Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C@H]([C@@H](C(OCCCC)=O)O)O)(OCCCC)=[O:2].[CH3:19][O:20][C:21]1[C:26]([CH3:27])=[C:25]([CH3:28])[C:24]([O:29][CH3:30])=[C:23]([CH3:31])[C:22]=1[CH2:32][CH:33]=[C:34]([CH3:37])[CH2:35][OH:36].C(OO)(C)(C)C.[OH-].[Na+]>C(Cl)Cl.C(OCC)C.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH3:19][O:20][C:21]1[C:26]([CH3:27])=[C:25]([CH3:28])[C:24]([O:29][CH3:30])=[C:23]([CH3:31])[C:22]=1[CH2:32][C@H:33]1[O:2][C@:34]1([CH3:37])[CH2:35][OH:36]
Reactant: COc1c(C)c(C)c(OC)c(CC=C(C)CO)c1C
Reactant: CCCCOC(=O)[C@@H](O)[C@H](O)C(=O)OCCCC
Agent: [Ti+4]
Agent: CC(C)(C)OO
Agent: CC(C)[O-]
Solvent: ClCCl
Solvent: CCOCC
Product: COc1c(C)c(C)c(OC)c(C[C@H]2O[C@]2(C)CO)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
0.594 ml of titanium tetraisopropoxide was dissolved in 10 ml of dry methylene chloride. Thereupon, 524 mg of dibutyl D-tartrate were added dropwise at -20° C. and the mixture was left to stand at -20° C. for 10 minutes. 197 mg of 4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-methyl-2-butenol were then added and subsequently a further 180 mg of tert.butyl hydroperoxide (80%) were added dropwise (as a solution in 0.5 ml of methylene chloride). The thus-obtained yellow solution was left to stand at -20° C. for 4 to 5 days, then treated with 5 ml of 1N sodium hydroxide solution, left to warm to room temperature and stirred for 1 hour. The phases were then separated, the aqueous phase was washed twice with methylene chloride, the organic phases were dried over sodium sulphate and concentrated. The colourless oil obtained was dissolved in 20 ml of ethyl ether and stirred with 5 ml of 1N sodium hydroxide solution for 1 hour. The phases were again separated, the aqueous phase was washed twice with ethyl ether, the organic phases were dried over sodium sulphate and concentrated. There were obtained 188 mg (98%) of (2R,3R)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2,3-epoxy-2-methylbutanol. [α]D20 +18.2° (c=2% in chloroform).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:32]=[CH:31][C:11]([C:12]([NH:14][C:15]2[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=2)[CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](O)=[O:26])[CH2:21][CH2:20]2)=[O:13])=[CH:10][CH:9]=1.C1C=NC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.CCN(C(C)C)C(C)C.CCN(C(C1C=CC=C(C)C=1)=O)CC>CN(C=O)C>[CH:1]1([NH:6][C:25]([CH:22]2[CH2:21][CH2:20][N:19]([CH2:18][C:17]3[CH:28]=[CH:29][CH:30]=[C:15]([NH:14][C:12](=[O:13])[C:11]4[CH:31]=[CH:32][C:8]([Cl:7])=[CH:9][CH:10]=4)[CH:16]=3)[CH2:24][CH2:23]2)=[O:26])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Nc1cccc(CN2CCC(C(=O)O)CC2)c1)c1ccc(Cl)cc1
Reactant: NC1CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN(CC)C(=O)c1cccc(C)c1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(CN2CCC(C(=O)NC3CCCC3)CC2)c1)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
