Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:15]3[CH:16]=[CH:17][C:18]4[C:22]([CH:23]=3)=[N:21][N:20]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:19]=4)[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13]O)[N:6]2[N:5]=[CH:4][N:3]=1.C(Br)(Br)(Br)[Br:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(C)=O>C1COCC1>[CH2:24]([N:20]1[CH:19]=[C:18]2[C:22]([CH:23]=[C:15]([C:8]3[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][Br:32])[N:6]4[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)[CH:16]=[CH:17]2)=[N:21]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrC(Br)(Br)Br
Reactant: Nc1ncnn2c(CCCO)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ncnn2c(CCCBr)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.3 %

Procedure:
To a solution of 3-[4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]propan-1-ol (step 4, example 24, 3.40 g, 8.53 mmol) in anhydrous THF (85 mL) at 0° C. was added carbon tetrabromide (3.68 g, 11.0 mmol, 1.3 eq) and triphenylphosphine (2.46 g, 9.4 mmol, 1.1 eq), and the reaction mixture was stirred at RT for 16 h. The reaction was poured into EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated at reduced pressure. The crude product was purified by MPLC eluted with 15% acetone/DCM to give 2.45 g (62.4%) of desired product as a white solid. 1H-NMR (DMSO-d6) 8.52 (s, 1H), 7.89 (s, 1H), 7.78 (d, 1H), 7.57 (s, 1H), 7.15 to 7.35 (m, 5H), 7.13 (d, 1H), 6.62 (s, 1H), 5.74 (s, 2H), 3.61 (t, 2H), 3.03 (t, 2H), 2.22 to 2.26 (m, 2H); LC-MS [M+H]+=461/463, RT=3.16 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][N:3]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10](=[O:12])[CH3:11])=[CH:4][N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(CO)cn1
Solvent: c1ccncc1
Product: CC(=O)OCc1ccc(C)nc1

Procedure:
2-Methyl-5-hydroxymethylpyridine (0.1 mole) is stirred in pyridine (50 ml.) with acetic anhydride (0.15 mole) at room temperature overnight. The mixture is concentrated to dryness, and the residue is dissolved in 70 ml. of water and extracted with 3×25 ml. of chloroform. After drying over magnesium sulfate, the chloroform is concentrated to dryness to give 2-methyl-5-acetoxymethylpyridine.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]1=[O:9].[OH2:10]>>[O:8]=[C:7]([CH2:2][CH3:1])[CH2:6][CH2:5][CH2:4][C:3]([OH:9])=[O:10]
Reactant: CC1C(=O)CCCC1=O
Reactant: O
Product: CCC(=O)CCCC(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A modification of the procedure of Ijima et al. Chem. Pharm. Bull. 19, 1053-5 (1971) was used. A solution of 2-methyl-1,3-cyclohexanedione (40 g, 0.317 mole, Aldrich) and Ba(OH)2.8H2O (360 g) in water (840 mL) was heated at reflux for 48 h. After standing overnight at room temperature and cooling to 0° C., the precipitated barium hydroxide was removed by suction filtration. CO2 gas (generated from Dry Ice) was bubbled through the filtrate to precipitate any remaining barium hydroxide as barium carbonate. The precipitate was removed by suction filtration, and water was removed in vacuum until crystallization started. The resulting mixture was acidified to pH 1 (conc. HCl) and extracted with OEt2 (3×300 mL). The extract was dried (Na2SO4) and stripped of solvent in vacuum giving 5-oxoheptanoic acid (Compound XXI) as a white solid (43.3-45.1 g, 95-99%, lit.112 69%): mp 48°-49.5° C. (lit.182 50° C.); IR (KBr pellet) cm-1 3000 (very br), 1725, 1710, 1690, 1460, 1435, 1420, 1380, 1340, 1280, 1210, 1120, 1085, 985, 910, 770, 685; 1H NMR (200 MHz, CDCl3) δ 10.2 (br, 1H), 2.51 (t, 7.1 Hz, 2H), 2.43 (q, 7.3 Hz, 2H), 2.40 (t, 7.1 Hz, 2H), 1.91 (rough pentet, 2H), 1.06 (t, 7.3 Hz, 3H); 13C NMR (22.5 MHz, CDCl3) δ 211.5, 178.6, 41.0, 36.0, 33.1, 18.7, 7.8; mass spectrum (16 eV) m/e (% base) 144 (M+, 4.1), 126 (61.3), 115 (88.8), 98 (40.0), 87 (40.1), 70 (21.3), 57 (100); TLC (OEt2, I2) Rf=0.37.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([NH2:17])([CH3:16])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[O:24]1[CH2:29][CH2:28][CH:27]([C:30](O)=[O:31])[CH2:26][CH2:25]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:16])([NH:17][C:30]([CH:27]2[CH2:28][CH2:29][O:24][CH2:25][CH2:26]2)=[O:31])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: O=C(O)C1CCOCC1
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)N)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)NC(=O)C3CCOCC3)c2c1N

