Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(OC1C=CC=C([N+]([O-])=O)C=1)OCC[O:5][CH2:6][CH2:7][O:8][C:9]1[CH:29]=[CH:28][C:12]2[C:13]#[C:14][C:15]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:19][C:16]=3[CH2:17][CH2:18][C:11]=2[CH:10]=1.CCN(CC)CC.[C:48]([NH:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][NH:64][C:65](=[O:79])[CH2:66][CH2:67][CH2:68][CH2:69][C@H:70]1[C@@H:78]2[C@@H:73]([NH:74][C:75]([NH:77]2)=[O:76])[CH2:72][S:71]1)([O:50][C:51]([CH3:54])(C)C)=[O:49]>CN(C=O)C>[O:76]=[C:75]1[NH:74][CH:73]2[CH2:72][S:71][CH:70]([CH2:69][CH2:68][CH2:67][CH2:66][C:65]([NH:64][CH2:63][CH2:62][O:61][CH2:60][CH2:59][O:58][CH2:57][CH2:56][NH:55][C:48](=[O:49])[O:50][CH2:51][CH2:54][O:5][CH2:6][CH2:7][O:8][C:9]3[CH:29]=[CH:28][C:12]4[C:13]#[C:14][C:15]5[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:19][C:16]=5[CH2:17][CH2:18][C:11]=4[CH:10]=3)=[O:79])[CH:78]2[NH:77]1
Reactant: CCCCOc1ccc2c(c1)CCc1cc(OCCOCCOC(=O)Oc3cccc([N+](=O)[O-])c3)ccc1C#C2
Reactant: CC(C)(C)OC(=O)NCCOCCOCCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCOc1ccc2c(c1)CCc1cc(OCCOCCOC(=O)NCCOCCOCCNC(=O)CCCCC3SCC4NC(=O)NC43)ccc1C#C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A solution of carbonate 16 (0.15 g, 0.28 mmol) in DMF (approximately 2 mL) was added to a solution of Et3N (0.5 g, 4.95 mmol) and N-Boc-N′-biotinyl-3,6-dioxaoctane-1,8-diamine (Ning et al., Angew. Chem. Int. Ed. 2008, 47:2253-2255) (0.01 g, 0.28 mmol) in DMF (10 mL) at room temperature. The reaction mixture was stirred overnight at room temperature, most solvent was evaporated under reduced pressure, and the residue was separated by chromatography on (CH2Cl2:MeOH 30:1) to provide 0.164 g (0.21 mmol, 75%) of 6b. 1H NMR δ 7.19 (d, J=8.4 Hz, 2H), 6.88 (dd, J=9.5, 2.5 Hz, 2H), 6.76 (td, J=8.2, 2.5, 2H), 6.74-6.65 (m, 1H), 6.54 (s, b, 1H), 5.74 (s, b, 1H), 5.60 (s, b 1H), 4.49-4.43 (m, 1H), 4.29-4.22 (m, 3H), 4.16-4.10 (m, 2H), 3.97 (t, J=6.5, 2H), 3.87-3.81 (m, 2H), 3.76 (m, 2H), 3.59-3.48 (m, 7H), 3.42 (m, 2H), 3.37-3.12 (m, 2H), 3.21-3.09 (m, 4H), 2.86 (dd, J=12.6, 4.7 Hz, 1H), 2.72 (d, J=12.7, 1H), 2.42 (d, J=10.9, 2H), 2.21 (t, J=7.4, 2H), 1.81-1.56 (m, 5H), 1.48 (sex, J=7.4 Hz, 2H), 1.44-1.36 (m, 2H), 1.32 (t, J=7.4 Hz, 1H), 0.98 (t, J=7.4, 3H); 13C NMR δ 173.4, 164.1, 158.7, 158.1, 156.5, 154.8, 126.66, 126.63, 116.80, 116.72, 116.59, 115.8, 111.91, 111.83, 110.67, 110.14, 70.09, 70.04, 69.95, 69.90, 69.80, 69.54, 67.78, 67.52, 63.88, 61.80, 60.2, 55.6, 45.6, 40.8, 40.5, 39.1, 36.63, 36.61, 35.9, 31.3, 28.22, 28.08, 25.6, 19.2, 13.8, 8.5.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:35])[NH:10][CH:11]([C:16]([N:18]1[CH2:22][CH2:21][CH:20]2[NH:23][CH2:24][CH:25]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=3)[CH:19]12)=[O:17])[C:12]([CH3:15])([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:46]1[N:51]=[CH:50][CH:49]=[CH:48][N:47]=1>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:35])[NH:10][CH:11]([C:16]([N:18]1[CH2:22][CH2:21][CH:20]2[N:23]([C:46]3[N:51]=[CH:50][CH:49]=[CH:48][N:47]=3)[CH2:24][CH:25]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=3)[CH:19]12)=[O:17])[C:12]([CH3:15])([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncccn1
Reactant: CC(C)(C)C(NC(=O)OCc1ccccc1)C(=O)N1CCC2NCC(Oc3ccc(F)c(F)c3)C21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(NC(=O)OCc1ccccc1)C(=O)N1CCC2C1C(Oc1ccc(F)c(F)c1)CN2c1ncccn1
Temperature: 80 °C
Reaction time: 12 h
Yield: 60.4 %

