Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25](O)=[O:26].[CH3:32][C:33]1[CH:34]=[N:35][C:36]([C:39]2([NH2:42])[CH2:41][CH2:40]2)=[N:37][CH:38]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([C:25](=[O:26])[NH:42][C:39]2([C:36]3[N:35]=[CH:34][C:33]([CH3:32])=[CH:38][N:37]=3)[CH2:40][CH2:41]2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: Cc1cnc(C2(N)CC2)nc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)c(F)c12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncc(C)cn5)CC4)ccc3C)c(F)c12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.04 g, 0.095 mmol, 1 eq), 1-(5-methylpyrimidin-2-yl)cyclopropanamine (130 mg, crude), Py-Bop (0.064 g, 0.12 mmol, 1.3 eq), in DMF at ambient temperature under nitrogen was added triethylamine (0.029 g, 0.28 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.023 g (44%). 1H NMR (400 MHz, CDCl3): δ 8.64 (s, 2H), 8.14 (bs, 1H), 7.99-7.95 (m, 2H), 7.82 (dd, J=2.0, 8.0 Hz, 1H), 7.66 (bs, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.21-7.15 (m, 3H), 6.18 (bs, 1H), 3.03 (d, J=4.8 Hz, 3H), 2.35 (s, 3H), 2.24 (s, 3H), 1.92 (m, 2H), 1.67 (m, 2H). 19F NMR (376.47 MHz, CDCl3) δ −76.71 (TFA), −110.50, −120.06. LCMS: (ES+) m/z=553.2 (M+H)+
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].C(Cl)Cl.[CH2:10]([O:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][NH:19]2)=[CH:15][CH:14]=1)[CH3:11].[CH3:22][O-:23].[Na+].CO>CCOCC>[CH2:10]([O:12][C:13]1[CH:21]=[C:20]2[C:16]([C:17]([C:1](=[O:5])[C:2]([O:23][CH3:22])=[O:3])=[CH:18][NH:19]2)=[CH:15][CH:14]=1)[CH3:11]
Reactant: C[O-]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOc1ccc2cc[nH]c2c1
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: CCOc1ccc2c(C(=O)C(=O)OC)c[nH]c2c1
Temperature: 4 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
A 2.0 M solution of oxalyl chloride in methylene chloride (6.65 mL, 13.3 mmol) was added to a solution of 6-ethoxyindole (2.0 g, 12.4 mmol) in ether (25 mL) dropwise over 10 min at 4° C. under N2. The resulting mixture was stirred for 1 h at 4° C. A 25% (w/w) sodium methoxide in methanol solution (6.2 mL, 28.5 mmol) was added at −78° C. The mixture was allowed to warm up to room temperature and stirred for 4 h. The reaction was quenched with water (50 mL) and extracted with methylene chloride. The organic solution was dried (MgSO4) and concentrated at reduced pressure. The residue was stirred in a solution of EtOAc (50 mL) and ether (50 mL) for 10 min. Solid was collected by filtration to give the title compound (2.2 g, 73%) after drying. 1H NR (CDCl3) δ 8.20 (s, 1H), 7.90 (d, J=9 Hz, 1H), 6.92 (s, 1H), 6.82 (d, J=9 Hz, 1H), 4.00 (q, J=6.5 Hz, 2H), 3.78 (s, 3H), 1.30 (t, J=6.5 Hz, 3H)
Reaction SMILES: BrC1C=C(C)C(C(N2CCC(N3CCCC3)CC2)=O)=C(C)C=1.[CH3:23][C:24]1[C:29]([C:30]([N:32]2[CH2:37][CH2:36][CH:35]([N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[CH2:34][CH2:33]2)=[O:31])=[C:28]([CH3:43])[N:27]=[C:26]([C:44]2[CH:45]=[N:46][CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=2)[CH:25]=1.N1CCC(N2CCC[C@H]2[CH2:65][O:66][C:67](=[O:74])[C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)CC1>>[CH3:23][C:24]1[C:29]([C:30]([N:32]2[CH2:37][CH2:36][CH:35]([N:38]3[CH2:39][CH2:40][CH2:41][C@H:42]3[CH2:65][O:66][C:67](=[O:74])[C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[CH2:34][CH2:33]2)=[O:31])=[C:28]([CH3:43])[N:27]=[C:26]([C:44]2[CH:45]=[N:46][CH:47]=[C:48]([C:50]([F:52])([F:53])[F:51])[CH:49]=2)[CH:25]=1
Reactant: O=C(OC[C@@H]1CCCN1C1CCNCC1)c1ccccc1
Reactant: Cc1cc(-c2cncc(C(F)(F)F)c2)nc(C)c1C(=O)N1CCC(N2CCCC2)CC1
Agent: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCCC2)CC1
Product: Cc1cc(-c2cncc(C(F)(F)F)c2)nc(C)c1C(=O)N1CCC(N2CCC[C@H]2COC(=O)c2ccccc2)CC1

