Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[N:11]=1.[N+](N[C:24]1[NH:29][C:28](=[O:30])[C:27]([CH3:31])=[CH:26][N:25]=1)([O-])=O.[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]\[C:35]([OH:37])=[O:36]>N1C=CC=CC=1.CC(C)=O>[CH3:31][C:27]1[C:28](=[O:30])[NH:29][C:24]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][C:10]2[N:11]=[C:7]([NH:6][C:5]([NH2:17])=[N:4][CH2:3][C:2]([F:1])([F:18])[F:19])[S:8][CH:9]=2)=[N:25][CH:26]=1.[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]\[C:35]([OH:37])=[O:36]
Reactant: NCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Reactant: Cc1cnc(N[N+](=O)[O-])[nH]c1=O
Agent: O=C(O)/C=C\C(=O)O
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: Cc1cnc(NCCCCc2csc(NC(N)=NCC(F)(F)F)n2)[nH]c1=O

Procedure:
A mixture of 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)thiazole (0.7 g.) and 2-nitroamino-5-methyl-4(3H)-pyrimidone (0.3 g.) was heated under reflux in pyridine (3 ml.) for 3.5 hours. The mixture was then evaporated to dryness and the residue purified by preparative thin layer chromatography using ethyl acetate/methanol/ 6:1:1 v/v/v for development. The appropriate band was extracted with chloroform/ethanol 1:1 v/v (200 ml.). Evaporation of the solvent to dryness gave a red gum which was treated in acetone with excess maleic acid to give 5-methyl-2-(4-[(-2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-yl]butylamino)pyrimid-4-one containing 1.75 equivalents of maleic acid. The n.m.r. of this compound in d6 dimethylsulphoxide using tetramethylsilane as internal standard (δ=0) included the following resonances (δ): 1.6 (multiplet, 4H); 1.8 (singlet, 3H); 3.3 (multiplet, 2H); 4.2 (quartet, 2H); 6.6 (singlet, 1H); 7.5 (singlet, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[CH:21]3)[N:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:28][O:29][C:30](=[O:39])[C:31]#[C:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1>>[CH3:28][O:29][C:30](=[O:39])[CH:31]=[C:32]([N:23]1[C:24]2[C:20](=[CH:19][C:18]([O:17][CH2:16][CH2:15][C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:27])[CH3:8])[N:10]=3)=[CH:26][CH:25]=2)[CH:21]=[CH:22]1)[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(CCOc2ccc3[nH]ccc3c2)n1
Reactant: COC(=O)C#Cc1cccnc1
Product: COC(=O)C=C(c1cccnc1)n1ccc2cc(OCCc3cccc(N(C)C(=O)OC(C)(C)C)n3)ccc21
Yield: 96 %

