Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[CH:11]=[CH2:12].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:9][C:3]1[C:2](/[CH:12]=[CH:11]/[C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=1
Reactant: Nc1ncc(Cl)cc1Br
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)/C=C/c1cc(Cl)cnc1N
Temperature: 150 °C
Yield: 44.9 %

Procedure:
A mixture of 3-bromo-5-chloro-2-pyridinamine (C. W. Murtiashaw, R. Breitenbach, S. W. Goldstein, S. L. Pezzullo, J. Quallich, R. Sarges, J. Org. Chem., 1992, 57, 1930) (8.56 g, 41.4 mmol), t-butyl acrylate (12 ml, 82 mmol), tri-o-tolylphosphine (2.92 g, 9.6 mmol) and palladium acetate (540 mg, 2.4 mmol) in triethylamine (130 ml) was heated in a sealed bomb to 150° C. for 10 hours. The reaction mixture was filtered, the residue washed with EtOAc and the combined filtrates evaporated to a dark brown oil. Purification by column chromatography upon silica gel using hexane-EtOAc (7:3) as eluant and subsequent crystallisation from hexane at −78° C. gave the title compound as a bright yellow solid (4.75 g, 18.6 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([F:10])[CH:3]=1.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14]>CN(C)C1C=CN=CC=1.CN(C=O)C.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:12][C:13]([OH:15])=[O:14])=[C:4]([F:10])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: O=C(O)CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)C=Cc1ccc(Br)cc1F
Yield: 85 %

Procedure:
A mixture of 4-bromo-2-fluorobenzaldehyde (12.4 g, 61 mmol), malonic acid (12.7 g, 122 mmol) and 4-dimethylamino pyridine (0.75 g, 6.1 mmol) in 20 mL of DMF was heated at 100 degrees Celsius for 2 hrs. After cooling, the reaction mixture was diluted with 300 mL water, and filtered. The solid was collected, and triturated in hexane. The solid was collected and dried in vacuum to give 12.7 g (85%) of a white solid. MS: calc'd 243 (M−H), exp 243 (M−H).
Reaction SMILES: [C-:1]#[C-:2].[Na+].[Na+].CN(C)P(N(C)C)(N(C)C)=O.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25]I)=[CH:19][CH:18]=1>CN(C)C=O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][C:1]#[CH:2])=[CH:19][CH:18]=1
Reactant: Fc1ccc(CCCI)cc1
Reactant: [C-]#[C-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C#CCCCc1ccc(F)cc1
Yield: 62 %

Procedure:
Subsequently, sodium acetylide (18% slurry in xylene) (50 ml) was added to hexamethylphosphoramide (20 ml) with stirring, and to the resulting mixture was furthermore added a solution of 3-(4-fluorophenyl)-1-iodopropane (7.00 g, 26.5 mmol) obtained above in dry dimethylformamide (20 ml) with stirring under ice-cooling, and then the resulting mixture was stirred at room temperature for 2 hours. After stirring, ice-cold water was added to the reaction mixture carefully with stirring under ice-cooling, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by flash chromatography on a silica gel column using hexane as the eluent to afford the title compound (2.67 g, yield: 62%) as a colorless oil.
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[CH2:20][CH2:19][CH:18]=[CH:17][C:8]=3[CH:9]=[CH:10][C:11](=[CH:12]/[CH:13]=[CH:14]/[CH:15]=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:21]([O:27][CH3:28])(=[O:26])[CH2:22][C:23]([CH3:25])=[O:24]>CCCCCC>[CH:1]1[C:6]2[C:7]3[CH2:20][CH2:19][CH:18]=[CH:17][C:8]=3[CH:9]=[CH:10][C:11](=[CH:12]/[CH:13]=[CH:14]/[CH:15]([OH:16])[CH2:25][C:23](=[O:24])[CH2:22][C:21]([O:27][CH3:28])=[O:26])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=C/C=C/C=C1C=CC2=C(CCC=C2)c2ccccc21
Solvent: CCCCCC
Product: COC(=O)CC(=O)CC(O)/C=C/C=C1C=CC2=C(CCC=C2)c2ccccc21