1-Cyclopentylamine (10.7 mg, 0.124 mmol) is added to a solution of [3-(4-chloro-benzoylamino)-benzyl]-piperidine-4-carboxylic acid (35.4 mg, 0.095 mmol) in DMF (0.5 mL). The resulting solution is treated with a solution of HOAT (15.5 mg, 0.114 mmol) in DMF (0.5 mL) followed by si-DCC (200 mg, 0.95 mmol/g, 0.19 mmol), and DIPEA (0.033 mL, 0.19 mmol). The mixture is stirred at 50° C. overnight. PI-DETA (7.99 mmol/g, 0.3 mmol, 37 mg) is added to the solution in order to scavenge the acid, PI-NCO (2.24 mmol/g, 0.3 mmol, 130 mg) is added to scavenge the amine in excess and the mixture is stirred for 1 h. The resin is filtered and washed with a mixture of MeOH/DCM 1:1, (4×1 mL). The resulting solution is evaporated under HV. The title compound is obtained by prep. HPLC F as a colourless powder: LC-MS A: tR=1.21 min; [M+H]+=440.1.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Br.[NH2:11][C@H:12]([C:16]1[O:17][C:18]([C:25]2[C:33]3[C:28](=[C:29]([Br:34])[CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)=[C:19]([C:21]([O:23][CH3:24])=[O:22])[N:20]=1)[CH:13]([CH3:15])[CH3:14].[C:35]([NH:45][C@H:46]([C:55](O)=[O:56])[CH2:47][C:48]1[CH:53]=[CH:52][C:51]([OH:54])=[CH:50][CH:49]=1)([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C([O-])(O)=O.[Na+]>CN(C)C=O>[CH2:38]([O:37][C:35]([NH:45][C@@H:46]([CH2:47][C:48]1[CH:53]=[CH:52][C:51]([OH:54])=[CH:50][CH:49]=1)[C:55]([NH:11][C@H:12]([C:16]1[O:17][C:18]([C:25]2[C:33]3[C:28](=[C:29]([Br:34])[CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)=[C:19]([C:21]([O:23][CH3:24])=[O:22])[N:20]=1)[CH:13]([CH3:15])[CH3:14])=[O:56])=[O:36])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Reactant: COC(=O)c1nc([C@@H](N)C(C)C)oc1-c1c[nH]c2c(Br)cccc12
Agent: Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1nc([C@@H](NC(=O)[C@H](Cc2ccc(O)cc2)NC(=O)OCc2ccccc2)C(C)C)oc1-c1c[nH]c2c(Br)cccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 107.6 %

Procedure:
To diisopropylethylamine (225 mL, 1,290 mmol) stirred at 0° C. was added a solution of the title compound of Example 6 (277.5 g, 586.5 mmol), Cbz-L-tyrosine (194.2 g 615.9 mmol) and TBTU (207.2 g, 1.1 eq) in dimethylformamide (anhydrous, 2.77 L). The reaction was allowed to warm to room temperature and stirred for 16 hours at which time HPLC indicated completion of reaction. The reaction solution was slowly poured into saturated aqueous NaHCO3 (12.0 L) and stirred for 30 min. The precipitate was filtered and the filter cake was thoroughly washed with water. The resulting brown material was dried to constant mass in a vacuum oven at 40° C. to yield the title compound (435 g). The title compound was further purified by recrystallization. The title compound was dissolved in isopropanol (9.0 L) at 70° C. The insoluble material was removed by filtration and the filtrate was heated while slowly adding hexanes (9.0 L). The suspension was allowed to cool to room temperature at which time an ice bath was applied. Once cooled the mixture was stirred at ice bath temperature for 30 min and filtered. The solid was washed with hexanes and dried to constant mass at 40° C. in a vacuum oven giving pure title compound (264 g, 61% yield). 1H NMR (CDCl3): consistent with proposed structure.
