Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1.[OH-].[Na+]>CO>[CH3:13][O:12][C:10]([C:9]1[CH:14]=[CH:15][C:6]([CH2:5][CH2:4][C:3]([OH:16])=[O:2])=[CH:7][CH:8]=1)=[O:11]
Reactant: COC(=O)CCc1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccc(CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.4 %

Procedure:
To a solution of methyl 4-(3-methoxy-3-oxopropyl)benzoate (5.05 g, 22.7 mmol) in methanol (120 ml) was added 1N aqueous sodium hydroxide solution (22.7 ml) at 0° C., and the mixture was stirred at room temperature for 16 hrs. After the reaction mixture was concentrated, the residue was dissolved in water, and the solution was washed with diethyl ether. To the aqueous layer was added 6N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was dissolved in chloroform, and insoluble materials were filtered off. The solvent was evaporated under reduced pressure, and the obtained residue was powderized with hexane to give the title compound (3.61 g) as a powder.
Reaction SMILES: C([Si]([O:8][C:9]1[C:10]([O:32][CH3:33])=[CH:11][C:12]2[CH:13]3[CH:21]([CH2:22][CH2:23][C:24]=2[CH:25]=1)[CH:20]1[C:16]([CH3:31])([CH:17]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH2:18][CH2:19]1)[CH2:15][CH2:14]3)(C)C)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:33][O:32][C:10]1[C:9]([OH:8])=[CH:25][C:24]2[CH2:23][CH2:22][CH:21]3[CH:13]([CH2:14][CH2:15][C:16]4([CH3:31])[CH:20]3[CH2:19][CH2:18][CH:17]4[O:26][CH2:27][CH2:28][O:29][CH3:30])[C:12]=2[CH:11]=1
Reactant: COCCOC1CCC2C3CCc4cc(O[Si](C)(C)C(C)(C)C)c(OC)cc4C3CCC12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COCCOC1CCC2C3CCc4cc(O)c(OC)cc4C3CCC12C
Reaction time: 8 h

Procedure:
A solution of TBS protected ether 50 (232 mg) in THF (10 mL) was treated with TBAF (0.5 mL, 1M solution in THF). After stirring overnight a standard aqueous work-up was carried out and the desired phenol 51 was purified by column chromatography (4:1 Hex/EA) to give a white solid which showed δH (400 MHz, CDCl3, ref. TMS=0) 6.77 (1H, s, ArH), 6.63 (1H, s, ArH), 5.50 (1H, s, OH), 3.85 (3H, s, ArOMe), 3.41-3.72 (5H, m, 2×OCH2 and CHOR), 3.40 (3H, s, OMe), 2.69-2.83 (6-CH2), 1.16-2.26 (13H, m) and 0.81 (3H, s, 18-Me); δC 144.5, 143.4, 131.7, 129.5 (all C), 114.6, 108.1, 89.6 (all CH), 72.3, 69.5 (both CH2), 59.1 (CH), 56.0 (CH3), 50.3, 44.2 (both CH), 43.3 (C), 38.6 (CH), 38.1, 28.9, 28.1, 27.2, 26.7, 23.0 (all CH2) and 11.6 (CH3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:32]1([O:38][C:39](Cl)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl.N1C=CC=CC=1.C(Cl)Cl>[CH3:24][N:21]1[C:22]([CH3:23])=[C:18]([C:16]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:39](=[O:40])[O:38][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:7]=3)=[CH:14][CH:13]=2)=[O:17])[C:19](=[O:31])[N:20]1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)cc2)c(=O)n(-c2ccccc2)n1C
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)cc2)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 42.4 %

Procedure:
A suspension of N-(4-((2-aminopyridin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (600 mg, 1.44 mmol) in DCM/pyridine (30 mL/20 mL) was cooled to 0° C., then a solution of phenylcarbonochloridate (565 mg, 3.61 mmol) in DCM (10 mL) was added to the mixture slowly over 1 hour. The reaction was stirred at rt for 2 hours, then diluted with DCM (200 mL). The mixture was washed with water (140 mL×4), followed by washing with brine (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/EtOAc (v/v)=2/1) to give the title compound as a white solid (327 mg, 42%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[SH:10].[OH-].[Na+].[C:13](=S)=[S:14]>C(O)C>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]2[S:10][C:13]([SH:14])=[N:1][C:2]=2[CH:7]=1
Reactant: COc1ccc(S)c(N)c1
Reactant: S=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2sc(S)nc2c1
Yield: 78.9 %

