Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH2:24]([CH2:26][NH2:27])[OH:25]>>[OH:25][CH2:24][CH2:26][NH:27][C:20]([C:17]1[S:16][C:15](/[CH:14]=[CH:13]/[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:23])=[N:19][CH:18]=1)=[O:22]
Reactant: NCCO
Reactant: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)O)s1
Product: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)NCCO)s1
Yield: 46 %

Procedure:
As described for example 77c, 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-thiazole-5-carboxylic acid (83 mg, 0.25 mmol) was converted, using ethanolamine instead of 4-aminotetrahydropyran, to the title compound (43 mg, 46%) which was obtained as an off white solid after purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) and trituration from methanol. MS: m/e=375.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:7][C:6](=[O:8])[CH2:5][C:4]([CH3:10])([CH3:9])[P:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][C:20]([CH:26]([CH3:28])[CH3:27])=[CH:19][C:18]=1[CH:29]([CH3:31])[CH3:30].[CH2:33](O)[CH2:34][CH2:35][OH:36].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:32][C:2]1([CH3:1])[P:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[C:22]([CH:23]([CH3:24])[CH3:25])=[CH:21][C:20]([CH:26]([CH3:28])[CH3:27])=[CH:19][C:18]=2[CH:29]([CH3:31])[CH3:30])[C:4]([CH3:9])([CH3:10])[CH2:5][C:6]2([O:36][CH2:35][CH2:34][CH2:33][O:8]2)[CH2:7]1
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P2C(C)(C)CC(=O)CC2(C)C)c(C(C)C)c1
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1cc(C(C)C)c(-c2ccccc2P2C(C)(C)CC3(CC2(C)C)OCCCO3)c(C(C)C)c1
Temperature: 125 °C
Yield: 66.3 %

Procedure:
A flask was charged with 0.40 g of 2,2,6,6-tetramethyl-1-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphinan-4-one (0.89 mmol, 1.0 equiv), 10 mL of argon-sparged toluene, 0.65 mL of 1,3-propanediol (8.9 mmol, 10 equiv) and 0.015 g of p-toluenesulfonic acid monohydrate (0.09 mmol, 0.1 equiv). The atmosphere was purged with argon and the reaction flask was equipped with a Dean-Stark trap and warmed in an oil bath at 125° C. for 20 h under argon atmosphere. The distilled toluene was collected in the Dean-Stark trap. The reaction mixture was cooled to room temperature, quenched with saturated aqueous sodium bicarbonate and partitioned between toluene and water. The aqueous solution was back extracted once with toluene, the combined organic solution was washed once with water, dried over potassium carbonate and concentrated in vacuo. The unpurified material was purified by flash chromatography over silica gel with gradient elution using acetone/heptane mixtures. After concentration, 0.3 g (66% yield) of 8,8,10,10-tetramethyl-9-(2′,4′,6′-triisopropylbiphenyl-2-yl)-1,5-dioxa-9-phosphaspiro[5.5]undecane was isolated as a solid. 1H NMR (C6D6, 500 MHz) δ ppm 1.02 (d, 6H, J=10 Hz), 1.12 (d, 6H, J=7 Hz), 1.24 (d, 6H, J=7 Hz), 1.31-1.28 (pent, 2H, J=5.5 Hz), 1.42 (d, 6H, J=20 Hz), 1.45 (d, 6H, J=7 Hz), 2.13 (d, 2H, J=14.5 Hz), 2.25 (dd, 2H, J=14.5, 6 Hz), 2.80 (sept, 2H, J=7 Hz), 2.86 (sept, 1H, J=7 Hz), 3.48 (t, 2H, J=5.5 Hz), 3.72 (t, 2H, J=5.5 Hz), 7.01 (td, 1H, J=7.5, 1.5 Hz), 7.08 (br t, 1H, J=7.5 Hz), 7.24 (s, 2H), 7.26-7.24 (m, 1H), 7.89 (br d, 1H, J=8 Hz); 31P NMR (C6D6, 200 MHz) δ ppm-2.7 (br singlet).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[O:7]([CH2:26][CH2:27][NH:28][C:29]([C:31]1[S:32][C:33]2[C:39](=[O:40])[CH:38]=[C:37](OC)[C:36](=[O:43])[C:34]=2[N:35]=1)=[O:30])[CH2:8][CH2:9][NH:10][C:11]([C:13]1[S:14][C:15]2[C:21](=[O:22])[CH:20]=[C:19](OC)[C:18](=[O:25])[C:16]=2[N:17]=1)=[O:12].CO>C(O)C.ClCCl>[O:7]([CH2:8][CH2:9][NH:10][C:11]([C:13]1[S:14][C:15]2[C:21](=[O:22])[CH:20]=[C:19]([NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[C:18](=[O:25])[C:16]=2[N:17]=1)=[O:12])[CH2:26][CH2:27][NH:28][C:29]([C:31]1[S:32][C:33]2[C:39](=[O:40])[CH:38]=[C:37]([NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[C:36](=[O:43])[C:34]=2[N:35]=1)=[O:30]
