Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:38]=[C:37]([Br:39])[CH:36]=[CH:35][C:10]=1[C:11]([N:13]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1)[CH2:14][C:15](=[O:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2>C(O)C>[Br:39][C:37]1[CH:38]=[C:9]2[C:10](=[CH:35][CH:36]=1)[C:11](=[O:12])[N:13]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1)[C:14]([C:15](=[O:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[C:1]2[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(CN(CC(=O)Cc2ccccc2)C(=O)c2ccc(Br)cc2C(=O)c2ccccc2)cc1
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: CS(=O)(=O)c1ccc(Cn2c(C(=O)Cc3ccccc3)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 1.4 %

Procedure:
[Step 2] To a solution (10 ml) of 2-benzoyl-4-bromo-N-(2-hydroxy-3-phenylpropyl)-N-(4-methanesulfonylbenzyl)benzamide (1.0 g) in DMSO was added triethylamine (2 ml), and pyridine sulfur trioxide complex (1.1 g) was added at room temperature. The mixture was stirred for 1 hr. and the reaction mixture was added to water. 10% Hydrochloric acid was added to acidify the aqueous layer, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-hexane:ethyl acetate=1:2) to give 2-benzoyl-4-bromo-N-(4-methanesulfonylbenzyl)-N-(2-oxo-3-phenylpropyl)benzamide (0.72 g). [Step 3] To a solution (6 ml) of 2-benzoyl-4-bromo-N-(4-methanesulfonylbenzyl)-N-(2-oxo-3-phenylpropyl)benzamide (0.3 g) in ethanol was added 1,8-diazabicyclo[5.4.0]undeca-7-ene (0.15 g), and the mixture was stirred at 80° C. for 12 hrs. The reaction mixture was concentrated under reduced pressure, water and 10% hydrochloric acid were added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel thin layer chromatography (hexane:ethyl acetate=2:1) and recrystallized (ethyl acetate-hexane) to give the title compound (4 mg).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][C:19]=1[C:27]([F:30])([F:29])[F:28]>>[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([N:2]([CH3:1])[C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:8]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[O:24])=[CH:20][C:19]=1[C:27]([F:30])([F:29])[F:28]
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: COc1ccc(C(=O)O)cc1C(F)(F)F
Product: COc1ccc(C(=O)N(C)c2cnccc2-c2ccccc2C)cc1C(F)(F)F

