Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][NH:11][C:12]1[CH:38]=[C:37]([N:39]2[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]2)[CH:36]=[CH:35][C:13]=1[C:14]([NH:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=3)[CH:24]=2)[NH:19][N:18]=1)=[O:15])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:33][C:31]1[CH:32]=[C:27]([CH:28]=[C:29]([F:34])[CH:30]=1)[CH2:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[NH:19][N:18]=[C:17]2[NH:16][C:14](=[O:15])[C:13]1[CH:35]=[CH:36][C:37]([N:39]2[CH2:40][CH2:41][N:42]([CH3:45])[CH2:43][CH2:44]2)=[CH:38][C:12]=1[NH:11][CH2:10][CH2:9][OH:8]
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NCCO[Si](C)(C)C(C)(C)C)c2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NCCO)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
2-[(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]-N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide (126 mg, 0.2 mmol) was dissolved in dry THF (3 mL) and 1M TBAF in THF (0.24 mL) was added at 0° C. The resulting solution was stirred overnight at room temperature. Reaction was quenched with water and extracted with ethyl acetate. Collected organic phases were dried over Na2SO4, filtered and evaporated to dryness. Residue was purified by column chromatography over silica gel (DCM/EtOH/NH3 5N in MeOH=85/15/1) affording 83 mg of title compound.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]2[N:9]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)=[CH:11][C:3]=12.[CH3:28][N:29](C)C=O>O.C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[Cl:8][C:7]1[CH:6]=[N:5][C:4]2[N:9]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=3)(=[O:20])=[O:19])[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)=[CH:11][C:3]=2[C:2]=1[C:28]#[N:29]
Reactant: CN(C)C=O
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C)c3)cc3c(Cl)c(Cl)cnc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C)c3)cc3c(C#N)c(Cl)cnc32)cc1
Temperature: 160 °C

Procedure:
A solution in a microwave vial of 4,5-dichloro-2-(1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Example 113C) (300 mg, 0.712 mmol) in anhydrous N,N-dimethylformamide (4 mL) was degassed by nitrogen sparge for about 20 minutes. The solution was treated with zinc cyanide (167 mg, 1.424 mmol) and tetrakis(triphenylphosphine)palladium (82 mg, 0.071 mmol). The reaction was degassed and back-filled with nitrogen, and heated in a Biotage Initiator microwave for 60 minutes at 160° C. The reaction was treated with additional zinc cyanide (83 mg, 0.712 mmol) and tetrakis(triphenylphosphine)palladium (41 mg, 0.035 mmol), and heated to 160° C. for 30 minutes by microwave irradiation. The reaction was diluted with water and ethyl acetate, and the layers were separated. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 25 to 40% ethyl acetate in hexanes, to provide the title compound. MS ESI(+) m/z 412.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[C:21]([C:28]([F:31])([F:30])[F:29])[CH:20]=1.N1C=CC=CC=1>C1COCC1>[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:24])=[C:21]([C:28]([F:29])([F:30])[F:31])[CH:20]=1
Reactant: COc1ccc(Nc2ccc(OC)cc2)cc1
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(N(C(=O)c2ccc(F)cc2C(F)(F)F)c2ccc(OC)cc2)cc1
Temperature: 90 °C
Yield: 84.2 %

