Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[OH:3][CH2:4][C@H:5]([N:11]1[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C@H:12]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)[CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9].I[CH:32]([CH3:34])[CH3:33].[OH-].[Na+]>CS(C)=O.CO>[CH:32]([O:3][CH2:4][C@H:5]([N:11]1[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C@H:12]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][CH:22]=1)[CH2:6][CH2:7][CH:8]([CH3:9])[CH3:10])([CH3:34])[CH3:33]
Reactant: CC(C)CC[C@H](CO)N1CC[C@@H](CC(=O)O)C[C@H]1c1ccc(C(F)(F)F)cc1
Reactant: CC(C)I
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CS(C)=O
Product: CC(C)CC[C@H](COC(C)C)N1CC[C@@H](CC(=O)O)C[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 13.5 %

Procedure:
Powdered KOH (375 mg, 6.68 mmol) was taken up in dry DMSO (1 ml) at RT under N2. The mixture was stirred for 10 minutes before the addition of {(2S,4R)-1-[(1R)-1-(hydroxymethyl)-4-methylpentyl]-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl acetic}acid (Step 1, 67 mg, 0.167 mmol) in dry DMSO (0.5+0.5+0.5 ml), followed by 2-iodopropane (0.334 ml, 3.34 mmol). After 24 hr MS further 2-iodopropane (0.334 ml, 3.34 mmol) was added and the reaction was maintained at RT for 3 days. The reaction was quenched with saturated aqueous NH4Cl and then partitioned between DCM and H2O. The aqueous layer was extracted with DCM (×3). The combined extracts were evaporated and the residue was diluted with MeOH and loaded on to a SCX cartridge (2 g). The cartridge was eluted with MeOH to wash off the DMSO, then 2N NH3 in MeOH to elute the products. The NH3/MeOH fractions were combined and evaporated. The residue was taken up in MeOH (2 ml) and 4N NaOH (aq, 0.2 ml, 0.8 mmol) was added. The mixture was stirred and heated to 60° C. for 2 hrs. After cooling to RT the MeOH was removed in vacuo and the residue was partitioned between DCM and H2O. 2N HCl (0.5 ml) was added. The pH of the aqueous layer was adjusted to ˜7 with NaHCO3 (aq). The aqueous layer was extracted with DCM (×3). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by reverse phase HPLC (ABZ+ column) to give the title compound (10 mg) as a colourless solid.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-]CC.[Na+].Br[CH2:13][CH2:14][Cl:15].O>C(O)C>[C:1]1([S:7][CH2:13][CH2:14][Cl:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: ClCCBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ClCCSc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74 %

Procedure:
Benzenethiol (15.0 g, 0.136 mol) was added to the solution of sodium ethoxide (0.20 mol) in 200 ml of anhydrous ethanol, and the mixture was stirred at room temperature for 15 minutes and then added to the solution of 1-bromo-2-chloroethane in 100 ml of ethanol. The resultant mixture was stirred at room temperature for 3 hours and poured into 300 ml of water. The mixture was extracted three times with ether and the combined organic layer was dried over magnesium sulfate. After removal of the solvent, the compound was purified by flash chromatography using heptane/ethyl acetate (100 to 97/3) as eluent in a yield of 74%.
Reaction SMILES: [CH2:1]([N:4]1[C:8]2=[C:9]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)[N:10]=[C:11]([C:13]([OH:15])=O)[CH:12]=[C:7]2[CH:6]=[C:5]1[CH3:26])[CH:2]=[CH2:3].[CH2:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH3:28]>>[CH2:1]([N:4]1[C:8]2=[C:9]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)[N:10]=[C:11]([C:13]([N:32]3[CH2:33][CH2:34][N:29]([CH2:27][CH3:28])[CH2:30][CH2:31]3)=[O:15])[CH:12]=[C:7]2[CH:6]=[C:5]1[CH3:26])[CH:2]=[CH2:3]
Reactant: C=CCn1c(C)cc2cc(C(=O)O)nc(N3CCc4ccccc4C3)c21
Reactant: CCN1CCNCC1
Product: C=CCn1c(C)cc2cc(C(=O)N3CCN(CC)CC3)nc(N3CCc4ccccc4C3)c21
Yield: 49 %

