Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[NH2:9][C:10]1[S:11][C:12]([N+:20]([O-:22])=[O:21])=[CH:13][C:14]=1[C:15](OCC)=O.O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:15]1[C:14]2[CH:13]=[C:12]([N+:20]([O-:22])=[O:21])[S:11][C:10]=2[N:9]=[C:1]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)[N:2]=1
Reactant: N#Cc1cccnc1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])sc1N
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cc2c(Cl)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 477, the reaction of 3-cyanopyridine and 2-amino-5-nitro-3-ethoxycarbonyl-thiophene, and the subsequent reaction with POCl3 yields 4-chloro-2-(pyridin-3-yl)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]([OH:14])=[CH:6][C:5]=1[CH3:15].[H-].[Na+].[CH3:19][N:20]([CH3:24])[C:21](Cl)=[S:22].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:10]([CH3:11])([CH3:12])[CH3:13])[C:7]([O:14][C:21](=[S:22])[N:20]([CH3:24])[CH3:19])=[CH:6][C:5]=1[CH3:15]
Reactant: COC(=O)c1cc(C(C)(C)C)c(O)cc1C
Reactant: CN(C)C(=S)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(C)(C)C)c(OC(=S)N(C)C)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-tert-butyl-4-hydroxy-2-methylbenzoic acid methyl ester from Example BBB (15.1 g, 68 mmol) in DMF (150 mL) was added NaH (3.3 g of a 60% dispersion, 82 mmol), and the mixture was stirred at room temperature for 1 hour. N,N-Dimethylthiocarbamoyl chloride (10.1 g, 82 mmol) was added all at once; the reaction mixture was stirred at 55° C. for 36 hours and then cooled to room temperature. H2O (200 mL) was added, and the solution was extracted with EtOAc. The combined extracts were washed with 1N NaOH, 1N HCl, and brine. The organic phase was dried (MgSO4) and concentrated. The residue was chromatographed on silica gel, eluting with 6:1 hexane:EtOAc, to give the title compound. 1H NMR (CDCl3) δ 1.37 (s, 9 H), 2.55 (s, 3 H), 3.39 (s, 3 H), 3.49 (s, 3 H), 3.89 (s, 3 H), 6.90 (s, 1 H), 8.01 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:29])=[C:16]([OH:30])[CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[C:32]([O-])([O-])=O.[K+].[K+].CI>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].COCCOC>[CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:23]([Cl:29])=[CH:24][CH:25]=[CH:26][C:27]=2[Cl:28])=[C:16]([O:30][CH3:32])[CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(OCc2c(Cl)cccc2Cl)c(O)c1)NC(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: COCCOC
Solvent: CI
Product: COC(=O)[C@H](Cc1ccc(OCc2c(Cl)cccc2Cl)c(OC)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a suspension of N-(tert-butoxycarbonyl)-4-(2,6-dichlorobenzyloxy)-3-hydroxy-L-phenylalanine methyl ester (0.45 g), K2CO3 (0.199 g), and n-Bu4NI (0.035 g) in DME (4.0 mL) was added CH3I (0.072 mL) and the mixture was stirred overnight at room temperature. DMF was removed and the residue was partitioned between water and EtOAc. The organic layer was separated and the aqueous solution was extracted with EtOAc. The combined extract was dried (MgSO4) and evaporated. The residue was purified by preparative TLC (silica gel; eluent: hexanes/CH2Cl2/EtOAc, 3:3:1) to yield 0.396 g of N-(tert-butoxycarbonyl)-4-(2,6-dichlorobenzyloxy)-3-methoxy-L-phenylalanine methyl ester. ESMS: m/z 484 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]([C:10]#[N:11])[C:8]#[N:9])=[C:4]([F:14])[CH:3]=1.[H-].[Na+].Br[CH2:18][CH2:19][F:20]>CN(C)C=O>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C:7]([CH2:18][CH2:19][F:20])([C:8]#[N:9])[C:10]#[N:11])=[C:4]([F:14])[CH:3]=1
Reactant: FCCBr
Reactant: N#CC(C#N)Cc1ccc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCF)Cc1ccc(Br)cc1F
Yield: 33.8 %

