Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N.O.[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[C:9]([C:17](=O)[C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:20][CH:19]=2)[CH:8]=1)([CH3:6])([CH3:5])[CH3:4]>C(O)C.[Zn].S([O-])([O-])(=O)=O.[Cu+2]>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[C:9]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:22][CH:23]=2)[CH:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccc(CC(=O)O)c(C(=O)c2ccc(CC(=O)O)cc2)c1
Agent: [Cu+2]
Agent: N
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1ccc(CC(=O)O)c(Cc2ccc(CC(=O)O)cc2)c1
Temperature: 80 °C
Yield: 59 %

Procedure:
A mixture of 25 ml of 30% aqueous ammonia and 12.5 ml of water was added to 17.5 g of active zinc powder. The mixture was heated at 80° C. with stirring. A saturated aqueous solution of copper sulfate (0.8 ml) was added, and then, a solution of 3.0 g of 4-t-butyl-2-(4-carboxymethylbenzoyl)phenylacetic acid in 25 ml of ethanol was added dropwise. The mixture was stirred at the same temperature for 30 hours. After the reaction, the reaction mixture was cooled, and the insoluble matter was separated by filtration. The filtrate was acidified with conc. hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The ethyl acetate was distilled off. Recrystallization of the residue from a mixture of ethyl acetate and n-hexane afforded 1.7 g of 4-t-butyl-2-(4-carboxymethylbenzyl)phenylacetic acid as colorless needle-like crystals having a melting point of 138° to 139° C.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:31]5[O:32][C:33]([CH:36]=O)=[CH:34][CH:35]=5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][S:39]([CH2:42][CH2:43][NH2:44])(=[O:41])=[O:40].[O-]S([O-])(=O)=O.[Mg+2].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.C(O)(=O)C.CO>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:31]5[O:32][C:33]([CH2:36][NH:44][CH2:43][CH2:42][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:34][CH:35]=5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ncnc4ccc(-c5ccc(C=O)o5)cc34)c2)no1
Reactant: CS(=O)(=O)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ncnc4ccc(-c5ccc(CNCCS(C)(=O)=O)o5)cc34)c2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.3 %

