Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[CH:2][CH2:3][N:4]([CH2:10][CH:11]=[CH2:12])[C:5](=[O:9])[O:6][CH2:7][CH3:8].[C:13]1([C@H:19]([NH:21][CH2:22]C(O)=O)[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[C:13]1([C@H:19]([N:21]2[C@@H:2]3[C@@H:11]([CH2:10][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:3]3)[CH2:12][CH2:22]2)[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=CCN(CC=O)C(=O)OCC
Reactant: C[C@@H](NCC(=O)O)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1C[C@H]2CCN([C@H](C)c3ccccc3)[C@H]2C1
Yield: 38.5 %

Procedure:
A mixture of ethyl N-(2-oxoethyl)-N-prop-2-enylcarbamate (Intermediate 41, 466 g, 2.7 mol) and 2-{[(1R)-1-phenylethyl]amino}acetic acid (Intermediate 43A, 490 g, 2.7 mol) in toluene (4 L) was refluxed overnight. The resulting mixture was filtered and the filtrate was concentrated in vacuo. Purification by FCC, eluting with 10:1 petrol-EtOAc, gave the title compound (300 g, 38%) as red oil; 1H NMR: (CDCl3) 1.10-1.40 (8H, m), 1.55 (1H, m), 1.90 (1H, m), 2.45 (1H, m), 2.77 (1H, m), 3.20-3.65 (5H, m), 4.10-4.20 (2H, m), 7.25-7.38 (5H, m).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:29])[CH2:13][O:14][C:15]1[CH:16]=[C:17]([NH:21]C(=O)OC(C)(C)C)[CH:18]=[CH:19][CH:20]=1.Cl.C(OCC)(=O)C>C(OCC)(=O)C>[NH2:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[O:14][CH2:13][CH:12]([OH:29])[CH2:11][N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1
Reactant: CC(C)(C)OC(=O)Nc1cccc(OCC(O)CN2CCc3ccccc3C2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1cccc(OCC(O)CN2CCc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (3-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropoxy)phenyl)carbamate (1.2 g, 3.01 mmol) in ethyl acetate (30 mL) was added HCl/ethyl acetate (20 mL). The reaction mixture was stirred at room temperature for 2 h. and the concentrated with the residue used in the next step without further purification.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([CH2:25][CH3:26])=[C:18]3[N:23]([CH:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19]3)=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:27][C:28](=[O:31])[C:29]#[CH:30]>>[C:28]([C:29]1[CH:30]=[C:24]2[N:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=13)[C:17]([CH2:25][CH3:26])=[C:16]2[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])=[CH:11][CH:12]=1)(=[O:31])[CH3:27]
Reactant: CCc1c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2)cn2ccccc12
Reactant: C#CC(C)=O
Product: CCc1c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2)c2cc(C(C)=O)c3cccc1n32
Yield: 45 %

Procedure:
2-(4-(tert-Butyldimethylsilanyloxymethyl)phenyl)-1-ethylindolizine was reacted with 3-butyn-2-one by the general synthetic principles outlined in example 73, step 1, to afford 4-acetyl-2-(4-(tert-butyldimethylsilanyloxymethyl)phenyl)-1-ethylpyrrolo[2,1,5-cd]indolizine in 45% yield. 1H-NMR (CDCl3, 200 MHz) δ: 0.17 (s, 6H); 0.99 (s, 9H); 1.47 (t, 3H); 2.72 (s, 3H); 3.22 (q, 2H); 4.86 (s, 2H); 7.51 (d, 2H); 7.74 (d, 2H); 7.80-7.96 (m, 3H); 8.48 (dd, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][CH3:11])[CH:6]=[C:5]([O:12][CH3:13])[C:4]=1[C:14]1[N:15]2[N:23]=[C:22]([CH3:24])[C:21]([N:25]([CH2:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28])=[C:16]2[S:17][C:18]=1[S:19][CH3:20].ClC1C=CC=C(C(OO)=[O:40])C=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:13][O:12][C:5]1[CH:6]=[C:7]([CH2:9][O:10][CH3:11])[CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[C:14]1[N:15]2[N:23]=[C:22]([CH3:24])[C:21]([N:25]([CH2:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28])=[C:16]2[S:17][C:18]=1[S:19]([CH3:20])=[O:40]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCN(CCC)c1c(C)nn2c(-c3c(OC)cc(COC)cc3OC)c(SC)sc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCN(CCC)c1c(C)nn2c(-c3c(OC)cc(COC)cc3OC)c(S(C)=O)sc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.4 %

