Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([C:37]2[N:38]=[N:39][NH:40][N:41]=2)[CH:23]=[C:24]([N+:34]([O-:36])=[O:35])[C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.ClCCl>[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([C:37]2[N:38]=[N:39][N:40]([C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=3)[N:41]=2)[CH:23]=[C:24]([N+:34]([O-:36])=[O:35])[C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: O=[N+]([O-])c1cc(-c2nn[nH]n2)cc(OCc2ccccc2)c1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(-c2nnn(-c3ccc(C(F)(F)F)cn3)n2)cc(OCc2ccccc2)c1OCc1ccccc1
Temperature: 25 °C

Procedure:
2-chloro-5-(trifluoromethyl)pyridine (0.181 g, 1.00 mmol) was added to a stirred suspension of 5-(3,4-bis-benzyloxy-5-nitro-phenyl)-2H-tetrazole (0.4 g, 1.00 mmol) and potassium carbonate (0.14 g, 1 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature till completion, then diluted with dichloromethane and washed with water. The organic phase was separated, dried over anhydrous magnesium sulphate, filtered and evaporated to dryness to leave a crude residue that was recrystallised from a dichloro-methane/isopropanol mixture to afford 2-(5-(3,4-bis(benzyloxy)-5-nitrophenyl)-2H-tetrazol-2-yl)-5-(trifluoromethyl)pyridine, 0.389 g (71%).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C:15]1[N:16]([CH3:22])[N:17]=[C:18]([CH3:21])[C:19]=1[F:20])(C)(C)C>C(Cl)Cl>[F:20][C:19]1[C:18]([CH3:21])=[N:17][N:16]([CH3:22])[C:15]=1[NH2:14]
Reactant: Cc1nn(C)c(NC(=O)OC(C)(C)C)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nn(C)c(N)c1F
Reaction time: 24 h

Procedure:
TFA (170 mmol) was added to a solution of (4-fluoro-2,5-dimethyl-2H-pyrazol-3-yl)-carbamic acid tert-butyl ester (Step BH2) (22.68 mmol) in CH2Cl2 (50 mL) at rt. After stirring for 24 h, the reaction mixture was quenched with 2N aqueous NaOH and extracted with CH2Cl2 (3×). The combined organic phases were dried (Na2SO4), filtered and concentrated to afford the title compound as a bright yellow solid which was used in the next step without further purification. ESI-MS: tR=0.38 min, [M+H]+ 130 (LC-MS 1).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[N:9]=[C:8]([OH:10])[CH:7]=[C:6]([CH3:11])[N:5]=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:1][C:7]1[C:8]([OH:10])=[N:9][C:4]([CH3:3])=[N:5][C:6]=1[CH3:11]
Reactant: Cc1cc(O)nc(C)n1
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1nc(C)c(Br)c(O)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66 %

Procedure:
The solution of bromine (5.1 g, 31.9 mmol) in chloroform (30 mL) was added dropwise to the solution of 2,6-dimethylpyrimidin-4-ol (3.43 g, 27.6 mmol) in chloroform (50 mL) at 0° C. Then the mixture was stirred at 25° C. for 12 hours. Saturated sodium sulfite solution was added to the mixture until the colour of the mixture changed to colourless. The organic phase was separated, dried over sodium sulphate, filtered, and then concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=15:1) to give 5-bromo-2,6-dimethylpyrimidin-4-ol as a white solid (3.7 g, 66%). 1H NMR (300 MHz, d6-DMSO): δ 2.33 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:27][CH2:28][CH2:29][CH3:30])[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[C:17]=2[C:16]2[N:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1>>[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:27][CH2:28][CH2:29][CH3:30])[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])[C:17]=2[C:16]2[N:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Reactant: CCCCN=C=O
Product: CCCCNC(=O)NCCCCn1c(CCCC)nc2c(N)nc3cccnc3c21
Yield: 65.8 %

Procedure:
Using the general method of Example 47, butyl isocyanate (54 μL, 0.48 mmol) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.15 g, 0.48 mmole) to provide 0.13 g of N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]- N′-butylurea as a white solid. Analysis: Calculated for C22H33N7O: %C, 64.21; %H, 8.08; %N, 23.82; Found: %C, 64.05; %H, 7.97; %N, 24.00.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([C:16](=[O:18])[NH2:17])[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[Br:19]Br>C(O)(=O)C>[Br:19][CH:11]1[CH2:10][C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)([C:16](=[O:18])[NH2:17])[CH2:14][CH2:13][C:12]1=[O:15]
Reactant: COc1cccc(C2(C(N)=O)CCC(=O)CC2)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1cccc(C2(C(N)=O)CCC(=O)C(Br)C2)c1
Temperature: 20 °C
Yield: 104.8 %

