Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(OC(C)(C)C)=O.[N+:8]1([O-:22])[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][C:12]=2[N:11]=[C:10](N)[N:9]=1)[CH2:18][CH2:17][CH2:16]3>CN(C=O)C>[N+:8]1([O-:22])[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][C:12]=2[N:11]=[CH:10][N:9]=1)[CH2:18][CH2:17][CH2:16]3
Reactant: Nc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Agent: CC(C)(C)ON=O
Solvent: CN(C)C=O
Product: [O-][n+]1ncnc2cc3c(cc21)CCC3
Temperature: 60 °C
Reaction time: 2 h
Yield: 43.3 %

Procedure:
tert-Butyl nitrite (90%, 2 mL, 14.8 mmol) was added to a stirred solution of amine 19 (1.0 g, 4.95 mmol) in DMF (50 mL) at 60° C. and the solution stirred at 60° C. for 2 h. The solution was cooled to 20° C. and the solvent evaporated. The residue was partitioned between EtOAc (150 mL) and water (150 mL), the organic fraction was washed with water (2×50 mL), washed with brine (50 mL) and dried and the solvent evaporated. The residue was purified by chromatography, eluting with 10% EtOAc/DCM, to give 1-oxide 64 (401 mg, 43%) as a white solid: mp (EtOAc/pet. ether) 130-131° C.; 1H NMR δ 8.91 (s, 1H, H-3), 8.28 (s, 1H, H-9), 7.82 (s, 1H, H-5), 3.11-3.19 (m, 4H, H-6, H-8), 2.24 (p, J=7.5 Hz, 2H, H-7); 13C NMR δ 154.9, 153.0, 150.0, 147.3, 134.6, 123.2, 114.4, 33.2, 32.9, 25.7. Anal. calcd for C10H9N3O: C, 64.2; H, 4.9; N, 22.5. Found: C, 64.1; H, 4.9; N, 22.5%.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[H-].[Na+].Br[CH2:24][CH2:25][O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1.O>CN(C)C=O>[Br:1][C:2]1[N:3]([CH2:24][CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CCOC3CCCCO3)c2c1

Procedure:
To a solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (5.00 g, 14.8 mmol) in N,N-dimethylformamide (50 ml) was added sodium hydride (60% in oil, 713 mg, 17.8 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr. 2-(2-Bromoethoxy)tetrahydropyran (2.90 ml, 19.2 mmol) was added to the reaction mixture under ice-cooling, and the mixture m was stirred at room temperature for 4 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give methyl 2-bromo-3-cyclohexyl-1-[2-(tetrahydropyran-2-yloxy)ethyl]-1H-indole-6-carboxylate as a crude product. The obtained crude product was used for Step 2 without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:18]=[CH:17][C:16](/[CH:19]=[C:20](\[C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)/[CH2:21][N:22]3[CH:26]=[CH:25][N:24]=[CH:23]3)=[CH:15][C:11]=2[C:12](O)=[O:13])=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:49][O:50][C:51](=[O:58])[C@H:52]([CH2:54][CH2:55][S:56][CH3:57])[NH2:53].CN1CCOCC1>CN(C1C=CN=CC=1)C.ClCCl>[F:33][C:30]1[CH:31]=[CH:32][C:27](/[C:20](/[CH2:21][N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)=[CH:19]\[C:16]2[CH:17]=[CH:18][C:10]([CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[C:11]([CH:15]=2)[C:12]([NH:53][C@@H:52]([CH2:54][CH2:55][S:56][CH3:57])[C:51]([O:50][CH3:49])=[O:58])=[O:13])=[CH:28][CH:29]=1
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: O=C(O)c1cc(/C=C(/Cn2ccnc2)c2ccc(F)cc2)ccc1CCc1ccc(F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)[C@H](CCSC)NC(=O)c1cc(/C=C(/Cn2ccnc2)c2ccc(F)cc2)ccc1CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-[2-(4-fluorophenyl)ethyl]-5-[(E)-2-(4-fluorophenyl)-3-(imidazol-1-yl)prop-1-en-1-yl]benzoic acid (0.3 g; 0.67 mmol), EDC (0.154 g; 0.8 mmol), HOBT (0.108 g; 0.8 mmol), DMAP (0.090 g; 0.74 mmol), L-methionine methyl ester hydrochloride (0.2 g; 1 mmol) and N-Methylmorpholine (110 μl; 1 mmol) in dichloromethane (20 ml) was stirred at room temperature overnight. The organic phase was washed with aqueous sodium bicarbonate, dried and evaporated. The residue was purified by flash chromatography. eluting with a gradient of dichloromethane/ethanol (1-3%) to give methyl (2S)-2-{5-[(E)-2-(4-fluorophenyl)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(2-(4-fluorophenyl)ethyl)benzamido}-4-methylsulfanylbutyrate as a white solid foam Yield=50%.
Reaction SMILES: [Cl:1][C:2]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][S:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11]2)(=[O:7])=[O:6].[CH:23]([C:25]1[NH:29][C:28]([CH3:30])=[C:27]([C:31]([OH:33])=[O:32])[C:26]=1[CH3:34])=O>>[Cl:1][C:2]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][S:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:23]\[C:25]1[NH:29][C:28]([CH3:30])=[C:27]([C:31]([OH:33])=[O:32])[C:26]=1[CH3:34])(=[O:6])=[O:7]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3cccc(Cl)c3Cl)ccc2N1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cccc(Cl)c4Cl)cc32)c(C)c1C(=O)O

