Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[C:15]3[C:10]([N:11]=[CH:12][CH:13]=[N:14]3)=[C:9]([O:17][C@@H:18]3[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]3)[CH:8]=2)[CH2:3][CH2:2]1.CS([C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1)(=O)=O.CCN(C(C)C)C(C)C>>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[C:15]3[C:10]([N:11]=[CH:12][CH:13]=[N:14]3)=[C:9]([O:17][C@@H:18]3[CH2:23][CH2:22][C@H:21]([NH:24][C:29]4[N:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:20][CH2:19]3)[CH:8]=2)[CH2:3][CH2:2]1
Reactant: N[C@H]1CC[C@@H](Oc2cc(N3CCOCC3)cc3nccnc23)CC1
Reactant: CS(=O)(=O)c1ncccn1
Solvent: CCN(C(C)C)C(C)C
Product: c1cnc(N[C@H]2CC[C@@H](Oc3cc(N4CCOCC4)cc4nccnc34)CC2)nc1
Temperature: 100 °C

Procedure:
As shown in step 9-iv of Scheme 9, to a solution so (cis) 4-(7-morpholinoquinoxalin-5-yl)oxycyclohexanamine (415 mg, 1.264 mmol) and 2-methylsulfonylpyrimidine (400 mg, 2.53 mmol) was added DIEA (490 mg, 661 μL, 3.79 mmol) and the reaction mixture was sealed in a vessel and heated to 100° C. for 16 hours. After this time, the volatiles were removed under a stream of nitrogen gas and the crude residue dissolved in minimal amount of DCM. Purification by medium pressure silica gel chromatography (0-10% MeOH/DCM, 1% Et3N] produced N-((cis)-4-((7-morpholinoquinoxalin-5-yl)oxy)cyclohexyl)pyrimidin-2-amine containing triethylamine hydrochloride as an impurity. Dissolved product in DCM and stirred with a silica-supported amine (Silabond Amine® 40-63 μm). The scavenger mixture was filtered, concentrated under reduced pressure, and dried under high vacuum to provide N-((cis)-4-((7-morpholinoquinoxalin-5-yl)oxy)cyclohexyl)pyrimidin-2-amine (Compound 28, 435 mg): 1H-NMR (400 MHz, CDCl3) δ 8.68 (d, J=1.9 Hz, 1H), 8.61 (d, J=1.9 Hz, 1H), 8.27 (s, 1H), 8.26 (s, 1H), 6.94 (d, J=2.4 Hz, 1H), 6.90 (d, J=2.4 Hz, 1H), 6.50 (t, J=4.8 Hz, 1H), 4.78 (s, 1H), 4.08-3.97 (m, 1H), 3.94-3.86 (m, 4H), 3.37-3.28 (m, 4H), 2.20 (d, J=9.1 Hz, 2H), 1.95-1.85 (m, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.COC1C=C(C)C=CC=1.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: Cc1cccc(C2CC2)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: COc1cccc(C)c1
Solvent: CO
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 74.7 %

Procedure:
To a mixture of 313 mg (purity: 96.0%; 1.82 mmol) of 4-hydroxy-3,6-dichloropyridazine and 839 mg (5.57 mmol) of 2-cyclopropyl-6-methylphenol were added 3-methoxytoluene (2.76 g) and 328 mg (5.56 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 376 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 75%) and 1.9 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.4%) were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][C:17](=[O:19])[CH3:18])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)([CH2:16][C:17]([OH:19])([CH3:28])[CH3:18])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)C[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 0 %

