Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17]CC)=[O:16])=[C:10]3[C@@H:9]3[CH2:20][CH2:21][N:8]3[C:7](=[O:22])[C:6]=2[CH:23]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([OH:17])=[O:16])=[C:10]3[C@@H:9]3[CH2:20][CH2:21][N:8]3[C:7](=[O:22])[C:6]=2[CH:23]=1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1cc(Cl)ccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ncn2c1[C@@H]1CCN1C(=O)c1cc(Cl)ccc1-2
Yield: 95.4 %

Procedure:
20.8 g (62.8 mmol) of ethyl (S)-7-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate in 250 ml of ethanol and 75 ml (75 mmol) of 1N sodium hydroxide solution were heated to reflux for 30 min. The alcohol was evaporated on a rotary evaporator. The residue was dissolved in 250 ml of water and acidified with 1N hydrochloric acid. The crystals were filtered off under suction, washed with water and dried in a vacuum. There were obtained 18.2 g (96%) of (S)-7-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid of m.p. 249°-250° (dec.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH:22][CH2:23][C:24]3[C:25]([NH:37][CH:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[C:26]4[CH:34]=[N:33][N:32]([CH2:35][CH3:36])[C:27]4=[N:28][C:29]=3[CH2:30][CH3:31])=[O:21])[CH:15]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:44][C@H:45]1[CH2:50][N:49]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54](B3OC(C)(C)C(C)(C)O3)[CH:53]=2)[CH2:48][CH2:47][N:46]1C(OC(C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:35]([N:32]1[C:27]2=[N:28][C:29]([CH2:30][CH3:31])=[C:24]([CH2:23][NH:22][C:20]([C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([C:12]([NH:11][CH2:10][C:4]4[CH:3]=[C:2]([C:54]5[CH:55]=[CH:56][CH:57]=[C:52]([CH2:51][N:49]6[CH2:48][CH2:47][NH:46][C@@H:45]([CH3:44])[CH2:50]6)[CH:53]=5)[C:7]([O:8][CH3:9])=[CH:6][CH:5]=4)=[O:13])[CH:15]=3)=[O:21])[C:25]([NH:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[C:26]2[CH:34]=[N:33]1)[CH3:36]
Reactant: C[C@H]1CN(Cc2cccc(B3OC(C)(C)C(C)(C)O3)c2)CCN1C(=O)OC(C)(C)C
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(OC)c(Br)c2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(OC)c(-c3cccc(CN4CCN[C@@H](C)C4)c3)c2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-{[3-Bromo-4-(methyloxy)phenyl]methyl}-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (0.033 g, 0.05 mmol), 1,1-dimethylethyl (2S)-2-methyl-4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperazinecarboxylate (0.0316 g, 0.076 mmol), potassium carbonate (0.021 g, 0.15 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.0029 g, 0.0025 mmol) were combined in dioxane (1.5 mL) and water (0.5 mL). The mixture was microwaved at 150° C. for 30 min. The reaction mixture was then diluted with EtOAc and washed with H2O. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. This was taken up in 10% TFA/CH2Cl2 and stirred at room temperature for 3 h. The solvents were pumped off and the crude product was purified using a Gilson HPLC with a TFA system. The purified compound was taken up in EtOAc, washed with 2.5 N NaOH, with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound a white solid. LC-MS m/z 759.2 (M+H)+, 1.35 min (ret time); mp 110-112° C. Analytical HPLC shows 100% purity, (ret time 9.95 min).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:16]([S:18](Cl)(=[O:20])=[O:19])[CH3:17]>ClCCl>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:18]([CH2:16][CH3:17])(=[O:20])=[O:19])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: CCS(=O)(=O)Cl
Reactant: N#Cc1ccc(-c2ccc(N)cc2)cc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-Amino-4′-cyanobiphenyl (1.03 g, 5.3 mmol) (TCI) was dissolved in a mixture of 8 ml dichloromethane/2 ml pyridine was treated with ethanesulfonyl chloride (0.61 g, 5.3 mmol) and stirred for 18 h at room temperature. The solution was diluted with dichloromethane and washed twice with 1N HCl. The organic phase was separated, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound. 1H NMR: 7.75 (d,2H,J=8 Hz), 7.67 (d,2H,J=8 Hz), 7.60 (d,2H,J=8 Hz), 7.37 (d,2H,J=8 Hz), 6.90 (s,1H), 3.22 (q,2H,J=8 Hz), 1.45 (t,3H,J=8 Hz).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH2:11][CH:12]([C:14]([O:16][CH3:17])=[O:15])[N:13]=2)=[CH:5][CH:4]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][CH:11]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[N:13]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)C1COC(c2ccc(C(F)(F)F)cc2)=N1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: COC(=O)c1coc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 75 °C
Reaction time: 36 h