Procedure:
In accordance with the same procedures as in Step 1 of Example 756, except for using 1-allyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Step 1 of Example 922 and 1-ethylpiperazine, the titled compound was obtained as a white solid. (Yield: 49%)
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:5]([NH2:6])=[C:4]([I:12])[CH:3]=1.O1CCCC1.[H][H]>C(O)CC>[Cl:1][C:2]1[CH:3]=[C:4]([I:12])[C:5]([NH2:6])=[C:7]([NH2:9])[CH:8]=1
Reactant: [H][H]
Reactant: Nc1c(I)cc(Cl)cc1[N+](=O)[O-]
Solvent: CCCO
Solvent: C1CCOC1
Product: Nc1cc(Cl)cc(I)c1N
Temperature: 25 °C
Yield: 96.3 %

Procedure:
1.5 g of 4-chloro-2-iodo-6-nitroaniline together with 50 ml of tetrahydrofuran and 10 ml of 1-propanol are initially introduced into a stirred autoclave. 5 mg of FeCl2.4H2O and 0.3 g Pt/Pb-CaCO3 catalyst are added to the solution, and hydrogenation is carried out at 130° C. and 20 bar of hydrogen. After the hydrogenation has come to a standstill, the reaction mixture is cooled to room temperature, the reactor is rendered inert with nitrogen and the catalyst is filtered off. After filtration, the solvent is removed by distillation to give 1.3 g of 4-chloro-6-iodo-1,2-phenylenediamine as a crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=3[CH3:24])[CH2:13][CH2:12]2)[C:8]([N+:25]([O-:27])=[O:26])=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C)C=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:66][N:67]([CH2:69][C:70]1[CH:71]=[C:72]([CH:75]=[CH:76][CH:77]=1)[CH2:73][NH2:74])[CH3:68]>O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=3[CH3:24])[CH2:13][CH2:12]2)[C:8]([N+:25]([O-:27])=[O:26])=[CH:7][C:3]=1[C:4]([NH:74][CH2:73][C:72]1[CH:75]=[CH:76][CH:77]=[C:70]([CH2:69][N:67]([CH3:68])[CH3:66])[CH:71]=1)=[O:5]
Reactant: CN(C)Cc1cccc(CN)c1
Reactant: Cc1ccc(C)c(N2CCN(c3cc(Cl)c(C(=O)O)cc3[N+](=O)[O-])CC2)c1
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
Solvent: O
Product: Cc1ccc(C)c(N2CCN(c3cc(Cl)c(C(=O)NCc4cccc(CN(C)C)c4)cc3[N+](=O)[O-])CC2)c1
Temperature: 25 °C
Yield: 97.6 %

Procedure:
In a 40 ml scintillation vial equipped with a magnetic stir bar and a nitrogen inlet, the 2-chloro-4-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-5-nitro-benzoic acid 12b (157.90 mg, 0.41 mmol) was taken up in clean, dry N,N-dimethylformamide (5.00 ml, 64.57 mmol) and the reaction mixture was stirred under nitrogen at room temperature until all solids had gone into solution. To the reaction was then added the HATU (184.80 mg, 0.49 mmol) followed by the N,N-diisopropylethylamine (0.14 ml, 0.80 mmol) and the mixture was stirred until all solids had gone into solution. The 3-dimethylaminomethyl-benzylamine (86.50 mg, 0.53 mmol) was then added to the reaction solution and the reaction was allowed to stir at room temperature overnight. The reaction was diluted with 15 ml of water and 15 ml of ethyl acetate. The layers were then separated and the product was extracted from the aqueous using ethyl acetate (3×20 ml). The organic phases were combined, washed with brine (1×25 ml) and with saturated aqueous lithium chloride solution (2×25 ml). The product solution was then dried over Na2SO4; the solution was then decanted and the solvent was removed under reduced pressure. The crude product, 2-chloro-N-(3-dimethylaminomethyl-benzyl)-4-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-5-nitro-benzamide 13a (214.40 mg, 0.40 mmol), was isolated as an amber oil and was carried on without further purification. LCMS (m/e)=537 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:10](=[O:16])[CH2:11][CH2:12][C:13]=2[O:14][CH3:15])=[C:4]([CH3:17])[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]=[O:35]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:17])[C:5]([C:9]2[C:10](=[O:16])[CH:11]([CH:34]([OH:35])[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=3)[CH2:12][C:13]=2[O:14][CH3:15])=[C:6]([CH3:8])[CH:7]=1
Reactant: O=Cc1ccccn1
Reactant: COC1=C(c2c(C)cc(Br)cc2C)C(=O)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC1=C(c2c(C)cc(Br)cc2C)C(=O)C(C(O)c2ccccn2)C1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2-(4-bromo-2,6-dimethylphenyl)-3-methoxycyclopent-2-enone (5 g, 17 mmol) in anhydrous tetrahydrofuran (50 ml) under nitrogen atmosphere is added lithium bis(trimethylsilyl)amide (22.4 ml, 20 mmol, 0.9M solution in tetrahydrofuran) dropwise at −75°C. The resulting solution is stirred at this temperature for 40 minutes, then a second solution of pyridine-2-carboxaldehyde (2.18 g, 20 mmol) in anhydrous tetrahydrofuran (50 ml) is added over 20 minutes. The resulting solution is stirred at −75°C. for 2 hours, then allowed to warm to room temperature and stir for a further 2 hours. The reaction mixture is quenched with ice cold water (30 ml), extracted with ethyl acetate (3×100 ml), then dried over sodium sulfate, filtered and the filtrate is concentrated in vacuo to afford 2-(4-bromo-2,6-dimethylphenyl)-5-(hydroxypyridin-2-ylmethyl)-3-methoxycyclopent-2-enone. This material is used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([CH2:21][S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:31]([O-])=O.[Na+].[OH-].[Na+].[ClH:37]>O>[ClH:37].[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:17](=[CH:19][CH:20]=2)[NH:18][N:31]=[C:21]3[S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1CS(=O)(=O)c1ccccc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)(c1ccccc1)c1n[nH]c2ccc(N3CCN(Cc4ccccc4)CC3)cc12
Reaction time: 0.67 h
Yield: 64 %

