Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]3[CH:15]=[C:14]([C:16]([O:18]CC)=[O:17])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-].Cl>C1COCC1.O>[C:1]1([C:7]2[S:8][C:9]3[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc2nc(-c3ccccc3)sc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccccc3)sc2c1
Yield: 100.4 %

Procedure:
Ethyl 2-phenyl-benzothiazole-6-carboxylate 1y (220 mg, 0.78 mmol) was stirred with LiOH (74 mg, 3.1 mmol) in THF (4 mL) and H2O (4 mL) for 16 h. Aqueous 1N HCl solution was added to the mixture to adjust pH to 3˜4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aq. NaCl, dried over Na2SO4 and concentrated to give 1z (200 mg).
Reaction SMILES: Cl.Cl.[I:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[N:10][C:11]=2[NH2:13])[N:6]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[N:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:26][O:27][CH2:28][CH2:29]Br>CN(C)C=O.[I-].[K+]>[I:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[N:10][C:11]=2[NH2:13])[N:6]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:29][CH2:28][O:27][CH3:26])[CH2:16][CH2:15]2)[N:5]=1
Reactant: Nc1ncnc2c1c(I)nn2C1CCNCC1
Reactant: COCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COCCN1CCC(n2nc(I)c3c(N)ncnc32)CC1
Temperature: 60 °C
Reaction time: 7 h
Yield: 52.1 %

Procedure:
To a mixture of 3-iodo-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (0.4 g, 0.00096 mol) and potassium carbonate (0.40 g, 0.0029 mol) in N,N-dimethylformamide (25 mL) was added 2-bromoethyl methyl ether (0.09 mL, 0.00096 mol) at room temperature. The heterogeneous mixture was stirred at 60° C. under an atmosphere of nitrogen for 7 hours. The reaction mixture was cooled to room temperature, and 2-bromoethyl methyl ether (0.045 mL, 0.00048 mol) was added. The mixture was stirred at 60° C. under an atmosphere of nitrogen for 16 hours. To the mixture to the room temperature, 2-bromoethyl methyl ether (0.019 mL, 0.00019 mol) and potassium iodide (0.008 g, 0.000048 mol) were added in order to complete the reaction. The mixture was stirred at 70° C. under an atmosphere of nitrogen for 7 hours. The solvent was removed under the reduced pressure. The residue was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane (4×50 mL). The combined organic extracts were washed with water, and brine, and dried over magnesium sulfate. The solvents were evaporated under the reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-50% over 30 min with 0.1 M ammonium acetate, 21 mL/min) to yield 3-iodo-1-[1-(2-methoxyethyl)-4-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.2 g, 0.0005 mol). RP-HPLC (Delta Pak C18, 5 μm, 300A, 15 cm; 5%-95% acetonitrile—0.1M ammonium acetate over 10 min, 1 mL/min) Rt 6.4 min. MS: MH+ 403
Reaction SMILES: [F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][NH:27]2.C1(C)C=CC=CC=1>C(O)(=O)C>[F:16][C:13]([F:14])([F:15])[C:10]([CH:11]=[N:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][NH:27]2)([OH:17])[CH2:9][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[O:20][CH3:21])([CH3:18])[CH3:19]
Reactant: Nc1cccc2[nH]ncc12
Reactant: COc1c(F)cccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1c(F)cccc1C(C)(C)CC(O)(C=Nc1cccc2[nH]ncc12)C(F)(F)F
Yield: 73.2 %

Procedure:
1.46 g (4.746 mmol) of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal is stirred with 632 mg (4.746 mmol) of 4-aminoindazole in 6.78 ml of glacial acetic acid for two days at room temperature. The reaction mixture is drawn off three times with toluene in a rotary evaporator, and the residue is chromatographed on silica gel (mobile solvent ethyl acetate/hexane). 1.47 g (73.5%) of the desired compound is isolated.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[CH3:24][C:25]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:26]=1[NH2:27]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([NH:27][C:26]4[CH:28]=[CH:29][C:30]([CH3:32])=[CH:31][C:25]=4[CH3:24])=[O:2])([CH2:9][CH2:8]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: Cc1ccc(N)c(C)c1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: Cc1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)c(C)c1

