Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:3]1=[S:14].[Cl:15][C:16]1[CH:17]=[C:18]([CH:23]([CH2:35][CH:36]=O)[CH2:24][N:25]([CH3:34])[C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:19]=[CH:20][C:21]=1[Cl:22]>>[ClH:15].[Cl:15][C:16]1[CH:17]=[C:18]([C@H:23]([CH2:35][CH2:36][N:11]2[CH2:12][CH2:13][CH:8]([N:4]3[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[C:3]3=[S:14])[CH2:9][CH2:10]2)[CH2:24][N:25]([CH3:34])[C:26](=[O:33])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: CN1CCCN(C2CCNCC2)C1=S
Reactant: CN(CC(CC=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Product: CN(C[C@@H](CCN1CCC(N2CCCN(C)C2=S)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Product: Cl

Procedure:
Using the procedure of Example 1, replacing 4-(2-oxo-1,3-oxazolidin-3-yl)piperidine with 4-(3-methyl-2-thioxoperhydropyrimidin-1-yl)-piperidine, and N-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide with the (S)-enantiomer, the title compound was obtained as a white solid; MS: m/z=547(M+1); Analysis for C28H36Cl2N4OS.1.70 HCl.0.10 (C2H5)2O: Calculated: C, 55.28; H, 6.32; N, 9.08; Found: C, 55.21; H, 6.37; N, 8.88.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:23][CH2:22][C@@:12]34[C:13]5[CH:14]=[C:15]([O:20]C)[CH:16]=[CH:17][C:18]=5[CH2:19][C@@H:6]2[C@:7]3([O:26][CH3:27])[C@H:8]([CH3:25])[CH2:9][C:10](=[O:24])[CH2:11]4)[CH2:3][CH2:2]1.B(Br)(Br)Br.[OH-].[NH4+].C(Cl)(Cl)[Cl:35]>CO.C(OCC)C>[ClH:35].[CH:1]1([CH2:4][N:5]2[CH2:23][CH2:22][C@@:12]34[C:13]5[CH:14]=[C:15]([OH:20])[CH:16]=[CH:17][C:18]=5[CH2:19][C@@H:6]2[C@:7]3([O:26][CH3:27])[C@H:8]([CH3:25])[CH2:9][C:10](=[O:24])[CH2:11]4)[CH2:2][CH2:3]1
Reactant: ClC(Cl)Cl
Reactant: COc1ccc2c(c1)[C@]13CCN(CC4CC4)[C@H](C2)[C@]1(OC)[C@H](C)CC(=O)C3
Agent: BrB(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: CO[C@@]12[C@H](C)CC(=O)C[C@@]13CCN(CC1CC1)[C@@H]2Cc1ccc(O)cc13
Product: Cl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 17-cyclopropylmethyl-3,14-dimethoxy -8α-methylmorphinan-6-one (30) (0.323 g, 0.874 mmol) in chloroform (5 ml) was slowly added over a 2 to 3 minute period to a solution of boron tribromide (1.266 g, 5.053 mmol) in chloroform. A tan colored precipitate formed, and the mixture was stirred for an additional 20 minutes. The mixture was then poured carefully into a mixture of ice (8 g) and ammonium hydroxide (4 ml). After stirring the mixture at 0° to 5° C. for 40 minutes, the layers were separated and the aqueous layer was extracted with chloroform (2×20 ml). The organic extracts were combined, washed with water, dried over NaSO4, filtered and concentrated under reduced pressure to give a gummy solid. The product was purified by column chromatography on silica gel using graded methanol/chloroform mixtures as eluant. Upon removal of the solvent a gum was obtained which was dissolved in a small volume of methanol whereupon dry diethyl ether was added and insoluble material was removed by filtration. To the clear solution was added a saturated solution of HCl in ether and the salt precipitated. The precipitated solid was separated by decantantion and dissolved in a small volume of methanol. Addition of dry diethyl ether to this methanolic solution gave pure 17-cyclopropylmethyl-3-hydroxy-14-methoxy-8α-methylmorphinan-6-one hydrochloride (31) as a cream colored solid (0.064 g, 19% theory).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:19]=1[CH:20]=O>>[OH:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:19]=1[CH:20]=[C:11]1[C:10]2[C:14](=[CH:15][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)[NH:13][C:12]1=[O:16]
Reactant: COc1ccc(C=O)c(O)c1
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Product: COc1ccc(C=C2C(=O)Nc3cc(-c4ccccc4)ccc32)c(O)c1
Yield: 68 %

