Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CCCCCC.[CH2:9]([OH:12])[CH:10]=[CH2:11].[Cl:13][C:14]([Cl:18])([Cl:17])[C:15]#[N:16]>CCOCC>[Cl:13][C:14]([Cl:18])([Cl:17])[C:15](=[NH:16])[O:12][CH2:9][CH:10]=[CH2:11]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: C=CCO
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOCC
Product: C=CCOC(=N)C(Cl)(Cl)Cl
Temperature: 25 °C

Procedure:
A suspension of 80% sodium hydride (945 mg., 31.5 mmol.; washed twice with 25 ml. of hexane) in dry ether (30 ml.) was treated dropwise with a solution of 2-propen-1-ol (21.4 ml., 18.3 g., 315 mmol.), in dry ether (45 ml.), stirred for 20 minut at room temperature under argon and then cooled to 0° C. (ice-salt bath). Trichloroacetonitrile (30 ml. or 42.3 g., 0.30 mole) was added over a period of 15 minutes and the brownish solution was stirred at 0° C. for 40 minutes, at 10° C. for 10 minutes and at room temperature for 10 minutes. The reaction mixture was concentrated to a syrup, treated with a solution of methanol (1.2 ml.) in pentane (30 ml.) and stirred vigorously for 5.0 minutes. The light brown precipitates were filtered off, washed with pentane (2×30 ml.) and the combined filtrates concentrated down to a light brown liquid. The liquid was redissolved in pentane (30 ml.), stirred for a few minutes, and the resulting suspension filtered, and the precipitates obtained washed with pentane (30 ml.), repeating the procedure at least one more time. The clear filtrate was concentrated and dried in vacuo to give 54.0 g. of title compound as a light red-colored liquid. This material was stored as a solution in hexane at 10° C.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][C:8](=[O:10])[CH3:9])(=[O:6])[O:4][CH3:5].[H-].[Na+].CC1C=CC(S([N:23]=[N+:24]=[N-])(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][P:3]([C:7](=[N+:23]=[N-:24])[C:8](=[O:10])[CH3:9])(=[O:6])[O:4][CH3:5]
Reactant: COP(=O)(CC(C)=O)OC
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.4 %

Procedure:
(2-oxo-propyl)-phosphonic acid dimethyl ester (20 g, 0.12 mol) was dissolved in toluene (500 mL) at 0° C. and NaH (4.8 g, 0.12 mol) was added in portions. After the gas evolution had ceased, a solution of 4-methyl-benzenesulfonyl azide (21.4 g, 1.1 mol) was added drop-wise and the mixture was stirred at room temperature for 16 hr. The mixture was diluted with hexanes, filtered through a pad of celite and rinsed with TMBE. The filtrate was concentrated to afford the title compound (16 g, 70%): 1H NMR (400 MHz, DMSO) delta 2.22 (s, 3H), 3.74 (s, 3H), 3.79 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][P:5]([CH2:9][C:10](=[O:12])[CH3:11])(=[O:8])[O:6][CH3:7].S([N:23]=[N+:24]=[N-])(C1C=CC(C)=CC=1)(=O)=O>C1C=CC=CC=1.O1CCCC1>[CH3:3][O:4][P:5]([C:9](=[N+:23]=[N-:24])[C:10](=[O:12])[CH3:11])(=[O:8])[O:6][CH3:7]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: COP(=O)(CC(C)=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To sodium hydride (188 mg of a 60% solution in mineral oil, 113 mg clean, 4.70 mmol) in 14 mL of benzene and 2.5 mL of tetrahydrofuran, add (2-oxo-propyl)-phosphonic acid dimethyl ester (743 mg, 618 μL, 4.48 mmol) as a solution in 5 mL of benzene at 0° C. dropwise. The mix remains white and produces some gas. After 1 h at 0° C., add tosyl azide (940 mg, 4.70 mmol) as a solution in 2.5 mL of benzene and warm the mixture to RT. After 2.3 hours, pour the mix through a plug of Celite® rinsing with tetrahydrofuran, benzene, and ether. Concentrate the filtrate and purify the residue by chromatography (Hexanes/EtOAc gradient) to provide 794 mg of (1-Diazo-2-oxo-propyl)-phosphonic acid dimethyl ester as a yellow solid. This material may be used directly. Exact Mass 192.03: mass spectrum (aspci): m/z=165.0 (M+1 (—N2).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][P:5]([CH2:9][C:10](=[O:12])[CH3:11])(=[O:8])[O:6][CH3:7].S([N:23]=[N+:24]=[N-])(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[CH3:3][O:4][P:5]([C:9](=[N+:23]=[N-:24])[C:10](=[O:12])[CH3:11])(=[O:8])[O:6][CH3:7]
Reactant: COP(=O)(CC(C)=O)OC
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Reaction time: 1 h
Yield: 80.7 %

