Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][C:10]([C:13]([OH:15])=O)=[N:9]2)=[CH:4][C:3]=1[CH3:16].C(OC([N:24]1[CH2:29][CH2:28][NH:27][C:26]([CH3:31])([CH3:30])[CH2:25]1)=O)(C)(C)C.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].CC1(C)CNCCN1C(C1N=CN(C2C=CC=CC=2)N=1)=O>>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[CH3:30][C:26]1([CH3:31])[CH2:25][NH:24][CH2:29][CH2:28][N:27]1[C:13]([C:10]1[N:11]=[CH:12][N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:16])[CH:4]=2)[N:9]=1)=[O:15]
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Reactant: Cc1cc(-n2cnc(C(=O)O)n2)ccc1F
Agent: CC1(C)CNCCN1C(=O)c1ncn(-c2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-n2cnc(C(=O)N3CCNCC3(C)C)n2)ccc1F

Procedure:
This intermediate was prepared from 1-(4-fluoro-3-methyl-phenyl)-1H-[1,2,4]triazole-3-carboxylic acid and 3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester in two steps according to the preparation of (2,2-dimethyl-piperazin-1-yl)-(1-phenyl-1-H-[1,2,4]-triazol-3-yl)-methanone trifluoroacetate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[O:15][CH:14]([CH2:17][NH2:18])[CH2:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>>[CH2:32]([O:31][C:29](=[O:30])[NH:18][CH2:17][CH:14]1[CH2:13][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)[C:16]=2[O:15]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cc1ccc(-c2cccc3c2OC(CN)C3)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cccc3c2OC(CNC(=O)OCc2ccccc2)C3)cc1
Yield: 92.6 %

Procedure:
Treatment of (±)-[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (0.385 g, 1.396 mmol) with diisopropylethylamine (0.270 g, 2.09 mmol) and benzyl chloroformate (0.285 g, 1.675 mmol) generally according to the procedure described for Intermediate 12 provided 0.483 g (93%) of (±)-benzyl[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as colorless oil. Rf=0.47 (silica, ethyl acetate:hexane 2:8); mp 83-86° C.; Anal. calcd. for C24H23NO3: C, 77.19; H, 6.21; N, 3.75. Found: C, 76.97; H, 5.99; N, 3.68. Chiral HPLC separation of (±)-benzyl[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralpak OD, methanol:carbon dioxide 1:1) provided two fractions. Fraction 1 (Rt=3.788 min Chiralpak OD, methanol:carbon dioxide 1:1); Fraction 2 (Rt=4.398 min, Chiralpak OD, methanol:carbon dioxide 1:1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH:14]1[C:22]2[C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[S:19][C:18]=2[C:17]([C:27]2[CH:28]=[C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35](B(O)O)[CH:34]=3)[CH:30]=[CH:31][CH:32]=2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C(O)C>[CH:14]1[C:22]2[C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[S:19][C:18]=2[C:17]([C:27]2[CH:28]=[C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:2]4[CH:7]=[C:6]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)[N:5]=[CH:4][N:3]=4)[CH:34]=3)[CH:30]=[CH:31][CH:32]=2)=[CH:16][CH:15]=1
Reactant: Clc1cc(-c2ccccc2)ncn1
Reactant: OB(O)c1cccc(-c2cccc(-c3cccc4c3sc3ccccc34)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc(-c2cc(-c3cccc(-c4cccc(-c5cccc6c5sc5ccccc56)c4)c3)ncn2)cc1
Temperature: 80 °C
Yield: 71 %

