C(S)c4nnc(C)s4)CS[C@H]23)n1
Yield: 58 %

Procedure:
Using the same procedure, 21.65 mmol of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid and 21.65 mmol of 7-amino-3-(5-methyl-1,3,4-thiadiazol-2-yl-mercaptomethyl)-3-cephem-4-carboxylic acid in 220 ml of dry acetonitrile were reacted for 3 hours at room temperature and 3 hours at 50° C.±5° C. to obtain a 58% yield of pure 7-[3-methyl-1,2,4-oxadiazol-5-yl-acetamido]-3-[5-methyl-1,3,4-thiadiazol-2-yl-mercaptomethyl]-3-cephem-4-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][N:15]=1)[CH2:7][CH2:6]2.[H][H].[ClH:25]>C(O)C.O.[Pd]>[ClH:25].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([C:14]1[N:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=1)[CH2:7][CH2:6]2
Reactant: [H][H]
Reactant: COc1cc2c(cc1OC)N(c1ccc([N+](=O)[O-])cn1)CC2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc2c(cc1OC)N(c1ccc(N)cn1)CC2
Yield: 70.8 %

Procedure:
5,6-Dimethoxy-1-(5-nitro-(2-pyridyl))-indoline was hyrogenated overnight with Pd (5%) on carbon in ethanol/water (8:2) in a shaking “duck”. When the uptake of hydrogen had come to an end, 10% hydrochloric acid was added, the catalyst was filtered off and the remainder was concentrated to dryness. The residue was recrystallized with ethanol and active carbon. The product 6-(5,6-dimethoxyindolin-1-yl)-3-pyridylamine hydrochloride was obtained in a yield of 70.8% (melting point: 168-171° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17]>O1CCCC1>[C:2]1([NH:1][C:15](=[O:19])[CH:16]([CH3:18])[CH3:17])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Cl
Reactant: Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 91 %

Procedure:
First, 26.2 g of aniline, 100 mL of tetrahydrofuran (THF), and 56.9 g of triethylamine (Et3N) were put in a 500 mL three-neck flask, and mixed. Then, under cooling in ice, a mixed solution of 30 g of isobutyryl chloride and 100 mL of THF was dripped through a 50 mL dropping funnel to the above mixed solution, and then the temperature was increased to room temperature and the solution was stirred for 19 hours to be reacted. After the reaction, this mixture was subjected to suction filtration to give a filtrate. The resulting filtrate was washed with water, and then saturated saline, and anhydrate magnesium sulfate was added for drying. After the drying, the mixture was subjected to gravity filtration, and the filtrate was concentrated, so that N-phenylisobutyramide was prepared (a white solid, yield: 91%). The synthetic scheme of Step 1 is shown by (a-10).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:17]3[C:18]([CH3:28])=[N:19][N:20]4[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22][C:21]=34)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)=[CH:4][CH:3]=1.[N:31]1([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:17]3[C:18]([CH3:28])=[N:19][N:20]4[CH:25]=[CH:24][C:23]([CH2:26][N:34]5[CH2:35][CH2:36][N:31]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32][CH2:33]5)=[CH:22][C:21]=34)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1nn2ccc(C=O)cc2c1-c1nc(Cc2ccc(Cl)cc2)c(-c2nnc[nH]2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1nn2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2c1-c1nc(Cc2ccc(Cl)cc2)c(-c2nnc[nH]2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.3 %

Procedure:
A mixture of 3-[4-(4-chlorobenzyl)-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methylpyrazolo[1,5-a]pyridine-5-carbaldehyde (0.0563 g, 0.109 mmol), tert-butyl 1-piperazinecarboxylate (60.8 mg, 0.326 mmol) and acetic acid (0.0800 mL, 1.41 mmol) in dry methylene chloride (10 mL) was stirred at rt for 15 min. Sodium triacetoxyborohydride (69.1 mg, 0.326 mmol) was added and the mixture was stirred at rt for 15 hours. The mixture was washed with saturated NaHCO3 solution and the aqueous layer was extracted with DCM. The DCM extract was washed with water, brine, dried over Na2SO4, filtered and evaporated to give a crude product which was purified by column chromatography on silica gel column using MeOH/DCM (0/100 to 5/95) to give solid product (0.0464 g, yield 70.5%). LCMS: (FA) ES+ 605, 607; ES− 603, 605. 1H NMR (400 MHz, CDCl3 and d4-methanol) δ: 8.23-8.25 (d, J=7.03 Hz, 1H), 8.20 (s, 1H), 7.94 (s, 1H), 7.29-7.31 (d, J=8.28 Hz, 2H), 7.15-7.17 (d, J=8.53 Hz, 2H), 6.86-6.89 (dd, J=7.28, 1.76 Hz, 1H), 4.53 (s, 2H), 3.45 (s, 2H), 3.33-3.36 (m, 4H), 2.62 (s, 3H), 2.35 (s, br, 4H), 1.37 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[CH:12][C:13]2[N:14]([CH3:40])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[C@H:37]([OH:39])[CH3:38])[N:16]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.CCO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([CH2:12][C:13]2[N:14]([CH3:40])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[C@H:37]([OH:39])[CH3:38])[N:16]=3)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](O)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=C3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[C@@H](O)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Reaction time: 16 h
Yield: 91.7 %

