Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:8]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[O:10][CH:11]=1)(=O)=O.[CH3:21][OH:22].C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(N(CC)CC)C.CN([CH:62]=[O:63])C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[O:10][CH:11]=[C:7]([C:21]([O:63][CH3:62])=[O:22])[N:8]=2)=[CH:13][CH:14]=1
Reactant: O=S(=O)(Oc1coc(-c2ccc(F)cc2)n1)C(F)(F)F
Reactant: CO
Reactant: CN(C)C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1coc(-c2ccc(F)cc2)n1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(4-fluorophenyl)-1,3-oxazol-4-yl trifluoromethanesulfonate (30 g, 96 mmol, WO2010/017079A1) in DMF (200 ml) was added methanol (78 ml, 1928 mmol) followed by palladium (II) acetate (2.164 g, 9.64 mmol) and dppp (3.98 g, 9.64 mmol). Triethylamine (26.9 ml, 193 mmol) was added and the reaction mixture was purged with CO for 3 minutes, placed under balloon pressure of CO, stirred at 65° C. for 2 h, allowed to cool to room temperature and poured onto ice water. The reaction mixture was extracted with DCM, dried over Na2SO4, filtered, concentrated and purified by flash chromatography (silica, 10-50% EtOAc/heptanes) to provide methyl 2-(4-fluorophenyl)-1,3-oxazole-4-carboxylate (7.4 g).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.O=P(Cl)(Cl)Cl.CN([CH:22]=[O:23])C.CC([O-])=O.[Na+].[OH-].[Na+]>ClC(Cl)C>[CH:22]([C:3]1[C:4]2[C:5]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=[CH:8][C:9]=2[NH:1][CH:2]=1)=[O:23]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cccc2[nH]ccc12
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: COC(=O)c1cccc2[nH]cc(C=O)c12
Temperature: 50 °C

Procedure:
A solution of methyl indole-4-carboxylate (250 mg, 1.43 mmol) in dichloroethane (2 mL) was treated with a solution of POCl3-DMF (1.5 equivalent (eq)) at room temperature (rt). The orange solution was heated at 50° C. for 1 hour. The reaction solution was poured into ice-cold aqueous (aq.) NaOAc (1 g in 2 mL), the aqueous solution was adjusted to pH=8 with 1M NaOH, and extracted with EtOAc (10 mL×3). The organic solution was washed with water and brine, dried (Na2SO4), filtered, and concentrated to give methyl 3-formyl-indole-4-carboxylate as an oil, 271 mg (93%). 1H NMR (300 MHz, d6-DMSO) δ 3.68 (s, 3H), 7.16 (t, 1H, J=7.8 Hz), 7.40 (dd, 1H, J=7.8, 0.8 Hz), 7.56 (d, 1H, J=7.8, 0.8 Hz), 8.16 (d, 1H, J=3.2 Hz), 10.00 (s, 1H), 12.30 (br s, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH3:19])=[CH:10][N:11]2[CH2:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl.C(Cl)Cl>CO.O>[CH3:18][O:17][CH2:16][CH2:15][CH2:14][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:13]=2)[C:9]([CH3:19])=[CH:10]1
Reactant: COCCCn1cc(C)c2ccc(C(=O)OC)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COCCCn1cc(C)c2ccc(C(=O)O)cc21
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(3-methoxy-propyl)-3-methyl-1H-indole-6-carboxylic acid methyl ester (1.56 g, 6.3 mmol) in MeOH (20 mL) and H2O (1 mL) is added NaOH (756 mg, 18.9 mmol) and the mixture is stirred at 50° C. overnight. Then neutralized by the addition of water and HCl 1.0 M (3 eq, 18.9 mmol). CH2Cl2 is added, the layers are separated, and the aqueous one is extracted twice with CH2Cl2. The combined organic layers are dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material is obtained in a pure form and is used in the next step without purification. MS (LC-MS): 248.0 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 4.93 min.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].N1C=CC=CC=1.[N+:24]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)C(Cl)=O)([O-:26])=[O:25]>C(Cl)(Cl)Cl>[CH3:12][O:11][C:9]1[C:8]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([NH:1][C:34]2[CH:33]=[CH:29][CH:28]=[C:27]([N+:24]([O-:26])=[O:25])[CH:35]=2)[CH:10]=1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: COCCOc1cc(C(N)=O)c(N)cc1OC
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COCCOc1cc(C(N)=O)c(Nc2cccc([N+](=O)[O-])c2)cc1OC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 2-amino-4-methoxy-5-(2-methoxyethoxy)benzamide (1.78 g, 7.40 mmol) and pyridine (2.40 mL, 29.6 mmol) in CHCl3 (40 mL) was added 3-nitrobenzoyl chloride (1.44 g, 7.8 mmol). The mixture was stirred at RT for 2.5 h upon which the mixture was concentrated in vacuo to give the desired product, which was used directly in the next step without purification.
