Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([O-:6])(O[O-])(=O)=[O:2].[K+].[K+].CS[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1/[C:17](/[CH2:47][CH3:48])=[C:18](\[C:34]1[CH:39]=[CH:38][C:37](/[CH:40]=[CH:41]/[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:36][CH:35]=1)/[C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1)[N:23]=[CH:22]2.[CH2:49](Cl)Cl.O>CO.O>[CH3:49][S:1]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1/[C:17](/[CH2:47][CH3:48])=[C:18](\[C:34]1[CH:35]=[CH:36][C:37](/[CH:40]=[CH:41]/[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:38][CH:39]=1)/[C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1)[N:23]=[CH:22]2)(=[O:6])=[O:2]
Reactant: ClCCl
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccccc2SC)c2ccc3c(cnn3C3CCCCO3)c2)cc1
Reactant: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccccc2S(C)(=O)=O)c2ccc3c(cnn3C3CCCCO3)c2)cc1
Reaction time: 8 h

Procedure:
Potassium peroxymonosulfate (521 mg, 0.85 mmol) was added to a slurry of (E)-ethyl 3-(4-((E)-2-(2-(methylthio)phenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate (156 mg, 0.28 mmol) in MeOH:H2O (1:1, 6 mL) at room temperature, and the reaction was stirred overnight. DCM and water were added, and the layers were separated. The aqueous layer was washed with DCM (×2). The organic layers were combined, washed with water, washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified on a silica gel column eluted with 0-50% ethyl acetate in hexane affording the title compound. 1H NMR (DMSO-d6, 300 MHz): δ 8.15 (s, 1H), 7.91 (d, 1H), 7.77-7.71 (m, 2H), 7.49-7.46 (m, 3H), 7.41-7.31 (m, 4H), 7.01 (d, 2H), 6.45 (d, 1H), 5.87 (dd, 1H), 4.12 (q, 2H), 3.92-3.85 (m, 1H), 3.82-3.69 (m, 1H), 2.93 (s, 3H), 2.46-2.27 (m, 2H), 2.09-1.97 (m, 3H), 1.85-1.67 (m, 1H), 1.63-1.51 (m, 2H), 1.18 (t, 3H), 0.83 (t, 3H). LCMS: 501 [(M-THP+H)+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Cl.Cl[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]Cl.C(N(CC)CC)C>C(O)CCC>[N:1]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: ClCCNCCCl
Reactant: Nc1ccc2[nH]ccc2c1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: c1cc2cc(N3CCNCC3)ccc2[nH]1
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 5-aminoindole (6.23 g, 47 mmol), bis(2-chloroethyl)amine hydrochloride (16.8 g, 96 mmol) and triethylamine (19 mL, 141 mmol) in butanol is heated at 100° C. for 8 hours, cooled to room temperature and concentrated in vacuo to give 9.46 g of 5-piperazin-1-yl-1H-indole.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][C@@H:24]([C@H:26]1[O:30][C:29](=[O:31])[C:28]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:27]1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[OH:25])=[N+]=[N-].O>C1COCC1>[NH2:20][CH2:23][C@@H:24]([C@H:26]1[O:30][C:29](=[O:31])[C:28]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:27]1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[OH:25]
Reactant: [N-]=[N+]=NC[C@H](O)[C@H]1OC(=O)C(OCc2ccccc2)=C1OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NC[C@H](O)[C@H]1OC(=O)C(OCc2ccccc2)=C1OCc1ccccc1
Reaction time: 1 h
Yield: 21.1 %

