Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:8]([CH3:15])=[C:9]2[C:12](O)=[O:13])=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:24])=O.CN(C)C=O>O1CCCC1>[CH3:20][O:19][C:17](=[O:18])[CH2:16][C:7]1[C:8]([CH3:15])=[C:9]([C:12]([Cl:24])=[O:13])[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=2)[CH:6]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C(=O)O)c1C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)Cc1cc2ccc(F)cc2c(C(=O)Cl)c1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 7-fluoro-3-methoxycarbonylmethyl-2-methyl-naphthalene-1-carboxylic acid (500 mg, 1.81 mmol) in anhydrous tetrahydrofuran (10 mL), was added oxalyl chloride (250 μL) and N,N-dimethylformamide (30 μL). The resulting mixture was stirred at 60° C. for 2 hours, and concentrated in vacuo to afford (4-chlorocarbonyl-6-fluoro-3-methyl-naphthalen-2-yl)-acetic acid methyl ester (526 mg, 99%) as a light yellow solid, which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[N:5]=[C:4]2[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:14]=[C:15]([CH3:16])[C:3]=12.[I-].[Na+].Cl.[OH-:26].[Na+]>CS(C)=O.O>[CH3:16][C:15]1[C:3]2[C:2](=[O:26])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[CH3:12])[NH:5][C:4]=2[N:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:14]=1
Reactant: [OH-]
Reactant: Cc1cccc2nc3c(c(C)nn3-c3ccccn3)c(Cl)c12
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cccc2[nH]c3c(c(C)nn3-c3ccccn3)c(=O)c12
Temperature: 100 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A solution of 4-chloro-3,5-dimethyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (1.65 g, 5.34 mmol), sodium iodide (0.96 g, 6.41 mmol) and conc. hydrochloric acid (1 mL) in dimethylsulfoxide (20 mL) was heated and stirred at 100° C. for 2 hours. The solution was cooled to room temperature, and the residue was poured into water. The mixture was made basic by the addition of a sodium hydroxide solution, and organic matter was extracted with 10% methanol/chloroform. The extract was washed with saturated brine and water, and dried over anhydrous magnesium sulfate, and the solvents were evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (ethyl acetate:hexane=90:10) to give the title compound (1.13 g, 73% yield).
Reaction SMILES: [C:1]([NH:6][C:7]1[C:12]([N+:13]([O-])=O)=[C:11]([CH3:16])[CH:10]=[CH:9][N:8]=1)(=O)[CH2:2][CH2:3][CH3:4]>C(O)(=O)C.C(O)C.[Fe]>[CH3:16][C:11]1[CH:10]=[CH:9][N:8]=[C:7]2[NH:6][C:1]([CH2:2][CH2:3][CH3:4])=[N:13][C:12]=12
Reactant: CCCC(=O)Nc1nccc(C)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCc1nc2c(C)ccnc2[nH]1
Temperature: 90 °C
Reaction time: 3 h
Yield: 65.5 %

Procedure:
A solution of 2-butyrylamino-4-methyl-3-nitropyridine (7.0 g) and iron powder (17.5 g) in a mixture of acetic acid (14 ml) and ethanol (100 ml) was stirred at 90° C. for 3 hours under nitrogen atmosphere. After being cooled to room temperature, the reaction mixture was filtered through Celite and the filtrate was evaporated in vacuo. Ethyl acetate and saturated aqueous sodium hydrogencarbonate were added to the residue until pH 7~8 and the resulting suspension was filtered through Celite. The organic layer of the filtrate was separated, washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified with silica gel column chromatography (eluent: ethyl acetate) to give 7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine (3.6 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[C:5]([F:12])=[CH:4][C:3]=1[NH:13][C@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([CH:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)[C:15]1=[O:33].[ClH:34].O1CCOCC1>C(Cl)Cl.CO>[ClH:34].[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[C:5]([F:12])=[CH:4][C:3]=1[NH:13][C@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([CH:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]2)[C:15]1=[O:33]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H](Nc3cc(F)c(S(C)(=O)=O)cc3F)C2=O)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: CS(=O)(=O)c1cc(F)c(N[C@H]2CCCN(C3CCNCC3)C2=O)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-tert-butyl 3-(2,5-difluoro-4-(methylsulfonyl)phenylamino)-2-oxo-1,4′-bipiperidine-1′-carboxylate (4.6 g, 9.4 mmol) was dissolved in CH2Cl2 (100 mL) and methanol (10 mL). 4N HCl in dioxane (24 mL, 94 mmol) was added and the reaction stirred at ambient temperature overnight. The reaction was concentrated to provide (S)-3-(2,5-difluoro-4-(methylsulfonyl)phenylamino)-1,4′-bipiperidin-2-one hydrochloride, which was used directly in the next step without purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:12]1[C:16]2[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:15]=2[NH:14][C:13]1=[O:25].[N+:26]([O-])([O-:28])=[O:27].[K+]>S(=O)(=O)(O)O>[OH:1][C:2]1[C:7]([N+:26]([O-:28])=[O:27])=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][C:3]=1[N:12]1[C:16]2[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:15]=2[NH:14][C:13]1=[O:25]
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1[nH]c2cc(C(F)(F)F)ccc2n1-c1cc(C(F)(F)F)ccc1O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc(C(F)(F)F)ccc2n1-c1cc(C(F)(F)F)cc([N+](=O)[O-])c1O
Temperature: 0 °C

