Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>CCOCC.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>[CH2:19]([O:26][C:27]1[N:28]=[CH:29][C:30]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=2[N+:16]([O-:18])=[O:17])=[CH:31][CH:32]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC1(C)OB(c2ccc(OCc3ccccc3)nc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)c([N+](=O)[O-])c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(OCc3ccccc3)nc2)c([N+](=O)[O-])c1

Procedure:
A mixture of tert-butyl 4-chloro-3-nitrophenylcarbamate (818 mg, 3 mmol), 2-(benzyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (933 mg, 3 mmol), tetrakis(triphenylphosphine)palladium (104 mg, 0.09 mmol), 10 mL of dioxane, and 6 mL of 1 M Na2CO3 was heated at reflux for 15 h. It was diluted with 50 mL Et2O and washed with brine (2×50 mL) and dried over MgSO4 and concentrated. The crude product was purified by silica chromatography (EtOAc/hexane) to afford tert-butyl 4-(6-(benzyloxy)pyridin-3-yl)-3-nitrophenylcarbamate (WZ02049) as a yellow wax (1.2 g, 95%). MS (ESI) m/z 444 (M+Na+).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:19]=[CH:18][NH:17][N:16]=3)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:19]=[CH:18][N:17]([C:22](=[O:24])[CH3:23])[N:16]=3)=[CH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(-c3cc[nH]n3)cc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)n1ccc(-c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.9 %

Procedure:
A solution of 3-[4-(-4-nitrophenoxy)phenyl]-1H-pyrazole (0.16 g, 0.57 mmol) in pyridine (12 mL) was treated with neat acetic anhydride (1.0 mL, 1.0 mmol) and allowed to stir at room temperature for 16 hours. The reaction was then diluted with ethyl acetate, washed several times with an aqueous 2N HCl solution, dried over sodium sulfate, and evaporated under reduced pressure. The crude product was purified by column chromatography, affording 116 mg (63%) of the title compound. TLC Rf 0.78 (70:30 hexane/ethyl acetate). 1H NMR (CDCl3): δ 8 8.31 (d, J=3.0 Hz, 1H), 8.22 (d, J=9.3 Hz, 2H), 7.94 (d, J=8.7 Hz, 2H), 7.17 (d, J=9.0 Hz, 2H), 7.07 (d, J=9.3 Hz, 2H), 6.77 (d, J=3.0 Hz, 1H), 2.78 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[O:11][CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[H][H]>O1CCCC1.[Ni]>[O:11]1[C:12]2[C:4]([NH2:1])=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:9][CH2:10]1
Reactant: O=[N+]([O-])c1cccc2c1OCC2
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cccc2c1OCC2

Procedure:
39.4 g of 2,3-dihydro-7-nitrobenzofuran (prepared by the method described in Journal of Heterocyclic Chemistry, vol. 5, No. 1, p. 1 (1968)) in 200 ml of tetrahydrofuran was hydrogenated in a Parr shaker (50 p.s.i.g. hydrogen pressure, Raney nickel catalyst, 3 hours, room temperature). The resulting mixture was filtered and the solvent was evaporated from the filtrate. The residue was recrystallized from ether to give 1, as a colorless solid, m.p.: 70°-72° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:8]=[C:7]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)[N:6]=1)([CH3:3])[CH3:2].[C:24]([C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1)([O:26][CH3:27])=[O:25]>C(N(CC)CC)C>[CH:1]([O:4][C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:8]=[C:7]([C:17]2[CH:23]=[CH:22][C:20]([NH:21][C:35]([NH:34][C:31]3[CH:32]=[CH:33][C:28]([C:24]([O:26][CH3:27])=[O:25])=[CH:29][CH:30]=3)=[O:36])=[CH:19][CH:18]=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1nc(-c2ccc(N)cc2)nc(N2CCOCC2)n1
Reactant: COC(=O)c1ccc(N=C=O)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)Nc2ccc(-c3nc(OC(C)C)nc(N4CCOCC4)n3)cc2)cc1
Reaction time: 48 h

