Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([CH:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([NH2:11])=[O:10])[C:4]1=[O:12])C.[CH:13]([N:16]([CH3:20])[CH2:17][CH2:18]N)([CH3:15])[CH3:14]>>[CH3:20][N:16]([CH:13]([CH3:15])[CH3:14])[CH2:17][CH2:18][NH:11][C:9](=[O:10])[CH2:8][N:5]1[CH2:6][CH2:7][CH2:3][C:4]1=[O:12]
Reactant: CCC1CCN(CC(N)=O)C1=O
Reactant: CC(C)N(C)CCN
Product: CC(C)N(C)CCNC(=O)CN1CCCC1=O

Procedure:
From 8.5 g. of ethyl 2-oxo-1-pyrrolidineacetamide and 11.6 g. of N-isopropyl-N-methylethylenediamine, following the procedure of Example 1, there is obtained N-[2-[methyl(1-methylethyl)amino]ethyl]-2-oxo-1-pyrrolidineacetamide; b.p. 152° C./0.07 mm.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23]3[CH:24]=[C:25]([CH3:29])[CH:26]=[CH:27][CH:28]=3)=[CH:20][CH:21]=2)[C:16]([CH2:30][NH2:31])=[CH:15]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(N(CC)CC)C>C1COCC1>[CH2:6]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23]3[CH:24]=[C:25]([CH3:29])[CH:26]=[CH:27][CH:28]=3)=[CH:20][CH:21]=2)[C:16]([CH2:30][NH:31][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:15]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCCn1cc(CN)c2cc(-c3cccc(C)c3)ccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCn1cc(CNS(C)(=O)=O)c2cc(-c3cccc(C)c3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
Methanesulfonyl chloride (33 μl, 0.434 mmol) was added to a solution of (1-octyl-5-m-tolyl-1H-indol-3-yl)methanamine (152 mg, 0.434 mmol) and triethylamine (91 μl, 0.651 mmol) in THF (4 mL) at 0° C. The reaction mixture was allowed to stir at room temp for 60 min, the precipitate formed was filtered off, the filtrate was concentrated, and the residue was subjected to column chromatography (silica gel, CH2Cl2) to give sulphonamide 22 in 61% yield.
Reaction SMILES: [C:1]1(=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=2[CH3:28])[C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([O:18]CC)=[O:17])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>CCO.C1COCC1>[C:1]1(=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=2[CH3:28])[C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)cc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(O)ccc1C(=C1CCCCC1)c1ccc(/C=C/C(=O)O)cc1
Temperature: 85 °C
Reaction time: 4 h
Yield: 100.8 %

Procedure:
To a solution of ethyl (2E)-3-{4-[cyclohexylidene(4-hydroxy-2-methylphenyl)methyl]phenyl}-2-propenoate (30) (0.42 g, 1.11 mmol) in a mixture of EtOH/THF (1 mL, 4 mL) was added an aqueous solution of 5M NaOH (1.4 mL, 7.00 mmol). The mixture was stirred at 85° C. for 4 h. Upon cooling, the mixture was acidified to pH=2 with an aqueous solution of 5 M HCl. The mixture was extracted with EtOAc (1×20 mL). The organics were washed with water and brine (1×10 mL each) and dried with MgSO4. Concentration yielded 0.39 g (100%) of compound 31. 1H NMR (400 MHz, DMSO-d6): δ 1.46-1.58 (m, 6H), 1.91-1.96 (m, 2H), 1.97 (s, 3H), 2.22-2.26 (m, 2H), 6.43 (d, J=16.1 Hz, 1H), 6.53 (m, 2H), 6.83-6.85 (m, 1H), 7.08 (d, J=8.1 Hz, 2H), 7.50 (d, J=16.2 Hz, 1H), 7.55 (d, J=8.1 Hz, 2H), 9.16 (s, 1H), 12.32 (s, 1H). LCMS (ESI): m/z 349 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[CH:36][C:37]([C:40]#[N:41])=[N:38][CH:39]=2)O1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:55].Cl>>[ClH:1].[ClH:55].[C:12]([C:6]1[C:5]([NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]2)=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([C:34]3[CH:35]=[CH:36][C:37]([C:40]#[N:41])=[N:38][CH:39]=3)=[N:3]2)=[N:8][CH:7]=1)(=[O:14])[CH3:13]
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3ccc(C#N)nc3)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1