Procedure:
A mixture of 2-amino-4-methoxybenzenethiol (7.0 g, 0.045 mole), sodium hydroxide (4.4 g, 0.11 mole) and carbon disulfide (8.06 g, 0.11 mole) in 90% aqueous ethanol (100 ml.) was heated at reflux for 2 hours, filtered, diluted with ice-water and acidified with hydrochloric acid to give 7.0 g of 5-methoxy-2-benzothiazolethiol which melts at 192°-4° C. after recrystallization from benzene.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)#[N:10].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:8][C:7]1[C:2]([C:14]2[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][CH:13]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1cccnc1Br
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: N#Cc1ccc(-c2ncccc2F)cc1
Temperature: 80 °C
Yield: 97.5 %

Procedure:
A mixture of 2-bromo-3-fluoropyridine (1.05 g, 6.0 mmol), 4-cyanophenylboronic acid (0.882 g, 6.0 mmol), Pd(PPh3)4 (0.138 g, 0.12 mmol), and aqueous sodium carbonate solution (2M, 6 mL), in dioxane (6 mL) was degassed for 15 minutes. The mixture was sealed, heated to 80° C. for 12 hours, washed with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated and purified by chromatography to yield 4-(3-fluoropyridin-2-yl)benzonitrile (1.16 g, 89%).
Reaction SMILES: N[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].[I-:17].[K+]>Cl.O>[I:17][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc2c(=O)[nH]cnc2c1
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: O=c1[nH]cnc2cc(I)ccc12
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 17.8 %

Procedure:
7-Amino-quinazolin-4-one (R. Dempsy and E. Skito, Biochemistry, 30, 1991, 8480) (1.61 g) was suspended in 6N HCl (20 ml) and cooled in an ice bath. A solution of sodium nitrite (0.75 g) in water (10 ml) was added dropwise over 15 minutes. After a further 10 minutes, a solution of potassium iodide (1.66 g) in water (5 ml) was added dropwise. The mixture was warmed to 20° C. and after 3 hours partitioned between ethyl acetate and sodium thiosulphate. The organic phase was dried and concentrated in vacuo to give the title compound (0.485 g); m/z (M+1+) 271.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:22][CH2:23]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=O)C.[Cl-].C[Al+]C.[CH2:30]([C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][NH2:40])=[CH:34][CH:33]=1)[CH3:31]>C1(C)C=CC=CC=1>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:3])[N:40]([CH2:39][CH2:38][C:35]3[CH:36]=[CH:37][C:32]([CH2:30][CH3:31])=[CH:33][CH:34]=3)[CH2:23][CH2:22]2)[CH2:11][CH2:10]1)(=[O:14])=[O:13]
Reactant: CCc1ccc(CCN)cc1
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCc1ccc(CCN2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1

Procedure:
This material was prepared in analogy to example 1 step D) from 1-(2-chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester, dimethylaluminium chloride in toluene and 2-(4-Ethyl-phenyl)-ethylamine. MS (ESI): 461.4 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[C:6]2[C:7]([O:12][C:13]3[N:18]=[CH:17][C:16]([NH:19][C:20]([C@H:22]([NH:25]C(=O)OC(C)(C)C)[CH2:23][CH3:24])=[O:21])=[CH:15][CH:14]=3)=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=2[O:4][CH2:3]1.Cl.C(O)(C)C.C([O-])(O)=O.[Na+]>C(OC(C)C)(=O)C>[NH2:25][C@H:22]([CH2:23][CH3:24])[C:20]([NH:19][C:16]1[CH:17]=[N:18][C:13]([O:12][C:7]2[C:6]3[C:2]([CH3:1])([CH3:33])[CH2:3][O:4][C:5]=3[C:10]([CH3:11])=[CH:9][CH:8]=2)=[CH:14][CH:15]=1)=[O:21]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2ccc(C)c3c2C(C)(C)CO3)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)C
Solvent: CC(C)O
Product: CC[C@@H](N)C(=O)Nc1ccc(Oc2ccc(C)c3c2C(C)(C)CO3)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
The 1,1-dimethylethyl {(1R)-1-[({6-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}amino)carbonyl]propyl}carbamate (Intermediate 187, 480 mg, 1.05 mmol) was dissolved in iso-propyl acetate (5 mL) and HCl 5-6N in isopropanol (1 ml, 5.25 mmol) was added. The solution was stirred at room temperature for 1 hour and then heated to ˜50-55° C. until complete conversion. The mixture was cooled to room temperature and treated with an aqueous saturated solution of NaHCO3. Two phases were separated and the organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol 95:5 as eluents affording the title compound (0.31 g) as yellowish foam.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Br:13][C:14]1[CH:22]=[C:21]2[C:17]([CH2:18][CH2:19][NH:20]2)=[CH:16][CH:15]=1>>[Br:13][C:14]1[CH:22]=[C:21]2[C:17]([CH2:18][CH2:19][N:20]2[C:2]2[C:3]3[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:16][CH:15]=1
Reactant: Brc1ccc2c(c1)NCC2
Reactant: Cc1[nH]c2ncnc(Cl)c2c1C
Product: Cc1[nH]c2ncnc(N3CCc4ccc(Br)cc43)c2c1C

