Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[N:7]=[C:8]([SH:11])[S:9][CH:10]=1)[CH3:2].[C:13]([O:17][C:18](=[O:21])[CH2:19]Br)([CH3:16])([CH3:15])[CH3:14]>>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[N:7]=[C:8]([S:11][CH2:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:21])[S:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)Cc1csc(S)n1
Reactant: CC(C)(C)OC(=O)CBr
Product: CCOC(=O)Cc1csc(SCC(=O)OC(C)(C)C)n1

Procedure:
The title compound was obtained by an operation similar to that of Example 2 and using (2-mercapto-1,3-thiazol-4-yl)acetic acid ethyl ester synthesized in Example 1 and bromoacetic acid tert-butyl ester to give {2-[(2-tert-butoxy-2-oxoethyl)thio]-1,3-thiazol-4-yl}acetic acid ethyl ester, followed by operations similar to those of Examples 3, 4 and 38.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1)[CH2:7][CH2:8][CH2:9][CH3:10].[C:19](OC(=O)C)(=[O:21])[CH3:20].C(N(CC)CC)C>ClCCl>[C:19]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1)[CH2:7][CH2:8][CH2:9][CH3:10])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCN(CCCCO)c1ccc(C=O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCN(CCCCOC(C)=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 249.4 g (1 mole) of 4-(N-4-hydroxybutyl-N-butylamino)benzaldehyde in dichloromethane are added 153.1 g (1.5 moles) of acetic anhydride, 151.8 g (1.5 moles) of triethylamine, and 8.5 g (7 mole %) of 4-N,N-dimethylaminopyridine. The reaction mixture is stirred at room temperature for 16 hours. The product solution is washed with cold 2N HCl and then with filtered through cotton, and evaporated to dryness.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]([OH:19])=O)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C(N(CC)CC)C.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>C(Cl)Cl.C1C=NC2N(O)N=NC=2C=1>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:19])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(C(=O)O)cc2C1
Reactant: C1COCCN1
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1Cc2ccc(C(=O)N3CCOCC3)cc2C1
Reaction time: 8 h

Procedure:
A mixture of N-t-butoxycarbonyl-5-carboxyisoindoline (D13) (300 mg), EDC (440 mg), HOAT (10 mg), triethylamine (0.4 ml) and morpholine (0.12 ml) in DCM (10 ml) was stirred overnight and then evaporated. The residue was redissolved in EtOAc (10 ml), washed with saturated NaHCO3 solution (10 ml), water (10 ml), brine (10 ml), dried (MgSO4) and evaporated. The residue was chromatographed on a silica gel flash column [step gradient 70-90% EtOAc in light petroleum 40-60] to give the title compound (D19) (314 mg). MS electrospray (+ion) 333 (MH+). 1H NMR δ (CDCl3): 7.30 (3H, m), 4.70 (2H, m), 4.67 (2H, m), 3.70 (8H, m), 1.52 (9H, s).
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[N:6]=[C:7]([C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2>C(O)C>[NH:2]([C:5]1[N:6]=[C:7]([C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2)[NH2:3]
Reactant: Cc1cccnc1-c1cc2cccnc2c(Cl)n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1cccnc1-c1cc2cccnc2c(NN)n1

Procedure:
To a solution of 98% hydrazine hydrate (7.4 g, 0.148 mol) in ethanol (100 mL) add 8-chloro-6-(3-methyl-2-pyridinyl)-1,7-naphthyridine (8.5 g, 0.0332 mol) and reflux for 2.5 hours. Concentrate the reaction mixture under reduced pressure, triturate the residual solid with water, filter and crystallize the isolated solid from benzene-petroleum ether to obtain the title compound, mp 115-6° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:10][CH2:9][C:8]2[C:11](=[O:20])[C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[C:14](=[O:15])[C:7]=2[CH2:6][CH2:5]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25](O)[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:17][O:16][C:13]1[C:14](=[O:15])[C:7]2[CH2:6][CH2:5][CH:4]([CH2:3][CH2:2][O:1][C:25]3[CH:24]=[C:23]([O:22][CH3:21])[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=3)[CH2:10][CH2:9][C:8]=2[C:11](=[O:20])[C:12]=1[O:18][CH3:19]
Reactant: COC1=C(OC)C(=O)C2=C(CCC(CCO)CC2)C1=O
Reactant: COc1cc(O)cc(OC)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC1=C(OC)C(=O)C2=C(CCC(CCOc3cc(OC)cc(OC)c3)CC2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.6 %