Procedure:
Following general procedure II, 1-(6-chloro-4-{trans-4-[(dimethylamino)methyl]cyclo-hexylamino}-1,5-naphthyridin-3-yl)ethanone (77 g, 0.21 mmol) was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (72 g, 0.32 mmol) followed by formation of the dihydrochloride salt to afford the desired product (100 g, 95%) as a light brown solid: 1H NMR (500 MHz, CD3OD) δ 9.46 (d, J=2.2 Hz, 1H), 9.21 (s, 1H), 8.70 (dd, J=8.2, 2.2 Hz, 1H), 8.63 (d, J=8.9 Hz, 1H), 8.47 (d, J=8.9 Hz, 1H), 8.17 (d, J=8.2 Hz, 1H), 5.58-5.50 (m, 1H), 3.14 (d, J=6.8 Hz, 2H), 2.94 (s, 6H), 2.77 (s, 3H), 2.49-2.42 (m, 2H), 2.05-1.97 (m, 3H), 1.75-1.65 (m, 2H), 1.39-1.27 (m, 2H); ESI MS m/z 429 [M+H]+; HPLC 96.2% (AUC), tR=8.88 min.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[F:27])[CH2:17][N:16]2[C:28](OC(C)(C)C)=[O:29])[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:75]([O:79][C:80]([NH:82][C:83](C)([CH3:87])[C:84](O)=O)=[O:81])([CH3:78])([CH3:77])[CH3:76]>>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[F:27])[CH2:17][N:16]2[C:28](=[O:29])[C:83]([NH:82][C:80](=[O:81])[O:79][C:75]([CH3:76])([CH3:78])[CH3:77])([CH3:87])[CH3:84])[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(Cl)ccc2F)=CC1c1cccc(O[Si](C)(C)C(C)(C)C)c1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N1CC(c2cc(Cl)ccc2F)=CC1c1cccc(O[Si](C)(C)C(C)(C)C)c1

Procedure:
A solution of tert-butyl 2-(3-{[tert-butyl(dimethyl)silyl]oxy }phenyl)-4-(5-chloro-2-fluorophenyl)-2,5dihydro-1H-pyrrole-1-carboxylate (3-2, 276 mg, 0.683 mmol, 1 equiv), triethylamine (277 mg, 2.73 mmol, 4 equiv), PYBOP (711 mg, 1.37 mmol, 2 equiv) and 2-[(tert-butoxycarbonyl)amino]-2-methylpropanoic acid (278 mg, 1.37 mmol, 2 equiv) in in DMP (10 mL) was warmed at 60° C. for 18 h. The solution was concentrated and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography. Elution with 10% ethyl acetate/hexanes to 20% ethyl acetate/hexanes gave tert-butyl 2-[2-(3{[tert-butyl(dimethyl)silyl]oxy}phenyl)-4-(5-chloro-2-fluorophenyl)-2,5-dihydro-1H-pyrrol-1yl]-1,1-dimethyl-2-oxoethylcarbamate (3-3) as a pale yellow gum. LRMS n/z (M+H) 588.9 found, 589.0 required.
Reaction SMILES: C[Si]([N:5]=[C:6]=[O:7])(C)C.[CH3:8][C:9]1([CH3:22])[C:13]([CH3:15])([CH3:14])[O:12][B:11]([C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH:21]=2)[O:10]1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:15][C:13]1([CH3:14])[C:9]([CH3:22])([CH3:8])[O:10][B:11]([C:16]2[CH2:17][CH2:18][N:19]([C:6]([NH2:5])=[O:7])[CH2:20][CH:21]=2)[O:12]1
Reactant: CC1(C)OB(C2=CCNCC2)OC1(C)C
Reactant: C[Si](C)(C)N=C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)OB(C2=CCN(C(N)=O)CC2)OC1(C)C
Reaction time: 3 h

