Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:15][CH:16]([CH2:36][O:37][C:38](=[O:54])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:17][O:18][C:19](=[O:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])(=[O:14])[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].S(Cl)(Cl)=O.[CH:59]1[C:64]([Cl:65])=[CH:63][C:62](O)=[C:61]([O:67][C:68]2[CH:69]=[CH:70][C:71]([Cl:75])=[CH:72][C:73]=2[Cl:74])[CH:60]=1>C1CCCCC1>[C:11]([O:13][C:62]1[CH:63]=[C:64]([Cl:65])[CH:59]=[CH:60][C:61]=1[O:67][C:68]1[CH:69]=[CH:70][C:71]([Cl:75])=[CH:72][C:73]=1[Cl:74])(=[O:12])[CH2:10][CH2:9][CH2:8][C:7]([O:15][CH:16]([CH2:36][O:37][C:38](=[O:54])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:17][O:18][C:19](=[O:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:14]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCC(=O)O
Reactant: Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Solvent: C1CCCCC1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCCCCCCC(=O)OCC(COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCC(=O)Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Temperature: 35 °C
Reaction time: 1.5 h

Procedure:
A mixture of cyclohexane (60 ml.), pyridine (1.43 ml.) and 2-hexadecanoyloxy-1-(hexadecanoyloxymethyl)ethyl hydrogen glutarate (B) (11.0 g.) was warmed to 35° C. The solution obtained was added dropwise during 45 minutes to a stirred solution of thionyl chloride (1.23 ml.) in cyclohexane (25 ml.) at 35° C. The mixture was then stirred for a further 1.5 hours at 35° C., cooled to 15° C. and a solution of triclosan (4.68 g.) and pyridine (1.56 ml.) in cyclohexane (20 ml.) added during 15 minutes. The mixture was stirred at ambient temperature for 16 hours, warmed to 35° C. and washed first with 0.5 M hydrochloric acid (100 ml.) and then with water (3×100 ml.), also heated to 35° C. The mixture was then dried (MgSO4) and evaporated to give 5-chloro-2-(2,4-dichlorophenoxy)phenyl 2-hexadecanoyloxy-1-(hexadecanoyloxymethyl)ethyl glutarate as a white solid, m.p. 44°-46° C., identical with the material obtained in Example 4 as judged by its NMR and mass spectral properties.
Reaction SMILES: CC1C(N2CCN(C(C3C=CC(I)=CC=3)=O)CC2)=NC=C(C)C=1.COC1C=CC(CN2C(=O)CNC2=O)=CC=1.[CH3:40][C:41]1[C:42]([N:48]2[CH2:53][CH2:52][N:51]([C:54]([C:56]3[CH:61]=[CH:60][C:59]([N:62]4[CH2:66][C:65](=[O:67])[N:64](CC5C=CC(OC)=CC=5)[C:63]4=[O:77])=[CH:58][CH:57]=3)=[O:55])[CH2:50][CH2:49]2)=[N:43][CH:44]=[C:45]([CH3:47])[CH:46]=1>>[CH3:40][C:41]1[C:42]([N:48]2[CH2:49][CH2:50][N:51]([C:54]([C:56]3[CH:61]=[CH:60][C:59]([N:62]4[CH2:66][C:65](=[O:67])[NH:64][C:63]4=[O:77])=[CH:58][CH:57]=3)=[O:55])[CH2:52][CH2:53]2)=[N:43][CH:44]=[C:45]([CH3:47])[CH:46]=1
Reactant: COc1ccc(CN2C(=O)CN(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)cc3)C2=O)cc1
Agent: COc1ccc(CN2C(=O)CNC2=O)cc1
Agent: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(=O)NC4=O)cc3)CC2)c(C)c1