Procedure:
To a solution of 7-(2-hydroxyethyl)-2,3-dimethoxy-4,5,6,7,8,9-hexahydro-1H-benzo[a]cycloheptene-1,4-dione (103 mg), 3,5-dimethoxyphenol (168 mg) and triphenylphosphine (125 mg) in THF (2 ml) was added a solution of diethyl azodicarboxylate (81 mg) in THF (1 ml) at room temperature. The reaction mixture was stirred at room temperature for 2 hr and then concentrated in vacuo. The residue was purified by alumina column chromatography(ethyl acetate:hexane=1:4) and then with recrystallization from ethyl acetate-hexane to obtain the entitled compound (108 mg).
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][CH:6]=1)=[O:4].[NH2:22][C@H:23]([CH2:25][OH:26])[CH3:24]>>[OH:26][CH2:25][C@@H:23]([NH:22][C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][CH:6]=1)=[O:4])[CH3:24]
Reactant: CCCCc1noc(C)c1CCc1ncc(C(=O)OC)s1
Reactant: C[C@H](N)CO
Product: CCCCc1noc(C)c1CCc1ncc(C(=O)N[C@@H](C)CO)s1
Yield: 81 %

Procedure:
As described for example 58, 2-[2-(3-butyl-5-methyl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid methyl ester (90 mg, 0.29 mmol) was converted, using L-alaninol instead of rac-2-amino-1-propanol, to the title compound (50 mg, 81%) which was obtained as a colourless oil. MS: m/e=352.4 [M+H]+.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[CH:5][CH:4]=1.C[Si]([Br:25])(C)C>C(Cl)Cl>[Br:25][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[CH:5][CH:4]=1
Reactant: C[Si](C)(C)Br
Reactant: CN(C)C(=O)Nc1ccccc1-c1ccc(CO)cc1
Solvent: ClCCl
Product: CN(C)C(=O)Nc1ccccc1-c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of the intermediate obtained in Step B in 4 ml of methylene chloride was treated with 0.16 mL (1.21 mmol) of trimethylsilylbromide. The reaction mixture was stirred at room temperature for 18 hours. T he reaction mixture was diluted with methylene chloride then washed with aqueous saturated sodium chloride (2×). The organic layer was dried over magnesium sulfate, filtered and evaporated under vacuum to yield 133 mg of crude product. 1NMR (400 Hz, CDCl3): δ 2.78 (s, 6H), 4.5 (s, 2H), 6.4 (br s, 1H), 7.08 (t, 1H), 7.16 (dd, 1H), 7.34 (m, 4H), 7.49 (d, 1H), 8.10 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1.C1C(=O)N([Br:24])C(=O)C1>O1CCCC1>[Br:24][C:12]1[CH:13]=[N:14][N:15]([CH3:16])[C:11]=1[C:3]1[CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[S:6][C:2]=1[CH3:1]
Reactant: COC(=O)c1cc(-c2ccnn2C)c(C)s1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2c(Br)cnn2C)c(C)s1
Yield: 77.6 %

Procedure:
A solution of methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (580 mg, 2.45 mmol) and n-bromosuccinimide (437 mg, 2.45 mmol) in tetrahydrofuran (12.300 ml) was stirred in a sealed tube for 1 h at 70° C. The solution was then partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated then purified via column chromatography (silica, 20% EtOAc in hexanes) yielding methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate (600 mg, 1.90 mmol, 78% yield) as a yellow oil: LCMS (ES) m/e 314, 316 (M, M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([NH2:11])[CH:3]=1.[CH3:12][C:13]1[C:18]([C:19](O)=[O:20])=[CH:17][N:16]=[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:14]=1.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>CN(C=O)C>[CH3:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([NH:11][C:19]([C:18]2[C:13]([CH3:12])=[N:14][C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:16][CH:17]=2)=[O:20])[CH:3]=1
Reactant: Cc1cn(N)c2cccnc12
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1cc(C)c2ncccc21
Temperature: 150 °C
Reaction time: 1 h

