Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH3:12])[N:4]([CH2:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([NH2:19])=[O:18])[N:3]=1.[CH3:23][C:24]1[S:28][C:27]([S:29](Cl)(=[O:31])=[O:30])=[CH:26][CH:25]=1.CS(C)=O>N1C=CC=CC=1>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[C:2]([NH:1][S:29]([C:27]1[S:28][C:24]([CH3:23])=[CH:25][CH:26]=1)(=[O:31])=[O:30])=[N:3][N:4]2[CH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([NH2:19])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)s1
Reactant: COc1cccc2c1c(N)nn2Cc1cccc(C(N)=O)c1
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(C)s1)nn2Cc1cccc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 44 %

Procedure:
3-{[3-Amino-4-(methyloxy)-1H-indazol-1-yl]methyl}benzamide (for a preparation see Intermediate 12) 22 mg, 0.07 mmol) was dissolved in pyridine (1.6 mL) and added to 5-methyl-2-thiophenesulfonyl chloride (20 mg, 0.1 mmol). The reaction mixture was shaken at room temperature for 5 min and then stood overnight at room temperature. DMSO (0.2 mL) was added to the reaction mixture and purified by MDAP on Atlantis column using Acetonitrile Water with a Formic acid modifier. The solvent was evaporated in vacuo using the Genevac to give the title compound (14.2 mg, 44%) LCMS (System A) RT=0.92 min, ES+ve m/z 457 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([N:18]([CH3:20])[CH3:19])[CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:21](OCC)(=[O:23])[CH3:22].C(OC(=O)C)(=O)C>O>[C:21]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10][CH2:11]1)[N:18]([CH3:20])[CH3:19])(=[O:23])[CH3:22]
Reactant: CN(C)C(CCCCO)C1(c2ccc(Cl)cc2)CCC1
Reactant: CCOC(C)=O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCCCCC(N(C)C)C1(c2ccc(Cl)cc2)CCC1

Procedure:
A mixture of the product of Example 144 (1.55 g), ethyl acetate (100 ml) and acetic anhydride (20 ml) was heated under reflux for 16 hours, cooled and poured into water. The resulting mixture was basified and extracted with ether. The extract was washed, dried and evaporated to give an oil which was purified by flash chromatography on a silica column using a 9:1 mixture of petroleum ether (b.p. 60°-80° C.) and acetone and then acetone as eluant to give 5-[1-(4-chlorophenyl)cyclobutyl]-5-dimethylaminopentyl acetate as an oil the boiling point of which was not determined.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][C:13]1[N:17](CCO)[C:16]([N+:21]([O-:23])=[O:22])=[CH:15][N:14]=1.[CH3:24][CH2:25]N=C=NCCCN(C)C.C1COCC1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH3:12][C:13]1[NH:17][C:16]([N+:21]([O-:23])=[O:22])=[CH:15][N:14]=1.[N+:1]([C:4]1[O:8][C:7]([C:9]([O:11][CH2:24][CH3:25])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])o1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1ncc([N+](=O)[O-])n1CCO
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc([N+](=O)[O-])o1
Product: Cc1ncc([N+](=O)[O-])[nH]1
Temperature: 25 °C
Reaction time: 10 h
Yield: 45.7 %

