Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:5]2.[CH3:25][Si:26]([CH3:31])([CH3:30])[CH2:27][C:28]#C>C(NC(C)C)(C)C.ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:11][C:9]1[CH:10]=[C:2]([C:28]#[C:27][Si:26]([CH3:31])([CH3:30])[CH3:25])[CH:3]=[C:4]2[C:8]=1[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:5]2
Reactant: O=C1c2c(Cl)cc(Br)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Reactant: C#CC[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: C[Si](C)(C)C#Cc1cc(Cl)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.7 %

Procedure:
A mixture of 5-bromo-7-chloro-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.210 g, 0.5 mmol), PdCl2(PPh3)2 (0.019 g, 0.05 mmol), and CuI (0.010 g, 0.05 mmol) in diisopropyl amine (4 mL) was treated with trimethyl-prop-2-ynyl-silane (0.141 mL, 1 mmol) and stirred at ambient temperature for 16 h. The reaction mixture diluted with dichloromethane (20 mL) filtered and concentrated. Silica gel column chromatography using 3:1 hexane-ethyl acetate afforded 7-chloro-2-(4-trifluoromethoxy-benzyl)-5-trimethylsilanylethynyl-2,3-dihydro-isoindol-1-one (0.100 g, 46%). GC-MS: 437 (M)+, 356 (M-81)+.
Reaction SMILES: [C:1]([Si:5]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[NH4+]>C(O)C.[Pd]>[C:1]([Si:5]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](OCc1ccc([N+](=O)[O-])cc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)[Si](OCc1ccc(N)cc1)(c1ccccc1)c1ccccc1
Yield: 91.6 %

Procedure:
To a stirred solution of 2a (5.00 g, 12.80 mmol) in ethanol (100 mL) was added Pd/C 10%(1.50 g) and ammonium fornate (4.60 g) in one portion at 20° C. After 1.5 h the catalyst was removed by filtration, the filtrate concentrated under vacuum and the residue partitioned between EtOAc:H2O. The organic layer was dried (MgSO4) and concentrated to give 3a as an oil yield: 4.24 g (91%) νmax /cm-1 (film): 3433, 3378 (NH2), 2931, 2857 (CH2, asym. sym.): 1H-NMR, δH : 1.00 (s, 9H. t-Bu), 4.57 (s, 2H. CH2), 4.98 (s broad, 2H, NH2), 6.52 (d, 2H, J=8.25 Hz, Harom3+5), 6.96 (d, 2H, Harom2+6), 7.42-7.46 (m, 5H, Ph), 7.62-7.65 (m, 5H, Ph): MS, (EI), (361.56); m/z: 361 (M+, 8), 304 (M-t-Bu, 100), 199 (Ph2SiOH+, 100); anal (C23H27NOSi), C, H, N.
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9])(=[O:6])=[O:5])([CH3:3])[CH3:2].CN(C)C=O.[H-].[Na+].[Cl:21][C:22]1[N:31]=[C:30](Cl)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1>O>[Cl:21][C:22]1[N:31]=[C:30]([NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: CC(C)S(=O)(=O)c1ccccc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nc2ccccc12
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a mixture of 2-(isopropylsulfonyl)aniline (450 mg) and N,N-dimethylformamide (10 mL), 55% sodium hydride in oil (200 mg) was added under ice cooling and stirred for 30 minutes, followed by addition of 2,4-dichloroquinazoline (500 mg). The reaction mixture was stirred for 30 minutes under ice cooling and further stirred overnight at room temperature. The reaction mixture was cooled on ice, diluted with water and then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=5:1-3:1) to give 2-chloro-N-[2-(isopropylsulfonyl)phenyl]quinazoline-4-amine (0.67 g) as a light-yellow solid.
Reaction SMILES: [NH2:1][C:2]1([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.CCN(CC)CC.[CH2:22]([C:30]1[O:34][C:33]([C:35](ON2C(=O)CCC2=O)=[O:36])=[CH:32][CH:31]=1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[CH3:8][N:5]1[CH2:4][CH2:3][C:2]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([NH:1][C:35]([C:33]2[O:34][C:30]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:31][CH:32]=2)=[O:36])[CH2:7][CH2:6]1
Reactant: CCOC(=O)CC1(N)CCN(C)CC1
Reactant: O=C(ON1C(=O)CCC1=O)c1ccc(CCc2ccccc2)o1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC1(NC(=O)c2ccc(CCc3ccccc3)o2)CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A stirred solution of ethyl 2-(4-amino-1-methylpiperidin-4-yl)acetate (16 mg, 0.077 mmol) in CH2Cl2 (1 mL) was treated with NEt3 (31 uL, 0.219 mmol), and 2,5-dioxopyrrolidin-1-yl 5-phenethylfuran-2-carboxylate, prepared as described in Preparation 5 (23 mg, 0.073 mmol). The reaction was stirred overnight, at room temperature, then the solvent removed in vacuo and the crude product purified by column chromatography to obtain the title compound (25 mg, 86%). 1H NMR (400 MHz, CD3OD) δ 7.29-7.16 (m, 5H), 7.00 (s, 1H), 6.17 (s, 1H), 4.06 (q, 2H, J=7.2 Hz), 3.05 (s, 4H), 2.88 (s, 2H), 2.75-2.69 (m, 2H), 2.54-2.48 (m, 2H), 2.41-2.31 (m, 5H), 1.87-1.81 (m, 2H), 1.15 (t, 3H, J=7.2 Hz); MS ESI 399.2 [M+H]+, calcd for [C23H30N2O4+H]+ 399.50.
Reaction SMILES: [F:1][C:2]1[C:10]2[C:9](=[O:11])[O:8][C:7](=O)[C:6]=2[C:5]([F:13])=[CH:4][CH:3]=1.C([NH2:16])=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]2[C:10]=1[C:9](=[O:11])[NH:16][C:7]2=[O:8]
Reactant: O=C1OC(=O)c2c(F)ccc(F)c21
Reactant: NC=O
Product: O=C1NC(=O)c2c(F)ccc(F)c21
Temperature: 0 °C

