Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:5][CH:4]=1.O1CCCC1.[OH-].[Li+]>C(O)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(CC(C)C)c2cc(-c3ccc(OC)nc3)oc2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(C(CC(C)C)Nc3ccc(C(=O)NCCC(=O)O)cc3)c(C)o2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
A mixture of 5-[4-(1-chloro-3-methylbutyl)-5-methylfuran-2-yl]-2-methoxypyridine (382 mg) obtained by the above-mentioned reaction, ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (378 mg), sodium carbonate (170 mg) and sodium iodide (240 mg) in N,N-dimethylacetamide (10 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (25% ethyl acetate/hexane to 65% ethyl acetate/hexane) to give ethyl 3-({[4-({1-[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)phenyl]carbonyl}amino)propanoate. The obtained ethyl 3-({[4-({1-[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)phenyl]carbonyl}amino)propanoate was dissolved in ethanol (2 mL) and tetrahydrofuran (2 mL) and 1N lithium hydroxide (0.9 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, water (10 mL) was added, and the mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (191 mg, 32%).
Reaction SMILES: C([Si]([S:11][Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])(C(C)C)C(C)C)(C)C.[H-].[Na+].[C:24]([C:26]1([CH2:49][CH:50]2[CH2:52][CH2:51]2)[CH2:31][CH2:30][C:29](OS(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(=O)=O)=[CH:28][CH2:27]1)#[N:25]>O1CCCC1.C1(C)C=CC=CC=1>[CH:50]1([CH2:49][C:26]2([C:24]#[N:25])[CH2:31][CH2:30][C:29]([S:11][Si:12]([CH:13]([CH3:14])[CH3:15])([CH:16]([CH3:17])[CH3:18])[CH:19]([CH3:20])[CH3:21])=[CH:28][CH2:27]2)[CH2:52][CH2:51]1
Reactant: CC(C)[Si](S[Si](C(C)C)(C(C)C)C(C)C)(C(C)C)C(C)C
Reactant: N#CC1(CC2CC2)CC=C(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)[Si](SC1=CCC(C#N)(CC2CC2)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.1 %

Procedure:
To a degassed, cooled (0° C.) solution of triisopropylsilylsulfide (11.1 g, 58.6 mmol) in tetrahydrofuran (60 ml) was added portionwise over 10 minutes sodium hydride (2.34 g, 60% dispersion in oil) and the mixture stirred until a clear solution formed. 1,1,2,2,3,3,4,4,4-Nonafluorobutane-1-sulfonic acid 4-cyano-4-cyclopropylmethylcyclohex-1-enyl ester (26.9 g, 58.6 mmol) was dissolved in anhydrous toluene (170 ml) and degassed for 30 minutes before addition of TIPS sodium sulfide solution and tetrakis triphenylphosphine palladium (0) (3.38 g, 2.93 mmol). On complete addition the mixture was plunged into an oil bath preheated to 90° C. After 15 min the mixture becomes dark brown in colour. After a further 15 min the mixture was allowed to cool to ambient temperature. The mixture was poured on to ice (200 g) and extracted with diethyl ether (2×200 ml). The combined organic layer was washed with water (200 ml), dried over anhydrous sodium sulphate, filtered and evaporated to give a brown oil. The oil was purified by dry flash column chromatography on silica eluting with isohexane on a gradient of dichloromethane (5-30%). Collecting appropriate fractions followed by evaporation gave a brown oil (20.5 g, 100%). 1H NMR δ (ppm)(CDCl3): 5.92 (1H, s), 2.61-2.54 (2H, m), 2.38-2.28 (1H, m), 2.21-2.10 (3H, m), 1.67-1.44 (2H, m), 1.33-1.23 (3H, m), 1.14 (18H, d, J=7.2 Hz), 0.95-0.85 (1H, m), 0.58-0.55 (2H, m), 0.20-0.18 (2H, m).
