Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=3)[NH:11][C:10]=2[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:25][C:26]#[N:27]>CN(C)C=O>[C:26]([CH2:25][N:11]1[C:12]2[C:17](=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[C:10]1[C:19]([O:21][CH2:22][CH3:23])=[O:20])#[N:27]
Reactant: CCOC(=O)c1[nH]c2ccc(Cl)cc2c1-c1ccccc1
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2n1CC#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of sodium hydride (from 7.2 gms., 0.15 mole 50% sodium hydride dispersed in mineral oil) in 125 ml fresh dimethyl formamide (DMF) is added ethyl 3-phenyl-5-chloroindole-2-carboxylate (45 gms, 0.15 mole), as a dry powder, in portions. The reaction is exothermic and requires a water bath to maintain the temperature between 45°-50° C. After stirring 15-20 minutes (at 35° C), chloroacetonitrile (12 grams, 0.15 mole) in 25 ml DMF is added slowly. The temperature rises to 45° C and the mixture is stirred overnight at ambient temperature. The mixture is then transferred to a one liter beaker and 500 ml of ice-water is added slowly. After 15-20 minutes the product is filtered off, washed well with water, and dried on a Buchner funnel. After recrystallization from ethanol the product gives a m.p. of 117°-19° C. There is obtained a total of 46 grams (90.2%), of sufficient purity for the next step. A sample is recrystallized from aqueous ethanol, washed with water and vacuum dried, m.p. 119°-120° C.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][C@H:4]2[CH3:23].CS(C)=O.FC(F)(F)C(O)=O.C1(N=C=NC2CCCCC2)CCCCC1>C(OC(=O)C)C.N1C=CC=CC=1.C1C=CC=CC=1>[CH3:23][C@H:4]1[C@@:3]2([CH:2]=[O:1])[C:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C:15]2=[O:21])=[CH:7][C:6](=[O:22])[CH2:5]1
Reactant: C[C@@H]1CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccccc1
Solvent: CS(C)=O
Product: C[C@@H]1CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C=O

Procedure:
19-Hydroxy-1β-methyl-4-androstene-3,17-dione is added to a mixture containing dimethylsulfoxide, benzene, pyridine, trifluoroacetic acid and N,N'-dicyclohexylcarbodiimide and allowed to react for 12 hours at room temperature. Ethylacetate is added and the reaction mixture is filtered. The filtrate is extracted with a solution of sodium bicarbonate, water and dried over magnesium sulfate. After evaporation of the solvent under reduced pressure, the residue is crystallized from ether to yield 1β-methyl-4-androstene-3,17,19-trione.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:31])[C:9]2[CH:14]=[C:13]([O:15]CC3C=CC=CC=3)[CH:12]=[C:11]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:10]=2)=[N:3]1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[OH:15][C:13]1[CH:14]=[C:9]([CH:10]=[C:11]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]=1)[C:8]([NH:7][C:4]1[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=1)=[O:31]
Reactant: Cn1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cn1ccc(NC(=O)c2cc(O)cc(OCc3ccccc3)c2)n1
Temperature: 140 °C
Yield: 48.3 %

Procedure:
A suspension of N-(1-methyl-1H-pyrazol-3-yl)-3,5-bis[(phenylmethyl)oxy]benzamide (1.0 g, 2.42 mmol) was dissolved in ethanol (12 mL) and ammonium formate (229 mg, 3.63 mmol) was added in one portion. The reaction was blanketed with argon and 10% palladium on activated carbon (10 mg) was added. This mixture was heated to 140° C. for 5 minutes in a Smith Creator microwave. The catalyst was filtered off and the volatiles removed in vacuo, the residue was chromatographed on silica, eluting with a gradient of 30-100% ethyl acetate in iso-hexane, to give the title compound as a white solid (378 mg).
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[N:8]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]4[CH:27]=[CH:26][C:25]([C:28]5[N:32]=[CH:31][N:30](COCC[Si](C)(C)C)[N:29]=5)=[CH:24][CH:23]=4)=[C:15]3[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(C(F)(F)F)=O>[NH:30]1[CH:31]=[N:32][C:28]([C:25]2[CH:24]=[CH:23][C:22]([C:21]3[CH:20]=[N:19][N:16]4[CH:17]=[CH:18][C:13]([N:8]5[C@@H:7]([C:1]6[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=6)[CH2:11][O:10][C:9]5=[O:12])=[N:14][C:15]=34)=[CH:27][CH:26]=2)=[N:29]1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccc(-c3cnn4ccc(N5C(=O)OC[C@@H]5c5ccccc5)nc34)cc2)n1
Solvent: O=C(O)C(F)(F)F
Product: O=C1OC[C@H](c2ccccc2)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)cc3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.1 %

