Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].I[CH2:24][CH:25]1[CH2:30][O:29][CH2:28][CH2:27][O:26]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(=O)CC.C(OCC)(=O)C>[O:26]1[CH2:27][CH2:28][O:29][CH2:30][CH:25]1[CH2:24][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: ICC1COCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: O=C1N(CC2COCCO2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
A mixture of 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.30 g, 1.03 mmol), 2-(iodomethyl)-1,4-dioxane (0.31 g, 1.35 mmol) and cesium carbonate (0.52 g, 1.58 mmol) in 2-butanone (7 mL) was stirred at reflux under nitrogen for 4 h. Once cooled, the reaction was diluted with ethyl acetate and the suspension was filtered through Celite. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography with dichloromethane/diethyl ether (14:1) to afford 1′-(1,4-dioxan-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one as an inseparable mixture with unreacted lactam (0.36 g). A mixture of this material, benzyl bromide (0.12 mL, 1.00 mmol) and cesium carbonate (0.50 g, 1.55 mmol) in 2-butanone (7 mL) was then stirred at reflux under nitrogen for 15 h. Work-up as described above and purified by flash column chromatography with (hexanes/ethyl acetate) (2:1, increased to 1:1) afforded 1′-(1,4-dioxan-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.24 g, 58%) as a colorless solid, along with 1′-benzyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.09 g, 24%) as a colorless solid. Characterization for 1-(1,4-dioxan-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one: mp 160-165° C. (hexanes); 1H NMR (300 MHz, CDCl3) (diastereomers) δ7.26-7.34 (m, 1H), 7.16 (d, J=7.5 Hz, 1H), 7.01-7.09 (m, 2H), 6.49 (s, 1H), 6.24 (s, 0.5H), 6.21 (s, 0.5H), 4.88 (d, J=8.9 Hz, 0.5 Hz), 4.87 (d, J=8.9 Hz, 0.5H), 4.64 (d, J=8.9 Hz, 0.5H), 4.63 (d, J=8.9 Hz, 0.5H), 4.22-4.16 (m, 2H), 4.15-4.09 (m, 2H), 3.99-3.78 (m, 4H), 3.76-3.55 (m, 4H), 3.47-3.37 (m, 1H); 13C NMR (75 MHz, CDCl3) (diastereomers) δ177.9, 177.8, 156.3, 155.3, 144.71, 144.69, 142.72, 142.66, 138.42, 138.39, 132.4, 132.3, 128.91, 128.85, 123.9, 123.8, 123.5, 121.3, 121.1, 111.7, 111.6, 109.6, 109.4, 99.49, 99.46, 80.2, 80.0, 73.32, 73.29, 69.4, 69.2, 66.8, 66.7, 66.52, 66.48, 64.6, 64.0, 58.1, 58.0, 41.85, 41.76; MS (ES+) m/z 396.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([C@@H:19]4[O:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]4)=[CH:15][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[ClH:32].CCOCC>O1CCOCC1>[ClH:32].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[CH:11][N:10]([C:13]3[CH:14]=[CH:15][C:16]([C@@H:19]4[O:24][CH2:23][CH2:22][NH:21][CH2:20]4)=[CH:17][CH:18]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(-n3cnc(-c4ccc(F)cc4)n3)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Fc1ccc(-c2ncn(-c3ccc([C@H]4CNCCO4)cc3)n2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
(S)-tert-butyl 2-(4-(3-(4-fluorophenyl)-1H-1,2,4-triazol-1-yl)phenyl)morpholine-4-carboxylate (201 mg, 0.47 mmol) was dissolved in dioxane (0.5 ml) and a solution of HCl in dioxane (4M, 1.75 ml, 7.1 mmol) was added. The reaction mixture was stirred for 3 h at 60° C. After cooling ether (2 ml) was added and the solid was filtered off. It was washed with ether and dried in vacuo to afford (S)-2-(4-(3-(4-fluorophenyl)-1H-1,2,4-triazol-1-yl)phenyl)morpholine hydrochloride as a white solid (170 mg, 99%). MS (ISP): 325.2 ([M+H]+).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:3]=1.[K+].[CH:25]([C:28]1[CH:29]=[CH:30][C:31]([S:34]([NH-:37])(=[O:36])=[O:35])=[N:32][CH:33]=1)([CH3:27])[CH3:26]>CS(C)=O>[CH:25]([C:28]1[CH:29]=[CH:30][C:31]([S:34]([NH:37][C:2]2[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:3]=2)(=[O:36])=[O:35])=[N:32][CH:33]=1)([CH3:27])[CH3:26]
Reactant: CC(C)c1ccc(S([NH-])(=O)=O)nc1
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1Cl
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)c1ccc(C(C)C)cn1
Yield: 99.2 %

