Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([C:35]([CH2:43][CH3:44])([CH2:41][CH3:42])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=2)[N:31]=1.C(=O)(O)[O-].[Na+]>C(O)C>[ClH:25].[ClH:25].[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([CH:32]=[C:33]([C:35]([CH2:41][CH3:42])([CH2:43][CH3:44])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(CC)(CC)c1cn2nc(Cl)ccc2n1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CC)(CC)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Product: Cl
Temperature: 90 °C
Reaction time: 2 h
Yield: 58.3 %

Procedure:
3.03 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 1.38 g of ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-ethylbutyrate were stirred at 160° C. for 1.5 hours, then at 180° C. for 2 hours. After the mixture was cooled to 90° C., ethanol and aqueous sodium bicarbonate were added, followed by extraction with ethyl acetate; the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (100:5:2). The desired fraction was collected, concentrated under reduced pressure and dissolved in 5 ml of ethyl acetate; 1.4 ml of a 4 N solution of hydrogen chloride in ethyl acetate was added, followed by concentration again. The residue was powdered by the addition of ethyl ether and dried to yield 893 mg of the title compound.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]21[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2.[BH4-].[Na+]>C(O)C>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]21[CH2:10][CH2:11][CH:12]([OH:15])[CH2:13][CH2:14]2
Reactant: O=C1CCC2(CC1)Cc1ccccc1C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC1CCC2(CC1)Cc1ccccc1C2

Procedure:
11'. A spiro(cyclohexane-1,2'-indan)-4-one [11] obtained in step (10) has its 4-keto function reduced, e.g., by mixing said compound in ethanol with sodium borohydride at moderate (room) temperature for from about 3 to about 8 hours, to produce a corresponding spiro(cyclohexane-1,2'-indan)-4-ol [14].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:33][C@H:34]1[CH2:38][CH2:37][CH2:36][O:35]1)(=O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][C@H:34]3[CH2:38][CH2:37][CH2:36][O:35]3)[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: O=S(=O)(OC[C@H]1CCCO1)C(F)(F)F
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Product: COc1cn(C(C[C@H]2CCCO2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
450 mg (purity 94%, 1.1 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in the presence of 1.35 ml (1.35 mmol, 1.2 eq.) of bis(trimethylsilyl)lithium amide (1M in THF) and 396 mg (1.7 mmol, 1.5 eq.) of (2R)-tetrahydrofuran-2-ylmethyl trifluoromethanesulphonate were reacted according to General Method 7B. Yield: 625 mg (purity 76%, 92% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:21]([O:23]C)=O)[C:5]2[NH:6][C:7]3[CH:8]=[C:9]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[CH:10]=[CH:11][C:12]=3[C:13]=2[N:14]=1.[NH3:25]>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:21]([NH2:25])=[O:23])[C:5]2[NH:6][C:7]3[CH:8]=[C:9]([N:15]4[CH2:16][CH2:17][O:18][CH2:19][CH2:20]4)[CH:10]=[CH:11][C:12]=3[C:13]=2[N:14]=1
Reactant: N
Reactant: COC(=O)c1cc(Br)nc2c1[nH]c1cc(N3CCOCC3)ccc12
Solvent: CO
Product: NC(=O)c1cc(Br)nc2c1[nH]c1cc(N3CCOCC3)ccc12
Temperature: 75 °C
Yield: 82 %

