Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[CH:12]=[C:13]1[C:19]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:18]=2[CH2:17][CH2:16][C:15]2[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:14]1=2>>[CH3:25][O:24][C:22]1[CH:21]=[CH:20][C:19]2[C:13](=[CH:12][C:6]3[CH:7]=[C:2]([OH:1])[CH:3]=[CH:4][CH:5]=3)[C:14]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:15]=3[CH2:16][CH2:17][C:18]=2[CH:23]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: COc1ccc2c(c1)CCc1cc(OC)ccc1C2=CBr
Product: COc1ccc2c(c1)CCc1cc(OC)ccc1C2=Cc1cccc(O)c1
Yield: 33.5 %

Procedure:
Following procedures essentially as described in Example 219, below, and using 3-hydroxyphenyl boronic acid (304 mg, 2.2 mmol) with 5-bromomethylene-2,8-dimethoxy-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (690 mg, 2 mmol) to give 990 mg crude product. Purify the crude product using column chromatography eluting with 8% EtOAc/hexane to 25% EtOAc/hexane to give 240 mg (33%) product as a colorless oil. MS (ES) 357 (M−1). HPLC shows 99% purity at t=3.33 min.
Reaction SMILES: C([O-])(=O)C.[C:5]([C:9]1[CH:14]=[CH:13][C:12]([I+:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6].[C:26]12([CH2:36][S:37]([O:40]C)(=[O:39])=[O:38])[C:33]([CH3:35])([CH3:34])[CH:30]([CH2:31][CH2:32]1)[CH2:29][C:27]2=[O:28]>C(OCC)(=O)C>[C:26]12([CH2:36][S:37]([O-:40])(=[O:38])=[O:39])[C:33]([CH3:35])([CH3:34])[CH:30]([CH2:31][CH2:32]1)[CH2:29][C:27]2=[O:28].[C:22]([C:19]1[CH:20]=[CH:21][C:16]([I+:15][C:12]2[CH:11]=[CH:10][C:9]([C:5]([CH3:8])([CH3:7])[CH3:6])=[CH:14][CH:13]=2)=[CH:17][CH:18]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: COS(=O)(=O)CC12CCC(CC1=O)C2(C)C
Agent: CC(=O)[O-]
Agent: CC(C)(C)c1ccc([I+]c2ccc(C(C)(C)C)cc2)cc1
Solvent: CCOC(C)=O
Product: CC1(C)C2CCC1(CS(=O)(=O)[O-])C(=O)C2

Procedure:
Ethyl acetate (50 ml) was added to bis(p-tert-butylphenyl)iodonium acetate (467 mg; 1 mmol) and methyl camphorsulfonate (259 mg; 1.05 mmol). The resultant mixture was refluxed for 24 hours while being stirred. The reaction mixture was cooled, and formed solid was removed through filtration. The solid was recrystallized from acetone, and dried under vacuum, to thereby yield 518 mg of bis(p-tert-butylphenyl)iodonium camphorsulfonate (yield: 83%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([NH2:26])=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13](B2OC(C)(C)C(C)(C)O2)=[CH:12][CH:11]=3)[CH2:3][CH2:2]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.Br[C:70]1[C:75]([CH3:76])=[CH:74][CH:73]=[CH:72][C:71]=1[C:77]1[O:78][C:79]([CH3:82])=[CH:80][N:81]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:76][C:75]1[CH:74]=[CH:73][CH:72]=[C:71]([C:77]2[O:78][C:79]([CH3:82])=[CH:80][N:81]=2)[C:70]=1[C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH2:26])[C:7]([N:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)=[CH:16]2
Reactant: Cc1cnc(-c2cccc(C)c2Br)o1
Reactant: CC1(C)OB(c2ccc3nc(N)c(N4CCOCC4)cc3c2)OC1(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1cnc(-c2cccc(C)c2-c2ccc3nc(N)c(N4CCOCC4)cc3c2)o1
Temperature: 130 °C