Procedure:
Triphenylphosphine (600 mg, 2.4 mmol) was added to a stirred solution of (R)-5-(2-azido-(S)-1-hydroxyethyl)-3,4-dibenzyloxy-5H-furan-2-one (5) (750 mg, 2 mmol) in THF (10 ml) and after a few minutes gas was evolved. The stirring was continued until the effervescence had ceased (typically 2-3 h) and water (2 ml) was then added and the mixture stirred for a further 1 hour. The THF was removed under reduced pressure and the residue partitioned between dichloromethane (25 ml) and water (25 ml). The organic phase was separated, dried (MgSO4), filtered and any volatile components evaporated under reduced pressure (45° C. at 8 mm/Hg) to leave a viscous orange residue which was purified by chromatography on silica. Initial elution with a dichloromethane:methanol (19:1) mixture removed the less polar by-products and the product was then isolated by elution with a dichloromethane:methanol (3:1) mixture as a pale yellow oil (150 mg; 21%) (Rf0.25).
Reaction SMILES: N[C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[NH2:8].[C:15]([O:19][C:20]([NH:22][C:23]1([C:28](O)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:15]([O:19][C:20]([NH:22][C:23]1([C:28]([NH:8][C:7]2[CH:6]=[CH:5][C:4](/[CH:9]=[CH:10]/[C:11]([O:13][CH3:14])=[O:12])=[CH:3][CH:2]=2)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: COC(=O)/C=C/c1ccc(N)c(N)c1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCCC1
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
Product: COC(=O)/C=C/c1ccc(NC(=O)C2(NC(=O)OC(C)(C)C)CCCC2)cc1
Reaction time: 8 h

Procedure:
To a solution of methyl (2E)-3-(3,4-diaminophenyl)acrylate (from Step 3.1 eq), 1-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylic acid (1 eq) in DMF (0.02 M), HATU (1 eq) and DIPEA (3 eq) were added. The reaction mixture was left at RT with stirring overnight. The resulting mixture was partitioned between EtOAc and HCl (1 N). The combined EtOAc layers were washed with brine, and the organic phase was dried over Na2SO4, separated, and evaporated in vacuo to afford methyl (2E)-3-{4-[({1-[(tert-butoxycarbonyl)amino]cyclopentyl}carbonyl)amino]phenyl}acrylate, which was used without further purification. MS (ES+) m/z 404 (M+H)+. The foregoing product was dehydrated by heating it at 65° C. in presence of acetic acid. (0.16 M); the reaction residue was purified by RP-HPLC (Conditions Symmetry (Waters) C18 Column, 7 micron, 19×300 mm; flow: 20 mL/min; Gradient: A H2O+0.1% TFA; B: MeCN+0.1% TFA; 70% A isocratic for 2 min., linear to 20% A in 16 min isocratic for 0.5 min. and linear to 10% A for 2 min). Fractions containing pure product were pooled and lyophilized to give methyl (2E)-3-(2-{1-[(tert-butoxycarbonyl)amino]-cyclopentyl}-1H-benzimidazol-5-yl)acrylate. MS (ES−) m/z 384 (M−H)−.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[S-:11][C:12]#[N:13].[K+].[N:15]1([C:23]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:24]=2[NH2:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C>O.C(#N)C>[C:2]([NH:13][C:12]([NH:25][C:24]1[CH:26]=[C:27]([C:30]([F:31])([F:32])[F:33])[CH:28]=[CH:29][C:23]=1[N:15]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[S:11])(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: N#C[S-]
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCCCCCC1
Agent: Cl
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NC(=S)Nc1cc(C(F)(F)F)ccc1N1CCCCCCC1)c1ccncc1
Temperature: 70 °C
Reaction time: 0.67 h
Yield: 46.8 %

