Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@@H:4]([NH:6][C:7]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[N:10]=[C:9]([C:20]([NH2:22])=[O:21])[CH:8]=1)[CH3:5])(=[O:3])[NH2:2].F[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([C@@H:4]([NH:6][C:7]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:24]3[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=3)=[CH:15][CH:14]=2)[N:10]=[C:9]([C:20]([NH2:22])=[O:21])[CH:8]=1)[CH3:5])(=[O:3])[NH2:2]
Reactant: N#Cc1ccc(F)cc1
Reactant: C[C@H](Nc1cc(C(N)=O)nc(-c2ccc(O)cc2)n1)C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H](Nc1cc(C(N)=O)nc(-c2ccc(Oc3ccc(C#N)cc3)cc2)n1)C(N)=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 36.4 %

Procedure:
A 50-mL vial with a screw-top septum was charged with 6-((S)-1-carbamoyl-ethylamino)-2-(4-hydroxy-phenyl)-pyrimidine-4-carboxylic acid amide (100 mg, 0.3 mmol), 4-fluorobenzo-nitrile (40 mg, 0.3 mmol), potassium carbonate (92 mg, 0.7 mmol), and N,N-dimethylformamide (5 mL). The flask was purged with nitrogen and heated to 100° C. for 16 h at which time the reaction was complete. The mixture was then diluted with 20 mL water and extracted with 2×20 mL EtOAc. The combined organic layers were dried over sodium sulfate and concentrated under vacuum. The residue was dissolved in 20% methanol/chloroform and passed through a short plug of silica gel. The fractions containing the desired material were concentrated and suspended in a solution of 20% EtOAc/hexane. The suspension was filtered by vacuum and air was allowed to pass over the cake for one hour. The cake was then transferred to a scintillation vial, powdered, and heated under vacuum for one hour to provide the title compound as a white solid (44 mg, 33%). 1H NMR (DMSO-d6): 8.66-8.59 (m, 2H), 8.35-8.28 (s, 1H), 8.02-7.95 (m, 1H), 7.91-7.84 (m, 2H), 7.79-7.70 (s, 1H), 7.59-7.51 (s, 1H), 7.25-7.15 (m, 4H), 7.14-7.08 (s, 1H), 7.05-6.97 (s, 1H), 4.64-4.49 (m, 1H), 1.43-1.31 (m, 3H). LC/MS: m/z 402[M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[S:7]1[C:11]2[CH:12]=[C:13]([N:16]3[CH2:20][CH2:19][N:18]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][C:26]=4[CH:27]=O)[C:17]3=[O:29])[CH:14]=[CH:15][C:10]=2[N:9]=[CH:8]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CO>C(O)(=O)C.C(Cl)(Cl)Cl>[S:7]1[C:11]2[CH:12]=[C:13]([N:16]3[CH2:20][CH2:19][N:18]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][C:26]=4[CH2:27][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[C:17]3=[O:29])[CH:14]=[CH:15][C:10]=2[N:9]=[CH:8]1
Reactant: C1COCCN1
Reactant: O=Cc1ccncc1N1CCN(c2ccc3ncsc3c2)C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C1N(c2ccc3ncsc3c2)CCN1c1cnccc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 20.5 %

Procedure:
Morpholine (0.032 mL, 0.3699 mmol) was added to a stirred solution of 3-(3-Benzothiazol-6-yl-2-oxo-imidazolidin-1-yl)-pyridine-4-carbaldehyde (I-177b: 100 mg, 0.3082 mmol) in acetic acid (2 mL) and stirred at room temperature for 4 hours. This was followed by the addition of NaBH(OAc)3 (98 mg, 0.4624 mmol). The resulting reaction mass was stirred at room temperature for 24 hours. The reaction was monitored by TLC (10% methanol in chloroform). The reaction mixture was concentrated under reduced pressure, added ice, basified using saturated NaHCO3 solution and extracted using ethyl acetate. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (2% methanol in chloroform) followed by preparative HPLC afforded 25 mg of the product (20.6% yield).
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=[O:6])[NH:4]1)(=[O:3])=[O:2].[Na].[OH2:14]>CN(C)C=O>[O:3]=[S:1]1(=[O:2])[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:5](=[O:6])[N:4]1[CH2:9][CH2:8][CH2:7][C:12](=[O:14])[CH3:11]
Reactant: O
Reactant: O=C1NS(=O)(=O)c2ccccc21
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(=O)CCCN1C(=O)c2ccccc2S1(=O)=O
Temperature: 170 °C