Procedure:
Secondary amine 24 (200 mg, 0.41 mmol), DIPEA (110 μL, 0.62 mmol), and 2-chloro-pyrimidine (62 mg, 0.53 mmol) were dissolved in DMF (4 mL) and stirred at 80° C. After 12 h, the reaction mixture was cooled to ambient temperature, diluted with water, and extracted with EtOAc. The combined organic extracts were washed with brine and dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (1:1 hexanes/EtOAc) to afford 140 mg (60%) of 29 as a colorless oil. Mass spectrum, m/z [566.0] (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH3:22])([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[C:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:37]S(C3C=CC(C)=CC=3)(=O)=O)[N:34]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:22][C:5]([O:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:37][CH2:36][CH2:35][C:33]2[N:34]=[C:30]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:31][C:32]=2[CH3:48])=[CH:9][CH:8]=1)[C:4]([OH:23])=[O:3]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Product: Cc1ccc(OC(C)(Cc2ccc(OCCc3nc(-c4ccccc4)oc3C)cc2)C(=O)O)cc1

Procedure:
The representative procedure (B) was utilized to prepare the title compound from 3-(4-hydroxyphenyl)-2-methyl-2-p-tolyloxypropionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[S:13][C:14]([NH:20][C:21]([C:23]4[CH:27]=[CH:26][S:25][CH:24]=4)=[O:22])=[C:15]([C:17]([NH2:19])=[O:18])[N:16]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:28]([O-])([O-])=O.[K+].[K+].C[I:35]>CN(C=O)C>[I-:35].[C:17]([C:15]1[N:16]=[C:12]([NH:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N+:1]([CH3:28])=[CH:2][CH:3]=[CH:4]3)[S:13][C:14]=1[NH:20][C:21]([C:23]1[CH:27]=[CH:26][S:25][CH:24]=1)=[O:22])(=[O:18])[NH2:19]
Reactant: NC(=O)c1nc(Nc2ccc3ncccc3c2)sc1NC(=O)c1ccsc1
Reactant: O=C([O-])[O-]
Reactant: CI
Agent: [K+]
Solvent: CN(C)C=O
Product: C[n+]1cccc2cc(Nc3nc(C(N)=O)c(NC(=O)c4ccsc4)s3)ccc21
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.8 %

