Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[Se:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[Li][CH2:16]CCC.CI.[Cl-].[NH4+].N>C(OCC)C>[CH3:16][C:12]1[Se:11][C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=2)=[CH:14][CH:13]=1
Reactant: CCCc1ccc(-c2ccc[se]2)cc1
Reactant: [Li]CCCC
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: CCOCC
Product: CCCc1ccc(-c2ccc(C)[se]2)cc1
Temperature: -70 °C
Reaction time: 3 h

Procedure:
3.0 g (12.0 mmol) of 2-(4-propylphenyl)selenophene are initially introduced in 30 ml of diethyl ether, and 9.4 ml (15.0 mmol, 15% soln. in hexane) of n-BuLi are metered in rapidly. The mixture is heated under reflux for 30 min and subsequently cooled to −70° C. 3.0 ml (48.2 mol) of methyl iodide are added in one portion, and the mixture is warmed to RT and stirred for 3 h. Sat. ammonium chloride soln. and conc. ammonia soln. are added, and the batch is stirred vigorously for a few minutes. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with 2 N hydrochloric acid and sat. sodium chloride soln. and dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane:EtOAc=20:1→10:1→5:1). The further purification is carried out by flash chromatography (SiO2 RP-18, ACN:water=9:1); 2-methyl-5-(4-propylphenyl)selenophene is obtained as a colourless solid (m.p. 31° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].[C:12]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C([BH3-])#N.[Na+].[OH-].[Na+]>C1COCC1.C(OCC)(=O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:15]([O:14][C:12]([N:19]1[CH2:24][CH2:23][CH:22]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]([F:9])([F:10])[F:11])[CH2:21][CH2:20]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: Nc1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.2 %

Procedure:
Titanium isopropoxide (2.5 mL, 8.46 mmol) was added to a solution of 2-aminobenzotrifluoride (0.6 mL, 4.82 mmol) and 1-Boc-4-piperidone (1.05 g, 5.26 mmol)) in THF (3 mL), the resulting mixture was stirred at ambient temperature for 4 hours, then sodium cyanoborohydride (0.800 g, 12.73 mmol) was added. The stirring was continued overnight. Aqueous sodium hydroxide (2.0 mL, 1.0 M) was added and the mixture was stirred for another 15 minutes. The reaction mixture was diluted with ethyl acetate (250 mL), washed with water, and brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography to afford 4-(2-trifluoromethylphenylamino)piperidine-1-carboxylic acid tert-butyl ester (1.58 g, 95%). MS (ES+) m/z 345.1 (M+1).
Reaction SMILES: [C:1]1([C:6](Cl)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]([CH3:23])[CH2:18][C:19](=[O:22])[NH:20][N:21]=2)=[CH:12][CH:11]=1>C1C=CC=CC=1>[C:1]1([C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]([CH3:23])[CH2:18][C:19](=[O:22])[NH:20][N:21]=3)=[CH:12][CH:11]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1cccs1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Solvent: c1ccccc1
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)c2cccs2)cc1
Yield: 51.9 %

Procedure:
A mixture of 1.1 g of 2-thenoyl chloride, 1.0 g of 6-(p-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone and 10 ml of benzene was treated in the same manner as described in Example 1 to effect reaction whereby 800 mg of the title compound was obtained. M.P. 256°-258° C.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([CH:16]3[CH2:21][C:20]4[C:22]([NH2:28])=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:19]=4[O:18][CH2:17]3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.Cl[CH2:31][CH2:32][N:33]([CH2:35][CH2:36]Cl)[CH3:34].C(=O)([O-])O.[Na+].N>C(O)CCC>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([CH:16]3[CH2:21][C:20]4[C:22]([N:28]5[CH2:36][CH2:35][N:33]([CH3:34])[CH2:32][CH2:31]5)=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:19]=4[O:18][CH2:17]3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COc1ccc(N)c2c1OCC(C(=O)Nc1ccc(N3CCOCC3)cc1)C2
Reactant: CN(CCCl)CCCl
Agent: Cl
Agent: N
Agent: O=C([O-])O
Solvent: CCCCO
Product: COc1ccc(N2CCN(C)CC2)c2c1OCC(C(=O)Nc1ccc(N3CCOCC3)cc1)C2
Yield: 52.1 %

