Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[O:16][CH:17]=[C:18]([CH2:20][O:21][C:22]2[CH:23]=[C:24]([CH2:28][C:29]([O:31]C)=[O:30])[CH:25]=[CH:26][CH:27]=2)[N:19]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[O:16][CH:17]=[C:18]([CH2:20][O:21][C:22]2[CH:23]=[C:24]([CH2:28][C:29]([OH:31])=[O:30])[CH:25]=[CH:26][CH:27]=2)[N:19]=1
Reactant: COC(=O)Cc1cccc(OCc2coc(CCc3nc(-c4ccccc4)oc3C)n2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1CCc1nc(COc2cccc(CC(=O)O)c2)co1
Temperature: 50 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a mixture of methyl 2-[3-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-4-oxazolyl]methoxy]phenyl]acetate (0.34 g), tetrahydrofuran (2 mL) and methanol (2 mL) was added a 1N aqueous sodium hydroxide solution (2 mL) and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid and water were added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (0.26 g, 79%) of 2-[3-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-4-oxazolyl]methoxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 127-128° C.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[C:11]=2[Cl:14])[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4].[CH:18]([C:20]([CH2:22][CH3:23])=[O:21])=[CH2:19].N12CCCN=C1CCCCC2>O1CCCC1.CCOC(C)=O>[CH2:1]([C:5]1([CH2:19][CH2:18][C:20](=[O:21])[CH2:22][CH3:23])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[C:11]=2[Cl:14])[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: C=CC(=O)CC
Reactant: CCCCC1Cc2c(ccc(OC)c2Cl)C1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCC1(CCC(=O)CC)Cc2c(ccc(OC)c2Cl)C1=O
Temperature: 60 °C
Yield: 93.9 %

Procedure:
A solution of 2-butyl-4-chloro-5-methoxy-1-indanone (200 mg, 0.79 mmol) in anhydrous tetrahydrofuran (0.8 mL) was placed under a nitrogen atmosphere and treated with ethyl vinyl ketone (0.118 mL, 1.19 mmol) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (0.024 mL, 0.158 mmol). The resulting solution was stirred and heated in an oil bath at 60° C. for 47 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc (20 mL) and washed with water (20 mL) containing 2N HCl (2 mL). The organic phase was washed with brine (10 mL), dried over MgSO4, filtered, and evaporated under vacuum to provide crude 2-butyl-4-chloro-5-methoxy-2-(3-oxopentyl)-1-indanone (250 mg) as an oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3]C1.[OH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][C:10]([CH2:18][OH:19])([CH2:11]3)[CH2:9]1)[CH2:15]2.[H-].[Na+].[CH2:22]([CH:24]1[O:26][CH2:25]1)Cl>C(Cl)(Cl)Cl>[CH2:22]([O:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:13][CH:12]([CH2:11][C:10]([CH2:18][O:19][CH2:3][CH:4]4[O:1][CH2:5]4)([CH2:16]3)[CH2:9]1)[CH2:17]2)[CH:24]1[O:26][CH2:25]1
Reactant: OCC12CC3CC(C1)CC(CO)(C3)C2
Reactant: C1CCOC1
Reactant: ClCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: C1C2CC3(COCC4CO4)CC1CC(COCC1CO1)(C2)C3
Reaction time: 12 h

Procedure:
300 ml of dehydrated tetrahydrofuran containing 19.6 g (0.1 mol) of 1,3-bis(hydroxymethyl)adamantane and 5.3 g (0.22 mol) of sodium hydride was stirred in a nitrogen atmosphere at the reflux temperature for 2 hours. Thereto was dropwise added 20.4 g (0.22 mol) of epichlorohydrin, followed by stirring at the reflux temperature for 12 hours. To the reaction mixture was added 200 ml of chloroform, followed by washing with water. The chloroform layer was dried with magnesium sulfate. The dried chloroform layer was subjected to distillation under reduced pressure for solvent removal, whereby was obtained a white solid and oily matter.
Reaction SMILES: [BH4-].[Li+].CC(C)(OC([CH2:9][NH:10][C:11]1[N:16]=[C:15]([CH2:17][C:18](OCC)=[O:19])[CH:14]=[CH:13][CH:12]=1)=O)C.O.C(OCC)(=O)C>O1CCCC1>[CH3:9][NH:10][C:11]1[N:16]=[C:15]([CH2:17][CH2:18][OH:19])[CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)Cc1cccc(NCC(=O)OC(C)(C)C)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CNc1cccc(CCO)n1
Temperature: 66 °C
Yield: 58 %