Procedure:
In analogy to the procedures described for intermediate 1 and for intermediate 4B,4,6-dimethyl-5′-trifluoromethyl-[2,3′]bipyridinyl-5-carboxylic acid (example 42) was converted into its acid chloride and reacted with benzoic acid (S)-1-piperidin-4-yl-pyrrolidin-2-ylmethyl ester (intermediate 3) to give benzoic acid (S)-1-[1-(4,6-dimethyl-5′-trifluoromethyl-[2,3′]bipyridinyl-5-carbonyl)-piperidin-4-yl]-pyrrolidin-2-ylmethyl ester, which was subsequently saponified to give the title compound as colorless amorphous solid. MS: 463.2 (MH+).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:38]1([CH2:44][CH2:45][OH:46])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36][N:41]5[CH2:42][CH2:43][N:38]([CH2:44][CH2:45][OH:46])[CH2:39][CH2:40]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCCl
Reactant: OCCN1CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCN1CCN(CCO)CC1
Temperature: 60 °C
Yield: 25.7 %

Procedure:
To a solution of (1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea from Example 27B (225 mg, 0.427 mmol) in DMF (3 mL) was added 2-piperazin-1-yl-ethanol (0.157 mL, 1.281 mmol) followed by diisopropylethylamine (0.223 mL, 1.281 mmol) and tetrabutylammonium iodide (157.72 mg, 0.427 mmol). The reaction mixture was heated at 60° C. for 2 days. Formation of the product was determined by LCMS. The crude reaction mixture was purified by preparative HPLC (using phenyl-hexyl reverse phase column eluted with gradient of solvent A=0.05% HOAc/H2O and solvent B=0.05% HOAc/CH3CN) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(3-(4-(2-hydroxyethyl)piperazin-1-yl)propoxy)-6-methoxyquinazolin-4-yloxy)phenyl)urea (68 mg, 26%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.45 (brs, 2H), 8.55 (s, 1H), 7.55 (d, 2H), 7.35 (d, 2H), 7.25 (d, 1H), 6.85 (d, 1H), 6.45 (s, 1H), 4.20 (m, 2H), 3.88 (s, 3H), 3.45 (m, 2H), 2.50-2.25 (m, 12H), 2.00 (m, 2H), 1.25 (s, 9H); LC-MS (ESI)m/z 620 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].[F:12][C:13]([F:18])([F:17])[CH2:14][CH2:15]I>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:15][CH2:14][C:13]([F:18])([F:17])[F:12])[N:6]=[C:5]2[I:11]
Reactant: FC(F)(F)CCI
Reactant: Clc1ccc2[nH]nc(I)c2c1
Product: FC(F)(F)CCn1nc(I)c2cc(Cl)ccc21
Yield: 39 %

