Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C@@H:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[CH2:28][C:29]1[N:33]([CH3:34])[C:32]2[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=2[N:30]=1.CNC1C=CC=CC=1N.ClCC(O)=O.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[CH3:34][N:33]1[C:32]2[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=2[N:30]=[C:29]1[CH2:28][N:11]([CH:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26]
Reactant: O=C1c2ccccc2C(=O)N1CCCCN[C@H]1CCCc2cccnc21
Reactant: Cn1c(CCl)nc2ccccc21
Agent: CNc1ccccc1N
Agent: O=C(O)CCl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cn1c(CN(CCCCN2C(=O)c3ccccc3C2=O)C2CCCc3cccnc32)nc2ccccc21
Temperature: 50 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
To a solution of (s)-2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione (3.89 g, 11.1 mmol) in acetonitrile (111 ml) was added 2-chloromethyl-1-methyl-1H-benzoimidazole (prepared by reaction of N-methyl-ortho-phenylenediamine with chloroacetic acid according to literature procedure Phillips, M. A. J. Chem. Soc. 1928, 2393; Goker, H.; Kus, C. Arch. Pharm. (Weinheim) 1995, 328, 425-430) (2.42 g, 13.4 mmol), diisopropylethylamine (1.93 ml, 11.1 ml), and potassium iodide (0.18 g, 1.11 ml). The mixture was stirred for 16 hours at 50° C. The mixture was concentrated, redissolved in methylene chloride (200 ml) and diluted with saturated NaCl (400 ml). The reaction was extracted with methylene chloride (3×300 ml) and the combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to afford a dark red oil. Purification via column chromatography on silica gel (CH2Cl2:MeOH:NH4OH, 95:4:1, v/v/v) afforded the product as a light red foam (5.12 g, 77%).
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[ClH:11].[CH2:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][N:13]1[C:22]1[N:23]=[CH:24][CH:25]=[C:26]2[C:30]([CH3:31])=[C:29]([CH3:32])[NH:28][C:27]=12>O1CCCC1>[ClH:11].[CH2:3]([N:28]1[C:27]2=[C:22]([N:13]3[CH2:14][CH2:15][C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:12]3)[N:23]=[CH:24][CH:25]=[C:26]2[C:30]([CH3:31])=[C:29]1[CH3:32])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCc1ccccc1
Reactant: Cc1[nH]c2c(N3CCc4ccccc4C3)nccc2c1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(C)n(Cc2ccccc2)c2c(N3CCc4ccccc4C3)nccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 17.6 %

Procedure:
Sodium hydride (60%; 40 mg, 0.999 mmol) and benzyl bromide (0.475 ml, 0.399 mmol) were added at 0° C. to a solution of 7-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine hydrochloride (92,3 mg, 0.333 mmol) prepared in Example 468 in anhydrous tetrahydrofuran (10 ml). The reaction mixture was stirred for 12 hours at room temperature and ice was added thereto. The reaction mixture was extracted with ethyl acetate. The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/5, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 23.7 mg of the titled compound as a white solid.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=O)[CH3:6].[C:9]([O-])(=O)[CH3:10].[C:13]([O-])(=O)C.[Pb+4].[CH:18]1[CH:23]=[CH:22]C=[CH:20][CH:19]=1>CO>[CH3:13][O:8][C:5]1[CH:6]=[C:23]([CH3:22])[CH:18]=[CH:19][C:20]=1[CH2:2][C:1]([O:4][CH2:9][CH3:10])=[O:3]
Reactant: CC(=O)[O-]
Reactant: c1ccccc1
Agent: [Pb+4]
Solvent: CO
Product: CCOC(=O)Cc1ccc(C)cc1OC

Procedure:
To a suspension of lead tetraacetate (16.8 g) in benzene (80 ml) was added a solution of 2-methoxy-4-methylacetophenone (5.35 g) in methanol (8.25 ml), and then boron trifluoride/diethyl ether complex (16.5 ml) was added dropwise to the mixture with stirring under ice cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was quenched with cold water, and extracted with benzene, and the organic layer was washed successively with saturated aqueous sodium hydrogencarbonate, water, and saturated brine, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane/ethyl acetate=15/1) to give ethyl 2-methoxy-4-methylphenylacetate (3.22 g).
Reaction SMILES: [OH:1][P:2]([O-:5])([O-:4])=[O:3].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.CC(OC([NH:33][C@@H:34]1[C:37](=[O:38])[O:36][CH2:35]1)=O)(C)C.FC(F)(F)C(O)=O.N[C@H]1COC1=O>CN(C=O)C.O>[P:2]([O:5][CH2:35][C@@H:34]([C:37]([OH:38])=[O:36])[NH2:33])([OH:4])([OH:1])=[O:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1COC1=O
Reactant: O=P([O-])([O-])O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: N[C@H]1COC1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](COP(=O)(O)O)C(=O)O
Reaction time: 72 h
Yield: 87.2 %

