Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.[C:6]1([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21](Cl)=[N:22][OH:23])=[CH:16][CH:15]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:25]([C:27]1[C:28]([NH2:33])=[N:29][CH:30]=[CH:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>O>[C:6]1([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]3[CH:26]=[C:25]([C:27]4[C:28]([NH2:33])=[N:29][CH:30]=[CH:31][CH:32]=4)[O:23][N:22]=3)=[CH:16][CH:15]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: ON=C(Cl)Cc1ccc(CNc2ccccc2)cc1
Reactant: C#Cc1cccnc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Nc1ncccc1-c1cc(Cc2ccc(CNc3ccccc3)cc2)no1
Temperature: 25 °C
Reaction time: 7 h
Yield: 8.9 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-phenylaminomethyl-phenyl)-acetohydroximoyl chloride (150 mg, 0.546 mmol) described in Manufacturing Example 73-1-6 and 3ethynyl-pyridin-2-ylamine (41 mg, 0.348 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (104 μL, 0.748 mmol), which was stirred for 7 hours at room temperature. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1-1:2) to obtain the title compound (11 mg, 6%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[C:18]1[O:19][C:20]2[CH:26]=[CH:25][C:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:23][C:21]=2[CH:22]=1)[CH2:5][N:6]1[CH2:9][CH:8]([C:10]([O:12]CC)=[O:11])[CH2:7]1.[Li+].[OH-].Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][N:6]2[CH2:7][CH:8]([C:10]([OH:12])=[O:11])[CH2:9]2)[CH:15]=[CH:16][C:17]=1[C:18]1[O:19][C:20]2[CH:26]=[CH:25][C:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:23][C:21]=2[CH:22]=1.[CH2:5]([NH2+:6][CH2:7][CH3:8])[CH3:4]
Reactant: CCOC(=O)C1CN(Cc2ccc(-c3cc4cc(Cc5ccccn5)ccc4o3)c(F)c2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC[NH2+]CC
Product: O=C(O)C1CN(Cc2ccc(-c3cc4cc(Cc5ccccn5)ccc4o3)c(F)c2)C1
Temperature: 24 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 1-(3-fluoro-4-(5-(pyridin-2-ylmethyl)benzofuran-2-yl)benzyl)azetidine-3-carboxylate (31 mg, 70 μmol) in THF (2 mL) was treated with 1M LiOH in H2O (0.4 mL) and stirred at 24° C. for 3 h, neutralized with 0.1M aqueous HCl, and evaporated. Purification by SFC (supercritical flash chromatography) resulted in title compound as its diethylammonium salt [hS1P1 EC50=31 nM]. 1H NMR (400 MHz, CD3OD) δ ppm 8.48 (d, J=0.8 Hz, 1H), 8.02 (t, J=7.9 Hz, 1H), 7.78 (t, J=5.9 Hz, 1H), 7.54 (s, 1H), 7.48 (d, J=10.0 Hz, 1H), 7.33-7.22 (m, 6H), 4.25 (s, 2H), 3.95 (s, 2H), 3.82 (t, J=8.6 Hz, 2H), 3.68 (t, J=8.5 Hz, 2H), 3.36-3.34 (m, 1H, partially overlapping with CD3OH signal), 3.05 (q, J=7.4 Hz, 2H), 1.31 (t, J=7.2 Hz, 3H). MS (ESI) m/z: Calculated: 416.2; Observed: 417.2 (M++1).
Reaction SMILES: [ClH:1].Cl.Cl.N[C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH:15]3[CH2:17][CH2:18][N:12]2[CH2:13][CH2:14]3)[CH:8]=[N:9][CH:10]=1.N(OCCC(C)C)=O.C(Cl)(Cl)[Cl:28].[CH:31]([OH:34])([CH3:33])[CH3:32]>>[ClH:28].[ClH:1].[CH:31]([O:34][C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH:15]3[CH2:17][CH2:18][N:12]2[CH2:13][CH2:14]3)[CH:8]=[N:9][CH:10]=1)([CH3:33])[CH3:32]
Reactant: Nc1cncc(C2CC3CCN2CC3)c1
Reactant: ClC(Cl)Cl
Reactant: CC(C)O
Agent: CC(C)CCON=O
Agent: Cl
Product: CC(C)Oc1cncc(C2CC3CCN2CC3)c1
Temperature: 25 °C
Yield: 55 %