Procedure:
Under argon, 2.15 g (11.68 mmol) of 4,7-difluoro-2-benzofuran-1,3-dione were stirred in 15 ml of formamide at 130° C. for 5 h. The cooled reaction mixture was then added to ice-water. A solid precipitated out. This solid was filtered off with suction and washed with water. The product was dried under high vacuum. This gave 0.45 g (21% of theory) of the target compound.
Reaction SMILES: O=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=2)[N:4]=[C:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:23]>CC#N>[Cl:23][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(=O)[nH]c2c1
Solvent: CC#N
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(Cl)nc2c1
Reaction time: 5 h
Yield: 55.8 %

Procedure:
Methyl 3-oxo-2-phenyl-3,4-dihydroquinoxaline-6-carboxylate (100 mg, 0.36 mmol, 1.00 equiv) and PCl5 (220 mg, 1.07 mmol, 3.00 equiv) in CH3CN (10 mL) was allowed to react, with stifling, for 5 hrs while the temperature was maintained at reflux in an oil bath. The reaction was then quenched by the addition of 50 mL of water, and the pH value of the solution was adjusted to 9 with saturated K2CO3. The resulting solution was extracted with 3×50 mL of ethyl acetate, the organic layers combined and dried over anhydrous sodium sulfate, and concentrated under vacuum, affording 60 mg (56%) of methyl 3-chloro-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][CH2:6][N:7]([S:31]([CH3:34])(=[O:33])=[O:32])[C:8]2[C:9]([CH:28]3[CH2:30][CH2:29]3)=[CH:10][C:11]3[C:15]([CH:16]=2)=[N:14][N:13]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:12]=3[C:24]([NH:26][CH3:27])=[O:25])[CH2:2]1.[CH2:35]=O.[BH4-].[Na+].O>CO>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([N:13]2[C:12]([C:24]([NH:26][CH3:27])=[O:25])=[C:11]3[C:15]([CH:16]=[C:8]([N:7]([CH2:6][CH2:5][CH:3]4[CH2:4][N:1]([CH3:35])[CH2:2]4)[S:31]([CH3:34])(=[O:33])=[O:32])[C:9]([CH:28]4[CH2:29][CH2:30]4)=[CH:10]3)=[N:14]2)=[CH:22][CH:21]=1
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(CCC3CNC3)S(C)(=O)=O)cc2nn1-c1ccc(Cl)cc1
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCC3CN(C)C3)S(C)(=O)=O)cc2nn1-c1ccc(Cl)cc1
Yield: 124 %