Procedure:
K2HPO4 (0.446 g, 3.28 mmol, dried 4 h at 130° C.) and 18-crown-6 ether (0.867 g, 3.28 mmol) were stirred 16 h in anhydrous DMF (10 mL). BOC-L-serine β-lactone (169 mg, 0.902 mmol) was deprotected to (S)-3-amino-2-oxetanone trifluoroacetic acid salt and added as a solution in DMF (3 mL). The mixture was stirred 3 days, diluted with H2O (to 50 mL), and applied to a column of AG1-X8 (trademark) (80 mL, 3 cm dia., OH- form). Elution (2 mL/min) with a linear gradient (0 to 3M over 10 L) of formic acid afforded O-phospho-L-serine 145.6 mg) in 87% yield after lyophilization: mp 170°-171° C. (dec) (lit. mp 175°-176° C. (dec)); [α]D 25 +7.2° (c 1.0, H2O) (lit. [α]D 25 +7.2° (c 1.0, H2O)); IR (KBr disk) 3420 (w, br), 3180 (w), 2700 (w), 2400-2260 (w), 1620 (w), 1560 (m), 1260 (m), 1089 (s), 1045 (s), 1000 (s), 970 (s), 740 (m), 810 (m) cm-1 ; 1H NMR (300 MHz, D2O+DC1)δ 4.37-4.27 (m, 2H, CH-CHH), 4.26-4.16 (m, 1H, CHH)31 ; 31p NMR (161.96 MHz, D2O+DC1) -0.45 (br (s). Anal. Calc. for C3H3NO6P: C, 19.47; H, 4.35; N, 7.57. Found: C, 19.27; H, 4.29; N, 7.82; POSFAB-MS (glycerol/HC1 ) 186 (MH+), 371 (M2H+); Rf 0.43 (System A).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:11][C:12]1[C:13]([O:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:14][CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:25]1[CH2:24][CH2:23][CH:22]([O:21][C:13]2[C:12]([CH3:11])=[CH:17][C:16]([N+:18]([O-:20])=[O:19])=[CH:15][N:14]=2)[CH2:27][CH2:26]1)=[O:5]
Reactant: Cc1cc([N+](=O)[O-])cnc1OC1CCNCC1
Reactant: O=C(Cl)c1ccccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc([N+](=O)[O-])cnc1OC1CCN(C(=O)c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add 2-fluoro-benzoyl chloride (1.74 g, 11.0 mmol) dropwise to a solution of 3-methyl-5-nitro-2-(piperidin-4-yloxy)-pyridine in dichloromethane (50 mL) and triethylamine (1.21 g, 12 mmol) and stir under N2 at room temperature for 2 hours. Wash the reaction mixture with distilled water (3×20 mL) followed by saturated aq. sodium chloride solution (1×20 mL). Dry the organic phase over sodium sulfate and concentrate to give (2-fluoro-phenyl)-[4-(3-methyl-5-nitro-pyridin-2-yloxy)-piperidin-1-yl]-methanone as a yellow solid.
Reaction SMILES: [CH:1]1(/[C:6](/[N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)=[CH:7]\[C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.O=O.[H][H]>>[CH:1]1([CH:6]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:31])[CH3:33])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)/C=C(\C1CCCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reactant: [H][H]
Agent: O=O
Product: COC(=O)CC(C1CCCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C

