Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[CH3:18])[CH3:9].[CH3:19][N:20]=[C:21]=[O:22]>C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.C(OCC)(=O)C>[CH3:19][NH:20][C:21](=[O:22])[O:17][C:14]1[CH:15]=[CH:16][C:11]([N:10]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[OH:1])[CH3:9])=[C:12]([CH3:18])[CH:13]=1
Reactant: CC(=Nc1ccc(O)cc1C)c1ccccc1O
Reactant: CN=C=O
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCOC(C)=O
Product: CNC(=O)Oc1ccc(N=C(C)c2ccccc2O)c(C)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 90 %

Procedure:
To a 350 milliliter glass pressure bottle equipped with a magnetic stirrer was added 4.83 grams (0.020 moles) of 4-[1-(2-hydroxyphenyl)ethylideneamino]-3-methylphenol prepared in Part A, 1.42 grams (0.025 moles) of methyl isocyanate, 100 milliliters of ethyl acetate and 5 drops of dibutyl tin diacetate. The resulting reaction mixture was stirred for 96 hours at room temperature, filtered and then washed twice with a 1% aqueous sodium bicarbonate solution followed by a single wash with saturated brine solution. After drying the reaction mixture over magnesium sulfate, it was concentrated under reduced pressure to give 5.36 grams (0.018 moles) of 4-[1-(2-hydroxyphenyl)ethylideneamino]-3-methylphenyl methylcarbamate in the form of an orange solid having a melting point of 133°-138° C. and the following structural formula: ##STR17##
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([CH3:15])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[NH2:21][C:22]1[CH:32]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:25]([OH:33])=[CH:24][CH:23]=1>C(O)C>[ClH:1].[CH2:13]([O:12][C:9]1[CH:10]=[C:11]2[C:6](=[N:7][C:8]=1[CH3:15])[N:5]=[CH:4][C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:2]2[NH:21][C:22]1[CH:32]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:25]([OH:33])=[CH:24][CH:23]=1)[CH3:14]
Reactant: CCOC(=O)c1cnc2nc(C)c(OCC)cc2c1Cl
Reactant: CCOC(=O)c1cc(N)ccc1O
Solvent: CCO
Product: CCOC(=O)c1cc(Nc2c(C(=O)OCC)cnc3nc(C)c(OCC)cc23)ccc1O
Product: Cl
Temperature: 25 °C

Procedure:
A mixture of ethyl 4-chloro-6-ethoxy-7-methyl-1,8-naphthyridine-3-carboxylate (2.0 g), absolute ethanol (30 ml) and ethyl 5-aminosalicylate (1.23 g) was boiled under reflux for 1 hour. The mixture was cooled to ambient temperature and filtered to give a solid which was recrystallised from IMS to give ethyl 5-(6-ethoxy-3-ethoxycarbonyl-7-methyl-1,8-naphthyridin-4-ylamino)salicylate hydrochloride, m.p. 208°-210° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([NH:13][CH2:14][CH2:15][OH:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[CH2:6]([N:13]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:14][CH2:15][O:16][S:2]([CH3:1])(=[O:4])=[O:3])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCNCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCN(Cc1ccccc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
Methanesulfonyl chloride (18.9 g, 0.1655 mol) was added dropwise at 0° C. to a solution of N-benzyl ethanolamine (10 g, 0.0662 mol, from step (i) above) and triethylamine (27.6 ml, 0.1987 mol) in dichloromethane (100 ml). The reaction mixture was stirred at RT for 3 h under nitrogen atmosphere and partitioned between water and dichloromethane. The organic layer was separated, washed with water and brine and dried over sodium sulfate. Thes solvent was evaporated under reduced pressure and the residue was purified by column chromatography over silica gel using 3% methanol in dichloromethane, as eluent to give the sub-title compound (12 g) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:16][C:17]1[C:18]([N:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][C:31]=3[O:35][CH3:36])[CH:26]2[CH3:37])=[N:19][C:20]([Cl:24])=[N:21][C:22]=1[CH3:23]>CN(C)C=O>[ClH:24].[CH3:16][C:17]1[C:18]([N:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][C:31]=3[O:35][CH3:36])[CH:26]2[CH3:37])=[N:19][C:20]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)=[N:21][C:22]=1[CH3:23]
Reactant: Nc1ccc(F)cc1
Reactant: COc1cccc2c1CCN(c1nc(Cl)nc(C)c1C)C2C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cccc2c1CCN(c1nc(Nc3ccc(F)cc3)nc(C)c1C)C2C
Product: Cl
Yield: 58.3 %