Procedure:
A solution of 3.5 g of 4,6-dichloro-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidine and 4.98 g of 5-isopropyl-2-pyridine sulfonamide potassium salt (Example 1, section e) in 40 ml of DMSO was stirred at room temperature for 4 h. The mixture was poured onto water and extracted twice with diethyl ether. The aqueous layer was acidified with acetic acid. The precipitate that formed was collected, washed with water and diethyl ether and dried to furnish 5.1 g of 5-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimi-dinyl]-2-pyridine sulfonamide as a white solid. LC-MS: tR=4.87 min, [M+1]+=513.32, [M−1]−=511.26.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]5[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=5)=[CH:26][C:25]=4F)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(C1C=CC(C2C=CN=CC=2)=C([F:51])C=1)#C>>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([C:24]4[CH:25]=[CH:26][C:27]([C:30]5[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=5)=[C:28]([F:51])[CH:29]=4)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:16])([F:17])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(-c2ccncc2)c(F)c1
Reactant: O=C1C(n2cc(-c3ccc(-c4ccncc4)cc3F)nn2)CCc2c(F)cccc2N1CC(F)(F)F
Product: O=C1C(n2cc(-c3ccc(-c4ccncc4)c(F)c3)nn2)CCc2c(F)cccc2N1CC(F)(F)F

