Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1Cl.[F-:12].[K+].[F-].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:12]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: [F-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(F)c(Cl)c1
Temperature: 165 °C
Yield: 81 %

Procedure:
A suspension of 1,500 parts of 3,4-dichloronitrobenzene, 900 parts of potassium fluoride and 10 parts of cesium fluoride in 800 parts of dimethylformamide is refluxed for 16 hours (165° C.). The mixture is worked up as described in Example 1(a). 1,110 parts (81% of theory) of 3-chloro-4-fluoronitrobenzene of melting point 41°-42° C. are obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])/[CH:7]=[C:8](\[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)/[CH3:9])([CH3:4])([CH3:3])[CH3:2].[C:19](#[N:22])[CH2:20][CH3:21].FC1C=CC(NC(=O)C)=CC=1>CC([O-])=O.CC([O-])=O.[Cu+2]>[C:1]([O:5][C:6]([C:7]1[C:19]([CH2:20][CH3:21])=[N:22][N:10]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[C:8]=1[CH3:9])=[O:18])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC#N
Reactant: C/C(=C/C(=O)OC(C)(C)C)Nc1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)Nc1ccc(F)cc1
Agent: CC(=O)[O-]
Product: CCc1nn(-c2ccc(F)cc2)c(C)c1C(=O)OC(C)(C)C

Procedure:
According to AVV A, (Z)-3-(4-fluorophenylamino)-but-2-enoic acid tert-butylester (251.3 mg, 1.0 mmol, 1.0 equiv.) was stirred with Cu(OAc)2 (544.9 mg, 3.0 mmol, 3.0 equiv.) into propionitrile (3.0 ml, 41.9 mmol, 41.9 equiv.) for 24 hours at 120° C. The dark-brown/blue raw product (295.9 mg) was analyzed by means of 1H and 19F-NMR-spectroscopy. The 19F-NMR spectra showed the desired product (δ=−112.7 ppm) and N-(4-fluorophenyl)-acetamide (δ=−118.0 ppm) in a ratio of 89:11. After purification by means of column chromatography (silica gel (50 g), pentane/EtOAc 98:2→70:30→0:100), the product was obtained in the form of a yellowish oil (222.9 mg, 0.73 mmol, 73%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C@H:11]3[CH2:15][CH2:14][CH2:13][NH:12]3)[O:10][C:5]2=[CH:4][C:3]=1[Cl:16].Cl.[CH2:18]=O>C(O)=O.CCOCC>[ClH:1].[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C@H:11]3[CH2:15][CH2:14][CH2:13][N:12]3[CH3:18])[O:10][C:5]2=[CH:4][C:3]=1[Cl:16]
Reactant: C=O
Reactant: Clc1cc2oc([C@H]3CCCN3)cc2nc1Cl
Agent: Cl
Solvent: O=CO
Solvent: CCOCC
Product: CN1CCC[C@@H]1c1cc2nc(Cl)c(Cl)cc2o1
Temperature: 60 °C
Yield: 46 %

