Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:27][N:28](C)[C:29](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:43]>C(OCC)(=O)C.CC(O)C>[ClH:43].[F:1][C:2]1[C:3]([CH2:27][NH:28][CH3:29])=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cccc(S(C)(=O)=O)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2cccc(S(C)(=O)=O)c2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of tert-butyl [(4-fluoro-5-(2-fluoropyridin-3-yl)-1-{[3-(methylsulfonyl)phenyl]sulfonyl}-1H-pyrrol-3-yl)methyl]methylcarbamate (504 mg) in ethyl acetate (3 mL) and 2-propanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (6 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethanol and water to give the title compound as a white solid (yield 358 mg, 78%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]2.CCN(C(C)C)C(C)C.Br[CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN1CCCC1=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:24]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:11]([OH:13])=[O:12])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cc2cc(Br)ccc2[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=C(O)c1cc2cc(Br)ccc2n1C(c1ccccc1)c1ccccc1
Temperature: 50 °C
Yield: 87.2 %

Procedure:
To 5-bromoindole-2-carboxylic acid (1.024 g, 4.26 mmol) in 1-methyl-2-pyrrolidinone (13 mL) at 0° C. were added iPr2NEt (25.6 mmol), tetrabutylammonium iodide (157 mg, 0.426 mmol) and bromodiphenylmethane (1.20 g, 4.86 mmol). The reaction mixture was heated at 50° C. for 21 h before partitioning between diethyl ether and ice water. After adjusting the pH to 3, the aqueous layer was extracted with diethyl ether. The organic layers were combined, washed with NaH2PO4, dried over MgSO4 and evaporated to dryness. Purification on silica gel column (15% EtOAc in hexane) yielded 1.51 g (87% yield) of the product.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:39])[N:10]([CH:12]([C:14](=[O:38])[NH:15][CH:16]([C:21]([N:23]1[CH2:27][CH2:26][CH:25]2[N:28]([C:32](=[O:37])[NH:33][CH:34]([CH3:36])[CH3:35])[CH2:29][CH:30]([OH:31])[CH:24]12)=[O:22])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:40]([N:47]=[C:48]=[O:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[NH4+].[OH-]>C(#N)C.CO>[CH2:1]([O:8][C:9](=[O:39])[N:10]([CH:12]([C:14](=[O:38])[NH:15][CH:16]([C:21]([N:23]1[CH2:27][CH2:26][CH:25]2[N:28]([C:32](=[O:37])[NH:33][CH:34]([CH3:35])[CH3:36])[CH2:29][CH:30]([O:31][C:48](=[O:49])[NH:47][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:24]12)=[O:22])[C:17]([CH3:18])([CH3:19])[CH3:20])[CH3:13])[CH3:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=NCc1ccccc1
Reactant: CC(C)NC(=O)N1CC(O)C2C1CCN2C(=O)C(NC(=O)C(C)N(C)C(=O)OCc1ccccc1)C(C)(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Product: CC(C)NC(=O)N1CC(OC(=O)NCc2ccccc2)C2C1CCN2C(=O)C(NC(=O)C(C)N(C)C(=O)OCc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.2 %

Procedure:
A solution containing 57 (280 mg, 0.51 mmol) and benzyl isocyanate (350 μL, 2.83 mmol) in acetonitrile (500 μL) was warmed to reflux. After 12 h, the reaction mixture was cooled to ambient temperature, diluted with MeOH, and treated with aqueous NH4OH (30%, 5 mL). The solution was concentrated in vacuo and the residue was dissolved in EtOAc, washed successively with 1N HCl, water, aqueous NaHCO3, and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by reverse-phase HPLC (2″ Dynamax® C18, 50-100% MeOH/water containing 0.1% HOAc over 20 min; Flow: 40 mL/min). The pure fractions were combined and concentrated to afford 58 as a white solid (250 mg, 72%). Mass spectrum, m/z [679.3] (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[S:8][CH2:7][CH2:6][CH2:5][S:4]1.C(C1SCCCS1)(OCC)=O.C(N(CC)CC)C.[C:27](Cl)(=[O:31])[C:28]([CH3:30])=[CH2:29]>C(Cl)Cl>[C:27]([O:1][CH2:2][CH:3]1[S:8][CH2:7][CH2:6][CH2:5][S:4]1)(=[O:31])[C:28]([CH3:30])=[CH2:29]
Reactant: C=C(C)C(=O)Cl
Reactant: OCC1SCCCS1
Agent: CCOC(=O)C1SCCCS1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OCC1SCCCS1
Reaction time: 2 h
Yield: 75.8 %