Procedure:
A solution of methyl 2-[4-(trifluoromethyl)phenyl]-1,3-oxazoline-4-carboxylate (1.33 g, 4.87 mmol) was stirred in toluene (60 ml) at 55° C. until all of the starting material was dissolved. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (5.53 g, 24.365 mmol) was then added in portions, and the resulting solution was stirred at 75° C. for 36 hours. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography, to provide methyl 2-[4-(trifluoromethyl)phenyl]-1,3-oxazole-4-carboxylate, a compound of formula (15).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1/[CH:11]=[CH:12]/[C:13](=[O:15])[CH3:14].O.[C:17]([OH:21])(=[O:20])[CH:18]=O>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1/[CH:11]=[CH:12]/[C:13](=[O:15])/[CH:14]=[CH:18]/[C:17]([OH:21])=[O:20]
Reactant: COc1ccc(/C=C/C(C)=O)c(OC)c1
Reactant: O=CC(=O)O
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(/C=C/C(=O)/C=C/C(=O)O)c(OC)c1

Procedure:
A solution of 19 g (92 mmol) of (E)-4-(2,4-dimethoxyphenyl)but-3-en-2-one and 8.4 g (92 mmol) of glyoxylic acid monohydrate in 24 ml of acetic acid was heated at reflux for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was extracted twice with 3N sodium hydroxide solution. The combined aqueous phases were treated with 3N hydrochloric acid to produce a strongly acidic reaction and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. Crystallization of the residue from methylene chloride/ether/hexane yielded (E,E)-6-(2,4-dimethoxyphenyl)-4-oxo-2,5-hexadienoic acid of melting point 195°-200°.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([NH2:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C1C=CN=CC=1)C>[F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([NH:13][S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cc(F)c(F)c2cccnc12
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1cc(F)c(F)c2cccnc12)c1ccccc1
Yield: 34 %

Procedure:
In a similar fashion using route 14 general procedure 27, 5,6-difluoroquinolin-8-amine (Intermediate 49) (120 mg, 0.67 mmol), benzenesulfonyl chloride (141 mg, 0.78 mmol) and DMAP (cat.) gave the title compound (73 mg, 35%) after purification by column chromatography with n-hexane/EtOH (1:1) as the eluent.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:18]=[CH:17][C:16]2[C:15]3[C:10](=[C:11]([F:22])[CH:12]=[C:13]([CH2:19][CH2:20][CH3:21])[CH:14]=3)[C:9](=O)[C:8]=2[C:7]=1[F:24])[CH2:2][CH2:3][CH3:4].C([SiH](CC)CC)C.O>FC(F)(F)C(O)=O>[CH2:1]([O:5][C:6]1[CH:18]=[CH:17][C:16]2[C:15]3[C:10](=[C:11]([F:22])[CH:12]=[C:13]([CH2:19][CH2:20][CH3:21])[CH:14]=3)[CH2:9][C:8]=2[C:7]=1[F:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc2c(c1F)C(=O)c1c(F)cc(CCC)cc1-2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCCCOc1ccc2c(c1F)Cc1c(F)cc(CCC)cc1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
Under exclusion of moisture, 3.8 g of 2-butyloxy-1,8-difluoro-6-propylfluoren-9-one (example 1) are dissolved in 50 ml of trifluoroacetic acid, and 4.6 ml of triethylsilane are added dropwise slowly at a temperature of 5-20° C. with gentle cooling. The mixture is subsequently stirred at room temperature for 1 h and then at 40-70° C. for 4 h. After cooling, the reaction mixture is added to water and extracted with dichloromethane. The combined org. phases are washed with water and 5% sodium hydrogencarbonate solution and dried over sodium sulfate. After the solvent has been removed in vacuo, the yellow residue is purified chromatographically on silica gel using 8:2 heptane/dichloromethane as eluent. After the solvent had been removed in vacuo, the product-containing fractions were recrystallized from heptane. 1.2 g of 2-butyloxy-1,8-difluoro-6-propylfluorene were obtained.
Reaction SMILES: [CH2:1]=[N:2][N:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[ClH:10].O1CCOCC1>C(OCC)C>[ClH:10].[CH3:1][NH:2][N:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: C=NN1CCCCCC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CNN1CCCCCC1
Yield: 53 %