Procedure:
This product is prepared in a manner analogous to that described in Example 1 from 4-chioro-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidine and 6-bromo-2,3-dihydroindole (1.1 equivalents, see WO 95/23141; CAS Reg. No. 63 839-24-7).
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([N:15]2[CH2:20][CH2:19][C:18]3([C:32]4[CH:31]=[N:30][N:29]([CH3:33])[C:28]=4[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:21]3)[CH2:17][CH2:16]2)=[O:14])=[C:9](OC)[CH:8]=1)(=[O:6])=[O:5])(C)C.F[C:37]1C=CC(C(N2CCC3(C4C=NN(C)C=4C4C=CC=CC=4O3)CC2)=O)=CC=1C.FC1C=CC(C(N2CCC3(C4C=NN(C)C=4C4C=CC=CC=4O3)CC2)=O)=C(C)C=1>>[CH3:33][N:29]1[C:28]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:21][C:18]3([CH2:19][CH2:20][N:15]([C:13]([C:10]4[CH:11]=[CH:12][C:7]([S:4]([CH3:1])(=[O:5])=[O:6])=[C:8]([CH3:37])[CH:9]=4)=[O:14])[CH2:16][CH2:17]3)[C:32]=2[CH:31]=[N:30]1
Reactant: COc1cc(S(=O)(=O)C(C)C)ccc1C(=O)N1CCC2(CC1)Oc1ccccc1-c1c2cnn1C
Reactant: Cc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)ccc1F
Agent: Cc1cc(F)ccc1C(=O)N1CCC2(CC1)Oc1ccccc1-c1c2cnn1C
Product: Cc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)ccc1S(C)(=O)=O

Procedure:
A mixture of (2-methoxy-4-(methylthio)phenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone (320 mg, 0.74 mmol) and 30% hydrogen peroxide (250 μL) in acetic acid (3 mL) was heated at 80° C. for 45 min. The mixture was diluted with water and was extracted with ethyl acetate. The organics were washed with sat. aq. NaHCO3 and brine. The organics were dried over sodium sulfate and evaporated to dryness. The crude material was purified by column chromatography eluting with 70-100% ethyl acetate in hexanes to give (2-methoxy-4-(methylsulfonyl)phenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone. ESI-MS m/z calc. 467.2. found 468.2 (M+1)+. Retention time: 1.29 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.76-7.70 (m, 1H), 7.63-7.41 (m, 4H), 7.28 (t, J=7.7 Hz, 1H), 7.18-7.04 (m, 2H), 4.46-4.35 (m, 1H), 4.14-4.05 (m, 3H), 3.98-3.90 (m, 3H), 3.53-3.36 (m, 1H), 3.28 (s, 3H), 3.30-3.14 (m, 2H), 2.09-1.77 (m, 4H). (4-(Isopropylsulfonyl)-2-methoxyphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone was also synthesized using the procedures described above. (1-Methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)(3-methyl-4-(methylsulfonyl)phenyl)methanone was synthesized from (4-fluoro-3-methylphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone using the procedures described above. (4-(Isopropylsulfonyl)-2-methylphenyl)(1-methyl-1′-1-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone was synthesized from (4-fluoro-2-methylphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone using the procedures above.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][NH:12][CH2:13]2)[CH2:9]1)=O)(C)(C)C.[ClH:16].[C@H:17]12C[C@H](NC1)CN2C(N)=O>>[ClH:16].[CH2:9]1[CH:10]2[CH2:11][NH:12][CH2:13][CH:14]2[CH2:15][N:8]1[C:6](=[O:5])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: NC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: Cl
Product: CC(=O)N1CC2CNCC2C1

Procedure:
The title product LL is prepared from hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester according to the procedure described for the synthesis of Intermediate P.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH2:13][C:14]3[CH2:15][NH:16][CH2:17][CH2:18][CH:19]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][CH:26]=[C:25]2[CH:32]1[CH2:34][O:33]1>CCO>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH2:13][C:14]3[CH2:15][N:16]([CH2:34][CH:32]([C:25]4[C:24]5[C:29](=[CH:30][CH:31]=[C:22]([O:21][CH3:20])[CH:23]=5)[N:28]=[CH:27][CH:26]=4)[OH:33])[CH2:17][CH2:18][CH:19]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: C1=C(CNCc2ccc3c(c2)OCCO3)CNCC1
Reactant: COc1ccc2nccc(C3CO3)c2c1
Solvent: CCO
Product: COc1ccc2nccc(C(O)CN3CCC=C(CNCc4ccc5c(c4)OCCO5)C3)c2c1