Procedure:
6-Phenyl-2-oxindole (50 mg, 0.3 mmol) was condensed with 2-hydroxy-4-methoxybenzaldehyde (50 mg, 0.33 mmol) using method B to give 70 mg (68%) of 3-(2-hydroxy-4-methoxybenzylidene)-6-phenyl-1,3-dihydroindol-2-one as a yellow/orange solid.
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C@H:9]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH2:19])[O:8][C@H:7]([CH2:20][C@@H:21]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:22][CH2:23][C@H:24]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:25]([OH:27])=[O:26])[C@H:6]1[OH:44])[CH:2]=C.[O:45]1CCCC1.I([O-])(=O)(=O)=[O:51].[Na+].[C:56](#[N:58])[CH3:57].O.[C:60]([OH:66])([C:62]([F:65])([F:64])[F:63])=[O:61].O>O.O.[Os](=O)(=O)(=O)=O.[K]>[NH2:19][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[C:16]=1[N:17]=[CH:18][N:10]2[C@@H:9]1[O:8][C@H:7]([CH2:20][C@@H:21]([NH:36][C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[CH2:22][CH2:23][C@H:24]([NH:28][C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[C:25]([OH:27])=[O:26])[C@@H:6]([OH:44])[C@H:5]1[O:4][CH2:1][CH:2]=[O:45].[C:56](#[N:58])[CH3:57].[OH2:51].[C:60]([OH:66])([C:62]([F:65])([F:64])[F:63])=[O:61]
Reactant: C=CCO[C@@H]1[C@H](O)[C@@H](C[C@H](CC[C@H](NC(=O)OC(C)(C)C)C(=O)O)NC(=O)OC(C)(C)C)O[C@H]1n1cnc2c(N)ncnc21
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Agent: [K]
Agent: [Na+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CC[C@H](NC(=O)OC(C)(C)C)C(=O)O)C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](OCC=O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 7-mL scintillation vial containing Compound 10 (2.0 mg, 0.0032 mmol) was added sequentially tetrahydrofuran (200 μL), water (132 μL), sodium periodate (3.3 mg, 0.015 mmol), and a mixture consisting of potassium osmium tetroxide dihydrate (68 μg, 0.00018 mmol) and water (68 μL). The reaction mixture was stirred overnight in the dark at room temperature. HPLC (Gemini C18, 110 {acute over (Å)}, 5μ, 250×4.6 mm, 1 mL/min, 5/95/0.05→50/50/0.05 ACN/H2O/TFA) showed complete disappearance of starting material. The reaction mixture was placed in the freezer overnight and the desired product isolated the following day by prep HPLC (Gemini C18, 110 {acute over (Å)}, 10μ, 250×21.2 mm, 20 mL/min, 5/95/0.05→50/50/0.05 ACN/H2O/TFA)—split peak collected at about 20.5 min. The relevant fractions were combined and concentrated to afford the title intermediate (1 mg, 50% yield) as a clear solid; LC/MS ESI+ m/z 624, ESI− m/z 622.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][C:7]=1[O:15]C.O>C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][C:7]=1[OH:15]
Reactant: COc1cc(CC#N)ccc1Cl
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: N#CCc1ccc(Cl)c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
BBr3 (16.6 g, 66 mmol) was slowly added to a solution of 2-(4-chloro-3-methoxyphenyl)acetonitrile (12 g, 66 mmol) in DCM (120 mL) at −78° C. under N2. The reaction temperature was slowly increased to room temperature. The reaction mixture was stirred overnight and then poured into ice and water. The organic layer was separated, and the aqueous layer was extracted with DCM (40 mL×3). The combined organic layers were washed with water, brine, dried over Na2SO4, and concentrated under vacuum to give (4-chloro-3-hydroxy-phenyl)-acetonitrile (9.3 g, 85%). 1H NMR (300 MHz, CDCl3) δ 7.34 (d, J=8.4 Hz, 1H), 7.02 (d, J=2.1 Hz, 1H), 6.87 (dd, J=2.1, 8.4 Hz, 1H), 5.15 (brs, 1H), 3.72 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][NH2:13].[CH:14]1([N:18]2[CH2:23][CH2:22][CH:21]([O:24][C:25]3[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][N:26]=3)[CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15]1>>[CH:14]1([N:18]2[CH2:23][CH2:22][CH:21]([O:24][C:25]3[N:26]=[CH:27][C:28]([C:29]4[N:13]([CH3:12])[C:4](=[O:6])[C:3]5[C:2](=[C:10]([CH3:11])[CH:9]=[CH:8][CH:7]=5)[N:1]=4)=[CH:31][CH:32]=3)[CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15]1
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: O=Cc1ccc(OC2CCN(C3CCC3)CC2)nc1
Reactant: CN
Product: Cc1cccc2c(=O)n(C)c(-c3ccc(OC4CCN(C5CCC5)CC4)nc3)nc12

