Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:15][CH2:14]1.CCOC(C)=O>CCO.[Pt]>[Cl:1][C:2]1[C:3]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:15][CH2:14]2)=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:7]=1)[NH2:8]
Reactant: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(Cl)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(Cl)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
To 1-[2-chloro-5-(methyloxy)-4-nitrophenyl]-4-[2-(methylsulfonyl)ethyl]piperazine (1.38 g, 3.65 mmol) in EtOH (30 mL) was added EtOAc to help with solubility. The catalyst, 5% sulfided platinum on carbon (0.138 g, 0.035 mmol) was added. The reaction was placed on a Fischer-Porter Hydrogenator under 50 psi of H2 gas and was allowed to stir at rt overnight. The catalyst was filtered off and the filtrate was concentrated in vacuo, adsorbed onto silica gel and flash chromatographed. The desired fractions were combined and concentrated to give the title compound of step B (0.880 g, 69%). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.58-6.70 (m, 2H), 4.64 (s, 2H), 3.74 (s, 3H), 3.22-3.37 (m, 2H), 3.04 (s, 3H), 2.84 (t, J=4.4 Hz, 4H), 2.74 (t, J=6.7 Hz, 2H), 2.50-2.63 (m, 4H).
Reaction SMILES: C[O-].[Na+].[N+:4]([C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([N+]([O-])=O)=[CH:14][CH:15]=3)[CH:10]([CH:23]3[O:27][CH2:26][CH2:25][O:24]3)[C:9]=2[CH:8]=1)([O-:6])=[O:5].CN(C)[CH:30]=[O:31]>O>[CH3:30][O:31][C:13]1[CH:14]=[CH:15][C:16]2[C:17]3[C:9](=[CH:8][C:7]([N+:4]([O-:6])=[O:5])=[CH:19][CH:18]=3)[CH:10]([CH:23]3[O:24][CH2:25][CH2:26][O:27]3)[C:11]=2[CH:12]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(C1OCCO1)c1cc([N+](=O)[O-])ccc1-2
Reactant: CN(C)C=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2c(c1)C(C1OCCO1)c1cc([N+](=O)[O-])ccc1-2
Reaction time: 2 h
Yield: 86 %

Procedure:
For a period of two hours, 8 parts of sodium methoxide was added to a solution of 10 parts of 2-(2,7-dinitro-9-fluorenyl)-1,3-dioxolane in 300 parts of dimethylformamide contained within a 5 liter flask at room temperature. The mixture was magnetically stirred for 20 hours. All of the mixture was then diluted with 1800 parts of water. A yellow solid was precipitated therefrom, collected on a filter, washed with water and dried under vacuum. The dried filtered product was further purified in a chromatography column packed with silica gel (Merck Grade 60) and developed by methylene chloride to provide 8.2 parts of product (86% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH2:12]([O:14][C:15]1[C:16](=O)[C:17](=[O:22])[C:18]=1[O:19]CC)[CH3:13]>C(O)C>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][C:16]2[C:17](=[O:22])[C:18](=[O:19])[C:15]=2[O:14][CH2:12][CH3:13])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: Nc1cccc2cccnc12
Solvent: CCO
Product: CCOc1c(Nc2cccc3cccnc23)c(=O)c1=O
Yield: 70.4 %

Procedure:
To a solution of 8-aminoquinoline (1.00 g, 6.94 mmol) in ethanol (20 mL) was added 3,4-diethoxy-3-cyclobutene-1,2-dione (1.03 mL, 6.94 mmol) and the resulting mixture was heated to reflux for 24 hours. The mixture was cooled, diluted with ethanol, and filtered. The crude product was triturated with chloroform/hexanes, then purified by chromatography (EtOAc/hexane) to give 1.31 g (70%) of product: 1H NMR (DMSO-d6) δ9.75 (br m, 1H), 8.86 (dd, 1H), 8.26 (br m, 1H), 8.20 (dd, 1H), 7.57 (m, 2H), 7.53 (dd, 1H), 4.95 (q, 2H), 1.59 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1.[Br:9]Br.[OH-].[Na+]>S(=O)(=O)(O)O.O>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[Br:9]
Reactant: Cc1cccc(N)n1
Reactant: BrBr
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(Br)c(N)n1
Temperature: 0 °C
Yield: 55.2 %

