Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:29])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:14][C:13]1=[O:28])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[C:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][C:15]1[CH2:16][N:12]([C@@H:4]([CH2:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([OH:29])=[O:2])[C:13](=[O:28])[CH:14]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2ccccc2C(C)(C)C)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccccc1OC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)O)C1
Temperature: 23 °C
Reaction time: 2 h
Yield: 137.5 %

Procedure:
To a stirred solution of (S)-2-[4-(2-t-butyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid methyl ester (585 mg, 0.001 mol) in tetrahydrofuran-water (3:1, 10 mL) was added lithium hydroxide (184 mg, 0.008 mol). The reaction mixture was stirred at 23° C. for 2 h. After this time, the mixture was concentrated and the reaction mixture was diluted with water. The reaction mixture was acidified with 2N hydrochloric acid, during which time precipitation occurred. The precipitate was removed by filtration, washed with cold water and dried in vacuo to obtain (S)-2-[4-(2-t-butyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid (530 mg, 94%) as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:20]O)[CH:16]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.FC(F)(F)C(O)=O.[Cl:40][C:41]1[CH:42]=[C:43]2[C:48](=[CH:49][CH:50]=1)[CH:47]=[C:46]([S:51]([N:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1)(=[O:53])=[O:52])[CH:45]=[CH:44]2.C(=O)(O)[O-].[Na+]>ClCCl.C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([CH2:20][N:57]3[CH2:56][CH2:55][N:54]([S:51]([C:46]4[CH:45]=[CH:44][C:43]5[C:48](=[CH:49][CH:50]=[C:41]([Cl:40])[CH:42]=5)[CH:47]=4)(=[O:53])=[O:52])[CH2:59][CH2:58]3)[CH:14]=[CH:13][C:12]=2[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)NCC1CCc2cc(CO)ccc2C1
Agent: O=[Cr](=O)([O-])Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NCC1CCc2cc(CN3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)ccc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In dichloromethane (5 ml), the (2RS)-2-(N-tert -butoxycarbonylaminomethyl)-6-hydroxymethyl-1,2,3,4-tetrahydronaphthalene (0.19 g) was dissolved. Pyridinium chlorochromate (0.17 g) was added to the resulting solution, followed by stirring at room temperature for 2 hours. The reaction mixture was purified as it was by chromatography on a silica gel column (hexane:ethyl acetate=4:1), whereby a colorless solid (0.16 g) was obtained. The resulting solid was dissolved in dichloromethane (8 ml), followed by the addition of 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine trifluoroacetate (0.24 g), triethylamine (80.0 μl) and sodium triacetoxyboron hydride (0.17 g). The resulting mixture was stirred at room temperature for 16 hours under an argon gas atmosphere. An aqueous solution of sodium bicarbonate was added to the reaction mixture. The resulting mixture was diluted with dichloromethane to separate the organic layer. The organic layer was dried over sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=3:1), whereby a colorless viscous liquid (0.33 g, 86%) was obtained.
Reaction SMILES: [I:1]I.N(OC(C)(C)C)=O.N[C:11]1[C:12]([Cl:21])=[C:13]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[C:14]([OH:16])=[O:15].N(OCCCC)=O>CS(C)=O.O>[Cl:21][C:12]1[C:11]([I:1])=[CH:19][C:18]([Cl:20])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: II
Reactant: Nc1cc(Cl)cc(C(=O)O)c1Cl
Agent: CC(C)(C)ON=O
Agent: CCCCON=O
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cc(Cl)cc(I)c1Cl
Temperature: 35 °C
Reaction time: 16 h
Yield: 84.8 %

Procedure:
In a flask 48.35 grams (0.191 mole) of iodine was dissolved in 90 mL of dimethyl sulfoxide. To this solution was added 29.47 grams (0.286 mole) of tertiary butyl nitrite. A solution of 39.25 grams (0.191 mole) of 3-amino-2,5-dichlorobenzoic acid in 130 mL of dimethyl sulfoxide was added dropwise to the solution of iodine and butyl nitrite. During this addition the temperature rose from 20° C. to 50° C., at which temperature the addition was stopped until the reaction mixture had cooled to 35° C. The addition was then completed. When the addition was complete, the reaction mixture was stirred for approximately 16 hours, then poured into water, and this mixture was extracted with ethyl acetate. The extracts were combined and washed with an aqueous solution of sodium hydrogen sulfate and finally with water. The combined extracts were dried over anhydrous sodium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure, yielding 51.34 grams of 2,5-dichloro-3-iodobenzoic acid as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:20])=[C:5]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)[N:6]=[N:7][CH:8]=1.CS(O[CH:26]1[CH2:29][N:28]([CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:27]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[C:31]1([CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:28]2[CH2:29][CH:26]([N:7]3[CH:8]=[C:3]([O:2][CH3:1])[C:4](=[O:20])[C:5]([C:9]4[N:13]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)[N:12]=[CH:11][CH:10]=4)=[N:6]3)[CH2:27]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COc1cnnc(-c2ccnn2-c2ccccc2)c1O
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cn(C2CN(C(c3ccccc3)c3ccccc3)C2)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 100 °C
Reaction time: 12 h
Yield: 9.6 %

