Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:30]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C>[Br:30][CH2:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc([N+](=O)[O-])cc1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(CBr)c(F)c1
Temperature: 25 °C
Yield: 88.5 %

Procedure:
To a stirred solution of 2-fluoro-1-methyl-4-nitrobenzene (1 g, 6.446 mmol) in carbon tetrachloride was added benzoyl peroxide (497 mg, 1.2847 mmol) and N-bromosuccinimide (1.377 g, 7.736 mmol). The reaction mixture was refluxed for 18 h, then cooled to room temperature. The mixture was dissolved in ethyl acetate, then washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was removed in vacuo to obtain 1-(bromomethyl)-2-fluoro-4-nitrobenzene (1.335 g) as a crude.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[CH3:19])[NH2:15].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[F:11][C:12]1[CH:13]=[C:14]([NH:15][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:16]=[CH:17][C:18]=1[CH3:19]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Cc1ccc(N)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(Nc2ncccc2[N+](=O)[O-])cc1F
Temperature: 140 °C
Reaction time: 0.67 h

Procedure:
A mixture of 2-chloro-3-nitropyridine (4.76 g, 30.0 mmol), 3-fluoro-4-methylaniline (3.75 g, 30.0 mmol) and potassium carbonate (8.29 g, 60.0 mmol) in dimethyl sulfoxide (30 mL) was stirred at 140° C. for 40 minutes. The reaction mixture was then cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the product as a black solid. Yield: 6.78 g, 27.4 mmol, 91%. 1H NMR (400 MHz, CDCl3) δ 10.11 (br s, 1H), 8.54 (dd, J=8.3, 1.8 Hz, 1H), 8.51 (dd, J=4.6, 1.8 Hz, 1H), 7.59-7.64 (m, 1H), 7.15-7.21 (m, 2H), 6.86 (dd, J=8.4, 4.6 Hz, 1H), 2.28 (d, J=2.0 Hz, 3H).
Reaction SMILES: [P:1](Cl)(Cl)Cl.[CH2:5]([C:21]1[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:24]=[C:23]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:22]=1[OH:35])[C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[C:8]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:7]=1[OH:20].C(N(CC)CC)C.[OH:43][CH:44]1[CH2:49][C:48]([CH3:51])([CH3:50])[N:47]([OH:52])[C:46]([CH3:54])([CH3:53])[CH2:45]1>C1(C)C=CC=CC=1>[C:27]([C:25]1[CH:24]=[C:23]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:22]2[O:35][P:1]([O:43][CH:44]3[CH2:49][C:48]([CH3:50])([CH3:51])[N:47]([OH:52])[C:46]([CH3:54])([CH3:53])[CH2:45]3)[O:20][C:7]3[C:8]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:9][C:10]([C:12]([CH3:15])([CH3:13])[CH3:14])=[CH:11][C:6]=3[CH2:5][C:21]=2[CH:26]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: ClP(Cl)Cl
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: CC(C)(C)c1cc(Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OP(OC1CC(C)(C)N(O)C(C)(C)C1)Oc1c(cc(C(C)(C)C)cc1C(C)(C)C)C2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
