Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C(S)C.[CH3:8][N:9]([CH3:33])[CH2:10][CH2:11][N:12]1[C:20](=[O:21])[C:19]2[C:18]3[C:22]4[CH:28]=[C:27]([O:29]C)[CH:26]=[CH:25][C:23]=4[S:24][C:17]=3[C:16]([CH3:31])=[CH:15][C:14]=2[C:13]1=[O:32]>C(Cl)Cl>[CH3:33][N:9]([CH3:8])[CH2:10][CH2:11][N:12]1[C:20](=[O:21])[C:19]2[C:18]3[C:22]4[CH:28]=[C:27]([OH:29])[CH:26]=[CH:25][C:23]=4[S:24][C:17]=3[C:16]([CH3:31])=[CH:15][C:14]=2[C:13]1=[O:32]
Reactant: COc1ccc2sc3c(C)cc4c(c3c2c1)C(=O)N(CCN(C)C)C4=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: Cc1cc2c(c3c1sc1ccc(O)cc13)C(=O)N(CCN(C)C)C2=O
Reaction time: 0.5 h
Yield: 93 %

Procedure:
690 mg of anhydrous aluminum chloride was suspended in 100 ml of methylene chloride. To the suspension was added 1.1 ml of ethanethiol at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Thereto was dropwise added, in 1 minute, a solution of 380 mg of 2-(2-dimethylaminoethyl)-9-methoxy-5-methyl-1H-[1]benzothieno[3,2-e]isoindole-1,3(2H)-dione dissolved in 100 ml of methylene chloride. The mixture was stirred at room temperature overnight. The solvent was removed by distillation under reduced pressure. The residue was mixed with 100 ml of ethyl acetate and 50 ml of an aqueous saturated sodium hydrogencarbonate solution. The mixture was stirred for 30 minutes. The resulting insoluble material was removed by filtration. The separated insoluble material was washed with 50 ml of ethyl acetate. The filtrate and the washings were combined. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from n-propanol to obtain 340 mg (yield: 93%) of 2-(2-dimethylaminoethyl)-9-hydroxy-5-methyl-1H-[1]benzothieno[3,2-e]isoindole-1,3(2H)-dione as yellow crystals.
Reaction SMILES: [F:1][C:2]1[S:6][C:5]([C:7](N(OC)C)=[O:8])=[CH:4][CH:3]=1.[CH3:13][Mg]Br>O1CCCC1>[F:1][C:2]1[S:6][C:5]([C:7](=[O:8])[CH3:13])=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)c1ccc(F)s1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1ccc(F)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 103.2 %

Procedure:
To a stirred solution of 5-fluoro-N-methoxy-N-methylthiophene-2-carboxamide (12.34 g, 65.2 mmol) in tetrahydrofuran (163 mL) at 0° C. under nitrogen is added methyl magnesium bromide (3 M solution in tetrahydrofuran, 32.6 mL, 97.8 mmol) over a period of 25 minutes, while maintaining the internal temperature below 10° C. The cooling bath is removed and the solution is allowed to warm to room temperature over 1 hour. A saturated solution of ammonium chloride (200 mL) is added and the mixture is stirred for 10 minutes. The mixture is diluted with diethyl ether (200 mL) and the phases are separated. The aqueous phase is re-extracted with diethyl ether (2×150 mL) and the combined organic extracts are dried over sodium sulfate, filtered, and concentrated under reduced pressure (keeping the water bath below 25° C.) to give the crude title compound (9.70 g, 103%) as a pale amber liquid. 1H NMR (CDCl3) δ 2.47 (s, 3H), 6.53 (dd, J=1.2, 4.3 Hz, 1H), 7.38 (t, J=4.0 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13].C(=O)([O-])[O-].[K+].[K+].[CH3:22][O:23][CH2:24]Cl.O>CN(C)C=O>[CH3:22][O:23][CH2:24][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[O:11][C:12]([F:13])([F:14])[F:15]
Reactant: COCCl
Reactant: CC(=O)c1ccc(O)c(OC(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(C(C)=O)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(4-hydroxy-3-trifluoromethoxyphenyl)ethanone (1.55 g) was dissolved in N,N-dimethylformamide (20 mL), and potassium carbonate (1.46 g) and chloromethyl methyl ether (0.64 mL) were added to the solution, and then the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (1.54 g) as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:13]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ccc(-c2cccc(O)c2)c2c1C(=O)NC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)Oc1cccc(-c2ccc(N)c3c2CNC3=O)c1
Yield: 59.5 %