Procedure:
The title compound was synthesized from {6-[2-(1H-indol-5-yloxy)-ethyl]-pyridin-2-yl}-methyl-carbamic acid tert-butyl ester and pyridin-3-yl-propynoic acid methyl ester, using the procedure described in Example 16, step (d1), in a 96% yield, as an E/Z isomeric mixture. 1H NMR (Cl3CD), δ: 8.74–8.64 (m, 2H), 7.68 (m, 0.4), 7.57–7.48 (m, 2H), 7.45 (m, 0.6H), 7.38 (m, 0.4H), 7.28 (m, 0.6H), 7.13 (m, 1H), 7.08 (m, 1H), 6.96 (d, 1H, J=7.0 Hz), 6.88 (d, 0.4H, J=3.5 Hz), 6.80–6.66 (m, 1.6H), 6.61 (d, 0.6H, J=3.2 Hz), 6.54 (d, 0.4H, J=3.5 Hz), 6.26 (s, 0.4H), 6.24 (s, 0.6H), 4.39 (m, 2H), 3.67 (s, 1.2H), 3.61 (s, 1.8H), 3.39 (m, 3H), 3.20 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Cl:10][C:11]1[N:12]=[CH:13][C:14]([C:17]([OH:19])=O)=[N:15][CH:16]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.Cl.[F:45][C:46]([F:51])([F:50])[C@H:47]([NH2:49])[CH3:48].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:10][C:11]1[N:12]=[CH:13][C:14]([C:17]([NH:49][C@H:47]([CH3:48])[C:46]([F:51])([F:50])[F:45])=[O:19])=[N:15][CH:16]=1
Reactant: C[C@@H](N)C(F)(F)F
Reactant: O=C(O)c1cnc(Cl)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)c1cnc(Cl)cn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
N,N-Diisopropylethylamine (1.3 mL, 7.5 mmol) was added to a mixture of 5-chloropyrazine-2-carboxylic acid (0.40 g, 2.5 mmol) (Matrix, Cat. #: 054028), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1.0 g, 2.8 mmol) and (2R)-1,1,1-trifluoropropan-2-amine hydrochloride (0.38 g, 2.5 mmol) in methylene chloride (10 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was worked up with saturated aqueous NaHCO3, and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-20%) to afford the desired product (0.64 g, 76%). LCMS (M+H)+: m/z, =253.9/255.9.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[CH:14]=[C:13]3[O:18][CH2:19][O:20][C:12]3=[CH:11][C:10]=2[NH:9][CH:8]=1)=[O:6].[H-].[Na+].Br.Br[CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[CH:14]=[C:13]3[O:18][CH2:19][O:20][C:12]3=[CH:11][C:10]=2[N:9]([CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:8]=1)=[O:6]
Reactant: Cc1ccc(C(=O)c2c[nH]c3cc4c(cc3c2=O)OCO4)cc1C
Reactant: BrCc1cccnc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3cccnc3)c3cc4c(cc3c2=O)OCO4)cc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 71 mg (0.22 mmol) of 7-(3,4-dimethyl-benzoyl)-5H-[1,3]dioxolo[4,5-g]quinolin-8-one, 23 mg of 60% sodium hydride, 72 mg of 3-bromomethylpyridine hydrobromide and 1.3 mL of N,N-dimethylformamide. Yield: 45 mg of a white solid: LC-MSD, m/z for C25H20N2O4 [M+H]+=413.5; HPLC retention time: 1.5 min.
Reaction SMILES: [CH2:1]([C:3]1[NH:13][C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].S(=O)(=O)(O)O.[N+:19]([O-])([O-:21])=[O:20].[K+].N>>[CH2:1]([C:3]1[NH:13][C:6]2=[N:7][C:8]([CH3:12])=[C:9]([N+:19]([O-:21])=[O:20])[C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CCc1nc2c(C)cc(C)nc2[nH]1
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCc1nc2c(C)c([N+](=O)[O-])c(C)nc2[nH]1
Temperature: 80 °C
Yield: 37 %

Procedure:
2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (2.17 g) was added to stirred fuming sulphuric acid (7 ml) and the resulting solution was warmed to 80° C. Potassium nitrate (3.0 g) was added in portions over a period of 10 minutes and the resulting mixture was heated am between 95 and 100° C. for 10 minutes, cooled, then poured onto ice (approx. 25 g). The mixture was neutralised with concentrated aqueous ammonia solution and then extracted with dichloromethane (2×50 ml). The combined extracts were dried over magnesium sulphate and the solvent was then evaporated. Recrystallization of the resulting residue from ethyl acetate (15 ml) gave the intermediate compound 2-ethyl-5,7-dimethyl-6-nitro-3H-imidazo-[4,5-b]pyridine (1.01 g; m.p. 146°-149° C.).
Reaction SMILES: Br[C:2]1[C:3]2[NH:7][C:6]([C:8](C3C=C(C(C)(C)C)C=C(C(C)(C)C)C=3)=[C:9]3[N:40]=[C:12]([C:13](Br)=[C:14]4[NH:38][C:17](=[C:18](C5C=C(C(C)(C)C)C=C(C(C)(C)C)C=5)[C:19]5[CH:20]=[CH:21][C:22]=1[N:23]=5)[CH:16]=[CH:15]4)[CH:11]=[CH:10]3)=[CH:5][CH:4]=2.C1C=CC(P(C2C(OC3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=3)=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:3]12[CH:2]=[C:22]3[N:23]=[C:19]([CH:20]=[CH:21]3)[CH:18]=[C:17]3[NH:38][C:14]([CH:15]=[CH:16]3)=[CH:13][C:12]3=[N:40][C:9]([CH:10]=[CH:11]3)=[CH:8][C:6]([NH:7]1)=[CH:5][CH:4]=2
Reactant: CC(C)(C)c1cc(-c2c3nc(c(Br)c4ccc([nH]4)c(-c4cc(C(C)(C)C)cc(C(C)(C)C)c4)c4nc(c(Br)c5ccc2[nH]5)C=C4)C=C3)cc(C(C)(C)C)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3

