Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Cl:13])[N:3]=1.[O:14]([CH3:16])[K].CCOC(C)=O>CO>[Cl:1][C:2]1[CH:11]=[C:10]([O:14][CH3:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Cl:13])[N:3]=1
Reactant: Clc1cc(Cl)c2c(Cl)cccc2n1
Reactant: CO[K]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(Cl)nc2cccc(Cl)c12
Temperature: 25 °C

Procedure:
To 2.4,5-trichloroquinoline (0.79 g, 3.4 mmol) was added KOMe (20.4 ml of a 0.5 M suspension in MeOH). The mixture was heated under reflux for 2.5 h. EtOAc was added and the solution was allowed to cool to room temperature. The solvent was evaporated in vacuo and the residue submitted to column chromatography (silica gel, EtOAc:hexanes 1:6→1:3). 4,5-Dichloro-2-methoxyquinoline eluted first, then 2,4,5-trichloroquinoline. followed by the title compound, a colourless solid, (0.43 g, 44%). δH (CDCl3) 4.04 (s, 3H), 6.77 (s, 1H), 7.50-7.60 (m, 2H), 7.85 (dd, J=6.7, 3.0, 1H); MS (AP+) 228 (MH+, 100%).
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17](=O)[NH:16][CH2:15]2.BrC1C=CC=C2C=1CNC2=[O:32]>>[OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:20]=[CH:19][CH:18]=[C:14]2[C:13]=1[CH2:17][NH:16][C:15]2=[O:32]
Reactant: O=C1NCc2c(Br)cccc21
Reactant: COc1ccc(-c2ccc3c(c2)CNC3=O)c(O)c1OC
Product: COc1ccc(-c2cccc3c2CNC3=O)c(O)c1OC

Procedure:
4-(2-Hydroxy-3,4-dimethoxy-phenyl)isoindolin-1-one is synthesized following the same procedure as the one described for the synthesis of Compound 307 using 4-bromo-2,3-dihydro-1H-isoindol-1-one as starting material.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[Se](=O)=[O:12].OO>CO>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N+:2]=1[O-:12]
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=[Se]=O
Agent: OO
Solvent: CO
Product: [O-][N+]1=Cc2ccccc2CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 1261.9 %

Procedure:
A mixture of 1.00 g of 1,2,3,4-tetrahydroisoquinoline, 0.042 g of selenium dioxide, 2.30 ml of 30% hydrogen peroxide in 20 ml of methanol is stirred at room temperature for 20 hours. The reaction mixture is concentrated in vacuo to a residue which is diluted with water and extracted with chloroform. The organic layer is dried and evaporated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 99:1 methanol-chloroform to give 0.703 g of the desired product as a solid.
Reaction SMILES: C([O:3][C:4](=O)/[CH:5]=[CH:6]/[C:7]1[C:8]([NH:16][CH2:17][CH3:18])=[N:9][C:10]([S:14][CH3:15])=[N:11][C:12]=1[CH3:13])C.N12CCCN=C1CCCCC2>CCN(C(C)C)C(C)C>[CH2:17]([N:16]1[C:8]2[N:9]=[C:10]([S:14][CH3:15])[N:11]=[C:12]([CH3:13])[C:7]=2[CH:6]=[CH:5][C:4]1=[O:3])[CH3:18]
Reactant: CCNc1nc(SC)nc(C)c1/C=C/C(=O)OCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(=O)ccc2c(C)nc(SC)nc21
Yield: 76.5 %

Procedure:
To a solution of (E)-ethyl-3-(4-(ethylamino)-6-methyl-2-(methylthio)pyrimidin-5-yl)acrylate (16.8 g, 59.8 mmol) in DIPEA was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 18.21 g, 119.6 mmol) at room temperature. Then the reaction mixture was heated to reflux and reacted for 15 h. After evaporation of solvent, the residue was triturated with acetone. The product 8-ethyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (10.77 g, 77% yield) was collected by filtration. NMR (400 MHz, CDCl3): δ 7.78 (d, J=9.6 Hz, 1H), 6.63 (d, J=9.6 Hz, 1H), 4.5 (q, J=7.2 Hz, 2H), 2.67 (s, 3H), 2.62 (s, 3H), 1.33 (t, J=7.2 Hz, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([N:12]2[C:16]3[CH:17]=[CH:18][C:19]([CH2:21][NH2:22])=[CH:20][C:15]=3[N:14]=[CH:13]2)[CH:9]=[CH:10][CH:11]=1.[CH:23](O)=[O:24]>>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([N:12]2[C:16]3[CH:17]=[CH:18][C:19]([CH2:21][NH:22][CH:23]=[O:24])=[CH:20][C:15]=3[N:14]=[CH:13]2)[CH:9]=[CH:10][CH:11]=1
Reactant: NCc1ccc2c(c1)ncn2-c1cccc(-c2nccs2)c1
Reactant: O=CO
Product: O=CNCc1ccc2c(c1)ncn2-c1cccc(-c2nccs2)c1
Yield: 33 %

