Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.Br[C:20]1[C:21]2[C:26]([CH:27]=[C:28]3[C:33]=1[CH:32]=[CH:31][CH:30]=[CH:29]3)=[CH:25][CH:24]=[CH:23][CH:22]=2.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.O.C(O)C>[CH:22]1[C:21]2[C:26](=[CH:27][C:28]3[C:33]([C:20]=2[C:13]2[CH:14]=[CH:15][C:10]([C:2]4[O:1][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[N:3]=4)=[CH:11][CH:12]=2)=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:25]=[CH:24][CH:23]=1
Reactant: Brc1c2ccccc2cc2ccccc12
Reactant: OB(O)c1ccc(-c2nc3ccccc3o2)cc1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: c1ccc2c(-c3ccc(-c4nc5ccccc5o4)cc3)c3ccccc3cc2c1

Procedure:
In a 200 mL three-neck flask, 3.7 g (15 mmol) of 4-(benzoxazol-2-yl)phenylboronic acid, 3.9 g (15 mmol) of 9-bromoanthracene, 3.3 g (31 mmol) of sodium carbonate, 60 mL of toluene, 15 mL of ethanol, and 15 mL of water were placed. The mixture was degassed by being stirred under reduced pressure, and the air in the flask was replaced with nitrogen. To the mixture, 0.16 g (0.14 mmol) of tetrakis(triphenylphosphine)palladium(0) was added, and the mixture was stirred under nitrogen stream at 110° C. for 6 hours. After a certain period, water was added to the mixture, and an aqueous layer was extracted with toluene. The obtained extracted solution and the organic layer were combined and washed with saturated saline, and the organic layer was dried with magnesium sulfate. The obtained mixture was gravity filtered, and the filtrate was condensed to give a solid. A toluene solution of the solid was subjected to suction filtration through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), and the filtrate was condensed. The solid was recrystallized with ethyl acetate/hexane, so that 3.3 g of target yellow powder was obtained in a yield of 57%.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[CH2:13](Br)[CH:14]=[CH2:15]>C(OCC)C>[CH2:15]([O:3][CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])[CH:14]=[CH2:13]
Reactant: CCOP(=O)(CO)OCC
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: C=CCOCP(=O)(OCC)OCC
Temperature: 20 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
To a hexane washed suspension of 60% sodium hydride (262mg, 6.5 mmol) in diethyl ether (10 ml) was added diethyl hydroxymethylphosphonate (lg, 5.95 mmol) and the reaction mixture stirred for 1 hour at 20° C. under nitrogen. Allyl bromide (0.94 g, 0.67 ml, 7.7 mmol) was then added dropwise and the reaction mixture stirred for 2 hours at 20° C. The solids were filtered off and the filtrate diluted with dichloromethane (30 ml). The solution was washed with water (2×30 ml), dried (MgSO4) and the solvent evaporated to give diethyl allyloxymethylphosphonate (0.85 g, 69%) as a clear liquid needing no further purification. νmax (film) 1260, 1030 and 960 cm-1 ; δH (CDCl3) 1.34(6H, t, J7.3 Hz, 2×CH3), 3.71(2H, d, J8.3 Hz, CH2P), 4.17(6H, m, 2×CH2CH3 +CH2OCH2P), 5.28(2H, m, CH2 =CH), 5.88(1H, m, CH2 =CH).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:18]=O)=[C:4]([CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:5]=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:27][C:28](=[O:30])[CH3:29])C=CC=CC=1>C1(C)C=CC=CC=1>[CH:18]([C:3]1[C:2]([CH3:1])=[C:7]([O:8][CH3:9])[C:6]([CH3:10])=[CH:5][C:4]=1[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:27][C:28](=[O:30])[CH3:29]
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)CCCc1cc(C)c(OC)c(C)c1C=O
Solvent: Cc1ccccc1
Product: COC(=O)CCCc1cc(C)c(OC)c(C)c1C=CC(C)=O

Procedure:
Methyl 4-(3,5-dimethyl-2-formyl-4-methoxyphenyl)butyrate (9.4 g) and 1-triphenylphosphoranylidene-2-propanone (21 g equiv) were heated and stirred at reflux in toluene for 48 hr. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography over silica with dichloromethane elution to give methyl 4-[2-(but-1-en-3-one-1-yl)-3,5-dimethyl-4-methoxyphenyl]butyrate as a pale yellow oil. Pmr spectrum (CDCl3 ; δ in ppm): 1.83-2.69 (6H,m); 2.25 (3H,s); 2.28 (3H,s); 2.41 (3H,s); 3.66 (3H,s); 3.70 (3H,s); 6.26 (1H,d); 6.89 (1H,s); 7.65 (1H,d).
