Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][C:10]([C:15]1[CH:20]=[CH:19][C:18]([O:21]CC3C=CC=CC=3)=[C:17]([O:29]CC3C=CC=CC=3)[CH:16]=1)=[C:9]([OH:37])[C:8]2=[O:38])(=[O:3])[CH3:2].C1(=O)[O:44][C:42](=[O:43])[CH2:41]C1>Cl.C(O)(=O)C.O.N1C=CC=CC=1>[OH:29][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[OH:21])[C:10]1[O:11][C:12]2[C:7]([C:8](=[O:38])[C:9]=1[OH:37])=[CH:6][C:5]([NH:4][C:1]([CH2:2][CH2:41][C:42]([OH:44])=[O:43])=[O:3])=[CH:14][CH:13]=2
Reactant: CC(=O)Nc1ccc2oc(-c3ccc(OCc4ccccc4)c(OCc4ccccc4)c3)c(O)c(=O)c2c1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)CCC(=O)Nc1ccc2oc(-c3ccc(O)c(O)c3)c(O)c(=O)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 18.4 %

Procedure:
A mixture of the protected flavonol (15) (500 mg, 0.985 mmol) in aqueous HCl (36%, 37 mL) and acetic acid (37 mL) was heated under reflux for 3 h. The mixture was then cooled on ice and diluted with water. The resulting suspension was centrifuged and the collected solid washed with water, then freeze-dried to afford the salt as a crude yellow solid (322 mg). A mixture of the crude yellow product and succinic anhydride (118 mg, 1.18 mmol) in pyridine was stirred at room temperature for 4 h. Water (1 mL) was added and the mixture was acidified with 6 M HCl. The mixture was left to stand at room temperature for 30 min, and the resulting suspension was centrifuged, and the collected solid was washed with water, freeze-dried and recrystallised from DMF/water to afford the succinamic acid (3) as a yellow powder (70.0 mg, 19%), m.p 257-258° C. 1H NMR (399.7 MHz, d6-DMSO) δ 2.54-2.60 (m, 4H, CH2CH2); 6.89 (d, 1H, J5′,6′ 8.5 Hz, H5′); 7.57 (dd, 1H, J2′,6′ 2.5, J5′,6′ 8.5 Hz, H6′); 7.66 (d, 1H, J7,8 9 Hz, H8); 7.73 (d, 1H, J2′,6′ 2.5 Hz, H2′); 7.85 (dd, 1H, J5,7 2.5, J7,8 9.0 Hz, H7); 8.43 (d, 1H, J5,7 2.5 Hz, H5); 9.29, 9.32, 9.59 (3 br s, 3×1H, 3×OH); 10.29 (s, 1H, NH); 12.20 (br s, 1H, CO2H). 13C NMR (100.5 MHz, d6-DMSO) δ 28.83, 31.11 (2C, CH2CH2); 112.7, 115.25, 115.65, 118.76, 120.00, 121.43, 122.39, 125.17, 135.80, 137.67, 145.12, 146.04, 147.63, 150.38 (14C, Ar); 170.46, 172.32, 173.93 (3C, 3×C═O). Low resolution mass spectrum (ESI) m/z 384.4 [C19H15NO8 (M-H)+ requires 384.08].
Reaction SMILES: [OH:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[N:5]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4](=[O:22])[C:3]=1[C:23]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:24].OC1N(C2C=CC=CC=2[N+:43]([O-:45])=[O:44])C(=O)N(CC2C=CC=CC=2)C(=O)C=1C(OCC)=O.C1CCN2C(=NCCC2)CC1.NCC(O)=O.Cl>C(O)C>[OH:1][C:2]1[N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[N+:43]([O-:45])=[O:44])[C:6](=[O:14])[N:5]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4](=[O:22])[C:3]=1[C:23]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:24]
Reactant: O=C(O)CNC(=O)c1c(O)n(-c2ccccc2)c(=O)n(Cc2ccccc2)c1=O
Reactant: CCOC(=O)c1c(O)n(-c2ccccc2[N+](=O)[O-])c(=O)n(Cc2ccccc2)c1=O
Agent: Cl
Agent: NCC(=O)O
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)CNC(=O)c1c(O)n(-c2ccccc2[N+](=O)[O-])c(=O)n(Cc2ccccc2)c1=O
Temperature: 170 °C

