Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3]([NH2:14])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[Br:17][C:18]1[CH:19]=[CH:20][C:21]([O:28][CH3:29])=[C:22]([S:24](Cl)(=[O:26])=[O:25])[CH:23]=1>N1C=CC=CC=1.C(O)(=O)C.C(OCC)(=O)C>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([O:28][CH3:29])=[C:22]([S:24]([NH:14][CH:3]([CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)[C:2]([F:1])([F:15])[F:16])(=[O:25])=[O:26])[CH:23]=1
Reactant: COc1ccc(Br)cc1S(=O)(=O)Cl
Reactant: NC(Cc1c[nH]c2ccccc12)C(F)(F)F
Solvent: CC(=O)O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc(Br)cc1S(=O)(=O)NC(Cc1c[nH]c2ccccc12)C(F)(F)F
Temperature: 65 °C
Reaction time: 16 h
Yield: 31.4 %

Procedure:
A mixture of 100 mg (0.44 mmol) of 2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethylamine and 143 mg (0.50 mmol) of 5-bromo-2-methoxybenzenesulfonyl chloride in 4 mL of pyridine was warmed at 65° C. After 16 hours, the mixture was cooled and concentrated to afford a thick oily residue. The residue was diluted with 10% acetic acid and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, decanted, and concentrated in vacuo. The crude material was purified by preparative TLC using ethyl acetate-hexanes (15:85). Material from the plate was isolated by suspending the silica gel in ethyl acetate followed by filtration. The filtrate was concentrated in vacuo to afford 66 mg (32%) of the title compound as a crystalline solid.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:8][CH2:7][CH2:6][N:5]([C:9](=[NH:12])[CH2:10][SH:11])[CH2:4]1.C1(S([C:21]2[CH:22]([CH3:45])[C@@H:23]3[C@@H:40]([C@H:41]([OH:43])[CH3:42])[C:39](=[O:44])[N:24]3[C:25]=2[C:26]([O:28]CC2C=CC([N+]([O-])=O)=CC=2)=[O:27])=O)C=CC=CC=1.C(OCC)C>CS(C)=O.C(#N)C>[O:2]=[C:3]1[NH:8][CH2:7][CH2:6][N:5]([C:9](=[NH:12])[CH2:10][S:11][C:21]2[C@H:22]([CH3:45])[C@@H:23]3[C@@H:40]([C@H:41]([OH:43])[CH3:42])[C:39](=[O:44])[N:24]3[C:25]=2[C:26]([OH:28])=[O:27])[CH2:4]1
Reactant: N=C(CS)N1CCNC(=O)C1
Reactant: CC1C(S(=O)c2ccccc2)=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@@H]12
Agent: Cl
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(SCC(=N)N3CCNC(=O)C3)[C@H](C)[C@H]12
Reaction time: 0.5 h

Procedure:
A suspension of 108 mg of 2-(3-oxopiperazin-1-yl)-2-iminoethylmercaptan hydrochloride in 0.8 ml of dimethyl sulfoxide was added, under ice-cooling, to a solution of 130 mg of p-nitrobenzyl (1RS,5S,6S)-2-phenylsulfinyl-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate in 1.4 ml of acetonitrile, and the mixture was stirred for 30 minutes. The reaction mixture was then poured into 50 ml of anhydrous diethyl ether, and the solvent was decanted off. The oily residue was dissolved in a mixture of 8 ml of tetrahydrofuran, 2.7 ml of water and 9.4 ml of 0.1M phosphate buffer solution (pH 7.0), and the resulting solution was subjected to catalytic hydrogenation at room temperature for 2 hours in the presence of 160 mg of palladium-carbon. The insolubles were filtered off over "Celite" (Trade Mark) filter aid, and the filtrate was extracted twice with 30 ml portions of diethyl ether. The aqueous phase was concentrated by evaporation under reduced pressure and the residue was purified through a Lobar column (Merck "LiChloprep RP-8", size B, two columns), eluted with 5% aqueous methanol, to give the title compound having the same properties as those of the product obtained in Example 13.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[OH-].[Li+]>O1CCCC1>[N:9]1([C:2]2[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=2)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: C1CNCCN1
Reactant: O=Cc1cnc(Cl)s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=Cc1cnc(N2CCNCC2)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 37.2 %