Procedure:
5-[(2,3-Dichlorobenzyl)sulfonyl]-1,3-dihydro-indol-2-one (315 mg, 1 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (170 mg, 1 mmol) to give the titled compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH:10]([CH3:12])[CH3:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH:13]([CH3:15])[CH3:14].[BH4-].[Na+]>ClCCl.CO.O>[NH2:1][C:2]1[C:9]([CH:10]([CH3:12])[CH3:11])=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1N
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CC(C)c1cc(CO)cc(C(C)C)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a mixed solution of this aldehyde (745 mg, 3.63 mmol) in dichloromethane (5 ml) and methanol (10 ml) was added sodium borohydride (280 mg, 7.40 mmol) with ice-cooling and stirred at room temperature for 1 hour. The reaction solution was diluted with water and extracted with chloroform. The organic layer was washed with a saturated sodium hydrochloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (silica gel 50 g, developing solvent; hexane:ethyl acetate=6:1 2:1) to provide 736 mg (yield 98%) of 4-amino-3,5-diisopropylbenzenemethanol as colorless oil.
Reaction SMILES: C1([C@H]2OC(=O)N[C@@H]2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([C:19]#[C:20]C3C=CC=CN=3)[CH:14]=2)C=CC=CC=1.Br[C:28]1[CH:29]=[C:30]([C@@H:34]2[C@@H:38]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[CH:40]=3)[O:37][C:36](=[O:46])[NH:35]2)[CH:31]=[N:32][CH:33]=1.C[Si](C#CC1C=CC=CN=1)(C)C>>[F:45][C:41]1[CH:40]=[C:39]([C@H:38]2[O:37][C:36](=[O:46])[NH:35][C@@H:34]2[C:30]2[CH:31]=[N:32][CH:33]=[C:28]([C:20]#[C:19][C:15]3[CH:14]=[CH:13][CH:18]=[CH:17][N:16]=3)[CH:29]=2)[CH:44]=[CH:43][CH:42]=1
Reactant: O=C1N[C@H](c2cncc(Br)c2)[C@@H](c2cccc(F)c2)O1
Reactant: O=C1N[C@H](c2ccnc(C#Cc3ccccn3)c2)[C@@H](c2ccccc2)O1
Agent: C[Si](C)(C)C#Cc1ccccn1
Product: O=C1N[C@H](c2cncc(C#Cc3ccccn3)c2)[C@@H](c2cccc(F)c2)O1

Procedure:
Prepared according to the same procedure as (4R,5R)-5-phenyl-4-(2-(pyridin-2-ylethynyl)pyridin-4-yl)oxazolidin-2-one, starting with (4R,5R)-4-(5-bromopyridin-3-yl)-5-(3-fluorophenyl)oxazolidin-2-one and 2-((trimethylsilyl)ethynyl)pyridine. 1H-NMR (CDCl3, 500 MHz) δ 8.80 (bs, 1H), 8.66 (d, J=3.7, 1H), 8.49 (bs, 1H), 7.94 (s, 1H), 7.75 (ddd, J=7.9, 7.6, 1.5, 1H), 7.58 (d, J=7.6, 1H), 7.41 (ddd, J=7.9, 7.9, 5.8, 1H), 7.33 (dd, J=7.3, 5.2, 1H), 7.09 (m, 3H), 6.97 (bs, 1H), 5.29 (d, J=7.6, 1H), 4.84 (d, J=7.3, 1H). 13C-NMR (CDCl3, 126 MHz) δ 164.2, 162.2, 158.4, 153.1, 150.3, 147.6, 142.3, 139.1 (d, J=6.7), 136.9, 136.6, 131.1, 131.0, 127.6, 123.8, 121.6 (d, J=2.9), 116.6 (d, J=21), 113.0 (d, J=23), 104.3, 92.8, 84.8, 62.5. Mass spec.: 360.0 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[C:6]([CH3:11])[C:7]=1[C:8](=[O:10])[CH3:9].[Br-:18].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[Br:18][CH2:9][C:8]([C:7]1[C:6]([CH3:11])=[CH:5][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3][C:2]=1[CH3:1])=[O:10]
Reactant: [Br-]
Reactant: CC(=O)c1c(C)cc(-c2ccccc2)cc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: Cc1cc(-c2ccccc2)cc(C)c1C(=O)CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 125.2 %