Procedure:
5,6-Dichloro-2-(2-(R)-pyrrolidinyl)furo[3,2-b]pyridine from Example 39b (56 mg, 0.22 mmol) was dissolved in an aqueous solution of 37% formaldehyde (excess) and 88% formic acid (excess). The aqueous mixture was heated to 60° C. for 1 hour and then allowed to cool to ambient temperature. The reaction mixture was washed with Et2O, basified with 15% NaOH solution and extracted with CH2Cl2 (2×). The organic phases were combined, dried (MgSO4), concentrated and chromatographed (silica gel; CHCl3 /MeOH, 98:2) to afford a solid. The solid was dissolved in Et2O (10 mL) and a saturated solution of HCl in Et2O was added dropwise. The solvent was removed and the product recrystallized from MeOH/Et2O to afford a white solid (31 mg, 46%): mp 244-246° C.; 1H NMR (D2O, 300 MHz) δ 2.27-2.37 (m, 2H), 2.47-2.71 (m, 2H), 2.93 (s, 3H), 3.38 (m, 1H), 3.78 (m, 1H), 4.81 (m, partially buried under H2O peak, 1H), 7.27 (s, 1H), 8.26 (s, 1H); MS (CI/NH3) m/z: 271 (M+H)+ ; Anal. Calcd for C12H12Cl2N2O.HCl: C, 46.85; H, 4.26; N, 9.11. Found: C, 46.53; H, 4.21; N, 8.82.
Reaction SMILES: II.Br[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[CH3:11].[N:12]1[C:19]([Cl:20])=[N:18][C:16](Cl)=[N:15][C:13]=1[Cl:14].Cl>C1COCC1.C1(C)C=CC=CC=1>[Cl:14][C:13]1[N:12]=[C:19]([Cl:20])[N:18]=[C:16]([C:4]2[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=2[CH3:11])[N:15]=1
Reactant: Cc1ccc(Br)c(C)c1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: Cl
Agent: II
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc(Cl)nc(Cl)n2)c(C)c1
Yield: 79.8 %

Procedure:
17.0 g (0.70 mol) of iodine-activated magnesium turnings in 25 ml of anhydrous THF are heated briefly to 60° C. Then 154.9 g (0.70 mol) of 4-bromo-m-xylene (in c. 90% purity) and 155 ml of THF are added dropwise over 30 min and the mixture is heated for 2 hours to reflux. After cooling, the Grignard solution is added over 1.5 hours to a mixture of 43.0 g (0.233 mol) of cyanuric chloride and 150 ml of THF, while keeping the temperature of the mixture in the range from 0° to 10° C. The mixture is then diluted with 210 ml of toluene, the resultant suspension is poured into 220 g of 12% aqueous HCl, the organic phase is separated, washed with a total amount of 280 g of water and concentrated. The resultant material is recrystallised from 2-butanol, giving the title compound with a melting point of 135.5°-137° C. in a yield of 79.8%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[C:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)#[N:25].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([C:24]#[N:25])[CH:31]=2)[CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Reactant: N#Cc1cccc(B(O)O)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: [I-]
Solvent: O
Solvent: COCCOC
Product: N#Cc1cccc(Cc2cccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)c2)c1
Yield: 21.3 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-(3-cyanobenzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.075 g; 0.216 mmol), 3-cyanophenylboronic acid (0.033 g; 0.226 mmol), tetrakis(triphenylphosphine)palladium(0) (0.013 g; 0.011 mmol), sodium carbonate (0.046 g; 0.432 mmol), sodium iodide (0.065 g; 0.432 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.019 g (21%) of the title compound as a white solid.
Reaction SMILES: CN.[CH2:3]([N:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:19])C1=S)C=C>C(O)C.ClCCl>[Cl:18][C:17]1[C:12]([NH:8][CH2:9][CH2:10][CH2:11][NH:6][CH3:3])=[C:13]([CH3:19])[CH:14]=[CH:15][CH:16]=1
Reactant: C=CCN1CCCN(c2c(C)cccc2Cl)C1=S
Agent: CN
Solvent: ClCCl
Solvent: CCO
Product: CNCCCNc1c(C)cccc1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 59.9 %

Procedure:
To an 8.03 M solution of methylamine in ethanol (31 mL) was added the hydrobromide salt of Example 12, Step B (8.6 g) and the mixture was stirred at ambient temperature for 17 hours. The ethanol was removed in vacuo and the residue was partitioned between dichloromethane and 1N sodium hydroxide. The organic phase was washed with brine, dried over sodium sulfate, and concentrated in vacuo to give a yellow oil. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with a solvent gradient (from 98:2 to 80:20 dichloromethane-methanol containing 0.2% ammonium hydroxide) gave the title compound (3.9 g, 84.1%) as a pale yellow oil, which was used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].[Br:13]N1C(=O)CCC1=O>CS(C)=O>[Br:13][C:8]1[C:7]([C:9]([F:10])([F:11])[F:12])=[CH:6][C:4]([NH2:5])=[CH:3][C:2]=1[Cl:1]
Reactant: Nc1cc(Cl)cc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CS(C)=O
Product: Nc1cc(Cl)c(Br)c(C(F)(F)F)c1
Yield: 95.7 %