Procedure:
The entitled compound was obtained according to the method of Example 15 but starting from 2-amino-3-methylbenzoic acid, methylamine and 6-[(1-cyclobutylpiperidin-4-yl)oxy]nicotinaldehyde.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH:7]1([NH2:12])[CH2:11][CH2:10][CH2:9][CH2:8]1.C(N(CC)CC)C>C1COCC1>[CH:7]1([NH:12][CH2:2][C:3]([O:5][CH3:6])=[O:4])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: NC1CCCC1
Reactant: COC(=O)CBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CNC1CCCC1
Reaction time: 8 h
Yield: 68.3 %

Procedure:
A solution of methyl bromoacetate (17.4 mL, 188 mmol) in THF (40 mL) was dropwise added to a solution of cyclopentylamine (18.6 mL, 188 mmol) and triethylamine (26.1 mL, 188 mmol) in THF (150 mL) at 0° C. Following addition, the reaction was allowed to reach room temperature and was stirred overnight. The triethylammonium salts were filtered and rinsed with scant THF. The combined filtrates were concentrated in vacuo. The desired product was distilled from the residuals under reduced pressure to yield 20.2 g of compound 225 (68% yield). 1H NMR (500 MHz, CDCl3) δ ppm 3.73 (s, 3 H) 3.41 (s, 2 H) 3.00-3.13 (m, J=12.90, 6.39, 6.39 Hz, 1 H) 1.77-1.87 (m, 2 H) 1.67-1.74 (m, 2 H) 1.48-1.59 (m, 2 H) 1.29-1.41 (m, 2 H) ppm.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7](O)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.S(Cl)([Cl:18])=O>>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7]([Cl:18])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:1]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccccc1-c1ccccc1
Product: c1ccc(-c2ccccc2)cc1

Procedure:
A mixture of 5.6 g of [1,1'-biphenyl]-2-carboxylic acid and 29 ml of thionyl chloride is heated on a steam bath for 0.5 hour and the volatiles removed under vacuum. Toluene (40 ml) is added (twice) and the solvent removed under vacuum to give 6.8 g of a yellow oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.Br.Br[CH2:16][CH2:17][NH2:18].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]2[O:8][CH2:16][CH2:17][N:18]=2)=[CH:5][CH:4]=1
Reactant: NCCBr
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ccc(C2=NCCO2)cc1
Reaction time: 18 h
Yield: 72.9 %