Reactant: CN(C)CCN
Reactant: COC1=CC(=O)c2sc(C(=O)NCCOCCNC(=O)c3nc4c(s3)C(=O)C=C(OC)C4=O)nc2C1=O
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: CN(C)CCNC1=CC(=O)c2sc(C(=O)NCCOCCNC(=O)c3nc4c(s3)C(=O)C=C(NCCN(C)C)C4=O)nc2C1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 5 %

Procedure:
81 μl (0.73 mmol; 2 eq.) of N,N-dimethylethylenediamine is added to 200 mg of N,N′-(oxydiethane-2,1-diyl)bis(5-methoxy-4,7-dioxo-4,7-dihydro-1,3-benzothiazole-2-carboxamide) in solution in 300 ml of anhydrous ethanol. The reaction mixture is stirred at 60° C. for 4 hours then the solvent is evaporated off under reduced pressure. The residue is purified on a silica column (eluent: methanol in dichloromethane: gradient of 0 to 20% over 30 minutes then for 15 minutes with 20% of methanol in dichloromethane) and 12 mg (yield=5%) of expected compound is obtained in the form of a red powder.
Reaction SMILES: [Cl:1][C:2]1[S:9][C:8]2[CH:7]=[C:6]([C:10]([NH:12][C@@H:13]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C@H:14]3[NH:22][CH3:23])=[O:11])[NH:5][C:4]=2[C:3]=1[Cl:24].C(N(CC)CC)C.[Cl:32][CH2:33][C:34](Cl)=[O:35]>C(Cl)Cl>[Cl:1][C:2]1[S:9][C:8]2[CH:7]=[C:6]([C:10]([NH:12][C@@H:13]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C@H:14]3[N:22]([C:34](=[O:35])[CH2:33][Cl:32])[CH3:23])=[O:11])[NH:5][C:4]=2[C:3]=1[Cl:24]
Reactant: CN[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)CCl)[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
2,3-Dichloro-N-[(1R,2R)-1-(methylamino)-2,3-dihydro-1H-inden-2-yl]-4H-thieno[3,2-b]pyrrole-5-carboxamide (Method 11; 300 mg, 0.79 mmol) and triethylamine (167 μL, 1.2 mmol) was dissolved in DCM (5 mL), chloroacetyl chloride (73 μL, 0.9 mmol) added and the reaction stirred at ambient temperature for 2 hours. The volatiles were removed by evaporation under reduced pressure and EtOAc (15 mL) added. The mixture was washed with water (10 mL), brine (10 ml), dried (MgSO4) and the volatiles were removed by evaporation under reduced pressure to give the title compound (310 mg, 86%) as a pale brown foam.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7].C(Cl)(=O)C([Cl:18])=O.CN(C)C=O>O1CCCC1>[F:1][C:2]([F:14])([F:13])[C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([Cl:18])=[O:7]
Reactant: Cc1c(C(=O)O)cccc1C(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Cl)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-trifluoromethyl-2-methylbenzoic acid 5.00 g, oxalyl dichloride 3.42 g, N,N-dimethylformamide about 50 mg and tetrahydrofuran 200 mL was stirred at 25° C. for one hour. The reaction mixtures were concentrated under reduced pressure to give 3-trifluoromethyl-2-methylbenzoic acid chloride.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.O.[NH2:13]N.[CH3:15][C:16]([CH2:18][CH3:19])=O>C(O)CC>[CH3:15][C:16]1[NH:13][C:2]2=[N:3][CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[C:7]2[C:18]=1[CH3:19]
Reactant: CCC(C)=O
Reactant: NN
Reactant: FC(F)(F)c1ccc(Cl)nc1
Solvent: O
Solvent: CCCO