Procedure:
The title compound was prepared in 39% yield from 5-chloro-3-iodo-indazole and 1,1,1-trifluoro-3-iodopropane according to the general procedure for Preparation 10A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 2.73-2.85 (2H, m), 4.59 (2H, t, J=7.2 Hz), 7.31 (1H, d, J=9.2 Hz), 7.43 (1H, dd, J=1.6, 8.4 Hz), 7.48 (1H, d, J=1.2 Hz).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Si:14]([CH3:17])([CH3:16])[CH3:15].C(O[B:22]1[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]1)(C)C.C(=O)=O.CC(C)=O.Cl>O1CCCC1.O>[F:6][C:7]1[C:12]([F:13])=[C:11]([B:22]2[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]2)[CH:10]=[CH:9][C:8]=1[Si:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: C[Si](C)(C)c1cccc(F)c1F
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OB(c2ccc([Si](C)(C)C)c(F)c2F)OC1(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
A 2.5 M solution of n-butyl lithium (9.5 mL, 24 mmol, 1.1 equiv) was added to a stirred solution of (2,3-difluorophenyl)trimethylsilane (4.0 g, 21 mmol, 1.0 equiv) in tetrahydrofuran (86 mL) at −78° C. The resulting very pale yellow solution was stirred at −78° C. for 1 h. 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.8 mL, 24 mmol, 1.1 equiv) was added and the pale yellow solution was allowed to slowly warm to 23° C., by allowing the dry ice/acetone bath to melt, and stirred for 20 h. The reaction mixture was diluted with water (200 mL), adjusted to approximately pH 4 using 1M hydrochloric acid, and extracted with dichloromethane (3×100 mL). The combined organic layers were dried (magnesium sulfate), gravity filtered, and concentrated by rotary evaporation to afford the title compound as a white powder (6.4 g, 96%): 1H NMR (400 MHz, CDCl3) δ 7.42 (ddd, J=7.5, 4.5, 0.5 Hz, 1H), 7.09 (ddd, J=7.5, 4, 1 Hz, 1H), 1.34 (s, 12H), 0.29 (d, J=1 Hz, 9H).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[N:9][CH:10]=1)[CH3:3].ClC1C=C(C=CC=1)C(OO)=[O:17].C(OCC)(=O)C.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>ClCCl>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[N+:9]([O-:17])[CH:10]=1)[CH3:1]
Reactant: Cc1ccc(OC(C)C)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(OC(C)C)c[n+]1[O-]
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 217.2 %

Procedure:
5-(1-methylethoxy)-2-methylpyridine (227 mg, 0.661 mmol) was dissolved in dichloromethane (7.5 mL), added 3-chloroperoxybenzoic acid (408 mg, 0.733 mmol) under ice-cold conditions, and the mixture was stirred at 0° C. for 45 minutes. The reaction solution was added ethyl acetate, saturated aqueous solution of sodium metabisulfite, and an aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (ethyl acetate), and 5-(1-methylethoxy)-2-methylpyridine 1-oxide (240 mg (yield 6%)) was obtained as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([C:11]2[NH:12][CH:13]=[CH:14][N:15]=2)=[C:5]([OH:10])[C:6]([CH3:9])=[N:7][CH:8]=1.CI.[C:18]([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[OH:1][CH2:2][C:3]1[C:4]([C:11]2[N:15]([CH3:18])[CH:14]=[CH:13][N:12]=2)=[C:5]([OH:10])[C:6]([CH3:9])=[N:7][CH:8]=1
Reactant: Cc1ncc(CO)c(-c2ncc[nH]2)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: Cc1ncc(CO)c(-c2nccn2C)c1O
Reaction time: 19 h