Procedure:
Prepared as in Example 24a from ethyl 4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate (Example 24b) and tetrahydro-2H-pyran-4-carboxylic acid as a pale-yellow solid (63%). MS 430 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[CH:6]=[CH:5]2.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)O1>>[N:15]1([CH2:14][CH2:13][O:12][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH:3]=[C:2]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH:11]=[CH:10]3)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Reactant: Brc1ccc2cc(OCCN3CCCC3)ccc2c1
Product: c1cncc(-c2ccc3cc(OCCN4CCCC4)ccc3c2)c1

Procedure:
The product from Example 37B and 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine were processed as described in Example 38, except that a second column chromatography was done to provide 10 mg of the title compound. 1HNMR (300 MHz, CD3OD) δ 1.86 (m, 4H), 2.74 (m, 4H), 3.02 (t, 2H), 4.29 (t, 2H), 7.23 (dd, 1H), 7.31 (d, 1H), 7.56 (ddd, 1H), 7.76 (dd, 1H), 7.86-7.93 (m, 2H), 8.10 (d, 1H), 8.20 (ddd, 1H), 8.52 (dd, 1H), 8.91 (dd, 1H); MS (ESI) m/z 319 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2.O.C(=O)([O-])[O-:18].[K+].[K+]>COCCOC>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]([OH:18])[CH2:10][CH:9]=[CH:8]2
Reactant: COC(=O)Cc1ccc2ncccc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1ccc2c(c1)C=CCN2O
Reaction time: 2 h

Procedure:
m-Perchlorobenzoic acid (6.85 g, 39.8 mmol) was added to a solution of commercially available quinolin-6-yl-acetic acid methyl ester (5.00 g, 24.8 mmol) in 1,2-dimethoxyethane at room temperature and stirred for 2 hours. Water was added and the solution was basified to pH 9-10 with saturated potassium carbonate and the product was extracted with ethyl acetate to give quantitative yield of (1-hydroxy-quinolin -6-yl)-acetic acid methyl ester. 1H NMR (400 MHz, CDCl3) δ 7.99 (d, 1H, J=8.4 Hz), 7.93 (d, 1H, J=8.4 Hz), 7.65 (m, 1H), 7.60 (m, 1H), 7.32 (d, 1H, J=8.8 Hz), 7.19 (s, 1H), 3.74 (s, 2H), 3.65 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.Cl[C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1.CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.[Cu]I>[Br:1][C:2]1[C:3]([O:16][C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2
Reactant: CC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C
Reactant: Cc1ccnc(Cl)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(Br)c(Oc3cc(C)ccn3)c2CC[C@@H]1C
Temperature: 120 °C
Yield: 42.3 %

Procedure:
A 20-mL microwave tube was charged with 1-[(2S)-6-bromo-5-hydroxy-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one (200 mg, 0.70 mmol), 2-chloro-4-methylpyridine (180 mg, 1.41 mmol), N,N-dimethylformamide (15 mL), copper (I) iodide (133 mg, 0.70 mmol), and cesium carbonate (700 mg, 2.10 mmol). The reaction mixture was heated with microwave radiation for 8 h at 120° C. After cooling to room temperature, the resulting mixture was diluted with ethyl acetate (50 mL), washed with water (3×15 mL) and brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified via column chromatography on silica gel (eluting with 2:1, ethyl acetate/petroleum ether) to afford 1-[(2S)-6-bromo-2-methyl-5-[(4-methylpyridin-2-yl)oxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one (111 mg, 42%) as a light yellow solid. MS (ESI, pos. ion) m/z 375, 377 [M+H]+.
Reaction SMILES: C(O[K])(C)(C)C.O1CCCC1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21]Cl)=[CH:15][CH:14]=1>O>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]=[CH2:21])=[CH:15][CH:14]=1
Reactant: ClCCOc1ccc(Br)cc1
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Solvent: O
Product: C=COc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 78.7 %

