Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](O)=[O:2].[NH2:4][C:5]1[C:6]2[C:31]([CH3:36])([C:32]([NH:34][NH2:35])=[O:33])[C:30](=[O:37])[NH:29][C:7]=2[N:8]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH2:21][C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[N:12]=2)[N:10]=1>C(#N)C>[NH2:4][C:5]1[C:6]2[C:31]([CH3:36])([C:32]([NH:34][NH:35][CH:1]=[O:2])=[O:33])[C:30](=[O:37])[NH:29][C:7]=2[N:8]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH2:21][C:22]([F:28])([F:27])[C:23]([F:25])([F:24])[F:26])[N:12]=2)[N:10]=1
Reactant: CC1(C(=O)NN)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(N)c21
Reactant: O=CO
Solvent: CC#N
Product: CC1(C(=O)NNC=O)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(N)c21
Temperature: 80 °C

Procedure:
Formic acid (3 mL, 78 mmol) was added to an acetonitrile solution (3 mL) of the intermediate from Step A (200 mg, 0.371 mmol). The reaction mixture was heated at 80° C. for 1.5 hours in a screw cap vial. The mixture was cooled, concentrated in vacuo and the residue diluted with EtOAc. The solution was then washed with saturated aqueous sodium bicarbonate, water and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a pale yellow solid which was used in the next step without further purification. m/z=513.97 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:24][CH2:25][CH2:26][CH2:27][OH:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:24][CH2:25][CH2:26][CH2:27][OH:28])=[O:21])=[CH:17][N:16]=3)=[CH:11][O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: NCCCO
Reactant: O=C(O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Product: O=C(NCCCO)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Yield: 60 %

Procedure:
As described for example 346b, 6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid (200 mg, 0.6 mmol) was converted, using 3-amino-1-propanol instead of ethanolamine, to the title compound (140 mg, 60%) which was obtained as a white solid. MS: m/e=385.9 [M−H]−.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][CH2:8][C:9]3[CH:15]=[CH:14][S:13][C:10]=3[C:11]=2[N:12]=1.[C:16]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>>[N:12]1[C:11]2[C:10]3[S:13][C:14]([C:28]4[CH:29]=[CH:30][C:25]([CH2:24][NH:23][C:16](=[O:17])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[CH:26][CH:27]=4)=[CH:15][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Brc1ccc2c(n1)-c1sccc1CCO2
Reactant: CC(C)(C)OC(=O)NCc1ccc(B(O)O)cc1
Product: CC(C)(C)OC(=O)NCc1ccc(-c2cc3c(s2)-c2ncccc2OCC3)cc1