Procedure:
To an ice cooled solution of 1-(2-Hydroxy-5-trifluoromethylphenyl)-5-trifluoromethyl-1,3-dihydro-2H-benzimidazol-2-one (1.38 mmol, 0.50 g) in concentrated sulphuric acid (6 ml) is added an ice cooled solution of potassium nitrate (1.38 mmol, 0.14 g) in concentrated sulphuric acid (8 ml). The reaction mixture is allowed to reach room temperature and is poured into ice. The crude product is collected by filtration and subjected to column chromatography using methylenechloride+methanol (9+1 ) as eluent. The fractions containing the product are concentrated in vacuo yielding the title compound as slightly yellow crystals, M.p.>360° C.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][C:6]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]3[C:16]([CH3:21])=[N:17][O:18][C:19]=3[CH3:20])[CH:13]=2)[NH:8][C:7]1=[O:22])C.O[Li].O.Cl>C1COCC1.CO.O>[CH3:21][C:16]1[C:15]([C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:22])[C:6]3([CH2:5][C:4]([OH:29])=[O:3])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:19]([CH3:20])[O:18][N:17]=1
Reactant: CCOC(=O)CC1(c2ccccc2)C(=O)Nc2ccc(-c3c(C)noc3C)cc21
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1noc(C)c1-c1ccc2c(c1)C(CC(=O)O)(c1ccccc1)C(=O)N2
Temperature: 25 °C
Yield: 62 %

Procedure:
Ethyl-2-(5-(3,5-dimethyl isoxazol-4-yl)-2-oxo-3-phenylindolin-3-yl)acetate (35 mg, 0.089 mmol) dissolved in THF/MeOH (2 mL/2 mL) was added LiOH.H2O (40 mg) in H2O (2 mL). The reaction was stirred at room temperature until complete consumption of the starting material as indicated by TLC. The reaction was added water, acidified with 3% HCl until pH<1 and extracted with EtOAc (3×5 mL). The combined extracts were washed with brine, dried over MgSO4 and concentrated under vacuum. The title compound was purified on Pre-TLC to afford the title compound as a white solid (20 mg, 62%). 1H NMR (400 MHz, DMSO-d6) δH 12.17 (s, 1H), 10.56 (s, 1H), 7.41 (s, 1H), 7.35-7.29 (m, 4H), 7.22-7.24 (m, 2H), 6.96 (d, J=8.0 Hz, 1H), 3.29-3.30 (m, 2H), 2.38 (s, 3H), 2.21 (s, 3H). MS (ESI) m/e [M+1]+ 363.
Reaction SMILES: C[O:2][P:3]([O:6][CH3:7])[O:4][CH3:5].Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=1)=[O:10]>>[CH2:21]([O:20][C:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][C:9]([P:3](=[O:2])([O:6][CH3:7])[O:4][CH3:5])=[O:10])=[CH:13][CH:14]=1)=[O:19])[CH3:22]
Reactant: CCOC(=O)c1ccc(OC(=O)Cl)cc1
Reactant: COP(OC)OC
Product: CCOC(=O)c1ccc(OC(=O)P(=O)(OC)OC)cc1