Procedure:
A mixture of the above ketal (3.2 gm, 15 mmol) and sodium saccharin (3.1 gm, 14 mmol) in dimethylformamide (15 mL) was heated at 170° C. for 5 hours. The cooled reaction mixture was poured into water and the crude product extracted into ethyl acetate. The dried extract was evaporated and the crude product was chromotographed on a column of silica gel eluting with a gradient of 20-40% EtOAc/hexane to give crystalline 1,1-dioxido-2-(4-oxo-pentyl)-1,2-benzisothiazol-3(2H)-one, melting point 90-93° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:22][CH3:23])=[C:4]([CH:8]=[C:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[Br:1][C:2]1[C:3]([CH2:22][CH3:23])=[C:4]([CH:8]=[C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1c(Br)cccc1C=C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1c(Br)cccc1C=C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[(3-bromo-2-ethylphenyl)methylidene]-1-piperidinecarboxylate (D136) (3 g, 7.89 mmol) in Dichloromethane (DCM) (100 mL) was added TFA (6.08 mL, 79 mmol). The reaction solution was stirred at room temperature for 2 hours. The solvent was evaporated in vacuo to afford 4-[(3-bromo-2-ethylphenyl)methylidene]piperidine (D137) (1.9 g), which was used directly without further purification. MS (ES): C14H18BrN requires 279.1. found 280.1 (M+H+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[O:16][CH3:17].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:15][O:14][C:12]1[CH:13]=[CH:8][C:9]([O:16][CH3:17])=[CH:10][C:11]=1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: COc1ccc(OC)c(Br)c1
Reactant: C1CNCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1ccc(OC)c(N2CCNCC2)c1
Temperature: 100 °C
Reaction time: 24 h
Yield: 48.8 %

Procedure:
1.98 g of piperazine, 1.0 g of 1-bromo-2,5-dimethoxybenzene, 800 mg of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene, 310 mg of palladium(II) acetate and 2.25 g of cesium carbonate are dissolved in 30 ml of 1,4-dioxane and stirred at 100° C. under an argon atmosphere for 24 hours. The reaction mixture is extracted with 50 ml of saturated sodium bicarbonate solution and 50 ml of saturated sodium chloride solution, and the combined aqueous phases are basified with 2N sodium hydroxide solution and extracted five times with 50 ml of dichloromethane each time. The combined organic phases are dried over MgSO4 and then the solvent is removed in vacuo. 500 mg of 1-(2,5-dimethoxyphenyl)piperazine are obtained as an amorphous solid.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH:12]=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][NH2:15].CO.[BH4-].[Na+].[ClH:20]>C(O)C>[ClH:20].[ClH:20].[CH3:14][NH:15][CH2:12][C:10]1[N:11]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:8][CH:9]=1
Reactant: O=Cc1c[nH]c(-c2ccccc2)n1
Reactant: CN
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CNCc1c[nH]c(-c2ccccc2)n1
Temperature: 65 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
To a solution of 2-phenyl-1H-imidazole-4-carbaldehyde (1.73 g) in ethanol (30 mL) was added 40% methylamine-methanol solution (2.36 g) and the mixture was stirred at 65° C. for 1 hr. The mixture was allowed to cool to room temperature, sodium borohydride (571 mg) was added and the mixture was stirred for 30 min. 1 mol/L Hydrochloric acid was added to the reaction mixture, and the mixture was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with tetrahydrofuran. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate-methanol=1:0→4:1) and dissolved in methanol (10 mL). A 4 mol/L hydrogen chloride-ethyl acetate solution (5 mL) was added, and the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound as colorless crystals (yield 1.06 g, yield 41%).
Reaction SMILES: O[C:2]1[C:11](O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[C:13]1([NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19].CN(C)C1C=CC=CC=1.C(Cl)Cl>C1(C)C=CC=CC=1.CCCCCCC>[CH:18]1[C:13]2[NH:20][C:11]3[CH:10]=[C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]4=[CH:3][C:2]=3[NH:19][C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: Nc1ccccc1N
Reactant: Oc1cc2ccccc2cc1O
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)Nc1cc3ccccc3cc1N2
Temperature: 25 °C
Yield: 76 %

