Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)C(O)=O)[CH2:6][CH2:5][CH2:4][CH2:3]1.C1(P([N:31]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.CCO[C:37](C)=[O:38]>C1(C)C=CC=CC=1.CCCCCC>[C:11]1([CH:7]2[C:2]3([CH2:3][CH2:4][CH2:5][CH2:6]3)[O:1][C:37](=[O:38])[NH:31]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(C)=O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)C(c1ccccc1)C1(O)CCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=C1NC(c2ccccc2)C2(CCCC2)O1
Temperature: 120 °C
Reaction time: 12 h
Yield: 31 %

Procedure:
To a 100 mL round bottom flask charged with 2-(1-hydroxycyclopentyl)-2-phenylacetic acid (3.5 g, 16.13 mmol, 1 eq.) in toluene (70 mL) were added TEA (2.5 eq) and diphenyl phosphoryl azide (2 eq). The resulting mixture was stirred at 120° C. for 12 hours. Reaction progress was monitored by TLC (TLC eluent: 30% EtOAc in hexane). The reaction mixture was cooled and toluene was removed under reduced pressure. The product thus obtained was purified by column chromatography using silica gel and eluting with 10% EtOAc in hexane to afford 4-phenyl-1-oxa-3-azaspiro[4.4]nonan-2-one (2 g, 31%). 1H NMR (300 MHz, CDCl3) δ: 8.06 (s, 1H), 7.28-7.41 (m, 5H), 4.78 (s, 1H), 1.88-2.03 (m, 2H), 1.23-1.70 (m, 5H), 0.97-1.03 (m, 1H). m/z (ESI) 218.3 (M+H)+.
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].CC(C)([O-])C.[K+].Cl[C:12]1[N:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:13]=1[C:14]([NH:16][CH:17]1[CH2:22][CH2:21][CH:20]([C:23]([F:26])([F:25])[F:24])[CH2:19][CH2:18]1)=[O:15]>C1COCC1.O>[Cl:31][C:29]1[CH:28]=[CH:27][C:13]([C:14]([NH:16][C@H:17]2[CH2:18][CH2:19][C@H:20]([C:23]([F:24])([F:25])[F:26])[CH2:21][CH2:22]2)=[O:15])=[C:12]([O:4][CH2:3][CH2:2][F:1])[N:30]=1
Reactant: O=C(NC1CCC(C(F)(F)F)CC1)c1ccc(Cl)nc1Cl
Reactant: OCCF
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(N[C@H]1CC[C@H](C(F)(F)F)CC1)c1ccc(Cl)nc1OCCF
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-Fluoroethanol (380 μL, 6.45 mmol) is added to potassium tert-butoxide (730 mg, 6.16 mmol) in THF (60 mL) and stirred for 5 min at rt. After the addition of 2,6-dichloro-N-(4-trifluoromethyl-cyclohexyl)-nicotinamide (2.00 g, 5.86 mmol) the reaction mixture is stirred for 1 h hour at rt, then diluted with water and concentrated. The residue is stirred in ice water, the precipitate is filtered off and dried.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:14](=[O:24])[CH2:13]2)[CH2:9]1)=O)(C)(C)C.CCN(CC)CC.[Cl:32][C:33]1[C:34]2[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][C:35]=2[S:36][C:37]=1C(Cl)=O.ClC1C2C=CC(C(F)(F)F)=CC=2SC=1C(O)=O>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:32][C:33]1[C:34]2[CH:44]=[CH:43][C:42]([C:45]([F:47])([F:46])[F:48])=[CH:41][C:35]=2[S:36][C:37]=1[C:6]([N:8]1[CH2:9][CH:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:19]=[CH:20][CH:21]=[CH:22][N:23]=3)[C:14](=[O:24])[CH2:13]2)[CH2:11]1)=[O:5]
Reactant: O=C(Cl)c1sc2cc(C(F)(F)F)ccc2c1Cl
Reactant: CC(C)(C)OC(=O)N1CC(N2CCN(c3ncccn3)C(=O)C2)C1
Agent: O=C(O)c1sc2cc(C(F)(F)F)ccc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1sc2cc(C(F)(F)F)ccc2c1Cl)N1CC(N2CCN(c3ncccn3)C(=O)C2)C1
Temperature: 25 °C