Procedure:
To a solution of 2-(quinolin-6-ylamino)-5-(thiophene-3-carboxamido)thiazole-4-carboxamide (50 mg, 0.126 mmol) in DMF (1 mL) was added K2CO3 (50 mg, 0.152 mmol) and. MeI (27 mg, 0.190 mmol) at rt. The mixture was stirred overnight at rt. The reaction was quenched by adding cold-water, and the reaction mixture was diluted with EtOAc. The resulting precipitates were collected by filtration and washed successively with EtOAc and water to afford 10 mg (15% yield) of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:10]([CH:11]=[O:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[C:20]([Mg]Br)#[C:21][CH3:22].C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:10]([CH:11]([OH:12])[C:20]#[C:21][CH3:22])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: CC#C[Mg]Br
Reactant: O=Cc1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC#CC(O)c1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
To a cold (−78° C.) suspension of 7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine-3-carbaldehyde (1.50 g, 5.47 mmol) in tetrahydrofuran (10 mL) was added 1-propynyl magnesium bromide (12.0 mL, 0.5 M in tetrahydrofuran, 6.02 mmol) dropwise. The reaction mixture was stirred at −78° C. for 1 hour, then at 0° C. for 2 hours. The resultant solution was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water and brine and the combined organics were dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (4:1 hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate) provided 1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-butyn-1-ol (1.3 g, 72%) as a white solid. Rf 0.44 (2:1 hexanes:ethyl acetate); 1H NMR (CDCl3) δ 7.99 (d, 1H), 7.78 (m, 2H), 7.14 (m, 3H), 6.95 (d, 1H), 5.70 (m, 1H), 2.21 (d, 1H), 1.85 (d, 3H); MS m/z 315 (M+1).
Reaction SMILES: C([Li])CCC.[CH2:6]([Cl:8])[Cl:7].[CH2:9]([N:16]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H:17]([C:25](O)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>CCCCCC.O1CCCC1.O>[Cl:7][CH:6]([Cl:8])[C:25](=[O:26])[C@@H:17]([N:16]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCCl
Reactant: O=C(O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(C(Cl)Cl)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.17 h
Yield: 99 %

Procedure:
Dehydrated tetrahydrofuran (15 ml) was cooled to −78° C. 1.53 M solution (6.5 ml) of n-butyllithium in hexane and then a solution of methylene chloride (0.8 ml) in dehydrated tetrahydrofuran (5 ml) were added thereto, and they were stirred for 10 minutes. A solution of benzyl ester (2.18 g) of N,N-dibenzyl-L-phenylalanine in dehydrated tetrahydrofuran (7 ml) was added to the obtained mixture, and they were stirred for 1 hour. 2 N hydrochloric acid (15 ml) and water (15 ml) were added to the reaction mixture to terminate the reaction. The temperature was elevated to room temperature. After the addition of water followed by the extraction with ethyl acetate, the obtained solutions in ethyl acetate were combined together and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered out. The solvent was evaporated under reduced pressure to obtain the intended (3S)-1,1-dichloro-3-dibenzylamino-4-phenyl-2-butanone (2.04 g) in a yield of 99%.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C@H:12]1[C:24](O)=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C(O)(=O)C>O1CCCC1.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][C@@H:12]1[CH2:24][OH:25])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)[C@H](C(=O)O)C1
Agent: B
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)[C@@H](CO)C1
Reaction time: 1 h
Yield: 78.5 %

Procedure:
To (S)-1-(benzyloxycarbonyl)4-(tert-butyloxycarbonyl)-piperazine-2-carboxylic acid (15.2 g, 0.04 mol) in tetrahydrofuran (200 ml) at 0° C. under argon was added borane (1M soln. in THF; 111 ml, 0.11 mol) dropwise over 15 min. The resulting mixture was stirred for 1 h, maintaining the temperature between 0° C. and 5° C., and then allowed to reach room temperature and stirred a further 18 h. The mixture was then carefully added, with stirring, to 5% g. acetic acid in water (1 l). After 1 h, the organics were evaporated in vacuo and the residual aqueous extracted with ethyl acetate (300 ml×4). The combined extracts were dried (Na2SO4), and evaporated in vacuo to a colourless oil. Chromatography on silica gel eluting with ethyl acetate-hexane mixtures afforded the title product (11 g, 75%) as a colourless oil.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)[CH:5]=1.[NH3:18]>O>[N:12]1([CH2:11][O:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([NH2:18])=[O:2])[CH:16]=[CH:15][CH:14]=[N:13]1
Reactant: COC(=O)c1cccc(OCn2cccn2)c1
Reactant: N
Solvent: O
Product: NC(=O)c1cccc(OCn2cccn2)c1
Temperature: 110 °C
Yield: 19 %