Procedure:
A mixture of 3-methyl-pyrrolo[3,2-b]pyridin-1-yl amine (839 mg, <5.71 mmol), 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (1.32 g, 6.13 mmol), HATU (2.6 g, 6.85 mmol), DIPEA (2.21 g 17.1 mmol) in DMF (17 mL) is stirred at 150° C. for 1 h. The reaction is quenched with water and ether. The water layer is concentrated in vacuo. The residue is chromatographed through silica gel eluting with a mixture of DCM, MeOH and triethylamine (9.5:0.5:0.05) to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide (134 mg). MS: 345 345 (M+H); 1H NMR (300 MHz, CD3OD): δ 9.22 (s, 1H), 8.79 (d, 1H), 8.64 (d, 1H), 8.40(d, 1H), 8.05 (t, 1H), 7.87 (d, 1H), 7.60 (t, 1H), 7.49 (s, 1H) 7.30 (dd, 1H), 2.87 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[N:7][N:8]([CH3:14])[C:9]=1[C:10]([O:12]C)=[O:11])=[O:4].O.[OH-].[Li+:17]>C1COCC1.C(O)C.O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[N:7][N:8]([CH3:14])[C:9]=1[C:10]([O-:12])=[O:11])=[O:4].[Li+:17]
Reactant: COC(=O)c1nnn(C)c1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COC(=O)c1nnn(C)c1C(=O)[O-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
To a solution of 1-methyl-1H-[1,2,3]triazole-4,5-dicarboxylic acid dimethyl ester (1 g, 5.025 mmol) in THF (20 mL) and ethanol (5 mL) was added at 0° C. a solution of lithium hydroxide monohydrate (169 mg, 4.02 mmol) in water (5 mL) over a period of 10 min. The reaction mixture was allowed to stir at 0° C. for 3 h. The mixture was diluted with water (10 mL) and washed with ethyl acetate (2×50 mL). The aqueous layer was evaporated under reduced pressure and the crude material thus obtained was dried by azeotropic distillation with toluene to afford the product as white solid (0.6 g, 3.24 mmol, 64.5%).
Reaction SMILES: [OH-].[K+].C1(C)C=CC=CC=1.[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:12]=1[C:13]([OH:15])=[O:14].Cl[CH2:22][C:23]([NH2:25])=[O:24]>C(OCC)(=O)C.O>[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:12]=1[C:13]([O:15][CH2:22][C:23]([NH2:25])=[O:24])=[O:14]
Reactant: NC(=O)CCl
Reactant: O=C(O)c1c(Cl)cccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: NC(=O)COC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Yield: 48.4 %

