Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:7]([I:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.N([O-])=[O:11].[Na+].[OH-].[Na+]>S(=O)(=O)(O)O>[Br:9][C:5]1[CH:6]=[C:7]([I:8])[C:2](=[O:11])[NH:3][CH:4]=1
Reactant: Nc1ncc(Br)cc1I
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]cc(Br)cc1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Amino-5-bromopyridine (CAS No. 1072-97-5) (300 g) was dissolved in a mixed solvent consisting of 1000 ml of acetic acid and 200 ml of water, 30 ml of concentrated sulfuric acid were gradually dropped thereinto under stirring. Then, 79.1 g of periodic acid hydrate and 176 g of iodine were added thereto, followed by stirring at 80° C. for 4 hours. To the reaction mixture were added periodic acid hydrate (40 g) and iodine (22 g), followed by further stirring at 80° C. for 2 hours. After cooling to room temperature, the reaction mixture was poured onto ice (3000 ml) and neutralized to pH 7.0 with 5N aqueous sodium hydroxide. The resulting crystals were collected by filtration, dissolved in a mixed solvent of ethyl acetate/diethyl ether, successively washed with aqueous sodium thiosulfate, water, 1N aqueous sodium hydroxide and brine, and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated, to give 392 g of 2-amino-5-bromo-3-iodopyridine (yield: 76%). 2-Amino-5-bromo-3-iodopyridine (100 g) was gradually added to 300 ml of concentrated sulfuric acid under ice-cooling. After the reaction mixture was stirred at room temperature for 2 hours, it was ice-cooled again. 35 g of sodium nitrite were gradually added thereto, followed by stirring at room temperature for 3 days and nights. The reaction solution was poured onto ice (3000 ml) and neutralized to pH 4.0 with sodium hydroxide. The resulting crystals were collected by filtration, washed with water and warm air-dried at 60° C. for one day and night, to give 102 g (quantitative) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:34])[C:10]2[CH:15]=[C:14]([CH2:16][C:17]3[C:18](=[O:29])[C:19]([O:27][CH3:28])=[C:20]([O:25][CH3:26])[C:21](=[O:24])[C:22]=3[CH3:23])[CH:13]=[CH:12][C:11]=2[O:30]C(=O)C)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+]>CO.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:34])[C:10]2[CH:15]=[C:14]([CH2:16][C:17]3[C:18](=[O:29])[C:19]([O:27][CH3:28])=[C:20]([O:25][CH3:26])[C:21](=[O:24])[C:22]=3[CH3:23])[CH:13]=[CH:12][C:11]=2[OH:30])=[CH:4][CH:3]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(Cl)nc3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(Cl)nc3)c2)=C(C)C1=O
Yield: 87.5 %

Procedure:
N-(6-Chloropyridin-3-yl)-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide (0.070 g, 0.144 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (1.5 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.056 g, 0.126 mmol, 88%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:21])[C:10]=1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:5]([OH:7])=O.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[F:21][C:9]1[CH:8]=[C:4]([C:5]([N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)=[O:7])[CH:3]=[C:2]([F:1])[C:10]=1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc(CNc2c(F)cc(C(=O)O)cc2F)cc1
Product: COc1ccc(CNc2c(F)cc(C(=O)N3CCN(C)CC3)cc2F)cc1

Procedure:
Using 3,5-difluoro-4-(4-methoxy-benzylamino)-benzoic acid (95.4 mg) obtained in Step B in Example 1-D-24 and 1-methyl-piperazine (43.3 μl) instead of 1-ethyl-piperazine, in the same manner as Step C in Example 1-D-24, the desired compound was obtained as a crude product (82 mg, 67%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:36])(C[Si](OC(C)C)(C)C)[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[N:25][N:24]=[N:23]3)=[CH:18][CH:17]=2)[C:12]1=[O:27])[CH3:10].[C:37](=O)(O)[O-:38].[Na+]>CO.O1CCCC1.OO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:36])([CH2:37][OH:38])[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]([N:22]3[CH:26]=[N:25][N:24]=[N:23]3)=[CH:20][CH:21]=2)[C:12]1=[O:27])[CH3:10]
Reactant: O=C([O-])O
Reactant: CC(C)O[Si](C)(C)C[C@](O)(c1ccccc1F)[C@@H](C)n1ccn(-c2ccc(-n3cnnn3)cc2)c1=O
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](n1ccn(-c2ccc(-n3cnnn3)cc2)c1=O)[C@](O)(CO)c1ccccc1F
Temperature: 50 °C
Yield: 57.4 %