Procedure:
A stirred solution of 4-(4-benzylpiperazin-1-yl)-2-[(phenylsulfonyl)methyl]-aniline (0.371 g, 0.88 mmol) in 4.0 M aqueous hydrochloric acid is cooled in an ice bath, treated dropwise with NaNO2 (91 mg, 1.32 mmol) in water, stirred for 40 min, treated with 2.5 M aqueous NaOH to pH ˜14 and filtered. The filtercake is dissolved in CH2Cl2, and chromatographed (silica gel, ethyl acetate as eluent) to afford the free indazole of the title product as a yellow solid (276 mg, 64%). The solid is dissolved in a mixture of ethanol and CH2Cl2, treated with 4.0 M HCl in dioxane, and concentrated in vacuo to give a solid residue. The residue is triturated with ethyl acetate to afford the title product as an off-white solid, 278 mg (57% yield), mp 177-180° C., identified by NMR and mass spectral analyses.
Reaction SMILES: Br[C:2]1[C:3]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:21])=[CH:15][CH:14]=2)=[N:4][N:5]([CH2:7][CH:8]2[CH2:12][CH2:11][CH2:10][O:9]2)[CH:6]=1.C1(S([N:38]2[C:42]3=[N:43][CH:44]=[CH:45][C:46](B4OC(C)(C)C(C)(C)O4)=[C:41]3[CH:40]=[CH:39]2)(=O)=O)C=CC=CC=1.C(=O)(O)[O-].[Na+]>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.CN(C)C=O>[C:23]1([NH:22][C:20]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([C:3]3[C:2]([C:46]4[CH:45]=[CH:44][N:43]=[C:42]5[NH:38][CH:39]=[CH:40][C:41]=45)=[CH:6][N:5]([CH2:7][CH:8]4[CH2:12][CH2:11][CH2:10][O:9]4)[N:4]=3)=[CH:14][CH:15]=2)=[O:21])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Nc1ccccc1)Nc1ccc(-c2nn(CC3CCCO3)cc2Br)cc1
Reactant: CC1(C)OB(c2ccnc3c2ccn3S(=O)(=O)c2ccccc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)Nc1ccc(-c2nn(CC3CCCO3)cc2-c2ccnc3[nH]ccc23)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 11 %