Procedure:
To a solution of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-oxopropyl)-1,3-oxazinan-2-one (5.25 g, 12.1 mmol) in anhydrous THF (100 mL) was added dropwise methylmagnesium bromide (20 mL, 60 mmol) at −78° C. under nitrogen. Then the mixture was stirred at rt for 2 h. The reaction mixture was cooled in an ice bath and quenched with aqueous NH4Cl. The layers were separated. The aqueous layer was extracted with EtOAc (15 mL), washed with a brine (30 mL), dried over Na2SO4 and concentrated in vacuo to give the crude product, which was purified by preparative HPLC and chiral HPLC to afford (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one (2.5 mg, 46%). 1H NMR (CDCl3): 1.08 (s, 3H), 1.12 (s, 3H), 1.48 (m, 3H), 1.99 (m, 1H), 2.10-2.24 (m, 4H), 2.35 (m, 1H), 2.85 (m, 1H), 5.61 (m, 1H), 6.80 (m, 2H), 6.99 (m, 2H), 7.15-7.28 (m, 5H).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].I[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27]([CH3:30])(=[O:29])=[O:28])(=[O:20])=[O:19])[CH:15]=2)[N:10]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[N:9]=1.C(N(C(C)C)CC)(C)C.[Cl-].[Li+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:30][S:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([NH:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[N:9]=[C:8]2/[CH:3]=[CH:2]/[C:1]([O:5][CH3:6])=[O:4])(=[O:19])=[O:20])(=[O:29])=[O:28]
Reactant: C=CC(=O)OC
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1nn(C(=O)OC(C)(C)C)c2ccc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)cc12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Methyl (E)-3-[5(2-methylsulfonylbenzenesulfonylamino)-1-tert-butoxycarbonylindazol-3-yl]acrylate can be obtained in the following way: 74 μL methyl acrylate are added dropwise to a solution, maintained under an atmosphere of argon and at a temperature in the region of 20° C., of 500 mg of tert-butyl 3-iodo-5-(2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 1.2 ml of diisopropylethylamine, 121 mg of lithium chloride, 11.6 mg of palladium acetate in 15 ml of anhydrous dimethylformamide, and the reaction medium is then heated for 1 hour at 60° C. and then for 1 hour at 80° C. After returning to a temperature in the region of 20° C., 15 ml of distilled water are added and the reaction medium is extracted with ethyl acetate. The pooled organic extracts are washed with distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The oil thus isolated is purified by chromatography on a column of silica gel with a cyclohexane/ethyl acetate (80/20 by volume) mixture as eluent. 90 mg of methyl (E)-3-[5(2-methylsulfonylbenzenesulfonylamino)-1-tert-butoxycarbonylindazol-3-yl]acrylate are thus obtained in the form of a white solid (Rf=0.90, silica gel thin layer chromatography, eluent: cyclohexane/ethyl acetate (50/50 by volume)).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.[C:7]([O:10][C:11](=O)[CH3:12])(=[O:9])[CH3:8].C(C1OC=CC=1Br)(=O)C.C(O)CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N+](C)([O-])=O.C1C=CC=CC=1>[Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]1([CH3:8])[O:10][CH2:11][CH2:12][O:9]1
Reactant: CC(=O)OC(C)=O
Reactant: Brc1ccoc1
Agent: CC(=O)c1occc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C[N+](=O)[O-]
Solvent: OCCO
Solvent: c1ccccc1
Product: CC1(c2occc2Br)OCCO1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
At 0°, a solution of anhydrous ferric chloride (2.7 g, 17.0 mmol) in 50 ml of nitromethane is added portionwise with stirring over a period of 5 hours to a mixture of 3-bromofuran (25.0 g, 170.0 mmol) and acetic anhydride (20.4 g, 200.0 mmol) in 50 ml of nitromethane. After addition is completed, the resulting mixture is stirred at RT for 17 hours and is then evaporated in vacuo. The residue is taken up in 200 ml of diethyl ether, treated with 3.0 g of activated charcoal and filtered. The filtrate is washed with 5% sodium bicarbonate and dried and the solvent is removed by rotoevaporation to give, after purification, 2-acetyl-3-bromofuran. A well-stirred mixture of 2-acetyl-3-bromofuran (13.7 g, 72.0 mmol), ethylene glycol (5.9 g, 94.0 mmol), p-toluenesulfonic acid (p-TSOH; 20 mg) and benzene (50 ml) is refluxed for 9 hours, after which additional ethylene glycol (1.8 g, 29.0 mmol) and p-TSOH (5 mg) is added and the refluxing is continued a further 16 hours. The reaction mixture is then washed with sat. sodium bicarbonate and with water and is dried. The solvent is removed by rotoevaporation to give 2-(3-bromo-2-furyl)-2-methyl-1,3-dioxolane. To a solution of 1.6M butyllithium in hexane (38 ml) and dry diethylether (40 ml), under N2, is added dropwise with stirring a solution of the above dioxolane (11.18 g, 48.0 mmol) in 40 ml of ether, keeping the temperature below -68°. After addition is completed, the mixture is stirred for 30 min. at -70°, and then a slurry of CO2 (50.0 g) in 100 ml of dry diethyl ether is added. The mixture is kept at -65° for 15 min. and is then allowed to warm to 10°. Water is added, followed by 10% sodium carbonate. The phases are separated and the organic phase is extracted. The combined aqueous phases are acidified with conc. HCl and extracted with ether. The organic phases are combined and dried and the solvent is removed by rotoevaporation. The resulting product is suspended in 5% HCl (85 ml) and stirred at RT for 2 hours, then extracted with ether and the combined ether phases are dried and evaporated to dryness. The crude product is purified to give 2-acetyl-3-furancarboxylic acid.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:12][CH:11]=1.C(O)(=O)C>CO>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:28][CH2:29][N:30]([CH2:2][CH2:1][C:3]3[CH:8]=[N:7][CH:6]=[CH:5][N:4]=3)[CH2:31][CH2:32]2)=[CH:12][CH:11]=1
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Reactant: C=Cc1cnccn1
Solvent: CO
Solvent: CC(=O)O
Product: Fc1ccc(Cn2c(NC3CCN(CCc4cnccn4)CC3)nc3ccccc32)cc1