Procedure:
A solution of C-[1-(3-thiazol-2-yl-phenyl)-1H-benzoimidazol-5-yl]-methylamine (1.4 g, 4.57 mmol) in formic acid (20 ml) was stirred at reflux for 3 hours. The mixture was evaporated in vacuo and the residue was partitioned between ethyl acetate and saturated, aqueous sodium carbonate. The organic layer was dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of dichloromethane and methanol (9:1 v/v) as the eluent to afford the desired product 0.5 g (33%). LC-ESI-HRMS of [M+H]+ shows 335.095 Da. Calc. 335.096657 Da. dev. −4.9 ppm.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:11]2[CH:12]=[N:13][CH:14]=[C:15]([CH:19]=2)[C:16]([OH:18])=[O:17])[NH:3]1.[CH2:20]([O:22][C:23]([C:25]1[C:29]([CH2:30][CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=[C:28]([CH:40]=O)[NH:27][C:26]=1[CH3:42])=[O:24])[CH3:21].N1CCCCC1.Cl>C(O)C>[CH2:20]([O:22][C:23]([C:25]1[C:29]([CH2:30][CH2:31][CH2:32][N:33]2[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]2)=[C:28]([CH:40]=[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][C:8]=3[C:11]3[CH:12]=[N:13][CH:14]=[C:15]([CH:19]=3)[C:16]([OH:18])=[O:17])[NH:3][C:2]2=[O:1])[NH:27][C:26]=1[CH3:42])=[O:24])[CH3:21]
Reactant: O=C1Cc2c(cccc2-c2cncc(C(=O)O)c2)N1
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1CCCN1CCN(C)CC1
Agent: Cl
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cncc(C(=O)O)c4)c32)c1CCCN1CCN(C)CC1
Temperature: 60 °C

Procedure:
A mixture of 5-(2-oxo-2,3-dihydro-1H-indol-4-yl)-nicotinic acid (51 mg, 0.2 mmol), 5-formyl-2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propyl]-1H-pyrrole-3-carboxylic acid ethyl ester (64 mg, 0.2 mmol) and piperidine (0.2 mL) in ethanol (1 mL) was heated in a sealed tube at 60° C. for 5 hours. The reaction was acidified with 1N HCl and the resulted precipitate was collected by vacuum filtration, washed with water and dried to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[CH:5]=[C:4]([CH3:11])[N+:3]=1[O-].P(Cl)(Cl)Cl.O.C(#N)C>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[CH:5]=[C:4]([CH3:11])[N:3]=1
Reactant: CCOc1cc(C)[n+]([O-])c(Br)c1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CCOc1cc(C)nc(Br)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 24 %

Procedure:
2-Bromo-6-methyl-4-ethoxy-pyridine 1-oxide (a total of 9.85 g, 42 mmol) was divided in two batches, suspended in ethyl acetate (anhydrous, total of 130 ml), phosphorus trichloride (total of 15 ml) was added dropwise and the mixtures were stirred at 50° C. for three hours. Then the mixture of each batch was poured onto crushed ice (250 ml each) with stirring, ethyl acetate (250 ml each) was added, the phases were separated and the organic phases were washed with water (2 times), dried (magnesium sulfate) and concentrated under reduced pressure. The residues were combined and purified by column chromatography (silica, petrolether/ethyl acetate 95:5) and then by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and acetonitrile) to give 2.2 g of a yellow oil (10 mmol, 24% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]([CH3:14])[CH3:13])[CH:10]=2)[CH:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[N:3]=1.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N:12]([CH3:14])[CH3:13])[CH:10]=3)[CH:5]=[C:4]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)[N:3]=2)=[CH:27][CH:26]=1
Reactant: COc1ccc(CN)cc1
Reactant: COc1cccc(-c2cc3ccc(N(C)C)cc3c(Cl)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nc(-c3cccc(OC)c3)cc3ccc(N(C)C)cc23)cc1
Temperature: 25 °C
Yield: 46.9 %