Procedure:
4-(trifluoromethyl)benzoyl chloride (4.6 mL, 31 mmol) was slowly added to a solution of 2-bromoethanamine hydrobromide (6.27 g, 30.6 mmol) and triethylamine (23 mL, 165 mmol) in dry DCM (150 mL) at 0° C. The reaction was stirred for 18 h, allowing the cooling bath to expire. The resulting mixture was filtered through a Buechner funnel and the filter cake was washed thoroughly with DCM. The collected filtrate was washed with water (100 mL), brine (75 mL), and dried (Na2SO4). The volume was reduced in vacuo to 5 mL and the resulting crystals were harvested. The remaining filtrate was again reduced in volume to provide a second crop of crystals to give a total of 4.8 g of 2-(4-(trifluoromethyl)phenyl)-4,5-dihydrooxazole. The combined crop of crystals were dissolved in CCl4 (200 mL) and the resulting solution was decanted away from a dark oily residue and was carried forward without further purification: LC/MS (m/z): 216.1 (MH+), tR=0.60 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([C:15]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[OH:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[C:40]([O:42][CH3:43])=[O:41].N1C=CC=CC=1.[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:43][O:42][C:40]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([C:15]([C:28]3[CH:29]=[CH:30][C:31]([O:34][C:35]([F:38])([F:36])[F:37])=[CH:32][CH:33]=3)([C:17]3[CH:18]=[CH:19][C:20]([O:23][C:24]([F:25])([F:26])[F:27])=[CH:21][CH:22]=3)[OH:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1)=[O:41]
Reactant: Nc1ccc(CN2CCC(C(O)(c3ccc(OC(F)(F)F)cc3)c3ccc(OC(F)(F)F)cc3)CC2)cc1
Reactant: COC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)Nc1ccc(CN2CCC(C(O)(c3ccc(OC(F)(F)F)cc3)c3ccc(OC(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 0.8 gram (0.0014 mole) of N-(4-aminophenylmethyl)-4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine in 15 mL of tetrahydrofuran was cooled to 0° C., and 0.11 mL of methyl chloroformate was added dropwise from a syringe. Upon completion of the addition, 0.12 mL of pyridine was added in one portion. The reaction mixture was allowed to warm to ambient temperature where it stirred for about 18 hours. After this time the reaction mixture was poured into a mixture of ethyl acetate and an aqueous solution saturated with sodium chloride. After a period of stirring, the organic layer was separated and dried with sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residual solid. The solid was subjected to column chromatography on silica gel, with pure methylene chloride, and 1:9, 1:4, 1:3, and 3:7 mixtures of acetone:methylene chloride as eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.45 gram of N-[4-(methoxycarbonylamino)phenylmethyl]-4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1.ClC1C=CC=C(C(OO)=[O:37])C=1.C(OCC)(=O)C>CCOCC>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH:14]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:15]2[CH:16]=[CH:17][N+:18]([O-:37])=[CH:19][CH:20]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(c1ccncc1)c1cc(F)ccc1F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCOCC
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1cc[n+]([O-])cc1)c1cc(F)ccc1F
Reaction time: 20 h
Yield: 79.7 %