Procedure:
A sample of 5.9 grams (0.105 mole) of potassium hydroxide was ground to a powder and placed in the reaction vessel. To this was added 270 ml of dry toluene, followed by 20.0 grams (0.105 mole) of 2,6-dichlorobenzoic acid. The stirred reaction mixture was heated under reflux while the water by-product was collected by azeotropic distillation using a Dean-Stark trap. A total of 2.8 ml of water was collected during a 30-minute period. At the end of this time the reaction mixture was cooled slightly and 2.0 grams of 1,4,7,10,13,16-hexaoxacyclooctadecane, followed by 9.8 grams (0.105 mole) of chloroacetamide were added. Upon completion of the addition the reaction mixture was heated under reflux for 18 hours. the reaction mixture was cooled to ambient temperature and the toluene layer was separated from the two-phase system and washed with one portion of 100 ml of water. An emulsion formed but was broken up by the addition of 100 ml of ethyl acetate. The organic layer was separated and dried with sodium sulfate. The mixture was filtered, and the filtrate evaporated under reduced pressure to a residual semi-solid. The solid was recrystallized twice from high-boiling petroleum ether-ethyl acetate using decolorizing carbon to give 12.6 grams of (aminocarbonyl)methyl 2,6-dichlorobenzoate; mp 113.5°-115.5°. The ir and the nmr spectra were consistent with the proposed structure.
Reaction SMILES: [CH2:1]([N:5]1[C:12](=[O:13])[C:11]2[CH2:14][CH:15]3[CH2:17][CH:6]1[CH:7]=[C:8]([S:18]([NH2:21])(=[O:20])=[O:19])[S:9][C:10]=2S3)[CH:2]([CH3:4])[CH3:3].OO[S:24]([O-:26])=[O:25].[K+].CO>O>[CH2:1]([N:5]1[C:12](=[O:13])[C:11]2[CH2:14][CH:15]3[CH2:17][CH:6]1[CH:7]=[C:8]([S:18]([NH2:21])(=[O:20])=[O:19])[S:9][C:10]=2[S:24]3(=[O:26])=[O:25])[CH:2]([CH3:4])[CH3:3]
Reactant: O=S([O-])OO
Reactant: CC(C)CN1C(=O)C2=C3SC(S(N)(=O)=O)=CC1CC(C2)S3
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)CN1C(=O)C2=C3SC(S(N)(=O)=O)=CC1CC(C2)S3(=O)=O
Reaction time: 24 h

Procedure:
5-Isobutyl-4-oxo-3,4,5,6-tetrahydro-2H-2,6-methanothieno[3,2-g]-1,5-thiazocine-8-sulfonamide (2 g, 5.8 mmol) was added to a mixture of Oxone® (10 g, 16.3 mmol) and methanol (25 ml). After 24 hours, the reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (3×50 ml). After drying over sodium sulfate, the solvent was evaporated under reduced pressure to yield 2.13 of a foam. A sample triturated with 1-chlorobutane gave material with mp 239°-241° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20]OS(C)(=O)=O)[CH2:15]3)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][N:37]4[CH2:38][CH2:39][N:34]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=5[O:27][CH3:26])[CH2:35][CH2:36]4)[CH2:15]3)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCC1CCCN(C(=O)C2(c3ccc(Cl)cc3)CCC2)C1
Reactant: COc1ccccc1N1CCNCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(CC2CCCN(C(=O)C3(c4ccc(Cl)cc4)CCC3)C2)CC1
Temperature: 25 °C
Yield: 43.1 %

Procedure:
To a solution of 2 (1.0 g, 2.60 mmol) in acetonitrile (25 mL) was added 1-(2-methoxyphenyl)piperazine (0.55 g, 2.86 mmol) and triethylamine (2 mL). The reaction was stirred and refluxed for 20 h. After cooling to room temperature, most of solvent was removed by rotary evaporation. The reaction mixture was partitioned between dichloromethane and water (50 mL each), and the organic layer was washed with sat. sodium carbonate (50 mL) and water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation. The organic residue was purified by flash chromatography on silica gel, eluting with dichloromethane/2.0 M ammonia in ethyl alcohol (96:4) to give 3 (0.54 g, 43%) as a light brown solid; C28H36ClN3O2, LRMS (m/z)=483 (MH+).
Reaction SMILES: B(C1C=CC(CCCC(O)=O)=CC=1)(O)O.[C:16]([C:18]1[CH:19]=[C:20]([NH:30][C:31](=[O:49])[CH2:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([B:41]3[O:46]CC(C)(C)C[O:42]3)=[CH:37][CH:36]=2)[CH:21]=[CH:22][C:23]=1[S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])#[N:17].[OH-].[Na+]>>[C:16]([C:18]1[CH:19]=[C:20]([NH:30][C:31](=[O:49])[CH2:32][CH2:33][CH2:34][C:35]2[CH:36]=[CH:37][C:38]([B:41]([OH:42])[OH:46])=[CH:39][CH:40]=2)[CH:21]=[CH:22][C:23]=1[S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])#[N:17]
Reactant: CC(C)S(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B3OCC(C)(C)CO3)cc2)cc1C#N
Agent: O=C(O)CCCc1ccc(B(O)O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)S(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Yield: 95.1 %

