Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.CN([C:30]([O:34][N:35]1N=NC2C=CC=N[C:36]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CONC.Cl>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15](=[O:17])[N:35]([O:34][CH3:30])[CH3:36])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)CC1CCCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.8 %

Procedure:
A solution of 2-carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (Beckett et al, J. Med. Chem., 563, 1969) (2.29 g, 10 mmol) in DMF (20 ml) was treated sequentially with N,N-diisopropylethylamine (4.0 ml), HATU (3.8 g, 10 mmol) and O,N-dimethyl-hydroxylamine.HCl (0.98 g, 10 mmol). The reaction mixture was stirred under argon at room temperature for 16 h. The volatiles were removed in vacuo and the residue was chromatographed (silica gel, diethyl ether) to afford the title compound as a white solid (2.60 g, 90%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(=O)C.[F:11][C:12]1[CH:13]=[C:14]([CH2:19][O:20][C:21]2[CH:35]=[CH:34][C:33]([CH:36]=O)=[CH:32][C:22]=2[C:23]([NH:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[O:24])[CH:15]=[CH:16][C:17]=1[F:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.ClCCl>[F:11][C:12]1[CH:13]=[C:14]([CH2:19][O:20][C:21]2[CH:35]=[CH:34][C:33]([CH2:36][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:32][C:22]=2[C:23]([NH:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[O:24])[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: O=Cc1ccc(OCc2ccc(F)c(F)c2)c(C(=O)Nc2cccnc2)c1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(Nc1cccnc1)c1cc(CN2CCOCC2)ccc1OCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Morpholine (0.05 ml, 0.54 mmol) and acetic acid (0.03 ml, 0.54 mmol) were added to solution of 2-([(3,4-difluorophenyl)methyl]oxy)-5-formyl-N-3-pyridinylbenzamide (may be prepared by Example 80; 200 mg, 0.54 mmol) in DCE (5 ml), and the mixture was stirred at room temperature for 10 min. Sodium triacetoxyborohydride (173 mg, 0.81 mmol) was then added and the mixture was warmed to 50° C. overnight. Saturated sodium hydrogencarbonate (10 ml) was added and the mixture stirred for 10 min before being diluted with dichloromethane (25 ml). The organic layer was separated and the aqueous phase was extracted with dichloromethane (25 ml), the organic were combined and evaporated under reduced pressure. The residue was purified by MDAP to yield the title compound. 82 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH2:11])[CH3:10])=[CH:5][CH:4]=1.CCN(CC)CC.Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)CBr
Reactant: COc1ccc([C@H](C)N)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)CN[C@@H](C)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.2 %

Procedure:
To a 0° C. solution of (S)-(−)-1-(4-methoxyphenyl)ethylamine (25 g, 165 mmol) and Et3N (46 mL, 330 mmol) in THF (350 mL) was added a solution of ethyl bromoacetate (27.5 mL, 248 mmol) in THF (50 mL) dropwise over 30 min. The reaction mixture was allowed to warm to room temperature, stirred overnight, then diluted with EtOAc and washed with water and a saturated NaCl solution. The organic layer was dried (Na2SO4) and concentrated under reduced pressure to give ethyl 2-{[(1S)-1-(4-methoxyphenyl)ethyl]amino}acetate (40 g, 100%) as a colorless oil: TLC (40% EtOAc/hex) Rf 0.4; 1H NMR (CDCl3) δ 1.25 (t, J=7.2 Hz, 3H), 1.37 (d, J=6.6 Hz, 3H), 2.03 (br s, 1H), 3.21 (d, J=17.6 Hz, 1H), 3.29 (d, J=17.6 Hz, 1H),), 3.76 (q, J=6.6 Hz, 1H), 3.81 (s, 3H), 4.16 (q, J=7.2 Hz, 2H), 6.87 (d, J=8.7 Hz, 2H), 7.23 (d, J=8.7 Hz, 2H); 13C NMR (CDCl3) δ 14.1, 24.2, 48.8, 55.2, 57.0, 60.6, 113.8, 127.8, 136.6, 158.7, 172.6; HPLC ES-MS m/z (rel abundance) 238 (MH+, 100%).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Cl[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=1.[CH2:16]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([N:33]2[CH2:38][CH2:37][NH:36][C@H:35]([CH3:39])[CH2:34]2)=[N:25][N:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C.O1CCOCC1>[CH2:16]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([N:33]2[CH2:38][CH2:37][N:36]([C:8]3[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=3)[C@H:35]([CH3:39])[CH2:34]2)=[N:25][N:24]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C[C@@H]1CN(c2nnc(Cc3ccccc3)c3ccccc23)CCN1
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2nnc(Cc3ccccc3)c3ccccc23)CCN1c1ccc(C#N)cn1
Yield: 42.2 %