Procedure:
By the method of Example 1, (E)-(10H,11H-dibenzo-[a,c]cyclohepten-5-ylidene)-2-butenal (1.25 g, 4.8 mmol) was reacted methyl acetoacetate. Chromatography on silica gel (1:4, ethyl a cetate:hexane as eluant) provided title product (0.6 g).
Reaction SMILES: [O:1]=O.[C:3]1([C:9]([C:11]2[CH:12]=[C:13]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)=C)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1C=C2C(C=C(C([O-])=O)C=C2)=CC=1.C1C=C2C(C=C(C([O-])=O)C=C2)=CC=1.[Co+2].C(O)(=O)C>[C:9]([C:11]1[CH:12]=[C:13]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])[CH:14]=[CH:15][CH:16]=1)(=[O:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=C(c1ccccc1)c1cccc(C(C)C(=O)O)c1
Reactant: O=O
Agent: [Co+2]
Agent: O=C([O-])c1ccc2ccccc2c1
Solvent: CC(=O)O
Product: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1

Procedure:
To a 300 ml reaction vessel with a stirrer were fed 15 g of α-(3-(1-phenylethenyl)phenyl)propionic acid obtained in Example 2, 0.03 g of cobalt naphthenate and 100 ml of acetic acid as a solvent and 150 ml/min of pure oxygen was fed into the vessel for 16 hours at a reaction temperature of 120° C. After the reaction, the solvent was removed by reduced-pressure distillation to obtain a solid substance. The solid substance was washed five times with 500 ml of water and it was dissolved in 500 ml of ether and washed three times again with water. After that, the ether was removed by reduced-pressure distillation and the product was finally recrystallized with benzene/petroleum ether mixture to obtain 9.8 g of α-(3-benzoylphenyl)propionic acid (ketoprofen). The properties such as melting point and the spectrum of the final product were the same as those of an authentic sample.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([C:15]2[O:19][C:18]([C:20]3[CH:25]=[CH:24][C:23](B4OC(C)(C)C(C)(C)O4)=[CH:22][CH:21]=3)=[N:17][C:16]=2[CH:35]([CH3:37])[CH3:36])[CH3:14])=[CH:8][C:7]=1[CH3:38].C([O-])([O-])=O.[Na+].[Na+].Cl[C:47]1[N:52]=[CH:51][CH:50]=[CH:49][N:48]=1>C1(C)C=CC=CC=1.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]>[CH:35]([C:16]1[N:17]=[C:18]([C:20]2[CH:21]=[CH:22][C:23]([C:47]3[N:52]=[CH:51][CH:50]=[CH:49][N:48]=3)=[CH:24][CH:25]=2)[O:19][C:15]=1[CH:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:39])=[C:7]([CH3:38])[CH:8]=1)[CH3:14])([CH3:37])[CH3:36]
Reactant: Clc1ncccn1
Reactant: COC(=O)CCc1ccc(OC(C)c2oc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2C(C)C)cc1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1cc(OC(C)c2oc(-c3ccc(-c4ncccn4)cc3)nc2C(C)C)ccc1CCC(=O)O
Temperature: 100 °C

