Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH2:21][CH3:22])([CH2:18][O:19][CH3:20])[CH2:13]1.[CH2:23](Br)[CH:24]=C>>[CH2:20]([O:19][CH2:18][C:14]1([CH2:21][CH3:22])[CH2:15][CH2:16][CH2:17][N:12]([CH2:11][CH:2]2[O:1][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][CH2:3]2)[CH2:13]1)[CH:23]=[CH2:24]
Reactant: C=CCBr
Reactant: CCC1(COC)CCCN(CC2COc3ccccc3O2)C1
Product: C=CCOCC1(CC)CCCN(CC2COc3ccccc3O2)C1

Procedure:
The procedure described for 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethyl-3-methoxymethylpiperidine was repeated except that allyl bromide was used instead of methyl iodide.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(-c2ccn(C)n2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1ccc(-c2ccc(C(=O)O)c(Cl)c2)n1
Temperature: 50 °C
Yield: 97.4 %

Procedure:
To a solution of 2-chloro-4-(1-methyl-1H-pyrazol-3-yl)-benzoic acid, methyl ester (6.85 g) in methanol (32 ml) was added 2.5 N sodium hydroxide solution (15.3 ml). The reaction was heated to 50° C. for one hour. The solvent was removed in vacuo, and the residue dissolved in water (250 ml), cooled in an ice bath, and acidified with 2N hydrochloric acid (24 ml). The resulting precipitate was filtered and dried to give a colorless solid (6.3 g) m.p. 232-233° C.; MS (+FAB), m/z: 236 (M+H)+.
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:7])[C:3]([F:6])([F:5])[F:4].[CH2:12]([O:19][C:20]([CH:22]1[CH2:27][CH2:26][CH:25]([CH2:28]OS(C(F)(F)F)(=O)=O)[CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F-].C[N+](C)(C)C.O>COCCOC>[CH2:12]([O:19][C:20]([CH:22]1[CH2:27][CH2:26][CH:25]([CH2:28][C:2]([F:7])([F:1])[C:3]([F:6])([F:5])[F:4])[CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(OCc1ccccc1)C1CCC(COS(=O)(=O)C(F)(F)F)CC1
Reactant: C[Si](C)(C)C(F)(F)C(F)(F)F
Agent: C[N+](C)(C)C
Agent: [F-]
Solvent: COCCOC
Solvent: O
Product: O=C(OCc1ccccc1)C1CCC(CC(F)(F)C(F)(F)F)CC1
Reaction time: 4 h
Yield: 18.5 %

Procedure:
(Pentafluoroethyl)trimethylsilane (105 mg, 0.548 mmol) was added to a solution of 4-trifluoromethanesulfonyloxymethyl-cyclohexanecarboxylic acid benzyl ester (cis:trans=4:1) (67.0 mg, 0.176 mmol) in DME (0.88 ml) at −30° C., and tetramethylammonium fluoride (21 mg, 0.22 mmol) was then added at −30 to −27° C. over one hour. The mixture was stirred for four hours while warming from −30° C. to 0° C. and further stirred at 0° C. for one hour. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was then dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=150/1) to give 4-(2,2,3,3,3-pentafluoro-propyl)-cyclohexanecarboxylic acid benzyl ester (cis:trans=11:1) (11.4 mg, 18%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[C:19]([CH:20]([OH:25])[CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:18][N:17]([C:26]3[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=3)[C:14]2=[CH:15][N:16]=1)[CH3:2].C(N(CC)C(C)C)(C)C.[C:44](OC(=O)C)(=[O:46])[CH3:45]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[C:19]([CH:20]([O:25][C:44](=[O:46])[CH3:45])[CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:18][N:17]([C:26]3[CH:27]=[CH:28][C:29]([CH:32]([CH3:33])[CH3:34])=[CH:30][CH:31]=3)[C:14]2=[CH:15][N:16]=1)[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1cccc(CC)c1-c1cc2c(C(O)CC(C)C)cn(-c3ccc(C(C)C)cc3)c2cn1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cccc(CC)c1-c1cc2c(C(CC(C)C)OC(C)=O)cn(-c3ccc(C(C)C)cc3)c2cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-[5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-3-methyl-butan-1-ol (20 mg, 0.044 mmol) in DCM (2 mL), N,N-diisopropylethylamine (15 μL, 0.08 mmol), acetic anhydride (6.6 μL, 0.06 mmol), and DMAP (1 mg) were added. The mixture is stirred at room temperature for 4 h. All volatiles are removed under reduced pressure and the residue is purified by chromatography to afford acetic acid 1-[5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-3-methyl-butyl ester as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:14][C:13](=O)[C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1.P(Cl)(Cl)([Cl:29])=O>>[Cl:29][C:13]1[N:14]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[C:10]([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)=[CH:11][C:12]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Cl
Temperature: 25 °C