In a flame-dried flask under nitrogen, 4.4 ml of phosphorous trichloride in 100 ml of dry toluene is treated with a solution of 21.27 grams of 2,2'-methylene-bis-(4,6-di-tert-butylphenol) and 13.9 ml of triethylamine in 80 ml of toluene at a temperature not exceeding 5° C. The reaction is stirred at ambient temperature for 12 hours and the suspension is cooled to 5° C. The mixture is treated with 8.61 grams of 4-hydroxy-1-oxyl-2,2,6,6-tetramethylpiperidine and 7 ml of triethylamine in 100 ml of dry toluene. After stirring the mixture at room temperature for 12 hours, the mixture is filtered and the filtrate concentrated under reduced pressure. The residue is crystallized from acetonitrile to give 17.0 grams of a pale red solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6](N)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[ClH:13].N([O-])=O.[Na+].O.O.[Cl-].[S:21](=[O:23])=[O:22]>C(O)(=O)C.O>[Cl:13][S:21]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:7]=1[C:8]([O:10][CH3:11])=[O:9])(=[O:23])=[O:22]
Reactant: Cl
Reactant: COC(=O)c1c(C)cccc1N
Reactant: O=S=O
Agent: O=N[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1c(C)cccc1S(=O)(=O)Cl
Temperature: 0 °C

Procedure:
The methyl 6-methylanthranilate so prepared (4.23 g, 0.026 mol) was dissolved in 25 ml of acetic acid and the solution cooled to 0° C. Concentrated hydrochloric acid (45 ml) was added to produce a tan slurry. A solution of 1.89 g (0.027 mol) of sodium nitrite in 8 ml water was added dropwise with stirring, the resulting orange solution was stirred at 0° C. for 1 hour and then added in 6 portions to a mixture of 2.18 g (0.013 mol) of cuptic chloride dihydrate and sulfur dioxide (6.3 g) in 33 ml of acetic acid and 6 ml of water at 0° C. The dark green solution was stirred at room temperature overnight, poured into 300 ml of ice-water, and the solid which separated was collected and dried by suction to provide 1.11 g of methyl 2-chlorosulfonyl-6-methylbenzoate which was immediately added to 100 ml of ice cold ammonium hydroxide and stirred at room temperature overnight. The solution was acidified to pH 1 with concentrated hydrochloric acid, and the resulting precipitate was collected and air-dried to provide 729 mg (12%) of 4-methylsaccharin, mp 224°-226° C.
Reaction SMILES: [F:1][C:2]([F:27])([C:23]([F:26])([F:25])[F:24])[C:3]([F:22])([F:21])[C:4]1([C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[O:8][CH:7]([CH2:9][OH:10])[CH2:6][O:5]1.[O-:28][C:29]#[N:30].[Na+].FC(F)(F)C(O)=O.O>C(Cl)Cl>[F:17][C:12]([F:18])([C:13]([F:16])([F:15])[F:14])[C:11]([F:19])([F:20])[C:4]1([C:3]([F:21])([F:22])[C:2]([F:1])([F:27])[C:23]([F:24])([F:25])[F:26])[O:8][CH:7]([CH2:9][O:10][C:29](=[O:28])[NH2:30])[CH2:6][O:5]1
Reactant: N#C[O-]
Reactant: OCC1COC(C(F)(F)C(F)(F)C(F)(F)F)(C(F)(F)C(F)(F)C(F)(F)F)O1
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)OCC1COC(C(F)(F)C(F)(F)C(F)(F)F)(C(F)(F)C(F)(F)C(F)(F)F)O1
Reaction time: 24 h

Procedure:
A solution of 44.0 grams (0.1 mol) of 2,2-bis(heptafluoropropyl)-4-hydroxymethyl-1,3-dioxolane prepared by the method disclosed in patent application Ser. No. 873,660 filed Nov. 3, 1969, in 250 ml methylene dichloride is treated with 13.0 grams of sodium cyanate while 22.8 grams trifluoroacetic acid is added dropwise. The reaction is carried out at 25°-35° C. for 24 hours. After the reaction is completed, a small amount of water is added to dissolve the salts and the methylene dichloride solution is separated and washed with water. Vacuum-stripping yields the desired product. The product, 2,2-bis(heptafluoropropyl)-4-carbamoyloxymethyl-1,3-dioxolane, is purified by crystallization from a mixture of benzene and hexane.