Procedure:
To the solid (S)-4-phenyl-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one (0.80 g, 1.4 mmol) was added TFA (20 mL) and the reaction stirred at room temperature for 3 hours. The reaction was concentrated and the residue slurried in methanol/acetonitrile (20 mL 1:1) and water (20 mL) added and the reaction stirred at ambient temperature for 1 hour. The organic solvents were removed in vacuo and the water layer basified to about pH 7 using a solution of saturated NaHCO3. The aqueous layer was then stirred for 5 minutes. The solids were filtered and dried in vacuo. The solids were then taken up in water and stirred for 2 hours. The solids were filtered and dried in vacuo. The solids were next slurried in methanol while nitrogen was bubbled through the solution for 2 hours. The slurry was concentrated to about 20 mL, and the solids filtered and dried in vacuo to give (S)-3-(3-(4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-phenyloxazolidin-2-one (0.19 g, 0.45 mmol, 31% yield). LCMS (APCI+) m/z 424 [M+H]+.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].[Cl:34][C:35]1[CH:40]=[C:39](B(O)O)[CH:38]=[CH:37][N:36]=1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([C:39]4[CH:38]=[CH:37][N:36]=[C:35]([Cl:34])[CH:40]=4)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(Br)cc3Cl)C[C@H]2C(=O)N2CCC(F)(F)C2)CC1
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(-c4ccnc(Cl)c4)cc3Cl)C[C@H]2C(=O)N2CCC(F)(F)C2)CC1

Procedure:
The title compound was prepared in analogy to example 196 using (1R,2R,4R)-4-(2-chloro-4-bromo-benzenesulfonyl)-2-(3,3-difluoro-pyrrolidine-1-carbonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (Example 187 step 4) and 2-chloropyridine-4-boronic acid. Light brown solid (58%). MS (EI): 597.1 (M+H)+.
Reaction SMILES: [K].[CH3:2][C:3]([CH3:11])([CH3:10])[CH2:4][CH2:5][S:6]([NH2:9])(=[O:8])=[O:7].[Cl:12][C:13]1[C:18]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])=[C:17](Cl)[N:16]=[C:15]([C:29]2[N:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[N:14]=1>CS(C)=O>[Cl:12][C:13]1[N:14]=[C:15]([C:29]2[N:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[N:16]=[C:17]([NH:9][S:6]([CH2:5][CH2:4][C:3]([CH3:11])([CH3:10])[CH3:2])(=[O:8])=[O:7])[C:18]=1[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27]
Reactant: CC(C)(C)CCS(N)(=O)=O
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1Cl
Agent: [K]
Solvent: CS(C)=O
Product: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)CCC(C)(C)C
Temperature: 120 °C
Reaction time: 6 h
Yield: 91.1 %