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2,4-dimethylaniline (42.3 μL) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(2,4-dimethylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (22.4 mg).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:9]1.C[O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:34][CH2:35]Cl>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:35][CH2:34][O:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[C:26]([OH:37])=[O:25])[CH2:20][CH2:19]2)=[CH:9]1
Reactant: COC(=O)c1ccccc1OCCCl
Reactant: Fc1ccc2c(C3CCNCC3)cn(CCC3OCCO3)c2c1
Product: O=C(O)c1ccccc1OCCN1CCC(c2cn(CCC3OCCO3)c3cc(F)ccc23)CC1
Yield: 22 %

Procedure:
This compound was prepared following the procedure described in Example 13 (part D) starting with 0.04 g (0.11 mmol) of 1-(2-[1,3]dioxolan-2-yl-ethyl)-6-fluoro-3-piperidin-4-yl-1H-indole and 0.03 g (0.15 mmol) of of 2-(2-chloro-ethoxy)-benzoic acid methyl ester. After purification over a Varian C18 column, 0.012 g (22% yield) were obtained.
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:13]2=[N:14][CH:15]=[C:16](Br)[N:17]=[C:12]2[C:11]([C:19](=[O:25])[NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:26][N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:36]#[N:37])[CH:34]=2)[C:29]([Sn](CCCC)(CCCC)CCCC)=[N:28]1.CN1C([Sn](CCCC)(CCCC)CCCC)C2C(=CC(C#N)=CC=2)N1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:1]([O:7][CH2:8][N:9]1[C:13]2=[N:14][CH:15]=[C:16]([C:29]3[C:30]4[C:35](=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=4)[N:27]([CH3:26])[N:28]=3)[N:17]=[C:12]2[C:11]([C:19](=[O:25])[NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(C#N)ccc12
Reactant: CC(C)(C)NC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(Br)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[Sn](CCCC)(CCCC)C1c2ccc(C#N)cc2NN1C
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COC(=O)C(C)(C)C)c2ccc(C#N)cc21
Temperature: 80 °C
Reaction time: 16 h
Yield: 48.5 %

Procedure:
In a round-bottomed flask, (2-bromo-7-(tert-butylcarbamoyl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)methyl pivalate (140 mg, 0.34 mmol) and 1-methyl-3-(tributylstannyl)-1H-indazole-6-carbonitrile (crude, containing some 2-methyl-3-(tributylstannyl)-1H-indazole-6-carbonitrile) was dissolved in DMF (5 mL) under nitrogen. Pd(PPh3)4 (20 mg, 0.017 mmol) and CuI (13 mg, 0.068 mmol) were added and mixture sonicated for 5 min while bubbling nitrogen. The reaction mixture was stirred at 80° C. for 16 hours. After solvent removal, the residue was purified by column chromatography on silica gel eluting with petroleum ether/EtOAc (3:1 to 1:1, v/v) to give (7-(tert-butylcarbamoyl)-2-(6-cyano-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)methyl pivalate (80 mg, 48.5%). MS: (M+H)+=488.3; 1H NMR (300 MHz, DMSO): δ 9.15 (s, 1H), 8.58-8.53 (m, 3H), 7.83 (s, 1H), 6.31 (s, 2H), 4.25 (s, 3H), 1.52 (s, 9H), 1.10 (s, 9H).
Reaction SMILES: CS[C:3]1[N:12]2[C:6]([CH:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH:10]=[CH:11]2)=[N:5][N:4]=1.[OH-:23].[K+]>>[C:17]1([CH:7]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH:10]=[CH:11][N:12]3[C:3](=[O:23])[NH:4][N:5]=[C:6]23)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CSc1nnc2n1C=Cc1ccccc1C2c1ccccc1
Reactant: [OH-]
Agent: [K+]
Product: O=c1[nH]nc2n1C=Cc1ccccc1C2c1ccccc1

Procedure:
3-Methylthio-11-phenyl-11H-s-triazolo[3,4-b][3]benzazepine was treated with potassium hydroxide and the reaction mixture was treated as described. This procedure provided 2,11-dihydro-11-phenyl-3H-s-triazolo[3,4-b][3]benzazepin-3-one as crystals. Colorless needles (as recrystallized from methanol), m.p. 258°-260° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([Cl:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[S:12](=[O:15])(=[O:14])=[O:13]>ClCCl.ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([S:12]([OH:15])(=[O:14])=[O:13])[C:9]([Cl:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cc1cccc(Cl)c1
Reactant: O=S(=O)=O
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: O=C(Cl)C(c1cccc(Cl)c1)S(=O)(=O)O
Temperature: 25 °C