Procedure:
3-(Pyrazol-1-ylmethoxy)-benzoic acid methyl ester (250 mg, 1.1 eq.) was taken in a pressure vessel along with 5 ml of aq. ammonia, heated at 110° C. for 12 hr. reaction mass was then poured in water (25 ml), extracted with dichloromethane (25 ml×4). Organic layer was dried over sodium sulphate and concentrated to obtain crude solid. Product was purified by column chromatography using 80% EtOAc-DCM as an eluent over 230-400 mesh silica gel. Pure product was obtained as solid powder (50 mg, 19%). 1H NMR (DMSO-d6, 400 MHz with D2O): δ 6.12 (s, 2H), 6.33 (m, 1H), 7.25 (m, 1H), 7.37 (m, 1H), 7.41 (m, 1H), 7.51 (m, 1H), 7.56 (m, 2H), 7.95 (br s, 1H), 7.99 (m, 1H). MS ES+ (218.0, 235.0—Ammonium adduct), HPLC (method 7) Rt=9.08 min.
Reaction SMILES: [CH2:1]([C:13]1[N:14]=[N:15][N:16]([CH2:18][C:19]([OH:21])=O)[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1N=NN(CC(O)=O)N=1)CCCCCCCCC.[CH3:41][O:42][C:43]1[CH:49]=[C:48]([O:50][CH3:51])[CH:47]=[C:46]([O:52][CH3:53])[C:44]=1[NH2:45].C(C1C=CC=C(C(C)C)C=1N)(C)C>>[CH2:1]([C:13]1[N:14]=[N:15][N:16]([CH2:18][C:19]([NH:45][C:44]2[C:46]([O:52][CH3:53])=[CH:47][C:48]([O:50][CH3:51])=[CH:49][C:43]=2[O:42][CH3:41])=[O:21])[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1nnn(CC(=O)O)n1
Reactant: COc1cc(OC)c(N)c(OC)c1
Agent: CC(C)c1cccc(C(C)C)c1N
Agent: CCCCCCCCCCc1nnn(CC(=O)O)n1
Product: CCCCCCCCCCCCc1nnn(CC(=O)Nc2c(OC)cc(OC)cc2OC)n1

Procedure:
When in the general procedure of Example 88 an appropriate amount of 5-dodecyl-2H-tetrazole-2-acetic acid was substituted for 5-decyl-2H-tetrazole-2-acetic acid and 2,4,6-trimethoxyaniline was substituted for 2,6-diisopropylaniline, the title compound was obtained, mp 144°-146° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([Cl:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>O>[Cl-:14].[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:15][CH2:16][CH2:17][NH+:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCN1CCCC1
Solvent: O
Product: CC(=O)Nc1ccc(S(=O)(=O)NCC[NH+]2CCCC2)cc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 9 h
Yield: 78 %

Procedure:
4-Acetylaminobenzenesulphonylchloride (21.9 g) was added in portions to a solution of 1-(2-aminoethyl)pyrrolidine (10.7 g, 0.9 mol) in water (250 ml). The mixture was stirred for 9 hours at room temperature. At the end of the reaction, the solution has pH 6-7. A portion of the mixture (165 ml) was removed and adjusted to pH 9.5. The precipitate from the mixture (4.9 g) was removed under suction and dissolved in ethyl acetate (170 ml). The solution was filtered and HCl gas was passed through. Precipitated chloride was isolated and recrystallised from absolute ethanol (350 ml) to give the product (27.2 g).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CN(C=O)C.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[CH2:23][N:22]([C:29](=[O:35])[CH:30](Br)[CH:31]([CH3:33])[CH3:32])[CH2:21][CH2:20]2>C(OCC)(=O)C.CCCCCC>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[CH2:23][N:22]([C:29](=[O:35])[CH:30]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:31]([CH3:33])[CH3:32])[CH2:21][CH2:20]2
Reactant: COc1cc2c(cc1OC)CN(C(=O)C(Br)C(C)C)CC2
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)CN(C(=O)C(Oc1ccccc1)C(C)C)CC2
Temperature: 80 °C
Reaction time: 10 h
Yield: 54.7 %