Procedure:
1-[(1R,2S)-2-(2-Fluorophenyl)-2-hydroxy-3-(isopropoxy dimethylsilyl)-1-methylpropyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (1 g) was dissolved in a mixture of methanol and tetrahydrofuran (1:1, 20 ml), to which an 30% aqueous solution of hydrogen peroxide (2 ml) and sodium bicarbonate (157 mg) were added. The mixture was heated at 50° C. for 4 hours, then cooled and extracted with ethyl acetate (100 ml). The extract was washed with water (30 ml), an aqueous solution of Na2S2O3 (30 ml×2) and a saturated aqueous solution of sodium chloride (30 ml) successively, dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluent:hexane/ethyl acetate=1/4) and recrystallized from diethyl ether (20 ml) to give 1-[(1R,2S)-2-(2-fluorophenyl)-2,3-dihydroxy-1-methyl propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (440 mg) as a colorless crystalline powder.
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)=[CH:11][CH:12]=2)[C:7]([CH3:27])([CH3:26])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH:28](=O)[CH2:29][CH:30]([CH3:32])[CH3:31].C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.C(#N)C>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([N:14]([CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[C:15]3[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=3)=[CH:11][CH:12]=2)[C:7]([CH3:27])([CH3:26])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(Nc2ccc3c(c2)C(C)(C)CCN3C(C)C)cc1
Reactant: CC(C)CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCOC(=O)c1ccc(N(CCC(C)C)c2ccc3c(c2)C(C)(C)CCN3C(C)C)cc1
Yield: 45.8 %

Procedure:
Ethyl 4-[(1-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)amino]benzoate (Compound 8, 37 mg, 0.10 mmol) was dissolved in a 10% acetic acid in acetonitrile solution (1.5 mL). The solution was treated with isovaleraldehyde (0.08 mL, 0.74 mmol) and then sodium cyanoborohydride (13 mg, 0.20 mmol) and the reaction mixture was stirred at room temperature for 5 hours. 1M aqueous NaOH was added until pH=6 and the solution was extracted with ether (2×), washed with brine, and dried (Na2SO4). The filtered solution was concentrated under reduced pressure and the residue purified by silica gel chromatography (5% ethyl acetate in hexanes) to give the title compound (20 mg, 45%) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:19]3[C:11](=[CH:12][C:13]4[O:17][CH:16]=[N:15][C:14]=4[C:18]=3[F:20])[N:10]([S:21]([CH:24]3[CH2:26][CH2:25]3)(=[O:23])=[O:22])C2=O)=[C:4]([Cl:28])[CH:3]=1.C[Si](C)(C)[O-].[K+]>C1COCC1>[F:20][C:18]1[C:14]2[N:15]=[CH:16][O:17][C:13]=2[CH:12]=[C:11]([NH:10][S:21]([CH:24]2[CH2:25][CH2:26]2)(=[O:22])=[O:23])[C:19]=1[NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[Cl:28]
Reactant: O=c1n(-c2ccc(Br)cc2Cl)c2c(F)c3ncoc3cc2n1S(=O)(=O)C1CC1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cc2ocnc2c(F)c1Nc1ccc(Br)cc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of 5-(4-bromo-2-chlorophenyl)-7-(cyclopropylsulfonyl)-4-fluoro-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one (100 mg, 0.21 mmol) in THF (10 mL) was added potassium trimethylsilanolate (40 mg, 0.31 mmol). After stirring at room temperature for 1 h, the reaction was quenched with saturated NH4Cl (aq.). The aqueous layer was extracted with ethyl acetate (10 mL×2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residual crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1-3:1, v/v) and the product was obtained as a white solid (60 mg, 63.4% yield). 1H NMR (400 MHz, CDCl3): δ 8.10 (s, 1H), 7.97 (s, 1H), 7.40 (m, 2H), 7.31-7.26 (m, 1H), 6.81 (s, 1H), 6.40-6.36 (m, 1H), 6.23 (s, 1H), 5.86-5.72 (m, 1H), 5.25-5.13 (m, 2H), 2.85 (d, 2H), 1.30-1.22 (m, 2H), 1.15-1.20 (m, 2H). 8.17 (s, 1H), 7.97 (s, 1H), 7.49 (dd, 1H), 7.35 (s, 1H), 7.26 (dd, 1H), 6.17 (m, 1H), 5.44 (s, 1H), 2.57 (m, 1H), 1.06-1.08 (m, 2H), 1.00-1.01 (m, 2H). MS APCI (+) m/z: 461.7, [M+H].
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.[CH3:10][O:11][C:12]1[CH:22]=[CH:21][C:15]([C:16](C(Cl)=O)=[O:17])=[CH:14][CH:13]=1>>[F:9][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([F:8])[CH:5]=1)[C:16]([C:15]1[CH:21]=[CH:22][C:12]([O:11][CH3:10])=[CH:13][CH:14]=1)=[O:17]
Reactant: Fc1cc(F)cc(Br)c1
Reactant: COc1ccc(C(=O)C(=O)Cl)cc1
Product: COc1ccc(C(=O)c2cc(F)cc(F)c2)cc1