Procedure:
32.4 g (0.3 mole) of 6-aminopicoline was dissolved in a mixture of 28 g of conc. sulfuric acid and 120 ml of water and the resulting solution was cooled in ice water. 52.8 g (0.33 mole) of bromine was added dropwise to the solution over 30 minutes at 0° C. The reaction solution was stirred for 20 minutes at room temperature and neutralized with cold aqueous NaOH solution. The resultant was filtered and the solid was purified with column chromatography using methylene chloride and ethyl acetate as an eluent to obtain 31 g of the title compound (yield 55%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:12]([C:22]([F:25])([F:24])[F:23])=[N:11][N:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Br:26]NC(=O)CCC(N)=O>C(OCC)(=O)C>[Br:26][CH2:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:19])([CH3:20])[CH3:21])[C:12]([C:22]([F:24])([F:25])[F:23])=[N:11][N:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: Cc1cc(C)cc(-c2nnc(C(F)(F)F)n2COCC[Si](C)(C)C)c1
Solvent: CCOC(C)=O
Product: Cc1cc(CBr)cc(-c2nnc(C(F)(F)F)n2COCC[Si](C)(C)C)c1

Procedure:
The product from step (x) (2 g), N-bromosuccinamide (1 g) in dry ethyl acetate (25 ml) was irradiated at reflux with a 500 Watt halogen lamp for 1 h. The cooled reaction mixture was partitioned with dilute sodium bicarbonate solution. The organic layer collected, dried (MgSO4) and solvent removed by evaporation under reduced pressure. Yield:2.5 g The product was not purified but used directly in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]#[N:21]>CN(C)C=O>[C:20]([CH2:19][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])#[N:21]
Reactant: COC(=O)c1cccc(O)c1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OCC#N)c1
Temperature: 0 °C
Yield: 6461 %

Procedure:
Methyl 3-hydroxybenzoate (10.00 g, 65.72 mmol) was dissolved in dimethylformamide (100 ml). With stirring the solution under ice-cooling, potassium carbonate (13.63 g, 98.58 mmol) and chloroacetonitrile (4.99 ml, 78.86 mmol) were added in that order, and the mixture was stirred at room temperature for 12 hours. The reaction solution was poured into ice-water and the crystals precipitated were collected by filtration. The resulting crystals were dissolved in chloroform, and the solution was washed with 5% potassium carbonate aqueous solution, 10% citric acid aqueous solution and brine in that order, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. By crystallizing the resulting residue from diethyl etherhexane, methyl 3-cyanomethoxybenzoate (811.80 g, 94%) was obtained.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[N:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[N:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].O>C1COCC1>[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[N:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15]
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Reactant: Cn1ccnc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cn1ccnc1N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 59.5 %

Procedure:
n-Butyllithium (1.6M in hexane, 20.76 mL, 33.22 mmol) was added dropwise to 1-methyl-1H-imidazole (CAS no. 616-47-7) (3 g, 36.54 mmol), in THF (10 mL) cooled to −70° C. over a period of 10 minutes under nitrogen. The resulting solution was stirred at −70° C. for 10 minutes. di-tert-Butyl diazene-1,2-dicarboxylate (CAS no. 870-50-8) (7.65 g, 33.22 mmol) in THF (6 ml) added dropwise over 10 minutes, not allowing the solution to rise above −65° C. After the addition was complete the solution was allowed to warm to ambient temperature overnight. Water (20 mL) added at RT. The THF was removed under vacuum. Extracted with EtOAc (2×40 mL). The organic extracts were combined, washed with brine (15 mL), dried over MgSO4 and reduced to give crude product. The crude product was purified by flash silica chromatography eluting with 20 to 100% EtOAc in isohexane to afford the product (6.17 g, 59.5%). m/z (ESI+) (M+H)+=313; HPLC tR=1.36 min.
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([C:17]([OH:19])=O)[CH:5]=1)([CH3:3])[CH3:2].[F:20][C:21]([F:32])([F:31])[C:22]1[N:27]=[CH:26][C:25]([C@H:28]([NH2:30])[CH3:29])=[CH:24][N:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([C:17]([NH:30][C@@H:28]([C:25]2[CH:24]=[N:23][C:22]([C:21]([F:32])([F:31])[F:20])=[N:27][CH:26]=2)[CH3:29])=[O:19])[CH:5]=1)([CH3:2])[CH3:3]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(C)C)n2)nc1
Reactant: C[C@@H](N)c1cnc(C(F)(F)F)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3cnc(C(F)(F)F)nc3)cc(C(C)C)n2)nc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.8 %