Procedure:
2,3-dihydroxynapthalene (10 g, 62.5 mmol), 1,2-phenylenediamine (6.75 g, 62.5 mmol) and N,N-dimethylaniline (54 ml) are placed into a round bottom flask under nitrogen atmosphere. Mixture is stirred at reflux. Reaction is monitored by TLC (CH2Cl2:Heptane/1:1) until all 2,3-dihydroxynaphthalene has reacted (˜3 hours). After cooling to room temperature, toluene (100 ml) is added and solid is collected by vacuum filtration. After washing with toluene (50 ml), ethanol (100 ml) and hexanes (50 ml), the product is dried under vacuum to yield 11.0 g (76% yield) of light yellow solid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([OH:28])=O)=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.[CH3:41][N:42](C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.CN>O1CCCC1.C(OCC)(=O)C.O.CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([NH:42][CH3:41])=[O:28])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Reactant: COc1cc(C(=O)O)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNC(=O)c1cc(OC)c(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.3 %

Procedure:
To a mixture of 0.05 g (0.11 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-benzoic acid (I-169), 0.06 g (0.16 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 2 mL of dimethylformamide was added 0.06 mL (0.32 mmole) of diisopropylethylamine. After stirring at room temperature for 30 minutes 0.16 mL (0.32 mmole) of 2M methylamine in tetrahydrofuran was added. The mixture was stirred at room temperature for 18 hours and then diluted with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with 1 M sodium hydroxide solution then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with hexanes-ethyl acetate (60:40) to give 0.027 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-N-methyl-benzamide (I-171).
Reaction SMILES: C([O:3][C:4](=[O:23])/[CH:5]=[CH:6]/[CH:7]=[C:8]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)C>CO.[OH-].[Na+]>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[CH:7]/[CH:6]=[CH:5]/[C:4]([OH:23])=[O:3])=[CH:14][CH:13]=1
Reactant: CCOC(=O)/C=C/C=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)/C=C/C=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 95 %

Procedure:
A mixture of (E)-5,5-bis(4-chlorophenyl)-2,4-pentadienoic acid ethyl ester (7.5 g) in methanol (30 mL) and 2N sodium hydroxide solution (15 mL) was heated at reflux for 30 minutes. The crude solid obtained from the usual work up, was crystallized from ether-hexane to yield 6.55 g of (E)-5,5-bis(4-chlorophenyl)-2,4-pentadienoic acid, mp 213°-215° C. Recrystallization of a portion from 2-propanol furnished the analytical sample, mp 214°-215° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[NH:15][C:16](=[O:21])[CH2:17][CH2:18][CH2:19]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[CH:32][CH:31]=2)=[CH:25][CH:24]=1>>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[NH:15][C:16](=[O:21])[CH2:17][CH2:18][CH2:19][N:39]1[CH2:38][CH2:37][N:36]([C:33]2[CH:32]=[CH:31][C:30]([CH2:29][C:26]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=3)=[CH:35][CH:34]=2)[CH2:41][CH2:40]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(Cc2ccccc2)c1NC(=O)CCCCl
Reactant: Fc1ccc(Cc2ccc(N3CCNCC3)cc2)cc1
Product: Cc1cccc(Cc2ccccc2)c1NC(=O)CCCN1CCN(c2ccc(Cc3ccc(F)cc3)cc2)CC1

Procedure:
The compound (14) synthesized in Reference Example 14 and the compound (5) synthesized in Reference Example 5 were used to produce the above compound in the same way as Example 1.
Reaction SMILES: Cl.[Sn](Cl)Cl.[N+:5]([C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)([O-])=O.C(=O)([O-])O.[Na+]>CO>[NH2:5][C:8]1[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=[CH:10][C:9]=1[N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCCC1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Solvent: CO
Product: Nc1cc(C(F)(F)F)ccc1N1CCCC1
Reaction time: 4 h
Yield: 102.5 %