Procedure:
To a mixture of 1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-(5-formylfuran-2-yl)quinazolin-4-yloxy]phenyl}urea (0.17 g. 0.34 mmol), 2-(methylsulfonyl)ethanamine (0.15 g. 1.2 mmol), and MgSO4 in CH2Cl2 was added acetic acid (4 drops), followed by MeOH (1 mL). After the mixture was stirred at room temperature for 1 hour, NaBH(OAc)3 (0.212 g, 1 mmol) was added. After stirring the mixture at room temperature for more 2 hours, more NaBH(OAc)3 (0.212 g, 1 mmol) was added and stirred at room temperature overnight. The reaction was quenched with water, basified with saturated NaHCO3, and extracted with CH2Cl2. The extracts were dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography with 2-6% MeOH/EtOAc as eluants to afford 1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-(5-{[2-(methylsulfonyl)ethylamino]methyl}furan-2-yl)quinazolin-4-yloxy]phenyl}urea as solid (0.052 g, 25%). 1H NMR (300 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.02 (s, 1H), 8.70 (s, 1H), 8.52 (s, 1H), 8.38 (d, 1H), 8.03 (d, 1H), 7.61 (s, 1H), 7.43 (t, 1H), 7.31 (d, 1H), 7.23 (d, 1H), 7.03 (d, 1H), 6.48 (m, 2H), 3.83 (br, 2H), 3.24 (t, 2H), 3.02 (s, 3H), 2.97 (br, 2H), 1.27 (s, 9H); LC-MS (ESI) m/z 605 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH:25][C:26]([C:28]4[S:29][CH:30]=[CH:31][CH:32]=4)=[NH:27])[CH:23]=3)[NH:18][CH:17]=2)[CH2:11]1)C(=O)OC(C)(C)C.FC(F)(F)C(O)=O.[NH4+].[OH-]>ClCCl>[CH3:1][NH:2][CH:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH:25][C:26]([C:28]4[S:29][CH:30]=[CH:31][CH:32]=4)=[NH:27])[CH:23]=3)[NH:18][CH:17]=2)[CH2:11]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCCC(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)C1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC1CCCC(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
tert-Butyl methyl(3-(5-(thiophene-2-carboximidamido)-1H-indol-3-yl)cyclohexyl)carbamate (0.30 g, 0.66 mmol) was treated with 20% trifluoroacetic acid (TFA) solution (31 mL) in dichloromethane at 0° C. and the mixture left to stir for 2 h at 0° C. The solution then was neutralized with 10% NH4OH, the organic layer separated and evaporated. The crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 1:4) to give the title product as a yellow solid (0.22 g, quantitative). 1H-NMR (DMSO-d6) δ 1.28-1.61 (m, 4H), 1.84-2.01 (m, 2H), 2.08-2.11 (m, 1H), 2.27-2.35 (m, 1H), 2.58 (s, 3H), 2.86-2.94 (m, 1H), 3.08-3.25 (m, 1H), 7.10 (d, 1H, J=8.4 Hz), 7.28 (d, 1H, J=2.1 Hz), 7.39 (pseudo t, 1H, J=4.5 Hz), 7.52 (d, 1H, J=8.4 Hz), 7.65 (s, 1H), 8.12 (d, 1H, J=3.6 Hz), 8.16 (d, 1H, J=4.5 Hz), 8.58 (s, 2H, NH), 9.61 (s, 1H); ESI-MS (m/z, %) 353 (100), ESI-HRMS calc. for C20H25N4S 353.1794 found 353.1792.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]=2[CH:14]=1)(=[O:3])[CH3:2].[BrH:15].BrBr>C(O)(=O)C>[Br:15][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11](=[O:12])(=[O:13])[CH2:10][CH2:9][C:8]=2[CH:14]=1)=[O:3]
Reactant: CC(=O)c1ccc2c(c1)CCS2(=O)=O
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Product: O=C(CBr)c1ccc2c(c1)CCS2(=O)=O
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of 5-acetyl-2,3-dihydrobenzothiophene-1,1-dioxide (8 g, 38.1 mmol) (obtained in preparation 17) dissolved in acetic acid (45 ml) under argon atmosphere, aqueous HBr (0.5 ml, 47%), bromine (5.84 g, 36.54 mmol) was added slowly at 15°-20° C. and the reaction mixture was stirred for about 0.5 h. Additional quantity of bromine (4.84 g) was slowly added and the stirring continued for further 10 h at 25°-30° C. Argon atmosphere was removed and the reaction mixture was kept open in the wave of blowing air in the fuming cup board to eliminate free bromine. The solid separated was filtered and washed with acetic acid (2×10 ml) followed by pet. ether to yield the title compound (10 g, 91%). mp. 68°-70° C.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.C(O)=O.[Cl:30][C:31]1[N:39]=[C:38](Cl)[C:37]([F:41])=[CH:36][C:32]=1[C:33]([OH:35])=[O:34]>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[Cl:30][C:31]1[N:39]=[CH:38][C:37]([F:41])=[CH:36][C:32]=1[C:33]([OH:35])=[O:34]
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=CO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)c1cc(F)cnc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 88.5 %

Procedure:
To a round-bottomed flask under a N2 atmosphere were added degassed DMF (270 mL), Pd(OAc)2 (0.05 eq, 2.7 g, 11.9 mmol), PPh3 (0.1 eq, 6.2 g, 23.8 mmol), and degassed Et3N (6 eq, 200 mL, 1428.6 mmol). The mixture was stirred for 20 minutes, HCOOH (3 eq, 28 mL, 714.3 mmol) was then added. 5 minutes later, 2,6-dichloro-5-fluoronicotinic acid (50 g, 238.1 mmol) was added. The mixture was stirred at 50° C. The reaction was followed by analysis (1H NMR) of a worked-up aliquot. When all starting material was consumed (24 h), the mixture was cooled to 0° C. and water (500 mL) was added. After 20 minutes, The mixture was filtered through a pad of Celite that was rinsed with water. The mixture was basified to pH 9 with 30% aq. NaOH and washed with EtOAc (2×). HCl (12 N) was added slowly to pH 1 and the solution was saturated with NaCl. The mixture was extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated under reduced pressure to give 37 g (88%) of a beige solid used in the next step without further purification.
Reaction SMILES: [C:1]1([C@@H:7]([CH3:10])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[CH:27]([S:30](Cl)(=[O:32])=[O:31])([CH3:29])[CH3:28]>CCCCCC.C(Cl)Cl>[C:1]1([C@@H:7]([CH3:10])[CH2:8][NH:9][S:30]([CH:27]([CH3:29])[CH3:28])(=[O:32])=[O:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: C[C@@H](CN)c1ccccc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)NC[C@H](C)c1ccccc1
Reaction time: 0.75 h
Yield: 92 %