Procedure:
In a similar manner to Step 1 of Example 304, 7-amino-4-(3-hydroxyphenyl)isoindolinone (137 mg, 0.569 mmol) was dissolved in acetonitrile (7.0 mL), and the solution was treated with tert-butyldimethylsilyl chloride (155 mg, 1.02 mmol) and DBU (0.154 mL, 1.02 mmol), followed by purification by flash column chromatography (chloroform) to obtain 7-amino-4-(3-tert-butyldimethylsilyloxyphenyl)isoindolinone (120 mg, yield 59%).
Reaction SMILES: [CH:1]1([CH2:6][C:7]([CH:9]2[C:14](=O)[CH2:13][CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10]2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][C:24]1[N:25]([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH2:38])=[NH:37])=[CH:31][CH:30]=2)[CH:26]=[CH:27][N:28]=1>>[CH:1]1([CH2:6][C:7]2[C:9]3[CH2:10][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:13][C:14]=3[N:38]=[C:36]([NH:35][C:32]3[CH:33]=[CH:34][C:29]([N:25]4[CH:26]=[CH:27][N:28]=[C:24]4[CH3:23])=[CH:30][CH:31]=3)[N:37]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nccn1-c1ccc(NC(=N)N)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C(=O)CC2CCCC2)C1
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(CC4CCCC4)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Yield: 39 %

Procedure:
tert-Butyl 4-(cyclopentylmethyl)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (199 mg, 39%) was synthesised from tert-butyl 3-(2-cyclopentylacetyl)-4-oxopiperidine-1-carboxylate and 1-(4-(2-methyl-1H-imidazol-1-yl)phenyl)guanidine (Example 41c) according to the general procedure for the synthesis of pyrimidines. MS (ES+) m/z 489.1 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[CH:7]([OH:8])[CH2:6][CH2:5][C:4]([CH3:10])([CH3:9])[C:3]=1[CH:11]=[CH:12][C:13](=[O:15])[CH3:14].O.O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].S(=O)(=O)(O)O>CCOCC>[CH3:1][C:2]1[C:7](=[O:8])[CH2:6][CH2:5][C:4]([CH3:9])([CH3:10])[C:3]=1[CH:11]=[CH:12][C:13](=[O:15])[CH3:14]
Reactant: CC(=O)C=CC1=C(C)C(O)CCC1(C)C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(=O)C=CC1=C(C)C(=O)CCC1(C)C
Temperature: 5 °C
Yield: 734.3 %

