Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:42]=[C:43]([NH2:47])[CH:44]=[N:45][CH:46]=2)[CH2:37][CH2:36]1.Cl[C:49]1[C:58]2[C:53](=[CH:54][C:55]([F:60])=[CH:56][C:57]=2[F:59])[N:52]=[C:51]([C:61]2[CH:62]=[CH:63][C:64]([N:67]([CH3:69])[CH3:68])=[N:65][CH:66]=2)[C:50]=1[CH3:70].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:69][N:67]([CH3:68])[C:64]1[N:65]=[CH:66][C:61]([C:51]2[C:50]([CH3:70])=[C:49]([NH:47][C:43]3[CH:44]=[N:45][CH:46]=[C:41]([N:38]4[CH2:39][CH2:40][O:35][CH2:36][CH2:37]4)[CH:42]=3)[C:58]3[C:53](=[CH:54][C:55]([F:60])=[CH:56][C:57]=3[F:59])[N:52]=2)=[CH:62][CH:63]=1
Reactant: Nc1cncc(N2CCOCC2)c1
Reactant: Cc1c(-c2ccc(N(C)C)nc2)nc2cc(F)cc(F)c2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(N(C)C)nc2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.023 g, 0.048 mmol), 5-morpholinopyridin-3-amine (0.064 g, 0.36 mmol), 5-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-N,N-dimethylpyridin-2-amine (0.1 g, 0.30 mmol) and Pd2dba3 (0.011 g, 0.012 mmol) and sodium tert-butoxide (0.072 g, 0.75 mmol) in toluene (3.0 mL) at 100° C. for 2 h. The crude product was purified by column chromatography on silica gel (0 to 100% DCM/MeOH/ammonium hydroxide (90/9/1)) to give the desired product 2-(6-(dimethylamino)pyridin-3-yl)-5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (2H, m), 7.87 (1H, dd, J=8.8, 2.5 Hz), 7.79 (1H, d, J=2.3 Hz), 7.56-7.59 (2H, m), 7.36 (1H, ddd, J=12.6, 9.5, 2.5 Hz), 6.76 (1H, d, J=8.8 Hz), 6.55 (1H, t, J=2.2 Hz), 3.70 (4H, m), 3.11-3.06 (10H, m), 2.19 (3H, s). Mass Spectrum (ESI) m/e=477.2 (M+1).
Reaction SMILES: [Cl:1][C@H:2]1[C@H:6]([CH2:7][CH2:8][CH2:9][C:10]2[S:14][C:13]([C:15]([O:17]C)=[O:16])=[CH:12][CH:11]=2)[C@@H:5](/[CH:19]=[CH:20]/[C@@H:21]([OH:28])[CH2:22][CH2:23][CH2:24][C@H:25]([OH:27])[CH3:26])[C@H:4]([OH:29])[CH2:3]1.[OH-].[Li+].CO.S([O-])(O)(=O)=O.[Na+]>C1COCC1>[Cl:1][C@H:2]1[C@H:6]([CH2:7][CH2:8][CH2:9][C:10]2[S:14][C:13]([C:15]([OH:17])=[O:16])=[CH:12][CH:11]=2)[C@@H:5](/[CH:19]=[CH:20]/[C@@H:21]([OH:28])[CH2:22][CH2:23][CH2:24][C@H:25]([OH:27])[CH3:26])[C@H:4]([OH:29])[CH2:3]1
Reactant: COC(=O)c1ccc(CCC[C@@H]2[C@@H](/C=C/[C@@H](O)CCC[C@@H](C)O)[C@H](O)C[C@H]2Cl)s1
Agent: O=S(=O)([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](O)CCC[C@H](O)/C=C/[C@@H]1[C@@H](CCCc2ccc(C(=O)O)s2)[C@H](Cl)C[C@H]1O
Yield: 58.7 %