Procedure:
To a solution of 6-isopropyl-5′-methyl-2,2′-bipyridine-4-carboxylic acid (25.0 mg, 0.07 mmol) in DMF (0.3 mL) were added hydrochloride salt of (1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethanamine (22.1 mg, 0.08 mmol), HATU (38.2 mg, 0.10 mmol) and diisopropylethylamine (58.5 μL, 0.34 mmol). The mixture was stirred at ambient temperature. After 20 min, the mixture was purified by reverse phase chromatography (C-18, 95% water/acetonitrile→25% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (24 mg), HRMS 430.1850 (M+1). 1H NMR (400 MHz, CDCl3): δ 8.96 (s, 2H), 8.48 (s, 1H), 8.43 (d, 8.1 Hz, 1H), 8.37 (s, 1H), 7.67 (d, J=8.2 Hz, 1H), 7.63 (s, 1H), 6.96 (d, J=6.7 Hz, 1H), 5.44-5.35 (m, 1H), 3.24-3.14 (m, 1H), 2.42 (s, 3H), 1.74 (d, J=7.2 Hz, 3H), 1.37 (d, J=6.9 Hz, 6H).
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][N:2]1[C:14]1[N:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][N:15]=1.CC(C)([O-])C.[K+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C.CCOC(C)=O>[CH2:30]([N:12]1[C:13]2[CH2:1][N:2]([C:14]3[N:15]=[CH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:19]=3)[CH2:3][CH2:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COC(=O)c1cnc(N2CCc3c([nH]c4ccccc34)C2)nc1
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(N2CCc3c(n(Cc4ccccc4)c4ccccc34)C2)nc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 77 %

Procedure:
To a stirred solution of Example 8 (200 mg, mmol) in DMF (mL) was added potassium t-butoxide (150 mg) at 0° C. After stirring at 0° C. for 15 min., benzyl bromide (0.1 mL, mmol) was added slowly. After completion of addition, the reaction mixture was allowed to attain room temperature and stirred for a further 3 hours. After completion of reaction, the reaction mixture was diluted with EtOAc. The organic layer was separated and washed with saturated sodium bicarbonate and water. After drying the organic layer using sodium sulfate, it was concentrated to obtain a crude product that was then purified by column chromatography to obtain methyl 2-(9-benzyl-1,3,4,9-tetrahydro-2H-b-carbolin-2-yl)pyrimidine-5-carboxylate (200 mg, 77.0% yield), m/e=398.9 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10][C:9]=2[NH:15][CH3:16])=[C:4]([O:17][CH3:18])[CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:28]=1)[C:23]([OH:25])=O>>[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:28]=1)[C:23]([N:15]([C:9]1[CH:10]=[N:11][C:12]([CH3:14])=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[O:17][CH3:18])[CH3:16])=[O:25]
Reactant: CNc1cnc(C)cc1-c1ccc(F)cc1OC
Reactant: CS(=O)(=O)c1cc(Cl)cc(C(=O)O)c1
Product: COc1cc(F)ccc1-c1cc(C)ncc1N(C)C(=O)c1cc(Cl)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 90, from 4-(4-fluoro-2-methoxyphenyl)-N,6-dimethylpyridin-3-amine and 3-chloro-5-(methylsulfonyl)benzoic acid (example 114, intermediate a) after a reaction time of 15.5 hours. The product was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Colorless oil (41%). MS (ESI): m/z=463.09 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[O:12][C:13]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19]4)=[CH:14][N:15]=2)=[CH:3]1.Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[O:12][C:13]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[CH:22]=[C:21]([O:26][CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:20]=[CH:19]4)=[CH:14][N:15]=2)=[CH:3]1
Reactant: COC(=O)CBr
Reactant: Cn1cc(-c2ncc(-c3ccc4cc(O)ccc4c3)o2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc2cc(-c3cnc(-c4cn(C)c5ccccc45)o3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
A mixture of 6-[2-(1-methyl-1H-indol-3-yl)-oxazol-5-yl]-naphthalen-2-ol (289 mg, 0.843 mmol), prepared in step 4 of Example 8, methyl bromoacetate (80 μL, 0.845 mmol) and cesium carbonate (852 mg, 2.61 mmol) in 50 mL of acetone was stirred under nitrogen at room temperature for 19 h (overnight). The acetone was removed under reduced pressure and the residue partitioned between methylene chloride and water. The organic layer was separated and the aqueous layer extracted two times with methylene chloride. The combined extracts were dried (MgSO4), filtered and the solvent removed under reduced pressure to give methyl ({6-[2-(1-methyl-1H-indol-3-yl)-1,3-oxazol-5-yl]-2-naphthyl}oxy)acetate (289 mg, 90%) as a tan solid, mp 187-189° C. Elemental Analysis for C25H20N2O4 Calc'd: C, 72.80; H, 4.89; N, 6.79. Found: C, 71.55; H, 4.86; N, 6.53
Reaction SMILES: C([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:21])([CH3:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:10][C:9]=1[N:22]1[N:26]=[C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]2=[N:23]1)C=CCCC.[CH3:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C(OCC)(=O)C>CN(C)C1C=CC=CC=1>[N:26]1[N:22]([C:9]2[CH:10]=[C:11]([C:14]([CH3:20])([CH3:21])[CH2:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH:12]=[C:13]([CH:33]([CH2:34][CH2:35][CH3:36])[CH:32]=[CH2:31])[C:8]=2[OH:7])[N:23]=[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=12
Reactant: CCCCCC
Reactant: CCCC=CCOc1ccc(C(C)(C)CC(C)(C)C)cc1-n1nc2ccccc2n1
Solvent: CCOC(C)=O
Solvent: CN(C)c1ccccc1
Product: C=CC(CCC)c1cc(C(C)(C)CC(C)(C)C)cc(-n2nc3ccccc3n2)c1O
Reaction time: 22 h
Yield: 84 %