Procedure:
A solution of intermediate 3c (prepared by procedures described in Example 4) in CH2Cl2 (2 mL) and TFA (0.5 mL) was stirred at room temperature for 1h. The solution was concentrated, and the residue was dissolved in CH2Cl2 (2.5 mL). To the resulting solution at 0° C. was added Et3N (0.11 mL, 0.79 mmol), followed by a solution of 3-chloro-6-trifluoromethyl-benzo[b]thiophene-2-carbonyl chloride 5a (prepared from 3-chloro-6-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid following the procedures described in Example 1, Step A) (0.14 mmol) in CH2Cl2 (1.5 mL). The reaction was slowly warmed up to room temperature in 2 h, and was then quenched with aq. NaHCO3. The mixture was extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated. Purification by column chromatography (silica gel, 3% MeOH/CH2Cl2) gave Cpd 8 as yellow solid (28 mg). MS 496 (M+H+).
Reaction SMILES: [CH2:1]([C:4]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3].[I:25]I>ClCCl.C(Cl)(Cl)Cl>[I:25][CH2:3][CH:2]1[CH2:1][C:4]2[C:5]3[C:6](=[N:7][CH:8]=[N:9][C:10]=3[CH:11]=[C:12]([O:16][CH3:17])[C:13]=2[O:14][CH3:15])[N:18]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C=CCc1c(OC)c(OC)cc2ncnc(Nc3ccccc3)c12
Reactant: II
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1cc2ncnc3c2c(c1OC)CC(CI)N3c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (5-allyl-6,7-dimethoxy-quinazolin-4-yl)-phenyl-amine (0.12 g, 0.37 mmol) (from Example 15, Step E, supra) in dichloromethane (20 mL) was added I2 (0.24 g, 1.87 mmol). The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with chloroform (100 mL), and washed with a saturated aqueous Na2SO3 solution. The organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:2:0.05) as eluent to give the desired 5-iodomethyl-7,8-dimethoxy-4-phenyl-5,6-dihydro-4H-1,3,4-triaza-phenalene as a pale yellow solid. (Yield 0.11 g, 66%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:38])=[C:4]([CH3:37])[C:5]2[O:9][C:8]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([C:18]([NH:20][CH2:21][CH:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=O)[CH2:14][CH2:13]3)([CH3:10])[CH2:7][C:6]=2[C:35]=1[CH3:36].[ClH:39].C(=O)([O-])O.[Na+]>O1CCCC1.O.C(OC(C)C)(C)C>[ClH:39].[ClH:39].[ClH:39].[NH2:1][C:2]1[C:3]([CH3:38])=[C:4]([CH3:37])[C:5]2[O:9][C:8]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([CH2:18][NH:20][CH2:21][CH:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:14][CH2:13]3)([CH3:10])[CH2:7][C:6]=2[C:35]=1[CH3:36]
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(C(=O)NCC(c3ccccc3)c3ccccc3)CC1)O2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)OC(C)C
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(CNCC(c3ccccc3)c3ccccc3)CC1)O2
Yield: 61 %

