Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[O:16])/[C:8](=[N:14]/[NH2:15])/[C:9]([O:11][CH2:12][CH3:13])=[O:10].[I:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.[H-].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C.O>[I:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:15]2[C:2]3[CH:6]=[CH:5][S:4][C:3]=3[C:7](=[O:16])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:14]2)=[CH:20][CH:19]=1
Reactant: BrCc1ccc(I)cc1
Reactant: CCOC(=O)/C(=N\N)C(=O)c1sccc1F
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1nn(Cc2ccc(I)cc2)c2ccsc2c1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Ethyl(2Z)-3-(3-fluoro-2-thienyl)-2-hydrazono-3-oxopropanoate (5.73 g, 23.5 mmol) and 4-iodobenzylbromide (7.31 g, 24.6 mmol, 1.05 equiv) were dissolved in degassed N,N-dimethylformamide (47 mL) and cooled to 0° C. Sodium hydride (1.03 g, 25.8 mmol, 1.1 equiv, 60% dispersion in mineral oil) was added portionwise over 30 minutes and was stirred for an additional 2 hours at 0° C. Additional sodium hydride (1.03 g, 25.8 mmol, 1.1 equiv, 60% dispersion in mineral oil) was added and the mixture was stirred at 0° C. for an additional 1 hour. The mixture was carefully treated with sodium bicarbonate (5 mL, aqueous saturated) and then poured into sodium bicarbonate (200 mL, aqueous saturated) and water (250 mL). The aqueous layer was treated with ethyl acetate (400 mL), upon which a thick precipitate formed. The mixture was filtered and the solid was collected and dried in vacuo, providing the titled compound. The filtrate (organic and aqueous) was extracted with ethyl acetate (2×400 mL) and the combined organic extracts were washed with brine (50 mL), dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 1:100; hexanes:ethyl acetate), providing additional titled compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([CH3:19])=[CH:15][C:16](O)=[O:17])[CH:5]=[CH:4][C:3]1=2.S(Cl)([Cl:23])=O>>[CH3:1][C:2]1([CH3:20])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([CH3:19])=[CH:15][C:16]([Cl:23])=[O:17])[CH:5]=[CH:4][C:3]1=2
Reactant: CC(=CC(=O)O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: O=S(Cl)Cl
Product: CC(=CC(=O)Cl)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
In a similar manner to that of Example 1(c), by reaction of 2.7 g (10 mmol) of 3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-butenoic acid with 800 μl of thionyl chloride, 2.9 g (100%) of the expected acid chloride are obtained, which product will be used subsequently in the synthesis without further purification.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][CH:9]([F:37])[CH2:10][NH:11][C:12]1[N:17]=[C:16]2[CH2:18][NH:19][CH2:20][CH2:21][C:15]2=[N:14][C:13]=1[N:22]1[CH2:27][CH2:26][CH:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])[CH2:24][CH2:23]1.CCN(C(C)C)C(C)C.FC(F)C(OC(=O)C(F)F)=O>C(Cl)Cl.CN(C=O)C>[F:37][CH:9]([F:8])[CH2:10][NH:11][C:12]1[N:17]=[C:16]2[CH2:18][N:19]([C:2](=[O:1])[CH:4]([F:7])[F:5])[CH2:20][CH2:21][C:15]2=[N:14][C:13]=1[N:22]1[CH2:23][CH2:24][CH:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])[CH2:26][CH2:27]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: Fc1ccc(OC2CCN(c3nc4c(nc3NCC(F)F)CNCC4)CC2)c(F)c1
Agent: O=C(OC(=O)C(F)F)C(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(C(F)F)N1CCc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NCC(F)F)nc2C1

