Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[CH:6]=1)[CH3:2].N1C=CC=CC=1.[CH2:19]([S:22](Cl)(=[O:24])=[O:23])[CH2:20][CH3:21].O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][S:22]([CH2:19][CH2:20][CH3:21])(=[O:24])=[O:23])[CH:6]=1)[CH3:2]
Reactant: CCCS(=O)(=O)Cl
Reactant: CCOC(=O)c1cccc(N)c1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CCCS(=O)(=O)Nc1cccc(C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 3-amino-benzoic acid ethyl ester (74, 5.0 g, 0.030 mol) in methylene chloride (30.0 mL) were added pyridine (3.67 mL, 0.045 mol) and propane-1-sulfonyl chloride (3.75 mL, 33.0 mmol). The reaction was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The desired compound was isolated by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a white solid (75, 6.0 g, 74.1%).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:18][C:19]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[N:26][C:25]=23)=[O:20])=[C:5]([C:7]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=2[O:14][CH:15]([F:17])[F:16])[N:6]=1.[CH2:30]([OH:33])[C:31]#[CH:32].C(N(CC)CC)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:13][C:11]1[CH:10]=[CH:9][C:8]([O:14][CH:15]([F:17])[F:16])=[C:7]([C:5]2[N:6]=[C:2]([C:32]#[C:31][CH2:30][OH:33])[S:3][C:4]=2[NH:18][C:19]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[N:26][C:25]=23)=[O:20])[CH:12]=1
Reactant: O=C(Nc1sc(Br)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1sc(C#CCO)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 25 °C
Yield: 78.5 %

Procedure:
To a solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [2-bromo-4-(5-chloro-2-difluoromethoxy-phenyl)-thiazol-5-yl]-amide (150 mg, 0.3 mmol), bis(triphenylphosphine)palladium(II) dichloride (11 mg, 0.015 mmol), copper(I)iodide (5 mg, 0.024 mmol) in THF (1 mL) was added propargyl alcohol (35 μL, 0.6 mmol) then triethylamine (1 mL) under an atmosphere of nitrogen. The resultant mixture was stirred at 50° C. for 3 hours before being cooled to room temperature. The mixture was partitioned between ethyl acetate and water. The phases were separated and the organic phase washed with brine, dried (Na2SO4) and evaporated. The resultant residue was purified by flash column chromatography on silica eluting with 80% ethyl acetate in cyclohexane to afford pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [4-(5-chloro-2-difluoromethoxy-phenyl)-2-(3-hydroxy-prop-1-ynyl)-thiazol-5-yl]-amide as a yellow solid (112 mg, 78%). LCMS (Method 3) [M+H]+=476.2, RT=3.19 min.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.C(#N)C.C(N(CC)CC)C.[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>>[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([C:4]1[NH:5][CH:6]=[C:2]([CH3:1])[N:3]=1)=[O:21]
Reactant: O=C(Cl)c1ccccc1F
Reactant: Cc1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c[nH]c(C(=O)c2ccccc2F)n1
Temperature: 140 °C
Yield: 67.4 %