Procedure:
N-{[6-Hydroxy-2,4-dioxo-1-phenyl-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine. A mixture of ethyl 6-hydroxy-1-(2-nitrophenyl)-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate (59 mg, 0.14 mmoles), DBU (80 mg, 0.52 mmoles) and glycine (40 mg, 0.53 mmoles) in ethanol (3 mL) was sealed in a flask and heated in a microwave reactor at 170° C. for 1 hour. The reaction mixture was poured into 1 molar hydrochloric acid and extracted with dichloromethane (×2) and washed with 1 molar hydrochloric acid. The title compound was obtained by purification by preparative HPLC (10-80% acetonitrile-water-0.1% TFA)(17 mg, 28%) 1H NMR (400 MHz, DMSO-d6) δ ppm 13.14 (br. s., 1 H), 10.04 (br. s., 1 H), 8.25 (dd, J=8.21, 1.14 Hz, 1 H), 7.93 (dt, J=7.71, 1.26 Hz, 1H), 7.71-7.81 (m, 2 H), 5.06 (s, 2 H), 4.14 (d, J=5.56 Hz, 2 H)
Reaction SMILES: [C:1]([CH2:4][N:5]([CH2:19][C:20]([OH:22])=O)[C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)([OH:3])=[O:2].C(=O)(O)[O-].[Na+].[C:28]([O:32][C:33]([NH:35][C@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>C(OC(=O)C)(=O)C>[C:28]([O:32][C:33]([NH:35][C@H:36]1[CH2:40][CH2:39][N:38]([C:20](=[O:22])[CH2:19][N:5]([CH2:4][C:1]([OH:3])=[O:2])[C:6]2[CH:7]=[CH:8][C:9]([O:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:10][CH:11]=2)[CH2:37]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: O=C(O)CN(CC(=O)O)c1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(CC(=O)O)c2ccc(Oc3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 44.9 %

Procedure:
A mixture of [carboxymethyl-(4-phenoxyphenyl)amino]acetic acid 19 (0.5 g, 1.66 mmol) in acetic anhydride (10 mL) was heated to reflux with stirring for 45 minutes. The reaction mixture was cooled to room temperature and poured into saturated aqueous sodium bicarbonate. Solid sodium bicarbonate was added and the mixture stirred until effervescence had ceased. The aqueous mixture was extracted with ethyl acetate (×2) and the organic fractions combined, washed with saturated aqueous sodium bicarbonate, brine, dried (Na2SO4) and evaporated to dryness. The residue was co-evaporated with toluene, dissolved in THF (10 mL) and added to (3S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine (0.39 g, 2.09 mmol). The reaction mixture was stirred for 3 days and then concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 10% hydrochloric acid (×2), brine, dried (Na2SO4) and evaporated to dryness. The crude product was crystallized from ethyl acetate to give the title compound as a cream powder (0.35 g, 45%). 1HNMR (300 MHz) (CDCl3) δ 1.45 (6H, s), 1.55 (3H, s), 1.8-2.4 (2H, m), 3.4-3.9 (5H, m), 4.05-4.75 (4H, m), 6.48 (2H, m), 6.90-7.07 (5H, m) and 7.28 (2H, t).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:11][C:12]([C@H:15]1[CH2:19][CH2:18][NH:17][C@H:16]1[CH3:20])([CH3:14])[CH3:13].C(=O)([O-])[O-].[Li+].[Li+]>>[F:1][C:2]1[CH:9]=[C:8]([N:17]2[CH2:18][CH2:19][C@H:15]([C:12]([OH:11])([CH3:14])[CH3:13])[C@@H:16]2[CH3:20])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Reactant: N#Cc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@H]1[C@@H](C(C)(C)O)CCN1c1ccc(C#N)c(F)c1

Procedure:
Using 2,4-difluorobenzonitrile (696 mg), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (1.04 g) and lithium carbonate (784 mg), the title compound was obtained as a colorless solid (yield: 838 mg) by an operation similar to that in Example 3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([Cl:7])=[O:6].[NH2:11][CH:12]1[CH:17]2[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]2)[CH2:13]1>CCOCC>[ClH:7].[N:14]12[CH2:19][CH2:18][CH:17]([CH2:16][CH2:15]1)[CH:12]([NH:11][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=1)[CH2:13]2
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: NC1CN2CCC1CC2
Solvent: CCOCC
Product: Cl
Product: O=C(NC1CN2CCC1CC2)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.3 %

