Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[N:5][CH:4]=1.[NH:17]1[CH2:22][CH2:21][O:20][C@@H:19]([CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:18]1.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH2:14][N:17]2[CH2:22][CH2:21][O:20][C@@H:19]([CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:18]2)=[N:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CNCCO1
Reactant: COc1cnc2ccc(=O)n(CC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cnc2ccc(=O)n(CCN3CCO[C@@H](CNC(=O)OC(C)(C)C)C3)c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of [7-(methoxy)-2-oxo-1,5-naphthyridin-1(2H)-yl]acetaldehyde (as the methyl hemiacetal) (0.500 g, 2.29 mmol) in 1:1 (MeOH/CHCl3) (25 mL) were added 1,1-dimethylethyl [(2R)-2-morpholinyl-methyl]carbamate (0.500 g, 2.29 mmol) and Na2SO4 (0.100 g) and the resulting solution stirred at ambient temperature for 18 h. Na(OAc)3BH (1.46 g, 6.87 mmol) was added and the solution stirred an additional 2 g. The reaction mixture was concentrated onto silica gel and chromatographed on a silica gel column) [0-100% Hexanes/EtOAc] to yield a yellowish oil. (0.460 g, 48%)
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[N:9]2)=[CH:4][CH:3]=1.[F:25][C:26]([F:34])([F:33])[CH2:27][CH:28]([OH:32])[C:29](O)=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[F:25][C:26]([F:34])([F:33])[CH2:27][CH:28]([OH:32])[C:29]([N:22]1[CH2:23][CH2:24][N:19]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=3)[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:7]=2)[CH2:20][CH2:21]1)=[O:30]
Reactant: O=C(O)C(O)CC(F)(F)F
Reactant: Cc1ccc2c(N3CCNCC3)nc(-c3ccccc3O)nc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(N3CCN(C(=O)C(O)CC(F)(F)F)CC3)nc(-c3ccccc3O)nc2c1
Yield: 69.2 %

