Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:5]OC[CH2:2]1.I[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9]C=1.CCCC[N+:17]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19]CC.[F-]>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].C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:26]([N:17]1[CH2:18][CH:19]=[C:24]([C:25]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:7]=2)[CH2:23][CH2:22]1)[C:27]1[CH:28]=[CH:29][CH:5]=[CH:1][CH:2]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: Ic1ccccc1
Reactant: C1CCOC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [F-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C1=C(c2ccccc2)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
To a 4-mL vial, added 100 mg (0.28 mmol) (7) and 6 mg (0.0058 mmol) Pd2dba3-CHCl3. Next added 0.3 mL THF, 48 μL (0.43 mmol) iodobenzene, and finally 1.1 mL (1.1 mmol) TBAF solution (1M in THF). Let stir at room temperature for 18 hours. At the end of the reaction, added 200 μL triethylamine, let stir briefly, concentrated in vacuo, and purified the crude material directly by silica gel chromatography (automated column, 12 g SiO2, 0% to 20% EtOAc in hexanes gradient). Obtained 63 mg (90%) of 1-Benzyl-4-phenyl-1,2,3,6-tetrahydro-pyridine as a yellow oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:15]([O:19][C:20](=[O:28])[NH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20](=[O:28])[NH:21][CH:22]1[CH2:27][CH2:26][N:25]([C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][CH:3]=2)[CH2:24][CH2:23]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: Ic1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(Oc3ccccc3)cc2)CC1
Yield: 29.9 %

Procedure:
The title compound (1.1 g, 30%) was prepared from 1-iodo-4-phenoxy-benzene (2.9 g, 10 mmol) and piperidin-4-yl-carbamic acid tert-butyl ester (2 g, 10 mmol) by the procedure described in step 1 of Example 4: MS (ESI) m/z 368 (M+H); 1H NMR (400 MHz, CDCl3) δ 1.46 (s, 9H), 1.51-1.61 (m, 3H), 2.05 (br, 2H), 2.81 (dd, J=1.6, 12 Hz, 2H), 3.52 (m, 2H), 3.60 (br, 1H), 4.47 (br, 1H), 6.90-6.96 (m, 6H), 7.03 (m, 1H), 7.28 (m, 2).
Reaction SMILES: [CH3:1][C:2]1([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH3:13])[C:3]1=O.C([SiH](CC)CC)C.C(OCC)(=O)C.O>FC(F)(F)C(O)=O>[CH3:1][C:2]1([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH3:13])[CH2:3]1
Reactant: COC(=O)C1(C)CCc2c(OC)cccc2C1=O
Agent: CC[SiH](CC)CC
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(C)CCc2c(cccc2OC)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 211.9 %

Procedure:
To a solution of 2-methyl-2-methoxycarbonyl-5-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene (2.0 g) in trifluoroacetic acid (20 ml) was added triethylsilane (2.0 ml) at room temperature. After being stirred for 6 hours at room temperature, the solution was poured into a mixture of ethyl acetate and water. The organic layer was washed with 1N--HCl solution, sat. NaHCO3, and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 2-methyl-2-methoxycarbonyl-5-methoxy-1,2,3,4-tetrahydronaphthalene (4.0 g).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:12]1([O:17][C:18]2[C:19]([O:47][CH3:48])=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]([CH2:28][CH2:29][O:30]C2CCCCO2)[C:25](=[O:37])[CH:24]=[C:23]3[NH:38][C:39]2[C:44]([Cl:45])=[CH:43][N:42]=[CH:41][C:40]=2[Cl:46])[CH2:16][CH2:15][CH2:14][CH2:13]1>CO>[CH:12]1([O:17][C:18]2[C:19]([O:47][CH3:48])=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]([CH2:28][CH2:29][OH:30])[C:25](=[O:37])[CH:24]=[C:23]3[NH:38][C:39]2[C:40]([Cl:46])=[CH:41][N:42]=[CH:43][C:44]=2[Cl:45])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)n(CCOC3CCCCO3)c2c1OC1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)n(CCO)c2c1OC1CCCC1
Reaction time: 8 h