Procedure:
Isonicotinoyl chloride hydrochloride (261 mg, 1.47 mmol) was added to an acetonitrile solution (15 mL) of potassium thiocyanate (70.9 mg, 0.730 mmol) and then the mixture was stirred at 70° C. for 40 minutes. The organic mixture was left to room temperature. An acetonitrile solution (5 mL) of 2-(azacyclooctan-1-yl)-5-(trifluoromethyl)aniline (200 mg, 0.730 mmol) and triethylamine (205 μL, 1.47 mmol) were added sequentially. The reaction solution was heated to 50° C. and then stirred for 1 hour. The organic mixture was left to room temperature and then water was added to the solution. The mixture was subjected to extraction three times with ethyl acetate, washed with saturated sodium chloride solution, dried on anhydrous sodium sulfate, subjected to suction filtration, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1), so that (N-isonicotinoyl-N′-[2-(azacyclooctan-1-yl)-5-(trifluoromethyl)phenyl]thiourea (Compound 7) (149 mg, 46.8%) was obtained as yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][S:17]([CH3:16])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: NCc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NCc1ccccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
To a 0° solution of 15 g of 2-(aminomethyl)pyridine, 15.44 g of triethylamine and 150 ml of methylene chloride is added 17.48 g of methanesulfonyl chloride in 100 ml of methylene chloride. The mixture is stirred at 0° C. for 1 hour followed by stirring at room temperature for 3 hours. The reaction is poured into saturated sodium bicarbonate and extracted with methylene chloride. The combined extracts are washed with saturated sodium chloride and concentrated in vacuo. The residue is purified by chromatography (silica gel: 10% methyl alcohol/ethyl acetate) to give 19.84 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][O:9]C([C@@H](NC([C@@H](N)CC(O)=O)=O)CC1C=CC=CC=1)=O>>[CH:8]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:9]
Reactant: Nc1ccccc1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Product: O=CNc1ccccc1
Yield: 65 %

Procedure:
The reaction was run as described in Example 1, however, 0.70 g (7.6 mmol) aniline was used. Analysis of the reaction showed that aspartame was formed in 65-70% yield. Formanilide was also formed.
Reaction SMILES: [Br:1][C:2]1[C:17]([CH3:18])=[CH:16][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[O:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[C:17]([CH3:18])=[CH:16][C:5]2[N:6]([CH:10]3[CH2:11][CH2:12][N:13]([CH:22]4[CH2:23][CH2:24][O:19][CH2:20][CH2:21]4)[CH2:14][CH2:15]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: O=C1CCOCC1
Reactant: Cc1cc2c(cc1Br)[nH]c(=O)n2C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc2c(cc1Br)[nH]c(=O)n2C1CCN(C2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 25.9 %

Procedure:
5-Bromo-6-methyl-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one (D37) (1.16 mmol, 359 mg) was dissolved in dichloromethane (20 mL) and tetrahydropyran-4-one (8.12 mmol, 7 eq, 813 mg), sodium triacetoxyborohydride (8.12 mmol, 1.72 g, 7 eq) and triethylamine (3.48 mmol, 352 mg, 3 eq, 0.48 ml) added. The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with dichloromethane, washed with aqueous NaOH (pH 12), and the product extracted with dichloromethane (×2). The combined organic layers were washed with aqueous NaOH (pH 12), dried (MgSO4) and the solvent removed under reduced pressure to afford the crude product. The product was purified by chromatography, eluting with 12+M, DCM/50% MeOH in DCM, 00%-50%, 8CVs), to afford 5-bromo-6-methyl-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one as a pale yellow solid (0.3 mmol, 111 mg, 26%). This was dissolved in dichloromethane (5 mL) and HCl (1M solution in ether) was added. The mixture was stirred at room temperature for 15 minutes. The solvents were removed under reduced pressure to afford the title compound as a white solid (0.02 mmol, 9 mg, 7%)
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:8](=[O:15])[NH:7][C:6]1=[O:16].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOCC>C1COCC1>[F:13][C:11]([F:12])([F:14])[C:9]1[C:8](=[O:15])[NH:7][C:6](=[O:16])[N:5]([CH2:4][CH2:3][CH:2]=[O:1])[CH:10]=1
Reactant: O=c1[nH]c(=O)n(CCCO)cc1C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=CCCn1cc(C(F)(F)F)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 50.4 %

