Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1([CH:8]=[N:9][OH:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH2:3]1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=[CH2:24])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21]2([O:10][N:9]=[C:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:24]2)[CH2:20][CH2:19]1)=[O:17])([CH3:13])([CH3:12])[CH3:14]
Reactant: ON=CC1(Cl)C=CC=CC1
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(c1ccccc1)=NO2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 1-chloro-1-hydroxyiminomethylbenzene (C) (93.6 g, 601 mmol) in DCM (400 ml) was slowly added dropwise to a solution of 4-methylene piperidine-1-carboxylic acid tert-butyl ester (B) (39.5 g, 200 mmol) in DCM (400 ml) at 0° C. A solution of triethylamine (6.7 ml) in DCM (400 ml) was then slowly added dropwise and the resulting mixture was stirred for 48 hours at RT.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([OH:28])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:29][CH:30]([F:41])[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH:38](O)[CH3:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([O:28][CH:38]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[O:31][CH:30]([F:29])[F:41])[CH3:39])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(O)c1ccccc1OC(F)F
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1OC(C)c1ccccc1OC(F)F

Procedure:
In a similar manner as described for example B31, 2.1 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-hydroxythiophene-2-carboxylate, 1.41 g of 1-[2-(difluoromethoxy)phenyl]ethanol, 3.33 g of triphenylphosphine (polymer bound, ˜3 mmol/g) and 2.3 g of di-tert-butyl azodicarboxylate in 60 ml anhydrous dichloromethane yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.FC1(F)C2C(=CC=CC=2)N(C2CCNCC2)C1=O.[CH3:34][CH:35]([CH3:48])[CH2:36][CH2:37][NH:38][C:39]([C:41]1[N:42]=[N:43][C:44](Cl)=[CH:45][CH:46]=1)=[O:40]>CN(C=O)C>[CH3:34][CH:35]([CH3:48])[CH2:36][CH2:37][NH:38][C:39]([C:41]1[N:42]=[N:43][C:44]([N:13]2[CH2:14][CH2:15][CH:10]([C:8](=[O:9])[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:11][CH2:12]2)=[CH:45][CH:46]=1)=[O:40]
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: CC(C)CCNC(=O)c1ccc(Cl)nn1
Agent: O=C1N(C2CCNCC2)c2ccccc2C1(F)F
Solvent: CN(C)C=O
Product: CC(C)CCNC(=O)c1ccc(N2CCC(C(=O)c3ccc(F)cc3)CC2)nn1
Yield: 36 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use (4-fluorophenyl)piperidin-4-ylmethanone to replace 3,3-difluoro-1-piperidin-4-yl-1,3-dihydroindol-2-one to react with 6-chloropyridazine-3-carboxylic acid (3-methylbutyl)amide in DMF, the title compound was obtained as a white powder in 36% yield. 1H NMR (300 MHz, CDCl3) δ 7.99-8.03 (m, 3H), 7.85-7.87 (m, 1H), 7.15-7.19 (m, 2H), 7.02 (d, J=9.6 Hz, 1H), 4.50-4.54 (m, 2H), 3.47-3.60 (m, 3H), 3.26-3.31 (m, 2H), 2.00-2.04 (m, 2H), 1.85-1.93 (m, 2H), 1.73-1.72 (m, 1H), 1.48-1.53 (m, 2H), 0.94 (d, J=6.6 Hz, 6H).