Procedure:
Then, 1.0 g of 4-chloro-6-phenylpyrimidine obtained in Step 1, 2.0 g of 3′-(dibenzothiophen-4-yl)-3-biphenylboronic acid, 5.3 mL of a 2M aqueous solution of potassium carbonate, 24 mL of toluene, and 3.0 mL of ethanol were put into a 100-mL three-neck flask equipped with a reflux pipe. Degasification by stirring under a reduced pressure was performed and the air in the flask was replaced with nitrogen. To this mixture, 61 mg of tetrakis(triphenylphosphine)palladium(0) (abbreviation: Pd(PPh3)4) was added and the mixture was heated at 80° C. for 7 hours to cause a reaction. An organic layer was extracted from the obtained mixture with the use of toluene and was washed with water and a saturated aqueous solution of sodium chloride. Anhydrous magnesium sulfate was added and gravity filtration was performed. After the solvent in this solution was distilled off, the obtained residue was dissolved in hot toluene and subjected to hot filtration through a filter aid in which Celite, alumina, Celite, Florisil, and Celite were stacked in this order. The solvent was distilled off and the obtained solid was recrystallized with toluene, so that 1.9 g of a white solid was obtained in a yield of 71%. Synthesis Scheme (D-2) of Step 2 is shown below.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][C:16](=[O:18])[NH:15][C:14]([CH3:19])=[C:13]1[C:20](O)=[O:21].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[Cl:34][C:35]1[C:43]2[C:38](=[CH:39][C:40]([F:45])=[C:41]([NH2:44])[CH:42]=2)[NH:37][N:36]=1>C(Cl)Cl.N1C=CC=CC=1.CCOC(C)=O.Cl>[Cl:34][C:35]1[C:43]2[C:38](=[CH:39][C:40]([F:45])=[C:41]([NH:44][C:20]([C:13]3[CH:12]([C:3]4[CH:4]=[CH:5][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:7][C:2]=4[F:1])[CH2:17][C:16](=[O:18])[NH:15][C:14]=3[CH3:19])=[O:21])[CH:42]=2)[NH:37][N:36]=1
Reactant: CC1=C(C(=O)O)C(c2ccc(C(F)(F)F)cc2F)CC(=O)N1
Reactant: Nc1cc2c(Cl)n[nH]c2cc1F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC1=C(C(=O)Nc2cc3c(Cl)n[nH]c3cc2F)C(c2ccc(C(F)(F)F)cc2F)CC(=O)N1
Temperature: 25 °C
Yield: 7.1 %

Procedure:
The product from Example 21, Step 2 (1.0 g, 3.152 mmol, 1.0 equiv) and oxalyl chloride (330 μL, 3.783 mmol, 1.2 equiv) in CH2Cl2 (12.5 mL) with catalytic DMF (20 μL) was stirred at room temperature for 45 minutes. The reaction mixture was concentrated en vacuo and half was redissolved in CH2Cl2 (5 mL). This solution was added dropwise over 5 minutes to a solution of the product from Example 39, step 2 (322 mg, 1.733 mmol, 1.1 equiv) in pyridine (4 mL) at −20° C. The reaction mixture was slowly warmed to room temperature over 3 hours. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was concentrated en vacuo. The residue was purified by flash chromatography (0-80% EtOAc in Hexanes) and further purified by reverse-phase HPLC (20-90% CH3CN/H2O, 0.1TFA over 13 minutes, retention time 8.11 min) to provide 60 mg (8%) of the title compound as a white solid. MS (ES+) m/e 485 [M+H]+
Reaction SMILES: [OH:1][P:2]([O-:5])([OH:4])=[O:3].[K+].C([O-])([O-])=O.[Ca+2:11]>O>[P:2]([O-:5])([O-:4])([O-:3])=[O:1].[Ca+2:11].[P:2]([O-:5])([O-:4])([O-:3])=[O:1].[Ca+2:11].[Ca+2:11]
Reactant: O=P([O-])(O)O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Agent: [K+]
Solvent: O
Product: O=P([O-])([O-])[O-]
Reaction time: 0.5 h

Procedure:
204 g of KH2PO4 was introduced into a receptacle containing 0.750 l of water at an ambient temperature of 20° C. After gentle stirring, 250 g of CaCO3 having an average particle size of 200 μm were introduced into the receptacle. The assembly was then stirred for 30 minutes using an Ultra Turrax machine equipped with an S25 KV25F spindle. This spindle was equipped at its submerged end with a rotor having an outer diameter of 18 mm, inserted into a stator having an outer diameter of 25 mm. The “gap” between the rotor and the stator was 0.5 mm. The rotor rotated at a speed of 9500 rpm. During the stirring, the pH was stabilized at 7.5. At the end of the stirring, a calcium phosphate gel was obtained containing 33% of solids and whose viscosity was 300 centipoise.
Reaction SMILES: FC(F)(F)S(O[CH:7]([C:12]1[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:8]([F:11])([F:10])[F:9])(=O)=O.[CH3:21][N:22]([C@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]>>[Cl:18][C:15]1[N:14]=[CH:13][C:12]([CH:7]([N:32]2[CH2:33][CH2:34][C@H:30]([N:22]([CH3:21])[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH2:31]2)[C:8]([F:11])([F:10])[F:9])=[CH:17][CH:16]=1
Reactant: O=S(=O)(OC(c1ccc(Cl)nc1)C(F)(F)F)C(F)(F)F
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCNC1
Product: CN(C(=O)OC(C)(C)C)[C@H]1CCN(C(c2ccc(Cl)nc2)C(F)(F)F)C1
Yield: 66.8 %

