Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:11](=[O:28])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C([N-]C(C)C)(C)C.[Li+].Cl[C:38]([O:40][C:41]1[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=1)=[O:39]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[C:11](=[O:28])[N:10]2[C:38]([O:40][C:41]2[CH:42]=[CH:43][C:44]([N+:47]([O-:49])=[O:48])=[CH:45][CH:46]=2)=[O:39])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CN2C(=O)NC(c3ccc(F)c(F)c3)c3ccccc32)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)N(C(=O)Oc3ccc([N+](=O)[O-])cc3)C(c3ccc(F)c(F)c3)c3ccccc32)cc1

Procedure:
The title compound was prepared by treating 10 (0.292 g, 0.767 mmol) with lithium diisopropylamide (2.0 M THF solution, 1.1 equivalents) in THF at −78° C. for 20 minutes followed by the rapid addition of 4-nitrophenyl chloroformate (1.5 equivalents) in THF. The 1H NMR was consistent with the assigned structure.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([I:10])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.[NH3:15]>CO>[I:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH2:15])=[O:2])=[CH:5][C:6]=1[N+:11]([O-:13])=[O:12]
Reactant: COC(=O)c1ccc(I)c([N+](=O)[O-])c1
Reactant: N
Solvent: CO
Product: NC(=O)c1ccc(I)c([N+](=O)[O-])c1
Yield: 95 %

Procedure:
A solution of 4-iodo-3-nitrobenzoic acid methyl ester (2.0 g, 6.5 mmol) in methanol (80 ml) is cooled to −15° C. To the solution, ammonia gas (about 1.02 g, 0.06 mol) is passed till saturation. The solution is kept at room temperature (25±2° C.) for 3 days. The solvent is then evaporated under reduced pressure to obtain 4-iodo-3-nitrobenzamide as an yellow solid (95% yield, 98% HPLC). The solid (1 g) is added to methanol (10 ml) and heated to 55° C. to get a clear solution. While the solution is hot, water (35 ml) is added and the precipitate so formed is filtered to obtain pure 4-iodo-3-nitrobenzamide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([Cl:24])[CH:3]=1.[C:25]([N:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33])(=[O:27])[CH3:26]>>[C:25]([N:28]1[CH2:32][CH2:31][N:30]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[C:4]([Cl:24])[CH:3]=2)[C:29]1=[O:33])(=[O:27])[CH3:26]
Reactant: CC(=O)N1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3Cl)CC2)c(C)c1
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C)cc4C)CC3)c(Cl)c2)C1=O
Yield: 53 %

Procedure:
Using (4-bromo-2-chlorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (409 mg) described in Preparation Example 119 and 1-acetylimidazolidin-2-one (192 mg) and by the reaction and treatment in the same manner as in Example 511, the title compound (242 mg) was obtained.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C([O:10][C:11](=[O:42])[CH:12]([CH2:36][C:37]([O:39]CC)=[O:38])[S:13][C:14](=[O:35])[CH:15]([CH3:34])[CH2:16][C:17]1[O:18][C:19]([C:22]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31](=[NH:33])[NH2:32])=[CH:27][CH:26]=2)=[O:23])=[CH:20][CH:21]=1)C.Cl.O1CCOCC1>O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:31]([C:28]1[CH:27]=[CH:26][C:25]([O:24][C:22]([C:19]2[O:18][C:17]([CH2:16][CH:15]([CH3:34])[C:14]([S:13][CH:12]([CH2:36][C:37]([OH:39])=[O:38])[C:11]([OH:42])=[O:10])=[O:35])=[CH:21][CH:20]=2)=[O:23])=[CH:30][CH:29]=1)(=[NH:32])[NH2:33]
Reactant: CCOC(=O)CC(SC(=O)C(C)Cc1ccc(C(=O)Oc2ccc(C(=N)N)cc2)o1)C(=O)OCC
Agent: Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CC(Cc1ccc(C(=O)Oc2ccc(C(=N)N)cc2)o1)C(=O)SC(CC(=O)O)C(=O)O
Yield: 27.4 %