Procedure:
Trimethylsilyl isocyanate (0.2205 mL, 1.629 mmol) was added to a room temperature solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (200.0 mg, 0.8145 mmol) and DIPEA (0.5675 mL, 3.258 mmol) in DCM (10 mL). The mixture was stirred for 3 hours, after which, it was partioned between DCM and sat. NaHCO3. The organic layer was concentrated in vacuo to afford the title compound as a tan solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(C(F)(F)F)[C:4]([OH:6])=[O:5].[OH-].[Na+].O>CO>[F:1][C:2]([F:17])([F:18])[CH:3]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)C(c1ccccc1)(C(F)(F)F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(c1ccccc1)C(F)(F)F
Temperature: 90 °C
Yield: 62 %

Procedure:
2.9 g (10 millimole) of methyl ester of α,α-bis(trifluoromethyl)phenylacetic acid, 2.5 g (63 millimole) of sodium hydroxide, 3.0 g of water and 3.0 ml of methanol were charged into an eggplant-type flask having a capacity of 100 ml, provided with a marine-type condenser and refluxed at a bath temperature of 90° C. for 6 hours. Methanol was distilled off from the reaction mixture under reduced pressure, and the residue was dissolved in 30 ml of 3N hydrochloric acid and then extracted with ether. The ether layer was dried with anhydrous MgSO4 and then concentrated under reduced pressure. The thus obtained residue was subjected to silica gel column chromatography, using n-hexane/dichloromethane as a mobile phase, whereby 1.26 g of α-(trifluoromethyl)phenylacetic acid was obtained (yield: 62%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:15]=[CH:16][CH2:17][NH:18][OH:19])=[CH:4][CH:3]=1.C[Si]([N:24]=[C:25]=[O:26])(C)C.[NH4+].[Cl-]>O1CCOCC1>[OH:19][N:18]([CH2:17][CH:16]=[CH:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[S:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:25]([NH2:24])=[O:26]
Reactant: ONCC=Cc1ccccc1Sc1ccc(F)cc1
Reactant: C[Si](C)(C)N=C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: NC(=O)N(O)CC=Cc1ccccc1Sc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-[3-[2-(4-fluorophenylthio)phenyl]prop-2-enyl]hydroxylamine (1.30 g; 4.7 mmol) in 24 ml of dry dioxane was added trimethylsilylisocyanate dropwise and the reaction mixture stirred at room temperature overnight. The mixture was poured into saturated NH4Cl and extracted twice with diethyl ether. The organics were combined, washed with 1N HCl and twice with water, and then brine, and dried over MgSO4. The solids were recrystallized from ethyl acetate and washed with cold diethyl ether to afford 0.76 g of the subtitle compound mp 124°-125° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:15]=[CH:14][C:9]([C:10](OC)=[O:11])=[CH:8][CH:7]=2)=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C>C1COCC1>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:15]=[CH:14][C:9]([CH2:10][OH:11])=[CH:8][CH:7]=2)=[CH:2]1
Reactant: COC(=O)c1ccc(-c2ccsc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCc1ccc(-c2ccsc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl (4-thien-3-yl)benzoate (552 g, 1.60 mmol) in THF (5 mL) at 0° C. was added 1.0 M lithium aluminum hydride in diethyl ether (1.60 mL, 1.60 mmol) over 10 minutes. The reaction was allowed to stir at ambient temperature for 3 hours, cooled to 0° C., and quenched by dropwise addition of water (0.10 mL), 4 N aq. NaOH (0.10 mL), and water (0.30 mL). The reaction was filtered through a pad of Celite and the filtrate evaporated in vacuo. The title compound was obtained as an oil and was used without furthur purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:42][O:43][C:44]1[C:45]2[N:58]=[C:57]([NH2:59])[S:56][C:46]=2[C:47]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[N:48][CH:49]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:59][C:57]1[S:56][C:46]2[C:47]([N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)=[N:48][CH:49]=[C:44]([O:43][CH3:42])[C:45]=2[N:58]=1)=[O:7]
Reactant: O=C(O)c1cccc(F)c1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)c3cccc(F)c3)nc12