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 4-methoxy-3-(trifluoromethyl)benzoic acid (CAS RN 213598-09-5) after a reaction time of 88 hours. Brown solid (4%). MS (ESI): m/z=401.15 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:23]=[O:24])[C:8]([OH:22])=[C:9]([C:11]2[CH:16]=[CH:15][C:14](OC(F)(F)F)=[CH:13][CH:12]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].BrC1C(O)=C(C=C(C(C)(C)C)C=1)C=O.[F:39][C:40]([F:51])([F:50])C1C=CC(B(O)O)=CC=1>>[C:1]([C:5]1[CH:6]=[C:7]([CH:23]=[O:24])[C:8]([OH:22])=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([C:40]([F:51])([F:50])[F:39])=[CH:15][CH:16]=2)[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(OC(F)(F)F)cc2)c1
Agent: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Product: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
5-(tert-Butyl)-2-hydroxy-4′-(trifluoromethyl)-[1,1′-biphenyl]-3-carbaldehyde was prepared as a yellow oil using the procedure described in Intermediate 5 from 3-bromo-5-(tert-butyl)-2-hydroxybenzaldehyde (Intermediate 4) and 4-(trifluoromethyl)phenylboronic acid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:16][N:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:18]=2[CH2:19][CH2:20][CH2:21][CH3:22])=[C:10]([C:34]([N:36]2[C@H:45]([CH2:46]O)[CH2:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:37]2)=[O:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.P([N:97]=[N+:98]=[N-:99])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1>C1COCC1.CCOC(C)=O>[N:97]([CH2:46][C@@H:45]1[CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37][N:36]1[C:34]([C:10]1[CH:9]=[C:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH:13]=[CH:12][C:11]=1[C:14]1[C:15]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:16][N:17]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18]=1[CH2:19][CH2:20][CH2:21][CH3:22])=[O:35])=[N+:98]=[N-:99]
Reactant: CCCCc1c(-c2ccc(C(=O)OC(C)(C)C)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)c(C(=O)OCC)nn1-c1ccccc1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1c(-c2ccc(C(=O)OC(C)(C)C)cc2C(=O)N2Cc3ccccc3C[C@H]2CN=[N+]=[N-])c(C(=O)OCC)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
To a solution of ethyl 4-(4-(tert-butoxycarbonyl)-2-((S)-3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5-butyl-1-phenyl-1H-pyrazole-3-carboxylate (113 mg, 0.177 mmol) in THF (2 mL) was added triphenylphosphine (55.8 mg, 0.213 mmol) followed by DIAD (0.041 mL, 0.213 mmol) and diphenyl phosphorazidate (58 mg, 0.21 mmol). After stirring at room temperature overnight, a second addition of all three reagents was added (1.2 eq each) and stirring was continued for 3 h. The reaction mixture was diluted with EtOAc, washed with sat. aq. sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (Isco 40 g column eluting with 0-50% EtOAc/hexanes) to give the title compound (86 mg, 73%). 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.25 (s, 0.5H), 8.15-8.10 (m, 1H), 7.97 (s, 0.5H), 7.51-7.34 (m, 5H), 7.25-6.90 (m, 5H), 5.04-4.97 (m, 1.5H), 4.41-3.97 (m, 3.5H), 3.50-3.01 (m, 3.5H), 2.88-2.46 (m, 3.5H), 1.66-1.62 (m, 3H), 1.61 (s, 4.5H), 1.60 (s, 4.5H), 1.18-0.94 (m, 4H), 0.64-0.56 (m, 3H); MS(ESI) m/z 663.5 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[O:5][CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[H-].[Na+].[OH:21][C@@H:22]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH3:38])[CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>C1COCC1>[CH3:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C@H:22]([O:21][C:2]1[CH:3]=[C:4]([O:5][CH2:6][C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26]
Reactant: Cc1ccccc1[C@H](O)CCC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(OCc2cccnc2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1[C@@H](CCC(=O)OC(C)(C)C)Oc1cc(OCc2cccnc2)ccc1[N+](=O)[O-]
Yield: 28.8 %

Procedure:
3-(3-Fluoro-4-nitrophenoxymethyl)pyridine (1.53 g) is added to a stirred suspension of sodium hydride (0.48 g, 60% dispersion in mineral oil) in THF (50 mL) at ambient temperature. A solution of tert-butyl (R)-4-hydroxy-4-(2-methylphenyl)butanoate (3.08 g) in THF (30 mL) is added dropwise to the mixture over 2 hours. The reaction mixture is concentrated under reduced pressure and the residue partitioned between water (100 mL) and ethyl acetate (100 mL). The aqueous layer is extracted three times with ethyl acetate (100 mL) and the combined organic phases were dried over magnesium sulphate, filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica eluting with ethyl acetate. Fractions homogeneous in the required product are combined and evaporated to give tert-butyl (R)-4-(2-methylphenyl)-4-(2-nitro-5-(3-pyridylmethoxy)phenoxy)butanoate (0.85 g) as a yellow gum.
Reaction SMILES: C([O-])(=O)C.[Na+].C(O)(=O)C.[Cl:10][C:11]1[CH:12]=[C:13]([CH:39]=[CH:40][C:41]=1[O:42][CH:43]([CH3:45])[CH3:44])[C:14]([NH:16][C@H:17]([CH2:36][CH2:37][OH:38])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:26]=[C:27]([C:31](=[N:33][O:34]C)[CH3:32])[N:28]([CH3:30])[CH:29]=2)=[CH:21][CH:20]=1)=[O:15].C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:10][C:11]1[CH:12]=[C:13]([CH:39]=[CH:40][C:41]=1[O:42][CH:43]([CH3:45])[CH3:44])[C:14]([NH:16][C@H:17]([CH2:36][CH2:37][OH:38])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[N:26]=[C:27]([C:31](=[N:33][OH:34])[CH3:32])[N:28]([CH3:30])[CH:29]=2)=[CH:23][CH:24]=1)=[O:15]
Reactant: CON=C(C)c1nc(-c2ccc(C[C@@H](CCO)NC(=O)c3ccc(OC(C)C)c(Cl)c3)cc2)cn1C
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CC(=NO)c1nc(-c2ccc(C[C@@H](CCO)NC(=O)c3ccc(OC(C)C)c(Cl)c3)cc2)cn1C
Temperature: 65 °C
Reaction time: 2 h
Yield: 22.8 %