Procedure:
To a suspension of NaH (60% in mineral oil, 0.83 g, 20.8 mmols) in THF (50 ml) was added dropwise at 0 C (2-oxo-propyl)-phosphonic acid dimethyl ester (3.1 g, 18.7 mmols) in THF (50 ml), and the solution was stirred at 0 C for one hour. Tosyl azide (4 g, 20 mmols) was added in one portion, stirred at 0 C for 10 minutes, filtered through Celite and concentrated. The residue was purified by column chromatography on silica gel using ethyl acetate to yield the title compound (2.9 g, 81%) as oil. (Eur. J. Org. Chem. 2003, 821-832.)
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10](O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(O)=O.[Na+].O.C(Cl)(Cl)(Cl)[Cl:40]>>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([Cl:40])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: O[C@@H]1CCN(Cc2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: Cl[C@H]1CCN(Cc2ccccc2)C1
Reaction time: 20 h
Yield: 72 %

Procedure:
To a stirred solution of (R)-1-benzyl-3-pyrrolidinol (886 mg, 5.0 mmol) in CCl4(20 ml) was added triphenylphosphine(1.574 g, 6.0 mmol) at rt. After 20 h stirring at reflux temperature, the solvent was evapolated. Saturated NaHCO3 aqueous solution and water was added to the residue, and the mixture was extracted with AcOEt. The extract was brine, dried(Na2SO4), and concentrated to give brown oil, which was purified by column chromatography (silica gel; 100 g, CH2Cl2/MeOH: 50/1-45/1) to give 706 mg(72%) of pale yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10](O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(O)=O.[Na+].O.C(Cl)(Cl)(Cl)[Cl:40]>[Cl-].[Na+].O.CCOC(C)=O>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([Cl:40])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: O[C@@H]1CCN(Cc2ccccc2)C1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cl[C@H]1CCN(Cc2ccccc2)C1
Reaction time: 20 h
Yield: 72 %

Procedure:
To a stirred solution of (R)-1-benzyl-3-pyrrolidinol (886 mg, 5.0 mmol) in CCl4 (20 ml) was added triphenylphosphine (1.574 g, 6.0 mmol) at rt. After 20 h stirring at reflux temperature, the solvent was evapolated. Saturated NaHCO3 aqueous solution and water was added to the residue, and the mixture was extended with AcOEt. The extract was brine, dried (Na2SO4), and concentrated to give brown oil, which was purified by column chromatography (silica gel; 100 g, CH2Cl2/MeOH: 50/1-45/1) to give 7.06 mg (72%) of pale yellow oil.
Reaction SMILES: ClC1C=C[CH:5]=[C:4]([C:8]([O:10]O)=[O:9])[CH:3]=1.FC(F)(F)S(O)(=O)=O>ClCCl>[CH3:5][C:4]1([CH3:3])[C:8](=[O:9])[O:10][CH2:4][C:8](=[O:9])[O:10]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)OC(=O)COC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
A solution of 1 g of cyclic keto-ester (7.8 mmol), 2.7 g of metachloroperbenzoic acid (2 eq.) and 70 μl of trifluoromethanesulphonic acid (0.1 eq.) in 20 ml of dichloromethane is left under stirring at ambient temperature for 3 hours. The solvent is eliminated under vacuum, then the medium is analyzed. NMR 1H reveals the complete conversion of the ring with 5 members and the formation of mostly 3,3-dimethyl-2,5-dioxane-1,4-dione (spectroscopic yield: 60%).
Reaction SMILES: [C:1]([CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]2[O:14][CH2:15][O:16][C:9]=12)C(O)=O)#[N:2].CN(C)C=O>O>[C:1]([CH2:3][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]2[O:14][CH2:15][O:16][C:9]=12)#[N:2]
Reactant: N#CC(Cc1cccc2c1OCO2)C(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: N#CCCc1cccc2c1OCO2
Temperature: 150 °C