Procedure:
General screening procedure for asymmetric hydrogenation using the substrate, (E)-methyl 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)acrylate (21), to afford optically enriched product, methyl 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanoate ((R)-22 or (S)-22): A 300 mL-volume autoclave with glass vial (20 mL) was charged with the substrate (21), the catalyst (metal, ligand, and catalyst precursor), and oxygen-free solvent (4-6 mL) under nitrogen. This autoclave was charged with hydrogen gas to the desired pressure and stirred at room temperature or heated with oil bath. After hydrogen gas was released, the reaction mixture was concentrated under reduced pressure. The residue was purified by eluting through a silica gel pad using a mixture of ethyl acetate and methanol (v/v=9/1) to afford product, methyl 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanoate ((R)-22 or (S)-22), for chemical conversion (HPLC and chiral HPLC), LC/MS and NMR spectroscopy and enantiomeric excess (% ee by chiral HPLC) determination.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([SH:28])[N:22]=1>>[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([S:28][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)[N:22]=1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Reactant: Cc1cc(C)nc(S)n1
Product: Cc1cc(C)nc(SCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)n1

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4,6-dimethyl-2-mercapto-pyrimidine.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:14]2[NH:13][C:12](=[O:15])[N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C)C=O>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][N:13]1[C:14]2[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][CH:8]=[CH:9][C:10]=2[N:11]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:12]1=[O:15])[CH3:37]
Reactant: CCC(CC)c1cccc2c1[nH]c(=O)n2C(=O)OC(C)(C)C
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1c(=O)n(C(=O)OC(C)(C)C)c2cccc(C(CC)CC)c21
Temperature: 85 °C
Reaction time: 8 h
Yield: 135.2 %

Procedure:
To a solution of tert-butyl 4-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate (Reference Example 7; 10.37 g, 34.11 mmol) in N,N-dimethylformamide (100 mL) was added potassium carbonate (5.18 g, 37.52 mmol) and ethyl 4-bromobutyrate (8.55 g, 37.52 mmol), and the mixture was stirred at 80-90° C. overnight. The reaction solution was concentrated to dryness and diluted with water (150 mL). The resulting mixture was extracted with ethyl acetate (100 mL×2). The combined extracts were washed with water (80 mL×2), brine (100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give 19.3 g of crude tert-butyl 3-(4-ethoxy-4-oxobutyl)-4-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate, which was used for the next step without further purification.
Reaction SMILES: C1C[O:4]CC1.[CH2:6]([C:9]1[C:10]([Cl:19])=[N:11][C:12]2[N:13]([N:16]=[CH:17][CH:18]=2)[C:14]=1[Cl:15])[CH:7]=C.I([O-])(=O)(=O)=O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>[Os](=O)(=O)(=O)=O.O>[Cl:19][C:10]1[C:9]([CH2:6][CH:7]=[O:4])=[C:14]([Cl:15])[N:13]2[N:16]=[CH:17][CH:18]=[C:12]2[N:11]=1
Reactant: C1CCOC1
Reactant: C=CCc1c(Cl)nc2ccnn2c1Cl
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=CCc1c(Cl)nc2ccnn2c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixed solution of THF (24 mL) and water (6 mL) containing 6-allyl-5,7-dichloropyrazolo[1,5-a]pyrimidine (1.82 g, 7.89 mmol), sodium periodate (5.12 g, 23.9 mmol) and osmium tetraoxide (2.5w/v % in tert-butanol, 3 mL, 0.23 mmol) were added with ice-cooling. After this mixture was stirred at room temperature for 3 hr, aqueous sodium sulfite was added here. The resultant mixture was extracted with ethyl acetate and the organic layer was washed with aqueous sodium hydrogen carbonate and then brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off to obtain 5,7-dichloro-6-(2-oxoethyl)pyrazolo[1,5-a]pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[N:7][C:6]=2[CH:13]=1.C(Cl)(=O)C(Cl)=O.[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[C:25]=1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:20][C:21]3[S:22][CH:23]=[C:24]([C:33]4[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=4)[C:25]=3[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:12])=[N:7][C:6]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)c1c(-c2ccc(Cl)cc2)csc1N
Reactant: O=C(O)c1nc2cc(Br)ccc2o1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)c1c(-c2ccc(Cl)cc2)csc1NC(=O)c1nc2cc(Br)ccc2o1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a suspension of 5-bromobenzo[d]oxazole-2-carboxylic acid (2A, 60 mg, 0.25 mmol) in DCM (5 ml) at room temperature was added oxalyl chloride (0.2 ml) and catalytic amount of DMF. The mixture was stirred at room temperature for 17 hours. The solvent was removed under vacuum to dryness. The residue was dissolved in DCM (5 ml) followed be addition of tert-butyl 2-amino-4-(4-chlorophenyl)thiophene-3-carboxylate (1A, 62 mg, 0.2 mmol) and DIEA (0.3 ml). The mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with DCM (5 ml) washed with 1N aqueous HCl (3×5 ml), water (1×5 ml), 1N aqueous NaOH (3×5 ml) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under vacuum to give analytically pure 3A which was used in the next step without further purification. LC-MS: calcd. for C23H18BrClN2O4S: 532 (M+1); found: 532.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11](O)=[O:12])[CH:6]=[CH:7][CH:8]=1.S(=O)(=O)(O)O>CO>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH2:11][OH:12])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)C=Cc1cccc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: CO
Product: OCC=Cc1cccc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 5.5 h
Yield: 71.3 %