Procedure:
A mixture of 2-amino-4′-bromoacetophene hydrochloride (10.0 g, 40 mmol), sodium acetate (16.4 g, 200 mmol), acetic acid (11.5 mL, 200 mmol) and compound 2 (19.2 g, 80 mmol) in dioxane (70 mL) was stirred at 65° C. until TLC showed no compound 2 left (about 2 h). The reaction mixture was carefully neutralized with saturated NaHCO3 solution and extracted with ethyl acetate. The organic solution was dried over Na2SO4 and concentrated. Purification with flash column chromatography (EtOAc:Hexs 1:1) gave product 3 (9.11 g, 79%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:35])=[C:6]([C:8]2[N:17]=[C:16]([NH:18][C@@H:19]3[CH2:23]B(C(OC(C)(C)C)=O)[C@@H:21](C(OC)=O)[CH2:20]3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1.[Cl-].[NH4+:37]>C(OCC)C.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:35])=[C:6]([C:8]2[N:17]=[C:16]([NH:18][C@H:19]3[CH2:20][C@H:21]([C:5]([OH:35])([CH3:6])[CH3:4])[NH:37][CH2:23]3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1
Reactant: [NH4+]
Reactant: COC(=O)[C@H]1C[C@H](Nc2nc(-c3cc(F)ccc3O)nc3ccccc23)CB1C(=O)OC(C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(O)[C@H]1C[C@H](Nc2nc(-c3cc(F)ccc3O)nc3ccccc23)CN1
Reaction time: 1 h
Yield: 31 %