Procedure:
50.5 g of 4-(3-methoxyphenyl)-4-carbamoyl-cyclohexanone are dissolved in 500 ml of acetic acid, and a solution of 32.7 g of bromine in 500 ml of acetic acid is added dropwise thereto at 20°C. under stirring. Then, the mixture is poured into ice-water and extracted with chloroform. The chloroform extract is washed with water, dried and then evaporated to remove solvent. 69.8 g of 2-bromo-4-(3-methoxyphenyl)-4-carbamoyl-cyclohexanone are obtained as crude oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.[CH3:31][S:32]([CH2:35][C:36](O)=[O:37])(=[O:34])=[O:33].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH3:31][S:32]([CH2:35][C:36]([NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1)=[O:37])(=[O:34])=[O:33]
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Reactant: CS(=O)(=O)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CC(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Yield: 88.3 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (150 mg, 0.363 mmol), (methylsulfonyl)acetic acid (75 mg, 0.544 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (104 mg, 0.544 mmol), 1-hydroxybenzotriazole (73 mg, 0.544 mmol), triethylamine (76 μL, 0.544 mmol) and N,N-dimethylformamide (5 mL) as starting materials and in the same manner as in Example 377, the title compound (171 mg, 88%) was obtained as a white powder.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([Cl:12])[N:3]=1.NC1C=CC=CN=1.[CH3:20][O:21][Na]>CO>[Cl:12][C:4]1[N:3]=[C:2]([O:21][CH3:20])[C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: Clc1cc2ccccc2c(Cl)n1
Reactant: CO[Na]
Agent: Nc1ccccn1
Solvent: CO
Product: COc1nc(Cl)cc2ccccc12
Temperature: 125 °C

Procedure:
Into a sealed tube were added 1,3-dichloroisoquinoline (501 mg, 2.45 mmol), 2-aminopyridine (31 mg, 0.33 mmol), cuprous monochloride (37.2 mg, 0.162 mmol), MeONa (824 mg, 5.92 mmol), MeOH (3 ml) and diglyne (8 ml). The tube was sealed, evacuated and filled with N2 three times. The combined mixture was heated at 125° C. for 3 days under an atmosphere of nitrogen. After that time, the mixture was treated with water (20 ml) and extracted with EtOAc (3×50 ml). The organic extracts were washed with water (3×30 ml), brine (30 ml), dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as light-yellow solid. 1H NMR (400 MHz, CDCl3): δ=4.15 (s, 3H), 7.26 (d, J=0.6 Hz, 1H), 7.51 (ddd, J=3.6, 4.6, 8.2 Hz, 1H), 7.64-7.69 (m, 2H), 8.20 (dd, J=8.4, 1.2 Hz, 1H). MS(ES+): m/z=194.08/196.01 (80/28) [MH+]. HPLC: tR=4.00 min (polar—5 min, ZQ3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C:14](=[O:20])[NH:13][C:12]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH2:27]([N:34]([CH2:36][CH2:37]Cl)[CH3:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C:14](=[O:20])[N:13]([CH2:37][CH2:36][N:34]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH3:35])[C:12]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: CN(CCCl)Cc1ccccc1
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3NC(=O)[C@@H]2OC(C)=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)Cc3ccccc3)C(=O)[C@@H]2OC(C)=O)cc1
Yield: 69.6 %

Procedure:
A mixture of 3.0 g of (-)-cis-2-(4-methoxyphenyl)-3-acetoxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 1.9 g of 2-(N-benzyl-N-methylamino)ethyl chloride.hydrochloride, 3.3 g of potassium carbonate and 80 ml of acetone is refluxed for 20 hours. Insoluble materials are removed by filtration, and the filtrate is evaporated under reduced pressure to remove solvent. The residue is dissolved in ethyl acetate, and the solution is washed with water, dried and evaporated to remove solvent. 2.9 g of (-)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(N-benzyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32].C(N(CC)CC)C>C(Cl)Cl>[C:31]([O:29][C@@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][C@H:23]1[N:13]1[C:12](=[O:30])[C:11]2[C:16](=[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:10]=2)[N:15]=[CH:14]1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2ncn1[C@@H]1CCCC[C@H]1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O[C@@H]1CCCC[C@H]1n1cnc2c(cc(Cc3ccc(Cl)nc3)c3ccccc32)c1=O
Temperature: 25 °C