Procedure:
Following Scheme 5, 2-bromo-6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepine and 4-(N-Boc-aminomethyl)-phenylboronic acid were reacted to give tert-butyl 4-(6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepin-9-yl)benzylcarbamate. MS: (ESI+)=409.1. Hydrogen chloride in dioxane (4 ml, 4 N) was added to a solution of 67 mg (0.16 mmol) of tert-butyl 4-(6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepin-9-yl)benzylcarbamate in 6 ml of methylene chloride and the mixture was stirred for 2 hours. The precipitate was collected, washed with methylene chloride and ethyl ether and dried in vacuum to give 335 (34 mg, 55%). MS: (ESI+) 309.1.
Reaction SMILES: [C:1]([CH:3]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23]([NH:26][C:27]([NH:29][CH2:30][CH2:31][CH3:32])=[O:28])(=[O:25])=[O:24])=[CH:13][CH:12]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C([O-])([O-])=O.[K+].[K+].[C:39](Cl)(=[O:44])[CH2:40][CH2:41][CH2:42][CH3:43]>CC(C)=O>[C:1]([CH:3]([N:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23]([NH:26][C:27]([NH:29][CH2:30][CH2:31][CH3:32])=[O:28])(=[O:25])=[O:24])=[CH:15][CH:16]=1)[C:39](=[O:44])[CH2:40][CH2:41][CH2:42][CH3:43])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCCCC(=O)Cl
Reactant: CCCNC(=O)NS(=O)(=O)c1ccccc1-c1ccc(CNC(C#N)C(=O)OCC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)NCCC)cc1)C(C#N)C(=O)OCC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1.7 g of the product of Stage A were dissolved in 50 ml of acetone and 0.79 g of K2CO3 and 0.45 ml of valeryl chloride were added. The mixture was stirred for 6 hours at ambient temperature and the insoluble part was filtered. The filtrate was evaporated to dryness, which after purification by chromatography (eluant: dichloromethane-ethyl acetate 4-1) yielded 295 mg of the expected product with a Rf (SiO2, dichloromethane ethyl acetate 4-1)=0.30.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([C:18]2[C:19]([CH3:25])=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=2)[CH:10]=[C:11]2[C:16]=1[NH:15][C:14](=[O:17])[CH:13]=[CH:12]2.[CH2:26]=[O:27].[Cl-].[NH4+]>CCCCCC.C1COCC1>[OH:27][CH2:26][C:7]1[CH:8]=[C:9]([C:18]2[C:19]([CH3:25])=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=2)[CH:10]=[C:11]2[C:16]=1[NH:15][C:14](=[O:17])[CH:13]=[CH:12]2
Reactant: C=O
Reactant: Cc1ccc(-c2cc(Br)c3[nH]c(=O)ccc3c2)c(C)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(-c2cc(CO)c3[nH]c(=O)ccc3c2)c(C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of n-butyl lithium [1.04 cm3 of a 1.6M solution in n-hexane] was added at -70° to a stirred solution of 8-bromo-6-[2,6-dimethyl-pyrid-3-yl]-2-(1H)-quinolone (0.25 g) in THF (20 cm3) under nitrogen. After 2 hours, gaseous formaldehyde [generated by sublimation of paraformaldehyde (0.3 g)] was passed over the solution, and, after stirring for a further 10 minutes, the mixture was allowed to warm to room temperature. Saturated ammonium chloride solution (10 cm3) was then added and the mixture was extracted with chloroform (3×50 cm3). The combined and dried (MgSO4) organic extracts were evaporated and the residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with dichloromethane:methanol, 19:1. Combination and evaporation of the appropriate fractions afforded 8-hydroxymethyl-6-[2,6-dimethylpyrid-3-yl]-2-(1H)-quinolone. 0.1H2O, m.p. 218.5°-221° (0.094 g).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:14][N:13]([CH2:15][CH2:16][C:17]([NH:19]C2C=CC=CC=2)=[O:18])[C:12](=[O:26])[CH2:11][N:10]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:9]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC=CC=1.[CH2:45](N)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[CH2:45]([NH:19][C:17](=[O:18])[CH2:16][CH2:15][N:13]1[CH2:14][CH:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9](=[O:37])[N:10]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)(=[O:28])=[O:29])[CH2:11][C:12]1=[O:26])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: NCc1ccccc1
Reactant: O=C(CCN1CC(Cc2ccccc2)C(=O)N(S(=O)(=O)c2ccc(Cl)cc2)CC1=O)Nc1ccccc1
Solvent: Nc1ccccc1
Product: O=C(CCN1CC(Cc2ccccc2)C(=O)N(S(=O)(=O)c2ccc(Cl)cc2)CC1=O)NCc1ccccc1

Procedure:
Instead of the starting material compound of Example 273, that is, aniline, benzylamine was used for the similar procedure as in Example 273 to obtain the title compound.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:29](I)=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[N+:31]([O-:33])=[O:32])[CH:21]=3)[C@H:14]2[CH3:34])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:37][C:38]1[C:43]([CH:44]([CH3:46])[CH3:45])=[CH:42][C:41](B(O)O)=[C:40]([O:50][CH3:51])[CH:39]=1.O>C(=O)([O-])[O-].[K+].[K+].C1COCC1>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:29]([C:41]4[CH:42]=[C:43]([CH:44]([CH3:46])[CH3:45])[C:38]([F:37])=[CH:39][C:40]=4[O:50][CH3:51])=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[N+:31]([O-:33])=[O:32])[CH:21]=3)[C@H:14]2[CH3:34])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc2cccc([N+](=O)[O-])c2cc1I
Reactant: COc1cc(F)c(C(C)C)cc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(F)c(C(C)C)cc1-c1cc2c([N+](=O)[O-])cccc2cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 85 °C