Procedure:
p-Toluenesulfonic acid (172 mg, 1.0 mmol) was added to a solution of 8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)quinolin-2(1H)-one (2.4 g, 4.4 mmol) and methanol (100 mL). After stirring overnight, the reaction was concentrated, diluted with dichloromethane (100 mL), and then washed with sat'd NaHCO3 (20 mL) followed by water (20 mL). The organic layer was dried, filtered, concentrated, and recrystallized from dichloromethane/petroleum ether (1:2) to give 8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-1-(2-hydroxyethyl)-7-methoxyquinolin-2(1H)-one: 1H NMR (400 MHz, DMSO-d6): δ 8.74 (s, 2H), 8.73 (s, 1H), 7.91 (d, 1H), 7.11 (d, 1H), 4.92 (s, 1H), 4.65 (t, 2H), 4.59 (m, 1H), 4.50 (t, 1H), 3.90 (s, 3H), 3.32 (m 2H), 1.80-1.48 (m, 8H); MS (ESI): 463.9.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[CH:4][C:3]=1[CH3:12].[Cl-].[Na+].[CH2:15]([Mg]Br)[CH3:16].Cl.O1CC[CH2:22][CH2:21]1>C(OCC)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])([CH2:15][CH3:16])[CH2:21][CH3:22])=[CH:4][C:3]=1[CH3:12]
Reactant: CC[Mg]Br
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: C1CCOC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Product: CCC(O)(CC)c1ccc(Br)c(C)c1
Temperature: 25 °C
Yield: 67 %

Procedure:
In a 4-liter SVL reactor equipped with a magnetic stirrer, a thermometer and a dropping funnel, introduce under nitrogen 198.7 g (0.867 mol) of methyl 4-bromo-3-methylbenzoate in solution in 1 liter of tetrahydrofuran. Cool the mixture to −5° C. with the aid of a bath of ice and sodium chloride. Add 636 cm3 of a 3M solution of ethylmagnesium bromide in diethyl ether, then allow the reaction temperature to increase to ambient temperature. After four hours of reaction, hydrolyze the reaction mixture with 2 liters of a 1 N hydrochloric acid solution. After decanting and separation, extract the aqueous phase with 0.5 liter of ethyl acetate. Wash the combined organic phases with 0.4 liter of water (3×). After drying over sodium sulfate, the product obtained after evaporation of the solvents is purified by chromatography on silica gel (heptane/ethyl acetate=95/5). This gives 150.2 g of 3-(4-bromo-3-methylphenyl)pentan-3-ol in the form of a colorless oil (Yield=67%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10]C)[CH:7]=[CH:6][C:4]=1[NH2:5].C[O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23]C)C(O)=O>>[OH:10][C:8]1[CH:7]=[CH:6][C:4]2[N:5]=[C:1]([C:20]3[CH:21]=[C:22]([OH:23])[C:14]([OH:13])=[CH:15][CH:16]=3)[O:2][C:3]=2[CH:9]=1
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: COc1ccc(N)c(OC)c1
Product: Oc1ccc2nc(-c3ccc(O)c(O)c3)oc2c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, from 2,4-dimethoxyaniline, and 3,4-dimethoxybenzoic acid and was obtained as a white solid, m.p. 282-284° C.; MS m/e 242 (M−H)+.
Reaction SMILES: [CH:1]([C:3]1[S:4][C:5]2[NH:6][C:7](=[O:16])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[N:15]=1)=[CH2:2].[CH3:17][NH:18][CH3:19]>C(Cl)Cl.CO>[CH3:17][N:18]([CH3:19])[CH2:2][CH2:1][C:3]1[S:4][C:5]2[NH:6][C:7](=[O:16])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[N:15]=1
Reactant: CNC
Reactant: C=Cc1nc2c([nH]c(=O)c3ccccc32)s1
Solvent: CO
Solvent: ClCCl
Product: CN(C)CCc1nc2c([nH]c(=O)c3ccccc32)s1
Temperature: 65 °C
Reaction time: 48 h
Yield: 63 %