Product: Cc1[nH]c2ncc(C(F)(F)F)cc2c1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 2-chloro-5-trifluoromethylpyridine (10 g 0.055 mol) and hydrazine mono hydrate (2,7 g, 0.055 mol) in 35 ml n-propanol was refluxed for 2 h and was then stirred 20 h at RT. To the solution was added 4,35 g (0.06 mol) methylethylketon and the mixture was refluxed for 30 min. After the solvent was removed under reduced pressure the residue was partitioned between methylene chloride and bicarbonate solution. The organic layer was dried over Na2SO4 and evaporated. The residue was solved in 80 ml diethylene glycol and refluxed for 5 h. The reaction mixture was poured into ice-water and extracted with methylene chloride. The organic layer was separated dried over Na2SO4 and evaporated. The residue was treated with warm petroleumether (60-80 ) wich was decantated and evaporated chromatography twice on silica gel with 1 methylene chloride/methanol 2 ethyl acetate, gave the desired product. (0,2 g 1.7% ).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].C[O-].[Na+].[CH2:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[CH:19]=[C:20]([CH:36]=[CH:37][CH:38]=2)[C:21](OCC(C)(N[S:28]([C:31](F)(F)F)(=[O:30])=[O:29])C)=[O:22])=[CH:10]1.C(OCC)(=[O:41])C>CN(C)C=O.O>[CH3:31][S:28]([OH:41])(=[O:30])=[O:29].[CH2:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[CH:19]=[C:20]([CH:36]=[CH:37][CH:38]=2)[C:21]([NH:4][C:3]([NH2:5])=[NH:2])=[O:22])=[CH:10]1
Reactant: CC(C)(COC(=O)c1cccc(C2=CCc3ccccc32)c1)NS(=O)(=O)C(F)(F)F
Reactant: CCOC(C)=O
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)O
Product: N=C(N)NC(=O)c1cccc(C2=CCc3ccccc32)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of guanidine hydrochloride (1.54 g) in N,N-dimethylformamide (5 ml) was added sodium methoxide (2.8 ml, 28% in methanol) under nitrogen atmosphere. After being stirred for 30 minutes at room temperature, to the reaction mixture was added a solution of 2-methyl-2-trifluoromethylsulfonylaminopropyl 3-(1H-inden-3-yl)benzoate (1.01 g) in N,N-dimethylformamide (5 ml). After being stirred for 23 hours at room temperature, the reaction mixture was poured into a mixture of ethyl acetate and water. The organic layer was successively washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (10:1). The eluted fractions containing the desired product were collected and evaporated in vacuo. The residue was dissolved in ethanol and crystallized from slight excess methanesulfonic acid. The crystalline was recrystallized from ethanol to give [3-(1H-inden-3-yl)benzoyl]guanidine methanesulfonate (0.22 g).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:18]2[C:19]([CH3:31])([CH3:30])[C:20](=[O:29])[N:21]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[N:22]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:32]([O:39][C:40]1[CH:41]=[CH:42][C:43]([CH3:49])=[C:44]([CH:48]=1)[C:45](O)=[O:46])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:18]2[C:19]([CH3:31])([CH3:30])[C:20](=[O:29])[N:21]([CH:23]3[CH2:24][CH2:25][N:26]([C:45]([C:44]4[CH:48]=[C:40]([O:39][CH2:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[CH:41]=[CH:42][C:43]=4[CH3:49])=[O:46])[CH2:27][CH2:28]3)[N:22]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ccc(OCc2ccccc2)cc1C(=O)O
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OCc1ccccc1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(OCc5ccccc5)ccc4C)CC3)C(=O)C2(C)C)cc1OCc1ccccc1

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-[3-(benzyloxy)-4-methoxyphenyl]-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B4*HCl) and 5-(benzyloxy)-2-methylbenzoic acid (compound F1) as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) to yield the title compound.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C@H:10]1[OH:19])=O)(C)(C)C.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=O)C.C(OCC)(=O)C.C(Cl)[Cl:52]>C1CCCCC1>[ClH:52].[NH2:8][CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C:10]1=[O:19]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N[C@@H]1Cc2ccccc2C[C@H]1O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cl