Procedure:
To S-{3-[5-(4-amidinophenoxycarbonyl)furan-2-yl]-2-methylpropionyl}thiomalic acid diethyl ester trifluoroacetic acid salt (40 mg, 0.065 mmol) obtained in step 1 was added 4N hydrochloric acid/dioxane solution:water=3:1 (500 μL), and the mixture was stirred at 60° C. overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by high performance liquid chromatography (acetonitrile-water, each containing 0.1% trifluoroacetic acid, 10-45%) to give the title compound (5.0 mg, 0.0089 mmol, 14%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH:17]=[CH:16][C:11]([C:12](OC)=[O:13])=[CH:10][N:9]=1.CCOC(C)=O.O>C1COCC1.C(OCC)C>[CH3:7][C:8]1[N:9]=[CH:10][C:11]([CH2:12][OH:13])=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(C)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(CO)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
To a solution of lithium aluminum hydride (1 M in diethyl ether, 80 mL, 80 mmol) in 20 mL THF at −78° C. under argon, a solution of methyl 6-methylnicotinate (6.05 g, 40 mmol) in 60 mL diethyl ether was added over 1 h. The resulting reaction mixture was stirred at −78° C. for 1 h before 12 mL EtOAc was added over 10 min. The reaction mixture was allowed to warm up to 0° C. and 12 mL water was added drop-wise over 10 min. The resulting mixture was stirred for 30 min, then filtered through Celite. The filtrate was dried (Na2SO4), filtered and concentrated to obtain 3.07 g (62%) of the title compound as an off-white solid. HPLC: retention time=0.19 min.
Reaction SMILES: [Br:1][CH:2]([CH2:12][CH2:13]Br)[C:3]([NH:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4].[H-].[Na+]>C1C=CC=CC=1.C(OCC)(=O)C>[Br:1][CH:2]1[CH2:12][CH2:13][N:5]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:3]1=[O:4]
Reactant: CCOC(=O)CNC(=O)C(Br)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1CCC(Br)C1=O
Reaction time: 0.17 h
Yield: 24.3 %

Procedure:
To a stirred solution of crude ethyl 2-(2,4-dibromobutanamido)acetate (2.847 g, 8.60 mmol) in benzene (8.6 mL) at 5° C. was added portionwise a 60% mineral oil dispersion (344 mg) of sodium hydride (206 mg, 8.60 mmol) over 20 minutes. The reaction was stirred an additional 10 minutes before being poured onto ice water and diluted with ethyl acetate. The layers were separated. The organic phase was brine-washed, dried over sodium sulfate, filtered, concentrated down, and dried. The mixture of starting dibromide and product was purified by eluting through a silica gel column with a 0 to 100% ethyl acetate/heptane gradient to afford the title racemic compound (523 mg, 24% yield) as a clear oil. MS (ESI) [m/e, (M+H)+]=251.5. 1H NMR (400 MHz, chloroform-d) δ ppm 4.46 (dd, J=7.07, 3.03 Hz, 1H), 3.96-4.28 (m, 4H), 3.63-3.72 (m, 1H), 3.43-3.53 (m, 1H), 2.63-2.76 (m, 1H), 2.34-2.43 (m, 1H), 1.26-1.34 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([O:13][CH3:14])[CH:12]=1)[C:9]([OH:15])=[N:8][CH:7]=[CH:6]2.I[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.O.CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([O:13][CH3:14])[CH:12]=1)[C:9](=[O:15])[N:8]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH:7]=[CH:6]2
Reactant: COc1cc(OC)c2c(O)nccc2c1
Reactant: COc1ccc(I)cc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(-n2ccc3cc(OC)cc(OC)c3c2=O)cc1
Temperature: 120 °C
Yield: 88 %