Procedure:
0.046 mole of the acid obtained in stage B is mixed with 19 ml of dimethylformamide and the mixture is then heated to 150° C. for 2 hours. The mixture is taken up with water and the product is extracted with ethyl ether. The organic phases are washed with sodium bicarbonate solution and then with water; they are dried and the solvent is evaporated off to obtain an oily residue.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][NH:8][C:7](=[O:11])[CH:6]=1)=O.CN(C=O)C.[Li+].[BH4-].CO>C1COCC1.CO.C(Cl)(Cl)Cl.O>[OH:2][CH2:3][C:5]1[CH:10]=[CH:9][NH:8][C:7](=[O:11])[CH:6]=1
Reactant: COC(=O)c1cc[nH]c(=O)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: O=c1cc(CO)cc[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Oxo-1,2-dihydropyridine-4-carboxylic acid methyl ester (1.8 g, 12.2 mmol), prepared as described in J. Org. Chem., 26, 428 (1961), was suspended in THF(100 ml). A small amount of DMF was added to help increase solubility. LiBH4 (61 mmol) was added and the reaction was stirred for 18 hours at room temperature. MeOH and H2O are added to quench the reaction. The reaction is then concentrated to yield a yellow oil. Flash chromatography (5% MeOH/CHCl3 to 20% MeOH/CHCl3) yielded 4-hydroxymethyl-1H-pyridin-2-one as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:18]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[NH:21][CH2:20][CH2:19]2.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:21]1[CH:22]2[CH2:25][CH2:26][N:18]([CH2:24][CH2:23]2)[CH2:19][CH2:20]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CN2CCC(CC2)N1
Reactant: CC(C)(C)OC(=O)n1c(Cl)nc2ccccc21
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)n1c(N2CCN3CCC2CC3)nc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.5 %

Procedure:
2-Chloro-benzoimidazole-1-carboxylic acid tert-butyl ester (333 mg, 1.32 mmol), 1,4-diazabicyclo[3.2.2]nonane (57%, 195 mg, 0.88 mmol), tri(dibenzylideneacetone)dipalladium (28 mg, 0.031 mmol), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (58 mg, 0.093 mmol), sodium tert-butoxide (208 mg, 2.17 mmol) and toluene (1.55 mL) were added to a flame dried round bottom flask purged with nitrogen. The mixture was placed in an oil bath at 80° C. for 18 h and then cooled to RT. The mixture was filtered through a pad of celite and washed with chloroform and methanol. The filtrate was concentrated and the residue was purified by chromatography (Biotage, 12M) eluting with 8% methanol in chloroform with 20 drops of NH4OH per liter of eluent to afford 104 mg (34%) of 2-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-benzoimidazole-1-carboxylic acid tert-butyl ester: MS (Cl) m/z 343.1 (M+1).
Reaction SMILES: [CH2:1]([P:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:36][CH2:35][CH2:34][C@H:23]1[C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([OH:30])=[O:29])=[O:25])=[O:21])[CH3:19])(CC1C=CC=CC=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H].O.N>C(O)C.O.C(O)(=O)C.[C].[Pd]>[CH2:1]([P:8](=[N:17][C@H:18]([C:20]([N:22]1[CH2:36][CH2:35][CH2:34][C@H:23]1[C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([OH:30])=[O:29])=[O:25])=[O:21])[CH3:19])=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Agent: [Pd]
Agent: N
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: C[C@H](N=[P+]([O-])Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Yield: 34.2 %

Procedure:
Dibenzylphosphoryl-L-alanyl-L-prolyl-L-proline (1.63 g, 3 mmole) was dissolved in a mixture of ethyl alcohol (50 ml), water (10 ml) and acetic acid (0.1 ml), and 5% palladium-carbon (200 mg) was added thereto. Hydrogen gas was passed through the mixture for 5 minutes while vigorously stirring. To the solution, concentrated ammonia water (1 ml) was added, and then the catalyst was removed by filtration. The filtrate was concentrated to an oily residue. This was dissolved in 1N ammonia water, and the thus obtained solution was passed through a column packed with a resin of porous polystyrene-divinylbenzene, HP-20, produced by Mitsubishi Chemical Industries LTD. The product was eluted from the column with acetonitrile solution, whose concentration was changed linearly from 1N NH3 water to 1N NH3 water, containing 33% acetonitrile. The main fractions were collected and the solvent was distilled off to obtain monobenzylphosphoryl-L-alanyl-L-prolyl-L-proline (430 mg, yield: 29.4%).
Reaction SMILES: [CH3:1][N:2]1[C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][CH:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+].Br[C:23]1[CH:24]=[C:25]([C:29]([O:31][CH3:32])=[O:30])[S:26][C:27]=1[Cl:28]>O1CCOCC1.O.C(Cl)Cl.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:28][C:27]1[S:26][C:25]([C:29]([O:31][CH3:32])=[O:30])=[CH:24][C:23]=1[C:6]1[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=1
Reactant: COC(=O)c1cc(Br)c(Cl)s1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2ccnn2C)c(Cl)s1
Temperature: 75 °C
Reaction time: 1.5 h