Procedure:
From 3-fluorobenzoic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 389 (M+H+, 100).
Reaction SMILES: Br[C:2]1[C:3](=[O:28])[NH:4][C:5]2[CH:6]=[C:7]([C:21]3[C:22]([CH3:27])=[N:23][O:24][C:25]=3[CH3:26])[CH:8]=[C:9]([S:12]([NH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)(=[O:14])=[O:13])[C:10]=2[CH:11]=1.[CH3:29][N:30](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:29]([C:2]1[C:3](=[O:28])[NH:4][C:5]2[CH:6]=[C:7]([C:21]3[C:22]([CH3:27])=[N:23][O:24][C:25]=3[CH3:26])[CH:8]=[C:9]([S:12]([NH:15][CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)(=[O:14])=[O:13])[C:10]=2[CH:11]=1)#[N:30]
Reactant: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2cc(Br)c(=O)[nH]c2c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2cc(C#N)c(=O)[nH]c2c1
Temperature: 135 °C

Procedure:
A mixture of 3-bromo-N-cyclopentyl-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydroquinoline-5-sulfonamide (16 mg, 0.034 mmol), zinc cyanide (20 mg, 5 equiv), Pd(PPh3)4 (4 mg, 10 mol %) and DMF was heated at 135° C. for 2 hours. The reaction mixture was purified by preparative HPLC to give 3-cyano-N-cyclopentyl-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydroquinoline-5-sulfonamide.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.[O-][Cl:11].[Na+]>C(O)(=O)C>[Cl:11][C:7]1[C:3]([C:2]([F:9])([F:8])[F:1])=[N:4][NH:5][CH:6]=1
Reactant: [O-]Cl
Reactant: FC(F)(F)c1cc[nH]n1
Agent: [Na+]
Solvent: CC(=O)O
Product: FC(F)(F)c1n[nH]cc1Cl

Procedure:
Following protocol K, 3-trifluoromethylpyrazole was treated with glacial acetic acid and NaOCl, yielding title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.[N+:25]([C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][CH2:37][CH:36](C(O)=O)[CH2:35]2)=[CH:30][CH:29]=1)([O-:27])=[O:26]>O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([CH:37]2[CH2:36][CH2:35][N:34]([C:31]3[CH:30]=[CH:29][C:28]([N+:25]([O-:27])=[O:26])=[CH:33][CH:32]=3)[CH2:39][CH2:38]2)=[O:9])[CH2:4][CH2:3]1.[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)[CH2:11]2)=[O:9])[CH2:6][CH2:7]1
Reactant: O=C(O)C1CCCN(c2ccc([N+](=O)[O-])cc2)C1
Agent: CN1CCN(C(=O)C2CCCN(c3ccc([N+](=O)[O-])cc3)C2)CC1
Solvent: O
Product: CN1CCN(C(=O)C2CCN(c3ccc([N+](=O)[O-])cc3)CC2)CC1