Reaction SMILES: [OH:1][C:2]1([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=2)[CH:4]=[C:3]1[CH3:14].C=O.[C:22](O)(=O)C.[H][H]>C(O)C.[Pd]>[CH3:22][NH:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH:4]=[C:3]([CH3:14])[C:2]2([CH2:15][C:16]([O:18][CH3:19])=[O:17])[OH:1]
Reactant: [H][H]
Reactant: COC(=O)CC1(O)C(C)=Cc2ccc([N+](=O)[O-])cc21
Reactant: CC(=O)O
Agent: [Pd]
Agent: C=O
Solvent: CCO
Product: CNc1ccc2c(c1)C(O)(CC(=O)OC)C(C)=C2

Procedure:
A solution of 0.05 mol of methyl 3-hydroxy-2-methyl-5-nitro-3-indenylacetate, 0.2 mol of 38% aqueous formaldehyde and 2 ml of acetic acid in 100 ml ethanol is reduced catalytically in the presence of a 10% Pd/C catalyst under 40 lb. p.s.i. hydrogen pressure at room temperature. The solution is filtered, evaporated and chromatographed on 300 g of silica gel to give methyl 5-methylamino-3-hydroxy-2-methyl-3-indenylacetate. The hydroxy ester is then dehydrated to methyl 5-dimethylamino-2-methyl-3-indenylacetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:15]1[CH:20]=[C:19]([F:21])[C:18]([C:22]([F:44])([F:43])[O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[C:34]([F:36])[C:33]([C:37]([F:40])([F:39])[F:38])=[C:32]([F:41])[CH:31]=3)=[C:26]([F:42])[CH:25]=2)=[C:17]([F:45])[CH:16]=1.[OH-].[NH3+]N>C1COCC1.O.CC(OC)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:43][C:22]([F:44])([C:18]1[C:19]([F:21])=[CH:20][C:15]([C:3]2[CH:4]=[CH:5][C:6]([CH2:8][CH2:9][CH3:10])=[CH:7][C:2]=2[F:1])=[CH:16][C:17]=1[F:45])[O:23][C:24]1[CH:25]=[C:26]([F:42])[C:27]([C:30]2[CH:35]=[C:34]([F:36])[C:33]([C:37]([F:40])([F:39])[F:38])=[C:32]([F:41])[CH:31]=2)=[CH:28][CH:29]=1
Reactant: Fc1cc(OC(F)(F)c2c(F)cc(Br)cc2F)ccc1-c1cc(F)c(C(F)(F)F)c(F)c1
Reactant: CCCc1ccc(B(O)O)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N[NH3+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: O
Product: CCCc1ccc(-c2cc(F)c(C(F)(F)Oc3ccc(-c4cc(F)c(C(F)(F)F)c(F)c4)c(F)c3)c(F)c2)c(F)c1

Procedure:
A mixture of 2.60 g (14.3 mmol) of 2-fluoro-4-propylbenzeneboronic acid, 7.0 g (13.1 mmol) of 4′-[(4-bromo-2,6-difluorophenyl)difluoromethoxy]-3,5,2′-trifluoro-4-trifluoromethylbiphenyl, 0.30 g (0.42 mmol) of bis(triphenyl-phosphine)palladium(II) chloride and 2.80 g (10.1 mmol) of sodium metaborate octahydrate is initially introduced in 40 ml of THF/water=3:1. 0.02 ml (0.4 mmol) of hydrazinium hydroxide is added, and the mixture is refluxed for 20 h. After cooling, the batch is diluted with MTBE, and the mixture is washed with water. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with water. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, n-heptane). The further purification is carried out by recrystallisation from ethanol and n-heptane, giving 4-[difluoro(3,5,2′-trifluoro-4′-propyl-biphenyl-4-yl)methoxy]-6,3′,5′-trifluoro-4′-trifluoromethylbiphenyl as a colourless solid.