Procedure:
The title compound was prepared by the same route as 6-fluoro-3-{4-[2-fluoro-4-(pyridin-4-yl)phenyl]-1H-1,2,3-triazol-1-yl}-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one using 4-(4-ethynyl-2-fluorophenyl)pyridine as the alkyne.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.C1COCC1.[CH2:17]([N:24]=[C:25]=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOCC>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH:9][C:25]([NH:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:26])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C=NCc1ccccc1
Reactant: NNC(=O)c1ccc(Cl)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1)NNC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred suspension of 4-chlorobenzoic acid, hydrazide (10.4932 g, 6.1508×10-2 mole) and dry THF (240 mL) was warmed with a heat gun until it was homogenous. To this stirred solution was added benzyl isocyanate (7.8 ml, 6.3×10-2 mole). After stirring overnight at room temperature, the reaction was diluted with ether. The precipitate was collected by filtration, washed with a little ether, and dried by suction Crystallization from ethanol afforded small colorless needles 15.69 g (84%), mp 244°-246° C.
Reaction SMILES: [O:1]=[C:2]1[O:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][CH2:3]1.CN(C=O)C.C(Cl)(=O)C([Cl:18])=O>C(Cl)Cl>[O:1]=[C:2]1[O:6][C@H:5]([C:7]([Cl:18])=[O:9])[CH2:4][CH2:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C1CC[C@@H](C(=O)O)O1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CC[C@@H](C(=O)Cl)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
To a solution of (2S)-5-oxotetrahydrofuran-2-carboxylic acid (compound 28a, 70 g, 539 mmol) and a drop of DMF in anhydrous DCM (500 mL) was added oxalyl dichloride (137 g, 1.07 mol) dropwise. The reaction mixture was stirred at room temperature for 3 hours. The reaction was then concentrated in vacuo to afford 70 g crude product of (2S)-5-oxotetrahydrofuran-2-carbonyl chloride (compound 28b), which was used in next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36]C)=[O:35])=[CH:32][CH:31]=2)=[O:29])[CH2:24][CH:23]1[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([C:30]2[CH:31]=[CH:32][C:33]([C:34]([OH:36])=[O:35])=[CH:38][CH:39]=2)=[O:29])[CH2:24][CH:23]1[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(C(=O)N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](c1cccc2ccccc12)N(CC1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 55 mg of methyl 4-{[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]carbonyl}benzoate were added 2.0 mL of THF, 1.0 mL of methanol, and 1.00 mL of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature overnight. It was neutralized by addition of 1.1 mL of 1 M hydrochloric acid, and then extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and dried to obtain 4-{[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]carbonyl}benzoic acid as a crude product(colorless foamy substance, 57.5 mg).
Reaction SMILES: [F:1][C:2]([F:27])([CH2:23][CH2:24][CH2:25][CH3:26])[C:3](=[O:22])[CH:4]=[CH:5][C@H:6]1[C@H:13]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[CH2:12][C@H:11]2[C@@H:7]1[CH2:8][C:9](=[O:21])[O:10]2>[Pd].C(OCC)(=O)C>[F:27][C:2]([F:1])([CH2:23][CH2:24][CH2:25][CH3:26])[C:3](=[O:22])[CH2:4][CH2:5][C@H:6]1[C@H:13]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[CH2:12][C@H:11]2[C@@H:7]1[CH2:8][C:9](=[O:21])[O:10]2
Reactant: CCCCC(F)(F)C(=O)C=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC1CCCCO1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCC(F)(F)C(=O)CC[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC1CCCCO1

Procedure:
The compound (82) (12.7 g) was catalytically hydrogenated over 5% palladium on carbon (catalytic amount) in ethyl acetate (300 ml) under hydrogen atmosphere to give the titled compound (83). Yield: 12.5 g (99%).
Reaction SMILES: [CH:1]1[C:2]([I:10])=[CH:3][C:4]([I:9])=[C:5]([OH:8])[C:6]=1[I:7].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)/[CH:18]=[C:19](/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])\[CH3:20].O>CN(C)C=O>[I:7][C:6]1[CH:1]=[C:2]([I:10])[CH:3]=[C:4]([I:9])[C:5]=1[O:8][CH2:17]/[CH:18]=[C:19](\[CH3:20])/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25]
Reactant: CC(C)=CCC/C(C)=C/CBr
Reactant: Oc1c(I)cc(I)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CCC/C(C)=C/COc1c(I)cc(I)cc1I
Temperature: 50 °C
Yield: 87 %