Procedure:
To a solution of Compound (6) (27 mg, 0.05 mmol) in MeOH (2 mL) was added, simultaneously, paraformaldehyde (30 mg) and sodium borohydride (30 mg). After 16 h at ambient temperature water (25 ml) was added and the aqueous layer was extracted into EtOAc (3×30 mL). The combined organics were washed with brine (25 mL), dried (MgSO4) and concentrated in vacuo to give a colourless oil (32 mg). The crude material was purified by reverse phase preparative LCMS: Acetonitrile/water (0.1% formic acid) to give Compound (7) (7.70 mg, 30%). ESI-MS m/z calculated for [M+H]+: 516.2. found: 516.1. 1H NMR (400 MHz, CD3CN, formate salt) δ 8.30 (s, 1H), 7.79 (s, 1H), 7.62-7.49 (m, 4H), 7.35 (s, 1H), 7.22 (br s, 1H), 3.84-3.70 (m, 2H), 3.70-3.56 (m, 2H), 3.38 (dd, J=16.0, 7.5 Hz, 2H), 3.07 (s, 3H), 2.89 (d, J=4.8 Hz, 3H), 2.75 (dt, J=15.4, 7.8 Hz, 1H), 2.51 (s, 3H), 2.35 (ddd, J=13.6, 8.1, 5.6 Hz, 1H), 1.87 (ddd, J=17.6, 11.0, 5.2 Hz, 2H), 1.11-0.98 (m, 3H), 0.65-0.57 (m, 1H).
Reaction SMILES: C([Li])(C)(C)C.CCCCC.[CH3:11][O:12][C:13]1[CH:26]=[CH:25][C:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:15][CH:14]=1.[CH3:27][Sn:28](Cl)([CH3:30])[CH3:29]>CCOCC>[CH3:11][O:12][C:13]1[CH:26]=[CH:25][C:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[C:15]([Sn:28]([CH3:30])([CH3:29])[CH3:27])[CH:14]=1
Reactant: C[Sn](C)(C)Cl
Reactant: COc1ccc(NC(=O)OC(C)(C)C)cc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: COc1ccc(NC(=O)OC(C)(C)C)c([Sn](C)(C)C)c1
Temperature: -20 °C
Reaction time: 5 h
Yield: 86.3 %

Procedure:
A solution of t-butyllithium in pentane (1.70M, 148 mL, 251 mmol, 2.50 equiv) was added via cannula to a solution of tert-butyl 4-methoxycarbanilate (22.4 g, 100 mmol, 1 equiv) in ether (500 mL) at -20° C., producing a cloudy yellow solution. After stirring at -20° C. for 5 h, the reaction mixture was cooled to -78° C. and a solution of trimethyltin chloride (50.0 g, 251 mmol, 2.50 equiv) in ether (50 mL) was added via cannula. After the addition, the reaction mixture was warmed to -20° C. and was stirred at that temperature for 30 min, then was stirred in an ice bath for 30 min. The product solution was partitioned between aqueous phosphate buffer solution (pH 7, 0.05M in sodium hydrogen phosphate and 0.05M in potassium dihydrogen phosphate, 600 mL) and ether (400 mL). The aqueous layer was separated and further extracted with ether (2×400 mL). The combined organic layers were dried over sodium sulfate and were concentrated. The product was purified by flash column chromatography (15% ethyl acetate-hexanes) to afford tert-butyl 4-methoxy-2-(trimethylstannyl)carbanilate (7) as a yellow oil (33.3 g, 85%).
Reaction SMILES: [Cl:1][O-].[Na+].[Cl:4][C:5]1[N:10]=[CH:9][C:8]2[CH:11]=[N:12][NH:13][C:7]=2[CH:6]=1.O.S([O-])([O-])=O.[Na+].[Na+]>CCO>[Cl:1][C:11]1[C:8]2[CH:9]=[N:10][C:5]([Cl:4])=[CH:6][C:7]=2[NH:13][N:12]=1
Reactant: [O-]Cl
Reactant: Clc1cc2[nH]ncc2cn1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Clc1cc2[nH]nc(Cl)c2cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.8 %

Procedure:
Sodium hypochlorite (121 mL, 195 mmol) was gradually added to a suspension of 6-chloro-1H-pyrazolo[4,3-c]pyridine (10 g, 65.1 mmol) in EtOH (100 mL) at 0° C. The reaction mixture was then stirred at room temperature for 10 minutes. Water and sodium sulfite (24.62 g, 195 mmol) were added, forming a clear solution, and the mixture was extracted with EtOAc. The organic phase was concentrated in vacuo to give 3,6-dichloro-1H-pyrazolo[4,3-c]pyridine (11.6 g, 61.7 mmol, 95% yield). MS ESI calc'd. for C6H4Cl2N3 [M+H]+ 188, found 188.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:15]=[C:14]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:13]=1[OH:26])([O-])=O>C(O)(C)C.C(N(CC)CC)C.[Pd]>[OH:26][C:13]1[C:14]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:15][C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:17][C:12]=1[N:11]1[N:10]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[N:1]1
Reactant: CC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)C)c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(C)(C)c1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)C)c1
Yield: 77 %