Procedure:
Tert-Butoxypotassium (33.7 g, 300 mmol) was added to a solution of tetrahydrofuran (hereinafter THF) (250 mL) containing 1-bromo-4-(2-chloroethoxy)benzene (58.6 g, 249 mmol) prepared in Example 6 (6a) over 10 minutes at −10° C. The mixture was stirred at room temperature for 21 hours, and water (500 mL) was added thereto. The resulting mixture was extracted with methyl tert-butyl ether (200 mL, 150 mL) twice. The organic layers were combined, washed with saturated brine (100 mL) twice, and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated. The resulting residue was dissolved in hexane (100 mL), and the precipitated insoluble substance was removed by filtration. The insoluble substance was further washed with hexane (5 mL) five times. The filtrates were combined, concentrated, and purified by silica gel column chromatography (hexane) to give 39.0 g of the title compound (colorless oil, yield: 79%).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].OS(O)(=O)=O.[CH3:21]O>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH3:15])[C:12]([O:14][CH3:21])=[O:13])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)c1ccc(CC(C)C)cc1

Procedure:
To a solution of 2-(4-isobutyl-phenyl)-propionic acid (5.00 g, 24.2 mmol) in anhydrous MeOH (150 mL) was added conc H2SO4 (catalytic) and heated to reflux for 5 hrs. After cooling, the solution was evaporated to dryness, the residue dissolved in methylene chloride, dried (MgSO4), filtered and evaporated to yield methyl 2-(4isobutyl-phenyl)-propionate as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.19 (2H, d, J=8,1 Hz), 7.09 (2H, d, J=8.1 Hz), 3.71 (1H, q, J=7.2 Hz), 3.66 (3H, s), 2.44 (2H, d, J=7.2 Hz), 1.84 (1H, app. septet, J=6.7 Hz), 1.48 (3H, d, J=7.2 Hz), 0.90 (6H, d, J=6.6 Hz).
Reaction SMILES: N1C=CN=C1.[OH:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([CH3:15])[CH:14]=1)[CH:10]=[O:11].Cl[Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19].O>C(OCC)C>[CH3:15][C:13]1[CH:12]=[C:9]([CH:8]=[C:7]([O:6][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])[CH:14]=1)[CH:10]=[O:11]
Reactant: Cc1cc(O)cc(C=O)c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOCC
Product: Cc1cc(C=O)cc(O[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
After adding 1.11 g of imidazole to a solution of 2.02 g of 3-hydroxy-5-methylbenzaldehyde [CAS No. 60549-26-0] in 20 ml of DIVEF, the reaction mixture was cooled to 0° C. Next, 3.56 ml of chlorotriisopropylsilane was added and the mixture was stirred at room temperature for 19 hours and 10 minutes. Water was added to the reaction mixture, and extraction was performed twice with diethyl ether. The organic layer was washed twice with water and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-diethyl ether) to give the title compound (3.86 g) as a yellow oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:19]=[CH:18][C:7]2[NH:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[CH:5]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([S:30](Cl)(=[O:32])=[O:31])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].O>CN(C=O)C>[Cl:3][C:4]1[CH:19]=[CH:18][C:7]2[N:8]([S:30]([C:24]3[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:22]([O:21][CH3:20])[CH:23]=3)(=[O:32])=[O:31])[C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[CH:5]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: O=c1[nH]c2ccc(Cl)cc2n1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(S(=O)(=O)n2c(=O)n(-c3ccccc3)c3cc(Cl)ccc32)cc1OC
Reaction time: 0.5 h

Procedure:
66 mg of sodium hydride as an 80% dispersion in oil were added in portions to a solution of 490 mg of 5-chloro-1,3-dihydro-3-phenyl-2H-benzimidazol-2-one in 5 ml of DMF and the reaction medium was stirred for 30 minutes. 520 mg of 3,4-dimethoxybenzenesulfonyl chloride were then introduced and the reaction medium was stirred overnight at room temperature. The solvent was then evaporated off under vacuum and the residue obtained was taken up with water. It was then extracted with DCM, washed with water and then dried over sodium sulfate and the solvent was evaporated off to dryness. The residue obtained was chromatographed on silica using a DCM/AcOEt mixture (95/5; v/v) as the eluent to give the expected product in the form of a white solid, which crystallized from absolute EtOH. m=0.71 g. M.p.=154° C.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([N:6]1[CH2:10][CH2:9][N:8]=[C:7]1SC)=[O:5].[NH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>O>[N:18]1([N:17]2[C:2]3[C:3](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:4](=[O:5])[N:6]3[CH2:10][CH2:9][N:8]=[C:7]23)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: CSC1=NCCN1C(=O)c1ccccc1F
Reactant: NN1CCOCC1
Solvent: O
Product: O=C1c2ccccc2N(N2CCOCC2)C2=NCCN12
Yield: 74 %