Procedure:
A solution of N-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (15 mg, 0.028 mmol), DIPEA (10.8 mg, 0.083 mmol), and 2,2-difluoroacetic anhydride (7.3 mg, 0.042 mmol) in DCM (278 μL) was stirred at room temperature for 2 h. The crude reaction mixture was diluted in DMF, filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR), and purified via HPLC Method A to give the title compound as a TFA salt (3 mg) as a clear oil. 1H NMR (400 MHz, methanol-d4, mixture of rotamers) δ ppm 1.92-2.02 (m, 2H), 2.09-2.17 (m, 2H), 2.80 (t, J=5.9 Hz, 0.8H), 2.86 (t, J=5.4 Hz, 1.2H), 2.96-3.04 (m, 2H), 3.34-3.43 (m, 2H), 3.77 (td, J=14.3, 4.0 Hz, 2H), 3.90 (t, J=5.8 Hz, 1.2H), 3.93 (t, J=6.1 Hz, 0.8H), 4.46 (tt, J=7.6, 3.7 Hz, 1H), 4.61 (s, 0.8H), 4.63 (s, 1.2H), 5.89-6.21 (m, 1H), 6.42-6.71 (m, 1H), 6.84-6.91 (m, 1H), 6.98 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 504.4.
Reaction SMILES: ClC1C=CC=C[C:3]=1[CH:4]=[O:5].[OH-].[Na+].[Cl:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[CH:15]=[CH:16][C:17](=[O:19])[CH3:18].S(=O)(=O)(O)O>C(O)C.C(OCC)(=O)C.CC(C)=O>[Cl:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[CH:15]1[CH2:3][C:4](=[O:5])[CH2:18][C:17](=[O:19])[CH2:16]1
Reactant: CC(=O)C=Cc1ccccc1Cl
Reactant: O=Cc1ccccc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CCO
Product: O=C1CC(=O)CC(c2ccccc2Cl)C1
Temperature: 90 °C
Yield: 73.7 %

Procedure:
2-Chlorobenzaldehyde (70.3 g) was added to a mixture of acetone (294 ml) and an aqueous solution (1.4 L) of sodium hydroxide (22.0 g) and the mixture was stirred at room temperature for 5 hours. An excessive acetone was distilled off under reduced pressure, and the residue was combined with ethyl acetate (1.4 L) and extracted. The ethyl acetate layer was washed with brine and dried (anhydrous magnesium sulfate), and then ethyl acetate was distilled off under reduced pressure to obtain a crude 2-chlorobenzalacetone (94.6 g) as a yellow oil. This oil was employed in the next step without a further purification. A 20% solution of sodium ethoxide in ethanol (170.1 g) was combined with diethyl malonate (80.1 g) at room temperature (resulting in instantaneous precipitation), and then with a solution of a crude 2-chlorobenzalacetone (94.6 g) in ethanol (40 ml). The reaction mixture was stirred with heating at 90° C. for 2 hours, allowed to stand to cool, and then cooled on ice (1 hour). The precipitate was recovered by a filtration, washed successively with ethyl acetate and isopropyl ether to obtain a crude 6-(2-chlorophenyl)-2-hydroxy-4-oxo-2-cyclohexenene-1-carboxylic acid ethyl ester monosodium salt (151.0 g) as a pale yellow powder. This powder was combined with 2M sodium hydroxide (350 ml) and stirred with heating at 100° C. for 2 hours. After allowing to stand to cool, 2.5 M sulfuric acid (350 ml) was added over a period of 15 minutes, and the mixture was stirred with heating at 100° C. for 2 hours. After allowing to stand to cool, ethyl acetate (1.4 L) was added and extracted. The ethyl acetate layer was washed with brine, dried (anhydrous magnesium sulfate), and then ethyl acetate was distilled off under reduced pressure. The precipitated crystal was washed successively with ethyl acetate-isopropyl ether (1:4) and isopropyl ether to obtain 5-(2-chlorophenyl)cyclohexane-1,3-dione (82.1 g) as a colorless crystal.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[N:16]=[C:17]=[S:18].C(N(CC)CC)C>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[N:16]1[C:5](=[O:7])[CH2:4][N:3]([CH2:1][CH3:2])[C:17]1=[S:18]
Reactant: CCNCC(=O)O
Reactant: Cc1cccc(Cl)c1N=C=S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(c2c(C)cccc2Cl)C1=S
Yield: 40.6 %