Procedure:
1 equivalent of bis-(4-methoxyphenyl)amine (1a) (0.73 g, 3.18 mmol) was mixed with 1.2 equivalents of 4-fluoro-2-trifluoromethylbenzoyl chloride (0.87 g, 3.82 mmol) and 6 equivalents of pyridine (1.51 g, 19.08 mmol) in a dry three-necked round-bottomed flask equipped with a magnetic stirring bar and a reflux condenser. The mixture was dissolved in anhydrous THF (20 mL) and heated to 90° C. for 20 hours. The reaction solution was cooled to room temperature and filtered. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography using silica-gel with EtOAc/hexanes (3/7 v/v) to afford the pure corresponding benzamide compound as a colorless oil, 1.12 g, 84.2% yield. 1H NMR (CDCl3, 300 MHz) δ 7.34-7.26 (m, 4H), 7.09-7.01 (m, 3H), 6.91 (d, 2H, J=8.7 Hz), 6.87 (d, 2H, J=8.7 Hz), 3.80 (s, 3H), 3.71 (s, 3H). MS m/z 442.1 (M+Na)+.
Reaction SMILES: C(N(CC)CC)C.C([C:11]1[CH:16]=[C:15](C(C)C)[CH:14]=[C:13]([CH:20]([CH3:22])C)[C:12]=1S(Cl)(=O)=O)(C)C.C[CH2:28][O:29]CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:13]1([CH2:20][C@H:22]2[CH2:28][O:29]2)[CH2:12][CH2:11][CH2:16][CH2:15][CH2:14]1
Reactant: CCOCC
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C1CCC(C[C@H]2CO2)CC1
Temperature: 0 °C
Reaction time: 14 h
Yield: 75 %

Procedure:
To a solution of the product from Example 15B in CH2Cl2 was added triethylamine (6.6 mL), 2,4,6-triisopropylbenzenesulfonyl chloride (11.5 g), and DMAP (0.386 g). After 14 hours, the reaction was diluted with ether, chilled to 0° C., filtered through celite, and concentrated. The residue was dissolved in ethanol (100 mL) and 1M NaOH (32 mL) was added. After 30 minutes, the reaction was carefully concentrated, diluted with water (100 mL), and extracted into ether (3×50 mL). The organic extracts were washed with brine (20 mL), dried (MgSO4), filtered, and concentrated to provide a colorless aromatic oil which was purified first by passage through a plug of silica gel eluting with 5% EtOAc/hexanes, then by bulb-to-bulb distillation under reduced pressure to provide 3.3 g (75%) of the title compound as a colorless aromatic oil.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].C([Li])CCC.[Cl:10][C:11]1[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([C:19](F)(F)F)[C:12]=1[NH2:13].O>C(OCC)C>[Cl:10][C:11]1[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([C:19]2[NH:3][CH2:2][CH2:1][N:4]=2)[C:12]=1[NH2:13]
Reactant: NCCN
Reactant: Nc1c(Cl)cc(Cl)cc1C(F)(F)F
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: Nc1c(Cl)cc(Cl)cc1C1=NCCN1
Yield: 36.2 %

Procedure:
To a solution of ethylene diamine (1.2 mL, 18 mmol) in ethyl ether (50 mL) at −20° C. was added n-butyl lithium (6.4 mL, 2.5 M in hexanes, 16 mmol). The mixture was stirred at 0° C. for 0.3 hour before the addition of 2,4-dichloro-6-trifluoromethyl aniline (0.92 g, 4.2 mmol). The mixture was stirred at 0° C. for an additional 1.5 hours, at which point water (0.36 mL, 20 mmol) was added and the solvent was removed under reduced pressure. Purification by flash column chromatography (silica gel, 1% to 10% methanol in dichloromethane) to give the title compound of Step A (0.35 g) as a yellow solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[C:18]([O:20]CC)=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:1]1([CH2:7][CH2:8][C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[C:18]([OH:20])=[O:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1nc2ccccn2c1CCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1nc2ccccn2c1CCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 128.9 %

