Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][C:20]=1[OH:26].C(Cl)CCl>C(#N)C>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:15](=[O:17])[CH2:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[C:20]([OH:26])[CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Reactant: Nc1ccc(Br)cc1O
Solvent: ClCCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)Nc2ccc(Br)cc2O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
To a solution of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (0.5 g, 2.055 mmol) in acetonitrile (6 mL) was added 2-amino-5-bromophenol (0.421 g, 2.24 mmol), followed by EDC (0.508 g, 2.65 mmol). The mixture was stirred at rt overnight. It was quenched with NH4Cl (aq, sat, 5 mL). The organic layer was separated; the aqueous layer was back extracted with EtOAc (3×5 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 60% EtOAc) to afford Compound 29A as a light yellow oil (412 mg, 47% yield). 1H NMR (500 MHz, CDCl3) δ 8.96 (s, 1H), 7.65 (s, 1H), 7.17 (d, J=1.9 Hz, 1H), 7.03-6.91 (m, 2H), 2.83-2.66 (m, 2H), 2.36 (d, J=7.1 Hz, 2H), 2.10 (m, 2H), 1.76 (d, J=12.6 Hz, 2H), 1.46 (s, 9H), 1.23-1.13 (m, 2H). LCMS (m/z)=414 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:5]=1[O:6][C:7]([CH3:13])([CH3:12])[C:8]([O:10]C)=[O:9]>CO>[CH3:3][C:4]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:5]=1[O:6][C:7]([CH3:13])([CH3:12])[C:8]([OH:10])=[O:9]
Reactant: COC(=O)C(C)(C)Oc1cc(C)cc(C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C)c(C)c(OC(C)(C)C(=O)O)c1
Reaction time: 12 h
Yield: 75 %

Procedure:
An aqueous solution of 8N sodium hydroxide (30 mL, 240 mmol) was added to a solution of methyl 2-(2,3,5-trimethylphenoxy)isobutyrate (29.0 g, 123 mmol) obtained in Reference Example 9 in methanol (290 ml) at room temperature and the mixture was stirred for 12 hours. The resulting mixture was concentrated under reduced pressure, and the residue was diluted with water. The aqueous layer was acidified by hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with water and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was crystallized from hexane to obtain 20.5 g (yield 75%) of the title compound. mp. 91–94° C.
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:13]1([C:19]#[C:20][C:21]2[CH:39]=[CH:38][C:24]([C:25]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH2:35])=[O:26])=[CH:23][CH:22]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[C:13]1([C:19]#[C:20][C:21]2[CH:39]=[CH:38][C:24]([C:25]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34]([NH:35][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:37])=[O:36])=[O:26])=[CH:23][CH:22]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCCCCCCCCC(=O)Cl
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1ccc(C#Cc2ccccc2)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1ccc(C#Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
In a stream of nitrogen, 0.30 ml (1.46 mmol) of decanoyl chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 500 mg (1.30 mmol) of 4-phenylethynyl-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 10 and 320 mg (2.60 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 540 mg (yield: 76.4%) of the title compound.