Procedure:
A solution of N-[4-(4-morpholinyl)phenyl]-5-amino-8-methoxy-3,4-dihydro-2H-1-benzopyran-3-carboxamide (270 mg, 0.7 mmol), bis (2-chloroethyl)-methylamine hydrochloride (288 mg, 1.5 mmol) and sodium hydrogen carbonate (126 mg, 1.5 mmol) in n-butanol (10 mL) was stirred at 90° C. for 2.5 h. 2 M ammonia (10 mL) was added at 50 ° C., the mixture was cooled and the phases were separated. The organic phase evaporated in vacuo and the residue was purified by column chromatography on silica gel using ethyl acetate/triethyl amine (100:8) as the eluent affording 170 mg (50% yield) of the title compound as white crystals: mp 202-204° C.; EIMS (70 eV) m/z (relative intensity) 466 (100 M+).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21](=[O:32])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24](CC(=O)C)[CH:23]=3)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[OH:35][CH2:36][CH2:37][CH2:38][C:39]#[C:40]C1C=CC(C(O)=O)=CC=1>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21](=[O:32])[C:22]3[CH:23]=[CH:24][C:25]([C:40]#[C:39][CH2:38][CH2:37][CH2:36][OH:35])=[CH:26][CH:27]=3)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CC(C)=O)c1
Reactant: O=C(O)c1ccc(C#CCCCO)cc1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(C#CCCCO)cc1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 29, using Intermediate 21 in place of 3-(2-oxopropyl)benzoic acid. ES/MS calcd. for C28H36N5O3+ 490.3. found m/z=490.4 (M+H)+.
Reaction SMILES: [CH:1]1[C:14]2[N:13]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:26]([O:28]C)=[O:27])=[CH:20][CH:19]=3)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[CH:11]1[C:12]2[N:13]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([O:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:26]([OH:28])=[O:27])=[CH:20][CH:19]=3)[C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[O:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)C(Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 68.4 %

Procedure:
To a solution of (±) methyl 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxypropanoate (300 mg, 0.6 mmol) obtained in example 34 in methanol (15 mL) was added 10% NaOH solution (5 mL). The reaction was stirred at room temperature for 10 h. Methanol was removed and the residue was acidified with 2N HCl, extracted with ethylacetated (3×10 mL). The organic layer was washed with water, brine, dried and concentrated The residue was chromatographed using 30% ethylacetate: pet. ether to afford a thick liquid which was triturated with per.ether to yield the title compound as a solid (192 mg, 66%). mp: 119-120° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:27])[C:19](=[N:25][OH:26])[C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C:15](=[O:28])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=[O:3])[CH3:2].[Na+].[Cl:30][CH2:31][CH2:32][N:33]=[C:34]=[O:35].Cl.P([O-])([O-])([O-])=O.C([O-])(=O)C>CN(C)C=O.C(N(CC)CC)C>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:27])[C:19](=[N:25][O:26][C:34](=[O:35])[NH:33][CH2:32][CH2:31][Cl:30])[C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C:15](=[O:28])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)C(=NO)c3cccs3)[C@H]2SC1
Reactant: O=C=NCCCl
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NOC(=O)NCCCl)c3cccs3)[C@H]2SC1

Procedure:
A solution of sodium 3-acetoxymethyl-7β-[2-hydroxyimino-2-(thien-2-yl)acetamido]ceph-3-em-4-carboxylate (syn-isomer; 0.89 g) in dimethylformamide (11 ml.) containing triethylamine (0.22 g) was treated with 2-chloroethylisocyanate (0.25 g). The solution was allowed to stand at room temperature for thirty minutes, then at 5° for a further hour. It was poured into cold (5°) 2N hydrochloric acid, extracted three times with ethyl acetate, and the combined extracts washed with 2N-hydrochloric acid then water then extracted three times with a cold (5°) saturated aqueous sodium bicarbonate solution. The combined aqueous extracts were washed with ethyl acetate, acidified (2N-hydrochloric acid) and apidly extracted with ethyl acetate. The combined extracts were dried, concentrated to ca. 5 ml., and the concentrate added dropwise to petroleum (b.p. 40°-60° 250 ml.) The precipitated solid was filtered and dried to give the title acid (0.8 g; 76%), [α]D +33° (c 0.7 DMSO) λmax. (pH 6 phosphate buffer) 264 nm. (ε 17,200), νmax. (Nujol), 1786 (β-lactam), 1734 (acetate), 1682 and 1508 cm.-1 (CONH), τ (DMSO-d6) values include 0.12 (doublet J 9 Hz; NH), 2.12, 2.56, 2.74 (three guartets; thienyl protons), 7.97 (s; OCOCH3).
Reaction SMILES: S(O[CH2:12][CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:14]1)(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].[C:29]1([N:35]2[C:39]3([CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)[C:38](=[O:45])[NH:37][CH2:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CN(C)C=O>>[O:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:21][CH2:22][CH:13]1[CH2:12][N:42]1[CH2:41][CH2:40][C:39]2([N:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:36][NH:37][C:38]2=[O:45])[CH2:44][CH2:43]1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccccc3O2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1NCN(c2ccccc2)C12CCN(CC1CCc3ccccc3O1)CC2
Yield: 54.6 %