Procedure:
6,8-Dimethoxyisoquinolin-1-ol (1.59 g, 7.75 mmol), 4-iodoanisole (2.72, 11.62 mmol), copper(I) iodide (0.30 g, 1.55 mmol), L-proline (0.36 g, 3.10 mmol) and anhydrous potassium carbonate (2.14 g, 15.50 mmol) were placed in a dry 250 mL three-necked round-bottomed flask fitted with a stirring bar and reflux condenser. The system was vacuumed and refilled with dry argon. Then, anhydrous methyl sulfoxide (50 mL) was added via a syringe under argon atmosphere. The reaction solution was stirred and heated to 120° C. for 20 h. Water (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (5×20 mL). The extracts were combined, washed with brine (3×10 mL) and dried over anhydrous MgSO4 followed by filtration and concentration to give a yellow residue. The yellow residue was purified by flash column chromatography (silica-gel, EtOAc) to give a pale-yellow solid product, 2.12 g, 88.0% yield. MS: m/z 312.9 [M+H]+. 1H NMR (DMSO-d6, 300 MHz): δ 7.31-7.26 (m, 3H), 7.02 (d, 2H, J=8.7 Hz), 6.71 (d, 1H, J=2.4 Hz), 6.54 (d, 1H, J=2.4 Hz), 6.45 (d, 1H, J=7.8 Hz), 3.87 (s, 3H), 3.81 (s, 3H), 3.79 (s, 3H).
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.[N+:9]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14])([O-:11])=[O:10]>CCOC(C)=O>[N+:9]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[N:14]=[C:4]=[O:3])([O-:11])=[O:10]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccccc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: O=C=Nc1ccccc1[N+](=O)[O-]

Procedure:
Method a (from 2-nitroanilines): To a solution of diphosgene (4.1 mL, 34.1 mmol) in EtOAc (40 mL) at 0° C. was added a solution of the 2-nitroaniline (45.5 mmol) in EtOAc (200–500 mL), and the mixture was heated to reflux for 18 h. The solvent was removed in vacuum to leave a brown solid, which was triturated with hot hexane (200 mL). The solid material was filtered off and the filtrate was concentrated under reduced pressure to leave the pure 2-nitrophenylisocyanate as a yellow solid. This material was refluxed in a mixture of excess tert-BuOH in CH2Cl2 for 2.5 h. Removal of the solvent left an orange solid which was purified by silica gel column chromatography with hexane/EtOAc to give the (2-nitro-phenyl)-carbamic acid tert-butyl ester as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11](=[NH:13])[NH2:12])[CH:5]=[CH:6][C:7]=1[F:8].[OH:14]/[CH:15]=[C:16](/[CH2:21][C:22]1[CH:23]=[N:24][C:25]([O:28][CH3:29])=[N:26][CH:27]=1)\[C:17](OC)=O.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[CH2:9][CH2:10][C:11]1[NH:12][CH:17]=[C:16]([CH2:21][C:22]2[CH:23]=[N:24][C:25]([O:28][CH3:29])=[N:26][CH:27]=2)[C:15](=[O:14])[N:13]=1
Reactant: N=C(N)CCc1ccc(F)c(Br)c1
Reactant: COC(=O)/C(=C\O)Cc1cnc(OC)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ncc(Cc2c[nH]c(CCc3ccc(F)c(Br)c3)nc2=O)cn1
Temperature: 130 °C
Yield: 42.8 %