Procedure:
To a 100-mL three-necked flask, 3.41 g of 2-hydroxymethyl-1,3-dithiane, which had been synthesized in accordance with the method known in the art (see Tetrahedron Letters, 41, 5653-5657 (2000)) using 2-carboethoxy-1,3-dithiane as a starting material, and 2.3 g of triethyl amine were added, and to this mixture 40 mL of dried methylene chloride were added and the resulting mixture was stirred with a stirrer bar coated with Teflon™ at 0° C. under nitrogen atmosphere. To the mixture, 2.3 g of methacryloyl chloride was slowly added through a dropping funnel, and the resulting mixture was reacted at 0° C. for 2 hours, and the temperature of the mixture was allowed to return to room temperature, followed by reacting for another 2 hours. After confirming consumption of the starting material by a thin layer chromatography (TLC), the reaction solution was poured into a 300-mL separatory funnel, washed with 100 mL of water, followed with 100 mL of saturated NaCl solution (brine), and dried with anhydrous sodium sulfate. From the obtained solution, the solvent was removed by an evaporator, to obtain an oily crude product. The crude product was purified by silica gel chromatography using a mixed solution of n-hexane and ethyl acetate to yield 3.64 g of 1,3-dithianylmethyl methacrylate (a dithiane derivative of the following formula 2) (yield: 79.4%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)(=[O:21])=[O:20])=[CH:15][C:14]=2[OH:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+].OS([O-])(=O)=O.[K+].[O-]S([O-])(=O)=O.[Na+].[Na+].C1C[O:48][CH2:47][CH2:46]1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)(=[O:21])=[O:20])=[CH:15][C:14]=2[O:29][CH2:46][CH2:47][OH:48])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(S(=O)(=O)c3cccc(F)c3)cc2O)C1
Agent: O=S(=O)([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(S(=O)(=O)c3cccc(F)c3)cc2OCCO)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91 %