Procedure:
To a 350 mL pressure vessel was added 4-methylimidazole (12 g, 146 mmol, 1 eq.) and a stirbar. Acetonitrile (35 mL, 670 mmol, 4.6 eq.) was added. Triethylamine (59 mL, 424 mmol, 2.9 eq.) was added and the mixture was stirred until it became homogeneous. 2-fluorobenzoyl chloride (67.2 g, 424 mmol, 2.9 eq.) was added. Upon addition of the acyl chloride, the mixture became warm and viscous. The vessel was sealed and heated at 140° C. for 2 h with stirring. During heating, the mixture turned black in color. The vessel was removed from the heat, allowed to cool, and its contents were diluted with acetone (50 mL). The mixture was stirred and transferred to a 2 L round-bottomed flask containing 7% aqueous HCl (1000 mL). Charcoal was added to the flask and the mixture was heated at reflux for 1.5 h. The mixture was allowed to cool almost to room temperature and then was filtered through a Celite pad followed by a rinse with 1N HCl (˜100 mL). The filtrate was placed in an ice bath and was made alkaline with aqueous NH4OH (35%) whereupon a solid precipitate formed. The solid was filtered and washed with copious amounts of dilute NH4OH to remove triethylamine hydrochloride salts. The solid was collected and placed under high vacuum, yielding the desired ketone 1 as a brown solid (20.1 g, 67%). LC/MSD (HP Series 1100 MSD) Expected MW: 204.07, Observed M+H: 205.0, Retention time: 1.13. 1H NMR, CD3OD, Varian 400 MHz δ 7.70 (t, 1H), 7.59 (m, 1H), 7.30 (t, 1H), 7.25-6.96 (m, 2H), 2.34 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](S(C)(=O)=O)[C:5]2[N:6]([C:8]([I:11])=[CH:9][N:10]=2)[CH:7]=1.[CH2:16]([NH2:20])[CH:17]([CH3:19])[CH3:18].O>CN1C(=O)CCC1>[Br:1][C:2]1[N:3]=[C:4]([NH:20][CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]2[N:6]([C:8]([I:11])=[CH:9][N:10]=2)[CH:7]=1
Reactant: CC(C)CN
Reactant: CS(=O)(=O)c1nc(Br)cn2c(I)cnc12
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)CNc1nc(Br)cn2c(I)cnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
To a stirred solution of 6-bromo-3-iodo-8-methanesulfonyl-imidazo[1,2-a]pyrazine (5.08 g, 12.64 mmol) in NMP (100 mL) was added 3.77 mL isobutylamine (2.77 g, 37.90 mmol, 3 eq) in one portion at rt. After stirring for 2 h at rt, 500 mL water was added and the mixture was extracted with ethyl acetate (3×200 mL). The organic phase was filtered, evaporated and the residue was recrystallized from MeOH/water to yield 3.87 g (77.52%) (6-bromo-3-iodo-imidazo[1,2-a]pyrazin-8-yl)-isobutyl-amine: 1H-NMR (300 MHz, d6-DMSO): δ=8.09 (1H, tr), 7.60 (1H, s), 7.54 (1H, s), 3.19 (2H, dd), 1.95 (1H, m), 0.85 (6H, d) ppm.
Reaction SMILES: BrCC[C:4]1[C:5]2[C:10](C=[C:12]3[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]3)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:18]1[CH2:22][O:21][CH2:20][CH2:19]1.CS(C)=[O:25]>>[CH:13]1[C:12]2[C:17](=[CH:4][C:5]3[C:10]([C:19]=2[CH2:20][O:21][CH2:22][CH2:18][OH:25])=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:16]=[CH:15][CH:14]=1
Reactant: C1CCOC1
Reactant: BrCCc1c2ccccc2cc2ccccc12
Reactant: CS(C)=O
Product: OCCOCc1c2ccccc2cc2ccccc12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a separate flask under an inert atmosphere was added 9-bromoethylanthracene, 10 mL anhydrous THF, and 5 mL anhydrous dimethylsulfoxide. The resulting mixture was added to the solution prepared above. The resulting reaction mixture was then stirred for 15 hrs at room temperature. The mixture was then slowly quenched using saturated NaHCO3. The products were extracted with dichloromethane and dried over sodium sulfate. The solvents were evaporated under reduced pressure and purified using flash column chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([S:16][CH2:17][CH2:18][CH3:19])=[C:14]([C:20]([OH:22])=O)[CH:13]=[N:12]2)=[CH:7][CH:6]=1)=[O:4].[CH3:23][NH:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[CH:25]1([N:24]([CH3:23])[C:20]([C:14]2[CH:13]=[N:12][N:11]([C:8]3[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=3)[C:15]=2[S:16][CH2:17][CH2:18][CH3:19])=[O:22])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CNC1CCCCC1
Reactant: CCCSc1c(C(=O)O)cnn1-c1ccc(C(=O)OC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCCSc1c(C(=O)N(C)C2CCCCC2)cnn1-c1ccc(C(=O)OC)cc1
Reaction time: 18 h
Yield: 78 %