Procedure:
A mixture of 1.27 parts of 2-ethenylpyrazine, 6.48 parts of 1-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine, 0.3 parts of acetic acid and 40 parts of methanol was stirred and refluxed for 48 hours. The solvent was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (88:12 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was washed with 2,2'-oxybispropane and crystallized from 27 parts of methylbenzene, yielding 2.4 parts of 1-(4-fluorophenylmethyl)-N-[1-[2-(2-pyrazinyl)ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 165.3° C. (compound 101).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Reactant: CCCCCCCCC=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCCCCCCC=C1SC(=O)N(CCCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.61 g (5.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 0.711 g (5.0 mmol) of 1-nonanal in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 1.5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=3/1) to yield 1.96 g (88.0%, yellow oily substance) of the desired product.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:6][N:7]([CH2:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1[C:24]1[CH:29]=[C:28]([CH:30]([CH3:32])[CH3:31])[CH:27]=[CH:26][C:25]=1[O:33][CH3:34])[C:8]1[N:9]=[N:10][NH:11][N:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:63][S:64][CH2:65][CH2:66]O.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1.O>[F:41][C:38]([F:39])([F:40])[C:36]1[CH:35]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:42])[F:43])[CH:37]=1)[CH2:6][N:7]([CH2:13][C:14]1[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:16][C:15]=1[C:24]1[CH:29]=[C:28]([CH:30]([CH3:31])[CH3:32])[CH:27]=[CH:26][C:25]=1[O:33][CH3:34])[C:8]1[N:9]=[N:10][N:11]([CH2:66][CH2:65][S:64][CH3:63])[N:12]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nn[nH]n1
Reactant: CSCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCSC)n1

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(2H-tetrazol-5-yl)-amine (300 mg) is dissolved in tetrahydrofuran (5 ml) and thereto are added triphenylphosphine (191 mg), 2-(methylthio)ethanol (63 μl), a 40% diethyl azodicarboxylate/toluene solution (332 μl) and the mixture is stirred at room temperature for 2 hours and a half. To reaction mixture is added water and the mixture is extracted with diethylether. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=12:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-[2-(2-methylsulfanyl-ethyl)-2H-tetrazol-5-yl]-amine (270 mg). MS (m/z): 692 [M+H]+
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:8][O:9][NH2:10].[C:11](Cl)(=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C(OC(=O)C)C>[CH3:8][O:9][NH:10][C:11](=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CON
Reactant: CCCCCCCCC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCCCCCCCC(=O)NOC
Reaction time: 8 h