Procedure:
To a solution of the (2R)-2-phenylpropylamine (1.2g, 8.87mmol) in hexane (16.0 mL) was added triethylamine (2.47 mL, 17.74 mmol) and dimethylaminopyridine (0.30 g, 2.47 mmol). Cooled reaction to 5° C., then added a solution of isopropylsulfonyl chloride (0.97 mL, 8.69 mmol) dissolved in methylene chloride (6.0 mL) over a period of 15.0 minutes. Stirred for 45.0 minutes, then stirred at room temperature for 120.0 minutes. Quenched reaction with IN HCl (20.0 mL) and extracted organic with methylene chloride (25.0 mL). Dried organic layer with anhydrous magnesium sulfate, filtered and concentrated filtrate to provide the final title compound, ((2R)-2-phenylpropyl)[(methylethyl)sulfonyl]amine, (1.93 g, 90.1%) an oil; 1H nmr (CDCl3, 300 MHz) δ 1.25 (d, 3H, J=6.9Hz), 1.29(d, 3H, J=6.9Hz), 1.30 (d, 3H, J=7.2 Hz), 2.98 (m, 1H), 3.05 (m, 1H), 3.22 (m, 1H), 3.36 (m, 1H), 3.89 (b, 1H), 7.23 (m, 2H), 7.34 (m, 2H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[Cl:22][C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[K+].[Br-]>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:30]3[CH2:29][CH2:28][N:27]([CH2:26][C:25]4[CH:33]=[CH:34][C:35]([Cl:36])=[C:23]([Cl:22])[CH:24]=4)[CH2:32][CH2:31]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: Clc1ccc(CN2CCNCC2)cc1Cl
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: [Br-]
Agent: [K+]
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1

Procedure:
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(3,4-dichloro-benzyl)-piperazine, yield 86%. White crystals, m.p. 229–230° C.; IR (KBr): ν 1717 (C═O) cm−1.
Reaction SMILES: C(O[C:9]([C:11]1[CH:16]=[CH:15][C:14](CO[Si](C(C)(C)C)(C)C)=[CH:13][CH:12]=1)=[CH2:10])C1C=CC=CC=1.[CH2:26]([O:33]C(C1C=CC=C(CO[Si](C(C)(C)C)(C)C)C=1)=C)C1C=CC=CC=1.ClCC=CC1C=CC=CC=1.[Si](Cl)(C(C)(C)C)(C)C.C>>[OH:33][CH2:26][CH:10]=[CH:9][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C=C(OCc1ccccc1)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Reactant: C=C(OCc1ccccc1)c1cccc(CO[Si](C)(C)C(C)(C)C)c1
Agent: C
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: ClCC=Cc1ccccc1
Product: OCC=Cc1ccccc1