Procedure:
To a dichloromethane (670 μl) solution of 3-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-6-methyl-2-(methylthio)-N,N-dipropylpyrazolo[5,1-b][1,3]thiazole-7-amine (31.5 mg, 0.068 mmol) was added 3-chloroperbenzoic acid (23.4 mg, 0.136 mmol), and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture, a saturated aqueous solution of sodium carbonate was added, the mixture was extracted with dichloromethane, and then, the organic layer was dried over anhydrous magnesium sulfate. The mixture was filtered to yield a filtrate, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by thin-layer silica gel chromatography (chloroform:methanol=12:1) to obtain 7.3 mg (0.0152 mmol) of the title compound.
Reaction SMILES: [C:1]1([CH2:7][C:8](O)([CH3:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:12]>>[C:1]1([CH2:7][C:8]([Cl:12])([CH3:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cl
Reactant: CC(C)(O)Cc1ccccc1
Product: CC(C)(Cl)Cc1ccccc1
Reaction time: 1 h

Procedure:
A mixture of 5.92 g (40 mmol) of 1-phenyl-2-hydroxy-2-methylpropane and 50 mL of conc. hydrochloric acid was stirred at ice bath temperature for 1 h and at RT for 3 h. The reaction mixture was then extracted with ether. The organic layer was dried over MgSO4. Solvent removal gave 1-phenyl-2-chloro-2-methylpropane.
Reaction SMILES: C([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22]([NH:24][C:25]3[CH:44]=[CH:43][C:28]([O:29][CH:30]4[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]4)=[C:27]([Cl:45])[CH:26]=3)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[CH:16]1)(=O)C1C=CC=CC=1.O>CO.O1CCCC1.[OH-].[Na+]>[Cl:45][C:27]1[CH:26]=[C:25]([NH:24][C:22]2[C:23]3[N:15]([CH2:14][CH2:13][O:12][CH2:11][CH2:10][OH:9])[CH:16]=[CH:17][C:18]=3[N:19]=[CH:20][N:21]=2)[CH:44]=[CH:43][C:28]=1[O:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])[CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Nc3ncnc4ccn(CCOCCOC(=O)c5ccccc5)c34)cc2Cl)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Nc3ncnc4ccn(CCOCCO)c34)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
tert-Butyl 4-{4-[(5-{2-[2-(benzoyloxy)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino]-2-chlorophenoxy}piperidine-1-carboxylate (636 mg) was dissolved in a mixed solvent of methanol (10 mL) and tetrahydrofuran (10 mL), 1N aqueous sodium hydroxide solution (2 mL) was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to basic silica gel column chromatography (eluent, methanol:ethyl acetate=0:100→10:90). The object fraction was concentrated under reduced pressure. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from ethyl acetate-diethyl ether to give the title compound (498 mg) as a white powder.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][CH:8]=[CH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:11]=2)=[CH:5][N:4]=[CH:3]1.N1C(C/C=C/C2C=CC(C(O)=O)=C(C3C=CC(F)=CC=3)C=2)=CN=C1>>[CH3:1][N:2]1[C:6]([CH2:7][CH:8]=[CH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[C:12]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH:11]=2)=[CH:5][N:4]=[CH:3]1
Reactant: COC(=O)c1ccc(C=CCc2cncn2C)cc1-c1ccc(F)cc1
Agent: O=C(O)c1ccc(/C=C/Cc2cnc[nH]2)cc1-c1ccc(F)cc1
Product: Cn1cncc1CC=Cc1ccc(C(=O)O)c(-c2ccc(F)cc2)c1