Procedure:
A mixture of 4-(4-isopropoxy-6-morpholino-1,3,5-triazin-2-yl)aniline (1.3 g, 4.1 mmol), triethylamine (2 ml) and 4-carbomethoxy-phenylisocyanate (1451 mg, 8.2 mmol) was stirred for 48 hours and quenched with water and washed well. The organic layer was dried and filtered. It was concentrated and purified by column chromatography by eluting it initially with 10% ethyl acetate: hexane and latter with 40% ethyl acetate:hexane. White solid; 600 mg, 30%; MS (ESI) m/z 492.5.
Reaction SMILES: [OH:1][C@H:2]([C@@H:5]1[C@H:8]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7](=[O:20])[N:6]1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[O:30][CH3:31])CO.I([O-])(=O)(=O)=O.[Na+]>CCOC(C)=O.O>[CH3:31][O:30][C:23]1[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=1[CH2:21][N:6]1[C:7](=[O:20])[C@@H:8]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:5]1[CH:2]=[O:1]
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2[C@@H](O)CO)c(OC)c1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2C=O)c(OC)c1
Temperature: 50 °C
Yield: 98.2 %

Procedure:
To a solution of benzyl ((2S,3S)-2-((R)-1,2-dihydroxyethyl)-1-(2,4-dimethoxybenzyl)-4-oxoazetidin-3-yl)carbamate (240 g, 0.557 mol) in EtOAc (4.5 L) was added a solution of sodium periodate (132 g, 0.617 mol) in water (1.125 L) and the bilayer was heated to 50° C. for 2 h, whereupon it was cooled to rt and the layers were separated. The aqueous layer was extracted with EtOAc (500 mL) and the combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated in vacuo to afford the title compound (218 g, 98%) as a pale yellow solid. LCMS: m/z=399.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 9.32 (d, J=3.2 Hz, 1H), 8.19 (d, J=8.5 Hz, 1H), 7.39-7.23 (m, 5H), 7.16 (d, J=8.3 Hz, 1H), 6.53 (d, J=2.4 Hz, 1H), 6.47 (dd, J=8.3, 2.4 Hz, 1H), 5.00-4.96 (m, 2H), 4.90 (dd, J=8.5, 5.8 Hz, 1H), 4.38 (d, J=14.5 Hz, 1H), 4.29 (d, J=14.5 Hz, 1H), 4.05 (dd, J=5.9, 3.3 Hz, 1H), 3.73 (s, 3H), 3.70 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:11]=[C:10]2[C:6](/[C:7](=[CH:13]/[C:14]3[NH:18][C:17]([CH3:19])=[C:16]([C:20](O)=[O:21])[C:15]=3[CH3:23])/[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[NH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[NH:62][C:63](=[O:74])[C:64]1[CH:69]=[CH:68][C:67]([NH:70][CH2:71][CH2:72][NH2:73])=[N:66][CH:65]=1>[Cl-].[Na+].O.CN(C=O)C>[NH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[NH:62][C:63](=[O:74])[C:64]1[CH:69]=[CH:68][C:67]([NH:70][CH2:71][CH2:72][NH:73][C:20]([C:16]2[C:15]([CH3:23])=[C:14](/[CH:13]=[C:7]3\[C:8](=[O:12])[NH:9][C:10]4[C:6]\3=[CH:5][CH:4]=[C:3]([C:2]([F:25])([F:1])[F:24])[CH:11]=4)[NH:18][C:17]=2[CH3:19])=[O:21])=[N:66][CH:65]=1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3cc(C(F)(F)F)ccc32)c(C)c1C(=O)O
Reactant: NCCNc1ccc(C(=O)Nc2ccccc2N)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1[nH]c(/C=C2\C(=O)Nc3cc(C(F)(F)F)ccc32)c(C)c1C(=O)NCCNc1ccc(C(=O)Nc2ccccc2N)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 59 %

Procedure:
5-(6-Trifluoromethyl-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (350 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and N-(2-aminophenyl)-6-(2-aminoethylamino)nicotinamide (284 mg, 1.05 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (356 mg, 59%) as a yellow solid. LC-MS (m/z) 604 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12](COCC[Si](C)(C)C)[C:11]=2[N:10]=[C:9]1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:38])([F:37])[F:36])[CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)C>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[NH:12][C:11]=2[N:10]=[C:9]1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:38])([F:36])[F:37])[CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1c(=O)[nH]c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccccc1
Agent: Cl
Solvent: CCO
Product: O=c1[nH]c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2Cc2ccccc2)[nH]1
Temperature: 80 °C
Reaction time: 16 h
Yield: 87.1 %