Procedure:
A glass microwave reaction vessel was charged with 3-morpholino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (0.055 g, 0.155 mmol, prepared as in Example 2, Step 1-2), potassium phosphate (0.131 g, 0.619 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.015 g, 0.031 mmol), Pd2 dba3 (0.142 g, 0.155 mmol), and 2-(2-bromo-3-methylphenyl)-5-methyloxazole (0.078 g, 0.310 mmol). The vessel was evacuated and flushed with N2 3× before dioxane (1.00 mL) and water (0.500 mL) (each degassed by bubbling N2 gas through the solution for 10 min prior to addition) were added. The reaction mixture was stirred and heated in a microwave reactor at 130° C. for 15 min. The reaction mixture was diluted with 10:1 saturated ammonium chloride/ammonium hydroxide and extracted with EtOAc. The combined organic extracts were washed with 10:1 saturated ammonium chloride/ammonium hydroxide, water, saturated sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel chromatography by eluting with 1:15:15 2M NH3 in MeOH/dichloromethane/sdiethyl ether, to provide the desired product which after triturating with diethyl ether gave 6-(2-methyl-6-(5-methyloxazol-2-yl)phenyl)-3-morpholinoquinolin-2-amine. MS (ESI, pos. ion) m/z: 401 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH:15]=O)[NH:11][C:10]=1[CH3:17])=[O:8])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2.C(OC)(=O)C.C(OC(C)C)(=O)C.N1CCCC1>C(OCC)(=O)C>[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: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: CC(=O)OC(C)C
Solvent: C1CCNC1
Solvent: CCOC(C)=O
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C

Procedure:
According to the process of the present invention, 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (IX) and 5-Fluoro-1,3-dihydro-indol-2-one (X) in esters like ethyl acetate, methyl acetate or isopropyl acetate are reacted in presence of catalytic amount of pyrrolidine as base at reflux temperature for 6-15 hours. The resultant Sunitinib base is again triturated with the same solvent at reflux temperature for 1-2 hours and isolated at a temperature ranging from 20-45° C., preferably at 25-35° and most preferably at 25-30° C. and dried at 60° C. for 5-20 hours to get Sunitinib base (I) as orange crystalline solid.
Reaction SMILES: [C:1]1([C:7]2([CH2:13][NH:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])=[O:16])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>C(OCC)(=O)C>[C:31]([N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH2:13][NH:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])[CH2:12][CH2:11]1)(=[O:33])[CH3:32]
Reactant: COc1ccccc1C(=O)NCC1(c2ccccc2)CCNCC1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccccc1C(=O)NCC1(c2ccccc2)CCN(C(C)=O)CC1

Procedure:
A solution of 0.1 g (0.31 mmol) of 4-phenyl-4-(3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl)piperidine (Example 2), 0.025 mL of pyridine (0.31 mmole) in 2 mL of acetic anhydride was mixed for 18 hr. The reaction was diluted with ethyl acetate and washed with saturated NaHCO3. The organic fraction was dried over MgSO4 and the filtrate was concentrated. The residue was purified by chromatography (silica, ethyl acetate) to give the title compound.
Reaction SMILES: [C:1]1([CH:7]2[O:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](Cl)(=[O:17])[CH2:14][CH2:15][CH3:16].C(N(CC)CC)C>ClCCl>[C:1]1([CH:7]2[CH2:8][N:9]([C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[CH2:10][CH2:11][O:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCC(=O)Cl
Reactant: c1ccc(C2CNCCO2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCOC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81 %

Procedure:
A solution of 2-phenylmorpholine (326 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and butanoyl chloride (266 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:3). The fractions containing 1-(2-phenylmorpholin-4-yl)butan-1-one are collected and the solvent is removed in vacuo to give 378 mg of colorless oil.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][O:7][C:5](=[O:6])[CH2:4]1)=[CH2:2].C([O-])(=O)C.[Na+].[CH3:14][OH:15]>>[OH:15][CH2:14][CH:3]([CH:1]=[CH2:2])[CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: CO
Reactant: C=CC1COC(=O)C1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: C=CC(CO)CC(=O)OC