Procedure:
Methyl 2-bromo-7-morpholino-5H-pyrido[3,2-b]indole-4-carboxylate (3.0 g, 7.69 mmol) was mixed with 7 N NH3 in MeOH (80 mL) in a pressure bottle. This was sealed and heated at 75° C. for 47 hrs. It was cooled to RT and the solid was collected by filtration, washed with MeOH, and air dried to afford 2-bromo-7-morpholino-5H-pyrido[3,2-b]indole-4-carboxamide (2.64 g, 6.33 mmol, 82% yield) as a yellow solid. MS (ESI) m/z 375.09 (M+H). 1H NMR (500 MHz, DMSO-d6) δppm 11.41 (1H, s), 8.42 (1H, br. s.), 7.96 (1H, d, J=8.85 Hz), 7.85-7.91 (2H, m), 7.19 (1H, d, J=1.83 Hz), 7.03 (1H, dd, J=8.70, 1.98 Hz), 3.72-3.85 (4H, m), 3.16-3.25 (4H, m).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH2:7][S:6][C:5]1=[O:10].[CH3:11][NH:12][CH3:13].O>CN(C=O)C>[CH3:11][N:12]([CH3:13])[CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH2:7][S:6][C:5]1=[O:10]
Reactant: CNC
Reactant: O=C1CSC(=O)N1CCBr
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCN1C(=O)CSC1=O
Temperature: 50 °C
Yield: 23.8 %

Procedure:
To a 35 ml seal tube, 3-(2-bromoethyl)thiazolidine-2,4-dione (1.5 g, 0.6.69 mmole) was taken in DMF (1 mL) under N2 atmosphere and dimethyl amine (2M solution in THF) (11 mL, 20.0 mmole) was added. The reaction mixture was heated to 50° C. for 16 hrs. After completion of the reaction, water was added to the reaction mixture and product was extracted with ethyl acetate. The combined organic layer was dried over Na2SO4 and evaporated to get the crude product which was purified using column purification using 60-120 mesh size neutral silica by eluting the compound with 2% MeOH in CH2Cl2 to yield 0.3 g of 3-(2-(dimethylamino)ethyl)thiazolidine-2,4-dione which was converted to 3-(2-(dimethylamino)-ethyl)-5-(4-(7-pivaloyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)benzylidene)-thiazolidine-2,4-dione as described in Example 6 above.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:23]=[CH:22][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[O:20][N:19]=[C:18]([CH3:21])[CH:17]=2)=[C:8]([CH:24]=[O:25])[CH:7]=1.[OH-:26].[K+]>O.C(O)C.[N+]([O-])([O-])=O.[Ag+]>[C:24]([C:8]1[CH:7]=[C:6]([C:2]2[O:1][CH2:5][CH2:4][N:3]=2)[CH:23]=[CH:22][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[O:20][N:19]=[C:18]([CH3:21])[CH:17]=1)([OH:26])=[O:25]
Reactant: Cc1cc(CCCCCOc2ccc(C3=NCCO3)cc2C=O)on1
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1cc(CCCCCOc2ccc(C3=NCCO3)cc2C(=O)O)on1
Reaction time: 0.03 h
Yield: 38.2 %

Procedure:
A solution of 4.7 g of silver nitrate in 6 ml of distilled water was added to a stirred suspension of 4.0 g of 5-{5-[4-(4,5-dihydro-2-oxazolyl)-2-formylphenoxy]pentyl}-3-methylisoxazole (Example 70) in 60 ml of ethanol. The mixture was stirred for about two minutes, and then a solution of 8.4 g of potassium hydroxide in 140 ml of water was slowly added. The latter mixture was stirred for two hours, then filtered and the filtrate acidified. The solid product was collected, washed with dilute hydrochloric acid, dried and recrystallized from methanol to give 1.6 g of 5-{5-[2-carboxy-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl}-3-methylisoxazole, m.p. 170°-171° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH:12]([O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)([CH3:14])[CH3:13]>C1(C)C=CC=CC=1>[CH:12]([O:15][C:16]1[CH:17]=[CH:18][C:19]([CH:20]=[N:9][C:8]2[CH:10]=[CH:11][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:22][CH:23]=1)([CH3:14])[CH3:13]
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: CC(C)Oc1ccc(C=O)cc1
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccc(C=Nc2ccc(S(C)(=O)=O)cc2)cc1