Procedure:
Prepared as described in Example 1, Step C, using 1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (1.50 g, 4.37 mmol) and (S)-tert-butyl methyl(pyrrolidin-3-yl)carbamate (1.2 g, 6.11 mmol) to afford tert-butyl (3S)-1-(1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-yl(methyl)carbamate (1.15 g, 67%).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[C:7]=1[CH3:13])([CH3:3])[CH3:2].O1CCOCC1.C(N(CC)CC)C.[CH3:28][C:29]1([CH3:36])[C:33]([CH3:35])([CH3:34])[O:32][BH:31][O:30]1>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.O.CCOC(C)=O>[CH:1]([O:4][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([B:31]2[O:32][C:33]([CH3:35])([CH3:34])[C:29]([CH3:36])([CH3:28])[O:30]2)[C:7]=1[CH3:13])([CH3:3])[CH3:2]
Reactant: CC1(C)OBOC1(C)C
Reactant: Cc1c(Br)cccc1C(=O)OC(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1C(=O)OC(C)C
Temperature: 100 °C
Reaction time: 16 h
Yield: 43 %

Procedure:
A 2-dram vial with a septa-containing screwcap was charged with a stirbar, 3-bromo-2-methyl-benzoic acid isopropyl ester ((Example 3: step a) 257 mg, 1 mmol), PdCl2(PPh3)2 (42 mg, 0.06 mmol), dioxane (4 mL), and triethylamine (420 μL, 3 mmol). Upon dissolution, 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (220 μL, 1.5 mmol) was added and the solution was vigorously stirred for 16 h at 100° C. After cooling to rt, EtOAc (30 mL) and water (10 mL) were added (gas evolution!) and the layers were separated. The organic layer was washed with NaHCO3 (2×10 mL), brine (10 mL), and was dried over sodium sulfate. Removal of the solvents in vacuo followed by SiO2 flash chromatography of the residue yielded the title compound (130 mg, 43%) as a light-yellow glass. 1H-NMR (CDCl3): δ 7.86 (dd, 1H, J=1.4, 7.4 Hz), 7.80 (dd, 1H, J=1.6, 7.7 Hz), 7.23 (t, 1H, J=7.7 Hz), 5.26 (heptet, 1H, J=6.3 Hz), 2.75 (s, 3H), 1.37 (m, 18H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH:10]=2)O1.Cl[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25]>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[N+:24]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:18]=1[C:9]1[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH:10]=1)([O-:26])=[O:25]
Reactant: CC1(C)OB(C2=CC(=O)CCC2)OC1(C)C
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C1C=C(c2ccncc2[N+](=O)[O-])CCC1
Temperature: 110 °C
Yield: 55 %

Procedure:
To a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-enone (1.0 equiv.) in degassed dioxane and 2M Na2CO3 was added 4-chloro-3-nitropyridine (1.2 equiv.) and Pd(dppf)Cl2-DCM (0.05 equiv.). The reaction was heated in an oil bath to 110° C. for 2 hours. Cooled to room temperature, then diluted with EtOAc, added H2O— dark solution, lots of emulsions. Filtered to get rid of the solids, then extracted the organic phase, dried with Na2SO4, and concentrated. The crude was purified via silica gel chromatography eluting with ethyl acetate and hexanes (1:1) to yield 3-(3-nitropyridin-4-yl)cyclohex-2-enone (55%, 2 steps). LC/MS=219 (M+H), LC=2.294 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][C:11]#[N:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.O.Cl.[OH-].[Na+]>COCCOC>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][CH2:10][CH2:11][NH2:12])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: N#CCSc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: NCCSc1cc(Cl)cc(Cl)c1
Yield: 81.8 %