Procedure:
A solution of RS 3-vinylbutyrolactone (3.5 g) and sodium acetate (2.56 g) in methanol (30 ml) was kept for 20 hours. Solvent was evaporated and the residue was partitioned between water and ether. The aqueous layer was extracted twice more with ether and the extracts combined, filtered through phase separating paper and evaporated. The residue was purified by filtration chromatography on silica gel (Merck 7736) starting with 1/9 ethyl acetate/hexane and progressing to 4/6 ethyl acetate/hexane as eluent to give methyl 4-hydroxy-3-vinylbutyrate as an oil; NMR(CDCl3) δ5.73(1H,m), 5.15(2H,m), 3.68(3H,s), 3.60(2H,t), 2.76(1H,m), 2.48(2H,m), 1.69(1H,t); m/e 145(M+H)+.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[CH2:9]=[CH:10][CH:11]=[CH2:12]>CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH:10]([CH:11]1[CH2:12][CH:3]1[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH2:9]
Reactant: C=CC=C
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: CC(=O)O
Product: C=CC1CC1C(=O)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
Butadiene (200 mL) was liquified at -70° C. and added to ethyl diazoacetate (20 g, 175 mmol) in a pressure vessel. The catalyst, rhodium (II) acetate dimer (300 mg, 0.7 mmol), was added and the reaction vessel sealed. The reaction mixture was allowed to warm to ambient temperature and the reaction vessel was shaken for 24 h at ambient temperature. The reaction mixture and the ethanol rinse of the reaction vessel were combined and this blue solution was filtered through 50 g of silica gel. The silica gel was washed with 2% diethyl ether in pentane until the blue color was eluted. The blue solution was then concentrated in vacuo at 0° C. and filtered through CeliteR filter aid to remove any remaining catalyst. The filtrate was distilled under reduced pressure (approximately 15 mm) to yield 18.6 g (76% yield) of ethyl 2-ethenylcyclopropane carboxylate as a clear colorless liquid, b.p. 22°-26° C.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([F:22])=[C:12]([N:16]2[CH2:19][CH:18]([O:20][CH3:21])[CH2:17]2)[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.O>CCOC(C)=O>[F:22][C:11]1[C:12]([N:16]2[CH2:17][CH:18]([O:20][CH3:21])[CH2:19]2)=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][OH:8]
Reactant: COC1CN(c2cccc(CO[Si](C)(C)C(C)(C)C)c2F)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC1CN(c2cccc(CO)c2F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-3-methoxyazetidine (121 mg) was mixed with THF (4 ml), and a 1 M TBAF/THF solution (0.8 ml) was added thereto, followed by stirring at room temperature for 1 hour. Water and EtOAc were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain [2-fluoro-3-(3-methoxyazetidin-1-yl)phenyl]methanol (72 mg).
Reaction SMILES: Cl.[CH:2]1([CH2:8][NH:9][CH2:10][CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16](OC)=[O:17])=[C:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])[CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Li+].[OH-].[NH2:31][C@H:32]([C:37]([O:39][CH3:40])=[O:38])[CH2:33][CH2:34][S:35][CH3:36].Cl.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CO.CN(C=O)C.CCOC(C)=O>[CH3:40][O:39][C:37](=[O:38])[C@H:32]([CH2:33][CH2:34][S:35][CH3:36])[NH:31][C:16](=[O:17])[C:15]1[CH:20]=[CH:21][C:12]([CH2:11][CH2:10][NH:9][CH2:8][CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)=[CH:13][C:14]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28]
Reactant: COC(=O)c1ccc(CCNCC2CCCCC2)cc1-c1ccccc1C
Reactant: COC(=O)[C@@H](N)CCSC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CCNCC2CCCCC2)cc1-c1ccccc1C
Yield: 91.2 %