Procedure:
To a dried round bottom flask fitted with a condenser was added methyl 6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate from Step A of Example 51 (1.50 g; 3.67 mmol) and excess phosphorous oxychloride (4 mL). The reaction mixture was heated to reflux for 16 hours. The reaction mixture was allowed to cool to room temperature, and the volatiles were removed in vacuo. The residue was redissolved in methylene chloride and washed with saturated NaHCO3 solution (2×), water, brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification was done by MPLC (silica gel; 0-10% ethyl acetate:hexane) to afford the desired product: m/e=428 (M+2) Rt=4.42 min on LCMS.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:10][CH3:11])[CH2:8][CH3:9])[N:5]=[CH:4][C:3]=1[C:12]([NH2:14])=[O:13].[CH:15]1([CH2:21][C:22](OC)=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([CH2:21][C:22]2[NH:14][C:12](=[O:13])[C:3]3[CH:4]=[N:5][N:6]([CH:7]([CH2:10][CH3:11])[CH2:8][CH3:9])[C:2]=3[N:1]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)CC1CCCCC1
Reactant: CCC(CC)n1ncc(C(N)=O)c1N
Product: CCC(CC)n1ncc2c(=O)[nH]c(CC3CCCCC3)nc21

Procedure:
The product is obtained in analogy to Example 1/stage 1c) starting from 200 mg (1.02 mmol) of 5-amino-1-(1-ethylpropyl)-1H-pyrazole-4-carboxamide and 482 mg (3.06 mmol) of methyl cyclohexylacetate.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Cl:25])[C:12]=1[NH:13][C:14]([C:16]1[CH:24]=[C:23]2[C:19]([CH:20]=[CH:21][NH:22]2)=[CH:18][CH:17]=1)=[O:15].CN(C)[CH:28]=[O:29]>>[Cl:25][C:11]1[CH:10]=[N:9][CH:8]=[C:7]([Cl:6])[C:12]=1[NH:13][C:14]([C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH:28]=[O:29])=[CH:21][NH:22]2)=[CH:18][CH:17]=1)=[O:15]
Reactant: O=C(Nc1c(Cl)cncc1Cl)c1ccc2cc[nH]c2c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2cc(C(=O)Nc3c(Cl)cncc3Cl)ccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of dimethylformamide (10 ml), under nitrogen and at 0° C., was treated with phosphorus oxychloride (0.6 ml). After stirring for 30 minutes at 0° C. the mixture was treated with a solution of N-(3,5-dichloro-pyridin-4-yl)-1H-indole-6-carboxamide [1.55 g, Example 1(bg)] in dimethylformamide (5 ml). The mixture was then heated at 40° C. for 45 minutes then cooled to room temperature and then partitioned between ethyl acetate (25 ml) and saturated sodium bicarbonate (50 ml). The organic layer was washed with water (75 ml) then dried over sodium sulphate then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and hexane (1:2, v/v) to yield the title compound (0.53 g) as a white solid. [Elemental analysis:—C, 53.83; H, 2.99; N, 12.31%. Calculated for C15H9Cl2N3O2:—C, 53.92; H, 2.71; N, 12.57%].
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@H:4]1[O:8][C@@H:7]([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13]([NH2:14])[C:12]=3[N:11]=[C:10]2[CH3:19])[C@H:6]([OH:20])[C@@H:5]1[OH:21].Cl[CH2:23][C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2CC)[C@H](O)[C@@H]1O>CN.C(O)C>[CH3:1][NH:2][CH2:3][C@H:4]1[O:8][C@@H:7]([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13]([NH2:14])[C:12]=3[N:11]=[C:10]2[CH2:19][CH3:23])[C@H:6]([OH:20])[C@@H:5]1[OH:21]
Reactant: CNC[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Reactant: CCc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CCl)[C@@H](O)[C@H]1O
Agent: CN
Solvent: CCO
Product: CCc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CNC)[C@@H](O)[C@H]1O