Procedure:
3-(3-Trifluoromethylphenyl)acrylic acid (3.0 g) was dissolved in methanol (30 ml), concentrated sulfuric acid (0.5 ml) was added, and the mixture was stirred at 100° C. for 5.5 hr. The reaction mixture was concentrated, and the residue was washed with water. The obtained white powder was dissolved in tetrahydrofuran (40 ml), 1M diisobutylaluminum hydride/toluene solution (26 ml) was added dropwise at −78° C., and the mixture was stirred as it was at −78° C. for 2 hr. Saturated Rochelle salt water, water and ethyl acetate were added to the reaction mixture, and the mixture was stirred at room temperature, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give the object product (2.0 g) as a colorless oil.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][O:16][CH3:17])[CH:9]=1.[CH3:18][O:19][N:20]([CH3:33])[C:21](=[O:32])[C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1Br.C(Cl)(Cl)Cl>C1COCC1.[Cl-].[Zn+2].[Cl-].[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:18][O:19][N:20]([CH3:33])[C:21]([C:22]1[C:23]([C:9]2[C:8]([O:7][CH3:6])=[CH:13][CH:12]=[CH:11][C:10]=2[O:14][CH2:15][O:16][CH3:17])=[CH:24][CH:25]=[C:26]([N+:28]([O-:30])=[O:29])[CH:27]=1)=[O:32]
Reactant: COCOc1cccc(OC)c1
Reactant: CON(C)C(=O)c1cc([N+](=O)[O-])ccc1Br
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COCOc1cccc(OC)c1-c1ccc([N+](=O)[O-])cc1C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
Butyllithium (8.28 ml. of 2.5M in hexane, 20.69 mmole) was added to a solution of 1-methoxy-3 methoxymethoxy benzene (3.62 g., 21.55 mmole, (T. Kaufman, R. Srivastava, R. Sindelar, J. Med. Chem. 1995, 38, 1437-1445) in. THF (15 mL) at −30° C. The solution was stirred at ambient temperature for 1 hour, cooled to at 0° C. and anhydrous zinc chloride beads (3.5 g, 25.67 mmole) added. The mixture was stirred for 2 hours at 25°. Then a solution of N-methoxy-N-methyl-2-bromo-5-nitrobenzamide (5.00 g, 17.24 mmole) dissolved in THF (20 mL) was added. Bis (triphenylphosphine) palladium dichloride (600 mg.) was added and the solution was stirred at 65° C. for 15 hours. After cooling, chloroform was added and the solution stirred with aqueous KHCO3. The precipitated zinc salts were filtered, the water layer removed and the organic layer dried (Na2SO4), filtered concentrated under reduced pressure and the residuepurified on silica gel eluting with 8% ethyl acetate in CH2Cl2 to provide the titled compound (5.68 g, 88% yield).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[CH3:15][O:16][CH2:17][CH2:18][NH2:19].N1C=CC=CC=1>ClCCl>[CH3:15][O:16][CH2:17][CH2:18][NH:19][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3]
Reactant: COCCN
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCCNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Yield: 33 %