Reaction SMILES: C([Li])CCC.[CH:6]([C@H:9]1[CH2:13][O:12][C:11](=[O:14])[NH:10]1)([CH3:8])[CH3:7].[C:15]1([CH2:21][CH2:22][C:23](Cl)=[O:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH:6]([C@H:9]1[CH2:13][O:12][C:11](=[O:14])[N:10]1[C:23](=[O:24])[CH2:22][CH2:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:8])[CH3:7]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CC(C)[C@H]1COC(=O)N1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)[C@H]1COC(=O)N1C(=O)CCc1ccccc1
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
68.3 ml (0.11 mol) of butyllithium (as a 1.6M solution in hexane) were added dropwise, at -78° C. and under an atmosphere of nitrogen, to a solution of 11.75 g (91.0 mmole) of 4(S)-isopropyl-2-oxazolidinone in 200 ml of anhydrous tetrahydrofuran; the mixture was then stirred for 30 minutes, after which a solution of 18.41 g (0.11 mole) of phenylpropionyl chloride in 100 ml of anhydrous tetrahydrofuran was added to it over a period of 10 minutes. The mixture was then stirred for 1 hour, after which it was mixed with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then removed by distillation under reduced pressure. The residue was purified by medium pressure column chromatography through silica gel (using a 1:3 by volume mixture of ethyl acetate and hexane as the eluent), followed by recrystallization from diisopropyl ether, to afford 20.12 g (yield 85%) of the title compound as white crystals, melting at 62°-63° C.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[I-].C[N+]1C=CN([C:20](=[O:29])[N:21]([CH3:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)C=1.C(N(CC)CC)C>C(#N)C>[CH3:12][C:11]1[C:2]([O:1][C:20](=[O:29])[N:21]([CH3:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1nc2ccccc2nc1O
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nc2ccccc2nc1OC(=O)N(C)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
A mixture of 2-hydroxy-3-methylquinoxaline (0.48 g, 3.00 mmol)), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours followed by heating at 50° C. for 3 days. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (50:50)) yielding the title compound (0.59 g, 67% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH:11]=O.[NH2:13][C:14]1[CH:15]=[C:16]([CH3:21])[CH:17]=[CH:18][C:19]=1[NH2:20]>C1(C)C=CC=CC=1.CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]1[NH:20][C:19]2[CH:18]=[CH:17][C:16]([CH3:21])=[CH:15][C:14]=2[N:13]=1
Reactant: O=Cc1n[nH]c2ccc(Cl)cc12
Reactant: Cc1ccc(N)c(N)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc2[nH]c(-c3n[nH]c4ccc(Cl)cc34)nc2c1
Temperature: 100 °C

Procedure:
A flask was charged with 5-chloro-1H-indazole-3-carbaldehyde (1.0 equivalent) and 3,4-diaminotoluene (1.0 equivalent) in toluene and EtOH. The reaction mixture was heated to 100° C. for 18 hours. The solvent was then evaporated, and the residue was purified by reverse phase HPLC yielding a white solid. LC/MS (m/z) 283.1 (MH+), Rt 2.5 minutes.
Reaction SMILES: CC1C=CC(NC(C2C=CC(CN3CCN(C)CC3)=CC=2)=O)=CC=1[NH:8][C:9]1N=CC=C(C2C=CC=NC=2)[N:14]=1.[CH3:38][C:39]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][C:40]=1[NH2:41].N#CN.[ClH:52]>>[ClH:52].[CH3:38][C:39]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][C:40]=1[NH:41][C:9]([NH2:14])=[NH:8]
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Agent: Cl
Agent: N#CN
Product: Cc1ccc([N+](=O)[O-])cc1NC(=N)N

Procedure:
The invention provides a process for preparation of imatinib base and pharmaceutically acceptable acid addition salts thereof, comprising (a) reacting 2-methyl-5-nitroaniline with cyanamide in the presence of hydrochloric acid to obtain 1-(2-methyl-5-nitrophenyl)guanidine hydrochloride; (b) converting 1-(2-methyl-5-nitrophenyl)guanidine hydrochloride to 1-(2-methyl-5-nitrophenyl)guanidine nitrate; (c) condensing 3-acetylpyridine with N,N-dimethylformamide dimethyl acetal to obtain 3-(dimethylamino)-1-(3-pyridinyl)-prop-2-en-1-one; (d) reacting 3-(dimethylamino)-1-(3-pyridinyl)-prop-2-en-1-one with 1-(2-methyl-5-nitrophenyl)guanidine nitrate to obtain N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine; (e) reducing N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine using hydrazine in the presence of Raney nickel to obtain N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidine-amine; (f) condensing N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidine-amine with 4-chloromethylbenzoyl chloride in the presence of an inorganic base to obtain 4-chloromethyl-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)benzamide; (g) condensing 4-chloromethyl-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)benzamide with an excess of N-methylpiperazine to obtain imatinib base; adding water or a mixture of water and an organic solvent; and isolating said imatinib base; and (h) optionally, converting imatinib base to a pharmaceutically acceptable acid addition salt of imatinib base.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH:6]([CH3:14])[CH:7]2OC.C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][C:6]([CH3:14])=[CH:7]2
Reactant: COC1c2cccc(CBr)c2CC1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1=Cc2cccc(CBr)c2C1

Procedure:
To a solution of 37.5 g (0.147 mol) of 4-(bromomethyl)-1-methoxy-2-methylindane in 600 ml of toluene 3.12 g (16.4 mmol) of TsOH was added at 110° C. This mixture was refluxed with Dean-Stark trap within 12 min and then passed through short column with Silica Gel 60 (40-63 um, d 90 mm, l 80 mm). The Silica Gel layer was additionally washed by 500 ml of toluene. The combined elute was evaporated to dryness. The product was isolated by flash chromatography on short column with Silica Gel 60 (40-63 um, d 90 mm, l 80 mm; eluent: hexanes). Yield 33.2 g (97%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C@@H:10]([NH2:12])[CH3:11])[CH:6]=[CH:7][C:8]=1[F:9].C([O:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[C:41]3[C:36](=[CH:37][C:38]([C:42](O)=[O:43])=[CH:39][CH:40]=3)[C:35]([CH3:45])=[C:34]2[CH3:46])=[CH:28][CH:27]=1)=[O:19])(C)(C)C>>[F:2][C:3]1[CH:4]=[C:5]([C@@H:10]([NH:12][C:42]([C:38]2[CH:37]=[C:36]3[C:41](=[CH:40][CH:39]=2)[N:33]([CH2:32][C:29]2[CH:28]=[CH:27][C:26]([C:21]4[C:20]([C:18]([OH:19])=[O:17])=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:31][CH:30]=2)[C:34]([CH3:46])=[C:35]3[CH3:45])=[O:43])[CH3:11])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@H](N)c1ccc(F)c(F)c1
Agent: Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3ccc(F)c(F)c3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(3,4-difluorophenyl)ethanamine hydrochloride and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 539 [M+H]+.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[C:10]([C:18]4[CH:23]=[C:22]([I:24])[C:21]([OH:25])=[C:20]([I:26])[CH:19]=4)=[C:11]4[C:16](=[CH:17][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH:15]=[CH:14][CH:13]=[CH:12]4.[C:27]([O:32]C)(=[O:31])[C@H:28]([CH3:30])O>>[CH:1]1[C:9]2[C:8]3[C:10]([C:18]4[CH:19]=[C:20]([I:26])[C:21]([O:25][C@H:28]([CH3:30])[C:27]([OH:32])=[O:31])=[C:22]([I:24])[CH:23]=4)=[C:11]4[C:16](=[CH:17][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH:15]=[CH:14][CH:13]=[CH:12]4
Reactant: Oc1c(I)cc(-c2c3ccccc3cc3sc4ccccc4c23)cc1I
Reactant: COC(=O)[C@H](C)O
Product: C[C@@H](Oc1c(I)cc(-c2c3ccccc3cc3sc4ccccc4c23)cc1I)C(=O)O

Procedure:
Prepared from of 4-(benzo[b]naphtho[2,3-d]thiophen-11-yl)-2,6-diiodo-phenol (Example 26) and commercially available (S)-lactic acid, methyl ester. White solid: mp 134-136: NMR (CDCl3): δ8.38 (s, 1 H), 7.95 (dd J=8, 6 Hz, 1 H), 7.93 (d, J=1 Hz, 2 H), 7.81 (d, J=8 Hz, 1 H), 7.58 (ddd, J=8, 7, 1 Hz, 1 H), 7.59-7.54 (m, 2 H), 7.49-7.40 (m, 2 H), 7.15(ddd, J=8, 7, 1 Hz, 1 H), 6.77 (d, J=8, 1 Hz, 1 H), 5.48 (q, J =7 Hz, 1 H), 1.82 (d, J=7 Hz, 2 H); MS (+FAB): [M+H]+, 651; Anal. Calc. for C26H16I2O3S: C, 46.18, H, 2.48, N, 0.00. Found: C, 46.60, H, 2.50, N, 0.21.