Procedure:
Using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (337 mg) described in Preparation Example 113 and 3-(4-methoxybenzyl)imidazolidine-2,4-dione (176 mg) described in Preparation Example 213 and by the reaction and treatment in the same manner as in Example 508, the title compound (61 mg) was obtained via 1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-3-(4-methoxybenzyl)imidazolidine-2,4-dione.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:17][CH2:18][CH3:19])=[O:5])[CH3:2].[CH:20]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:25][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:17][CH2:18][CH3:19])=[O:5])[CH3:2]
Reactant: NC1CCCC1
Reactant: CCCc1cccc2c(Cl)c(C(=O)OCC)cnc12
Product: CCCc1cccc2c(NC3CCCC3)c(C(=O)OCC)cnc12

Procedure:
4-Chloro-8-propyl-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.9 mmol) was treated with cyclopentylamine following general procedure B to afford 4-cyclopentylamino-8-propyl-quinoline-3-carboxylic acid ethyl ester (260 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid using general procedure D and then transformed into the corresponding ethylamide (170 mg) following general procedure E.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:18]([Cl:30])[CH:17]=1)=[N:8][CH:9]=[N:10]2.[OH:31][C@H:32]1[CH2:37][CH2:36][O:35][C:33]1=[O:34]>C1(C)C(C)=CC=CC=1>[Cl:30][C:18]1[CH:17]=[C:16]([NH:15][C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[CH:14][C:5]=3[O:4][CH2:3][CH2:2][NH:1][C:33](=[O:34])[C@@H:32]([OH:31])[CH2:37][CH2:36][OH:35])[N:10]=[CH:9][N:8]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: O=C1OCC[C@@H]1O
Reactant: NCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Solvent: Cc1ccccc1C
Product: O=C(NCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)[C@@H](O)CCO
Temperature: 130 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
5-(2-aminoethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 2.6, preparation of starting materials, 0.5 g, 1.19 mmol) was heated to 130° C. in xylene (20 ml) until it had dissolved. (S)-(−)-α-hydroxy-γ-butyrolactone (0.10 ml, 1.31 mmol) was added and the mixture was stirred at 130° C. for 3 hours. More (S)-(−)-α-hydroxy-γ-butyrolactone (0.05 ml, 0.66 mmol) was added and the mixture was heated for a further 2 hours. The resultant precipitate was filtered off while the mixture was hot, washed with diethyl ether (3×10 ml) and dried to give the title compound as a solid (430 mg, 69%); NMR spectrum (DMSO-d6) 1.38-1.55 (m, 1H), 1.69-1.85 (m, 1H), 3.37-3.50 (m, 2H), 3.61-3.77 (m, 2H), 3.89-4.00 (m, 1H), 4.28-4.45 (m, 3H), 5.29 (s, 2H), 5.51 (d, 1H), 7.13 (d, 1H), 7.22 (d, 1H), 7.28-7.41 (m, 2H), 7.49-7.62 (m, 2H), 7.71 (t, 1H), 8.01 (d, 1H), 8.14-8.25 (m, 1H), 8.45 (s, 1H), 8.59 (d, 1H), 9.82 (s, 1H); Mass spectrum MH+ 523.9.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6](Cl)[N:5]=2.[CH:20]1([CH:25]([OH:28])[C:26]#[CH:27])[CH2:24][CH2:23][CH2:22][CH2:21]1>CN(C)C=O.C(N(CC)CC)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6]([C:27]#[C:26][CH:25]([CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[OH:28])[N:5]=2
Reactant: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(Cl)nc21
Reactant: C#CC(O)C1CCCC1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(C#CC(O)C3CCCC3)nc21