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:7][CH2:6][CH:5]([C:8]2[S:25][C:11]3[N:12]=[C:13]([CH3:24])[N:14]=[C:15]([CH2:16][NH:17][C:18]([CH3:23])([CH3:22])[CH2:19][O:20][CH3:21])[C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.N1(CO)C2C=CC=C[C:30]=2N=N1.ClCCCl.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>O>[F:26][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([C:8]2[S:25][C:11]3[N:12]=[C:13]([CH3:24])[N:14]=[C:15]([CH2:16][N:17]([CH3:30])[C:18]([CH3:23])([CH3:22])[CH2:19][O:20][CH3:21])[C:10]=3[CH:9]=2)[CH2:4][CH2:3]1
Reactant: OCn1nnc2ccccc21
Reactant: COCC(C)(C)NCc1nc(C)nc2sc(C3CCC(F)(F)CC3)cc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: COCC(C)(C)N(C)Cc1nc(C)nc2sc(C3CCC(F)(F)CC3)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
To a mixture of N-{[6-(4,4-difluorocyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl}-1-methoxy-2-methylpropan-2-amine (110 mg), 1H-benzotriazole-1-methanol (86 mg), and DCE was added NaBH(OAc)3 (182 mg), followed by stirring at room temperature for 4 hours. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure. The residue was purified by basic silica gel column (hexane/EtOAc) to obtain N-{[6-(4,4-difluorocyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl}-1-methoxy-N,2-dimethylpropan-2-amine (93 mg). This product was dissolved in MeOH, and fumaric acid (27 mg) was added thereto, followed by concentration under reduced pressure to obtain N-{[6-(4,4-difluorocyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl}-1-methoxy-N,2-dimethylpropan-2-aminefumarate (117 mg).
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C:5]1[C:6]([O:43][CH3:44])=[C:7]([NH:15][C:16]([C:18]2[N:19]([CH3:42])[C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:27][N:28]2[CH2:33][CH2:32][N:31]([C:34]([CH:36]3[CH2:40][CH2:39][CH2:38][N:37]3[CH3:41])=[O:35])[CH2:30][CH2:29]2)=[O:17])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1.C(N(CC)CC)C.[C:52](Cl)(=[O:55])[CH2:53][CH3:54]>ClCCl>[C:11]([C:9]1[CH:10]=[C:5]([NH:4][C:52](=[O:55])[CH2:53][CH3:54])[C:6]([O:43][CH3:44])=[C:7]([NH:15][C:16]([C:18]2[N:19]([CH3:42])[C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:27][N:28]2[CH2:29][CH2:30][N:31]([C:34]([C@@H:36]3[CH2:40][CH2:39][CH2:38][N:37]3[CH3:41])=[O:35])[CH2:32][CH2:33]2)=[O:17])[CH:8]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: COc1c(N)cc(C(C)(C)C)cc1NC(=O)c1cc2cccc(CN3CCN(C(=O)C4CCCN4C)CC3)c2n1C
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Nc1cc(C(C)(C)C)cc(NC(=O)c2cc3cccc(CN4CCN(C(=O)[C@@H]5CCCN5C)CC4)c3n2C)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
150 mg of 1-methyl-7-[4-(1-methyl-pyrrolidine-2-carbonyl)-piperazin-1-ylmethyl]-1H-indole-2-carboxylic acid-(3-amino-5-tert-butyl-2-methoxy-phenyl)-amide trihydrochloride are dissolved in 2 ml of dichloromethane and combined successively with 160 μl triethylamine as well as 25 μl propionyl chloride. The mixture is stirred for 2 hours at ambient temperature, the solvents are eliminated in vacuo and the residue is purified by preparative HPLC (method 3).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH3:14][C:15]1([CH3:22])[NH:19][C:18](=[O:20])[NH:17][C:16]1=[O:21].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:14][C:15]1([CH3:22])[C:16](=[O:21])[N:17]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=2)[C:18](=[O:20])[NH:19]1
Reactant: CC1(C)NC(=O)NC1=O
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Yield: 46 %

Procedure:
A mixture of 4-fluoro-2-(trifluoromethyl)benzonitrile (5.67 mg, 30 mmoles), 5,5-dimethyl-hydantoin (7.68 g, 60 mmoles), K2CO3 (8.28 g, 60 mmoles) in DMF (45 ml) is distributed in equal parts into three tubes to be placed in a microwave oven. Under magnetic stirring, each tube is irradiated at 140° C. for 20 minutes. The reaction masses are then combined, poured into water (200 ml) and extracted with AcOEt (2×75 ml). The organic phases are combined, washed with salt water, dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure and the residue crystallized from Et20 (25 ml). After recrystallization from EtOH (75 ml), the powder is filtered and dried under vacuum. The expected compound is obtained in the form of a white solid with a yield of 46% (4.1 g). Melting point: 212-213° C.