Procedure:
Ethyl 3-(2-phenylethyl)imidazo[1,2-a]pyridine-2-carboxylate (883 mg) was dissolved in ethanol (50 ml), 2N aqueous sodium hydroxide solution (3 ml) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, neutralized with 1N hydrochloric acid, subjected to DIAION HP-20 (manufactured by Mitsubishi Chemical), and washed with water. The fraction eluted with acetone was concentrated under reduced pressure to give 3-(2-phenylethyl)imidazo[1,2-a]pyridine-2-carboxylic acid (1.03 g). The obtained 3-(2-phenylethyl)imidazo[1,2-a]pyridine-2-carboxylic acid (341 mg), tert-butyl (3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (370 mg) and N,N-diisopropylethylamine (862 μl) were dissolved in acetonitrile (20 ml), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (561 mg) was added and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated, and the residue was diluted with aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue, was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (9:1) was concentrated under reduced pressure to give the object product (522 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:24]=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[CH3:23])[CH2:12][CH2:13][CH2:14][N:7]21.C[Si](C)(C)[C:28]([F:31])([F:30])[F:29].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1>[Br:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[CH3:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:25])[C:28]([F:31])([F:30])[F:29])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1ccc(N2CCCn3c2nc2c(Br)ccc(C=O)c23)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(N2CCCn3c2nc2c(Br)ccc(C(O)C(F)(F)F)c23)c(C)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.3 %

Procedure:
To a solution of 9-bromo-1-(4-methoxy-2-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (249 mg, 0.622 mmol) in tetrahydrofuran (3 mL) was added trimethyl(trifluoromethyl)silane (0.276 mL, 1.87 mmol) and tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 0.124 mL, 0.124 mmol) at 0° C. After the mixture was stirred at 0° C. for 15 min, to the reaction mixture was added trimethyl(trifluoromethyl)silane (0.276 mL, 1.87 mmol) and tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 0.124 mL, 0.124 mmol) at 0° C. After the mixture was stirred at 0° C. for 15 min, to the mixture was added 1N hydrochloric acid (3 mL) at 0° C., and the reaction mixture was stirred at 0° C. for 10 min. The mixture was quenched with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-80% ethyl acetate/n-hexane gradient mixture to give the title compound as a yellow solid (241 mg, 0.512 mmol, 82%).
Reaction SMILES: N[CH:2]1[C:6]2([CH2:9][CH2:8][CH2:7]2)[CH2:5][N:4]([C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[CH2:3]1.[C:18]([O:22][C:23](NC(C1C=CC=CC=1)C#N)=[O:24])([CH3:21])([CH3:20])[CH3:19]>O1CCCC1>[C:18]([O:22][C:23]([CH:2]1[C:6]2([CH2:9][CH2:8][CH2:7]2)[CH2:5][N:4]([C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[CH2:3]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NC(C#N)c1ccccc1
Reactant: C[C@H](c1ccccc1)N1CC(N)C2(CCC2)C1
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1CC(C(=O)OC(C)(C)C)C2(CCC2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.2 %

Procedure:
To an ice-cooled solution of 2.9 g of 8-amino-6-[1-(R)-phenylethyl]-6-azaspiro[3.4]octane in 30 ml of tetrahydrofuran there was added 3.3 g of 2-(tertbutoxycarbonylamino)-2-phenylacetonitrile and the resulting mixture was stirred at room temperature for 30 min. The solvent was removed under reduced pressure, and ethyl acetate was added to the resulting residue. The mixture was washed with a 1N sodium hydroxide aqueous solution three times and then dried. The solvent was removed under reduced pressure and the resulting residue was purified by column chromatography using 50 g of silica gel. The column was eluted with chloroform, chloroform containing methanol and 4.1 g of the titled compound was obtained from a eluate when the eluant was chloroform containing 1% (v/v) of methanol.
Reaction SMILES: C(Cl)Cl.C[O:5][C:6]1[C:7]([CH3:17])=[C:8]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:9]([O:11][CH3:12])=[S:10].B(Br)(Br)Br>CO>[OH:5][C:6]1[C:7]([CH3:17])=[C:8]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:9]([O:11][CH3:12])=[S:10]
Reactant: COC(=S)c1ccc(C)c(OC)c1C
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: COC(=S)c1ccc(C)c(O)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
To 90 ml methylene chloride, was dissolved methyl 3-methoxy-2-methyl-4-methylthiobenzoate in an amount of 10 g (0.044 mole), and the resulting solution was then fed dropwise into 90 ml methylene chloride solution of boron tribromide in an amount of 8.4 ml (0.088 mole) at a temperature ranging from 5 to 10° C. After stirring the mixture for 4 hours at an ambient temperature, the mixture was further fed dropwise with 50 ml methanol under cooling with ice and washed with water and then with saturated saline solution. After drying the mixture with anhydrous magnesium sulfate, the solvent remained therein was distillated out under reduced pressure to obtain methyl 3-hydroxy-2-methyl-4-methylthiobenzoate in an amount of 9.2 g. The yield was 98%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([OH:14])[CH3:13])[CH:10]=2)[N:5]=[C:4]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[S:18](=[O:27])(=[O:26])[CH2:17][CH2:16]2)[CH:3]=1.[CH2:28]([NH2:32])[CH2:29][CH2:30][NH2:31]>>[NH2:31][CH2:30][CH2:29][CH2:28][NH:32][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([OH:14])[CH3:13])[CH:10]=2)[N:5]=[C:4]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[S:18](=[O:27])(=[O:26])[CH2:17][CH2:16]2)[CH:3]=1
Reactant: CC(O)c1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NCCCN
Product: CC(O)c1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCCN)c2c1
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 41.2 %

