Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N+:24]([O-])=O)=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([O:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1>C(OCC)(=O)C.Cl.[Pd].ClCCl>[NH2:24][C:5]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:23][C:8]2[C:9]([C:19]([O:21][CH3:22])=[O:20])=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[O:11][C:7]=2[CH:6]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(C3CC3)cc12
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(C3CC3)cc12

Procedure:
A solution of methyl 5-cyclopropyl-2-(4-fluorophenyl)-6-nitro-1-benzofuran-3-carboxylate (3.175 g, 8.94 mmol) in ethyl acetate (250 mL) containing 2M HCl (17 drops) was stirred with 10% palladium on carbon (0.951 g, 0.894 mmol) under an atmosphere of hydrogen at 21° C. for 16 hours. The reaction mixture was filtered through celite and the filtrate was evaporated under vacuum to give a dark green solid. This was dissolved in dichloromethane, washed with sodium bicarbonate solution, separated by hydrophobic frit, then evaporated to dryness and purified by flash chromatography, eluting over silica gel with a gradient of 0-30% ethyl acetate in cyclohexane. Appropriate fractions were combined and evaporated under vacuum to give the methyl 6-amino-5-cyclopropyl-2-(4-fluorophenyl)-1-benzofuran-3-carboxylate. LCMS (m/z, ES+)=326 (M+H+).
Reaction SMILES: [Na+].[Cl:2][C:3]1[C:4]([F:17])=[CH:5][C:6]([N+:14]([O-])=O)=[C:7]([NH:9][CH2:10][C:11]([O-])=[O:12])[CH:8]=1.O.O.[Sn](Cl)Cl>C(O)C>[Cl:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][C:4]=1[F:17])[NH:14][C:11](=[O:12])[CH2:10][NH:9]2
Reactant: O=C([O-])CNc1cc(Cl)c(F)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1CNc2cc(Cl)c(F)cc2N1
Temperature: 25 °C
Yield: 59.4 %

Procedure:
A suspension of N-(5′-chloro-4′-fluoro-2′-nitrophenyl)glycine sodium salt (0.650 g, 2.61 mmol) and tin (11) chloride dihydrate (1.770 g, 7.845 mmol) in ethanol (10.5 mL) was refluxed for 1 h. It was then cooled to room temperature and 5 mL ethanol was removed under vacuum. The precipitated solid was collected by filtration under vacuum, washed with ethanol (3 mL) and dried to obtain 0.311 g (59%) title compound as an off-white powder; 1H NMR (DMSO-d6) δ 3.69 (s, 2H), 6.08 (s, 1H), 6.65 (d, 1H, J=9.9 Hz), 6.71 (d, 1H, J=7.2 Hz), 10.39 (s, 1H). The solvent from the filtrate was removed under vacuum. The residue was diluted with water (15.0 mL) and the pH was adjusted with 10% Na2CO3 to ˜9. The resulting suspension was extracted with ethyl acetate (50 mL). The ethyl acetate was dried over anhydrous Na2SO4 and removed under vacuum to yield further 0.118 g (22%) of pure (1H NMR) title compound for a combined yield of 81%.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:20]([O:21]C(=O)C)[C@H:19]([O:25]C(=O)C)[C@@H:18]([CH2:29][O:30]C(=O)C)[O:17][C@H:6]1[S:7][CH2:8][CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)C.C[O-].[Na+]>CO>[S:7]([CH2:8][CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:6]1[O:17][C@H:18]([CH2:29][OH:30])[C@@H:19]([OH:25])[C@H:20]([OH:21])[C@@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](SCC=Cc2ccccc2)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OC[C@H]1O[C@@H](SCC=Cc2ccccc2)[C@@H](O)[C@@H](O)[C@@H]1O