Procedure:
A clean dry 2 L 3 necked flask was fitted with reflux condenser, addition funnel, stir bar, nitrogen inlet and outlet, temperature sensor, and heating mantle. The flask was purged using a stream of nitrogen. Lithium borohydride (4.36 g, 200 mmol) was added all at once. Tetrahydrofuran (THF, 150 mL) was charged into the addition funnel and was added to the solid with stirring over a 10-minute period. After dissolution, the mixture was heated to 66° C. Ethyl 6-[[(1,1-dimethylethoxy)carbonyl]methylamino]-2-pyridineacetate (110 g, 374 mmol) was dissolved in THF (400 ml) and charged into the addition funnel. The ethyl 6-[[(1,1-dimethylethoxy)carbonyl]methylamino]-2-pyridineacetate solution was added to the LiBH4 solution in as dropwise manner over a period of 25 minutes. The addition rate was controlled so as to maintain a gentle reflux. The mixture was heated to reflux for 5 h, the heat was turned off, and the reaction was allowed to stir overnight at 23° C. The reaction mixture was cooled to 10° C. and was treated with water (250 mL) in a dropwise manner. The mixture was stirred for 30 min and ethyl acetate (250 mL) was added. The mixture was stirred for 5 minutes and the layers were allowed to separate. The organic layer was washed with 2×250 mL saturated sodium chloride. The organic layers were stripped to thick oil in a 2 L round bottom flask. The residue was dissolved in ethyl acetate (200 mL) and was extracted with 1 N HCl (2×250 mL). The organic layer was discarded and the acid layer was placed in a 2 L 3 neck round bottom flask. The flask was heated to 50° C. for 1 h. The mixture was cooled to 10° C. and the solution was treated with 4 N NaOH (˜350 mL) to a pH of 10. The basic solution was extracted with ethyl acetate (3×150 mL). Care was taken to keep the pH of the aqueous phase above pH=9. The ethyl acetate extracts were combined, washed with water (150 mL) and concentrated to provide the title compound as a thin yellow oil, 33.5 g, yield=58%)
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][N:20]=1>CN(C=O)C>[CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][N:20]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCC(NCc2ccccc2)CC1
Reactant: N#Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OC2CCC(NCc3ccccc3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 88.3 %

Procedure:
Add dropwise a solution of 4-benzylamino-cyclohexanol (675 mg, 3.28 mmol) in DMF (2 mL) to a suspension of NaH (196 mg, 4.92 mmol) in DMF (3 mL). Stir at room temperature for 45 min then at 50° C. for additional 40 min. Add a solution of 6-chloro-nicotinonitrile (500 mg, 3.61 mmol) in DMF (1.8 mL) dropwise and stir overnight at 60° C. Cool down the reaction mixture and evaporate the solvent. Wash the residue with water (10) and extract with EtOAc/hex (2/1, 15 mL). Combine the organic layers and dry over sodium sulfate. Filter and concentrate. Purify the resulting residue through an SCX column. Further purified by chromatography [CH2Cl2/NH3 (2.0M in methanol) 20/1] to provide the title compound (890 mg, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:11]([CH3:28])[C:12]2[C:13]([N:27]=1)=[C:14]([CH:25]=O)[CH:15]=[C:16]1[C:21]=2[C:20](=[O:22])[NH:19][C:18]([CH3:23])=[C:17]1[CH3:24].[CH2:29]([CH2:31][NH2:32])[OH:30].[BH3-]C#N.[Na+]>CO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[N:11]([CH3:28])[C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH3:23])=[C:17]([CH3:24])[C:16]=3[CH:15]=[C:14]([CH2:25][NH:32][CH2:31][CH2:29][OH:30])[C:13]=2[N:27]=1
Reactant: NCCO
Reactant: Cc1[nH]c(=O)c2c(cc(C=O)c3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1[nH]c(=O)c2c(cc(CNCCO)c3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.2 %