Reaction SMILES: CO[CH:3]([O:22]C)[C:4]1[CH:8]=[CH:7][S:6][C:5]=1[CH:9]([O:20][CH3:21])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.C([Li])CCC.CN(C)[CH:31]=[O:32].S(=O)(=O)(O)O>O1CCCC1.CCCCCC>[CH3:21][O:20][CH:9]([C:5]1[S:6][C:7]([CH:31]=[O:32])=[CH:8][C:4]=1[CH:3]=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: COc1ccc(C(OC)c2sccc2C(OC)OC)cc1OC
Reactant: CN(C)C=O
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C(OC)c2sc(C=O)cc2C=O)cc1OC
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
16.9 g of 3-dimethoxymethyl-2-(α-methoxy-3,4-dimethoxybenzyl)thiophene are dissolved in 200 ml of tetrahydrofuran. 37.5 ml of 1.6M n-butyl lithium in hexane are added dropwise thereto at -78° C., and the reaction mixture is warmed up to -30° C. gradually. After the mixture is chilled at -78° C., 4.3 ml of N,N-dimethylformamide are added thereto. The mixture is stirred for 30 minutes. The reaction mixture is warmed up to ambient temperature. The mixture is acidified with diluted sulfuric acid, stirred for one hour and extracted with chloroform. The extract is washed with aqueous sodium bicarbonate solution and water, dried and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography [solvent: hexane-ethyl acetate (2:1)], and the eluate is condensed. 14.6 g of 2-(α-methoxy-3,4-dimethoxybenzyl)thiophen-3,5-dicarbaldehyde are obtained as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][C:3]=1[C:4](OC)=[O:5].[CH:22]([NH2:24])=O.C[O-].[Na+].Cl>CN(C)C=O.CO.O>[CH2:15]([O:14][C:9]1[CH:8]=[C:3]2[C:2](=[CH:11][C:10]=1[O:12][CH3:13])[N:1]=[CH:22][NH:24][C:4]2=[O:5])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC=O
Reactant: COC(=O)c1cc(OCc2ccccc2)c(OC)cc1N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc2nc[nH]c(=O)c2cc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
Methyl 2-amino-5-(benzyloxy)-4-methoxybenzoate (5.0 g) was dissolved in N,N-dimethylformamide (150 ml) and methanol (30 ml). Formamide (3.5 ml) and sodium methoxide (2.8 g) were added to the solution. The mixture was heated to 100° C. and was then stirred overnight. The reaction solution was then cooled to room temperature, and 10 ml of water was then added. The reaction solution was neutralized with a 1 M aqueous hydrochloric acid solution to precipitate a solid. The solid was collected by filtration, was washed with water and ether, and was then dried through a vacuum pump to give 3.7 g (yield 76%) of the title compound.
Reaction SMILES: ClCCCl.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:19]([N:26]1[CH2:29][CH:28]([C:30](O)=O)[CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[SH:40]>C(Cl)Cl>[C:22]([O:21][C:19]([N:26]1[CH2:29][CH:28]([C:30]2[S:40][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=2)[CH2:27]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: Nc1ccccc1S
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(c2nc3ccccc3s2)C1
Temperature: 80 °C

Procedure:
To 10 mL DCE was added 533 mg (3.7 mmol) phosphorus pentoxide and 1.57 mL (7.36 mmol) bis-trimethylsilyl ether and the mixture was heated at 80° C. for 15 minutes. 0.19 g (0.92 mmol) N-boc-azetidine-3-carboxylic acid and 108 μL (1.01 mmol) 2-aminothiophenol were added and the mixture heated at 85° C. for 20 minutes. After cooling to room temperature the mixture was diluted with 20 mL DCM and washed with 1 M Na2CO3 (2×10 mL). The organic layer was dried with Na2SO4. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, hexane/EtOAc 1:1).