Procedure:
A suspension of 1 g (3.56 mmol) of 2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxamide in 25 ml of a dimethylformamide/triethylamine mixture (V/V; 2.5/1) is placed in a 10 ml microwave tube. This suspension is sparged with argon for 10 minutes and then 0.931 g (7.5 mmol) of (±)-1-cyclopentylprop-2-yn-1-ol, 0.068 g of CuI (0.36 mmol) and 0.125 g of bis(triphenylphosphine) palladium(II)dichloride (0.18 mmol) are successively added.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[C:7](=[O:13])[N:8]([CH3:12])[CH2:9][CH2:10][CH:11]=1.[NH2:15][O:16][K].C(O)(=O)C>CO.C(OCC)(=O)C>[OH:16][NH:15][C:3](=[O:2])[CH2:4][CH2:5][C:6]1[C:7](=[O:13])[N:8]([CH3:12])[CH2:9][CH2:10][CH:11]=1
Reactant: COC(=O)CCC1=CCCN(C)C1=O
Reactant: NO[K]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CN1CCC=C(CCC(=O)NO)C1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
50 mg of 3-(1-methyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid methyl ester prepared from the above Step 1 was dissolved in methanol (0.25 mM) and then 0.122 ml of 1.7M NH2OK suspension solution in methanol (0.207 mM) was added thereto at 0° C. and the resulting mixture was stirred for 3 hrs at room temperature. The resulting mixture was neutralized with 0.02 ml of acetic acid, diluted with 10 ml of ethyl acetate, filtered and concentrated in vacuo. The resulting compound was purified by column chromatography on Silica gel with methanol/chloroform (1:20) solvent mixture as an eluant to give 19 mg of the title compound (j2) (yield: 35%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]([C:8]([F:11])=[CH:9][CH:10]=1)[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[CH2:19]([NH:26][CH2:27][CH2:28][OH:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>O1CCCC1.CN(C)C=O>[CH2:19]([N:26]([CH2:27][CH2:28][OH:29])[C:5](=[O:7])[C:4]1[C:8]([F:11])=[CH:9][CH:10]=[C:2]([Br:1])[C:3]=1[F:12])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCCNCc1ccccc1
Reactant: O=C(O)c1c(F)ccc(Br)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(c1c(F)ccc(Br)c1F)N(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.2 %

Procedure:
To a solution of 3-bromo-2,6-difluorobenzoic acid (2.00 g, 8.44 mmol) and N,N-dimethylformamide (0.1 ml) in tetrahydrofuran (40 ml) was added dropwise oxalyl chloride (1.47 ml, 16.9 mmol) in a water bath, and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure. The residue was added under ice-cooling to a solution of N-benzylethanolamine (1.28 ml, 8.44 mmol) and triethylamine (1.77 ml, 12.7 mmol) in tetrahydrofuran (50 ml), and the mixture was stirred at 0° C. for 15 min and at room temperature for 1 hr. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solution of diethyl ether and diisopropyl ether to give the desired product (2.10 g, 67.3%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26]>N1C=CC=CC=1>[CH2:25]([NH:27][C:28]([NH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1)=[O:29])[CH3:26]
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: CCN=C=O
Solvent: c1ccncc1
Product: CCNC(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.1 %

Procedure:
To a solution of N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol) in pyridine (4.0 mL) was added ethyl isocyanate (490 μL, 6.19 mmol), and the mixture was stirred at room temperature for 16 hr. The solvent was evaporated under reduced pressure and water was added to the residue. The mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate/ethanol and filtrated to give the title compound (142 mg, 58%) as a white powder.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:7]=12.[Na].[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:7]=12)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCc1ccccc1
Reactant: Cc1[nH]c2c(Cl)nncc2c1C
Agent: [Na]
Product: Cc1[nH]c2c(OCc3ccccc3)nncc2c1C
Temperature: 0 °C
Reaction time: 30 h

Procedure:
1.35 g (0.0074 mole) of 7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine was added to a solution, obtained by adding 0.26 g (0.011 mole) of sodium to 25 ml of benzyl alcohol at room temperature, and the resulting mixture was heated at 115° C. and, in the course of the heating, 10 ml of benzyl alcohol were additionally added thereto. The heating was continued for 30 hours with stirring. After completion of the reaction, the reaction mixture was poured into ice-water and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure and benzyl alcohol was distilled off under reduced pressure. The residue was purified by column chromatography through silica gel using a 20:1 mixture of chloroform and methanol as an eluent to give 1.15 g of 7-benzyloxy-2,3-dimethylpyrrolo[2,3-d]pyridazine as a pale yellow powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]2=[O:23])=[CH:3][CH:2]=1.[BH4-].[Na+].[OH-].[Na+].Cl>CO.O>[N:1]1[CH:2]=[CH:3][C:4]([CH2:7][C:8]2([CH2:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]2=[O:23])=[CH:5][CH:6]=1
Reactant: O=C1C(=Cc2ccncc2)c2ccccc2N1c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1N(c2ccccc2)c2ccccc2C1(Cc1ccncc1)Cc1ccncc1
Reaction time: 0.83 h
Yield: 147.3 %