Procedure:
A mixture of N-{4-[4-bromo-1-(tetrahydro-2-furanylmethyl)-1H-pyrazol-3-yl]phenyl}-N′-phenylurea (0.147 mmol), 1-(phenylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (0.162 mmol), N,N-dimethylformamide (1.5 mL), saturated aqueous sodium bicarbonate (0.44 mL) and tetrakis(triphenylphosphine)palladium(0) (0.007 mmol) in a sealed tube was stirred at 100° C. for 18 hrs. The solution was cooled to room temperature, filtered though Celite and concentrated in vacuo. The residue was dissolved in methanol (5 mL) and 6.0N aqueous sodium hydroxide (1 mL) and stirred at 70° C. for 6 h. The reaction mixture was concentrated in vacuo, dissolved in water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by Gilson reverse phase HPLC afforded the title compound as a white solid (11%). ESMS [M+H]+: 479.4
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[NH:11][C:10]1[C:9](=[O:16])[CH2:8][CH2:7][CH2:6][C:5]2=1.[CH3:17][Mg]Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[NH:11][C:10]1[C:9]([CH3:17])([OH:16])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C1CCCc2c1[nH]c1cc(Cl)c(Cl)cc21
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC1(O)CCCc2c1[nH]c1cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 9.3 %

Procedure:
To a solution of 6,7-dichloro-2,3,4,9-tetrahydro-1H-carbazol-1-one (0.1 g, 0.4 mmol) in anhydrous THF (5 mL) cooled to 0° C., MeMgCl (1.3 mL, 3.95 mmol, 3M in THF) was added dropwise. The reaction mixture was slowly warmed to room temperature and stirred for 5 h, cooled to 0° C., and then quenched with saturated NH4Cl (10 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4 and the solvent was removed under reduced pressure to give the crude material which was purified by column chromatography [EtOAc-hexane (1:9) as eluant] to give the title compound as a pale brown solid (0.01 g, 10%). 1H NMR (500 MHz. DMSO-d6, δ in ppm) 7.75 (s, 1H), 7.60 (s, 1H), 5.96 (s, 1H), 5.15 (s, 1H), 2.19-2.17 (m, 1H), 2.0-1.82 (m, 2H), 1.62-1.59 (m, 1H), 1.45 (s, 3H), 1.43-1.41 (m, 1H), 0.98-1.11 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-])=O.N1C=CC=CC=1.[NH4+]=S>C(O)C.O>[N+:10]([C:8]1[CH:9]=[C:4]([NH2:1])[CH:5]=[C:6]([N:13]2[CH:14]=[CH:15][CH:16]=[CH:17]2)[CH:7]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cc(-n2cccc2)cc([N+](=O)[O-])c1
Solvent: O
Solvent: CCO
Solvent: c1ccncc1
Product: Nc1cc(-n2cccc2)cc([N+](=O)[O-])c1
Reaction time: 4 h
Yield: 98 %

Procedure:
To a solution of 1-(3,5-dinitro-phenyl)-1H-pyrrole (8.2 g, 35.19 mmol) and pyridine (10 ml) in ethanol (100 ml), at 80° C., was added a 20% aqueous solution of ammonium sulfide (38.4 ml, 140.76 mmol, 4.0 eq.) in water (10 ml). The mixture was stirred at the same temperature for 4 h. The mixture was quenched with ice water (200 ml) and the precipitated solid was filtered. The filtered solid was dried under vacuum to afford the product in 98% yield (7.0 g).
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:10][C:11]([Sn](CCCC)(CCCC)CCCC)=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])[CH:2]=[CH2:3].Br[C:36]1[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[CH:37]=1>CN(C=O)C.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>[CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:10][C:11]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[CH:37]=2)=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])[CH:2]=[CH2:3]
Reactant: Cc1cc(Br)ccn1
Reactant: C=CCn1ccnc1-c1sc([Sn](CCCC)(CCCC)CCCC)cc1-c1ccc(Cl)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: C=CCn1ccnc1-c1sc(-c2ccnc(C)c2)cc1-c1ccc(Cl)cc1Cl
Temperature: 90 °C
Yield: 70.9 %