Procedure:
To a solution of 3-{2-[2-((R)-1-hydroxyethyl)benzoimidazol-1-yl]-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethylene}azetidine-1-carboxylic acid tert-butyl ester (167 mg, 0.31 mmol) in EtOAc (5 mL) and EtOH (5 mL) was added 20% Pd(OH)2/C (160 mg) and the resulting mixture stirred under an atmosphere of H2 for 16 h. The reaction mixture was filtered through Celite® and the filtrate concentrated in vacuo affording the title compound (156 mg, 93%). LCMS (method A): RT 3.07 min [M+H]+ 549.4
Reaction SMILES: [F:1][CH2:2][C:3]([NH:5][C:6]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[CH3:18])=[O:9])=O.B(F)(F)F.CCOCC>C(O)(=O)C>[F:1][CH2:2][C:3]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[CH3:18])[C:8](=[O:9])[C:7]2[C:6](=[CH:22][CH:21]=[C:20]([N+:23]([O-:25])=[O:24])[CH:19]=2)[N:5]=1
Reactant: Cc1ccc(NC(=O)c2cc([N+](=O)[O-])ccc2NC(=O)CF)c(C)c1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1ccc(-n2c(CF)nc3ccc([N+](=O)[O-])cc3c2=O)c(C)c1
Yield: 68.6 %

Procedure:
4.0 g of N-(2-fluoroacetamido-5-nitrobenzoyl)-2,4-dimethylaniline are added to a mixture of 30 ml of acetic acid and 3.5 g of boron trifluoride etherate, and the mixture is stirred under heating at 100° to 105° C. for 30 minutes. The mixture is cooled and concentrated under reduced pressure to remove acetic acid. 50 ml of water are added to the residue, and the mixture is neutralized with potassium carbonate. The mixture is extracted with chloroform, and the extract is washed with water and dried. The chloroform solution is concentrated under reduced pressure to remove solvent. Isopropanol is added to the residue, and crystalline precipitates are collected by filtration. The thus-obtained crystals (3.0 g, M.p. 198°-200° C.) are recrystallized from a mixture of dimethylformamide and ethanol (1:2). 2.6 g of 2-fluoromethyl-3-(2,4-dimethylphenyl)-6-nitro-4(3H)-quinazolinone are obtained as colorless prisms.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[C:9]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[NH:10][NH2:11].[BH3-]C#N.[Na+]>CO.C([O-])(O)=O.[Na+].CCOC(C)=O>[C:14]([O:13][C:9]([NH:10]/[N:11]=[CH:1]/[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NN
Reactant: C=CCCCCC=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C=CCCCC/C=N/NC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 61.6 %

Procedure:
To a solution of 46 (68 mg, 0.610 mmol) and tert-butyl carbazate (81 mg, 0.613 mmol) in MeOH (5 mL) was added ground molecular sieves (115 mg, 3A). The mixture was stirred for 3 h after which it was filtered through celite and evaporated. The residue was dissolved in dry THF (3 mL) and AcOH (3 mL). NaBH3CN (95 mg, 1.51 mmol) was added and the solution was stirred over night. The reaction mixture was diluted with saturated NaHCO3 solution (6 mL) and EtOAc (6 mL). The organic phase washed with brine, saturated NaHCO3, brine, dried over MgSO4 and evaporated. The cyanoborane adduct was hydrolyzed by treatment with MeOH (3 mL) and 2 M NaOH (1.9 mL). The mixture was stirred for 2 h and the MeOH was evaporated. H2O (5 mL) and DCM (5 mL) were added and the water phase was extracted three times with DCM. The combined organic phases were dried and evaporated. Purification by flash column chromatography (toluene/ethyl acetate 9:1 with 1% triethylamine and toluene/ethyl acetate 6:1 with 1% triethylamine) provided 47 (85 mg, 61%) as an oil.
Reaction SMILES: O[C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(Cl)(=O)C([Cl:24])=O>CN(C=O)C>[Cl:24][C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1C(O)=C(c2ccccc2)C(=O)N1c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C1C(Cl)=C(c2ccccc2)C(=O)N1c1ccccc1
Reaction time: 0.5 h