Procedure:
To a solution of 2-chlorothiazole-5-carboxaldehyde (Example 53; 378 mg, 2.6 mmol) in aqueous tetrahydrofuran (9.75 mL tetrahydrofuran, 0.25 mL of water, 40:1) at 25° C. was added piperazine (0.55 g, 6.4 mmol) followed by lithium hydroxide (129 mg, 3.0 mmol). After stirring for 24 h at room temperature, the solvents were removed under reduced pressure. The residual solid was diluted with water (50 mL) and neutralized to pH 7 with 1N hydrochloric acid solution. The resulting solids were filtered, washed with water, dried under vacuum and flash chromatographed (silica gel, 10% methanol in dichloromethane) to yield 2-(piperazin-1-yl)thiazole-5-carboxaldehyde (191 mg, 38% yield) as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C([O-])=O.[C:34]([C@H:37]1[CH2:41][CH2:40][NH2+:39][CH2:38]1)([OH:36])=[O:35].CCN(C(C)C)C(C)C>ClCCCl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:39]3[CH2:40][CH2:41][C@H:37]([C:34]([OH:36])=[O:35])[CH2:38]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCC(F)(F)CC1
Reactant: O=C(O)[C@H]1CC[NH2+]C1
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC[C@H](C(=O)O)C3)ccc2n1CC1CCC(F)(F)CC1
Reaction time: 2 h

Procedure:
2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (1.2 g, 2.9 mmol) was added to a solution of (3S)-3-carboxypyrrolidinium trifluoroacetate (0.50 g, 2.3 mmol) and DIPEA (3 mL, 17 mmol) in DCE (20 mL) at 80° C. The reaction mixture was stirred for 2 hrs. and the solvent was concentrated. The product was purified by MPLC on silica gel using 30% acetone in DCM containing 1% of AcOH to provide the title compound as white solid. Yield: 600 mg (42%); MS (ESI) (M+H)+=484.1.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[NH:18]1[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19]1.C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[OH:23][CH:20]1[CH2:21][CH2:22][N:18]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]4[CH2:17][CH2:16]4)=[O:14])[N:8]=[CH:9]3)=[CH:4][CH:3]=2)[CH2:19]1
Reactant: OC1CCNC1
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: O=C(Nc1cc2ccc(N3CCC(O)C3)cc2cn1)C1CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 16.1 %

Procedure:
Dioxane (50 mL) was added to a mixture of N-(7-bromoisoquinolin-3-yl)cyclopropanecarbox-amide (200 mg, 0.69 mmol), pyrrolidin-3-ol (122 mg, 1.28 mmol), Pd2(dba)3 (120 mg, 0.14 mmol), biphenyl-2-yldi-tert-butylphosphine (78 mg, 0.25 mmol) and sodium tert-butoxide (80 mg, 0.82 mmol). After the reaction mixture was stirred at 100° C. under nitrogen overnight, the mixture was filtered, concentrated and purified by prep HPLC and prep TLC to give the product (33.1 mg, 16.2%). LCMS (ESI): RT (Min)=0.86, M+H+=298.0, method=B. 1H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.82 (s, 1H), 8.22 (s, 1H), 7.65 (d, J=9.2 Hz, 1H), 7.19 (d, J=9.2 Hz, 1H), 6.80 (s, 1H), 4.99 (s, 1H), 4.45 (s, 1H), 3.50-3.48 (m, 1H), 3.45-3.36 (m, 2H), 3.20-3.12 (m, 1H), 2.25-2.05 (m, 1H), 1.85-2.05 (m, 2H), 0.80-0.75 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19](Br)=[CH:20][N:21]=2)[N:18]=1)[CH3:12])([CH3:4])([CH3:3])[CH3:2].[C:24]([C:27]1[S:31][C:30](B(O)O)=[CH:29][CH:28]=1)(=[O:26])[CH3:25].O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].ClCCl>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([C:30]3[S:31][C:27]([C:24](=[O:26])[CH3:25])=[CH:28][CH:29]=3)=[CH:20][N:21]=2)[N:18]=1)[CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(CCCNC(=O)OC(C)(C)C)c1ccc2ncc(Br)n2n1
Reactant: CC(=O)c1ccc(B(O)O)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: CC(=O)c1ccc(-c2cnc3ccc(N(C)CCCNC(=O)OC(C)(C)C)nn23)s1