Procedure:
A mixture of 1-chloroimine isoquinoline II (500 mg, 1.6 mmol), 4-methoxy benzylamine (877 mg, 6.4 mmol), and potassium carbonate (2 g, 15 mmol) in DMF was refluxed overnight. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic extracts were washed with water, dried, and concentrated. The residue was purified by column chromatography on silica gel with n-hexane-ethyl acetate (3:1) to afford compound III (310 mg, 47%). 1H NMR (300 MHz, CDCl3) δ: 7.74-7.62 (m, 3H), 7.45-7.33 (m, 4H), 7.22 (m, 1H), 6.92 (m, 3H), 6.66 (m, 1H), 5.24 (s, 1H), 4.91 (d, 2H), 3.91 (s, 3H), 3.85 (s, 3H), 3.09 (s, 6H).
Reaction SMILES: B.C1C[O:5]CC1.N#N.[CH2:9]([C:12]1[C:17]2[O:18][C@@H:19]([CH2:22][O:23][S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH2:20][O:21][C:16]=2[CH:15]=[CH:14][C:13]=1[N+:34]([O-:36])=[O:35])[CH:10]=[CH2:11].[OH-].[Na+].OO.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.C(O)C>[OH:5][CH2:11][CH2:10][CH2:9][C:12]1[C:17]2[O:18][C@@H:19]([CH2:22][O:23][S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH2:20][O:21][C:16]=2[CH:15]=[CH:14][C:13]=1[N+:34]([O-:36])=[O:35]
Reactant: C1CCOC1
Reactant: C=CCc1c([N+](=O)[O-])ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Agent: B
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc([N+](=O)[O-])c(CCCO)c3O2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
A 1M solution of BH3.THF (11.00 ml, 11.00 mmole) was placed in a 100 ml round-bottom flask equipped with N2 line, dropping funnel and thermometer. The solution was cooled to 0° C. in an ice-water bath. To this cooled solution was added dropwise, (R)-toluene-4-sulfonic acid 8-allyl-7-nitro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester (2.25 g, 5.56 mmole) in 10 ml of dry THF over a 10 minute period. The reaction was allowed to reach room temperature and then stirred overnight. It was then cooled to 0° C. and to it was added dropwise 2.42 ml of absolute ethanol and 6.16 ml (18.5 mmole) of a 3 N NaOH solution. After a few minutes, 4.2 ml of a 30% aqueous H2O2 solution was added over a 20 minute period. The mixture was heated to 48° C. for three hours. The mixture was then cooled to 0° C. and to it was added 6.08 g of K2CO3. The mixture was stirred for 0.5 hr and then left standing overnight. The following morning the solid had disappeared. The reaction was diluted with water and extracted with ethyl acetate. The organic layer washed with brine, dried over MgSO4, filtered and concentrated to yield a clear viscous oil (1.20 g, 51%) of (R)-toluene-4-sulfonic acid 8-(3-hydroxy-propyl)-7-nitro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:8]=2)[CH:6]=1.[C:27]([NH:31][S:32]([C:35]1[S:36][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:38][CH:39]=1)(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][S:32]([C:35]1[S:36][C:37]([C:2]2[N:3]=[CH:4][N:5]([C:7]3[CH:12]=[C:11]([C:13]([F:14])([F:16])[F:15])[CH:10]=[C:9]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=4)[N:8]=3)[CH:6]=2)=[CH:38][CH:39]=1)(=[O:33])=[O:34])([CH3:30])([CH3:28])[CH3:29]
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(-n3cnc(I)c3)n2)cc1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)s1