Procedure:
To a solution of 1-(3,5-dimethyl-[1,1′-biphenyl]-4-yl)ethanone (1.89 g, 8.43 mmol) in acetonitrile (16.9 mL) was added tetrabutylammoniumtribromide (TBABr3, 4.07 g, 8.43 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-bromo-1-(3,5-dimethyl-[1,1′-biphenyl]-4-yl)ethanone (3.2 g), which was used directly for the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:23])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:6]([CH:11]=1)[C:7](OC)=[O:8].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(=O)=O.CC(C)=O>C1COCC1>[Br:1][C:2]1[CH:11]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:12][C:13](=[O:23])[C:14]([O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[C:7]2[OH:8]
Reactant: COC(=O)c1cc(Br)ccc1NC(=O)COc1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: O=c1[nH]c2ccc(Br)cc2c(O)c1Oc1ccc(Cl)cc1
Reaction time: 0.08 h

Procedure:
To a suspension of methyl 5-bromo-2-(2-(4-chlorophenoxy)acetamido)benzoate (5.15 g, 12.9 mmol, Intermediate 7: step a) in THF (140 mL) at −78° C. was added potassium bis(trimethylsilyl)amide (0.5 M in toluene, 76.7 mL, 38.4 mmol) over 4 minutes, and the mixture was stirred for 5 minutes. The dry-ice/acetone bath was replaced an with an ice-water bath and the reaction was stirred for 1.5 hours. The reaction was then quenched with water and ethyl acetate was added. The organic layer was removed and the aqueous layer was acidified with 2 N HCl (kept pH above 2). An off-white precipitate formed which was filtered and the solid was dried overnight in the air to yield the title compound.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@H:23]([OH:32])[CH2:24][CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)([OH:8])=[O:7].[C:33](=O)([O-])O.[Na+].[C:38]([OH:43])(=[O:42])[C:39]([OH:41])=[O:40]>CO.CCOCC>[C:38]([OH:43])(=[O:42])[C:39]([OH:41])=[O:40].[CH3:33][O:7][C:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C@H:23]([OH:32])[CH2:24][CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[CH:19][CH:20]=2)[CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: O=C([O-])O
Reactant: O=C(O)c1cccc(-c2ccc(OC[C@H](O)CCc3cccnc3)cc2)c1
Agent: O=C(O)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1cccc(-c2ccc(OC[C@H](O)CCc3cccnc3)cc2)c1
Temperature: 25 °C

Procedure:
Concentrated sulfuric acid (2.5 ml) was added to a suspension of (2R)-1-(3'-carboxybiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol (0.5 g) in methanol (50 ml). The mixture was heated at reflux for 10 hours. The mixture was cooled to room temperature and made basic by addition of aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with dichloromethane:methanol (19:1) to give an oil which was converted to the oxalate salt upon treatment with oxalic acid (excess) in ether to give the title compound as a solid (0.482 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@H:18]([CH2:21][O:22]C)[CH2:19][CH3:20])[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].I[Si](C)(C)C.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@H:18]([CH2:21][OH:22])[CH2:19][CH3:20])[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6]
Reactant: CC[C@@H](COC)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CC#N
Product: CC[C@@H](CO)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reaction time: 16 h
Yield: 82.9 %