Procedure:
The procedure was the same as reported above for 4a using 3b (1.00 g, 3.18 mmol) and 33% methylamine/ethanol solution (30 mL). After column chromatography (elution with 5:1:0.3 chloroform:methanol:NH4OH), a yellow glassy solid was obtained: 498 mg (50%); MS m/z 309 (M+H)+; 1HNMR (DMSO-d6) δ 8.08 (bs, 1H, H-2), 7.13 (bs, 2H, 6-NH2), 5.70 (d, 1H, H-1′, J1′,2′=6.6 Hz), 5.30 (d, 1H, 2′-OH, J2′-2′OH=6.4 Hz), 5.16 (d, 1H, 3′-OH, J3′-3′OH=4.5 Hz), 5.08 (ddd, 1H, H-2′, J1′,2′=6.6 Hz, J2′,3′=5.4 Hz, J2′-2′OH=6.4 Hz), 4.14-4.18 (m, 1H, H-3′), 3.96-4.0 (m, 1H, H-4′), 2.88 (q, 2H, 8-CH2CH3), 2.64-2.78 (m, 2H, 5′-CH2), 2.29 (s, 3H, 5′NH—CH3), 1.30 (t, 3H, 8CH2CH3).
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[N:18]([O-])=O.[Na+]>O.[Zn]>[CH2:15]([O:14][C:12]([CH2:11][CH2:10][CH2:9][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][C:6]([NH2:18])=[CH:5][CH:4]=1)=[O:13])[CH3:16]
Reactant: O=N[O-]
Reactant: CCOC(=O)CCCN(C)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [Zn]
Solvent: O
Product: CCOC(=O)CCCN(C)c1ccc(N)cc1
Reaction time: 0.5 h
Yield: 38.3 %

Procedure:
Ethyl 4-(N-methylanilino)butyrate (J.C.S. Perkin I, 1972, 1803) (22 g) was dissolved by addition of conc. hydrochloric acid (60 ml) under ice-cooling. To the solution was added a solution of sodium nitrite (8 g) in water (10 ml) dropwise at 0° to 4° C. with vigorous stirring. The mixture was stirred at the same temperature for 30 minutes. Then zinc powder (30 g) was added at below 10° C. The resulting mixture was further stirred for 30 minutes at 15° C. The zinc was filtered off. The filtrate was made alkaline with sodium bicarbonate and then was extracted with ether. The ether layer was dried over anhydrous sodium sulfate and concentrated. The residue was subjected to column chromatography on silica gel and developed with ethyl acetate/hexane (1:1) to obtain N-ethoxycarbonylpropyl-N-methyl-p-phenylenediamine (9 g).
Reaction SMILES: O1CCOCC1.Cl[C:8]1[N:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]2[CH2:17][CH2:16]2)[C:9]=1[NH2:18].C(=O)([O-])[O-].[Na+].[Na+].[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>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.O>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:17][CH2:16]3)[C:9]=2[NH2:18])=[CH:28][CH:27]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Nc1c(Cl)ncnc1NC1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1c(NC2CC2)ncnc1-c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
In a reactor carousel test tube which had been dried by heating and preheated to 100° C., the degassed diluent mixture dioxane (20 ml)/water (7 ml) was added to 6-chloro-N-cyclopropylpyrimidine-4,5-diamine (10 g, 54.1 mmol) and sodium carbonate (17.22 g, 162 mmol). 5 mol % of tetrakis(triphenylphosphine)palladium(0) and 4-chlorophenylboronic acid (108.2 mmol) were added, and the reaction mixture was stirred at 90° C. overnight. The solution was cooled, filtered and concentrated and the residue was recrystallised from acetonitrile.
Reaction SMILES: [Si]([O:8][C:9]([C@H:11]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:12][C@@H:13]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[C@@H:14]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:10])(C(C)(C)C)(C)C.[Li+:42].[OH-]>O1CCOCC1>[Li+:42].[Si:31]([O:30][C@H:13]([CH2:12][C@H:11]([C:9]([O-:10])=[O:8])[CH2:38][CH:39]([CH3:40])[CH3:41])[C@@H:14]([NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:34]([CH3:36])([CH3:35])[CH3:37])([CH3:33])[CH3:32]
Reactant: CC(C)C[C@H](C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)O[Si](C)(C)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)C[C@H](C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 48.8 %