Reaction SMILES: [OH:1][C:2]([P:8]([OH:11])(=[O:10])[OH:9])([P:4]([OH:7])(=[O:6])[OH:5])[CH3:3].[C:12](Cl)(=[O:16])[C:13]([CH3:15])=[CH2:14].Cl>C(N(CC)CC)C>[C:12]([O:1][C:2]([P:4]([OH:7])(=[O:5])[OH:6])([P:8]([OH:11])(=[O:9])[OH:10])[CH3:3])(=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(O)(P(=O)(O)O)P(=O)(O)O
Agent: Cl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC(C)(P(=O)(O)O)P(=O)(O)O
Temperature: 25 °C
Yield: 65 %

Procedure:
To 5 g (0.024 mol) of 1-hydroxyethane-1,1-diphosphonic acid in 30 ml of triethylamine was gradually added 15.7 g (0.15 mol) of methacryloyl chloride with ice cooling. After the temperature was raised to room temperature, the mixture was stirred for ten hours. The reaction solution was acidified with aqueous hydrochloric acid and then extracted with diethyl ether. The resulting aqueous phase was alkalized with sodium hydroxide and then extracted again with diethyl ether. The resulting aqueous phase was chromatographed over Amberlite 120B (trade mark, Rohm & Haas Co.) and the solvent of the eluate was evaporated to give 4.3 g of a colorless oily substance which was identified to be 1-methacryloxyethane-1,1-diphosphonic acid (yield 65%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([CH2:12]Cl)=[O:11].[CH3:14][C:15]1[NH:19][CH2:18][CH2:17][N:16]=1>[N+](C)([O-])=O>[CH3:14][C:15]1[N:19]([CH2:12][C:10](=[O:11])[NH:9][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:8])[CH2:18][CH2:17][N:16]=1
Reactant: CC1=NCCN1
Reactant: Cc1cccc(C)c1NC(=O)CCl
Solvent: C[N+](=O)[O-]
Product: CC1=NCCN1CC(=O)Nc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 10.0 gm. (0.05 M) of 2-chloro-2',6'-acetoxylidide in 100 ml. of nitromethane add 21.35 gm (0.254 M) of lysidine. Stir the solution at room temperature for about 17 hours. Follow the progress of the reaction by thin layer chromatography on silica gel (acetonitrile: ammonium hydroxide: methanol, 85:10:5). At the completion of the reaction, remove the solvent in vacuo, to the residue add 150 ml. of water, adjust the pH to about 7.0 with conc. hydrochloric acid. Extract the resultant solution with 3×100 ml. methylene chloride and discard. Adjust the pH of the water layer to about 11-11.5 with 50% sodium hydroxide. Extract with 4×200 ml. of methylene chloride. Take the combined latter extracts and wash 3×50 ml. of water. Dry the methylene chloride extracts over Na2SO4. Evaporate the solvents to provide the title compound.