Procedure:
2-(7-Methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (87 mg, 0.27 mmol), 4,4,4-trifluoro-2-hydroxybutanoic acid (43 mg, 0.27 mmol), HATU (0.12 g, 0.33 mmol) and triethylamine (45 μL, 0.33 mmol) were stirred in DMF (3 mL) at room temperature overnight. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and water, dried over Na2SO4 and concentrated. Purification via silica gel chromatography using 0-20% EtOAc in 1:1 CH2Cl2: hexanes gave 4,4,4-trifluoro-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)butan-1-one as an off-white solid (86 mg, 66%). 1H NMR (400 MHz, CDCl3) d 8.46 (dd, J=8.0, 1.7 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.70 (s, 1H), 7.41-7.37 (m, 1H), 7.31 (dd, J=8.5, 1.5 Hz, 1H), 7.05-7.03 (m, 1H), 6.97-6.93 (m, 1H), 4.80-4.75 (m, 1H), 4.07-3.68 (m, 9H), 2.56 (s, 3H), 2.50-2.39 (m, 2H) ppm; LC/MS: m/z 461.3 (M+H)+ at 2.49 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:13](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:10])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Nc1cccc(Br)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Solvent: ClCCl
Product: CN(c1cccc(Br)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of N-(3-bromo-phenyl)-methanesulfonamide (1.0 g, 4.0 mmol) and potassium carbonate (0.61 g, 4.4 mmol) in acetone (10 mL) was added iodomethane (0.30 mL, 4.8 mmol). The mixture was stirred at room temperature for 18 hours, diluted with dichloromethane (30 mL), filtered through a plug of diatomaceous earth and evaporated under reduced pressure. N-(3-Bromo-phenyl)-N-methyl-methanesulfonamide was isolated a tan viscous oil (1.08 g, 100%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.53 (s, 1H), 7.43 (d, J=7.9 Hz, 1H), 7.35 (d, J=8.2 Hz, 1H), 7.29-7.23 (m, 1H), 3.32 (s, 3H), 2.86 (s, 3H). MS=286, 288 (MH)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH2:26]([NH2:32])[CH2:27][CH2:28][CH2:29][CH2:30][NH2:31]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][NH2:32])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NCCCCCN
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCCCCN)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and pentane-1,5-diamine. MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CDCl3) δ ppm 7.96 (d, J=7.6 Hz, 1 H), 7.54 (d, J=6.8 Hz 1 H), 7.42 (m, 2 H), 7.30 (d, J=6.4 Hz, 1 H), 7.21 (m, 2 H), 5.81 (s, 1 H), 5.03 (s, 2 H), 4.61 (m, 2 H), 3.49 (brs, 2 H), 3.19 (m, 2 H), 2.71 (d, J=6.40 Hz, 2 H), 2.94 (m, 2 H), 2.34 (s, 3 H), 1.61 (s, 2 H), 1.49 (m, 4 H).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([NH:11][C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[O:22])=[O:10])[CH2:5][CH2:4]1.[CH3:32][I:33]>ClCCl>[I-:33].[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:21]([C:13]2[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:12]=2[NH:11][C:9]([CH:6]2[CH2:7][CH2:8][CH:3]([N+:2]([CH3:32])([CH3:31])[CH3:1])[CH2:4][CH2:5]2)=[O:10])=[O:22])=[CH:25][CH:26]=1
Reactant: CN(C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cc3)oc3ccccc23)CC1
Reactant: CI
Solvent: ClCCl
Product: C[N+](C)(C)C1CCC(C(=O)Nc2c(C(=O)Nc3ccc(Cl)cc3)oc3ccccc23)CC1
Product: [I-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Trans-3-[4-(dimethylamino)cyclohexylcarbonylamino]-N-(4-chlorophenyl)benzofuran-2-carboxamide (106 mg) obtained in Example 308 is dissolved in dichloromethane (5 ml), and thereto is added methyl iodide (30 μl), and the mixture is stirred at room temperature for 5 hours. To the reaction solution is poured dichloromethane diethyl ether (1/5, 25 ml), and the precipitates are collected by filtration to give the title compound (126 mg).
Reaction SMILES: [NH:1]([C:5]1[C:10]2[O:11][CH2:12][CH2:13][O:14][C:9]=2[C:8]([C:15]([OH:17])=[O:16])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].C(OC(=O)C)(=O)C.[N+:25]([O-:28])([OH:27])=[O:26]>C(O)(=O)C>[N+:25]([C:6]1[CH:7]=[C:8]([C:15]([OH:17])=[O:16])[C:9]2[O:14][CH2:13][CH2:12][O:11][C:10]=2[C:5]=1[NH:1][C:2]([CH3:4])=[O:3])([O-:27])=[O:26].[N+:25]([C:7]1[CH:6]=[C:5]([NH:1][C:2]([CH3:4])=[O:3])[C:10]2[O:11][CH2:12][CH2:13][O:14][C:9]=2[C:8]=1[C:15]([OH:17])=[O:16])([O-:28])=[O:26]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(C(=O)O)c2c1OCCO2
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1c([N+](=O)[O-])cc(C(=O)O)c2c1OCCO2
Product: CC(=O)Nc1cc([N+](=O)[O-])c(C(=O)O)c2c1OCCO2
Temperature: 20 °C

Procedure:
42 g of 8-acetamino-1,4-benzodioxane-5-carboxylic acid, 75 ml of acetic acid and 75 ml of acetic anhydride were introduced into a balloon flask and then a solution of 17.5 ml of nitric acid (d=1.49) in 17 ml of acetic acid was added, with the temperature being left rising. After dissolution and crystallization, 50 ml of acetic acid were added. The mixture was agitated at 40°-45° C. and then cooled to 20° C. The precipitate was dried off, washed with acetic acid and water and dried. 13.5 g of a 50% mixture of 7-nitro-8-acetamino-1,4-benzodioxane-5-carboxylic acid and 6-nitro-8-acetamino-1,4-benzodioxane-5-carboxylic acid were obtained. The 7-nitro-8-acetamino-1,4-benzodioxane-5-carboxylic acid was separated and then treated according to the process of Example 31 with isobutyl chloroformate and diethylamioethylamine. N-(diethylaminoethyl)-7-nitro-8-acetamino-1,4-benzodioxane-5-carboxamide was obtained. The structure was confirmed by nuclear magnetic resonance analysis.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:19][CH2:18][CH:17]([O:20][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCOc1ccc(S(=O)(=O)N2CCC(O)C2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOc1ccc(S(=O)(=O)N2CCC(OS(C)(=O)=O)C2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.6 %