Procedure:
4-[3-(1-Methylimidazol-5-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoic acid was prepared from methyl 4-[3-(1-methylimidazol-5-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate using a similar method to that described for 4-[(E)-3-(imidazol-5-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoic acid in Example 37.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[CH:4][N:3]=1.[C:11]1([NH:17][C:18]([N:20]2[C:28]3[C:23](=[CH:24][C:25]([NH2:29])=[CH:26][CH:27]=3)[CH:22]=[CH:21]2)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.N1C=CC=CC=1.C(OCC)C>C(OC(O)C)C>[C:11]1([NH:17][C:18]([N:20]2[C:28]3[C:23](=[CH:24][C:25]([NH:29][C:6]4[C:5]([C:9]#[N:10])=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=4)=[CH:26][CH:27]=3)[CH:22]=[CH:21]2)=[O:19])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc2c(ccn2C(=O)Nc2ccccc2)c1
Reactant: N#Cc1cnc(N)cc1Cl
Agent: CCOC(C)O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: N#Cc1cnc(N)cc1Nc1ccc2c(ccn2C(=O)Nc2ccccc2)c1
Temperature: 130 °C
Reaction time: 4 h
Yield: 35.7 %

Procedure:
2-Amino-4-chloro-5-cyanopyridine (200 mg, 1.30 mmol, Production example 215-3) was dissolved in ethoxyethanol (13.0 ml); 5-aminoindole-1-carboxylic acid phenylamide (408 mg, 1.62 mmol, Production example 201-2) and pyridine hydrochloride (315 mg, 2.73 mmol) were added thereto; and the reaction mixture was heated and stirred at 130° C. for 4 hours. After cooling to room temperature, the reaction mixture was partitioned between a saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate; the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia NH, hexane:ethyl acetate=2:3, ethyl acetate, ethyl acetate:methanol=95:5 in this order). The pale yellow oil obtained was solidified with diethyl ether; the crystals were suspended with diethyl ether, filtered off, washed with diethyl ether, and dried to yield the title compound (171 mg, 0.464 mmol, 35.7%) as colorless crystals.
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.[Mg].Br[C:14]1[CH:22]=[CH:21][C:17]2[O:18][CH2:19][O:20][C:16]=2[CH:15]=1>C1COCC1>[O:18]1[C:17]2[CH:21]=[CH:22][C:14]([C:7]3([OH:10])[CH2:6][CH2:5][C:4]4([O:3][CH2:2][CH2:1][O:11]4)[CH2:9][CH2:8]3)=[CH:15][C:16]=2[O:20][CH2:19]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Brc1ccc2c(c1)OCO2
Agent: [Mg]
Solvent: C1CCOC1
Product: OC1(c2ccc3c(c2)OCO3)CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 85.3 %

Procedure:
A solution of 1,4-cyclohexanedione monoethylene ketal (31.2 g, 0.2 mole) in 100 ml dry THF was added to a -60° C. solution of the Grignard reagent prepared from magnesium metal (7.2 g, 0.3 mole) and 5-bromo-1,3-benzodioxole (60.3 g, 0.3 mole). The mixture was allowed to warm to 25° C. and quenched with saturated NH4Cl and extracted with ether. The extracts were dried with Na2SO4 and the solvent removed in vacuo. The residue was crystallized from isopropyl ether to give the product (47.5 g, 85%, m.p: 103°-104° C.).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH3:26][C:27]1([CH3:61])[C:51]2[C:31]([CH:32]=[C:33]3[CH:50]=[C:49]4[C:36]([C:37]5[C:42]([C:43]6[C:48]4=[CH:47][CH:46]=[CH:45][CH:44]=6)=[CH:41][CH:40]=[CH:39][CH:38]=5)=[CH:35][C:34]3=2)=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28]1.C([O-])([O-])=O.[Na+].[Na+].CCO>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.C1(C)C=CC=CC=1>[CH3:61][C:27]1([CH3:26])[C:51]2[C:31]([CH:32]=[C:33]3[CH:50]=[C:49]4[C:36]([C:37]5[C:42]([C:43]6[C:48]4=[CH:47][CH:46]=[CH:45][CH:44]=6)=[CH:41][CH:40]=[CH:39][CH:38]=5)=[CH:35][C:34]3=2)=[CH:30][C:29]([C:2]2[C:3]3[C:8]([C:9]([C:16]4[CH:25]=[CH:24][C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[CH:17]=4)=[C:10]4[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]4)=[CH:7][CH:6]=[CH:5][CH:4]=3)=[CH:28]1
Reactant: Brc1c2ccccc2c(-c2ccc3ccccc3c2)c2ccccc12
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)C=C(c2c3ccccc3c(-c3ccc4ccccc4c3)c3ccccc23)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Temperature: 90 °C
Yield: 53 %