Procedure:
The mixture of 3-(3-bromo-4-fluorophenyl)propanimidamide (3.28 g, 13.38 mmol), methyl (2Z)-3-hydroxy-2-{[2-(methyloxy)-5-pyrimidinyl]methyl}-2-propenoate (1.5 g, 6.69 mmol) and K2CO3 (2.77 g, 20.07 mmol) in NMP (20 mL) was heated with a microwave reactor at 130° C. for 2 h. The mixture was purified with a reverse phase Biotage to provide the title compound (1.2 g, 40.6% yield). LCMS: rt=2.52 min, [M+H+]=419
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:7]=1.N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:20]([CH3:19])(=[O:22])=[O:21])[CH:7]=1
Reactant: Brc1cncc(C2CCCN2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)N1CCCC1c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a stirred solution of 3-bromo-5-(2-pyrrolidinyl)pyridine (0.2 g, 0.881 mmol) and pyridine (0.157 mL, 1.937 mmol) in DCM (1 mL) is added methanesulfonyl chloride in DCM (1 mL) dropwise. The mixture is stirred at room temperature for 2 h. The mixture is concentrated. The resulting crude product is purified by normal phase chromatography using 0-3% MeOH in DCM as the gradient to afford 3-bromo-5-(1-methanesulfonyl-pyrrolidin-2-yl)-pyridine (211.2 mg, 79% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([C:23]([OH:26])([CH3:25])[CH3:24])[CH2:18]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][C@@H:28]([CH2:31][CH3:32])[CH2:29][NH2:30]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)[C@@H:17]([OH:21])[CH2:18][C@@H:19]([C:23]([OH:26])([CH3:25])[CH3:24])[C:20]([NH:30][CH2:29][C@@H:28]([CH3:27])[CH2:31][CH3:32])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@H](C)CN
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1C[C@@H](C(C)(C)O)C(=O)O1
Product: CC[C@H](C)CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(C)(C)O
Yield: 92.5 %

Procedure:
A solution of 500 mg (1.35 mmoles) of (3S, 5S)-5-[(1S)-1-(N-t-butoxycarbonylamino)-2-cyclohexylethyl]-3-(1-hydroxy-1-methylethyl)dihydrofuran-2(3H)-one (prepared as described in Preparation 6) in 1.00 g (11.5 mmoles) of 2(S)-methylbutylamine was stirred at 100° C. for 4 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was purified by medium pressure silica gel column chromatography (using a 20:1 by volume mixture of methylene chloride and methanol as eluent), to give 570 mg (yield 92%) of the title compound as white crystals, melting at 64°-67° C.
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:20][C:19]=3[Cl:35])=[CH:14][CH:13]=2)[C:9]([CH3:36])=[N:8][C:7]=1[CH3:37])(=[O:5])[NH2:4]>CC(O)(C)C>[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:20][C:19]=3[Cl:35])=[CH:14][CH:13]=2)[C:9]([CH3:36])=[N:8][C:7]=1[CH3:37])(=[O:5])[NH2:4]
Reactant: CCOC(=O)CCNC(=O)Cc1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: Cc1nc(C)c(-c2ccc(-c3ccc(CC(=O)NCCC(=O)O)cc3Cl)cc2)nc1C(N)=O
Temperature: 45 °C
Reaction time: 5 h
Yield: 15.5 %

Procedure:
Potassium hydroxide (131 mg, 2.34 mmol) was added in one portion to ethyl 3-(2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetamido)propanoate (Intermediate 16-1; 386.5 mg, 0.78 mmol) in t-BuOH (5038 μL) at RT. The resulting solution was stirred at 45° C. for 5 hours a precipitate formed. The reaction mixture was quenched with 2M HCl (5 mL), The reaction mixture was evaporated to dryness and redissolved in water (10 mL), and filtered through nylon, washed with water and dried under vacuum. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 3-(2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetamido)propanoic acid (56.4 mg, 15.47%) as a white solid.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].C(N(CC)CC)C.C(=O)=O.[N+](C1C=CC([O:28][C:29](=O)[C@@H:30]2[CH2:34][CH2:33][CH2:32][N:31]2[C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])=CC=1)([O-])=O.Cl>O1CCOCC1.O>[C:35]([N:31]1[CH2:32][CH2:33][CH2:34][C@H:30]1[C:29]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:28])([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CC(C)[C@H](N)C(=O)O
Agent: Cl
Agent: O=C=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)O
Reaction time: 20 h
Yield: 68.4 %