Procedure:
The reaction mixture of 5-Nitro-2-furoic acid (157 mg, 1.0 mmol), metronidazole (161 mg, 0.94 mmol), EDCI (260 mg, 1.3 mmol), DMAP (10 mg, 0.1 mmol) and THF (5 ml) was stirred at room temperature for 10 h. Evaporation of THF gave a residue which was dissolved in ethyl acetate. The organic layer of ethyl acetate was washed with H2O, 5% Na2CO3, H2O and brine, and then dried over MgSO4. The solvent was removed under vacuum. The resulting solid was recrystallized from C2H5OH to give 134 mg (44.6%) 2-methyl-5-nitro-1H-imidazole-1-ethyl 5-nitro-2-furoate. m.p.: 150-152° C.
Reaction SMILES: [CH2:1]([S:3]([NH:6][C@@H:7]([CH:11]([CH3:13])[CH3:12])[C:8]([OH:10])=O)(=[O:5])=[O:4])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][NH2:45])=[CH:39][C:38]=1[O:46][CH3:47])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl>O1CCCC1>[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][NH:45][C:8](=[O:10])[C@@H:7]([NH:6][S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH:11]([CH3:13])[CH3:12])=[CH:39][C:38]=1[O:46][CH3:47])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCS(=O)(=O)N[C@H](C(=O)O)C(C)C
Reactant: COc1cc(CCN)ccc1OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCS(=O)(=O)N[C@H](C(=O)NCCc1ccc(OCc2ccccc2)c(OC)c1)C(C)C
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
21.1 g of (S)-2-(ethylsulfonylamino)-3-methyl-butyric acid and 12 ml of N-methylmorpholine are cooled in 450 ml of tetrahydrofuran, with stirring, to −20° C. 13.2 ml of chloroformic acid isobutyl ester are added dropwise thereto over 10 min and the reaction mixture is subsequently stirred for 1 hour at −10° C. It is then cooled to −20° C. and a solution of 26.1 g of 2-(4-benzyloxy-3-methoxyphenyl)-ethylamine in 100 ml of tetrahydrofuran is added dropwise over 20 min. The reaction mixture is then stirred for 4 hours without cooling, the internal temperature gradually rising to room temperature. The reaction mixture is introduced into 400 ml of 2N hydrochloric acid and extracted twice with 500 ml of ethyl acetate each time. The organic phases are washed once with 250 ml of 2N hydrochloric acid, once with 250 ml of saturated sodium chloride solution, twice with 250 ml of 2N potassium hydrogen carbonate solution each time and once with 250 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated, yielding (S)-2-(ethylsulfonylamino)-3-methyl-butyric acid N-[2-(4-benzyloxy-3-methoxyphenyl)-ethyl]-amide, which can be purified by recrystallisation from tert-butyl methyl ether, m.p. 140-142° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH2:10]([O:14]C(Cl)Cl)CCC>C(=S)=S.[Ti](Cl)(Cl)(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]=[O:14])=[CH:2]1
Reactant: CCCCOC(Cl)Cl
Reactant: c1ccc2sccc2c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: S=C=S
Product: O=Cc1csc2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 15.2 %

Procedure:
To a solution of benzothiophene (1.08 g, 8.0 mmol) in carbon disulfide (20 mL) at 0° C. was added titanium tetrachloride (3 mL, 27.3 mmol) followed by dichloromethyl n-butyl ether (1.24 g, 7.9 mmol) slowly dropwise. The reaction mixture was warmed to 25° C. and stirred for 1.5 h. The reaction was quenched with conc. hydrochloric acid solution (1 mL), diluted with chloroform (60 mL) and washed with water (50 mL), saturated sodium bicarbonate solution (2×30 mL) and brine (30 mL). The organic layer was dried (MgSO4), filtered, concentrated and flash chromatographed (silica gel, 2.5-5% diethyl ether in petroleum ether) to afford benzothiophene-3-carboxaldehyde (195 mg, 15% yield) as a yellow solid.
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CC(C)=O.[CH2:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)[CH3:18].Cl>[OH-].[Na+]>[CH2:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:24])=[CH:21][CH:20]=1)[CH3:18]
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: CCc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCc1ccc(C(=O)N[C@H](Cc2ccccc2)C(=O)O)cc1
Yield: 84.1 %

Procedure:
D-Phenylalanine 2 g (12 mmole) was dissolved in 10% aqueous sodium hydroxide solution (10 ml), and acetone (10 ml) was added. An acetone (5 ml) solution of 4-ethyl benzoyl choride (2.5 g, 15 mmole) and a 10% aqueous sodium hydroxide solution were added dropwise to the mixture obtained above while stirring and cooling with ice over 20 minutes, the reaction solution being maintained at pH 10. The reaction solution was returned to the room temperature, stirred for 3 hours, and made an acidic with a dilute hydrochloric acid solution to precipitate crystals. The crystals were filtered, washed with water and recrystallized from ethyl acetate to obtain N-(4-etylbenzoyl)-D-phenylalanine (3.0 g, yield 83%).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[NH2:11][C:12]1[S:13][C:14]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH2:31])[CH:26]=2)=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[N:16]=1.[C:32](=[O:35])([O-])O.[Na+]>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[N:16]=[C:12]([NH:11][C:32](=[O:35])[C:3]3[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=3)[S:13][C:14]=2[C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:2]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=3)=[O:9])[CH:26]=2)=[CH:18][CH:19]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: O=C([O-])O
Reactant: COc1ccc(-c2nc(N)sc2-c2ccnc(N)c2)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(-c2nc(NC(=O)c3cccnc3)sc2-c2ccnc(NC(=O)c3cccnc3)c2)cc1
Temperature: 70 °C
Reaction time: 19 h
Yield: 33 %