Procedure:
To a solution of (3,5-dichlorophenylthio)acetonitrile (1.2g) in 3.0 mL of ethylene glycol dimethyl ether is added 0.61 mL of 10M borane dimethyl sulfide complex and the mixture heated at reflux for 0.5 hours. The reaction is cooled in an ice bath and 2.0 mL of water and 2.0 mL of concentrated hydrochloric acid is added. This mixture is heated at reflux for 0.5 hr. The clear solution is then cooled and basified with 5N sodium hydroxide and extracted with ether. The ether extract is dried over potassium carbonate, filtered and concentrated to give 1.0 g of a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][S:5][CH2:4][C:3]1=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:23])[C:16]([O:18]C(C)(C)C)=[O:17])=[CH:11][CH:10]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[O:1]=[C:2]1[CH2:7][CH2:6][S:5][CH2:4][C:3]1=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:23])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1
Reactant: CC(C(=O)OC(C)(C)C)c1ccc(C=C2CSCCC2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC(C(=O)O)c1ccc(C=C2CSCCC2=O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.5 %

Procedure:
tert-Butyl 2-[4-(4-oxothian-3-ylidenemethyl)phenyl]propionate (220 mg) obtained in Example 1 was dissolved in chloroform (2.0 ml), to the solution was added trifluoroacetic acid (2.0 ml), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with water, and extracted with chloroform. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/2) to give the title compound (160 mg, 87%).
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21](/[C:23](/[CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:24]\[C:25]([NH2:27])=[O:26])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[H][H]>C(Cl)Cl.C(O)C(F)(F)F>[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C@H:23]([CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[CH2:24][C:25]([NH2:27])=[O:26])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]
Reactant: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn(/C(=C\C(N)=O)C4CCCC4)c3)ncnc21
Reactant: [H][H]
Solvent: OCC(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn([C@@H](CC(N)=O)C4CCCC4)c3)ncnc21
Temperature: 50 °C
Reaction time: 20 h

Procedure:
A solution of (4-{1-[(1Z)-3-amino-1-cyclopentyl-3-oxoprop-1-en-1-yl]-1H-pyrazol-4-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (10, 215 mg) in a mixture of methylene chloride (CH2Cl2, 12.5 mL) and trifluoroethanol (CF3CH2OH, 0.25 mL) in a pressure glass tube was treated with the catalyst Rh(COD)(SSRR-TangPhos)BF4 (8.8 mg) under nitrogen before the reaction mixture was pressurized with hydrogen gas to 40 bar pressure. The reaction mixture was stirred at 50° C. under this hydrogen pressure for 20 h. When HPLC analysis showed that the substrate was completely consumed, the reaction mixture was cooled down to room temperature. The enantiomeric excess of the reaction mixture was determined to be 88% ee (94% of the first peak, (S)-11; 6% of the second peak, (R)-11) by chiral HPLC analysis. The reaction mixture was filtered through a thin silica gel pad and the pad was washed with methylene chloride (5 mL). The filtrate was then concentrated under reduced pressure to dryness. The resultant foamy solid (180 mg) was charged with a mixture of heptane (5 mL) and ethyl acetate (EtOAc, 5 mL). White solids precipitated out upon stirring at 20° C. The slurry was stirred at 20° C. for 16 h. The solid was collected by filtration and the chiral HPLC analysis for the collected solids (52 mg) showed a 66.0% of enantiomeric excess favoring the first peak (83.0% of the first peak, (S)-11; 17.0% of the second peak, (R)-11). The filtrate obtained was then evaporated to dryness. The resultant oil (108 mg) was analyzed by chiral HPLC and showed a 99.6% of enantiomeric excess favoring the first peak (99.83% of the first peak, (S)-11; 0.17% of the second peak, (R)-11). This result showed in principle that the optical purity of the asymmetric hydrogenation product can be significantly enhanced by selective removal of the minor enantiomer by precipitation of the solid using a suitable solvent system such as ethyl acetate/heptane as described.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][NH:20][C:19](=[O:23])[CH:18]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3].CS(OC1CCN(C(OC(C)C)=O)CC1)(=O)=O.F[C:42]1[CH:47]=[CH:46][C:45]([S:48]([CH3:51])(=[O:50])=[O:49])=[CH:44][C:43]=1[CH3:52].BrC1C=CC(C#N)=CC=1.C(=O)([O-])[O-].[K+].[K+].N1C2C(=CC=CC=2O)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]I>[CH3:52][C:43]1[CH:44]=[C:45]([S:48]([CH3:51])(=[O:50])=[O:49])[CH:46]=[CH:47][C:42]=1[N:20]1[CH:21]=[CH:22][C:17]([O:16][CH:13]2[CH2:14][CH2:15][N:10]([C:7]3[N:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][N:6]=3)[CH2:11][CH2:12]2)=[CH:18][C:19]1=[O:23]
Reactant: CCCc1cnc(N2CCC(Oc3cc[nH]c(=O)c3)CC2)nc1
Reactant: Cc1cc(S(C)(=O)=O)ccc1F
Agent: [Cu]I
Agent: CC(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: N#Cc1ccc(Br)cc1
Product: CCCc1cnc(N2CCC(Oc3ccn(-c4ccc(S(C)(=O)=O)cc4C)c(=O)c3)CC2)nc1