Procedure:
A suspension of 5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4-ol (200 mg), 1-(diphenylmethyl)azetidin-3-yl methanesulfonate (354 mg) and cesium carbonate (729 mg) in DMF (5 mL) was stirred at 100° C. for 12 hr, and water was added. The reaction mixture was extracted with ethyl acetate, the extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (35 mg).
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[C:3](NC1C=CC(C2CCNCC2)=CC=1)=[O:4].[NH2:19][C:20]1[CH:21]=[C:22]([CH:26]2[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1.C1(C(Cl)=O)CC1>>[NH:29]1[CH2:28][CH2:27][CH:26]([C:22]2[CH:21]=[C:20]([NH:19][C:3]([CH:2]3[CH2:18][CH2:1]3)=[O:4])[CH:25]=[CH:24][CH:23]=2)[CH2:31][CH2:30]1
Reactant: CC(C)C(=O)Nc1ccc(C2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(N)c2)CC1
Agent: O=C(Cl)C1CC1
Product: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1

Procedure:
Prepared by the procedure for 2-methyl-N-[4-(4-piperidinyl)phenyl]propanamide using tert-butyl 4-(3-aminophenyl)-1-piperidinecarboxylate and cyclopropanecarbonyl chloride: Anal. Calcd for C15H20N2O+0.15CH2Cl2: C, 70.8; H, 7.87; N, 10.9. found: C, 70.9; H, 7.68; N, 11.1; ESMS m/e: 245.0 (M+H)+.
Reaction SMILES: COC1C=CC([CH2:7][N:8](C)[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:21]4[CH:26]=[C:25]([NH2:27])[C:24]([F:28])=[CH:23][C:22]=4[Cl:29])[C:15](=[O:20])[N:16]3[CH3:19])=[CH:11][N:10]=2)=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:27][C:25]1[C:24]([F:28])=[CH:23][C:22]([Cl:29])=[C:21]([C:14]2[C:15](=[O:20])[N:16]([CH3:19])[C:17]3[C:12]([CH:13]=2)=[CH:11][N:10]=[C:9]([NH:8][CH3:7])[CH:18]=3)[CH:26]=1
Reactant: COc1ccc(CN(C)c2cc3c(cn2)cc(-c2cc(N)c(F)cc2Cl)c(=O)n3C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1cc2c(cn1)cc(-c1cc(N)c(F)cc1Cl)c(=O)n2C
Yield: 72.9 %

Procedure:
A solution of 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-2-chloro-4-fluorophenyl)-1-methyl-1,6-naphthyridin-2(1H)-one (3 g, 6.6 mmol) in DCM (50 mL) was treated with TFA (20 mL) and the mixture was heated to reflux overnight. The mixture was concentrated under reduced pressure, the residue was dissolved in 10% HCl (50 mL), washed with EtOAc, neutralized with satd. NaHCO3 and extracted with EtOAc (3×). The combined organics were washed with brine, dried (Na2SO4) and concentrated in vacuo to give 3-(5-amino-2-chloro-4-fluorophenyl)-1-methyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one (1.6 g, 72% yield) 1H NMR (300 MHz, DMSO-d6): δ 8.36 (s, 1H), 7.66 (s, 1H), 7.17 (d, J=10.8 Hz, 1H), 7.05 (m, 1H), 6.71 (d, J=9.6 Hz, 1), 6.15 (s, 1H), 5.30 (s, 2H), 3.47 (s, 3H), 3.42 (s, 1H), 2.84 (d, J=4.4 Hz, 3H); MS (ESI) m/z: 333.1 [M+H]+
Reaction SMILES: C(O[C:6]([N:8]1[CH:12]2[CH2:13][CH2:14][CH2:15][CH:11]2[N:10](C)[C:9]1=[O:17])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:6][N:8]1[CH:12]2[CH2:13][CH2:14][CH2:15][CH:11]2[NH:10][C:9]1=[O:17]
Reactant: CN1C(=O)N(C(=O)OC(C)(C)C)C2CCCC21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)NC2CCCC21
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.2 %