Procedure:
A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-iodo-5-nitro-2-naphthyl)methyl]-4-methyl-1,3-oxazolidin-2-one (34.0 mg, 0.0545 mmol), (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (23.1 mg, 0.0109 mmol), and 1,1′-bis(di-t-butylphosphinoferrocene)palladium dichloride (3.5 mg, 0.00545 mmol) in 1N aqueous potassium carbonate (2 mL) and THF (2 mL) was heated at 85° C. in a sealed tube for 2 h. The reaction mixture was cooled to room temperature and water (10 mL) was added. The mixture was extracted with EtOAc (3×20 mL) and the combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-30% EtOAc in hexanes gradient) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[3-(4-fluoro-5-isopropyl-2-methoxyphenyl)-5-nitro-2-naphthyl]methyl}-4-methyl-1,3-oxazolidin-2-one. Rf=0.23 (20% EtOAc/hexanes). LCMS calc.=665.2; found=664.9 (M+1)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers): δ 8.46 (s, 1H); 8.26 (d, J=7.5 Hz, 1H); 8.17 (t, J=9.0 Hz, 1H); 8.07 (s, 0.5H); 7.95 (s, 0.5H); 7.85 (s, 1H); 7.69 (s, 2H); 7.58 (t, J=7.9 Hz, 1H); 7.14 (d, J=8.4 Hz, 0.5H); 7.10 (d, J=8.4 Hz, 0.5H); 6.72 (d, J=12.0 Hz, 0.5H); 6.71 (d, J=12.0 Hz, 0.5H); 5.57 (d, J=8.1 Hz, 0.5H); 5.44 (d, J=8.0 Hz, 0.5H); 4.97 (d, J=15.9 Hz, 0.5H); 4.93 (d, J=15.9 Hz, 0.5H); 4.29 (d, J=15.9 Hz, 0.5H); 4.03 (d, J=15.8 Hz, 0.5H); 3.91-3.83 (m, 0.5H); 3.77 (m, 3.5H); 3.26-3.18 (m, 1H); 1.28-1.24 (m, 4.5H); 1.20 (d, J=6.9 Hz, 1.5H); 0.58 (d, J=6.5 Hz, 1.5H); 0.40 (d, J=6.6 Hz, 1.5H).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][C:8](Cl)=O)[CH2:6][CH2:5][CH2:4][CH2:3]1.[NH2:11][C:12]1[CH:17]=[C:16]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH:15]=[CH:14][C:13]=1[NH:24][CH2:25][CH:26]1[CH2:28][CH2:27]1>>[CH:26]1([CH2:25][N:24]2[C:13]3[CH:14]=[CH:15][C:16]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:17][C:12]=3[N:11]=[C:8]2[CH2:7][C:2]2([CH3:1])[CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:27][CH2:28]1
Reactant: CC1(CC(=O)Cl)CCCC1
Reactant: CC(C)S(=O)(=O)c1ccc(NCC2CC2)c(N)c1
Product: CC(C)S(=O)(=O)c1ccc2c(c1)nc(CC1(C)CCCC1)n2CC1CC1

Procedure:
The title compound was prepared according to the procedure described in Step C of Example 5 from (1-methylcyclopentyl)acetyl chloride (Step A) and 2-amino-1-(N-cyclopropylmethylamino)-4-(isopropylsulfonyl)benzene (Step E of Example 1).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][C:16]=3[CH3:23])=[O:13])[CH:7]=2)[CH2:3][CH2:2]1.[CH3:27][O:28][CH2:29][CH2:30][NH2:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][NH:31][CH2:30][CH2:29][O:28][CH3:27])=[CH:17][C:16]=3[CH3:23])=[O:13])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(C=O)cc2C)ncn1
Reactant: COCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(CNCCOC)cc2C)ncn1
Reaction time: 15 h