Procedure:
To a 300 mL sealed flask was added 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (8.14 g, 39.1 mmol), potassium carbonate (12.98 g, 94 mmol), methyl 4-bromo-5-chloro-2-thiophenecarboxylate (8 g, 31.3 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.40 g, 0.78 mmol) in 1,4-dioxane (50 ml) and H2O (6 ml). After stirring for 90 min at 75° C., the reaction solution was diluted with DCM (100 mL) and washed with H2O. The organic layer was dried Na2SO4, filtered and concentrated. The reaction residue was purified on silica gel [hexanes/EtOAc, 2:1] to give the product [5.7 g, 70%] as a tan solid: LCMS (ES) m/z 258 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH:15]=O)[NH:11][C:10]=1[CH3:17])=[O:8])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2.N1CCCC1>O1CCCC1>[CH3:2][CH2:1][N:3]([CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12](/[CH:15]=[C:24]2/[C:23]3[CH:22]=[C:21]([F:20])[CH:29]=[CH:28][C:27]=3[NH:26][C:25]/2=[O:30])[NH:11][C:10]=1[CH3:17])=[O:8])[CH2:18][CH3:19]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (5.0 g 0.018 moles) and 5-Fluoro-1,3-dihydro-indol-2-one (2.705 g; 0.018 moles) in tetrahydrofuran were reacted in presence of catalytic amount of pyrrolidine (0.08 mL) as base at reflux temperature for 2-8 hours. The resultant Sunitinib base was triturated in tetrahydrofuran at reflux temperature for 1-2 hours and isolated at 25-30° C. and dried at 60° C. for 5-20 hours to get Sunitinib base (I) as orange crystalline solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH:15]=O)[NH:11][C:10]=1[CH3:17])=[O:8])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2.CO.N1CCCC1>C(O)CCC.C(O)(C)C.C(O)C>[CH3:2][CH2:1][N:3]([CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12](/[CH:15]=[C:24]2/[C:23]3[CH:22]=[C:21]([F:20])[CH:29]=[CH:28][C:27]=3[NH:26][C:25]/2=[O:30])[NH:11][C:10]=1[CH3:17])=[O:8])[CH2:18][CH3:19]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: CO
Solvent: C1CCNC1
Solvent: CC(C)O
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C

Procedure:
According to the process of the present invention, 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (IX) and 5-Fluoro-1,3-dihydro-indol-2-one (X) in alcoholic solvents like methanol, ethanol, isopropyl alcohol or n-butanol are reacted in presence of catalytic amount of pyrrolidine as base at reflux temperature for 2-8 hours. The resultant Sunitinib base is again triturated with the same solvent at reflux temperature for 1-2 hours and isolated at a temperature ranging from 20-45° C., preferably at 25-35° and most preferably at 25-30° C. and dried at 60° C. for 5-20 hours to get Sunitinib base (I) as orange crystalline solid. This synthetic procedure for the manufacture of Sunitinib base is adopted from WO 01/60814.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH:15]=O)[NH:11][C:10]=1[CH3:17])=[O:8])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2.N1CCCC1>C(O)C>[CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12](/[CH:15]=[C:24]2\[C:25](=[O:30])[NH:26][C:27]3[C:23]\2=[CH:22][C:21]([F:20])=[CH:29][CH:28]=3)[NH:11][C:10]=1[CH3:17])=[O:8])[CH3:2]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: C1CCNC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (809 g), 5-fluoro-1,3-dihydro-indol-2-one (438 g), ethanol (8000 mL) and pyrrolidine (13 mL) were heated at 78° C. for 3 hours. The mixture was cooled to room temperature and the solids collected by vacuum filtration and washed with ethanol. The solids were stirred with ethanol (5900 mL) at 72° C. for 30 minutes. The mixture was cooled to room temperature. The solids were collected by vacuum filtration, washed with ethanol and dried under vacuum at 54° C. for 130 hours to give 5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (1013 g, 88% yield) as an orange solid. 1H-NMR (dimethylsulfoxide-d6) δ 0.98 (t, 6H, 2×CH3), 2.43, 2.44 (2×s, 6H, 2×CH3), 2.50 (m, 6H, 3×CH2), 3.28 (q, 2H, CH2), 6.84, 6.92, 7.42, 7.71, 7.50 (5×m, 5H, aromatic, vinyl, CONH), 10.88 (s, 1H, CONH), 13.68 (s, 1H, pyrrole NH). MS m/z 397 [M−1].
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH:15]=O)[NH:11][C:10]=1[CH3:17])=[O:8])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2.N1CCCC1>C1CCCCC1>[CH3:2][CH2:1][N:3]([CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12](/[CH:15]=[C:24]2/[C:23]3[CH:22]=[C:21]([F:20])[CH:29]=[CH:28][C:27]=3[NH:26][C:25]/2=[O:30])[NH:11][C:10]=1[CH3:17])=[O:8])[CH2:18][CH3:19]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: C1CCCCC1
Solvent: C1CCNC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (5.0 g 0.018 moles) and 5-Fluoro-1,3-dihydro-indol-2-one (2.705 g; 0.018 moles) in cyclohexane were reacted in presence of catalytic amount of pyrrolidine (0.08 mL) as base at reflux temperature for 2-8 hours. The resultant Sunitinib base was triturated in cyclohexane at reflux temperature for 1-2 hours and isolated at 25-30° C. and dried at 60° C. for 5-20 hours to get Sunitinib base (I) as orange crystalline solid.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=2[N:5]=[CH:6][N:7]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][NH:30][CH:31]=2)O1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)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>[NH:29]1[CH:28]=[C:27]([C:2]2[C:3]3[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH:31]=[N:30]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Temperature: 125 °C