Procedure:
To a suspension of 2-vinyl-4H-1,3-thiazolo[5,4-c]isoquinolin-5-one (0.05 g, 0.22 mmol) and CH2Cl2/methanol (6 ml; 1/1) was added dimethylamine (0.33 ml of 2M solution in THF, 0.66 mmol). After stirring at 65° C. for 48 hours, the reaction mixture was concentrated under reduced pressure and purified by flash-chromatography (CH2Cl2/methanol, 90/10). Recrystallization from methanol/diethyl ether yielded 0.038 g (a 63% yield) of the title compound as a white solid. m.p. 236-240° C. (dec.); 1H NMR (400 MHz, DMSO) δ 2.85 (s, 6H, (CH2)2N(CH3)2), 3.52-3.56 (m, 4H, (CH2)2N(CH3)2), 7.56-7.59 (m, 1H, Ar), 7.84-7.87 (m, 1H, Ar), 8.19-8.26 (m, 2H, Ar), 12.37 (bs, NH); 13C NMR (100.6 MHz, DMSO) δ 29.71, 44.26, 56.79, 124.03, 125.74, 128.69, 129.79, 133.45, 134.44, 135.15, 158.51, 162.72.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24]([NH2:27])[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Br:36])[CH:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:37]1[CH:42]=C[CH:40]=[CH:39][CH:38]=1.ClC(Cl)([O:46]C(=O)OC(Cl)(Cl)Cl)Cl.C1(N)CC1>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24]([NH:27][C:42]([NH:37][CH:38]3[CH2:40][CH2:39]3)=[O:46])[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Br:36])[CH:31]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: c1ccncc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCOc1c(-c2cccc(Br)c2)c(=O)[nH]c2cc(Cl)c(N)cc12
Agent: NC1CC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCCC1CCOc1c(-c2cccc(Br)c2)c(=O)[nH]c2cc(Cl)c(NC(=O)NC3CC3)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-{2-[6-amino-3-(3-bromophenyl)-7-chloro-2-oxo-1,2-dihydroquinolin-4-yloxy]-1-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (20 mg in 1.0 mL methylene chloride) at 0° C. was added 0.009 mL pyridine followed by 4 mg triphosgene and the mixture allowed to stir at 0° C. for 1 hour. At this time 0.012 mL of cyclopropylamine was added via syringe and the reaction mixture warmed to room temperature. After 2 hours, the mixture was diluted with 20 mL ethyl acetate and washed with saturated ammonium chloride (10 mL) and brine (10 mL). The organic portion was dried over magnesium sulfate then concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (hexane:ethyl acetate, 2:1; then 1:1; then 0:1) to give the title compound (14 mg).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Cl:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH2:8][OH:9].[N:14]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:33])[CH:31]=[CH2:32])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C>C1COCC1.CN(C=O)C>[Cl:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH2:8][O:9][C:1]([N:17]1[CH2:16][CH2:15][N:14]([S:20]([C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:30](=[O:33])[CH:31]=[CH2:32])=[CH:27][CH:28]=2)(=[O:21])=[O:22])[CH2:19][CH2:18]1)=[O:2]
Reactant: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCNCC2)cc1
Reactant: O=C(Cl)Cl
Reactant: OCc1ccccc1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCN(C(=O)OCc3ccccc3Cl)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 12 %

Procedure:
Phosgene (0.5 ml, 20% solution in toluene) was added in one portion to a stirred solution of 2-chlorobenzyl alcohol (0.1 g, 0.7 mmol) in THF (2 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After this time the reaction mixture was concentrated under vacuum and the resulting residue was diluted with DMF (2 ml) and added drop wise to a stirred solution of N-[4-(piperazine-1-sulfonyl)-phenyl]-acrylamide (0.16 g, 0.54 mmol) and diisopropylethylamine (0.19 ml, 1.1 mmol) in DMF (4 ml). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. After this time the reaction mixture was concentrated under vacuum and the residue was purified by Prep HPLC to give the title compound (0.029 g, 12% yield) as a white powder.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([N:20]=[C:21]=[O:22])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1.[NH2:25][OH:26]>C(Cl)Cl>[F:1][C:2]([F:23])([F:24])[C:3]1[CH:4]=[C:5]([NH:20][C:21](=[O:22])[NH:25][OH:26])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1
Reactant: O=C=Nc1ccc(Oc2ccc3ccccc3c2)c(C(F)(F)F)c1
Reactant: NO
Solvent: ClCCl
Product: O=C(NO)Nc1ccc(Oc2ccc3ccccc3c2)c(C(F)(F)F)c1
Yield: 97.5 %