Procedure:
A solution of 6-((cyclopropylmethyl)(propyl)amino)-N-(4-formyl-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 29, 100 mg; 0.28 mmol) in DCM (5 ml) was treated with 2-methoxyethanamine (Aldrich, 112.7 mg; 0.42 mmol) followed by polymer supported triacetoxy borohydride (150 mg). After stirring for 15 hours the mixture was filtered and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9](OC3CCOCC3)[C:10]=2[N:11]=1.[CH:19]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20]1.CC(C)([O-])C.[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:24][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[C:10]=2[N:11]=1
Reactant: NC1CCCC1
Reactant: Clc1ccc2ncnc(OC3CCOCC3)c2n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Clc1ccc2ncnc(NC3CCCC3)c2n1
Temperature: 25 °C
Yield: 34.6 %

Procedure:
A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, step D) (0.100 g, 0.500 mmol), cyclopentanamine (0.054 ml, 0.550 mmol), PdCl2(dppf)-CH2Cl2Adduct (4.08 mg, 5.00 mmol) and sodium tert-butoxide (0.096 g, 1.00 mmol) in dioxane (2.50 ml) was refluxed for 3 hours. After cooling to room temperature, the reaction mixture was filtered through a Celite pad and washed with CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=1:1) to give 6-chloro-N-cyclopentylpyrido[3,2-d]pyrimidin-4-amine (0.043 g, 35%) as a yellow oil. 1H-NMR (CDCl3, Varian 400 MHz)): δ 1.60-1.83 (6H, m), 2.15-2.21 (2H, m), 4.55-4.60 (1H, m), 6.96 (1H, d, J=6.4 Hz), 7.59-7.62 (1H, m), 8.02-8.04 (1H, m), 8.63 (1H, s).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH:19]1[CH2:24][CH2:23][CH:22]([C:25]([NH2:27])=[O:26])[CH2:21][CH2:20]1>O1CCCC1.O>[C:25]([CH:22]1[CH2:23][CH2:24][N:19]([CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:20][CH2:21]1)(=[O:26])[NH2:27]
Reactant: NC(=O)C1CCNCC1
Reactant: BrCCOc1ccccc1CCc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)C1CCN(CCOc2ccccc2CCc2ccccc2)CC1
Yield: 82.3 %

Procedure:
A solution of 2 g of 2-(2-bromoethoxy)bibenzyl and 1.7 g of 4-piperidinecarboxamide in 20 ml of tetrahydrofuran and 10 ml of water was stirred at 70° C. for 10 hours. The reaction mixture was concentrated and to the residue was added 1 N NaOH aqueous solution. The resultant crystals were filtered, washed well with water and then recrystallized from ethanol to give 1.9 g (82% yield) of 2-[2-(4-carbamoylpiperidino)ethoxy]bibenzyl, m. p. 60°-63° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH3:29])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH2:27][CH3:28])[N:6]=2.[NH:30]1[CH2:33][CH:32]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH2:31]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:27]([C:19]1[N:18]([C:7]2[N:6]=[C:5]3[C:10]([N:11]=[C:3]([CH2:2][N:30]4[CH2:33][CH:32]([N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)[CH2:31]4)[N:4]3[CH3:29])=[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:8]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=1)[CH3:28]
Reactant: C1CN(C2CNC2)CCO1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CCl)n(C)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.4 %