Reaction SMILES: C(N(CC)CC)C.Br.[CH3:9][N:10]1[CH2:14][CH2:13][N:12]([CH3:15])[C:11]1=[NH:16].[C:17]1([N:23]=[C:24]=[S:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)(Cl)Cl>[CH3:9][N:10]1[CH2:14][CH2:13][N:12]([CH3:15])[C:11]1=[N:16][C:24]([NH:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[S:25]
Reactant: CN1CCN(C)C1=N
Reactant: S=C=Nc1ccccc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN1CCN(C)C1=NC(=S)Nc1ccccc1

Procedure:
30.4 g (0.3 mol) of triethylamine are added to a suspension of 58.2 g (0.3 mol) of 1,3-dimethyl-2-imino-imidazolidine hydrobromide in 470 ml of chloroform, at 5°, with stirring. A solution of 40.6 g (0.3 mol) of phenyl isothiocyanate in 235 ml of chloroform is then added dropwise and the reaction mixture is refluxed for 15 hours. After cooling, it is washed with water, dried over sodium sulfate and evaporated in vacuo. Crude N-(1,3-dimethyl-2-imidazolidinylidene)-N'-phenyl-thiourea is obtained and after recrystallisation from ethanol this melts at 195°-196°.
Reaction SMILES: Br.[NH2:2][C@H:3]([C:5]([N:7]1[CH2:20][CH2:19][CH2:18][C@H:8]1[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10])=[O:6])[CH3:4].[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([NH:2][C@H:3]([C:5]([N:7]1[CH2:20][CH2:19][CH2:18][C@H:8]1[C:9]([NH:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:10])=[O:6])[CH3:4])(=[O:23])[CH3:22]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)Nc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: Br
Solvent: c1ccncc1
Product: CC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
2 g (0.00585 mol) of L-alanyl-L-proline anilide hydrobromide were dissolved in 40 ml of dry pyridine and 1.1 ml (0.0117 mol) of acetic anhydride were added. The solution was stirred at room temperature for 1 hour and then evaporated. Final traces of pyridine were removed by addition of 20 ml of toluene ane re-evaporation. The residue was dissolved in 100 ml of chloroform and the solution washed with 80 ml of saturated sodium chloride solution, dried over magnesium sulphate and evaporated to an oil. This oil crystallised from ethyl acetate/petroleum ether to give 1.64 g (93%) of N-acetyl-L-alanyl-L-proline anilide of melting point 163°-165° C.; [α]D20 =-186.2° (c=1.022% in methanol).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[CH3:7].[C:23]1([Mg]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[NH4+].[Cl-]>O1CCCC1.CCOCC>[OH:2][C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:4][CH2:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)([C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)[CH3:7]
Reactant: COC(=O)CCC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(CCC(O)(c1ccccc1)c1ccccc1)(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