Procedure:
A pale-yellow oil obtained using the compound (1.20 g, 9.5 mmol) obtained in step A and according to the method of Reference Example 37, step C was dissolved in diethyl ether (15 ml), 4N hydrochloric acid-dioxane solution (1.8 ml) was added with stirring under ice-cooling, and the solution was concentrated under reduced pressure to give the title compound (0.85 g, yield 53%) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=[CH:15][CH:16]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH:14]=[CH:15][CH:16]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(Nc2nc(Cl)ncc2F)c1

Procedure:
2,4-Dichloro-5-fluoropyrimidine (800 mg, 4.8 mmoL), tert-butyl (3-aminophenyl)carbamate (996 mg, 4.8 mmoL) and Hunig's base (948 uL, 5.75 mmoL) were dissolved in THF (20 mL). The reaction mixture was heated at reflux overnight. After cooling, partitioned between water/brine (10 mL), agitated and separated the layers. Dried organic phase over sodium sulfate, and the solvent was removed via rotary evaporation. Titration with EtOAc and Heptane gave after filtration a white solid, 1 g. LC/MS (RT=2.03/(M+1)) 339.1.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13](B(O)O)=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][C:21]=1[F:28].C(N(CC)CC)C>C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:28][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:20]=1[C:13]1[O:14][C:10]2[CH:9]=[CH:8][C:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:18][C:11]=2[CH:12]=1)[CH:24]=[O:25]
Reactant: O=Cc1ccc(Br)c(F)c1
Reactant: OB(O)c1cc2cc(N3CCCCC3)ccc2o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=Cc1ccc(-c2cc3cc(N4CCCCC4)ccc3o2)c(F)c1
Yield: 25.2 %

Procedure:
A mixture of 5-(piperidin-1-yl)benzofuran-2-ylboronic acid (50 mg, 0.204 mmol), 4-bromo-3-fluorobenzaldehyde (37 mg, 0.184 mmol), triethylamine (0.56 mL, 4.1 mmol) and bis(triphenylphosphine)palladium(II) chloride (14 mg, 0.02 mmol) in ethanol (5 mL) was irradiated in a microwave instrument at 100° C. for 20 min. The reaction mixture was cooled, and the solvent was removed. The residue was purification by silica gel chromatography on ISCO system yielding the title compound (15 mg, 15% yield). ESI-MS: 324.2 (M+H)+, 1H NMR (400 MHz, CDCl3) δ 10.00 (s, 1H), 8.19 (t, 1H), 7.75 (d, 1H), 7.67 (d, 1H), 7.43 (d, 1H), 7.35 (d, 1H), 7.14-7.11 (m, 2H), 3.13 (m, 4H), 1.77 (m, 4H), 1.59 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].F[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[CH:10][C:11]([O:14][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N+:23]([O-:25])=[O:24])=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COC(=O)c1ccc(O)cc1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2ccccc2[N+](=O)[O-])cc1C(=O)OC
Temperature: 100 °C