Procedure:
The procedure from Step 1 of Example 1 was followed except that: 1-bromo-3,5-difluorobenzene was used instead of tribromobenzene and 4-methoxybenzoyl carbonyl chloride was used in place of benzoyl chloride to provide a product with mass spectrum corresponding the structure of 3,5-difluoro-4′-methoxybenzophenone.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[CH2:18][C@H:17]2[NH:19][CH2:20][C:21]2[O:25][C:24]([NH:26]C(=O)OC(C)(C)C)=[N:23][N:22]=2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCOCC1>[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C@@H:16]2[CH2:18][C@H:17]2[NH:19][CH2:20][C:21]2[O:25][C:24]([NH2:26])=[N:23][N:22]=2)=[CH:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)Nc1nnc(CN[C@@H]2C[C@H]2c2ccc(OCc3ccccc3)cc2)o1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1nnc(CN[C@@H]2C[C@H]2c2ccc(OCc3ccccc3)cc2)o1
Reaction time: 18 h
Yield: 51.9 %

Procedure:
HCl in 1, 4 dioxane (1 mL) was added to a solution of tert-butyl (5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-yl)carbamate (100 mg) in 1, 4 dioxane (1 mL) at 0° C. and stirred for 18 h. After completion, the solvent was evaporated and residue was dissolved in water (10 mL), basified with Na2CO3 solution, extracted with EtOAc (3×5 mL) The combined extracts were washed with water (5 mL), brine (5 mL), dried over anhydrous Na2SO4, filtered and evaporated. The crude residue was purified by column chromatography using MeOH: CHCl3 (5:95) as eluent to afford 5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine (40 mg, 52%) as a white solid.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:16]=[C:17]=[O:18])(=[O:15])=[O:14])=[CH:9][CH:8]=1)=[O:6])[CH:2]=[CH2:3].[NH2:19][C:20]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23]>>[CH2:1]([O:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([S:13]([N:16]2[C:22](=[O:23])[C:21]3[C:20](=[CH:28][C:27]([Cl:29])=[CH:26][CH:25]=3)[NH:19][C:17]2=[O:18])(=[O:15])=[O:14])=[CH:11][CH:12]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1ccc(S(=O)(=O)N=C=O)cc1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Product: C=CCOC(=O)c1ccc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)cc1
Yield: 34.7 %