Procedure:
A 100 mL three-neck round-bottom flask equipped with a mechanical stirrer, argon inlet and pressure equalizing addition funnel is charged with ethylacetate (40 mL) and 1 M aqueous solution of potassium carbonate (20 mL, 2 eq). The reaction mixture is cooled in a salt water/ice bath. Methoxyamine hydrochloride (5.06 g, 1 eq) is added to the reaction mixture followed by a dropwise addition of nonanoyl chloride (10.58 g, 1 eq). The reaction stirs at room temperature overnight. The reaction is diluted with ethylacetate and separated from the aqueous. The organic layer is washed with deionized water (1×50 mL), dried over sodium sulfate, filtered, and concentrated under vacuum.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2].[C:14](Cl)(Cl)=[O:15]>O1CCOCC1>[CH:1]([O:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([N:11]=[C:14]=[O:15])=[CH:12][CH:13]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: O=C(Cl)Cl
Reactant: CC(C)OC(=O)c1ccc(N)cc1
Solvent: C1COCCO1
Product: CC(C)OC(=O)c1ccc(N=C=O)cc1

Procedure:
A solution of 125.3 g of 4-isopropoxycarbonylaniline in 160 ml of dioxane was added dropwise within 30 minutes at 0°-10° C. to a solution of 100 ml of phosgene in 300 ml of dioxane while stirring. The reaction mixture was then stirred at 20° C. for 30 minutes and then heated to boiling; the solvent was distilled off and the residue was distilled under reduced pressure. The desired 4-isopropoxycarbonylphenyl isocyanate was obtained in a yield of 136.8 g; boiling point 87°-88° C./0.2 mm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@H:4]([NH:15][C:16](=[O:19])[CH2:17]Cl)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([O:13][CH3:14])[CH:7]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.ClCCl>[CH3:1][O:2][C:3](=[O:20])[C@H:4]([NH:15][C:16](=[O:19])[CH2:17][NH:28][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([O:13][CH3:14])[CH:7]=1
Reactant: COC(=O)[C@@H](Cc1ccc(C)c(OC)c1)NC(=O)CCl
Reactant: NCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1ccc(C)c(OC)c1)NC(=O)CNCc1ccccc1
Temperature: 35 °C
Reaction time: 1.5 h

Procedure:
To a solution of (2R)-2-[N-(chloroacetyl)amino]-3-(3-methoxy-4-methylphenyl)propionic acid methyl ester (1.85 g) in N,N-dimethylformamide (15 ml) were added successively benzylamine (1.65 g) and potassium carbonate (1.28 g) at 20° C. After stirring at 35° C. for 1.5 hour, the mixture was poured into a mixture of ice-water (20 ml) and dichloromethane (20 ml). After adjusting the mixture to pH 9 with a diluted aqueous hydrochloric acid solution with stirring, the organic layer was separated, washed with an aqueous sodium chloride solution (20 ml), dried over magnesium sulfate and the solvent was evaporated under reduced pressure to give (2R)-2-[N-(benzylaminoacetyl)amino]-3-(3-methoxy-4-methylphenyl)-propionic acid methyl ester in the form of an oily substance. A solution of (2R)-2-[N-(benzylaminoacetyl)-amino]-3-(3-methoxy-4-methylphenyl)propionic acid methyl ester obtained by the above process and acetic acid (0.18 ml) in isopropyl alcohol (10 ml) was stirred under reflux for 12 hours. After cooling the mixture to room temperature, isopropyl ether was added to the mixture. The produced precipitates were collected by filtration and washed with isopropyl ether to give (3R)-1-benzyl-3-(3-methoxy-4-methylbenzyl)piperazine-2,5-dione (1.45 g) in the form of colorless crystals.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:11]=1[C:12]([C:14]1([Br:22])[N:16]=[C:15]1[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[C:1]([O:9][C:10]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:11]=1[C:12]1[O:13][N:16]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:14]=1[Br:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1=NC1(Br)C(=O)c1cc(Cl)ccc1OC(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1noc(-c2cc(Cl)ccc2OC(=O)c2ccccc2)c1Br
Yield: 62.9 %