Procedure:
5.6 g (13.8 mmol) of 2-(2-hex-2-enyloxy-5-(1,1,3,3-tetramethylbutyl)-phenyl)-2H-benzotriazole, prepared as described above, in 100 ml of N,N-dimethylaniline were heated to reflux. The reaction was traced by tlc. (hexane:ethyl acetate=7:3). After 22 hours the reaction was complete. N,N-dimethylaniline was distilled off and the product freed from residual amine in a high vacuum to yield 4.7 g (84%) of 2-(benzotriazole-2-yl)-4-(1,1,3,3-tetramethylbutyl)-6-(1-hexen-3-yl)-phenol as an orange liquid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][C:19]4[C:14](=[C:15]([NH2:24])[N:16]=[C:17]([NH2:23])[N:18]=4)[C:13]=3[CH:12]=[CH:11]2)=[CH:5][CH:4]=1.B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][C:19]4[C:14](=[C:15]([NH2:24])[N:16]=[C:17]([NH2:23])[N:18]=4)[C:13]=3[CH:12]=[CH:11]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2ccc3c4c(N)nc(N)nc4ccc32)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Nc1nc(N)c2c(ccc3c2ccn3Cc2ccc(O)cc2)n1

Procedure:
Treat a suspension of 3.2 g. of 7-[(4-methoxyphenyl)-methyl]-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine in 100 ml of methylene chloride at -5° C. with 34 ml. of 0.92 M boron tribromide in methylene chloride. Keep the reaction at 20° C. for 18 hours and dilute with 100 ml. of water. Filter the resulting precipitate, stir in an aqueous potassium carbonate solution, filter, wash with water and dry. Crystallize the precipitate twice from methanol and once from dimethylformamide to obtain 0.63 g. of the title product, m.p. 292° C. (dec.), NMR (dDMSO): δ 5.33 (singlet, N--CH2 --C6H5O), 6.67 (doublet, J=9 Hz, 5H), 6.72 (doublet, J=3 Hz, 9H), 7.51 (doublet, J=3 Hz, 8H), 7.75 (doublet, J=9 Hz, 6H) p.p.m.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1csc2nc(Cl)nc(NCc3ccccc3)c12
Reactant: c1c[nH]cn1
Product: Cc1csc2nc(-n3ccnc3)nc(NCc3ccccc3)c12

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: N1[CH:5]=[N:4][C:3](SCCO)=N1.[C:10]1([C:16]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:17]2[CH:21]=[N:20][C:19]([CH2:22][CH2:23][CH2:24][OH:25])=[N:18]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:32]1([C:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:17]2[CH:21]=[N:20][C:19]([CH2:22][CH2:23][CH2:24][O:25][C:5]3[CH:15]=[C:10]([C:16]#[N:17])[CH:11]=[CH:3][N:4]=3)=[N:18]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: OCCCc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: OCCSc1nc[nH]n1
Product: N#Cc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1