Procedure:
(3-{[3-(5-Acetyl-thiophen-2-yl)-imidazo[1,2-b]pyridazin-6-yl]-methyl-amino}-propyl)-carbamic acid tert-butyl ester was prepared and isolated similarly to the procedure detailed in example 5.6.17 from a mixture of {3-[(3-bromo-imidazo[1,2-b]pyridazin-6-yl)-methyl-amino]-propyl}-carbamic acid tert-butyl ester (0.5 g, 1.3 mmol), 5-acetyl-2-thiopheneboronic acid [206551-43-1] (0.3 g, 1.5 mmol), potassium phosphate tribasic monohydrate [27176-10-9] (0.5 g, 2.5 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane [95464-05-4] (0.1 g, 0.1 mmol) in a solution of 30% (v/v) water in 1,2-dimethoxyethane (30 mL) to afford 0.16 g of yellow powder, mp. 148-149° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.37 (s, 9H) 1.78 (quin, J=6.95 Hz, 2H) 2.54 (s, 3H) 3.05 (q, J=6.57 Hz, 2H) 3.17 (s, 3H) 3.61 (t, J=7.20 Hz, 2H) 6.88 (br. s., 1H) 7.12 (d, J=9.85 Hz, 1H) 7.82 (d, J=4.29 Hz, 1H) 7.92 (d, J=9.85 Hz, 1H) 7.97 (d, J=4.04 Hz, 1H) 8.20 (s, 1H). LRMS (ESI) m/z 430.1 [(M+H)]+, calc'd for C21H27BN5O3S: 429.55.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](SC)=[N:7][CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1.[NH3:23]>C(OCC)(=O)C>[NH2:23][C:8]1[C:9]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2)[CH:5]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH2:6][N:7]=1
Reactant: N
Reactant: CSC1=NCC(c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc21
Solvent: CCOC(C)=O
Product: NC1=NCC(c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc21
Reaction time: 15 h

Procedure:
A solution of 0.45 g of 6-chloro-1-methylthio-4-(4-nitrophenyl)-3,4-dihydroisoquinoline and 30 ml of ammonia-saturated THF solution was heated in an autoclave at 80° C. for 10 hours and then at 12° C. for a further 15 hours. Subsequent MPLC on an MPRC cartridge and a mixture of 20 parts by volume of ethyl acetate:10 parts by volume of n-heptane:3 parts by volume of glacial acetic acid leads to elution of starting material (6-chloro-1-methylthio-4-(4-nitrophenyl)-3,4-dihydroisoquinoline). Subsequent elution with methanol results in 1-amino-6-chloro-4-(4-nitrophenyl)-3,4-dihydroisoquinoline.
Reaction SMILES: [CH3:1][N:2](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][C:30]([OH:32])=O.CN.C(O)C>CN(C)C=O.C(Cl)Cl.C(OCC)(=O)C>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][C:30]([NH:2][CH3:1])=[O:32]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)Cc1ccccc1Cl
Agent: CN
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)Cc1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 78.4 %

Procedure:
At 0° C., 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (28.1 g, 0.15 mol) was added to a solution of 1-hydroxybenzotriazole (19.8 g, 0.15 mol) and 2-chlorophenylacetic acid (Aldrich 19,063-2, 25.0 g, 0.15 mol) in N,N-dimethylformamide (150 ml) and DCM (50 ml). The reaction mixture was stirred for 20 min at 0° C. A 33% solution of methylamine in ethanol (365 ml, 2.9 mol) was added. The reaction mixture was stirred for 56 hours at room temperature. It was diluted with ethyl acetate (300 ml) and washed with a 10% aqueous solution of sodium hydrogensulphate (400 ml). The aqueous phase was extracted with ethyl acetate (2×150 ml). The combined organic layers were washed with a saturated solution of sodium hydrogencarbonate (400 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (300 g), using ethyl acetate/heptane 2:1 as eluent, to give 21.6 g of 2-(2-chlorophenyl)-N-methylacetamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[C:13](=O)[CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.Cl.[NH2:21][OH:22].N1C=CC=CC=1.O>CO>[OH:22]/[N:21]=[C:13](/[C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH:7]=[CH:8][CH:9]=1)\[CH2:14][NH:15][C:16](=[O:18])[CH3:17]
Reactant: NO
Reactant: COc1ccc2cccc(C(=O)CNC(C)=O)c2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CO
Product: COc1ccc2cccc(/C(CNC(C)=O)=N/O)c2c1