Procedure:
A solution of 76 mg of ester 11 (0.17 mmol) in 1 mL of THF was hydrolyzed with 360 uL of aqueous lithium hydroxide (0.5M, 0.18 mmol)) and 0.2 mL of methanol at 24° C. for 6 h. The mixture was acidified by addition of solid sodium hydrogen sulfate (25 mg, 0.18 mmol) and the residual water was removed in vacuo. The residual solid was extracted with ethyl acetate and the product acid was purified by PLC on a 0.5 mm thick preparative silica gel plate eluted in 10% methanol:90% ethyl acetate. Extraction of the UV-active band yielded 43 mg of free acid 12 as an oil (54% yield); 1H NMR (CD3OD): 1.13 (d, J=6.3 Hz, 3H), 1.28-1.63 (m, 8H), 1.75-2.21 (m, 6H), 2.86 (t, J=7 Hz, 2H), 3.70 (m, 1H), 4.04 (m, 3H), 5.52 (m, 2H), 6.86 (br s, 1H), 7.58 (br s, 1H). HPLC purity was 100 A %. LCMS (ESI: M+-H20): 413.2.
Reaction SMILES: Br[C:2]1[N:3]([CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33](C(OC)=O)[CH:34]=2)[CH:29]=[CH:28]1.C([O-])([O-])=O.[Na+].[Na+].N1C2C(=C(B(O)O)C=CC=2)C=C1>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:11]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:8]=3)[N:3]([CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[C:2]=2[C:31]2[C:30]3[CH:29]=[CH:28][NH:27][C:35]=3[CH:34]=[CH:33][CH:32]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CC(=O)N(C)C)c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: OB(O)c1cccc2[nH]ccc12
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccc4[nH]ccc34)n(CC(=O)N(C)C)c2c1
Yield: 95 %

Procedure:
To a solution of methyl 2-bromo-3-cyclohexyl-1-[2-(dimethylamino)-2-oxoethyl]-1H-indole-6-carboxylate (prepared from commercially available methyl indole-6-carboxylate as described in WO 2004/087714) in dioxane (0.15 M) were added 6 eq of Na2CO3 (2 M aqueous solution), 1.5 eq of 1H-indol-4-ylboronic acid and 0.2 eq of bis(triphenylphosphine)palladium(II) dichloride. The mixture was heated at reflux for 1.5 h. The reaction mixture was filtered and then the filtrate was diluted with EtOAc. The organic phase was washed with aqueous Na2CO3, brine and dried over Na2SO4 before being filtered and concentrated in vacuo. The crude was purified by flash chromatography (Biotage cartridge, 6.0:4.0 EtOAc/PE) to afford the title compound (95%). MS (ES+) m/z 458 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11](OCC)=[O:12])=[O:10])=[C:4]([N+:16]([O-:18])=O)[CH:3]=1>CN(C)C=O.[Ni]>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([NH:8][C:9](=[O:10])[C:11](=[O:12])[N:16]2[OH:18])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccc(Br)cc2n(O)c1=O

Procedure:
A solution of 4-bromo-1-ethoxalylamino-2-nitrobenzene (1.0 g, 3.2 mmol) in 50 ml of N,N-dimethylformamide was hydrogenated at atmospheric pressure and room temperature in the presence of a small amount of Raney-Ni. The catalyst was removed by filtration, and the filtrate was evaporated to dryness. The residue was tritureted with ethanol affording 0.68 g (84%) of the title compound. M.p.>250° C. dec.; 1H-NMR (DMSO-d6): 6.98-7.63 (m. 3H ArH) appr. 11.9 (very broad s 1H NH): IR (KBr): 1700 cm-1 ; MS (m/e): 256 (M+, 62%), 258 (M+2)+, 58%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][CH2:12][CH2:13][NH2:14]>>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:14][CH2:13][CH2:12][O:11][CH3:10])[CH:5]=[CH:4][CH:3]=1
Reactant: COCCN
Reactant: O=Cc1cccc(Br)n1
Product: COCCNCc1cccc(Br)n1
Yield: 93.7 %

Procedure:
The title compound was prepared in a manner similar to that described in Example 18, Step C, using 6-bromo-pyridine-2-carbaldehyde (0.275 g, 1.48 mmol) and 2-methoxy-ethylamine (0.111 g, 1.48 mmol). The crude product was purified (SiO2: 0-5% MeOH/DCM) to yield the title compound (0.34 g, 94%).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:21])[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][N:11]2[CH2:14][CH3:15])=[CH:6][C:5]=1[F:22])(=[O:3])[CH3:2].C(O[CH:28](OC(C)(C)C)[N:29]([CH3:31])[CH3:30])(C)(C)C>CN(C)C=O>[CH2:19]([O:18][C:16]([C:9]1[C:8](=[O:21])[C:7]2[C:12](=[CH:13][C:4]([C:1]([CH:2]=[CH:28][N:29]([CH3:31])[CH3:30])=[O:3])=[C:5]([F:22])[CH:6]=2)[N:11]([CH2:14][CH3:15])[CH:10]=1)=[O:17])[CH3:20]
Reactant: CCOC(=O)c1cn(CC)c2cc(C(C)=O)c(F)cc2c1=O
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2cc(C(=O)C=CN(C)C)c(F)cc2c1=O
Temperature: 70 °C