Procedure:
Using 0.25 g of (4-bromo-2-fluorobenzyl)malononitrile, 3 ml of N,N-dimethylformamide, 0.10 g of sodium hydride (60% in oil), and 0.13 g of 1-bromo-2-fluoroethane, and according to the process described in the Production Example 1, there was obtained 0.10 g of 2-(4-bromo-2-fluorobenzyl)-2-(2-fluoroethyl)malononitrile (the present compound (67)).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10]([NH2:12])=[S:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)=O.CN(C)C=O>O>[C:1]1([CH2:7][CH2:8][NH:9][C:10]2[S:11][CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][CH:18]=3)[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=S)NCCc1ccccc1
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc(-c2csc(NCCc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
A mixture of N-(2-phenylethyl)thiourea (3.60 g, 20 mmol), 2-bromo-1-[4-(trifluoromethyl)phenyl]ethanone (5.34 g, 20 mmol) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 16 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained solid was washed with hexane to give the title compound (5.2 g, yield 74%) as pale-yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[NH:9])=[N:6][CH:7]=1.C([O:13][C:14](=O)[CH:15]([CH2:19][CH3:20])[C:16]([CH3:18])=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:10]=[C:14]([OH:13])[C:15]([CH2:19][CH3:20])=[C:16]([CH3:18])[N:9]=2)=[N:6][CH:7]=1
Reactant: N=C(N)c1ccc(N)cn1
Reactant: CCOC(=O)C(CC)C(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCc1c(C)nc(-c2ccc(N)cn2)nc1O
Reaction time: 24 h

Procedure:
To a solution of compound of example 12 (0.2 g, 1.47 mmol) in water (5 mL) and ethanol (2.5 mL) was added ethyl-2-ethylacetoacetate (0.379 g, 2.35 mmol) and sodium carbonate (0.280 g, 2.64 mmol) at room temperature and the reaction mixture was stirred for 24 hours. Ethanol was removed under reduced pressure, and the reaction mixture was diluted with water and extracted with ethyl acetate (3×20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography using silica gel and 1% methanol in chloroform as an eluent to obtain the title compound.
Reaction SMILES: OO.C(O[C:10]([C:12](F)(F)F)=[O:11])(C(F)(F)F)=O.C(C1N=[N+:20]([O-:31])[C:21]2[CH:30]=[C:29]3[C:25]([CH2:26][CH2:27][CH2:28]3)=[CH:24][C:22]=2[N:23]=1)C.C(O)(C(F)(F)F)=[O:33].N>C(Cl)Cl.C(Cl)(Cl)Cl>[N+:20]([C:21]1[CH:30]=[C:29]2[C:25]([CH2:26][CH2:27][CH2:28]2)=[CH:24][C:22]=1[NH:23][C:10](=[O:11])[CH3:12])([O-:31])=[O:33]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C(O)C(F)(F)F
Reactant: CCc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Agent: N
Agent: OO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])CCC2
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
H2O2 (70%, 0.15 mL, ca. 2.9 mmol) was added dropwise to a stirred solution of TFAA (0.40 mL, 2.9 mmol) in DCM (5 mL) at 0° C. The solution was stirred at 20° C. for 10 min, then cooled to 0° C., and added to a solution of 1-oxide 67 (60 mg, 0.29 mmol) and TFA (0.05 mL, 0.63 mmol) in CHCl3 (5 mL) at 0° C. Another aliquot of H2O2 (0.15 mL) was added after 24 h, and the solution stirred at 20° C. for another 24 h. The solution was made basic with dilute aqueous NH3 solution and extracted with CHCl3 (3×10 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with 5% EtOAc/DCM, to give (i) starting material 67 (18 mg, 30%) and (ii) 1,4-dioxide 68 (32 mg, 48%) as a yellow solid: mp 140-142° C.; 1H NMR δ 8.32 (s, 1H, H-9), 8.27 (s, 1H, H-5), 3.13-3.23 (m, 6H, H-6, H-8, CH2), 2.26 (q, J=7.5 Hz, 2H, H-7), 1.43 (t, J=7.5 Hz, 3H, CH3); 13C NMR δ 155.7, 155.1, 150.6, 139.1, 133.8, 115.9, 113.9, 33.4, 32.8, 25.6, 23.9, 9.31. Anal. calcd for C12H13N3O2.½CH3OH: C, 60.7; H, 6.1; N, 17.0. Found: C, 60.3; H, 5.7; N, 16.8%.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[N:9][N:10]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)[CH:11]=1>N1C=CC=CC=1>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[N:9][N:10]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][N:19]([C:22]3[N:23]=[CH:24][CH:25]=[CH:26][N:27]=3)[CH2:20][CH2:21]2)[CH:11]=1)(=[O:4])=[O:3]
Reactant: Nc1cnn(CCCCN2CCN(c3ncccn3)CC2)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cnn(CCCCN2CCN(c3ncccn3)CC2)c1
Reaction time: 1 h