Procedure:
The mixture from 31.8 g (0.1 mol) of 2-tosyloxymethyl-chroman, 7.1 g (0.07 mol) of anhydrous sodium carbonate and 23.1 g (0.1 mol) of 1-phenyl-1,3,8-triazaspiro[4.5]-decan-4-one in 240 mol of anhydrous dimethylformamide (DMF) is stirred at 110° C. for 6 h and then poured onto ice (500 g). After extracting with ethyl acetate (5×100 ml), washing the organic extracts with water, drying over anhydrous sodium sulphate and evaporating the organic phase in a water jet vacuum, 65.7 g of solvent-containing crystalline crude product are obtained which, recrystallised twice from ethyl acetate, yields 20.6 g of the title compound of m.p. 192-193.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[C:10]([CH2:13][CH2:14][CH2:15]OS(C)(=O)=O)[NH:11][CH:12]=2)=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)=[C:10]([CH2:13][CH2:14][CH2:15][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[NH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)OCCCc1[nH]cc(-c2ccc(F)cc2)c1-c1ccncc1
Solvent: ClCCl
Product: Fc1ccc(-c2c[nH]c(CCCN3CCOCC3)c2-c2ccncc2)cc1

Procedure:
4-(4-fluorophenyl)-2-(3-mesyloxypropyl)-3-(4-pyridyl)pyrrole (0.25 g, 0.0007 mol) was refluxed for 16 hours in CH2Cl2 (50 mL) and morpholine (0.25 mL). The solution was cooled and diluted with CH2Cl2 (˜100 mL), then washed with H2O (3×50 mL). The organics were dried over Na2SO4 and evaporated in vacuo to give an oil. This oil was purified on SiO2 eluting with 10% MeOH in CH2Cl2 to give 4-(4-fluorophenyl)-2-(3-morpholinopropyl)-3-(4-pyridyl)pyrrole isolated as a solid (0.088 g, 36% yield). 1HNMR (DMSO-d6) δ 11.12 (1H, s, NH), 8.42 (2H, d), 7.05 (6H, m), 6.95 (1H, d), 3.55 (4H, t), 2.62 (2H, t), 2.29 (6H, m), 1.71 (2H, m).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:15](=[O:16])[C:14]([OH:17])=[C:13]2[C:8]([CH2:9][CH2:10][N:11]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=3)[C:12]2=[O:18])=[C:7]1[C:28]([O:30][CH3:31])=[O:29].[CH3:32][NH2:33]>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[F:26])[CH2:19][N:11]1[CH2:10][CH2:9][C:8]2[C:13](=[C:14]([OH:17])[C:15](=[O:16])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:33][CH3:32])[C:7]=2[C:28]([O:30][CH3:31])=[O:29])[C:12]1=[O:18]
Reactant: CN
Reactant: COC(=O)c1c2c(c(O)c(=O)n1CCCCCl)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1CCOC1
Product: CNCCCCn1c(C(=O)OC)c2c(c(O)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Temperature: 60 °C

Procedure:
A mixture of methyl 2-(4-chlorobutyl)-6-(3-chloro-4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate (0.10 g, 0.21 mmol), methylamine in tetrahydrofuran (1 mL, 2M), and tetra-n-butylammonium iodide in tetrahydrofuran (5 mL) was heated at 60° C. for 3 days. The reaction mixture was concentrated under vacuum. The residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the title compound. This was used in the following step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[N:9])[N:3]=1.[CH3:10][S-:11].[Na+]>O1CCCC1>[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([S:11][CH3:10])[N:3]=1)#[N:9]
Reactant: C[S-]
Reactant: N#Cc1cccc(Cl)n1
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1cccc(C#N)n1
Temperature: 90 °C
Reaction time: 18 h
Yield: 101.2 %