Procedure:
When using the general procedure of Example 5, a 23% by weight suspension of 2-nitro-2'-hydroxy-3',5'-di-tert-butylazobenzene in isopropanol/triethylamine (1/0.18) was hydrogenated at 45° C. at 1 atmosphere pressure for 3 hours in the presence of 3% of a 5% palladium on charcoal catalyst the above noted product was obtained in a yield of 77%.
Reaction SMILES: [CH2:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N+:15]([O-:17])=O)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].C[O-].[Na+].C(Cl)[Cl:22]>CO.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([Cl:22])=[N:15][OH:17])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: ClCCl
Reactant: CCCCOCc1ccc(CC[N+](=O)[O-])cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCOCc1ccc(CC(Cl)=NO)cc1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 99 %

Procedure:
To a solution of 1-butoxymethyl-4-(2-nitroethyl)-benzene (55 mg, 0.23 mmol) described in Manufacturing Example 4-1-3 in methanol (2 mL) was added sodium methoxide (1.49 M methanol solution, 47.3 μL, 0.23 mmol) at 0° C. The reaction solution was stirred for 35 minutes at room temperature, and concentrated under a reduced pressure. To a solution of the residue in methylene chloride (2 mL) was added titanium (IV) chloride (28 μL, 0.23 mmol) under nitrogen atmosphere at −78° C., which was then stirred for 30 minutes at 0° C. The reaction solution was partitioned into water and ethyl acetate at 0° C. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the magnesium sulfate was removed by filtration. The organic layer was filtered with silica gel, and the filtrate was evaporated under a reduced pressure to obtain the title compound (59 mg, 99%) as a crude product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:7][C:8]([OH:10])=[O:9])[S:5][CH:6]=1.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:7][C:8]([OH:10])=[O:9])[S:5][C:6]=1[C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1csc(CC(=O)O)c1
Product: Cc1cc(CC(=O)O)sc1C(=O)c1ccccc1
Yield: 44.1 %

Procedure:
Using the procedure of Example 15, 6.65 gm of 4-methyl-thiophene-2-acetic acid and 5.96 gm of benzoyl chloride were reacted to obtain 4.87 gm of 4-methyl-5-benzoyl-thiophene-2-acetic acid melting at 86° C. The product occurred as a colorless solid soluble in benzene, ether, ethanol, chloroform and acetone and insoluble in water.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:33])[C:28]([CH3:32])([CH3:31])[CH:29]=[CH2:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].I[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:33])[C:28]([CH3:32])([CH3:31])/[CH:29]=[CH:30]/[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Ic1ccccc1
Reactant: C=CC(C)(C)C(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C(C)(C)/C=C/c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 59, Step 1, using 1-{4′-[4-(1-hydroxy-2,2-dimethyl-but-3-enyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and iodobenzene.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].[OH-].[Na+].[F:54][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>C(O)(=O)C>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:42])[CH3:43])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@:9]([F:54])([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@](C)(F)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Reaction time: 2 h
Yield: 87.8 %

Procedure:
Erythromycin A (5 g, 6.813 mmole) was dissolved in glacial acetic acid (20 mL) at room temperature and stirred for 2 hours. The pH of the mixture was adjusted to 4.3 with 6N sodium hydroxide (approx. 12.5 mL) while the temperature was maintained below 20° C. 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (2.4 g, 6.813 mmole) was added and stirring continued for an additional 3 hours at 22° C. The reaction was worked up in the same manner as Example 1 to afford 4.5 g of crude flurithromycin. This material was recrystallized as described in Example 1 to yield 2.6 g (51% yield) of flurithromycin.
Reaction SMILES: [NH:1]1[CH:5]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:3]=[N:2]1.Cl[C:16]1[N:21]=[N:20][C:19]([N:22]2[CH2:27][CH2:26][CH:25]([N:28]3[C:36]4[C:31](=[CH:32][CH:33]=[C:34]([F:37])[CH:35]=4)[CH2:30][CH2:29]3)[CH2:24][CH2:23]2)=[CH:18][CH:17]=1>>[NH:2]1[CH:3]=[C:4]([C:16]2[N:21]=[N:20][C:19]([N:22]3[CH2:23][CH2:24][CH:25]([N:28]4[C:36]5[C:31](=[CH:32][CH:33]=[C:34]([F:37])[CH:35]=5)[CH2:30][CH2:29]4)[CH2:26][CH2:27]3)=[CH:18][CH:17]=2)[CH:5]=[N:1]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Fc1ccc2c(c1)N(C1CCN(c3ccc(Cl)nn3)CC1)CC2
Product: Fc1ccc2c(c1)N(C1CCN(c3ccc(-c4cn[nH]c4)nn3)CC1)CC2