Procedure:
In a closed system, a solution of 3-fluorobenzoyl chloride (7.93 g, 0.050 mole) in 30 ml ether was added dropwise to a stirred solution of 3-aminoquinuclidine (6.3 g, 0.050 mole) in 100 ml ether. After the addition was completed, the mixture was stirred at ambient temperature for 16 hr. The solid hydrochloride salt was collected under a nitrogen atmosphere and vacuum dried for 2 hr, to yield 13.11 g (92.1%). The salt was recrystallized from absolute ethanol-isopropyl ether to give 8.87 g of a white solid. The material was recrystallized from ethanol, and vacuum dried for 12 hr at 70° C., m.p. 257°-258° C.
Reaction SMILES: [C:1]([O:12]C)(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-])=[O:7])=[CH:4][CH:3]=1.O.[NH2:15][NH2:16].Cl>CO>[C:1]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:15][NH2:16])=[O:7])=[CH:4][CH:3]=1)([OH:12])=[O:11]
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Reactant: NN
Agent: Cl
Solvent: CO
Solvent: O
Product: NNC(=O)c1ccc(C(=O)O)cc1

Procedure:
In 1 l of methanol was dissolved 180 g of monomethyl terephthalate, and the solution was slowly added dropwise to 500 ml of hydrazine hydrate (50%) at room temperature while stirring. After the drop-wise addition, the mixture was heat-refluxed for 5 hours while stirring. A hydrochloric acid aqueous solution was slowly added to the reaction mixture to adjust to a pH of about 1 to thereby precipitate white crystals. Two liters of water was added to the system, followed by stirring for a while. The formed crystals were collected by filtration under reduced pressure, washed twice with 200 ml of water, and dried to obtain 160 g of p-carboxybenzhydrazide (melting point: 235-236° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[CH3:8].[F:11][C:12]([F:19])([F:18])[CH:13]([OH:17])[C:14](O)=O.Cl.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[NH:9][C:14]([CH:13]([OH:17])[C:12]([F:19])([F:18])[F:11])=[N:10][C:4]=2[CH:3]=1
Reactant: Cc1cc(N)c(N)cc1C
Reactant: O=C(O)C(O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc2nc(C(O)C(F)(F)F)[nH]c2cc1C
Temperature: 108 °C

Procedure:
4,5-Dimethyl-benzene-1,2-diamine (5.04 g; 37.0 mmoles) and 3,3,3-trifluoro-2-hydroxy-propionic acid (8.01 g; 55.6 mmoles) were suspended in 6N HCl (9 mL; 54 mmoles) under a nitrogen atmosphere. The reaction was stirred vigorously and heated to 108° C. for 18 hrs, then cooled to room temperature. The reaction was diluted with water (100 mL) and with ethyl acetate (100 mL), then sodium bicarbonate (6.90 g; 81.00 mmoles) was added slowly and in portions to quench the reaction. The aqueous layer was separated and extracted with ethyl acetate (3×40 mL). The extracts were combined, washed with water (30 mL) and brine (30 mL), then dried over Na2SO4. The filtrate was concentrated in vacuo to yield a crude brown solid which was purified by column chromatography (SiO2; 30% ethyl acetate/CH2Cl2) to yield the title compound as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([S:15](Cl)(=[O:17])=[O:16])=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[NH2:21][C:22]1[S:23][CH:24]=[CH:25][N:26]=1.CC#N>N1C=CC=CC=1>[S:23]1[CH:24]=[CH:25][N:26]=[C:22]1[NH:21][S:15]([C:9]1[CH:8]=[C:7]2[C:12]([CH2:13][CH2:14][N:5]([C:3](=[O:4])[C:2]([F:20])([F:19])[F:1])[CH2:6]2)=[CH:11][CH:10]=1)(=[O:17])=[O:16]
Reactant: Nc1nccs1
Reactant: O=C(N1CCc2ccc(S(=O)(=O)Cl)cc2C1)C(F)(F)F
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(N1CCc2ccc(S(=O)(=O)Nc3nccs3)cc2C1)C(F)(F)F
Temperature: 60 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
2-(2,2,2-Trifluoro-acetyl)-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl chloride (8.4 g, 0.03 mol) was dissolved in pyridine (10 mL) and heated to 60° C. 2-Aminothiazole (2.5 g, 0.03 mol) was added slowly and the reaction mixture was stirred at 60° C. for 1 hour. Complete conversion to product was observed by LC/MS (10-99% CH3CN). The crude reaction mixture was then purified via column chromatography using 5% MeOH/CH2Cl2 to obtain the sulfonamide (7.0 g, 0.018 mmol, 70% yield). LC/MS (10-99% CH3CN), M/Z: M+1 obs=392.0; tR=2.65 min.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:3]=1[O:4][C:5]1[C:6]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][N:24]=2)(=[O:22])=[O:21])=[N:7][C:8]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:9][C:10]=1[CH2:11]O.P(Cl)(Cl)(Cl)(Cl)[Cl:39]>O=P(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:3]=1[O:4][C:5]1[C:6]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][N:24]=2)(=[O:22])=[O:21])=[N:7][C:8]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[N:9][C:10]=1[CH2:11][Cl:39]
Reactant: COc1ccc(Cl)c(Oc2c(CO)nc(N3CCOCC3)nc2NS(=O)(=O)c2ccc(C(C)C)cn2)c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Cl)c(Oc2c(CCl)nc(N3CCOCC3)nc2NS(=O)(=O)c2ccc(C(C)C)cn2)c1
Yield: 72.6 %