Procedure:
To a solution of 1-(4-Butoxy-benzenesulfonyl)-pyrrolidin-3-ol (1.50 g, 5 mmol) in dichloromethane (8 ml) was added triethylamine (0.61 g, 6 mmol) and cooled to 0° C. A solution of methanesulfonyl chloride (0.46 ml, 6 mmol) in dichloromethane (2 ml) was then introduced slowly, and the resulting suspension was stirred at 0° C. for 15 min., and at room temperature for 2 h. The solvent was evaporated, and the residue was stirred with 10 ml of water, 5 ml of saturated sodium carbonate solution, and 20 ml of hexanes. The resulting suspension was filtered, and the precipitate was washed with water and hexanes, and dried to give 1.88 g of a white solid; m.p. 80-81° C.; MS (ES) m/z 377.9 (MH+); HRMS (El) Calcd. for C15H23NO6S2 (M+): 377.0967, Found: 377.0969.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:7][CH:6]=2)[CH3:2].[H-].[Na+].CCCCCC.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C.O>[C:24]1([CH2:23][N:4]2[C:5]3[C:10](=[C:9]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:7][CH:6]=3)[CH:11]=[C:3]2[CH2:1][CH3:2])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCc1cc2c([N+](=O)[O-])cccc2[nH]1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCC
Product: CCc1cc2c([N+](=O)[O-])cccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 90.8 %

Procedure:
2-Ethyl-4-nitro-1H-indole (4.75 g, 25 mmol) was added to a mixture of 1.0 g (25 mmol) of 60% NaH/mineral oil (washed with hexane before adding DMF) in 40 ml DMF. After 45 minutes, 3.0 ml (25 mmol) of benzyl bromide was added. The mixture was stirred at room temperature for four hours, diluted with water, and extracted with EtOAc. The EtOAc solution was washed with brine, dried over MgSO4, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with 20% EtOAc/Hexane to give 6.36 g (91%) of 1-Phenylmethyl-2-ethyl-4-nitro-1H-indole as an oil.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: C1CCNCC1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCCCC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and piperidine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=371.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:12][C:11](=[O:13])[C:10]([S:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:9]1.[C:23]1(O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.C(OCC)(=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:12][C:11](=[O:13])[C:10]([S:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:21])=[CH:9]1
Reactant: Oc1ccccc1
Reactant: O=C(O)CCCCCSC1=CC(OC2CCCCO2)CC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCCCCSC1=CC(OC2CCCCO2)CC1=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.5 %

Procedure:
686 mg (2.09 mmoles) of 4(RS)-tetrahydropyranyloxy-2-(5-carboxypentylthio)-2-cyclopentenone and 295 mg (3.14 mmoles) of phenol were dissolved in 10 ml of dichloromethane, and 0.1 ml of pyridine was added. To the solution was added 10 ml of a dichloromethane solution of 860 mg (4.18 mmoles) of dicyclohexylcarbodiimide. The mixture was stirred at room temperature for 18 hours. After the reaction, ethyl acetate was added to the reaction mixture. The organic layer was washed successively with an aqueous solution of sodium bicarbonate, an aqueous solution of potassium bisulfate, and an aqueous solution of sodium chloride, dried, and then concentrated. The residue was chromatographed on a silica gel column using hexane/ethyl acetate (7/2) as an eluent to give 653 mg (1.62 mmoles; yield 77.3%) of 4(RS)-tetrahydropyranyloxy-2-(5-phenoxycarbonylpentylthio)-2-cyclopentenone.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[C:9]1([NH:15][C:16]2[N:20]=[CH:19][NH:18][N:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(NC(C)C)(C)C>C(#N)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:18]2[CH:19]=[N:20][C:16]([NH:15][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:17]2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: c1ccc(Nc2nc[nH]n2)cc1
Solvent: CC(C)NC(C)C
Solvent: CC#N
Product: Clc1cc(-n2cnc(Nc3ccccc3)n2)ncn1
Temperature: 25 °C