Procedure:
Nicotinoyl chloride hydrochloride (0.72 g, 4.1 mmol) and 4-dimethylaminopyridine (0.05 g, 0.4 mmol) were added to a solution of 4-[2-amino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]-2-pyridylamine (0.41 g, 1.4 mmol) in N,N-dimethylacetamide (10 mL) and the mixture was stirred at 70° C. for 19 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous solution of sodium hydrogencarbonate (50 mL) was added. The resulting crude crystals were collected by filtration and washed with water. The crude crystals were recrystallized from ethanol to obtain 0.23 g (0.44 mmol, yield 33%) of the title compound.
Reaction SMILES: [CH2:1]([CH:3]1[C:12]2[CH:11]=[C:10]3[NH:13][C:14](=O)[CH:15]=[C:16]([OH:17])[C:9]3=[CH:8][C:7]=2[NH:6][CH2:5][CH2:4]1)[CH3:2].[OH-].[K+].S([O:26][CH3:27])(OC)(=O)=O.O.[CH3:29]N(C)C=O>>[CH2:1]([CH:3]1[C:12]2[CH:11]=[C:10]3[N:13]([CH3:14])[C:27](=[O:26])[CH:15]=[C:16]([O:17][CH3:29])[C:9]3=[CH:8][C:7]=2[NH:6][CH2:5][CH2:4]1)[CH3:2]
Reactant: CN(C)C=O
Reactant: COS(=O)(=O)OC
Reactant: CCC1CCNc2cc3c(O)cc(=O)[nH]c3cc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCC1CCNc2cc3c(OC)cc(=O)n(C)c3cc21

Procedure:
2 g (8.2 mmol) of 9-ethyl-4-hydroxy-6,7,8,9-tetrahydro-1H-pyrido[2,3-g]quinol-2-one are suspended in 25 ml of dimethylformamide and treated with 6.7 g (0.12 mol) of potassium hydroxide. 8.6 g (0.07 mol) of dimethyl sulfate are added dropwise thereto at at most 60° C. (cooling with ice/sodium chloride bath). The suspension is discharged into 200 ml of water. A well filterable precipitate is formed, which is filtered off with suction and dried.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]([CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)[CH2:7][C:8]([OH:10])=[O:9])=[O:5])[CH3:3].O=[C:21]([CH2:25][CH3:26])[C:22]([OH:24])=[O:23].C([BH3-])#N.[Na+]>>[C:22]([CH:21]([NH:1][C@H:2]([C:4]([N:6]([CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)[CH2:7][C:8]([OH:10])=[O:9])=[O:5])[CH3:3])[CH2:25][CH3:26])([OH:24])=[O:23]
Reactant: CCC(=O)C(=O)O
Reactant: C[C@H](N)C(=O)N(CC(=O)O)C1Cc2ccccc2C1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCC(N[C@@H](C)C(=O)N(CC(=O)O)C1Cc2ccccc2C1)C(=O)O
Yield: 30.1 %

Procedure:
By using 1.0 g of L-alanyl-N-(indan-2-yl)glycine, 6.0 g of 2-oxo-butyric acid and 1.0 g of sodium cyanoborohydride in a similar procedure to that of Example 1, there can be obtained 0.4 g of N-(1-carboxypropyl)-L-alanyl-N-(indan-2-yl)glycine as colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[N+](C1C=CC([O:30][C:31](=O)[NH:32][C:33]2[CH:34]=[N:35][C:36]([O:39][CH:40]3[CH2:43][CH2:42][CH2:41]3)=[CH:37][CH:38]=2)=CC=1)([O-])=O.C(Cl)Cl>CC(C)=O>[CH:40]1([O:39][C:36]2[N:35]=[CH:34][C:33]([NH:32][C:31]([N:18]3[CH2:19][CH2:20][CH:15]([C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][N:7]=4)[CH2:16][CH2:17]3)=[O:30])=[CH:38][CH:37]=2)[CH2:41][CH2:42][CH2:43]1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Reactant: O=C(Nc1ccc(OC2CCC2)nc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CC(C)=O
Solvent: ClCCl
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(OC5CCC5)nc4)CC3)c2cc1OC
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 72.8 %

