Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH3:19][O:20][C@:21]1([C:39]2[CH:40]=[C:41]([C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([CH:51]=[CH2:52])[CH:46]=3)[CH:42]=[CH:43][CH:44]=2)[CH2:25][N:24](C(OCC[Si](C)(C)C)=O)[C@H:23]([C:35]([O:37][CH3:38])=[O:36])[CH2:22]1>C1COCC1.CCOC(C)=O>[CH3:19][O:20][C@:21]1([C:39]2[CH:40]=[C:41]([C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([CH:51]=[CH2:52])[CH:46]=3)[CH:42]=[CH:43][CH:44]=2)[CH2:25][NH:24][C@H:23]([C:35]([O:37][CH3:38])=[O:36])[CH2:22]1
Reactant: C=Cc1cccc(-c2cccc([C@]3(OC)C[C@@H](C(=O)OC)N(C(=O)OCC[Si](C)(C)C)C3)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=Cc1cccc(-c2cccc([C@@]3(OC)CN[C@H](C(=O)OC)C3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.6 %

Procedure:
TBAF (1.0M in THF, 19 mL, 19 mmol) was added to a solution of (2S,4R)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-methoxy-4-(3′-vinylbiphenyl-3-yl)pyrrolidine-1,2-dicarboxylate (2.3 g, 4.78 mmol) in THF (30 mL) and stirred at r.t. overnight. The reaction was diluted with EtOAc and washed with water and then brine. The organic layer was collected, dried over MgSO4, filtered and evaporated to give (2S,4R)-methyl 4-methoxy-4-(3′-vinylbiphenyl-3-yl)pyrrolidine-2-carboxylate (1.75 g, 5.19 mmol, 100% yield) as a yellow oil. LCMS: rt=1.42 min. [M-OMe]+=306; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([S:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:34]>ClCCl>[Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([S:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:34])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(Sc4ccccc4)cc3c2C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(S(=O)c4ccccc4)cc3c2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
To a solution of the product of Example 91, step A (50 mg, 0.12 mmol) in dichloromethane (2.0 mL) at −10° C. was added a solution of m-chloroperoxybenzoic acid (18 mg, 0.108 mmol) in dichloromethane (1.0 mL) drop wise. The reaction mixture was stirred at ambient temperature for 2 h, concentrated in vacuo and purified by column chromatography (SiO2, 4:1 hexanes/ethyl acetate) providing tert-butyl 6-chloro-8-(phenylsulfinyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (30 mg, 58%) as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ 7.68-7.63 (m, 3H), 7.51-7.45 (m, 4H), 4.55 (s, 2H), 3.86-3.77 (m, 2H), 2.93-2.85 (m, 2H), 1.50 (s, 9H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]#[N:9].[O-]CC.[Na+].[CH2:14]([O:16][C:17](=[O:21])[CH:18]=[N+:19]=[N-:20])[CH3:15].C(=O)=O>C(O)C.O>[NH2:9][C:8]1[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:20][NH:19][C:18]=1[C:17]([O:16][CH2:14][CH3:15])=[O:21]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: N#CCc1ccccn1
Agent: CC[O-]
Agent: O=C=O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1[nH]nc(-c2ccccn2)c1N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
2-Pyridylacetonitrile (10 ml, 94.0 mmol) was added dropwise over 20 minutes to an ice-cooled solution of sodium ethoxide (34 ml, 2.76M, 94.0 mmol) in ethanol (50 ml), and the mixture stirred at 0° C. for 30 minutes. Ethyldiazoacetate (9.9 ml, 94.0 mmol) was added dropwise over 15 minutes and the reaction allowed to warm to room temperature and stirred for a furter 18 hours. Water (300 ml) was added, the mixture neutralised with solid carbon dioxide, and the resulting precipitate filtered and dried to afford the title compound, (13.0 g, 60%) as a brown solid.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:28])[C@H:15]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([CH3:27])[CH:21]=1)[CH2:16][CH:17]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38][NH:39][CH3:40])=[CH:32][C:31]=1[CH3:41].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:28])[C@H:15]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([CH3:27])[CH:21]=1)[CH2:16][CH2:17][N:39]([CH2:38][CH2:37][CH2:36][C:33]1[CH:34]=[CH:35][C:30]([F:29])=[C:31]([CH3:41])[CH:32]=1)[CH3:40])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNCCCc1ccc(F)c(C)c1
Reactant: Cc1cc(O[C@H](CC=O)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)ccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1cc(CCCN(C)CC[C@@H](Oc2ccc(F)c(C)c2)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-4-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(4-fluoro-3-methylphenoxy)-4-oxobutanal (35 mg, 0.091 mmol) in 3 mL DCE was added 3-(4-Fluoro-3-methylphenyl)-N-methylpropan-1-amine (22 mg, 0.12 mmol) followed by NaBH(OAc)3 (29.5 mg, 0.14 mmol) and AcOH (7.2 mg, 0.12 mmol) at room temperature. The mixture was stirred for 8 h at the room temperature. The reaction was quenched by pouring into 10 mL 5% aqueous NaOH and diluted with ethyl acetate. The mixture was extracted with more ethyl acetate (3×15 mL) and the combined organic layers washed with brine (2×10 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product used directly in the next step without further purification.