Procedure:
Solid Na2CO3 (50 mg, 0.47 mmol, 1.5 eq) is added to a solution of 6-chloronicotinonitrile (50 mg, 0.36 mmol, 1.2 eq), 1-benzyl-4-((R)-3-methyl-piperazin-1-yl)-phthalazine (100 mg, 0.31 mmol, 1.0 eq) in DMF (1 mL) and dioxane (2 mL) in a microwave vial. The vial is sealed and irradiated in the microwave at 180° C. (high absorption setting) for 30 minutes. The reaction mixture is concentrated, dichloromethane is added and is washed with water then brine. The organic fraction is dried over sodium sulfate, and is evaporated under reduced pressure, then purified by flash chromatography (50%-90% EtOAc/Hexane) to afford the title compound as a white solid (55 mg, 42% yield).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=[O:12])=[N:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH:29]=[N:30][NH:31]3)O1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH:31]1[C:32]2[C:28](=[C:27]([C:2]3[N:3]=[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[C:5]4[S:10][C:9]([CH:11]=[O:12])=[N:8][C:6]=4[N:7]=3)[CH:35]=[CH:34][CH:33]=2)[CH:29]=[N:30]1
Reactant: O=Cc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1nc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
A mixture of 5-chloro-7-morpholinothiazolo[4,5-d]pyrimidine-2-carbaldehyde 43, 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole 1 and sodium carbonate were suspended in toluene, ethanol and water. To this was added bis(triphenylphosphine)palladium(II) chloride and the reaction vessel was flushed with argon. The reaction mixture was microwaved at 120° C. for 1 h and then partitioned between DCM and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting residue was purified using flash chromatography to yield 5-(1H-indazol-4-yl)-7-morpholinothiazolo[4,5-d]pyrimidine-2-carbaldehyde 55.
Reaction SMILES: N1C=CC=CC=1.CN(C1C=CC=CN=1)C.C1(P(Cl)Cl)C=CC=CC=1.C(OC[CH:31]1[CH2:38][N:37]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])=[CH:41][CH:40]=2)[CH2:36][CH:35](COCCCC)[O:34][P:33](=[O:70])([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[O:32]1)CCC>ClCCl>[CH2:46]([O:45][C:42]1[CH:43]=[CH:44][C:39]([N:37]2[CH2:36][CH2:35][O:34][P:33](=[O:70])([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[O:32][CH2:31][CH2:38]2)=[CH:40][CH:41]=1)[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57]
Reactant: CCCCCCCCCCCCOc1ccc(N2CC(COCCCC)OP(=O)(c3ccccc3)OC(COCCCC)C2)cc1
Agent: CN(C)c1ccccn1
Agent: ClP(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCOc1ccc(N2CCOP(=O)(c3ccccc3)OCC2)cc1
Yield: 21 %

Procedure:
It is prepared from 4-dodecyloxy-N,N-di(2-hydroxy)ethyl aniline (3.66 g, 10 mmol), pyridine (2 g, 25 mmol), dimethylaminopyridine (0.2 g) and phenylphosphonous dichloride (2.15 g, 11 mmol) in dichloromethane as described for compound 200 to obtain a white solid 1 g (21%).
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][N:6]([C:13]2[CH:18]=[C:17]([F:19])[C:16]([Br:20])=[CH:15][C:14]=2[F:21])[N:5]=1)(=O)[CH3:2].[CH3:22]OC(OC)N(C)C.[C:30]1([NH:36][NH2:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[Br:20][C:16]1[C:17]([F:19])=[CH:18][C:13]([N:6]2[CH:7]=[C:8]([O:11][CH3:12])[C:9](=[O:10])[C:4]([C:1]3[N:36]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:37]=[CH:22][CH:2]=3)=[N:5]2)=[C:14]([F:21])[CH:15]=1
Reactant: COc1cn(-c2cc(F)c(Br)cc2F)nc(C(C)=O)c1=O
Reactant: COC(OC)N(C)C
Reactant: NNc1ccccc1
Product: COc1cn(-c2cc(F)c(Br)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 23 %