Reaction SMILES: [C:1](Cl)(=O)C.[N+:5]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]([OH:18])=[O:17])[CH:11]=[CH:12][CH:13]=1)([O-:7])=[O:6]>CO>[CH3:1][O:17][C:16](=[O:18])[CH:15]=[CH:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([N+:5]([O-:7])=[O:6])[CH:9]=1
Reactant: CC(=O)Cl
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Solvent: CO
Product: COC(=O)C=Cc1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Acetyl chloride (6.5 ml, 0.09 mol) was added dropwise to methanol (130 ml) at −15° C. temperature. The reaction mixture was stirred for 30 min. simultaneously allowing to warm up to 0° C. 3-(3-Nitro-phenyl)-acrylic acid (21) (25 g, 0.13 mol) was added by small portions to the mixture at 0° C. and the resulting reaction mixture was stirred overnight at ambient temperature. The forming precipitate was filtered, washed with methanol and dried affording the title compound in a form of white crystals (26.58 g, 98%).
Reaction SMILES: [F:1][C:2]1([F:11])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[O:3]1.C([Li])CCC.CN(CCN(C)C)C.B(OC)(OC)[O:26]C.COB(OC)C1C2OC(F)(F)OC=2C=CC=1.[OH-].[Na+].OO.Cl>CCCCCC.C(OCC)C>[OH:26][C:10]1[C:4]2[O:3][C:2]([F:1])([F:11])[O:6][C:5]=2[CH:7]=[CH:8][CH:9]=1
Reactant: FC1(F)Oc2ccccc2O1
Reactant: COB(OC)OC
Agent: CN(C)CCN(C)C
Agent: COB(OC)c1cccc2c1OC(F)(F)O2
Agent: Cl
Solvent: CCOCC
Solvent: CCCCCC
Product: Oc1cccc2c1OC(F)(F)O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
15.8 g (100 mmol) of 2,2-difluoro-1,3-benzodioxole are metallated according to Example 2, at -20° C., with 70 ml (110 mmol) of n-butyllithium (1.58M in hexane) and 12.8 g (110 mmol) of TMEDA in 120 ml of hexane. To the white suspension there is added dropwise at -100° C., over a period of 5 minutes, a solution of 10.4 g (100 mmol) of trimethyl borate in 50 ml of diethyl ether. When the reaction mixture has warmed up and has been stirred for 30 minutes at room temperature, there are added to the precipitated dimethoxy-(2,2-difluoro-1,3-benzodioxol-4-yl)borane, while cooling with ice, 35 ml of 3N sodium hydroxide solution, immediately followed by the addition, over a period of 10 minutes, of 32 ml (~310 mmol) of 30% hydrogen peroxide solution. The yellow-orange emulsion is adjusted to pH 3 with 10% HCl. The aqueous phase is extracted three times with 150 ml of diethyl ether each time. The organic solutions are washed three times with 100 ml of 2N FeSO4 solution each time, then twice with 100 ml of 20% sodium bisulfite solution each time and finally with 50 ml of brine, dried over MgSO4 and concentrated in a vacuum rotary evaporator. Upon distillation of the residue, 8.4 g (48%) of the product distil over in the form of a pale yellow oil at boiling point (b.p.) 135°-139° C./25 mbar.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH3:8].ClC1C=CC=C(C(OO)=[O:17])C=1>ClCCl>[CH2:7]([C@H:6]1[C@@H:5]([CH2:4][CH2:3][O:2][CH3:1])[O:17]1)[CH3:8]
Reactant: CC/C=C\CCOC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC[C@@H]1O[C@@H]1CCOC
Yield: 79.7 %

Procedure:
27.4 g of (Z)-1-methoxy-3-hexene were dissolved in dichloromethane (850 ml) and cooled to 10°. 62 g of ca 70% m-chloroperbenzoic acid corresponding to 1.05 eq., were added in portions. The mixture was allowed to react during 15 hours and was then transferred into an extraction funnel wherein it was washed with an aqueous solution of NaOH and then with water to neutrality. After separation and drying of the organic layer on Na2SO4, the residue was distilled over a 5 cm long Vigreux type column at 51-52°/1.5×103Pa to give 24.9 g (80%) of the desired compound in the form of a colourless liquid which presented the following analytical data:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:8][N:7]=1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>O1CCCC1>[C:17]([NH:2][CH2:3][CH2:4][O:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:8][N:7]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCCOc1cc(-c2ccccc2)on1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCCOc1cc(-c2ccccc2)on1)c1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