Procedure:
A solution of 5-chlorosulfonyl-2-oxindole (5 g), 2-methoxyethylamine (2.25 mL) and pyridine (7 mL) in dichloromethane (30 mL) was stirred at room temperature for 4 hours. The reaction was concentrated and dichloromethane (15 mL) was added. The precipitate was filtered, washed with dichloromethane and dried to give 1.9 g (33%) of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid (2-methoxy-ethyl)-amide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][OH:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][O:12][S:20]([CH3:19])(=[O:22])=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1cccc(CCO)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCc1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(3-nitro-phenyl)-ethanol (1 eq) in dichloromethane at 0° C. was added pyridine (4 eq) and methanesulfonyl chloride (2 eq). After stirring at 0° C. for one hour, then room temperature overnight, the mixture was diluted with dichloromethane and washed once with water, once with 1 N HCl, dried with anhydrous sodium sulfate, filtered and concentrated. The product was clean enough to be taken on to the next step without purification. MH+=246.0.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]([CH3:27])[CH2:22][C:23](=[O:26])[NH:24][N:25]=2)=[CH:16][CH:15]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]([CH3:27])[CH2:22][C:23](=[O:26])[NH:24][N:25]=3)=[CH:16][CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)COc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.1 g of 4-dimethylaminopyridine and 5.1 g (0.025 mole) of 4-chlorophenoxyacetyl chloride are added to 5.1 g (0.025 mole) of 6-(4-amino-phenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone in 20 ml of pyridine. The mixture is stirred at room temperature for 5 hours and concentrated, water is added and the mixture is extracted with methylene chloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:16][O:17][CH3:18])([C:13]([OH:15])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClCCl.C(Cl)(=O)C(Cl)=O.[Cl-].[Cl-].[F:30][C:31]([F:43])([F:42])[C:32]1[CH:33]=[N:34][C:35]2[CH2:36][CH2:37][NH:38][CH2:39][C:40]=2[CH:41]=1.C(N(CC)CC)C>ClCCl.CN(C=O)C>[CH3:18][O:17][CH2:16][C:10]1([C:13]([N:38]2[CH2:37][CH2:36][C:35]3[N:34]=[CH:33][C:32]([C:31]([F:30])([F:42])[F:43])=[CH:41][C:40]=3[CH2:39]2)=[O:15])[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1
Reactant: COCC1(C(=O)O)CCN(C(=O)OC(C)(C)C)C1
Reactant: FC(F)(F)c1cnc2c(c1)CNCC2
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC1(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound was prepared according to general procedure C described in connection with Scheme 2. To 1-(tert-butoxycarbonyl)-3-(methoxymethyl)pyrrolidine-3-carboxylic acid (3 g, 11.6 mmol) in dichloromethane (30 mL) was added 2M oxalyl chloride dichloromethane solution (17 mL, 34 mmole) and a few drops of DMF at room temperature. The mixture was stirred at RT for 2 hours and concentrated to dryness under the reduced pressure. 3-(Trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine dichloride (3.19 g, 11.6 mmole) in 30 dichloromethane and triethyl amine (3.1 g, 30 mmole) was added to the above residue at 0° C. The mixture was stirred at 0° C. for 1 h, diluted with dichloromethane (100 mL) and washed with sodium bicarbonate solution (2×50 mL) and water (3×100 mL), dried over sodium sulfate and purified by silica chromatography using 2.5% MeOH in CH2Cl2 as eluent to give product (1.7 g, 33% yield). 1H NMR (400 MHz, CD3OD): δ 8.70 (s, 1H), 7.68 (m, 1H), 4.80 (s, 2H), 4.10-2.95 (m, 13H), 2.40-2.15 (m, 2H), 1.48 (s, 9H); MS (ESI) m/z: Calculated for C21H28F3N3O4: 443.2. found: 466 (M+Na)+.
Reaction SMILES: [CH2:1]([O:7][C:8](=[O:19])[CH2:9][CH2:10][CH:11]([OH:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH:3]=[CH:4][CH2:5][CH3:6].N1C=CC=CC=1.CN(C1C=CC=CN=1)C.[C:35](Cl)(=[O:49])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]>O1CCCC1.O>[CH2:1]([O:7][C:8]([CH2:9][CH2:10][CH:11]([O:18][C:35](=[O:49])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:19])[CH2:2][CH:3]=[CH:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCCCCCC(=O)Cl
Reactant: CCC=CCCOC(=O)CCC(O)CCCCCC
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: CCC=CCCOC(=O)CCC(CCCCCC)OC(=O)CCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.5 %

Procedure:
To a mixture of 1.10 g of 4-hydroxy-decanoic acid hex-3-enyl ester, 0.64 g pyridine and 0.1 g dimethylaminopyridine in 5 ml tetrahydrofuran was slowly added a solution of 1.10 g myristoyl chloride in 5 ml tetrahydrofuran. The mixture was stirred for 16 hours at room temperature. Water was then added and the mixture extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, 2N hydrochloric acid, water, dried over magnesium sulfate and evaporated to dryness. The residue was chromatographed on silica gel to give 1.81 g of a colorless liquid.