Procedure:
Ethyl 3-(2-benzoyloxy-5-chloro-benzoyl)-3-bromo-3H-azirine-2-carboxylate (55 mg, 0.12 mmol) was heated at reflux in dry toluene for 2 hours. After evaporation of the solvent, crude solids (34 mg) were obtained and purified by preparative TLC (EtOAc:hexane/1:2). Rf=0.73 (fluorescent). 1H NMR (d6-acetone) δ=7.60 (1H, d); 7.50 (1H, dd); 7.40 (1H, d); 7.30 (5H, m); 5.25 (2H, s); 4.42 (2H, q) and 1.40 (3H, t). LCMS: (M+1)+=438.0 (RT=7.09 min.)
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[C:23]([OH:24])=[CH:22][C:21]3[C:20]([CH3:26])([CH3:25])[CH2:19][CH2:18][C:17]([CH3:28])([CH3:27])[C:16]=3[CH:15]=2)=[O:13])[CH:8]=[C:7]([F:29])[C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].I[CH2:37][CH3:38]>CC(C)=O>[F:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[C:23]([OH:24])=[CH:22][C:21]3[C:20]([CH3:25])([CH3:26])[CH2:19][CH2:18][C:17]([CH3:28])([CH3:27])[C:16]=3[CH:15]=2)=[O:13])[CH:8]=[C:7]([F:29])[C:3]=1[C:4]([O:6][CH2:37][CH3:38])=[O:5]
Reactant: CCI
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)Nc3cc(F)c(C(=O)O)c(F)c3)c(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1c(F)cc(NC(=O)c2cc3c(cc2O)C(C)(C)CCC3(C)C)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2,6-difluoro-4-[(3-hydroxy-5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-naphthalene-2-carbonyl)-amino]-benzoic acid (Compound B, 56 mg, 0.13 mmol) in 4 ml of acetone was added potassium carbonate (36 mg, 0.26 mmol) and iodoethane (0.012 ml, 0.14 mmol). The reaction mixture was stirred at room temperature for 4 hours then concentrated and purified by column chromatography with ethyl acetate: hexane (1:9) to yield the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([NH:10]N)[N:3]=1>[Ni].CO>[NH2:10][C:4]1[C:5]([F:9])=[CH:6][C:7]([F:8])=[C:2]([F:1])[N:3]=1
Reactant: NNc1nc(F)c(F)cc1F
Agent: [Ni]
Solvent: CO
Product: Nc1nc(F)c(F)cc1F
Reaction time: 12 h
Yield: 92.6 %

Procedure:
Charged in a hydrogenation reactor were 100 ml of methanol, 16.3 g of the compound obtained in Step 2 of Example 1 and 8.0 g of Raney nickel catalyst, and H2 gas was introduced therein, followed by allowing the reduction to proceed at room temperature for 12 hours. The reaction mixture was filtered through Cellite® to remove the catalyst. The filtrate was concentrated under a reduced pressure to obtain 13.7 g of the title compound as a solid (purity: 99.1%).
Reaction SMILES: [CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([C:13]#[CH:14])[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2].CN(CCN(C)C)C.Br[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu](I)I.C1COCC1>[CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([C:13]#[C:14][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1cccc(Br)n1
Reactant: C#Cc1ccc2nnc(C(C)C)n2c1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: Cc1cccc(C#Cc2ccc3nnc(C(C)C)n3c2)n1
Temperature: 60 °C
Reaction time: 5 h
Yield: 38.3 %

Procedure:
To a 250 mL round bottom flask was added 1.47 grams (7.94 mmol) of 3-Isopropyl-6-ethynyl-[1,2,4]triazolo(4,3-a)pyridine, 40 mL of anhydrous THF, 40 mL of TMEDA, 279 mg (0.4 mmol) of bis(triphenylphosphine)palladium (II) chloride, 151 mg (0.8 mmol) of copper iodide, and 1.8 mL (15.9 mmol, d=1.512) of 2-bromo-6-methylpyridine. Argon gas was bubbled into the reaction mixture for 5 minutes. The reaction mixture was stirred at 60° C. for 5 hours. The reaction mixture was cooled and concentrated to dryness. The residue was suspended in a mixture of ethyl acetate and water (80 mL each) and filtered through celite that was packed with ethyl acetate. The celite was washed with 100 mL of ethyl acetate. After separating the organic layer, the filtrate was extracted with 50 mL of ethyl acetate. All the organic layers were combined, washed with 100 mL of water, then washed with 100 mL of brine, dried over magnesium sulfate, filtered, and concentrated. Product was purified by flash column chromatography (Biotage flash 40M silica gel packed cartridge) using a 0 to 80% ethyl acetate/chloroform solvent step-gradient which yielded 840 milligrams (38%) of an orange syrup. HPLC tR=4.27 min (100%), LC-MS=277 (M+1).