Reaction SMILES: O=[Si]=O.[C:4]([CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)#[N:5].[NH3:15].[H][H]>>[NH:5]1[CH:13]2[CH:8]([CH2:9][CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6][CH2:4]1.[NH2:5][CH2:4][CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[NH2:15]
Reactant: [H][H]
Reactant: N#CCCC1CCCCC1=O
Reactant: N
Agent: O=[Si]=O
Product: C1CCC2NCCCC2C1
Product: NCCCC1CCCCC1N

Procedure:
Through a tubular reactor (diameter 16 mm, packing height 50 cm, oil-heated double jacket), installed up-stream of the hydrogenation reactor and packed with 41.6 g (92 ml) of a zeolite type Y which had been extruded with Aerosil 200 (ratio Y-type zeolite to Aerosil 200 9:1, ratio SiO2 to Al2O3 6:1), there were passed upwardly, per hour, 36.7 g of 2-(2-cyanoethyl)-cyclohexanone (purity 96%, 0.233 mole) and 1.475 ml of liquid ammonia (885 g, 52.1 moles) at a pressure of 250 bar and a temperature of 70° C. Hydrogen was then added to the stream at a rate of 150 standard liters (6.7 moles) per hour, and the effluent from this in-line imination reactor was passed upwardly through the hydrogenation reactor at a pressure of 250 bar and a temperature of 120° C. The product mixture was depressurized to standard pressure and fed to the top of a column (length 46 cm, diameter 3 cm) held at 40° C. and packed with 5 mm wire mesh rings in which the ammonia was removed. After an on-stream time of 19.9 hours distillation of the product had yielded, besides 189.7 g of decahydroquinoline, 431.2 g of 2-(3-aminopropyl)-cyclohexylamine, this corresponding to a yield of 2-(3-aminopropyl)-cyclohexylamine of 59.6% of theory.
Reaction SMILES: Cl.[C:2]1([CH:8]([O:15][C:16]([C:18]2[N:23]3[C:24](=[O:27])[C@@H:25]([NH2:26])[C@H:22]3[S:21][CH2:20][C:19]=2[O:28][S:29]([CH3:32])(=[O:31])=[O:30])=[O:17])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([O:37][C:38]([NH:40][C:41]1[S:42][CH:43]=[C:44](/[C:46](=[N:50]/[O:51][C:52]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)/[C:47](O)=[O:48])[N:45]=1)=[O:39])([CH3:36])([CH3:35])[CH3:34].CN1CCOCC1.P(Cl)(Cl)(OC1C=CC=CC=1)=O>ClCCl.Cl.O>[C:2]1([CH:8]([O:15][C:16]([C:18]2[N:23]3[C:24](=[O:27])[C@@H:25]([NH:26][C:47](=[O:48])/[C:46](/[C:44]4[N:45]=[C:41]([NH:40][C:38]([O:37][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:39])[S:42][CH:43]=4)=[N:50]\[O:51][C:52]([C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)[C@H:22]3[S:21][CH2:20][C:19]=2[O:28][S:29]([CH3:32])(=[O:31])=[O:30])=[O:17])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O)cs1
Agent: Cl
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(OS(C)(=O)=O)CS[C@H]23)cs1
Reaction time: 0.07 h
Yield: 91.9 %

Procedure:
To a suspension of 7β-amino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochloride (37.27 g: 75 mMol.) and (Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetic acid (45.63 g; 86 mMol.) in dichloromethane (600 ml) is added at -30° C. N-methylmorpholine (27.2 ml: 0.25 Mol.) over 3 minutes. After 4 minutes, phenyl dichlorophosphate (12.3 ml: 82 mMol.) is added to the mixture. After stirring over 3 hours, the mixture is diluted with 10% hydrochloric acid (40 ml) and water and extracted with ethyl acetate. The extract is washed with water, aqueous sodium hydrogen carbonate, dilute hydrochloric acid, and water, dried over sodium sulfate, and concentrated under reduced pressure. The residue is dissolved in isopropanol (2 liters) by warming and cooled to give 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester (67 g). Colorless powder. Yield: 92%.