Reaction SMILES: [C:1]1([S:7]([C@H:10]2[CH:16]=[C:15](SC3C=CC=CC=3)C[CH2:13][C@@H:12]([OH:24])[C@H:11]2C)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]([O:29][C:30](=O)[CH3:31])(=[O:28])[CH3:27].C(N(CC)CC)C.[I-].[Na+].Cl[Si](C)(C)C.O>ClCCl.C(#N)C.Cl[Hg]Cl>[C:1]1([S:7]([C@@H:10]2[CH2:11][C:12](=[O:24])[CH2:13][CH2:31][C@H:30]([O:29][C:26](=[O:28])[CH3:27])[C@@H:16]2[CH3:15])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H]1[C@H](O)CCC(Sc2ccccc2)=C[C@@H]1S(=O)(=O)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: Cl[Hg]Cl
Agent: [I-]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: CC(=O)O[C@H]1CCC(=O)C[C@@H](S(=O)(=O)c2ccccc2)[C@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
To a solution of 21 (4.63 g, 12.38 mmol) in dichloromethane (62 mL) was added acetic anhydride (1.40 mL, 14.9 mmol), triethylamine (2.61 mL, 18.6 mmol), and a catalytic amount of N,N-dimethylaminopyridine. The solution was stirred for 30 minutes at room temperature, diluted with dichloromethane (60 mL), washed with water (100 mL) and 5% HCl solution (100 mL). The organic layer was washed with a saturated NaHCO3 solution (100 mL), dried over MgSO4, and concentrated to give a light yellow oil. To a heterogeneous mixture of HgCl2(6.72 g, 24.8 mmol) and sodium iodide (5.53 g, 37.1 mmol) in acetonitrile (180 mL) was added chlorotrimethylsilane (4.71 mL, 37.1 mmol) at room temperature, followed by the addition of water (0.67 mL, 37.1 mmol). After 5 min, a solution of acetylated compound of 21 in acetonitrile (120 mL) was added. The reaction was allowed to stir at room temperature for 16 h. The contents of the reaction were filtered through a pad of celite. The filtrate was treated with water (500 mL) and the product extracted with diethyl ether. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated. The product was purified via flash column chromatography using silica gel to give 41 (3.41 g, 85%). 1H NMR (300 MHz, CDCl3) δ 7.89 (d, J=7.2 Hz, 2H), 7.69 (t, J=7.5 Hz, 1H), 7.59 (t, J=7.2 Hz, 2H), 4.84 (m, 1H), 3.51 (dd, J=12.9 Hz, 4.2 Hz, 1H), 3.00 (m, 1H), 2.88 (dd, J=17.7 Hz, 12.9 Hz, 1H), 2.67 (dd, J=17.7, 4.5 Hz, 1H), 2.41 (m, 2H), 2.02 (s, 3H), 1.90 (m, 1H), 1.71 (m, 1H), 1.00 (d, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 207.0, 169.6, 137.0, 134.2, 129.5, 128.7, 75.8, 60.8, 38.9, 33.9, 24.6, 21.0, 7.3; LRMS (CI) m/z 325 (M+H), 265 (M+H-AcOH).
Reaction SMILES: N1C(C)=CC=CC=1C.[Cl:9][C:10]1[C:19]2[C:14](=[C:15]([OH:21])[CH:16]=[CH:17][C:18]=2[Cl:20])[N:13]=[CH:12][N:11]=1.[Br:22]Br>C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Br:22][C:16]1[C:15]([OH:21])=[C:14]2[C:19]([C:10]([Cl:9])=[N:11][CH:12]=[N:13]2)=[C:18]([Cl:20])[CH:17]=1
Reactant: Oc1ccc(Cl)c2c(Cl)ncnc12
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1cccc(C)n1
Product: Oc1c(Br)cc(Cl)c2c(Cl)ncnc12

Procedure:
2,6-Lutidine (0.27 mL, 0.248 g, 2.32 mmol) is added to a solution of 4,5-dichloro-8-quinazolinol (0.5 g, 2.33 mmol) in chloroform at ice bath temperature. A solution of bromine in carbontetrachloride (2.4 mL, 1.0 molar) is then added dropwise to the reaction mixture and a precipitate forms. The reaction mixture is diluted with chloroform, washed sequentially with water and saturated NaHCO3 solution, dried over MgSO4 and concentrated in vacuo to give the title product as a yellow solid, 0.7 g, mp 156.5° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][N:10]=[C:9]2[CH2:14][C@@H:15]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)=[C:4]([F:27])[CH:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH:45]=[C:44]3[C:39]([CH:40]=[CH:41][CH:42]=[N:43]3)=[CH:38][CH:37]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[F:27][C:4]1[CH:3]=[C:2]([C:36]2[CH:45]=[C:44]3[C:39]([CH:40]=[CH:41][CH:42]=[N:43]3)=[CH:38][CH:37]=2)[CH:7]=[CH:6][C:5]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[C:9]1[CH2:14][C@@H:15]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]1