Procedure:
1.76 g (6.60 mmol) of 4-allyloxycarbonylbenzenesulfonylisocyanate and 1.13 mg (6.60 mmol) of 2-amino-4-chlorobenzoic acid were treated in the same way as in Example 1 to obtain 965 mg of the above-identified compound (yield 34.8%). Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δppm, DMSO-d6):4.87 (2H,d), 5.31 (1H,d), 5.43 (1H,d), 6.00-6.11 (1H,m), 7.12 (1H,s), 7.22 (1H,d), 7.85 (1H,d), 8.23 (2H,d), 8.32 (2H,d), 11.69 (1H,br).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]([C:13]1[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[C:18]([O:24][CH3:25])[CH:19]=3)[N:14]=1)[CH2:8]2.[BrH:28]>>[Br:28][CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]([C:13]1[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[C:18]([O:24][CH3:25])[CH:19]=3)[N:14]=1)[CH2:8]2
Reactant: COc1cc2nc(N3CCc4c(CO)cccc4C3)[nH]c(=O)c2cc1OC
Reactant: Br
Product: COc1cc2nc(N3CCc4c(CBr)cccc4C3)[nH]c(=O)c2cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 91 %

Procedure:
2-(5-Hydroxymethyl-3,4-dihydro-1H-isoquinolin-2-yl)-6,7-dimethoxy-1H-quinazolin-4-one 22a (0.2 g, 0.54 mmol) was dissolved to room temperature in 5 mL of 48% hydrobromic acid and stirred to room temperature for 24 h. The precipitated product was separated by filtration, rinsed with water, dried to yield 0.21 g (91%) 2-(5-bromomethyl-3,4-dihydro-1H-isoquinolin-2-yl)-6,7-dimethoxy-3H-quinazolin-4-one 23a.
Reaction SMILES: C(Cl)CCl.[NH:5]([C:7]1[C:8]2[N:9]([CH:17]=[CH:18][CH:19]=2)[C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH2:6].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[C:29](O)=[O:30].C(=O)(O)[O-].[Na+]>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O>[CH:17]1[N:9]2[C:10]3[C:15]([N:16]=[C:7]([NH:5][NH:6][C:29]([C:21]4[NH:20][C:28]5[C:23]([CH:22]=4)=[CH:24][CH:25]=[CH:26][CH:27]=5)=[O:30])[C:8]2=[CH:19][CH:18]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: NNc1nc2ccccc2n2cccc12
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NNc1nc2ccccc2n2cccc12)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61.6 %

Procedure:
To a stirred solution of EDC (94 mg, 0.49 mmol) and DMAP (cat.) in ethyl acetate (15 mL), compound 14a (77 mg, 0.39 mmol) and 2-indolecarboxylic acid (63 mg, 0.39 mmol) were added, portion wise, within 15 minutes. The resulting mixture was stirred at room temperature for 24 h, then shaken with sodium bicarbonate saturated solution and water. Evaporation of the dried extract gave a residue which was crystallized to give compound 6 as a white solid (82 mg, 62% yield); mp 186° C. (dichloromethane/light petroleum); IR (KBr) 3255, 1680 cm−1; 1H NMR (DMSO-d6) 6.75 (s, 1H), 7.05 (m, 1H), 7.20 (m, 4H), 7.40 (m, 3H), 7.65 (m, 1H), 8.10 (m, 1H), 8.35 (s, 1H), 9.55 (bs, 1H), 10.65 (bs, 1H), 11.80 (bs, 1 H). MS (CI) m/z 342 (MH+). Anal. Calcd. for C20H15N5O: C, H, N.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][C:17]([OH:19])=O)[CH2:11]2)=[O:8])=[CH:4][CH:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:23][CH2:22]1>>[CH3:20][N:21]1[CH2:22][CH2:23][CH:24]([N:27]2[CH2:32][CH2:31][N:30]([C:17](=[O:19])[CH2:16][N:12]3[CH2:13][CH2:14][CH2:15][CH:10]([NH:9][C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)=[O:8])[CH2:11]3)[CH2:29][CH2:28]2)[CH2:25][CH2:26]1
Reactant: O=C(O)CN1CCCC(NC(=O)c2ccc(Cl)s2)C1
Reactant: CN1CCC(N2CCNCC2)CC1
Product: CN1CCC(N2CCN(C(=O)CN3CCCC(NC(=O)c4ccc(Cl)s4)C3)CC2)CC1