Procedure:
To a mixture of 3-chloro-5-(trifluoromethyl)aniline (3.25 g, 16.6 mmol, Eq: 1.00) in dimethylsulfoxide (43.4 ml) was added N-bromosuccinimide (3.11 g, 17.4 mmol, Eq: 1.05) in 5 portions over 2.5 hr (622 mg each 30 min). 2 h after the last addition, the reaction mixture was partitioned between 10% aqueous sodium sulfite and ethyl acetate. The organic layer was washed with aqueous sat. sodium carbonate, water (3 times) and brine then adsorbed unto silica (6 g) and purified on silica gel (column 120 g, Hexane/ethyl acetate 90:10 to 65:35) to give 4.36 g (96%) of a yellow solid.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH3:29])([CH3:28])[CH2:20]1)=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+]>CO>[CH3:28][C:21]1([CH3:29])[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:10]([NH2:9])=[S:11])[CH2:20]1
Reactant: CC1(C)CN(c2ccccc2NC(=S)NC(=O)c2ccccc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CN(c2ccccc2NC(N)=S)c2ccccc21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 2f (60 mg, 0.149 mmol) in MeOH was added 1N NaOH (0.2 mL, 0.2 mmol). The reaction mixture was stirred at 50° C. for 2 h. The solvent was evaporated under reduced pressure and co-evaporated with toluene to afford 2 g (35 mg, 80%). MS (ES) m/z 298 [M+H]30 .
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[CH3:21][N:22]([CH3:32])[C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:30]([NH:29][C:26]3[CH:27]=[CH:28][C:23]([N:22]([CH3:32])[CH3:21])=[CH:24][CH:25]=3)=[O:31])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: CN(C)c1ccc(N=C=O)cc1
Product: CN(C)c1ccc(NC(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1

Procedure:
1-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-3-(4-dimethylamino-phenyl)-urea was prepared starting from intermediate D and 4-(dimethylamino)-phenylisocyanate. MS calcd. for C25H24ClN4O2 [(M+H)+] 447.2, obsd. 447.2.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](I)[CH3:26]>CN(C)C=O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:25][CH3:26])=[C:4]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[N:3]=1
Reactant: Clc1ccc(Nc2nc(Cl)nc3[nH]cnc23)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1cnc2c(Nc3ccc(Cl)cc3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the product from step (i) (1.04 g), potassium carbonate (1.025 g) and ethyl iodide (0.637 g) in N,N-dimethylformamide (15 ml ) was stirred vigorously at room temperature for 2 h. The mixture was partitioned between ethyl acetate and water, the organics washed with water, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 2:1 ethyl acetate in isohexane. Yield 0.63 g
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14])(=[O:5])[C:2]([CH3:4])=[CH2:3].COC1C=CC(O)=CC=1.[Cl:24][SiH:25]([Cl:27])[Cl:26]>O1CCCC1.O.O.O.O.O.O.[Cl-].[Cl-].[Cl-].[Cl-].[Pt+4]>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][Si:25]([Cl:27])([Cl:26])[Cl:24])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: Cl[SiH](Cl)Cl
Reactant: C=CCCCCCCOC(=O)C(=C)C
Agent: [Pt+4]
Agent: COc1ccc(O)cc1
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCCCCCCCC[Si](Cl)(Cl)Cl
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A reaction vessel fitted with a stirrer was charged with 50 g of 7-octenyl methacrylate, 250 mg of hydroquinone monomethyl ether and 1.5 cc of 1% chloroplatinic acid hexahydrate solution in tetrahydrofuran, and the mixture was heated to 40° C. To the mixture was added gradually 42 g of trichlorosilane with stirring, while the temperature of the mixture was kept at 45° C. or below. After the addition, the mixture was heated to 60° C. and reaction was conducted at this temperature for 1 hour to obtain 8-methacryloyloxyoctyltrichlorosilane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:3]=1.CC(C)([O-])C.[K+].Cl[CH2:25][CH2:26][C@@H:27]1[CH2:31][C@@H:30]([O:32][Si](C(C)(C)C)(C)C)[CH2:29][N:28]1[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].C(OCC)(=O)C>CN(C)C(=O)C>[C:43]([O:42][C:40]([N:28]1[CH2:29][C@H:30]([OH:32])[CH2:31][C@H:27]1[CH2:26][CH2:25][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)=[O:41])([CH3:46])([CH3:45])[CH3:44]
Reactant: Oc1ccc(F)cc1CCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CCOc1ccc(F)cc1CCc1ccc(F)cc1
Reaction time: 0.17 h
Yield: 67.6 %