Procedure:
(4-Methyl-piperazin-1-yl)-[1-(4-nitro-phenyl)-piperidin-4-yl]-methanone was prepared in a similar manner as (4-Methyl-piperazin-1-yl)-[1-(4-nitro-phenyl)-piperidin-3-yl]-methanone of Example 443a after substituting 1-(4-Nitro-phenyl)-piperidine-4-carboxylic acid for 1-(4-Nitro-phenyl)-piperidine-3-carboxylic acid. (4-Methyl-piperazin-1-yl)-[1-(4-nitro-phenyl)-piperidin-3-yl]-methanone was isolated as a yellow solid from water (570 mg, 86%). LC: 100%; LC/MS (E/I+) 333.13 (M+H).
Reaction SMILES: Cl.[N:2]1[N:3]([CH2:7][C:8]([OH:10])=O)[N:4]=[CH:5][CH:6]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:38]=[CH:39][CH:40]=1)[CH2:15][C@H:16]1[CH2:20][NH:19][C@H:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)=[O:22])[CH2:17]1>>[N:4]1[N:3]([CH2:7][C:8]([N:19]2[CH2:20][C@H:16]([CH2:15][C:14]3[CH:38]=[CH:39][CH:40]=[C:12]([F:11])[CH:13]=3)[CH2:17][C@H:18]2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)=[CH:26][CH:25]=2)=[O:22])=[O:10])[N:2]=[CH:6][CH:5]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2cccc(F)c2)CN1
Reactant: O=C(O)Cn1nccn1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2cccc(F)c2)CN1C(=O)Cn1nccn1
Yield: 39 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2H-1,2,3-triazol-2-yl)acetic acid hydrochloride and (2S,4R)-4-(3-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 49, (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(3-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (74 mg, 39%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.96 (s, 1H), 7.79 (s, 2H), 7.57-7.51 (m, 2H), 7.38-7.29 (m, 1H), 7.22-6.90 (m, 10H), 5.56-5.41 (m, 2H), 4.52-4.54 (m, 1H), 3.84-3.77 (m, 1H), 2.79-2.63 (m, 3H), 2.01-1.87 (m, 2H). MS (EI) for C28H25F2N5O3. found 517.9 (MH+).
Reaction SMILES: Cl[C:2]([C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([O:11][C:12](=[O:14])[CH3:13])=[C:6]([CH3:15])[CH:5]=1)=[O:3].[NH2:16][C:17]1[C:22]([C:23](O)=[O:24])=[CH:21][N:20]=[CH:19][CH:18]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:10][C:8]1[CH:9]=[C:4]([C:2]2[O:3][C:23](=[O:24])[C:22]3[CH:21]=[N:20][CH:19]=[CH:18][C:17]=3[N:16]=2)[CH:5]=[C:6]([CH3:15])[C:7]=1[O:11][C:12](=[O:14])[CH3:13]
Reactant: Nc1ccncc1C(=O)O
Reactant: CC(=O)Oc1c(C)cc(C(=O)Cl)cc1C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C)cc(-c2nc3ccncc3c(=O)o2)cc1C
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a solution of acetic acid 4-chlorocarbonyl-2,6-dimethylphenyl ester (2.32 g, 10.0 mmol) in anhydrous CH2Cl2 (30 mL) were added 4-amino-nicotinic acid (4) (1.10 g, 8.00 mmol) and pyridine (2.37 g, 30.0 mmol). The reaction mixture was stirred at room temperature under nitrogen for 40 hours. Solvent was evaporated. The residue was diluted with methanol (20 mL). The solid separated was filtered, washed with methanol (2×10 mL) and dried under vacuum to give acetic acid 2,6-dimethyl-4-(4-oxo-4H-pyrido[4,3-d][1,3]oxazin-2-yl)-phenyl ester (6) as yellow solid. Yield: 1.99 g (64%).
Reaction SMILES: [C:1]([CH:4]([S:28]([CH3:30])=[O:29])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:26][CH3:27])=[C:10]([CH:25]=1)[C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[O:12])(=[O:3])[NH2:2].C1C=C(Cl)C=C(C(OO)=[O:39])C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([CH:4]([S:28]([CH3:30])(=[O:39])=[O:29])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:26][CH3:27])=[C:10]([CH:25]=1)[C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=1)=[O:12])(=[O:3])[NH2:2]
Reactant: COc1ccc(CC(C(N)=O)S(C)=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CC(C(N)=O)S(C)(=O)=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Reaction time: 3 h
Yield: 70.8 %

Procedure:
To 274 mg of 5-[2-carbamoyl-2-(methylsulfinyl)ethyl]-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide were added 100 ml of methylene chloride and 155 mg of mCPBA, and the mixture was stirred for 3 hours. Saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the insolubles were filtered off. The organic layer was washed with saturated aqueous solution of sodium bicarbonate and saturated brine in sequence and dried over anhydrous sodium sulfate. Solvent was distilled off under reduced pressure, and the residue obtained was purified by means of column chromatography (silica gel, methylene chloride:methanol=50:1 to 20:1) to obtain 201 mg of aimed product as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:9][C:10]([OH:14])([C:12]#[CH:13])[CH3:11].C(N(CC)CC)C>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:13]#[C:12][C:10]([CH3:11])([OH:14])[CH3:9])=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(O)C#Cc1ccc(Cl)nn1
Temperature: 80 °C