Procedure:
To a solution of 1-allyl-2-[3-(2,4-dichlorophenyl)-5-(tributylstannyl)-2-thienyl]-1H-imidazole (300 mg, 0.48 mmol) and 4-bromo-2-picoline (68.9 mg, 0.40 mmol) in DMF (10.0 mL) was added bis(triphenylphosphine)palladium dichloride (14.1 mg, 0.02 mmol) under atmosphere of Argon then the mixture was heated at 90° C. for 1 h. After cooling to room temperature, the solvent was evaporated and the residue was purified by column chromatography (SiO2, elution with 3-5% MeOH in DCM) to give 121 mg of product (67%). LC/MS (AA) ES+ 428. 1H NMR (400 MHz, d6 DMSO) δ: 8.48 (d, J=4.8 Hz, 1H), 7.93 (s, 1H), 7.72 (d, J=2.1 Hz, 1H), 7.60 (br s, 1H), 7.50-7.53 (m, 1H), 7.41 (dd, J=2.1, 8.4 Hz, 1H), 7.18-7.21 (m, 2H), 7.03 (d, J=1.1 Hz, 1H), 5.53-5.64 (m, 1H), 5.04 (dd, J=1.3, 10.3 Hz, 1H), 4.82 (dd, J=1.3, 17.1 Hz, 1H), 4.26-4.31 (m, 2H), 2.51 (s, 3H).
Reaction SMILES: Br[C:2]1[C:3]([NH:9][C:10](=[O:13])[CH2:11]I)=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.C(N(C(C)C)CC)(C)C.[O:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1>C(#N)C>[Br:8][C:6]1[N:7]=[C:2]2[N:29]([CH:26]3[CH2:27][CH2:28][O:23][CH2:24][CH2:25]3)[CH2:11][C:10](=[O:13])[NH:9][C:3]2=[N:4][CH:5]=1
Reactant: O=C(CI)Nc1ncc(Br)nc1Br
Reactant: NC1CCOCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(C2CCOCC2)c2nc(Br)cnc2N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
To a solution of N-(3,5-dibromopyrazin-2-yl)-2-iodoacetamide (See Example 5.B) (6.6 g, 15.8 mmol) and diisopropylethylamine (4.0 g, 31.6 mmol) in acetonitrile (50 mL) was added tetrahydro-2H-pyran-4-amine (6.4 g, 63.2 mmol) and the mixture was stirred at ambient temperature for 16 h. The solvent was removed under reduced pressure and the residue which was purified by chromatography on silica gel (5-20% ethyl acetate in petroleum ether) to give the title compound (1.98 g, 40% yield). MS (ESI) m/z 313.1 [M+1]+.
Reaction SMILES: [CH3:1][CH:2]([NH2:5])[C:3]#[CH:4].Cl.CCN(CC)CC.[Cl:14][C:15]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>C1COCC1>[CH3:1][CH:2]([NH:5][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][CH:22]=[C:23]([C:24]([F:25])([F:26])[F:27])[C:15]=1[Cl:14])[C:3]#[CH:4]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Reactant: C#CC(C)N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CC(C)NC(=O)c1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the suspension of but-3-yn-2-amine.HCl salt (10 g, 94.7 mmol, 1.0 equiv.) in THF (150 mL), Et3N (27.5 mL, 199 mmol, 2.1 equiv.) and (2-chloro-3-(trifluoromethyl)benzoyl chloride (23.1 g, 94.7 mmol, 1.0 equiv.) were added sequentially at 0° C. The reaction mixture was then stirred at room temperature for 16 hours. The precipitate was filtered off and washed with THF. The filtrate solution was concentrated and re-dissolved in EtOAc. The EtOAc solution was washed with saturated NaHCO3 and brine, dried over Na2SO4, concentrated. Trituration of the crude product from EtOAc/hexanes afforded Intermediate 233: (23 g, 83.8 mmol, 88%) as a white solid. 1H NMR (600 MHz, CDCl3) δ 7.82-7.75 (dd, J=7.9, 1.6 Hz, 1H), 7.73-7.66 (dd, J=7.7, 1.6 Hz, 1H), 7.48-7.41 (dd, J=8.2, 7.3 Hz, 1H), 6.35-6.02 (d, J=7.9 Hz, 1H), 5.09-4.90 (dqd, J=8.1, 6.9, 2.3 Hz, 1H), 2.47-2.20 (m, 1H), 1.58-1.54 (d, J=6.9 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 164.7, 137.9, 132.5, 129.4 (q, JC—F=31.5 Hz), 129.1, 129.0 (q, JC—F=5.2 Hz), 127.1, 122.5 (q, JC—F=273.4 Hz), 83.2, 71.2, 37.8, 22.1. HRMS-ESI (m/z): [M+H]+ calcd for C12H10ClF3NO, 276.0398. found, 276.0390.
Reaction SMILES: [NH2:1][S:2]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:13])[CH:11]=2)[N:6]([CH3:14])[C:5]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:3].[Mn]([O-])(=O)(=O)=[O:21].[Na+]>>[CH3:14][N:6]1[C:7]2[C:12](=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:4]([S:2](=[O:21])(=[O:3])[NH2:1])=[C:5]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)c1c(S(N)=O)c2cc(C)ccc2n1C
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [Na+]
Product: CCOC(=O)c1c(S(N)(=O)=O)c2cc(C)ccc2n1C
Yield: 104.8 %