Procedure:
After 4-fluoroaniline(0.32 ml, 3.3 mmol) and triethylamine(0.46 ml, 3.3 mmol) were added to a solution of 5,6-dimethyl-2-chloro-4-(5-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.7 g, 2.2 mmol) in dimethylformamide (5 ml), 0.55 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 25.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[OH:14].N1C=CC=CC=1.[C:21](Cl)(=[O:23])[CH3:22]>O1CCOCC1>[C:21]([NH:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:11])([CH3:13])[CH3:12])[CH:7]=[CH:6][C:5]=1[OH:14])(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)c1ccc(O)c(CN)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC(=O)NCc1cc(C(C)(C)C)ccc1O
Temperature: 0 °C

Procedure:
43 g (0.2 mole) of 2-aminomethyl-4-(1,1-dimethylethyl)-phenol hydrochloride are suspended in 400 ml of 1,4-dioxane, and 40 ml of pyridine are added. 40 ml (0.55 mole) of acetyl chloride are added dropwise while stirring and cooling with ice. The mixture is then stirred for 2.5 hours at 90° and poured into ice water, and the precipitate which has crystallized out is filtered off with suction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]=[C:14](Cl)[C:15]([F:18])([F:17])[F:16].[CH2:20]([NH:23][CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22].C(N(CC)CC)C.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]=[C:14]([N:23]([CH2:24][CH2:25][CH3:26])[CH2:20][CH2:21][CH3:22])[C:15]([F:18])([F:17])[F:16]
Reactant: FC(F)(F)C(Cl)=Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CCCNCCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(CCC)C(=Nc1c(Cl)cc(C(F)(F)F)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
First, 0.17 g (0.50 mmol) of N-(2,6-dichloro-4-trifluoromethylphenyl)-2,2,2-trifluoroacetoimidoyl chloride was dissolved in 10 ml of N,N-dimethyl formamide, to which 0.10 g (0.50 mmol) of dipropylamine and 0.10 g (0.50 mmol) of triethylamine were added, and the mixture was stirred at room temperature for 3 hours. Water was poured into the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give 0.18 g of N′-(2,6-dichloro-4-trifluoromethylphenyl)-2,2,2-trifluoro-N,N-dipropylacetamidine (hereinafter referred to as present compound 56).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]#[C:10][C@@H:11]([OH:13])[CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>N1C=CC=CC=1>[C:14]([O:13][C@H:11]([C:10]#[C:9]/[CH:8]=[CH:7]/[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:12])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](O)C#C/C=C/c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)O[C@@H](C)C#C/C=C/c1ccccc1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
To a solution of alcohol 7 (400 mg, 2.32 mmol) in pyridine (pyridine was distilled over CaH2 and stored over KOH; 4.6 mL) at 23° C. was added acetic anhydride (1.10 mL, 11.6 mmol). The resulting mixture was stirred for 2 h at 23° C. The reaction was quenched by 1 N aqueous HCl (10 mL) at 0° C. and diluted with EtOAc (5 mL). The mixture was poured into a separatory funnel. The layers were separated and the aqueous layer was extracted with EtOAc (3×3 mL). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue via flash chromatography (silica gel 40 mL; 5→30% EtOAc in hexanes) afforded acetate 8 (486 mg, 98%, 95% ee; the ee value was determined by HPLC((S,S) Whelk; 25 cm, 1.0 mL/min, hexanes/iPrOH=95/5).) as a colorless oil.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[OH:22])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:23][C:24](C)=[CH:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][C:31]([C:34](O)=[O:35])=[CH:30][CH2:29]1.C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C>O.O1CCCC1>[CH2:27]([CH:28]1[CH2:33][CH2:32][C:31]([C:34]([O:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][CH2:14][CH2:13][CH2:12][CH:9]2[CH2:8][CH2:7][CH:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:11][CH2:10]2)=[O:35])=[CH:30][CH2:29]1)[CH2:26][CH2:25][CH2:24][CH3:23]
Reactant: CCCCC[C@H]1CC[C@H](CCCCc2ccccc2O)CC1
Reactant: CC(C)=CCCC1CC=C(C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: O
Product: CCCCCC1CC=C(C(=O)Oc2ccccc2CCCCC2CCC(CCCCC)CC2)CC1
Reaction time: 8 h