Procedure:
Concentrated hydrochloric acid (1.36 ml, 16.3 mmol) and anhydrous tin dichloride (1.55 g, 8.16 mmol) were sequentially added at 0° C. to a methanol (4 ml) solution of 1-[2-nitro-4-(trifluoromethyl)phenyl]pyrrolidine (606 mg, 2.33 mmol), obtained as described in Referential Example 3-1. The resulting mixture was stirred for four hours. A saturated solution of sodium hydrogen carbonate was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50 g, hexane/ethyl acetate=15/1). Thus, 1-[2-amino-4-(trifluoromethyl)phenyl]pyrrolidine (550 mg, quant.) was yielded as a red-orange colored oily material.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:30](=[O:31])[C:11]2=[CH:12][N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1>CO>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:13]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]3=[N:9][N:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[CH3:1])[C:30](=[O:31])[C:11]3=[CH:12]2)=[CH:26][CH:25]=1
Reactant: Cc1ccccc1-n1nc2c3ccccc3n(Cc3ccc([N+](=O)[O-])cc3)cc-2c1=O
Solvent: CO
Product: Cc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(N)cc3)cc-2c1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2-(2-Methylphenyl)-5-(4-nitrobenzyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 755, 50 mg, 0.12 mmol) was suspended in methanol (5 mL) and the mixture was sparged under an atmosphere of nitrogen. The mixture was treated with Raney Ni (˜20 mg, spatula tip) and sparged under an atmosphere of hydrogen (1 atm). The mixture was, stirred vigorously for 6 hours at ambient temperature, sparged under an atmosphere of nitrogen, filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative reverse phase HPLC (90:10 to 5:95; water containing 0.1% trifluoroacetic acid:acetonitrile containing 0.1% trifluoroacetic acid), providing the titled compound: 1H-NMR (400 MHz, CD3OD) δ 8.96 (1H, s), 8.34 (1H, d, J=6.4 Hz), 7.82 (1H, d, J=8.6 Hz), 7.67-7.58 (2H, m), 7.44-7.36 (6H, m), 7.29 (2H, d, J=8.2 Hz), 5.82 (2H, s), 2.27 (3H, s), ppm; low resolution mass spectrometry (ES+) m/z 381.0 (M+H)+; calculated for C24H20N4O: 381.2].
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:11]1(C)C=CC=CC=1.C=O.[OH-].[Na+]>O>[CH2:2]([O:9][N:10]=[CH2:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NOCc1ccccc1
Reactant: Cc1ccccc1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: C=NOCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
O-Benzyl-hydroxylamine hydrochloride (125.0 g, 0.78 mol) was combined with toluene (400 mL) under nitrogen. The resulting slurry was cooled in an ice bath and formalin (37%, 75 mL) was added. A 50% solution of NaOH (70 mL) was added portionwise maintaining an internal temperature of not more than 35° C. After the addition of NaOH was complete, water (100 mL) was added and the reaction mixture was stirred at ambient temperature for 2.5 hours. The layers were then separated and the aqueous layer was extracted with toluene. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The resulting oil was distilled (65-70° C., 10 torr) to obtain formaldehyde O-benzyl-oxime. 1H NMR (400 MHz, CDCl3) δ ppm 5.12-5.13 (s, 2 H) 6.46 (d, J=8.23 Hz, 1 H) 7.08 (d, J=8.23 Hz, 1 H) 7.28-7.35 (m, 1 H) 7.36 (dd, J=4.19, 0.62 Hz, 4 H).
Reaction SMILES: [O-]CC.[K+].C(O)C.[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:26](OCC)(=[O:32])[C:27]([O:29]CC)=[O:28]>C1(C)C=CC=CC=1.C(OCC)C>[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:26](=[O:32])[C:27]([OH:29])=[O:28])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: CC[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(O)C(=O)Cc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
Potassium ethoxide (505 g; 6 mole) was added to a solution of ethanol (710 ml) and diethyl ether (4.8 l) and the mixture was cooled to 0° C. 4-(Benzyloxy)-1-methyl-2-nitrobenzene (639.8 g; 3 mole) dissolved in diethyl oxalate (900 g; 6.16 mole) and toluene (1500 ml) was added slowly during 30 minutes. The reaction mixture was stirred for 3 hours at 0° C. and then allowed to stand cold over night. After 5 days at room temperature the reaction mixture was filtered and the filter cake was washed with diethyl ether (2 l). The cake was then treated with water (10 l), sodium hydroxide (5 M, 0.8 l) and extracted three times with diethyl ether (3×3 l). The water phase was cooled and acidified in two steps while stirring with hydrochloric acid:water (1:1, 0.9 l). First to pH 5 and the reaction mixture was then stirred for 1 hour before the acidification continued to pH 2. The reaction mixture was cooled in an ice:sodium chloride bath. Filtration after 1 hour gave 849.5 g (89.8%) of 3-(4-benzyloxy-2-nitrophenyl)-2-oxopropanoic acid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]([F:19])([F:18])[O:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11](=[O:14])[CH2:12]Br>CO>[N:1]([CH2:12][C:11]([C:10]1[CH:15]=[CH:16][CH:17]=[C:8]([O:7][C:6]([F:5])([F:18])[F:19])[CH:9]=1)=[O:14])=[N+:2]=[N-:3]
Reactant: O=C(CBr)c1cccc(OC(F)(F)F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Product: [N-]=[N+]=NCC(=O)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
Add sodium azide (583 mg, 8.96 mmol) to a solution of 3-(trifluoromethoxy)-phenacyl bromide (2.17 g, 7.66 mmol) in methanol (20 mL). Stir at room temperature for 2 h. Concentrate the mixture in vacuo. Dissolve the residue in EtOAc (20 mL) and wash with water (10 mL). Dry the organic layer (Na2SO4), filter, and concentrate filtrate in vacuo to provide 2-azido-1-(3-(trifluoromethoxy)phenyl)ethanone (1.70 g, 91%). 1H-NMR (CDCl3): δ7.83 (m, 1H), 7.77 (s, 1H), 7.56 (m, 1H), 7.49 (m, 1H), 4.55 (s, 2H).
Reaction SMILES: C([Li])CCC.[C:6]([C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)([CH3:9])([CH3:8])[CH3:7].[C:15](=[O:17])=[O:16]>C1COCC1>[C:6]([C:10]1[O:11][C:12]([C:15]([OH:17])=[O:16])=[CH:13][CH:14]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: O=C=O
Reactant: CC(C)(C)c1ccco1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(=O)O)o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
n-Butyllithium (25 mL, 40 mmol, 1.6 M in hexane solution, 1.1 equiv) is added dropwise to a solution of 4.5 g of 2-t-butylfuran (36 mmol) in 60 mL of dry THF at −78° C. under N2. After 30 min, the cooling bath is replaced with an ice bath and the mixture stirred at 0° C. for 1 h. Dry CO2, generated from dry ice and dried over an anhydrous Na2SO4 tower, is bubbled into the reaction mixture over 20 min at −78° C. and then at 0° C. The reaction mixture is acidified with 1 M HCl to pH 1, then extracted with ethyl acetate. The organic layer is washed with brine, dried (NaSO4) and concentrated to give 4.2 g of 2-tertbutyl 5-furanoic acid as a pale yellow solid (69%). 1H NMR (CDCl3) d 11.0 (br s, 1H), 7.19 (d, 1H, J=3.3 Hz), 6.11 (d 1H, J=3.3 Hz), 1.29 (s, 9H).
Reaction SMILES: [F:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].[Br:11]Br>C(O)(=O)C>[Br:11][C:7]1[CH:6]=[C:5]([F:10])[C:3]([NH2:4])=[C:2]([F:1])[C:8]=1[CH3:9]
Reactant: BrBr
Reactant: Cc1ccc(F)c(N)c1F
Solvent: CC(=O)O
Product: Cc1c(Br)cc(F)c(N)c1F
Reaction time: 1 h
Yield: 81.3 %