Procedure:
To a solution of 8-chloromethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (107 mg, 0.26 mmol) and 4-azetidin-3-ylmorpholine (44 mg, 0.31 mmol) in DMF (3 mL) was added K2CO3 (106 mg, 0.77 mmol). The resulting mixture was allowed to stir at room temperature for 16 h. The reaction mixture was dissolved in EtOAc, washed with H2O (×4) then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-5%). The resulting residue was further purified by Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH, followed by reverse phase HPLC (Phenomenex Luna C18, 20 mM Et3N in water on a gradient of 20 mM Et3N in acetonitrile 95:5 to 2:98) to afford 309 as a white solid (14 mg, 11%). LCMS (Method G): RT 5.74 min, [M+H]+ 518.3. 1H NMR (CDCl3, 400 MHz): δ 8.02-7.98 (m, 1 H); 7.77-7.73 (m, 1 H); 7.27-7.23 (m, 2 H); 4.35 (m, 4 H); 3.89-3.82 (m, 6 H); 3.83 (s, 3 H); 3.72 (m, 4 H); 3.56 (m, 2H); 3.34 (q, J=7.5 Hz, 2 H); 3.15-3.03 (m, 3 H); 2.34 (m, 4 H) and 1.44 (t, J=7.5 Hz, 3 H)
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7]Cl)=[N:4][CH:3]=1.[CH3:9][S-:10].[Na+]>CN(C=O)C>[Br:1][C:2]1[S:6][C:5]([CH2:7][S:10][CH3:9])=[N:4][CH:3]=1
Reactant: C[S-]
Reactant: ClCc1ncc(Br)s1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCc1ncc(Br)s1
Reaction time: 8 h
Yield: 28.4 %

Procedure:
5-Bromo-2-(chloromethyl)thiazole (177 mg, 0.833 mmol) was stirred in DMF (10 mL) under nitrogen at room temperature and sodium thiomethoxide (117 mg, 1.67 mmol) was added. The mixture was stirred overnight and concentrated. The residue was slurried in ethyl acetate (30 ml), washed with water, dried over sodium sulfate, and concentrated to give a brown oil which was purified by ISCO CombiFlash® chromatography with Heptane:DCM (100:0 to 0:100 over 10 column volume and held for a further 10 CV to give the product as a brown oil (53 mg 28%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C@:5]([OH:16])([CH3:15])[C@@H:6]([C@H:8]1[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[O:9]1)[OH:7])[CH3:2].[C:18](Cl)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:17])[C@:5]([OH:16])([CH3:15])[C@@H:6]([C@H:8]1[CH2:12][O:11][C:10]([CH3:13])([CH3:14])[O:9]1)[O:7][C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)[C@@](C)(O)[C@H](O)[C@H]1COC(C)(C)O1
Solvent: c1ccncc1
Product: CCOC(=O)[C@@](C)(O)[C@H](OC(=O)c1ccccc1)[C@H]1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
To a solution of compound 42 (245 mg, 0.99 mmol) in dry pyridine (3 mL) is added dropwise a solution of BzCl (300 mg, 2.1 mmol) in pyridine (1 mL). After the mixture is stirred at room temperature for 2 h, the reaction is quenched with H2O (1 mL). The mixture is concentrated to dryness and the residue is partitioned between CH2Cl2 and sat. NaHCO3 solution. The organic phase is dried (anh. Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography with 5% EtOAc in hexanes to give 43 (247 mg, 71%) as a solid. Anal. Calcd for C18H24O7: C, 61.35; H, 6.86. Found: C, 60.95; H, 6.73.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1O)=[CH:13][C:12]([Br:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:20])=O>CN(C)C=O>[Br:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:15]2[Cl:20]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2ccc(Br)cc2c1O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2ccc(Br)cc2c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
Suspend 6-bromo-4-hydroxyquinoline-3-carboxylic acid ethyl ester (11 g, 37 mmol) in anhydrous dimethylformamide (148.6 mL) under nitrogen atmosphere. Add phosphoryl chloride (20.7 mL, 222 mmol, 6 eq.) via syringe over 5 minutes and stir vigorously at room temperature for 3 hours. Quench the reaction by pouring the mixture into ice water (1.5 L) and continue stirring until all the ice has melted. Obtain the solid formed by filtration, rinse with water and allow complete drying to afford the titled compound (11.4 g, 94%). MS (ESI) m/z (M+H)+ 314.0, 316.0.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:27][CH2:28][CH2:29][C:30]1[N:31]=[C:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[S:33][CH:34]=1.[CH3:43][C:44]([CH3:46])=[O:45]>C1COCC1>[OH:45][C:44]([C:34]1[S:33][C:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:41])[CH3:40])=[N:31][C:30]=1[CH2:29][CH2:28][O:27][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][O:21]1)([CH3:46])[CH3:43]
Reactant: CC(C)(C)OC(=O)Nc1nc(CCOC2CCCCO2)cs1
Reactant: CC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nc(CCOC2CCCCO2)c(C(C)(C)O)s1
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
To a solution of diisopropylamine (9.5 mL, 67.2 mmol) in THF (100 ml) was added butyllithium (42 mL, 1.6M in hexanes, 67.2 mmol) drop wise at −78° C. and stirred for 30 min. Thus obtained LDA solution was immediately added by cannulation to a solution of Example 89C (7.36 g, 22.4 mmol) in THF (100 ml) at −78° C. and stirred for 30 min at the same temperature. Then, dry acetone (8.2 ml, 112 mmol, Acros) was added slowly and the reaction mixture was removed from cold bath and allowed to reach room temperature for overnight while stirring. The reaction mixture was quenched with saturated aqueous NH4Cl solution (100 mL) and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (SiO2, 0-100% ethyl acetate in hexanes) to afford 4.6 g (53%) of the title compound. MS (ESI+) m/z 387 (M+H)+
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5]=2[C:15](=[O:17])[CH3:16])[CH2:3][CH2:2]1.[Br:18]Br>C(Cl)(Cl)(Cl)Cl.CC(O)=O>[Br:18][CH2:16][C:15]([C:5]1[C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:7][O:8][C:4]=1[CH:1]1[CH2:3][CH2:2]1)=[O:17]
Reactant: BrBr
Reactant: CC(=O)c1c(-c2ccccc2)noc1C1CC1
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(CBr)c1c(-c2ccccc2)noc1C1CC1
Temperature: 25 °C
Yield: 96 %