3-(2-Aminoethoxy)-5-phenylisoxazole hydrochloride (240 mg) was suspended in anhydrous tetrahydrofuran (5 ml), and the suspension was cooled to 5° C. Benzoyl chloride (168 mg) and triethylamine (243 mg) were added thereto, followed by stirring of the resulting mixture at the same temperature for 30 minutes. At the end of this time, the reaction mixture was added to ice-cold water (40 ml) and extracted with ethyl acetate (40 ml×2). Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to obtain the title compound (276 mg, 90%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]([CH3:16])([CH3:15])[CH:13]=[O:14])[CH:9]=[CH:10][CH:11]=1.CC(C)=[O:24].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.CCOC(C)=O>[CH3:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]([CH3:16])([CH3:15])[C:13]([OH:24])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cccc(C)c1COc1cccc(C(C)(C)C=O)c1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1COc1cccc(C(C)(C)C(=O)O)c1
Reaction time: 3 h

Procedure:
To a stirred solution of 2-(3-(2,6-Dimethylbenzyloxy)phenyl)-2-methylpropanal (Step D, 1.9 g, 6.7 mmol) in acetone (40 ml) was added drop wise jones reagent (10 ml) at room temperature. The reaction mixture was stirred for 3 hours, and was taken in EtOAc and washed with water, brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (chloroform:methanol, 95:5 spiked with acetic acid) to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[C:5]([O:12][C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[N:16]=[CH:15][N:14]=2)[C:4]([CH3:27])=[N:3]1.[CH:28](OC)=[O:29].[H-].[Na+].C(O)(=O)C>CN(C)C=O>[CH3:11][O:10][C:8](=[O:9])/[C:7](/[C:6]1[N:2]([CH3:1])[N:3]=[C:4]([CH3:27])[C:5]=1[O:12][C:13]1[CH:18]=[C:17]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[N:16]=[CH:15][N:14]=1)=[CH:28]/[OH:29]
Reactant: COC(=O)Cc1c(Oc2cc(Oc3ccccc3F)ncn2)c(C)nn1C
Reactant: COC=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)/C(=C/O)c1c(Oc2cc(Oc3ccccc3F)ncn2)c(C)nn1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3.5 g (9.3 mmol) of methyl {1,3-dimethyl-4-[6-(2-fluorophenoxy)pyrimidin-4-yloxy]pyrazol-5-yl}acetate and 10 ml of methyl formate in 10 ml of dimethyl formamide is slowly added dropwise to a suspension of 0.5 g (20.0 mmol) of sodium hydride (95%) in 40 ml of dimethyl formamide, while keeping the temperature below 30° C. The reaction mixture is stirred for 2 hours at room temperature, acidified with acetic acid and, after addition of 200 ml of ice-water, extracted with 200 ml of ethyl acetate. The organic phase is washed with water and sodium chloride solution, dried and concentrated under vacuum, giving E-methyl-2-{1,3-dimethyl-4-[6-(2-fluorophenoxy)pyrimidin-4-yloxy]pyrazol-5-yl}-3-hydroxyacrylate as a brown resin, which is stirred together with 1.8 g (13.0 mmol) of potassium carbonate and 0.9 ml (6.7 mmol) of dimethyl sulfate in 40 ml of acetone for 3 hours at room temperature. The reaction mixture is filtered, the filtrate is diluted with 50 ml of water and extracted with 100 ml of ethyl acetate. The organic phase is washed with sodium chloride solution, dried and concentrated under vacuum. The residue is chromatographed over silica gel tetrahydrofuran/n-hexane (1:1) as eluant, giving E-methyl-2-{1,3-dimethyl-4-[6-(2-fluorophenoxy)pyrimidin-4-yloxy]pyrazol-5-yl}-3-methoxyacrylate as a yellow resin; MS: 414 (M+, 44%), 75 (100).