Reaction SMILES: O1CCOCC1.[Cl-:7].[NH2:8][C:9]([NH:11][C:12]1[NH:13][C:14]2[C:19]([C:20]=1[C:21]([NH2:23])=[O:22])=[CH:18][CH:17]=[C:16]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH:32]C(OC(C)(C)C)=O)=[CH:26][CH:25]=1)[CH:15]=2)=[O:10]>>[ClH:7].[NH2:8][C:9]([NH:11][C:12]1[NH:13][C:14]2[C:19]([C:20]=1[C:21]([NH2:23])=[O:22])=[CH:18][CH:17]=[C:16]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH2:32])=[CH:26][CH:25]=1)[CH:15]=2)=[O:10]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(-c2ccc3c(C(N)=O)c(NC(N)=O)[nH]c3c2)cc1
Reactant: [Cl-]
Solvent: C1COCCO1
Product: Cl
Product: NCCc1ccc(-c2ccc3c(C(N)=O)c(NC(N)=O)[nH]c3c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4 N Hydrogene chloride dioxane solution (15 mL) was added to 2-aminocarbonylamino-6-[4-(2-tert-butoxycarbonylaminoethyl)phenyl]indole-3-c arboxamide (Compound 7-33, 65 mg, 0.15 mmol) under ice-cooling, and the mixture was stirred at room temperature overnight. After the reaction mixture was concentrated under reduced pressure, the precipitated solid was washed with ethyl acetate (3 mL), and dried under reduced pressure to give the title compound (56 mg) quantitatively as a slightly yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([Cl:11])[CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[N:17][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(C)C=CC=CC=1>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.O.CCO>[Cl:11][C:4]1[CH:3]=[C:2]([C:15]2[CH:16]=[N:17][CH:18]=[C:13]([Cl:12])[CH:14]=2)[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]=12
Reactant: OB(O)c1cncc(Cl)c1
Reactant: Clc1cc(Cl)c2c(n1)CCC2
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: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Clc1cncc(-c2cc(Cl)c3c(n2)CCC3)c1
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 30.1 %

Procedure:
A 25-mL round bottom flask was charged with 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.300 g, 1.59 mmol), 5-chloro3-pyridinyl boronic acid (0.301 g, 1.91 mmol), tetrakis(triphenylphosphine)palladium(0) (0.092 g, 0.08 mmol), and Cs2CO3 (1.56 g, 4.78 mmol). Toluene (8 ml), EtOH (2 ml) and water (4 ml) were added. The resulting mixture was stirred under Ar at 90° C. for 2.5 h. After this time, the mixture was cooled to rt, filtered through celite, and the filtrate concentrated under reduced pressure. The residue was purified by chromatography on silica using hexane/ethyl acetate (10:0 to 0:10) as eluent to afford the title compound (0.127 g, 30%) as a white solid. MW=265.14. 1H NMR (CDCl3, 500 MHz) δ 8.99 (d, J=2.0 Hz, 1H), 8.59 (d, J=2.5 Hz, 1H), 8.30 (t, J=2.5 Hz, 1H), 7.50 (s, 1H), 3.15 (t, J=7.5 Hz, 2H), 3.05 (t, J=7.5 Hz, 2H), 2.21 (quin, J=7.5 Hz, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH3:4])O.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Li]CCCC.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:1]=[CH:2][CH3:4].[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)O
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=CC
Temperature: -78 °C
Reaction time: 0.02 h

Procedure:
To a solution of O-protected pyridine dimethylcarbinol (3.0 g, 10.6 mmol) in THF (50 mL) at −78° C. was added n-BuLi 2.5 N in hexanes (4.7 ml, 11.7 mmol) followed, 1 min later, by phenylthionochloroformate (2.76 g, 16.0 mmol). The reaction was stirred at −78° C. for 40 min, then allowed to warm to RT and stirred 4 h. The final mixture was treated with saturated NaHCO3, extracted with DCM and AcOEt and combined organic layers were dried over Na2SO4 and concentrated. Purification of the residue by flash chromatography over silica gel (eluting hexane to DCM) afforded 1.5 g of O-protected pyridine propene as well as 1.8 g of starting O-protected pyridine dimethylcarbinol.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH:5]([NH:36]C(OC(C)(C)C)=O)[C:6]([NH:8][CH:9]([C:32]([O:34][CH3:35])=[O:33])[CH2:10][C:11]1[CH:31]=[CH:30][C:14]([O:15][C:16]2[CH:29]=[CH:28][C:19]([CH:20]=[C:21]3[S:25][C:24](=[O:26])[NH:23][C:22]3=[O:27])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1)=[O:7].[ClH:44]>ClCCl>[ClH:44].[CH3:1][S:2][CH2:3][CH2:4][CH:5]([NH2:36])[C:6]([NH:8][CH:9]([C:32]([O:34][CH3:35])=[O:33])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:15][C:16]2[CH:17]=[CH:18][C:19]([CH:20]=[C:21]3[S:25][C:24](=[O:26])[NH:23][C:22]3=[O:27])=[CH:28][CH:29]=2)=[CH:30][CH:31]=1)=[O:7]
Reactant: COC(=O)C(Cc1ccc(Oc2ccc(C=C3SC(=O)NC3=O)cc2)cc1)NC(=O)C(CCSC)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C(Cc1ccc(Oc2ccc(C=C3SC(=O)NC3=O)cc2)cc1)NC(=O)C(N)CCSC
Yield: 80.6 %

Procedure:
A solution of 5-[4-(4-(2-(4-methylthio-2-t-butoxycarbonylaminobutyramido)-2-methoxycarbonylethyl)phenoxy)benzylidene]thiazolidin-2,4-dione (1.38 g, 2.2 mmol) in dichloromethane (30 ml) was bubbled with HCl gas at −10° C. for 80 minutes. The excess HCl gas was removed by N2 bubbling and the solvent was removed by distillation to furnish the title compound (1 g, yield 80.6%).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[CH:9]=[O:10].C(=O)([O-])[O-].[Na+].[Na+].[Cl:17]Cl>ClC1C=CC=CC=1>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]([Cl:17])=[O:10]
Reactant: ClCl
Reactant: Cc1nn(C)c(Cl)c1C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Clc1ccccc1
Product: Cc1nn(C)c(Cl)c1C(=O)Cl
Reaction time: 4 h
Yield: 74 %

Procedure:
To a solution of 48.5 g of 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde in 230 ml of chlorobenzene are added 36 g of sodium carbonate. Subsequently, 3.9 g of 2,2-azoisobutyronitrile (AIBN) are added at 60° C., and, within 4 hours, 24 g of chlorine gas are introduced and a further 6 g of AIBN are added. After the gas introduction has ended, the reaction solution is stirred for a further 30 minutes. The solid is filtered off and washed with a little chlorobenzene. After the solvent has been removed, 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbonyl chloride is obtained in a yield of 74%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1I)[C:16]#[N:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[CH:23]=[CH2:24].C(N(CC)CC)C.C(OCC)(=O)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([C:16]#[N:17])[CH:18]=[CH:19][C:20]=1[CH:24]=[CH:23][C:22]([O:26][CH2:27][CH3:28])=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCOc1cc(C#N)ccc1I
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C=Cc1ccc(C#N)cc1OCCCNC(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
4.5 g (11.2 mmol) of 3-[3-(t-butoxycarbonylamino)propoxy]-4-iodobenzonitrile was dissolved in 20 ml of DMF. 6.0 ml (56 mmol) of ethyl acrylate, 6.2 ml (56 mmol) of triethylamine and 56 mg (0.22 mmol) of palladium acetate were added to the obtained solution, and they were stirred at 100° C. overnight. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].CN(C)C1C=C(N(C)C)C=CC=1[C:16]1(C2C=CC(N(C)C)=CC=2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:18](=[O:19])[O:17]1>S(=O)(=O)(O)O>[N+:1]([C:22]1[CH:21]=[C:20]2[C:25]([CH2:16][O:17][C:18]2=[O:19])=[CH:24][CH:23]=1)([O-:4])=[O:2]