Reactant: CC1(C)OB(c2ccc3cccnc3c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2F)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4cccnc4c3)cc2F)C1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A solution of 1,1-dimethylethyl (3S)-3-{[4-(4-bromo-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]methyl}-1-pyrrolidinecarboxylate (0.770 mmol) in dioxane (6 mL) was treated with 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (0.770 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (50 mg), and 2M aq potassium carbonate (3 mL). The reaction mixture was purged with nitrogen, sealed, and stirred at 110° C. for 1 h. The solution was cooled to room temperature and the dioxane layer separated from the aqueous layer. The dioxane layer was removed via pipette and was passed through a plug of celite and sodium sulfate. The plug was washed with dioxane (6 mL). All dioxane filtrates were combined and concentrated in vacuo. Silica gel chromatography (0-20% methanol:ethyl acetate) was utilized in purifying the title compound (250 mg, 65%). MS(ES)+ m/e 490.2 [M+H]+.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCCCC1[N:15]1[C:19](B(O)O)=[CH:18][C:17]([C:23]([F:26])([F:25])[F:24])=[N:16]1.Br[C:28]1[C:29]([N:48]2[CH2:52][CH2:51][C@@H:50]([OH:53])[CH2:49]2)=[N:30][CH:31]=[C:32]([CH:47]=1)[C:33]([NH:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][C:43]([Cl:46])([F:45])[F:44])=[CH:38][CH:37]=1)=[O:34].C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:46][C:43]([F:44])([F:45])[O:42][C:39]1[CH:40]=[CH:41][C:36]([NH:35][C:33](=[O:34])[C:32]2[CH:47]=[C:28]([C:19]3[NH:15][N:16]=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:18]=3)[C:29]([N:48]3[CH2:52][CH2:51][C@@H:50]([OH:53])[CH2:49]3)=[N:30][CH:31]=2)=[CH:37][CH:38]=1
Reactant: OB(O)c1cc(C(F)(F)F)nn1C1CCCCO1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cc(C(F)(F)F)n[nH]2)c1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
K3PO4 (135 mg, 0.635 mmol), 1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-pyrazol-5-ylboronic acid (112 mg, 0.424 mmol) and Pd(PPh3)4 (12.24 mg, 10.59 mmol) were added to a solution of (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 9.2, 100 mg, 0.212 mmol) in toluene (2 mL) and the RM was stirred at 110° C. for 2 h under an argon atmosphere. The RM was filtered through Hyflo®, washed with water and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (Silica gel column, 12 g, DCM/EtOH from 99:1 to 94:6). The resulting intermediate was dissolved in DCM (2 mL), treated with TFA (0.462 mL, 5.99 mmol) and stirred for 1 h at RT. The RM was diluted with EtOAc (20 mL), treated with sat. aq. Na2CO3 (20 mL) and extracted with EtOAc. The combined extracts were washed with brine (20 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product which was purified by flash chromatography (Silica gel column, 4 g, DCM/EtOH from 99:1 to 9:1). Fractions containing pure product were combined and the solvent was evaporated off under reduced pressure to give a residue which was triturated in DCM/n-hexane, filtered and dried to give the title product as a white solid. HPLC (Condition 5) tR=6.545 min, UPLC-MS (Condition 3) tR=1.10 min, m/z=518.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.71-1.95 (m, 2H) 2.94 (d, J=11.34 Hz, 1H) 3.24 (m, 2H) 3.44 (m, 1H) 4.17-4.32 (m, 1H) 4.91 (br. s, 1H) 6.88 (s, 1H) 7.34 (d, J=8.21 Hz, 2H) 7.86 (d, J=9.38 Hz, 2H) 8.12 (s, 1H) 8.81 (s, 1H) 10.17 (s, 1H) 13.94 (s, 1H).