Procedure:
To a stirred solution of 2-(5-amino-3-pyridyl)-1-azabicyclo[2.2.2]octane trihydrochloride (50 mg, 0.16 mmol) in dry isopropanol (5 mL) was added isoamyl nitrite (0.1 mL, 0.97 mmol) and the reaction mixture was refluxed for 2 h. When TLC analysis of the reaction mixture showed the absence of starting material, the mixture was allowed to warm to ambient temperature and then the solvent was removed under vacuum. A white solid was obtained upon the addition of dry diethyl ether. The solid was dissolved with heating in a minimum amount of chloroform, and the solution kept over night at 4° C. to induce crystallization. The solid thus obtained was filtered and dried under vacuum for 24 h to afford 2-(5-isopropoxy-3-pyridyl)-1-azabicyclo[2.2.2]octane dihydrochloride (28 mg, 55%) as colorless needles.
Reaction SMILES: [Si]([O:8][C@H:9]([CH3:42])[C@@H:10]([NH:31][C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[C:34]([Cl:40])[C:33]=1[CH3:41])[C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([O:23][Si](C(C)(C)C)(C)C)[CH:17]=2)=[N:14][N:15]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:40][C:34]1[C:33]([CH3:41])=[C:32]([NH:31][C@@H:10]([C:11]2[O:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([OH:23])[CH:17]=3)=[N:14][N:15]=2)[C@H:9]([OH:8])[CH3:42])[CH:39]=[CH:38][C:35]=1[C:36]#[N:37]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(F)c(O[Si](C)(C)C(C)(C)C)c3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(F)c(O)c3)o2)[C@@H](C)O)ccc(C#N)c1Cl
Temperature: -55 °C
Yield: 91.7 %

Procedure:
4-((1R,2R)-2-(tert-butyldimethylsilyloxy)-1-(5-(3-(tert-butyldimethylsilyloxy)-4-fluoro phenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2-chloro-3-methylbenzonitrile (1.11 g, 1.76 mmol) was dissolved in THF (40 mL) and cooled down to −55° C. under N2 atmosphere. TBAF (1.0 M solution in THF, 4.21 ml, 4.22 mmol) was added to the pre-cooled solution slowly and the temperature allowed to rise gradually. After the reaction was complete, it was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc. Purification with column chromatography gave the desired product (650 mg) Mp 106-110° C., 1H NMR(400 MHz, acetone-d6, δ in ppm): 7.63 (dd, J=3.9 Hz, 1H), 7.49 (m, 2H), 7.30 (m, 1H), 6.89 (d, J=9 Hz, 1H), 5.87 (d, J=9 Hz, 1H), 5.05 (m, 1H), 4.52 (m, 1H), 2.37 (s, 3H), 1.40 (d, J=6 Hz, 3H).
Reaction SMILES: [OH:1][C@@H:2]([C:6]1[CH:7]=[C:8]([F:25])[C:9]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[N:10][CH:11]=1)[C@@H:3]([OH:5])[CH3:4].Cl.O1CCOCC1.C(OCC)C>C(Cl)Cl>[F:25][C:8]1[CH:7]=[C:6]([C@H:2]([OH:1])[C@@H:3]([OH:5])[CH3:4])[CH:11]=[N:10][C:9]=1[N:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1
Reactant: C[C@H](O)[C@@H](O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1COCCO1
Product: C[C@H](O)[C@@H](O)c1cnc(N2CCNCC2)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
To a solution of 106 (3.0 g, 8.65 mmol) in DCM (25 mL) was added 4N HCl in dioxane (2.51 mL, 43.2 mmol). The resulting reaction mixture was stirred at a temperature of about 25° C. in a closed vessel for 16 h; a suspension formed. The suspension was stirred with diethyl ether; a solid precipitated. The precipitate was collected by filtration and washed several times with ether to provide 107 (91% yield) as a tan solid which, being >99% pure as analyzed by LC/MS, was used directly in the next step.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH:18][C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=4)[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:63][CH:64]1[CH2:69][CH2:68][N:67](C(OC(C)(C)C)=O)[CH2:66][CH2:65]1>O1CCCC1.ClCCl>[NH:67]1[CH2:68][CH2:69][CH:64]([NH:63][C:23](=[O:25])[C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:16]3[N:17]=[C:10]4[C:9]([C:5]5[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:29])[F:28])[CH:4]=5)=[CH:14][CH:13]=[CH:12][N:11]4[N:15]=3)=[CH:27][CH:26]=2)[CH2:65][CH2:66]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(O)c1ccc(Nc2nc3c(-c4cccc(C(F)(F)F)c4)cccn3n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCNCC1)c1ccc(Nc2nc3c(-c4cccc(C(F)(F)F)c4)cccn3n2)cc1
Reaction time: 16 h
Yield: 42.3 %