Procedure:
A mixture of 1-[4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-yl]ethanol (150 mg, 0.387 mmol) and propane-1,3-diamine (55 mg, 0.74 mmol) was heated with stirring in a sealed 0.5 mL of microwave process vial for 1.5 hours at 150° C. under microwave irradiation. The reaction mixture was purified by preparative HPLC and SPE to afford 70.2 mg of the desired product (yield was 41.2%). MS obsd. (ESI+) [(M+H)+] 441, 1H NMR (400 MHz, CD3OD) δ ppm 8.10-8.05 (m, 2 H), 7.86-7.80 (d, J=7.6 Hz, 1 H), 7.78-7.75 (m, 2 H), 7.72-7.62 (t, J=1.2 Hz, 1 H), 7.60-7.50 (t, J=1.2 Hz, 1 H), 5.94 (s, 1 H), 5.30 (s, 2 H), 4.98-4.92 (m, 1 H), 4.58-4.45 (m, 2 H), 3.78-3.70 (t, J=2.8 Hz, 2 H), 3.62-3.53 (t, J=4.4 Hz, 2 H), 3.10-3.02 (t, J=6.8 Hz, 2 H), 2.12-2.02 (m, 2 H), 1.50-1.40 (d, J=6.4 Hz, 3 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl.Cl[CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Reactant: ClCc1ccncc1
Agent: Cl
Product: CCOC(=O)N1CCC(c2cn(Cc3ccncc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
This compound was prepared following the procedure described in example 13 (part B) at room temperature for 15 hours, starting with 11 g (40 mmol) of 4-(1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester and 8 g (48 mmol) of 4-chloromethyl-pyridine hydrochloride, stirring at room temperature for 18 hours. After standard work-up, 11.8 g (81% of the yield) of 4-(1-pyridin-4-ylmethyl-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [F:1][C:2]([F:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:26]=[CH:27][C:28]=2[F:29])[CH2:19][CH2:18]1>>[F:12][C:2]([F:1])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:30][C:31](=[O:35])[CH:32]([CH3:33])[CH3:34])[CH:26]=[CH:27][C:28]=2[F:29])[CH2:19][CH2:18]1)=[O:5]
Reactant: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C(F)(F)c1ccccc1
Product: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCNC(=O)C(F)(F)c3ccccc3)CC2)c1