Procedure:
To a solution of (3aSR,6aRS)-3-methyl-2-oxo-hexahydro-cyclopentaimidazole-1-carboxylic acid tert-butyl ester (Example 106, step 2) (1.99 g, 8.28 mmol) in 30 ml of dichloromethane was added trifluoroacetic acid (7.55 g, 5.1 ml, 66.3 mmol, 8 equiv.) and the yellow solution was stirred at for 5 h at room temperature. The reaction mixture was quenched by addition of saturated sodium bicarbonate solution and the pH of the aqueous phase was set to 9. After workup with dichloromethane/water, the organic phases were dried, filtered and concentrated in vaccuo to yield 1.07 g of an off-white solid, which was taken up in cold ethyl acetate and filtered to yield the title compound (822 mg, 71%) as a crystalline white solid which was directly used in the next step without further characterisation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][C:18](=O)[CH:19]([CH3:21])[CH3:20])[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:18]([CH:19]([CH3:21])[CH3:20])[N:24]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: NN1CCCC1
Reactant: CC(C)C(=O)CC(C(=O)c1ccccc1)c1ccc(F)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)c1cc(-c2ccc(F)cc2)c(-c2ccccc2)n1N1CCCC1

Procedure:
20 g of molecular sieve 3 Å are added to 15 g (50 mmol) of the compound from Example 2 and 20 g (164 mmol) of N-aminopyrrolidine hydrochloride in 150 ml of toluene AR and the mixture is heated to reflux for 48 hours. The mixture is cooled, filtered and washed well with toluene. The toluene solutions are combined and extracted 3×using 1N hydrochloric acid. The organic phase is subsequently washed using saturated sodium hydrogen carbonate solution, dried over magnesium sulphate and concentrated in vacuo. The residue is stirred with a little ethanol, cooled and filtered off with suction. After drying in a desiccator, 2.3 g of substance are obtained.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:8][CH:7]=[CH:6][CH2:5][CH2:4]1.[OH-].[Na+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][CH:13]=1>O1CCOCC1.O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:2][N:3]2[CH2:4][CH:5]=[CH:6][CH2:7][CH2:8]2)=[O:20])=[CH:14][CH:13]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: NN1CC=CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccc(F)cc1)NN1CC=CCC1
Temperature: 5 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
N-Amino-1,2,3,6-tetrahydropyridine hydrochloride (3.42 g) was dissolved in a mixture of dioxane (30 ml) and water (20 ml). The solution was adjusted to pH 7.5 with 1N-aqueous sodium hydroxide and to the resultant mixture was added a solution of 4-fluorophenylisocyanate (0.548 g) in dioxane (5 ml). Then, the mixture was kept to pH 7.5 and stirred for 2 hours at 5° C. After evaporation of organic solvent, the crystalline product was collected by filtration and recrystallized from diisopropyl ether to give white needles of N-[[(4-fluorophenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine (0.73 g). mp: 156°-157° C.
Reaction SMILES: C[O-].[Na+].[CH3:4][N:5]1[C:13]([CH3:14])=[C:12]2[C:7]([CH:8]=[C:9]([NH2:15])[CH:10]=[CH:11]2)=[N:6]1.C=O.[BH4-].[Na+].[OH-].[Na+].Cl.[CH:23](OC(C)C)(C)C>CO.C(OCC)(=O)C>[CH3:23][NH:15][C:9]1[CH:10]=[CH:11][C:12]2[C:7]([CH:8]=1)=[N:6][N:5]([CH3:4])[C:13]=2[CH3:14]
Reactant: Cc1c2ccc(N)cc2nn1C
Reactant: CC(C)OC(C)C
Agent: C=O
Agent: C[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CNc1ccc2c(C)n(C)nc2c1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
Sodium methoxide (19 gm) was dissolved in methanol (610 ml) and then added 2,3-dimethyl-2H-indazol-6-amine (13 gm). The reaction mixture was stirred for 15 minutes and then added paraformaldehyde (3.9 gm). The contents were heated to 60° C. and stirred for 10 hours. The reaction mass was then cooled to room temperature and maintained for 4 hours 30 minutes. Sodium borohydride (2.8 gm) was added to the reaction mass slowly at room temperature and then heated to reflux. The reaction mass was maintained for 2 hours at reflux and then cooled to room temperature. The reaction mass was stirred for 14 hours at room temperature and then added sodium hydroxide solution (1M, 100 ml). The pH of the reaction mass was adjusted to 8.0 to 8.5 with hydrochloric acid solution (40 ml) and then added ethyl acetate (400 ml). Then the layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was dried with sodium sulfate and treated with carbon. The combined organic layers were washed with sodium chloride solution and dried with sodium sulfate. The organic layer was treated with carbon and filtered through hi-flow bed. The solvent was distilled off under vacuum at below 50° C. to obtain a residual mass. To the residual mass was added diisopropyl ether (75 ml) and stirred for 1 hour, filtered. The solid obtained was dried to give 10 gm of N,2,3-trimethyl-2H-indazol-6-amine.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([C:27](OC(C)(C)C)=[O:28])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.FC(F)(F)C(O)=O.[F:41][C:42]([F:53])([F:52])[O:43][C:44]1[CH:51]=[CH:50][C:47]([CH2:48][NH2:49])=[CH:46][CH:45]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>C(Cl)Cl.CN(C=O)C.O>[F:41][C:42]([F:52])([F:53])[O:43][C:44]1[CH:51]=[CH:50][C:47]([CH2:48][NH:49][C:27]([N:24]2[CH2:25][CH2:26][N:21]([C:18]3[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@:2]4([CH3:1])[O:6][C:5]5=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]5[CH2:3]4)=[CH:16][CH:17]=3)[CH2:22][CH2:23]2)=[O:28])=[CH:46][CH:45]=1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(OC[C@@]3(C)Cn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@]1(COc2ccc(N3CCN(C(=O)NCc4ccc(OC(F)(F)F)cc4)CC3)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
Tert-butyl (R)-4-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethoxy)phenyl]-piperazine-1-carboxylate prepared in Example 148 (120 mg, 0.26 mmol) was dissolved in methylene chloride (5 ml). To the solution, trifluoroacetic acid (5 ml) was added followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, then added methylene chloride (2 ml) and triethylamine (2 ml). The solution was stirred at room temperature for 5 minutes and then concentrated under reduced pressure. The residue was dissolved in DMF (10 ml). To the solution, a mixture of 4-trifluoromethoxybenzylamine (125 mg, 0.65 mmol) and 1,1′-carbonyldiimidazole (110 mg, 0.68 mmol) in DMF (5 ml) stirred at room temperature for 3 hours was added followed by stirring at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=200/1) and crystallized from methylene chloride-isopropyl ether to afford (R)-4-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethoxy)phenyl]piperazine-1-carboxylic acid 4-trifluoromethoxybenzylamide (48 mg, yield 32%) as a white powder.
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][C:7]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:6][C:5]1=[O:14])[C:2]#[CH:3].I[C:16]1[CH:28]=[CH:27][C:19]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:18][CH:17]=1.C(N(CC)CC)C>C(#N)C.ClCCl.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.[Cu](I)I>[N:21]1([CH2:20][C:19]2[CH:18]=[CH:17][C:16]([C:3]#[C:2][CH2:1][N:4]3[CH2:8][C:7]4([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]4)[O:6][C:5]3=[O:14])=[CH:28][CH:27]=2)[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1
Reactant: C#CCN1CC2(CCCCC2)OC1=O
Reactant: Ic1ccc(CN2CCOCC2)cc1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC#N
Product: O=C1OC2(CCCCC2)CN1CC#Cc1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.1 %