Procedure:
To a solution, pre-cooled to 0° C., of 140 g (0.068 mol) of 4-(2,6,6-trimethyl-3-hydroxy-cyclohex-1-en-1-yl)-but-3-en-2-one in 500 ml of ether are added dropwise over a period of 10 minutes 700 ml of an aqueous solution, cooled to 0° C., of 202.6 g of sodium dichromate dihydrate and 186 g of concentrated sulphuric acid with intensive cooling and good stirring so that a temperature of 5° C. is not exceeded. The mixture is then stirred for a further 5 minutes at 5° C., treated with 500 ml of ether, the ether phase is washed three times with water, three times with soda solution and again three times with water, dried over sodium sulphate and concentrated. Distillation of the resulting 125 g of crude product over a 10 cm Widmer column gave 103 g of more than 94% pure 4-(2,6,6-trimethyl-3-oxocyclohex-1-en-1-yl)-but- 3-en-2-one of boiling point 109°-110° C./0.05 mm Hg; melting point 50°-51° C.
Reaction SMILES: [C:1]([N:3]1[C:11]2[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[C:5]2[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]1=2)#[CH:2].Br[C:19]1[N:20]=[CH:21][S:22][CH:23]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(=O)(O)[O-]>O>[CH3:17][N:14]1[CH2:15][CH2:16][C:4]2[N:3]([C:1]#[C:2][C:19]3[N:20]=[CH:21][S:22][CH:23]=3)[C:11]3[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=3[C:5]=2[CH2:13]1
Reactant: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Reactant: Brc1cscn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C#Cc2cscn2)CCN(C)C1
Temperature: 120 °C
Yield: 5.4 %

Procedure:
A mixture of 5-ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (163 mg, 0.731 mmol), 4-bromo-thiazole (100 mg, 0.60 mmol), dichlorobistriphenylphosphinepalladium(II) (12 mg, 0.01 mmol) and TBAF.3H2O (575 mg, 1.82 mmol) was heated at 80° C. (observed exothermic temperature was 120° C.) for 5 min by microwave. After completion of reaction (monitored by TLC&LCMS), the mixture was poured into water (20 mL) and saturated bicarbonate was added. The mixture was extracted with EtOAc (3×20 mL), the organic layer was washed with water (3×50 mL), dried over sodium sulfate and concentrated under vacuum to obtain 10 mg of 2,8-dimethyl-5-thiazol-4-ylethynyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, free base) δ (ppm): 8.80 (s, 1H), 7.56 (s, 1H), 7.44 (d, 2H), 7.18 (s, 1H), 7.08 (d, 1H), 3.64 (s, 2H), 3.0 (m, 2H), 2.90 (m, 2H), 2.60 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH:11]=O>CCOCC.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][O:16][C:15]1[CH:14]=[CH:13][C:10]([CH:11]=[CH2:1])=[CH:9][C:8]=1[O:7][CH3:6]
Reactant: [Li]CCCC
Reactant: COc1ccc(C=O)cc1OC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Product: C=Cc1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of n-butyllithium (4 mL, 2,5 M solution in hexane, 10 mmol) (Aldrich) in ether (30 mL) was added methyltriphenylphosphonium bromide (3.57 g, 10 mmol) (Aldrich) over a period of 5 min. The reaction mixture was stirred for 4 h at room temperature. To the resulting orange solution was added 3,4-dimethoxybenzaldehyde (1.82 g, 11 mmol) (Aldrich) dropwise. The solution became colorless, and a white precipitate separated. The mixture was then heated to reflux and immediately allowed to cool to room temperature. The precipitate was removed by filtration. The precipitate was washed with ether and the combined ethereal filtrates were washed with water until neutral and then dried over anhydrous MgSO4. The solvent was removed and the residue, 1,2-dimethoxy-4-ethenyl -benzene, was used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:21]=[C:22]([Si](C)(C)C)[S:23][CH:24]=3)=[CH:16][CH:15]=2)[CH:5]=[CH:4][C:3]=1[S:29]([NH2:32])(=[O:31])=[O:30].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:21]=[CH:22][S:23][CH:24]=3)=[CH:16][CH:15]=2)[CH:5]=[CH:4][C:3]=1[S:29]([NH2:32])(=[O:30])=[O:31]
Reactant: Cc1cn(-c2ccc(S(N)(=O)=O)c(F)c2)c(-c2ccc(-c3csc([Si](C)(C)C)n3)cc2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cn(-c2ccc(S(N)(=O)=O)c(F)c2)c(-c2ccc(-c3cscn3)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
To a stirred solution of 2-fluoro-4-[4-methyl-2-[4-(2-trimethylsilylthiazol-4-yl)phenyl]-1H-imidazol-1-yl]benzenesulfonamide (crude, 0.634 mmol) in THF (3 mL) was added tetrabutylammonium fluoride (0.95 mL, 1.0 M solution in THF, 0.95 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred for 30 minutes. The reaction mixture was added water (20 mL) and extracted with ethyl acetate (20 mL×3). The organic layer was washed with water and brine. After dried over MgSO4 and concentration in vacuo. The crude mixture was purified by flash chromatography eluting with hexane/ethyl acetate (1/3). The resulting solid was recrystallized from ethyl acetate-hexane to give the title compound (0.116 g, 44.1% yield, via 2 steps).
Reaction SMILES: [C:1]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12])([O:3][CH2:4][CH3:5])=[O:2].[Br:13]Br>C(OCC)C>[Br:13][CH:8]1[CH2:9][CH2:10][CH2:11][CH:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])[C:7]1=[O:12]
Reactant: BrBr
Reactant: CCOC(=O)C1CCCCC1=O
Solvent: CCOCC
Product: CCOC(=O)C1CCCC(Br)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.1 %