Procedure:
3-Trifluoromethyl-4-(2-naphthyloxy)phenyl isocyanate (16.5 g) was dissolved in 100 ml of methylene chloride, and the resulting solution was added dropwise to 10 ml of an aqueous solution containing 4 g of hydroxylamine at a temperature below 20° C. Precipitated crystals were collected on a filter, washed with water and dried to obtain 17.7 g of N'-[3-trifluoromethyl-4-(2-naphthyloxy)phenyl]-N-hydroxyurea. Thereafter, 17.7 g of the product and 12.5 g of dimethyl sulfate were dissolved in 200 ml of toluene, and after addition of 0.16 g of tetra-n-butylammonium bromide to the mixture, 11 ml of 10 N sodium hydroxide were dropwise added thereto at 20°-22° C. After stirring at room temperature, the reaction mixture was diluted with water, followed by extraction with benzene. The benzene layer was washed with water, and the solvent was removed under reduced pressure. The oily substance obtained was purified by column chromatography (silica gel, 100-120 mesh; eluting solvent, tetrahydrofuran-benzene (1:3) mixture) to obtain 16.2 g of N'-[3-trifluoromethyl-4-(2-naphthyloxy)phenyl]-N-methoxy-N-methylurea. The product was confirmed to be the same product as obtained in Example 1 by IR, NMR, TLC and melting point.
Reaction SMILES: [F:1][C:2]1([F:12])[CH2:6]C(F)C(F)(F)[C:3]1([F:11])[F:10].[C:13]([O-:17])(=[O:16])[CH:14]=[CH2:15].CC1C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=1>>[F:1][C:2]([F:12])([CH:3]([F:11])[F:10])[CH2:6][OH:16].[C:13]([O-:17])(=[O:16])[CH:14]=[CH2:15]
Reactant: FC1CC(F)(F)C(F)(F)C1(F)F
Agent: C=CC(=O)[O-]
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Product: OCC(F)(F)C(F)F