Procedure:
The title compound was prepared from 2-(4-iodo-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (example E.23) (0.966 g, 2.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.829 g, 2.4 mmol) according to the general procedure VI. Obtained as a white solid (0.158 g, 14%). MS (ISP) 575.2 [(M+H)+].
Reaction SMILES: [F:1][C:2]1([F:31])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([N:15](C(OC(C)(C)C)=O)[NH:16]C(OC(C)(C)C)=O)[CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.[C:32]([CH2:38][C:39]#[N:40])(=O)[C:33]([CH3:36])([CH3:35])[CH3:34].Cl.C([O-])(O)=O.[Na+]>C(O)C>[C:33]([C:32]1[CH:38]=[C:39]([NH2:40])[N:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([CH2:8][N:5]3[CH2:4][CH2:3][C:2]([F:31])([F:1])[CH2:7][CH2:6]3)[CH:10]=2)[N:16]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1cccc(CN2CCC(F)(F)CC2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2cccc(CN3CCC(F)(F)CC3)c2)n1
Yield: 43.9 %

Procedure:
A mixture of Intermediate 12b (1.30 g, 2.94 mmol), pivaloyl acetonitrile (0.37 g, 2.94 mmol), and concentrated HCl (1.5 mL) in ethanol (10 mL) was heated under reflux for 3 h. The cooled mixture was taken to ca. pH 7 with aqueous saturated NaHCO3, and the mixture partitioned between water (15 mL) and EtOAc (3×15 mL). The combined organic extracts were washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated, and the residue purified by FCC, eluting with 0-100% EtOAc in pentane, to give the title compound as a pale yellow solid (450 mg, 43%). LCMS (Method 1): Rt 1.93 min, m/z 349 [MH+].
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=[C:10]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[CH2:11][C:12]#[N:13]>CO>[C:1]1([N:7]2[C:12]([NH2:13])=[CH:11][C:10]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccccc1
Reactant: N#CCC(=O)c1cccs1
Solvent: CO
Product: Nc1cc(-c2cccs2)nn1-c1ccccc1
Temperature: 120 °C
Yield: 98.9 %

Procedure:
Phenyl hydrazine (143 mg, 1.32 mmol) and 3-oxo-3-(2-thienyl)propionitrile (200 mg, 1.32 mmol) were placed in a microwave vial and dissolved in methanol (660 μL). The vial was sealed, placed in a microwave oven and heated at 120° C. for 40 minutes. After this period, the reaction mixture was concentrated to dryness in vacuo. The residue was redissolved in ethyl acetate and the organic solution washed with water, saturated aqueous NaHCO3 and brine, respectively. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude material was purified by flash chromatography (20-50% ethyl acetate/hexanes gradient) to afford the desired intermediate, 2-phenyl-5-thiophen-2-yl-2H-pyrazol-3-ylamine (315 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[S:9][C:10]([Br:13])=[CH:11][CH:12]=1)(=[O:7])=[O:6].CCN(C(C)C)C(C)C.[C:23](Cl)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25].O>C(Cl)Cl>[Br:13][C:10]1[S:9][C:8]([S:5]([NH:4][CH2:3][CH2:2][NH:1][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:6])=[O:7])=[CH:12][CH:11]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCCNS(=O)(=O)c1ccc(Br)s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)C(=O)NCCNS(=O)(=O)c1ccc(Br)s1
Temperature: 0 °C
Yield: 94.8 %

Procedure:
A mixture of N-(2-aminoethyl)-5-bromothiophene-2-sulfonamide (2.5 g, 8.77 mmol, 1.0 eq) and DIPEA (3.4 g, 26.3 mmol, 3.0 eq) in CH2Cl2 (100 mL) was stirred at 0° C., pivaloyl chloride (2.1 g, 17.5 mmol, 2 equiv.) was added drop-wise. Then, the mixture was stirred at 0° C. for 0.5 h. Water was added and the reaction was extracted with EA (3×80 ml). The combined organic layers were dried (Na2SO4), filtered, evaporated and purified by silica gel chromatography (PE/EA=10:1 as eluant) to afford N-(2-(5-bromothiophene-2-sulfonamido)ethyl)pivalamide (3.07 g, 95.0%). LC-MS (m/z)=368.9 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:11][CH:10]([C:24]([OH:26])=O)[CH2:9]1)=[O:7].[F:27][C:28]1[CH:29]=[C:30]([C:34](=[N:36]O)[NH2:35])[CH:31]=[CH:32][CH:33]=1>>[F:27][C:28]1[CH:29]=[C:30]([C:34]2[N:36]=[C:24]([CH:10]3[CH2:11][CH:12]([C:14]4[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:18][CH:19]=4)[CH2:13][N:8]([C:6]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[O:7])[CH2:9]3)[O:26][N:35]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: NC(=NO)c1cccc(F)c1
Reactant: COCCNC(=O)N1CC(C(=O)O)CC(c2ccc(C(F)(F)F)cc2)C1
Product: COCCNC(=O)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)no2)C1