Procedure:
The general procedure was used to couple 5,15-dibromo-10,20-di(3,5-di-tert-butylphenyl)porphyrin (0.043 g, 0.05 mmol) with (+)-dihydrocholesterol (0.1556 g, 0.4 mmol), using Pd2(dba)3 (0.0046 g, 0.005 mmol) and DPEphos (0.0107 g, 0.02 mmol) in the presence of Cs2CO3 (0.0652 g, 0.2 mmol). The reaction was conducted in toluene (5 mL) at 100° C. for 18 h. The title compound was isolated by flash column chromatography (silica gel, ethyl acetate:hexanes (v/v)=1:20) as purple solids (0.059 g, 79%). 1H NMR (300 MHz, CDCl3): δ 9.46 (d, J=4.8 Hz, 4H), 8.87 (d, J=4.8 Hz, 4H), 8.09 (d, J=2.1 Hz, 4H), 7.81 (t, J=1.8 Hz, 2H), 5.01 (m, 2H), 2.26-0.61 (m, 92H), 1.57 (s, 36H), −2.48 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 148.9, 140.8, 135.8, 130.6, 129.9, 127.4, 121.0, 120.8, 91.6, 56.3, 56.1, 54.2, 44.9, 42.5, 39.9, 39.5, 37.0, 36.1, 35.8, 35.7, 35.4, 35.0, 31.8, 29.3, 28.7, 28.2, 28.0, 24.1, 23.8, 22.8, 22.5, 21.9, 18.6, 12.6, 12.0. UV-vis (CHCl3, λmax, nm): 420, 521, 560, 604, 661. HRMS-MALDI ([M+H]+): calcd for C102H147N4O2, 1460.1519, found 1460.1522 with an isotope distribution pattern that is the same as calculated one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si](C(C)C)(C(C)C)C(C)C)[CH:9]=[CH:10][C:3]=12.C([Li])(CC)C.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28]>O1CCCC1>[Cl:1][C:2]1[C:7]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12
Reactant: CCOC(=O)Cl
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ccnc21
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc2[nH]ccc2c1Cl
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]-pyridine (15 g) in tetrahydrofuran (150 mL) was added 1M sec-butyllithium in tetrahydrofuran (97 mL) dropwise at −78° C. The mixture was stirred at −78° C. for 1 hour. To the mixture was added ethyl chloroformate (9.29 mL) and the mixture was stirred at −78° C. for 0.5 hour. The reaction mixture was quenched with saturated ammonium chloride aqueous solution and extracted with EtOAc. The extract was wash with water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (120 mL) and to the solution was added 1M tetra-n-butylammonium fluoride in tetrahydrofuran (56 mL). The mixture was stirred at ambient temperature for 1 hour and then extracted with EtOAc. The extract was washed with water, dried over MgSO4 and concentrated under reduced pressure. The residue was with diisopropyl ether to give ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: COc1cc(O)ccc1C=O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1cc(OC2CCCCO2)ccc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To a solution of 2-methoxy-4-hydroxy-benzaldehyde (2.40 g, 15.8 mmol) and 3,4-dihydro-2H-pyran (3.6 mL, 39.5 mmol) in 50 mL methylene chloride was added pyridinium p-toluenesulfonate (0.397 g, 1.58 mmol). The reaction mixture was stirred at room temperature overnight at which time the reaction was concentrated to one-half its original volume. The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate and water. The organic layer was dried (magnesium sulfate), filtered, and concentrated. Medium pressure silica gel chromatography of the residue (5% ethyl acetate/hexanes) afforded 2.13 g (58%) of the title compound of Step A. MS 152.9 (M+1-THP)+
Reaction SMILES: CC1(C)[O:7][C:6](=[O:8])[CH:5]([CH2:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])[C:4](=[O:18])[O:3]1.C(O)(C(F)(F)F)=O.[O-]S([O-])(=O)=O.[Ca+2]>O>[C:13]([C:12]1[CH:11]=[C:10]([CH:17]=[CH:16][CH:15]=1)[CH2:9][CH:5]([C:4]([OH:18])=[O:3])[C:6]([OH:8])=[O:7])#[N:14]
Reactant: CC1(C)OC(=O)C(Cc2cccc(C#N)c2)C(=O)O1
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: N#Cc1cccc(CC(C(=O)O)C(=O)O)c1