Reaction SMILES: [C:1]([C:4]1[CH:39]=[CH:38][C:7]([C:8]([NH:10][C@H:11]([C:15]([N:17]2[CH2:37][CH2:36][CH2:35][C@H:18]2[C:19]([NH:21][CH:22]([CH:32]([CH3:34])[CH3:33])[C:23](=[O:31])[C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])=[O:20])=[O:16])[CH:12]([CH3:14])[CH3:13])=[O:9])=[CH:6][CH:5]=1)(O)=[O:2].C(Cl)(=O)C(Cl)=O.[CH3:46][NH:47][CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1.CN1CCOCC1>CN(C=O)C>[CH3:46][N:47]([CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1)[C:1]([C:4]1[CH:39]=[CH:38][C:7]([C:8]([NH:10][C@H:11]([C:15]([N:17]2[CH2:37][CH2:36][CH2:35][C@H:18]2[C:19]([NH:21][CH:22]([CH:32]([CH3:34])[CH3:33])[C:23](=[O:31])[C:24]([F:29])([F:30])[C:25]([F:27])([F:26])[F:28])=[O:20])=[O:16])[CH:12]([CH3:14])[CH3:13])=[O:9])=[CH:6][CH:5]=1)=[O:2]
Reactant: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)c1ccc(C(=O)O)cc1)C(C)C)C(=O)C(F)(F)C(F)(F)F
Reactant: CNCCN1CCOCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)c1ccc(C(=O)N(C)CCN2CCOCC2)cc1)C(C)C)C(=O)C(F)(F)C(F)(F)F
Yield: 56.6 %

Procedure:
The acid of Example 13 (b) (0.36 g, 0.64 mmol) was activated with oxalyl chloride (0.07 mL, 0.83 mmol) and DMF (3 drops) and coupled with 4-[2-(methylamino)ethyl]-morpholine (92 mg, 0.64 mmol) using NMM (0.14 mL, 1.28 mmol) according to the method described in Example 5 (h). Purification by flash chromatography (75:25 acetone:EtOAc) gave 0.25 g (57%) of the title compound (7:1 L-L-L:L-L-D) as an off-white foam. TLC: Rf 0.19 (3:1 acetone:EtOAc). 1H NMR (partial): δ7.88-7.82 and 7.52-7.46 (pr m, 4H, aryl), 7.42 (br d, J=7.6 Hz, 1H, NH), 6.84 (br d, J=8.8 Hz, 1H, NH), 5.02-4.96 (m, 1H, CH), 4.85 (dd, J=8.6, 7.0 Hz, 1H, CH), 4.72 (dd, J=8.0, 2.0 Hz, 1/8H, CH of Pro), 4.6 (dd, J=8.1, 2.9 Hz, 7/8H, CH of Pro), 1.14-0.82 (m, 12H, 4×CH3). 19F NMR: δ−82.12 (s, CF3, major isomer), −82.15 (s, CF3, minor isomer), −121.52 and −122.70 (AB quartet, J=294 Hz, CF2, minor isomer), −121.54 and −122.58 (AB quartet, J=294 Hz, CF2, major isomer). MS (DCI/CH4): m/z (rel intensity) 691 (26), 690 (MH+, 100), 374 (62), 317 (18), 113 (22), 100 (43), 84 (36), 83 (23). HRMS (C32H45F5N5O6) (MH+): calcd, 690.3290; obsd, 690.3274.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.Br.[F:16][C:17]1[CH:45]=[CH:44][C:20]([O:21][CH2:22][CH2:23][CH2:24][N:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[N:27]([CH2:34][C:35]3[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=3)[C:26]2=[NH:43])=[CH:19][CH:18]=1.C([BH3-])#N.[Na+].C(O)(=O)C>C1COCC1.O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:39][C:38]3[CH:37]=[CH:36][C:35]([CH2:34][N:27]4[C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[N:25]([CH2:24][CH2:23][CH2:22][O:21][C:20]5[CH:19]=[CH:18][C:17]([F:16])=[CH:45][CH:44]=5)[C:26]4=[NH:43])=[CH:42][CH:41]=3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(CN2CCNCC2)cc1
Reactant: N=c1n(CCCOc2ccc(F)cc2)c2ccccc2n1Cc1ccc(C=O)cc1
Agent: Br
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N=c1n(CCCOc2ccc(F)cc2)c2ccccc2n1Cc1ccc(CN2CCN(Cc3ccc(Cl)cc3)CC2)cc1
Temperature: 55 °C
Reaction time: 16 h
Yield: 11.7 %

Procedure:
To a solution of 1-(4-chloro-benzyl)-piperazine (70 mg, 0.33 mmol) in THF (10 ml) was added 4-{3-[3-(4-fluoro-phenoxy)-propyl]-2-imino-2,3-dihydro-benzoimidazol-1-ylmethyl}-benzaldehyde, hydrobromide salt (0.20 g, 0.41 mmol), sodium cyanoborohydride (31 mg, 0.49 mmol), H2O (1 drop) and glacial acetic acid (0.068 ml). The reaction was warmed to 55° C. where it was maintained for 6 h. After this time, the mixture was cooled to rt and stirred for 16 h. The mixture was concentrated under reduced pressure and then partitioned between 1N HCl and EtOAc. The organic layer was removed and the aqueous phase was made basic using 10% K2CO3. The basic aqueous phase was extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by chromatography on silica eluting with MeOH/dichloromethane provided 1-{4-[4-(4-chloro-benzyl)-piperazin-1-ylmethyl]-benzyl}-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine (23 mg, 11%). HPLC-MS 598 [M+1]+, 300.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][C:7](C)([C:13](OCC)=O)[C:8]([O:10]CC)=[O:9])=[CH:4][CH:3]=1.C>O.C(O)C.[OH-].[Na+]>[CH3:13][CH:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:20][CH:19]=1)[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)C(C)(Cc1ccc(Br)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(Cc1ccc(Br)cc1)C(=O)O
Temperature: 205 °C
Yield: 88 %

Procedure:
A solution of sodium hydroxide (34.0 g) in water (155 ml) was added to a solution of diethyl 2-(4-bromobenzyl)-2-methylmalonate (29.2 g) in ethanol (165 ml), and then heated under reflux for 9 hours. The reaction mixture was cooled, the solvent was evaporated and the residue taken up in water (150 ml). Sodium hydroxide pellets were added (25.4 g) and the reaction mixture was heated under reflux for 2 hours. The reaction mixture was then cooled and acidified to pH<1 with concentrated hydrochloric acid, which caused precipitation of a solid. The reaction mixture was extracted with diethyl ether (3×150 ml), the combined organic layers were dried (MgSO4) and then the solvent was evaporated to give a white solid. This solid was heated at 205° C. for 20 minutes, cooled to ambient temperature, dissolved in 1.0 M sodium hydroxide solution (150 ml), treated with activated charcoal and then filtered through diatomaceous earth. The resulting clear solution was re-acidified and then extracted with diethyl ether (3×150 ml). The combined organic layers were dried (MgSO4) and evaporated to give a yellow oil which crystallised on standing to give 2-methyl-3-(4-bromophenyl)propanoic acid as a white solid (18.2 g), m.p. 69-70° C.; mass spectrum (+ve CI): 243 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6](=[C:22]1[S:26][C:25](=[S:27])[N:24]([CH2:28][C:29]([OH:31])=[O:30])[C:23]1=[O:32])[C:7]1[N:8]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[S:14])[S:10][CH:11]=1)=[O:5])[CH3:2].[CH2:33](O)[CH3:34].O1CCOCC1.Cl>O>[CH2:1]([O:3][C:4]([C:6](=[C:22]1[S:26][C:25](=[S:27])[N:24]([CH2:28][C:29]([O:31][CH2:33][CH3:34])=[O:30])[C:23]1=[O:32])[C:7]1[N:8]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[S:14])[S:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCO
Reactant: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=S)Nc2ccccc2)n1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)CN1C(=O)C(=C(C(=O)OCC)c2csc(NC(=S)Nc3ccccc3)n2)SC1=S
Reaction time: 108 h

Procedure:
A mixture comprising 10 g of 5-{1-ethoxycarbonyl-1-[2-(3-phenylthioureido)thiazol-4-yl]methylene}rhodanine-3acetic acid 20 g of ethanol and 150 ml of a 4N dioxane solution of hydrogen chloride was left to stand at room temperature for 4.5 days. The reaction mixture was then poured into water and extracted with ethyl acetate. The extract was washed with aqueous potassium carbonate solution and then with aqueous sodium chloride solution, and was then dried over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography, using as eluent a 1:1 by volume mixture of hexane and ethyl acetate. The resulting crystalline product was recrystallised from a 1:5 by volume mixture of hexane and ethyl acetate, giving a yellow powder having the following physical properties.