Procedure:
α-Benzyloxy[4-(tert-butyldimethylsilyloxymethyl)styrene] and α-Benzyloxy[3-(tert-butyldimethylsilyloxymethyl)styrene] (Formula II, R1 =(tert-butyldimethylsilyloxymethyl)phenyl, R2 =benzyl). (Hydroxymethyl)styrene was prepared from (chloromethyl)styrene (a 2:3 mixture of para and meta isomers) by a sequence described in Polymer, 1973, 14, 330. It was treated with tert-butyldimethylsilyl chloride following the general directions found in Journal of the American Chemical Society, 1972, 94, 6190. Method C was used to convert the 25 resulting compound to the required alkoxystyrene: 1H NMR (CCl4) δ 0.70 (6H, s), 0.94 (9H, s), 4.17 (1H, d, J 2.4 Hz), 4.63 (3H, broadened s), 4.83 (2H, s), 7.0-7.6 (9H, m); MS (CH4) 355 (MH+, 4%), 91 (100%).
Reaction SMILES: [CH2:1]([C:4]1([OH:19])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)[CH:2]=[CH2:3].C([O:24]O)(C)(C)C.C1(C)C=CC=CC=1>CCCCCC.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[V]>[O:24]1[CH2:3][CH:2]1[CH2:1][C:4]1([OH:19])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2
Reactant: C=CCC1(O)c2ccccc2CCc2ccccc21
Reactant: CC(C)(C)OO
Agent: [V]
Agent: CC(=O)/C=C(/C)O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: OC1(CC2CO2)c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 49.6 %

Procedure:
To a stirred, refluxing solution of 35.7 g (0.14 mol) of 5-allyl-5-hydroxy-10,11-dihydro-5H-dibenzo[a,d]cycloheptene 10 (R. D. Hoffsommer, et al, supra) in 500 ml of hexane was added 0.5 g of vanadium (III) acetylacetonate followed by the dropwise addition of 25.1 g (0.22 mol) of 70% tert-butylhydroperoxide. The resulting yellow mixture was refluxed for 4 hrs., then 100 ml of toluene was added. The reaction was allowed to cool to room temperature and stand for 12 hrs. Excess hydroperoxide was destroyed by the addition of 300 ml of aqueous sodium sulfite (Na2SO3) solution (10%). The organic phase was separated, dried over anhydrous MgSO4, filtered and evaporated. Recrystallization of the solid from CHCl3 -hexane gave 18.5 g (50% yield) of the epoxide 11, m.p. 116°-118° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]1[CH2:14][OH:15])[CH3:2]>[O-2].[O-2].[Mn+4].ClCCl>[CH2:1]([N:3]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]1[CH:14]=[O:15])[CH3:2]
Reactant: CCn1c(CO)nnc1-c1ccncc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCn1c(C=O)nnc1-c1ccncc1
Reaction time: 2 h

Procedure:
Dichloromethane (4 mL) was added to a vial containing (4-ethyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-methanol (56.7 mg, 0.279 mmol) and manganese dioxide (364.3 mg, 4.19 mmol) was added. The vial was sealed and the reaction was allowed to stir for two hours. The reaction was filtered through celite and concentrated to yield the title compound. 1H NMR (CDCl3) δ (ppm): 10.21 (s, 1H), 8.88 (d, 2H), 7.63 (d, 2H), 4.45 (q, 2H), 1.48 (t, 3H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[N:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:41][C:42]1[CH:47]=[CH:46][C:45](O)=[CH:44][CH:43]=1>C1COCC1>[Br:41][C:42]1[CH:47]=[CH:46][C:45]([O:21][CH2:20][CH2:19][C:16]2[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=2)=[CH:44][CH:43]=1
Reactant: Oc1ccc(Br)cc1
Reactant: OCCc1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Brc1ccc(OCCc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
Diethyl azodicarboxylate (4.44 mL, mmol, 40%) was slowly added to a solution of 2-pyridin-4-yl-ethanol (1.00 g, 8.12 mmol), triphenylphosphine (2.56 g, 9.74 mmol), and 4-bromophenol (1.40 g, 8.12 mmol) in THF (40.6 mL) at 0° C. under nitrogen. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was quenched with water (150 mL) and extracted with ethyl acetate (200 mL). The organics were washed with 1N aqueous NaOH (100 mL) and brine (100 mL). The organics were dried (Na2SO4), filtered, and concentrated. The crude material was crystallized with ether:heptanes (1:1, ˜25 mL) and the solid was removed via filtration and washed with ether:heptanes. The combined filtrates were concentrated and further purified via flash chromatography using an Analogix SF25-40g column and ethyl acetate in heptane (0-30%) as the eluant to afford the title compound as a clear liquid (1.20 g, 46.2%). LC-MS m/z 278.4 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.11 (t, 2 H) 4.19 (t, J=6.44 Hz, 2 H) 6.77 (d, J=8.98 Hz, 2 H) 7.22-7.26 (m, 2 H) 7.38 (d, J=4.69 Hz, 2 H) 8.54-8.57 (m, 3 H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:32])[C:5]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([C:23]([CH3:31])([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:6][CH:7]=1.[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1[NH:38][C:39](N1C=CN=C1)=[O:40].CCN(C(C)C)C(C)C>CN(C=O)C>[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1[NH:38][C:39]([N:13]1[CH2:12][CH2:11][CH:10]([N:9]([CH2:8][C:5]2[C:4]([CH3:32])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:16][C:17]2[C:22]([C:23]([CH3:24])([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH3:31])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:15][CH2:14]1)=[O:40]
Reactant: Cc1cc(Cl)cnc1CN(Cc1ncccc1C(C)(C)c1ccccc1)C1CCNCC1
Reactant: O=C(Nc1ncc[nH]1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Cl)cnc1CN(Cc1ncccc1C(C)(C)c1ccccc1)C1CCN(C(=O)Nc2ncc[nH]2)CC1
Temperature: 75 °C
Reaction time: 3 h