Procedure:
To the 30 wt % 1,1,2,2,3,3,4-heptafluorocyclopentane solution of a perfluoropolyetherurethane acrylate composition, 0.06 g of butylhydroxytoluene was added, followed by dissolution while stirring. The resultant solution was warmed to 50° C. and 1,1,2,2,3,3,4-heptafluorocyclopentane was distilled off under reduced pressure (under about 100 mmHg for about 1.5 hours). 460 g of 2,2,3,3-tetrafluoropropanol was added and then distilled off under reduced pressure (under about 70 mmHg for about 2 hours) to obtain a 20 wt % 2,2,3,3-tetrafluoropropanol solution of a perfluoropolyetheracrylate composition (“20 wt % fluorine alcohol solution B of a perfluoropolyetherurethane acrylate composition”).
Reaction SMILES: [CH3:1][C:2]([C@H:4]1[C:7]([CH3:9])([CH3:8])[C@@H:6]([CH2:10][C:11]([OH:13])=[O:12])[CH2:5]1)=[O:3].[C:14](Cl)(=O)C(Cl)=O.CCN([CH:26]([CH3:28])[CH3:27])C(C)C>CN(C=O)C.C(O)(C)(C)C>[C:26]([O:12][C:11](=[O:13])[CH2:10][CH:6]1[CH2:5][CH:4]([C:2](=[O:3])[CH3:1])[C:7]1([CH3:8])[CH3:9])([CH3:28])([CH3:14])[CH3:27]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(=O)[C@@H]1C[C@H](CC(=O)O)C1(C)C
Reactant: O=C(Cl)C(=O)Cl
Solvent: CC(C)(C)O
Solvent: CN(C)C=O
Product: CC(=O)C1CC(CC(=O)OC(C)(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
S-Pinonic acid 5 (39.9 g, 216 mmol) was dissolved in a solution of oxalyl chloride (222 mL, 444 mmol, 2.0 M in CH2Cl2) and a few drops of DMF were then added. The solution was stirred at room temperature for 3 h, and the solvent was removed in vacuo. t-Butanol (389 mL) and DIEA (42.8 mL, 244 mmol) were added and the reaction mixture was stirred at room temperature for 16 hour before removing the solvent in vacuo. EtOAc (500 mL) was added to the slurry and was subsequently washed with H2O (500 mL) and saturated NaHCO3 (500 mL). The aqueous layers were combined and extracted with EtOAc (150 mL×2). The organic layers were combined and dried with brine and MgSO4 concentrated to yield crude 7. The oil was purified by chromatography (hexane-EtOAc, 5:1 to 4:1) to yield 7 (47.8 g, 93%) as a yellow liquid.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([CH:15]([O:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([N:27]2[C:32](=[O:33])[C:31]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([C:41]4[C:42]([C:47]#[N:48])=[CH:43][CH:44]=[CH:45][CH:46]=4)=[CH:37][CH:36]=3)=[C:30]([CH2:49][CH2:50][CH3:51])[N:29]3[N:52]=[CH:53][N:54]=[C:28]23)[CH2:23][CH2:22]1)[C:16]([OH:19])([CH3:18])[CH3:17])[CH3:14]>O>[CH2:13]([CH:15]([O:20][C@H:21]1[CH2:22][CH2:23][C@H:24]([N:27]2[C:32](=[O:33])[C:31]([CH2:34][C:35]3[CH:36]=[CH:37][C:38]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=4[C:47]4[NH:3][C:4](=[O:7])[O:5][N:48]=4)=[CH:39][CH:40]=3)=[C:30]([CH2:49][CH2:50][CH3:51])[N:29]3[N:52]=[CH:53][N:54]=[C:28]23)[CH2:25][CH2:26]1)[C:16]([OH:19])([CH3:17])[CH3:18])[CH3:14]
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(CC)C(C)(C)O)CC2)c2ncnn12
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OC(CC)C(C)(C)O)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.23 g), sodium hydrogen carbonate (0.37 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 4′-({4-[trans-4-(1-ethyl-2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.12 g) was added, and the mixture was stirred at 90° C. for 11 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.044 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.040 mL) were added, and the mixture was stirred at room temperature for 4 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 M hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.080 g, 56%).
Reaction SMILES: C1([C@H]([N:9]2[CH2:14][CH2:13][O:12][C@@H:11]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=3)[CH2:10]2)C)C=CC=CC=1.C([O-])=O.[NH4+].O1CCCC1.CO>[Pd].O>[NH:9]1[CH2:14][CH2:13][O:12][C@@H:11]([C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:19][CH:20]=2)[CH2:10]1
Reactant: CC(=O)Nc1ccc([C@H]2CN([C@H](C)c3ccccc3)CCO2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc([C@H]2CNCCO2)cc1
Temperature: 95 °C
Reaction time: 3 h
Yield: 131.2 %

Procedure:
To a solution of N-(4-((2S)-4-((1R)-1-phenylethyl)morpholin-2-yl)phenyl)acetamide (6.47 g, 20 mmol) and ammonium formate (6.3 g, 100 mmol) in mixture of tetrahydrofuran (136 ml), methanol (270 ml) and water (70 ml) was added 10% palladium on carbon (wet, 270 mg) and the solution was stirred at 95° C. for 3 hours. After filtration, the solvent was removed in vacuo and the residue was partitioned between water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give N-(4-((2S)-morpholin-2-yl)phenyl)acetamide (5.78 g, quant.) as an yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:28])[C:9]2[CH:27]=[CH:26][C:12]3[N:13]([CH3:25])[C:14]([NH:16][CH:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH3:18])=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:40])=[C:34]([S:36]([NH2:39])(=[O:38])=[O:37])[CH:35]=1>>[ClH:1].[CH3:40][C:33]1[CH:32]=[CH:31][C:30]([NH:29][C:2]2[N:7]=[C:6]([N:8]([CH3:28])[C:9]3[CH:27]=[CH:26][C:12]4[N:13]([CH3:25])[C:14]([NH:16][CH:17]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH3:18])=[N:15][C:11]=4[CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:35][C:34]=1[S:36]([NH2:39])(=[O:38])=[O:37]
Reactant: Cc1ccc(N)cc1S(N)(=O)=O
Reactant: CC(Nc1nc2cc(N(C)c3ccnc(Cl)n3)ccc2n1C)c1ccccc1
Product: Cc1ccc(Nc2nccc(N(C)c3ccc4c(c3)nc(NC(C)c3ccccc3)n4C)n2)cc1S(N)(=O)=O
Product: Cl