Procedure:
A mixture of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (114.1 mg, 418 μmol), as prepared in Example 1d, (6-cyclobutoxy-pyridin-3-yl)-carbamic acid 4-nitro-phenyl ester (151 mg, 459 μmol), as prepared in the preceding step, and DCM (818 μL) was treated with TEA (63 μL, 455 μmol) in one portion, and stirred under air at 45° C. for 30 min. The reaction mixture was then directly applied to a flash silica column (3:4 hex/acetone) to provide the title compound as a foam (141.1 mg, 73%). This material was taken up in 2 M K2CO3 (2 mL) and extracted with DCM (2×2 mL). The combined organic layers were dried (Na2SO4), concentrated, and repurified with a silica flash column (9:2 EtOAc/acetone) to provide analytically pure title compound as an off-white foam (84.4 mg, 44%). 1H NMR (300 MHz, CDCl3) δ 9.08 (s, 1H), 7.97 (d, 1H), 7.77 (dd, 1H), 7.34 (s, 1H), 7.26 (s, 1H), 6.67 (d, 1H), 6.39 (br s, 1H), 5.11 (m, 1H), 4.32-4.22 (m, 2H), 4.07 (s, 3H), 4.06 (s, 3H), 3.60 (tt, 1H), 3.18 (td, 2H), 2.51-2.37 (m, 2H), 2.24-1.94 (m, 6H), 1.89-1.57 (m, 2H). LC-MS (ESI): calcd mass 463.2, found 464.3 (MH+). Anal. Calcd for C25H29N5O4: C, 64.78; H, 6.31; N, 15.11. Found: C, 64.64; H, 6.24; N, 15.04.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH2:22][NH:23][C:24](=[O:31])[CH2:25][C:26]([O:28]CC)=[O:27])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[OH-].[Na+].CO.Cl>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH2:22][NH:23][C:24](=[O:31])[CH2:25][C:26]([OH:28])=[O:27])[S:12][C:13]=2[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC(=O)NCc1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2nc(CNC(=O)CC(=O)O)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 57.1 %

Procedure:
A mixture of 4,5-bis(4methoxyphenyl)-2-ethoxycarbonylacetylaminomethylthiazole (0.43 g) and 4N sodium hydroxide (3 ml), methanol (5 ml) and water (5 ml) was stirred at ambient temperature for 4.5 hours. After allowing to cool to room temperature, the mixture was poured to water, and the aqueous layer was adjusted to pH 1 with 10% hydrochloric acid, and extracted with diethyl ether. The organic layer was washed with water and brine, and dried over magnesium sulfate and treated with activated charcoal. After filtration, the filtrate was evaporated in vacuo. The resulting residue was triturated with isopropyl ether and diethyl ether, to give 4,5-bis(4-methoxyphenyl)-2-(carboxyacetylaminomethyl)thiazole (0.23 g).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[C:8]([N:34]([CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])[CH3:35])=[CH:9][C:10]([O:32][CH3:33])=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]([CH3:29])[CH:21]=3)[C:17]([C:30]#[N:31])=[CH:16][N:15]=2)[CH:12]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:30]([C:17]1[C:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH3:29])[CH:21]=2)=[N:19][C:14]([NH:13][C:11]2[C:10]([O:32][CH3:33])=[CH:9][C:8]([N:34]([CH2:36][CH2:37][N:38]([CH3:39])[CH3:40])[CH3:35])=[C:7]([NH:6][C:1](=[O:4])[CH:2]=[CH2:3])[CH:12]=2)=[N:15][CH:16]=1)#[N:31]
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N(C)CCN(C)C)c(N)cc1Nc1ncc(C#N)c(-c2cn(C)c3ccccc23)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(Nc2ncc(C#N)c(-c3cn(C)c4ccccc34)n2)c(OC)cc1N(C)CCN(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
A solution of acryloyl chloride (0.035 mL, 0.44 mmol) in CH2Cl2 (1 mL) was added to a mixture of 2-{[5-amino-4-(2-dimethylaminoethyl-methylamino)-2-methoxyphenyl]-amino}-4-(1-methylindol-3-yl)pyrimidine-5-carbonitrile (Intermediate 102, 171 mg, 0.36 mmol) and DIPEA (0.120 mL, 0.73 mmol) in CH2Cl2 (3 mL) at 0° C., then the mixture was stirred at 0° C. for 1 h. The mixture was then diluted with CH2Cl2, washed twice with sat. NaHCO3, and then water, then dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-5% methanolic ammonia in CH2Cl2 gave the title compound (68 mg, 36%) as a yellow solid; 1H NMR: (100° C.) 2.22 (6H, s), 2.40 (2H, t), 2.76 (3H, s), 2.98 (2H, t), 3.77 (3H, s), 3.90 (3H, s), 5.69 (1H, dd), 6.17 (1H, dd), 6.40 (1H, dd), 7.02-7.06 (2H, m), 7.21-7.25 (1H, m), 7.49 (1H, d), 8.23 (1H, d), 8.45 (1H, s), 8.47 (1H, s), 8.63 (1H, s), 8.86 (1H, s), 9.59 (1H, s); m/z: ES+ MH+ 525.32.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:18]([O-:20])=[O:19])=[C:7]([N:9](S(C)(=O)=O)[S:10]([CH3:13])(=[O:12])=[O:11])[CH:8]=1.O1CCCC1.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:18]([O-:20])=[O:19])=[C:7]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:8]=1
Reactant: COc1ccc([N+](=O)[O-])c(N(S(C)(=O)=O)S(C)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])c(NS(C)(=O)=O)c1
Reaction time: 18 h