Procedure:
A solution of 4 (500 mg) in dry methanol (10 ml) is deacetylated with sodium methoxide (25 mg), and worked up in the normal manner to give a crystalline mass. Recrystallization from isopropanol affords 5 in near quantitative yield (323 mg); m.p. 145°-146° C.; [α]D27 -215±1.0° (C 0.97, methanol).
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[CH:9]([NH2:10])[CH:8]([OH:11])[CH:7]([N:12]2[CH:20]=[N:19][C:18]3[C:13]2=[N:14][CH:15]=[N:16][C:17]=3[NH:21][CH2:22][C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=2[O:30][CH2:31][CH:32]2[O:37][CH:36]3[O:38]C(C)(C)[O:40][CH:35]3[CH:34]3[O:43]C(C)(C)[O:45][CH:33]23)[O:6]1)=[O:4].FC(F)(F)C(O)=O.O>C(Cl)(Cl)Cl>[CH3:1][NH:2][C:3]([C@@H:5]1[C@@H:9]([NH2:10])[C@@H:8]([OH:11])[C@H:7]([N:12]2[CH:20]=[N:19][C:18]3[C:13]2=[N:14][CH:15]=[N:16][C:17]=3[NH:21][CH2:22][C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=2[O:30][CH2:31][CH:32]2[CH:33]([OH:45])[CH:34]([OH:43])[CH:35]([OH:40])[CH:36]([OH:38])[O:37]2)[O:6]1)=[O:4]
Reactant: CNC(=O)C1OC(n2cnc3c(NCc4cc(Cl)ccc4OCC4OC5OC(C)(C)OC5C5OC(C)(C)OC45)ncnc32)C(O)C1N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClC(Cl)Cl
Product: CNC(=O)[C@H]1O[C@@H](n2cnc3c(NCc4cc(Cl)ccc4OCC4OC(O)C(O)C(O)C4O)ncnc32)[C@H](O)[C@@H]1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.9 %

Procedure:
To a solution of 3-amino-5-{6-[5-chloro-2-(2,2,7,7-tetramethyltetrahydro-bis[1,3]dioxolo[4,5-b;4′,5′-d]pyran-5-ylmethoxy) benzylamino]purin-9-yl}-4-hydroxytetrahydrofuran-2-carboxylic acid methylamide (59 mg, 0.09 mmol) in chloroform (7 mL) was added trifluoroacetic acid (0.7 mL). This reaction was stirred under anhydrous conditions at room temperature for 2 h. After this time period water was added (10 mL) and the reaction was stirred at room temperature for 5 days. The solvent was removed with a rotary evaporator and the resulting solid was then triturated with Et2O to afford the title compound as a beige powder (60 mg). Mp 212.0-218.0° C. C24H30ClN7O9. MW 596.00. MS 596.1 (M+H)+.
Reaction SMILES: CC(C[Al]CC(C)C)C.[CH2:10]([N:17]([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]([Cl:34])[CH:28]=1)[C@H:18]([C:22](OCC)=[O:23])[CH:19]([CH3:21])[CH3:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(OCC)C>O>[CH2:10]([N:17]([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]([Cl:34])[CH:28]=1)[CH:18]([CH:19]([CH3:21])[CH3:20])[CH2:22][OH:23])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)[C@H](C(C)C)N(Cc1ccccc1)c1ccc(F)c(Cl)c1
Agent: CC(C)C[Al]CC(C)C
Solvent: O
Solvent: CCOCC
Product: CC(C)C(CO)N(Cc1ccccc1)c1ccc(F)c(Cl)c1
Temperature: 23 °C
Reaction time: 5 h

Procedure:
Dibal-H (7.08 mL, 7.08 mmol) was added as a 1.0 N solution in CH2CL2 at −78° C. to crude ethyl N-benzyl-N-(3-chloro-4-fluorophenyl)valinate (8-2, 0.322 g, 0.885 mmol). The mixture stirred for 5 h as it warmed to 23° C. Diethyl ether (40 mL) and H2O (1.2 mL) were added and mixture continued stirring for 20 min before filtering. The filtrate was concentrated and purified by reverse-phase liquid chromatography (Semi Prep YMC C-18 Reverse Phase Column 5% CH3CN/H2O to 95% CH3CN/H2O with 0.1% TFA present) to provide 2-[benzyl(3-chloro-4-fluorophenyl)amino]-3-methylbutan-1-ol (8-3) as a brown oil. 1H NMR (300 MHz, CDCl3) 7.37-7.171 (m, 5H), 6.92-6.86 (m, 2H), 6.67 (ddd, J=9.16, 3.35, 3.35 Hz, 1H), 4.45 (s, 2H), 3.91-3.87 (m, 1H), 3.68-3.55 (m, 2H), 2.04-1.92 (m, 1 μl), 1.70 (brs, 1H), 1.00 (d, J=6.72 Hz, 3H), 0.91 (d, J=6.71, 3H).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:10]([F:21])=[CH:11][C:12]([O:19][CH3:20])=[C:13]([NH:15]C(=O)C)[CH:14]=2)[CH2:3]1.Cl>C(O)C>[CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:10]([F:21])=[CH:11][C:12]([O:19][CH3:20])=[C:13]([CH:14]=2)[NH2:15])[CH2:3]1
Reactant: COc1cc(F)c(N2C[C@@H](C)N[C@@H](C)C2)cc1NC(C)=O
Agent: Cl
Solvent: CCO
Product: COc1cc(F)c(N2C[C@@H](C)N[C@@H](C)C2)cc1N