Procedure:
A suspension of the product of Example 23 (30 mg, 0.07 mmol) in MeOH (5 mL) was treated with ethanolamine (44 μL, 0.72 mmol) and NaBH3CN (14 mg, 0.22 mmol), and stirred at room temperature for 16 h. The resulting mixture was concentrated and the residue was diluted with water. The precipitated solid was filtered to give the title compound (12 mg, 36%). mp decomp. above 250° C.; MS (CI) 460 (MH+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[N:54]([C:57]1[CH:58]=[C:59]([CH:62]=[CH:63][CH:64]=1)[C:60]#[N:61])=[C:55]=[O:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:55]([NH:54][C:57]2[CH:64]=[CH:63][CH:62]=[C:59]([C:60]#[N:61])[CH:58]=2)=[O:56])[CH2:48]1
Reactant: O=C(C[C@@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: N#Cc1cccc(N=C=O)c1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(NC(=O)N2CC[C@@H](CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)C2)c1
Yield: 77 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 3-isocyanatobenzonitrile as the starting materials in 77% yield. LCMS for C31H29ClN9O2 (M+H)+: m/z=594.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].O>ClCCl>[CH3:22][S:23]([O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:14])(=[O:25])=[O:24]
Reactant: CC(C)(C)OC(=O)NCCOCCO
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCOCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
tert-Butyl[2-(2-hydroxyethoxy)ethyl]carbamate (Step 1, 3.73 g, 18 mmol) was diluted in dichloromethane (75 mL) and cooled to 0° C. Triethylamine (3.0 mL, 22 mmol) was added, followed by methanesulfonyl chloride (1.7 mL, 22 mmol). After stirring at rt for 1 h, water was added. The aqueous layer was separated and extracted with dichloromethane. The combined organics were dried and concentrated in vacuo to afford the title compound as an oil. 1H NMR (CDCl3) δ: 1.44 (9H, s), 3.06 (3H, s), 3.32 (2H, m), 3.56 (2H, t), 3.72 (2H, m), 4.36 (2H, m).
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:6]=1[CH:12](O)[CH2:13][NH:14][C:15]([NH:21]C(OC)=O)=[N:16][C:17]([O:19][CH3:20])=[O:18].C(N(CC)CC)C.S(Cl)(C)(=O)=O>CO>[CH3:20][O:19][C:17]([NH:16][C:15]1[NH:21][CH:12]([C:6]2[C:5]([Cl:4])=[CH:10][CH:9]=[CH:8][C:7]=2[Cl:11])[CH2:13][N:14]=1)=[O:18]
Reactant: COC(=O)N=C(NCC(O)c1c(Cl)cccc1Cl)NC(=O)OC
Agent: CS(=O)(=O)Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NC1=NCC(c2c(Cl)cccc2Cl)N1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
To 5 l of a methylene chloride solution containing 550 g of 1-(2',6'-dichlorophenyl)-2-(2',3'-bis-methoxycarbonylguanidino) ethanol was added 530 ml of triethylamine. The mixture was stirred until a clear solution formed. Mesyl chloride, 160 ml was then added dropwise with stirring at such a rate that the solution temperature did not pass 35° C. The reaction was complete after 30 minutes. One liter of methanol was added to the reaction mass and the resulting mixture filtered. To the filtrate was added 4 l of methanol and a solution of 270 g of sodium hydroxide in 550 ml of deionized water. The mixture was vigorously agitated and heated to about 40° C. for one hour. The reaction solution was then vacuum distilled until approximately 5 l of distillate had been collected. After addition of 8 l of deionized water to the distillation flask, vacuum distillation was continued, collecting 3 l of distillate. The pot residue was cooled to about 20° C. and stirred for about 1 hour. The imidazole product precipitated from the residual reaction solution and was filtered, washed with 3 l of deionized water then 1 liter of methanol. Drying at 65° C. in a vacuum oven gave 403 g of 4,5-dihydro-2-methoxycarbonylamino-5-(2',6'-dichlorophenyl)imidazole, m.p. 231°-232° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[N:12]1[C:16](=[O:17])[C:15]2[CH2:18][CH2:19][CH2:20][CH2:21][C:14]=2[C:13]1=[O:22].S(Cl)([Cl:26])(=O)=O>ClC(Cl)=C(Cl)Cl.C1(NC2CCCCC2)CCCCC1>[Cl:26][C:6]1[C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]([N:12]2[C:13](=[O:22])[C:14]3[CH2:21][CH2:20][CH2:19][CH2:18][C:15]=3[C:16]2=[O:17])=[C:2]([F:1])[CH:7]=1
Reactant: CC(C)Oc1ccc(F)c(N2C(=O)C3=C(CCCC3)C2=O)c1
Reactant: O=S(=O)(Cl)Cl
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: ClC(Cl)=C(Cl)Cl
Product: CC(C)Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Reaction time: 2 h
Yield: 83.1 %