Procedure:
L-Valine (30 mmol, 3.52 g) and triethylamine (60 mmol, 8.36 mL) were combined in 275 mL of 1:1 dioxane-water. Solid carbon dioxide pieces were added with stirring to achieve pH 8.5, and then N-CBZ-L-proline 4-nitrophenyl ester (Sigma, 30 mmol, 11.11 g) was added to the solution with stirring at room temperature. After 20 hours, the clear yellow solution was acidified by gradual addition of 1 N HCl, concentrated by rotary evaporation at reduced pressure, and diluted with ethyl acetate. The organic phase was separated, washed with water (5×) and brine (2×), dried (MgSO4), and rotovapped to give an oil residue. Crystallization of this residue from hot ethyl acetate-hexane afforded 7.15 g (68%) of N-CBZ-L-prolyl-L-valine as a white solid, m.p. 132°-134° C., lit. m.p. 134°-136° C.; G. R. Pettit, "Synthetic Peptides," Vol. 1, 154 (1970).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[NH:17][C:18](=O)[C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21]([N+:28]([O-:30])=[O:29])[CH:20]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1(C)C=CC=CC=1.P(Cl)(Cl)(Cl)=O>C(#N)C>[CH3:10][O:9][C:8]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[C@H:11]1[C@H:12]([CH2:13][CH2:14][CH2:15][CH2:16]1)[N:17]=[C:18]2[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21]([N+:28]([O-:30])=[O:29])[CH:20]=1
Reactant: COc1ccc([C@H]2CCCC[C@H]2NC(=O)c2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1OC
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2c(cc1OC)[C@@H]1CCCC[C@@H]1N=C2c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1

Procedure:
7.5 g of (−)-cis-N-[2-(3,4-dimethoxyphenyl)cyclohexyl]-3,4-dinitrobenzamide (compound A1) are dissolved in 120 ml of acetonitrile or toluene and 3.5 ml of phosphorus oxychloride and the solution is stirred overnight at 80° C. The reaction mixture is concentrated under reduced pressure and the residue is extracted with satd. sodium hydrogencarbonate solution and ethyl acetate. The organic phases are dried using sodium sulfate and concentrated. The residue is recrystallized from ethyl acetate. M.p.: 162-165° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[C:15]2[CH:16]=[CH:17][O:18][C:14]=2[C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].C([O-])(=O)C.[NH4+]>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[C].[Pd].O.O1CCOCC1>[F:9][C:10]1[C:15]2[CH2:16][CH2:17][O:18][C:14]=2[C:13]([C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)=[CH:12][CH:11]=1
Reactant: OB(O)c1ccc(F)c2ccoc12
Reactant: Oc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: Oc1ccc(-c2ccc(F)c3c2OCC3)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 11 %

Procedure:
1,4-Dioxane (12 mL) and water (4 mL) were added to 4-bromophenol (315 mg, 1.82 mmol), 4-fluorobenzofuran-7-boronic acid (360 mg, 2.00 mmol), sodium carbonate (405 mg, 3.82 mmol), and Pd(dppf)Cl2 (catalytic amount), and stirred at 100° C. for 2 hours and a half. The reaction solution was concentrated under reduced pressure. To the residue, ethyl acetate and 1N hydrochloric acid were added and stirred. After that, the insoluble material was filtered off, and extraction was performed with ethyl acetate. The organic phase was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane/ethyl acetate). To the resulting solid (352 mg, 1.54 mmol), ammonium acetate (59 mg, 0.770 mmol) was added. After dissolved in methanol (35 mL), the reaction was carried out using a continuous hydrogenation reaction apparatus (10% palladium-carbon, 50 bar, 50° C., 1 mL/minute, once). The reaction solution was concentrated under reduced pressure. The resulting residue was dissolved in ethanol (35 mL) and chloroform (1 mL), and reacted using a continuous hydrogenation reaction apparatus (10% palladium-carbon, 50 bar, 60° C., 1 mL/minute, 3 times). The reaction solution was concentrated under reduced pressure. The resulting residue was purified by reversed-phase HPLC in the same manner as in Step 2 of Example 1 to thus obtain the title compound.
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.S(=O)(=O)(O)O.[CH3:20][CH2:21]O>>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:10]([O:12][CH2:20][CH3:21])=[O:11])=[CH:13][CH:14]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCO
Reactant: O=C(O)c1ccc(-n2cccn2)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(-n2cccn2)cc1
Reaction time: 71 h