Procedure:
3,3-dimethylbutane-1-sulphonic acid amide potassium salt (616 mg) was added to a solution of 4,6-dichloro-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)-pyrimidine (Can. Pat. Appl. 2071193) (353 mg) in dry dimethyl sulphoxide (10 ml) and the resulting mixture stirred at 120° C. for 6 hours under nitrogen. The reaction mixture was allowed to cool and then partitioned between ethyl acetate (30 ml ) and 2N aqueous hydrochloric acid (30 ml ) and the organic phase separated. The aqueous was extracted with ethyl acetate (30 ml) and the organic phases combined, washed (water 2×20 ml), dried (Na2SO4) and evaporated under reduced pressure. Column chromatography on silica eluting with a solvent gradient of pentane:ethyl acetate 50:50 changing to 0:100 and finally ethyl acetate:methanol 98:2 gave N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-3,3-dimethyl-1-butanesulfonamide as an off-white solid (440 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1.[CH:33]#[C:34][CH:35]([OH:38])[CH2:36][CH3:37]>>[F:27][C:24]([F:26])([F:25])[C:23]([C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:13][CH2:12][CH:11]([S:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[C:2]([C:33]#[C:34][CH:35]([OH:38])[CH2:36][CH3:37])[CH:3]=1)([OH:32])[C:28]([F:30])([F:29])[F:31]
Reactant: O=S(=O)(c1ccccc1)C1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2Br)CC1
Reactant: C#CC(O)CC
Product: CCC(O)C#Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCC(S(=O)(=O)c2ccccc2)CC1

Procedure:
Following the procedure described for Example 152, 2-(3-bromo-4-(4-(phenylsulfonyl)piperidin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol was coupled to 1-pentyn-3-ol (Aldrich, St. Louis, Mo.) to afford 1-(5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-(4-(phenylsulfonyl)piperidin-1-yl)phenyl)pent-1-yn-3-ol as a light yellow solid and a mixture of enantiomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[N:12]1[CH2:17][C:16]2[CH:18]=[N:19][C:20]([N:22](OC)[CH3:23])=[CH:21][C:15]=2[N:14]([CH2:26][CH3:27])[C:13]1=[O:28].[H][H]>[Pd]>[NH2:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([Cl:1])=[C:3]([N:12]2[CH2:17][C:16]3[CH:18]=[N:19][C:20]([NH:22][CH3:23])=[CH:21][C:15]=3[N:14]([CH2:26][CH3:27])[C:13]2=[O:28])[CH:4]=1
Reactant: CCN1C(=O)N(c2cc([N+](=O)[O-])c(F)cc2Cl)Cc2cnc(N(C)OC)cc21
Reactant: [H][H]
Agent: [Pd]
Product: CCN1C(=O)N(c2cc(N)c(F)cc2Cl)Cc2cnc(NC)cc21
Yield: 86.6 %

Procedure:
3-(2-Chloro-4-fluoro-5-nitrophenyl)-1-ethyl-7-(methoxy(methyl)amino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (2.7 g, 6.6 mmol), Pd/C (1.4 g) and hydrogen (30 psi) were combined at 45° C. by the procedure of Example A4 to provide 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(methylamino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (2 g, 87.0% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.72 (s, 1 H), 7.24 (d, J=10.8 Hz, 1 H), 6.81 (d, J=9.2 Hz, 1 H), 6.44 (bs, 1 H), 6.02 (s, 1 H), 5.42 (s, 2 H), 4.50 (d, J=13.2 Hz, 1 H), 4.38 (d, J=13.2 Hz, 1 H), 3.77 (m, 2 H), 2.76 (d, J=4.8 Hz, 3 H), 1.15 (t, J=7.2 Hz, 3 H); MS (ESI) m/z: 350.2[M+H]+.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[CH:11]=[C:12]([CH:14]=[C:15]([C:17]2[S:21][CH:20]=[N:19][CH:18]=2)[CH:16]=1)[NH2:13].[CH3:22][C:23]1([CH3:34])[CH:28]([CH3:29])[C:27](=[O:30])[CH2:26][CH2:25][CH:24]1[C:31]([OH:33])=[O:32]>C1COCC1.CCOC(C)=O>[NH2:13][C:12]1[CH:14]=[C:15]([C:17]2[S:21][C:20]([C:27]3([OH:30])[CH2:26][CH2:25][CH:24]([C:31]([OH:33])=[O:32])[C:23]([CH3:22])([CH3:34])[CH:28]3[CH3:29])=[N:19][CH:18]=2)[CH:16]=[C:10]([CH3:9])[CH:11]=1
Reactant: CC1C(=O)CCC(C(=O)O)C1(C)C
Reactant: Cc1cc(N)cc(-c2cncs2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(N)cc(-c2cnc(C3(O)CCC(C(=O)O)C(C)(C)C3C)s2)c1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 12.3 %