Procedure:
1-(3-Hydroxy-propyl)-5-trifluoromethyl-1H-pyrimidine-2,4-dione (Prep20, 100 mg, 0.42 mmol) was dissolved in dry THF (5 mL), the solution was then cooled to 0° C. and Dess-Martin periodinane (300 mg, 0.71 mmol) was added. The mixture was stirred at 0° C. for 1.5 hours. Et2O was added and the mixture washed with aqueous saturated NaHCO3 solution. The organic phase was dried (Na2SO4) and evaporated. The crude was purified by flash chromatography with ethyl acetate-petroleum ether (1-1) to give 50 mg of title compound (68% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[C:16]([Cl:17])=[C:15]([O:18][CH:19]([F:21])[F:20])[N:14]([CH3:22])[N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:26])=O>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[C:16]([Cl:17])=[C:15]([O:18][CH:19]([F:21])[F:20])[N:14]([CH3:22])[N:13]=2)=[CH:7][C:3]=1[C:4]([Cl:26])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1nc(-c2cc(C(=O)O)c(Cl)cc2F)c(Cl)c1OC(F)F
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cn1nc(-c2cc(C(=O)Cl)c(Cl)cc2F)c(Cl)c1OC(F)F
Reaction time: 0.5 h

Procedure:
A solution of 8 g (22 mmol) of 2-chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-4-fluorobenzoic acid in 100 ml of toluene was treated with 1 drop of dimethylformamide and 8.6 g (67 mmol) of oxalyl chloride. After the mixture had been stirred for 30 minutes at reflux temperature, it was cooled and concentrated. Yield: quantitative.
Reaction SMILES: [CH:1]1([CH:7]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>Cl.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.[Pt]=O>[CH:1]1([CH:7]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Fc1ccc(C(c2ccncc2)C2CCCCC2)cc1
Agent: O=[Pt]
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: Cl
Product: Fc1ccc(C(C2CCCCC2)C2CCNCC2)cc1
Yield: 50 %