Procedure:
The title compound was prepared following the procedure of example one with N5-(2-Chloro-pyrimidin-4-yl)-1,N5-dimethyl-N2-(1-phenyl-ethyl)-1H-benzoimidazole-2,5-diamine (98 mg, 0.25 mmol) and 5-amino-2-methyl-benzenesulfonamide (46 mg, 0.25 mmol) as a white solid (90 mg, 63%). 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ 9.85 (br s, 2H), 8.52 (s, 1H), 7.83 (d, J=6.3 Hz, 1H), 7.65-7.68 (dd, J=8.1 and 1.8 Hz, 1H), 7.51-7.57 (m, 3H), 7.34-7.39 (m, 2H), 7.25-7.30 (m, 4H), 7.15-7.22 (m, 2H), 5.70 (d, J=6.3 Hz, 1H), 5.22 (m, 1H), 3.74 (s, 3H), 3.47 (s, 3H), 2.51 (s, 3H), 1.63 (d, J=6.6 Hz, 3H). MS (ESI) m/z=543 [M+H]+.
Reaction SMILES: C([O:5][C:6](=[O:46])[C:7]([O:10]/[N:11]=[C:12](/[C:33]1[N:34]=[C:35]([NH:38]C(OC(C)(C)C)=O)[S:36][CH:37]=1)\[C:13]([NH:15][C@H:16]1[C@@H:19]([CH2:20][N:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]2=[O:27])[N:18]([S:28]([OH:31])(=[O:30])=[O:29])[C:17]1=[O:32])=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:38][C:35]1[S:36][CH:37]=[C:33](/[C:12](=[N:11]/[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:46])=[O:5])/[C:13](=[O:14])[NH:15][C@H:16]2[C@@H:19]([CH2:20][N:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]3=[O:27])[N:18]([S:28]([OH:31])(=[O:29])=[O:30])[C:17]2=[O:32])[N:34]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2ccccc2=O)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1ccccc1=O)c1csc(N)n1)C(=O)O
Yield: 20.4 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (3S,4R)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-oxo-4-((2-oxopyridin-1(2H)-yl)methyl)azetidine-1-sulfonic acid (61 mg, 0.089 mmol), DCM (891 μL) and TFA (412 μl, 5.35 mmol). The crude residue 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 (9.6 mg, 19%) as a white powder. LCMS: Rt=0.57 min, m/z=529.1 (M+1) Method 2m_acidic_polar; 1H NMR (400 MHz, D2O) δ 7.59 (d, J=6.7 Hz, 1H), 7.56-7.48 (m, 1H), 7.05 (s, 1H), 6.50 (d, J=9.0 Hz, 1H), 6.39 (t, J=6.7 Hz, 1H), 5.30 (d, J=5.9 Hz, 1H), 4.47 (dd, J=14.5, 2.7 Hz, 1H), 4.07 (dd, J=14.5, 8.6 Hz, 1H), 1.37 (s, 3H), 1.36 (s, 3H).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH2:7]([C:11]1[O:15][N:14]=[C:13]([C:16]2[CH2:17][NH:18][CH2:19][CH2:20][CH:21]=2)[CH:12]=1)CCC.[C:22](N1CCC(Cl)=C(C2C=C(CCCC)ON=2)C1)(=[O:29])C1C=CC=CC=1>>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:22][O:29][CH2:7][C:11]1[O:15][N:14]=[C:13]([C:16]2[CH2:17][NH:18][CH2:19][CH2:20][CH:21]=2)[CH:12]=1
Reactant: CCCCc1cc(C2=CCCNC2)no1
Reactant: CCCCc1cc(C2=C(Cl)CCN(C(=O)c3ccccc3)C2)no1
Agent: O=C(O)C(=O)O
Product: COCc1cc(C2=CCCNC2)no1

Procedure:
3-(5-Butyl-3-isoxazolyl)-1,2,5,6-tetrahydropyridine oxalate starting from 1-benzoyl-4-chloro-3-(5-butyl-3-isoxazolyl)-1,2,5,6-tetrahydropyridine. M.p. 188°-91° C.