Procedure:
A solution of the crude resultant compound of Example 166 (0.075 mmol) in 2 mL of dioxane was treated with 0.6 mL (0.3 mmol) of LiOH (0.5 M in H2O) and allowed to stir at ambient temperature for 2 days. After removal of the solvent, purification by flash column chromatography using 3% methanol/chloroform gave 18.3 mg (49%) of the desired compound (Rf 0.10, 2% methanol/chloroform).
Reaction SMILES: [NH3:1].CO.[Cl:4][C:5]1[CH:6]=[C:7]2[C:13]3([CH2:17][CH2:16][N:15]([C:18](=[O:24])[C:19]([O:21]CC)=O)[CH2:14]3)[CH2:12][N:11]([C:25](=[O:33])[NH:26][C:27]3[S:28][C:29]([Cl:32])=[CH:30][N:31]=3)[C:8]2=[CH:9][CH:10]=1>O1CCCC1>[NH2:1][C:19](=[O:21])[C:18]([N:15]1[CH2:16][CH2:17][C:13]2([C:7]3[C:8](=[CH:9][CH:10]=[C:5]([Cl:4])[CH:6]=3)[N:11]([C:25]([NH:26][C:27]3[S:28][C:29]([Cl:32])=[CH:30][N:31]=3)=[O:33])[CH2:12]2)[CH2:14]1)=[O:24]
Reactant: N
Reactant: CCOC(=O)C(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Cl)cc12
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)C(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 62 %

Procedure:
A saturated solution of ammonia-methanol (0.5 mL) and tetrahydrofuran (0.5 mL) were added to the ethyl 2-(5-chloro-1-((5-chlorothiazol-2-yl)carbamoyl)spiro[indoline-3,3′-pyrrolidin]-1′-yl)-2-oxoacetate (50 mg, 0.106 mmol) obtained in Example 43, and the obtained mixture was then stirred at room temperature for 14 hours. Thereafter, the reaction solution was concentrated in vacuo, and the obtained residue was then washed with chloroform to obtain the captioned compound (29.0 mg, 62%) in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[N:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][N:9]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([OH:20])=O)[CH2:10]2)=[O:4].C(N(CC)CC)C.CCCP(=O)=O.[CH:37]([C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43])([CH3:39])[CH3:38]>CN(C1C=CN=CC=1)C.ClCCCl>[CH:37]([C:40]1[CH:41]=[C:42]([NH:43][C:18]([C:17]2[CH:16]=[C:15]([N:9]3[CH2:10][C:11]4[CH:12]=[N:13][CH:14]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:6]=4[CH2:7][CH2:8]3)[CH:23]=[CH:22][CH:21]=2)=[O:20])[CH:44]=[CH:45][CH:46]=1)([CH3:39])[CH3:38]
Reactant: COC(=O)c1cncc2c1CCN(c1cccc(C(=O)O)c1)C2
Reactant: CC(C)c1cccc(N)c1
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cncc2c1CCN(c1cccc(C(=O)Nc3cccc(C(C)C)c3)c1)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.7 %