Procedure:
687 mg of 4-fluoro-2-[2-(4-fluorophenyl)ethyl]phenol (prepared as described in Preparation 6) were dissolved in 12 ml of N,N-dimethylacetamide, and then 212 mg of potassium t-butoxide were added to the resulting solution, whilst ice-cooling. The resulting mixture was then stirred for 10 minutes, after which 687 mg of (2S,4R)-2-(2-chloroethyl)-1-t-butoxycarbonyl-4-t-butyldimethylsilyloxypyrrolidine were added. The resulting mixture was then stirred at room temperature for 14 hours. At the end of this time, 135 mg of potassium t-butoxide were added to the reaction mixture, and the mixture was stirred at 40° C. for 4 hours, after which 300 ml of ethyl acetate were added. The resulting reaction mixture was washed with water and with a saturated aqueous solution of sodium chloride, in that order. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate. It was then concentrated by evaporation under reduced pressure. The resulting oily substance was purified by silica gel column chromatography, using a 2:3 by volume mixture of hexane and ethyl acetate as the eluent, to give 571 mg (yield 74%) of the title compound as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:15]([C:17]3[CH:22]=[C:21]([Cl:23])[C:20]([CH3:24])=[C:19]([Br:25])[C:18]=3[O:26][CH3:27])[CH3:16])[N:9]=[C:10]([CH:11]([OH:14])CO)[C:3]=12.C(O)(=O)C.I([O-])(=O)(=O)=O.[Na+]>O1CCCC1.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:15]([C:17]3[CH:22]=[C:21]([Cl:23])[C:20]([CH3:24])=[C:19]([Br:25])[C:18]=3[O:26][CH3:27])[CH3:16])[N:9]=[C:10]([CH:11]=[O:14])[C:3]=12
Reactant: COc1c(C(C)n2nc(C(O)CO)c3c(N)ncnc32)cc(Cl)c(C)c1Br
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COc1c(C(C)n2nc(C=O)c3c(N)ncnc32)cc(Cl)c(C)c1Br
Reaction time: 2 h

Procedure:
To a solution of 1-{4-amino-1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}ethane-1,2-diol (0.10 g, 0.22 mmol) in tetrahydrofuran (1.6 mL)/water (1.0 mL) was added acetic acid (0.0032 mL, 0.057 mmol) and sodium periodate (0.140 g, 0.657 mmol) at 0° C. After stirring for 2 h, the reaction mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and concentrated to give the desired crude product which was used directly in the next step. LCMS calculated for C16H16BrClN5O2 (M+H)+: m/z=424.0; Found: 423.9
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:23]([O-:25])=[O:24])=[C:5](OS(C(F)(F)F)(=O)=O)[CH:6]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:8]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:34](B1OC(C)(C)C(C)(C)O1)([CH3:36])=[CH2:35]>CN(C)C=O.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:34]([C:5]1[CH:6]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[N+:23]([O-:25])=[O:24])([CH3:36])=[CH2:35]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: COc1cc(N2CCOCC2)cc(OS(=O)(=O)C(F)(F)F)c1[N+](=O)[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)c1cc(N2CCOCC2)cc(OC)c1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 16 h
Yield: 51.7 %