Procedure:
3-Prop-2-ynyl-1-oxa-3-aza-spiro[4.5]decan-2-one(55 mg, 0.284 mmol), 4-(4-iodo-benzyl)-morpholine(95 mg, 0.313 mmol), tetrakis(triphenylphosphine)palladium (17 mg, 0.0142 mmol), copper iodide (6 mg, 0.0284 mmol) and triethylamine (0.12 mL, 0.853 mmol) were mixed in acetonitrile (1 mL) under argon. The reaction mixture was stirred at room temperature for 1 hour and then diluted with dichloromethane (6 mL). The mixture was washed with water (4 mL), washed with brine (4 mL), dried over sodium sulfate and concentrated. The residue was purified on silica gel eluting with 10 to 25% ethyl acetate in hexanes. The isolated product was treated with 2M hydrochloric acid in diethyl ether to make the hydrochloric acid salt. The salt was then dissolved in water, washed with hexanes and the aqueous phase then made alkaline using aqueous saturated sodium bicarbonate. The aqueous mixture was then extracted with dichloromethane and the organic phase dried over sodium sulfate and concentrated to give the product as an off-white solid (43 mg, 41%). 1H NMR (300 MHz, CDCl3): δ 7.38 (d, 2H), 7.29 (d, 2H), 4.31 (s, 2H), 3.71 (t, 4H), 3.49 (s, 2H), 3.4 (s, 2H), 2.43 (t, 4H), 1.83 (m, 4H), 1.54 (m, 6H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:20][C@H:19]1[CH2:34][OH:35])=[O:17])([CH3:14])([CH3:13])[CH3:12].[Cl-].[NH4+]>ClCCl.C(N(CC)CC)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:25])[CH2:20][C@@H:19]1[CH:34]=[O:35])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C[C@@H]1C=O
Reaction time: 0.17 h
Yield: 101.8 %