Procedure:
A mixture of 3-acetyl-1-(4-bromo-2,5-difluorophenyl)-5-methoxypyridazin-4(1H)-one (3.57 g, 10 mmol) and N,N-dimethylformamide dimethyl acetal (16 mL) was stirred at 100° C. for 5 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in AcOH (20 mL) and added phenylhydrazine (2.0 mL, 20 mmol). This mixture was stirred at 130° C. for 3 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane/AcOEt (1/0 to 0/1) and recrystallized from iPr2O/AcOEt to give the title compound (1.05 g, 23% yield) as a pale yellow solid: mp 211-213° C.; NMR (300 MHz, DMSO-d6): δ ppm 3.77 (3H, s), 7.02 (1H, d, J=1.9 Hz), 7.09 (1H, dd, J=8.9, 6.6 Hz), 7.22-7.62 (5H, m), 7.80 (1H, d, J=1.9 Hz), 8.07 (1H, dd, J=10.2, 6.0 Hz), 8.49 (1H, d, J=2.3 Hz). LC-MS (ESI) m/z 460 [M+H]+. Anal. Calcd for C20H13BrF2N4O2: C, 52.31; H, 2.85; N, 12.20. Found: C, 52.51; H, 2.95; N, 12.20.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:41])[CH2:13][CH2:12][N:11]([C:14](=[O:38])[C@H:15]([NH:19][C:20]([C@@H:22]3[CH2:26][CH2:25][C:24]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])([CH2:27][CH:28]=[O:29])[CH2:23]3)=[O:21])[CH:16]([CH3:18])[CH3:17])[CH2:10][C:9]2([CH3:40])[CH3:39])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:41])[CH2:13][CH2:12][N:11]([C:14](=[O:38])[C@H:15]([NH:19][C:20]([C@@H:22]3[CH2:26][CH2:25][C:24]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])([CH2:27][CH2:28][OH:29])[CH2:23]3)=[O:21])[CH:16]([CH3:17])[CH3:18])[CH2:10][C:9]2([CH3:39])[CH3:40])=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](NC(=O)[C@@H]1CCC(CC=O)(NC(=O)OC(C)(C)C)C1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)[C@@H](NC(=O)[C@@H]1CCC(CCO)(NC(=O)OC(C)(C)C)C1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of tert-butyl(3R)-3-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamoyl)-1-(2-oxoethyl)cyclopentylcarbamate (from step D, 60 mg, 0.101 mmol) in MeOH (2 mL) at −78° C. was added NaBH4 (7.67 mg, 0.203 mmol). The resulting mixture was stirred at −78° C. for 1 hour. The solvent was removed under reduced pressure and to the residue was added ethyl acetate (10 mL). The resulting mixture was washed with water (2 mL), brine (2 mL), dried over Na2SO4 and concentrated to yield t-butyl(3R)-3-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamoyl)-1-(2-hydroxyethyl)cyclopentylcarbamate (58 mg, 0.098 mmol, 96% yield) as a solid. MS (ESI+) m/z 594 M+
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=5)=[CH:18]4)=[CH:13][C:12]=3[OH:31])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:32][O:33][CH2:34][CH2:35][O:36][CH2:37]Cl>>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=5)=[CH:18]4)=[CH:13][C:12]=3[O:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: COCCOCCl
Reactant: COC(=O)c1ccc(-c2ccc3cc(O)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1
Product: COCCOCOc1cc2ccc(-c3ccc(C(=O)OC)cc3)cc2cc1C12CC3CC(CC(C3)C1)C2
Yield: 54.1 %