Procedure:
To a mixture of 3-[5-(methoxycarbonyl)-3,4-dihydro-2,7-naphthyridin-2(1H)-yl]benzoic acid (63 mg, 0.20 mmol), triethylamine (0.056 mL, 0.40 mmol), and catalytic DMAP in 2.0 mL 1,2-dichloroethane at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.143 mL, 0.24 mmol). After 10 min at rt, 3-isopropylaniline (0.042 mL, 0.30 mmol) was added and the reaction stirred at rt for 1 hour. The reaction was quenched into aqueous NaHCO3 solution, extracted with EtOAc, the EtOAc layer washed with H2O, dilute aqueous NaHCO3 solution, brine, dried with anhydrous Na2SO4 and rotary evaporated. This material was chromatographed eluting with CHCl3/EtOAc to give the title compound as a light yellow solid (59 mg, 68%). 1H NMR (Acetone-d6) δ: 9.39 (br. s., 1H), 8.89 (s, 1H), 8.66 (s, 1H), 7.72-7.74 (m, 1H), 7.66-7.71 (m, 2H), 7.35-7.44 (m, 2H), 7.25-7.30 (m, 2H), 7.00 (d, J=7.6 Hz, 1H), 4.60 (s, 2H), 3.91 (s, 3H), 3.66-3.71 (m, 2H), 3.37 (t, J=5.9 Hz, 2H), 2.91 (spt, J=6.9 Hz, 1H), 1.25 (d, J=7.0 Hz, 6H)
Reaction SMILES: [CH3:1][CH2:2][OH:3].[NH2:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8].OS(O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>O>[CH2:2]([O:3][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][CH:12]=[N:13][C:5]=1[NH2:4])[CH3:1]
Reactant: Nc1ncccc1C(=O)O
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cccnc1N
Temperature: 75 °C
Reaction time: 8 h

Procedure:
EtOH (500 mL) was added to 2-amino-nicotinic acid (25 g), followed by H2SO4 (25 mL, conc), and the mixture stirred at 75° C. overnight. The reaction mixture was then redissolved in H2O, neutralized with Na2CO3 (aq), and the resulting precipitate filtered and dried to provide 2-amino-nicotinic acid ethyl ester, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:26])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:10](=[O:17])[NH:11]2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[C:40](OC(=O)C)([F:42])[F:41]>O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:26])=[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[C:10]([O:17][CH:40]([F:42])[F:41])=[N:11]2
Reactant: CC(=O)OC(F)(F)Cl
Reactant: COC(=O)COc1ccc(F)c2[nH]c(=O)c(Cc3ccc(F)cc3)c(C)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(F)c2nc(OC(F)F)c(Cc3ccc(F)cc3)c(C)c12
Temperature: 70 °C
Reaction time: 120 h

Procedure:
A mixture of [8-fluoro-3-(4-fluorobenzyl)-4-methyl-2-oxo-1,2-dihydroquinolin-5-yloxy]acetic acid methyl ester (0.48 g), N,N-dimethylformamide (6.0 mL), potassium carbonate (0.72 g) and acetic acid chlorodifluoromethyl ester (1.7 mL) was stirred at 70° C. for 5 days. The mixture was diluted with Water, extracted with ethyl acetate and the combined extracts washed with water and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:6 by volume), followed by washing with diethyl ether gave title compound as a white solid, 0.29 g.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][NH2:5])[CH3:2].[C:10](OC)(=[O:14])/[CH:11]=[CH:12]/[CH3:13]>CCCCCC>[CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][NH:5][C:10](=[O:14])/[CH:11]=[CH:12]/[CH3:13])[CH3:2]
Reactant: C/C=C/C(=O)OC
Reactant: CCCCC(CC)CN
Solvent: CCCCCC
Product: C/C=C/C(=O)NCC(CC)CCCC
Yield: 72 %

Procedure:
In a flask, 2.6 g (0.02 mol) of 2-ethylhexylamine and 1.0 g (0.01 mol) of methyl crotonate were admitted and refluxed for 6 hours. The reaction mixture was dissolved in n-hexane, washed first with diluted hydrochloric acid and then with 10% sodium hydroxide solution, and subsequently dried with sodium sulfate. The residue was recrystallized from n-hexane, obtaining 1.42 g of N-(2-ethylhexyl)-crotonamide (yield: 72.1%). Usual analysis was carried out to identify the compound. The results are shown below.
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[F:10][C:11]1[CH:24]=[CH:23][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19](O)=[CH:18][CH:17]=2)=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:24]=[CH:23][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([O:1][CH:2]3[CH:7]4[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]4)[CH2:3]3)=[CH:18][CH:17]=2)=[CH:13][CH:12]=1
Reactant: OC1CN2CCC1CC2
Reactant: Oc1ccc(Oc2ccc(F)cc2)cc1
Product: Fc1ccc(Oc2ccc(OC3CN4CCC3CC4)cc2)cc1