Procedure:
A mixture of 1.04 g (6.09 mmol) of 4-methylsulfonylaniline (obtained in reference example 1), 1.00 mL (6.09 mmol) of 4-isopropoxybenzaldehyde (obtained in reference example 3) and 25 mL of toluene was heated at reflux in a Dean-Stark for 2 days. The solvent was removed and the crude product obtained was directly used in the next reaction.
Reaction SMILES: [OH-:1].[Na+:2].C([OH:5])C.CO.[CH:8]1[N:12]=[CH:11][N:10]([CH2:13][C:14]([P:20]([OH:23])([OH:22])=[O:21])([P:16]([OH:19])([OH:18])=[O:17])[OH:15])[CH:9]=1>O.CC(O)C>[CH:8]1[N:12]=[CH:11][N:10]([CH2:13][C:14]([P:16]([O-:19])([OH:18])=[O:17])([P:20]([O-:22])([OH:23])=[O:21])[OH:15])[CH:9]=1.[OH2:5].[OH2:1].[OH2:5].[OH2:5].[Na+:2].[Na+:2]
Reactant: CCO
Reactant: [OH-]
Reactant: O=P(O)(O)C(O)(Cn1ccnc1)P(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(C)O
Product: O=P([O-])(O)C(O)(Cn1ccnc1)P(=O)([O-])O
Temperature: 25 °C

Procedure:
A solution of sodium hydroxide (0.7 g) in a mixture of water (80% v/v)/Ethanol or Methanol or IPA (20% v/v, 10 volumes per grams of ZLD-Ac form XII) (38 ml) was added drop-wise to a suspension of Zoledronic acid form XII (4.98 g) in a mixture of water (80% v/v)/Ethanol or Methanol or IPA (20% v/v, 10 volumes per grams of ZLD-Ac) (212 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed and dried in a vacuum oven at 50° C. for 24 hours to give Zoledronate disodium crystal form VII.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4](=[O:13])[C:5](=[O:12])[NH:6]2.Cl[C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=O)[C:18](=O)N2>>[C:16]1([CH:17]([C:18]2[CH:9]=[CH:10][CH:2]=[CH:3][CH:4]=2)[N:6]2[C:7]3[C:3](=[C:2]([F:1])[CH:10]=[CH:9][C:8]=3[CH3:11])[C:4](=[O:13])[C:5]2=[O:12])[CH:20]=[CH:21][CH:22]=[CH:23][CH:15]=1
Reactant: O=C1Nc2cccc(Cl)c2C1=O
Reactant: Cc1ccc(F)c2c1NC(=O)C2=O
Product: Cc1ccc(F)c2c1N(C(c1ccccc1)c1ccccc1)C(=O)C2=O

Procedure:
Following the procedure as described in PREPARATION 4A, and making non-critical variations using 4-fluoro-7-methyl-1H-indole-2,3-dione (Cassebaum, J. Prakt. Chem. (1960) 12:91-92) to replace 4-chloro-1H-indole-2,3-dione, 1-(diphenylmethyl)-4-fluoro-7-methyl-1H-indole-2,3-dione was obtained (45%) as a brown solid: 1H NMR (300 MHz, CDCl3) δ7.38-7.27 (m, 11H), 6.81 (s, 1H), 6.71 (dd, J=8.3, 8.3 Hz, 1H), 2.27 (s, 3H); MS (ES+) m/z 367.7 (M+23).
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[CH2:4][CH2:5][C:6]2([CH2:17][CH2:18][CH2:19][CH3:20])[C:14]=1[C:13]1[C:8](=[CH:9][C:10]([O:15][CH3:16])=[CH:11][CH:12]=1)[CH2:7]2.C([Sn](CCCC)(CCCC)[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][O:35][CH3:36])=[CH:29][CH:28]=1)CCC>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>[CH2:17]([C:6]12[CH2:5][CH2:4][C:3](=[O:21])[C:2]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][O:35][CH3:36])=[CH:29][CH:28]=3)=[C:14]1[C:13]1[C:12](=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=1)[CH2:7]2)[CH2:18][CH2:19][CH3:20]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(OCOC)cc1
Reactant: CCCCC12CCC(=O)C(Br)=C1c1ccc(OC)cc1C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCC12CCC(=O)C(c3ccc(OCOC)cc3)=C1c1ccc(OC)cc1C2
Temperature: 100 °C
Reaction time: 22 h
Yield: 84.5 %