Procedure:
To a solution of 3,6-dichloropyridazine (250 mg, 1.68 mmol) and 2-methylbut-3-yn-2-ol (282 mg, 3.36 mmol) in DMF (4 mL) were added CuI (64 mg, 0.33 mmol), triethylamine (0.47 mL, 3.36 mmol), and palladium tetrakis triphenylphosphine (194, 0.168 mmol). The solution was degassed and heated to 80° C. overnight. The residue was worked up with EtOAc and water, dried with MgSO4, filtered, and concentrated. Column chromatography on silica gel 100% Hex to 100% EtOAc provided the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10]([CH3:12])([CH3:11])[S:9][CH2:8][CH2:7][N:6]1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:4].[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[O:29][CH2:30][CH2:31][C:32]#[C:33][CH2:34]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(OCC)(=O)C>[CH3:11][C:10]1([CH3:12])[S:9][CH2:8][CH2:7][N:6]([S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:34][C:33]#[C:32][CH2:31][CH2:30][O:29][CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][O:23]3)=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH:5]1[C:3]([O:2][CH3:1])=[O:4]
Reactant: OCC#CCCOC1CCCCO1
Reactant: COC(=O)C1N(S(=O)(=O)c2ccc(O)cc2)CCSC1(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C1N(S(=O)(=O)c2ccc(OCC#CCCOC3CCCCO3)cc2)CCSC1(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 62 %

Procedure:
To a solution of 3.31 g (9.6 mmol) of of 4-(4-hydroxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid methyl ester and 2.12 g (11.5nmmol) of 5-(tetrahydro-2H-pyran-2-yloxy)-2-pentyn-1-ol in 15 mL of THF was added 3.0 g (11.5 mmol) of triphenylphosphine, followed by dropwise addition of 1.8 mL (11.5 mmol) of diethyl azodicarboxylate. The resulting solution was stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate:hexanes (1:9) to provide 3.03 g (62%) of methyl 2,2-dimethyl-4-[(4-{[5-(tetrahydro-2H-pyran-2-yloxy)-2-pentynyl]oxy}phenyl)sulfonyl]-3-thiomorpholine carboxylate as a colorless oil. Electrospray Mass Spec: 534.4 (M+Na)+
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]=[CH:16][CH:17]=[CH:18][C:11]=2[NH:10][C:9]1=[O:19])([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][C:23]([NH:25][C:26]1[CH:31]=[C:30]([Cl:32])[C:29]([O:33][CH3:34])=[CH:28][C:27]=1[O:35][CH3:36])=[O:24].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>O>[C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]=[CH:16][CH:17]=[CH:18][C:11]=2[N:10]([CH2:22][C:23](=[O:24])[NH:25][C:26]2[CH:31]=[C:30]([Cl:32])[C:29]([O:33][CH3:34])=[CH:28][C:27]=2[O:35][CH3:36])[C:9]1=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2cccnc2c1=O
Reactant: COc1cc(OC)c(NC(=O)CBr)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)OC(C)(C)C)c(=O)c3ncccc32)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 25 ml round bottomed flask charged with (2,4-Dioxo-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl)-acetic acid t-butyl ester (14.9 mg, 0.054 mmol), 2-Bromo-N-(5-chloro-2,4-dimethoxy-phenyl)-acetamide (26.5 mg, 0.06 mmol), and Cs2CO3 (50.9 mg, 0.11 mmol) is treated with DMF (3 ml) and the solution stirred at RT. After 2 hours, the reaction mixture is treated with water and stirred for 10 minutes. The product is extracted into EtOAc and washed with water (3×10 ml). The organic portions are dried (MgSO4), filtered and concentrated to give the title compound, [M+H]+ 505