Procedure:
To 2.0 (6.5 mmol) of ethyl 7-acetyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate in 50 ml of dimethylformamide was added 1.71 ml (1.25 eq) of bis-t-butoxydimethylaminomethane. The mixture was heated at 70° C. for 18 hours. The mixture was then concentrated and the residue treated with ether and filtered to give 1.95 g of 7-(2'-dimethylaminoethenyl)carbonyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester, mp 176°-179° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]2[NH:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][CH:8]=1>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH:11]2[NH:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C=CC2CCCCC(=O)N2)c1
Agent: [Pd]
Solvent: CO
Product: COc1cccc(CCC2CCCCC(=O)N2)c1

Procedure:
The title material of Example 163 in MeOH is hydrogenated over Pd on carbon in a standard Parr apparatus by the method of Example 35 to generate the title product.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:11][C:10]2[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C:5]=2[CH:4]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:1][CH2:2][C:3]1[S:11][C:10]2[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C:5]=2[CH:4]=1)(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCc2sc(CO)cc2C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2sc(COS(C)(=O)=O)cc2C1
Reaction time: 2 h

Procedure:
To a dichloromethane solution (22 ml) of tert-butyl 2-(hydroxymethyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (5.3 mmol) was added triethylamine (21.2 mmol) and methane sulfonyl chloride (7.95 mmol) at 0° C. and the resulting reaction mixture was stirred at same temperature for 2 h (monitored by TLC). The reaction was diluted with dichloromethane, successively washed with water and brine and finally dried over sodium sulfate. Evaporation of the organic layer under reduced pressure gave the crude product which was used directly in the next step. Yield: quantitative
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:11]2[CH2:13][O:12]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH2:28]>C(O)(C)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[CH2:9][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:11]([OH:12])[CH2:13][NH:28][CH2:27][C:26]1[CH:29]=[CH:30][CH:31]=[C:24]([O:23][CH3:22])[CH:25]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1
Reactant: COc1cccc(CN)c1
Solvent: CC(C)O
Product: COc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)OC(C)(C)C)c1
Temperature: 85 °C

Procedure:
tert-Butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE 3, 245 mg, 0.82 mmol) is suspended in isopropyl alcohol (6 mL) and 3-methoxybenzylamine (160 microL, 1.22 mmol) is added with stirring at 20–25 degrees C. This mixture is heated to gentle reflux (bath temp 85 degrees C.) under nitrogen for 2 hours, whereupon the resulting mixture is concentrated under reduced pressure to give the title compound. The title compound is purified by flash chromatography (2–5% methanol/methylene chloride; gradient elution) to give purified title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH3:16][C:17](C)([O-])[CH3:18].[K+].IC(C)C>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:17]([CH3:18])[CH3:16])[N:6]=[C:5]2[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1n[nH]c2ccc(F)cc12
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)I
Product: CCOC(=O)c1nn(C(C)C)c2ccc(F)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.6 %

Procedure:
To a stirred solution of ethyl 5-fluoro-1H-indazole-3-carboxylate (487 mg, 2.3 mmol, J. Heterocycl. Chem. 1964, 1, 239-241) in tetrahydrofuran (4 mL) was added potassium tert-butoxide (289 mg, 2.57 mmol) at 0° C. After stirring at 0° C. for 1 h, 2-iodopropane (438 mg, 2.57 mmol) was added to the mixture. The resulting mixture was stirred at room temperature for 20 h and concentrated under reduced pressure. The mixture was diluted with ethyl acetate (50 mL), washed with water (30 mL) and brine (30 mL). The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (10:1 to 2:1) to give 205 mg (35%) of the title compound as a yellow crystal.
Reaction SMILES: Cl.Cl.Cl.[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C@H:11]([C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[CH2:17][CH2:16]1)=[O:14])[NH2:12].[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:37](O)=[O:38])[CH:35]=2)[CH:30]=[CH:29]1>>[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:37]([NH:12][C@@H:11]([C:13]([N:15]3[CH2:16][CH2:17][CH:18]([CH:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)[CH2:19][CH2:20]3)=[O:14])[CH2:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][N:4]=3)=[O:38])[CH:35]=2)[CH:30]=[CH:29]1
Reactant: CN1CCC(C2CCN(C(=O)[C@H](N)Cc3ccccn3)CC2)CC1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: Cl
Product: CN1CCC(C2CCN(C(=O)[C@@H](Cc3ccccn3)NC(=O)c3ccc4cc[nH]c4c3)CC2)CC1