Procedure:
From 16.1 g (0.13 mole) of trimethylphosphite and 22.8 g (0.10 mole) of 4-ethoxycarbonylphenyl chloroformate. (100° C., 3 hours). Yield 26.7 g (88%). Bp0.05 205°-7° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)C1C=CC=CC=1.[CH3:24][CH:25]([OH:28])[CH:26]=[CH2:27]>>[OH:8][C:9]1[CH:14]=[C:13]([CH2:27][CH2:26][CH:25]([OH:28])[CH3:24])[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:21])(=[O:22])[NH:19][C:18](=[O:23])[CH2:17]1
Reactant: C=CC(C)O
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Product: CC(O)CCc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one and but-3-en-2-ol analogous to Example 44: (M−1)−=299; HPLC retention time=1.16 min (method B)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]#[N:11])[CH2:6][CH2:5]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].O>O1CCCC1>[CH3:1][O:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH2:11])[CH2:6][CH2:5]1
Reactant: COCC1CCC(C#N)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COCC1CCC(CN)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of EXAMPLE 454D (460 mg) in tetrahydrofuran (15 mL) was added 2M lithium aluminum hydride in tetrahydrofuran (2.252 mL) slowly. The reaction mixture was stirred at room temperature for 1 hour, refluxed for 1 hour and cooled. Sodium hydroxide (2 ml of 2M solution) and water (5 mL) was added. The solid was filtered off and washed with ether. The filtrate was concentrated. The residue was mixed with dichloromethane (50 mL) and the resulting mixture was dried over Na2CO3, filtered, and concentrated to provide the title compound.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:26][CH:25]=[C:24]([CH3:27])[N:19]3[C:20](=[O:23])[C:21]=2I)[CH2:3][CH2:2]1.[F:28][C:29]([F:41])([F:40])[O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:26][CH:25]=[C:24]([CH3:27])[N:19]3[C:20](=[O:23])[C:21]=2[C:34]2[CH:33]=[CH:32][C:31]([O:30][C:29]([F:28])([F:40])[F:41])=[CH:36][CH:35]=2)[CH2:3][CH2:2]1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: COc1cccc(/C=C/c2nc3scc(C)n3c(=O)c2I)c1OCC1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cccc(/C=C/c2nc3scc(C)n3c(=O)c2-c2ccc(OC(F)(F)F)cc2)c1OCC1CC1
Yield: 46.8 %

Procedure:
The title compound was prepared from Intermediate 17 (100 mg, 0.202 mmol) and 4-trifluoromethoxyphenylboronic acid (58 mg, 0.283 mmol) using Pd[(C6H5)3P]4 (90 mg, 0.008 mmol) and sodium carbonate (128 mg, 1.213 mmol) in toluene (10 ml) and ethanol (5 ml) and water (4 ml) according to the procedure outlined in Example 1 to afford crude residue which was purified by column chromatography using 10% ethyl acetate in petroleum ether to afford 50 mg of the desired product; 1H NMR (300 MHz, DMSO-d6) δ 0.24-0.26 (m, 2H), 0.48-0.50 (m, 2H), 0.90-1.10 (m, 1H), 2.65 (s, 3H), 3.67 (d, J=6.9 Hz, 2H), 3.76 (s, 3H), 6.83 (d, J=15.6 Hz, 2H), 6.90-6.91 (m, 2H), 6.98-7.01 (m, 4H), 7.43 (s, 4H), 8.10 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 529.19 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[N:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[N:33][CH:32]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)(Cl)Cl>[O:30]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:35]3[CH:36]=[N:31][CH:32]=[N:33][CH:34]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: OB(O)c1cncnc1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3-c2cncnc2)CC1
Yield: 8 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), pyrimidine-5-boronic acid, copper(II) acetate, pyridine and using chloroforme instead of dichloromethane as solvent, to give the desired product as a colorless solid (8%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](Cl)[N:12]=[C:11]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:41])[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)=[CH:25][C:24]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>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]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:12]=[C:13]([C:24]2[CH:25]=[C:26]([NH:29][C:30](=[O:41])[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:39])([F:38])[F:40])[CH:32]=3)[CH:27]=[CH:28][C:23]=2[CH3:22])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc(OCc2ccccc2)cc(N2CCOCC2)n1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc(OCc2ccccc2)cc(N2CCOCC2)n1
Temperature: 108 °C

Procedure:
A mixture of 4-(4-(benzyloxy)-6-chloropyridin-2-yl)morpholine (1.0 equiv.), N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(trifluoromethyl)benzamide (1.2 equiv.), sodium carbonate (2 M, 8 equiv.) and PdCl2(dppf) (0.5 equiv.) in DME (0.1 M) were heated to 108° C. for 13 min in the microwave. After removing the DME soluble portion and concentrating, the resulting solid was partitioned between EtOAc and water. The organic phase was washed with brine and then dried over magnesium sulfate. The solution was concentrated and dried under vacuo to give crude N-(3-(4-(benzyloxy)-6-morpholinopyridin-2-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide and was used in the next step without further purification. LCMS (m/z) (M+H)=548.2, Rt=0.99 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:26])[NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1)[CH3:9].[C:27]([CH2:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)#[N:28]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:26])[NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:33]2[CH:34]=[CH:35][C:30]([CH2:29][C:27]#[N:28])=[CH:31][CH:32]=2)=[CH:20][CH:19]=1)[CH3:9]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1F
Reactant: N#CCc1ccc(B(O)O)cc1
Product: Cc1noc(-c2ccc(-c3ccc(CC#N)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1F