Reaction SMILES: CO[C:3](=[O:18])[C:4]([C:6]1[CH:7]=[C:8]([O:16][CH3:17])[CH:9]=[C:10]2[C:14]=1[N:13]([CH3:15])[CH:12]=[CH:11]2)=O.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28][C:29]([NH2:31])=[O:30])=[CH:20]1.CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[CH3:15][N:13]1[C:14]2[C:10](=[CH:9][C:8]([O:16][CH3:17])=[CH:7][C:6]=2[C:4]2[C:3](=[O:18])[NH:31][C:29](=[O:30])[C:28]=2[C:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:19][CH:20]=2)[CH:11]=[CH:12]1
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Reactant: COC(=O)C(=O)c1cc(OC)cc2ccn(C)c12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc(C2=C(c3c[nH]c4ccccc34)C(=O)NC2=O)c2c(ccn2C)c1
Temperature: 50 °C
Yield: 56.5 %

Procedure:
To a mixture of (1-methyl-5-methoxy-1H-indol-7-yl)-oxo-acetic acid methyl ester (0.27 g, 1.1 mmol) and 2-(1H-indol-3-yl-acetamide (0.17 g, 1 mmol) in DMF (5 mL) was added a solution of potassium tert-butoxide in THF (1.0 M, 4 mL, 4 mmol) at room temperature. The reaction mixture was heated at 50° C. for 7 h, cooled to room temperature, quenched with water, and the mixture extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium bicarbonate and brine, dried (sodium sulfate), filtered and concentrated. Flash column chromatography on silica gel eluting with chloroform and acetone gave 3(1-methyl-5-methoxy-1H-indol-7-yl)-4-(1H-indol-3-yl]-pyrrole-2,5-dione (210 mg, 56.5%). 1H NMR (d6-DMSO, 400 MHz) 3.52 (s, 3H), 3.56 (s, 3H), 6.35˜6.46 (m, 1H), 6.28 (d, J=2.93 Hz, 1H), 6.41 (t, J=2.44 Hz, 1H), 6.88 (t, J=6.84 Hz, 1H), 7.02 (d, J=2.44 Hz, 1H), 7.10 (d, J=3.42 Hz, 1H), 7.24 (d, J=7.82, 1H), 7.80 (d, J=2.93, 1H), 11.03 (s, 1H), 11.76 (m, 1H); MS (ES, m/z): C22H17N3O3: 372.2 (M++1); 370.3 (M+−1).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[NH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:31])[CH2:29]Br)=[C:23]([Cl:32])[CH:22]=1)(=[O:20])=[O:19]>CN(C=O)C>[NH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:31])[CH2:29][O:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=2)=[C:23]([Cl:32])[CH:22]=1)(=[O:20])=[O:19]
Reactant: NS(=O)(=O)c1ccc(NC(=O)CBr)c(Cl)c1
Reactant: Oc1cccc(Oc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(NC(=O)COc2cccc(Oc3ccccc3)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A stirred solution of 37 mg (0.198 mmol) of 3-phenoxyphenol (1-1) in 1 mL anhydrous DMF under nitrogen was treated with 10 mg (0.397 mmol) of 60% NaH dispersion. The resulting mixture was stirred at room temperature for 4 hours and then treated with 65 mg (0.198 mmol) of N-[4-(aminosulfonyl)-2-chlorophenyl]-2-bromoacetamide (A-3). This mixture was then stirred at room temperature for an additional 4 hours. The reaction was concentrated in vacuo, and the residue was purified by reverse phase prep LC on a Gilson unit. Clean product fractions were combined and concentrated in vacuo to give the desired product 1-2 as a white solid. MS: M+1=433.2.