Procedure:
To a solution of rac-6-[(6-chloropyridin-3-yl)methyl]-3-[trans-2-hydroxycyclohexyl]benzo[h]quinazolin-4(3H)-one (0.040 g, 0.095 mmol) in 2 mL of CH2Cl2 at 0° C. was added acetic anhydride (0.011 mL, 0.11 mmol) and triethylamine (0.026 mL, 0.20 mmol). The mixture was warmed to rt and after 15 h, concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 461.9 for [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]([F:30])([F:29])[F:28])=[N:4][N:5]([CH2:8][CH:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([Cl:25])=[CH:19][C:18]=3[Cl:26])[CH2:13][CH2:12]2)[NH2:10])[C:6]=1[CH3:7].C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:27]([F:30])([F:29])[F:28])=[N:4][N:5]([CH2:8][CH:9]([NH:10][S:39]([CH3:38])(=[O:41])=[O:40])[CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([Cl:25])=[CH:19][C:18]=3[Cl:26])[CH2:13][CH2:12]2)[C:6]=1[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(N2CCC(C(N)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)c(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(N2CCC(C(Cn3nc(C(F)(F)F)c(Cl)c3C)NS(C)(=O)=O)CC2)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
A 25-mL round bottom flask was charged with 2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)-1-(1-(2,4-dichloro-5-methoxyphenyl)piperidin-4-yl)ethanamine (23 mg, 0.047 mmol), anhydrous DCM (2 mL), and triethylamine (0.016 mL, 0.118 mmol). The resultant solution was treated with methanesulfonyl chloride (5.50 μL, 0.071 mmol) and stirred at RT for 1 h. After this time, the mixture was concentrated on a rotary evaporator, and the resultant residue was partitioned between EtOAc and saturated sodium bicarbonate. The organic phase was washed with brine, dried (MgSO4) and concentrated to give the crude product. The crude product was purified by flash chromatography (4 g silica gel cartridge, EtOAc/hexanes) to afford Example 4 g (22 mg, 0.039 mmol, 82% yield). LC-MS: 563.0 (M+H); tR=4.18 min (method c). 1H-NMR (400 MHz, CDCl3) δ ppm 7.16 (1 H, s), 6.49 (1 H, s), 4.59 (1 H, d, J=9.23 Hz), 4.20-4.26 (1 H, m), 4.09-4.15 (1 H, m), 3.76-3.81 (3 H, m), 3.59 (1 H, d, J=6.15 Hz), 3.30-3.39 (2 H, m), 2.65 (3 H, s), 2.48-2.54 (2 H, m), 2.23-2.32 (3 H, m), 1.91 (1 H, s), 1.75-1.81 (1 H, m), 1.55-1.62 (2 H, m).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4](P(=O)(OC)OC)[O:3]1.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27].C(N(CC)CC)C>O1CCCC1>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2](=[O:1])[O:3]2)=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27]
Reactant: COP(=O)(OC)C1OC(=O)c2ccccc21
Reactant: O=Cc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1OC(=Cc2ccc(F)c([N+](=O)[O-])c2)c2ccccc21