Procedure:
To a solution of 7-benzyl-8-(3-(trifluoromethoxy)phenoxy)-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (0.59 g, 1.07 mmol) in ethanol (20 mL) was added concentrated HCl (2 mL). The reaction was stirred at 80° C. for 16 h. The reaction was concentrated and partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase was washed with brine, dried over sodium sulfate, and concentrated to give 7-benzyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (390 mg, 87.1% yield) as yellow oil. LCMS retention time 1.543 min; LCMS MH+ 419.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([NH:38][C:39](=[O:44])[CH2:40][C:41](O)=[O:42])[CH:33]=[CH:34][C:35]=1[O:36][CH3:37].C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:41](=[O:42])[CH2:40][C:39]([NH:38][C:32]1[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:30]([O:29][CH3:28])[CH:31]=1)=[O:44]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: COc1ccc(NC(=O)CC(=O)O)cc1OC
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(NC(=O)CC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.9 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (30 mg, 0.071 mmol), 3-(3,4-dimethoxyphenylamino)-3-oxopropanoic acid (34.2 mg, 0.143 mmol), DMAP (17.44 mg, 0.143 mmol), and EDC (41.1 mg, 0.214 mmol) were dissolved in DMF (1.5 ml). The reaction was stirred at RT overnight to achieve completion. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was washed with HCl 1N, Na2CO3 sat. sol. and brine, dried over Na2SO4 and concentrated under vacuum. The crude product was purified by Preparative reverse-phase HPLC to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(3,4-dimethoxyphenylamino)-3-oxopropanoyloxy)-ethyl)pyridine 1-oxide (20 mg, 43.7% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].C(Cl)Cl.C(O)(=O)C.[F:23][CH:24]([F:27])[CH2:25][NH2:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[F:23][CH:24]([F:27])[CH2:25][NH:26][CH:11]1[CH2:10][CH2:9][C:8]2[CH:15]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[CH2:13][CH2:12]1
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc2CC1
Reactant: NCC(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(c1)CCC(NCC(F)F)CC2
Reaction time: 0.08 h

Procedure:
Charge 2-Nitro-5,6,8,9-tetrahydrobenzocyclohepten-7-one (750.00 mg, 3.6548 mmol) to Methylene chloride (20 mL, 300 mmol) and Acetic acid (200 uL, 4 mmol). Allow to stir for 5 min. Charge 2,2-difluorethylamine (0.292 ml, 3.65 mmol) and sodium triacetoxyborohydride (1.55 g, 7.31 mmol). Allow suspension to stir for 2.5 hours. LC at 2.5 hours conforms that starting ketone has been consumed. Pour reaction into 200 ml water and 100 ml saturated sodium bicarbonate solution and extract with 2×100 ml portions of methylene chloride. The combined organic was dried over magnesium sulfate, filtered and evaporated to a yellow oil (approximately 1.0 g). The resulting crude yellow oil was chromatographed on a 12 g Isco cartridge using a gradient of 0-60% EtOAc in hexanes as the eluent. (2,2-Difluoro-ethyl)-(2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-amine was isolated as a beige oil (625 mg, 63% yield). 1H-NMR (CDCl3) δ 7.98 (m, 2H), 7.24 (m, 1H), 5.82 (m, 1H), 3.02 (m, 4H), 2.88 (m, 1H), 2.76 (m, 2H), 2.08 (m, 2H), 1.38 (m, 2H). LC/MS (ESI+): 271 (M+H).
Reaction SMILES: [C:1]([S:4][CH:5]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].OS(O)(=O)=O>C(Cl)Cl>[C:12]([O:8][C:7](=[O:9])[CH2:6][CH:5]([S:4][C:1](=[O:3])[CH3:2])[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([CH3:17])([CH3:13])[CH3:11]
Reactant: CC(=O)SC(CCc1ccccc1)CC(=O)O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(=O)SC(CCc1ccccc1)CC(=O)OC(C)(C)C
Temperature: -78 °C