Procedure:
Under nitrogen atmosphere, to a solution of oxalyl chloride (1.64 ml) in dichloromethane (34 ml) under −65° C., was added dropwise a solution of dimethyl sulfoxide (2.0 ml) in dichloromethane (15 ml) and stirred for 10 minutes at the same temperature. A solution of (2S)-2-(hydroxymethyl)piperazine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (3.29 g) in dichloromethane (24 ml) was dropped into the above solution over 5 minutes under −65° C. The reaction mixture was stirred at the same temperature for 15 minutes, then stirred at −45° C. for 90 minutes. Triethylamine (7.85 ml) was added to the solution under −40° C., and the mixture was stirred at 0° C. for 20 minutes. The mixture was poured into saturated aqueous ammonium chloride (100 ml). The organic layer was washed with brine, dried over magnesium sulfate, and evaporated to give (2R)-2-formylpiperazine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (3.33 g) as a colorless syrup.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]2([CH2:11][C:12]([OH:19])([C:15]([F:18])([F:17])[F:16])[CH:13]=O)[CH2:10][CH2:9]2)[CH:7]=1.[CH3:22][O:23][C:24]([C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[NH2:36])[N:27]=1)=[O:25]>C(O)(=O)C.C1(C)C=CC=CC=1>[CH3:22][O:23][C:24]([C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[N:36]=[CH:13][C:12]([OH:19])([C:15]([F:18])([F:16])[F:17])[CH2:11][C:8]2([C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[O:20][CH3:21])[CH2:10][CH2:9]2)[N:27]=1)=[O:25]
Reactant: COc1ccc(F)cc1C1(CC(O)(C=O)C(F)(F)F)CC1
Reactant: COC(=O)c1ccc2c(N)cccc2n1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(N=CC(O)(CC3(c4cc(F)ccc4OC)CC3)C(F)(F)F)cccc2n1

Procedure:
Analogously to Example 37, 306 mg (1.2 mmol) of 5-{3-[1-(5-fluoro-2-methoxyphenyl)cycloprop-1-yl]-2-hydroxy-2-(trifluoromethyl)propanal is reacted with 170 mg (0.84 mmol) of 5-aminoquinoline-2-carboxylic acid methyl ester in 4.0 ml of concentrated acetic acid and 20 ml of toluene. After working-up and purification on silica gel with hexane-ethyl acetate (0–70%), 204 mg (49% of theory) of the product is obtained.
Reaction SMILES: [N:1]([C@H:4]([C@H:14]1[O:18][C:17](=[O:19])[C@H:16]([CH3:20])[CH2:15]1)[CH2:5][O:6]CC1C=CC=CC=1)=[N+]=[N-].[ClH:21].O1CCOCC1.[H][H]>C(O)C.[C].[Pd]>[ClH:21].[NH2:1][C@H:4]([C@H:14]1[O:18][C:17](=[O:19])[C@H:16]([CH3:20])[CH2:15]1)[CH2:5][OH:6]
Reactant: [H][H]
Reactant: C[C@@H]1C[C@@H]([C@H](COCc2ccccc2)N=[N+]=[N-])OC1=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: C[C@@H]1C[C@@H]([C@@H](N)CO)OC1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A suspension of 7.56 g of (3R,5S)-5-[(S)-1-azido-2-benzyloxyethyl]-3-methyldihydrofuran-2-one obtained in Example (76e) (27.5 mmol), 15.0 ml of a solution of 4 N hydrochloric acid in dioxane (60.0 mmol) and 1.88 g of 10% palladium-carbon (50% wet) in ethanol (150 ml) was stirred under a hydrogen atmosphere at room temperature for six hours. Hydrogen in the reaction vessel was replaced by nitrogen, and then the reaction mixture was diluted with 100 ml of ethanol. Palladium-carbon was separated by filtration washed with ethanol. The solvent was evaporated from the filtrate under reduced pressure to obtain crude (3R,5S)-5-[(S)-1-amino-2-hydroxyethyl]-3-methyldihydrofuran-2-one hydrochloride.