Procedure:
Using methods substantially equivalent to those described in Method D-1, the subtitled compound was prepared from 1-[β-(2-pyridinyl)-D-alanyl]-4-(1-methylpiperidin-4-yl)piperidine trihydrochloride and indole-6-carboxylic acid (32%).
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[C:16]([NH:18][C:19]2[C:20]3[CH:28]=[C:27]([N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[N:26]=[CH:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[C:65]([NH2:69])([CH3:68])([CH3:67])[CH3:66]>CN(C=O)C>[C:65]([NH:69][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][CH:13]=[C:5]([O:4][C:3]2[CH:14]=[CH:15][C:16]([NH:18][C:19]3[C:20]4[CH:28]=[C:27]([N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)[N:26]=[CH:25][C:21]=4[N:22]=[CH:23][N:24]=3)=[CH:17][C:2]=2[CH3:1])[CH:6]=1)([CH3:68])([CH3:67])[CH3:66]
Reactant: CC(C)(C)N
Reactant: Cc1cc(Nc2ncnc3cnc(N4CCCC4)cc23)ccc1Oc1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Nc2ncnc3cnc(N4CCCC4)cc23)ccc1Oc1cccc(C(=O)NC(C)(C)C)c1
Yield: 35.2 %

Procedure:
A solution of 3-[2-Methyl-4-(6-pyrrolidin-1-yl-pyrido[3,4-d]pyrimidin-4-ylamino)-phenoxy]-benzoic acid (72 mg, 0.16 mmol), HATU (93 mg, 0.24 mmol), NEt3 (50 mg, 0.48 mmol), and tert-butyl amine (24 mg, 0.33 mmol) in DMF (1.5 mL) was shaken at 60° C. for 12 h. The reaction was concentrated and purified by preparative HPLC to give a yellow solid (28 mg, 35%). LRMS: 497.3 (MH+); 1H NMR (DMSO-d6, 400 MHz): δ 9.65 (s, 1H), δ 8.81 (s, 1H), δ 8.36 (s, 1H), δ 7.77-7.81 (m, 3H), δ 7.54 (d, J=7.78, 1H), δ 7.42 (t, J=7.78, 1H), δ 7.34-7.35 (m, 1H), δ 7.14 (s, 1H), δ 7.00-7.069 (m, 2H), δ 3.50-3.54 (m, 4H), δ 2.21 (s, 3H), δ 2.00-2.09 (m, 4H), δ 1.37 (s, 9H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH3:10][NH:11][CH2:12][CH2:13][OH:14]>>[OH:14][CH2:13][CH2:12][N:11]([C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6])[CH3:10]
Reactant: CNCCO
Reactant: N#Cc1cccc(F)c1
Product: CN(CCO)c1cccc(C#N)c1

Procedure:
By treating 3-fluorobenzonitrile with N-methylethanolamine under heating, 3-(N-2-hydroxyethyl-N-methylamino)benzonitrile was obtained (F: 177). This benzonitrile was treated in the same manner as in Reference Example 2 to obtain 3-(N-2-hydroxyethyl-N-methylamino)benzylamine. F: 181.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:43]=[C:44]([C:48]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[O:49])[CH:45]=[N:46][CH:47]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:43]=[C:44]([C:48]([N:50]6[CH2:51][CH2:52][O:53][CH2:54][CH2:55]6)=[O:49])[CH:45]=[N:46][CH:47]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: O=C(c1cncc(Br)c1)N1CCOCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cncc(C(=O)N4CCOCC4)c3)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (50 mg) and (5-bromo-pyridin-3-yl)-morpholin-4-yl-methanone (38 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of [5-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyridin-3-yl]-morpholin-4-yl-methanone was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-228) as a yellow powder (45 mg, 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(Br)cc1
Reactant: OB(O)c1cccs1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2cccs2)cc1
Temperature: 100 °C
Yield: 38.6 %

Procedure:
To a solution of 0.5 g (1.6 mmol) of material from Example 27, 0.3 g (2.3 mmol) of thiophene-2-boronic acid and 0.3 g (2.3 mmol) of potassium carbonate in 7 mL of dioxane and 2 mL of water was added 0.1 g (0.1 mmol) of tetrakis(triphenylphosphine)palladium (0). The mixture was heated to 100° C. for 16 hours cooled to ambient temperature, diluted with 5 mL of water and extracted three times with 5 mL each of ethyl ether. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was recrystallized from ethyl ether, filtered and dried in vacuo to afford 0.2 g (47%) of the title compound.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>ClCCl>[N:21]1([S:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: C1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)c1ccc(S(=O)(=O)N2CCCCC2)cc1
Yield: 65 %