Reaction SMILES: [C:1]1(=O)[CH2:4][CH2:3][CH2:2]1.[NH:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[NH2:7]>CCCCCC>[C:1]1(=[N:7][NH:6][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C1CCC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NN=C1CCC1
Yield: 73.3 %

Procedure:
A reaction mixture of cyclobutanone (7.01 g, 100 mmol) and tert-butyl hydrazinecarboxylate (13.22 g, 100 mmol) in hexane (100 mL) was heated under reflux for 2 hours. After cooling down, a precipitate was formed and collected. It was then triturated with isopropanol (5 mL) and hexane (50 mL) to give a white solid as final product tert-butyl 2-cyclobutylidenehydrazinecarboxylate (13.5 g, 73.3 mmol, 73.3% yield). 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.50 (s, 9H) 1.96-2.08 (m, 2H) 2.75-2.84 (m, 2H) 2.93-3.05 (m, 2H). MS m/z 207 (M+Na+), Retention time: 1.420 min. (acid).
Reaction SMILES: [NH:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([N:21]1[CH2:26][C:25]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=2)([CH2:27][CH2:28][CH2:29]OS(C)(=O)=O)[CH2:24][O:23][C:22]1=[O:43])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[I-].[K+].[C:46](OC(=O)C)(=[O:48])[CH3:47].Cl>CN(C=O)C.CCOCC.O>[ClH:41].[CH2:14]([N:21]1[CH2:26][C:25]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=2)([CH2:27][CH2:28][CH2:29][N:11]2[CH2:12][CH2:13][CH:8]([N:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:46](=[O:48])[CH3:47])[CH2:9][CH2:10]2)[CH2:24][O:23][C:22]1=[O:43])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CS(=O)(=O)OCCCC1(c2ccc(Cl)c(Cl)c2)COC(=O)N(Cc2ccccc2)C1
Reactant: c1ccc(NC2CCNCC2)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CC(=O)N(c1ccccc1)C1CCN(CCCC2(c3ccc(Cl)c(Cl)c3)COC(=O)N(Cc3ccccc3)C2)CC1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A mixture of 1.76 g of 4-anilinopiperidine, 2 g of the compound obtained in step C of EXAMPLE 8 and 0.75 g of potassium iodide in 10 ml of DMF is heated at 50° C. for 1 hour 30 minutes. The reaction mixture is poured into water and extracted with AcOEt, the organic phase is washed three times with water and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using DCM and then a DCM/MeOH mixture (96/4; v/v) as the eluent. The product obtained is taken up with 10 ml of acetic anhydride and the reaction mixture is stirred for 48 hours at RT. It is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed twice with 20% aqueous ammonia solution, twice with water and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The product obtained is taken up with a saturated solution of gaseous HCl in ether and the solvent is evaporated off under vacuum to give 1.4 g of the expected product after crystallization from AcOEt. M.p.=195° C.
Reaction SMILES: C([O:4][CH2:5][C@@H:6]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([N:19]2[CH:27]=[N:26][C:25]3[C:20]2=[N:21][C:22]([I:29])=[N:23][C:24]=3Cl)[O:7]1)(=O)C.[NH3:30]>>[NH2:30][C:24]1[N:23]=[C:22]([I:29])[N:21]=[C:20]2[C:25]=1[N:26]=[CH:27][N:19]2[C@H:8]1[C@H:9]([OH:15])[C@H:10]([OH:11])[C@@H:6]([CH2:5][OH:4])[O:7]1
Reactant: N
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Product: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 6 h
Yield: 80 %

Procedure:
To a flask containing 6.0 g (11.1 mmol) [(2R,3R,4R,5R)-3,4-diacetyloxy-5-(6-chloro-2-iodopurin-9-yl)oxolan-2-yl]methyl acetate (6.4) was added 100 ml of liquid NH3 at −78° C. and the solution was allowed to stir for 6 hours. After which time it was allowed to come to room temperature overnight with concurrent evaporation of the NH3 to yield a brown oil. The product was crystallized from hot isopropanol to provide 6.5 (80%), m.p. 143-145° C., r.f.=0.6 in 20% MeOH/CHCl3. 1H NMR (300 MHz, DMSO-d6) 8.24 (s, 1H), 7.68 (s, 2H), 5.75 (d, J=6.16, 1H), 5.42 (d, J=5.40 Hz, 1H), 5.16 (d, J=4.62 Hz, 1H), 4.99 (t, J=5.39 Hz, 1H), 4.67 (d, J=4.81 Hz, 1H), 4.06 (d, J=3.37 Hz, 1H), 3.89 (m, 1H), 3.54 (m, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.CS(C)=O.C(N(CC)CC)C>C(Cl)Cl>[O:1]=[C:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC(=O)C1