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([Cl:10])[C:7]([N+:11]([O-:13])=[O:12])=[C:6](Cl)[CH:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH2:22]([NH:29][C:6]1[CH:5]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[N:9]=[C:8]([Cl:10])[C:7]=1[N+:11]([O-:13])=[O:12])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1c(Cl)cc(C2CC2)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1c(NCc2ccccc2)cc(C2CC2)nc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.1 %

Procedure:
6-Cyclopropyl-2,4-dichloro-3-nitro-pyridine (160 mg, 0.8 mmol) was dissolved in THF (2 mL) and triethylamine (104□l, 0.8 mmol) and benzylamine (81□l, 0.8 mmol) were added. The mixture was stirred at room temperature under a nitrogen atmosphere for 48 hours by which time a yellow precipitate had formed. The volatiles were removed in vacuo and the residue was stored in a stoppered flask at room temperature for 10 days. The residue was purified by column chromatography on silica gel eluting with 99:1 DCM:MeOH then 98:2 DCM:MeOH to give the title compound (185 mg) as a yellow crystalline solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][CH:24]([CH2:27][NH:28]C(=O)OC(C)(C)C)[CH2:23][CH2:22]2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]2[CH2:48][CH2:47][N:46]([C:49](=[O:51])[CH3:50])[CH2:45][CH2:44]2)=[CH:39][CH:38]=1.C[Si](Cl)(C)C>CCCCO>[NH2:28][CH2:27][CH:24]1[CH2:25][CH2:26][N:21]([C:4]2[C:5]3[CH:10]=[CH:9][N:8]([S:11]([C:14]4[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=4)(=[O:13])=[O:12])[C:6]=3[N:7]=[C:2]([NH:36][C:37]3[CH:38]=[CH:39][C:40]([N:43]4[CH2:44][CH2:45][N:46]([C:49](=[O:51])[CH3:50])[CH2:47][CH2:48]4)=[CH:41][CH:42]=3)[N:3]=2)[CH2:22][CH2:23]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N4CCC(CNC(=O)OC(C)(C)C)CC4)nc(Cl)nc32)cc1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(N4CCC(CN)CC4)c4ccn(S(=O)(=O)c5ccc(C)cc5)c4n3)cc2)CC1
Yield: 17.1 %

Procedure:
A mixture of tert-butyl (1-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)methylcarbamate (303 mg, 0.583 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (191 mg, 0.872 mmol) and trimethylsilyl chloride (0.400 mL, 3.16 mmol) in n-BuOH (6 mL) was stirred at 135° C. for 40 h. n-BuOH was removed in vacuo. The residue was purified by HPLC to give 1-(4-(4-(4-(4-(aminomethyl)piperidin-1-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (60 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:15])=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]#[CH:13])[C:6]=2[CH:14]=1.[CH2:16]=[C:17]1[O:21][C:19](=[O:20])[CH2:18]1.N1(C2C=CN=CC=2)CCCC1>C1C=CC=CC=1>[C:19]([NH:1][C:2]1[C:3]([F:15])=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]#[CH:13])[C:6]=2[CH:14]=1)(=[O:20])[CH2:18][C:17]([CH3:16])=[O:21]
Reactant: C#CCn1c(=O)sc2cc(F)c(N)cc21
Reactant: C=C1CC(=O)O1
Agent: c1cc(N2CCCC2)ccn1
Solvent: c1ccccc1