Procedure:
N-(2-Fluoro-5-isopropoxyphenyl)-3,4,5,6-tetrahydrophthalimide (II: R=isopropyl) (2 g) and dicyclohexylamine (0.01 g) were dissolved in tetrachloroethylene (20 ml), and a solution of sulfuryl chloride (1 g) in tetrachloroethylene (5 ml) was added dropwise thereto at 80° C. in 2 hours. After completion of the addition, the resultant mixture was stirred at the same temperature as above for 2 hours, followed by extraction with ethyl acetate. The extract was concentrated, and the precipitated crystals were collected by filtration to give 1.85 g of N-(4-chloro-2-fluoro-5-isopropoxyphenyl)-3,4,5,6-tetrahydrophthalimide (I: R=isopropyl). M.P., 81°-82° C.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[N:11][NH:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4].Cl[C:16]([F:21])([F:20])C([O-])=O.[Na+]>CN1CCCC1=O.C(OCC)(=O)C>[F:20][CH:16]([F:21])[N:12]1[C:13]2[C:9](=[CH:8][CH:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:14]=2)[CH:10]=[N:11]1.[F:20][CH:16]([F:21])[N:11]1[CH:10]=[C:9]2[C:13]([CH:14]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=[CH:8]2)=[N:12]1
Reactant: O=[N+]([O-])c1ccc2cn[nH]c2c1
Reactant: O=C([O-])C(F)(F)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc2cn(C(F)F)nc2c1
Product: O=[N+]([O-])c1ccc2cnn(C(F)F)c2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
60% Sodium hydride (including 40% liquid paraffin as an additive) (1.2 g) was added to a solution of 6-nitro-1H-indazole (5.90 g) and sodium chlorodifluoroacetate (9.15 g) in N-methylpyrrolidinone (100 ml). Thereafter, the reaction solution was stirred at room temperature for 15 minutes, and further stirred at 100° C. for 30 minutes. The reaction solution was diluted with ethyl acetate, and washed successively with water and a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum. The residue was purified by column chromatography on silica gel (developing solvent:hexane-ethyl acetate) to obtain 1-(difluoromethyl)-6-nitro-1H-indazole and 2-(difluoromethyl)-6-nitro-2H-indazole as a mixture.
Reaction SMILES: [C@@H:1]12[C:7](=[O:8])[NH:6][C@@H:5]1[CH2:4][CH2:3][NH:2]2.[C:9]1([N:15]=[C:16]=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[O:8]=[C:7]1[C@@H:1]2[C@@H:5]([CH2:4][CH2:3][N:2]2[C:16](=[O:17])[NH:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6]1
Reactant: O=C1N[C@@H]2CCN[C@H]12
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C1N[C@@H]2CCN(C(=O)Nc3ccccc3)[C@H]12

Procedure:
100 mg (0.89 mmol) of (1S,5R)-2,6-diazabicyclo[3.2.0]heptan-7-one were dissolved in 5 ml of chloroform and heated to boiling under reflux. Phenyl isocyanate (0.1 ml, 0.89 mmol) and 1 drop of triethylamine were added. thereto and the mixture was left to react at the boiling temperature for 1 hour. After concentration the residue was chromatographed over silica gel (0.063-0.2 mm particle size) with ethyl acetate:ethanol=3:2.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:7]([CH2:8][N:9](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:6][N:5]([CH2:24][C@@H:25]2[C@H:28]([NH:29][C:30](=[O:66])/[C:31](=[N:45]\[O:46][C:47]3([C:50]([O:52]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:51])[CH2:49][CH2:48]3)/[C:32]3[N:33]=[C:34]([NH:37]C(OC(C)(C)C)=O)[S:35][CH:36]=3)[C:27](=[O:67])[N:26]2[S:68]([OH:71])(=[O:70])=[O:69])[N:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:37][C:34]1[S:35][CH:36]=[C:32](/[C:31](=[N:45]/[O:46][C:47]2([C:50]([OH:52])=[O:51])[CH2:49][CH2:48]2)/[C:30]([NH:29][C@@H:28]2[C:27](=[O:67])[N:26]([S:68]([OH:71])(=[O:69])=[O:70])[C@@H:25]2[CH2:24][N:5]2[N:6]=[C:7]([CH2:8][NH2:9])[C:3]([CH2:2][NH2:1])=[N:4]2)=[O:66])[N:33]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2nc(CN)c(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1nn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)nc1CN
Yield: 19 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-2-((4-(aminomethyl)-5-((bis(tert-butoxycarbonyl)amino)methyl)-2H-1,2,3-triazol-2-yl)methyl)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-4-oxoazetidine-1-sulfonic acid (109 mg, 0.11 DCM (1.1 mL), and TFA (0.49 mL, 6.36 mmol) for 2 h. The crude residue was purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min) affording the title compound (12 mg, 19%). LCMS: Rt=0.46 min, m/z=559.2 (M+1), Method 2m_acidic; 1H NMR (400 MHz, D2O): δ 7.16 (s, 1H), 5.61 (d, J=5.6 Hz, 1H), 5.07-4.88 (m, 3H), 4.34 (s, 4H), 1.39-1.13 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH:22]=[CH2:23].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(C(C)C)C(C)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:26]([O:25][C:21](=[O:24])/[CH:22]=[CH:23]/[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1)[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cn2)CC1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 93.5 %