Procedure:
1.8 g (16 mmol) of methanesulphonyl chloride are added slowly to a cooled solution of 4.4 g (14.6 mmol) of 4-amino-1-(4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl}-1H-pyrazole, Example 16, in 30 ml of pyridine. The mixture is left for 1 hour at 0° C., left at room temperature for 4 hours and poured into ice-cold water, the resulting mixture is extracted with chloroform and 3.7 g of 4-methylsulphonamido-1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl}-1H-pyrazole are obtained, which product may be recrystallised in ethyl ether, with a melting point of 132° C.
Reaction SMILES: C(O[C:4]([C:6]1[S:10][C:9]([O:11][CH2:12][C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:8][CH:7]=1)=[O:5])C.[CH2:25]([CH2:27][NH2:28])[OH:26]>>[OH:26][CH2:25][CH2:27][NH:28][C:4]([C:6]1[S:10][C:9]([O:11][CH2:12][C:13]2[C:14]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:8][CH:7]=1)=[O:5]
Reactant: NCCO
Reactant: CCOC(=O)c1cnc(OCc2c(-c3ccccc3)noc2C)s1
Product: Cc1onc(-c2ccccc2)c1COc1ncc(C(=O)NCCO)s1
Yield: 59 %

Procedure:
As described for example 127, 2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-thiazole-5-carboxylic acid ethyl ester (100 mg, 0.28 mmol) was converted, using ethanolamine instead of isopropylamine, to the title compound (62 mg, 59%) which was obtained as a colourless gum after purification by chromatography (silica, 0 to 3% methanol in dichloromethane). MS: m/e=360.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][CH:12]=C)[C:9](=[O:14])[S:8][C:5]2=[N:6][CH:7]=1.CO.[O:17]=[O+][O-].CSC>C(Cl)Cl.O=O>[F:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][CH:12]=[O:17])[C:9](=[O:14])[S:8][C:5]2=[N:6][CH:7]=1
Reactant: C=CCn1c(=O)sc2ncc(F)cc21
Reactant: O=[O+][O-]
Agent: O=O
Solvent: ClCCl
Solvent: CSC
Solvent: CO
Product: O=CCn1c(=O)sc2ncc(F)cc21
Temperature: 25 °C

Procedure:
6-Fluoro-1-(2-propen-1-yl)[1,3]thiazolo[5,4-b]pyridin-2(1H)-one (0.046 g, 0.22 mmole) was dissolved in DCM (8 ml) and MeOH (1 ml) and the solution cooled to −70° C. A gas mixture containing ozone in oxygen was bubbled through the solution for 20 mins to give a pale green solution. Argon was then bubbled through the solution for 5 mins then dimethyl sulphide (0.064 ml, 0.87 mmole) added. The mixture was allowed to warm to rt then evaporated to dryness to give a crude product which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[O:11])[O:9][C:8]([CH3:13])([CH3:12])[O:7][C:6]=2[CH:14]=1.CCN(C(C)C)C(C)C.[CH:24]1([CH2:29][CH2:30][C:31](Cl)=[O:32])[CH2:28][CH2:27][CH2:26][CH2:25]1>C(Cl)Cl>[CH:24]1([CH2:29][CH2:30][C:31]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[O:11])[O:9][C:8]([CH3:12])([CH3:13])[O:7][C:6]=3[CH:14]=2)=[O:32])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: CC1(C)OC(=O)c2ccc(N)cc2O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OC(=O)c2ccc(NC(=O)CCC3CCCC3)cc2O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
To a cold (0° C.) solution of 7-amino-2,2-dimethyl-4H-1,3-benzodioxine-4-one (1.93 g, 10.0 mmol) and DIEA (1.55 g, 12.00 mmol) in DCM (50 mL) was added drop-wise a solution of 3-cyclopentylpropionyl chloride (Aldrich, 1.93 g, 12.0 mmol) in DCM. The reaction was stirred at 0° C. for 1 hr, then at rt for 3 hrs. The reaction mixture was washed with an aqueous solution of HCl (1N). The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. Purification by flash chromatography on silicagel (EtOAc/c-Hex (30/70)) gave 3.05 g (96%) of the title compound as a pale yellow oil. HPLC, Rt: 4.26 min (purity: 99.6%). LC/MS, M+(ESI): 318.2, M−(ESI): 316.2. 1H NMR (CDCl3) δ: 8.13 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.58 (d, J=1.9 Hz, 1H), 7.05 (dd, J=1.9 Hz, J=8.4 Hz, 1H), 2.41 (t, J=7.6 Hz, 2H), 1.80-1.45 (m, 15H), 1.17-1.00 (m, 2H).
Reaction SMILES: [C:1]1([C@H:7]2[C:12]3[NH:13][C:14]4[C:19]([C:11]=3[CH2:10][C@H:9]([C:20](OC)=[O:21])[NH:8]2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24]([N:28]=[C:29]=[O:30])[CH2:25][CH2:26][CH3:27]>>[CH2:24]([N:28]1[C:20](=[O:21])[C@H:9]2[N:8]([C@@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:12]3[NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:11]=3[CH2:10]2)[C:29]1=[O:30])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCN=C=O
Reactant: COC(=O)[C@H]1Cc2c([nH]c3ccccc23)[C@H](c2ccccc2)N1
Product: CCCCN1C(=O)[C@@H]2Cc3c([nH]c4ccccc34)[C@H](c3ccccc3)N2C1=O