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.C1CCCCCC1.N1CCCC1>C1CCCCC1.C1CCCC1>[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
Agent: C1CCCCCC1
Solvent: C1CCNC1
Solvent: C1CCCC1
Solvent: C1CCCCC1
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 non-polar alicyclic hydrocarbon solvents like cyclopentane, cyclohexane or cycloheptane are reacted in presence of catalytic amount of pyrrolidine as base at reflux temperature for 1-6 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.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:8]([O-])(=O)[C@@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)O.C([N:21](C(C)C)C(C)C)C>C1(C)C=CC=CC=1>[C:11]1([C@H:9]([NH:21][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:8])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)CBr
Reactant: O=C([O-])[C@H](O)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CN[C@H](C)c1ccccc1
Temperature: 25 °C
Yield: 62.3 %

Procedure:
Ethyl bromoacetate (4.14 g; 24.8 mmol) was treated with (R) α-methylbenzylamine (3 g, 24.8 mmol) and ethyldiisopropylamine (3.2 g; 24.8 mmol) in toluene (100 mL). After heating at reflux for 18 hours, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 20% ethyl acetate/pentane) to provide the title compound (3.2 g, 63% yield). MS (DCl/NH3) m/z 208 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[C:15]2[N:16]([C:28]([CH:31]=O)=[CH:29][N:30]=2)[C:17]2[C:22]([N:23]=1)=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2.[BH4-].[Na+]>CO>[CH2:1]([NH:8][CH2:31][C:28]1[N:16]2[C:17]3[C:22]([N:23]=[C:14]([NH:13][CH2:12][CH2:11][CH2:10][OH:9])[C:15]2=[N:30][CH:29]=1)=[CH:21][C:20]([C:24]([F:26])([F:27])[F:25])=[CH:19][CH:18]=3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=Cc1cnc2c(NCCCO)nc3cc(C(F)(F)F)ccc3n12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCCCNc1nc2cc(C(F)(F)F)ccc2n2c(CNCc3ccccc3)cnc12
Temperature: 30 °C
Reaction time: 17 h

Procedure:
To a solution of the benzylamine (13 μL, 0.12 mmol) in methanol (400 μL) was added 4-[(3-hydroxypropyl)amino]-7-(trifluoromethyl)imidazo[1,2-a]quinoxaline-1-carbaldehyde (35 mg, 0.10 mmol). The reaction mixture was stirred at 30° C. for 17 h. After addition of NaBH4 (5 mg, 0.12 mmol), the mixture was stirred at 30° C. for 5 h. Then it was concentrated, diluted in ethyl acetate, washed with an aqueous saturated solution of ammonium chloride and extracted with ethyl acetate. The combined organic phases were dried over Na2SO4, filtered, concentrated in vacuo to give, after purification by preparative TLC (dichloromethane/methanol 9/1), the title compound (32 mg, 75%) as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]([CH2:13][OH:14])[CH2:11][CH2:10][CH:9]1[CH2:15][OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([N:8]1[CH:12]([CH2:13][O:14][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:11][CH2:10][CH:9]1[CH2:15][OH:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC1CCC(CO)N1Cc1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC1CCC(CO)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To a solution of 1-benzyl-2,5-bis(hydroxymethyl)-pyrrolidine (30 g) and imidazole (27.8 g) in dimethylformamide (300 ml) was added portionwise t-butyldimethylsilyl chloride (20.4 g) at room temperature. After stirring for 1 hour at room temperature, water (0.9 l) and ethyl acetate (1.4 l) was added to the mixture. After shaking, aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layer was washed with water (3 times) and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was column chromatographed on silica gel (eluent:nexane/ethyl acetate, 8:2-7:3 V/V) to give 1-benzyl-5-t-butyldimethylsilyloxymethyl-2-hydroxymethylpyrrolidine (16.8 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([S:16][CH3:17])[C:4]=1[C:5]([OH:7])=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:51][C:52]([O:55][C:56](=[O:64])[NH:57][CH:58]1[CH2:62][CH2:61][CH2:60][CH:59]1[NH2:63])([CH3:54])[CH3:53]>CN(C)C=O>[C:52]([O:55][C:56](=[O:64])[NH:57][CH:58]1[CH2:62][CH2:61][CH2:60][CH:59]1[NH:63][C:5](=[O:7])[C:4]1[C:8]([S:16][CH3:17])=[CH:9][C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][C:3]=1[O:2][CH3:1])([CH3:54])([CH3:51])[CH3:53]