Procedure:
A Grignard solution of MeMgl (0.270 mL, 3M in diethyl ether, 0.810 mmol) was added to a solution of (2R,4R)-1-tert-butyl 2-methyl 4-(2-(5-fluoro-2-hydroxyphenyl)quinazolin-4-ylamino)borolane-1,2-dicarboxylate (0.039 g, 0.081 mmol, prepared as described in Synthesis 89-A) in THF (1 mL) and the solution refluxed for 10 h. Saturated aqueous ammonium chloride (20 mL) was added and the aqueous phase extracted with ethyl acetate (3×20 mL). Organic phases were combined, dried (MgSO4) and concentrated. The resulting crude Boc-protected amine was stirred with 4M HCl in dioxane (6 mL) for 1 h. The mixture was concentrated and the crude purified by ion exchange chromatography on SCX-2 Isolute acidic resin (2 g), eluting with methanol and then 1 M ammonia in methanol. Further purification by silica column chromatography (3 cm plug of silica), eluting with 20% methanol in dichloromethane, gave the title compound as a solid (0.012 g, 31%).
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCCl.[Al+3].[Cl-].[Cl-].[Cl-].[C:26](Cl)(=[O:28])[CH3:27]>C(OCC)(=O)C>[C:26]([C:4]1[CH:5]=[CH:6][C:1]([C@H:7]2[CH2:8][CH2:9][C@H:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][CH2:12]2)=[CH:2][CH:3]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C[C@H]1CC[C@H](c2ccccc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C[C@H]1CC[C@H](c2ccc(C(C)=O)cc2)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A 500 mL round bottom flask with a stir bar was charged with the product of Example 1B (3 g, 12.2 mmol) and 60 mL of dichloromethane. The reaction solution was cooled to 0° C. and AlCl3 (4.86 g, 36.5 mmol) was added in portions. The mixture was allowed to stir for 20 min, and then acetyl chloride (954 μL, 13.4 mmol) was added dropwise. After stirring for 15 minutes, the reaction mixture was slowly pored into a beaker with ice water and diluted with 120 mL of ethyl acetate. The layers were separated and the organic layer washed with 1 N NaHCO3 (×2), brine (×2), dried over Na2SO4, and filtered. Evaporation of the solvents afforded the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04-1.17 (m, 2 H), 1.18 (t, 3 H), 1.39-1.62 (m, 3 H), 1.68-1.88 (m, 5 H), 2.17-2.26 (m, 2 H), 2.52-2.57 (s, 3 H), 4.07 (q, J=7.12 Hz, 2 H), 7.25-7.46 (m, 2 H), 7.77-7.94 (m, 2H); MS (ESI) m/z 247 [M+H]+.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10](Cl)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C([C@H]1CC[C@H](C(O)=O)CC1)(C)C.[NH2:25][C@@H:26]([C:34]([OH:36])=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O.CC(C)=O>[CH3:2][CH:1]([CH3:3])[C@@H:4]1[CH2:9][CH2:8][C@@H:7]([C:10]([NH:25][C@H:26]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]([OH:36])=[O:35])=[O:11])[CH2:6][CH2:5]1
Reactant: CC(C)[C@H]1CC[C@H](C(=O)Cl)CC1
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Agent: CC(C)[C@H]1CC[C@H](C(=O)O)CC1
Solvent: O
Solvent: CC(C)=O
Product: CC(C)[C@H]1CC[C@H](C(=O)N[C@H](Cc2ccccc2)C(=O)O)CC1

Procedure:
U.S. Pat. No. 7,208,622 describes a process in which trans-4-isopropylcyclohexane carbonyl chloride (i.e. a derivative of trans-4-isopropylcyclohexane carboxylic acid) is reacted with D-phenylalanine in the presence of a caustic solution followed by acidification in a mixture of water and acetone and crystallization at 58-72° C. which results in Form H of nateglinide.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.Cl.[CH2:23]([NH2:25])[CH3:24]>CO.C(Cl)Cl>[CH2:23]([NH:25][CH2:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:24]
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Reactant: CCN
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCNCc1ccc2[nH]c(C(N)=O)c(Sc3ccccc3)c2c1

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph) (80 mg, 0.27 mmol) with ethylamine hydrochloride (23.9 mg, 0.30 mmol) as described in General Procedure X to afford Iad (53.0 mg, 60.4%) as an ivory colored solid, tlc Rf=0.1 (10% MeOH/CH2Cl2−0.2% Et3N), m/z obs=326 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Br)=[CH:7][CH:6]=1.C(=O)([O-])[O-:15].[Ca+2].O>O1CCOCC1>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:15])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(CBr)cc1
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)Cc1ccc(CO)cc1

Procedure:
To a stirring solution of 15 in dioxane (0.4 M) at room temperature under nitrogen was added calcium carbonate (5.5 eq) and H2O (0.8 M). The reaction was refluxed overnight then vacuum filtered. The dioxane was removed under reduced pressure. The reaction mixture was diluted with H2O then extracted with dichloromethane (3×). The organic phases were combined, dried over sodium sulfate, filtered and concentrated in vacuo to afford the product. (77%) 1H NMR (400 MHz, CDCl3) δ 7.33 (d, 2H), 7.27 (d, 2H), 4.67 (s, 2H), 3.69 (s, 3H), 3.63 (s, 2H), 1.78 (br s, 1H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([O:5][CH2:6][C:7]([CH3:12])([CH3:11])[C:8](=[O:10])[CH3:9])=[O:4].[Br:15]Br.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[F:1][C:2]([F:13])([F:14])[C:3]([O:5][CH2:6][C:7]([CH3:11])([CH3:12])[C:8](=[O:10])[CH2:9][Br:15])=[O:4]
Reactant: CC(=O)C(C)(C)COC(=O)C(F)(F)F
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(COC(=O)C(F)(F)F)C(=O)CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.5 %