Procedure:
To a solution of 4-(8-(3-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid (1.0 g, 2.5 mmol, 1 equiv), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.14 g, 3.00 mmol, 1.2 equiv), N,N-diisopropylethylamine (484 mg, 3.74 mmol, 1.5 equiv) in 2:1 tetrahydrofuran/dichloromethane (50 mL) was added tert-butyl 4-amino-1-piperidinecarboxylate (0.60 g, 3.0 mmol, 1.2 equiv) at room temperature. After 16 h, the reaction mixture was filtered, and the filtrate was concentrate. The resulting residue was dissolved in 1:1 trifluoroacetic acid/tetrahydrofuran (50 mL) at room temperature. After 2 h, the reaction mixture was concentrated in vacuo. Purification by preparative HPLC provided product (508 mg, 42%). LCMS (ESI) m/z: 481.0; 1H NMR (400 MHz, DMSO-d6) δ: 10.06 (s, 1H), 8.85 (d, J=7.6 Hz, 1H), 8.60 (s, 1H), 8.38 (d, J=8.8 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.84 (br s, 2H), 7.72-7.79 (m, 3H), 7.32 (d, J=7.6 Hz, 2H), 7.15 (m, 1H), 4.02 (m, 1H), 3.27-3.32 (m, 2H), 2.95-3.05 (m, 2H), 1.87-1.94 (m, 2H), 1.41-1.48 (m, 2H).
Reaction SMILES: [CH2:1](I)[CH3:2].[Br:4][C:5]1[C:13]2[O:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][C:9]=2[CH:8]=[C:7]([F:17])[CH:6]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Br:4][C:5]1[C:13]2[O:12][C:11]([C:14]([O:16][CH2:1][CH3:2])=[O:15])=[CH:10][C:9]=2[CH:8]=[C:7]([F:17])[CH:6]=1
Reactant: CCI
Reactant: O=C(O)c1cc2cc(F)cc(Br)c2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(F)cc(Br)c2o1
Temperature: 55 °C
Yield: 90.1 %

Procedure:
Ethyl iodide (4.6 ml, 57.2 mmol) was added to a mixture of 7-bromo-5-fluoro-benzofuran-2-carboxylic acid (3.7 g, 14.3 mmol) and sodium bicarbonate (4.8 g, 57.2 mmol) in anhydrous dimethylformamide (40 mL). The mixture was heated at 55° C. for 18 h, cooled to rt, quenched with water (20 mL) and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2; hexane/DCM; 4/1) to give 3.7 g (90%) of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([NH:32][S@:33]([C:35]([CH3:38])([CH3:37])[CH3:36])=[O:34])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.CO.[Li+].[OH-]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([NH:32][S@:33]([C:35]([CH3:38])([CH3:37])[CH3:36])=[O:34])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:31]=[CH:30][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(N2CCC([C@@H](N[S@@](=O)C(C)(C)C)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)N[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-(4-((R)-(4′-chlorobiphenyl-2-yl)((S)-1,1-dimethylethylsulfinamido)methyl)piperidin-1-yl)benzoate (INTERMEDIATE 128, 0.40 g, 0.62 mmol) in THF (4.3 ml) was added MeOH (1.4 ml) and a solution of LiOH (0.09 g, 4.44 mmol) in water (1.4 ml). The reaction mixture was stirred at 40° C. overnight. The reaction mixture was cooled to rt, concentrated under reduced pressure, and the residue suspended in water. The suspension was cooled to 0° C., acidified to pH ˜2 using 1N HCl aq., filtered, and the filtercake dried in a vacuum oven to provide the title compound (0.38 g, yield: almost quantitative).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([NH:13][CH3:14])[C:6]([C:15]([OH:17])=[O:16])=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33].C(=O)([O-])O.[Na+]>C1COCC1>[CH2:35]([O:34][C:32]([N:13]([CH3:14])[N:7]1[C:6]([C:15]([OH:17])=[O:16])=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[C:8]1=[O:12])=[O:33])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CNn1c(C(=O)O)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OCc1ccccc1)n1c(C(=O)O)c(-c2ccccc2)c2cc(Cl)ccc2c1=O