Procedure:
Following the procedure of Example 1(a), but reacting 980 mg (2.4 mmol) of methyl 4-[7-(1-adamantyl)-6-hydroxy-2-naphthyl]benzoate with 330 μl (28.6 mmol) of methoxyethoxymethyl chloride, 650 mg (55%) of the expected compound were obtained in the form of an oil.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[F:19][C:20]([F:33])([F:32])[O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=1>>[N:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:18])[N:2]([NH:1][C:29](=[O:30])[CH2:28][C:25]3[CH:26]=[CH:27][C:22]([O:21][C:20]([F:32])([F:19])[F:33])=[CH:23][CH:24]=3)[N:11]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccc(OC(F)(F)F)cc1
Product: O=C(Cc1ccc(OC(F)(F)F)cc1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-[4-(trifluoromethoxy)phenyl]acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (dd, J=7.9, 1.3 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.97-8.01 (m, 1H), 7.89-7.93 (m, 1H), 7.50-7.52 (m, 2H), 7.34-7.37 (m, 2H), 3.80-3.84 (m, 4H), 3.75 (s, 2H), 3.07-3.11 (m, 2H); MS (ESI+) M/Z 449 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][S:9][C:10]2[NH:14][C:13]3=[CH:15][S:16][CH:17]=[C:12]3[N:11]=2)=[N:6][CH:7]=1.[H-].[Na+].[C:20](=O)([O:31]C1C=CC=CC=1)[O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1>CN(C=O)C>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][O:21][C:20]([N:11]2[C:12]3=[CH:17][S:16][CH:15]=[C:13]3[N:14]=[C:10]2[S:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=2)=[O:31])=[CH:24][CH:25]=1
Reactant: COc1ccc(COC(=O)Oc2ccccc2)cc1
Reactant: Cc1ccc(CSc2nc3cscc3[nH]2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)n2c(SCc3ccc(C)cn3)nc3cscc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1.3 g (5 mmol) of 2-(5-methyl-2-picolylmercapto)-1H-thieno[3,4-d]imidazole dissolved in 15 ml of anhydrous DMF were added, under nitrogen, 275 mg (6 mmol) of sodium hydride. After the mixture had been heated at 40°-50° C. for 10 min, at room temperature 1.92 g (7.5 mmol) of 4-methoxybenzyl phenyl carbonate (prepared from 4-methoxybenzyl alcohol and phenyl chloroformate) were added, and the mixture was heated at 30°-40° C. for 10 minutes and stirred at room temperature for 1 hour. The solvent was removed by distillation in vacuo, and water was added to the residue. The oily/resinous precipitate was taken up in CH2Cl2, and the solution was dried over MgSO4 and the solvent was evaporated off. The residue crystallized from diethyl ether and was recrystallized from isopropanol. Melting point 120°-121° C.
Reaction SMILES: [C:1]12([C:7]3[O:8][C:9]4[CH:19]=[C:18]([N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22])[C:17](B5OC(C)(C)C(C)(C)O5)=[CH:16][C:10]=4[C:11]=3[C:12]([NH:14][CH3:15])=[O:13])[CH2:6][CH:5]1[CH2:4][CH2:3][CH2:2]2.Cl[C:36]1[CH:37]=[CH:38][C:39]2[O:52][CH2:51][N:42]3[C:43]4[CH:44]=[CH:45][CH:46]=[C:47]([F:50])[C:48]=4[CH:49]=[C:41]3[C:40]=2[N:53]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O>[C:1]12([C:7]3[O:8][C:9]4[CH:19]=[C:18]([N:20]([CH3:25])[S:21]([CH3:24])(=[O:22])=[O:23])[C:17]([C:36]5[CH:37]=[CH:38][C:39]6[O:52][CH2:51][N:42]7[C:43]8[CH:44]=[CH:45][CH:46]=[C:47]([F:50])[C:48]=8[CH:49]=[C:41]7[C:40]=6[N:53]=5)=[CH:16][C:10]=4[C:11]=3[C:12]([NH:14][CH3:15])=[O:13])[CH2:6][CH:5]1[CH2:4][CH2:3][CH2:2]2
Reactant: CNC(=O)c1c(C23CCCC2C3)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Fc1cccc2c1cc1n2COc2ccc(Cl)nc2-1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(C23CCCC2C3)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 110 °C
Reaction time: 2 h
Yield: 16.6 %