Procedure:
3-Acetylsulfanyl-5-phenyl-pentanoic acid was taken up in DCM (15 mL) with stirring in a pressure bottle. c.H2SO4 (1 mL) was added and the solution cooled to −78° C. Isobutylene gas was bubbled through this solution until the volume had doubled. The pressure vessel was sealed and allowed to warm to room temperature and stirred overnight. The reaction was re-cooled to −78° C. and opened and warmed to room temparature. The excess isobuylene gas was allowed to evaporate and then the reaction solution was poured into a stirred 1 M Na2CO3 solution. The product was extracted into DCM and washed with brine, dried and filtered and evaporated under reduced pressure to give an orange oil (10.64 g, 34.5 mmol). 1H-NMR δ(CDCl3) 7.27-7.14 (5H, m), 3.88 (1H, m), 2.80-2.51 (4H, m), 2.34 (3H, s), 1.97-1.84 (2H, m) and 1.43 (9H, s).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14]([NH:16][C@@H:17]1[C:23](=[O:24])[NH:22][C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[O:19][C@@H:18]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[O:24]=[C:23]1[NH:22][C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[O:19][C@H:18]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@H:17]1[NH:16][C:14](=[O:15])[C@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[NH2:8]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@H](N)C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1
Yield: 99.9 %

Procedure:
N2-[tert-Butoxycarbonyl]-N1-[(2R,3S)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]-L-leucinamide (64f) (83 mg, 0.177 mmol) was dissolved in 5:1 (v/v) dichloromethane:trifluoroacetic acid and kept at ambient temperature for 1 h. The solution was evaporated and the residue dissolved in ethyl acetate. The solution was extracted in succession with saturated aqueous sodium bicarbonate and brine then the organic solution was dried, filtered and evaporated to afford the title compound (65 mg, 99%) as a yellow oil. MS APCI, m/z=368 (M+1). LC/MS: 1.63 min.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[CH-:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.[Fe+2:16].[Mg].Cl[SiH:19]([CH3:21])[CH3:20]>>[CH3:20][SiH:19]([CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][C-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[CH-:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.[Fe+2:16]
Reactant: ClCCCC[c-]1cccc1
Reactant: C[SiH](C)Cl
Agent: [Fe+2]
Agent: [Mg]
Agent: c1cc[cH-]c1
Product: C[SiH](C)CCCC[c-]1cccc1

Procedure:
In the third reaction stage 4-chlorobutylferrocene was reacted with magnesium metal under Grignard type reaction conditions to form the corresponding Grignard intermediate compound which reacted with chlorodimethylsilane in-situ to give 4-(dimethylsilyl)butylferrocene
Reaction SMILES: [N:1]1[CH:6]=[C:5]([O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=[O:15])[CH:9]=2)[CH:4]=[N:3][CH:2]=1.[CH2:17](O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[N:3]1[CH:4]=[C:5]([O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH:9]=2)[CH:6]=[N:1][CH:2]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1cc(Oc2cncnc2)ccn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1cc(Oc2cncnc2)ccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 37.1 %

Procedure:
4-(Pyrimidin-5-yloxy)picolinic acid (1.43 g, 6.58 mmol, 1.00 eq), benzyl alcohol (1.02 mL, 9.88 mmol, 1.50 eq), PS—PPh3 (5.51 g, 14.5 mmol, 2.20 eq) and THF (66 mL) were added to a flame-dried round-bottom flask. The mixture was cooled to 0° C. and diisopropyl azodicarboxylate (2.07 mL, 10.5 mmol, 1.60 eq) was added dropwise. The reaction was allowed to warm to rt and stirred for 1 h. The reaction was filtered and washed with EtOAc. The combined organics were concentrated in vacuo and purified by flash chromatography on silica gel to afford 750 mg (37%) of the title compound as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 9.16 (s, 1H), 8.87 (s, 2H), 8.64 (d, J=5.7 Hz, 1H), 7.66 (d, J=2.5 Hz, 1H), 7.47-7.40 (m, 2H), 7.40-7.38 (m, 1H), 7.38-7.32 (m, 3H), 5.36 (s, 1H); [M+1]+: 308.1.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]=[O:13].[C:14]1([SH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:8][N:7]1[C:2]([S:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]([CH:12]=[O:13])[C:4](=[O:11])[N:5]([CH3:10])[C:6]1=[O:9]
Reactant: Sc1ccccc1
Reactant: Cn1c(Cl)c(C=O)c(=O)n(C)c1=O
Product: Cn1c(Sc2ccccc2)c(C=O)c(=O)n(C)c1=O

Procedure:
The process described in Method D was followed. 6-Chloro-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde (1.50 g, 7.40 mmol) and benzenethiol were used to obtain the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH2:10].[C:11](OCC)(=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[CH2:8][CH2:9][N:10]=[C:22]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: NCCNCCOCCO
Reactant: CCCCCCCCCCCC(=O)OCC
Product: CCCCCCCCCCCC1=NCCN1CCOCCO
Yield: 50.6 %