Procedure:
5-(hydroxymethyl)-4-(1H-imidazol-2-yl)-2-methylpyridin-3-ol (1.03 g, 5.0 mmol) was suspended in DMF (50 mL) and methyl iodide (0.31 mL, 5 mmol) was added at rt. The reaction mixture was stirred over a period of 19 h and a further portion of methyl iodide (0.125 mL, 2 mmol) was added and stirred over a period of 23 h. Aq. K2CO3 solution (10 mL) and water (50 mL) was added and extracted with ethyl acetate (2×50 mL). Combined organic layers were dried over MgSO4 (10 g) and evaporated to a volume of 20 mL. After 3 days at room temperature, the crystallized product was filtered off and dried to give (600 mg) the title compound as a light beige solid.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.C1(C)C=CC=CC=1.[CH2:27]([O:29][C:30](=[O:43])[C:31]([CH3:42])([CH3:41])[CH2:32][C:33](=O)[CH2:34][S:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH3:28].CC([O-])=O.[Na+]>O.C(O)(=O)C>[CH2:27]([O:29][C:30](=[O:43])[C:31]([CH3:42])([CH3:41])[CH2:32][C:33]1[N:8]([CH2:7][C:6]2[CH:18]=[CH:19][C:3]([Br:2])=[CH:4][CH:5]=2)[C:10]2[C:15]([C:34]=1[S:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH3:28]
Reactant: CCOC(=O)C(C)(C)CC(=O)CSC(C)(C)C
Reactant: COc1ccc(N(N)Cc2ccc(Br)cc2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OC)ccc2n1Cc1ccc(Br)cc1
Reaction time: 0.5 h

Procedure:
N-(4-Bromo-benzyl)-N-(4-methoxy-phenyl)-hydrazine hydrochloride (1.0 eq) was added to a reaction flask containing toluene (10.0-fold, V/W of starting material). To this reaction mixture was added acetic acid (5.0-fold, V/W of starting material), followed by 5-tert-butylsulfanyl-2,2-dimethyl-4-oxo-pentanoic acid ethyl ester (1.05 eq) and NaOAc (2.3 eq). The reaction mixture was agitated at room temperature for about 4 days after which cold water (15.0-fold, V/W of starting material) was added to the reaction and stirred for about 30 minutes. The organic layer was collected and the aqueous layer washed with toluene to recover additional product. The organic portions were collected and washed with water and saturated brine solution. The organic layer was subsequently dried over Na2SO4 and concentrated under reduced pressure. A slurry of collected compound was made with methanol (5.0-fold, V/W of starting material) at 0-5° C. for about 4 hours. The solid was collected and washed with cold methanol. Any remaining solvent was removed by drying under reduced pressure.
Reaction SMILES: ClCC([NH:5][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([NH:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[O:18])([CH2:9]3)[CH2:7]1)[CH2:13]2)=O.NC(N)=S.C(O)C.[OH-].[Na+]>O.C(O)(=O)C>[NH2:5][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([NH:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[O:18])([CH2:9]3)[CH2:7]1)[CH2:13]2
Reactant: O=C(CCl)NC12CC3CC(C1)CC(NC(=O)c1ccccn1)(C3)C2
Agent: NC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: NC12CC3CC(C1)CC(NC(=O)c1ccccn1)(C3)C2
Temperature: 78 °C
Reaction time: 8 h
Yield: 102.6 %

Procedure:
To a 40 ml vial containing pyridine-2-carboxylic acid [3-(2-chloro-acetylamino)adamantan-1-yl]-amide (1.69 g, 4.85 mmol, from step 2) and thiourea (0.56 g, 7.4 mmol), was added ethanol (20.0 mL), and acetic acid (4.0 mL). The mixture was stirred at 78° C. overnight. The reaction solution was cooled to rt, poured into water (100 mL), and the pH of the solution was adjusted to 10-13 using 10 N aq. NaOH. The mixture was transferred into a separation funnel, extracted with DCM (3×150 mL). Combined organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to afford 1.35 g (95.4%) of crude title compound, pyridine-2-carboxylic acid (3-amino-adamantan-1-yl)-amide, as an oil, which became a colorless solid upon standing at room temperature. LC-MS (Gradient: acetonitrile in water, 10-85%, in 1.7 minutes with a cycle time of 2 min. Flow rate: 5.0 mL/min. Mobile phase additive: 30 mM of ammonium formate. Column: Inertsil® C8, 50×4.6 mm, 3 μm particle size (GL Sciences, Tokyo, Japan)): Retention time: 0.63 min; purity (UV254): 93%; ESI-MS m/z: 272 (M+H)+. It was used in the next step, amidation, without further purification.
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:12]([N:4]1[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]([O:1][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:3]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1c[nH]nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
A mixture of ethyl 3-hydroxy-1H-pyrazole-4-carboxylate (11.53 g), benzyl bromide (18 ml), potassium carbonate (21.12 g), and N,N-dimethylformamide (300 ml) was stirred for 5 hours at 80° C. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with diluted hydrochloric acid and then with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 1-benzyl-3-benzyloxy-1H-pyrazole-4-carboxylate (13.52 g, yield: 95%) was obtained as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 71–72° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]=[C:4]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:3]=1.Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][O:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=3)[N:5]=[C:4]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:3]=2)=[CH:24][CH:25]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)c1cc(O)c2cc(C(F)(F)F)ccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1cc(OCc2ccc(OC)cc2)c2cc(C(F)(F)F)ccc2n1
Temperature: 70 °C