Procedure:
100 mg (0.267 mmol) of the compound from Example 105A and 77 mg (0.497 mmol) of 3-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 2. Yield: 64 mg (55% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:21])[CH2:12][NH:13][C:14]2[C:15](=[O:20])[NH:16][N:17]=[CH:18][CH:19]=2)[CH2:7][CH2:6]1.Br[CH2:31][C:32]#[C:33][CH3:34]>>[CH2:31]([N:16]1[C:15](=[O:20])[C:14]([NH:13][CH2:12][C:11]([N:8]2[CH2:9][CH2:10][CH:5]([O:4][C:3]3[CH:22]=[C:23]([C:26]([F:29])([F:27])[F:28])[CH:24]=[CH:25][C:2]=3[Cl:1])[CH2:6][CH2:7]2)=[O:21])=[CH:19][CH:18]=[N:17]1)[C:32]#[C:33][CH3:34]
Reactant: O=C(CNc1ccn[nH]c1=O)N1CCC(Oc2cc(C(F)(F)F)ccc2Cl)CC1
Reactant: CC#CCBr
Product: CC#CCn1nccc(NCC(=O)N2CCC(Oc3cc(C(F)(F)F)ccc3Cl)CC2)c1=O
Yield: 9 %

Procedure:
Compound 46 is prepared from intermediate 7b and from 1-bromo-but-2-yne following synthesis method 6 (yield: 9%).
Reaction SMILES: [CH3:1][C:2]([C:4](Cl)=[O:5])=[CH2:3].[Al+3].[Cl-].[Cl-].[Cl-].[CH2:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1>C(Cl)Cl>[CH3:1][CH:2]1[C:4](=[O:5])[C:13]2=[CH:14][C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=3[CH:11]=[C:12]2[CH2:3]1
Reactant: C=C(C)C(=O)Cl
Reactant: c1ccc2c(c1)CCCC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1Cc2cc3c(cc2C1=O)CCCC3
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Methacryl chloride (37.5 ml, 375 mmol) was added at −70° C. to well-stirred suspension of AlCl3 (100 g, 750 mmol) in CH2Cl2 (600 ml). After 20 min tetrahydronaphthalene (49.5 g, 375 mmol) was added. Reaction mixture was allowed to warm to room temperature, stirred for 16 h and poured into ice water-HCl (1 l/150 ml). Organic layer was separated, water layer was extracted by CH2Cl2 (2100 ml). Combined organic phases were washed by water, aq. NaHCO3, dried over MgSO4 and evaporated. Vacuum distillation (130-140° C./0.5 Torr) a mixture of ketones. After storage within 5 days desired isomer stays liquid and can be separated by decantation. The yield 30 g (40%).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:49][CH2:50][C:51]([N:53]1[CH2:58][CH2:57][N:56]([C:59](=[O:71])[C:60]2[CH:65]=[C:64]([F:66])[CH:63]=[CH:62][C:61]=2[C:67]([F:70])([F:69])[F:68])[CH2:55][CH2:54]1)=[O:52]>CN(C=O)C.O>[F:66][C:64]1[CH:63]=[CH:62][C:61]([C:67]([F:69])([F:68])[F:70])=[C:60]([CH:65]=1)[C:59]([N:56]1[CH2:57][CH2:58][N:53]([C:51](=[O:52])[CH2:50][NH:49][C:22](=[O:24])[C:21]2[CH:20]=[CH:19][C:18]([N:15]3[CH2:14][CH2:13][N:12]([CH3:11])[CH2:17][CH2:16]3)=[CH:26][CH:25]=2)[CH2:54][CH2:55]1)=[O:71]
Reactant: CN1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc(C(=O)NCC(=O)N3CCN(C(=O)c4cc(F)ccc4C(F)(F)F)CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 41.5 %