Procedure:
The same method as employed in the preparation of Example 1 but starting from trans methyl 1,2,3,4-tetrahydro-1-phenyl-9H-pyrido[3,4-b]indole-3-carboxylate and butyl isocyanate gave after recrystallization from 2-propanol, the title compound as white crystals m.p.: 240-243° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[S:11][C:12]1[N:16]=[CH:15][NH:14][N:13]=1.C(#N)C.C([O-])([O-])=[O:21].C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+].Cl.[OH2:39]>>[CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[S:11]([C:12]1[N:16]=[CH:15][NH:14][N:13]=1)(=[O:21])=[O:39]
Reactant: O
Reactant: Cc1nc2ccccn2c1Sc1nc[nH]n1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CC#N
Product: Cc1nc2ccccn2c1S(=O)(=O)c1nc[nH]n1
Reaction time: 4 h

Procedure:
To a mixture of 3-(2-methylimidazo[1,2-a]pyridin-3-yl)thio-1H-1,2,4-triazole (Example 50-a) (230 mg), acetonitrile (5 ml) and water (5 ml) was added sodium percarbonate (630 mg) in small portions on a water bath at 30° C. At this temperature the reaction mixture was stirred for 4 hours. To the reaction solution was added water (7.5 ml), and then concentrated hydrochloric acid was added dropwise on an ice bath, followed by adjusting the pH to about 4. The reaction mixture was stirred as it was for 30 minutes, and precipitated crystals were collected by filtration, washed with water, and dried to the title compound (139 mg).
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][Cl:24]>CCO>[ClH:24].[CH3:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][S:18][C:9]1[NH:8][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1
Reactant: Cc1cccc(CCl)c1
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Solvent: CCO
Product: Cc1cccc(CSC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)c1
Product: Cl
Temperature: 25 °C
Yield: 58 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 3-methylbenzyl chloride (0.207 mL, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 180 mg of the product 212. 1H NMR (DMSO-d6) δ 11.21 (s, 2H), 7.50-7.20 (m, 4H), 7.20-6.90 (m, 6H), 6.90-6.65 (m, 4H), 5.73 (s, 2H), 4.75 (s, 2H), 2.32 (s, 3H); MS: m/z 359 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([O:10][C:11]([F:14])([F:13])[F:12])[CH:3]=1.O=[C:16]([CH3:25])[CH2:17][C:18]([O:20][CH2:21][CH2:22][C:23]#[N:24])=[O:19].[NH2:26][C:27]1[CH:32]=[CH:31][NH:30][C:29](=[O:33])[CH:28]=1>CC(O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[C:28]3[C:29](=[O:33])[NH:30][CH:31]=[CH:32][C:27]=3[NH:26][C:16]([CH3:25])=[C:17]2[C:18]([O:20][CH2:21][CH2:22][C:23]#[N:24])=[O:19])=[C:4]([O:10][C:11]([F:14])([F:13])[F:12])[CH:3]=1
Reactant: Nc1cc[nH]c(=O)c1
Reactant: O=Cc1ccc(Br)cc1OC(F)(F)F
Reactant: CC(=O)CC(=O)OCCC#N
Solvent: CC(C)O
Product: CC1=C(C(=O)OCCC#N)C(c2ccc(Br)cc2OC(F)(F)F)c2c(cc[nH]c2=O)N1
Reaction time: 72 h