Procedure:
A solution of 3-chlorophenylacetyl chloride (1.89 g, 10 mmole) in dichloromethane (20 ml) was treated with a suspension of sulphur trioxide--dioxane complex (15 mmole) in dichloroethane at 0° C. The mixture was stirred at room temperature for eighteen hours and evaporated, νmax. (CH2Cl2) 1790 cm-1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([C:16]([O:18]C)=[O:17])[CH:13]=[C:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:11]=1)#[N:2].O1CCOCC1.[OH-].[Li+]>O>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:11]=[C:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[C:14]([C:16]([OH:18])=[O:17])[CH:15]=1)#[N:2]
Reactant: CCOC(=O)c1cc(C(=O)OC)cc(-c2ccc(C)cc2C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(C(=O)O)cc(-c2ccc(C)cc2C#N)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A round-bottom flask was charged with 3-ethyl 5-methyl 2′-cyano-4′-methylbiphenyl-3,5-dicarboxylate (0.12 g, 0.33 mmol), 1,4-dioxane (10 mL), and a solution of lithium hydroxide (9 mg, 0.4 mmol) in water (2 mL). The mixture was stirred at room temperature for 2 h. The volatiles were removed under reduced pressure and the residue was acidified with 1 N HCl, and extracted with CH2Cl2. The separated organic phase was dried and concentrated. The residue was purified via flash chromatography to afford the desired product as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH3:13])[C:6]([CH:14]=[O:15])=[CH:5]2.[BH4-].[Na+]>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH3:13])[C:6]([CH2:14][OH:15])=[CH:5]2
Reactant: CNc1nc2ccc(C)cc2cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNc1nc2ccc(C)cc2cc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a stirred solution of 6-methyl-2-(methylamino)quinoline-3-carbaldehyde MDE 32036 (134 mg, 0.67 mmol) in THF (10 mL) at 0° C. in a 50 mL round-bottomed flask equipped with a magnetic stirrer was added NaBH4 (25 mg, 0.66 mmol) and the mixture was stirred overnight at RT then cooled in an ice bath before quenching by addition of a 6 N aq. HCl solution (0.45 mL). After stirring for 15 min at +4° C., the mixture was basified with a 2 N aq. NaOH solution (1.35 mL). THF was then removed at 40° C. under vacuum and the solution was extracted with CH2Cl2 (50 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 50:50) provided, after evaporation and drying, 6-methyl-2-(methylamino)quinolin-3-yl)methanol MDE32060 as a white solid (73 mg, 55% yield).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[NH2:6][C:7]1[NH:16][C:15](=[O:17])[C:14]2[C:13]3[CH:18]=[CH:19][C:20]([Br:22])=[CH:21][C:12]=3[CH2:11][CH2:10][C:9]=2[N:8]=1>>[NH2:6][C:7]1[NH:16][C:15](=[O:17])[C:14]2[C:13]3[CH:18]=[C:19]([S:2]([Cl:1])(=[O:5])=[O:3])[C:20]([Br:22])=[CH:21][C:12]=3[CH2:11][CH2:10][C:9]=2[N:8]=1
Reactant: O=S(=O)(O)Cl
Reactant: Nc1nc2c(c(=O)[nH]1)-c1ccc(Br)cc1CC2
Product: Nc1nc2c(c(=O)[nH]1)-c1cc(S(=O)(=O)Cl)c(Br)cc1CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.3 %

Procedure:
Chlorosulfonic acid(100 g) was added to 3-amino-8-bromo-5,6-dihydrobenzo[f]quinazolin-1(2H)-one(5.20 g,17.8 mmole) and the solution stirred overnight at room temperature. The reaction mixture was poured over ice, the collected solid washed with water, and dried under high vacuum to give 3-amino-8-bromo-5,6-dihydrobenzo[f]quinazolin-1(2H)-one-9-sulfonyl chloride(7.25 g, 90%). 1H NMR (DMSO-d6, 200 MHz) δ: 2.67-2.75 (m, 2H, Ar CH2), 2.81-2.88 (m, 2H, Ar CH2), 7.43 (s, 1H, Ar), 8.23 (br s, 2H, NH2), 8.91(s, 1H, Ar), 9.90-10.50 (v br s, 1H, NH). Anal Calculated for C12H9BrClN3O3S 1/2 H2O0.9/20 H2SO4: C,32.48; H,2.48; N,9.47; S,10.46. Found: C,32.68; H,2.37; N,9.20; S,10.40.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([N:16]3[CH2:22][CH:21]4[O:23][CH:18]([CH2:19][CH2:20]4)[CH2:17]3)[CH:13]=[C:12]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=3)[N:11]=2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([N:16]3[CH2:17][CH:18]4[O:23][CH:21]([CH2:20][CH2:19]4)[CH2:22]3)[CH:13]=[C:12]([C:24]3[CH:25]=[CH:26][C:27]([NH2:30])=[CH:28][CH:29]=3)[N:11]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(-c2cc(N3CC4CCC(C3)O4)nc(-c3ccc([N+](=O)[O-])cc3)n2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(-c2cc(N3CC4CCC(C3)O4)nc(-c3ccc(N)cc3)n2)cc1
Reaction time: 40 h