Procedure:
To a solution of 3-hydroxy-5-({(1S)-1-[(methyloxy)methyl]propyl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide (500 mg, 1.6 mmol) in acetonitrile (25 mL), iodotrimethylsilane (1.11 mL, 7.8 mmol) was added and the resulting mixture stirred for 16 hours. Saturated sodium hydrogencarbonate solution (10 mL) was added, the solution stirred for 10 mins, saturated aqueous sodium thiosulfate (5 mL) was added then the acetonitrile was removed in vacuo. The residual aqueous layer was extracted with ethyl acetate (3×40 mL) and the organic layers combined, dried (MgSO4), filtered and evaporated and purified by column chromatography, eluting with 85% ethyl acetate in isohexane, to give the title compound as a colourless foam (405 mg). 1H NMR δ (d6-DMSO): 0.95 (t, 3H), 1.5-1.8 (m, 2H), 3.5 (m, 2H), 3.8 (s, 3H), 4.3 (m, 1H), 4.8 (t, 1H), 6.45 (s, 1H), 6.55 (s, 1H), 6.9 (s, 1H), 7.05 (s, 1H), 7.55 (s, 1H), 9.6 (s, 1H); m/z 306 (M+H)+
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:28])[N:9]2[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[C-:29]#[N:30].[K+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C(#N)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:29]([C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:28])[N:9]2[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:26])[CH3:24])[CH2:16][CH2:15]2)=[CH:4][CH:3]=1)#[N:30]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccc(Br)cc32)CC1
Reactant: [C-]#N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccc(C#N)cc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of tert-butyl {1-[2-(7-bromo-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 16) (9.85 g, 21.9 mmol) and potassium cyanide (2.14 g, 32.8 mmol) in dry acetonitrile (60 mL) was degassed and flushed with nitrogen three times. Tributyltinchloride (0.059 mmol, 1.13 mL of a 51.6 mM solution in heptane) was added, followed by 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (63 mg, 0.11 mmol) and tris(dibenzylideneacetone)dipalladium (0) (100 mg, 0.11 mmol) and it was degassed and flushed with nitrogen like above. The mixture was stirred for 30 minutes at room temperature and then degassed and flushed with nitrogen again. It was heated at 85° C. for 20 hours. The solvent was removed under reduced pressure and the residue taken up in dichloromethane (500 mL) and washed with water (200 mL). The aqueous phase was back-extracted once with dichloromethane (200 mL) and combined organic phases were dried over sodium sulfate. Solvent was removed under reduced pressure and the residue was crystallized from acetonitrile (60 mL) to give the product as a colorless solid, 6.57 g (76%), mp 202° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=2[F:33])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14](/[CH:18]=[CH:19]/[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCCCCC.C(OCC)(=O)C>C(O)C.O1CCOCC1.[Ni]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=2[F:33])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[N:13]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(c1cccc(/C=C/c2ccccn2)n1)c1cc(F)ccc1F
Agent: [Ni]
Solvent: C1COCCO1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1cccc(CCc2ccccn2)n1)c1cc(F)ccc1F
Reaction time: 1.5 h
Yield: 60.9 %

Procedure:
To a mixed solution of (E)-2-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-6-(2-pyridin-2-ylvinyl)pyridine (180 mg, 0.373 mmol) in ethanol (5 ml) and 1,4-dioxane (2 ml) was added an ethanol suspension (1 ml) of Raney nickel. Under a hydrogen atmosphere of 1 atmospheric pressure, the resulting mixture was vigorously stirred for 1.5 hours. After filtration of the reaction mixture, the filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=3:2 eluate was concentrated under reduced pressure, followed by recrystallization from hexane:ethyl acetate to give the title compound (110 mg, 0.227 mmol, 61%) as a white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:30])[CH3:9])=[CH:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O>>[O:30]=[C:11]1[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12]1
Reactant: OB(O)c1ccccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCNS(C)(=O)=O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccccn2)cc1)N1CC[C@](CCCNS(C)(=O)=O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from N-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl)methanesulfonamide and pyridine-2-boronic acid following procedures analogous to those described in Example 75 Step 1. LC-MS Method 2 tR=1.017 min, m/z=494.1; 1H NMR (CDCl3) 1.37-1.48 (m, 1H), 1.49 (d, 3H), 1.67 (m, 1H), 1.82-1.99 (m, 2H), 2.05-2.18 (m, 1H), 2.12-2.23 (m, 2H), 2.82 (m, 4H), 3.00 (m, 2H), 4.25 (m, 1H), 5.65 (m, 1H), 6.96 (d, 2H), 7.14-7.29 (m, 6H), 7.55 (d, 1H), 7.65 (m, 3H), 8.58 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:34]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:36])=[O:35])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3cnccn3)cc2)c1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3cnccn3)cc2)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step B was prepared from 3-{3-[(4-pyrazin-2-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, of Step A, and benzenesulfonyl chloride following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 8.98 (s, 1H), 8.60 (m, 1H), 8.50 (d, 1H), 7.87 (m, 4H), 7.63 (m, 1H), 7.56 (m, 2H), 7.17 (d, 2H), 7.12 (m, 1H), 7.02 (d, 1H), 6.87 (d, 1H), 6.78 (s, 1H), 4.37 (s, 2H), 4.32 (s, 2H), 3.64 (s, 3H), 2.78 (t, 2H), 2.47 (t, 2H); MS 502 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[Cl:9][C:10]1[CH:11]=[C:12]([N:15]=[C:16]=[O:17])[S:13][CH:14]=1.O>CN(C=O)C.C1(C)C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[C:12]([NH:15][C:16]([N:8]=[C:7]2[NH:6][C:4](=[O:5])[CH2:3][N:2]2[CH3:1])=[O:17])[S:13][CH:14]=1
Reactant: O=C=Nc1cc(Cl)cs1
Reactant: CN1CC(=O)N=C1N
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CN1CC(=O)NC1=NC(=O)Nc1cc(Cl)cs1
Temperature: 65 °C
Reaction time: 5 h