Procedure:
A solution of 3-[4-(1-{4-isopropyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazol-5-yl}-ethoxy)-2-methyl-phenyl]-propionic acid methyl ester (130 mg, 0.250 mmol) in toluene (3 mL) is bubbled with nitrogen gas for 10 minutes. To this, Pd(dppf)Cl2 (10 mg), Na2CO3 (1.0 mL, 2.0 M), 2-chloropyrimidine (43 mg, 0.375 mmol) are added. The resulting suspension is stirred and heated at 100° C. for 8 hours and quenched with water (1.0 mL). The mixture is extracted with EtOAc (20 mL×2) and the combined organics are dried (Na2SO4), concentrated, and purified on silica gel chromatography column with 20–50% EtOAc/Hexanes to yield the pyrimidine intermediate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH2:15][CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([OH:14])=O)[S:10][CH:11]=1.[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CCN(C(C)C)C(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH2:15][CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:39])[F:40])[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:14])[S:10][CH:11]=1
Reactant: CCn1ncc(Cl)c1-c1csc(C(=O)O)c1
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCn1ncc(Cl)c1-c1csc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c1
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of 4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (0.26 g, 1.0 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (0.35 g, 1.1 mmol) and DIPEA (0.5 mL, 2.86 mmol) in DCM (5 mL) at 25° C. was added PyBrOP (0.6 g, 1.2 mmol) in one portion. After 2 h, the solution was concentrated and purified via column chromatography (silica, 20-50% EtOAc/hexane) affording the title compound (0.54 g, 91%) as a white solid: LC-MS (ES) m/z=588 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12]([OH:14])[CH3:13])[CH2:11][O:10]1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26](=O)[NH:25][CH:24]=[N:23]2)=[CH:18][CH:17]=1.ClC1C=CC(N2C(=O)N([C@H](C)[C@]3(C4C=CC(F)=CC=4F)OC3)C=N2)=CC=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[C:26]([O:14][C@@H:12]([C@@:9]3([C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])[CH2:11][O:10]3)[CH3:13])=[N:25][CH:24]=[N:23]2)=[CH:20][CH:21]=1
Reactant: O=c1[nH]cnn1-c1ccc(Cl)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Agent: C[C@@H](n1cnn(-c2ccc(Cl)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](Oc1ncnn1-c1ccc(Cl)cc1)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 19.1 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.34 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl] ethanol and 1.15 g of 2-(4-chlorophenyl)-3(2H,4H)-1,2,4-triazolone, 2-(4-chlorophenyl)-4-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3(2H,4H)-1,2,4-triazolone (519 mg) and 424 mg of (2R)-2-[(1R)-1-[1-(4-chlorophenyl)-1H-1,2,4-triazol-5-yloxy]ethyl]-2-(2,4-difluorophenyl)oxirane were obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li])CCC.I[C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1.O>C1COCC1.CCOCC.CCOC(C)=O.[Cl-].[Cl-].[Zn+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1
Reactant: COc1ccccc1Br
Reactant: Brc1ccc(I)cc1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccccc1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.5 %

Procedure:
To a solution of 2-bromoanisole (3.5 g, 18.7 mmol) in 40 mL of THF at -7° C. is added n-butyl lithium (11.7 mL of a 1.6 M solution in THF, 18.7 mmol). The solution is stirred for 15 minutes. After this time, ZnCl2 (20 mL of a 1 M solution in Et2O, 20 mmol) is added. The solution is allowed to warm to ambient temperature, and stirred for 3 hours. After this time, a solution of 4-iodobromobenzene (5.6 g, 19.8 mmol) and tetrakis(triphenylphosphine)-palladium(0) (1.1 g, 1 mmol) in 30 mL of THF is added. The reaction mixture is stirred for 16 hours. After this time, the solution is poured into 100 mL of H2O. The solution is diluted with EtOAc. The organic layer is washed with 2 N NH4OH, H2O and saturated NaCl. The organic layer is dried over MgSO4, filtered, and concentrated. The crude product is purified by column chromatography eluting with gradient of 10% CH2Cl2 /hexanes to 20% CH2Cl2 /hexanes to afford the title compound (2.61 g, 10 mmol) as a crystalline solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][C:14]1[C:15]([Br:28])=[C:16]([C:25]([OH:27])=[O:26])[C:17]([Br:24])=[C:18]([C:22]=1[Br:23])[C:19]([OH:21])=[O:20]>O1CCOCC1>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:13][C:14]2[C:22]([Br:23])=[C:18]([C:19]([OH:21])=[O:20])[C:17]([Br:24])=[C:16]([C:15]=2[Br:28])[C:25]([OH:27])=[O:26])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1c(Br)c(C(=O)O)c(Br)c(C(=O)O)c1Br
Solvent: C1COCCO1
Product: O=C(Nc1c(Br)c(C(=O)O)c(Br)c(C(=O)O)c1Br)c1ccc([N+](=O)[O-])cc1