Procedure:
Example 136 was prepared from 2,2-difluoro-2-phenylacetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 7.61–7.56 (m, 2H), 7.41–7.34 (m, 4H), 7.21–7.17 (m, 1H), 7.14 (s, 1H), 6.88 (t, 1H, J=9.5 Hz), 3.39 (q, 2H, J=5.7 Hz), 3.08–3.01 (m, 2H), 2.84–2.74 (m, 1H), 2.50 (t, 2H, J=5.1 Hz), 2.38 (septet, 1H, J=7.2 Hz), 2.08–1.99 (m, 2H), 1.81–1.73 (m, 4H), 1.72–1.64 (m, 2H), 1.17 (d, 6H, J=7.2 Hz); ESMS m/e: 476.2 (M+H)+.
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:22])[C:17]([O:19]CC)=[O:18])=[CH:12][CH:11]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[N:6][C:5]=12.C(O)C.[OH-].[Na+]>O>[N:1]1[C:2]([C:10]2[CH:11]=[CH:12][C:13]([CH:16]([CH3:22])[C:17]([OH:19])=[O:18])=[CH:14][CH:15]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[N:6][C:5]=12
Reactant: CCOC(=O)C(C)c1ccc(-c2cn3cccnc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C(=O)O)c1ccc(-c2cn3cccnc3n2)cc1
Yield: 70.3 %

Procedure:
A mixture of 4.4 g of ethyl 2-[4-(imidazo[1,2-a]pyrimidin-2-yl)-phenyl]propionate, 50 ml of ethanol, 0.72 g of sodium hydroxide and 5 ml of water is heated under reflux for 2 hours. The ethanol is distilled off, and acetone is added to the residue. The crystalline precipitate is dissolved in water, and the solution is adjusted to pH 6 by addition of dilute hydrochloric acid. The crystalline precipitate is filtered off and washed with water to give 2.8 g of 2-[4-(imidazo[1,2-a]pyrimidin-2yl)phenyl]propionic acid as colorless crystals melting at 248°C with decomposition.
Reaction SMILES: OO.[F:3][C:4]1[CH:5]=[C:6]([N:17]2[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]2=[O:27])[CH:7]=[CH:8][C:9]=1[C:10]1[S:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=1.[C:28]([OH:31])(=[O:30])[CH3:29]>>[C:24]([NH:23][CH2:22][C@@H:20]1[O:19][C:18](=[O:27])[N:17]([C:6]2[CH:7]=[CH:8][C:9]([C:10]3[S:11][CH:12]([O:31][C:28](=[O:30])[CH3:29])[C:13](=[O:16])[NH:14][N:15]=3)=[C:4]([F:3])[CH:5]=2)[CH2:21]1)(=[O:26])[CH3:25]
Reactant: CC(=O)O
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=NNC(=O)CS3)c(F)c2)C(=O)O1
Agent: OO
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=NNC(=O)C(OC(C)=O)S3)c(F)c2)C(=O)O1
Temperature: 65 °C
Yield: 82 %

Procedure:
Hydrogen peroxide (30% aqueous sol, 0.0558 ml, 0.546 mmol) is added to N-{3-[3-Fluoro-4-(5-oxo-5,6-dihydro-4H-[1,3,4]thiadiazin-2-yl)-phenyl]-2-oxo-oxazolidin-5(S)-ylmethyl}-acetamide (0.100 g, 0.273 mmol) in acetic acid (2 ml) and is heated at 65° C. overnight. The reaction mixture is evaporated to dryness and the residue is purified by PTLC (10% MeOH/DCM) to give white solid (0.089 g, 82%); 1HNMR (300 MHz, DMSO-d6) δ 1.82 (s, 3H), 2.09 (s, 3H), 3.41 (t, J=5.5 Hz, 2H), 3.56 (dd, J=6.6, 9.1 Hz, 1H), 4.14 (t, J=9.1 Hz, 1H), 4.70-4.80 (m, 1H), 7.42 (dd, J=2.2, 8.8 Hz, 1H), 7.59 (dd, J=2.2, 14 Hz, 1H), 7.65 (t, J=8.5 Hz, 1H), 8.25 (t, J=5.8 Hz, 1H); mp 174-7; MS (m/z): [M+H]+=425.
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[O:14][CH2:15][C:16]3[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:17]=3[N:18]=1)[CH2:9][CH2:8]2.[Cl:24][CH2:25][C:26](Cl)=[O:27]>>[Cl:24][CH2:25][C:26]([NH:23][C:21]1[CH:20]=[CH:19][C:17]2[N:18]=[C:13]([NH:12][CH:10]3[C:11]4[C:7](=[CH:6][CH:5]=[CH:4][C:3]=4[O:2][CH3:1])[CH2:8][CH2:9]3)[O:14][CH2:15][C:16]=2[CH:22]=1)=[O:27]
Reactant: O=C(Cl)CCl
Reactant: COc1cccc2c1C(NC1=Nc3ccc(N)cc3CO1)CC2
Product: COc1cccc2c1C(NC1=Nc3ccc(NC(=O)CCl)cc3CO1)CC2
Yield: 97.2 %