Procedure:
A mixture of 4-hydroxyphthalic acid dimethyl ester (1.23 g, 5.95 mmol), o-fluoronitro-benzene (0.81 ml, 7.64 mmol), and potassium carbonate (1.66 g, 12 mmol) in dry DMF (25 ml) was heated at 100° C. for 1 hour. The mixture was cooled to room temperature, filtered and the filtrate evaporated to dryness in vacuo to give 4-(2-nitrophenoxy)phthalic acid dimethyl ester as a yellow oil (yield: 1.97 g, (100%)). 1H—NMR (CDCl3) in ppm: δ 3.9 (6H, 2xs); 7.1-7.2 (2H,m); 7.2 (1H,d); 7.3-7.4 (1H,m); 7.6-7.7 (1H,m); 7.84 (1H,d); 8.03 (1H, d.d.).
Reaction SMILES: Cl.[NH2:2][C:3]1([C:6]([NH:8][C@H:9]([B:14]2[O:18][C@@H:17]3[CH2:19][C@@H:20]4[CH2:23][C@H:22]([C@:16]3([CH3:26])[O:15]2)[C:21]4([CH3:25])[CH3:24])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])[CH2:5][CH2:4]1.[C:27](OC(=O)C)(=[O:29])[CH3:28].CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:27]([NH:2][C:3]1([C:6]([NH:8][C@H:9]([B:14]2[O:18][C@@H:17]3[CH2:19][C@@H:20]4[CH2:23][C@H:22]([C@:16]3([CH3:26])[O:15]2)[C:21]4([CH3:24])[CH3:25])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])[CH2:5][CH2:4]1)(=[O:29])[CH3:28]
Reactant: CC(C)C[C@H](NC(=O)C1(N)CC1)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)NC1(C(=O)N[C@@H](CC(C)C)B2O[C@@H]3C[C@@H]4C[C@@H](C4(C)C)[C@]3(C)O2)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 93.2 %

Procedure:
To a solution of 1-amino-N-{(1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}cyclopropane-carboxamide hydrochloride (0.50 g, 1.30 mmol) in DMF (5.0 mL) was added acetic anhydride (0.15 g, 1.43 mmol). The reaction mixture was cooled to 0° C., and DIEA (0.34 g, 2.6 mmol) was added slowly over 1 h. The reaction was allowed to stir at 0° C. After 1.5 h, the reaction mixture was diluted with H2O (20 mL) and washed with EtOAc (2×30 mL). The organic layers were combined and washed with H2O (2×20 mL), dried over MgSO4, filtered, and concentrated to give the title compound (0.473 g, 93%). LC/MS: Rt=1.78 min, ES+391 (Formic Acid method).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][CH3:17])[CH2:13][C@H:12]1[C:18]([NH2:21])=[N:19][OH:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([C:28]([O:30][CH3:31])=[O:29])#[C:23][C:24]([O:26][CH3:27])=[O:25]>C(Cl)(Cl)Cl>[CH3:27][O:26][C:24](=[O:25])[C:23]([O:20][N:19]=[C:18]([NH2:21])[C@@H:12]1[CH2:13][C@@H:14]([O:16][CH3:17])[CH2:15][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[CH:22][C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)C#CC(=O)OC
Reactant: CO[C@@H]1C[C@@H](C(N)=NO)N(C(=O)OCc2ccccc2)C1
Solvent: ClC(Cl)Cl
Product: COC(=O)C=C(ON=C(N)[C@@H]1C[C@@H](OC)CN1C(=O)OCc1ccccc1)C(=O)OC
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To benzyl-(2S,4R)-2-[amino(hydroxyimino)methyl]-4methoxypyrrolidine-1-carboxylate, dissolved in chloroform, dimethyl acetylendicarboxylate (1.1 eq.) was added. The mixture was refluxed for 1 hour and left stirring at 40° C. overnight. The chloroform was removed in vacuo and the crude product purified by flash chromatography on silica gel (eluent ethyl acetate:petroleum ether=40:60). Two isomers were present in ratio 7:3.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([OH:12])[C:5](Br)=[CH:4][CH:3]=1.[CH:14]([C:16]1[O:17][CH:18]=[CH:19][C:20]=1B1OC(C)(C)C(C)(C)O1)=[O:15].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([OH:12])[C:5]([C:20]2[CH:19]=[CH:18][O:17][C:16]=2[CH:14]=[O:15])=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccoc2C=O)OC1(C)C
Reactant: COC(=O)c1c(N)ccc(Br)c1O
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(N)ccc(-c2ccoc2C=O)c1O
Temperature: 65 °C
Yield: 88 %