Procedure:
4-(Chlorosulfonyl)benzoic acid (CAS 10130-89-9) (441 mg, 2.0 mmol) and triethylamine (202 mg, 2.0 mmol) are dissolved in dichloromethane (20 mL) and stirred under nitrogen while piperidine (340 mg, 4.0 mmol) in dichloromethane (5 mL) is added to the mixture at room temperature. After 18 h the reaction mixture is concentrated. The crude material is slurried in aqueous NaHCO3, washed with diethyl ether, and separated. Ethyl acetate is added to the aqueous layer and the pH adjusted to 2 with 1N HCl. The layers are separated and the aqueous layer is extracted with EtOAc (2×). The EtOAc extracts are combined, washed with brine, dried over Na2SO4 and evaporated. The residue is purified by silica-gel column chromatography (0-8% MeOH/CH2Cl2 gradient) to give 350 mg (65%) of the title compound. MS (ES+) 270.1 (M+H)+.
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.Cl.CN(CCCN=C=NCC)C.C(N(CC)CC)C.[CH:31]1([CH2:34][N:35]2[C:43]([N:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[N:42][C:41]3[C:36]2=[N:37][C:38]([C:56]2[CH:57]=[N:58][C:59]([NH2:62])=[N:60][CH:61]=2)=[N:39][C:40]=3[N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)[CH2:33][CH2:32]1.C(OC([NH:70][CH2:71][C:72](O)=[O:73])=O)(C)(C)C>ClCCl.CO.CN(C)C=O>[NH2:70][CH2:71][C:72]([N:47]1[CH2:48][CH2:49][N:44]([C:43]2[N:35]([CH2:34][CH:31]3[CH2:32][CH2:33]3)[C:36]3[C:41]([N:42]=2)=[C:40]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)[N:39]=[C:38]([C:56]2[CH:61]=[N:60][C:59]([NH2:62])=[N:58][CH:57]=2)[N:37]=3)[CH2:45][CH2:46]1)=[O:73]
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCNCC4)n(CC4CC4)c3n2)cn1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: NCC(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC2CC2)CC1
Reaction time: 72 h
Yield: 17.6 %

Procedure:
1-Hydroxybenzotriazole monohydrate (33.8 mg, 0.22 mmol), 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (63.4 mg, 0.33 mmol), and triethylamine (82.9 μl, 0.60 mmol) were added to an N,N-dimethylformamide suspension (2.0 ml) of 5-[9-(cyclopropylmethyl)-6-morpholin-4-yl-8-piperazin-1-yl-9H-purin-2-yl]pyrimidin-2-amine (96.2 mg, 0.22 mmol) and N-tert-butoxycarbonyl-glycine (46.3 mg, 0.26 mmol) at room temperature. The resulting mixture was stirred for 3 days and then the reaction mixture was poured into dichloromethane-methanol (10:1), washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was dissolved in dichloromethane (4.0 ml) followed by the addition of trifluoroacetic acid (2.0 ml) with ice cooling. The resulting mixture was stirred at room temperature for 2 hours and the concentrated, dichloromethane was added to the residue, and the resulting mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The resulting mixture was extracted with dichloromethane-methanol (10:1), dried over anhydrous sodium sulfate, and then filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (dichloromethane:methanol=5:1) to give the title compound (19.1 mg, 18%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[S:8][C:7]=2[CH:14]=1.[Li]CCCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:32])(=O)=O)=CC=1>C1COCC1>[F:32][C:10]1[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:15])([F:1])[F:16])=[CH:14][C:7]=2[S:8][C:9]=1[C:11]([OH:13])=[O:12]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: O=C(O)c1cc2ccc(C(F)(F)F)cc2s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1sc2cc(C(F)(F)F)ccc2c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid 10a (2.031 mmol, 0.50 g) in THF (8 mL) at −70° C. was treated with a 1.6 M solution of n-BuLi in hexanes (4.26 mmol, 2.66 mL). After 1 h at −70° C., N-fluorobenzenesulfonimide (2.64 mmol, 0.833 g) in THF (2 mL) was slowly added and the reaction was warmed to room temperature. After 1 h the mixture was partitioned between dilute aqueous HCl and EtOAc. The organic layer was washed with water and brine, and then concentrated. The residue was triturated with CH2Cl2. The off-white precipitate was filtered and collected to provide 61a.