Procedure:
3-Hydroxy quinuclidine (Aldrich, 254 mg, 2 mmol) was treated with 4-(4-fluoro-phenoxy)-phenol (Aldrich, 205 mg, 1 mmol) according to the procedure of Example 1A. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.45) as oil (230 mg, yield, 73%). 1H NMR (MeOH-d4, 300 MHz) δ 1.40–1.52 (m, 1H), 1.64–1.87 (m, 2H), 1.98–2.15 (m, 1H), 2.20–2.25 (m, 1H), 2.66–3.00 (m, 5H), 3.30–3.40 (m, 1H), 4.48(m, 1H), 6.61 (dt, J=10.5, 2.4 Hz, 1H), 6.71(dd, J=8.1, 2.3 Hz, 1H), 6.76 (tdd, J=8.4, 2.3, 1.0 Hz, 1H), 6.87–7.00 (m, 3H), 7.22–7.32 (m, 2H) ppm. MS (DCl/NH3) m/z 314 (M+H)+.
Reaction SMILES: C(S([O:8][N+:9]([O-])=[O:10])(=O)=O)(F)(F)F.[CH2:12]([O:14][C:15]([N:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=2)[C@H:20]([N:28]([CH2:33][C:34]2[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[C:36]([C:44]([F:47])([F:46])[F:45])[CH:35]=2)[C:29]([O:31][CH3:32])=[O:30])[CH2:19][C@@H:18]1[CH3:48])=[O:16])[CH3:13].O>ClCCl>[CH2:12]([O:14][C:15]([N:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][C:25]=2[N+:9]([O-:10])=[O:8])[C@H:20]([N:28]([CH2:33][C:34]2[CH:35]=[C:36]([C:44]([F:47])([F:45])[F:46])[CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:39]=2)[C:29]([O:31][CH3:32])=[O:30])[CH2:19][C@@H:18]1[CH3:48])=[O:16])[CH3:13]
Reactant: O=[N+]([O-])OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)N1c2ccc(Cl)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)N1c2c(cc(Cl)cc2[N+](=O)[O-])[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 96.5 %

Procedure:
To a pre-dried flask under nitrogen atmosphere was prepared a slurry of F3CSO3NO2 (2.6 mmol) in 9 mL of dichloromethane [ref. J. Org. Chem. 1973, 38 (25), 4243]. The solution was cooled to −78° C. and a solution of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-chloro-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 32) (0.72 g, 1.3 mmol) in anhydrous dichloromethane (5 mL) was added. The reaction was stirred at −78° C. for 1.5 h, then warmed to 0° C. and stirred for 1 h and 40 min. Water (30 mL) was then added, and the mixture was extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give the title product (0.75 g, 96%). MS m/z 598 (M++H); 1H NMR (CDCl3) δ 7.85 (bs, 1H), 7.8 (bs, 1H), 7.7 (bs, 1H), 7.65 (bs, 1H), 7.1 (bs, 1H), 3.80 (s, 3H).
Reaction SMILES: [C:1](=[NH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][C:17]1=[O:22]>ClCCCl>[C:1](=[N:14][CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][C:17]1=[O:22])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCCNC1=O
Reactant: N=C(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: O=C1NCCCC1N=C(c1ccccc1)c1ccccc1
Temperature: 80 °C
Yield: 78.7 %

Procedure:
Benzophenone imine (3 mL, 17.87 mmol) was added to a solution of 3-aminopiperidin-2-one [CAS 1892-22-4] (2 g, 17.52 mmol) and molecular sieves in DCE (50 mL) under nitrogen and the reaction was warmed to 80° C. for 18 hours. The solvent was evaporated and the residue applied to a 100 g SNAP column, eluting with 50 to 100% EtOAc/ihexane to afford 3-(benzhydrylideneamino)-piperidin-2-one (D21) (3.84 g, 13.796 mmol, 78.7% yield) as a colourless solid.