Procedure:
DIPEA (350 mg, 0.5 mL, 2.7 mmol) was added to a stirred solution of 4-(4-methyl-piperazin-1-yl)-benzoic acid hydrochloride salt (116 mg, 0.45 mmol) in DMF (5 mL). HOBT (67 mg, 0.5 mmol) and EDCI (216 mg, 1.12 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (184 mg, 0.5 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and filtered the solid residue. The obtained residue was purified by preparative HPLC to afford 100 mg (41.3% yield) N-{2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-4-(4-methyl-piperazin-1-yl)-benzamide. LCMS Purity: 88.3%. 1H NMR (DMSO-d6): δ 10.4 (s, 1H), 8.4 (s, 1H), 8.0 (t, 1H), 7.86 (d, 2H), 7.64 (m, 2H), 7.1 (d, 2H), 4.2-3.96 (m, 4H), 3.66-3.4 (m, 8H), 3.24-3.0 (m, 6H), 2.9 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH:8]=O)[S:5][C:6]=1[CH3:7].Cl.[NH2:11][OH:12].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CCOC(C)=O>[CH3:1][C:2]1[N:3]=[C:4]([CH:8]=[N:11][OH:12])[S:5][C:6]=1[CH3:7]
Reactant: Cc1nc(C=O)sc1C
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1nc(C=NO)sc1C
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 4,5-dimethylthiazole-2-carbaldehyde (987 mg, 7.0 mmol) in 1,4-dioxane (35 mL) was added hydroxylamine hydrochloride (1.45 g, 21 mmol) and K2CO3 (3.8 g, 28 mmol). The resulting mixture was stirred at 100° C. for 2 hours and then diluted with EtOAc (150 mL), washed with H2O (30 mL*2). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product which was used for next step without further purification. LCMS m/z (M+H) 157.1 found, 157.1 required.
Reaction SMILES: [NH2:1][C:2](=[N:39][C:40](=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:27]2[NH:31][C:30](=[O:32])[N:29]([C:33]3[N:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[N:28]=2)[C:11]2[C:12]([F:26])=[C:13]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=2)[O:14][CH2:15][CH2:16][O:17][C:18](=[O:20])[CH3:19])=[CH:5][CH:4]=1.Cl[CH2:49][O:50][C:51](=[O:58])[C:52]([CH3:57])([CH3:56])[CH2:53][O:54][CH3:55].C(=O)([O-])O.[K+].CN(C=O)C>O.C(OCC)(=O)C>[C:18]([O:17][CH2:16][CH2:15][O:14][C:13]1[C:12]([F:26])=[C:11]([CH:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([NH2:1])=[N:39][C:40](=[O:47])[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:8][CH:7]=2)[C:27]2[N:31]=[C:30]([O:32][CH2:49][O:50][C:51](=[O:58])[C:52]([CH3:57])([CH3:56])[CH2:53][O:54][CH3:55])[N:29]([C:33]3[N:34]=[CH:35][CH:36]=[CH:37][N:38]=3)[N:28]=2)[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=1)(=[O:20])[CH3:19]
Reactant: COc1cc(OCCOC(C)=O)c(F)c(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Reactant: COCC(C)(C)C(=O)OCCl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COCC(C)(C)C(=O)OCOc1nc(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2cc(OC)cc(OCCOC(C)=O)c2F)nn1-c1ncccn1
Temperature: 55 °C
Reaction time: 15 h
Yield: 34.1 %

Procedure:
Under nitrogen atmosphere, a mixture of acetic acid 2-{3-[(4-{amino[benzoylimino]methyl}phenylamino)-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl]-2-fluoro-5-methoxyphenoxy)ethyl ester (441 mg), 3-methoxy-2,2-dimethylpropionic acid chloromethyl ester (Example 4a, 373 mg), potassium hydrogen carbonate (241 mg), and DMF (20 mL) was stirred at 55° C. for 15 hours. The resulting mixture was poured into ethyl acetate (200 mL) and water (50 mL). After shaking the resulting mixture, the organic layer was collected, sequentially washed twice with water (50 mL) and with saturated aqueous sodium chloride solution (50 mL), and dried over anhydrous magnesium sulfate. The resulting mixture was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by NAM silica gel column chromatography (mixed solvent of methanol-ethyl acetate) to obtain the captioned compound (184 mg).