Procedure:
To a solution of 1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-yl)methyl]-N-(2,2-diphenylethyl)-4-piperidinecarboxamide (1.0 g) in tetrahydrofuran (20 mL) was added 12 mL of 1 M borane tetrahydrofuran complex solution in tetrahydrofuran dropwise with ice-cooling and the mixture was refluxed under nitrogen gas for 6 hours. After this reaction mixture was cooled with ice, 8 mL of 5N-hydrochloric acid was added dropwise, followed by stirring. The mixture was added dropwise to a suspension of sodium hydrogen carbonate (4 g) in water/diisopropyl ether for neutralization and extracted with 2 portions of ethyl acetate. The pooled organic layer was washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated. After the residue was dissolved in methanol, 10 mL of 5N-hydrochloric acid was added and the mixture was refluxed for 1 hour. After ice-cooling, the mixture was diluted with 20 mL of 5N-aqueous sodium hydroxide and extracted with 3 portions of diethyl ether. The pooled organic layer was washed with water and saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate/triethylamine=30:10:1 to 20:10:1) to recover 1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-yl)methyl]-N-(2,2-diphenylethyl)-4-piperidinemethylamine. After this product was dissolved in methanol, a stoichiometric excess of 10% HCl solution in methanol was added dropwise and the resulting mixture was concentrated under reduced pressure to provide 0.74 g of the title compound.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][C:12]1[N:13]([C:17]2[CH:41]=[CH:40][C:20]([C:21]([N:23]3[CH2:28][CH2:27][CH:26]([N:29]4[C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH2:33][CH2:32][C:30]4=[O:31])[CH2:25][CH2:24]3)=[O:22])=[CH:19][CH:18]=2)[CH:14]=[CH:15][N:16]=1)([O-])=O.O.[OH-].[Na+]>C(O)C>[NH2:2][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][C:12]1[N:13]([C:17]2[CH:41]=[CH:40][C:20]([C:21]([N:23]3[CH2:28][CH2:27][CH:26]([N:29]4[C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH2:33][CH2:32][C:30]4=[O:31])[CH2:25][CH2:24]3)=[O:22])=[CH:19][CH:18]=2)[CH:14]=[CH:15][N:16]=1
Reactant: O=C(c1ccc(-n2ccnc2Sc2ccccc2[N+](=O)[O-])cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ccccc1Sc1nccn1-c1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To the mixture of conc. hydrochloric acid (3.2 ml) and ethanol (2 ml) is added 1-[1-{4-[2-(2-nitrophenyl)thio-1-imidazolyl]benzoyl}-4-piperidinyl]-3,4-dihydrocarbostyril (2.0 g), and thereto is added dropwise a solution of stannous chloride dihydrate (2.7 g) in ethanol (4 ml) at a temperature below 25° C. with water-cooling, and the mixture is stirred at room temperature for two hours. The mixture is poured into ice-water and basified with aqueous sodium hydroxide solution, extracted with chloroform, washed with water, and dried over sodium sulfate. After concentrated under reduced pressure, the resulting residue is purified by silica gel column chromatography (eluent; chloroform:methanol=50:1-25:1), and further dissolved in methanol. The mixture is added dropwise with stirring into water (about 40 ml) and the resulting precipitates are collected by filtration and dried to give 1-[1-{4-[2-(2-aminophenyl)thio-1-imidazolyl]benzoyl}-4-piperidinyl}-3,4-dihydrocarbostyril (1.6 g) as white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH2:12][O:13][CH3:14])=[C:6](Br)[CH:5]=1.[CH2:17](OB(C=C)OCCCC)[CH2:18]CC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:5]=[C:6]([CH:17]=[CH2:18])[C:7]([O:11][CH2:12][O:13][CH3:14])=[C:8]([F:10])[CH:9]=1
Reactant: COCOc1c(F)cc(C(=O)OC)cc1Br
Reactant: C=CB(OCCCC)OCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: C=Cc1cc(C(=O)OC)cc(F)c1OCOC
Temperature: 100 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
To a solution of 3-bromo-5-fluoro-4-methoxymethoxybenzoic acid methyl ester (300 mg) and vinylboronic acid dibutyl ester (226 mg) in toluene (4 mL)-ethanol (2 mL) were added dichlorobis(triphenylphosphine)palladium (II) (36 mg) and an aqueous solution (1 mL) of sodium carbonate (217 mg). The mixture was stirred at 100° C. for 8 hours, and then allowed to stand for cooling down to room temperature. The resulting insoluble materials were filtered through a Celite pad, and the filtrate was concentrated in vacuo. The residue was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After concentration in vacuo, the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=30:1, v/v) to give the title compound (190 mg).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:23][C:22]([C:24]([OH:26])=[O:25])=[CH:21][C:9]=3[N:10]([CH2:18][O:19][CH3:20])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li]C(CC)C.CN(CCN(C)C)C.CN([CH:43]=[O:44])C>C1COCC1>[CH:1]1([C:7]2[C:8]3[S:23][C:22]([C:24]([OH:26])=[O:25])=[C:21]([CH:43]=[O:44])[C:9]=3[N:10]([CH2:18][O:19][CH3:20])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)C=O
Reactant: COCn1c(-c2ccccc2)c(C2CCCCC2)c2sc(C(=O)O)cc21
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COCn1c(-c2ccccc2)c(C2CCCCC2)c2sc(C(=O)O)c(C=O)c21
Temperature: -10 °C
Reaction time: 0.08 h
Yield: 85 %