Procedure:
Methyl 4-(N-(cyclohexylmethyl)aminoethyl)-2-(2-methylphenyl)benzoate hydrochloride (1.33 g, 3.31 mmol) was treated with sat. LiOH (1.3 mL, 6.95 mmol) in 50 mL methanol at 60° C. until no starting material remained by tlc. The solution was evaporated to dryness and treated with Met-OMe.HCl (0.99 g, 4.96 mmol), EDAC (1.26 g, 6.6 mmol), HOBt (1.5 g, 9.9 mmol), and TEA (to pH 6˜7) in 25 mL DMF. Standard aqueous workup followed by flash chromatography (100% EtOAc) provided 1.5 g of the title compound. MS m/e 497 (M−H)−.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH3:27][C:28]([CH3:34])([CH3:33])[CH2:29][C:30](O)=[O:31]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:30](=[O:31])[CH2:29][C:28]([CH3:34])([CH3:33])[CH3:27])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: CC(C)(C)CC(=O)O
Agent: Cl
Product: CC(C)(C)CC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, off-white solid (83 mg, 78%), MS (ISP) m/z=425.3 [(M+H)+], mp 174° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 3,3-dimethyl-butyric acid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH3:13][N:14]([CH3:16])[NH2:15]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:15][N:14]([CH3:16])[CH3:13])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Reactant: CN(C)N
Solvent: CN(C)C=O
Product: Cc1csc2c(NN(C)C)nc(Cl)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
In DMF was dissolved 700 mg (3.4 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine, and then a solution of 450 mg (7.5 mmol) of 1,1-dimethylhydrazine was added dropwise to the resulting solution under ice cooling over 5 minutes. The reaction solution was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for further one hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 173 mg (yield: 20.9%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:18]2[CH:22]=[CH:21][N:20]=[C:19]2[CH2:23]O)=[C:8]([CH:17]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])([O-:3])=[O:2].[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:18]2[CH:22]=[CH:21][N:20]=[C:19]2[CH2:23][N:29]2[C:25](=[O:35])[C:26]3=[CH:34][CH:33]=[CH:32][CH:31]=[C:27]3[C:28]2=[O:30])=[C:8]([CH:17]=1)[C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:10])([O-:3])=[O:2]
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1-n1ccnc1CO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1-n1ccnc1CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 17, 5-nitro-2-[2-(hydroxymethyl)imidazol-1-yl]benzophenone is treated with phthalimide and triphenylphosphine and finally with diethyl azodicarboxylate to give 5-nitro-2-[2-(phthalimidomethyl)imidazol-1-yl]benzophenone.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:30][C@@H:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=1)[OH:32])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[C:19]([S:26][CH:27]([CH3:29])[CH3:28])[CH:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:40]([O:43][CH2:44][CH2:45][CH2:46][S:47]([NH2:50])(=[O:49])=[O:48])(=[O:42])[CH3:41].C1CCN2C(=NCCC2)CC1.Cl>O1CCCC1.C(OCC)(=O)C>[C:40]([O:43][CH2:44][CH2:45][CH2:46][S:47]([NH:50][C:23]([C:20]1[CH:21]=[CH:22][C:17]([C:14]2[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:30][C@@H:31]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=3)[OH:32])=[CH:16][CH:15]=2)=[CH:18][C:19]=1[S:26][CH:27]([CH3:29])[CH3:28])=[O:24])(=[O:48])=[O:49])(=[O:42])[CH3:41]
Reactant: CC(C)Sc1cc(-c2ccc(CCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)O
Reactant: CC(=O)OCCCS(N)(=O)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)OCCCS(=O)(=O)NC(=O)c1ccc(-c2ccc(CCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)cc1SC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
To a solution of 4′-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-3-(isopropylthio)-4-biphenylcarboxylic acid (150 mg) in tetrahydrofuran (1.5 ml) was added N,N′-carbonyldiimidazole (64 mg) and stirred at room temperature for 30 minutes. To the mixture were added 3-(aminosulfonyl)propyl acetate (67 mg) and 1,8-diazabicyclo[5.4.0]-7-undecene (55 μl) and stirred at room temperature, and then stirred at 50° C. for 3 hours. The reaction mixture was poured into 0.1N hydrochloric acid and ethyl acetate and the organic layer was separated. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to give 3-[[[[4′-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-3-(isopropylthio)-4-biphenylyl]carbonyl]amino]sulfonyl]propyl acetate (72 mg). To a solution of the product (72 mg) in methanol (2.0 ml) and tetrahydrofuran (2.0 ml) was added sodium hydroxide aqueous solution (1N, 532 μl) and stirred at room temperature for 10 minutes. To the mixture was added hydrochloric acid aqueous solution (1N, 532 μl) and diluted with ethyl acetate. The solution was poured into water and ethyl acetate and the organic layer was separated. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified with silica gel column chromatography to give tert-butyl [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-[4′-[[[(3-hydroxypropyl)sulfonyl]amino]carbonyl]-3′-(isopropylthio)-4-biphenylyl]-ethyl]carbamate (49 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[Cl:17].C([O-])([O-])=O.[Cs+].[Cs+].[Cl:24][C:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([O:40][CH3:41])[C:26]=1[OH:42]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:17][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:29]3[CH:28]=[C:27]([O:40][CH3:41])[C:26]([OH:42])=[C:25]([Cl:24])[CH:30]=3)[CH:3]=2)[N:8]=[CH:7][C:6]=1[C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13]
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(Cl)c3c2)cc(Cl)c1O
Temperature: 40 °C
Yield: 16.9 %