Reaction SMILES: Br[C:2]1[C:3](=[O:31])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[CH:8][CH:7]=[C:6]([O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][CH2:22]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[N:58]1[CH:63]=[C:62](B(O)O)[CH:61]=[N:60][CH:59]=1>>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:18][CH2:19][CH2:20][N:21]4[CH2:22][CH2:23][N:24]([S:27]([CH3:30])(=[O:28])=[O:29])[CH2:25][CH2:26]4)=[CH:7][CH:8]=3)[C:3](=[O:31])[C:2]=2[C:62]2[CH:63]=[N:58][CH:59]=[N:60][CH:61]=2)=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2ccc(Cl)cc2)CC1
Reactant: OB(O)c1cncnc1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(c2cncnc2)=C3c2ccc(Cl)cc2)CC1
Yield: 50 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(4-chlorophenyl)-6-(2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy)-1H-inden-1-one obtained in Step 1 of Example 53 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 5-pyrimidinylboronic acid instead of 3-pyridinylboronic acid, and being purified by prep HPLC (CH3CN/H2O=7:3) to obtain the title compound (50%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:29][CH3:30])=[C:10]([CH2:19][NH:20][C:21]([C:23]3([C:26](O)=[O:27])[CH2:25][CH2:24]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH2:31][CH2:32][C:33]1[CH:34]=[CH:35][C:36]([F:60])=[C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]3[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C@@H:48]([CH3:59])[CH2:47]3)[CH:40]=2)[CH:38]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:29][CH3:30])=[C:10]([CH2:19][NH:20][C:21]([C:23]3([C:26]([NH:31][CH2:32][C:33]4[CH:34]=[CH:35][C:36]([F:60])=[C:37]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]6[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:56])([CH3:58])[CH3:57])=[O:53])[C@@H:48]([CH3:59])[CH2:47]6)[CH:40]=5)[CH:38]=4)=[O:27])[CH2:25][CH2:24]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(CN)ccc3F)c2)CCN1C(=O)OC(C)(C)C
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)C1(C(=O)O)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)C1(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)[C@@H](C)C4)c3)c2)CC1

Procedure:
5-(Aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (30.0 mg, 0.1 mmol) and 1,1-cyclopropanedicarboxylic acid (0.1 mmol) was dissolved in DCM (3 mL), added in HOBt (1.0 eq, 14.0 mg), EDC (1.0 eq, 19.0 mg). The resultant solution was stirred overnight. The solution was purified by Gilson to yield 1-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-cyclopropanecarboxylic acid. 1-[({[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-cyclopropanecarboxylic acid was dissolved in 3 mL DCM with 1,1-dimethylethyl (2S)-4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (41.3 mg, 0.1 mmol), added in HOBt (1.0 eq, 14.0 mg) and EDC (1.0 eq, 19.0 mg). The resultant solution was stirred overnight and then was purified by reverse phase hplc using a Gilson (0.1% TFA conditions) to yield 1,1-dimethylethyl (2S)-4-[(5′-{[({1-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]cyclopropyl}carbonyl)-amino]methyl}-2′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate.
Reaction SMILES: CN([C:4]([O:8][N:9]1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[C:30]([Cl:31])=[C:29]([CH3:32])[NH:28][C:27]=1[C:33]([NH:35][CH:36]1[CH2:41][CH2:40][N:39]([C:42]2[N:47]=[C:46]([S:48][CH3:49])[N:45]=[C:44]([C:50]([OH:52])=O)[CH:43]=2)[CH2:38][CH2:37]1)=[O:34].Cl.O(N)C>CN(C=O)C.CCOC(C)=O.O>[Cl:25][C:26]1[C:30]([Cl:31])=[C:29]([CH3:32])[NH:28][C:27]=1[C:33]([NH:35][CH:36]1[CH2:37][CH2:38][N:39]([C:42]2[N:47]=[C:46]([S:48][CH3:49])[N:45]=[C:44]([C:50]([NH:9][O:8][CH3:4])=[O:52])[CH:43]=2)[CH2:40][CH2:41]1)=[O:34]
Reactant: CSc1nc(C(=O)O)cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CON
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(SC)n1
Yield: 81.2 %

Procedure:
HATU (197 mg, 0.52 mmol) was added to a solution of TEA (0.14 ml, 1.0 mmol), 6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-2-(methylthio)pyrimidine-4-carboxylic acid (Example 7, 230 mg, 0.52 mmol) and methoxylamine hydrochloride (43 mg, 0.52 mmol) in DMF (3 ml) under nitrogen. The resultant mixture was stirred overnight at room temperature, then diluted with EtOAc (50 ml) and water (10 ml) and the organic phase was separated. The organic phase was washed with 1 N HCl (5 ml), saturated NaHCO3 solution (5 ml) and brine (5 ml). The aqueous layers were back extracted with EtOAc (25 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum to give 400 mg of crude product. which was purified by preparative reversed-phase HPLC (water/acetonitrile gradient, 20-95%) to give 200 mg of the title compound.