Procedure:
A mixture of 4-bromo-9a-butyl-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (800 mg, 2.29 mmol), Pd(PPh3)4 (132 mg, 0.114 mmol), and tributyl-(4-methoxymethoxy-phenyl)-stannane (1.174 g, 2.75 mmol) in anhydrous toluene (11.5 mL) was placed under a nitrogen atmosphere and heated with stirring in an oil bath at 100° C. After 22 hours, the mixture was cooled to room temperature and evaporated under vacuum to a dark oil (2.208 g). This material was purified by chromatography on EM silica gel 60 (230-400 mesh, 115 mL dry), using 4:1 hexanes-EtOAc as eluting solvent, to afford 9a-butyl-7-methoxy-4-(4-methoxymethoxy-phenyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-one (787 mg) as a yellow gum.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH:21]=[O:22])[CH2:17][CH2:16]1>CN(C)C=O>[N+:1]([C:4]1[N:5]([CH2:12][CH2:13][CH2:14][CH:15]2[CH2:16][CH2:17][N:18]([CH:21]=[O:22])[CH2:19][CH2:20]2)[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2]
Reactant: O=CN1CCC(CCCBr)CC1
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=CN1CCC(CCCn2ccnc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The mixture of 2-nitroimidazole (11.3 g, 0.1M) and 50% by weight NaH in mineral oil (4.8 g, 0.1M) in dimethylformamide (50 ml) was stirred at room temperature for 1/2 hr. The solution of 4(3-bromo-propyl)-1-piperidine carboxaldehyde (23.4, 0.1M) in dimethylformamide (20 ml) was added to the above mixture and heated at 110° C. for 15 min. After the reaction, the solvent was removed in vacuo wand water (100 ml) was added and the mixture was extracted with ethylacetate (72×100 ml). The extracts, dried over Na2SO4, were concentrated and purified on silica gel columns, eluted with 5% by volume MeOH--95% by volume CH2Cl2 to give 4-[3-(2-nitro-1H-imidazol-1-yl)propyl]-piperidinecarboxaldehyde (22.8 g).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=2[CH2:18][CH2:19][CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1>CN(C=O)C.CCOC(C)=O>[N:31]1[CH:32]=[CH:33][C:28]([NH:27][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][C:9]([O:8][CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[C:10]([CH2:18][CH2:19][CH3:20])[CH:11]=2)=[CH:29][CH:30]=1
Reactant: CCCc1cc(C(=O)O)ccc1OCC1CCCCC1
Reactant: Nc1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1cc(C(=O)Nc2ccncc2)ccc1OCC1CCCCC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 22-6 (770 mg, 2.78 mmol) in 10 mL of (CH2Cl)2 and 0.05 mL of DMF was added 0.26 mL (3.05 mmol) of oxalyl chloride. The resulting solution was heated at 50° C. for 30 min, cooled to 0° C. and treated with 1.20 g (13.8 mmol) of 4-aminopyridine. Stirring was continued for 2 h before the heterogeneous mixture was diluted with 50 mL of EtOAc and quenched with 25 mL of 5% Na2CO3. The organic extract was washed with sat'd NH4Cl (3×50 mL), water (2×25 mL), brine (25 mL) and dried over MgSO4. Evaporation of the solvent and column chromatography (EtOAc) afforded product 22-7.
Reaction SMILES: [CH3:1][N:2]([C:7]1[S:8][C:9]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:3][CH2:4][NH:5][CH3:6].N1C=CC=CC=1.[C:25](Cl)(=[O:27])[CH3:26]>C(Cl)Cl>[CH3:6][N:5]([CH2:4][CH2:3][N:2]([CH3:1])[C:7]1[S:8][C:9]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=2[N:11]=1)[C:25](=[O:27])[CH3:26]
Reactant: CNCCN(C)c1nc2ccc([N+](=O)[O-])cc2s1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N(C)CCN(C)c1nc2ccc([N+](=O)[O-])cc2s1
Yield: 100 %