Procedure:
A mixture of product from Step 3 (883 mg, 3 mmol) in ethanol (40 ml) containing concentrated hydrochloric acid (2 ml) was heated at reflux for 15 hours. After cooling, the mixture was purified using an SCX ion exchange cartridge (Varian bond-elute) eluting with methanol and then 2M ammonia in methanol. The appropriate basic fractions were reduced in vacuo to afford the title compound (D18). MS (ES+) m/e 254 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:13])[CH:8]=2)[N:3]=1.[Cl:14][C:15]1[N:20]=[C:19](Cl)[CH:18]=[C:17]([CH3:22])[N:16]=1.Cl>C(O)CO.O>[Cl:14][C:15]1[N:20]=[C:19]([NH:13][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([CH3:1])[CH:11]=[C:10]3[NH2:12])[CH:18]=[C:17]([CH3:22])[N:16]=1
Reactant: Cc1cc(N)c2cc(N)ccc2n1
Reactant: Cc1cc(Cl)nc(Cl)n1
Agent: Cl
Solvent: O
Solvent: OCCO
Product: Cc1cc(Nc2ccc3nc(C)cc(N)c3c2)nc(Cl)n1
Reaction time: 4.5 h
Yield: 27 %

Procedure:
Diaminoquinoline 7 (72.0 g, 0.416 mol) and 2,4-dichloro-6-methylpyrimidine (8) (67.8 g, 0.416 mol) were suspended in ethylene glycol (1 L). Addition of 37% HCl (35 mL, 0.43 mol) resulted in a yellow solution which was heated to and held at 50° C. for 4.5 h. The mixture was diluted with chilled water (1 L) which resulted in a thick white paste-like precipitate and the mixture was filtered through Celite. The Celite and solid containing the product and bis-substituted by-product was slurried in water (4 L) and the Celite and insoluble by-product were removed by filtration. The filtrate pH was adjusted to 14 using 1N aqueous NaOH (1 L) resulting in precipitation of product which was removed by filtration. The damp product was transferred to a rotovap flask and dried in vacuo by azeotropic water removal with toluene (3×1.5 L). Product 9 was obtained as an off-white solid (33.4 g, 27% yield; Notebook reference A134-137). Another batch of 9 (7.4 g, 17% yield; Notebook reference A 134-134) was similarly obtained by reaction of 7 (25.0 g, 0.144 mol) and recovery as above; MS [M+1]=300, 302; 13C NMR (DMSO) δ 167.51, 162.58, 159.22, 157.61, 151.05, 145.99, 133.17, 128.96, 125.39, 117.38, 114.23, 102.45, 102.26, 24.68, 23.19.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][NH:12]C(OC(C)(C)C)=O)[O:8][N:7]=1)=[O:5])[CH3:2].Cl>C(O)C.O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][NH2:12])[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(CNC(=O)OC(C)(C)C)on1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)c1cc(CN)on1
Temperature: 20 °C
Reaction time: 22 h
Yield: 91.7 %