Procedure:
A mixture of triiodophenol (10.0 g, 21.2 mmol), milled potassium carbonate (3.1 g, 22.5 mmol, 1.06 eq) and geranyl bromide (4.0 ml, 20.2 mmol) in dimethyl formamide (25 ml) was heated to 50° C. for 2 hrs and cooled. The mixture was poured into 300 ml of water and extracted with ethyl acetate. The ethyl acetate extract was filtered through a short pad of silica gel, then alumina, eluting with ethyl acetate-hexanes (1:1). The eluent was concentrated under high vacuum to give the product in 87% yield as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=3[OH:21])[C:8]=2[Cl:13])[N:3]=1.Cl.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=3[O:21][CH2:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=3)[C:8]=2[Cl:13])[N:3]=1
Reactant: Nc1nc(N)c2c(Cl)c(-c3cc(Cl)ccc3O)ccc2n1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(N)c2c(Cl)c(-c3cc(Cl)ccc3OCc3ccccn3)ccc2n1
Reaction time: 2 h
Yield: 72.8 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 0.5 gram (0.002 mole) of 2,4-diamino-5-chloro-6-(5-chloro-2-hydroxyphenyl)quinazoline, 0.3 gram (0.002 mole) of pyridin-2-ylmethyl chloride hydrochloride, and 0.5 gram (0.004 mole) of potassium carbonate in 5 mL of N,N-dimethylformamide was heated at 60° C. for about 24 hours. After this time, the reaction mixture was concentrated under reduced pressure to a residue. The residue was taken up in 100 mL of water and was stirred for about 2 hours. The resultant solid was collected by filtration, yielding 0.6 gram of 2,4-diamino-5-chloro-6-[5-chloro-2-(pyridin-2-ylmethoxy)phenyl]quinazoline. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1C(C1C=C(C)C=CC=1C1C=NN(C)C=1)=O.[CH3:25][C:26]1[N:31]=[C:30]([C:32]([OH:34])=O)[C:29]([N:35]2[N:39]=[CH:38][CH:37]=[N:36]2)=[CH:28][CH:27]=1>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:32]([C:30]1[C:29]([N:35]2[N:39]=[CH:38][CH:37]=[N:36]2)=[CH:28][CH:27]=[C:26]([CH3:25])[N:31]=1)=[O:34]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)n1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, using 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid. ESI-MS (m/z): 315 [M+1]+.
Reaction SMILES: [CH:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=[O:8])=[O:2].O>C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>[CH:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:2]
Reactant: COC(=O)CCCCC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: O=CCCCCC(=O)O
Yield: 40.9 %

Procedure:
36 g of methyl 5-formylvalerate, 90 g of water and 1 g of p-toluene sulfonic acid were refluxed for 8 hours, the methanol formed being distilled off constantly. Fractional distillation under reduced pressure gave 13.3 g (yield 41% of theory) of 5-formylvaleric acid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[O:5][C:6]([CH2:9][S:10][CH2:11][CH2:12][NH:13][C:14](SC)=[CH:15][N+:16]([O-:18])=[O:17])=[CH:7][CH:8]=1.[NH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[C:28]([CH2:32][N:33]([CH3:35])[CH3:34])[CH:29]=[CH:30][CH:31]=1>>[CH3:34][N:33]([CH2:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[O:25][CH2:24][CH2:23][CH2:22][NH:21][C:14]([NH:13][CH2:12][CH2:11][S:10][CH2:9][C:6]1[O:5][C:4]([CH2:3][NH:2][CH3:1])=[CH:8][CH:7]=1)=[CH:15][N+:16]([O-:18])=[O:17])[CH3:35]
Reactant: CNCc1ccc(CSCCNC(=C[N+](=O)[O-])SC)o1
Reactant: CN(C)Cc1cccc(OCCCN)c1
Product: CNCc1ccc(CSCCNC(=C[N+](=O)[O-])NCCCOc2cccc(CN(C)C)c2)o1