Procedure:
3-[4-(3-Fluoro-benzenesulfonyl)-2-hydroxy-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (120 mg) was dissolved in THF (2 mL) and lithiumborohydride (7.94 mg, 0.365 mmol) was added under argon atmosphere. The reaction mixture was stirred at room temperature for 6 hours, then cooled to 0-5° C. and a solution of 10% KHSO4/Na2SO4 was carefully added until pH 2 was reached. The resulting mixture was extracted with EtOAc, and the combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The resulting crude material was purified via flash chromatography (hexane/EtOAc, 1/1) to give 103 mg (91% yield) of 3-[4-(3-fluoro-benzenesulfonyl)-2-(2-hydroxy-ethoxy)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][N:9]=1)(=O)=O.[C:16]([O:20][C:21](=[O:26])[NH:22][CH2:23][CH2:24][NH2:25])([CH3:19])([CH3:18])[CH3:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][NH:25][CH2:24][CH2:23][NH:22][C:21](=[O:26])[O:20][C:16]([CH3:18])([CH3:17])[CH3:19])=[N:9][CH:10]=1)#[N:15]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CS(=O)(=O)OCCc1ccc(C#N)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCNCCc1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(5-cyanopyridin-2-yl)ethyl methanesulfonate (4.0 g, crude), tert-butyl(2-aminoethyl)carbamate (4.8 g, 30 mmol) and K2CO3 (3.2 g, 30 mmol) in 40 mL of DMF was stirred overnight at room temperature. The reaction mixture was poured into ice water and extracted with EtOAc (100 mL×3). The combined EtOAc layer was washed with brine and concentrated. The residue was purified by silica gel column (DCM:MeOH=10:1) to afford the title compound.
Reaction SMILES: C([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:12]=1)=[O:10])C1C=CC=CC=1>C(O)C.[C].[Pd]>[CH2:26]([O:25][C:23]([CH2:22][CH2:21][CH2:20][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([C:9]([OH:10])=[O:8])=[CH:12]1)=[O:24])[CH3:27]
Reactant: CCOC(=O)CCCn1cc(C(=O)OCc2ccccc2)c2ccccc21
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCCn1cc(C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of ethyl 4-(3-benzyloxycarbonyl-1-indolyl)-butyrate and 10% palladium carbon in ethanol was stirred at room temperature for 1.5 hours under a hydrogen atmosphere. Removal of the catalyst and evaporation of the solvent afforded the object product.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CC(N(C)C)=O.[F:14][C:15]([F:27])([F:26])[C:16]1[CH:17]=[C:18](Cl)[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23].[OH-].[Na+]>O>[F:14][C:15]([F:26])([F:27])[C:16]1[CH:17]=[C:18]([S:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23]
Reactant: Sc1ccccn1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=[N+]([O-])c1ccc(Sc2ccccn2)cc1C(F)(F)F
Yield: 85.5 %

Procedure:
A mixture of 25 g of 2-mercaptopyridine, 70 ml of dimethylacetamide and 45.7 g of 3-trifluoromethyl-4-nitrochlorobenzene was heated at 80° to 90° C. and 35 g of 40% NaOH aq. solution was added to the mixture. After the reaction, the reaction mixture was poured into water and the product was extracted with ethyl ether and the ether phase was washed with a dilute NaOH aq. solution and then, with water and dried with anhydrous sodium sulfate and ether was distilled off to obtain 52 g of 2-trifluoromethyl-4-(pyridine-2-ylthio) nitrobenzene.
Reaction SMILES: [C:1]1([CH:7]([NH2:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)=[O:19])[CH3:16]>C1(C)C=CC=CC=1>[C:1]1([CH:7]([NH:14][CH:23]2[CH2:24][CH2:25][N:20]([C:18]([O:17][CH2:15][CH3:16])=[O:19])[CH2:21][CH2:22]2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)N1CCC(=O)CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(NC(c2ccccc2)c2ccccc2)CC1
Reaction time: 0.33 h
Yield: 91 %

Procedure:
In a reactor fitted with a water trap, a solution of 1,1-diphenylmethylamine (5.0 g) and 1-ethoxycarbonyl-4-piperidone (4.7 g) in toluene (70 mL) was refluxed for 4 hours. This reaction mixture was concentrated under reduced pressure and he residue was dissolved in 50 mL of ethanol. After the solution was cooled with ice, 2.1 g of sodium cyanoborohydride and a small amount of bromocresol green were added. Then, 4N-HCl solution in methanol was added dropwise until the reaction mixture had turned yellow and the mixture was further stirred for 20 minutes. This reaction mixture was poured into an access of aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5:1 to 65:35) to provide 8.4 g of the title compound. Yield 91%.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[C:9]([Cl:15])[C:8]=1[Cl:16])(=O)=O.[C:19]1(B(O)O)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[Cl:15][C:9]1[C:8]([Cl:16])=[C:7]([C:27]2[C:28]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:24]=[CH:25][CH:26]=2)[CH:12]=[CH:11][C:10]=1[CH:13]=[O:14]
Reactant: O=Cc1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1Cl
Reactant: OB(O)c1cccc2ccccc12
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: Cc1ccccc1
Product: O=Cc1ccc(-c2cccc3ccccc23)c(Cl)c1Cl
Reaction time: 16 h