Procedure:
After dissolving compound 6a (2.00 g, 7.54 mmol) in MC (10 ml) and anhydrous DMF (10 ml), oxalyl chloride (1.90 g, 15.0 mmoL) was added thereto and the agitation for 30 minutes was carried out. After the identification of the reaction progress with TLC, the reaction was terminated. Then, three times extractions were carried out with EA and three times washings were carried out with brine. Water was removed by using Na2SO4, solvents were removed and then, the column chromatography was carried out with EA/HX ( 1/9). As the result, Compound 7a was obtained.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:22])[C@@H:4]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([F:13])[CH:7]=1.C1COCC1.[BH4-].[Na+]>C(O)C>[Cl:1][CH2:2][C@@H:3]([OH:22])[C@@H:4]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:5][C:6]1[CH:7]=[C:8]([F:13])[CH:9]=[C:10]([F:12])[CH:11]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)C(=O)CCl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CCl
Reaction time: 2 h

Procedure:
To a 250 mL 3-neck round bottom flask equipped with magnetic stir bar, nitrogen inlet and thermocouple, is added tert-butyl (1S)-3-chloro-1-(3,5-difluorobenzyl)-2-oxopropylcarbamate (III, Step 2, 4.4 g, 0.0132 moles, 1 equivalent) followed by THF (20 mL) and ethanol (30 mL) then cooled to −78°. Once the mixture is cooled, sodium borohydride (2.0 g, 0.0527 moles, 4 equivalents) is added as a solid portion wise over 30 min keeping the internal temperature below −70°. Once this addition is complete, the contents are stirred for 2 hr at −78° then warmed to 0° and stirred an additional 1 hr. The mixture is quenched by the addition of saturated potassium bisulfate (15 mL) and water (15 mL). This slurry is stirred for 30 min at 20–25° then concentrated under reduced pressure to half its volume. The mixture is then cooled to 0° and stirred for 30 min. After this time, the resultant solids are collected by filtration and washed with water (2×50 mL) then dried under reduced pressure at 50° to give crude product. A syn/anti ratio of 4–9:1 has been observed. The desired product is recrystallized from hexanes/ethanol (25/1) to give the title compound, NMR (DMSO-d6) δ 6.89–7.16, 5.61, 3.64–3.83, 3.19, 2.69 and 1.41; CMR (DMSO-d6) δ 163.67, 161.24, 155.44, 112.70, 101.55, 78.04, 72.99, 54.29, 48.24, 35.97 and 28.37.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.C([Mg]Br)(C)C.C[Si]([N:21]=[C:22]=[S:23])(C)C>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([C:22](=[S:23])[NH2:21])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: Cc1cnc2c(c1)CCCC2
Reactant: C[Si](C)(C)N=C=S
Agent: CC(C)[Mg]Br
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cnc2c(c1)CCCC2C(N)=S
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3-Methyl-5,6,7,8-tetrahydroquinoline (7.3 g, 0.05 mol.) was added to a solution of isopropylmagnesium bromide [prepared from isopropylbromide (6.15 g, 0.05 mol), magnesium (1.44 g, 0.06 mol) in ether (10 ml.)] and the solution heated at 60° to remove the ether by distillation. Toluene (5 ml.) was added and the reaction mixture was heated at 120° for 2 hours, cooled, diluted with toluene (30 ml) and this solution was added to a solution of trimethylsilyl isothiocyanate (7.85 g, 0.06 mol) in toluene (50 ml.) at 0° C. The reaction mixture was stirred at room temperature for 12 hours. The solution of 3-methyl-5,6,7,8-tetrahydroquinoline-8-(N-bromomagnesio-N-trimethylsilyl)thiocarboxamide was diluted with water (15 ml.) causing hydrolysis to 3-methyl-5,6,7,8-tetrahydroquinoline-8-(N-trimethylsilyl) thiocarboxamide and subsequent hydrolysis to the title compound and the pH adjusted to 2.0 with Conc. HCl. The aqueous solution was extracted with ether and the extracts discarded. The aqueous solution was adjusted to pH 9.0 with Na2CO3 and extracted with chloroform (3 × 50 ml.). The combined extracts were washed with brine, dried and the solvent removed to give a mixture of 3-methyl-5,6,7,8-tetrahydroquinoline and the title compound (5%) which was isolated by chromatography and identified by comparison with authentic material.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@@H:15]([CH2:16][CH2:17][C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[NH:14][C:13]1=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].O>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@@H:15]([CH2:16][CH2:17][C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[N:14]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:13]1=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(N[C@@H]1C(=O)N[C@@H]1CCc1ccco1)OCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)[C@@H](NC(=O)OCc2ccccc2)[C@H]1CCc1ccco1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.8 %