Reaction time: 3 h
Yield: 51.6 %

Procedure:
To a mixture of tert-butyl 3-hydroxyazetidine-1-carboxylate (10.0 g, 57.7 mmol), dimethyl sulfoxide (24.0 mL, 338 mmol), triethylamine (40 mL, 300 mmol) and methylene chloride (2.0 mL) was added sulfur trioxide-pyridine complex (40 g, 200 mmol) portionwise at 0° C. The mixture was stirred for 3 hours, quenched with brine, and extracted with methylene chloride. The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (0-6% ethyl acetate (EtOAc) in hexanes) to give tert-butyl 3-oxoazetidine-1-carboxylate (5.1 g, 52% yield).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[O:11]=[C:12]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC(=O)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
To a −78° C. solution of 2M oxalyl chloride (31.8 mL, 63.5 mmol) in 200 mL DCM was added DMSO (9.01 mL, 127 mmol), followed by the slow addition by addition funnel of a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (10.0 g, 57.7 mmol) in 200 mL DCM. The cloudy reaction mixture was stirred at −78° C. for 15 minutes, then a solution triethylamine (32.2 mL, 231 mmol) in 40 mL DCM was added slowly by addition funnel. The reaction mixture was stirred another 15 minutes, the bath was removed, and the reaction was allowed to warm to ambient temperature and stirred for 15 hours. Water and brine were added, and the mixture was extracted with DCM. The combined extracts were dried (Na2SO4), filtered and concentrated. The crude was purified on silica gel (3-20% ethyl acetate in hexanes gradient) to give the desired product (9.0 g, 91.1% yield) as a white solid.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[O:5]=[C:6]([CH:8]=[C:9]([CH3:11])[CH3:10])[CH3:7].[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:10][C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH2:8][C:6](=[O:5])[CH3:7]
Reactant: CC(=O)C=C(C)C
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)CC(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a slurry of AlCl3 (40.0 g, 0.3 mole) in benzene (90 mL) maintained at 10° C. under argon was added dropwise mesityl oxide (0.2 mole, 19.63 g). Upon completion of the addition the reaction was stirred at room temperature for 1.5 hours. The reaction mixture was poured onto ice/10% HCl (350 g). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organics were washed with distilled H2O, saturated NaHCO3 solution, saturated NaCl solution and dried over Na2SO4. The solvent was recovered under vacuum and the crude product (31.6 g) was vacuum distilled (b.p.=107° C. @ 3.0 mmHg) to obtain 24.5 g (69%) of the title A compound as a colorless oil. MS: (M+H)+ @ 177.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:29])([CH3:28])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[NH:18][C:17]1=[O:27])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[C:31]([O:35][C:36]([NH:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[C:46]1[CH:51]=[CH:50][C:49]([CH2:52]O)=[CH:48][CH:47]=1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:29])([CH3:28])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:52][C:49]2[CH:48]=[CH:47][C:46]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[CH2:39][NH:38][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])=[CH:51][CH:50]=2)[C:17]1=[O:27])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CO)cc1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2NC1=O
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)C(C)(C)NC(=O)OCc3ccccc3)CCc3ccccc32)cc1