Procedure:
A flask containing a mixture of 3-((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)methyl)benzonitrile (4.53 g, 17.5 mmol, Intermediate 70: step a) TFA (30 mL) and water (14 mL) was equipped with a reflux condenser and Drierite® at the outlet, then heated in a 65° C. oil bath for 4 hours. The mixture was concentrated and the title compound was precipitated from water and filtered.
Reaction SMILES: [O:1]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[CH2:12])[Si](C(C)(C)C)(C)C.BrN1C(=O)CCC1=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F-].[F-].[K+].[F-].[Na+].[F-].[F-].[Ca+2]>O1CCCC1.Cl(O)(=O)(=O)=O.C(OCC)C>[CH:11]([C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=1[OH:1])=[CH2:12]
Reactant: C=Cc1ccccc1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C1CCC(=O)N1Br
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=Cc1ccccc1O

Procedure:
2-ethenyl phenol was synthesized according to the procedure of Corson et al. (J. Org. Chem., 1958, 23, 544) and silated by standard procedures. 2-t-butyldimethylsiloxy styrene (550 mg, 2.03 mmoles) was dissolved in tetrahydrofuran (4.0 mL). Exo-1-methyl-4-(1-methylethyl)-7-oxabicyclo[2.2.1]heptane-2-ol (690 mg, 4.06 mmoles) and N-bromosuccinimide were added. One drop of perchloric acid (70%) was added. The reaction was stirred for 11/2 hrs after which time a 1M solution of tetrabutylammonium fluoride in THF (2.5 mL) (any fluoride source, such as KF, NaF, CaF2, HF will suffice) was added and the solution was stirred for an hour. The reaction mixture was diluted with diethyl ether and washed with H2O. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. It was then chromatographed on SiO2 (10-20% Et2O/hexane) to obtain 210 mg of the desired product in about 95% purity.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:12]([CH3:18])[CH2:13][C:14](=[O:17])[NH:15][N:16]=3)=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.[C:19](Cl)(=[O:21])[CH3:20]>O1CCCC1>[C:19]([N:4]1[C:5]2[CH:10]=[C:9]([C:11]3[CH:12]([CH3:18])[CH2:13][C:14](=[O:17])[NH:15][N:16]=3)[CH:8]=[CH:7][C:6]=2[O:1][CH2:2][CH2:3]1)(=[O:21])[CH3:20]
Reactant: CC1CC(=O)NN=C1c1ccc2c(c1)NCCO2
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)N1CCOc2ccc(C3=NNC(=O)CC3C)cc21
Yield: 61 %