Procedure:
In a 100-ml round-bottom flask, the compound obtained in Step G (4.2 mmol) is dissolved in 25 ml of methanol. Hydroxylamine hydrochloride (16.8 mmol) and pyridine (21.1 mmol) are added and then the reaction mixture is heated at reflux, with magnetic stirring, for 3 hours. After cooling, the reaction mixture is poured into 50 ml of water. The precipitate formed is filtered off under suction, washed with water and recrystallised from toluene to yield the title product in the form of a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([CH2:17][OH:18])[N:13]=[CH:12][C:11]=2[C:10]([CH3:20])([CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([CH2:17][O:18][S:29]([CH3:28])(=[O:31])=[O:30])[N:13]=[CH:12][C:11]=2[C:10]([CH3:20])([CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(CO)cc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(COS(C)(=O)=O)cc21
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To 6-hydroxymethyl-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (0.268 g, 0.96 mmol) and triethylamine (0.417 mL, 3 mmol) in EtOAc (4.8 mL) was added methanesulfonyl chloride (0.224 mL, 2.9 mmol) at 0° C. The reaction was stirred at the same temperature for 1 h. Water (5 mL) was added and the aqueous mixture extracted with EtOAc (3×5.0 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and the solvent removed in vacuo to give the title compound (0.279 g,) as a pale yellow oil. MS: [M+H]+=357.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.Cl>[CH2:21]([O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10]
Reactant: CCCCCCCCCCCCBr
Reactant: Oc1ccc(I)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOc1ccc(I)cc1

Procedure:
4-Iodophenol (3.03 g, 1.38×10−2 mol), 1-bromododecane (6.65 ml, 2.77×10−2 mol) and K2CO3 (3.81 g, 2.76×10−2 mol) were dissolved in 50 ml of dry DMF and refluxed for 3.5 h under N2. After cooling, the solution was diluted with water, 2M HCl, and extracted with CH2Cl2. The combined organic layers were washed with saturated aq. NaHCO3, water, and dried over Na2SO4. The product was chromatographed on silica gel with 3:1 hexane:CHCl3 as the eluent. Yield=5.274 g (98% based on 3.03 g of 4-iodophenol). 1H NMR (250 MHz, CDCl3): δ 7.53 (d, 2H, J=8.8 Hz, Ph), 6.67 (d, 2H, J=9.0 Hz, Ph), 3.90 (t, 2H, J=6.5 Hz, —OCH2—), 1.76 (quint, 2H, J=6.6 Hz, —OCH2CH2—), 1.13-1.48 (m, 18H, —CH2—), 0.88 (t, 3H, J=6.4 Hz, —CH3). CI MS m/z: 388.125 (M+) (calcd 388.126).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:15](=[O:23])[CH:16]=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14].O>CN(C)C=O.[Cu]Cl>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:15]([C:16]1[NH:3][N:2]=[N:1][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C=CC(=O)c1ccc(OC)c(OC)c1
Agent: Cl[Cu]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nn[nH]c1C(=O)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
Copper(I) chloride (7.5 mg, 0.075 mmol) was added at room temperature to a solution (1.0 mL) of sodium azide (74 mg, 1.1 mmol) in N,N-dimethylformamide. A solution (1.5 mL) of ethyl 4-(3,4-dimethoxyphenyl)-4-oxo-2-butenate (200 mg, 0.76 mmol) in N,N-dimethylformamide was added to this mixed solution at 5° C. The temperature of the reaction solution was raised to room temperature before the reaction solution was stirred for 8 hr. After the completion of the reaction, the reaction solution was poured into iced water, and the mixture was extracted with a saturated aqueous sodium hydrogencarbonate solution. The aqueous layer was adjusted to pH 1.8 by the addition of 2 N hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then removed by evaporation under the reduced pressure. The oil thus obtained was dried in vacuo to give ethyl 5-(3,4-dimethoxybenzoyl)-1H-1,2,3-triazole-4-carboxylate (149 mg, 65%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][C:44]([NH2:50])([C:47](=[O:49])[NH2:48])[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].[F:51][C:52]1[CH:60]=[C:59]([C:61]([F:64])([F:63])[F:62])[CH:58]=[CH:57][C:53]=1[C:54](O)=[O:55]>CN(C=O)C>[C:34]([O:38][C:39]([N:41]1[CH2:42][CH2:43][C:44]([C:47](=[O:49])[NH2:48])([NH:50][C:54](=[O:55])[C:53]2[CH:57]=[CH:58][C:59]([C:61]([F:62])([F:63])[F:64])=[CH:60][C:52]=2[F:51])[CH2:45][CH2:46]1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C(N)=O)CC1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc(C(F)(F)F)cc2F)(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
HATU (939 mg, 2.47 mmol) and DIPEA (525 μL, 3.09 mmol) were added to a solution of 4-amino-4-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 2.06 mmol) and 2-fluoro-4-trifluoromethyl-benzoic acid (514 mg, 2.47 mmol) in DMF (10 mL). The mixture was stirred at room temperature for 19 hours and then quenched with a saturated aqueous ammonium chloride solution. The reaction mixture was diluted with EtOAc, and the organic layer was then washed with H2O and saturated brine, dried over MgSO4 and concentrated under reduced pressure. The resulting residue was triturated with n-hexane and EtOAc and then collected by filtration to give 4-carbamoyl-4-(2-fluoro-4-trifluoromethyl-benzoylamino)-piperidine-1-carboxylic acid tert-butyl ester as a white solid. This was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:7][C:6]2[CH:8]=[CH:9][C:10]([CH2:12][CH:13]([N:15]([CH2:22][CH3:23])[C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH3:14])=[CH:11][C:5]=2[O:4]1.[C:24]1(=[O:30])[O:29][C:27](=[O:28])[CH2:26][CH2:25]1.C(N(CC)CC)C>ClCCCl.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH2:22]([N:15]([C:16](=[O:21])[C:17]([F:18])([F:20])[F:19])[CH:13]([CH3:14])[CH2:12][C:10]1[CH:9]=[CH:8][C:6]2[O:7][CH:3]([CH2:2][NH:1][C:24](=[O:30])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])[O:4][C:5]=2[CH:11]=1)[CH3:23]
Reactant: CCN(C(=O)C(F)(F)F)C(C)Cc1ccc2c(c1)OC(CN)O2
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCN(C(=O)C(F)(F)F)C(C)Cc1ccc2c(c1)OC(CNC(=O)CCC(=O)O)O2
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 86.8 %