Procedure:
To a suspension of 4,6-dichloro-pyrimidine (292 mg, 1.96 mmol) in 5 ml anhydrous acetonitrile was added phenyl-(1H-[1,2,4]triazol-3-yl)-amine together with diisopropylamine (0.4 ml, 4.0 mmol). The mixture was heated at reflux in a sealed tube overnight. The reaction was cooled to room temperature and the solid was collected by filtration. The solid was washed with cold ether and dried under vacuum. Analytical data: LC/MS showed M+1=273.1, and M−1+271.2, retention time is 3.5 min. NMR in DMSO-d6: 9.78 (s, 1H); 9.28 (s, 1H); 8.90 (s, 1H); 7.90 (s, 1H); 7.65 (d, 2H); 7.28 (dd, 2H); 6.90 (dd, 1H).
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([C:23](=[O:26])[NH:24][CH3:25])=[CH:19][C:18]=4[O:27][CH3:28])[N:12]=[CH:11][C:10]=3[N:9]3[CH:29]=[N:30][C:31](C(OCC=C)=O)=[C:8]3[C@H:7]2[CH2:38][CH3:39])[CH2:5][CH2:4][CH2:3][CH2:2]1.O>C(#N)C1C=CC=CC=1.C1(C)C=CC=CC=1.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>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([C:23]([NH:24][CH3:25])=[O:26])=[CH:19][C:18]=4[O:27][CH3:28])[N:12]=[CH:11][C:10]=3[N:9]3[CH:29]=[N:30][CH:31]=[C:8]3[C@H:7]2[CH2:38][CH3:39])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CCOC(=O)c1ncn2c1[C@@H](CC)N(C1CCCC1)c1nc(Nc3ccc(C(=O)NC)cc3OC)ncc1-2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: N#Cc1ccccc1
Product: CC[C@@H]1c2cncn2-c2cnc(Nc3ccc(C(=O)NC)cc3OC)nc2N1C1CCCC1
Temperature: 155 °C
Yield: 11.8 %

Procedure:
A mixture of (R)-allyl 5-cyclopentyl-6-ethyl-3-(2-methoxy-4-(methylcarbamoyl)phenylamino)-5,6-dihydroimidazo[1,5-f]pteridine-7-carboxylate 1-3 (37 mg, 0.07 mmol) and tetrakis(triphenylphosphine)palladium(0) (7 mg) in benzonitrile (0.5 ml) and toluene saturated with water (0.5 ml) was heated under microwave irradiation at 155° C. for 1 hour. The mixture was cooled down to room temperature and evaporated to dryness. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, concentrated in vacuo and partitioned between ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The organic phase was dried over magnesium sulphate and concentrated in vacuo to afford the title compound as a white solid (3.7 mg, 12% yield); 1H NMR (CDCl3) 0.73-0.85 (3H, m), 1.50-2.20 (10H, m), 3.00, 3.02 (3H, 2×s), 3.95, 3.96 (3H, 2×s), 4.50-4.65 (1H, m), 4.66-4.75 (1H, m), 6.10-6.24 (1H, m), 6.85-6.94 (1H, m), 7.21-7.30 (1H, m), 7.40-7.49 (1H, m), 7.68-7.75 (1H, m), 7.89-7.97 (1H, m), 8.20-8.28 (1H, m), 8.48-8.55 (1H, m); LC/MS M+1 (obs.) 448.61, LC/MS M−1 (obs.) 446.72.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+].[CH:36]1([C:41]([O:43][CH:44](Cl)[CH3:45])=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1>CN(C=O)C>[CH:36]1([C:41]([O:43][CH:44]([N:14]2[C:11]3=[N:12][CH:13]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH:9]=[C:10]3[C:16]([C:17](=[O:18])[C:19]3[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:20]=3[F:33])=[CH:15]2)[CH3:45])=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CC(Cl)OC(=O)C1CCCC1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(C)OC(=O)C3CCCC3)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Yield: 38.2 %

Procedure:
The title compound was prepared according to the procedure as described in Example 12 Step 2 using N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.3 g, 0.61 mmol) in anhydrous DMF (2.5 mL), KOH (69 mg, 1.23 mmol) and a solution of 1-chloroethyl cyclopentanecarboxylate (108 mg, 0.61 mmol) in anhydrous DMF (0.5 mL). The curde product was purified by a silica gel column chromatography (PE/EtOAc (v/v)=5/1) and recrystallized in PE to give the title compound as a white solid (147 mg, 38%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH:18]([N-]C(C)C)(C)[CH3:19].[Li+].C(Br)C.[Cl-].[NH4+]>O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C>[C:1]([O:5][C:6](=[O:17])[CH:7]([CH2:18][CH3:19])[CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)(C)OC(=O)CCNC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCBr
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCC(CNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 38.9 %