Procedure:
50 9 of para-nitrobenzoic acid chloride and 75 g of 5-amino-2,4,6-tribromoisophthalic acid in 400 ml of dioxane are maintained for 18 hours at the reflux temperature. After cooling, the precipitate is filtered off, washed with 50 ml of dioxane and dried.
Reaction SMILES: C[O:2][C:3](=[O:10])[CH2:4][CH2:5][C:6]([CH2:8]Cl)=[O:7].[CH2:11]([O:13][C:14](=[O:22])[CH2:15][CH:16](Cl)[C:17]([CH2:19]Cl)=[O:18])C.COC(=O)CCC(C)=O>>[C:3]([OH:10])(=[O:2])[CH2:4][CH2:5][C:6]([CH3:8])=[O:7].[CH3:11][O:13][C:14](=[O:22])[CH2:15][CH2:16][C:17]([CH3:19])=[O:18]
Reactant: COC(=O)CCC(=O)CCl
Reactant: CCOC(=O)CC(Cl)C(=O)CCl
Agent: COC(=O)CCC(C)=O
Product: CC(=O)CCC(=O)O

Procedure:
Preparation of 5-chlorolevulinic acid methyl ester from a mixture of 3-chloro-, 5-chloro-, 3,5-dichlorolevulinic acid ethyl ester and levulinic acid methyl ester consisting of the same product ratio, which is obtained by the bromination of both levulinic acid and levulinic acid methyl ester according to the Examples 1 and 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].OS(O)(=O)=O.[CH3:22][CH2:23]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH3:16])([CH3:15])[C:12]([O:14][CH2:22][CH3:23])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(C)(C)C(=O)O)cc1OC
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)(C)c1ccc(OC)c(OC)c1
Temperature: 25 °C

Procedure:
A solution of 2-(3,4-dimethoxyphenyl)-2-methylpropanoic acid (2.5 g, 11.15 mmol) in EtOH (50 mL) with H2SO4 (cat.) was heated at reflux 12 h. The mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc and washed with satd NaHCO3 and brine. The organic layer was dried over MgSO4, filtered and concentrated to give ethyl 2-(3,4-dimethoxyphenyl)-2-methylpropanoate (2.81 g, quant), which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 6.95-6.78 (m, 3H), 4.14 (q, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 1.56 (s, 6H), 1.19 (t. 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9](OC)=[O:10])=[C:4]([N+:17]([O-:19])=O)[CH:3]=1.O>[Pt].C(O)(=O)C>[OH:19][N:17]1[C:4]2[C:5](=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]1=[O:10]
Reactant: COC(=O)C(C(=O)OC)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)C1C(=O)N(O)c2cc(Cl)ccc21
Temperature: 60 °C