Procedure:
The title compound was prepared by the procedure described in Example 19 using 9.2 g of N-ethyl glycine, 9.1 g of 2-chloro-6-methylphenyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. Purification was achieved by flash chromatography on silica gel (methylene chloride). Crystallization from ethanol afforded the title compound (5.4 g) as a creamy solid, m.p. 124°-126° C. Anal. Calcd. for. C12H13Cl N2O S: C, 53.63; H, 4.87; N, 10.42. Found: C, 53.43; H, 4.79; N, 10.28. Mass spectrum (El, M.+) m/z 268/270.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:36]I)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][CH3:34])[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:36][O:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[N:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[CH:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][CH3:34])[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccccc2OCC)C1
Reactant: Oc1ccc(-c2ncc(Cl)cn2)cc1
Product: CCOC(=O)C1(COc2ccc(-c3ncc(Cl)cn3)cc2)CCN(C(=O)c2ccccc2OCC)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 4-(5-chloro-pyrimidin-2-yl)-phenol (Preparation 19) and 1-(2-ethoxy-benzoyl)-3-iodomethyl-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 16) to afford the racemate as a white solid (103 mg, 36.3%)
Reaction SMILES: [C:1](#[N:5])/[CH:2]=[CH:3]/[CH3:4].O1CCCC1.[O:11]1[CH2:16][CH2:15][N:14]([CH:17]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[C:22]([N+:32]([O-:34])=[O:33])[CH:21]=2)[C:18]#[N:19])[CH2:13][CH2:12]1.[OH-].[K+]>O.CO>[O:29]1[CH2:30][CH2:31][N:26]([C:23]2[CH:24]=[CH:25][C:20]([C:17]([C:18]#[N:19])([N:14]3[CH2:15][CH2:16][O:11][CH2:12][CH2:13]3)[CH:3]([CH3:4])[CH2:2][C:1]#[N:5])=[CH:21][C:22]=2[N+:32]([O-:34])=[O:33])[CH2:27][CH2:28]1
Reactant: C/C=C/C#N
Reactant: N#CC(c1ccc(N2CCOCC2)c([N+](=O)[O-])c1)N1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(CC#N)C(C#N)(c1ccc(N2CCOCC2)c([N+](=O)[O-])c1)N1CCOCC1
Reaction time: 6 h

Procedure:
A solution of 8.0 parts of crotononitrile in 20 parts by volume of tetrahydrofuran is added to a stirred mixture of 16.5 parts of α-morpholino-α(4-morpholino-3-nitrophenyl)-acetonitrile in 150 parts by volume of tetrahydrofuran and 1.5 parts of potassium hydroxide in 5 parts by volume of methanol at room temperature under an atmosphere of nitrogen. The reaction mixture is stirred for a further 6 hours, diluted with 500 parts by volume of water and extracted with 4×250 parts by volume of ethyl acetate. The combined organic extracts are dried over magnesium sulphate and concentrated under vacuum. The resulting crude product is triturated with a mixture of 50 parts by volume of ethyl acetate and hexane. The solid product is collected, washed with ethyl acetate and dried at 80° under vacuum to give 4-(4-morpholino-3-nitrophenyl)-4-(cyano)-4-(morpholino)-3-methylbutyronitrile having melting point 175°-177° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]#[N:28])=[CH:17][CH:16]=1.Cl>CO>[C:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([CH2:14][NH:13][C:5]2[C:6]([N+:10]([O-:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([O:2][CH3:1])=[O:36])=[CH:16][CH:17]=1)#[N:28]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1N(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: COC(=O)c1cccc([N+](=O)[O-])c1NCc1ccc(-c2ccccc2C#N)cc1
Temperature: 68 °C
Reaction time: 1.5 h
Yield: 75 %