Procedure:
A mixture of 2-chloro-6-cyanopyridine (0.70 g, 5.0 mmol), sodium thiomethoxide (0.39 g, 5.5 mmol) and tetrahydrofuran (50 ml) was stirred at 90° C. for 18 hrs. The reaction mixture was concentrated under reduced pressure, combined with water and extracted with ethyl acetate. The extract was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure to give the titled compound as an oil (0.76 g, 98%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].[F:7][C:8]1[C:17]2[NH:16][CH:15]=[C:14]3[C:18](=[O:30])[N:19]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=4)[C:24](Cl)=[O:25])[N:20]=[C:13]3[C:12]=2[CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.Cl>O1CCCC1>[F:7][C:8]1[C:17]2[NH:16][CH:15]=[C:14]3[C:18](=[O:30])[N:19]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=4)[C:24]([NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[O:25])[N:20]=[C:13]3[C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: COCCCN
Reactant: O=C(Cl)c1cccc(-n2nc3c4cccc(F)c4[nH]cc-3c2=O)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCCNC(=O)c1cccc(-n2nc3c4cccc(F)c4[nH]cc-3c2=O)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69 %

Procedure:
3-Methoxypropylamine (0.026 g, 0.29 mmol) was added to a stirred solution of 3-(6-fluoro-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoyl chloride (intermediate 4) (26 mg 0.29 mmol) in tetrahydrofuran (2 ml) and the mixture stirred at room temperature for 15 min. Triethylamine (0.2 ml, 1.4 mmol) was then added and the resulting mixture stirred overnight. 1M Hydrochloric acid (3-4 ml) was added dropwise to precipitate a yellow solid which was filtered and dried under suction to give the amide (79 mg, 0.20 mmol) as a yellow solid, LCMS m/z 395.25 [M+H]+ @ RT 1.04 min; δH(400 MHz, (CD3)2SO) 8.59 (1H, m), 8.57 (1H, s), 8.39 (1H, app d J 9.3 Hz), 8.08 (1H, app d J 7.3 Hz), 7.66-7.53 (5H, m), 3.37-3.33 (4H, m), 3.27 (3H, s), 1.83-1.77 (2H, m).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[OH:26].C([O-])(=O)C.[Na+]>O1CCOCC1.O>[N+:11]([C:8]1[CH:9]=[CH:10][C:2]2[O:26][C:20]3[CH:21]=[C:22]([CH3:25])[CH:23]=[CH:24][C:19]=3[NH:18][C:4](=[O:6])[C:3]=2[CH:7]=1)([O-:13])=[O:12]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: Cc1ccc(N)c(O)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: Cc1ccc2c(c1)Oc1ccc([N+](=O)[O-])cc1C(=O)N2
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 41.8 %

Procedure:
A mixture of 20.2 g (0.1 mole) of 2-chloro-5-nitrobenzoic acid and 8.4 ml thionyl chloride in 100 ml of dioxane was refluxed for 90 minutes. The solution was cooled to 50° C. and added to a suspension of 12.3 g (0.1 mole) of 2-amino-5-methyl phenol in 50 ml of water. After about half of the acid chloride was added, 8.2 g sodium acetate was added, then the rest of the acid chloride was added dropwise. The reaction mixture was stirred for 45 minutes at 50° C. Ice water was added to the mixture with stirring, and the resulting precipitate was filtered and washed with water. The filter cake was dissolved in 150 ml of water containing 4 g of NaOH and stirred for 1 hour at 85°-95° C., then cooled to room temperature. The cooled solution was acidified with HCl, filtered, and washed with water. The precipitate was dried to yield 11.3 g (42%) of 2-nitro-7-methyldibenz[b,f][1,4]oxazepin-11(10H)-one, mp 264°-266° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([NH2:10])=[N:7][C:6]=2[CH:11]=1.FC(F)(F)S(O[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=1)(=O)=O.[F-].[K+].C(Cl)Cl>CN(C=O)C>[NH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([C:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=3)=[CH:11][C:6]=2[N:7]=1
Reactant: Nc1nc2cc(Br)ccc2o1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3oc(N)nc3c2)CC1
Temperature: 90 °C
Reaction time: 12 h
Yield: 44.7 %

Procedure:
5-Bromobenzo[d]oxazol-2-amine (824 mg, 3.9 mmol) and tert-butyl 4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (1.8 g, 5.8 mmol), Potassium fluoride (674 mg, 11.61 mmol) were dissolved in DMF under N2 atmosphere. This mixture was purged with N2 for 30 mins Pd(dppf)2Cl2.CH2Cl2 (252 mg, 0.3 mmol) was added to the above mixture and again purged with N2 for 30 mins. The reaction mixture was stirred at 90° C. for 12 h. Work up (EtOAc/H2O) followed by column purification on combiflash using a gradient mixture of EtOAc and Petether (1:1) as eluent afforded the titled compound (550 mg) as an off-white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.38-7.36 (m, 2H), 7.26-7.22 (m, 2H), 7.02 (d, J 7.9, 1H), 6.05 (s, 1H), 4.01-3.90 (m, 2H), 3.49-3.55 (m, 2H), 2.50-2.40 (m, 2H), 1.50 (s, 9H).
Reaction SMILES: [CH:1]1([C:11]([O:13]C)=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH3:10])=[O:8].[OH-].[Na+]>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[CH3:10][O:9][C:7]([C@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C@H:1]1[C:11]([OH:13])=[O:12])=[O:8]
Reactant: COC(=O)C1CCCCC1C(=O)OC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: COC(=O)[C@H]1CCCC[C@H]1C(=O)O
Temperature: 30 °C
Yield: 88.6 %