Procedure:
A mixture of 4-[(cyclohexyl)(4-fluorophenyl)methyl]pyridine (10.42 g, 0.039 mole), platinum oxide (1.5 g), and 10 drops of concentrated hydrochloric acid in 200 ml of glacial acetic was subjected to hydrogenation at 80° C. and 300 psi overnight, after which NMR analysis showed 50% desired product and 50% starting material. The reaction was repeated using 5% platinum on carbon at 85° C. and 1400 psi overnight. The reaction mixture was then cooled to room temperature and filtered. Solvent was removed by rotary evaporator. The oil obtained was dissolved in chloroform, and the solution was extracted with 5% sodium hydroxide and water. The chloroform layer was dried over sodium sulfate and filtered, and the solvent removed to give 9.94 g of brown oil. NMR analysis showed a 75%-25% mixture of product and starting material. The 9.94 g of oil obtained was dissolved in methanol and subjected to flash chromatography on silica gel using methanol and ammonium hydroxide-methanol for elution. Fractions of similar purity were combined and solvent removed. The clear oil obtained was dried in vacuo overnight at 80° C., to give 5.86 g (60% yield) of title compound as a clear oil.
Reaction SMILES: [CH2:1]([C:4]1[CH:12]=[CH:11][C:7]2=[N:8][O:9][N:10]=[C:6]2[CH:5]=1)[CH:2]=C.CO.C[N+]1([O-])CC[O:19]CC1.I([O-])(=O)(=O)=O.[Na+]>O.C1COCC1>[N:8]1[O:9][N:10]=[C:6]2[CH:5]=[C:4]([CH2:1][CH:2]=[O:19])[CH:12]=[CH:11][C:7]=12
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCc1ccc2nonc2c1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=CCc1ccc2nonc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-Allyl-2,1,3-benzoxadiazole (4.1 g, 26 mmol) in a solution of MeOH (30 mL), THF (50 mL), and water (20 mL) was added Osium Tetraoxide (6.0 mL 4% aq. solution, 0.77 mmol) and NMO (4.5 g, 38 mmol). The mixture was allowed to stir at 25° C. for 16 hours. TLC showed complete reaction. The reaction was diluted with water (200 mL) and extracted with EtOAc (200 mL×2). The extractions were combined, washed with brine, dried over sodium sulfate, and concentrated. The resulting product was redissolved in water and methanol (50 mL each), and cooled to 0° C. To that solution was added an aqueous solution of sodium periodate (7.2 g, 33 mmol). TLC showed complete reaction within 15 minutes. The reaction was diluted with water (100 mL) and extracted with EtOAc (100 mL×2). The extractions were combined, washed with brine, dried over sodium sulfate, and concentrated to obtain the product which was used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]2[CH:13]=[CH:12][N:11]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:6]=2[C:7](=[O:10])[NH:8][CH:9]=1.I[CH3:25].O>CN(C)C=O>[Br:3][C:4]1[C:5]2[CH:13]=[CH:12][N:11]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:6]=2[C:7](=[O:10])[N:8]([CH3:25])[CH:9]=1
Reactant: CI
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Br)c[nH]c(=O)c32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Br)cn(C)c(=O)c32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
Sodium hydride (0.875 g, 36.5 mmol, 1.46 g of a 60% in oil dispersion) was added to a stirring solution of Example 1d (11.2 g, 30.4 mmol) in dimethylformamide (217 mL) under nitrogen. After 30 minutes, iodomethane (2.27 mL, 36.5 mmol) was added and the solution was stirred at room temperature for 3 h. Upon addition of water (250 mL) a precipitate formed. The precipitate was collected by vacuum filtration, rinsed with water (50 mL) and dried in a vacuum oven at 55° C. overnight to provide 11.2 g of the title compound (96%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]#[C:11][C:12]1[N:13]=[C:14]2[C:19]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:18][CH:17]=[C:16]([C:26]3[CH:38]=[CH:37][C:29]([C:30]([O:32]C(C)(C)C)=[O:31])=[CH:28][CH:27]=3)[N:15]2[CH:39]=1.C(O)(C(F)(F)F)=O.O>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]#[C:11][C:12]1[N:13]=[C:14]2[C:19]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:18][CH:17]=[C:16]([C:26]3[CH:38]=[CH:37][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=3)[N:15]2[CH:39]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cnc(N3CCOCC3)c3nc(C#Cc4nc5ccccc5s4)cn23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1ccc(-c2cnc(N3CCOCC3)c3nc(C#Cc4nc5ccccc5s4)cn23)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of compound 81c (49 mg, 0.09 mmol) in dichloromethane (4 mL), TFA (1 mL, 13 mmol) was added. The mixture was stirred at rt for 18 h and concentrated under reduced pressure. The oil obtained was dissolved in dichloromethane and water was added. The resultant precipitate was collected by filtration to afford the title compound 11. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 13.18 (s, 1H), 8.60 (s, 1H), 8.20 (d, J=8.2 Hz, 1H), 8.13-8.11 (m, 3H), 7.85 (d, J=8.3 Hz, 2H), 7.66-7.57 (m, 3H), 4.29 (m, 4H), 3.82 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C26H20N5O3S: (M+H) 482.1. Found 482.4.
Reaction SMILES: [CH2:1]([C:3]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH3:24])[CH:18]=1)([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:9]=2[CH:10]=1)[CH2:4][CH3:5])[CH3:2].Br[CH2:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([C:3]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[C:19]([CH3:24])[CH:18]=1)([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:9]=2[CH:10]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1cc2cc(CO)ccc2o1
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2cc(CO)ccc2o1
Yield: 101.9 %