Procedure:
A solution of trifluoro-methanesulfonic acid (3-methoxy-5-morpholin-4-yl-2-nitro-phenyl)ester (15.0 g, 38.7 mmol), potassium phosphate (24.6 g, 116 mmol) and 2-isopropenyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (8.4 g, 50.3 mmol) in dimethylformamide (80 ml) is degassed and flushed with argon for 20 min. To the reaction mixture is added 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (2.9 g, 3.9 mmol) and the resulting mixture is stirred at 120° C. for 16 h. After completion of the reaction (monitored by TLC), the mixture is diluted with water (50 ml) and extracted with ethyl acetate (3×70 ml). The combined organic layers are washed water (50 ml), brine (50 ml), dried over anhydrous sodium sulfate and evaporated in vacuo to get the crude product, which is purified by flash column chromatography (silica gel, 5% acetone/hexane) to yield 4-(3-isopropenyl-5-methoxy-4-nitro-phenyl)-morpholine (5.6 g, 20.0 mmol, 52%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([I:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[C:15]([O:20]C)[CH:14]=[C:13]([O:22]C)[C:12]=2[C@@H:24]1[CH2:28][CH2:27][N:26]([CH3:29])[C@H:25]1[CH2:30][OH:31].Cl.N1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CO>[Cl:1][C:2]1[C:7]([I:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[C:15]([OH:20])[CH:14]=[C:13]([OH:22])[C:12]=2[C@@H:24]1[CH2:28][CH2:27][N:26]([CH3:29])[C@H:25]1[CH2:30][OH:31]
Reactant: COc1cc(OC)c2c(=O)cc(-c3cccc(I)c3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4cccc(I)c4Cl)oc23)[C@@H]1CO
Temperature: 180 °C

Procedure:
A mixture of compound of example 60 (0.430 g, 0.77 mmol) and pyridine hydrochloride (2.0 g, 17.30 mmol) was heated at 180° C. for a period of 2.5 hours. The reaction mixture was diluted with methanol (60 mL) and basified with solid Na2CO3 to pH 10. The reaction mixture was filtered, and washed with methanol. The organic layer was concentrated and the residue purified by column chromatography using 0.01% ammonia and 4.5% methanol in chloroform as eluent to afford the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][N:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.O.O.[Sn](Cl)Cl.Cl>C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[NH:14][N:13]=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccn[nH]2)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(-c2ccn[nH]2)cc1
Yield: 95.3 %

Procedure:
To a solution of 5-(4-nitrophenyl)pyrazole (10.1 g) in ethanol (100 ml) was added Tin(II) chloride dihydrate (35.7 g) and concentrated hydrochloric acid (25.5 ml). After the addition was completed, the reaction mixture was refluxed for 3 hours. After cooling, the solvent was evaporated and strongly basified (NaOH solution) and then extracted with chloroform. The extract was washed with brine, dried (MgSO4) and evaporated to dryness to obtain the title compound (8.1 g).
Reaction SMILES: [H-].[Na+].[C:3]([C:8]1[CH:22]=[CH:21][C:11]([CH2:12]P(=O)(OCC)OCC)=[CH:10][CH:9]=1)([O:5][CH2:6][CH3:7])=[O:4].[CH3:23][C:24]1([CH3:37])[C:29]2[CH:30]=[CH:31][C:32]([C:34](=O)[CH3:35])=[CH:33][C:28]=2[O:27][CH2:26][CH2:25]1.Cl>CS(C)=O>[CH3:23][C:24]1([CH3:37])[C:29]2[CH:30]=[CH:31][C:32]([C:34]([CH3:35])=[CH:12][C:11]3[CH:10]=[CH:9][C:8]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:22][CH:21]=3)=[CH:33][C:28]=2[O:27][CH2:26][CH2:25]1
Reactant: CC(=O)c1ccc2c(c1)OCCC2(C)C
Reactant: CCOC(=O)c1ccc(CP(=O)(OCC)OCC)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(C=C(C)c2ccc3c(c2)OCCC3(C)C)cc1
Temperature: 40 °C
Yield: 60.3 %