Product: C#CCn1c(=O)sc2cc(F)c(NC(=O)CC(C)=O)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 4.7 g of 5-amino-6-fluoro-3-(2-propynyl)-2-benzothiazolinone, 1.93 g of diketene and 0.05 g of 4-pyrrolidinopyridine in 250 ml of benzene is stirred at room temperature for 30 minutes and subsequently held at 50° C. for 30 minutes. In this manner there is obtained a solution of 5-acetoacetylamino-6-fluoro-3-(2-propynyl)-2-benzothiazolinone which is used as such in the next reaction step without isolation of the product.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[CH:28][C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[CH:21]=2)=[CH:12][CH:11]=1)[C:6](O)=[O:7])=[O:4].S(Cl)(Cl)=O.[NH3:34]>C1C=CC=CC=1.C(OCC)(=O)C>[C:6]([CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[CH:28][C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[CH:21]=2)=[CH:12][CH:11]=1)[C:3]([O:2][CH3:1])=[O:4])(=[O:7])[NH2:34]
Reactant: N
Reactant: COC(=O)C(Cc1ccc(OCCOc2ccc3c(c2)CCCC3)cc1)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1ccc(OCCOc2ccc3c(c2)CCCC3)cc1)C(N)=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
To a solution of 2-(methoxycarbonyl)-3-[4-[2-(5,6,7,8-tetrahydro-2-naphthoxy)ethoxy]phenyl]propionic acid (2.10 g, 5.29 mmol) in benzene (20 ml) at room temperature is added thionyl chloride (0.76 g, 6.34 mmol). Then the mixture was heated at 80° C. for 90 min. After cooled to rooms temperature, the solvent is removed under a vacuum. To the residue is added 28% ammonia solution (5.49 ml, 79.30 mmol) at room temperature. The mixture is stirred for 30 min, dissolved in ethyl acetate (20 ml), washed with brine (3×15 ml), dried over sodium sulfate, and concentrated. The crude product is crystallized from ethanol to give title compound (1.09 g, 52%). HRMS calcd for C23H27NO5: 397.4711. Found: 397.4713. MA calcd for C23H27NO5: C, 69.50%; H, 6.85%; N, 3.52%. Found: C, 69.62%; H, 6.83%; N, 3.53%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].B([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)(O)O.C(N(CC)CC)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]([CH3:12])=[C:2]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[CH:3]=1)=[O:6]
Reactant: COC(=O)c1ccc(C)c(Br)c1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C)c(-c2ccc(C(=O)O)cc2)c1
Temperature: 100 °C
Yield: 71.3 %

Procedure:
A stirred solution of methyl 3-bromo-4-methylbenzoate (2.6 g, 0.011 mole) in dry DMF (20 ml) under argon was treated with 4-boronobenzoic acid (1.85 g, 0.011 mole) and tetrakis (triphenylphosphine) palladium (O) (400 mg), followed by triethylamine (4.68 ml, 0.046 mole). The mixture was heated at 100° C. for 18 hours, then concentrated in vacuo. The residue was treated with ethyl acetate and extracted with 10% NaHCO3 solution. The basic extract was acidified with dil. HCl and extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated in vacuo to afford the title compound as a light orange solid (2.12 g, 85%).