Procedure:
6-(3,4-Dihydro-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydro-5-methylpyridazin-3-one was suspended in tetrahydrofuran and one equivalent of acetyl chloride was added. After one half hour at 0° C., the solvent was removed in vacuo, and the product was crystallized from ethanol in 61% yield, mp 185.5°-186° C.
Reaction SMILES: CC(C)=O.[CH2:5]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O[C:19]([CH3:23])([CH3:22])[C:20]#[N:21]>CN(C)C(=O)C>[CH2:5]([N:12]1[CH2:17][CH2:16][N:15]([C:19]([CH3:23])([CH3:22])[C:20]#[N:21])[CH2:14][CH2:13]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(O)C#N
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CC(=O)N(C)C
Solvent: CC(C)=O
Product: CC(C)(C#N)N1CCN(Cc2ccccc2)CC1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
4.5 ml of acetone, 20 g of dry MGSO4, 10 g of N,N-dimethylacetamide, 10 g of 1-benzylpiperazine and 9.5 ml of 2-hydroxyisobutyronitrile are mixed together and heated at 45° C. for 48 hours with vigorous stirring. The reaction mixture is poured onto ice and left stirring for 30 minutes. The mixture is extracted with ether, the organic phase is washed several times with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. 13 g of the expected product are obtained.
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](O)([CH3:24])[CH3:23])=[C:18]([Cl:26])[CH:17]=1.O>ClCCl>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH3:23])[CH3:24])=[C:18]([Cl:26])[CH:17]=1
Reactant: CC(C)(O)c1ccc(Br)cc1Cl
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(C)c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.9 %

Procedure:
Triethylsilane (1.8 mL) and trifluoroacetic acid (5.8 mL) were added to a solution of 2-(4-bromo-2-chlorophenyl)propan-2-ol (1.9 g) in dichloromethane (76 mL), and the mixture was stirred at room temperature for one day. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane only) to give the title compound as a colorless oil (1.74 g, 98%).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH2:24]O)[CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:37])[N:34]([CH3:36])[CH3:35])=[CH:28][CH:27]=2)=[N:4]1)[CH3:2].[CH3:38][CH2:39][N:40](CC)[CH2:41][CH3:42].CS(Cl)(=O)=O.N1CCCC1>C(Cl)Cl>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH2:24][N:40]5[CH2:41][CH2:42][CH2:38][CH2:39]5)[CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:26]2[CH:27]=[CH:28][C:29]([NH:32][C:33](=[O:37])[N:34]([CH3:36])[CH3:35])=[CH:30][CH:31]=2)=[N:4]1)[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCn1cc(-c2ccnc3[nH]c(-c4cccc(CCO)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCNC1
Product: CCn1cc(-c2ccnc3[nH]c(-c4cccc(CCN5CCCC5)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
To a stirred solution of N′-[4-(1-ethyl-4-{2-[3-(2-hydroxyethyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)phenyl]-N,N-dimethylurea (210 mg, 0.42 mMol) in CH2Cl2 (15 mL) was added at 0° C. Et3N (120 uL, 0.86 mmol) and methanesulfonyl chloride (40 uL, 0.52 mmol). After stirring for 3 h, pyrrolidine (2 mL, 24 mmol) was added. The reaction was allowed to warm to RT, stirred for 18 h, and evaporated to dryness under vacuum. Purification by Gilson HPLC provided the title compound (25%) as a pale yellow solid. ESMS [M+H]+: 548.4.
Reaction SMILES: [CH3:1][C:2]1[C:7](OS(C(F)(F)F)(=O)=O)=[CH:6][CH:5]=[CH:4][N:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[Br:39][C:40]1[C:41](I)=[CH:42][C:43]([Cl:46])=[N:44][CH:45]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[Br:39][C:40]1[C:41]([C:7]2[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:42][C:43]([Cl:46])=[N:44][CH:45]=1
Reactant: Clc1cc(I)c(Br)cn1
Reactant: Cc1ncccc1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncccc1-c1cc(Cl)ncc1Br
Temperature: 80 °C