Procedure:
The concentrate obtained in Working Example 2(2) (methyl2-[N-t-butoxycarbonyl-N-[(2′-cyanobiphenyl-4-yl)methyl]amino]-3-nitro-benzoate [BBN]) and methanol (3200 L) were mixed, and 35% concentrated hydrochloric acid (1050 L) was added to the mixture at 30° C. or less for about 4 hours. The mixture was heated to reflux temperature (67-69° C.) at a speed of 10° C. or less/hour, and stirred for about 1.5 hours under reflux. The reaction solution was cooled, to which was added methanol (800 L), and the solution was stirred at 3-10° C. for about 1 hour. The precipitated crystals were separated, washed with methanol and dried to give methyl 2-[[(2′-cyano-biphenyl-4-yl)methyl]amino]-3-nitro-benzoate [MBN] (407 kg; yield based on MPB: 75%).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:17]3[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18]3)=[O:16])=[CH:10][CH:9]=2)[N:4]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>CN(C=O)C.CO>[N:26]1([CH2:2][C:3]2[O:7][N:6]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:17]4[CH2:25][C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH2:18]4)=[O:16])=[CH:10][CH:9]=3)[N:4]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: C1COCCN1
Reactant: O=C(Nc1ccc(-c2noc(CCl)n2)cc1)N1Cc2ccccc2C1
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(Nc1ccc(-c2noc(CN3CCOCC3)n2)cc1)N1Cc2ccccc2C1
Temperature: 50 °C

Procedure:
To a 20 mL vial was added N-(4-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)phenyl)isoindoline-2-carboxamide (50 mg, 0.141 mmol) and morpholine (36.8 mg, 0.423 mmol) in DMF (470 μl). The mixture was heated to 50° C. for 30 minutes, cooled, and diluted with 2 mL methanol. Chromatography provided the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.69 (s, 1H), 7.92 (d, J=8.8 Hz, 2H), 7.80 (d, J=8.9 Hz, 2H), 7.35 (ddd, J=8.8, 3.9, 2.4 Hz, 4H), 4.80 (s, 4H), 3.95 (s, 2H), 3.68-3.48 (m, 4H), 2.62-2.51 (m, 5H); MS (ESI(+)) m/e 406 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]2[C:21]([C:22]3[CH:34]=[CH:33][O:32][C:23]=3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:2].[H][H]>C(O)C.C(O)=O.[OH-].[Pd+2].[OH-]>[CH2:35]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]2[C:21]([C:22]3[CH:34]=[CH:33][O:32][C:23]=3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:36]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCc1occc1-2
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=CO
Solvent: CCO
Product: CCN(CC)CCCc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCc1occc1-2
Reaction time: 8 h
Yield: 65 %

Procedure:
A solution of methyl 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzene-sulfonylamino]-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 4, 0.210 g) in ethanol (6 mL) was added to a flask containing palladium hydroxide (0.020 g) and formic acid (3 drops) under nitrogen. The nitrogen atmosphere was replaced by hydrogen and the mixture was stirred under an atmosphere of hydrogen overnight. The reaction mixture was filtered through Celite and the filtrate was evaporated to dryness. The residue was dissolved in ethyl acetate and washed with 10% aqueous potassium carbonate solution, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of 2M ammonia in methanol and DCM, with a gradient of 0-10% to give methyl 7-[2-(3-diethylaminopropyl)-4-fluorobenzenesulfonylamino]-4H-furo[2,3-c]chromene-6-carboxylate (0.137 g).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][NH:5][C:6](=[O:17])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1.C[O-].[Na+].C(O)(=O)C>CO.C1(C)C=CC=CC=1>[OH:2][C:3]1[CH2:4][NH:5][C:6](=[O:17])[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1
Reactant: COC(=O)CNC(=O)Cc1cccc([N+](=O)[O-])c1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C1NCC(O)=C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 25.4 %