Procedure:
Example 178 was prepared according to the procedures described in Example 162 substituting 4-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)pyridin-2(1H)-one for isopropyl 4-(methylsulfonyloxy)piperidine-1-carboxylate and 1-fluoro-2-methyl-4-(methylsulfonyl)benzene for 4-bromobenzonitrile in Step C except that the reaction was heated at 160° C. for 20 min. with copper(I) iodide, potassium carbonate and quinolin-8-ol in a Microwave as described in Step A of Example 1 instead of reflux at 120° C. in the presence of cesium carbonate for 10 h. 1H NMR (500 MHz, CDCl3) δ ppm 8.21 (br. s., 2 H), 7.92 (s, 1 H), 7.88 (d, J=7.70 Hz, 1 H), 7.40 (d, J=7.70 Hz, 1H), 7.06 (d, J=6.05 Hz, 1 H), 5.93-6.11 (m, 2 H), 4.58 (br. s., 1 H), 4.21 (br. s., 2 H), 3.56-3.80 (m, 2 H), 3.08 (s, 3 H), 2.41 (t, J=7.42 Hz, 2 H), 2.28 (s, 3 H), 2.09 (d, J=9.90 Hz, 2 H), 1.87 (br. s., 2 H), 1.48-1.65 (m, 2 H), 0.93 (t, J=7.42 Hz, 3H). MS (ESI) 483 (M+H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[CH3:8][C:9]1[C:17]([CH3:18])=[C:16]2[C:12]([CH2:13][CH2:14][NH:15]2)=[CH:11][C:10]=1[OH:19]>C(O)=O>[OH:19][C:10]1[CH:11]=[C:12]2[C:16](=[C:17]([CH3:18])[C:9]=1[CH3:8])[N:15]([CH:1]=[O:3])[CH2:14][CH2:13]2
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(O)cc2c(c1C)NCC2
Solvent: O=CO
Product: Cc1c(O)cc2c(c1C)N(C=O)CC2
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 95.9 %