Product: NC1Cc2ccccc2CC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon to a solution of trans-3 tert-butoxycarbonylamino-1,2,3,4-tetrahydro-2-naphthalenol (2.02 g) in methylene chloride (40 ml) was added pyridinium dichromate (4.3 g), molecular sieves 3A (6.3 g) and acetic acid (0.76 ml). After 1 hour stirring at room temperature the mixture was poured on a silica gel column (120 g, elution with ethyl acetate: cyclohexane, 1:3) to afford a crude material which was recrystallized from a diethyl ether/cyclohexane mixture to give the title compound (634 mg) as a white solid, m.p. 104°-105° C.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)C=C.Cl.CN(C)[C:18]1[CH:23]=CC=C[CH:19]=1>>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13][C:14]=1[CH2:23][CH:18]=[CH2:19]
Reactant: CN(C)c1ccccc1
Reactant: C=CCOc1ccc(C(=O)OC)cc1
Agent: Cl
Product: C=CCc1cc(C(=O)OC)ccc1O
Temperature: 210 °C
Yield: 64 %

Procedure:
A mixed solution of methyl 4-(2-propen-1-yl)oxybenzoate (19.17 g, 0.10 mol) and N,N-dimethylaniline (40 mL) was heated under reflux at 210° C. for 18 hours. Dilute hydrochloric acid (1 mol/L) was added to the reaction solution, followed by extraction with ethyl acetate. Then, the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 12.26 g of the title compound (yield: 64%) as a colorless powder.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[C:15]([O:17]C)=O.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH2:29])=[NH:28])=[CH:22][CH:21]=1.[O-]CC.[Na+]>C(O)C>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27]2[N:28]=[C:15]([OH:17])[C:3]3[CH2:4][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:6][CH2:7][C:2]=3[N:29]=2)=[CH:24][CH:25]=1
Reactant: N=C(N)Nc1ccc(Br)cc1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2nc(Nc3ccc(Br)cc3)nc(O)c2C1
Yield: 88.5 %

Procedure:
1-tert-Butyl 3-methyl 4-oxopiperidine-1,3-dicarboxylate (1 g, 3.89 mmol), 1-(4-bromophenyl)guanidine (0.832 g, 3.89 mmol) and sodium ethoxide (0.264 g, 3.89 mmol) in ethanol (8 mL) were heated to 100° C. in a microwave reactor for 15 minutes. The reaction mixture was allowed to reach room temperature, the solid obtained was filtered and washed with cold ethanol and dried in a vacuum oven yielding tert-butyl 2-(4-bromophenylamino)-4-hydroxy-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (1.45 g, 72%). The compound was used in the next step without purification. MS (ESI) (M+H) m/z 423
Reaction SMILES: CC1C=CC(NC(C2C=CC(CN3CCN(C)CC3)=CC=2)=O)=CC=1NC1N=CC=C(C2C=CC=NC=2)N=1.CO[C:40](=[O:55])[C:41]1[CH:46]=[CH:45][C:44]([CH2:47][N:48]2[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]2)=[CH:43][CH:42]=1.[N+:56]([C:59]1[CH:60]=[C:61]([CH:63]=[CH:64][C:65]=1[CH3:66])[NH2:62])([O-:58])=[O:57]>>[CH3:66][C:65]1[CH:64]=[CH:63][C:61]([NH:62][C:40](=[O:55])[C:41]2[CH:42]=[CH:43][C:44]([CH2:47][N:48]3[CH2:49][CH2:50][N:51]([CH3:54])[CH2:52][CH2:53]3)=[CH:45][CH:46]=2)=[CH:60][C:59]=1[N+:56]([O-:58])=[O:57]
Reactant: COC(=O)c1ccc(CN2CCN(C)CC2)cc1
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Agent: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1[N+](=O)[O-]

Procedure:
U.S. Pat. No. 5,521,184 and application WO 03/066613 describe several synthetic routes for preparing Imatinib. One synthetic process, described in Scheme 1, comprises reacting 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid methyl ester with 3-nitro-4-methyl-aniline to obtain N-(4-methyl-3-nitrophenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide, which is subsequently reduced to obtain N-(3-amino-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide. The latter is reacted with cyanamide (NH2CN) in a mixture of concentrated hydrochloric acid solution and n-butanol to produce N-(3-guanidino-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide, which is subsequently reacted with 3-dimethylamino-1-pyridin-3-yl-propenone to obtain Imatinib.