Procedure:
A suspension of (3-nitrophenylacetyl)aminoacetic acid methyl ester (13 g, 0.05 mol) in methanol (40 ml) and toluene (56 ml) was added to a stirred solution of sodium methoxide in methanol (prepared by dissolving sodium (1.5 g, 0,065 mol) in methanol (30 ml)), under nitrogen. The mixture was heated at reflux for 18 h. After this time more sodium methoxide in methanol (prepared by dissolving sodium (0.56 g, 0.024 mol)in methanol (15 ml)) was added and the mixture heated for a further 18 h. The solution was then cooled to ambient temperature and acetic acid added to pH5. The mixture was evaporated in vacuo and azeotroped with toluene (2×20 ml). The residue was chromatographed on silica gel, using 94:6:0.6 dichloromethane:methanol:acetic acid as the eluant, to afford the tetramic acid (2.8 g, 25%) as a yellow solid. mp 245°-247° C. (dec.). 1H NMR (360MHz, D6 -DMSO) δ3.85 (2H, s), 7.31 (1H, brs), 7.57 (1H, dd, J: 8 and 8Hz), 7.93 (1H, dd, J=8 and 1.5Hz), 8.60 (1H, d, J=8Hz), 9.08 (1H, s).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.[C:14]1([SH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCCC(C)C.C(OCC)(=O)C>C1(C)C=CC=CC=1>[C:1](=[O:5])([S:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)Cl
Reactant: Sc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)C(=O)Sc1ccccc1
Yield: 72.4 %

Procedure:
Isobutanoyl chloride (528 μL, 5.0 mmol) in 15 mL toluene was added to a solution of triethylamine (0.70 mL, 5.0 mmol) and thiophenol (0.51 mL, 5.0 mmol) in 10 mL toluene. Reaction monitoring was accomplished by TLC: iso-hexane/ethyl acetate 25:1; Rf=0.47. Workup yielded 653 mg (72%) S-phenyl isobutanethioate 6 as pale yellow oil.
Reaction SMILES: Cl.[F:2][C:3]([F:34])([F:33])[C:4]1[CH:5]=[C:6]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH:19]=[CH:18][C:17]=2[O:28]COC)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.C(=O)([O-])O.[Na+]>CO>[F:34][C:3]([F:2])([F:33])[C:4]1[CH:5]=[C:6]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH:19]=[CH:18][C:17]=2[OH:28])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: COCOc1ccc(-c2ccccn2)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(-c2ccccn2)ccc1O
Yield: 47.5 %

Procedure:
Methanol (3 ml) and concentrated hydrochloric acid (0.5 ml) were added to N-[3,5-bis(trifluoromethyl)phenyl]-2-methoxymethoxy-5-(pyridin-2-yl)benzamide (37.9 mg, 0.08 mmol), and the mixture was refluxed for 2 hours. After cooling, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=2:1) to give the title compound (16.2 mg, 47.2%) as a white powder.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:6]2[NH:7][C:8]([C:14]3[C:23]([F:24])=[CH:22][CH:21]=[C:20]4[C:15]=3[N:16]=[C:17]([NH:26][CH:27]3[CH2:29][CH2:28]3)[C:18]([CH3:25])=[N:19]4)=[CH:9][C:10]=2[C:11]([OH:13])=O)[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C=O)C.C(Cl)Cl>[CH:27]1([NH:26][C:17]2[C:18]([CH3:25])=[N:19][C:20]3[C:15]([N:16]=2)=[C:14]([C:8]2[NH:7][C:6]4[C:3]5([CH2:5][CH2:4]5)[NH:2][C:11](=[O:13])[C:10]=4[CH:9]=2)[C:23]([F:24])=[CH:22][CH:21]=3)[CH2:29][CH2:28]1
Reactant: Cc1nc2ccc(F)c(-c3cc(C(=O)O)c(C4(N)CC4)[nH]3)c2nc1NC1CC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc2ccc(F)c(-c3cc4c([nH]3)C3(CC3)NC4=O)c2nc1NC1CC1
Reaction time: 0.67 h
Yield: 50.1 %