Procedure:
Prepared from rac-N2-(7-methoxy-indan-1-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 10) (620 mg, 2.00 mmol) and chloroacetyl chloride (168 ul, 2.10 mmol) according to the procedure described for Example 3 step A. Obtained the title compound as a light yellow solid (750 mg, 97%), MS (ISP) m/e=386.1 [(M+H)+] and 388 [(M+2+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]([C:26]1[CH:27]=[C:28](OB(O)O)[CH:29]=[CH:30][CH:31]=1)=[O:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:30]4[CH:31]=[C:26]([CH:27]=[CH:28][CH:29]=4)[C:24]([O:23][CH3:22])=[O:25])[CH2:17]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2ccc(OCC3CCCNC3)cc2)cc1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Product: COC(=O)c1cccc(N2CCCC(COc3ccc(-c4ccc(Cl)cc4)cc3)C2)c1
Yield: 58.2 %

Procedure:
Using 3-[(4′-chlorobiphenyl-4-yl)oxymethyl]piperidine (125 mg, 0.414 mmol) and 3-(methoxycarbonyl)phenylboric acid (149 mg, 0.828 mmol), the same procedure was followed as in Example 2 to give 105 mg (58%) of the desired compound as a colorless powder.
Reaction SMILES: [C:1]([C:5]1[CH:25]=[CH:24][C:8]2[NH:9][C:10]([C@@:12]([NH:16]C(=O)OC(C)(C)C)([CH3:15])[CH2:13][OH:14])=[N:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[ClH:26]>O1CCOCC1>[NH2:16][C@:12]([C:10]1[NH:9][C:8]2[CH:24]=[CH:25][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=2[N:11]=1)([CH3:15])[CH2:13][OH:14].[ClH:26]
Reactant: CC(C)(C)OC(=O)N[C@](C)(CO)c1nc2cc(C(C)(C)C)ccc2[nH]1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc2[nH]c([C@](C)(N)CO)nc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl [(1S)-1-(5-tert-butyl-1H-benzimidazol-2-yl)-2-hydroxy-1-methylethyl]carbamate (Preparation 26, 94 mg, 0.27 mmol) in dioxane (3 mL) was added 4M HCl in dioxane (4 mL) and the reaction stirred at room temperature for 3 hours. The reaction was concentrated in vacuo, azeotroping with toluene (2×10 mL) to afford a gummy solid. The residue was triturated with TBME (15 mL) to afford the title compound as the bis HCl salt (90 mg, 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8](O)[N:7]=[CH:6]2.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:8]1[N:7]=[CH:6][C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1
Reactant: COc1cc2cnc(O)nc2cc1OC
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2cnc(Cl)nc2cc1OC
Yield: 38 %

Procedure:
Phosphorus oxychloride (50 ml) was added to 5.0 g of the 6,7-dimethoxy-2-hydroxyquinazoline synthesized in Referential Example 89. They were heated and reacted for 8 hours under reflux. After allowing the reaction mixture to cool down, phosphorus oxychloride was distilled off under reduced pressure and the residue was dissolved in dichloromethane. After washing the dichloromethane solution once with a saturated aqueous solution of sodium bicarbonate, once with water and then once with saturated saline, the solution was dried with anhydrous sodium sulfate. The solvent was distilled under reduced pressure and the residue was purified by column chromatography (silica gel; eluent: 50:1 mixed solvent of dichloromethane and methanol), thereby obtaining 2.1 g of the intended product as crystals (yield: 38%).