Procedure:
To a methylene chloride solution (20 ml) of the 4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridine (221 mg, 0.58 mmol) obtained in Example 142 was added 3-chloroperbenzoic acid (100 mg, 0.58 mmol) and the mixture was stirred for 20 hours. The reaction mixture was diluted with ether (60 ml), followed by washing with a saturated aqueous solution of sodium bicarbonate, water and brine. The solution was dried and then filtered. The filtrate was then concentrated under reduced pressure. The residue thus obtained was subjected to silica gel chromatography (ethyl acetate) to yield the title compound (183 mg, 80%). The compound was then crystallized from ethanol and obtained as colorless needle crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=S)=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([C:18]1[CH:23]=[C:22]([O:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][CH3:32])=[C:27]([NH2:33])[CH:26]=2)[CH:21]=[CH:20][N:19]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CO>[C:11]([O:15][C:16]([C:18]1[CH:23]=[C:22]([O:24][C:25]2[CH:30]=[CH:29][C:28]3[N:31]([CH3:32])[C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[N:33][C:27]=3[CH:26]=2)[CH:21]=[CH:20][N:19]=1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Fc1ccc(N=C=S)cc1
Reactant: CNc1ccc(Oc2ccnc(C(=O)OC(C)(C)C)c2)cc1N
Solvent: CO
Product: Cn1c(Nc2ccc(F)cc2)nc2cc(Oc3ccnc(C(=O)OC(C)(C)C)c3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with 4-fluorophenylisothiocyanate (1 eq), 4-(3-Amino-4-methylamino-phenoxy)-pyridine-2-carboxylic acid tert-butyl ester (1 eq), and MeOH. The reaction was maintained stirring at room temperature overnight. Ferric chloride, (1.5 eq) was added and the resulting mixture was stirred overnight. The reaction was partitioned with EtOAc and water, and filtered through Celite. The layers were separated and the aqueous phase was neutralized with saturated Na2CO3 solution. The resulting aqueous phase was extracted with EtOAc and the mixture was filtered through Celite. The phases were separated and the aqueous phase was again extracted and filtered. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to give a brown solid. The crude residue was purified by trituration in hot toluene to furnish the desired product. LCMS m/z 435.6 (MH+), tR=2.12 min.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C@@:6]([C:16]([OH:18])=[O:17])([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:7].[CH3:19]O>>[CH3:19][O:17][C:16](=[O:18])[C@:6]([CH3:5])([CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[NH2:7]
Reactant: CO
Reactant: C[C@](N)(CCc1ccccc1)C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@](C)(N)CCc1ccccc1
Reaction time: 8.5 h

Procedure:
430 ml methanol are cooled to -10° C. in an ice/sodium chloride mixture and reacted with 21.3 ml thionyl chloride (exothermic reaction). 44.5 g (0.23 mol α-methyl-homo-phenylalanine are added dropwise at room temperature. Boiling under reflux occurs for 8.5 hours, the mixture is concentrated in a rotary evaporator, taken up with H2O (350 ml) and reacted with 150 ml 25% Nh4OH solution. Extraction with dichloromethane occurs 5× and the combined extracts are dried over calcium carbonate and concentrated in a rotary evaporator. Yellowish oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([CH2:30]N3CCN(C)CC3)=[CH:28][CH:29]=2)=[O:23])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[Cl:38]CC1C=CC(C(Cl)=O)=CC=1>>[Cl:38][CH2:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]([NH:21][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[C:7]([NH:8][C:9]3[N:14]=[C:13]([C:15]4[CH:20]=[N:19][CH:18]=[CH:17][CH:16]=4)[CH:12]=[CH:11][N:10]=3)[CH:6]=2)=[O:23])=[CH:25][CH:26]=1
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Product: Cc1ccc(NC(=O)c2ccc(CCl)cc2)cc1Nc1nccc(-c2cccnc2)n1

Procedure:
Scheme 3 illustrates a third synthetic pathway for preparation of imatinib base, referred to herein as “Method C.” This method is described in WO 2004/108699 and in J. Med. Chem. 2005, 48(1), 249-255, and comprises the condensation of 4-methyl-N-3-(4-pyridin-3-yl-pyrimidin-2-yl)benzene-1,3-diamine with 4-chloromethylbenzoyl chloride to yield 4-chloromethyl-N-(4-methyl-3-((4-pyridin-3-yl)-pyrimidin-2-ylamino)-phenyl)-benzamide, followed by the reaction of 4-chloromethyl-N-(4-methyl-3-((4-pyridin-3-yl)-pyrimidin-2-ylamino)-phenyl)-benzamide with N-methylpiperazine.
Reaction SMILES: [ClH:1].C(O)C.O[N:6]=[C:7]([C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[C:8]([O:10][CH2:11][CH3:12])=[O:9]>[Pd]>[ClH:1].[NH2:6][CH:7]([C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(=NO)C(=O)C(C)C
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(N)C(=O)C(C)C
Reaction time: 8 h