Procedure:
0.2 g of the compound obtained in Example 38 in 3.5 ml of POCl3 was stirred with 0.083 g of PCl5 at 20° C. for 2 hours. Thereafter, the POCl3 was distilled off and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate (sic). The organic phase was washed with water, dried and the solvent was evaporated. The residue was chromatographed over silica gel with chloroform-methanol, thereafter recrystallized from dichloromethane-ethanol. 0.150 g of 5-isopropyl-pyridine-2-sulphonic acid 5-(2-chloro-5-methoxy-phenoxy)-6-chloromethyl-2-morpholin-4-yl-pyrimidin-4-ylamide, m.p. 205° C., was obtained.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([C:20]([OH:22])=[O:21])[CH2:3]1.[N+:23]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1)([O-:25])=[O:24].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[O:8])[C@H:4]([C:20]([O:22][CH2:30][C:29]2[CH:32]=[CH:33][C:26]([N+:23]([O-:25])=[O:24])=[CH:27][CH:28]=2)=[O:21])[CH2:3]1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 89.8 %

Procedure:
(2S,4R)-4-Hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine-2-carboxylic acid (930 mg, 3 mmol), 4-nitrobenzylbromide (660 mg, 3.05 mmol) and potassium carbonate (209 mg, 1.51 mmol) were stirred together in N,N-dimethylformamide (lOml) for 3.5 h. The mixture was poured into water (100 ml)/ethyl acetate (100 ml) and the layers separated. The aqueous layer was re-extracted with ethyl acetate (50 ml). The combined organic layers were washed with water (50 ml),×4), brine (20 ml), dried (MgSO4) and evaporated under reduced pressure. The residue was chromatographed on silica gel, eluting with ethyl acetate hexane mixture, followed by ethyl acetate to give the title compound (1.20 g, 90%) as a mixture of conformers/rotamers; νmax (CH2Cl2) 3610, 3470, 2960, 1735, 1710, 1610, 1535, and 1350 cm-1 ; δH (400 MHz, CDCl3) 1.90 (1H, broad d, J ca 7.4 Hz), 2.05-2.20 (1H, m), 2.3-2.5 (1H, m), 3.6-3.8 (2H, m), 4.58 (1H, broad d, J ca 9.3 Hz), 4.63 (1H, approx dt J 1.9, 8.1 Hz), 5.05-5.35 (4H, m,) 7.30-7.50 (4H, m), and 8.1-8.2 (4H, m); [Mass spectrum: M+ (445)].
Reaction SMILES: [S:1]([O:7][CH2:8][CH3:9])([O:4][CH2:5]C)(=[O:3])=[O:2].C[C:11]1[NH:12][CH:13]=[CH:14][N:15]=1.[CH2:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C(O)C>[CH2:8]([O:7][S:1]([O-:4])(=[O:2])=[O:3])[CH2:9][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[CH2:13]([N+:12]1[CH:23]=[CH:22][N:15]([CH3:14])[CH:11]=1)[CH3:5]
Reactant: CCOS(=O)(=O)OCC
Reactant: Cc1ncc[nH]1
Reactant: CCCCCCCCO
Solvent: CCO
Product: CCCCCCCCOS(=O)(=O)[O-]
Product: CC[n+]1ccn(C)c1