Procedure:
A mixture of methyl 6-amino-3-bromo-2-hydroxybenzoate (prepared according to Wang et al, Bioorg Med Chem Lett, 2007, 17, 2817; 1.84 g), 2-formylfuran-3-boronic acid pinacol ester (1.99 g), tri-tert-butylphosphonium tetrafluoroborate (0.218 g), cesium carbonate (7.33 g) and tris-(dibenzylideneacetone)dipalladium (0.343 g) in dioxane (75 mL) and water (9.4 mL) was heated at 65° C., under nitrogen, for 1 hour. After cooling, the mixture was diluted with ethyl acetate and water and the organic layer was separated, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 10-50% to give methyl 6-amino-3-(2-formylfuran-3-yl)-2-hydroxybenzoate (1.72 g) as a yellow solid. The material was used without further characterisation.
Reaction SMILES: [C:1]([C:3]1([OH:13])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)#[N:2].Cl.[CH2:15]([OH:17])[CH3:16]>>[CH2:15]([O:17][C:1]([C:3]1([OH:13])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)=[NH:2])[CH3:16]
Reactant: CCO
Reactant: N#CC1(O)CCCc2ccccc21
Agent: Cl
Product: CCOC(=N)C1(O)CCCc2ccccc21

Procedure:
The cyanohydrin of Example 4 (6.0 g, 34.7 mmol) was dissolved in 60 ml ethanol and perfused with hydrogen chloride for 30 minutes. After a 16 hour reaction period at 0° C. the mixture was evaporated in vacuo to a solid which was triturated with ether. The residue was taken up in 200 ml chloroform and washed with 2×50 ml saturated sodium bicarbonate, 1×50 ml brine, dried over sodium sulfate, filtered, and concentrated to a solid; 5.3 g (71%), mp 84°-86° C.
Reaction SMILES: [C:1]([C:3]1[CH:39]=[CH:38][C:6]([CH2:7][O:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:37])[NH:28][CH2:29][CH2:30][O:31]C(=O)C(C)=C)[CH:21]=2)=[O:11])=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].Cl.O>CO>[C:1]([C:3]1[CH:39]=[CH:38][C:6]([CH2:7][O:8][NH:9][C:10](=[O:11])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([NH:28][CH2:29][CH2:30][OH:31])=[O:37])[CH:21]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: C=C(C)C(=O)OCCNC(=O)Nc1cc(CNc2ccccc2C(=O)NOCc2ccc(C#N)cc2)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#Cc1ccc(CONC(=O)c2ccccc2NCc2ccnc(NC(=O)NCCO)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred suspension of 2-methyl-acrylic acid 2-[3-(4-{[2-(4-cyanobenzyloxy-carbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-ureido]-ethyl ester (Example 533, 500 mg) in methanol (10 ml) was added 2 M aqueous sodium hydroxide (5 ml). The reaction mixture was stirred at room temperature for 20 minutes. The pH of the mixture was adjusted to 5 by addition of 4 M hydrochloric acid and water (15 ml) was added. The resulting precipitated material was isolated by filtration and dried in vacuo, and gave the title compound. 13C-NMR (DMSO-d6) δ 167.4, 154.8, 153.8, 151.1, 148.6, 146.7, 141.8, 132.6, 132.1, 129.1, 128.0, 118.6, 115.1, 114.8, 113.0, 111.6, 110.8, 109.3, 76.0, 60.2, 45.3, 41.8.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[C:20](=[O:21])[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[C:13]1=[O:22])[NH:8][C:7](=[O:23])[CH2:6][NH:5]2.[OH-].[Na+].O.OO>CCOCC>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[C:13](=[O:22])[C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=3[C:20]1=[O:21])[NH:8][C:7](=[O:23])[CH:6]=[N:5]2
Reactant: O=C1CNc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc2N1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc2[nH]c(=O)cnc2cc1F
Yield: 74.9 %