Procedure:
Prepared as described in Example 36, Step 6 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-fluoro-phenyl)-ethyl ester and 4-cyanomethylphenylboronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O-])=[O:15])=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])[CH:5]=[CH:6][CH:7]=1.[NH2:26][CH2:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29].Cl.CN(C)CCCN=C=NCC.C(OCC)(=O)C>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14](=[O:15])[NH:26][CH2:27][C:28](=[O:29])[NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: NCC(=O)Nc1ccccc1
Reactant: CC1=C(C(=O)[O-])C(c2cccc(Cl)c2)C(C(=O)OCCC#N)=C(C)N1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)NCC(=O)Nc2ccccc2)C(c2cccc(Cl)c2)C(C(=O)OCCC#N)=C(C)N1

Procedure:
179 mg (0.49 mmol) of mono(2-cyanoethyl) 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, 245mg (1.63 mmol) of 2-amino-N-phenylacetamide, 129 mg (0.67 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 11 mg (0.09 mmol) of 4-dimethylaminopyridine were stirred in 10 ml of dichloromethane at room temperature overnight. Ethyl acetate was added to the reaction mixture, and the product was washed with 1 N hydrochloric acid and then with a saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (chloroform/methanol=100/1) to obtain the title compound.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:13][CH:14]([CH2:18][CH3:19])[C:15](Cl)=[O:16]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:15](=[O:16])[CH:14]([CH3:13])[CH2:18][CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)O
Reactant: CCC(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of t-butyl alcohol (40.7 g, 549 mmol), Et3N (70 mL, 505 mmol), and DMAP (0.366 mL, 3 mmol) in anhydrous CH2Cl2 (100 mL) at 0° C. was added 2-methyl-butyryl chloride (38 g from step 1). The reaction was stirred at 0° C. for 2 h and then room temperature overnight. The cloudy reaction mixture was filtered through celite and concentrated. The residue was diluted with Et2O and washed with 0.1 N HCl. The organic layer was dried (MgSO4), filtered, and concentrated. The residue was distillated at ˜100° C. bath temperature under weak in-house vacuum twice to give the desired 2-methyl-butyric acid tert-butyl ester 2-2 as a clear oil (42 g, ˜85% purity by 1HNMR analysis). 1HNMR (CDCl3, 500 Hz): 2.28-2.20 (m 1H), 1.68-1.56 (m, 1H), 1.44 (s, 9H), 1.46-1.37 (m, 1H), 1.44 (s, 9H), 1.09 (d, J=7.0 hz, 3H), 0.9 (t, J=7.3 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:31])[CH:5]=[C:6]([Cl:30])[C:7]=1[CH2:8][C@@H:9]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH:22]([F:24])[F:23])=[C:17]([O:25][CH2:26][CH:27]2[CH2:29][CH2:28]2)[CH:16]=1)[O:10][C:11](=[O:14])[CH2:12][OH:13].[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][N:34]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:30][C:6]1[CH:5]=[N+:4]([O-:31])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@H:9]([O:10][C:11](=[O:14])[CH2:12][O:13][C:37](=[O:38])[C:36]1[CH:40]=[CH:41][C:33]([Cl:32])=[N:34][CH:35]=1)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH:22]([F:24])[F:23])=[C:17]([O:25][CH2:26][CH:27]2[CH2:29][CH2:28]2)[CH:16]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: O=C(CO)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(COC(=O)c1ccc(Cl)nc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Yield: 78 %