Procedure:
1-(4-methoxycarbonylphenyl)-5-propylsulfanyl-pyrazole-4-carboxylic acid (Intermediate #7), (160 mg, 0.5 mmol), N-methylcyclohexylamine (57 mg, 0.5 mmol), HOBT (81 mg, 0.6 mmol) and DIPEA (174 μL, 1.0 mmol) were dissolved in DMF (5 mL) and treated at ambient temperature with EDCI (115 mg, 0.6 mmol). The mixture was stirred at ambient for 18 h and then diluted with ethyl acetate (50 mL), washed with water (3×20 mL) and brine, dried (MgSO4) and volatiles removed by evaporation. The residue was purified by chromatography on silica gel (12 g silica 0-70% EtOAc/isohexane) to give the title compound as a colourless gum (162 mg, 78%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][S:10]([C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[N:29]([CH2:30][C:31]([O:33][CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])=[O:32])[N:28]=[C:27]([C:39]([F:42])([F:41])[F:40])[CH:26]=3)=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11]>>[Br:1][C:26]1[C:27]([C:39]([F:42])([F:41])[F:40])=[N:28][N:29]([CH2:30][C:31]([O:33][CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])=[O:32])[C:25]=1[C:22]1[CH:23]=[CH:24][C:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([S:10]([CH3:9])(=[O:12])=[O:11])[CH:14]=2)=[CH:20][CH:21]=1
Reactant: CN(C)CCOC(=O)Cn1nc(C(F)(F)F)cc1-c1ccc(-c2cccc(S(C)(=O)=O)c2)cc1
Reactant: O=C1CCC(=O)N1Br
Product: CN(C)CCOC(=O)Cn1nc(C(F)(F)F)c(Br)c1-c1ccc(-c2cccc(S(C)(=O)=O)c2)cc1

Procedure:
Following bromination with N-bromosuccinimide, the title compound 40 is prepared starting from 2-(dimethylamino)ethyl 2-(5-(3′-(methylsulfonyl)biphenyl-4-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetate 39.
Reaction SMILES: [OH-].[Na+].[CH:3](=[CH:12][C:13](=[O:15])[CH3:14])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)([O-:18])=[O:17]>C(O)C>[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[CH:14][C:13](=[O:15])[CH:12]=[CH:3][CH:4]=[CH:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: CC(=O)C=CC=Cc1ccccc1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(C=CC=Cc1ccccc1)C=Cc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 92.2 %

Procedure:
16.2 g of a 10% strength NaOH solution were added dropwise, while cooling slightly, to a mixture of 46.5 g of cinnamalacetone, 45.4 g of p-nitrobenzaldehyde and 160 ml of ethanol at 25° C. The reaction mixture became clear after a short time, and a yellow solid subsequently separated out. The mixture was stirred for one hour, after which the solid was filtered off under suction, washed with diethyl ether, and dried under reduced pressure to give 76 g (91% of theory) of 1-(4-nitrophenyl)-7-phenyl-1,4,6-heptatrien-3-one of melting point 168°-170° C.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:15]1[CH2:39][CH2:40][NH:41][S:42]([CH2:45][C:46]1[CH:51]=[CH:50][C:49]([Cl:52])=[C:48]([Cl:53])[CH:47]=1)(=[O:44])=[O:43])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+]>CO>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:38]=[CH:37][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:15]1[CH2:39][CH2:40][NH:41][S:42]([CH2:45][C:46]1[CH:51]=[CH:50][C:49]([Cl:52])=[C:48]([Cl:53])[CH:47]=1)(=[O:43])=[O:44])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)CCc2c(CCNS(=O)(=O)Cc3ccc(Cl)c(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(S(=O)(=O)CCc2c(CCNS(=O)(=O)Cc3ccc(Cl)c(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 93 %