Procedure:
An acetonitrile solution of ethyl 4-hydroxy-6-(trifluoromethyl)quinoline-2-carboxylate (50 g, 175 mmol) and 1-(chloromethyl)-4-methoxybenzene (33 ml, 245 mmol), is treated with Cs2CO3 (80 g, 245 mmol) and heated at 70° C. for 18 h. Salts were removed by filtration and the solvent removed under vacuum. The residue was dissolved in EtOAc and washed with water and sat NaCl. Organic layer dried over Na2SO4 and evaporated under vacuum. The resulting solid was recrystallized from EtOAc/Hex to give the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][CH:16]1[CH2:19][C:18]2([CH2:23][C:22]([C:24]3[CH:29]=[N:28][C:27]4[N:30](CC5C=CC(OC)=CC=5)[N:31]=[CH:32][C:26]=4[C:25]=3[NH:42][CH:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)=[N:21][O:20]2)[CH2:17]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClC(Cl)C.C(OCC)(=O)C>[CH2:8]([O:15][CH:16]1[CH2:19][C:18]2([CH2:23][C:22]([C:24]3[CH:29]=[N:28][C:27]4[NH:30][N:31]=[CH:32][C:26]=4[C:25]=3[NH:42][CH:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)=[N:21][O:20]2)[CH2:17]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COc1ccc(Cn2ncc3c(NC4CCOCC4)c(C4=NOC5(C4)CC(OCc4ccccc4)C5)cnc32)cc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: c1ccc(COC2CC3(CC(c4cnc5[nH]ncc5c4NC4CCOCC4)=NO3)C2)cc1

Procedure:
Trifluoroacetic acid (0.41 gm, 3.61 mmol) was added to the solution of 5-[2-(benzyloxy)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1-(4-methoxybenzyl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (0.4 gm, 0.72 mmol) (step a) in dichloroethane (5 ml) and the reaction mixture was refluxed for about 2 hours under inert atmosphere. It was cooled, diluted with ethyl acetate, washed with saturated sodium bicarbonate, water and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:10][C:11]([CH:13]2[CH2:17][CH:16]([O:18][C:19]3[C:28]4[C:23](=[C:24]([Cl:38])[C:25]([O:29][CH2:30][CH2:31][N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[CH:26][CH:27]=4)[N:22]=[C:21]([C:39]4[N:40]=[C:41]([NH:44][CH:45]([CH3:47])[CH3:46])[S:42][CH:43]=4)[CH:20]=3)[CH2:15][N:14]2[C:48](=[O:64])[CH:49]([NH:54][C:55]([O:57][CH:58]2[CH2:63][CH:62]3[CH:60]([CH2:61]3)[CH2:59]2)=[O:56])[C:50]([CH3:53])([CH3:52])[CH3:51])=[O:12])[CH2:7][CH:6]1[CH2:8][CH3:9])=[O:4].[Li+].[OH-].CO.Cl>O>[CH:60]12[CH2:61][CH:62]1[CH2:63][CH:58]([O:57][C:55]([NH:54][CH:49]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:48]([N:14]1[CH2:15][CH:16]([O:18][C:19]3[C:28]4[C:23](=[C:24]([Cl:38])[C:25]([O:29][CH2:30][CH2:31][N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[CH:26][CH:27]=4)[N:22]=[C:21]([C:39]4[N:40]=[C:41]([NH:44][CH:45]([CH3:46])[CH3:47])[S:42][CH:43]=4)[CH:20]=3)[CH2:17][CH:13]1[C:11]([NH:10][C:5]1([C:3]([OH:4])=[O:2])[CH2:7][CH:6]1[CH2:8][CH3:9])=[O:12])=[O:64])=[O:56])[CH2:59]2
Reactant: CCC1CC1(NC(=O)C1CC(Oc2cc(-c3csc(NC(C)C)n3)nc3c(Cl)c(OCCN4CCOCC4)ccc23)CN1C(=O)C(NC(=O)OC1CC2CC2C1)C(C)(C)C)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC1CC1(NC(=O)C1CC(Oc2cc(-c3csc(NC(C)C)n3)nc3c(Cl)c(OCCN4CCOCC4)ccc23)CN1C(=O)C(NC(=O)OC1CC2CC2C1)C(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 92.9 %