Procedure:
A solution (0.2 M) of 6-cyclohexyl-4-(methoxymethyl)-5-phenyl-4H-thieno[3,2-b]pyrrole-2-carboxylic acid in THF was added dropwise to a solution (0.6 M) of sec-BuLi (3 eq.) and TMEDA (3 eq.) in THF at −78° C. After 5 min at −78° C., the resulting solution was treated with DMF (10 eq.) then was allowed to warm up at −10° C. The mixture was quenched with water and poured into aqueous HCl (0.1 N) and extracted with AcOEt. The combined organic phase was dried and concentrated to give the title compound (85%) as a solid, that was used as such.
Reaction SMILES: [N:1]1([CH2:10][CH2:11][CH2:12][CH2:13]O)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.S(Cl)([Cl:17])=O>ClC(Cl)Cl>[Cl:17][CH2:13][CH2:12][CH2:11][CH2:10][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=S(Cl)Cl
Reactant: OCCCCn1cnc2ccccc21
Solvent: ClC(Cl)Cl
Product: ClCCCCn1cnc2ccccc21
Reaction time: 3 h
Yield: 45 %

Procedure:
To a stirred mixture of 50 parts of 1H-benzimidazole-1-butanol and 375 parts of trichloromethane are added dropwise 35.2 parts of sulfinyl chloride. Upon completion, stirring is continued for 3 hours at reflux temperature. The reaction mixture is evaporated. The residue is taken up in trichloromethane. The whole is washed with ammonium hydroxide and the solvent is evaporated. The residue is purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated, yielding 22 parts (45%) of 1-(4-chlorobutyl)-1H-benzimidazole as an oily residue.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]([CH2:11][C@H:12]([NH2:16])[C:13]([OH:15])=O)=[O:10])=[CH:3][CH:2]=1.[CH2:17](N(CC)CC)C.[C:24](OC(=O)C)(=[O:26])[CH3:25].[OH-].[K+]>CN(C)C1C=CN=CC=1.O>[C:24]([NH:16][CH:12]([C:13](=[O:15])[CH3:17])[CH2:11][C:9]([O:8][CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)=[O:10])(=[O:26])[CH3:25]
Reactant: CCN(CC)CC
Reactant: N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(=O)NC(CC(=O)OCc1ccccc1)C(C)=O
Yield: 82.8 %

Procedure:
β-Benzyl L-aspartate (400 g, 1.79 mol) was suspended in triethylamine (748 ml, 5.37 mol) and acetic anhydride (676 ml, 7.16 mol) was dropwise added at 0° C. with stirring. After stirring for 30 minutes, 4-dimethylaminopyridine (20.0 g, 0.16 mol) was portionwise added under ice-cooling. The mixture was stirred overnight at room temperature, and ice was added under ice-cooling. At the end of the exothermic process, water (700 ml) was added. A 7.5N aqueous solution of potassium hydroxide was portionwise added to make its pH 9. The mixture was extracted three times with ethyl acetate (1,000 ml), and the organic layer was washed twice with 1N hydrochloric acid (1,000 ml), twice with a saturated aqueous solution of sodium hydrogencarbonate (500 ml) and with saturated brine (500 ml) in order. The layer was dried over magnesium sulfate and concentrated to dryness to give 390 g of the title compound.
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.[C:31]([OH:40])(=[O:39])[C@@H:32]([C@H:34]([C:36]([OH:38])=[O:37])[OH:35])[OH:33]>C(O)C.N1CCCC1>[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].[C:31]([O-:40])(=[O:39])[C@@H:32]([C@H:34]([C:36]([O-:38])=[O:37])[OH:35])[OH:33]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
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
Product: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.5 %