Procedure:
To 3.0 g (26.5 mM) of creatinine in 50 ml of anhydrous DMF was added with stirring a solution of 4-chloro-2-thienyl isocyanate in 25 ml of toluene. After stirring at 65° C. for 5 hrs., the mixture was cooled, added to 200 ml of water and filtered to separate a precipitate, which was recrystallized from ethanol and then ethyl acetate to give 1.0 g of the above urea as a light tan solid, m.p. 203°-204° C. (dec.) containing 1/8 mole of ethyl acetate of recrystallization.
Reaction SMILES: CC(O)(C)C.[CH3:6][O:7][C:8]([CH3:13])=[CH:9][C:10](=O)[CH3:11].Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>C1COCC1>[CH3:6][O:7][C:8]1[CH:13]=[C:17]([CH3:18])[C:16]2[C:10]([CH:9]=1)=[CH:11][CH:19]=[CH:20][CH:15]=2
Reactant: COC(C)=CC(C)=O
Reactant: Brc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: COc1cc(C)c2ccccc2c1
Temperature: 42.5 °C
Reaction time: 2 h
Yield: 36.8 %

Procedure:
A solution of t-BuOH (44.5 g, 600 mmol) in dry THF (240 mL) was added dropwise to a suspension of NaNH2 (84.4 g, 2.2 mmol) in dry THF (480 mL) under nitrogen. The resulting mixture was heated for 2 h at 40-45° C. After the mixture was cooled, a solution of 4-methoxypent-3-en-2-one (68.5 g, 600 mmol) in dry THF (480 mL) was added dropwise at 30-40° C. The resulting mixture was stirred at 45° C. for 2 h. A solution of bromobenzene (47.1 g, 300 mmol) in dry THF (240 mL) was added and the mixture was stirred at 55° C. for 6 h. The mixture was allowed to cool to room temperature overnight. The mixture was poured into ice, acidified with an aqueous 3 M HCl solution to pH 4-5 and extracted with EtOAc. The combined organic extracts were concentrated under reduced pressure, and the residue was diluted with acetone (480 mL) and stirred with conc. HCl solution (24 mL) for 10 min. The mixture was diluted with EtOAc (200 mL) and washed with saturated brine (200 mL). The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was subjected to flash chromatography (700 g silica gel with dry-loading, eluting by 2% EtOAc in heptanes to give orange oil (19 g, yield: 37%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[CH:11]1[C:16]2[C:17]([O:19][C:20](=[O:21])[C:15]=2[CH:14]=[C:13]2[C:22]([O:24][C:25](=[O:26])[C:12]=12)=O)=O>CC(N(C)C)=O>[CH:9]1[CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]([N:7]2[C:25](=[O:26])[C:12]3[C:13](=[CH:14][C:15]4[C:20](=[O:21])[N:7]([C:6]5[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=5)[C:17](=[O:19])[C:16]=4[CH:11]=3)[C:22]2=[O:24])[CH:8]=1
Reactant: O=c1oc(=O)c2cc3c(=O)oc(=O)c3cc12
Reactant: Nc1cccc([N+](=O)[O-])c1
Solvent: CC(=O)N(C)C
Product: O=c1c2cc3c(=O)n(-c4cccc([N+](=O)[O-])c4)c(=O)c3cc2c(=O)n1-c1cccc([N+](=O)[O-])c1
Temperature: 108 °C

Procedure:
To a stirred solution of 27.6 grams (0.20 mole) m-nitroaniline in 320 ml. DMAC was added 21.8 grams (0.10 mole) PMDA. A precipitate separated in about one minute. The mixture was heated to 108° C. over 40 minutes, during which time the precipitate changed from tan to lustrous yellow. The mixture was cooled to room temperature and filtered. The solid product was washed with benzene and dried to give yellow crystals of N,N'-bis(m-nitrophenyl) pyromellitimide having a melting point of 388° C.