Procedure:
13.7 g (92.6 mmoles) N-[2-(2-Hydroxyethoxy)ethyl]ethylenediamine and 19.6 g (86 mmoles) of ethyl dodecanoate were mixed and heated in a flask equipped with a Dean-Stark trap. After the separated ethanol and water were distilled off, the residue was kugelrohr distilled at 160°-170° C./0.1 mm to give 13.6 g (50.7%) of crude product. Recrystallization from ethyl acetate/hexane gave white crystalline material, m.p. 58°-60° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH:10]2[O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]3[O:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:31]=3[CH:41]=2)=[CH:5][CH:4]=1.[NH:42]1[CH:46]=[C:45]([C:47]2[CH:48]=[C:49]([OH:53])[CH:50]=[CH:51][CH:52]=2)[N:44]=[CH:43]1>>[NH:42]1[CH:46]=[C:45]([C:47]2[CH:48]=[C:49]([CH:50]=[CH:51][CH:52]=2)[O:53][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[O:16])[CH2:11][CH:10]3[O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]4[O:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:31]=4[CH:41]=3)=[CH:5][CH:4]=2)[N:44]=[CH:43]1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(CCl)cc3)cc21
Reactant: Oc1cccc(-c2c[nH]cn2)c1
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(COc4cccc(-c5c[nH]cn5)c4)cc3)cc21

Procedure:
Analogously to Method I, 0.107 g of benzyl 4-(4-chloromethylphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 270b) and 0.0444 g of 3-(1H-imidazol-4-yl)phenol are reacted. The title compound is obtained as an orange oil. Rf=0.19 (200:10:1 dichloromethane-methanol-conc. ammonia); Rt=4.89.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>Cl>[Cl:23][C:21]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[C:14]([NH:13][C:2]2[C:11]3[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:22]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Agent: Cl
Product: O=C(O)c1ccc(Cl)cc1Nc1ccnc2cc(Cl)ccc12

Procedure:
4,7-Dichloroquinoline and 2-amino-4-chloro benzoic acid are refluxed in dilute hydrochloric acid for 1 hour to give 4-chloro-2-(7-chloro-4-quinolylamino)benzoic acid.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[C:10](=[C:11]3[C:16]=1[CH:15]=[C:14]([F:17])[CH:13]=[CH:12]3)[CH:9]=[CH:8][CH:7]=[CH:6]2)[CH3:2].[BH4-].[Na+].FC(F)(F)C(O)=O.C1C=CC2C3C=CC=CC=3NCC=2C=1.C(N(CC)CC)C.[Cl:48][C:49]1[CH:50]=[C:51]([S:57](Cl)(=[O:59])=[O:58])[CH:52]=[CH:53][C:54]=1[O:55][CH3:56]>O1CCCC1.ClCCl>[CH:14]1[CH:13]=[CH:12][C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[NH:4][CH2:3][C:16]=2[CH:15]=1.[CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]1[S:57]([C:51]1[CH:52]=[CH:53][C:54]([O:55][CH3:56])=[C:49]([Cl:48])[CH:50]=1)(=[O:58])=[O:59])[CH3:2]
Reactant: CCc1nc2ccccc2c2ccc(F)cc12
Reactant: COc1ccc(S(=O)(=O)Cl)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Agent: c1ccc2c(c1)CNc1ccccc1-2
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(OC)c(Cl)c1

Procedure:
The intermediate dihydrophenanthridine was prepared from 6-ethyl-8-fluorophenanthridine, (Example 40, Step b, 0.40 g, 1.8 mmol), by treatment with sodium borohydride (0.40 g, 10.6 mmol) and trifluoroacetic acid (0.55 mL, 7.1 mmol) in tetrahydrofuran (7 mL). In a separate, second step, the dihydrophenanthridine was treated with triethylamine (0.9 mL, 6.4 mmol) and 3-chloro-4-methoxybenzenesulfonyl chloride (0.51 g, 2.1 mmol, 2.1 equivalents) in dichloromethane (5 mL), according to the procedure and in the same manner as described in Example 32, Method A, Step d, to afford 6-ethyl-8-fluoro-5-[(3-chloro-4-methoxyphenyl)sulfonyl]-5,6-dihydrophenanthridine as a crude product, which was utilized without further purification.