Reaction SMILES: O1CCOCC1.[F:7][C:8]([F:45])([F:44])[C:9]1[CH:10]=[C:11]([C@H:19]2[O:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[C:31](B4OC(C)(C)C(C)(C)O4)=[CH:30][N:29]=[C:28]([S:41][CH3:42])[N:27]=3)[C@H:20]2[CH3:43])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.Br[C:47]1[C:48]([O:54][CH3:55])=[N:49][CH:50]=[C:51]([Cl:53])[CH:52]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:17][C:15]([F:16])([F:18])[C:13]1[CH:12]=[C:11]([C@H:19]2[O:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[C:31]([C:47]4[C:48]([O:54][CH3:55])=[N:49][CH:50]=[C:51]([Cl:53])[CH:52]=4)=[CH:30][N:29]=[C:28]([S:41][CH3:42])[N:27]=3)[C@H:20]2[CH3:43])[CH:10]=[C:9]([C:8]([F:7])([F:44])[F:45])[CH:14]=1
Reactant: CSc1ncc(B2OC(C)(C)C(C)(C)O2)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Reactant: COc1ncc(Cl)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1COCCO1
Product: COc1ncc(Cl)cc1-c1cnc(SC)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 170 °C
Reaction time: 0.17 h

Procedure:
A dioxane (17.3 mL) solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-{[2-(methylsulfanyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-4-yl]methyl}-1,3-oxazolidin-2-one (INTERMEDIATE 21, 2.0 g, 3.46 mmol), 3-bromo-5-chloro-2-methoxypyridine (0.925 g, 4.16 mmol) and 2M potassium phosphate tribasic (3.5 mL, 7.00 mmol) in a microwave vial was evacuated and charged three times with nitrogen. Then Pd(Ph3P)4 (0.400 g, 0.346 mmol) was added and the reaction vial was capped. The reaction was stirred for 10 minutes at 170° C. in a microwave reactor. LCMS showed complete conversion to the product. The reaction was diluted with acetonitrile (5 mL) and filtered through a 2 g plug of RP C18 silica, rinsing with 10 mL acetonitrile. The filtrate was concentrated and the crude was purified by silica gel chromatography, eluting with a gradient of 0-50% ethyl acetate/hexanes to give the title compound as a pale yellow foam. LCMS (M+H)+: 593.3
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)[NH2:3].CN(C)/[CH:14]=[CH:15]/[C:16](=O)[CH:17](OC)[O:18]C.CC(=O)C.Cl>C(O)C>[CH:17]([C:16]1[N:2]([C:4]2[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=2)[N:3]=[CH:14][CH:15]=1)=[O:18]
Reactant: COC(OC)C(=O)/C=C/N(C)C
Reactant: N#Cc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Solvent: CC(C)=O
Product: N#Cc1ccc(-n2nccc2C=O)cc1
Temperature: 25 °C
Yield: 33.9 %

Procedure:
A solution of 4-hydrazinylbenzonitrile hydrochloride (10.14 g, 59.78 mmol, 1.00 equiv), (E)-4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (17.6 g, 101.61 mmol, 1.70 equiv), propan-2-one (30 mL) and 6N hydrochloric acid (30 mL) in ethanol (300 mL) was stirred at 78° C. for 3.5 h. The resulting mixture was cooled to room temperature and concentrated under vacuum. Water (300 mL) and ethyl acetate (200 mL) were added to dissolve the residue. The resulting mixture was extracted with ethyl acetate (2×200 mL). The combined organic layers was washed with water (1×100 mL) and brine (1×100 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-20% of ethyl acetate in petroleum ether to give 4 g (34%) of 4-(5-formyl-1H-pyrazol-1-yl)benzonitrile as a yellow solid. 1H-NMR (300 MHz, CDCl3): δ 9.87 (s, 1H), 8.09-7.98 (m, 3H), 7.85-7.83 (m, 2H), 7.36 (d, J=1.5 Hz, 1H) ppm. LCMS (method A, ESI): RT=1.28 min, m/z=198.0 [M+H]+.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH2:22](Cl)[CH:23]=[CH2:24]>CN(C=O)C>[CH2:24]([O:21][C:18]1[CH:19]=[CH:20][C:15]([N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=3)[CH2:14][CH2:13]2)=[CH:16][CH:17]=1)[CH:23]=[CH2:22]