Procedure:
Phenol (50 μl, 0.569 mmol) and sodium hydride (60% in a mineral oil, 10 mg) were added to a DMF (2 ml) solution of 1-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)-3-methyl-2-bromobutan-1-one (54 mg, 0.152 mmol) obtained in Reference example 16, and the mixture was stirred at 80° C. for 10 hours and cooled to room temperature. The reaction solution was diluted with ethyl acetate and hexane (1:1, 50 ml), washed with a 1 N aqueous sodium hydroxide solution (30 ml) and 1 N hydrochloric acid (30 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to preparative thin layer chromatography using ethyl acetate and hexane (1:1) as an eluent to obtain the captioned compound (30.7 mg, 55%) as a yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:26][C:27]1[CH:31]=[CH:30][NH:29][N:28]=1.O=P(Cl)(Cl)Cl.O>N1C=CC=CC=1>[N:29]1[NH:28][C:27]([NH:26][C:8]([C:5]2[C:4]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:23])[F:24])[CH:16]=3)(=[O:13])=[O:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:10])=[CH:31][CH:30]=1
Reactant: Nc1cc[nH]n1
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccn[nH]1)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
A 0° C. mixture of 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid (41 mg, 0.1 mmol, 1 equiv) and 3-aminopyrazole (21 mg, 2.5 equiv) in 0.5 mL of pyridine was treated with 11 L (1.1 equiv) of POCl3 for 5 minutes. After addition of 1 mL of water, the mixture was subjected to preparative reverse phase HPLC to give 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid (2H-pyrazol-3-yl)-amide. 1H NMR (400 MHz, CDCl3) δ 11.95 (s, 1H), 10.37 (s, 1H), 8.24 (m, 2H), 8.18 (s, 1H), 8.00 (dd, 1H), 7.63 (d, 1H), 7.60 (d, 1H), 6.80 (d, 1H); MS (ES) (M+H)+ expected 480.0. found 480.0.
Reaction SMILES: P(Br)(Br)([Br:3])=O.[CH2:6]([O:10][C:11]([C:13]1[N:14]=[C:15](O)[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][CH:19]=[C:18]([S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:17]=2)=[O:12])[CH2:7][CH2:8][CH3:9].C(=O)(O)[O-].[Na+].O>C(#N)C>[CH2:6]([O:10][C:11]([C:13]1[N:14]=[C:15]([Br:3])[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][CH:19]=[C:18]([S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:17]=2)=[O:12])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOC(=O)c1nc(O)c2cc(Sc3ccccc3)ccc2c1O
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCCCOC(=O)c1nc(Br)c2cc(Sc3ccccc3)ccc2c1O
Reaction time: 1 h
Yield: 68.2 %

Procedure:
To a solution of 4.59 g of phosphorous oxybromide (16 mmol) in 25 ml of anhydrous acetonitrile were added 1.11 g of 1,4-dihydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (3 mmol) and the mixture was refluxed gently with stirring for 1 h. Then 5.04 g of sodium bicarbonate (60 mmol) were added, followed by the dropwise addition of 8 ml of water. After stirring at ambient temperature for 90 min the mixture was concentrated in vacuo to about one third of its volume, 40 ml of water were added and the mixture was extracted with 30 ml of ethyl acetate. The mixture was filtered by suction. The organic phase was separated, dried over MgSO4, and filtered through a pad of silica gel. Evaporation in vacuo gave 0.885 g of the title compound; 1H NMR (CDCl3): δ=11.84 (s, 1H), 8.21 (d, 1H), 7.91 (d, 1H), 7.40 to 7.55 (m, 6H), 4.46 (t, 2H), 1.84 (m, 2H), 1.48 (m, 2H), 0.98 (t, 3H).
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]\[C:33]([OH:35])=[O:34]>CO.ClCCl>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[CH2:31]([C:30]([OH:37])=[O:36])[C@H:32]([OH:10])[C:33]([OH:35])=[O:34]
Reactant: O=C(O)/C=C\C(=O)O
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: ClCCl
Solvent: CO
Product: O=C(O)C[C@H](O)C(=O)O
Temperature: 27.5 °C
Reaction time: 1 h