Procedure:
8.0 gm (29 millimols) of ethyl 3-aminosulfinyl-1,5-dimethyl-indole-2-carboxylate were reacted analogous to Example 18(c) with 3.0 gm (19 millimols) of sodium permanganate to yield b 5.9 gm (70% of theory) of ethyl 1,5-dimethyl-3-sulfamoyl-indole-2-carboxylate, M.p.: 148° C., and 2.0 gm (28% of theory) of 4,7-dimethyl-2H-isothiazolo[4,5-b]-indole-3(2H)-one-1,1-dioxide; M.p.: 295° C. (decompositon).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([OH:14])=O)[C:5]([CH3:19])=[N:4][C:3]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29].C(OC(Cl)=O)C(C)C.CN1CCOCC1.Cl.[CH3:46][NH:47][C:48](=[O:51])[CH2:49][NH2:50]>CC(N(C)C)=O.CN(C1C=CN=CC=1)C.ClCCl>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([NH:50][CH2:49][C:48]([NH:47][CH3:46])=[O:51])=[O:14])[C:5]([CH3:19])=[N:4][C:3]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29]
Reactant: CNC(=O)CN
Reactant: Cc1ccc(C(=O)O)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Br)c1=O
Agent: CC(C)COC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CNC(=O)CNC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
To a solution of 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (1.0 g, 0.022 mol) in dimethylacetamide (10.0 mL) at −20° C. was added isobutylchloroformate (0.36 g, 0.0028 mol), followed by dropwise addition of N-methylmorpholine (0.30 g, 0.003 mol) and stirred for 10 min under nitrogen atmosphere. The reaction mixture was then stirred at room temperature for 20 min, cooled to 0° C., and added N-methylmorpholine (0.30 g, 0.003 mol) followed by the addition of N-methylglycine amide hydrochloride (0.35 g, 0.0028 mol) and DMAP (0.025 g). The reaction mixture was stirred at room temperature for 4 h, and concentrated in vacuo. The resulting the residue was purified by reverse-phase HPLC using 10-90% CH3CN/Water gradient (40 min) at a flow rate of 80 mL/min. The appropriate fractions (MH+, m/z=535) were combined, and freeze-dried to give a white solid. This was dissolved in dichloromethane (25 mL), washed successively with 5% sodium bicarbonate (2×20 mL), water (2×20 mL), dried (Na2SO4), and concentrated to dryness to afford the racemic title compound (0.75 g, 65%) as a white amorphous substance: 1H NMR (CD3OD/400 MHz) δ 7.96 (dd 1H, J=1.6 Hz, 8.0 Hz), 7.72 (d, 1H, J=1.6 Hz), 7.62 (m, 1H), 7.56 (d, 1H, J=8.0 Hz), 7.01 (m, 2H), 5.55 (abq, 2H), 3.99 (s, 2H), 2.74 (s, 3H), 2.18 (s, 3H), and 2.14 (s, 3H); ES-HRMS m/z 535.0792 (M+H calcd for C23H22N4O4F2 Br requires 535.0787). 19F NMR (CD3OD/400 MHz) −111.85 (m) and −115.91 (m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[CH:10]2)=[CH:5][CH:4]=1.[OH-].[Na+].[Mn]([O-])(=O)(=O)=[O:19].[K+]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[CH:12][C:11]([C:14]([OH:19])=[O:15])=[CH:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-n2ccc(C=O)c2)cc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: COc1ccc(-n2ccc(C(=O)O)c2)cc1

Procedure:
Next, 1-(4-methoxyphenyl)pyrrole-3-carbaldehyde was added to an aqueous solution (100 ml) of sodium hydroxide (4.38 g) and an aqueous pyridine solution (water 100 ml and pyridine 180 ml) of potassium permanganate (8.65 g) at 20-30° C., and stirred at room temperature for six hours. After completion of the reaction, the reaction solution was filtered through Celite, the filtrate was acidified by the addition of hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, concentrated in vacuo and the precipitated solid was purified with ethyl acetate/n-hexane to give the titled compound (8.52 g).