Procedure:
A mixture of 6.6 g (17.2 mmol) of 9-bromo-10-(naphthalene-2-yl)anthracene, 8.1 g (17.2 mmol) of 2-(10,10-dimethyl-10H-indeno[1,2-b]triphenylen-12-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 0.2 g (0.172 mmol) of Tetrakis(triphenylphosphine)palladium, 13 ml of 2M Na2CO3, 30 ml of EtOH and 100 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 24 h. After the reaction finish, the mixture was allowed to cool to room temperature. Than 500 ml MeOH was added, while stirring and the precipitated product was filtered off with suction. To give 5.9 g (yield 53%) of yellow product which was recrystallized from toluene. MS(m/z,FAB+): 646.4; 1H NMR (CDCl3, 400 MHz): chemical shift(ppm) 9.14 (s, 1H), 8.90 (d, J=7.80 Hz, 1H), 8.82 (d, J=7.92 Hz, 1H), 8.79 (s, 1H), 8.73 (d, J=7.88 Hz, 2H), 8.23 (d, J=7.72 Hz, 1H), 8.11 (d, J=8.24 Hz, 1H), 8.07˜8.02 (m, 2H), 7.96 (d, J=7.40 Hz, 1H), 7.89 (d, J=8.64 Hz, 2H), 7.78˜7.59 (m, 10H), 7.42˜7.33 (m, 4H), 7.20 (d, J=7.40 Hz, 1H), 1.76 (s, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]([C:9]2[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)[OH:8])=[CH:5][N:4]=[N:3]1>O1CCOCC1.CCOC(C)=O.[O-2].[O-2].[Mn+4]>[CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:10]=[N:11][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:13][CH:14]=2)=[O:8])=[CH:5][N:4]=[N:3]1
Reactant: Cn1nncc1C(O)c1ccc(C(F)(F)F)nc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cn1nncc1C(=O)c1ccc(C(F)(F)F)nc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a 25 mL flask containing (1-methyl-1H-1,2,3-triazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol (1 g, 3.87 mmol, Intermediate 53: step a) in 1,4-dioxane (10 mL) was added manganese dioxide (2.67 g, 30.65 mmol). The mixture was stirred in an 80° C. oil bath for 2 hours, then cooled to room temperature, diluted with EtOAc and filtered through Celite®. The solvents were removed under reduced pressure and the residue chromatographed (0-100% EtOAc/heptane gradient) to provide the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH:3]([NH2:6])[C:4]#[CH:5].[Cl:8][CH2:9][CH2:10][N:11]=[C:12]=[O:13].C(N(CC)CC)C>ClCCl>[Cl:8][CH2:9][CH2:10][NH:11][C:12]([NH:6][CH:3]([CH:2]([CH3:7])[CH3:1])[C:4]#[CH:5])=[O:13]
Reactant: C#CC(N)C(C)C
Reactant: O=C=NCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CC(NC(=O)NCCCl)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 256 mg of 4-methylpent-1-yn-3-amine (Formula 23) in 10 mL of dichloromethane was added 0.5 mL of 2-chloroethyl isocyanate and 0.5 mL of triethylamine. After the mixture was stirred at room temperature for 2 hours, the solvent was removed and column chromatography (40% ethyl acetate/hexane) gave 210 mg of 1-(2-Chloroethyl)-3-(4-methylpent-1-yn-3-yl)urea (Formula 24) as a white solid. 1H NMR (300 MHz, CDCl3) δ 0.95-1.01 (m, 6H), 1.84-1.93 (m, 1H), 2.25-2.26 (m, 1H), 3.51-3.63 (m, 4H), 4.40-4.45 (m, 1H).
Reaction SMILES: [CH:1]([C:4]1[C:5](OS(C(F)(F)F)(=O)=O)=[N:6][C:7]([O:12][CH3:13])=[N:8][C:9]=1[O:10][CH3:11])([CH3:3])[CH3:2].[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24](B(O)O)[CH:23]=1.C([O-])([O-])=O.[Na+].[Na+]>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].COCCOC>[CH:1]([C:4]1[C:5]([C:24]2[CH:23]=[N:22][C:31]3[C:26]([CH:25]=2)=[CH:27][CH:28]=[CH:29][CH:30]=3)=[N:6][C:7]([O:12][CH3:13])=[N:8][C:9]=1[O:10][CH3:11])([CH3:3])[CH3:2]
Reactant: COc1nc(OC)c(C(C)C)c(OS(=O)(=O)C(F)(F)F)n1
Reactant: OB(O)c1cnc2ccccc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: COc1nc(OC)c(C(C)C)c(-c2cnc3ccccc3c2)n1
Temperature: 130 °C
Yield: 49.7 %