Reaction SMILES: [P:1]([O-:13])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[K+].C(=O)([O-])O.[Na+].C(OC(C)C)(=O)C.[Cl:27][CH2:28]OS(Cl)(=O)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[P:1]([O:13][CH2:28][Cl:27])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:2]
Reactant: O=S(=O)(Cl)OCCl
Reactant: CC(C)(C)OP(=O)([O-])OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: CC(=O)OC(C)C
Product: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Temperature: 35 °C
Reaction time: 0.75 h
Yield: 90 %

Procedure:
To a mixture of potassium ditert-butyl phosphate (261 kg, 1.00 mol eq), tetra-n-butylammonium hydrogensulphate (18.5 kg, 0.05 mol eq) and sodium hydrogencarbonate (400 kg, 4.50 mol eq) in water (1150 kg) is added isopropyl acetate (1275 kg). The mixture is warmed to about 35° C. and then to this is added chloromethylchlorosulphate (313 kg, 1.80 mol eq) over about 4 hours. The mixture is further stirred for about 45 minutes, cooled to about 25° C. and then the layers separated. The organic phase is cooled to about 10° C. and washed twice with 2% w/v aqueous potassium hydrogencarbonate solution (2×800 kg) and then with a mixed 2% w/v potassium hydrogencarbonate and 20% w/v potassium hydrogencarbonate aqueous solution (640 kg). The resulting organic solution is then distilled at <100 mbar to half volume, maintaining the temperature below 45° C. The resulting mixture is filtered, washing the filter with isopropyl acetate (115 kg), to give the title compound as a solution, with typical solution strength of about 25% w/v and yield of about 90%. This solution is then used directly in Example 1, Step C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1>C1CCCCC1>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:11][CH2:10][CH2:9][CH:8]([CH3:12])[CH3:7]
Reactant: CC1CCCC1
Solvent: CCCCCC
Solvent: C1CCCCC1
Product: CCCC(C)C

Procedure:
A hexanes stream, conventionally produced in petroleum refining, comprising normal hexane, isohexanes, methylcyclopentane, and cyclohexane is isomerized to produce primarily cyclohexane and to recover normal hexane by first fractionating the hexanes stream in a first fractionation step in a manner and under conditions to produce a normal hexane-isohexane rich overhead stream and a methylcyclopentane-cyclohexane rich bottoms stream, the bottoms stream is isomerized in the presence of an isomerization catalyst and under conditions sufficient to maximize the conversion of methylcyclopentane to cyclohexane, the overhead from the first fractionation step and the effluent from the isomerization step is then fractionated in at least one stage of a second fractionation step in a manner and under conditions to produce separate streams, comprising isohexanes, normal hexane, cyclohexane, and unreacted methylcyclopentane and the methylcyclopentane is recycled to the isomerization step and/or the first fractionation step. Since an original hexane stream usually contains benzene, it is preferred that the original hexane stream be hydrogenated to convert the benzene to cyclohexane prior to passing the feed to the first fractionation step.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].[F:10][C:11]1[C:16]([CH:17]([S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[S:18]([C:21]([F:24])([F:23])[F:22])(=[O:20])=[O:19])=[C:15]([F:32])[C:14]([F:33])=[C:13](F)[C:12]=1[F:35].O.Cl>N1C=CC=CC=1>[CH2:1]([O:7][C:13]1[C:12]([F:35])=[C:11]([F:10])[C:16]([CH:17]([S:18]([C:21]([F:24])([F:22])[F:23])(=[O:19])=[O:20])[S:25]([C:28]([F:29])([F:30])[F:31])(=[O:26])=[O:27])=[C:15]([F:32])[C:14]=1[F:33])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCO
Reactant: O=S(=O)(C(c1c(F)c(F)c(F)c(F)c1F)S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCOc1c(F)c(F)c(C(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)c(F)c1F
Temperature: -20 °C
Reaction time: 5 h
Yield: 99 %

Procedure:
Hexanol (1.5 mL, 12 mmol) was added to a pyridine (10 mL) solution dissolved with 60% sodium hydride containing mineral oil (0.56 g, 14 mmol) at 0° C., and the resultant solution was stirred for 1 hour at room temperature. After the solution was cooled to −20° C., pentafluorophenylbis(triflyl)methane (0.89 g, 2 mmol) was added. The reaction solution was stirred at −20° C. for 5 hours. After the reaction, the solution was acidified with 4 M hydrochloric acid water, and was extracted with diethylether. After drying with magnesium sulfate, the solution was filtrated, and the solvent was removed under reduced pressure. The crude product was purified by sublimation (0.2 to 0.3 torr, 65° C.), and 4-hexanoxy-2,3,5,6-tetrafluorophenylbis(triflyl)methane was obtained at 99% yield (1.02 g, 1.98 mmol).