Reaction SMILES: [CH:1]1([C:4]2[C:13]([CH:14]=O)=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1.[C:23](#[N:25])[CH3:24].C[O-].[Na+].Cl>C1(C)C=CC=CC=1.O1CCCC1>[CH:1]1([C:4]2[C:13]([CH:14]=[CH:24][C:23]#[N:25])=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: CC#N
Reactant: O=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N#CC=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Yield: 87.2 %

Procedure:
In a flask similar to that of Example 6 were placed under argon atmosphere 1.74 g (5.98 mmol) of 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde, 0.80 mL (15.2 mmol) of acetonitrile, 8.0 mL of tetrahydrofuran (dielectric constant at 25° C.: 7.58), and 0.41 g (7.55 mmol) of sodium methoxide. The content was reacted at 52° C. for 4.5 hours. The resulting mixture was chilled in an ice bath. To the chilled mixture were slowly added under stirring 30 mL of toluene and 7.0 mL (7.00 mmol) of hydrochloric acid (1 mol/L), successively. The separated organic portion was taken out. After washing with two portions of saturated aqueous sodium chloride solution (10 mL), the organic portion was dried over anhydrous magnesium sulfate. The organic portion was then filtered and analyzed by high performance liquid chromatography (absolute quantitative analysis). It was confirmed that 1.64 g (yield: 88%) of 3-[2-cyclopropyl-4-(4-fluoro-phenyl)-3-quinolyl]prop-2-enenitrile was produced.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])=[CH:9][CH:10]=[C:5]2[NH:4][C:3]1=[O:19].[CH3:20][C:21]1([CH2:24]O)[CH2:23][CH2:22]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH3:1][N:2]1[C:6]2=[N:7][C:8]([C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])=[CH:9][CH:10]=[C:5]2[N:4]([CH2:20][C:21]2([CH3:24])[CH2:23][CH2:22]2)[C:3]1=[O:19]
Reactant: CC1(CO)CC1
Reactant: Cn1c(=O)[nH]c2ccc(-c3ccccc3C#N)nc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cn1c(=O)n(CC2(C)CC2)c2ccc(-c3ccccc3C#N)nc21
Reaction time: 1 h

Procedure:
2-(3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)benzonitrile (4-1) (50 mg, 0.2 mmol), 1-methylcyclopropanemethanol (52 mg, 0.6 mmol), Diisopropyl azodicarboxylate (121 mg, 0.6 mmol), and triphenylphosphine (157 mg, 0.6 mmol) were added to a microwave vial under nitrogen and dissolved with DCM (1 mL). The reaction was stirred for one hour, and desired product was observed via LCMS. The mixture was diluted with methanol and purified using reverse phase chromatography (10-100%, 0.1% TFA in H2O/Acetonitrile); the desired fractions were collected and concentrated to produce 2-{3-methyl-1-[(1-methylcyclopropyl)methyl]-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl}benzonitrile (4-2). HRMS (M+H)+: observed=319.1551, calculated=319.1553.