Procedure:
A slurry of 3-(4-pyridinylmethylidene)-1-phenylindolin-2-one (80 g, 0.268M) in methanol (600 mL) was cooled to 6°. Sodium borohydride pellets (0.2 g each, 3.19 g total 0.084M) were added over 20 minutes with gentle cooling. The mixture was stirred for 50 minutes, cooled to 7°, and 10N sodium hydroxide (64 mL, 0.64M) added over 11 minutes. A solution of 4-picolychloride hydrochloride (4.85 g, 0.296M) in water (160 mL) was then added over 28 minutes while maintaining a temperature of 10°-15°. Cooling was then removed, and 10N sodium hydroxide (80 mL, 0.8M) added over 10 minutes. The mixture was stirred for 2 hours and then water (580 mL) added over 45 minutes. The slurry was cooled to 10°-15°, stirred for 10 minutes, and the solids collected by filtration. The solids were then reslurried in water (450 mL), filtered, and washed with water. Drying in a vacuum oven at 85°-95° yielded 89.4 g (85%) crude title compound. This crude product (85 g) was recrystallized in isopropanol and water to yield 77.3 g of the title compound (90% recovery). M.P.: =186°-188°.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[N:11]1)(C)(C)C.[C:19]([OH:25])([C:21]([F:24])([F:23])[F:22])=[O:20]>C(Cl)Cl>[OH:25][C:19]([C:21]([F:24])([F:23])[F:22])=[O:20].[N+:15]([C:13]1[CH:12]=[N:11][N:10]([CH2:9][CH2:8][NH2:7])[CH:14]=1)([O-:17])=[O:16]
Reactant: CC(C)(C)OC(=O)NCCn1cc([N+](=O)[O-])cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCn1cc([N+](=O)[O-])cn1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To an ice-cooled solution of tert-butyl(2-(4-nitro-1H-pyrazol-1-yl)ethyl)carbamate (5.50 g, 21.49 mmol) in DCM (55 mL), TFA (20 mL, 261.16 mmol) was added dropwise. The resulting solution was stirred at 0° C. for 3 h, then the reaction mixture was concentrated in vacuo to obtain 2-(4-nitro-1H-pyrazol-1-yl)ethanamine-TFA salt as an off-white paste, which was used in the next step without further purification. LC-MS conditions A: tR=0.21 min, no ionization.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[C:13]([F:23])=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.C(OC([N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>COCCOC.[Cl-].[Na+].O.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:23][C:13]1[C:12]([CH2:11][C:8]2[N:6]3[N:7]=[C:2]([C:34]4[CH:35]=[N:31][NH:32][CH:33]=4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[C:21]([F:22])[CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Fc1cc2ncccc2c(F)c1Cc1cnc2ccc(Cl)nn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1cc2ncccc2c(F)c1Cc1cnc2ccc(-c3cn[nH]c3)nn12
Temperature: 90 °C
Reaction time: 11 h