Procedure:
By a method similar to that in Reference Example 17 and using, instead of 2-(1H-1,2,4-triazol-3-ylthio)ethanol, 3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propan-1-ol obtained in Reference Example 26, the title compound was obtained as a white powder (314 mg, 88%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[OH:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:18][C:11]1[C:10]([CH3:9])=[CH:15][C:14]([Br:16])=[CH:13][C:12]=1[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(Br)cc(C)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(Br)cc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
11.7 mL (96.5 mmol) benzylbromide were added dropwise to 20 g (96.5 mmol) 2,6-dimethyl-4-bromophenol and 16.5 g (118 mmol) potassium carbonate in 300 mL acetone and stirred overnight at RT. The precipitate formed was suction filtered, washed with acetone and the filtrate was evaporated down. The residue was dissolved in DCM, filtered through Alox and washed with DCM. The filtrate was evaporated down.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15].[CH2:16](Br)[CH:17]=[CH2:18].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:18][CH:17]=[CH2:16])[C:10]=1[OH:15]
Reactant: C=CCBr
Reactant: Oc1ccccc1Sc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: C=CCc1cccc(Sc2ccccc2Cl)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
A mixture of 2-(2-chlorophenylthio)phenol (33 g), allyl bromide (25 g) and dried potassium carbonate (29 g) in methyl isobutyl ketone (200 ml) was refluxed under heating for 1.5 hours. After cooling to the ambient temperature, the reaction mixture was filtered, and the filtrate was evaporated under reduced pressure. The resultant oily residue was stirred at 230° C. for 3 hours and then distilled under reduced pressure to give oily 2-(2-chlorophenylthio)-6-allylphenol (32.2 g) bp 157°-162° C./0.7 mmHg.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C@H:26]4[CH2:30][CH2:29][CH2:28][NH:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:31])[NH:6]2.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C@H:26]4[CH2:30][CH2:29][CH2:28][N:27]4[S:33]([CH3:32])(=[O:35])=[O:34])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:31])[NH:6]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@H]1CCCN1
Reactant: CS(=O)(=O)Cl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@H]1CCCN1S(C)(=O)=O
Yield: 56.8 %

Procedure:
Using an analogous procedure to that described for the preparation of Example 22, 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(2R)-pyrrolidin-2-ylmethoxy]quinazoline (160 mg, 0.38 mmol), (prepared as described for the starting material in Example 13), was reacted with methanesulphonyl chloride (35 μl, 0.45 mmol). The product was purified by column chromatography, eluting with methanol/methylene chloride (2/98) to give 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-{[(2R)-1-(methylsulfonyl)pyrrolidin-2-yl]methoxy}quinazoline (108 mg, 57%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][CH:14]([CH2:23][CH2:24][OH:25])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]>ClCCl>[CH3:8][S:9]([O:13][CH:14]([CH2:23][CH2:24][O:25][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CCCCC(O)CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCCCC(CCOS(C)(=O)=O)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
Under an argon atmosphere, triethylamine (0.7 ml, 5.05 mmol) and methanesulfonyl chloride (0.3 ml, 3.71 mmol) were added to a solution of (±)-methyl 6,8-dihydroxyoctanoate (320 mg, 1.68 mmol) in dichloromethane (8.4 ml) at 0° C. The mixture was stirred at 0° C. for 30 min, then quenched with ice water (20 ml) and extracted with dichloromethane (20 ml). The organic extract was washed with 2 M hydrochloric acid (20 ml), saturated sodium bicarbonate solution (20 ml) and brine (20 ml). The organic phase was dried over magnesium sulphate and the solvent was evaporated under reduced pressure to give the crude product which was purified using flash column chromatography with hexane-ethyl acetate (2:3) to give (±)-methyl 6,8-bis(methylsulfonyloxy)octanoate (581 mg, 99% yield) as a clear yellow oil. Rf 0.30 (hexane-ethyl acetate, 3:2).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][N:6]1[C:15](=[O:16])[CH2:14][C:9]2([CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:8][C:7]1=[O:17].[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(N(C(C)C)CC)(C)C>CC#N>[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][O:5][N:6]2[C:15](=[O:16])[CH2:14][C:9]3([CH2:13][CH2:12][CH2:11][CH2:10]3)[CH2:8][C:7]2=[O:17])[CH2:30][CH2:29]1
Reactant: O=C1CC2(CCCC2)CC(=O)N1OCCCBr
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CC2(CCCC2)CC(=O)N1OCCCN1CCN(c2ccc3ccccc3n2)CC1

Procedure:
A mixture of 8-(3-bromopropyloxy)-8-azaspiro[4.5]decan-7,9-dione (5.7 g), 1-(2-quinolinyl)piperazine (4.0 g) and diisopropylethylamine (6.6 ml) in 100 ml of dry CH3CN was heated to 80° with stirring under N2.