Procedure:
To a degassed solution of 2-(bicyclo[3.1.0]hexan-1-yl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (100 mg, 0.20 mmol), 2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (67 mg, 0.24 mmol), K3PO4 (109 mg, 0.41 mmol) in 1,4-Dioxane (5 mL) and H2O (0.5 ml) was added Pd(dba)3 (5 mg), X-Phos (5 mg) under N2, then the mixture was stirred at 110° C. for 2 hours. The reaction mixture was cooled to RT and filtered. The filtrate was washed with H2O, brine, extracted with DCM, and dried over Na2SO4. After concentration, the residue was purified by prep-HPLC to give the product of 2-(bicyclo[3.1.0]hexan-1-yl)-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (20 mg, yield: 16%). 1H-NMR (CDCl3, 400 MHz) δ 8.12 (s, 1H), 7.55 (s, 1H), 7.46 (s, 2H), 7.21 (s, 2H), 7.12 (d, J=8.0 Hz, 1H), 6.86 (q, J=8.0 Hz, 1H), 6.17 (d, J=4.0 Hz, 1H), 5.60 (s, 2H), 3.38 (s, 3H), 3.05 (d, J=4.8 Hz, 3H), 2.67 (s, 3H), 2.14˜2.22 (m, 2H), 2.11˜2.16 (m, 2H), 2.01˜2.09 (m, 2H), 1.91˜1.98 (m, 1H), 1.84 (d, J=4.0 Hz, 2H). MS (M+H)+: 601.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:17][CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:26]2)=[N:23][CH:24]=1.[Cl:39][C:40]1[CH:45]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH:43]=[C:42]([F:55])[C:41]=1[OH:56]>>[Cl:39][C:40]1[CH:45]=[C:44]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16][CH2:17]2)=[O:13])=[C:5]3[NH:18][C:19]2[CH:20]=[CH:21][C:22]([N:25]3[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:26]3)=[N:23][CH:24]=2)[CH:43]=[C:42]([F:55])[C:41]=1[OH:56]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CCC4)cnc4ccc(Cl)nc34)cn2)C1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CCC4)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)nc34)cn2)C1
Yield: 103.5 %

Procedure:
Following general procedure II, (S)-tert-butyl (1-(5-((6-chloro-3-(cyclobutanecarbonyl)-1,5-naphthyridin-4-yl)amino)pyridin-2-yl)piperidin-3-yl)carbamate (110 mg, 0.20 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (82 mg, 0.30 mmol) to afford the product (134 mg) which was carried forward without any purification: ESI MS m/z 647 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([CH:14]=[O:15])=[CH:4]1)[CH3:2].[O-:16][Mn](=O)(=O)=O.[K+].CCOCC>CC(C)=O.O>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]([OH:16])=[O:15])=[CH:4]1)[CH3:2]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCn1cc(C=O)c2ccc(OC)cc21
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: O
Product: CCn1cc(C(=O)O)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 58.4 %

Procedure:
1-Ethyl-6-methoxy-1H-indole-3-carbaldehyde (600 mg, 2.95 mmol) is dissolved in acetone (85 mL). A solution of KMnO4 (450 mg, 2.85 mmol) in H2O (28 mL) is added. This is stirred at room temperature for 5 hours. Another solution of KMnO4 (450 mg, 2.85 mmol) in H2O (25 mL) is then added. After stirring for another hour at room temperature, the reaction is complete. The reaction mixture is quenched with 10% H2O2 (1.5 mL), and is then filtered through celite. The filtrate is stripped down under vacuum to roughly ⅓ of the volume. The residue is acidified with 6N HCl, and is extracted into ethyl acetate. Purification by silica gel column (hexanes/acetone/acetic acid, 70/30/1) yields crude product. Trituration with ether yields pure 1-ethyl-6-methoxy-1H-indole-3-carboxylic acid (365 mg, 56%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]([CH3:16])=[N:14][N:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:8]=2[N:9]=[C:10](Br)[CH:11]=1)=[O:5])[CH3:2].[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]([CH3:16])=[N:14][N:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:8]=2[N:9]=[C:10]([C:33]2[CH:34]=[CH:35][C:30]([O:29][CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][O:23]3)=[CH:31][CH:32]=2)[CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(Br)nc2c1c(C)nn2C1CCCCO1
Reactant: OB(O)c1ccc(OC2CCCCO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1cc(-c2ccc(OC3CCCCO3)cc2)nc2c1c(C)nn2C1CCCCO1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 92.3 %

Procedure:
To a mixture of 6-bromo-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (6.00 g), 4-(tetrahydro-2H-pyran-2-yloxy)-phenylboronic acid (4.34 g) and potassium carbonate (2.93 g) in DME/water (v/v=2/1, 200 mL) was added at r.t. under Ar-atmosphere palladium(0) bis(tri-tert-butylphosphine) (0.42 g) and the mixture was stirred at 85° C. for 90 min. To the mixture water was added and it was extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by flash chromatography (silica, heptane/ethyl acetate) to give 3-methyl-1-(tetrahydro-pyran-2-yl)-6-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (7.00 g, 92%). This material was dissolved in isopropanol (30 mL), and 1N sodium hydroxide solution (15 mL) was added. The solution was stirred overnight, then the mixture was contentrated in vacuo to about a third of its volume. The precipitated solid was isolated by filtration and dried in air giving the sodium salt of 3-methyl-1-(tetrahydro-pyran-2-yl)-6-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (6.2 g, 87%).