Procedure:
2-Carbethoxy-cyclohexanone (5.0 g, 29.4 mmol) was dissolved in diethyl ether (30 mL). To this solution bromine (4.93 g, 30.8 mmol) was added drop wise at room temperature. The reaction was stirred for 1 hour at room temperature, quenched with water and the layers were separated. The organic layer was washed with aqueous thiosulfate solution and brine, dried over sodium sulfate and filtered. The solvent was removed under reduced pressure to yield the crude title compound (7.48 g, 100%) which was used directly in the next step without further purification. 1H NMR (CDCl3, 300 MHz): δ (ppm)=4.94 (t, 1H), 4.20 (q, 1H), 2.37 (dt, 1H), 2.25 (m, 1H), 2.09 (m, 2H), 1.74 (m, 2H), 1.24 (t, 3H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]([NH2:16])[CH3:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:18][C:19](=O)[C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:27]Br.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:26][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:20]=1[C:19](=[O:18])[N:16]([CH:14]([C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][CH:12]=1)[CH3:15])[CH2:27]2
Reactant: CC(N)c1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)c1c(Cl)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(c1ccc(Oc2ccccc2)cc1)N1Cc2cccc(Cl)c2C1=O
Reaction time: 16 h
Yield: 33.8 %

Procedure:
A mixture of 1-(4-phenoxyphenyl)ethylamine (121 mg, 0.57 mmol), 2-bromomethyl-6-chloro-benzoic acid methyl ester (150 mg, 0.57 mmol), and K2CO3 (1 g, 7.2 mmol) in toluene (10 mL) was heated at reflux with stirring for 16 h. Workup and silica gel column chromatography using a gradient of hexanes to 30% ethyl acetate in hexanes afforded 7-chloro-2-[1-(4-phenoxyphenyl)-ethyl]-2,3-dihydroisoindol-1-one (70 mg, 34%). GC/MS gave: m/z (rel.int.) 365 (M+, 9), 363 (M+23), 350 (25), 348 (63), 211 (32), 196 (65), 168 (33), 152 (54), 141 (27), 124 (27), 115 (27), 89 (35), and 77 (100). 1H NMR (300 MHz, CDCl3): δ 1.68 (d, 3H), 3.99 (d, 1H), 4.15 (d, 1H), 5.79 (q, 1H), 6.98 (br t, 4H), 7.13 (t, 1H), 7.26-7.10 (br m, 7H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:27]([O-])=O)[C:5]([NH:8][CH2:9][CH2:10][CH:11]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[N:6][CH:7]=1.[Cl-].[NH4+].C(O)C>[Fe].O1CCCC1>[NH2:27][C:4]1[C:5]([NH:8][CH2:9][CH2:10][CH:11]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: CC(C)(C)OC(=O)NC(CCNc1ncc(Br)cc1[N+](=O)[O-])C(=O)OC(C)(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(CCNc1ncc(Br)cc1N)C(=O)OC(C)(C)C