Procedure:
A mixture of Example 5A (0.20 g, 0.62 mmol), 1-naphthylboronic acid (0.13 g, 0.74 mmol), Pd(PPh3)4 (20 mg), and 2M Na2CO3 (0.62 mL) in toluene (2.0 mL) was heated to 100° C., stirred for 16 hours, and concentrated. The concentrate was purified by flash column chromatography on silica gel with hexanes to 5:1 hexanes/ethyl acetate to provide the desired product.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16](=[O:20])(=[O:19])[NH:17][CH3:18])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[F:28][C:29]([F:42])([F:41])[C:30]1[S:34][C:33]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[N:32][N:31]=1>>[CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16]([NH:17][CH3:18])(=[O:20])=[O:19])=[CH:12][C:8]=2[C:9]([N:38]2[CH2:37][CH2:36][N:35]([C:33]3[S:34][C:30]([C:29]([F:41])([F:28])[F:42])=[N:31][N:32]=3)[CH2:40][CH2:39]2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: FC(F)(F)c1nnc(N2CCNCC2)s1
Reactant: CNS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)O)c1
Solvent: O=C(O)C(F)(F)F
Product: CNS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)N2CCN(c3nnc(C(F)(F)F)s3)CC2)c1
Yield: 46 %

Procedure:
Prepared in analogy to example 1 (b) from 2-cyclopentyloxy-5-methylsulfamoyl-benzoic acid (Example A29) and 1-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-piperazine trifluoroacetate (Example 62(b)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to yield the title compound as a white solid (yield 46%). MS (m/e): 520.3 (M+H+, 100%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.I[C:7]1[CH:8]=[C:9]([CH3:14])[CH:10]=[C:11]([CH3:13])[CH:12]=1>CCCCCC.C(OCC)(=O)C>[CH3:14][C:9]1[CH:8]=[C:7]([N:1]2[CH:5]=[CH:4][CH:3]=[CH:2]2)[CH:12]=[C:11]([CH3:13])[CH:10]=1
Reactant: c1cc[nH]c1
Reactant: Cc1cc(C)cc(I)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(-n2cccc2)c1
Yield: 99 %

Procedure:
Using general procedure B, pyrrole (83 μL, 1.2 mmol) was coupled with 5-iodo-m-xylene to give the crude product. Column chromatography (2×15 cm, hexane:ethyl acetate 9:1) provided 0.170 g (99% yield) of the product as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.07 (t, J=7.0 Hz, 2H), 7.02 (s, 2H), 6.89 (s, 1H), 6.33 (t, J=7.0 Hz, 2H), 2.37 (s, 6H).
Reaction SMILES: [Na].[SH:2][C:3]1[NH:4][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:11]=1.[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:14]=1[CH2:15]Cl.O>C(O)C.CN(C=O)C>[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:14]=1[CH2:15][S:2][C:3]1[NH:4][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:11]=1
Reactant: Fc1cccc(Cl)c1CCl
Reactant: Sc1nc2cnccc2[nH]1
Agent: [Na]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cccc(Cl)c1CSc1nc2cnccc2[nH]1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a solution of 0.34 g (0.015 g atom) of sodium in 70 mL of ethanol was added 2.0 g (0.013 mol) of 2-mercapto-1H-imidazo[4,5-c]pyridine. After stirring at room temperature for 25 minutes, the reaction mixture was evaporated to dryness in a rotary evaporator. To the residue was added 40 mL of DMF. To the resulting solution was added dropwise 2.33 g (0.013 mol) of 2-chloro-6-fluorobenzyl chloride in 3 mL of DMF. The reaction mixture was stirred overnight at room temperature and was then poured into 400 mL of chilled water. The precipitate that formed was collected by filtration and amounted to 3.11 g. An analytical sample (m.p. 224°-226° C.) was obtained by recrystallization from ethanol.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:25])[CH:21](Br)[CH2:22][CH3:23])=[CH:15][C:11]=1[C:12]([NH2:14])=[O:13].[SH:26][C:27]1[N:28]=[N:29]C=[CH:31][N:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>C(OCC)(=O)C.CN(C=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:25])[CH:21]([S:26][C:27]2[NH:28][N:29]=[CH:31][N:32]=2)[CH2:22][CH3:23])=[CH:15][C:11]=1[C:12]([NH2:14])=[O:13]
Reactant: CCC(Br)C(=O)Nc1ccc(-c2cc3ccccc3s2)c(C(N)=O)c1
Reactant: Sc1nccnn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(Sc1ncn[nH]1)C(=O)Nc1ccc(-c2cc3ccccc3s2)c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(1-Benzothien-2-yl)-5-[(2-bromobutanoyl)amino]benzamide (Example 9A; 50 mg) is introduced into DMF (1 ml) and, after addition of 3-mercapto-1,2,4-triazine (15 mg) and cesium carbonate (78 mg), stirred at RT overnight. The reaction mixture is mixed with ethyl acetate (50 ml) and 0.5N hydrochloric acid (50 ml), the aqueous phase is extracted with ethyl acetate (twice 50 ml), and the combined organic phases are washed with saturated sodium chloride solution (twice 100 ml). The organic phase is dried over magnesium sulfate and concentrated in a rotary evaporator. The residue is purified on a preparative HPLC. 14 mg (26% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:3]=1O[C@@H](C)C(O)=O.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[N:21][C:20]=2[CH:30]=1>>[Cl:1][C:2]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:3]=1[NH:21][CH:20]([CH3:30])[C:19]([NH:15][C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22]([C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)=[N:21][C:20]=2[CH:30]=1)=[O:23]
Reactant: C[C@H](Oc1cccc(Cl)c1Cl)C(=O)O
Reactant: Nc1ccc2oc(-c3ccncc3)nc2c1
Product: CC(Nc1cccc(Cl)c1Cl)C(=O)Nc1ccc2oc(-c3ccncc3)nc2c1