Procedure:
Dissolve N,N′-dimethyl-N-(6-nitro-benzothiazol-2-yl)-ethane-1,2-diamine (0.255 g, 0.957 mmol) in CH2Cl2 (10 mL) and add pyridine (0.1 mL, 1.2 mmol). Add acetyl chloride (0.102 mL, 1.43 mmol) and shake the mixture overnight at room temperature. Concentrate the reaction mixture in vacuo (adsorbing onto silica gel) and subject the mixture to silica gel flash column chromatography (40 g column, eluting with 1-10% MeOH/CH2Cl2) to yield the desired product (0.295 g, 100%). mass spectrum (m/e): 309.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:20]([N:21]([C:23](=[O:30])[CH2:24][CH2:25][C:26]([O:28]C)=[O:27])[CH3:22])=[CH:19][CH:18]=[C:17]([Cl:31])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.[OH-].[Na+].Cl>CO.C(Cl)(Cl)Cl>[C:26]([CH2:25][CH2:24][C:23]([N:21]([C:20]1[C:2]([Cl:1])=[C:3]([C:17]([Cl:31])=[CH:18][CH:19]=1)[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2)[CH3:22])=[O:30])([OH:28])=[O:27]
Reactant: COC(=O)CCC(=O)N(C)c1ccc(Cl)c(COc2cccc3ccc(C)nc23)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CCC(=O)O)c3Cl)c2n1
Yield: 82.4 %

Procedure:
To a solution of 8-[2,6-dichloro-3-[N-(3-methoxycarbonylpropionyl)-N-methylamino]benzyloxy]-2-methylquinoline (303 mg) in methanol (3 ml) was added 1N aqueous solution of sodium hydroxide (1.0 ml) at ambient temperature. The mixture was stirred for 1 hour and neutralized to pH 4 with 1N hydrochloric acid. The reaction mixture was diluted with chloroform and washed with water. The aqueous layer was saturated with sodium chloride and extracted with chloroform. The combined organic layers were dried over magnesium sulfate and evaporated in vacuo to give 8-[3-[N-(3-carboxypropionyl)-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (242 mg) as an off-white powder.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[C:6]([O:16][CH3:17])[C:5]([Cl:18])=[CH:4][CH:3]=1.[C:19]([C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>>[C:8]([C:7]1[C:6]([O:16][CH3:17])=[C:5]([Cl:18])[CH:4]=[CH:3][C:2]=1[NH:1][S:29]([C:26]1[CH:27]=[CH:28][C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:24][CH:25]=1)(=[O:31])=[O:30])(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1c(Cl)ccc(N)c1C(=O)c1ccccc1
Product: COc1c(Cl)ccc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1C(=O)c1ccccc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 131 mg of ((6-Amino-3-chloro-2-methoxy-phenyl)-phenyl-methanone and 116 mg of 4-tert-butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.23 (s, 9H), 3.74 (s, 3H), 6.73 (d, 1H, J=2.8 Hz), 7.16 (dd, 1H, J=9.2 Hz, 3.2 Hz), 7.33 (d, 2H, J=8.4 Hz), 7.50 (d, 2H, J=6.0 Hz), 7.56 (d, 2H, J=8.8 Hz), 7.68 (d, 1H, J=9.2 Hz), 8.82 (d, 2H, J=6.4 Hz), 9.38 (s, 1H). MS: m/z 458.1 (M++1).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=[CH:17]3)=[CH:10][CH:9]=1.Cl[CH2:29][C:30]1[C:31]([C:38]2[C:43]([Cl:44])=[CH:42][CH:41]=[CH:40][C:39]=2[Cl:45])=[N:32][O:33][C:34]=1[CH:35]([CH3:37])[CH3:36]>CN(C)C=O>[Cl:44][C:43]1[CH:42]=[CH:41][CH:40]=[C:39]([Cl:45])[C:38]=1[C:31]1[C:30]([CH2:29][O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=[CH:17]4)=[CH:12][CH:13]=2)=[C:34]([CH:35]([CH3:37])[CH3:36])[O:33][N:32]=1
Reactant: COC(=O)c1cccc2cc(-c3ccc(O)cc3)ccc12
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc12
Temperature: 65 °C
Yield: 48.3 %