Procedure:
A stirred solution of dimethyl 3-oxo-1,3-dihydroisobenzofuran-1-ylphosphonate (20 g, 0.083 mol) and 4-fluoro-3-nitrobenzaldehyde (13.97 g, 0.083 mol) in tetrahydrofuran (120 ml) was cooled to 15° C. and triethylamine (11.5 ml, 0.083 mol) was added dropwise at <25° C. The mixture thickened at this point, so further tetrahydrofuran (50 ml) was added to aid stirring. The mixture was stirred at ambient temperature for 65 hours and the resulting solid was collected by filtration. The filtrate was concentrated in vacuo, the residue was triturated with water (30 ml) and the resulting solid was collected by filtration. The two crops of solid were combined and suspended in water (120 ml). The mixture was stirred at ambient temperature for 30 minutes and the resulting solid was collected by filtration and dried in vacuo for 24 hours to give crude 3-(4-fluoro-3-nitrobenzylidene)-3H-isobenzofuran-1-one, still slightly wet with water, which was used directly in the next stage.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH2:23])[CH:19]=3)[N:14]=1)[CH2:9][CH2:8]2.[N:24]1([CH2:29][C:30](O)=[O:31])[CH:28]=[CH:27][N:26]=[CH:25]1>>[N:24]1([CH2:29][C:30]([NH:23][C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[N:14]=[C:13]([NH:12][CH:10]2[C:11]4[C:7](=[CH:6][CH:5]=[CH:4][C:3]=4[O:2][CH3:1])[CH2:8][CH2:9]2)[CH:22]=[CH:21]3)=[O:31])[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: O=C(O)Cn1ccnc1
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)Cn4ccnc4)ccc3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method described in example 6 from rac-N2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine and imidazol-1-yl-acetic acid; MS: m/e=414.3 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[CH:11][C:10]=1[O:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.S(=O)(=O)(O)O.[N+:36]([O-])([OH:38])=[O:37]>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([O:25][CH3:26])=[CH:11][C:12]([C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])=[C:23]([N+:36]([O-:38])=[O:37])[CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C(=O)OCc2ccccc2)ccc1OCc1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(C(=O)OCc2ccccc2)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
Benzyl 4-(benzyloxy)-3-methoxybenzoate (135 g) was dissolved in dichloromethane (339 ml). Glacial acetic acid (175.5 g) was added and the mixture cooled to 110° C. Concentrated sulfuric acid (151.6 g) was added in a controlled manner maintaining the temperature of the reaction mixture below 25° C. Concentrated nitric acid (61.6 g) was then added in 15 minutes keeping the temperature of the reaction mixture below 25° C. The reaction mixture was then heated to 40° C. and stirred for 3 hours. The lower aqueous layer was removed and the organic layer was washed twice with water (2×168 ml). The organic layer was distilled to at atmospheric pressure to remove dichloromethane (186 ml). Isopropanol (339 ml) was added to the reaction mixture at 40° C. The reaction mixture was held at 40° C. for 15 minutes. The resulting suspension was then cooled to 20° C. within 30 minutes, then to 5° C. and held at this temperature for one hour. The product (benzyl 4-(benzyloxy)-5-methoxy-2-nitrobenzoate) was isolated by filtration, washed with isopropanol (336 ml) and dried at less than 25° C. Yield: 135.7 g, 89.6%; NMR Spectrum (CDCl3) 3.9 (s, 3H), 5.2 (s, 2H), 5.3 (s, 2H), 7.1 (s, 1H), 7.3-7.4 (m, 100H), 7.5 (s, 1H); Mass Spectrum (M+H)+=394.1.
Reaction SMILES: [C:1]([C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH2:10][OH:11])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[OH-].[K+].[O-:17][Mn](=O)(=O)=O.[K+]>O1CCOCC1.O>[C:1]([C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]([OH:17])=[O:11])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(C)(C)C(=O)c1cccc(CO)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Yield: 93.2 %

Procedure:
3-Pivaloylbenzyl alcohol (0.80 g, 4.16 mmol) was dissolved in dioxane (20 ml). A solution of KOH (0.35 g, 6.30 mmol) in water (5 ml) was added followed by KMnO4 (145 g, 9.17 mmol). The mixture was stirred at room temperature over the weekend. The solution was filtered through Celite and extracted with ether. The aqueous phase was acidified with dil. HCl and extracted with ether (3×50 ml). The organic layer was dried over magnesium sulphate and concentrated in vacuo to afford the title compound as a white solid (0.80 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH2:13][CH:14]([OH:16])[CH3:15])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Br:17]Br.[OH-].[Na+]>C(O)(=O)C.O>[Br:17][C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[NH:12][CH2:13][CH:14]([OH:16])[CH3:15])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2
Reactant: CC(O)CNc1ccnc2cc(Cl)ccc12
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(O)CNc1c(Br)cnc2cc(Cl)ccc12
Reaction time: 1.5 h
Yield: 50.6 %

Procedure:
A mixture of 12 g of 7-chloro-N-(2-hydroxypropyl)-4-quinolinamine in 112 ml of acetic acid was stirred at room temperature and to it 8 g of bromine was added dropwise over a thirty minute period. After 1.5 hours, a solid formed which was isolated by filtration, dissolved in water and basified with sodium hydroxide, whereupon a solid formed which was collected by filtration. Recrystallization from ethanol yielded 8 g of solid with a melting point of 161°-163° C.
Reaction SMILES: Cl[C:2]1[N:27]=[CH:26][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=4)=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[O:28]1[CH2:32][CH2:31][O:30][CH:29]1[C:33]1[O:37][C:36]([Sn](CCCC)(CCCC)CCCC)=[CH:35][CH:34]=1>O1CCOCC1>[O:28]1[CH2:32][CH2:31][O:30][CH:29]1[C:33]1[O:37][C:36]([C:2]2[N:27]=[CH:26][C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]5[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=5)=[CH:13][CH:12]=4)[C:4]=3[CH:3]=2)=[CH:35][CH:34]=1
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4cnc(Cl)cc34)cc2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Solvent: C1COCCO1
Product: Fc1cccc(COc2ccc(Nc3ncnc4cnc(-c5ccc(C6OCCO6)o5)cc34)cc2)c1