Procedure:
To a stirred solution of 2,2-dimethyl-3-oxobutyl trifluoroacetate (W. C. Lumma, Jr. and O. H. Ma, J. Org. Chem., 1970, 35, 2391-2393, 8.45 g, 39.8 mmol) in chloroform (26 mL) was added bromine (1.93 mL, 37.8 mmol) in chloroform (14 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 h. The mixture was poured into crashed ice/water, and aqueous Na2S2O3 (20 mL) and aqueous NaH2PO4 (40 mL) were added. After the mixture was extracted with chloroform (3×30 mL), the extract was dried over magnesium sulfate and concentrated. Distillation of the residue at 99-102° C. under diminished pressure (3.4 mmHg) afforded 3.58 g (30%) of the title compound as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]2[C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:4]=2[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:18](Cl)(=[O:21])[CH2:19][CH3:20].Cl>ClCCl>[CH3:1][C:2]1[O:6][C:5]2[C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:18](=[O:21])[CH2:19][CH3:20]
Reactant: Cc1cc2cccc([N+](=O)[O-])c2o1
Reactant: CCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(=O)c1c(C)oc2c([N+](=O)[O-])cccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 2-methyl-7-nitrobenzo[b]furan (177 mg) and aluminum chloride (200 mg) in dichloromethane (5 ml) was added dropwise propionyl chloride (0.18 ml). The mixture was stirred at ambient temperature for 3 hours and poured into a mixture of ice and 1N-hydrochloric acid. The separated oil was extracted with dichloromethane and the extract was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was crystallized from diethyl ether to give 2-methyl-7-nitro-3-propionylbenzo[b]furan (215 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH:32]([NH2:34])[CH3:33]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:13])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:34][CH:32]([C:28]1[S:27][CH:31]=[CH:30][CH:29]=1)[CH3:33]
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CC(N)c1cccs1
Product: CC(Nc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)c1cccs1
Yield: 66.5 %

Procedure:
Use a method similar to the General Procedure 5-3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (200 mg, 0.47 mmol) with (±)-1-thiophen-2-yl-ethylamine (prepared as described in J. Amer. Chem. Soc. 1942, 64, 477-479) (200 mg, 1.57 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 9:1 and 4:1) to give (±)-7-chloro-6-[(1-thiophen-2-yl-ethyl)-amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (126 mg, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH:9]([CH3:17])[C:8](=[O:18])[N:7]([CH3:19])[C:6]=2[CH:20]=1.[NH:21]([C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1)[C:22]([NH2:24])=[NH:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:23]=[C:22]([NH:21][C:25]4[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=4)[N:24]=[CH:13][C:10]=3[CH:9]([CH3:17])[C:8](=[O:18])[N:7]([CH3:19])[C:6]=2[CH:20]=1
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Reactant: CC1C(=O)N(C)c2cc(Cl)ccc2C(=O)C1=CN(C)C
Product: CC1C(=O)N(C)c2cc(Cl)ccc2-c2nc(Nc3ccc(C(=O)O)cc3)ncc21