Procedure:
6-(6-Chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-5,7-difluoro-quinoline (Stage 171.2, 100 mg, 0.299 mmol) was dissolved in DME (3 mL) under argon atm. 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester (136 mg, 0.449 mmol) was added, followed by 2 M K2CO3 (0.40 mL) and PdCl2(PPh3)2 (10.5 mg, 0.015 mmol). The RM was stirred at 90° C. for 11 h. It was then taken into a mixture of EtOAc and brine and extracted. The combined organic phase was dried on Na2SO4. After evaporation of the solvent the crude was purified by flash chromatography in silica gel with the eluent DCM/MeOH=10:1. The collected fractions containing product were concentrated, dried under vacuo. The title compound was obtained as a white solid (tR 2.97 min (conditions 13), MH+=363).
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>CCCCCC>[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: CCCCCC
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 n-hexane 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 n-hexane 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: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[O:3]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[N:42]1([CH2:47][CH2:48][NH2:49])[CH2:46][CH2:45][CH2:44][CH2:43]1>C(Cl)Cl.CCOC(C)=O>[N:42]1([CH2:47][CH2:48][NH:49][C:13](=[O:15])[C:12]2[CH:11]=[CH:10][C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:1])([CH3:18])[O:3]3)=[CH:17][CH:16]=2)[CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: NCCN1CCCC1
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(C(=O)NCCN3CCCC3)cc2)OC1(C)C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
To a solution of 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid (248.1 mg, 1 mmol), EDC (191.7 mg, 1 mmol) and HOBt (135.1 mg, 1 mmol) in DCM (3 mL), was added diisopropylethylamine (DIEA) (0.26 ml, 1.5 mmol). After stirring vigorously for 0.5 hours, 2-pyrrolidin-1-yl-ethylamine (0.15 ml, 1.2 mmol) was added. The mixture was stirred overnight, diluted with EtOAc (20 ml) and washed twice with brine. The organic layer was dried with sodium sulfate and concentrated to provide the crude product (230 mg, 66.8% yield), which used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[NH:9][CH:10]=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC[CH:15]([CH2:32]C([O-])=O)[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:20][CH:19]=1>CS(C)=O.[Na+].[Cl-]>[C:1]([O:5][C:6]([C:8]1[N:9]([CH2:32][CH:15]([O:7][C:6](=[O:5])[CH3:8])[CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:23]=2)[CH:10]=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc[nH]1
Reactant: CCCCCCCCc1ccc(OCC(CBr)CC(=O)[O-])cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCCCCc1ccc(OCC(Cn2cccc2C(=O)OC(C)(C)C)OC(C)=O)cc1
Temperature: 110 °C
Reaction time: 0.25 h

Procedure:
0.145 g (0.867 mmol) tert-butylpyrrole-2-carboxylate is dissolved in 10 ml absolute DMSO, mixed with 0.107 g (0.952 mmol) potassium-tert-butylate and stirred at 110° C. for 15 minutes. A solution of 0.333 g (0.864 mmol) [1-bromo-3-(4-octylphenoxy)propan-2-yl]acetate in 10 ml absolute DMSO is added drop-wise. Following heating at 110° C. for 30 minutes and subsequent cooling, hydrolysis is carried out in saturated NaCl solution. Four extractions with diethyl ether, combination of organic phases, concentration to half the volume on the rotary evaporator, three wash steps with saturated NaCl solution, drying on sodium sulfate, filtration and reconcentration on the rotary evaporator leave as the crude product a yellow oil which is purified on silica gel by means of flash column chromatography (flow agent: petroleum ether/ethyl acetate 80:20) and yields the product as a colorless oil.
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]([CH2:36][O:37]CC1C=CC=CC=1)[C:12]([NH:14][CH2:15][C@@H:16]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:13])C1C=CC=CC=1>C(O)C.[Pd]>[C:24]([O:23][C:21](=[O:22])[NH:20][CH2:19][CH2:18][CH2:17][C@H:16]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:15][NH:14][C:12](=[O:13])[C@@H:11]([NH2:10])[CH2:36][OH:37])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CNC(=O)[C@H](COCc1ccccc1)NC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCC[C@@H](CNC(=O)[C@@H](N)CO)NC(=O)OC(C)(C)C

Procedure:
A solution of 128 mg (0.77 mmol) of benzyl[(1S)-1-[(benzyloxy)methyl]-2-({(2S)-2,5-bis[(tert-butoxycarbonyl)amino]pentyl}amino)-2-oxoethyl]carbamate (Example 127A) in 50 ml of ethanol is hydrogenated after the addition of 13 mg of palladium on activated carbon (10%) at RT under atmospheric pressure for 48 h. The mixture is filtered through kieselguhr and the residue is washed with ethanol. The filtrate is evaporated to dryness in vacuo. The product is purified by preparative RP-HPLC (mobile phase water/acetonitrile gradient: 90:10→5:95).