Procedure:
Similarly prepared as per compound 8 procedure, using (S)-2-(2,3-dichlorophenyl) propanoic acid 7 and compound 4 (4-pyridine) to obtained title compound Q60 as white solid (71%). 1H NMR (CDCl3, 400 MHz) δ 1.72 (d, J=6.8 Hz, 3H), 3.95 (dq, J=7.2 Hz, J=3.2 Hz, 1H), 4.79 (d, J=2.8 Hz, 1H), 6.56 (d, J=8.4 Hz, 1H), 6.96 (d, J=8 Hz, 1H), 7.09 (t, J=8 Hz, 1H), 7.46 (dd, J=9.2 Hz, J2=2 Hz, 1H), 7.54 (d, J=8.4 Hz, 1H), 8.06 (d, J=4 Hz, 2H), 8.09 (d, J=1.6 Hz, 1H), 8.56 (s, 1H), 8.8 (bs, 2H); 13C NMR (CDCl3, 100 MHz) δ 20.0, 56.4, 110.8, 111.1, 112.4, 118.6, 119.6, 120.9, 121.2, 128.4, 133.5, 134.3, 134.7, 142.4, 144.1, 148.0, 150.9, 161.7, 171.7; C21H17N4O2Cl2 (M+H)+ calcd. 427.0729 found 427.0724.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][C:8]2[C:9](=[O:18])[N:10]=[C:11]([NH:14][N+:15]([O-:17])=[O:16])[NH:12][CH:13]=2)[CH:4]=[N:3]1.[CH3:19]CN(C(C)C)C(C)C.CI>C(Cl)(Cl)Cl>[CH3:19][N:12]1[CH:13]=[C:8]([CH2:7][C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[C:9](=[O:18])[N:10]=[C:11]1[NH:14][N+:15]([O-:17])=[O:16]
Reactant: Cn1cc(Cc2c[nH]c(N[N+](=O)[O-])nc2=O)cn1
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: ClC(Cl)Cl
Product: Cn1cc(Cc2cn(C)c(N[N+](=O)[O-])nc2=O)cn1
Temperature: 23 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
A solution of 5-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-(nitroamino)-4(1H)-pyrimidinone (500 mg, 1.998 mmol) and DIPEA (1.745 mL, 9.99 mmol) in chloroform (5 mL) was mixed with methyl iodide (0.150 mL, 2.398 mmol). The reaction mixture was stirred at 23° C. overnight. Purification via HPLC then afforded the title compound (103 mg, 19.51% yield). LCMS: rt=1.46 min, [M+H+]=265.1
Reaction SMILES: Br[CH2:2][C:3]1([CH3:15])[CH2:7][C:6]2[C:8]([CH3:14])=[CH:9][C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[C:16]1([CH:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[NH:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.O>[CH3:15][C:3]1([CH2:2][N:27]2[CH2:28][CH2:29][CH:24]([NH:23][CH:22]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:25][CH2:26]2)[CH2:7][C:6]2[C:8]([CH3:14])=[CH:9][C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1
Reactant: c1ccc(C(NC2CCNCC2)c2ccccc2)cc1
Reactant: Cc1cc(C)c2c(c1C)OC(C)(CBr)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(C)c2c(c1C)OC(C)(CN1CCC(NC(c3ccccc3)c3ccccc3)CC1)C2
Temperature: 177 °C
Reaction time: 4 h
Yield: 88.8 %