Procedure:
1-({1-[2-(Bicyclo[3.1.0]hex-3-yloxycarbonylamino)-3,3-dimethylbutyryl]-4-[8-chloro-2-(2-isopropylaminothiazol-4-yl)-7-(2-morpholin-4-yl-ethoxy)quinolin-4-yloxy]pyrrolidine-2-carbonyl}-amino)-2-ethyl-cyclopropanecarboxylic acid methyl ester (12 g, 13 mmol) was dissolved in TI-IF (200 ml), LiOH (11 g, 260 mmol) in H2O (200 ml) was added, followed by MeOH (200 ml). The mixture was kept stirring at room temperature for 20 h. Upon completion of the reaction, 4 N HCl in H2O was added to adjust pH to 7 at 0° C. The mixture was extracted with EtOAc (2×400 ml). The combined organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo to give 1-({1-[2-(bicyclo[3.1.0]hex-3-yloxycarbonylamino)-3,3-dimethyl-butyryl]-4-[8-chloro-2-(2-isopropylamino-thiazol-4-yl)-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-pyrrolidine-2-carbonyl}-amino)-2-ethyl-cyclopropanecarboxylic acid as a yellow solid (11 g, 93% yield). LCMS found 911.52 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[N:19]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:20]3[C:25]([N:26]=2)=[CH:24][N:23]=[CH:22][N:21]=3)[CH2:13][CH2:12]1.C(=O)([O-])O.[Na+]>C(O)C>[F:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][N:19]2[C:18]([NH:17][CH:14]3[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][NH:8][C:2]4[N:7]=[CH:6][CH:5]=[CH:4][N:3]=4)[CH2:16][CH2:15]3)=[N:26][C:25]3[C:20]2=[N:21][CH:22]=[N:23][CH:24]=3)=[CH:33][CH:32]=1
Reactant: Clc1ncccn1
Reactant: NCCN1CCC(Nc2nc3cncnc3n2Cc2ccc(F)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Fc1ccc(Cn2c(NC3CCN(CCNc4ncccn4)CC3)nc3cncnc32)cc1
Yield: 67 %

Procedure:
A mixture of 1.7 parts of 2-chloropyrimidine, 5.5 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-9-[(4-fluorophenyl)methyl]-9H-purin-8-amine, 1.5 parts of sodium hydrogen carbonate and 160 parts of ethanol was stirred and refluxed for 20 hours. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 4.5 parts (67%) of 9-[(4-fluorophenyl)methyl]-N-[1-[2-(2-pyrimidinylamino)ethyl]-4-piperidinyl]-9H-purin-8-amine; mp. 164.1° C. (compound 164).