Procedure:
A solution of (2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-(1,2,5,6-tetrahydro-pyridin-3-ylmethyl)-amine (0.06 g, 0.23 mmol) and 6-methoxy-4-oxiranylquinoline (0.06 g, 0.29 mmol) in EtOH (2 ml) was heated at 80° C. for 14 hours. The reaction mixture was concentrated and the residue was purified by chromatography on silica gel (DCM/MeOH 9/1).
Reaction SMILES: [CH3:1][C:2]1[N:3]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:4]=[CH:5][C:6]=1[CH2:7][OH:8].CS(C)=O.S(=O)(=O)=O.C(=O)([O-])O.[Na+]>C(N(CC)CC)C>[CH3:1][C:2]1[N:3]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:11])[CH:4]=[CH:5][C:6]=1[CH:7]=[O:8]
Reactant: Cc1c(CO)ccn1S(=O)(=O)c1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(C=O)ccn1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.7 %

Procedure:
To a mixture of [2-methyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol (6.35 g), dimethyl sulfoxide (50 mL) and triethylamine (25 mL) was added sulfur trioxide.pyridine complex (4.57 g), and the mixture was stirred at room temperature for 12 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:1) to give a white title compound (yield 5.27 g, 84%).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[CH2:25]=[O:26]>C1COCC1.CN1C(=O)N(C)CCC1>[OH:26][CH2:25][C:13]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: C=O
Reactant: CCOC(=O)C1c2ccccc2Oc2ccccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)C1(CO)c2ccccc2Oc2ccccc21
Temperature: -50 °C
Yield: 68 %

Procedure:
A mixture of 1.5 g (5.9 mmol) of ethyl 9H-xanthene-9-carboxylate in 20 ml of THF and 1.6 ml of DMPU under an inert atmosphere is cooled to −50° C. 4 ml (6.4 mmol) of BuLi (1.6 M in hexane) are added dropwise to this medium with stirring, and the medium is then left stirring for 10 minutes at −40° C. After allowing the reaction medium to warm to 10° C., a flow of formaldehyde generated from 5.4 g (0.18 mol) of sublimed paraformaldehyde entrained by a stream of nitrogen is bubbled in. After stirring for 2 hours at room temperature, the suspension is dispersed in 50 ml of water. The reaction medium is then extracted twice with 100 ml of ether. The combined organic phases are dried over Na2SO4. After evaporation, the residual oil is chromatographed on silica. Eluent: CH2Cl2. 1.1 g of a yellow oil are obtained (yield: 68%).
Reaction SMILES: C[O:2][C:3]1[C:13]2[CH2:12][CH2:11][N:10]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][C:4]=1[CH3:20]>C(Cl)Cl>[OH:2][C:3]1[C:13]2[CH2:12][CH2:11][N:10]([C:14](=[O:19])[C:15]([F:18])([F:16])[F:17])[CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][C:4]=1[CH3:20]
Reactant: COc1c(C)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Solvent: ClCCl
Product: Cc1ccc2c(c1O)CCN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
Add borontribromide (21.6 mL, 1.0 M solution in DCM) to a solution of 6-methoxy-7-methyl-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (3.1 g, 10.8 mmol) in DCM (200 mL) at 0° C. under nitrogen. Warm to room temperature and stir overnight. Dilute with DCM and wash with water. Dry the organic layer over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 9:1) to obtain the desired intermediate as a solid (2.74 g, 93%). MS (ES+) m/z: 274 (M+H)+.
Reaction SMILES: P(Br)(Br)[Br:2].[C:5]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(Cl)(Cl)Cl>[C:5]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][Br:2])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: OCCCCCc1ccccc1
Reactant: BrP(Br)Br
Solvent: ClC(Cl)Cl
Product: BrCCCCCc1ccccc1