Procedure:
To a round-bottom flask equipped with a stirbar is added phenol 3H (R=pentyl) (5 g), (4-(4-Methyl-3-pentenyl)-1-cyclohexenyl)carboxylic acid (R=n-pentyl) (3.3 g), dicyclohexylcarbodiimide (5.11 g), dimethylaminopyridine (202 mg), and anhydrous tetrahydrofuran (50 mL). The reaction is stirred overnight, at which time the solution is poured into water and extracted with 1:1 hexanes:ethyl acetate. The combined organic layers are washed with brine and dried over potassium carbonate, and the solution is concentrated in vacuo. Filtration through silica gel using 10% ethyl acetate in hexanes gives the pure product.
Reaction SMILES: CC([C:5]1[C:6]([S:17]([NH2:20])(=[O:19])=[O:18])=[C:7]([S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[N:8]([CH3:10])[CH:9]=1)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[S:11]([C:7]1[N:8]([CH3:10])[CH:9]=[CH:5][C:6]=1[S:17]([NH2:20])(=[O:19])=[O:18])(=[O:12])=[O:13]
Reactant: CN(C)S(=O)(=O)c1c(S(N)(=O)=O)c(C(C)(C)C)cn1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1c(S(N)(=O)=O)ccn1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6.95 g (21 mmol) of N3 -(1,1-dimethylethyl)-N2,N2,1-trimethyl-1H-pyrrole-2,3-disulfonamide in 75 mL of methylene chloride under a nitrogen atmosphere was added 75 mL of TFA. The reaction mixture was allowed to stir at room temperature overnight ca. 16 hours. The reaction mixture was concentrated in vacuo. Three portions of diethyl ether were added to the solid residue and removed by evaporation to remove residual TFA. The solids were suspended in diethyl ether and filtered to yield 4.52 g of the title compound as a solid, m.p. 146°-148° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([OH:19])=O)[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[NH2:25][C:26]1[CH:34]=[C:33]2[C:29]([C:30](=[O:35])[NH:31][NH:32]2)=[C:28]([F:36])[CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([NH:25][C:26]3[CH:34]=[C:33]4[C:29]([C:30](=[O:35])[NH:31][NH:32]4)=[C:28]([F:36])[CH:27]=3)=[O:19])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: Nc1cc(F)c2c(=O)[nH][nH]c2c1
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: CCC(C(=O)Nc1cc(F)c2c(=O)[nH][nH]c2c1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
100 mg (0.28 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 51 mg (0.31 mmol, 1.1 eq.) of 6-amino-4-fluoro-1,2-dihydro-3H-indazol-3-one were reacted according to General Method 6. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 6 mg (4% of theory)
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=[C:29]([N:36]2[CH2:40][CH2:39][C:38](F)(F)[CH2:37]2)C2N=NNC=2N=1)(C)(C)C.Br.BrCCC1C=CC=CN=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH2:15][C:40]3[CH:39]=[CH:38][CH:37]=[CH:29][N:36]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: Br
Agent: BrCCc1ccccn1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(CCc3ccccn3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(2-bromoethyl)pyridine hydrobromide and isolated as colorless gum. MS (m/e): 387.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])=[O:9])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[C:22](=O)([O-])[O-].[Cs+].[Cs+].IC.O>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([O:14][CH3:22])=[O:13])=[O:9])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: Nc1ccc(C(=O)c2ccccc2C(=O)O)cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccccc1C(=O)c1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-[(4-amino-3-nitrophenyl)carbonyl]benzoic acid (10 g, 35 mmol) in DMF (50 mL) was treated with cesium carbonate (23 g, 70 mmol) followed by iodomethane (2.2 mL, 35 mmol). The mixture was stirred at rt for 1 h, after which time 50 mL of water was added. A yellow precipitate formed. The solid was collected by filtration, rinsed with water, and dried in vacuo. Desired methyl 2-[(4-amino-3-nitrophenyl)carbonyl]benzoate was obtained as a yellow solid (8.36 g, 27.8 mmol, 80% yield). 1H NMR (400 MHz, d6-DMSO): 8.12 (br s, 2H), 8.10 (d, 1H), 7.78-7.75 (m, 2H), 7.70 (m, 1H), 7.48 (dd, 1H), 7.10 (d, 1H), 3.64 (s, 3H); MS (EI) for C15H12N2O5: 323 (MNa+).
Reaction SMILES: [OH-].[Na+].Cl[CH2:4][CH:5]([OH:9])[CH2:6][CH2:7][Cl:8].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1>O>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:4][CH:5]([OH:9])[CH2:6][CH2:7][Cl:8])=[CH:13][CH:12]=1
Reactant: OC(CCl)CCCl
Reactant: Oc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OC(CCCl)COc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 37 %