Procedure:
4-[1-Ethyl-1-(5-hydroxymethyl-benzofuran-2-yl)-propyl]-2-methyl-phenol (653 mg, 2.02 mmol) and 1-bromopinacolone (555 mg, 3.10 mmol) and K2CO3 (570 mg, 4.13 mmol) in acetone (40 mL) are reacted analogous to Example 18-E to give the title compound (870 mg, 100%).
Reaction SMILES: C([C:5]1([NH:31]C(=O)[O-])[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:17]([CH3:18])=[CH:16][C:15]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])=[C:14]([Br:29])[C:13]2=[O:30])=[CH:7][CH2:6]1)(C)(C)C.O1CCOCC1>Cl.C(OCC)C>[NH2:31][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][N:12]2[C:17]([CH3:18])=[CH:16][C:15]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])=[C:14]([Br:29])[C:13]2=[O:30])=[CH:9][CH:10]=1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1CC1=CCC(NC(=O)[O-])(C(C)(C)C)C=C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
1-tert-butyl-4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}phenylcarbamate (Step 1) (6.14 g, 11.47 mmol) was suspended in 4N HCl in dioxane (5.74 mL, 22.94 mmol). The reaction mixture was stirred at room temperature for 1 hour then diluted with diethyl ether. The precipitate was collected by filtration and washed with diethyl ether (3×30 mL) to afford a tan solid (3.45 g, 69%). 1H NMR (400 MHz, DMF-d6) δ 7.64 (app dt, J=6.58, 8.59 Hz, 1H), 7.31 (ddd, J=2.55, 9.53, 10.61 Hz, 1H), 7.29-7.12 (m, 5H), 6.56 (s, 1H), 5.28 (s, 2H), 5.27 (s, 2H), 2.28 (s, 3H) ES-HRMS m/z 435.0516 (M+H calcd for C20H18BrF2N2O2 requires 435.0514).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][OH:13].[H][H]>[Pd].C(O)C>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][OH:13]
Reactant: [H][H]
Reactant: Nc1c(CCO)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(CCO)c1N

Procedure:
A suspension of 10% palladium on carbon (66 mg) and 2-(2-amino-3-nitrophenyl)ethanol [See Seno, Kaoru; Hagishita, Sanji; Sato, Tomohiro; Kuriyama, Kaoru; J. Chem. Soc. Perkin Trans. 1; 2012 (1984) for the synthesis of this reagent] (531.5 mg, 2.92 mmol) in absolute ethanol (50 mL) was shaken under 40 psi hydrogen for 3 hours. After filtration and concentration, crude 2-(2,3-diaminophenyl)ethanol (474.4 mg) was obtained as a red oil, which crystallized on standing: Rf=0.08 (75% ethyl acetate in hexanes); 1H NMR (DMSO-d6) δ2.58 (t, 2H, J=6.9 Hz), 3.53 (t, 2H, J=7.2 Hz), 4.32 (br s, 5H), 6.29 (m, 2H), 6.40 (dd, 1H, J=6.9, 2.1 Hz).
Reaction SMILES: [N:1]1([C:7]2[N:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:15]=[C:11]3[N:10]=[C:9]([NH:22][NH2:23])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:24][C:25]1[O:26][C:27]2[C:33]([CH:34]=O)=[CH:32][CH:31]=[CH:30][C:28]=2[CH:29]=1.C(O)(=O)C>C(O)C>[CH3:24][C:25]1[O:26][C:27]2[C:33]([CH:34]=[N:23][NH:22][C:9]3[CH:8]=[C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[N:12]4[N:13]=[C:14]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[CH:15]=[C:11]4[N:10]=3)=[CH:32][CH:31]=[CH:30][C:28]=2[CH:29]=1
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Reactant: Cc1cc2cccc(C=O)c2o1
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc2cccc(C=NNc3cc(N4CCOCC4)n4nc(-c5ccccc5)cc4n3)c2o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.8 %

Procedure:
To a solution of 7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl-hydrazine (25 mg, 0.081 mM) in absolute ethanol (2.0 mL), there were added 2-methyl-7-formyl-benzofuran (19 mg, 0.12 mM) and acetic acid (2.0 μL) and the mixture was stirred at room temperature for 3 hours. The precipitated solid was recovered through filtration and washed with ethanol to thus give the title compound (28 mg, yield: 78%).