Reactant: CC(C)(C)OC(=O)NC1CCCC1N
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoic acid (intermediate A, 1.1 g, 4.1 mmol) was dissolved in 40 mL dimethylformamide. N,N-Diisopropyl ethyl amine (763 mg, 5.9 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.57 g, 4.1 mmol) were added. After 5 minutes of stirring at room temperature [(1RS,2SR)-2-aminocyclopentyl-carbamic acid 1,1-dimethylethyl ester (CAS 365996-19-6) (993 mg, 5 mmol) was added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated off. The residue was taken up in 2N sodium carbonate solution and ethyl acetate and was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (heptane ethyl acetate 100:0->1:1) yielded the title compound as a white solid (1.8 g, 100%), MS: m/e=449.2 [(M+H)+].
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[F:13][C:14]1[C:22]([O:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([OH:36])=[C:31]([O:34][CH3:35])[CH:32]=3)[N:27]=[N:26][CH:25]=2)=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]([CH3:37])[NH:18]2.[Br:38][CH2:39][CH2:40][CH2:41]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C>[Br:38][CH2:39][CH2:40][CH2:41][O:36][C:30]1[CH:29]=[C:28]2[C:33]([C:24]([O:23][C:22]3[C:14]([F:13])=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:37])=[CH:16]4)=[CH:25][N:26]=[N:27]2)=[CH:32][C:31]=1[O:34][CH3:35]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1O
Reactant: OCCCBr
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1OCCCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
DEAD (0.47 ml, 2.95 mmol) was added dropwise to a solution of 4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxycinnoline (0.5 g, 1.47 mmol), (prepared as described in Example 4), 3-bromopropan-1-ol (0.2 ml, 2.21 mmol) and triphenylphosphine (0.78 g, 2.95 mmol) in DMF (10 ml). The mixture was stirred for 1 hour at ambient temperature and the volatiles were removed under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/methylene chloride (1/1). The fractions containing the expected product were combined and evaporated to give 7-(3-bromopropoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxycinnoline (0.6 g, 88%) (purity 80%; contaminated by some triphenylphosphine oxide).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1)#[CH:2].[CH2:10]([O:12][C:13](=[O:17])/[CH:14]=[CH:15]\I)[CH3:11]>>[CH2:10]([O:12][C:13](=[O:17])[CH:14]=[CH:15][C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1)[CH3:11]
Reactant: C#Cc1ccc(C)cc1
Reactant: CCOC(=O)/C=C\I
Product: CCOC(=O)C=CC#Cc1ccc(C)cc1

Procedure:
The general procedure was used to convert 1-Ethynyl-4-methyl-benzene and (Z)-ethyl-3-iodoacrylate to the title product. Purification by flash chromatography (10% ethyl acetate in hexane as the eluent) gave the analytically pure product as a light yellow oil (350 mg, 85% yield). 1H NMR (400 MHz, CDCl3) δ 7.43-7.41 (d, J=8.1, 2H), 7.16-7.14 (d, J=7.9, 2H), 6.37-6.34 (d, J=11.4, 1H), 6.12-6.09 (d, J=11.4, 1H), 4.29-4.23 (q, J=7.1, 2H), 2.36 (s, 3H), 1.35-1.31 (t, J=7.1, 3H). 13C NMR (100 MHz, CDCl3) δ 164.92, 139.62, 132.12, 129.28, 127.83, 123.14, 119.76, 101.77, 86.19, 60.44, 21.66, 14.42. Anal. Calcd. for C14H14O2: C, 78.48; H, 6.59; Found C, 78.22; H, 6.78.