Procedure:
10 g of HCl are introduced into 200 ml of ethanol. 46 g of ethyl 2-hydroxyimino4-methyl-3-oxopentanoate are dissolved in this mixture, 5 g of Pd (10% on carbon) are added and the mixture is stirred under an atmosphere of hydrogen (5 bar) for 8 hours. The reaction mixture is filtered through Celite and the solvent is removed under reduced pressure. This gives 45 g of ethyl 2-amino-4-methyl-3-oxopentanoate hydrochloride as a white solid. C8H15NO3*HCl (209.5), MS(ESI)=188 (M+H+).
Reaction SMILES: [CH3:1][C:2](=[N:7][OH:8])[C:3]([CH3:6])=[N:4][OH:5].[CH3:9][S:10](Cl)(=[O:12])=[O:11].C(N(CC)CC)C>O1CCOCC1>[CH3:9][S:10]([O:5][N:4]=[C:3]([CH3:6])[C:2]([CH3:1])=[N:7][O:8][S:10]([CH3:9])(=[O:12])=[O:11])(=[O:12])=[O:11]
Reactant: CC(=NO)C(C)=NO
Reactant: CS(=O)(=O)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=NOS(C)(=O)=O)C(C)=NOS(C)(=O)=O
Yield: 77.3 %

Procedure:
To 300 ml of 1,4 dioxane in a round-bottom flask was added 11.6 g (0.1 mole) of dimethylglyoxime. When the solid had completely dissolved, 22.9 g (0.2 mole) of methanesulfonyl chloride was added. The mixture was stirred and 20.2 g (0.2 mole) triethylamine was added dropwise. The reaction mixture was stirred for 51/2 hours during which time a precipitate was formed. The dioxane was removed by evaporation under reduced pressure. The residue was stirred in ice water, then filtered. The solid product was dissolved in dichloromethane and dried over anhydrous sodium sulfate. The slurry was filtered and the solvent was removed in a rotary evaporator. The solid residue was stirred in cold ethanol, then filtered and dried in a vacuum oven, giving 21.05 g (77% yield) of di-(methanesulfonyl)-dimethylglyoxime with mp 169-172° C.
Reaction SMILES: O.[PH2]([O-])=O.[Na+].[CH2:6]([O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#N)=[C:16]([NH:22][CH2:23][C@H:24]([OH:26])[CH3:25])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.N1C=CC=CC=1CC(O)=[O:35].O>[Ni]>[CH2:6]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:35])=[C:16]([NH:22][CH2:23][C@H:24]([OH:26])[CH3:25])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)Cc1ccccn1
Reactant: C[C@@H](O)CNc1cc(OCc2ccccc2)ccc1C#N
Agent: [Ni]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: O
Product: C[C@@H](O)CNc1cc(OCc2ccccc2)ccc1C=O
Temperature: 45 °C
Reaction time: 7 h
Yield: 90 %

Procedure:
Sodium hypophosphite hydrate (986 g, 11.2 mol) and Raney nickel (500 g of a 50% aqueous suspension) were added to a solution of the product from Step B (790 g, 2.8 mol) in a 2:1:1 mixture of pyridine-acetic acid-water (7 L). The mixture was stirred at 45° C. for 7 h, then cooled to 25° C. overnight and filtered through a filter-aide rinsing with water and ethyl acetate. The filtrate was washed with saturated sodium hydrogenphosphate to pH 5, water and brine, dried over sodium sulfate and concentrated. During concentration, 4 L of heptane was added to azeotropically remove pyridine. After 8 L of solvent had been removed the product solidified. Heptane (5 L) was added and the solid was triturated, isolated by filtration and vacuum dried at 35° C. to yield the desired product (722 g, 90%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].[CH3:23][C:24]1[O:28][C:27]([CH2:29][NH2:30])=[CH:26][CH:25]=1>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH:18][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:30][CH2:29][C:27]3[O:28][C:24]([CH3:23])=[CH:25][CH:26]=3)[CH:8]=2)[N:3]=1
Reactant: COc1ccccc1CN
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: Cc1ccc(CN)o1
Product: COc1ccccc1CNc1ccc2cc(NCc3ccc(C)o3)ccc2n1

Procedure:
The title compound, MS: m/e=374.1 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-methoxybenzylamine and 5-methyl-2-furanmethanamine.