A solution of 4,4-bis(4-hydroxyphenyl)pentanoic acid methyl ester (4.58 g, 15.3 mmol) in 100 mL of anhydrous tetrahydrofuran was cooled to 0° C. and treated dropwise with phenylmagnesium bromide (10 mL of a 3M solution in ether). Additional tetrahydrofuran (50 mL) was added to the reaction mixture followed by phenylmagnesium bromide (10.4 mL of a 3M solution in ether). The reaction was warmed to room temperature and stirred for 3 hours. The reaction was cooled to 0° C. and treated with phenylmagnesium bromide (10.2 mL of a 3M solution in ether). The reaction mixture was warmed to room temperature and stirred for 18 hours. The reaction mixture was cooled to 0° C. and treated with saturated aqueous NH4Cl solution (100 mL). The organic phase was collected and the aqueous phase was extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified by chromatography (silica gel, 40% ethyl acetate/hexanes) to give the title compound (6.22 g, 96%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9]2)=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[CH:3]=1.[C:25](Cl)(=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29].C(N(CC)CC)C>CC(N(C)C)=O>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:4]1[CH:3]=[C:2]([NH:1][C:25](=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29])[CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][N:8]([C:12](=[O:17])[C:13]([F:16])([F:14])[F:15])[CH2:9]2
Reactant: CCCCC(=O)Cl
Reactant: Nc1cc2c(c(-c3ccccc3Cl)c1)CCN(C(=O)C(F)(F)F)C2
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CCCCC(=O)Nc1cc2c(c(-c3ccccc3Cl)c1)CCN(C(=O)C(F)(F)F)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.1 %

Procedure:
1-[7-amino-5-(2-chloro-phenyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2,2,2-trifluoro-ethanone (71 mgs, 0.2 mmoles) was dissolved in anhydrous dimethylacetamide (1 ml) to which was added valeryl chloride (36 ul, 0.3 mmoles) and finally triethylamine (41.6 ul, 0.3 mmoles). The vial was flushed with nitrogen and stirred at room temperature overnight. The product was twice purified by semi-preparative C18 HPLC (11.5 mgs, 13.1% yield, 94% pure, CO-AAW00030).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[CH3:17][CH:18]([CH2:20][CH2:21][CH2:22][C@H:23]([C@@H:25]1[C@:43]2([CH3:44])[C@H:28]([C@H:29]3[C@H:40]([CH2:41][CH2:42]2)[C@:38]2([CH3:39])[C:32]([CH2:33][C@H:34]([CH2:36][CH2:37]2)[OH:35])=[CH:31][CH2:30]3)[CH2:27][CH2:26]1)[CH3:24])[CH3:19].C(O)(=O)C>O1CCCC1.[Pd]>[NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[CH3:19][CH:18]([CH2:20][CH2:21][CH2:22][C@H:23]([C@@H:25]1[C@:43]2([CH3:44])[C@H:28]([C@H:29]3[C@H:40]([CH2:41][CH2:42]2)[C@:38]2([CH3:39])[C:32]([CH2:33][C@H:34]([CH2:36][CH2:37]2)[OH:35])=[CH:31][CH2:30]3)[CH2:27][CH2:26]1)[CH3:24])[CH3:17]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [Pd]
Agent: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@H](N)C(=O)O

Procedure:
Z-Ala-cholesterol (0.48 mmol) is placed in tetrahydrofuran (20 ml) and glacial acetic acid (3 ml) and hydrogenated in the presence of 5% palladium on charcoal for 2 hours. The reaction mixture is filtered and concentrated in vacuo.