Procedure:
A mixture of 2.73 g (11.3 mmol) trifluoro-methanesulfonic acid 2-methyl-pyridin-3-yl ester, 3.16 g (12.4 mmol) bis(pinacolato)diboron, 3.33 g (33.9 mmol) potassium acetate and 0.46 g (0.56 mmol) dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct in 75 ml N,N-dimethylformamide was heated at 80° C. over night under argon. After cooling to room temperature 5.40 g (17.0 mmol) 5-bromo-2-chloro-4-iodo-pyridine, another portion of 0.46 g (0.56 mmol) dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct and 30 ml of a deoxygenated 2 M aqueous solution of sodium carbonate were added. The reaction mixture was heated at 80° C. for 4.5 h. After cooling to room temperature the mixture was diluted with water and extracted with three portions of tert-butyl methyl ether. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 1.00 (31%) of the title compound as a light yellow solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1([OH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([O:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCOCc1ccccc1
Reactant: Oc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccc(Oc3ccccc3)cc2)nc1CCOCc1ccccc1
Temperature: 100 °C
Yield: 78.9 %

Procedure:
A mixture of 4-(2-benzyloxy-ethyl)-2-(4-bromo-phenyl)-5-methyl-oxazole (0.025 mol, 9.2 g), phenol (0.03 mol, 2.8 g), K3PO4 (0.05 mol, 10.6 g), 2-(di-tert-butylphosphino)biphenyl (1.8 mmol, 0.54 g) and Pd(OAc)2 (1.2 mmol, 0.28 g) in toluene (350 mL) was degassed with nitrogen and heated at 100° C. for 18 h. Additional Pd(OAc)2 (0.5 g) and phosphine ligand (1.0 g) were added, and the mixture was heated 5 h at 100° C. The reaction was concentrated and purified directly by silica gel chromatography (4/1 hexanes/ethyl acetate) to give the title compound (7.6 g).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[I-:11].[Na+]>CC(C)=O>[I:11][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: ClCCN1CCOCC1
Reactant: [I-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCN1CCOCC1
Temperature: 25 °C
Yield: 59.2 %

Procedure:
A mixture of 4-(2-chloro-ethyl)-morpholine hydrochloride (5 g, 26.9 mmole), and sodium iodide (20 g, 134.4 mmole) in acetone (50 ml) was refluxed for 16 hours. After cooled to room temperature, the reaction was partitioned between CHCl3 and brine. The aqueous layer was extracted with CHCl3 (2×25 ml). The combined organic layers were washed with brine, and dried over anhydrous Mg2SO4. Removal of the solvent gave 4-(2-iodo-ethyl)-morpholine as a pale yellowish oil (3.84 g, 59%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C-:17]#[N:18].[Na+].S(=O)(O)[O-].[Na+]>CCOCC.O>[C:17]([CH:6]([OH:7])[C:5]1[CH:8]=[CH:9][C:2]([F:1])=[C:3]([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:4]=1)#[N:18]
Reactant: O=Cc1ccc(F)c(Oc2ccccc2)c1
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: N#CC(O)c1ccc(F)c(Oc2ccccc2)c1
Reaction time: 2 h

Procedure:
To a solution of 4-fluoro-3-phenoxybenzaldehyde (0.39 g, 1.8 mmol) in 25 ml of ether is added 25 ml of water followed by sodium cyanide (0.149 g, 3.04 mmol). The mixture is stirred vigorously while a solution of sodium bisulfite (0.257 g, 2.47 mmol) in 15 ml of water is added over about 5 minutes. The reaction mixture is stirred for two hours. The organic phase is separated, washed with water, dried over calcium sulfate and solvent evaporated to give α-cyano-4-fluoro-3-phenoxybenzyl alcohol