Reaction SMILES: [C:1]([CH2:8][N:9]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][N:16]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:15][CH2:14][CH2:13][N:12]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-])=O)=[CH:35][CH:34]=2)[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCOCC>C(O)C.[Pd].C([O-])([O-])=O.[Ca+2]>[C:1]([CH2:8][N:9]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][N:16]([CH2:23][C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:15][CH2:14][CH2:13][N:12]([CH2:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([NH2:39])=[CH:37][CH:38]=2)[CH2:11][CH2:10]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)CN1CCCN(CCc2ccc([N+](=O)[O-])cc2)CCN(CC(=O)OC(C)(C)C)CCCNCC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CN1CCCN(CCc2ccc(N)cc2)CCN(CC(=O)OC(C)(C)C)CCCNCC1
Yield: 100 %

Procedure:
To a solution of compound (8) (1.15 g, 1.99 mmol) in absolute ethanol (100 ml) was added 5% Pd/CaCO3 (0.31 g) to which lead (Pb) had been added as an inhibitor. The resultant mixture was stirred at an ambient temperature under H2 atmosphere for 12 hours. The reaction mixture was filtered through a celite pad and washed with ethanol (2×20 ml). The solvent was evaporated from the combined filtrate in vacuo to give an oily residue, which was then treated with Et2O to obtain a white solid of compound (10) (1.09 g, 98% yield). 1H NMR (500 MHz, CDCl3): δ 6.90-6.88 (dd, 2H), 6.55-6.54 (dd, 2H), 3.28-3.25 (dd, 4H), 2.96-2.94 (m, 2H), 2.88-2.86 (m, 2H), 2.81-2.79 (m, 2H), 2.70-2.68 (m, 2H), 2.64-2.62 (m, 2H), 2.56 (brs, 8H), 2.47 (brs, 2H), 1.86 (brs, 2H), 1.60 (brs, 2H), 1.39-1.37 (dd, 18H); 13C NMR (125 MHz, CDCl3): δ 178.1, 170.5, 170.4, 144.5, 129.9, 129.2, 115.1, 81.1, 80.9, 55.3, 55.0, 54.8, 52.0, 51.7, 51.3, 50.4, 48.6, 48.3, 48.22, 45.8, 30.9, 28.1, 24.4, 23.8, 22.8; HRMS (FAB) calculated for C30H54N5O4: 548.4176 [(M+H)+], measured value: 548.4172 [(M+H)+].
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=1.Cl.[F:17][C:18]1[CH:23]=[C:22]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[CH:20][C:19]=1[N:28]1[C:32]2=[N:33][CH:34]=[N:35][C:36]([S:37][CH:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)=[C:31]2[CH:30]=[N:29]1.C(N(CC)CC)C>ClCCl.CN(C=O)C>[Br:7][C:8]1[O:12][C:11]([C:13]([N:41]2[CH2:42][CH2:43][CH:38]([S:37][C:36]3[N:35]=[CH:34][N:33]=[C:32]4[N:28]([C:19]5[CH:20]=[CH:21][C:22]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:23][C:18]=5[F:17])[N:29]=[CH:30][C:31]=34)[CH2:39][CH2:40]2)=[O:15])=[CH:10][CH:9]=1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(SC4CCNCC4)ncnc32)c(F)c1
Reactant: O=C(O)c1ccc(Br)o1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(-n2ncc3c(SC4CCN(C(=O)c5ccc(Br)o5)CC4)ncnc32)c(F)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 48.5 %

Procedure:
Oxalyl chloride (0.51 mmol, 45 μL) and DMF (catalytic amount) were added to 5-bromo-furan-2-carboxylic acid (0.18 mmol, 36 mg) in dichloromethane (3 mL). The reaction mixture was stirred for 40 minutes at room temperature. The organic solvents were removed in vacuo. The concentrate was re-dissolved in dichloromethane and 1-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-ylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride (0.16 mmol, 70 mg) and triethylamine (0.47 mmol, 66 μL) were added and stirred for 1.5 hours at room temperature. The progress of the reaction was monitored by thin layer chromatography and LCMS. Purification by HPLC provided Compound A115 as a white solid (45 mg, 41%). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.74 (s, 1H); 8.25 (s, 1H); 7.87 (m, 3H); 7.00 (d, 1H); 6.49 (s, 1H); 4.50 (h, 1H); 4.34 (m, 2H); 3.42 (s broad, 2H); 2.70 (s, 3H); 2.28 (m, 2H); 1.85 (m, 2H). Exact mass calculated for C22H19BrFN5O4S2 580.45, found 582.3 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.CC1(C)C(C)(C)OB([C:18]2[CH:19]=[CH:20][C:21]3[S:25][CH:24]=[N:23][C:22]=3[CH:26]=2)O1>>[S:25]1[C:21]2[CH:20]=[CH:19][C:18]([C:2]3[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=3)=[CH:26][C:22]=2[N:23]=[CH:24]1