Procedure:
To a stirred solution of 5-(tert-butoxycarbonylaminomethyl)-isoxazole-3-carboxylic acid ethyl ester (1.954 g) (EP 0451790) in ethanol (15 ml) was added a solution of 4.0M hydrogen chloride in 1,4-dioxane (23 ml). The mixture was stirred at 20° C. for 22 h and the solvent evaporated in vacuo to give the title compound (1.128 g) as a pale brown solid.
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14]2)=[N:10][C:11]=1[NH2:12].[Cl:24][C:25]1[CH:26]=[N:27][N:28]([C:30]2([C:33](=N)OCC)[CH2:32][CH2:31]2)[CH:29]=1.C(N(CC)CC)C>C(O)C>[Cl:24][C:25]1[CH:26]=[N:27][N:28]([C:30]2([C:33]3[NH:12][C:11]4=[N:10][C:9]([N:13]5[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14]5)=[CH:8][CH:7]=[C:6]4[N:5]=3)[CH2:32][CH2:31]2)[CH:29]=1
Reactant: CCOC(=O)[C@@H]1CCCN(c2ccc(N)c(N)n2)C1
Reactant: CCOC(=N)C1(n2cc(Cl)cn2)CC1
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H]1CCCN(c2ccc3nc(C4(n5cc(Cl)cn5)CC4)[nH]c3n2)C1
Yield: 81.2 %

Procedure:
Acetic acid (4.3 g, 67.2 mmol) was added to a solution of (R)-ethyl 1-(5,6-diaminopyridin-2-yl)piperidine-3-carboxylate (890 mg, 3.36 mmol), ethyl 1-(4-chloro-1H-pyrazol-1-yl)cyclopropanecarbimidate (445 mg, 1.78 mmol) and triethylamine (0.8 mL, 5.92 mmol) in ethanol (25 mL) at room temperature under a nitrogen atmosphere. The mixture was heated at reflux for 16 h, then was concentrated under reduced pressure. The resulting residue was partitioned between ethyl acetate and water. The organics were dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified via column chromatography (100-200 mesh silica gel, 20-60% ethyl acetate in petroleum ether) to afford (R)-ethyl 1-(2-(1-(4-chloro-1H-pyrazol-1-yl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-3-carboxylate (600 mg). MS (ES+) (M+H) 415.2859.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2[C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[OH:24])[N:9]=[N:8][CH:7]=1)=[O:5])[CH3:2].[F:25][C:26]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:27]=1[CH2:28]Br>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2[C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[O:24][CH2:28][C:27]2[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:26]=2[F:25])[N:9]=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnnc(C2=C(c3cc(Cl)ccc3O)CCC2)c1
Reactant: Fc1ccc(CBr)c(F)c1
Product: CCOC(=O)c1cnnc(C2=C(c3cc(Cl)ccc3OCc3ccc(F)cc3F)CCC2)c1

Procedure:
Prepared by general procedure F(iii) but using 6-{2-[5-chloro-2-(hydroxy)phenyl]cyclopent-1-enyl}-pyridazine-4-carboxylic acid ethyl ester instead of 6-{2-[5-methyl-2-(hydroxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylic acid ethyl ester and 2,4-difluorobenzyl bromide instead of 4-fluorobenzyl bromide.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([Cl:7])=[C:3]1[C:8]([O:10][CH3:11])=[O:9].[C:12]([O:16][C:17]([NH:19][C:20]1([C:23](O)=[O:24])[CH2:22][CH2:21]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:12]([O:16][C:17]([NH:19][C:20]1([C:23]([NH:1][N:2]2[CH:6]=[CH:5][C:4]([Cl:7])=[C:3]2[C:8]([O:10][CH3:11])=[O:9])=[O:24])[CH2:22][CH2:21]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: COC(=O)c1c(Cl)ccn1N
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(Cl)ccn1NC(=O)C1(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 30.9 %

Procedure:
To a stirred solution of methyl 1-amino-3-chloro-1H-pyrrole-2-carboxylate (1.50 g, 8.59 mmol) in DCM (50 mL) was added 1-((tert-butoxycarbonyl)amino) cyclopropanecarboxylic acid (2.59 g, 12.9 mmol), HOBT (1.58 g, 10.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (2.47 g, 12.9 mmol) and DIPEA (3.00 mL, 17.2 mmol) at room temperature. The reaction mixture was stirred at room temperature for 12 h then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and washed with water (2×30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by CombiFlash ISCO (REDISEP®, SiO2, 12 g, 50% EtOAc/petroleum ether) to give methyl 1-(1-((tert-butoxycarbonyl)amino)cyclopropanecarboxamido)-3-chloro-1H-pyrrole-2-carboxylate (950 mg, 30.9%) as a white solid. LCMS Condition B-16: retention time 0.87 min, [M+1]=358.1. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.01-1.06 (m, 2H), 1.30-1.38 (m, 2H), 1.41 (s, 9H), 3.74 (s, 3H), 6.27 (s, 1H), 6.99 (d, J=2.4 Hz, 1H), 7.46 (d, J=2.4 Hz, 1H), 11.08 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[C:35]1([CH2:41][S:42](Cl)(=[O:44])=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCOCC1>[NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][N:23]([S:42]([CH2:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[O:44])=[O:43])[CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1
Reactant: Nc1nc(N2CCNCC2)c2nc(CCc3ccc(F)cc3)sc2n1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(N2CCN(S(=O)(=O)Cc3ccccc3)CC2)c2nc(CCc3ccc(F)cc3)sc2n1
Temperature: 90 °C
Reaction time: 16 h
Yield: 11.5 %