Procedure:
To a solution of 2,6-difluoro-3-methylaniline (5 g, 34.9 mmol) in acetic acid (50 ml) was added dropwise a solution of bromine (1.97 ml, 38.4 mmol) in acetic acid (10 ml) at 55° C. The reaction mixture was stirred for 1 hour and then poured to water/ice. A solid was filtered, washed with water and dried in a vacuum oven. 6.3 g of a black solid were obtained (yield=81%).
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][C:5]=2[O:4][CH:3]=1.C(OC([NH:32][C@H:33]([C:35](O)=[O:36])[CH3:34])=O)(C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1.FC(F)(F)C(O)=O>>[NH2:32][CH:33]([CH3:34])[C:35]([NH:1][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:15])=[O:16])=[CH:12][C:5]=2[O:4][CH:3]=1)=[O:36]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CS(=O)(=O)Nc1cc2occ(N)c(=O)c2cc1Oc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: CC(N)C(=O)Nc1coc2cc(NS(C)(=O)=O)c(Oc3ccccc3)cc2c1=O

Procedure:
3-Amino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was reacted with N-tert-butoxycarbonylalanine in the presence of dicyclohexylcarbodiimide. The reaction product was treated with trifluoroacetic acid to obtain 3-(2-aminopropionyl)amino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.