Procedure:
Triton B (1.94 mL, 4.3 mmols) was added dropwise to a stirred, cooled (-30° C.) solution of (3S,4R)-3-benzyloxycarbonylamino-4-[2-(2-furyl)ethyl]azetidin-2-one (1.35 g, 4.3 mmols) in N,N-dimethylformamide (15 mL). Stirring was continued for 0.25 hr. at -30° C. The mixture was allowed to warm to 0° C. during about 0.25 hr and then was recooled to -30° C. when a solution of t-butyl bromoacetate (0.764 mL, 4.73 mmols) in DMF (3 mL) was added dropwise. Stirring was continued at -30° C. for 0.25 hr., 1hr at 0° C. and then for 2 hr at ambient temperatures, when additional t-butyl bromoacetate (0.3 mL) was added. The mixture was stirred for an additional 1hr and was poured into H2O. The mixture was extracted twice with ethyl acetate. The extracts were washed twice with H 2 O, followed by saturated NaCl and then dried over MgSO4. The ethyl acetate was removed and the residue flash chromatographed on SiO2 (40 g) with methylene chloride-methanol (98:2) to afford 1.47 g (80% yield) of the title compound as a viscous oil which crystallized. Recrystallization from ethyl acetate-hexanes afforded colorless crystals, mp 82-84° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:62])([CH3:61])[C@H:42]([N:46]1[CH2:50][C:49](=[O:51])[N:48]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([CH3:59])[N:54]=2)[C:47]1=[O:60])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]([CH3:62])([CH3:61])[C@H:42]([N:46]1[CH2:50][C:49](=[O:51])[N:48]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([CH3:59])[N:54]=2)[C:47]1=[O:60])[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: Cc1cccc(CN2C(=O)CN([C@H](C(=O)O)C(C)(C)C)C2=O)n1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CC(=O)N(Cc2cccc(C)n2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
A solution containing the product from Example 2C (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with the product from Example 46E (0.020 g, 0.046 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.035 mL, 0.201 mmol), stirred at 25° C. for 1 hour, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane to give the title compound (0.020 g, 64% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.85 (s, 9 H), 0.88 (s, 9 H), 1.54 (m, 2 H), 2.41 (s, 3 H), 2.65 (m, 4 H), 3.08 (d, J=18.02 Hz, 1 H), 3.51 (s, 3 H), 3.72 (m, 1 H), 3.89 (m, 2 H), 4.17 (m, 2 H), 4.39 (s, 1 H), 4.67 (m, 3 H), 6.66 (d, J=9.93 Hz, 1 H), 7.06 (m, 7 H), 7.23 (d, J=8.46 Hz, 2 H), 7.31 (m, 1 H), 7.66 (t, J=7.54 Hz, 1 H), 7.87 (m, 6 H), 8.64 (d, J=4.41 Hz, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([C:18]([O:20]C(C)(C)C)=[O:19])[C:11]([O:13]C(C)(C)C)=[O:12])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([C:11]([OH:13])=[O:12])[C:18]([OH:20])=[O:19])[CH3:2]
Reactant: CCOC(=O)CCCCCC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCCCCC(C(=O)O)C(=O)O
Reaction time: 8 h
Yield: 95.3 %

Procedure:
To a solution of triester 61 (500 mg, 1.395 mmol) in CH2Cl2 (20 mL) was added TFA (2.0 mL) and the reaction mixture stirred overnight. Volatile components were evaporated under vacuum, and the residue repeatedly dissolved in CH2Cl2 and evaporated to remove all traces of TFA. A solid 62 (327 mg, 1.33 mmol) was obtained and used directly in the next step without further purification. 1H-NMR (400 MHz, DMSO-d6) δ 12.62 (br s, 2H), 4.03 (q, 2H), 3.16 (t, 1H), 2.25 (t, 2H), 1.67 (m, 2H), 1.49 (m, 2H), 1.25 (m, 4H), 1.16 (t, 3H).