Procedure:
2-(3,4-Dihydro-6-fluoro-2(1H)-quinoxalinon-7-yl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.43 g) was added to a mixture of sodium hydroxide (0.16 g), water (2.1 ml) and 30% aqueous hydrogen peroxide (0.21 ml), and the resultant mixture was stirred at room temperature for 16 hours. Ether was added thereto to separate an aqueous layer, which was adjusted to pH 4 with acetic acid. The precipitated crystals were collected by filtration and washed with water to give 2-(6-fluoro-2(1H)-quinoxalinon-7-yl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.32 g). m.p., >300° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][CH2:10][OH:11].C([OH:15])C>O.C(O)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[CH3:1][C:2]1([CH3:12])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][C:10]([OH:15])=[O:11]
Reactant: CC1(C)[C@H]2CC[C@@H](CCO)[C@@H]1C2
Reactant: CCO
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)[C@H]2CC[C@@H](CC(=O)O)[C@@H]1C2
Temperature: 15 °C
Reaction time: 8 h

Procedure:
A solution of chromium trioxide (42.6 g CrO3, 426 mmol) in water (40 mL) was diluted with acetic acid (350 mL). The solution was cooled to 15° C. and the product from Example 4A (27 g, 160 mmol) was added dropwise. The solution was left to stand at room temperature overnight. Ethanol (20 mL) was added to destroy the excess of CrO3. The mixture was heated at 50° C. for 15 minutes and then concentrated under reduced pressure. The residue was suspended in water, acidified to pH 2 and extracted 3 times with ether. The ethereal solution was concentrated and the residue was dissolved in hexanes. The organic solution is decanted from the green tar and concentrated under reduced pressure. The residue was dissolved in 10% aqueous NaOH and neutral impurities were extracted with ether (discarded). The aqueous phase was acidified to pH 2 and extracted with hexanes, dried with Na2SO4, concentrated, cooled and filtered to give 10.9 g of title compound (crystals melting point: 50-53° C.).
Reaction SMILES: [C:1]([CH:3]([C:7]1[CH2:12][CH2:11][CH2:10][C:9](=[O:13])[CH:8]=1)[C:4]([NH2:6])=[O:5])#[N:2].[CH3:14]N(C)C=O.C(OCC)(OCC)OCC>C(OCC)(=O)C>[O:5]=[C:4]1[C:3]([C:1]#[N:2])=[C:7]2[C:8]([C:9](=[O:13])[CH2:10][CH2:11][CH2:12]2)=[CH:14][NH:6]1
Reactant: N#CC(C(N)=O)C1=CC(=O)CCC1
Reactant: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCOC(OCC)OCC
Product: N#Cc1c2c(c[nH]c1=O)C(=O)CCC2

Procedure:
75 parts of α-cyano-3-oxo-1-cyclohexen-1-acetamide in 400 parts by volume of dimethylformamide and 75 parts of triethyl orthoformate are heated on a steam bath for 3 hours to 16 hours. Solvent was then removed in vacuum to give a syrup which is taken up in ethyl acetate. Cooling of this solution gives 2,3,5,6,7,8-hexahydro-3,8-dioxo-4-isoquinolinecarbonitrile which is identical to the product of Example 3.