Procedure:
A suspension of 3.5 g of tert-butyl 4-[(5-bromo-3-nitropyridin-2-yl)amino]-2-tert-butoxycarbonylaminobutanoate, 1.23 g (22 mmol) of iron powder and 20 g (0.373 mol) of ammonium chloride in 40 ml of a 1:1 mixture of ethanol and tetrahydrofuran is heated at reflux for two hours. After this time the reaction mixture is filtered on a bed of celite, which is rinsed with 100 ml of ethanol. The filtrate is concentrated under reduced pressure and then the residue is taken up in 20 ml of water. The mixture is then extracted with three times 50 ml of ethyl acetate. The organic phases are combined, washed with 50 ml of a saturated aqueous sodium chloride solution, dried over sodium sulfate and then concentrated under reduced pressure. An oil is recovered which is purified by chromatography on a silica column, eluting with a mixture of dichloromethane and methanol. This gives 2.93 g of the expected product in the form of a solid, used as it is in the remainder of the synthesis.
Reaction SMILES: [F:1][C:2]([F:42])([O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][C:38]([F:41])([F:40])[F:39])=[CH:30][CH:29]=1)[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][C:15]2[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[C:17]([N+:24]([O-])=O)[CH:16]=2)=[O:12])=[CH:5][CH:4]=1>CN(C)C=O.O.[Zn]>[F:1][C:2]([F:42])([O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][C:38]([F:41])([F:40])[F:39])=[CH:30][CH:29]=1)[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[C:17]([NH2:24])[CH:16]=2)=[O:12])=[CH:5][CH:4]=1
Reactant: O=C(/C=C/c1ccc(C(F)(F)Oc2ccc(OCCCC(F)(F)F)cc2)cc1)OCc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [Zn]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(N)cc(COC(=O)/C=C/c2ccc(C(F)(F)Oc3ccc(OCCCC(F)(F)F)cc3)cc2)c1
Yield: 70.1 %

Procedure:
4.99 g (8.38 mmol) of 3,5-dinitrobenzyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]-methyl}-phenyl)prop-2-enoate are dissolved in a mixture of 54 mL of N,N-dimethylformamide and 6 mL water. 13.9 g (51.4 mmol) ferric chloride hexahydrate are added. 5.60 g (85.7 mmol) zinc powder is added portion wise within 60 minutes. The mixture is allowed to react for 2 hours. The reaction mixture is partitioned between ethyl acetate and water and filtrated. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Filtration of the residue on 200 g silica gel using toluene:ethyl acetate 1:3 as eluent and crystallization from ethyl acetate:hexane mixture yields 3.15 g of 3,5-diaminobenzyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]-methyl}-phenyl)prop-2-enoate as yellow crystals.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)=[CH:33][CH:32]=2)[C:15](=[O:29])[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][N:18]2C(OC(C)(C)C)=O)=[N:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)=[CH:35][CH:36]=2)[C:15](=[O:29])[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][NH:18]2)=[N:2]1
Reactant: COc1ccc(-c2ccc(CN(CCCNc3nsc4ccccc34)C(=O)CC3CCCN3C(=O)OC(C)(C)C)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2ccc(CN(CCCNc3nsc4ccccc34)C(=O)CC3CCCN3)cc2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 129.5 %