Procedure:
0.5 g of a 50% suspension of sodium hydride in mineral oil were suspended in 15 ml of dimethyl sulfoxide and treated under argon with a solution of 3.2 g of diethyl (4-carbethoxybenzyl)phosphonate in 10 ml of dimethyl sulfoxide. The mixture was subsequently heated to 40° C. for 20 minutes, cooled to room temperature, a solution of 0.87 g of 3,4-dihydro-4,4-dimethyl-7-acetyl-2H-1-benzopyran in 5 ml of dimethyl sulfoxide was added dropwise thereto and the mixture was heated to 40° C. for 1 hour. The reaction mixture obtained was poured on to ice/water, acidified with 1N hydrochloric acid and extracted repeatedly with ether. The organic phase was washed with water, dried and evaporated. There was obtained a yellowish oil which, after filtration over a short column (silica gel, eluting agent hexane/ethyl acetate=9:1), crystallized from hexane and yielded 0.9 g of ethyl p-[2-(3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-7-yl)propenyl]benzoate, m.p. 48°-50° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.[W]>[Br:10][CH2:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: Cc1cc(C)cc(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: [W]
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(Cl)cc(CBr)c1
Temperature: 25 °C
Yield: 66.1 %

Procedure:
The mixture of 1-Chloro-3,5-dimethyl-benzene (32 g, 0.23 mol) and N-bromosuccinimide (40.5 g, 0.23M) in carbon tetrachloride (400 ml) was refluxed for 3 hr under a light of 500 W tungsten light. After cooling to room temperature, the mixture was filtered and the filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, hexane) to afford 33 g (68%) of a white solid. 1H NMR (200 MHz, CDCl3) δ: 2.32 (3H, s), 4.39 (2H, s), 7.10 (2H, s), 7.18 (1H, s).
Reaction SMILES: [CH2:1]([C:8]1[N:12]2[C:13]3[S:27][C:26]4[CH2:28][N:29](C(O)=O)[CH2:30][CH2:31][C:25]=4[C:14]=3[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])=[N:16][CH2:17][C:11]2=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C>[CH2:1]([C:8]1[N:12]2[C:13]3[S:27][C:26]4[CH2:28][NH:29][CH2:30][CH2:31][C:25]=4[C:14]=3[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])=[N:16][CH2:17][C:11]2=[N:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)N1CCc2c(sc3c2C(c2ccccc2Cl)=NCc2nnc(Cc4ccccc4)n2-3)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Clc1ccccc1C1=NCc2nnc(Cc3ccccc3)n2-c2sc3c(c21)CCNC3
Reaction time: 48 h
Yield: 77.7 %

Procedure:
A mixture containing ethyl ester of 1-benzyl-6-(2-chlorophenyl)-7,10-dihydro-4H-pyrido[4′,3′;4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-9(8H)-carboxylic acid (3.6 g, 0.0071 mol) and potassium hydroxide (4.4 g, 0.078 mol) is heated under reflux in ethanol for 6 hours then left under agitation at ambient temperature for 48 hours. The solid is filtered on frit, washed with a minimum quantity of ethanol. After adding water, extraction is carried out with dichloromethane followed by drying over magnesium sulphate. The solvent is evaporated off and the product is purified by crystallization from an ethyl acetate/isopropanol 50/50 mixture, followed by leaving in a refrigerator for 48 hours then filtering on frit while washing with a solvent mixture: ethyl acetate-isopropanol (50-50). Washing is finally carried out with isopentene followed by drying under vacuum. 2.46 g (77%) of the desired product is obtained in the form of a beige coloured solid. Melting point: 191–192° C.