Procedure:
To a solution of 6.63 g (25 mmol) N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (I) and 3.78 g (25 mmol) 5-fluoroindolin-2-one (II) in ethanol (400 ml), 0.25 ml of pyrrolidine was added and mixture was refluxed for 5 h. To a boiling reaction mixture, a solution of L-tartaric acid (1.88 g, 12.5 mmol) in ethanol (20 ml) was added and a solution was left to cool to room temperature, with slow (as slow as possible) stirring. The stirring was continued for another 16 hours, then the product was filtered to get 4.20 g of sunitinib L-tartarate. Melting point: 219-223° C. (Form III), ratio sunitinib/tartaric acid (according to NMR) 2:1.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH2:14][C:15]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]=2[NH:27][CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])=[O:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH2:14][C:15]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]=2[NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)CC(=O)c2ccc3ccccc3c2NCC(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCN(C(=O)CC(=O)c2ccc3ccccc3c2NCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.2 %

Procedure:
To a solution of 2-[((4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl)carbonyl][(1,1-dimethylethoxycarbonyl)methyl]aminonaphthalene (147 mg, 0.30 mmol) in CH2Cl2 (2.0 mL) was added TFA (3.0 mL). The resulting reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was evaporated in vacuo to afford an oil, which was diluted with water (15 mL), adjusted to pH 4.5 by saturated NaHCO3, then extracted by ethyl acetate (3×15 mL). The organic layer was evaporated in vacuo to afford 2-[((4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl)carbonyl][carboxymethyl]aminonaphthalene (90 mg) as a solid; NMR (CDCl3) 1.26 (t, 3), 3.24–3.30 (m, 2), 3.35–3.42 (m, 6), 3.57 (m, 2), 4.14 (q, 2), 4.52 (s, 2), 7.48 (d, 1), 7.58 (m, 2), 7.84–7.94 (m, 4) ppm.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[CH3:17][C:18]1([CH3:25])[O:22][CH:21]([CH2:23][OH:24])[CH2:20][O:19]1.[H-].[Na+].[Cl-].[Na+]>C(OC)(C)(C)C.CN(C)C=O>[CH3:17][C:18]1([CH3:25])[O:22][CH:21]([CH2:23][O:24][C:2]2[S:6][N:5]=[C:4]([S:7][CH2:8][O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:3]=2)[CH2:20][O:19]1
Reactant: CC1(C)OCC(CO)O1
Reactant: Clc1nc(SCOCc2ccccc2)ns1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CC1(C)OCC(COc2nc(SCOCc3ccccc3)ns2)O1
Reaction time: 2 h
Yield: 70 %

Procedure:
To 3 g of N,N-dimethylformamide, 350 mg of 5-chloro-3-benzyloxymethylthio-1,2,4-thiadiazole and 169 mg of 2,2-dimethyl-1,3-dioxolane-4-methanol were dissolved, and added 56 mg of sodium hydride (60% in oil) at about 0° C., followed by stirring at same tempareture for 2 hours. Then, to the reaction mixture, t-butylmethylether and saturated sodium chloride aqueous solution were added, and separeted to two layers. The organic layer was dried by anhydrous sodium salfate, and concentrated. The residue obtaind was subjected to column chromatography to obtain 330 mg of 5-(2,2-dimethyl-1,3-dioxolane-4-yl)methoxy-3-benzyloxymethylthio-1,2,4-thiadiazole.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Al](Cl)(C)C.[CH3:13][N:14]([CH3:39])[C:15]([C:17]1[N:22]=[CH:21][C:20]([O:23][C:24]2[C:29]3[CH:30]=[C:31]([CH3:33])[O:32][C:28]=3[CH:27]=[C:26]([C:34](OCC)=[O:35])[CH:25]=2)=[CH:19][N:18]=1)=[O:16].CC1CCCO1>COC.O>[CH3:39][N:14]([CH3:13])[C:15]([C:17]1[N:22]=[CH:21][C:20]([O:23][C:24]2[C:29]3[CH:30]=[C:31]([CH3:33])[O:32][C:28]=3[CH:27]=[C:26]([C:34](=[O:35])[NH:8][C:5]3[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=3)[CH:25]=2)=[CH:19][N:18]=1)=[O:16]
Reactant: Cc1cnc(N)cn1
Reactant: CCOC(=O)c1cc(Oc2cnc(C(=O)N(C)C)nc2)c2cc(C)oc2c1
Agent: COC
Agent: C[Al](C)Cl
Solvent: O
Solvent: CC1CCCO1
Product: Cc1cnc(NC(=O)c2cc(Oc3cnc(C(=O)N(C)C)nc3)c3cc(C)oc3c2)cn1
Temperature: 25 °C