Procedure:
To a rapidly stirring solution of 22.5 g (0.56 mole) of sodium hydroxide in 400 ml of water was added, dropwise, 73.8 g (0.52 mole) of freshly distilled 1,4-dichloro-2-butanol. The mixture was stirred for 15 min at ambient temperature. To this mixture was added, over a 45 min period, a solution obtained by adding 75.0 g (0.43 mole) of 4-bromophenol to a solution of 18.0 g (0.47 mole) of sodium hydroxide in 430 ml of water. The mixture was stirred vigorously for 30 hr and then cooled to an ice bath. The suspended solid was collected by filtration, rinsed with water several times and air dried. Recrystallization from ethyl ether-petroleum ether (b.p. range 30°-60° C.) gave 44.2 g (37%) of white solid, m.p. 75°-78° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:9][CH2:10]OS(C)(=O)=O)(=O)=O.[CH:22]1([NH2:25])[CH2:24][CH2:23]1>C1COCC1>[CH:22]1([N:25]2[CH2:10][CH2:9][N:8]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:7][CH2:6]2)[CH2:24][CH2:23]1
Reactant: CS(=O)(=O)OCCN(CCOS(C)(=O)=O)C(=O)C(F)(F)F
Reactant: NC1CC1
Solvent: C1CCOC1
Product: O=C(N1CCN(C2CC2)CC1)C(F)(F)F
Temperature: 48 °C

Procedure:
The product prepared as in Example 8 above, methanesulfonic acid 2-[(2-methanesulfonyloxy-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-ethyl ester (3.6 g) was dissolved in THF (18 mL). Cyclopropylamine (1.14 g, 20 mmol) was then added neat to the reaction mixture. The reaction mixture was then heated at 48° C. for 72 hours. The reaction mixture was then concentrated to a thick oil and the oil was chromatographed using 25-35% ethylacetate-hexanes mixture to yield the title compound as the late eluting fraction and isolated as thick brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([O:13]C)[CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([CH3:15])[CH:3]=1.B(Br)(Br)Br>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([OH:13])[CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([CH3:15])[CH:3]=1
Reactant: COc1ccc(F)c2c(Cl)cc(C)nc12
Agent: BrB(Br)Br
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1cc(Cl)c2c(F)ccc(O)c2n1
Temperature: 25 °C