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:33](=[O:34])[CH:32]=[N:31][C:30]5[CH:35]=[CH:36][C:37]([F:39])=[N:38][C:29]4=5)[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.[ClH:40].C(OCC)(=O)C>CO>[ClH:40].[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][NH:12][CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:33](=[O:34])[CH:32]=[N:31][C:30]5[CH:35]=[CH:36][C:37]([F:39])=[N:38][C:29]4=5)[CH2:22][CH2:21]3)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)cnc3ccc(F)nc32)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: O=c1cnc2ccc(F)nc2n1CCN1CCC(NCc2cc3c(cn2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 90 mg of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(6-fluoro-3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidin-4-yl)carbamate in 1 mL of methanol, 1 mL of a 4 mol/L hydrogen chloride/ethyl acetate solution was added, and the mixture was stirred at room temperature for 1 hour. The solid was filtered off to obtain 76 mg of 4-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-6-fluoropyrido(2,3-b)pyrazin-3(4H)-one hydrochloride.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[N:38]2[C:33]([CH:34]=[N:35][C:36](OS(C(F)(F)F)(=O)=O)=[N:37]2)=[CH:32][CH:31]=1.COCC(O)C.C(N(CC)C(C)C)(C)C.Cl>>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[N:38]2[C:33]([CH:34]=[N:35][C:36]([NH:21][C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:16]=3)=[N:37]2)=[CH:32][CH:31]=1
Reactant: COc1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(N)c2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1ccccc1-c1ccc2cnc(Nc3cccc(OC4CCNCC4)c3)nn12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(3-Amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (94 mg, 0.32 mmol), Trifluoro-methanesulfonic acid 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (100 mg, 0.3 mmol), 1-Methoxy-2-propanol (0.3 mL, 3 mmol), and N,N-Diisopropylethylamine (2 mL, 10 mmol) was heated and let stir overnight at 80° C. Concentrated added Hydrogen Chloride (2 mL, 60 mmol) and stir at room temperature for half and hour. The reaction was concentrated, dissolved in 2 mL DMSO, filtered and placed onto the Gilson. The pure fractions were frozen and lypholyzed over night to give [7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[3-(piperidin-4-yloxy)-phenyl]-amine
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:13][N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[CH2:24][CH2:23][CH2:22][C:21]4=[O:25])[CH2:16][CH2:15]3)[N:8]2[CH2:11][CH3:12])=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:3]=1.[Si]([N:39]1[C:47]2[C:42](=[C:43](B(O)O)[C:44]([F:48])=[CH:45][CH:46]=2)[CH:41]=[CH:40]1)(C(C)(C)C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[CH2:11]([N:8]1[C:7]([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:24][CH2:23][CH2:22][C:21]3=[O:25])[CH2:16][CH2:15]2)=[N:6][C:5]2[C:9]1=[N:10][C:2]([N:39]1[C:47]3[C:42](=[CH:43][C:44]([F:48])=[CH:45][CH:46]=3)[CH:41]=[CH:40]1)=[N:3][C:4]=2[N:26]1[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1)[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)n1ccc2c(B(O)O)c(F)ccc21
Reactant: CCn1c(CN2CCC(N3CCCC3=O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
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: C1COCCO1
Solvent: O
Product: CCn1c(CN2CCC(N3CCCC3=O)CC2)nc2c(N3CCOCC3)nc(-n3ccc4cc(F)ccc43)nc21
Temperature: 140 °C
Yield: 9.1 %

Procedure:
A mixture of 1-[1-(2-chloro-9-ethyl-6-morpholin-4-yl-9H-purin-8-ylmethyl)-piperidin-4-yl]-pyrrolidin-2-one (115 mg, 0.26 mmol), [1-(tert-butyldimethylsilanyl)-5-fluoro-1H-indol-4-yl]boronic acid (105 mg, 0.36 mmol), Pd(PPh3)4 (30 mg, 10 mol %) and cesium carbonate (167 mg, 0.51 mmol) in dioxane/water (5:2 mL) was purged with nitrogen gas then heated at 140° C., for 30 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography (Si-PPC, MeOH:DCM, gradient 0:100 to 07:93) to give 109 as a colourless oil (13 mg, 9%). LCMS (Method F) RT 8.15 min, [M+H]+ 547.3. 1H NMR (CDCl3, 400 MHz): δ 8.74 (dd, J=9.1, 4.8 Hz, 1H); 8.30 (d, J=3.6 Hz, 1H); 7.28-7.24 (m, 1H); 7.08-6.99 (m, 1H); 6.58 (d, J=3.6 Hz, 1H); 4.42-4.30 (m, 6H); 4.09-3.97 (m, 1H); 3.88 (t, J=4.75 Hz, 4H); 3.72 (s, 2H); 3.35 (t, J=7.0 Hz, 2H); 2.95 (d, J=11.3 Hz, 2H); 2.39 (t, J=8.1 Hz, 2H); 2.32-2.22 (m, 2H); 2.06-1.95 (m, 2H); 1.77-1.61 (m, 4H); 1.52 (t, J=7.15 Hz, 3H)