Procedure:
Using general procedure D {3-[(5-chloro-thiophene-2-carbonyl)-amino]-piperidin-1-yl}-acetic acid (containing 2 mol equivalents of sodium chloride) was coupled with 1-(N-methyl-4-piperidyl)-piperazine to give 5-chloro-thiophene-2-carboxylic acid (1-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-piperidin-3-yl)-amide. Off-white solid. 468.5 ([M+H]+)
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[C:34](Cl)(=[O:39])[CH2:35][CH:36]([CH3:38])[CH3:37]>>[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:27][CH2:28][N:29]([C:34](=[O:39])[CH2:35][CH:36]([CH3:38])[CH3:37])[CH2:30][CH2:31]4)[N:24]=[CH:25][C:18]=23)=[CH:32][CH:33]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Reactant: CC(C)CC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CC(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4)ncnc32)CC1

Procedure:
1-{4-[4-(4-Methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-3-methyl-butan-1-one was prepared according to General Procedure I by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with isovaleryl chloride (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 0.93 (d, 6H, J=6.2 Hz), 1.93-2.06 (m, 4H), 2.25-2.28 (m, 2H), 2.80-2.85 (m, 1H), 3.30 (methyl sulfonyl and water peak), 4.04-4.08 (m, 1H), 4.54-4.58 (m, 1H), 5.06-5.10 (m, 1H), 7.63-7.65 (m, 2H), 8.05-8.07 (m, 2H), 8.38 (s, 1H), 8.57 (s, 1H). Mass spectrum MH+=458.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([F:14])[C:7]=1[C:15](O)([CH3:20])[C:16]([F:19])([F:18])[F:17].N1C=CC=CC=1>>[Cl:3][C:15]([C:7]1[C:6]([F:5])=[CH:11][C:10]([O:12][CH3:13])=[CH:9][C:8]=1[F:14])([CH3:20])[C:16]([F:19])([F:18])[F:17]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(F)c(C(C)(O)C(F)(F)F)c(F)c1
Solvent: c1ccncc1
Product: COc1cc(F)c(C(C)(Cl)C(F)(F)F)c(F)c1
Yield: 94 %

Procedure:
A thionyl chloride (25 ml) solution of 2-(2,6-difluoro-4-methoxyphenyl)-1,1,1-trifluoropropan-2-ol (8.7 g, 34.1 mmol) and pyridine (26 mg, 0.34 mmol) was stirred at 70° C. for 3 hours. Then, the reaction was concentrated in vacuo and diluted with water. The product was extracted with hexane and the organic layer was dried over sodium sulfate, filtered and concentrated to furnish 8.84 g (94% yield) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH2:14][CH3:15])=[N:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[C:16]1([CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH2:14][CH3:15])=[N:10][N:11]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][CH2:23][CH2:22][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: BrCCCCCCOCCCCc1ccccc1
Reactant: CCc1n[nH]c2cc(C(=O)OC)ccc12
Product: CCc1nn(CCCCCCOCCCCc2ccccc2)c2cc(C(=O)OC)ccc12
Yield: 55.6 %

Procedure:
This compound was prepared according to the method of Preparation 3, using 137 mg (0.671 mmol, 1.0 equiv) 3-ethyl-1H-indazole-6-carboxylic acid methyl ester and 273 mg (0.872 mmol, 1.3 equiv) 6-(4-phenyl-butoxy)-hexyl bromide as starting materials to give 163 mg (56%) of a yellow oil: HRMS calcd for C27H36N2O3+H: 437.2804. Found 437.2833.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH:4]=[CH:5][C:6]1[S:7][C:8]([C:11](=[O:37])[NH:12][CH2:13][C@H:14]([NH:22][C:23]([O:25][CH2:26][C:27]23[CH2:36][CH:31]4[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]4)[CH2:28]2)[CH2:34]3)=[O:24])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:9][CH:10]=1.[N+](=[CH2:41])=[N-]>CCOCC.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:1][O:2][C:3]([CH:4]1[CH2:41][CH:5]1[C:6]1[S:7][C:8]([C:11](=[O:37])[NH:12][CH2:13][C@H:14]([NH:22][C:23]([O:25][CH2:26][C:27]23[CH2:36][CH:31]4[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]4)[CH2:28]2)[CH2:34]3)=[O:24])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:9][CH:10]=1)=[O:38]
Reactant: COC(=O)C=Cc1ccc(C(=O)NC[C@H](NC(=O)OCC23CC4CC(CC(C4)C2)C3)C(=O)OC(C)(C)C)s1
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: COC(=O)C1CC1c1ccc(C(=O)NC[C@H](NC(=O)OCC23CC4CC(CC(C4)C2)C3)C(=O)OC(C)(C)C)s1