Procedure:
Lithium diisopropylamide (5110 μl, 9.20 mmol) was added to a −78° C. solution of 3-methyl-5-(1,3-thiazol-5-yl)aniline (500 mg, 2.63 mmol) in THF (7 mL). The reaction was allowed to warm to −60° C. while aging for 30 min. The solution was cooled to −78° C. and 2,2,3-trimethyl-4-oxocyclohexanecarboxylic acid (600 mg, 3.26 mmol) in THF (6 mL) was added portionwise, maintaining an internal temperature below −65° C. After 5 min at −78° C. the reaction was warmed to room temperature, diluted with EtOAc and washed with aqueous saturated ammonium chloride (3×). The combined aqueous portion was extracted with 10% IPA:CHCl3 (3×). The combined organic layers were dried under reduced pressure to yield 4-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-4-hydroxy-2,2,3-trimethylcyclohexanecarboxylic acid (121 mg, 12%) as a yellow oil. MS ESI: [M+H]+ m/z 375.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]#[N:8])(=[O:4])[CH:2]=[CH2:3].[CH2:9]([NH:11][CH2:12][CH3:13])[CH3:10]>>[CH2:9]([N:11]([CH2:12][CH3:13])[CH2:3][CH2:2][C:1]([O:5][CH2:6][C:7]#[N:8])=[O:4])[CH3:10]
Reactant: C=CC(=O)OCC#N
Reactant: CCNCC
Product: CCN(CC)CCC(=O)OCC#N
Reaction time: 10 h

Procedure:
At 20 to 30° C., 22.2 g of cyanomethyl acrylate was added to 14.6 g of diethylamine, which was stirred for 10 hours, obtaining cyanomethyl 3-diethylaminopropionate.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[N:7]2[CH2:8][CH2:9][NH:10][C:11]3([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:6]2=[CH:5][CH:4]=1.CCN(CC)CC.[CH3:33][N:34]=[C:35]=[O:36]>C1COCC1>[CH3:33][NH:34][C:35]([N:10]1[C:11]2([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:13][CH2:12]2)[C:6]2=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:24])[F:25])[N:7]2[CH2:8][CH2:9]1)=[O:36]
Reactant: CN=C=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)NCCn1c(C(F)(F)F)ccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)N1CCn2c(C(F)(F)F)ccc2C12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
To tert-butyl 6-(trifluoromethyl)spiro[3,4-dihydro-2H-pyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (600 mg, 1.67 mmol), THF (3 mL) and Et3N (698 μL, 5.01 mmol) was added methyl isocyanate (199 μL, 3.34 mmol). The mixture was allowed to stir at room temperature for 2 h. The mixture was charged with additional Et3N (698 μL, 5.01 mmol) and methyl isocyanate (199 μL, 3.34 mmol), and the reaction was stirred at room temperature for 3 d. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (40 mL) and washed with water (3×10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield tert-butyl 2-(methylcarbamoyl)-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (680 mg, 97%). ESI-MS m/z calc. 416.2, found 417.4 (M+1)+; Retention time: 1.73 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.14 (q, J=4.3 Hz, 1H), 6.56 (d, J=3.4 Hz, 1H), 6.03 (d, J=3.9 Hz, 1H), 3.88 (t, J=5.4 Hz, 2H), 3.73 (t, J=5.4 Hz, 2H), 3.69-3.55 (m, 2H), 3.23-3.03 (m, 2H), 2.78-2.62 (m, 2H), 2.56 (d, J=4.4 Hz, 3H), 1.76-1.60 (m, 2H), 1.40 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)=O.[CH:18]1([C:21](=O)[CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:20][CH2:19]1.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>C(O)C>[CH3:26][O:25][C:23]([C:22]1[C:21]([CH:18]2[CH2:20][CH2:19]2)=[N:1][C:2]2[C:3]([C:9]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)=[CH:4][C:5]([Cl:8])=[CH:6][CH:7]=2)=[O:24]
Reactant: Nc1ccc(Cl)cc1C(=O)c1cccc(Cl)c1
Reactant: COC(=O)CC(=O)C1CC1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCO
Product: COC(=O)c1c(C2CC2)nc2ccc(Cl)cc2c1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.5 %