Procedure:
To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-piperazin-1-yl-thiazolo[5,4-d]pyrimidine (80 mg, 0.22 mmol) in 1,4-dioxane (4 ml) was added diisopropylethylamine (0.49 mmol, 81 μL) and phenylmethanesulfonyl chloride (0.25 mmol). The reaction was stirred at 90° C. for 16 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 1% CH3OH in CH2Cl2), yielding the pure title compound (13 mg) which was characterized by its mass spectrum: MS m/z (%): 513 ([M+H]+, 100).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)=[O:3].[CH3:11][CH2:12][N:13]([CH2:16][CH2:17][OH:18])[CH2:14][CH3:15].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu].[Cu]I>[CH2:12]([N:13]([CH2:14][CH3:15])[CH2:16][CH2:17][O:18][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=1)[CH3:11]
Reactant: CCN(CC)CCO
Reactant: CC(=O)c1ccc(Br)cc1
Agent: [Cu]
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CCN(CC)CCOc1ccc(C(C)=O)cc1
Temperature: 25 °C
Yield: 82.4 %

Procedure:
A mixture of 4-bromoacetophenone (5 g, 25 mmol), the diethylaminoethanol (3.5 g, 38 mmol), K2CO3 (2g), copper powder (0.5 g) and copper(I) iodide (2.5 g) in DMSO (30 ml) was heated at 120° C. until TLC showed consumption of the starting material. After cooling to RT, the mixture was poured onto aqueous NH3 (28%, 100 ml), extracted with CH2Cl2 (3×100 ml). The combined organic extracts were dried (Na2SO4), filtered and the CH2Cl2 distilled in vacuo. The crude product was purified by column chromatography on silica gel, eluting with EtOAc-MeOH (95:5) to furnish the pure compound (4.85 g, 82%).
Reaction SMILES: [N:1]([CH:4]([C:21]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=1)[CH2:5][N:6]1[CH2:13][CH:12]2[CH2:14][CH:8]([CH2:9][N:10]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11]2)[CH2:7]1)=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH:4]([C:21]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=1)[CH2:5][N:6]1[CH2:7][CH:8]2[CH2:14][CH:12]([CH2:11][N:10]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:9]2)[CH2:13]1
Reactant: CC(C)OC(=O)N1CC2CC(CN(CC(N=[N+]=[N-])c3ccc(C#N)cc3)C2)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)OC(=O)N1CC2CC(CN(CC(N)c3ccc(C#N)cc3)C2)C1
Yield: 98 %