Procedure:
To a solution (76 ml) of 6-chloro-2-methylamino-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (3.8 g) in THF were added triethylamine (4.0 ml) and benzyl chloroformate (3.6 ml) at 0° C. with stirring, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1-dichloromethane/methanol/acetic acid=50/10/1) to give the title compound (2.5 g) as yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:30])[C:14]([C:15]([NH:17][C:18]34[CH2:25][CH2:24][C:21]([C:26]([O:28]C)=[O:27])([CH2:22][CH2:23]3)[CH2:20][CH2:19]4)=[O:16])=[C:10]2[CH:9]=[C:8]([CH3:31])[CH:7]=1.[OH-].[Li+].C(O)=O>C1COCC1.CO>[F:36][C:32]1[CH:33]=[CH:34][CH:35]=[C:2]([F:1])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:30])[C:14]([C:15]([NH:17][C:18]34[CH2:19][CH2:20][C:21]([C:26]([OH:28])=[O:27])([CH2:22][CH2:23]3)[CH2:24][CH2:25]4)=[O:16])=[C:10]2[CH:9]=[C:8]([CH3:31])[CH:7]=1
Reactant: COC(=O)C12CCC(NC(=O)c3c(C)nn4c(OCc5c(F)cccc5F)cc(C)cc34)(CC1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: O=CO
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)NC34CCC(C(=O)O)(CC3)CC4)c2c1
Temperature: 40 °C
Reaction time: 10 h
Yield: 75 %

Procedure:
56 mg (0.113 mmol) of methyl 4-[({7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl}carbonyl)amino]bicyclo[2.2.2]octane-1-carboxylate from Example 152 were dissolved in 1.1 ml of THF/methanol (5/1), and 8.1 mg (0.339 mmol) of lithium hydroxide were added. The mixture was stirred at 40° C. for 10 h. After cooling, the mixture was acidified with 20 μl of formic acid and purified by means of preparative HPLC (RP18 column, eluent:acetonitrile/water gradient with addition of 0.05% formic acid). 41 mg of the target compound were obtained (75% of theory).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13]3)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C1C(=O)N([Cl:28])C(=O)C1>C1COCC1>[Cl:28][C:16]1[C:17]2[C:12](=[CH:11][C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)=[CH:19][CH:18]=2)[CH:13]=[CH:14][C:15]=1[OH:20]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(-c2ccc3cc(O)ccc3c2)cc1F
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc3c(Cl)c(O)ccc3c2)cc1F

Procedure:
The title compound was prepared by reacting 6-(3-fluoro-4-methoxylphenyl)-2-naphthol (1 g, 3.73 mmol) and NCS (748 mg, 5.60 mmol) in THF (35 mL) according to method A to yield 780 mg (69%) of brown solid: mp 137–139° C.; 1H NMR (DMDO-d6): δ 3.89 (3H, s), 7.26–7.33 (2H, m), 7.61 (1H, d, J=8.63 Hz), 7.71 (1H, dd, J=13.08 Hz, J=2.16 Hz), 7.84 (1H, d, J=8.93 Hz), 7.92 (1H, dd, J=8.92 Hz, J=1.80 Hz), 8.06 (1H, d, J=8.86 Hz), 8.19 (1H, d, J=1.55 Hz), 10.52 (1H, s); MS (ESI) m/z 301/303(M−H)−.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH2:11][CH2:10][O:9][C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.N12CCN(CC1)CC2.[CH3:20][N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[C:29]([S:30]([N:33]=[C:34]=[O:35])(=[O:32])=[O:31])[C:24]=2[N:23]=[N:22]1>C(#N)C.O>[CH3:1][C:2]1[C:3]2[CH2:11][CH2:10][O:9][C:4]=2[N:5]=[C:6]([NH:8][C:34]([NH:33][S:30]([C:29]2[C:24]3[N:23]=[N:22][N:21]([CH3:20])[C:25]=3[CH:26]=[CH:27][CH:28]=2)(=[O:31])=[O:32])=[O:35])[N:7]=1
Reactant: Cn1nnc2c(S(=O)(=O)N=C=O)cccc21
Reactant: Cc1nc(N)nc2c1CCO2
Agent: C1CN2CCN1CC2
Solvent: CC#N
Solvent: O
Product: Cc1nc(NC(=O)NS(=O)(=O)c2cccc3c2nnn3C)nc2c1CCO2
Reaction time: 4 h