Procedure:
1-(1-(6-(1H-pyrazol-4-yl)pyridazin-3-yl)piperidin-4-yl)-6-fluoroindoline was prepared according to the procedure described in Example 1, Method A, STEP 4, reacting pyrazole-4-boronic acid pinacol ester and 1-(1-(6-chloropyridazin-3-yl)piperidin-4-yl)-6-fluoroindoline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH2:31]([N:34]=[C:35]=[O:36])[CH:32]=[CH2:33]>>[CH2:31]([NH:34][C:35]([NH:30][C:29]1[C:9]([C:3]2[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:10][C:11]2[CH:16]=[N:15][C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[N:13][C:12]=2[N:28]=1)=[O:36])[CH:32]=[CH2:33]
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Reactant: C=CCN=C=O
Product: C=CCNC(=O)Nc1nc2nc(NCCCN3CCN(C)CC3)ncc2cc1-c1c(Cl)cccc1Cl
Yield: 26.2 %

Procedure:
6-(2,6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine (1.0 g) from Example 36 was reacted with 0.186 g of allyl isocyanate according to the general procedure of Example 37. The product was purified by chromatography and crystallized from ethyl acetate to give 0.31 g of 1-allyl-3-{6-(2,6-dichlorophenyl)-2-[3-(4-methyl-piperazin-1-yl)-propylamino]-pyrido[2,3-d]pyrimidin-7-yl}-urea, ESMS (20/80 MeOH/CH3CN+0.1% AcOH): M+ +H=529 (Base), 472, 446; mp 104-108° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:20][O:21][CH2:22][CH2:23][NH:24][CH2:25][CH3:26]>>[CH2:25]([N:24]([CH2:16][C:15]1[CH:18]=[CH:19][C:12]([C:10]([N:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]2)=[O:11])=[CH:13][CH:14]=1)[CH2:23][CH2:22][O:21][CH3:20])[CH3:26]
Reactant: CC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Reactant: CCNCCOC
Product: CCN(CCOC)Cc1ccc(C(=O)N2CCN(C(C)C)CC2)cc1

Procedure:
Prepared from the product of Example 15 and (2-methoxy-ethyl)-ethyl-amine.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:16])[CH2:7][N:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:4].Br[CH2:18][CH2:19]Br>C(OCC)C.CS(C)=O>[CH:9](=[N:8][C:7]1([C:6]([O:5][CH2:3][CH3:4])=[O:16])[CH2:19][CH2:18]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)CN=Cc1ccccc1
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CCOC(=O)C1(N=Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
25.2 g (1.05 moles) of sodium hydride are added a little at a time under nitrogen to 100 g (0.523 mole) of N-benzylideneglycine ethyl ester and 45.1 ml (0.523 mole) of 1,2-dibromoethane in 500 ml of dry diethyl ether and 170 ml of dry dimethylsulfoxide, so that the well-stirred mixture remains at from 20° to 30° C. The mixture is stirred at room temperature overnight and filtered, and 1 l of water is added to the filtrate. The ethereal phase is separated off, washed with twice 200 ml of water, dried over sodium sulfate and evaporated under reduced pressure to give 80 g (70%) of ethyl N-benzylidene-1-aminocyclopropanecarboxylate as an oil.
Reaction SMILES: N1C=CC=CC=1.[C:7]1([N:13]=[C:14]=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:16][C:17]1[S:18][C:19]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)=[C:20]([CH3:27])[C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1(C)C=CC=CC=1>[CH3:27][C:20]1[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:17]([NH:16][C:14]([NH:13][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:15])[S:18][C:19]=1[C:28]1[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCOC(=O)c1c(N)sc(-c2ccc([N+](=O)[O-])cc2)c1C
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(NC(=O)Nc2ccccc2)sc(-c2ccc([N+](=O)[O-])cc2)c1C
Temperature: 97.5 °C
Reaction time: 4 h
Yield: 93.4 %

Procedure:
Toluene (500 ml), pyridine (12.27 g, 155.06 mmol) and phenyl isocyanate (14.58 g, 122.41 mmol) were added to ethyl 2-amino-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate (25.00 g, 81.61 mmol), and the mixture was stirred at 95-100° C. for 4 hours. It was confirmed that starting materials were almost disappeared. After the reaction solution was stirred for 2 hours under ice-cooling, the crystals were isolated with a centrifuging machine and washed with cold toluene (150 ml). The crystals were dried under vacuum at 60° C. for 8 hours to give ethyl 4-methyl-5-(4-nitrophenyl)-2-(3-phenylureido)thiophene-3-carboxylate (32.42 g, 76.20 mmol, 93.4%)