Procedure:
10.00 g (31.17 mmol) of the compound from Example 6A and 6.41 g (31.17 mmol) of 2-cyanoethyl 3-oxobutanoate [Yamamoto, T., et al., Bioorg. Med. Chem. Lett. 16, 798-802 (2006)] are introduced into 100 ml of 2-propanol and, after adding 4.09 g (37.17 mmol) of 4-aminopyridin-2(1H)-one [Searls, T., McLaughlin, L. W., Tetrahedron 55, 11985-11996 (1999)], stirred at the reflux temperature for three days. After cooling, the solvent is removed under reduced pressure, and the crude product is purified by column chromatography (silica gel; mobile phase: dichloromethane/methanol 10:1). 7.38 g (36% of theory) of the title compound are obtained.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Br:9][CH2:10][CH2:11]Br.O.CCOC(C)=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:11][CH2:10][Br:9])=[CH:6][N:7]=1
Reactant: BrCCBr
Reactant: Oc1ccc(Br)nc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: BrCCOc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
6-Bromo-3-hydroxypyridine (2 g, 11.56 mmol) was dissolved in anhydrous DMF (20 mL); to which 1,2-dibromoethane (10 g, 57.82 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, water (100 mL) was added to it and extraction was carried out using EtOAc (30 mL×3). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified using silica gel column chromatography to provide Q-1-I (2.7 g, 86% yield). LCMS: m/z; 280.0 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][N:16]=[C:17]([CH3:39])/[C:18](=[N:35]/[O:36][CH2:37][CH3:38])/[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH:26]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[CH3:27])=[CH:21][CH:20]=1)=NOC.[CH3:41]N.[CH2:43]([OH:45])C>>[CH3:1][O:2][C:3](=[O:40])[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][N:16]=[C:17]([CH3:39])[C:18](=[N:35][O:36][CH2:37][CH3:38])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH:26]([C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)[CH3:27])=[CH:21][CH:20]=1)=[CH:41][O:45][CH3:43]
Reactant: CCO/N=C(/C(C)=NOCc1ccccc1C(=NOC)C(=O)OC)c1ccc(OC(C)c2ccc(Cl)cc2)cc1
Reactant: CCO
Reactant: CN
Product: CCON=C(C(C)=NOCc1ccccc1C(=COC)C(=O)OC)c1ccc(OC(C)c2ccc(Cl)cc2)cc1
Reaction time: 96 h