Procedure:
In a 5 mL microwave reaction tube, trifluoro-methanesulfonic acid 5-isopropyl-2,6-dimethoxy-pyrimidin-4-yl ester (30 mg, 0.091 mmol), 3-quinoline boronic acid (19 mg, 1.2 eq.) and Pd(dppf)2Cl2 (7.4 mg, 10%) were mixed with 2 mL DME and 0.18 mL 2M aqueous Na2CO3 (4 eq.). The reaction mixture was heated in microwave at 130° C. for 40 minutes. The reaction mixture was concentrated down and purified by reverse phase prep HPLC (MeCN/water) to give a white powder (14 mg, 50%). LC-MS shows 310.2 (M+1).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][C:14]([CH2:18][C:19]([O:21]CC)=[O:20])=[C:15]([CH3:17])[N:16]=2)=[CH:8][CH:7]=1.[OH-].[Na+].Cl>C(O)C>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][C:14]([CH2:18][C:19]([OH:21])=[O:20])=[C:15]([CH3:17])[N:16]=2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)Cc1sc(-c2ccc(OCCCCl)cc2)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(-c2ccc(OCCCCl)cc2)sc1CC(=O)O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl {2-[4-(3-chloropropoxy)phenyl]-4-methyl-1,3-thiazol-5-yl}acetate i102 (0.5 g, 1.41 mmol, 1 eq) and sodium hydroxide (0.2 g, 5 mmol, 3.5 eq) in ethanol (15 ml) is stirred at 60° C. for 1 h 30. A 1 N hydrochloric acid solution (6 ml) is added and ethanol is removed under vacuum. The residue is dissolved in ethyl acetate (200 ml). The organic layer is washed with water (2×50 ml), brine, dried over magnesium sulfate, filtered and concentrated to yield 0.5 g of {2-[4-(3-chloropropoxy)phenyl]-4-methyl-1,3-thiazol-5-yl}acetic acid i103 as a white solid. This solid is used as such in the next step.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:19][CH:18]=[CH:17][N:5]2[C:6](=[O:16])[C:7]=1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[CH3:20][O:21][C:22]1[C:23]([O:30][CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O.[O-]CC.[Na+]>C(O)C>[CH3:20][O:21][C:22]1[C:23]([O:30][CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[C:24](/[CH:25]=[CH:1]/[C:2]2[N:3]=[C:4]3[S:19][CH:18]=[CH:17][N:5]3[C:6](=[O:16])[C:7]=2[C:8]2[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(C#N)cc1
Reactant: COc1cccc(C=O)c1OCC(C)(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(C#N)cc2)c1OCC(C)(C)C

Procedure:
The title compound was prepared from Intermediate 4 (400 mg, 1.496 mmol), 3-methoxy-2-neopentyloxybenzaldehyde (465 mg, 2.094 mmol) and sodium ethoxide (203 mg, 2.992 mmol) in ethanol (25 ml) according to the procedure described in Example 9 to give 290 mg of the product as a light yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 1.03 (s, 9H), 3.53 (s, 2H), 3.77 (s, 3H), 6.77 (d, J=15.6 Hz, 1H), 6.99 (br s, 3H), 7.51-7.57 (m, 3H), 7.91-7.99 (m, 3H), 8.26 (d, J=15.0 Hz, 1H); ESI-MS (m/z) 472.26 (M+H)+.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[CH2:6]([C:17]1[O:18][CH2:19][CH2:20][N:21]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]C>C(OCC)C>[C:1]([O:5][CH2:19][CH2:20][NH:21][C:17](=[O:18])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)O
Reactant: CCCCCCCCCCCC1=NCCO1
Solvent: CCOCC
Product: C=CC(=O)OCCNC(=O)CCCCCCCCCC
Temperature: 80 °C