Procedure:
In a 250 ml Schlenk flask, 58.75 g (0.381 moles) of diethyl sulfate was slowly added dropwise to 31.28 g (0.381 moles) of methylimidazole with ice cooling and under a blanket gas. Stirring of the mixture was continued at room temperature over night. After the addition of 62.72 g (0.482 moles; 1.26 equ.) of 1-octanol and 0.67 g of Lewatite K-2629 washed with acetone and dried under high vacuum (acidic ion-exchanger), the mixture was allowed to react over night at 140° C., and at the same time, the by-product ethanol formed was removed from the reaction mixture by sparging with an argon stream. The remaining volatile fractions were subsequently removed under high vacuum at 80° C. The product, 1-ethyl-3-methylimidazolium 1-octyl sulfate, was obtained as a medium-viscous, slightly yellow liquid in quantitative yield.
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]2[O:25][CH:26]=[C:27]([C:29]([N:31]3[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH:32]3[CH2:44][O:45][C:46]3[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=3)=[O:30])[N:28]=2)=[CH:19][CH:18]=1>CO>[ClH:1].[ClH:1].[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:24]2[O:25][CH:26]=[C:27]([C:29]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH:32]3[CH2:44][O:45][C:46]3[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=3)=[O:30])[N:28]=2)=[CH:21][CH:22]=1
Reactant: COc1ccc(Nc2nc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3COc3cccnc3)co2)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(C(=O)N3CCNCC3COc3cccnc3)co2)cc1
Reaction time: 8 h
Yield: 73 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(2-(4-methoxyphenylamino)oxazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt (35.5 mg, 0.057 mmol) in MeOH (1 mL). After stirring overnight, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The fractions containing the desired product were concentrated under reduced pressure, dissolved in MeOH (1 mL), and treated with 4 M HCl in 1,4-dioxane (6 mL). The mixture was concentrated under reduced pressure to give 20 mg (73%) of the title compound as a white solid. LC-MS: RT=3.51 min, [M+H]+=410.0.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[CH2:25]([Si:27]([CH2:37][CH3:38])([CH2:35][CH3:36])[C:28]1[O:32][CH:31]=[C:30]([CH:33]=[O:34])[CH:29]=1)[CH3:26]>O1CCCC1>[OH:34][CH:33]([C:30]1[CH:29]=[C:28]([Si:27]([CH2:35][CH3:36])([CH2:37][CH3:38])[CH2:25][CH3:26])[O:32][CH:31]=1)[CH2:2][C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:3]
Reactant: CC[Si](CC)(CC)c1cc(C=O)co1
Reactant: CCCCCCCCCCCCOC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOC(=O)CC(O)c1coc([Si](CC)(CC)CC)c1

Procedure:
A solution of dodecyl acetate (240 mg, 1.04 mmol) in tetrahydrofuran (2 ml) was added to a solution of lithium diisopropylamide (1.04 mmol; =generated from 0.15 ml of diisopropylamine and 0.42 ml n-butyl lithium at -78°) in tetrahydrofuran (10 ml) at -78° under argon. After 1h, a solution of 5-triethylsilyl-3-furaldehyde (200 mg, 0.95 mmol) in tetrahydrofuran (1 ml) was added. Stirring was continued for 15h while the cooling bath attained room temperature. The mixture was quenched with water and was extracted thoroughly with ethyl acetate. Evaporation of the dried (magnesium sulfate) extracts gave an oil which was purified by a silica column using 20% ethyl ether/hexane to give the titled ester.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:17][C@@H:18]2[CH2:23][CH2:22][C@H:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:20][CH2:19]2)=[CH:4][C:5]([O:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1.[F:28][C:29]1[CH:39]=[CH:38][C:32]([C:33]([N:35]=[C:36]=S)=[O:34])=[CH:31][CH:30]=1>>[F:28][C:29]1[CH:30]=[CH:31][C:32]([C:33](/[N:35]=[C:36]2/[N:17]([C@@H:18]3[CH2:19][CH2:20][C@H:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:22][CH2:23]3)[C:3]3[CH:4]=[C:5]([O:8][CH2:9][CH2:10][N:11]4[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]4)[N:6]=[CH:7][C:2]=3[NH:1]/2)=[O:34])=[CH:38][CH:39]=1.[C:33](/[N:35]=[C:36]1/[N:17]([C@@H:18]2[CH2:19][CH2:20][C@H:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:22][CH2:23]2)[C:3]2[CH:4]=[CH:5][N:6]=[CH:7][C:2]=2[NH:1]/1)(=[O:34])[C:32]1[CH:38]=[CH:39][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)[C@H]1CC[C@@H](Nc2cc(OCCN3CCCCC3)ncc2N)CC1
Reactant: O=C(N=C=S)c1ccc(F)cc1
Product: COC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Product: COC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccccc3)[nH]c3cnccc32)CC1
Yield: 55.3 %