Procedure:
To a solution of 558 mg (1.67 mmol) of 2J in 25 mL of 1,2 dichloroethane was added 435 mg (4.34 mmol) of succinic anhydride, 280 μL (2 mmol) of triethylamine and 112 mg (0.91 mmol) of 4-DMAP. The reaction mixture was allowed to stir at 40° C. under argon atmosphere for 2.5 hours. It was then diluted with 50 mL of ethyl acetate and washed with 3×30 mL of 5% ammonium chloride solution. The organic layer was dried (anhydrous Na2SO4) and concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography to give 629 mg (1.45 mmol, 86%) of 2K as a colorless gum (M+H, 433).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:5]=[C:4]([CH:17]=[O:18])[C:3]=1[Cl:19].CC(=CC)C.P([O-])([O-])(O)=[O:26].[Na+].[Na+].Cl([O-])=O.[Na+]>O.C(O)(C)(C)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[N:5]=[C:4]([C:17]([OH:26])=[O:18])[C:3]=1[Cl:19]
Reactant: O=P([O-])([O-])O
Reactant: Nc1c(F)c(Cc2ccc(F)cc2)nc(C=O)c1Cl
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: Nc1c(F)c(Cc2ccc(F)cc2)nc(C(=O)O)c1Cl
Temperature: 70 °C

Procedure:
A microwave vial equipped with a magnetic stir bar was charged with 4-amino-3-chloro-5-fluoro-6-(4-fluorobenzyl)picolinaldehyde (280 mg, 0.991 mmol) and t-butanol (4.95 mL). The mixture was treated with H2O (1.651 mL), 2-methylbut-2-ene (0.94 mL, 0.991 mmol), sodium hydrogenphosphate (281 mg, 1.981 mmol), and finally sodium chlorite (269 mg, 2.97 mmol) was added in one portion. The mixture was heated to 70° C. in the microwave for 2 h. An aliquot of the reaction mixture was analyzed by LC-MS. LC-MS analysis showed one major product with the correct mass for the desired product. The reaction mixture was diluted with EtOAc (15 mL) and washed with 1 M HCl (1×5 mL), H2O (1×5 mL) and saturated NaCl (1×5 mL). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The crude material was stirred with Et2O (5 mL). After stiffing, the solid was removed by vacuum filtration washing with Et2O. The solid was air-dried for several hours and then dried under vacuum. 4-Amino-3-chloro-5-fluoro-6-(4-fluorobenzyl)picolinic acid (40 mg, 12.84%) was isolated as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 11.60 (s, 1H), 7.22 (m, 2H), 7.00 (m, 2H), 5.03 (s, 2H), 4.08 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −115.76, −139.38; ESIMS m/z 297 ([M−H]−).