Procedure:
The amine from above (230 mg, 0.50 mmol), and imidazole-1-carboxylic acid (1H-imidazol-2-yl)-amide (300 mg, 1.0 mmol) were combined in DMF (2.5 mL) and treated with DIPEA (0.52 mL, 3.0 mmol). The solution was stirred at 75° C. for 3 hours and then concentrated under reduced pressure. This afforded, after column chromatography with silica gel (50:1:0.2 CH2Cl2:MeOH:NH4OH), COMPOUND 309 (180 mg, 65%). 1H NMR (CDCl3): δ 1.17 (q, 2H, J=12.3 Hz), 1.55 (d, 2H, J=12.3 Hz), 1.61 (s, 6H), 2.29 (s, 3H), 2.53 (m, 3H), 3.36 (s, 2H), 3.64 (s, 2H), 4.08 (d, 2H, J=12.9 Hz), 6.68 (s, 2H), 7.00 (d, 2H, J=7.5 Hz), 7.08 (m, 1H), 7.19 (m, 3H), 7.36 (s, 1H), 7.85 (d, 1H, J=7.5 Hz), 8.20 (s, 1H), 8.48 (br d, 1H, J=3.3 Hz). 13C NMR (CDCl3) δ 18.87, 28.30 (2C), 31.29 (2C), 42.88, 44.58 (2C), 54.13, 55.33, 58.30, 121.67, 126.02 (2C), 126.32, 128.88 (2C), 130.40, 134.13, 135.41, 137.73, 143.49, 144.91 (2C), 145.48, 146.91 (2C), 149.84, 155.60, 156.53, 158.59. ES-MS m/z 559 (M+H). Anal. Calcd. for C31H36N7OCl.0.3CH2Cl2: C, 64.42; H, 6.32; N, 16.80; Cl, 9.72. Found: C, 64.26; H, 6.35; N, 16.64; Cl, 9.47.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[C:30]([OH:33])(=[O:32])[CH3:31].C(O)C>O>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[C:30]([O-:33])(=[O:32])[CH3:31]
Reactant: CC(=O)O
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: O
Solvent: CCO
Product: CC(=O)[O-]
Temperature: 60 °C