Procedure:
In a 500 mL round-bottomed flask was placed 3-[2,6-bis-(4-nitro-phenyl)-pyrimidin-4-yl]-8-oxa-3-aza-bicyclo[3.2.1]octane (15) in ethanol (100 ml). A catalytic amount of Pd on charcoal (wet) was added and the mixture was stirred under a hydrogen atmosphere for 40 h. The mixture was filtered over Celite™, rinsed with MeOH, and concentrated. The crude product was added to a silica gel column and eluted with ethyl acetate in hexanes (40-100%) to give 295 mg of the title compound (0.79 mmol).
Reaction SMILES: OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:6].[CH2:16]([C:18]1[N:19]=[N+:20]([O-:38])[C:21]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:24][C:22]=2[N:23]=1)[CH3:17].FC(F)(F)C(O)=O>C(Cl)Cl.C(Cl)(Cl)Cl.N>[CH2:16]([C:18]1[N:19]=[N+:20]([O-:38])[C:21]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[CH:24][C:22]=2[N+:23]=1[O-:6])[CH3:17]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCc1nc2cc(OCCCN3CCOCC3)ccc2[n+]([O-])n1
Agent: N
Agent: OO
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1n[n+]([O-])c2ccc(OCCCN3CCOCC3)cc2[n+]1[O-]
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 25.9 %

Procedure:
Hydrogen peroxide (70%; 0.53 mL, ca. 10.43 mmol) was added dropwise to a stirred solution of trifluoroacetic anhydride (1.45 mL, 10.43 mmol) in DCM (20 mL) at 5° C. The solution was stirred at 20° C. for 10 min, then cooled to 5° C., added to a solution of 1-oxide 31 (260 mg, 1.04 mmol) and trifluoroactic acid (0.17 mL, 2.23 mmol) in CHCl3 (20 mL) at 5° C. The solution was stirred at 20° C. for 24 h, diluted with dilute aqueous NH3 solution (50 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by column chromatography, eluting with 5% MeOH/DCM to give 1,4-dioxide 32 (90 mg, 32%) as a bright yellow solid, mp 123-126° C.; 1H NMR δ 8.36 (d, J=9.5 Hz, 1 H, H-8), 7.77 (d, J=2.6 Hz, 1 H, H-5), 7.36 (dd, J=9.5, 2.6 Hz, 1 H, H-7), 4.29 (t, J=6.4 Hz, 2 H, CH2), 3.72 (t, J=4.6 Hz, 4 H, 2×CH2O), 3.21 (q, J=7.5 Hz, 2 H, CH2), 2.54 (t, J=7.0 Hz, 2 H, CH2), 2.47 (t, J=4.6 Hz, 4 H, 2×CH2N), 2.10-2.04 (m, 2 H, CH2), 1.44 (t, J=7.5 Hz, 3 H, CH3); 13C NMR δ 165.1, 157.1, 141.5, 129.6, 124.4, 123.4, 98.0, 68.1, 66.9 (2), 55.0, 53.7 (2), 25.9, 24.1, 9.3. Anal. Calcd for C16H22N4O4: C, 57.5; H, 6.3; N, 16.8. Found: C, 57.2; H, 6.5; N, 16.5%.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:15]=[CH:14][C:7]2[C:8](=[O:13])[NH:9][S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.O>CN(C=O)C>[Br:3][C:4]1[CH:15]=[CH:14][C:7]2[C:8](=[O:13])[N:9]([CH2:22][C:21]3[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)[S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=1
Reactant: O=C1NS(=O)(=O)c2cc(Br)ccc21
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)c3ccc(Br)cc3S2(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 60% NaH (10.1 mg, 0.254 mmol) in DMF (1 mL), 6-bromobenzo[d]isothiazol-3(2H)-one 1,1-dioxide (55.4 mg, 0.212 mmol) was added portionwise at 0° C. The resulting mixture was stirred at rt for 15 min and p-methoxy benzyl chloride (27.6 μL, 0.212 mmol) was added dropwise. The reaction mixture was heated to 70° C. overnight, allowed to cool to rt, and treated with water (20 mL). The aqueous layer was extracted with EtOAc (3×50 mL) and the combined organic layers were dried over Na2SO4, filtered, and concentrated. The resulting solid was recrystallized from hexane/DCM to obtain compound 38a. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.08 (d, J=1.5 Hz, 1H), 7.89 (dd, J=8.2, 1.6 Hz, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.35 (d, J=8.6 Hz, 2H), 6.79 (d, J=8.6 Hz, 2H), 4.76 (s, 2H), 3.71 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Li]CCCC.CN([CH:17]=[O:18])C>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH:17]=[O:18])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Product: O=Cc1ccc(Br)cn1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 2,5-dibromopyridine (1.0 eq.) in Tol (O. 1M) at −78° C. was added n-BuLi (1.0Seq.). The mixture was stirred for 2 h at −78° C. then DMF (3.0 eq.) was added. The final mixture was stirred for 12 h at −78° C., quenched using saturated aqueous NH4Cl and extracted with Et2O (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 9:1) afforded the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:32](OCC)[O:33]CC)=[C:5]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])[C:7]=1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]>CC(C)=O.Cl>[CH3:1][C:2]1[NH:3][C:4]([CH:32]=[O:33])=[C:5]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])[C:7]=1[C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: CCOC(=O)C1=C(C(OCC)OCC)NC(C)=C(C(=O)OCc2ccccc2)C1c1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C=O)NC(C)=C(C(=O)OCc2ccccc2)C1c1ccccc1[N+](=O)[O-]
Yield: 100.9 %