Procedure:
A mixture of 4.0 g of 2-[[[(1-methyl-2-(4-(1-{4-chlorophenyl}-ethoxy)-phenyl)-2-E-[ethoxyimino]ethylidene)amino]oxy]methyl]-α-(methoxyimino)-phenylacetic acid methyl ester and 5.3 ml of a 8M solution of methylamine in ethanol is left to stand at room temperature for 4 days. The mixture is then concentrated by evaporation in vacuo. The residue is taken up with methyl acetate; the solution is washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation in vacuo. The residue is recrystallised from methyl acetate/hexane 1:1 to yield the title compound having a melting point of 81-83° C. (compound 3-4.2).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2([CH3:11])[CH2:10][NH:9]2)[C:5]([F:12])=[CH:4][N:3]=1.P(C1C=CC=CC=1)(C1C=CC=CC=1)(C1C=CC=CC=1)=O.[N+:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[S:42](Cl)(=[O:44])=[O:43])([O-:35])=[O:34].CN1CCOCC1>C1COCC1.O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2([CH3:11])[CH2:10][N:9]2[S:42]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N+:33]([O-:35])=[O:34])(=[O:43])=[O:44])[C:5]([F:12])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CC1(c2cc(Br)ncc2F)CN1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: CC1(c2cc(Br)ncc2F)CN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of crude 2-bromo-5-fluoro-4-(2-methyl-aziridin-2-yl)-pyridine (3.17 g as a 45% mixture with Ph3PO, 6.17 mmol) and 2-nitrobenzene-1-sulfonyl chloride (1.368 g, 6.17 mmol) in THF (23.15 mL) and H2O (7.72 mL) was added N-methylmorpholine and the reaction mixture was stirred at rt for 1.5 h. Alox neutral (2-3 spatula) was added and the reaction mixture was filtered through celite, washed with DCM and the filtrates were diluted with DCM and 1M aq. NaHCO3 soln. The phases were separated and the aq. phase was reextracted twice with DCM. The combined org. phases were dried over Na2SO4 and concentrated. Flash chromatography on silica gel (heptane:EtOAc 4:1 to 3:1) followed by recrystallization from EtOAc/hexane yielded the title compound as a colourless solid. HPLC RtH4=1.11 min; ESIMS: 416, 418 [(M+H)+]; 1H NMR (400 MHz, CDCl3): δ 8.31-8.30 (m, 1H), 8.23 (d, 1H), 7.86-7.77 (m, 3H), 7.68 (d, 1H), 3.28 (s, 1H), 2.78 (s, 1H), 2.09 (s, 3H).
Reaction SMILES: C(OP([CH:9]=[C:10]1[NH:16][CH2:15][CH2:14][N:13]([CH3:17])[C:12]2[CH:18]=[C:19](Br)[CH:20]=[CH:21][C:11]1=2)(=O)OCC)C.[CH:23]([Sn](CCCC)(CCCC)CCCC)=[CH2:24].[H-].[Na+].[Cl:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][C:48]=1[Cl:49])[CH:44]=O>O1CCOCC1>[ClH:40].[ClH:40].[Cl:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][C:48]=1[Cl:49])[CH:44]=[CH:9][C:10]1=[N:16][CH2:15][CH2:14][N:13]([CH3:17])[C:12]2[CH:18]=[C:19]([CH:23]=[CH2:24])[CH:20]=[CH:21][C:11]1=2
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOP(=O)(C=C1NCCN(C)c2cc(Br)ccc21)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=Cc1ccc2c(c1)N(C)CCN=C2C=Cc1ccc(Cl)c(Cl)c1
Product: Cl
Temperature: 80 °C
Reaction time: 18 h
Yield: 52.8 %

Procedure:
To 123 mg (0.32 mmol) of (8-bromo-1-methyl-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-ylidenemethyl)phosphonic acid diethyl ester (prepared as described in Example 41) in 2 ml of dioxane was added 120 mg (0.38 mmol) of vinyl tributylstannane, followed by 11.1 mg (0.016 mmol)of palladium (II) bis-triphenylphosphine-dichloride. The mixture was heated at 80° C. for 18 hours. To the mixture at ambient temperature was added 22 mg (0.55 mmol) of sodium hydride (60% dispersion in mineral oil). After 5 minutes 57 mg (0.33 mmol) of 3,4-dichlorobenzaldehyde was added and the mixture was stirred for 18 hours. The solvent was removed and the product was purified by column chromatography eluting with 1-4% methanol/dichloromethane and treated with 0.10 ml of 4M hydrogen chloride in dioxan. The solvent was evaporated and the residue was dissolved from acetone/petroleum ether (40 60° C.). The solvent was removed to give 25 mg of (E)-5-(3,4-dichlorostyryl)-2,3-dihydro-1-methyl-8-vinyl-1H-1,4-benzodiazepine dihydrochloride as a red solid; MS: 357 (M+).
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[N:6]([CH2:15][CH2:16]CO)[CH:5]=1)(O)=[O:2].S(Cl)([Cl:21])=O.[C:23]([Cl:27])(Cl)(Cl)Cl>>[Cl:21][C:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[N:6]([CH2:15][CH2:16][CH2:23][Cl:27])[CH:5]=1)=[O:2]
Reactant: O=C(O)c1cn(CCCO)c(=O)c2ccccc12
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cn(CCCCl)c(=O)c2ccccc12

Procedure:
Then, 12.5 g of 4-carboxy-2-(3-hydroxypropyl)-1(2H)-isoquinolone was added to a mixture of 50 ml of carbon tetrachloride and 25 ml of thionyl chloride, and the resulting mixture was heated at reflux for 2 hours. The solvent was distilled off and the residue was dissolved in dichloromethane. The solution was washed with water, dried and the solvent was distilled off. The resulting crystals were recrystallized from a mixture of ethyl acetate and petroleum ether to obtain 12.8 g of 4-chlorocarbonyl-2-(3-chloropropyl)-1(2H)-isoquinolone having a melting point of 101° C. as colorless prisms.