Procedure:
tert-Butyl 2-(2-((3-(benzo[d]isothiazol-3-ylamino)propyl)((4′-methoxybiphenyl-4-yl)methyl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate (20 mg, 0.033 mmol) was dissolved in methylene chloride (0.5 mL) and cooled in an ice-bath. A cooled solution of trifluoroacetic acid (1.0 mL) in methylene chloride (1.0 mL) was added to the mixture, dropwise. The reaction was allowed to stir for 3 h at 0° C. The solution was concentrated under reduced pressure to yield N-(3-(benzo[d]isothiazol-3-ylamino)propyl)-N-((4′-methoxybiphenyl-4-yl)methyl)-2-(pyrrolidin-2-yl) acetamide (22 mg) as a solid. 1H NMR (300 MHz, CDCl3): 8.15-8.20 (m, 1H), 7.45-7.70 (m, 6H), 7.15-7.20 (m, 2H), 6.90-6.95 (m, 2H), 4.60-4.75 (m, 1H), 4.45-4.55 (m, 1H), 3.95-4.10 (m, 2H), 3.85 (s, 3H), 3.60-3.75 (m, 2H), 3.35-3.45 (m,2H), 3.15-3.25 (m, 2H), 2.75-2.85 (m,1H), 1.90-2.00 ppm (m, 1H). MW=515 confirmed by LC-MS, tr=4.50 min (Method B) MH+=514-516.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[N:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]=[S:12]>CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:11]([NH:10][C:13](=[O:14])[O:15][CH2:16][CH3:17])=[S:12])=[N:7][CH:8]=1
Reactant: COc1ccc(N)nc1
Reactant: CCOC(=O)N=C=S
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)NC(=S)Nc1ccc(OC)cn1
Reaction time: 15 h
Yield: 62.3 %

Procedure:
To a solution of 5-methoxypyridin-2-amine (1.05 g, 8.43 mmol) in dimethyl sulfoxide (5 mL) was added ethyl isothiocyanatoformate (1.44 g, 11.0 mmol), and the mixture was stirred for 15 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate (×3). The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was dried to give the title compound (1.34 g, 62%) as a white solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[C:30]([C:32]1[CH:37]=[CH:36][N:35]=[C:34](Cl)[CH:33]=1)#[N:31]>>[C:30]([C:32]1[CH:37]=[CH:36][N:35]=[C:34]([N:20]2[CH2:21][CH2:22][C:16]3[C:15]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])=[N:14][C:13]([C:10]4[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=4)=[N:18][C:17]=3[CH2:19]2)[CH:33]=1)#[N:31]
Reactant: N#Cc1ccnc(Cl)c1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(c2cc(C#N)ccn2)C3)cc1

Procedure:
Compound ei was prepared according to the procedure described in Example 2 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with 4-cyano-2-chloropyridin. LC-MS: m/z=+499 (M+H)+.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:29]=[CH:28][C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[N:13][N:12]=2)=[CH:8][C:7]=1[O:30]C>ClCCl>[Cl:5][C:6]1[CH:29]=[CH:28][C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[N:13][N:12]=2)=[CH:8][C:7]=1[OH:30]
Reactant: COc1cc(Nc2nnc(Cc3ccncc3)c3ccccc23)ccc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cc(Nc2nnc(Cc3ccncc3)c3ccccc23)ccc1Cl
Reaction time: 18 h

Procedure:
A solution of 2 ml boron tribromide (≈1 M in CH2Cl2) is mixed with a suspension of 0.19 g (0.50 mmol) 1-(4-chloro-3-methoxyanilino)-4-(4-pyridylmethyl)phthalazine (Example 68B) in 4 ml dichloromethane at 0° C. under a nitrogen atmosphere. The resinous mixture is left to stand for 18 h at RT, the dichloromethane phase is then decanted, and the glutinous residue stirred with 10 ml THF and 5 ml sat. NaHCO3 solution. The resulting suspension is filtered, the filter residue washed with THF and discarded. The THF phase is separated and dried (Na2SO4), concentrated by evaporation, chromatographed (SiO2; acetate/CH3OH, 40:1→19:1) and title compound crystallized from acetonitrile/methanol: m.p.: 245-246° C.; HPLC: tRet(Grad5-40)=8.8; FAB MS (M+H)+=363.