Procedure:
To a mixture of (2-amino-5-chlorophenyl)(3-chlorophenyl) methanone (81 mg, 0.31 mmol, 1 eq) and methyl 3-cyclopropyl-3-oxopropanoate (56.2 mg, 0.40 mmol, 1.3 eq) in ethanol (3 ml) was added ytterbium triflate (19 mg, 0.03 mmol, 0.1 eq) and the yellow solution was stirred overnight at room temperature. The resultant precipitate was filtered and washed with a small amount of ethanol to give the desired product (49 mg, 43%) as a white solid which did not require any further purification. MS (ESI): 372.1 (M+H)+.
Reaction SMILES: C[C@@H]1[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@@]2(O)O[C@H]([C@H](C(O)=O)[C@@H](O)C2)C[C@@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H:58]([NH2:64])[C@H]2O)C=CC=CC=CC=CCCC=CC=C1.[O:66]=[CH:67][C@@H:68]([C@H:70]([C@H:72]([C@@H:74]([CH2:76]O)[OH:75])[OH:73])[OH:71])[OH:69]>CN(C)C=O>[CH3:58][NH:64][CH2:76][C@@H:74]([C@H:72]([C@@H:70]([C@@H:68]([CH2:67][OH:66])[OH:69])[OH:71])[OH:73])[OH:75]
Reactant: C[C@@H]1[C@H](O)[C@@H](C)C=CC=CCCC=CC=CC=CC=C[C@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](N)[C@H]2O)C[C@@H]2O[C@](O)(C[C@@H](O)[C@H](O)CC[C@@H](O)C[C@@H](O)C[C@@H](O)CC(=O)O[C@H]1C)C[C@H](O)[C@H]2C(=O)O
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Agent: C[C@@H]1[C@H](O)[C@@H](C)/C=C/C=C/CC/C=C/C=C/C=C/C=C/[C@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](N)[C@H]2O)C[C@@H]2O[C@](O)(C[C@@H](O)[C@H](O)CC[C@@H](O)C[C@@H](O)C[C@@H](O)CC(=O)O[C@H]1C)C[C@H](O)[C@H]2C(=O)O
Solvent: CN(C)C=O
Product: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Yield: 398.5 %