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-1,3-dimethyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-o) and 4-guanidinobenzoic acid were converted to I-68 (6%) after purification by C-18 RP LC-MS chromatography: HRMS Calcd. for C21H17ClN4O3: 409.1067, Found 409.1052.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][S:6]([CH3:9])(=[NH:8])=[O:7])[CH3:2].[I:11][C:12]1[C:13]([NH2:21])=[N:14][CH:15]=[C:16]([CH:20]=1)[C:17](O)=[O:18].C(NC(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[NH2:21][C:13]1[N:14]=[CH:15][C:16]([C:17]([N:8]=[S:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:10])([CH3:9])=[O:7])=[O:18])=[CH:20][C:12]=1[I:11]
Reactant: CCOC(=O)CS(C)(=N)=O
Reactant: Nc1ncc(C(=O)O)cc1I
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CS(C)(=O)=NC(=O)c1cnc(N)c(I)c1
Temperature: 70 °C

Procedure:
A solution of ethyl(S-methylsulfonimidoyl)acetate was dissolved in anhydrous DMF (1 mL) and treated with 5-iodo-6-amino-nicotinic acid (82 mg, 1.05 eq), diisopropylamine (0.1 mL, 2 eq), and BOP (149 mg, 1.1 eq) with stirring. The reaction mixture was heated to 70° C. for 6 hours and then partitioned between EtOAc and aq NH4Cl. The organic layer was separated, washed with saturated aq NaHCO3 (1×) and brine (1×), and dried over Na2SO4. The organic phase was filtered and concentrated. The residue as purified by gradient column chromatography (EtOAc-Hexane 1:9 to 2:3). Concentration of the product containing fractions provided the title compound as a brown oil (24 mg).
Reaction SMILES: C(N1CC[CH2:6][CH:5](CCN2C(OC)=NC3C2=NC(O[C@@H](C)CCC)=NC=3N)[CH2:4]1)C.[CH2:29]([O:33][C:34]1[N:42]=[C:41]2[C:37]([N:38]=[C:39]([O:54][CH3:55])[N:40]2[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH:48]2[CH2:53][CH2:52][CH2:51][NH:50][CH2:49]2)=[C:36]([NH2:56])[N:35]=1)[CH2:30][CH2:31][CH3:32].IC(C)C>>[CH2:29]([O:33][C:34]1[N:42]=[C:41]2[C:37]([N:38]=[C:39]([O:54][CH3:55])[N:40]2[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH:48]2[CH2:53][CH2:52][CH2:51][N:50]([CH:5]([CH3:6])[CH3:4])[CH2:49]2)=[C:36]([NH2:56])[N:35]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCN(CC)C3)c2n1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCC3CCCNC3)c2n1
Solvent: CC(C)I
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCC3CCCN(C(C)C)C3)c2n1

Procedure:
Prepared similarly to Intermediate 46 from 2-(butyloxy)-8-(methyloxy)-9-[5-(3-piperidinyl)pentyl]-9H-purin-6-amine and 2-iodopropane.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[O:3].Cl.[CH3:8][Si:9]([O:12][C:13](=[O:19])[C@H:14]([CH:16]([CH3:18])[CH3:17])[NH2:15])([CH3:11])[CH3:10]>>[CH3:11][Si:9]([O:12][C:13](=[O:19])[C@H:14]([CH:16]([CH3:17])[CH3:18])[NH:15][C:1](=[O:5])[C:2]([CH3:4])=[O:3])([CH3:8])[CH3:10]
Reactant: CC(=O)C(=O)Cl
Reactant: CC(C)[C@H](N)C(=O)O[Si](C)(C)C
Agent: Cl
Product: CC(=O)C(=O)N[C@H](C(=O)O[Si](C)(C)C)C(C)C

Procedure:
A method of synthesizing pyruvyl-valine according to the invention comprises the steps of reacting sodium pyruvate with oxalyl chloride to yield pyruvyl chloride, then reacting the pyruvylchloride with a suspension of valine trimethylsilyl ester hydrochloride to yield pyruvyl-valine trimethylsilyl ester and then subjecting the pyruvyl-valine trimethylsilyl ester to hydrolysis to yield pyruvyl-valine. The pyruvyl-valine synthesized via the route set forth above serves as a pyruvyl-amino acid pyruvate precursor.