Reaction SMILES: [NH:1]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@@H:2]([C:27](O)=[O:28])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:26])[NH:8][S:9]([C:12]1[C:24]([CH3:25])=[C:23]2[C:17]([O:18][C:19]([CH2:22]2)([CH3:21])[CH3:20])=[C:15]([CH3:16])[C:13]=1[CH3:14])(=[O:11])=[O:10].CN1CCOCC1.[NH2:44][C@H:45]([C:53]([NH:55][C@H:56]([C:69]([O:71][CH3:72])=[O:70])[CH2:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[CH:60][CH:59]=1)=[O:54])[C@@H:46]([CH3:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49]>CN1C(=O)CCC1.C(Cl)(Cl)Cl>[NH:1]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@@H:2]([C:27]([NH:44][C@@H:45]([C:53]([NH:55][C@@H:56]([C:69]([O:71][CH3:72])=[O:70])[CH2:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[CH:60][CH:59]=1)=[O:54])[C@H:46]([CH3:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:28])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:26])[NH:8][S:9]([C:12]1[C:24]([CH3:25])=[C:23]2[C:17]([O:18][C:19]([CH2:22]2)([CH3:20])[CH3:21])=[C:15]([CH3:16])[C:13]=1[CH3:14])(=[O:11])=[O:10]
Reactant: COC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@@H](N)[C@@H](C)OC(C)(C)C
Reactant: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O)c(C)c2c1OC(C)(C)C2
Solvent: ClC(Cl)Cl
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@H](NC(=O)[C@@H](CCCNC(=N)NS(=O)(=O)c1c(C)c(C)c2c(c1C)CC(C)(C)O2)NC(=O)OC(C)(C)C)[C@H](C)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
A clear solution of 3.73 g (7.08 mmoles) of Boc-D-Arg(Pbf)-OH (Bachem Feinchemikalien, cat. No A-3750) in 75 ml of dry NMP, comprising 0.85 ml (7.79 mmoles) of NMM was chilled to −10° C. under shaking. Then, 1.02 ml (7.79 mmoles) of IBCF diluted in 6 ml of CHCl3 were added drop-wise. After 30 minutes, a solution of 2.88 g (7.08 mmoles) of H-L-Thr(tBu)-L-Tyr(tBu)-OMe in 75 ml of CHCl3 was added drop-wise in 20 minutes. The reaction mixture was kept for 2 h at 0° C. and overnight at room temperature. The solvent was evaporated under vacuum and the crude material was purified by flash chromatography on silica gel column, using a mixture of AcOEt-hexane as eluent. There were thus obtained 5.58 g (6.08 mmoles, yield 86%) of Boc-D-Arg(Pbf)-D-Thr(tBu)-D-Tyr(tBu)-OMe, as pure oil (TLC and RP-HPLC).
Reaction SMILES: Cl[C@H:2]1[CH2:7][C@@H:6]([O:8][CH2:9][O:10][CH3:11])[CH2:5][N:4]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:3]1.[CH:22]1[C:32]2[CH2:31][O:30][C:29]3[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=3[NH:27][C:26]=2[CH:25]=[CH:24][CH:23]=1>>[CH3:11][O:10][CH2:9][O:8][C@H:6]1[CH2:5][N:4]([CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C@@H:2]([CH2:3][N:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:32]=3[CH2:31][O:30][C:29]3[CH:33]=[CH:34][CH:35]=[CH:36][C:28]2=3)[CH2:7]1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Reactant: COCO[C@@H]1C[C@H](Cl)CN(CCc2ccc(OC)cc2)C1
Product: COCO[C@@H]1C[C@H](CN2c3ccccc3COc3ccccc32)N(CCc2ccc(OC)cc2)C1

Procedure:
(3S,5R)-(+)-3-chloro-5-(methoxymethoxy)-1-(4-methoxyphenethyl)piperidine was coupled with 5,11-dihydrodibenzo[b,e][1,4]oxazepine as described in Example 1 to give (+)-5,11-dihydro-5-[[(2R,4R)-4-(methoxymethoxy)-1-(4-methoxyphenethyl)pyrrolidin-2-yl]methyl]dibenzo[b,e][1,4]oxazepine in 4.30 g (72.6%) yield as pale yellow oil.