Procedure:
Sunitinib (2.0 g) was suspended in 10% methanol in dichloromethane at 25° C. , followed by addition of maleic acid (0.58 g) .The reaction mass was maintained under stirring at 25-30° C. for 60 minutes. The solids obtained were filtered, suck dried and dried under vacuum for a period of 10 hrs at 60° C. to obtain sunitinib maleate. (2.3 g; yield: 89%)
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH:10]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:11]([O:13]CC(C1C=CC=CC=1)=O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.Cl>O1CCCC1.CO.[OH-].[Na+]>[CH2:1]([O:8][CH:9]([CH2:37][CH2:38][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][CH2:1][CH2:2][CH2:3][CH3:4])[CH:10]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:11]([OH:13])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCCCCCCC(OCc1ccccc1)C(CCCCCCCCCCCCCC)C(=O)OCC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCCC(OCc1ccccc1)C(CCCCCCCCCCCCCC)C(=O)O
Temperature: 70 °C
Yield: 120.3 %

Procedure:
Phenacyl 3t-(t-butyldimethyl siloxy)-2-n-tetradecyl-11icosenoate (V)(798 mg, 1.06 millimole) was dissolved in a mixed solvent of tetrahydrofuran (15.8 ml) and methanol (15.8 ml), and 1N sodium hydroxide solution (3.2 ml) was added. The reaction mixture was heated for 1.5 hours at 70° C., and water (150 ml) was added thereto. The reaction mixture was acidified with 2N hydrochloric acid (pH:about 2) and was extracted twice with ethyl acetate. The organic phase was washed with water and dried over anhydrous sodium sulfate, and the inorganic salt was filtered off, and the solvent was distilled off from the filtrate. The obtained residue was purified over a silicagel column (n-hexane:ethyl acetate=93:7) to give 3-(t-butyldimethylsilyloxy)-2- n-tetradecyl-11-icosenoic acid (VI)(410 mg, yield 60.9%) in the form of pale yellow oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([N:11]1[C:15]2[C:16]([O:24][C@H:25]3[CH2:29][N:28](C(OC(C)(C)C)=O)[C@H:27]([C:37]([O:39][CH3:40])=[O:38])[CH2:26]3)=[N:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[C:14]=2[C:13]([CH3:41])=[CH:12]1)[CH:9]=[CH2:10]>C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:8]([N:11]1[C:15]2[C:16]([O:24][C@H:25]3[CH2:29][NH:28][C@H:27]([C:37]([O:39][CH3:40])=[O:38])[CH2:26]3)=[N:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[C:14]=2[C:13]([CH3:41])=[CH:12]1)[CH:9]=[CH2:10]
Reactant: C=CCn1cc(C)c2c3ccccc3nc(O[C@@H]3C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C3)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C=CCn1cc(C)c2c3ccccc3nc(O[C@H]3CN[C@H](C(=O)OC)C3)c21
Reaction time: 4 h
Yield: 100 %

Procedure:
TFA (3 mL) was added to a solution of 1-tert-butyl 2-methyl (2S,4R)-4-[(3-allyl-1-methyl-3H-pyrrolo[2,3-c]quinolin-4-yl)oxy]pyrrolidine-1,2-dicarboxylate (1.30 g, 2.79 mmol) in DCM (20 mL). The mixture was stirred for 4 h, then diluted with PhMe and concentrated under reduced pressure. The residue was taken up in EtOAc and washed with saturated aqueous NaHCO3 and brine. The organic phase was dried over Na2SO4 and concentrated to give the title compound (1.02 g, 98%) as an oil that was used without further purification in subsequent steps. LCMS (ES+) m/z 366 (M+H)+.
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[N+:18]([O-])([OH:20])=[O:19]>C(OC(=O)C)(=O)C.S(=O)(=O)(O)O>[N+:18]([C:17]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=1[NH:7][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])([O-:20])=[O:19]
Reactant: CCCCC(=O)Nc1cccc(C(=O)OC)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CCCCC(=O)Nc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 36 %

Procedure:
To a solution of methyl 3-valerylaminobenzoate (2.3 g) in acetic anhydride (12 ml) was added dropwise fuming nitric acid (1.4 ml) while stirring under ice-cooling. To the mixture was added one drop of conc. sulfuric acid and the mixture was stirred for two hours. To the reaction mixture was added ice-water and it was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium bicarbonate and water and then dried. The solvent was evaporated to dryness, and the residue was purified by column chromatography on silica gel to afford a brown oil (1.0 g, 36%).