Procedure:
The compound was synthesized analogously to example 3, step b) from 108 mg (0.2 mmol) of 3-(5-(((2S)-2-(1-adamantylmethoxycarbonylamino)-2-tert-butoxycarbonylethyl)carbamoyl)-2-thienyl)-acrylic acid methyl ester and a diazomethane solution in ether (generated from 0.5 g of N-nitroso-N-methyl-urea) in the presence of 10 mg palladium diacetate. 105 mg of a colourless oil were obtained which was sufficiently pure for use in the subsequent step.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4](O)(=O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[CH3:1][N:2]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH3:4])[CH3:3]
Reactant: CNC
Reactant: CCCCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCCCN(C)C

Procedure:
N,N-dimethylheptadecylamine (b.p. 117° @ 0.15 mmHg) was prepared from dimethylamine and heptadecanoic acid by the method described in Example 14.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([OH:24])=[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]([CH3:25])[NH:6]2.C(=O)([O-])[O-].[K+].[K+].[C:32]([N:35]1[CH2:40][CH2:39][N:38](OCCCCl)[CH2:37][CH2:36]1)(=[O:34])[CH3:33].CN1C[CH2:50][CH2:49][C:48]1=O>>[C:32]([N:35]1[CH2:36][CH2:37][N:38]([CH2:48][CH2:49][CH2:50][O:24][C:18]2[CH:17]=[C:16]3[C:21]([C:12]([O:11][C:10]4[C:2]([F:1])=[C:3]5[C:7](=[CH:8][CH:9]=4)[NH:6][C:5]([CH3:25])=[CH:4]5)=[N:13][CH:14]=[N:15]3)=[CH:20][C:19]=2[O:22][CH3:23])[CH2:39][CH2:40]1)(=[O:34])[CH3:33]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1O
Reactant: CN1CCCC1=O
Reactant: CC(=O)N1CCN(OCCCCl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCN(C(C)=O)CC1
Temperature: 90 °C
Yield: 71 %

Procedure:
4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-7-hydroxy-6-methoxyquinazoline (250 mg, 0.74 mmol), (prepared as described for the starting material in this example hereinbefore), and potassium carbonate (112 mg, 0.81 mmol) were stirred together in N-methylpyrrolidinone (3 ml). 1-Acetyl-4-(3-chloropropoxy)piperazine (166 mg, 0.81 mmol) in N-methylpyrrolidinone (1 ml) was added and the mixture heated at 90° C. for 3 hours. The mixture was cooled, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (97/3) to give 7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (268 mg, 71%) as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7].COCCO[AlH2-]OCCOC.[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:9]=[CH:10][CH:11]=1
Reactant: CSc1cccc(C(=O)O)c1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CSc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.3 %

Procedure:
To a suspension of 3-methylsulfanyl-benzoic acid (38 g, 0.226 mol) in Toluene (500 mL) was added 200 mL of Red-Al® dropwise at 50° C. over 30 minutes. After stirring at room temperature for 3 hours, NaOH 10% (250 mL) was added while cooling with an ice-bath and then stirred overnight. The organic layer was separated and the water layer extracted twice with toluene (2×100 mL). The combined organic layers were dried (K2CO3), concentrated and distilled under reduced pressure to give the desired product (23.8 g, 68%). MS: 152,7 (M+131 ).