Procedure:
A 1.8 g (6.7 mmol) amount of phosphorus tribromide was added to a chloroform solution (20 ml) of 3.3 g (20 mmol) of 5-phenyl-1-pentanol and the resulting solution was heated at reflux for 4 hours. When the reaction was traced by TLC, the starting materials were found to still remain in the reaction mixture, and so 0.2 g of phosphorus tribromide was further added and heated at reflux. Afterwards, the reaction solution was washed with water and dried with anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. Thus, 4.30 g of a crude 5-phenylpentyl bromide was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[C@H:4]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)=[O:25])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])[CH:5](C)C.BrC1C=C2C(CN([C@@H](COC)C(OC)=O)[C:46]2=[O:49])=CC=1.CC1(C)C(C)(C)OB(C2C=CC(NC(NC3C=CC=C(C(F)(F)F)C=3)=O)=CC=2)O1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:46][O:49][CH2:5][C@H:4]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:36])[F:35])[CH:28]=4)=[O:25])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])[C:3]([O:2][CH3:1])=[O:38]
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)cc2C1=O
Reactant: COC[C@@H](C(=O)OC)N1Cc2ccc(Br)cc2C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC1(C)OB(c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)OC1(C)C
Solvent: ClCCl
Product: COC[C@@H](C(=O)OC)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)cc2C1=O

Procedure:
The compound of example 354 was prepared analogous to compound of example 330 by reaction of the compound of example 353, compound of example 327 and Pd(dppf)Cl2: CH2Cl2.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH:7]2[O:11][CH2:12][CH2:13][CH2:14][CH:6]12.C([O-])([O-])=O.[K+].[K+].[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]2[C:39]3[C:34](=[CH:35][C:36]([O:41][CH3:42])=[C:37]([OH:40])[CH:38]=3)[N:33]=[CH:32][N:31]=2)[CH:25]=[CH:26][C:27]=1[F:28]>CN(C=O)C>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]2[C:39]3[C:34](=[CH:35][C:36]([O:41][CH3:42])=[C:37]([O:40][CH2:2][CH2:3][CH2:4][N:5]4[CH2:10][CH2:9][CH2:8][CH:7]5[O:11][CH2:12][CH2:13][CH2:14][CH:6]45)[CH:38]=3)[N:33]=[CH:32][N:31]=2)[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: ClCCCN1CCCC2OCCCC21
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCCC2OCCCC21
Temperature: 80 °C
Reaction time: 7 h
Yield: 23.4 %

Procedure:
A mixture of 5-(3-chloropropyl)octahydro-2H-pyrano[3,2-b]pyridine (0.23 g), K2CO3 (0.26 g) and 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (0.30 g) in 20 mL of DMF was stirred at 80° C. for 7 h and cooled to rt. To this, 50 mL of ice-water was added and the mixture was extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column eluting agent: 20:1 (v/v) DCM/MeOH) to afford the title compound as a pale yellow solid (0.11 g, 25.00%), HPLC: 96.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 501.3 (M+1); 1H NMR (400 MHz, d6-DMSO) δ: 9.54 (s, 1H), 7.78 (d, J=4.0 Hz, 1H), 7.70 (t, J=8.0 Hz, 1H), 7.64 (s, 2H), 7.24 (d, J=4.2 Hz, 1H), 7.09 (t, J=8.0 Hz, 1H), 4.19 (m, 2H), 3.93 (s, 3H), 3.33-3.30 (m, 2H), 2.51-2.49 (m, 4H), 2.14-1.93 (m, 6H), 1.74-1.71 (m, 3H), 1.36-1.23 (m, 3H) ppm.
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=[O:2].Br[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]3[N:19]([C:21]([C:24]4([C:27]5[CH:28]=[C:29]6[C:34](=[CH:35][CH:36]=5)[N:33]=[CH:32][CH:31]=[CH:30]6)[CH2:26][CH2:25]4)=[CH:22][N:23]=3)[CH:20]=2)=[CH:11][C:10]=1[F:37]>>[F:37][C:10]1[CH:11]=[C:12]([C:15]2[CH:16]=[N:17][C:18]3[N:19]([C:21]([C:24]4([C:27]5[CH:28]=[C:29]6[C:34](=[CH:35][CH:36]=5)[N:33]=[CH:32][CH:31]=[CH:30]6)[CH2:26][CH2:25]4)=[CH:22][N:23]=3)[CH:20]=2)[CH:13]=[CH:14][C:9]=1[C:15]1[CH:12]=[CH:11][C:3]([C:1]([N:19]([CH3:20])[CH3:18])=[O:2])=[N:17][CH:16]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Fc1cc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)ccc1Br
Product: CN(C)C(=O)c1ccc(-c2ccc(-c3cnc4ncc(C5(c6ccc7ncccc7c6)CC5)n4c3)cc2F)cn1

Procedure:
This compound was prepared as a TFA salt starting from 6-{1-[6-(4-bromo-3-fluorophenyl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinoline using procedures analogous to those for Example 85. LCMS: (M+H)=529.0.