Procedure:
A mixture of dimethyl 4-chloro-2-nitrophenylmalonate (30 g, 0.10 mol), 5% Pt/C (0.15 g), water (3 mL), and acetic acid (95 mL) were charged to an autoclave reactor. The sealed autoclave was flushed with nitrogen, then charged with hydrogen (75 psig). The reaction mixture was mixed with the hydrogen, kept at constant pressure, by rapid stirring. Hydrogen was consumed over 1 hour at 30-40° C. The reaction mixture was then heated to 60° C. for 10 minutes to complete the hydrogenation with in situ cylization forming methyl N-hydroxy-6-chloro-2-oxindole-3-carboxylate. The hydrogen was then vented and replaced with nitrogen. The mixture was then heated at 105° C. for 1 hour to effect the in situ hydrolysis and decarboxylation of N-hydroxy-6-chloro-2-oxindole-3-carboxylate to N-hydroxy-6-chloro-2-oxindole. The reaction mixture was cooled to 80° C. and emptied under nitrogen pressure from the reactor as a slurry. This slurry was stirred under nitrogen until it cooled to 45° C. Filtration afforded a crude product contaminated with the catalyst. This solid was dissolved in hot tetrahydrofuran (450 mL) and filtered through a Celite pad with vacuum. Concentration to 100 mL followed by the addition of hexane (100 mL) afforded a slurry which was filtered. The solid was dried in vacuo to yield 9.85 g of N-hydroxy-6-chloro-2-oxindole (1H-NMR). Isolated yield: 54% on dimethyl 4-chloro-2-nitrophenylmalonate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][C:17]=1[O:25][CH3:26])=[O:4].Cl.CN(C)CCCN=C=NCC.[CH3:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[S:46]([NH2:49])(=[O:48])=[O:47]>O1CCCC1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:49][S:46]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[CH3:39])(=[O:47])=[O:48])=[O:22])=[CH:18][C:17]=1[O:25][CH3:26])=[O:4]
Reactant: COC(=O)c1ccc2c(c1)c(Cc1ccc(C(=O)O)cc1OC)cn2C
Reactant: Cc1ccccc1S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)c(Cc1ccc(C(=O)NS(=O)(=O)c3ccccc3C)cc1OC)cn2C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
To a solution of 4-(5-methoxycarbonyl-1-methylindol-3-ylmethyl)-3-methoxybenzoic acid (125.9 g) in tetrahydrofuran (3.0 L, distilled from sodium benzophenone ketyl) (prepared by heating at 50° C. until dissolution was complete, followed by cooling to room temperature with an ice-water bath) was added 4-dimethylaminopyridine (56.6 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (102.4 g), and the mixture was stirred one hour. To the mixture was added 2-methylbenzenesulfonamide (67.1 g), and the reaction mixture was stirred about 3 days (for convenience). The reaction mixture was diluted with ethyl acetate (2.0 L) and washed with 1N hydrochloric acid (twice) and brine (3 times, until neutral), and the aqueous extracts were back washed with ethyl acetate. The combined ethyl acetate solution was dried (MgSO4), and partially evaporated to give a slurry of solid in ethyl acetate (about 0.5 L) which was refrigerated overnight. Collection of the solid afforded the crude product (158.5 g, 88%, essentially pure by TLC) as a light pink solid. Recrystallization by dissolution in hot tetrahydrofuran (1.5 L), filtration while hot, dilution with ethyl acetate (2.0 L), and boiling down to a final volume of about 2.5 L afforded a first crop of 4-(5-methoxycarbonyl-1-methylindol-3-ylmethyl)-3-methoxy-N-(2-methylphenylsulfonyl)benzamide (105.5 g, 59%) as a white solid; mp 211°-213° C.; NMR (250 MHz, DMSO-d6): 2.60 (s, 3H, ArCH3), 3.76 (s, 3H, NCH3), 3.82 (s, 3H, CO2CH3), 3.92 (s, 3H, ArOCH3), 4.04 (s, 2H, ArCH2Ar'), 7.15 (d, 1H), 7.22 (s, 1H), 7.38-7.58 (m, 6H), 7.75 (dd, 1H), 8.03 (dd, 1H), 8.17 (d, 1H). (Two additional crops (35.5 g, 20%) and crude product (39.5 g) from concentration of the mother liquors were also obtained.)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=O)=[N:2]1.Cl.[NH2:17][OH:18].O>CN(C)C=O>[O:1]1[CH2:6][CH2:5][O:4][C:3]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=[N:17][OH:18])=[N:2]1
Reactant: NO
Reactant: O=C(C1=NOCCO1)c1ccccc1O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: ON=C(C1=NOCCO1)c1ccccc1O
Yield: 60.8 %