Procedure:
A suspension of 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethylbenzofuran (1.0 g), N-(diphenylmethyl)-4-piperidinamine (1.5 g), and potassium carbonate (0.77 g) in N,N-dimethylacetamide (4 mL) was stirred under argon gas at 177° C. for 4 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3) to provide the title compound (1.5 g). Yield 97%.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@@H:8]([CH2:11][C:12]3[N:13]([C:18]4[CH:23]=[CH:22][C:21](B5OC(C)(C)C(C)(C)O5)=[CH:20][C:19]=4[F:33])[C:14](=[O:17])[NH:15][N:16]=3)[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.Br[C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[NH:41][CH:40]=[N:39][C:38]2=[O:45].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@@H:8]([CH2:11][C:12]3[N:13]([C:18]4[CH:23]=[CH:22][C:21]([C:35]5[CH:36]=[C:37]6[C:42](=[CH:43][CH:44]=5)[NH:41][CH:40]=[N:39][C:38]6=[O:45])=[CH:20][C:19]=4[F:33])[C:14](=[O:17])[NH:15][N:16]=3)[CH2:7]2)=[O:5])[CH2:3][CH2:2]1
Reactant: CC1(C)OB(c2ccc(-n3c(C[C@@H]4CCN(C(=O)C5CC5)C4)n[nH]c3=O)c(F)c2)OC1(C)C
Reactant: O=c1nc[nH]c2ccc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4[nH]cnc(=O)c4c3)cc2F)C1
Temperature: 25 °C
Yield: 11 %

Procedure:
A solution of 5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (0.238 mmol) in 1,4-dioxane (1.5 mL) was treated with 6-bromo-4(1H)-quinazolinone (0.238 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)-dichloromethane adduct (10 mg) and 2M aq potassium carbonate (0.715 mmol). The reaction mixture was purged with nitrogen, sealed, and irradiated in a microwave at 150° C. for 15 min. The reaction mixture was cooled to room temperature and was diluted with water (50 mL). The aqueous layer was acidified to pH˜4 using 1N aq HCl and was extracted with dichloromethane. The organic layer was dried over sodium sulfate, treated with Si-Thiol (Silicycle, 20 mg), filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC (10-40% acetonitrile w/0.1% TFA/water w/0.1% TFA). The product fractions from the HPLC were combined, adjusted to pH˜5 with the addition of saturated aq sodium bicarbonate, and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting product was then purified by flash chromatography (0-10% methanol/dichloromethane). The resulting product was suspended in water (0.5 mL) and was lyophilized to afford the title compound as an amorphous white solid (11%). MS(ES)+ m/e 475.1 [M+H]+.