Procedure:
4-Chloro-5-fluoro-8-methoxy-2-methyl-quinoline (0.440 g, 1.95 mmol) was coevaporated in anhydrous toluene (2×15 mL). The residue was dissolved in anhydrous DCM (25 mL) and BBr3 (1 M in DCM, 9.8 mL, 9.8 mmol) was added dropwise at −75° C. The reaction mixture was allowed to warm to room temperature over 3.5 h. The reaction mixture was then concentrated in vacuo and the residue was partitioned between DCM (10 mL) and water (7 mL). The pH of the aqueous layer was adjusted to 8 by the addition of saturated aqueous NaHCO3 solution and the aqueous layer was extracted with DCM (2×30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS (m/z): 212.3 [M+H+].
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]3[CH2:17][CH2:18][CH:19]([CH2:21][CH2:22][C:23]([O:25]C)=[O:24])[O:20][C:15]=3[C:14]=2[CH2:29][CH2:30][CH3:31])=[C:6]([CH2:34][CH:35]2[CH2:37][CH2:36]2)[C:5]=1[O:38][CH3:39])=[O:3]>C(OCC)(=O)C.CO.C(O)(=O)C>[NH2:1][C:2]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]3[CH2:17][CH2:18][CH:19]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[O:20][C:15]=3[C:14]=2[CH2:29][CH2:30][CH3:31])=[C:6]([CH2:34][CH:35]2[CH2:37][CH2:36]2)[C:5]=1[O:38][CH3:39])=[O:3]
Reactant: CCCc1c(OCCCOc2ccc(C(N)=O)c(OC)c2CC2CC2)ccc2c1OC(CCC(=O)OC)CC2
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCc1c(OCCCOc2ccc(C(N)=O)c(OC)c2CC2CC2)ccc2c1OC(CCC(=O)O)CC2

Procedure:
The compound of Example 74 is saponified as described in Example 62. Chromatography on silica gel with ethyl acetate/methanol/acetic acid (95:4.5:0.5) as eluant gives the product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]2[CH:20]([NH:22][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][NH:27]3)[CH3:21])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:32]C1N=C2C(NC=N2)=C(Br)N=1.BrC1N=CN=C2C=1NC=N2.BrC1C2C(NC(C3N(C4C=CC=C(F)C=4)C(=O)C4C(=CC=CC=4C)N=3)C)=NC=NC=2NC=1>>[NH2:32][C:30]1[N:29]=[C:28]2[C:24]([N:25]=[CH:26][NH:27]2)=[C:23]([NH:22][CH:20]([C:10]2[N:9]([C:4]3[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=3)[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH3:21])[N:31]=1
Reactant: CC(Nc1ncnc2[nH]cnc12)c1nc2ccccc2c(=O)n1-c1cc(F)cc(F)c1
Reactant: Nc1nc(Br)c2[nH]cnc2n1
Agent: Brc1ncnc2nc[nH]c12
Agent: Cc1cccc2nc(C(C)Nc3ncnc4[nH]cc(Br)c34)n(-c3cccc(F)c3)c(=O)c12
Product: CC(Nc1nc(N)nc2[nH]cnc12)c1nc2ccccc2c(=O)n1-c1cc(F)cc(F)c1

Procedure:
Compound 99 was prepared using the general procedure described above with respect to compound 95, but 2-amino-6-bromopurine was substituted for 6-bromopurine in step D. ESI-HS m/z 435 (MH+). Compound 96 is shown below.
Reaction SMILES: O1CCC[CH2:2]1.[CH3:6][CH:7]([CH:25]([CH3:31])[CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:8][N:9]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:11]([CH3:24])[CH2:10]1.C[Br:33]>C(#N)C>[Br-:33].[CH3:2][N+:9]1([CH2:8][CH:7]([CH3:6])[CH:25]([CH3:31])[CH2:26][C:27]([CH3:28])([CH3:30])[CH3:29])[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:16][CH:15]=2)[CH:11]([CH3:24])[CH2:10]1
Reactant: CBr
Reactant: CC(CN1CC(C)C(c2ccc(C(C)(C)C)cc2)C1)C(C)CC(C)(C)C
Reactant: C1CCOC1
Solvent: CC#N
Product: CC(CC(C)(C)C)C(C)C[N+]1(C)CC(C)C(c2ccc(C(C)(C)C)cc2)C1
Product: [Br-]
Reaction time: 8 h