Procedure:
To a mixture of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-hydroxyacetoxy)ethyl)pyridine 1-oxide (See Scheme 21, step 6-9) (200 mg, 0.418 mmol), 6-chloronicotinic acid (72.5 mg, 0.460 mmol) and EDC (240 mg, 1.255 mmol) in dry DCM (10 ml), DMAP (51.1 mg, 0.418 mmol) was added, and stirring was continued for a week-end at room temperature. The solvent was evaporated; the residue was portioned between sat. sol. NaHCO3 and ethyl acetate, the organic phase was washed with brine, dried over sodium sulfate and evaporated, the residue was purified by flash chromatography on silica gel (eluent: DCM/MeOH/32% NH4OH 98/2/0.2) and (S)-3,5-dichloro-4-(2-(2-(6-chloronicotinoyloxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)pyridine 1-oxide was obtained as a white solid (202 mg, 0.327 mmol, 78% yield, MS/ESI+ 617.2 [MH]+).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13](OC(C)(C)C)=O)[CH2:9][CH2:8]2)[N:3]=[CH:2]1.C(O)(C(F)(F)F)=O.ClC1[C:33]([Cl:34])=[CH:32][N:31]=[C:30]([NH2:35])[C:29]=1[N+:36]([O-:38])=[O:37]>C(Cl)Cl>[Cl:34][C:33]1[C:13]([N:10]2[CH2:9][CH2:8][N:7]([CH2:6][C:4]3[N:3]=[CH:2][S:1][CH:5]=3)[CH2:12][CH2:11]2)=[C:29]([N+:36]([O-:38])=[O:37])[C:30]([NH2:35])=[N:31][CH:32]=1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cscn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(Cl)c(N2CCN(Cc3cscn3)CC2)c1[N+](=O)[O-]
Reaction time: 1 h
Yield: 31.3 %

Procedure:
tert-Butyl 4-(thiazol-4-ylmethyl)piperazine-1-carboxylate (0.220 g, 0.79 mmol, 1.1 eq) was dissolved in DCM (2 mL) and the mixture cooled in a ice-water bath before the dropwise addition of TFA (2 mL). Stirring was continued at this temperature for 1 h. The solvents were removed in vacuo and the resulting crude material was azeotroped with toluene and dried. 4-(piperazin-1-ylmethyl)thiazole (supposedly 0.140 g, 0.79 mmol, 1.1 eq) was suspended in iPrOH (0.8 mL) and DIPEA (0.3 mL). To this solution, 4,5-dichloro-3-nitropyridin-2-amine (0.15 g, 0.72 mmol, 1 eq) was added and the mixture was heated and stirred for 17 h at 65° C. The mixture was filtered, washed with iPrOH (3×3 mL), Et2O (2×3 mL) and dried to give the title compound as a bright yellow powder (0.080 g, 27%); 1H-NMR (500 MHz, DMSO-d6): δ 2.52-2.60 (m, 4H, piperazine N(CH2)2), 3.07 (m, 4H, piperazine N(CH2)2), 3.72 (s, 2H, NCH2), 6.94 (s, 2H, NH2), 7.54 (s, 1H, thiazole 5-H), 8.05 (s, 1H, pyridine 6-H), 9.04 (s, 1H, thiazole 2-H); LC (Method B)-MS (ESI, m/z): Rt=1.71 min—355/357 [(M+H)+, Cl isotopic pattern].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=1)=[O:10].[CH3:18][C:19]([C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)([C:21]1[O:22][CH:23]=[CH:24][N:25]=1)[CH3:20]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:32]([C:29]2[CH:28]=[CH:27][C:26]([C:19]([CH3:20])([C:21]3[O:22][CH:23]=[CH:24][N:25]=3)[CH3:18])=[CH:31][CH:30]=2)(=[O:33])=[O:34])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)=[O:10])[CH:4]=1
Reactant: Cc1cccc(C(=O)c2cc(Cl)ccc2N)n1
Reactant: CC(C)(c1ccc(S(=O)(=O)Cl)cc1)c1ncco1
Product: Cc1cccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)c3ncco3)cc2)n1

Procedure:
The title compound was prepared from (2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-2-yl)-methanone and 4-(1-methyl-1-oxazol-2-yl-ethyl)-benzenesulfonyl chloride following the general procedure described for the preparation of N-aryl-benzenesulfonamides. MS: m/z 496 (M++1).
Reaction SMILES: O[C:2]1[C:10]([NH:11][C:12](=[O:14])[CH3:13])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:15])[CH2:5][CH2:6]2.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH3:13][C:12]1[O:14][C:2]2[C:3]3[C:4](=[O:15])[CH2:5][CH2:6][C:7]=3[CH:8]=[CH:9][C:10]=2[N:11]=1
Reactant: CC(=O)Nc1ccc2c(c1O)C(=O)CC2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1C
Product: Cc1nc2ccc3c(c2o1)C(=O)CC3
Yield: 84.7 %

Procedure:
N-(4-Hydroxy-3-oxo-2,3-dihydro-1H-inden-5-yl)acetamide (469 mg, 2.29 mmol) and pyridinium p-toluenesulfonate (115 mg, 0.457 mmol) were heated under reflux in xylene (23 mL) for 2.5 hr. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→100/0) to give the title compound (363 mg, yield 85%).