Procedure:
To a mixture of 4-chloro-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (1.4 g, 0.0049 mol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.4 g, 0.0074 mol) in DMF (40 mL, 0.5 mol) was added potassium carbonate (2.0 g, 0.015 mol) in 15 mL of water. The mixture was purged with a steady stream of nitrogen for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.41 g, 0.00036 mol) was added and the reaction was heated to 125° C. for 30 min. The mixture was allowed to cool then diluted with ethyl acetate. The diluted reaction mixture was washed with water, brine, dried over Na2SO4 and concentrated to give a solution in a small volume of DMF (about 2-3 mL). Water was added, causing the material to form a gum on the walls of the flask. Then water was decanted, and the solids were dissolved in ethyl acetate. The solution was dried over Na2SO4, and concentrated in vacuo to afford a yellow solid. The product was triturated with ethyl ether to yield 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine as a white powder which was dried under vacuum (1 g, 60%). 1H NMR (300 MHz, CDCl3): δ □10.80 (br s, 1H), 8.93 (s, 1H), 8.46 (s, 2H), 7.46 (d, 1H), 6.88 (d, 1H), 5.73 (s, 2H), 3.61 (dd, 2H), 0.98 (dd, 2H), 0.00 (s, 9H); MS (ES): 316 (M+1).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:10]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][NH:23][CH3:24])[CH2:17][CH2:16]2)=[N:11][CH:12]=[CH:13][N:14]=1.[CH3:25][N:26]1[CH:30]=[C:29]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[N:27]1>ClCCl.C(=O)(O)[O-].[Na+]>[Cl:8][C:9]1[C:10]([N:15]2[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][N:23]([CH3:24])[S:31]([C:29]3[CH:28]=[N:27][N:26]([CH3:25])[CH:30]=3)(=[O:33])=[O:32])[CH2:19][CH2:20]2)=[N:11][CH:12]=[CH:13][N:14]=1
Reactant: CNCCN1CCN(c2nccnc2Cl)CC1
Reactant: Cn1cc(S(=O)(=O)Cl)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCN1CCN(c2nccnc2Cl)CC1)S(=O)(=O)c1cnn(C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
Add triethylamine (0.852 mL, 6.116 mmol) to a stirring solution of [2-(3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-ethyl]-methyl-amine (0.500 g, 1.529 mmol) in dichloromethane (10 mL). Add 1-methyl-1H-pyrazole-4-sulfonyl chloride (0.331 g, 1.834 mmol) at room temperature. Stir at room temperature for 18 hr. Dilute with dichloromethane and saturated aqueous sodium bicarbonate. Separate and extract the aqueous layer with dichloromethane. Combine the organic layers, dry over sodium sulfate, filter, and concentrate. Purify the resulting material by silica gel chromatography eluting with hexanes:acetone 6:4 to 4:6 to afford the title preparation (0.514 g, 84% yield). MS ES: m/z=400 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][CH:9]=[C:10]([C:12](OCC)=[O:13])[N:11]=2)[CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][CH:9]=[C:10]([CH2:12][OH:13])[N:11]=2)[CH:2]=1
Reactant: CCOC(=O)c1csc(-c2cccnc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1csc(-c2cccnc2)n1
Yield: 16 %

Procedure:
In substantially the same manner as in Reference Example 77, ethyl 2-(3-pyridyl)-4-thiazolecarboxylate was reduced by lithium aluminum hydride to give 2-(3-pyridyl)-4-thiazolylmethanol. The yield was 16%. Recrystallization from ethyl acetate-hexane gave colorless needles, mp 121-122° C.