Procedure:
A solution of 10.0 g (42.0 mmoles) of the product of Example 1 in 50 ml of N-aminomorpholine was heated to reflux for 10 minutes. The clear solution deposited crystals on cooling. This mixture was diluted with water (100 ml) and a white, crystalline solid was collected, washed with water, and air-dried to give 8.47 g of 2,10-dihydro-10-(4-morpholinyl)imidazo[2,1-b]quinazolin-5(3H)-one. Melting point 250°-251° C. Total yield 74%. This compound exhibits the following formula ##STR5##
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].Cl.[CH:21]([NH:23][CH2:24][CH:25]1[O:30][CH2:29][CH2:28][NH:27][CH2:26]1)=[O:22].N12CCCN=C1CCCCC2>C(#N)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:27]3[CH2:28][CH2:29][O:30][CH:25]([CH2:24][NH:23][CH:21]=[O:22])[CH2:26]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: O=CNCC1CNCCO1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCOC(CNC=O)C3)c(F)c21
Reaction time: 8 h

Procedure:
A solution of 813 mg of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 650 mg of 2-(formylaminomethyl)morpholine hydrochloride and 1.0 g of 1,8-diazabicyclo[5.4.0]undec-7-ene in 10 ml of acetonitrile is refluxed for 3 hours and allowed to stand at room temperature overnight. The precipitated crystals are collected by filtration and successively washed with acetonitrile, water and acetone to give 1-ethyl-6,8-difluoro-7-[2-(formylaminomethyl)morpholino]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, melting at 234°-236° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([NH:11]C(=O)OC(C)(C)C)=[CH:8][C:6]=2[N:7]=1.FC(F)(F)C(O)=O.ClCCl>>[Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([NH2:11])=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Yield: 99.3 %

Procedure:
Tert-butyl 2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-ylcarbamate (800 mg) was treated with 5 mL of trifluoroacetic acid/dichloromethane (1:1). The reaction mixture was stirred at room temperature until complete. The reaction mixture was evaporated. The residue was diluted with ethyl acetate (100 mL), washed with saturated sodium bicarbonate (50 mL) and brine (50 mL). The aqueous layer was back-extracted with ethyl acetate (2×60 mL), and then washed with saturated sodium bicarbonate and brine. The combined organic layers were dried over MgSO4, filtered and evaporated to afford 580 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-amine.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([C:10](=[O:15])[C:11](Br)([CH3:13])[CH3:12])[CH:4]=1>C(O)C.C1C=CC=CC=1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]2[O:9][C:11]([CH3:13])([CH3:12])[C:10](=[O:15])[C:5]=2[CH:4]=1
Reactant: CC(C)(Br)C(=O)c1cc(Cl)ccc1O
Agent: [Na]
Solvent: c1ccccc1
Solvent: CCO
Product: CC1(C)Oc2ccc(Cl)cc2C1=O
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 82.5 %

Procedure:
With stirring under ice-cooling, 3 g of metallic sodium were added in 100 ml of absolute ethanol to dissolve the metal. Then, 12.5 g (0.045 mol) of 4-chloro-2-(2-bromoisobutyryl)phenol dissolved in 60 ml of benzene was added to the said solution dropwise for about 15 minutes under heating to reflux (internal temperature: 80° C.). After the completion of the dropping, the stirring was continued for additional 30-60 minutes with heating and the solution was vacuum-concentrated to one third in volume. The solution concentrated was diluted with large amount of water, and the solution was extracted with ether. The ether layer was washed with water, then vacuum-concentrated to dryness to produce 10 g of crude crystallized subject compound, 5-chloro-2,2-dimethyl-4-benzofuran. Then, the crude product was recrystallized from methanol, to obtain 7.3 g (yield: 82.5%) of the subject compound in colorless pillow crystal.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=O.[NH:11]1[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH2:1][N:11]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12]2)=[CH:4][CH:5]=1)#[N:8]
Reactant: COC(=O)C1CNC1
Reactant: N#Cc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(=O)C1CN(Cc2ccc(C#N)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
A mixture of 4-formylbenzonitrile (510 mg, 3.89 mmol), methyl azetidine-3-carboxylate (590 mg, 3.89 mmol), acetic acid (0.245 mL, 4.28 mmol) and ˜1 gm of powdered 4 Angstrom molecular sieves in DCE (15 mL) was stirred briskly at RT for 1 hr. At this time, sodium triacetoxyborohydride (907 mg, 4.28 mmol) was added and the reaction mixture was stirred at RT for 2 hr. After filtering through a sintered glass funnel, the filtrate was concentrated to a residue that was partitioned between EtOAc (50 mL) and saturated sodium bicarbonate solution (50 mL). The organic layer was washed with brine (50 mL), dried (MgSO4) and concentrated to afford a colorless oil that was chromatographed on a 12 gm Isco silica gel cartridge, eluting with a 0-100% EtOAc/Hex gradient. The essentially pure fractions were concentrated to afford methyl 1-(4-cyanobenzyl)azetidine-3-carboxylate (765 mg, 3.32 mmol). HPLC retention time=0.49 minutes [broad peak] (PHENOMENEX® Luna 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1% TFA over a 2 minute gradient. MS:(M+H)=231.23. 1H NMR (400 MHz, CDCl3) δ ppm 3.32-3.36 (m, 3H) 3.49-3.58 (m, 2H) 3.67 (s, 2H) 3.72 (s, 3H), 7.39 (d, J=8.6 Hz, 2H) 7.60 (d, J=8.3 Hz, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.F[C:16]1[C:21]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:20][N:19]=[C:18]2[NH:27][CH:28]=[C:29]([NH:30][C:31]([CH:33]3[CH2:35][CH2:34]3)=[O:32])[C:17]=12>C(O)(CC)C>[CH:33]1([C:31]([NH:30][C:29]2[C:17]3[C:18](=[N:19][CH:20]=[C:21]([O:22][CH2:23][CH2:24][O:25][CH3:26])[C:16]=3[N:1]3[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]3)[NH:27][CH:28]=2)=[O:32])[CH2:34][CH2:35]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: COCCOc1cnc2[nH]cc(NC(=O)C3CC3)c2c1F
Solvent: CCC(C)O
Product: COCCOc1cnc2[nH]cc(NC(=O)C3CC3)c2c1N1CCC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 150 °C
Reaction time: 24 h
Yield: 46.7 %