Procedure:
30 g of tetrahydrofuran are added to 40 g of 1-(2,3,5,5-tetramethylhexyl)-3-methyl-4-(p-tert-butyl-phenyl)-pyrrolidine. For the formation of the quaternary salt, 40 g of a solution of methyl bromide in acetonitrile (20% strength) are added. When the mixture stands overnight, the quaternary salt crystallizes out. Filtration with suction gives 20.5 g of product of melting point 250° C. At 270° C., pronounced discoloration occurs.
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[CH3:29][O:30][C:31]1[CH:32]=[C:33](O)[CH:34]=[CH:35][CH:36]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[CH3:29][O:30][C:31]1[CH:36]=[C:35]([CH:34]=[CH:33][CH:32]=1)[O:1][C@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Reactant: COc1cccc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1cccc(O[C@@H](CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 46.5 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 3-methoxyphenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (3.1 mg, 46.6% yield) as a thick oil: 1HNMR (400 MHz, CDCl3) δ 7.47 (d, 1H, J=6.7 Hz), 7.42 (s, 1H), 7.3–7.20 (m, 3H), 7.20 (m, 3H), 7.07 (t, 1H, J=8.4 Hz), 6.97 (apparent d, 1H, J=6.7 Hz), 6.40 (m, 3H), 5.27 (apparent dd, 1H, J=5.3, 8.0 Hz), 3.74 (s, 3H), 3.38 (m, 2H), 2.93 (m, 2H), 2.61 (s, 1H), 2.53 (apparent sept, partially hidden, 1H, J=6.5 Hz), 2.30–2.10 (m, 6H), 1.82 (m, 2H), 1.25 (d, 6H, J=6.9 Hz); ESMS m/e: 487.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[CH:3]=[CH:4][N+:5]([O-])=O.[C:10]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:11][C:12]([CH3:14])=O.[Na].[F:20][C:21]1[CH:27]=[CH:26][C:24](N)=[CH:23][CH:22]=1>CCOCC.C1(C)C=CC=CC=1>[CH2:17]([O:16][C:10]([C:11]1[C:3]([C:2]([CH3:9])([CH3:8])[CH3:1])=[CH:4][N:5]([C:24]2[CH:26]=[CH:27][C:21]([F:20])=[CH:22][CH:23]=2)[C:12]=1[CH3:14])=[O:15])[CH3:18]
Reactant: Nc1ccc(F)cc1
Reactant: CC(C)(C)C=C[N+](=O)[O-]
Reactant: CCOC(=O)CC(C)=O
Agent: [Na]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C(C)(C)C)cn(-c2ccc(F)cc2)c1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3,3-dimethyl-1-nitro-but-1-ene (6.2 g, 36 mmol) and ethyl acetoacetate, sodium salt (5.76 g, 36 mmol) in ether (50 mL) was stirred at 0° C. for 30 min; then the reaction was quenched with saturated ammonium chloride aqueous solution, the ether layer was washed with saturated NaCl aqueous solution dried over anhydrous sodium sulfate, filtered, concentrated, to give a mixture, which was used next reaction without further purification and characterization. The above mixture was refluxed with 4-fluoroaniline (4.09 mL, 43.2 mmol), and TsOH monohydrate (343 mg, 1.8 mmol) in toluene (100 mL) was refluxed overnight, the generated water was collected with a Dean-Stark distillation apparatus; then the reaction was cooled to room temperature, diluted with EtOAc, washed with diluted HCl aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated NaCl aqueous solution respectively, then dried over anhydrous sodium sulfate filtered, concentrated, the residue was purified with column to give a slightly brown oil, the title product (1.904 g); The title compound, ESI MS (m/z): 304 (M+H+).