Procedure:
Methyl 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoate (1 eq), THF (0.1M), MeOH (1 mL/1 mL THF), and NaOH (1N) (11 eq) were stirred together overnight. Solvents were removed and the resulting residue was taken up in water. The solution was acidified with 1N HCl and collected resulting precipitate by filtration. Obtained 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoic acid (white-yellow solid) in 93% yield. HRMS calc for [C38H33Cl3N2O6S2—H] 793.07728 found 793.07629
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:30][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:4][C:5]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])=[C:6]([CH:19]=1)[C:7]([O:9]CC1C=CC(F)=CC=1F)=[O:8].[OH-].[Li+].O.Cl>O1CCCC1>[Br:1][C:2]1[C:3]([CH2:30][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:4][C:5]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])=[C:6]([CH:19]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(OCc1ccc(F)cc1F)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccc(F)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccc(F)cc1F
Temperature: 50 °C

Procedure:
To a solution of (2,4-difluorophenyl)methyl 5-bromo-2-{[(2,4-difluorophenyl)methyl]oxy}-4-(4-morpholinylmethyl)benzoate (may be prepared as described in Description 21; 833 mg, 1.466 mmol) in tetrahydrofuran (4 ml) was added lithium hydroxide (211 mg, 8.79 mmol) and water (1 ml). The mixture was heated at 50° C. for 4 hours, cooled and neutralised with 2M hydrochloric acid (3.66 ml, 7.33 mmol). The solvent was removed in vacuo to yield the title compound as a white solid. 648 mg.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[O:15][CH:16]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:23][C:24]1(C)[C:28](C)(C)OB(C(C)=C)O1.C([O-])(=O)C.[K+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.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>[CH2:23]=[C:24]([C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[O:15][CH:16]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1)[CH3:28]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)CCc1nc(-c2cc(Br)cc(C(F)(F)F)c2)co1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=C(C)c1cc(-c2coc(CCC(=O)OC)n2)cc(C(F)(F)F)c1
Temperature: 100 °C
Yield: 69.4 %

Procedure:
A suspension of methyl 3-(4-(3-bromo-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (Reference Example 44, 0.605 g, 1.60 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.404 g, 2.40 mmol) and potassium acetate (2.36 g, 24.0 mmol) in toluene (50.0 mL) and water (1.00 mL) was evacuated and purged with nitrogen. To this reaction mixture was added tetrakis(triphenylphosphine)palladium(0) (0.277 g, 0.240 mmol) and the resulting reaction mixture was heated at 100° C. for 10 h. After this time, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The resultant residue was purified by flash column chromatography (silica gel, hexanes/ethyl acetate 9:1) to provide methyl 3-(4-(3-(prop-1-en-2-yl)-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (0.377 g, 68%) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:27][OH:28])=[C:24]([CH:29]=[CH2:30])[N:23]=[C:22]3[O:31][CH2:32][CH3:33])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C.C>[OH-].[OH-].[Pd+2].O>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:27][OH:28])=[C:24]([CH2:29][CH3:30])[N:23]=[C:22]3[O:31][CH2:32][CH3:33])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: C=Cc1nc(OCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c1C=NO
Agent: [Pd+2]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1nc(CC)c(C=NO)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.3 %