Procedure:
To a solution of 4-(1H-pyrazol-1-yl)benzoic acid (CAS 160209-00-0, 678 mg, 3.60 mmol) in absolute EtOH (10 mL) was added sulfuric acid (0.1 mL) at room temperature. The reaction mixture was heated to reflux and stirred for 71 h, then concentrated under reduced pressure. The residue was partitioned between sat. aq. NaHCO3 (60 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to provide the title compound as an off white solid (711 mg, 91%): 1H NMR (400 MHz, CDCl3, δ in ppm) 8.14 (d, J=8.6 Hz, 2H), 8.01 (d, J=2.5 Hz, 1H), 7.78 (d, J=8.8 Hz, 2H), 7.78-7.75 (m, 1H), 6.51 (t, J=1.8 Hz, 1H), 4.39 (q, J=7.2 Hz, 2H), 1.41 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:24])[C@H:12]2[C@@H:15](OS(OCC)(=O)=O)[CH3:16])[C:9]=1[C:25]([O:27][CH3:28])=[O:26])(=[O:3])[CH3:2].C([O-])(=O)C.[K+]>C(O)C>[C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:24])/[C:12]/2=[CH:15]/[CH3:16])[C:9]=1[C:25]([O:27][CH3:28])=[O:26])(=[O:3])[CH3:2]
Reactant: CCOS(=O)(=O)O[C@@H](C)[C@@H]1C(=O)N2C(C(=O)OC)=C(S/C=C/NC(C)=O)C[C@H]12
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Product: C/C=C1/C(=O)N2C(C(=O)OC)=C(S/C=C/NC(C)=O)C[C@H]12
Yield: 47 %

Procedure:
Methyl (5R,6R)-3-[(E)-2-acetamidoethenylthio]-6-[(S)-1-ethoxysulphonyloxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (e22) (42 mg) was taken up in ethanol (2 ml) and treated with anhydrous potassium acetate (50 mg). After 90 minutes the solvent was removed by evaporation and the product dissolved in ethyl acetate (10 ml) and washed with water (10 ml), and with brine (10 ml) and then dried (MgSO4) and evaporated. The i.r. and u.v. spectra of crude material showed that the ethylidene compound had been formed. This was purified by chromatography on silica gel to give methyl (5R,6E)-3-[(E)-2-acetamidoethenylthio]-6-ethylidene-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (e34) (14 mg). νmax (CH2Cl2) 1780, 1705, 1625 cm-1. δ[CDCl3 +1 drop (CD3)2CO] 1.79 (3 H, d, J 7 Hz, CH3CH=), 2.02 (3H, s, CH3CO), 2.90 (1H, dd, J 18 Hz and 8.5 Hz, HA of ABX), 3.16 (1H, dd, J 18 and 9.5 Hz, HB of ABX), 3.78 (3H, s, OCH3), 4.69 (1H, broad t, CH.CH2), 5.84 (1H, d, J 14 Hz SCH:CH), 6.33 (1H, broad q, J 7 Hz, CH3CH=), 7.18 (1H, dd, J 14 and 10 Hz, NH.CH=CH), 8.86 (1H, broad d, J 10 Hz, CONH.CH) p.p.m.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[C:5]([OH:8])(=[O:7])[CH3:6]>>[C:5]([O:8][C:2]([CH3:3])([CH3:1])[CH3:4])(=[O:7])[CH3:6].[CH3:3][C:2](=[CH2:1])[CH3:4]
Reactant: CC(=O)O
Agent: C=C(C)C
Product: CC(=O)OC(C)(C)C

Procedure:
U.S. Pat. No. 3,102,905 describes a process for producing t-butyl acetate by the reaction of isobutylene and acetic acid in the presence of an organic sulfonic acid in the liquid phase. The crude product is then purified by means of distillation to give t-butyl acetate free of isobutylene.