Reactant: CN(C)c1ccc(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3ccccc32)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1OCc2ccc([N+](=O)[O-])cc21

Procedure:
Three portions of a mixture of concentrated nitric acid (0.6 ml. each portion) and concentrated sulfuric acid (0.66 ml. each portion) were added to a mixture of 3-(2,4-bis(dimethylamino)phenyl)-3-(4-(dimethylamino)phenyl)phthalide (4.17 g.) and concentrated sulfuric acid (20 ml.) with cooling. After each addition the temperature was allowed to rise to room temperature. The resulting mixture was poured onto ice and the resulting mixture was basified, affording 3-(2,4-bis(dimethylamino)phenyl)-3-(4-(dimethylamino)phenyl5 or 6-nitrophthalide (I: X=Y4 =(CH3)2N, Y2 =Z4 =Z7 =H, Z5 or Z6 =O2N and the other of Z5 or Z6 =H) or a mixture of both.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:28])=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH:17]4[CH2:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22]([F:26])[CH:23]=5)[CH2:18]4)[CH2:12][CH2:11]3)[C:6]=2[CH:27]=1.[Li]C(C)(C)C.[CH3:34][C:35]([CH3:37])=[O:36]>C1COCC1>[F:1][C:2]1[C:3]([CH3:28])=[CH:4][C:5]2[N:9]=[C:8]([C:35]([OH:36])([CH3:37])[CH3:34])[N:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:16][CH:17]4[CH2:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22]([F:26])[CH:23]=5)[CH2:18]4)[CH2:14][CH2:15]3)[C:6]=2[CH:27]=1
Reactant: CC(C)=O
Reactant: Cc1cc2ncn(C3CCN(CC4Cc5ccc(F)cc5C4)CC3)c2cc1F
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1cc2nc(C(C)(C)O)n(C3CCN(CC4Cc5ccc(F)cc5C4)CC3)c2cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 17 %

Procedure:
To a solution of 6-fluoro-1-[1-(5-fluoro-indan-2-ylmethyl)-piperidin-4-yl]-5-methyl-1H-benzoimidazole (25 mg, 0.065 mmol) in anhydrous THF (2 mL) was added tert-BuLi (0.058 mL, 1.7 M in pentane) at −78° C. After stirring for 10 minutes, anhydrous acetone (0.008 mL) was added and the reaction mixture was stirred at −78° C. for 40 minutes. After quenching with 1 M HCl (0.2 mL) the mixture was allowed to warm to rt. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate. The organic layers were washed with saturated NaHCO3, brine, and dried over Na2SO4. The extracts were removed and the residue was purified by flash chromatography (20/1 CH2Cl2/CH3OH) to afford 2-{6-fluoro-1-[1-(5-fluoro-indan-2-ylmethyl)-piperidin-4-yl]-5-methyl-1H-benzoimidazol-2-yl}-propan-2-ol (5 mg, 17%) as a white solid.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][CH:24]([CH:26]([CH3:28])[CH3:27])[CH2:23]2)=[C:4]([C@H:10]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[F:29][C:30]1[CH:47]=[CH:46][C:33]([CH2:34][CH2:35][O:36][C:37]2[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=2)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[C:18]([O:17][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:40]2[CH:39]=[CH:38][C:37]([O:36][CH2:35][CH2:34][C:33]3[CH:32]=[CH:31][C:30]([F:29])=[CH:47][CH:46]=3)=[CH:42][CH:41]=2)[C:3]=1[N:22]1[CH2:25][CH:24]([CH:26]([CH3:28])[CH3:27])[CH2:23]1)[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CC(C(C)C)C2)c1Br