Procedure:
Cesium carbonate (352 g, 1.08 mol) was added to a mechanically stirred solution of methyl 6-(4-hydroxyphenyl)-1-naphthoate (199 g, 0.72 mol) in dimethylformamide (1 L) under N2. The resulting suspension was heated to 65° C. for 30 min followed by addition of 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole (280 g, 0.92 mol) in dimethylformamide (500 mL). The mixture was heated at 65° C. for 18 h, cooled to room temperature and partitioned between ethyl acetate (1 L) and water (1 L). The ethyl acetate layer was backwashed with water (2×1 L) and concentrated to a thick black syrup. This syrup was triturated with hexane (500 mL) and ethyl acetate (300 mL) for 2 h. Filtration gave 190 g of the product as beige crystals. 1H NMR (DMSO-d6): 8.77 (d, J=9 Hz, 1H), 8.23-8.20 (m, 2H), 8.09 (d, J=7 Hz, 1H), 7.92 (dd, J=2, 9 Hz, 1H), 7.69 (d, J=9 Hz, 2H), 7.63-7.51 (m, 4H), 6.91 (d, J=9 Hz, 2H), 4.86 (s, 2H), 3.92 (s, 3H), 3.45 (septet, J=7 Hz, 1H), 1.33 (d, J=7 Hz, 6H). ESI-LCMS m/z 546 (M+H)+.
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([N+](=O)[O-])cc1N
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
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: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:16]=[N:17][C:18](Cl)=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:26]=[N:27][C:28]([NH2:31])=[N:29][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:16]=[N:17][C:18]([NH:31][C:28]3[N:29]=[CH:30][C:25]([Cl:24])=[CH:26][N:27]=3)=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ncc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(Cl)nc2)COC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(Nc3ncc(Cl)cn3)nc2)COC1(C)C
Temperature: 100 °C
Reaction time: 8 h
Yield: 34.9 %

Procedure:
In a pressure tube, (S)-4-[2-(6-chloro-pyridin-3-yl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.94 g), 5-chloropyrimidin-2-amine (357 mg) and cesium carbonate (1.35 g) were combined with dioxane (5 ml) to give a yellow suspension. The mixture was degassed by bubbling through argon for several minutes. Xantphos (96 mg) and tris(dibenzylideneacetone)dipalladium chloroform complex (86 mg) were then added and the tube was sealed. The reaction mixture was stirred at 100° C. overnight. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography (SiO2; gradient: 0% to 70% EtOAc in hexane) to afford (S)-4-{2-[6-(5-chloro-pyrimidin-2-ylamino)-pyridin-3-yl]-ethyl}-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (417 mg, 35%) as a yellow solid. MS (ISP): 436.3 ([{37Cl}M+H]+), 434.4 ([{35Cl}M+H]+), 380.3 ([{37Cl}M+H—C4H8]+), 378.3 ([{35Cl}M+H—C4H8]+).