Reaction time: 0.25 h
Yield: 83.9 %

Procedure:
To a solution of 819 mg (2.07 mmol) of 2-benzyloxycarbonylamino-2-methyl- N-[2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl]propanamide (Step A) in 7.0 mL of dry dimethylformamide under nitrogen at 0° C. was added 83 mg (2.1 mmol) of 60% sodium hydrideil dispersion. After stirring for 15 minutes, a solution of 810 mg (2.1 mmol) of 2'-[(t-butoxycarbonylamino)methyl]-1,1'-biphenyl-4-methanol, methanesulfonate ester (Step F) in 2.0 mL of dimethylformamide was added by cannula. The flask which originally contained the methanesulfonate ester was rinsed with 1.0 mL of dimethylformamide which was added to the reaction mixture. After stirring at 0° C. for 15 minutes, the reaction mixture was diluted with 400 mL of ethyl acetate and 50% saturated ammonium chloride. The mixture was transferred to a separatory funnel and the aqueous layer was separated. The organic layer was washed with 100 mL of saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate, filtered and the solvent removed under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (55:45) to afford 1.2 g (84%) of the product as a white foam. 1H NMR (200 MHz, CDCl3): δ 1.38 (s, 9H), 1.48 (s, 3H), 1.52 (s, 3H), 1.78 (s, 1H), 2.35-2.70 (m, 3H), 4.18 (d, 6 Hz, 2H), 4.38-4.62 (m, 2H), 4.82 (d, 16 Hz, 1H), 5.05 (s, 2H), 5.25 (d, 16 Hz, 1H), 5.32 (s, 1H), 7.08 (d, 6 Hz, 1H), 7.12-7.43 (m, 18H). FAB-MS: calculated for C41 H46N4O6 690; found 691(M+H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](Cl)=[O:15])=[CH:9][CH:8]=1.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:14](=[O:15])[CH2:13][C:10]2[CH:11]=[CH:12][C:7]([S:6][CH3:5])=[CH:8][CH:9]=2)=[CH:20][CH:19]=1
Reactant: CSc1ccc(CC(=O)Cl)cc1
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CSc1ccc(CC(=O)c2ccc(F)cc2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
A mixture of fluorobenzene (181 mL) and aluminum chloride (18.5 g, 139 mmol) was treated with a solution of 4-methylthiophenyl acetic chloride (21.9 g, 120 mmol) in 37 mL of fluorobenzene. When the addition was completed, the mixture was stirred at 50° C. for 3 h. The reaction mixture was then poured into ice water and stirred for 1 h. It was extracted with chloroform and washed with 5% aqueous sodium bicarbonate solution and with brine. The organic layer was separated and dried over anhydrous sodium sulfate. The drying agent was filtered and the filtrate concentrated in vacuum to give 15.6 g (55%) of the desired compound as a yellow solid.
Reaction SMILES: C([BH3-])#N.[Na+].[Br:5][C:6]1[CH:7]=[C:8]([CH:11]=O)[S:9][CH:10]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(=O)(O)[O-].[Na+]>C(O)C.C(O)(=O)C>[Br:5][C:6]1[CH:7]=[C:8]([CH2:11][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[S:9][CH:10]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: Brc1csc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
Sodium cyanoborohydride (2 g) was added portionwise to a stirred mixture of 4-bromo-2-thiophenecarbaldehyde (4.78 g), morpholine (2.1 g), glacial acetic acid (1.8 g) and ethanol (125 ml). The mixture was stirred at ambient temperature for 1 hour. The mixture was poured into a saturated aqueous sodium bicarbonate solution and extracted with methylene chloride. The organic phase was washed with brine and evaporated. The resultant oil was partitioned between a dilute (10%) aqueous hydrochloric acid solution and methylene chloride. The aqueous phase was basified by the addition of a saturated aqueous sodium bicarbonate solution and extracted with methylene chloride. The organic extract was dried (MgSO4) and evaporated to give 4-bromo-2-morpholinomethylthiophene (3.2 g); NMR Spectrum: 2.4 (t, 4H), 3.55 (t, 4H), 3.65 (s, 2H), 6.95 (d, 1H), 7.5 (d, 1H).