Procedure:
tert-Butyl 4-(5-bromopyridin-2-yl)piperazine-1-carboxylate (800 mg) was dissolved in DMF (4 ml), and ethyl acrylate (368 mg), palladium(II) acetate (27 mg), tris(2-methylphenyl)phosphine (290 mg), and DIPEA (1.26 g) were added thereto, followed by stirring at 100° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and then EtOAc was added thereto. The insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and then the obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain tert-butyl 4-{5-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]pyridin-2-yl}piperazine-1-carboxylate (790 mg).
Reaction SMILES: CO[C:3]1[C:4](=[O:26])[C:5]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:18]=[CH:17][CH:16]=2)=[N:6][N:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:8]=1.[CH2:27]([Br:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(#N)C>[Br-:34].[CH2:27]([N+:12]1[CH:13]=[CH:14][C:9]([N:7]2[CH:8]=[CH:3][C:4](=[O:26])[C:5]([C:15]3[N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:18]=[CH:17][CH:16]=3)=[N:6]2)=[CH:10][CH:11]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1cn(-c2ccncc2)nc(-c2ccnn2-c2ccccc2)c1=O
Reactant: BrCc1ccccc1
Solvent: CC#N
Product: O=c1ccn(-c2cc[n+](Cc3ccccc3)cc2)nc1-c1ccnn1-c1ccccc1
Product: [Br-]

Procedure:
5-Methoxy-3-(1-phenyl-1H-pyrazol-5-yl)-1-pyridin-4-ylpyridazin-4(1H)-one (0.49 g) and benzylbromide (0.25 mL) were dissolved in acetonitrile (30 mL), and the mixture was heated under reflux overnight. The solvent was evaporated under reduced pressure, and the obtained crystals were washed with ethyl acetate to give the title compound (0.73 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10]2)=[C:5]2[NH:15][CH:16]=[C:17]([C:18](=[O:22])[C:19]([OH:21])=O)[C:4]=12.[O:23]=[C:24]1[C:33]([C:34]#[N:35])=[CH:32][C:31]2[CH2:30][NH:29][CH2:28][CH2:27][C:26]=2[N:25]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10]2)=[C:5]2[NH:15][CH:16]=[C:17]([C:18](=[O:22])[C:19]([N:29]3[CH2:28][CH2:27][C:26]4[N:25]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[C:24](=[O:23])[C:33]([C:34]#[N:35])=[CH:32][C:31]=4[CH2:30]3)=[O:21])[C:4]=12
Reactant: N#Cc1cc2c(n(-c3ccccc3)c1=O)CCNC2
Reactant: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)O)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)N3CCc4c(cc(C#N)c(=O)n4-c4ccccc4)C3)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 4.4 %

Procedure:
To a solution of 2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (70 mg, 0.232 mmol), 2-oxo-1-phenyl-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carbonitrile (58.4 mg, 0.232 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (90 mg, 0.279 mmol) in DMF (2 mL) was added N,N-diisopropylethylamine (0.406 mL, 2.324 mmol). The mixture was stirred at room temperature for 4 hours, and diluted with EtOAc (100 mL) and washed with 5% of NaHCO3 (20 mL), and brine (20 mL). The organic layer was dried over MgSO4 and concentrated under vacuum. The residue was purified by prep. HPLC and silica gel column (using EtOAc) to give 6-(2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetyl)-2-oxo-1-phenyl-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carbonitrile (6.1 mg, 10.27 μmol, 4.42% yield). LCMS: m/z 535.09 (M+H)+, 1.65 min (method 7). 1H NMR (500 MHz, chloroform-d) δ ppm 11.07 (s, 1H) 9.05-9.12 (m, 1H) 8.18-8.27 (m, 1H) 7.45-7.78 (m, 5H) 7.14-7.21 (m, 2H) 4.50-4.73 (m, 2H) 3.95-4.04 (m, 3H) 3.64-3.90 (m, 2H) 2.53-2.57 (m, 3H) 2.42-2.50 (m, 2H).