Procedure:
To a solution of N-(5-Methoxy-2-nitro-phenyl)-N-(methylsulfonyl)methanesulfonamide (7.70 g) in Tetrahydrofuran (200 mL, 2 mol) was added 1 M of Sodium hydroxide in Water (50 mL). The mixture was stirred for 18 hours. The mixture was poured into a separatory funnel and the aqueous layer (bottom layer) was separated. The aqueous layer was washed with Ethyl Acetate (100 mL). The organic layers were combined, dried over magnesium sulfate, filtered and evaporated. N-(5-Methoxy-2-nitro-phenyl)-methanesulfonamide isolated as an orange solid (5.59 g, 76%).
Reaction SMILES: [O:1]=[C:2]([C:8]1[S:9][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:11][CH:12]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.N1CCCCC1.C1C=CC=CC=1.C(O)(=O)C>>[Cl:19][C:20]1[CH:27]=[CH:26][C:23](/[CH:24]=[C:3](/[C:2]([C:8]2[S:9][C:10]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)=[CH:11][CH:12]=2)=[O:1])\[C:4]([O:6][CH3:7])=[O:5])=[CH:22][CH:21]=1
Reactant: COC(=O)CC(=O)c1ccc(-c2ccncc2)s1
Reactant: O=Cc1ccc(Cl)cc1
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: COC(=O)/C(=C\c1ccc(Cl)cc1)C(=O)c1ccc(-c2ccncc2)s1
Temperature: 92 °C
Yield: 65.8 %

Procedure:
To a 100 mL round bottom flask was added a solution of methyl 3-oxo-3-(5-pyridin-4-yl-2-thienyl)propanoate (0.150 g, 0.574 mmol), 4-chlorobenzaldehyde (0.097 g, 0.689 mmol) and piperidine (0.006 mL, 0.057 mmol) in anhydrous benzene (10.00 mL, 111.9 mmol). Acetic acid (0.023 mL, 0.401 mmol) was added and the reaction mixture was fitted with a Dean-Stark trap and the bath was heated to 92° C. and allowed to reflux for 18 hours. The reaction was cooled to ambient temperature and concentrated under reduced pressure. The crude material was dry loaded onto silica gel and then purified using ISCO (12 g cartridge, gradient hexanes to 100% EtOAc over 30 min) to afford the title compound (0.145 g, 63%) as a white solid. LC/MS (AA) ES+ 384, 386. 1H NMR (dmso-d6, 400 MHz): δ 8.66-8.65 (m, 2H), 8.00 (d, 1H), 7.84-7.75 (m, 4H), 7.47-7.46 (m, 4H), 3.76 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[H-].[Na+].I[CH3:16].Cl>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:16])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(O)cc(OC)c1
Reaction time: 0.5 h
Yield: 33.3 %