Procedure:
(6-Chloropyrido[3,4-d]pyrimidin-4-yl)-(4-(3-fluorobenzyloxy)-phenyl)-amine (1.85 g) and 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)-furan (3.82 g) in dioxan (40 ml) were reacted together as in Procedure B. The mixture was evaporated and the residue suspended in dichloromethane. This was then filtered through Celite® and the solvent evaporated. The gummy residue was then triturated with hexane giving a beige solid (1.74 g); m/z 485 (M+1)+.
Reaction SMILES: Cl.[Br:2][C:3]1[N:12]=[C:6]2[CH2:7][CH:8]([NH2:11])[CH2:9][CH2:10][N:5]2[N:4]=1.C(Cl)Cl.[CH3:16][N:17]1[C:21]([C:22](Cl)=[O:23])=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=2)[CH:19]=[N:18]1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C>[Br:2][C:3]1[N:12]=[C:6]2[CH2:7][CH:8]([NH:11][C:22]([C:21]3[N:17]([CH3:16])[N:18]=[CH:19][C:20]=3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=3)=[O:23])[CH2:9][CH2:10][N:5]2[N:4]=1
Reactant: Cc1cccc(-c2cnn(C)c2C(=O)Cl)n1
Reactant: NC1CCn2nc(Br)nc2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(-c2cnn(C)c2C(=O)NC2CCn3nc(Br)nc3C2)n1
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
The 2-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-amine hydrochloride (38 mg) obtained in (Example 5.16) <Step 6> was added at 0° C. to a methylene chloride (1 ml) solution of the 1-methyl-4-(6-methylpyridin-2-yl)-1H-pyrazole-5-carbonyl chloride (35 mg) obtained in (Example 5.47) <Step 1> and triethylamine (0.06 ml). The obtained mixture was stirred for 30 minutes. Thereafter, a saturated sodium hydrogen carbonate aqueous solution (2 ml) was added to the reaction solution, and the mixed solution was then purified by LC/MS, so as to obtain the title compound (29 mg) in the form of a white solid.
Reaction SMILES: Cl[C:2]1[N:6]=[CH:5][N:4]([C:7]2[N:12]=[C:11]([CH3:13])[CH:10]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[N:8]=2)[N:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[CH3:13][C:11]1[CH:10]=[C:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:8]=[C:7]([N:4]2[CH:5]=[N:6][C:2]([C:28]3[CH:29]=[CH:30][C:25]([NH2:24])=[N:26][CH:27]=3)=[N:3]2)[N:12]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(Cl)n2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(-c3ccc(N)nc3)n2)n1

Procedure:
The title compound was prepared from 2-(3-chloro-[1,2,4]triazol-1-yl)-4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.65) (0.17 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a light brown solid (0.032 g, 16%). MS (ISP) 398.1 [(M+H)+]; mp 244° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C@:11]([OH:17])([CH3:16])[C:12]([F:15])([F:14])[F:13].[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:26]([NH:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:27])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C@:11]([OH:17])([CH3:16])[C:12]([F:13])([F:15])[F:14]
Reactant: C[C@@](O)(C(=O)Nc1ccc(N)cc1Cl)C(F)(F)F
Reactant: O=C=Nc1ccccc1
Solvent: CCOCC
Product: C[C@@](O)(C(=O)Nc1ccc(NC(=O)Nc2ccccc2)cc1Cl)C(F)(F)F
Reaction time: 22 h

Procedure:
A mixture of (R)-N-[2-chloro-4-aminophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 208) (0.198 g) and phenyl isocyanate (0.09 ml) in diethyl ether (10 ml) was stirred for 22 hours then evaporated to dryness. The residue was partitioned between water (25 ml) and ethyl acetate (50 ml). The organic phase was washed with brine (25 ml), dried and concentrated by evaporation to give the title compound (170 mg) as a foam. NMR: 1.66 (s, 3H), 7.04 (t, 1H), 7.35 (m, 3H), 7.52 (d, 1H), 7.71 (s, 1H), 7.86 (m, 2H), 8.77 (s, 1H), 8.92 (s, 1H), 9.63 (s, 1H); MS (ESP−): 400.