Procedure:
A mixture of N-methyl-5-[[[2-[(1-methylthio-2-nitroethenyl)amino]ethyl]thio]methyl]-2-furanmethanamine (1.6 g) (prepared from the oxalate salt) and 3-(3-aminopropoxy)-N,N-dimethylbenzenemethanamine (1.15 g) was heated at 98°-100° for 3 hours. The oily product was chromatographed (silica/methanol-0.88 ammonia 79:1) and the appropriate eluate evaporated to dryness to give the title compound as a hydrate as an amber oil (2.12 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[NH:18][C:9]2=[N:10][CH:11]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:13]=[C:8]2[CH:7]=1.[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.[H-].[Na+].CN(C)C=O>O>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:18]2[C:9]3=[N:10][CH:11]=[C:12]([S:14]([CH3:17])(=[O:15])=[O:16])[CH:13]=[C:8]3[CH:7]=[C:6]2[C:2]2[O:1][CH:5]=[CH:4][N:3]=2)=[CH:22][CH:21]=1
Reactant: CS(=O)(=O)c1cnc2[nH]c(-c3ncco3)cc2c1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1cnc2c(c1)cc(-c1ncco1)n2Cc1ccc(F)cc1
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
A mixture of 2-(oxazol-2-yl)-5-methanesulfonyl-1H-pyrrolo[2,3-b]pyridine (0.19 g), 4-fluorobenzyl bromide (0.16 g), sodium hydride (32 mg, 60% purity) and dimethylformamide (10 ml) was stirred at 15 to 30° C. for 30 minutes. To the reaction mixture was added water, and the precipitated crystals were filtered off and dissolved in ethyl acetate. The solution was dried over sodium sulfate and concentrated under reduced pressure. The resulting residue (0.14 g) was recrystallized (ethyl acetate/hexane) to obtain 92 mg of the desired product.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=1)[CH2:6][CH3:7])C.[OH-].[Na+]>C(O)C.O>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([CH:5]([CH2:6][CH3:7])[C:4]([OH:17])=[O:3])=[CH:9][CH:10]=1)(=[O:16])[CH3:15]
Reactant: CCOC(=O)C(CC)c1ccc(C(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC(C(=O)O)c1ccc(C(C)=O)cc1
Yield: 123.8 %

Procedure:
To a solution of 4-acetylphenylbutyric acid ethyl ester (50.0 g, 0.21 mol) in ethanol (1250 mL) was added, dropwise, a solution of sodium hydroxide (50.0 g) in water (1250 mL). All was stirred at reflux over 4 hours. The solution was concentrated to half volume and then acidified to a pH equal to 1.0 using hydrochloric acid (1N). The resulting precipitate was collected and washed with water to give 4-acetylphenylbutyric acid (53.76 g, 0.26 mol, 99%) as a white solid. mp=50°-52° C.; 1H NMR (CDCl3) d 7.9 (d, 2H, J=8.1 Hz), 7.25 (d, 2H, J=9.1 Hz), 2.75 (t, 2H, J=7.7 Hz), 2.6 (s, 3H), 2.4 (t, H, J=7.3 Hz), 2.0 (quintet, 2H, J=7.4 Hz).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[CH3:9]O>>[ClH:1].[NH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: CO
Reactant: NCCCC(=O)O
Agent: Cl
Product: COC(=O)CCCN
Reaction time: 0.08 h

Procedure:
Anhydrous HCl was slowly bubbled into a heterogeneous mixture of 20.64 g (0.2 mole) of 4-aminobutyric acid in 200 ml of methanol at room temperature. After adding the HCl for about 5 minutes the reaction mixture warmed to a gentle reflux at which time it was submerged into a 0° C. ice bath. HCl addition was continued for an additional 5 minutes after the reaction mixture was cooled. The reaction mixture was then placed under nitrogen and refluxed for 17 hours. The solvent was evaporated in vacuo giving 30.70 g of a white solid, mp 110°14 115° C. The title compound was used in the next step without further purification.
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].[C:12]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:12]([CH:13]([C@H:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][N+:1]([O-:3])=[O:2])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:19])[CH3:22]
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)[C@@H](C[N+](=O)[O-])c1ccccc1
Temperature: -20 °C
Reaction time: 48 h

Procedure:
[(S,S)-N-(pentamethylbenzenesulfonyl)-1,2-diphenylethylenediamine](hexamethylbenzene)ruthenium (13.7 mg, 0.02 mmol, S/C=50), trans-β-nitrostyrene (149 mg, 1.0 mmol), diethyl malonate (152 μl, 1.0 mmol) and toluene (1 ml) were added into Schlenk (20 ml) under an argon atmosphere, and stirred at −20° C. for 48 hours. The reaction solution was purified by flash column chromatography (hexane/acetone=80/20, SiO2), showing that the yield of the product was 89%. The optical purity was measured by HPLC (CHIRALPACK AD manufactured by Daicel Co., Ltd., hexane:2-propanol=95:5, flow rate 0.5 ml/min, detection by 210 nm), resulting to 93% ee.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:16]([CH3:29])=[C:17]([CH3:28])[C:18]4[O:22][C:21]([CH3:24])([CH3:23])[CH:20](O)[C:19]=4[C:26]=3[CH3:27])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:26]([CH3:27])=[C:19]([CH3:20])[C:18]4[O:22][C:21]([CH3:24])([CH3:23])[CH:28]([N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[C:17]=4[C:16]=3[CH3:29])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: C1CCNC1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)C(C)(C)O4)CC2)cc1
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(N3CCCC3)C(C)(C)O4)CC2)cc1
Yield: 48 %