Procedure:
A solution of iso-propyl 7-[2-azido-2-(4-cyanophenyl)ethyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (from step (vii) above; 7.51 g; 19.5 mmol) in aqueous ethanol (85%) was hydrogenated over 5% Pd/C at 1 atm until tlc indicated that the reaction was complete. The catalyst was removed by filtration through a pad of Celite®, and the filtrate concentrated under reduced pressure to give the title compound in 98% yield.
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:4]=1)=[CH2:2].[C:12]([NH:18][C:19]1[N:20]=[C:21]([OH:30])[C:22]2[CH:28]=[C:27](Br)[CH:26]=[N:25][C:23]=2[N:24]=1)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:12]([NH:18][C:19]1[N:20]=[C:21]([OH:30])[C:22]2[CH:28]=[C:27]([CH:2]=[CH:1][C:3]3[NH:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:4]=3)[CH:26]=[N:25][C:23]=2[N:24]=1)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: C=Cc1ccc(C(=O)OC)[nH]1
Reactant: CC(C)(C)C(=O)Nc1nc(O)c2cc(Br)cnc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1ccc(C=Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)[nH]1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
A mixture of methyl 5-vinylpyrrole-2-carboxylate (298 mg, 2.0 mmol), 2-pivaloylamino4-hydroxy-6-bromopyrido[2,3-d]pyrimidine (683 mg, 2.1 mmol), palladium acetate (22.5 mg, 0.1 mmol), tri-o-tolylphosphine (60.9 mg, 0.2 mmol), and triethylamine (7.0 mL) in acetonitrile (20 mL) was heated overnight at reflux. The reaction mixture was cooled to room temperature, and the solid which formed collected by filtration, washed with cold acetonitrile, and dried to give methyl 5-[2-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)ethenyl]pyrrole-2-carboxylate as a yellow solid (706 mg, 89%). The product can be used in the next step without further purification. An analytical sample, mp >260° C., was obtained by recrystallization from methanol: 1H NMR (DMSO-d6) δ 12.28 (s, 1H), 12.08 (s, 1H), 11.40 (s, 1H), 8.93 (s, 1H), 8.40 (s, 1H), 7.36 (d, 1H, J=16.6 Hz), 7.27 (d, 1H, J=16.6 Hz), 6.81 (m, 1H), 6.48 (m, 1H), 3.76 (s, 3H), 1.23 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH3:15][CH:16]([OH:20])[C:17]#[C:18][CH3:19].[H-].[Na+].O>CN(C)C=O>[F:14][C:10]1[CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([O:20][CH:16]([CH3:15])[C:17]#[C:18][CH3:19])[N:3]=[CH:4][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CC#CC(C)O
Reactant: Fc1cccc(-c2cc(Cl)ncn2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CC(C)Oc1cc(-c2cccc(F)c2)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
In 5 ml of N,N-dimethylformamide were dissolved 246 mg of 4-chloro-6-(3-fluorophenyl)pyrimidine and 119 mg of 3-pentyn-2-ol, to which 57 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 8 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 200 mg of 4-(3-fluorophenyl)-6-(1-methyl-2-butynyloxy)pyrimidine (the present compound (173)).
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[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[C:60]([Cl:66])[CH:61]=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][N:68]=2)[C:56]=1[CH3:73].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]>[Cl:66][C:60]1[CH:61]=[CH:62][C:63]([F:65])=[C:64]2[C:59]=1[N:58]=[C:57]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][N:68]=1)[C:56]([CH3:73])=[C:55]2[NH:47][C:46]1[C:41]([N:38]2[CH2:39][CH2:40][O:35][CH2:36][CH2:37]2)=[N:42][CH:43]=[C:44]([N:48]2[CH2:49][CH2:50][O:51][CH2:52][CH2:53]2)[CH:45]=1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2ccccn2)nc2c(Cl)ccc(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(-c2ccccn2)nc2c(Cl)ccc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.025 g, 0.052 mmol), 2,5-dimorpholinopyridin-3-amine (0.103 g, 0.39 mmol), 4,8-dichloro-5-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (0.1 g, 0.33 mmol), Pd2dba3 (0.012 g, 0.013 mmol) and sodium tert-butoxide (0.078 g, 0.812 mmol) in toluene (3.3 mL) at 120° C. for 3 h. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product 8-chloro-N-(2,5-dimorpholinopyridin-3-yl)-5-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.67 (1H, m), 8.19 (1H, dt, J=7.8, 1.1 Hz), 7.90-7.92 (1H, td, J=7.7, 1.8 Hz), 7.86 (1H, d, J=12.0 Hz), 7.73 (1H, dd, J=8.4, 5.1 Hz), 7.63 (1H, d, J=2.7 Hz), 7.38 (1H, ddd, J=7.6, 4.8, 1.3 Hz), 7.12 (1H, dd, J=12.9, 8.4 Hz), 6.45 (1H, d, J=2.2 Hz), 3.94 (4H, br. s.), 3.81 (4H, m), 3.18 (4H, br. s.), 3.09 (4H, m), 2.34 (3H, s). Mass Spectrum (ESI) m/e=535.2 (M+1).