Procedure:
To a solution of 1-(5-cyclopropyl-3-phenyl-isoxazol-4-yl)-ethanone (3.34 g, 14.6 mmol) in carbontetrachloride (9.7 mL) and AcOH (0.4 mL) at 48° C. was added a solution of bromine (0.79 mL, 14.6 mmol) in carbontetrachloride (7.8 mL) over 10 min keeping the temperature below 50° C. After addition the reaction mixture was allowed to cool down to room temperature and poured into ice-water (50 mL). The layers were separated and the aqueous layer extracted with dichloromethane. The combined organic layers were then washed with water and brine, dried over sodium sulphate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate: 100:0 to 80:20) afforded the title compound (4.29 g, 95%) which was obtained as an off-white solid. MS m/e (EI): 305.0/307.0 [M].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:14][Mg]Br>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:13])([CH3:14])[C:9]([F:11])([F:12])[F:10])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Br)cc1)C(F)(F)F
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)(c1ccc(Br)cc1)C(F)(F)F
Temperature: 0 °C

Procedure:
4′-Bromo-2,2,2-trifluoracetophenone (1.80 mL, 11.9 mmol) was dissolved in tetrahydrofuran (60 mL), cooled to 0° C., and methylmagnesium bromide (19.8 mL, 59.3 mmol) was added. The reaction mixture was maintained at 0° C. for 1 hour and then allowed to warm to ambient temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, concentrated in vacuo and the crude residue was purified directly by MPLC on silica gel (using a gradient elution of 0-25% ethyl acetate in hexanes to afford a racemic mixture of the title compound. The mixture was resolved to the constituent enantiomers by Chiral SFC purification (Chiral Technology AZ-H 2.1×25 cm, 5 uM column; mobile phase: 5% methanol/CO2) to afford the title compounds as single enantiomers. Intermediate #11-1: First enantiomer to elute; (S or R)-2-(4-Bromophenyl)-1,1,1-trifluoropropan-2-ol; 1H NMR (500 MHz, CDCl3) δ 7.53-7.52 (d, 2H), 7.46-7.45 (d, 2H), 2.64 (bs, 1H), 1.76 (s, 3H). Intermediate #11-2: Second enantiomer to elute; (S or R)-2-(4-Bromophenyl)-1,1,1-trifluoropropan-2-ol; 1H NMR (500 MHz, CDCl3) δ 7.53-7.52 (d, 2H), 7.46-7.45 (d, 2H), 2.64 (bs, 1H), 1.76 (s, 3H).