Procedure:
A solution of Sunitinib acetate was prepared in the following way: 10 g Sunitinib Base (1 eq) was suspended in 50 ml of water, then 1.58 g (1.05 eq) of acetic acid was added under stirring obtaining a solution. This solution was heated to 60° C. Then 160 ml of ethanol were added at this temperature.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1>C(OCC)(=O)C.[O-2].[Mn+4].[O-2]>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[O:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(F)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: COc1ncc(F)cc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To (5-fluoro-2-methoxy-pyridin-3-yl)-methanol (36, 8 g, 50.9 mmol) in 300 mL of ethyl acetate, manganese(IV) oxide (39.8 g, 458 mmol) was added and the mixture stirred at room temperature overnight. The reaction mixture was filtered through celite, and the celite bed rinsed with ethyl acetate. The filtrate was concentrated under vacuum, then passed through a plug of silica, eluting with 50% ethyl acetate in heptane to provide the desired compound as a light yellow solid (37, 4.5 g, 29.0 mmol, 57.0% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([CH3:22])[CH:21]=1)[CH:17]=O>C(O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:22][C:20]2[CH:19]=[C:16]([CH3:17])[CH:15]=[C:14]([Br:13])[CH:21]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: Cc1cc(Br)cc(C=O)c1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CCO
Product: CCOC(=O)c1ccc(N=Cc2cc(C)cc(Br)c2)cc1
Temperature: 25 °C
Yield: 41.9 %

Procedure:
A mixture of 4-amino-benzoic acid ethyl ester (8.3 g, 50.3 mmol) and 3-bromo-5-methyl-benzaldehyde (11.0 g, 50.3 mmol) in ethanol (100 mL) was prepared. The reaction mixture was heated to reflux for 2 hours. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-{[1-(3-bromo-5-methyl-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (7.3 g, 50%) as a white solid: LC/MS m/e calcd for C17H16BrNO2 M+: 346.2, observed: 346.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][N:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)=[O:4].I[CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:14][CH3:15])[N:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc([N+](=O)[O-])n[nH]1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc([N+](=O)[O-])cc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5-nitro-2H-pyrazole-3-carboxylic acid methyl ester (525, 2.50 g, 0.0146 mol) in N,N-dimethylformamide (62.5 mL) were added iodoethane (1.2 mL, 0.016 mol) and potassium carbonate (4.17 g, 0.0301 mol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid (526, 1.3 g, 44.7%).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C:7](=[CH:9][CH:10]=O)[CH3:8])[CH3:3].[CH2:12]([C:16]([CH3:18])=[O:17])[CH:13]([CH3:15])[CH3:14]>O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH3:14][CH:13]([CH2:12][C:16](=[O:17])[CH:18]=[CH:10][CH:9]=[C:7]([CH3:8])[CH2:6][CH2:5][CH:4]=[C:2]([CH3:1])[CH3:3])[CH3:15]
Reactant: CC(=O)CC(C)C
Reactant: CC(C)=CCCC(C)=CC=O
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: O
Product: CC(C)=CCCC(C)=CC=CC(=O)CC(C)C
Temperature: 160 °C
Yield: 32.5 %

Procedure:
Into a 2 liter autoclave are charged citral (152 grams), methyl isobutyl ketone (500 grams) and zinc acetate dihydrate (38 grams). The reaction mixture is heated at 160° C. for a period of 12 hours. After filtering the catalyst the organic layer is washed with 10% salt solution. Distillation yielding 76 grams (32% yield) of the product, B.P. 126°-141° C./1 mmHg.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:3]=1.[K+].[CH2:25]([S:27]([NH-:30])(=[O:29])=[O:28])[CH3:26].Cl>CS(C)=O>[Cl:17][C:6]1[N:5]=[C:4]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:3]=[C:2]([NH:30][S:27]([CH2:25][CH3:26])(=[O:29])=[O:28])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1Cl
Reactant: CCS([NH-])(=O)=O
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: CCS(=O)(=O)Nc1nc(-c2ncccn2)nc(Cl)c1Oc1ccccc1OC
Reaction time: 240 h
Yield: 83.2 %

Procedure:
To a solution of 4,6-dichloro-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl (prepared as described in [6] and [11]) (1.74 g) in DMSO (5 ml) was added ethanesulfonamide potassium salt (1.62 g). Stirring was continued for 10 days at rt. The reaction mixture was poured onto ice/water and acidified by 2N HCl. The precipitate was filtered off, washed with water and dried at HV to give ethanesulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl-4-yl]-amide (1.75 g) as a white powder. LC-MS: tR: 3.77, [M+H]+: 422.15.