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:25]([O:29][C:30](=[O:39])[CH2:31][O:32][CH:33]1[CH2:37][CH:36]([OH:38])[CH:35]=[CH:34]1)([CH3:28])([CH3:27])[CH3:26].O.Cl>CN(C=O)C>[C:25]([O:29][C:30](=[O:39])[CH2:31][O:32][C@H:33]1[CH2:37][C@@H:36]([O:38][C:2]2[C:3]3[C:10]([C:11]4[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=4)=[C:9]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[O:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:35]=[CH:34]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)COC1C=CC(O)C1
Reactant: CCc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(-c2c(-c3ccccc3)oc3ncnc(O[C@H]4C=C[C@@H](OCC(=O)OC(C)(C)C)C4)c23)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Dissolve 390.7 mg (1.17 mmol) of 4-chloro-5-(4-ethylphenyl)-6-phenylfuro[2,3-d]pyrimidine and 250 mg (1.17 mmol) of cis-(+/−)-{[(4-hydroxycyclopent-2-en-1-yl]oxy}acetic acid tert-butyl ester in 0.95 ml of DMF, cool to 0° C. and add 0.58 ml (1.17 mmol) of phosphazene base P2-t-Bu (2 M solution in THF). After the end of the addition, warm the mixture to RT and stir for a further 1 h. Then add the reaction mixture to water, adjust to pH 7 with 1N hydrochloric acid and extract three times with dichloromethane. Combine the organic phases, wash with satd. sodium chloride solution, dry over magnesium sulphate and concentrate under reduced pressure. Isolate the crude product by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 20:1→5:1). 510 mg (85.3% of theory) of the target compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].C(NCCNC(C)C)(C)C.[Cl:20][CH2:21][C:22](Cl)=[O:23].CCOC(C)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][C:22](=[O:23])[CH2:21][Cl:20]
Reactant: O=C(Cl)CCl
Reactant: Cc1cccc(C)c1O
Agent: CC(C)NCCNC(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1OC(=O)CCl
Temperature: -78 °C
Yield: 94.6 %

Procedure:
Under a nitrogen atmosphere: 2,6-dimethylphenol (1.0 equivalent, 40 mmoles) was dissolved in dichloromethane (40 mL) and diisopropyl ethylene diamine (1.3 equivalents, 53.2 mmoles). This solution was cooled to −78° C. Chloroacetylchloride was added all at once. The reaction was followed by 1TLC (25 EtOAc:75 Hexanes) until reaction was complete (˜10 minutes). The reaction was extracted using water and ether. The ether layer was washed with water and then brine, dried (MgSO4), filtered, rinsed with ether, and concentrated under vacuum. The concentrate was purified by silica gel column chromatography using hexanes as eluant, to afford 10.5 grams (94.6% yield) of chloro-acetic acid 2,6-dimethyl-phenyl ester product as a tan oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]([C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[C:6]=2[CH:25]=1.[Br:26][CH2:27][CH2:28][CH2:29]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[C:7]([C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:29][CH2:28][CH2:27][Br:26])=[CH:19][CH:18]=3)[C:6]=2[CH:25]=1
Reactant: O=C(c1ccc(O)cc1)c1c(-c2ccccc2)oc2ccc(Cl)cc12
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(c1ccc(OCCCBr)cc1)c1c(-c2ccccc2)oc2ccc(Cl)cc12

Procedure:
A mixture of 3.2 g. (9.2 mmol.) of 5-chloro-3-(4-hydroxybenzoyl)-2-phenylbenzofuran, 3.5 ml. (0.035 mol.) of 1,3-dibromopropane and 4.0 g. (0.029 mol.) of potassium carbonate in 100 ml. of acetone is refluxed for three hours. After cooling, the reaction mixture is filtered and the filtrate is concentrated to give 5-chloro-3-[4-(3-bromopropoxy)benzoyl]-2-phenylbenzofuran.