Procedure:
5 g of nystatin and 1.5 g of galactose were suspended in 50 ml of dimethyl formamide and next the procedure was carried out as in Example IV. 4.2 g of N-methylglucamine salt of N-glycosyl nystatin of E1 cm1% =600 at 304 nm and IC50 =0.45 mcg/ml were obtained. Original antibiotic: E1 cm1% =790 at 304 nm, IC50 =0.18 mcg/ml.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[N:26]1([CH2:32][CH2:33][NH2:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:34][CH2:33][CH2:32][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NCCN1CCCCC1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCN3CCCCC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2-(piperidin-1-yl)ethanamine. MS obsd. (ESI+) [(M+H)+] 465, 1H NMR (400 MHz, CDCl3) δ ppm 8.04 (d, J=7.6 Hz, 1 H), 7.67 (d, J=7.6 Hz, 1 H), 7.51 (m, 2 H), 7.38 (t, J=7.6 Hz, 1 H), 7.30 (m, 2 H), 5.74 (m, 1 H), 5.12 (s, 2 H), 4.6 (brs, 2 H), 3.58 (s, 2 H), 3.28 (m, 2 H), 2.75 (t, J=8.4 Hz, 2 H), 2.46 (m, 7 H), 1.62 (m, 4 H), 1.52 (m, 2 H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:42])[CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:25][CH2:24]2)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OCC)(=O)C.[Cl-].[NH4+]>O1CCCC1>[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][C:18]([CH:21]([OH:42])[CH2:22][N:23]2[CH2:24][CH2:25][N:26]([CH:29]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:27][CH2:28]2)=[CH:19][CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(CN1CCN(C(c2ccccc2)c2ccccc2)CC1)c1ccc(OCc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC(CN1CCN(C(c2ccccc2)c2ccccc2)CC1)c1ccc(OCc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
In 24 ml of tetrahydrofuran was suspended 0.60 g (16 mmol) of lithium aluminum hydride, to which a suspension consisting of 24 ml of tetrahydrofuran and 3.0 g (6.3 mmol) of 1-(4-benzyloxyphenyl)-2-(4-diphenylmethylpiperazinyl)ethanone was added portionwise under ice-cooled conditions. After being stirred for 0.5 hour, the resultant mixture was added dropwise with 5 ml of ethyl acetate, followed by further addition of 50 ml of ethyl acetate. The thus prepared solution was poured into an aqueous solution of ammonium chloride, and the organic layer was separated. The organic layer was washed twice with saturated saline and then dried over anhydrous sodium sulfate. The solvent was removed, and the residue was recrystallized from a mixed solvent of ethanol and chloroform to give 2.37 g of 1-(4-benzyloxyphenyl)-2-(4-diphenylmethylpiperazinyl)ethanol (yield: 79%).
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([CH3:19])[CH:13]=[C:12](Cl)[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([Mg]Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([CH3:19])[CH:13]=[C:12]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(Cl)nc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Reactant: Cl[Mg]Cc1ccccc1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(Cc2ccccc2)nc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Reaction time: 0.08 h
Yield: 40.9 %

Procedure:
To a solution of 2-anilino-7-chloro-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (100 mg, 0.277 mmol) in THF was added Ni(dppp)Cl2 (37.0 mg, 0.069 mmol). After stirring for 5 min, benzylmagnesium chloride (2M, 1.45 mL, 2.90 mmol) was added dropwise via syringe and the mixture was allowed to stir for 24 h. The mixture was quenched with 1 N HCl and extracted with EtOAc. The organic layer was washed brine, dried over MgSO4, and concentrated in vacuo. Purification by preparative HPLC (10% MeNC in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) provided 2-anilino-7-benzyl-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (47.3 mg, 41%): LCMS RT: 2.85 min, MH+: 418.3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[C:6]=1[CH3:23])[CH3:2].Br[C:26]1[CH:27]=[N:28][CH:29]=[C:30]([CH3:32])[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:26]3[CH:27]=[N:28][CH:29]=[C:30]([CH3:32])[CH:31]=3)[C:13]=2[CH3:22])[C:6]=1[CH3:23])[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1C
Reactant: Cc1cncc(Br)c1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cncc(C)c3)c3cc(Cl)ccc23)c1C

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-2-methyl-benzoic acid ethyl ester and 3-bromo-5-methylpyridine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([S:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11](=[O:18])[CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[CH2:19]=O.S(=O)(=O)(O)O>O1CCOCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([S:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11](=[O:18])[C:12]([CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17]1)=[CH2:19]
Reactant: C=O
Reactant: CSc1ccc(C(=O)CC2CCCC2)c(Cl)c1Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: C=C(C(=O)c1ccc(SC)c(Cl)c1Cl)C1CCCC1

Procedure:
2',3'-dichloro-4'-methylthio-2-cyclopentylacrylophenone is prepared following substantially the same procedure described in Example 3, Step B, using the following substances: 2',3'-dichloro-4'-methylthio-2-cyclopentylacetophenone (54.5 g., 0.18 mole), paraformaldehyde (21.6 g., 0.72 mole), concentrated sulfuric acid (9.65 g.) and dioxane (450 ml.).