Procedure:
To a solution of the 5-methyl-2-aminopyrazine (38.9 g, 356 mmol) in dimethylether (315 mL) in a 3-neck flask equipped with overhead stirring and a condensor at 0° C. was added Me2AlCl (1M solution in hexanes) (715 mL). The mixture was warmed at room temperature and stirred for 1.5 hours. In a separate flask, ethyl 4-(2-(dimethylcarbamoyl)pyrimidin-5-yloxy)-2-methylbenzofuran-6-carboxylate (1-2a: 52.6 g, 142.5 mmol) was dissolved in dimethylether (210 mL). This mixture was then added to the complexed amine. A gum precipitated upon scratching the flask and dissipated into a solid. The resultant reaction was refluxed for 3.5 hours HPLC indicated 93% complete. Five liters of Rochelles salt made up in water and 2 liters of 2-methyltetrahydrofuran was added to the mixture. The reaction mixture was then poured into the biphasic system. The mixture was allowed to stir with overhead stirring for 14 hours, after which time, a yellow solid precipitated. The solid was collected through filteration. The solid retained was washed with 2-methyltetrahydrofuran. The resultant solid was dried in vacuo oven overnight to afford the title compound N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide (2): (49.98 g, 81%)
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].CCN(C(C)C)C(C)C.[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2([C:37]([F:40])([F:39])[F:38])[O:27][N:26]=[C:25]([C:28]3[S:32][C:31]([CH:33]([NH2:35])[CH3:34])=[C:30]([CH3:36])[CH:29]=3)[CH2:24]2)[CH:19]=[C:20]([Cl:22])[CH:21]=1>ClCCl>[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2([C:37]([F:39])([F:38])[F:40])[O:27][N:26]=[C:25]([C:28]3[S:32][C:31]([CH:33]([NH:35][C:1](=[O:4])[CH2:2][CH3:3])[CH3:34])=[C:30]([CH3:36])[CH:29]=3)[CH2:24]2)[CH:19]=[C:20]([Cl:22])[CH:21]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1C(C)N
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)NC(C)c1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Reaction time: 19 h
Yield: 30.9 %

Procedure:
Propionyl chloride (20 mg) and Hünig base (70 μl) are added to a solution of 1-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophen-2-yl}-ethylamine (60 mg) in dichloromethane (1 ml). After 19 hours at room temperature, the reaction is quenched with water. The reaction mixture is extracted three times with dichloromethane. The combined organic phases are dried over MgSO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield N-(1-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophen-2-yl}-ethyl)-propionamide (21 mg, compound 1.49 in Table 1) as a light yellow oil. MS (HPLC/MS): 479 (MH+). Retention time: 2.01 min.
Reaction SMILES: [N:1]([O-])=O.[Na+].[Cl:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[C:7]=1[NH2:20]>C(O)(=O)C.C(Cl)Cl>[Cl:5][C:6]1[C:7]2[N:20]=[N:1][N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])[C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: O=N[O-]
Reactant: Cc1ccccc1Nc1ncnc(Cl)c1N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1ccccc1-n1nnc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.6 %

Procedure:
Sodium nitrite (0.323 g, 4.69 mmol) was added to 6-chloro-N4-o-tolylpyrimidine-4,5-diamine (Intermediate AP5)(1 g, 4.26 mmol) in acetic acid (50% Aq) (25 mL)and DCM (25 mL) at room temperature. The resulting solution was stirred at room temperature for 15 minutes. The reaction mixture was separated and the organic phase was washed with water (10 mL), dried (MgSO4) and evaporated to give crude 7-chloro-3-o-tolyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (0.980 g, 94%) that was used without further purification.