Reactant: Oc1cc(F)cc(Br)c1
Reactant: CC1(C)OB(c2ccc3scnc3c2)OC1(C)C
Product: Oc1cc(F)cc(-c2ccc3scnc3c2)c1

Procedure:
Compound 3-(benzo[d]thiazol-5-yl)-5-fluorophenol (W190) was prepared using the general procedure for Suzuki coupling reaction between 3-bromo-5-fluorophenol (57 mg, 0.3 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (78 mg, 0.3 mmol), as a white solid (60 mg, 81%). 1H NMR (400 MHz, acetone-d6) δ 9.30 (s, 1 H), 9.02 (brs, 1 H), 8.30 (d, J=1.6 Hz, 1 H), 8.19 (d, J=8.4 Hz, 1 H), 7.45 (dd, J=8.4, 2.0 Hz, 1 H), 7.07 (t, J=1.6 Hz, 1 H), 7.02 (dt, J=10.0, 2.0 Hz, 1 H), 6.64 (dt, J=10.4, 2.4 Hz, 1 H); MS (ESI) m/z 275 (M+H+).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br:13]Br>ClCCCl>[Br:13][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[CH:5]=[O:12]
Reactant: O=Cc1ccccc1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=Cc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
To a mixture of 1,2-dichloroethane (250 g) with 98% aluminum chloride (0.65 mol, 88.6 g) was added 97% benzaldehyde (0.50 mol, 54.6 g) over 1 hour at 40° C. After bromine (0.55 mol, 88.0 g) was added over 2 hours at 40° C., this mixture was stirred for 2 hours at the same temperature. After the reaction mixture being added to ice water (375.0 g) and stirred thoroughly, this was allowed to stand and separated. The organic phase was washed with 100 ml of water, further with 100 ml of 0.5% aqueous solution of sodium carbonate, and finally with 100 ml of water. Then, 241.0 g of solvent were recovered and the residue was distilled, obtaining 83.5 g of 3-bromobenzaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11](=[O:20])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[Br:21]Br>C(Cl)Cl.O>[Br:21][C:10]1[C:11](=[O:20])[C:12]2[C:17]([C:9]=1[C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1)=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2
Reactant: COc1ccc2c(c1)C(c1cc(F)cc(F)c1)=CC2=O
Reactant: BrBr
Solvent: ClCCl
Solvent: O
Product: COc1ccc2c(c1)C(c1cc(F)cc(F)c1)=C(Br)C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
To a solution of 3-(3,5-difluorophenyl)-5-methoxy-1H-inden-1-one (810 mg, 2.98 mmol) obtained in Step 2 in CH2Cl2 (10 mL) at 0° C. was added dropwise a solution of Br2 (571 mg, 3.57 mmol) in CH2Cl2 (3 mL). The mixture was stirred for 3 h at room temperature. The reaction was diluted with H2O (10 mL) and extracted with CH2Cl2. The extracts were washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (CH2Cl2/hexanes) to afford the desired product (1.0 g, 95%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([CH3:23])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][N:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25].C(=O)([O-])[O-].[K+].[K+].[CH2:32]([CH:34]1[O:36][CH2:35]1)Br.O>CN(C)C=O>[CH3:25][O:24][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:32][CH:34]1[CH2:35][O:36]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:12][C:13]1[C:14]([CH3:23])=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][N:17]=2
Reactant: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1O
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1OCC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
3-[7-Hydroxy-6-methoxy-quinolin-4-yloxy]-2-methyl-[1,8]naphthyridine (130 mg) was dissolved in N,N-dimethylformamide (4 ml) to prepare a solution. Potassium carbonate (162 mg) and epibromohydrin (0.1 ml) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (83 mg, yield 55%).