Procedure:
At 80° C., 4.14 g (0.02 mol) of (5,6-dihydro-1,4,2-dioxazin-3-yl)-(2-hydroxy-phenyl)-methanone (III-1) in 20 ml of dimethylformamide are stirred with 2.1 g (0.03 mol) of hydroxylamine hydrochloride for 2 hours. The reaction mixture is poured into water and the resulting mixture is extracted with ethyl acetate, and the organic phase is dried over sodium sulphate and concentrated under reduced pressure. 4.7 g of crude product consisting of 15% E isomer and 57.5% Z isomer (HPLC) are obtained. The crude product is chromatographed over silica gel using a mixture of diethyl ether and petroleum ether (1:1). 2.7 g (60.8% of theory) of (5,6-dihydro-1,4,2-dioxazin-3-yl)-(2-hydroxy-phenyl)-methanone oxime (V-1) are obtained (content according to HPLC analysis: 93.4%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24](O)=[O:25])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([F:36])([F:35])[F:34].[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24]([N:47]4[CH2:48][CH2:49][N:44]([C:42]([O:41][C:37]([CH3:40])([CH3:38])[CH3:39])=[O:43])[CH2:45][CH2:46]4)=[O:25])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([F:36])([F:34])[F:35]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Reaction time: 8 h

Procedure:
10-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 1, Step F (1.0 g, 2.04 mmol), 1-(tert-butoxycarbonyl)piperazine (0.46 g, 2.47 mmol) and 1-hydroxybenzotriazole monohydrate (0.30 g, 2.22 mmol) were dissolved in N,N-dimethylformamide (8 mL). 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (0.43 g, 2.24 mmol) was then added followed by N,N-diisopropylethyl amine (0.55 mL, 3.09 mmol). The reaction mixture was stirred overnight, diluted with ethyl acetate and washed with water and saturated aqueous sodium bicarbonate. The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown oil. Purification by flash chromatography using a solvent gradient from 30% to 50% ethyl acetate in hexane provided the desired title compound, which was redissolved in dichloromethane and evaporated to dryness in vacuo to a white foam (1.1 g).
Reaction SMILES: [C:1](#[N:4])[CH2:2][CH3:3].[CH3:5]OCOC>>[C:1](#[N:4])[CH2:2][CH3:3].[C:1](#[N:4])[C:2]([CH3:5])=[CH2:3]
Reactant: COCOC
Solvent: CCC#N
Product: C=C(C)C#N

Procedure:
With a mixture of propionitrile and methylal in a mol ratio of 1:1, a propionitrile conversion of 18 percent is obtained with a methacrylonitrile selectivity of 85 percent.
Reaction SMILES: [F:1][B-](F)(F)F.N#[O+].C(OC([N:15]1[CH2:22][CH2:21][C@:20]2([CH3:26])[C:23]([CH3:25])([CH3:24])[C@H:16]1[CH2:17][C:18]1[C:30](N)=[CH:29][CH:28]=[CH:27][C:19]=12)=O)(C)(C)C>O1CCOCC1.CO>[F:1][C:30]1[C:18]2[CH2:17][C@@H:16]3[C:23]([CH3:25])([CH3:24])[C@:20]([CH3:26])([C:19]=2[CH:27]=[CH:28][CH:29]=1)[CH2:21][CH2:22][NH:15]3
Reactant: F[B-](F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@@]2(C)c3cccc(N)c3C[C@@H]1C2(C)C
Agent: N#[O+]
Solvent: C1COCCO1
Solvent: CO
Product: CC1(C)[C@H]2Cc3c(F)cccc3[C@]1(C)CCN2
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of nitrosonium tetrafluoroborate (0.25 g) in 1,4-dioxane (2 mL) is added to a solution of (2R,6S)-10-amino-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylic acid tert-butyl ester (0.10 g) in dioxane (2 mL). The solution is heated to 50° C. and stirred at this temperature overnight. The reaction solution is diluted with methanol and then concentrated under reduced pressure. The residue is purified by HPLC on reversed phase (MeCN/H2O/F3CCO2H) to yield the title product.