Procedure:
Using a procedure analogous to that used to prepare 2B, 9D (625 mg, 1.29 mmol) was reacted with NaOH to give 9E (508 mg, 95%) as a brown foam. MS (ESI) m/z 413.2 (M−H)−.
Reaction SMILES: [CH:1]1([NH:7][C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24](O)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:1]1([NH:7][C:8]([CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:31])[C:25]4[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:14][CH2:15]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cccnc1
Reactant: Nc1cccc(CN2CCC(C(=O)NC3CCCCC3)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(CN2CCC(C(=O)NC3CCCCC3)CC2)c1)c1cccnc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 1-(3-amino-benzyl)-piperidine-4-carboxylic acid cyclohexylamide BB-1 (200 mg, 0.57 mmol) in DCM (5 mL) are added successively nicotinic acid (70 mg, 0.57 mmol), HOBT (154 mg, 1.14 mmol), DMAP (14 mg, 0.11 mmol) and DIPEA (0.29 mL, 1.7 mmol). A solution of EDC hydrochloride (163 mg, 0.85 mmol) in DCM (2 mL) is added and the reaction mixture is stirred for 4 days at RT. The mixture is diluted with DCM (10 mL) and washed twice with sat.aq. NaHCO3 (20 mL). The combined organic phases are dried over MgSO4 and filtered. The solvent is evaporated under reduced pressure. The residue is dissolved in acetonitrile and purified by prep. HPLC E. LCMS C: tR=0.56 min; [M+H]+=421.4. 1H-NMR (DMSO-d6): δ 1.1-1.3 (m, 5H), 1.5-1.7 (m, 9H), 1.8-1.9 (m, 2H), 2.0-2.1 (m, 1H), 2.84 (d, J=9, 2H), 3.4-3.5 (m, 3H), 7.03 (d, J=7, 1H), 7.30 (t, J=7, 1H), 7.5-7.8 (m, 4H), 8.29 (d, J=8, 1H), 8.7-8.8 (m, 1H), 9.11 (s, 1H), 10.4 (s, 1H).
Reaction SMILES: C(OC([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][C:23]3([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][N:32]=[C:31](Cl)[N:30]=4)[CH2:25][CH2:24]3)=[CH:16][CH:17]=2)[CH2:12]1)=O)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[C].[Pd]>[CH2:39]([O:38][C:36]([C:23]1([CH2:22][O:21][C:15]2[CH:14]=[C:13]3[C:18]([CH2:19][CH2:20][NH:11][CH2:12]3)=[CH:17][CH:16]=2)[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][N:30]=2)[CH2:25][CH2:24]1)=[O:37])[CH3:40]
Reactant: CCOC(=O)C1(COc2ccc3c(c2)CN(C(=O)OCc2ccccc2)CC3)CCN(c2ccnc(Cl)n2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C1(COc2ccc3c(c2)CNCC3)CCN(c2ccncn2)CC1
Yield: 146.3 %

Procedure:
To a solution of 7-[1-(2-chloropyrimidin-4-yl)-4-ethoxycarbonylpiperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (263 mg) in ethanol(5 ml) were added 7.5% palladium carbon (120 mg) and ammonium formate (200 mg) with ice-cooling, and the mixture was stirred under reflux for 30 min. After completion of the reaction, the solvent was evaporated and water was added to the obtained residue. The mixture was extracted with chloroform and the organic layer was washed with aqueous sodium hydrogencarbonate solution and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dried under reduced pressure to give the title compound (270 mg).
Reaction SMILES: [OH:1]/[N:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[O-]Cl.[Na+].[C-:26]#[N:27].[K+]>C(Cl)Cl.[Cl-].[Na+].O>[C:26](/[C:3](=[N:2]\[OH:1])/[C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)=[CH:8][CH:9]=1)#[N:27]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(/C=N/O)cc2)CC1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(/C(C#N)=N/O)cc2)CC1
Reaction time: 1 h