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:4]2[C:9]([C:10]=1[C:11](O)=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[N:20]1([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[C:29]([O:28][C:26]([N:20]1[CH2:25][CH2:24][N:23]([C:11]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:2]=2[Cl:1])=[O:12])[CH2:22][CH2:21]1)=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1c(Cl)n(-c2ccccc2)c2ccccc12
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(Cl)n(-c3ccccc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
To a solution of 2-chloro-1-phenyl-1H-indole-3-carboxylic acid (cf. CA 1079739) (3.00 g, 11.0 mmol), tert-butyl 1-piperazinecarboxylate (2.06 g, 11.0 mmol), EDC (2.33 g, 12.1 mmol) and HOAT (1.73 g, 12.7 mmol) in DMF (12 ml) was added NMM (3.65 ml, 33.1 mmol), and the reaction mixture was stirred at room temperature overnight. The mixture was quenched with water and extracted with EA. The organic layer was separated, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (EA/HEP 1:3). 4.51 g of the title compound were obtained.
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[CH2:3][CH:4]([NH:12][C:13]([C:15]1[CH:20]=[C:19]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:16]=1[CH2:29][CH2:30][C:31](O)=[O:32])=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.B#B.O>O1CCCC1>[CH3:1][CH:2]([CH3:34])[CH2:3][CH:4]([NH:12][C:13]([C:15]1[CH:20]=[C:19]([CH2:21][O:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:18]=[CH:17][C:16]=1[CH2:29][CH2:30][CH2:31][OH:32])=[O:14])[C:5]1[CH:6]=[CH:7][C:8]([F:11])=[CH:9][CH:10]=1
Reactant: CC(C)CC(NC(=O)c1cc(COc2ccccc2)ccc1CCC(=O)O)c1ccc(F)cc1
Agent: B#B
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC(NC(=O)c1cc(COc2ccccc2)ccc1CCCO)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
To a solution of the compound prepared in Example 6(40) (2.00 g) in tetrahydrofuran (5 ml) was added dropwise diborane (1M solution in tetrahydrofuran, 8.6 ml) at 0° C. under an atmosphere of argon. The mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride subsequently, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with hexane-ethyl acetate to give the title compound (1.67 g) having the following physical data.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](I)=[N:11][C:12]([Cl:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Br)(C)C.[CH:22](=[O:24])[CH3:23].[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]([CH:22]([OH:24])[CH3:23])=[N:11][C:12]([Cl:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC=O
Reactant: Clc1ccc(OCc2ccccc2)c(I)n1
Agent: CC(C)[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1nc(Cl)ccc1OCc1ccccc1
Reaction time: 1 h
Yield: 52 %

Procedure:
To a solution (100 mL) of 3-(benzyloxy)-6-chloro-2-iodopyridine (17.4 g) synthesized above in tetrahydrofuran was added a 1.0 M solution (60.2 mL) of isopropylmagnesium bromide in tetrahydrofuran at −45° C., and the mixture was stirred at the same temperature for 1 hr. Acetaldehyde (10.2 mL) was added to the reaction mixture, and the mixture was stirred at −45° C. for 30 min then at room temperature for 2 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, tetrahydrofuran was evaporated in an evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-30% ethyl acetate/hexane) to give the title object compound (6.82 g, 52%) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[C:10]([NH2:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][N:6]=1.[Cl:24][C:25]1[C:30]([C:31](O)=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:27][CH:26]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:24][C:25]1[C:30]([C:31]([NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:9]=2[N:8]=[CH:7][N:6]=[C:5]3[O:4][C:3]2[CH:16]=[C:17]([C:20]([F:22])([F:23])[F:21])[CH:18]=[CH:19][C:2]=2[F:1])=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:27][CH:26]=1