Procedure:
51.99 g acrylic acid and 0.3 g BHT were heated in a round-bottom flask to 80° C. Under stirring, 81.3 g molten undecyl oxazoline was slowly added during 1 hour maintaining the reaction temperature at 80° C . After stirring for another hour at 80° C. the reaction mixture was poured into 200 ml diethyl ether and washed with water, twice with a 10% sodium bicarbonate solution and twice with water. After drying on magnesium sulfate, filtration and evaporation in vacuo of the solvent 100.5 g of N-acryloxyethylundecylamide was obtained.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:27])[CH2:18][C:19]3[CH:20]=[N:21][C:22](Cl)=[C:23]([F:25])[CH:24]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C.O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:27])[CH2:18][C:19]3[CH:24]=[C:23]([F:25])[C:22]([C:33]4[CH:32]=[CH:31][N:30]=[C:29]([CH3:28])[CH:34]=4)=[N:21][CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(NC(=O)Cc3cnc(Cl)c(F)c3)nc2)CC1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3cnc(-c4ccnc(C)c4)c(F)c3)nc2)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a sealed tube were added N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(6-chloro-5-fluoropyridin-3-yl)acetamide 190-5 (59 mg, 0.15 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 183-2 (49 mg, 0.23 mmol), Pd(PPh3)4 (9 mg, 0.08 mmol), Na2CO3 (79 mg, 0.75 mmol), Toluene (0.8 mL), H2O (0.8 mL) and ethanol (0.2 mL). The reaction mixture was stirred at 100° C. overnight. After cooling to room temperature, the solvents were removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(3-fluoro-2′-methyl-2,4′-bipyridin-5-yl)acetamide 190. MS m/z 449.2 (M+1); 1H NMR 400 MHz (MeOD) δ 8.48-8.46 (m, 2H), 7.96 (s, 1H), 7.87 (d, 1H), 7.81 (s, 1H), 7.75-7.69 (m, 2 Hz), 7.36 (dd, 1H), 3.84 (s, 2H), 3.67 (t, 2H), 3.62 (t, 2H), 3.13 (t, 2H), 3.08 (t, 2H), 2.56 (s, 3H), 2.08 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[N:7][CH:6]=1)[CH3:2].C(O)(=O)[C@@H]([C@H](C(O)=O)O)O>C(O)C.[Pt]=O>[CH2:1]([O:3][C:4]([CH:5]1[CH:10]([CH3:11])[CH2:9][CH2:8][NH:7][CH2:6]1)=[O:12])[CH3:2]
Reactant: CCOC(=O)c1cnccc1C
Agent: O=[Pt]
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CCO
Product: CCOC(=O)C1CNCCC1C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
A Parr bottle was charged with ethyl-4-methylnicotinoate (5.01 g, 30.32 mmol), L-(+)-tartaric acid (4.67 g, 31.2 mmoL) and platinum oxide (Adams catalyst, 827 mg). The material was taken up in absolute ethanol (100 mL) and shaken on the PARR overnight under hydrogen atmosphere (50 psi). The material was filtered through a plug of celite, and the filtrate was concentrated on the rotovap such that about 85% of the solvent was removed. The remainder was taken up in ethyl acetate (120 mL) and aqueous saturated sodium bicarbonate solution (120 mL) and shaken in a separatory funnel. The ethyl acetate phase was collected. The aqueous phase was treated with 2N sodium hydroxide solution (25 mL) and shaken with ethyl acetate (100 mL). The ethyl acetate phase was collected and the aqueous phase back extracted with ethyl acetate (100 mL). The organic phases were combined, dried (MgSO4), filtered and stripped to provide 4.7 g of (+/−)-4-methyl-piperidine-3-carboxylic acid ethyl ester as a mobile yellow oil. MS (M+H)+=172.