Procedure:
To tert-butyl 4-{4-[(E)-(hydroxyimino)methyl]phenyl}piperazine-1-carboxylate (1.593 g, 5.22 mmol) in CH2Cl2 (25 mL) was gradually added Javex (approx. 10% NaOCl, 19.5 mL,.26.1 mmol) and the reaction mixture stirred for 1 hour. Potassium cyanide (3.4 g, 52.2 mmol) was added and the reaction stirred for 1 hour. The reaction was poured into brine and the product extracted with EtOAc (2×), dried over Na2SO4, concentrated in vacuo with silica gel (to pre-adsorb product on silica gel) and purified by flash chromatography over silica gel (EtOAc/Hex, 1/1) to afford tert-butyl 4-(4-[(Z)-cyano(hydroxyimino)methyl]phenyl}piperazine-1-carboxylate.
Reaction SMILES: C(O[C:5]([C:7]1[N:8]([NH:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH:9]=[CH:10][CH:11]=1)=[O:6])C=C.[CH3:18][S:19]([N:22]([CH3:39])[C:23]1[CH:38]=[CH:37][C:26]2[NH:27][C:28]([CH2:33][C:34](O)=[O:35])=[CH:29][S:30](=[O:32])(=[O:31])[C:25]=2[CH:24]=1)(=[O:21])=[O:20].[O-]CC.[Na+].C(O)C>ClCCl.CN(C)C=O>[OH:6][C:5]1[C:7]2[N:8]([CH:9]=[CH:10][CH:11]=2)[N:12]([CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[C:34](=[O:35])[C:33]=1[C:28]1[NH:27][C:26]2[CH:37]=[CH:38][C:23]([N:22]([CH3:39])[S:19]([CH3:18])(=[O:21])=[O:20])=[CH:24][C:25]=2[S:30](=[O:31])(=[O:32])[CH:29]=1
Reactant: CN(c1ccc2c(c1)S(=O)(=O)C=C(CC(=O)O)N2)S(C)(=O)=O
Reactant: C=CCOC(=O)c1cccn1NCCC(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: ClCCl
Product: CC(C)CCn1c(=O)c(C2=CS(=O)(=O)c3cc(N(C)S(C)(=O)=O)ccc3N2)c(O)c2cccn21
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.2 %

Procedure:
1-(3-Methyl-butylamino)-1H-pyrrole-2-carboxylic acid allyl ester (Example 1c, 0.112 g, 0.473 mmol) and [7-(methanesulfonyl-methyl-amino)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl]-acetic acid (Example 7e, 0.164 g, 0.473 mmol) were dissolved in a 3:1 mixture of dichloromethane and N,N-dimethylformamide (4 mL) at 25° C. A solution of N,N-dicyclohexylcarbodiimide (0.473 mL, 1.0 M in dichloromethane, 0.473 mmol) was added and the reaction mixture was stirred at 25° C. for 1 h then filtered. The filtrate was concentrated in vacuo and the residue was dissolved in ethanol (4 mL) at 25° C. A 21% solution of sodium ethoxide in ethanol (0.368 mL, 1.14 mmol) was added and the reaction mixture was heated at 80° C. for 6 h. After cooling to 25° C., the mixture was partitioned between 0.5 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Sequential purification of the residue by flash column chromatography (Merck silica gel 60, 40-63 μm, 5{tilde over (0)}→100% ethyl acetate in hexanes) and preparative HPLC [column=Luna 5μ C18(2) 100 Å Axia 50×21.2 mm Id; eluent=0→100% acetonitrile in water (both containing 0.05% trifluoroacetic acid) over 7.0 min, flow=30 mL/min] afforded the desired product, N-{3-[4-hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-7-yl}-N-methyl-methanesulfonamide (0.060 g, 0.119 mmol, 25% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 0.94 (6H, d, J=6.4 Hz), 1.50-1.54 (2H, m), 1.64-1.70 (1H, m), 2.99 (3H, bs), 3.28 (3H, bs), 4.29-4.32 (2H, m), 5.74 (1H, s), 6.12 (1H, bs), 6.49 (1H, bs), 6.90 (1H, bs), 7.30 (1H, bs), 7.60 (1H, bs), 7.82 (1H, bs). LC-MS (ESI) calcd for C22H26N4O6S2 506.13, found 507.25 [M+H+].