Procedure:
Using 5-(4-(4-methoxyphenyl)piperazin-1-yl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol and pyrrolidine obtained in Reference Example 18, the title compound was obtained in the same manner as in Example 57. Yield 48% mp. 124–126° C. (methanol).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]3(CC3)[CH2:9][NH:10][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C=O.[CH3:18][C:19]([CH3:21])=O>>[CH:19]([N:10]1[CH2:9][CH2:8][C:7]2[C:12](=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:11]1)([CH3:21])[CH3:18]
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCC21CC1
Reactant: CC(C)=O
Agent: C=O
Product: CC(C)N1CCc2ccc([N+](=O)[O-])cc2C1

Procedure:
870 mg of the entitled compound was obtained as a colorless solid according to the same method as in Production Example 10-6), for which, however, the compound obtained in Production Example 22-1) was used in place of 7′-nitro-1′,2′-dihydro-3′H-spiro[cyclopropane-1,4′-isoquinoline] used in Production Example 10-6), and acetone was used in place of aqueous formaldehyde solution.
Reaction SMILES: Cl.[F:2][C:3]1([F:8])[CH2:7][CH2:6][NH:5][CH2:4]1.[CH:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)=O.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[F:2][C:3]1([F:8])[CH2:7][CH2:6][N:5]([CH2:9][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:13][CH2:12]2)[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: FC1(F)CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(CN2CCC(F)(F)C2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3,3-difluoropyrrolidine hydrochloride (965 mg, 6.722 mmol), tert-butyl 4-formylpiperidine-1-carboxylate (1.720 g, 8.066 mmol), DIPEA (955.6 mg, 1.288 mL, 7.394 mmol) and crushed 4A MS (965 mg) in DCE (30 mL) were stirred at ambient temperature for 3 hours. NaBH(OAc)3 (2.848 g, 13.44 mmol) was added and the reaction stirred at ambient temperature for a further 16 hours. The mixture was filter through Celite (washing with DCM) and the filtrate concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 80 g column, eluting with 0 to 10% MeOH/DCM, loaded in DCM) to give the sub-title product as a colourless oil that was used directly into next step without further purification. LC-MS ES+: 305.1.
Reaction SMILES: CS([O:5][CH:6]1[CH2:9][N:8]([C:10]2[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])[CH2:7]1)(=O)=O.O[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]=1>>[F:21][C:20]([F:23])([F:22])[C:17]1[CH:18]=[N:19][C:10]([N:8]2[CH2:9][CH:6]([O:5][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]=3)[CH2:7]2)=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(C(F)(F)F)cnc1N1CC(OS(C)(=O)=O)C1
Reactant: Oc1cccc(C(F)(F)F)n1
Product: COC(=O)c1cc(C(F)(F)F)cnc1N1CC(Oc2cccc(C(F)(F)F)n2)C1

Procedure:
The title compound (D89) (25 mg) was prepared according to the experimental procedure described in Description 88 starting from methyl 2-(3-((methylsulfonyl)oxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinate (D68) (120 mg, 0.34 mmol) and 2-Hydroxy-6-(trifluoromethyl)pyridine (55.12 mg, 0.34 mmol, commercially available from Fluorochem#032990).