Procedure:
Intermediate (17c) (3.5 g, 7.7 mmol) was dissolved in ethanol (100 mL, 2 mol). Pearlman's Catalyst, wet (0.1:0.4:0.5, palladium hydroxide:carbon black:water, 660 mg) was added. The mixture was degassed and stirred at room temperature under hydrogen for 3 hours. The palladium was filtered off and the solute was concentrated to yield intermediate (17d) (3.3 g). MS m/z: [M+H+] calcd for C26H31N3O4, 450.2. found 450.3.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][NH:13][C:12](=[O:16])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:18][CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31].O>CN(C)C=O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:18][CH2:19][CH2:20][N:21]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])[C:12](=[O:16])[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CCCN2C(=O)c3ccccc3C2=O)C(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
Sodium hydride (60% in oil, 1.78 g, 44.5 mmol) was added in a small portions to a stirred solution of 4-tert-butoxycarbonyl-2-oxopiperazine (8.00 g, 40.0 mmol) in N,N-dimethylformamide (100 ml) at room temperature and the mixture was stirred at room temperature for 1 hour. Then, N-(3-bromopropyl)phthalimide (12.5 g, 46.6 mmol) was added to the mixture. After stirring at room temperature for 1 hour, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was successively washed with water, brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel (150 g) with hexane-ehtyl acetate (1:1) to give 4-tert-butoxycarbonyl-1-(3-phthalimidopropan-1-yl)-2-oxopiperazine as a colorless oil (9.02 g, 55%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:22][C:23]([C:25]2([NH:40]C(=O)OC(C)(C)C)[CH2:30][CH2:29][N:28]([C:31]3[C:32]4[CH:39]=[CH:38][NH:37][C:33]=4[N:34]=[CH:35][N:36]=3)[CH2:27][CH2:26]2)=[O:24])[CH2:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)=[CH:11][CH:10]=1>ClCCl>[NH2:40][C:25]1([C:23]([NH:22][CH:15]([C:12]2[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=2)[CH2:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)=[O:24])[CH2:26][CH2:27][N:28]([C:31]2[C:32]3[CH:39]=[CH:38][NH:37][C:33]=3[N:34]=[CH:35][N:36]=2)[CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NC(Cc2nccs2)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1(C(=O)NC(Cc2nccs2)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 25 °C
Yield: 56.6 %

Procedure:
TFA (2.0 mL) was added to a suspension of tert-butyl 4-(1-(4-chlorophenyl)-2-(thiazol-2-yl)ethylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 96) (918 mg, 0.95 mmol) in dichloromethane (20 mL) under argon. The resulting solution was stirred at room temperature for one night. The solvents were removed in vacuo and the reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions were evaporated to dryness to afford 4-amino-N-(1-(4-chlorophenyl)-2-(thiazol-2-yl)ethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (259 mg, 56.8%) as a white powder.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)=O.[C:12](#[N:15])[CH:13]=C.C(N1CCOCC1)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(OC)C=CC=CC=1>[CH:7]([C:6]1[CH:10]=[CH:11][C:3]([CH:1]=[CH:13][C:12]#[N:15])=[CH:4][CH:5]=1)=[O:8]
Reactant: C=CC#N
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCN1CCOCC1
Solvent: COc1ccccc1
Product: N#CC=Cc1ccc(C=O)cc1
Temperature: 120 °C
Reaction time: 12 h
Yield: 50.9 %

Procedure:
0.0018 g (0.008 millimol) of palladium acetate, 6.74 g (40 millimols) of 4-formylbenzoyl chloride, 3.29 g (50 millimols) of acrylonitrile and 5.12 ml (40 millimols) of N-ethylmorpholine are added to 80 ml of anisole. The mixture is stirred for 12 hours at 120° C., under argon. The crude product is distilled in vacuo and is then recrystallised from isopropanol. 3.2 g (52% of theory) of 4-formylcinnamonitrile are obtained in the form of white crystals.
Reaction SMILES: [I:1][C:2]1[C:6]([C:7](O)=[O:8])=[CH:5][N:4]([CH3:10])[N:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2[C:20]([NH2:26])=[CH:21][CH:22]=[C:23]([F:25])[CH:24]=2)[CH:15]=[CH:16][C:17]=1[Cl:18].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[NH:26][C:7]([C:6]2[C:2]([I:1])=[N:3][N:4]([CH3:10])[CH:5]=2)=[O:8])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: Nc1ccc(F)cc1-c1ccc(Cl)c(Cl)c1
Reactant: Cn1cc(C(=O)O)c(I)n1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(C(=O)Nc2ccc(F)cc2-c2ccc(Cl)c(Cl)c2)c(I)n1
Yield: 56.5 %