Procedure:
To a suspension of (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (104 mg, 0.320 mmol), Pd(dppf)Cl2 (23 mg, 0.03 mmol), and Cs2CO3 (0.95 mL, 1.0 M in H2O) in dioxane (5 mL) was added 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (109 mg, 0.384 mmol). The reaction mixture was degassed with N2 gas and the vessel was sealed and heated to 40° C. for 18 h. The reaction mixture was cooled, diluted with ethyl acetate, and filtered. The solution was concentrated and subjected to column chromatography (silica, hexanes/ethyl acetate) to afford the desired product (21 mg, 13%) as a light brown solid: 1H NMR (300 MHz, CDCl3) δ 8.91 (s, 1H), 8.43 (d, J=1.9 Hz, 1H), 8.19 (t, J=7.5 Hz, 1H), 8.10-7.91 (m, 1H), 7.36 (d, J=1.9 Hz, 1H), 7.13 (d, J=1.8 Hz, 1H), 6.03 (s, 1H), 4.04 (s, 3H), 2.77-2.50 (m, 1H), 1.50-1.37 (m, 2H), 1.35-1.10 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7]4=[C:8]([C:17](=[O:20])[NH:18][N:19]=[C:6]4[C:5]=2[CH:4]=1)[CH:9]=[CH:10][CH:11]=3.[CH3:21][N:22]([CH3:27])[CH2:23][C:24](O)=[O:25].C(Cl)CCl>CN(C=O)C.CN(C1C=CN=CC=1)C>[O:20]=[C:17]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[O:13][C:14]4[CH:15]=[CH:16][C:3]([CH2:2][O:1][C:24](=[O:25])[CH2:23][N:22]([CH3:27])[CH3:21])=[CH:4][C:5]=4[C:6]([C:7]=23)=[N:19][NH:18]1
Reactant: CN(C)CC(=O)O
Reactant: O=c1[nH]nc2c3c(cccc13)Oc1ccc(CO)cc1-2
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN(C)CC(=O)OCc1ccc2c(c1)-c1n[nH]c(=O)c3cccc(c13)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
To a solution of compound 57 (0.5 mmol) in anhydrous DMF was added dimethyl glycine (0.75 mmol) and EDC (0.75 mmol) and DMAP (catalytic amount). The reaction mixture was stirred at room temperature overnight. Solvent was removed in vacuo. To the residue, 100 mL of ethyl acetate was added. The organic layer was washed with water, and brine, then dried with MgSO4. The Solvents were removed to afford a colorless oil, which was re-crystallized in EtOAc/Hexanes to afford an off-white solid 59 in 30% yield. MS (ES+): 352; MP: 227-230° C.; 1H-NMR (CDCl3, 400 MHz): 10.15 (s, 1H), 8.14 (d, J=2.0 Hz, 1H), 8.06 (dd, J=8.0 and 1.0 Hz, 1H), 7.80 (t, J=8.0 Hz, 1H), 7.53 (dd, J=8.0 and 1.0 Hz, 1H), 7.47 (dd, J=8.5 and 2.0 Hz, 1H), 7.22 (d, J=8.5 Hz, 1H), 5.21 (s, 2H), 3.26 (s, 2H), 2.37 (s, 6H); Anal. Calcd. for C19H17N3O4: C, 64.95; H, 4.86; N, 11.96. Found: C, 64.95; H, 4.78; N, 12.14.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:21][C:22]([O:25][C:26](=[O:38])[NH:27][CH:28]([CH3:37])[C:29](=[O:36])[NH:30][CH:31]1[CH2:35][CH2:34][NH:33][CH2:32]1)([CH3:24])[CH3:23].C(N(CC)CC)C>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:33]4[CH2:34][CH2:35][CH:31]([NH:30][C:29](=[O:36])[CH:28]([NH:27][C:26]([O:25][C:22]([CH3:24])([CH3:23])[CH3:21])=[O:38])[CH3:37])[CH2:32]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)NC1CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(NC(=O)OC(C)(C)C)C(=O)NC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Yield: 61.5 %

Procedure:
A suspension of 1.4 g (50 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1.92 g (7.5 mmol) of [1-methyl-2-oxo-2-[(3-pyrrolidinyl)amino]ethyl]-carbamic acid 1,1-dimethylethyl ester, 1.5 g (15 mmol) of triethylamine and 75 ml of acetonitrile was heated at reflux for five hours. The solvent was removed in vacuo and the residue was partitioned between chloroform/water (250 ml each) and acidified to pH 2.0 at 0° with 6.0M hydrochloric acid. The solid was removed by filtration, washed with water and dried in vacuo to give 2.4 g of the title compound, mp 185°-187°.