Procedure:
Into a 2-L jacketed vessel set at 30° C. was placed dimethyl cyclohexane-1,2-dicarboxylate (2, 84.6 g, 0.42 mol) and 900 mL of 0.1M potassium phosphate buffer, pH 8. The mixture was continuously stirred at 30° C. and PLE (600 mg, 10200 units) was added. The mixture was stirred for 91 hours and the pH was maintained at 8 by addition of 5M NaOH solution. An aliquot from the mixture was analyzed by GC to confirm that residual starting material was less than 5%. The reaction mixture was then filtered through a Celite™ bed and the filtrate was extracted with 250 mL MTBE to remove residual starting material. The aqueous phase was then acidified to pH 4 with concentrated HCl and extracted with 3×500 mL MTBE. The combined extracts were dried over magnesium sulfate and solvent was removed under reduced pressure, to yield 69.28 g (88% yield) of (1R,2S)-2-(methoxycarbonyl)cyclohexane carboxylic acid (4) as a colorless oil with e.e.=79%.
Reaction SMILES: CC(O)=O.[C:5]1([CH2:11][CH2:12][C:13]([NH:15][C@H:16]([C:24]([NH:26][C@H:27]2[C@@H:30]([O:31][CH:32]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:33][O:34][Si](C(C)(C)C)(C)C)[NH:29][C:28]2=[O:48])=[O:25])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:14])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CO.C(OCC)(=O)C>C1COCC1>[C:5]1([CH2:11][CH2:12][C:13]([NH:15][C@H:16]([C:24]([NH:26][C@H:27]2[C@@H:30]([O:31][CH:32]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:33][OH:34])[NH:29][C:28]2=[O:48])=[O:25])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:14])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(O[C@H]1NC(=O)[C@H]1NC(=O)[C@H](Cc1ccccc1)NC(=O)CCc1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CCc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)N[C@@H]1C(=O)N[C@@H]1OC(CO)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
A THF solution of 1 N BU4NF (0.84 ml, 0.84 mmole) containing AcOH (35 mg, 0.56 mmole) was added to a solution of (3S,4R)-3-{N-(3-phenylpropionoyl)-L-phenylalanyl}amino-4-{2-(tert-butyldimethylsilyl)oxy-1-phenylethoxy}-azetidin-2-one (430 mg, 0.70 mmole) in THF (5 ml) at 0-5° C. The mixture was stirred at room temperature for 3 hrs, then poured into a silica gel column. The column was eluented with methanol-ethyl acetate (5:95) and 260 mg of (3S,4R)-3-{N-(3-phenylpropionoyl)-L-phenylalanyl}amino-4-(2-hydroxy-1-phenylethoxy)-azetidin-2-one was obtained (74% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.Br[CH:18]=[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27])[CH3:20].N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:18]=[C:19](\[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])/[CH3:20])[C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(=CBr)c1ccccc1F
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C/n1c2c(c3cc(Cl)ccc31)CCN(C)CC2)c1ccccc1F
Temperature: 85 °C

Procedure:
9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (234 mg, 1 mmol), 1-(1-bromoprop-1-en-2-yl)-2-fluorobenzene (260 mg, 1.2 mmol), L-proline (0.2 mmol), CuI (19 mg, 0.1 mmol) and potassium phosphate tribasic (424 mg, 2 mmol) in DMF was stirred at RT and purged with nitrogen. The reaction mixture was heated at 85° C. overnight. An additional 1 eq. of reagents was added and the mixture heated for an additional 24 h. The DMF was evaporated and the residue was poured into water. The precipitate obtained was filtered and purified by silica gel chromatography (100-200-mesh) using 0-5% MeOH:DCM as eluant followed by reverse phase HPLC to separate the isomers. 1HNMR (CD3OD, TFA salt) δ (ppm): 7.36 (d, 1H), 7.18 (m, 1H), 7.11 (s, 1H), 6.98 (dd, 1H), 6.92 (m, 3H), 6.86 (s, 1H), 3.60 (m, 2H), 3.10 (m, 3H), 3.0 (s, 3H), 2.90 (m, 3H), 2.30 (s, 3H).