Procedure:
At room temperature, 273 mg (1.0 mmol) of 3-iodo-1-methyl-1H-pyrazole-4-carboxylic acid, 213 mg (0.83 mmol) of 3′,4′-dichloro-5-fluorobiphenyl-2-amine, 0.3 ml (1.67 mmol) of N,N-diisopropyl-ethylamine and 583 mg (1.25 mmol) of bromotripyrrolidinophosphonium hexafluorophosphate were stirred in 5 ml of methylene chloride for 3 days. The mixture was washed with saturated sodium bicarbonate solution and then with water. Removal and concentration of the organic phase gave 910 mg of crude product. Purification by column chromatography on silica gel 60 using methylene chloride/diethyl ether 5:1 gave 230 mg (53.5% of theory) of N-(3′,4′-dichloro-5-fluoro-1,1′-biphenyl-2-yl)-3-iodo-1-methyl-1H-pyrazole-4-carboxamide (compound No. 6 from table 1) of log P (pH 2.3)=3.42.
Reaction SMILES: [CH:1](N1CCCCC1)=[O:2].[CH2:9]([CH:14]1[CH2:19][CH2:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([Li])=[C:22]([F:27])[C:21]=2[F:28])=[CH:16][CH2:15]1)[CH2:10][CH2:11][CH2:12][CH3:13].C1C=CC=CC=1.C([Li])CCC>O1CCCC1.O1CCCC1.CN(C)CCN(C)C>[CH2:9]([CH:14]1[CH2:19][CH2:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH:1]=[O:2])=[C:22]([F:27])[C:21]=2[F:28])=[CH:16][CH2:15]1)[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: [Li]c1ccc(C2=CCC(CCCCC)CC2)c(F)c1F
Reactant: O=CN1CCCCC1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCCCCC1CC=C(c2ccc(C=O)c(F)c2F)CC1
Temperature: -20 °C

Procedure:
0.12 mol of N-formylpiperidine in 20 ml of tetrahydrofuran is added at -70° C. to 0.1 mol of 4-(4-pentylcyclohex-1-enyl)-2,3-difluorophenyllithium (prepared from the benzene with n-butyllithium in tetrahydrofuran/tetramethylethylenediamine analogously to Example 1a)) and the mixture is warmed to -20° C. during the course of 1 hour. Acidifying and customary working up gives the aldehyde.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:21])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[NH:13][C:14]1[CH:15]=[N:16][C:17]([F:20])=[CH:18][CH:19]=1)=[O:4].Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][NH:27]3)[CH3:21])=[C:7]([NH:13][C:14]2[CH:15]=[N:16][C:17]([F:20])=[CH:18][CH:19]=2)[CH:8]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)C(=O)Nc1ccc(F)cc1Nc1ccc(F)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)C(=O)Nc1ccc(F)cc1Nc1ccc(F)nc1
Temperature: 100 °C
Yield: 94.1 %

Procedure:
A mixture of (S)-2-amino-N-[4-fluoro-2-(6-fluoropyridin-3-ylamino)phenyl]propionamide (193 mg, 0.66 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (165 mg, 0.69 mmol) and DIPEA (0.34 mL, 1.98 mmol) in n-butanol (1 mL) was heated at 100° C. in a sealed vial for 16 h. After cooling to RT, the volatiles were removed in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge then washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to afford the title compound as a red solid (255 mg, 94%). LCMS (Method C): RT 2.40 min [M+H]+ 411.2.