Procedure:
(R)-tert-Butyl piperidin-3-ylcarbamate (307 mg, 1.53 mmol) was added to N-(4-fluoro-5-(2-methoxyethoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (150 mg, 0.511 mmol) in s-BuOH (3 mL), and the reaction was stirred at 150° C. for 24 hours in a sealed tube. After cooling down and concentration, the residue was purified by reverse phase chromatography (SP4, 25M, water/ACN 90/10→0/100, 30 CV) to yield (R)-tert-butyl 1-(3-(cyclopropanecarboxamido)-5-(2-methoxyethoxy)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (113 mg, 46.7% yield) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9][CH2:10][OH:11])=[C:4]([F:12])[CH:3]=1.N1C=CC=CC=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>ClCCl.CN(C)C1C=CN=CC=1>[C:19]([O:11][CH2:10][CH2:9][C:5]1[C:4]([F:12])=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[F:8])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: OCCc1c(F)cc(Br)cc1F
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCCc1c(F)cc(Br)cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 84.9 %

Procedure:
A solution of 2-(4-bromo-2,6-difluorophenyl)ethanol (1.392 mmol) in dichloromethane (2 mL) was treated with pyridine (4.00 mL), acetic anhydride (4.18 mmol), and 4-(dimethylamino)pyridine (0.070 mmol). The reaction was stirred at room temperature for three days. At this point, the reaction contents were concentrated to in vacuo to minimum volume. The material was diluted with water (50 mL) and was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aq sodium bicarbonate, twice with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a beige oil (330 mg, 76% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.95 (s, 3 H) 2.91 (t, J=6.32 Hz, 2 H) 4.18 (t, J=6.44 Hz, 2 H) 7.47 (d, J=7.07 Hz, 2 H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11]C(OCC2C=CC=CC=2)=O)=[CH:5][C:4]=1[F:22])#[N:2].C(Cl)Cl.[H][H]>C1COCC1.[Pd]>[NH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:22])[CH:5]=1
Reactant: [H][H]
Reactant: N#Cc1ccc(CCNC(=O)OCc2ccccc2)cc1F
Agent: [Pd]
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#Cc1ccc(CCN)cc1F
Yield: 100 %

Procedure:
Into a 100 mL single neck flask were placed N-[2-(4-cyano-3-fluorophenyl)ethyl](phenylmethoxy)carboxamide (2 g, 6.7 mmol) in THF: MeOH (25:25 mL). The mixture was treated with a 10% palladium on carbon (0.5 g, 25 mol%) and stirred under the hydrogen balloon for 12 hour. The reaction mixture was filtered through a Celite® cake. The filtrate was concentrated under reduced vacuum to provide the intermediate title compound, 4-(2-aminoethyl)-2-fluorobenzenecarbonitrile, (1.1 g, 100%) as a white solid. Electron spray M.S. 165 (M*+1).