Procedure:
The title compound was prepared from cis-methyl 4-(5-amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarboxylate and 4-fluorobenzoyl isothiocyanate using a method analogous to the preparation of cis-methyl 4-((E)-2-(benzoylimino)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylate (100 mg, 55.3% yield). MS m/z=524.2 [M+H]. Calc'd for C28H34FN5O4: 523.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19-1.30 (m, 2H) 1.34-1.45 (m, 2H) 1.46-1.60 (m, 4H) 1.66-1.91 (m, 5H) 2.17-2.27 (m, 2H) 2.35-2.49 (m, 3H) 2.53-2.62 (m, 2H) 2.78-2.90 (m, 1H) 3.75 (s, 3H) 4.29-4.46 (m, 2H) 4.55-4.70 (m, 1H) 6.94 (s, 1H) 7.23-7.36 (m, 2H) 8.19-8.31 (m, 3H) 12.70 (s, 1H).
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:42])(=[O:41])[CH2:31][C:32]([CH2:37][C:38]([OH:40])=[O:39])([C:34]([OH:36])=[O:35])[OH:33]>C(O)C>[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]([O-:42])(=[O:41])[CH2:31][C:32]([CH2:37][C:38]([O-:40])=[O:39])([C:34]([O-:36])=[O:35])[OH:33].[F:28][C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][CH:22]=1)[NH:25][C:26](=[O:27])[CH2:18]2
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: CCO
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Product: O=C1Cc2cc(F)ccc2N1
Temperature: 25 °C

Procedure:
Sunitinib (1.19 g, 2.99 mmol) dissolved in ethanol (120 ml) and citric acid (0.63 g, 3.29 mmol) dissolved in ethanol (10 ml) were combined while heating, and left to cool to room temperature to give sunitinib citrate with melting points 167-173° C. (Form I), 185-198° C. (Form II) and 215-222° C. (Form III).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:22]=[CH:21][C:10]([CH2:11][N:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]3=O)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:22]=[CH:21][C:10]([CH2:11][N:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]3=[S:32])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: COc1cccn(Cc2ccc(-c3ccncc3)cc2)c1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COc1cccn(Cc2ccc(-c3ccncc3)cc2)c1=S
Yield: 124.9 %

Procedure:
Reaction of 146i (0.13 g, 0.45 mmol) and Lawesson's reagent (0.11 g, 0.27 mmol) in toluene according to method described for synthesis of 147a afforded 104 mg of 147i (76%) as yellow solid with greenish tinge. 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J=5.9 Hz, 2H), 7.55 (d, J=8.3 Hz, 2H), 7.39 (m, 5H), 6.67 (dd, J=7.8, 1.1 Hz, 1H), 6.58 (dd, J=73, 6.7 Hz, 1H), 5.95 (s, 2H), 3.89 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 173.29, 159.15, 150.11, 147.43, 137.67, 136.17, 131.78, 128.58, 127.28, 121.35, 111.72, 109.67, 58.54, 56.66. HRMS (EI) calcd for C18H16N2OS [M]+ 308.0983. found 308.0975.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.[C:9]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>>[C:12]([O:11][C:9]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=2)[CH2:18][CH2:17]1)=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: Fc1ccc(I)cn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(I)cn2)CC1

Procedure:
By carrying out the procedure as described in preparation 1, but using 2-fluoro-5-iodopyridine instead of 2-chloro-5-(trifluoromethyl)pyridine and N-Boc-piperazine instead of cis-2,6-dimethylpiperazine, the title compound is obtained in the form of an oil.