Reactant: Nc1cccc2c(Oc3cc(C(F)(F)F)ccc3F)ncnc12
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Oc4cc(C(F)(F)F)ccc4F)ncnc23)c1F
Yield: 13.6 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-(2-fluoro-5-(trifluoromethyl)phenoxy)quinazolin-8-amine (Intermediate-22, 300 mg, 0.93 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 322 mg, 1.12 mmol), oxalyl chloride (212 mg, 1.68 mmol), DMF (1 drop) and DIPEA (360 mg, 2.79 mmol) in CH2Cl2 (10 mL) to afford 75 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.97 (s, 1H), 8.92-8.90 (d, J=7.2 Hz, 1H), 8.81 (s, 1H), 8.19-8.10 (m, 3H), 7.89-7.84 (m, 2H), 7.77-7.71 (t, J=9.9 Hz, 1H), 7.40-7.32 (m, 2H), 4.31-4.29 (d, J=6.0 Hz, 2H), 1.13 (s, 9H); MS (m/z): 593.31 (M+H)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1.CN(C)[C:16](=[O:18])[CH3:17]>CCCCCC.C(OCC)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:16](=[O:18])[CH3:17])=[N:8][CH:9]=1
Reactant: CC(=O)N(C)C
Reactant: Clc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(=O)c1ccc(Cl)cn1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Under cooling at −78° C., 1.56M n-butyllithium in hexane (27 mL) was added dropwise to 2-bromo-5-chloropyridine (6.8 g) in diethyl ether (45 mL), and then N,N-dimethylacetamide (5 mL) was added dropwise thereto, followed by stirring for 30 minutes. The reaction mixture was partitioned by use of saturated aqueous ammonium chloride and ethyl acetate. The organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, and the residue was purified through silica gel column chromatography (hexane-ethyl acetate), to thereby give 1-(5-chloro-2-pyridyl)ethanone as a solid (3.26 g, 59%).
Reaction SMILES: [NH2:1][C:2](=[O:41])[CH2:3][C:4]1[CH:40]=[CH:39][CH:38]=[CH:37][C:5]=1[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24](C(OCC4C=CC=CC=4)=O)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[N:9]=1.C1CCCCC1>CN(C=O)C.C(Cl)Cl.[Pd]>[N:21]1([C:18]2[CH:17]=[CH:16][C:15]([NH:14][C:10]3[N:9]=[C:8]([CH2:7][CH2:6][C:5]4[CH:37]=[CH:38][CH:39]=[CH:40][C:4]=4[CH2:3][C:2]([NH2:1])=[O:41])[CH:13]=[CH:12][N:11]=3)=[CH:20][CH:19]=2)[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]1
Reactant: NC(=O)Cc1ccccc1CCc1ccnc(Nc2ccc(N3CCN(C(=O)OCc4ccccc4)CC3)cc2)n1
Agent: [Pd]
Solvent: ClCCl
Solvent: C1CCCCC1
Solvent: CN(C)C=O
Product: NC(=O)Cc1ccccc1CCc1ccnc(Nc2ccc(N3CCNCC3)cc2)n1
Temperature: 25 °C
Reaction time: 19 h
Yield: 2.6 %

Procedure:
To a solution of benzyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (A6) (73 mg, 0.13 mmol) in DMF (5 mL) under nitrogen, was added a slurry of 10% Pd/C (20 mg) in DMF. The resulting mixture was stirred under an atmosphere of hydrogen at room temperature for 19 hours then filtered through a 2.0 PFTE filter. The filtrate was evaporated in vacuo and the residue was loaded onto a SCX (5 g) column using MeOH. The column was washed with 2 column volumes of MeOH followed by 3 column volumes of 1% MeNH2 in MeOH. The 1% MeNH2 in MeOH filtrate was evaporated in vacuo to give a pale brown oil which was taken up in DCM (0.5 mL) and cyclohexane (1 mL) and sonicated. The resulting precipitate was filtered and the filter cake dried in vacuo to give the title compound 1 as a white solid (1.4 mg, 90% purity). 1H-NMR: (400 MHz, d4-MeOH) δ 8.22-8.16 (m, 1H), 7.57-7.48 (m, 2H), 7.20 (m, 4H), 7.01-6.93 (m, 2H), 6.60 (dd, J=5.0, 2.8 Hz, 1H), 3.63 (d, J=2.3 Hz, 2H), 3.18-3.12 (m, 4H), 3.09 (dd, J=9.2, 6.4 Hz, 5H), 2.93-2.83 (m, 3H). LC-MS Method A: rt 4.305 min; m/z 417.2 [m+H]+.