Reactant: OB(O)c1ccc(OCCc2ccc(F)cc2)cc1
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: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CC(C(C)C)C2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
The Pd(Ph3P)4 (38.1 mg, 0.033 mmol) was added to a nitrogen purged and degassed solution of (S)-isopropyl 2-(5-bromo-4-(3-isopropylazetidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (150 mg, 0.33 mmol), (4-(4-fluorophenethoxy)phenyl)boronic acid (94 mg, 0.36 mmol), and sodium carbonate (209 mg, 1.98 mmol) in dioxane (4.5 mL) and water (0.9 mL) and stirred in a screw-capped pressure vessel for 4 h at 90° C. The reaction was allowed to cool, diluted with EtOAc, and the organic layer was washed with brine and dried (Na2SO4). The crude product was charged (DCM) to a 24 g ISCO silica gel cartridge and gradient elution (5-75% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(tert-butoxy)-2-(5-(4-(4-fluorophenethoxy)phenyl)-4-(3-isopropylazetidin-1-yl)-2,6-dimethylpyridin-3-yl)acetate 152 mg (78%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.39-7.36 (m, 2H), 7.31-7.30 (m, 1H), 7.14 (t, J=8.8 Hz, 2H), 7.00 (d, J=8.8 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.82-6.80 (m, 1H), 5.18 (s, 1H), 5.03-4.98 (m, 1H), 4.21 (t, J=6.6 Hz, 2H), 3.43-3.25 (series m, 4H), 3.05 (t, J=6.6 Hz, 2H), 2.27 (s, 3H), 2.01 (s, 3H), 2.01-1.98 (m, 1H), 1.48-1.44 (m, 1H), 1.21-1.19 (m, 6H), 1.10 (s, 9H), 0.68 (d, J=6.6 Hz, 3H), 0.63 (d, J=6.6 Hz, 3H). UPLC (M+H)=591.6.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Br:18]C1C=CC=C(C=1)OC1C=CC=CC=1C#N.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[Br:18][C:3]1[CH:2]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([O:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:4]=1
Reactant: Oc1ccccc1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: N#Cc1ccccc1Oc1cccc(Br)c1
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Solvent: CC#N
Product: O=Cc1ccc(Br)cc1Oc1ccccc1
Yield: 46 %

Procedure:
The title compound was prepared in a 46% yield from 5-bromo-2-fluoro-benzaldehyde and phenol in a manner similar to that described for the preparation of 5-bromo-phenoxybenzonitrile: 1H NMR (DMSO-d6, 400 MHz) δ 10.32(s, 1H), 7.92(s, 1H), 7.81(d, 1H), 7.46(t, 2H), 7.27(t, 1H), 7.18(d, 2H), 6.90(d, 1H) RP-HPLC (Hypersil HS, 5 μm, 100 A 4.6×250 mm; 25%-100% acetonitrile—0.05 M ammonium acetate over 10 min, 1 ml/min) tr 13.08 min.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][C:15]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[C:19]([CH2:25][CH3:26])[CH:18]=4)=[N:14][N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:30][C@@H:31]([OH:34])[CH2:32][OH:33]>C(O)(C)C.[OH-].[Na+].CC(=O)OCC>[CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][C:15]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH2:30][C@@H:31]([OH:34])[CH2:32][OH:33])=[C:19]([CH2:25][CH3:26])[CH:18]=4)=[N:14][N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1cc(-c2nnc(-c3cc(OC)nc(C4CCCC4)c3)o2)cc(C)c1O
Reactant: OC[C@H](O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCc1cc(-c2nnc(-c3cc(OC)nc(C4CCCC4)c3)o2)cc(C)c1OC[C@@H](O)CO
Temperature: 70 °C
Reaction time: 48 h
Yield: 71.8 %

Procedure:
A mixture of 4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,3,4]oxadiazol-2-yl]-2-ethyl-6-methyl-phenol (100 mg, 264 μmol) and (S)-3-chloro-propane-1,2-diol (244 mg, 2.64 mmol) in isopropanol (4 mL) and 3 N aq. NaOH (1 mL) is stirred at 70° C. for 48 h. The mixture is diluted with EA (50 mL), washed with 1 M aq. NaOH solution (20 mL) followed by brine (20 mL), dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC to give the title compound (86 mg) as a white solid; LC-MS**: tR=0.83 min, [M+H]+=454.12; 1H NMR (CDCl3): δ1.33 (t, J=7.5 Hz, 3H), 1.65-1.80 (m, 2H), 1.83-1.96 (m, 4H), 2.05-2.15 (m, 2H), 2.42 (s, 3H), 2.78 (q, J=7.3 Hz, 2H), 3.19-3.30 (m, 1H), 3.82-3.99 (m, 4H), 4.02 (s, 3H), 4.15-4.23 (m, 1H), 7.22 (s, 1H), 7.48 (s, 1H), 7.84 (s, 1H), 7.86 (s, 1H).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:38]([O:42][C:43]([N:45]1[CH2:49][CH2:48][CH:47]([CH2:50]OS(C)(=O)=O)[CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:38]([O:42][C:43]([N:45]1[CH2:49][CH2:48][CH:47]([CH2:50][N:19]2[C:20]3[C:25](=[CH:24][C:23]([O:26][CH:27]([F:28])[F:29])=[CH:22][CH:21]=3)[C:17]([C:14]3[N:15]=[C:16]4[C:8]([C:6](=[O:7])[NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:9][N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:11]4=[N:12][CH:13]=3)=[N:18]2)[CH2:46]1)=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)C1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC4CCN(C(=O)OC(C)(C)C)C4)c4ccc(OC(F)F)cc34)nc12
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
A round-bottomed flask was charged with 2-(5-difluoromethoxy-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (120 mg, 0.23 mmol), 3-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (crude from Step 1, 215 mg, 0.54 mmol), cesium carbonate (258 mg, 0.79 mmol) and DMF (1 ml). The reaction mixture was stirred at 110° C. for 1.5 h then cooled to room temperature, quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over 12 g silica gel with EtOAc/hexanes (gradient: 0-40% EtOAc). The appropriate fractions were combined and concentrated and the residue was triturated with petroleum ether to afford 138 mg (86%) of 3-{3-[7-tert-butylcarbamoyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-5-difluoromethoxy-indazol-1-ylmethyl}-pyrrolidine-1-carboxylic acid tert-butyl ester as a light yellow powder.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[C:5]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[H-].[Na+].I[CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1.O>O1CCCC1>[Cl:1][CH2:2][CH2:3][C:4]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[C:5]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)=[CH:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: ICCOCCOC1CCCCO1
Reactant: Oc1ccc(C(=C(CCCl)c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: ClCCC(=C(c1ccccc1)c1ccc(OCCOCCOC2CCCCO2)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
4-(4-Chloro-1,2-diphenyl-but-1-enyl)phenol (0.33 g, 0.001 mol) was dissolved in tetrahydrofuran (3 ml) under a nitrogen atmosphere. Sodium hydride (0.036 g, 0.0015 mol) was added to the solution and the mixture was stirred at room temperature for an hour. 2-[2-(2-iodo-ethoxy)-ethoxy)-tetrahydropyran (0.6 g, 0.002 mol) was added and the mixture was refluxed for 3 hours. After cooling and adding water the mixture was extracted three times with ethyl acetate. The organic phase was dried with sodium sulphate and evaporated to dryness. The residue was used in the next reaction step without further purification.