Procedure:
To formic acid (100 mL) was added acetic anhydride (23 mL, 0.24 mol) under ice-cooling, and the mixture was stirred at room temperature for 40 minutes. To this solution was added 2,3-dihydro-6,7-dimethyl-1H-indole-5-ol (20.0 g, 0.12 mol) under ice-cooling, and the mixture was stirred at room temperature for 75 minutes. The reaction mixture was concentrated under reduced pressure, and dissolved in the mixture of chloroform-methanol. To this was added an aqueous solution of sodium bicarbonate solution to neutralize, the organic layer was separated, and the aqueous layer was extracted with chloroform three times. The combined organic layers were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The solid was washed with diisopropyl ether to obtain 22.0 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]1[O:14][CH2:13][CH2:12][O:11]1.[C:15]([N:19]1[C@H:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][O:21][C:20]1=[O:30])(=[O:18])[CH:16]=[CH2:17].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:11]1[CH2:12][CH2:13][O:14][CH:10]1[C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1/[CH:17]=[CH:16]/[C:15]([N:19]1[C@H:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][O:21][C:20]1=[O:30])=[O:18]
Reactant: C=CC(=O)N1C(=O)OC[C@H]1c1ccccc1
Reactant: COc1ccc(Br)c(C2OCCO2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: COc1ccc(/C=C/C(=O)N2C(=O)OC[C@H]2c2ccccc2)c(C2OCCO2)c1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
A mixture of Compound 20 (2.6 g, 10.0 mmol), (R)-3-acryloyl-4-phenyloxazolidin-2-one (2.2 g, 10.0 mmol), tri-o-tolyl phosphine (0.30 g, 1.0 mmol) and palladium acetate (0.11 g, 0.5 mmol) in triethylamine (35 mL) under argon was stirred under reflux for 90 min. The resulting reaction mixture was cooled to room temperature and concentrated in vacuo. The residue obtained was purified by flash column chromatography (hexanes/ethyl acetate 95:5 to 60:40) to give Compound 21 (3.2 g, 81%) as a light yellow oil: 1H NMR (500 MHz, CDCl3) δ 8.19 (d, J=15.5 Hz, 1H), 7.81 (d, J=15.5 Hz, 1H), 7.40 (d, J=8.5 Hz, 1H), 7.41-7.30 (m, 5H), 7.17 (d, J=3.0 Hz, 1H), 6.91 (dd, J=8.5, 3.0 Hz, 1H), 6.01 (s, 1H), 5.54 (dd, J=9.0, 3.5 Hz, 1H), 4.73 (t, J=9.0 Hz, 1H), 4.30 (dd, J=9.0, 4.0 Hz, 1H), 4.32-4.28 (m, 2H), 4.13-4.10 (m, 2H), 3.85 (s, 3H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[CH:4][CH:3]=1.[C:16]([NH:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])(=[O:19])[CH:17]=[CH2:18].C(N(CC)C(C)C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CN(C=O)C>[CH3:9][O:8][C:6]1[N:7]=[C:2](/[CH:18]=[CH:17]/[C:16]([NH:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:19])[CH:3]=[CH:4][C:5]=1[N:10]1[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]1
Reactant: COc1nc(Br)ccc1-n1cnc(C)c1
Reactant: C=CC(=O)NNC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1nc(/C=C/C(=O)NNC(=O)OC(C)(C)C)ccc1-n1cnc(C)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 87.2 %

Procedure:
DMF (52 mL) was added to the 6-Bromo-2-methoxy-3-(4-methyl-1H-imidazol-1-yl)pyridine (13.0 g, 48.5 mmol) and the tert-Butyl 2-acryloylhydrazinecarboxylate (9.9 g, 53.3 mmol) at room temperature under nitrogen atmosphere, And the mixture was stirred at 50° C. for 10 minutes. Tri(o-tolyl)phosphine (885 mg, 2.90 mmol), Palladium (II) acetate (327 mg, 1.45 mmol) and N,N-diisopropylethylamine (12.7 mL, 72.7 mmol) were added to the mixture, and the reaction mixture was stirred at 100° C. for 4 hours. The reaction mixture was cooled to room temperature and filtrated through Celite. The residue was washed twice with DMF (6 mL). Water (104 mL) was added dropwise to the filtrate at room temperature over 10 minutes. The mixture was stirred at room temperature for 15 hours. After the mixture was filtrated, the residue was washed with water/DMF=2:1 (30 mL) and MTBE (30 mL). The obtained solid was suspended in MTBE (50 mL) at room temperature for 2 hours, filtrated and dried under the reduced pressure to obtain the title compound (15.8 g, 87% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([CH2:26][N:27]5[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]5)=[CH:22][CH:21]=4)[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4[CH:21]=[CH:22][C:23]([CH2:26][N:27]5[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]5)=[CH:24][CH:25]=4)[N:14]=3)=[CH:11][N:10]([CH2:37][CH2:36][N:35]([CH3:39])[CH3:34])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CN1CCN(Cc2ccc(Nc3nccc(-c4c[nH]nc4-c4ccc(Cl)cc4)n3)cc2)CC1
Reactant: CN(C)CCO
Product: CN(C)CCn1cc(-c2ccnc(Nc3ccc(CN4CCN(C)CC4)cc3)n2)c(-c2ccc(Cl)cc2)n1

Procedure:
The title compound is prepared as described in Example 55, starting from {4-[3-(4-chloro-phenyl)1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl-methyl)-phenyl]-amine (Example 32) and 2-dimethylamino-ethanol (Fluka).