Procedure:
To a stirred solution of 5,6-dihydro-4-methylfuro(2,3-d)pyrimidin-2-amine (0.08 g) and 1,4-diazabicyclo[2,2,2]octane (catalytic amount) in acetonitrile (5 mL) was added 0.125M 1-methyl-1H-benzotriazole-4-sulfonylisocyanate in acetonitrile (4.0 mL) under a nitrogen atmosphere. After stirring for 4 hours, the reaction was diluted with water (20 mL) and the precipitate was filtered, washed with water and ether, and dried to give 0.09 g of the title compound as a white solid. m.p. 234°-240° C. with decomposition.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[C:10]2[S:14]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15].CI.[C:29](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[N:12]([CH3:29])[N:11]=[C:10]2[S:14]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2c(OCCCl)cccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nc(S(=O)(=O)c2cccc3ccccc23)c2cccc(OCCCl)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 7-(2-chloro-ethoxy)-3-(naphthalene-1-sulfonyl)-1-H-indazole (0.7 g, 1.8 mmoles), methyl iodide (0.28 mL, 2.17 mmoles), and potassium carbonate (0.29 g, 2.17 mmoles) in DMF (10 mL) was stirred together in a round bottom flask at room temperature for 2 hours. Reaction mixture was diluted with H2O, extracted with EtOAc, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by HPLC using as eluent 30% EtOAc/hexane to afford the title compound as an off-white solid, 0.55 g, 1.375 mmoles.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C([CH2:13][S:14]([CH2:17][S:18]([CH2:21][C:22](O)=O)(=[O:20])=[O:19])(=[O:16])=[O:15])(O)=O>C(O)(=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:13]/[S:14]([CH2:17][S:18](/[CH:21]=[CH:22]/[C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:20])=[O:19])(=[O:16])=[O:15])=[CH:4][CH:3]=1
Reactant: O=C(O)CS(=O)(=O)CS(=O)(=O)CC(=O)O
Reactant: O=Cc1ccc(Cl)cc1
Solvent: CC(=O)O
Product: O=S(=O)(/C=C/c1ccc(Cl)cc1)CS(=O)(=O)/C=C/c1ccc(Cl)cc1
Yield: 80 %

Procedure:
A solution of 4-chlorobenzaldehyde (2 mmol) and carboxymethane-sulfonylmethanesulfonyl-acetic acid (1 mmol) in acetic acid (10 mL) was subjected to General Procedure 1, to yield the title compound in 80% yield. m.p. 178-180° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([F:10])=[CH:8][C:7]([Br:11])=[C:6]([F:12])[CH:5]=1)=[O:3].[C:13](=O)([O:17]CC)[O:14][CH2:15][CH3:16].[H-].[Na+]>>[Br:11][C:7]1[C:6]([F:12])=[CH:5][C:4]([C:2]([CH2:1][C:13]([O:14][CH2:15][CH3:16])=[O:17])=[O:3])=[C:9]([F:10])[CH:8]=1
Reactant: CC(=O)c1cc(F)c(Br)cc1F
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(=O)c1cc(F)c(Br)cc1F
Temperature: 80 °C