Procedure:
To a 50-mL round-bottomed flask was added 2-(1-aminocyclopropyl)-5-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (283e; 0.30 g, 0.718 mmol), DIEA (Aldrich) (0.75 mL, 4.31 mmol) in DMF (1.8 mL) and DCM (1.8 mL). Then 1H-benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) (Matrix innovation, Quebec City, Canada) (0.45 g, 0.86 mmol) was added into the reaction mixture. The overall mixture was stirred under inert atmosphere 40 min. The mixture was partially concentrated (removed DCM) in vacuo, then diluted with water and stirred 10 min. The precipitate was collected by filtration. The solids were triturated from hot EtOH in a sealed tube. The solids were collected by filtration, washed with Et2O, and dried in a reduced pressure oven (40° C.) overnight. This gave 2′-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)-1′H-spiro[cyclopropane-1,6′-pyrrolo[3,4-b]pyrrol]-4′(5′H)-one (283) (0.13 g, 0.36 mmol, 50% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.61 (br. S, 1H), 7.74 (br. s, 1H), 7.62-7.70 (m, 2H), 6.92 (br. s, 1H), 1.38-1.45 (m, 2H), 1.35 (br. s, 3H), 0.75-0.84 (m, 2H), 0.72 (br. s, 4H). m/z (ESI, +ve) 364 (M+H).
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]([CH3:18])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[N:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].C[O-].[Na+].CO.[Na]>>[NH2:17]/[C:16](=[N:21]\[OH:22])/[C:15]1[N:14]=[CH:13][N:12]2[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:7]=3[C:8](=[O:19])[N:9]([CH3:18])[CH2:10][C:11]=12
Reactant: CN1Cc2c(C#N)ncn2-c2cccc(F)c2C1=O
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1Cc2c(/C(N)=N/O)ncn2-c2cccc(F)c2C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2 g (7.8 mmol) of 7-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbonitrile and 1.1 g (15.6 mmol) of hydroxylamine hydrochloride were added to a freshly prepared solution of sodium methylate in methanol (from 0.27 g (11.7 mmol) of sodium in 50 ml of methanol), whereupon the mixture was stirred at room temperature for 16 hours. Subsequently, the suspension was evaporated and treated with 100 ml of water. The precipitate obtained was filtered off and dried in a high vacuum. There were obtained 2 g (89%) of (E)-and/or (Z)-3-(amino-hydroxyimino-methyl)-7-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as a colourless foam, Rf=0.25 (silica gel, methylene chloride/methanol 9:1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH:8]=O)=[CH:4][CH:3]=1.[NH2:12][NH:13][C:14]([NH2:16])=[S:15]>>[F:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH:8]=[N:12][NH:13][C:14]([NH2:16])=[S:15])=[CH:4][CH:3]=1
Reactant: O=CC=Cc1ccc(F)cc1
Reactant: NNC(N)=S
Product: NC(=S)NN=CC=Cc1ccc(F)cc1
Yield: 53 %

Procedure:
The compound is prepared according to the method described in example 1A from 4-fluorocinnamaldehyde (1.5 mmoles) and from thiosemicarbazide (1.5 mmoles). Yield 53%.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[F:22][C:23]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>C(Cl)Cl>[C:1]([NH:5][C:6]1[C:11]([NH:12][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:23]=2[F:22])=[CH:10][CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1cccc(F)c1F
Reactant: CC(C)(C)Nc1ncccc1N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)Nc1ncccc1NC(=O)c1cccc(F)c1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of N2-tert-butylpyridine-2,3-diamine in dry DCM (150 mL) was added DIEA (17 mL, 95.5 mmol). The solution was cooled to 0° C. and carefully added 2,3-difluorobenzoyl chloride (8.35 g, 47.30 mmol). The reaction was allowed to warm up to RT and stirred for 1 hr. The mixture was then washed with water, saturated NaHCO3, and dried over MgSO4. Removal of the solvent by evaporation, the residue was purified by silica gel chromatography (5%-60% EtOAc/hexane) to yield N-(2-(tert-butylamino)pyridin-3-yl)-2,3-difluorobenzamide (4.0 g, 13.10 mmol); LC-MS m/e=306.1 (M+H).