Procedure:
To a solution of methyl 3,5-dihydroxybenzoate (28.0 g) in DMF (300 mL) was added 60% sodium hydride (4.70 g) at 0° C., and the mixture was stirred for 30 min. Iodomethane (23.7 g) was added dropwise, and the mixture was stirred at 0° C. for 1 hr. 1N Hydrochloric acid (300 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (10.1 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[N:15]=[CH:16][N:17]([C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[CH3:75][NH:76][O:77][CH3:78]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:10](=[O:12])[N:76]([O:77][CH3:78])[CH3:75])[CH2:13][C:14]1[N:15]=[CH:16][N:17]([C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:18]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)NC(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)OC(C)(C)C
Yield: 90.2 %

Procedure:
2-tert-Butoxycarbonylamino-3-(1-trityl-1H-imidazol-4-yl)-propionic acid (4.56 g, 9.18 mmol), DIPEA (3.55 g, 4.79 mL, 27.53 mmol), BOP (4.26 g, 9.63 mmol) and N,O-dimethylhydroxylamine hydrochloride (940 mg, 9.63 mmol) in DMF (100 mL) were stirred overnight. The DMF was removed and CH2Cl2 added. The solution was washed with dilute aqueous HCl (1M, 4X), water and brine. The solution was dried, filtered and the solvent removed. The product was chromatographed (silica gel, EA/PE, Rf 0.38 EA) to afford the title compound (4.475 g, 90.4%). ESMS 541 (M+H+) 1H NMR (500 MHz, CDCl3) δ 1.39 (9H, s), 2.92 (1H, dd, J=6.13, 14.45), 2.98 (1H, dd, J=5.63, 14.45), 3.13 (3H, s), 3.73 (3H, s), 4.87 (1H, m), 5.61 (1H, d, J=6.95 Hz), 6.57 (1H, s), 7.11 (6H, m), 7.32 (9H, m), 7.46 (1H, s). 13C NMR (CDCl3) 28.19, 30.34, 31.02, 50.55, 61.49, 75.62, 79.34, 119.74, 127.98, 129.59, 135.19, 137.95, 141.77, 155.19, 171.77.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[C:13]2[C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][N:16]=[C:15]3[S:24][N:25]=[C:26]([CH3:27])[C:14]=23)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[C:13]2[C:18]([C:19]([OH:21])=[O:20])=[CH:17][N:16]=[C:15]3[S:24][N:25]=[C:26]([CH3:27])[C:14]=23)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cnc2snc(C)c2c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(S(=O)(=O)N(Cc2cccnc2)c2c(C(=O)O)cnc3snc(C)c23)cc1

Procedure:
Following the procedure of Example 39, a 2.25 g sample of the above ester was hydrolysed with KOH to give 0.46 g of 4-[(4-methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-3-methylisothiazolo[5,4-b]pyridine-5-carboxylic acid as a white solid, m.p. 234-236° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.Cl.[Cl:18][C:19]1[N:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=1.CCN(CC)CC>O.CS(C)=O>[Cl:18][C:19]1[N:20]=[N:21][C:22]([N:14]2[CH2:15][CH2:16][CH:11]([N:8]3[C:9]4[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=4)[CH2:6][CH2:7]3)[CH2:12][CH2:13]2)=[CH:23][CH:24]=1
Reactant: Fc1ccc2c(c1)N(C1CCNCC1)CC2
Reactant: Clc1ccc(Cl)nn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: Fc1ccc2c(c1)N(C1CCN(c3ccc(Cl)nn3)CC1)CC2
Temperature: 80 °C
Reaction time: 1 h

Procedure:
In a 100 mL flask was placed 6-fluoro-1-(piperidin-4-yl)indoline as its corresponding HCl salt, prepared as in STEP 2 above (7.7 g, 30 mmol, 1 equiv) and 3,6-dichloropyridazine (4.69 g, 31.5 mmol, 1.05 equiv). DMSO (40 mL) and Et3N (12.54 mL, 90 mmol, 3 equiv) were added sequentially. The resulting mixture was heated at 80° C. for 7 h. The resulting mixture was then poured into vigorously stirred H2O (800 mL) and stirred for 1 h. The resulting solid was filtered and washed with H2O (30 mL×2), 50% Et2O/hexane (30 mL×2), and the dried to yield 1-(1-(6-chloropyridazin-3-yl)piperidin-4-yl)-6-fluoroindoline as a solid.