Procedure:
t-Butyloxycarbonyl-β-alanine t-butyl ester (2.26 g) was added dropwise to a solution of lithium diisopropylamide (LDA) (6.9 ml, 13.8 mmol) in tetrahydrofuran (10 ml) at -78° C. and hexamethylphosphoroamide (HMPA) (2 ml) was added thereto. The temperature of the reaction solution was elevated gradually to -20° C. over 1 hour and lowered again to -78° C. To the reaction solution, ethyl bromide (0.76 ml) was added dropwise. The temperature of the solution was elevated to 0° C. over 2 hours and the reaction was stopped by adding a saturated aqueous solution of ammonium chloride. After the solvent was distilled off, the residue was dissolved in ethyl acetate and washed sequentially with a 5% aqueous solution of sodium hydrogencarbonate, a 5% aqueous solution of citric acid and a saturated aqueous solution of NaCl 3 times each. The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was then distilled off to yield an oil. The obtained oil was applied to a silica gel column (2.5×40 cm) and eluted with a mixed solution (hexane:ethyl acetate=40:1). The desired fractions were collected and the solvents were distilled off to yield an oil of N-t-butyloxycarbonyl-α-ethyl-β-alanine-t-butyl ester (0.98 g, 38.9%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:28]1[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=[O:34])[CH2:29]1>C(O)CCC>[N:18]1[C:19]2[C:14](=[CH:13][C:12]([CH2:11][N:8]3[C:6]4=[N:7][C:2]([N:28]5[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=[O:34])[CH2:29]5)=[CH:3][N:4]=[C:5]4[N:10]=[N:9]3)=[CH:21][CH:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: Brc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: O=C(O)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: O=C(O)C1CCN(c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)C1
Temperature: 120 °C
Yield: 39.3 %

Procedure:
A mixture of 6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline, (350 mg, 1.03 mmol), potassium carbonate (436 mg, 3.16 mmol), and 3-pyrrolidine carboxylic acid (236 mg, 2.05 mmol) in n-butanol (10.0 mL) was heated in the microwave at 120° C. for 60 minutes. The reaction mixture was cooled to room temperature, filtered, rinsed with ethyl acetate, and the filtrate was concentrated. The crude product was purified by flash chromatography using a Horizon purification system on a 25S column eluting with chloroform containing 0.1% acetic acid/methanol (0.5-7%) to afford 1-[1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl]pyrrolidine-3-carboxylic acid (152 mg, 39%).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([CH2:11][CH2:12][C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=3)[N:9]=2)[N:4]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:3]=1[C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]2)=[CH:33][CH:32]=1.C([Li])CCC.[C:49](=[O:51])=[O:50]>O1CCCC1>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([CH2:12][CH2:11][C:8]2[N:9]=[C:10]3[C:2]([C:49]([OH:51])=[O:50])=[C:3]([C:31]4[CH:36]=[CH:35][C:34]([N:37]5[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]5)=[CH:33][CH:32]=4)[N:4]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:5]3=[N:6][CH:7]=2)[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=1
Reactant: COc1cc(CCc2cnc3c(n2)c(Br)c(-c2ccc(N4CCN(C)CC4)cc2)n3COCC[Si](C)(C)C)cc(OC)c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(CCc2cnc3c(n2)c(C(=O)O)c(-c2ccc(N4CCN(C)CC4)cc2)n3COCC[Si](C)(C)C)cc(OC)c1
Reaction time: 0.17 h

Procedure:
The a stirred solution of 7-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-6-[4-(4-methylpiperazin-1-yl)phenyl]-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[2,3-b]-pyrazine (55 mg, 82.7 μmol) in tetrahydrofuran (2 mL), n-butyllithium (2.5 M in hexanes, 50 μL, 0.125 mmol) was added at 78° C. After 10 minutes, dry CO2 (prepared by passing the CO2 through drying tube) was bubbled into the reaction. After 20 minutes, the reaction was quenched with saturated aqueous NH4Cl, then extracted with methylene chloride. The combined organic layers were dried over MgSO4, then concentrated to give the crude product (50 mg), which was used directly in the next step. LCMS calculated for C34H46BN5O5Si (M+H)+: m/z=632.3. Found: 632.3.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([CH2:14][CH2:15][O:16]C3CCCCO3)[C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([CH2:14][CH2:15][OH:16])[C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: COC(=O)c1cccc2c1ccn2CCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)c1cccc2c1ccn2CCO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-1H-indole-4-carboxylic acid methyl ester (120 mg, 0.396 mmol) in MeOH (10 ml) is added p-toluenesulfonic acid monohydrate (7.25 mg, 0.04 mmol). The reaction is stirred at room temperature for 16 hours and the solvent is removed in vacuo. The residue is dissolved in MeOH (3 ml) and loaded onto a 1 g PEAX cartridge washed with MeOH (20 ml). The filtrate is concentrated in vacuo to give 1-(2-Hydroxy-ethyl)-1H-indole-4-carboxylic acid methyl ester; [M+H]+ 220