Procedure:
In a substantially similar manner to that of Example 2-6), was treated a mixture of benzyl 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate (1.5 g) in acetone (15 ml) and 6 N hydrochloric acid (1.5 ml) to give a reddish brown oil which was crystallized and washed with n-hexane to give crystals (1.30 g) of benzyl 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate,
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[CH:9]=2)[N:4]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:3]=1.[CH2:40]([N:47]1[CH:51]=[C:50](B2OC(C)(C)C(C)(C)O2)[CH:49]=[N:48]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:40]([N:47]1[CH:51]=[C:50]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)=[CH:13][CH:12]=4)[CH:9]=3)[N:4]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:3]=2)[CH:49]=[N:48]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Reactant: CC1(C)OB(c2cnn(Cc3ccccc3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4ccccc4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Yield: 95.8 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (intermediate 41) (200 mg, 0.303 mmol) was coupled with 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 15) (130 mg, 0.455 mmol) using sodium carbonate (81 mg, 0.759 mmol) and Pd(PPh3)2Cl2 (11 mg, 0.015 mmol) in toluene/ethanol/water (10/2/1 ml) to afford 200 mg (95.6% yield) of titled compound after purification by column (Silica gel 6/120) using 50% EtOAc/hexane as eluent. MS: m/z=689.3 (M+1).
Reaction SMILES: [F:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]([F:13])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:14][CH2:12][C:11]1[C:2]([F:1])=[C:3]([C:8]([F:13])=[CH:9][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(F)ccc(C)c1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(F)ccc(CBr)c1F
Temperature: 25 °C
Yield: 107 %

Procedure:
To a room temperature solution of methyl 2,6-difluoro-3-methylbenzoate (9.35 g, 50.2 mmol, 1.0 equiv) and N-bromosuccinimide (11.6 g, 65.3 mmol, 1.3 equiv) in carbon tetrachloride (230 mL) was added catalytic AIBN (−200 mg) as a solid in one portion. The resulting reaction mixture was heated to reflux overnight. After the reaction mixture was allowed to cool to room temperature, it was washed with aq. satd. NaHCO3. The aqueous layer was extracted with dichloromethane, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to provide 14.24 g (>100% mass recovery) of unpurified bromide, which was taken on to the next step without purification.