Procedure:
To a stirred mixture of 18 g 4-bromo-2,5-difluoroacetophenone and 233 ml diethyl carbonate cooled in an ice-bath was slowly added 6.4 g sodium hydride (60% in oil). The reaction mixture was heated at 80° C. for 90 min. and then added to 700 ml ice containing 25 ml acetic acid. The aqueous mixture was extracted with ether, and the ether extracts were washed with sodium chloride solution, dried (magnesium sulfate) and concentrated. The residue was distilled, collecting the material (15.33 g) boiling at 85°-135° C. (0.05 mm). The latter material was chromatographed on 185 g silica gel (Kieselgel 60) using 20% ether in hexane as eluant to give 6.69 g ethyl 4-bromo-2,5-difluorobenzoylacetate as the first product to be eluted.
Reaction SMILES: [Cl:1][C:2]1[C:22]([N+:23]([O-])=O)=[CH:21][CH:20]=[C:19]([Cl:26])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[C:11]2[O:17][CH3:18].[Sn](Cl)Cl.[OH-].[Na+].ClCCl>CO>[NH2:23][C:22]1[C:2]([Cl:1])=[C:3]([C:19]([Cl:26])=[CH:20][CH:21]=1)[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[C:11]2[O:17][CH3:18]
Reactant: COc1cc(C)nc2c(OCc3c(Cl)ccc([N+](=O)[O-])c3Cl)cccc12
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(C)nc2c(OCc3c(Cl)ccc(N)c3Cl)cccc12
Yield: 71.8 %

Procedure:
To a suspension of 8-(2,6-dichloro-3-nitrobenzyloxy)-4-methoxy-2-methylquinoline (1.75 g) in methanol (17 ml) was added tin (II) chloride (3.37 g) at ambient temperature. The mixture was refluxed for 1 hour. After cooling, the mixture was adjusted to pH 10 with 1 N sodium hydroxide solution. To this mixture was added dichloromethane (50 ml) and the precipitate was removed by filtration. The filtrate was extracted with dichloromethane twice. The organic layer was washed with water and brine. After dried over magnesium sulfate, the solvent was removed in vacuo to give 8-(3-amino-2,6-dichlorobenzyloxy)-4-methoxy-2-methylquinoline (1.16 g) as a colorless powder.
Reaction SMILES: [O:1]=[C:2]1[CH:7]2[CH2:8][CH:4]([CH2:5][CH:6]2[C:9]([OH:11])=O)[O:3]1.[CH2:12]([O:14][C:15]([C:17]1([NH2:22])[CH2:19][CH:18]1[CH:20]=[CH2:21])=[O:16])[CH3:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[CH2:12]([O:14][C:15]([C:17]1([NH:22][C:9]([CH:6]2[CH2:5][CH:4]3[CH2:8][CH:7]2[C:2](=[O:1])[O:3]3)=[O:11])[CH2:19][CH:18]1[CH:20]=[CH2:21])=[O:16])[CH3:13]
Reactant: O=C(O)C1CC2CC1C(=O)O2
Reactant: C=CC1CC1(N)C(=O)OCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CC1CC1(NC(=O)C1CC2CC1C(=O)O2)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a solution of 3-oxo-2-oxa-bicyclo[2.2.1]heptane-5-carboxylic acid (857 mg, 5.5 mmol), in DMF (14 ml) and DCM (25 ml) at room temperature, was added 1-amino-2-vinylcyclopropanecarboxylic acid ethyl ester (1.15 g, 6.0 mmol), HATU (2.29 g, 6.0 mmol) and DIPEA (3.82 ml, 22 mmol). The reaction was stirred under N2-atmosphere at ambient temperature for 1 h. LC/MS analysis showed complete conversion and the reaction mixture was concentrated in vacuo. The residue was re-dissolved in DCM (100 ml) and 0.1 M HCl (aq) and the layers separated. The organic phase was washed with NaHCO3 (aq) and brine, dried (MgSO4) and filtered. Removal of the solvent in vacuo afforded the title compound (1.6 g, 99%). LC/MS (Method A): tR=2.46 min, >95%, m/z (ESI+)=294(MH+)
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)=[CH:5][CH:4]=1.Br[CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>O>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][N:12]([CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=3)[CH2:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(OCCBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(OCCN2CC=C(c3ccc(F)cc3)CC2)cc1

Procedure:
A mixture of 2.15 g. of 4-(p-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride, 2.5 g. of p-(2-bromoethoxy)-nitrobenzene, 2.8 g. of potassium carbonate, 20 ml. of ethanol and 2 ml. of water is refluxed for 3 days. After filtration the crude product crystallizes from the hot reaction mixture. It is purified by chromatography on silica gel using methylene chloride for elution. The 4-(p-fluorophenyl)-1,2,3,6-tetrahydro-1-[2-(p-nitrophenoxy)ethyl]pyridine obtained melts at 104°-107° after recrystallization from ethanol.