Reactant: C=CCCl
Reactant: Oc1ccc(N2CCN(c3ccncc3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(N2CCN(c3ccncc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85.7 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.4 g) was added to a stirred suspension of 4-[4-(4-pyridyl)piperazin-1-yl]phenol (2.55 g) in DMF (25 ml) and the mixture stirred for 20 minutes at room temperature. Allyl chloride (0.756 g) was added dropwise and stirring continued for 20 hours. Ice-water (75 ml) was added and the mixture extracted three times with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO4) and evaporated. The residue was triturated with hexane and filtered to give 4-[4-(4-pyridyl)piperazin-1-yl]phenol allyl ether (2.5 g) as a solid;
Reaction SMILES: N.[H][H].[CH2:4]([NH2:16])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[CH2:4]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH3:4])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCN
Reactant: [H][H]
Agent: N
Product: CCCCCCCCCCCCNCCCCCCCCCCCC

Procedure:
The same procedure as in Example 13 was repeated except for using the catalyst (K) produced in Preparation Example 10 in place of the catalyst (G), flowing ammonia and hydrogen through the autoclave at rates of 13.1 g (0.77 mol)/h and 4.3 L (0.19 mol)/h, respectively, thereby conducting the reaction for 6 h. The resultant reaction product was analyzed in the same manner as in Example 7. As a result, it was confirmed that the conversion of the raw alcohol was 65.5%, the selectivity to lauryl amine was 85.5%, the amount of dilauryl amine produced is 7.3%, and the amount of the other by-products produced was 2.2%.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C@@H:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH3:19])[C:12]=2[CH3:20])[N:7]1[C:21](=[O:24])[CH2:22]Cl)=O)C.[NH3:25]>CO.O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C@H:8]2[N:7]3[C:21](=[O:24])[CH2:22][NH:25][C:4](=[O:3])[C@@H:6]3[CH2:10][CH2:9]2)=[C:12]([CH3:20])[C:13]=1[CH3:19]
Reactant: N
Reactant: CCOC(=O)[C@H]1CC[C@@H](c2ccc(OC)c(C)c2C)N1C(=O)CCl
Solvent: O
Solvent: CO
Product: COc1ccc([C@@H]2CC[C@H]3C(=O)NCC(=O)N32)c(C)c1C
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of the crude cis-1-(2-chloroacetyl)-5-(4-methoxy-2,3-dimethyl-phenyl)pyrrolidine-2-carboxylic acid ethyl ester (˜16.56 mmol) and ca. 7 M NH3 in MeOH (50 mL) is stirred in a sealed flask at room temperature for 2.5 days. The mixture is then diluted with water (ca. 200-300 mL). The resulting suspension is cooled to 0° C. and stirred well. The mixture is then filtered and the solid thoroughly washed with water followed by Et2O. Drying affords cis-6-(4-methoxy-2,3-dimethylphenyl)hexahydropyrrolo[1,2-a]pyrazine-1,4-dione as a slightly off-white powder. 1H NMR (CDCl3, 400 MHz): 6.70 (br, 1H), 6.68 (d, J=8.6 Hz, 1H), 6.64 (d, J=8.6 Hz, 1H), 5.38 (d, J=8.8 Hz, 1H), 4.29 (dd, J=10.8, 6.4 Hz, 1H), 4.10, 3.93 (ABXq, JAB=16.8 Hz, JAX=1.0 Hz, JBX=4.8 Hz, 2H), 3.77 (s, 3H), 2.43-2.31 (m, 1H), 2.26 (s, 3H), 2.24-2.11 (m, 2H), 2.16 (s, 3H), 1.85 (dd, J=12.2, 5.8 Hz, 1H). Electrospray MS: m/z 289 [M+1].