Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18](O)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:31][C@H:32]([C:37]([O:39][CH3:40])=[O:38])[CH2:33][CH2:34][S:35][CH3:36].ON1C(=O)C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.CN1CCOCC1>CN(C=O)C.C(OCC)(=O)C.CCCCCC.C(OCC)(=O)C>[CH3:40][O:39][C:37](=[O:38])[C@H:32]([CH2:33][CH2:34][S:35][CH3:36])[NH:31][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][CH:23]=[C:15]([CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:12]2)[C:16]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(C(=O)O)c2-c2ccccc2)CC1
Reactant: COC(=O)[C@@H](N)CCSC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=c1c2ccccc2nnn1O
Solvent: CN1CCOCC1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCSC)NC(=O)c1cccc(CN2CCN(C(=O)OC(C)(C)C)CC2)c1-c1ccccc1
Yield: 48 %

Procedure:
A solution of the product of Example 290A (0.544 g, 1.37 mmol), L-methionine, methyl ester hydrochloride (0.553 g, 2.74 mmol), 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (1.14 g, 6.85 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.34 g, 6.85 mmol), and N-methylmorpholine (0.980 g, 9.59 mmol) in DMF (14 nlL) was stirred at ambient temperature for 16 hours. The mixture was diluted with ethyl acetate and then extracted with a 2:1 mixture of H2O and saturated aqueous NaHCO3 (2×), a 1:1 mixture of the same (2×) and brine (2×). The organic phase was dried (MgSO4) and concentrated to provide an amber oil. Radial chromatography (1:1 hexane-ethyl acetate) afforded the desired compound (0.356 g, 48%) as an amber oil.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[N:19](COCC[Si](C)(C)C)[CH:20]=[C:21]([C:23]#[N:24])[N:22]=2)=[O:17])=[C:11]([C:33]2[CH2:38][CH2:37][C:36]([CH3:40])([CH3:39])[CH2:35][CH:34]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.CCO.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:39][C:36]1([CH3:40])[CH2:37][CH2:38][C:33]([C:11]2[CH:10]=[C:9]([S:6](=[O:7])(=[O:8])[NH2:5])[CH:14]=[CH:13][C:12]=2[NH:15][C:16]([C:18]2[NH:19][CH:20]=[C:21]([C:23]#[N:24])[N:22]=2)=[O:17])=[CH:34][CH2:35]1
Reactant: CC1(C)CC=C(c2cc(S(=O)(=O)NC(C)(C)C)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CC=C(c2cc(S(N)(=O)=O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Yield: 40.6 %

Procedure:
A solution of 100 mg (0.171 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [4-tert-butylsulfamoyl-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with 62.0 μL EtOH, 67.0 μL (0.616 mmol) of anisole, and TFA (750 μL) at RT for 18 h. EtOH (3 mL) was added, the mixture was concentrated, the residue was subjected again to the conditions above except that 900 μL of TFA was used, and then was subjected a third time with 1.70 mL of TFA. Solvents were evaporated in vacuo. Purification of the residue by RP-HPLC (C18) with 20-100% CH3CN in 0.1% TFA/H2O over 30 min afforded 27.7 mg (41%) of the title compound as a white solid: 1H-NMR (CD3OD; 400 MHz): δ 8.40 (d, 1H, J=8.8 Hz), 7.92 (s, 1H), 7.71 (dd, 1H, J=8.8, 2.4 Hz), 7.62 (d, 1H, J=2.4 Hz), 5.80-5.73 (m, 1H), 2.30-2.21 (m, 2H), 2.08-1.99 (m, 2H), 1.60-1.50 (m, 2H), 1.02 (s, 6H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH3:27][S:28]([NH:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)(=[O:30])=[O:29].C(=O)(O)[O-].[Na+].O>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:35]2[CH:34]=[CH:33][C:32]([NH:31][S:28]([CH3:27])(=[O:29])=[O:30])=[CH:37][CH:36]=2)[CH:3]=1)=[O:15]
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(NS(C)(=O)=O)cc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Yield: 37.4 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (75 mg, 0.2 mmol) and {4-[(methylsulfonyl)amino]phenyl}boronic acid (43.1 mg, 0.2 mmol) in DME/water (3 ml:1 ml). PdCl2(dppf)-CH2Cl2 adduct (8.2 mg, 0.01 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (50.6 mg, 0.6 mmol) was added, the vessel was sealed, and the reaction mixture was irradiated (microwave) at 150° C. for 25 min. After cooling, 2 mL of water was added to the black mixture and solids that precipitated were filtered. DCM/MeOH (1:1) was added, the mixture was pre-absorbed on silica gel and purified by silica gel chromatography (eluent: gradient 0 to 90:10:1 DCM/MeOH/NH4OH). The isolated product was suspended in EtOAc heated, and sonicated. Some hexanes was added and the contents allowed to cool to room temperature. Solids that precipitated were filtered. The solid was then suspended in EtOH, heated, and sonicated. After cooling to room temperature, the solids were filtered and dried to afford the title compound (38 mg, 36%) as a beige solid. LCMS E-S (M+H)=509.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.57 (s, 1 H), 10.05 (br. s., 1 H), 8.93 (t, J=4.93 Hz, 1 H), 8.35 (s, 1 H), 8.24 (m, J=8.59 Hz, 2 H), 8.11 (s, 1 H), 7.37 (m, J=8.84 Hz, 2 H), 5.91 (s, 1 H), 5.32 (quin, J=6.69 Hz, 1 H), 4.41 (d, J=4.80 Hz, 2 H), 3.08 (s, 3 H), 2.23 (s, 3 H), 2.13 (s, 3 H), 1.55 (s, 3 H), 1.54 (s, 3 H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]([NH:11][C:12]2[N:17]=[C:16]([C@:18]3([CH3:36])[CH2:23][C@@H:22]([C:24]([F:27])([F:26])[F:25])[O:21][C:20]([NH:28]C(=O)OC(C)(C)C)=[N:19]3)[C:15]([F:37])=[CH:14][CH:13]=2)=[O:10])=[N:7][CH:8]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:28][C:20]1[O:21][C@H:22]([C:24]([F:25])([F:27])[F:26])[CH2:23][C@:18]([C:16]2[N:17]=[C:12]([NH:11][C:9](=[O:10])[C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=3)[CH:13]=[CH:14][C:15]=2[F:37])([CH3:36])[N:19]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2nc(NC(=O)c3ccc(C#N)cn3)ccc2F)C[C@@H](C(F)(F)F)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@]1(c2nc(NC(=O)c3ccc(C#N)cn3)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To a solution of tert-butyl ((4S,6S)-4-(6-(5-cyanopicolinamido)-3-fluoropyridin-2-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)carbamate (7l, 0.096 g, 0.18 mmol) in DCM (3 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 1 h and the solvent was removed under reduced pressure. The residue was treated with 1 N NaOH (5 mL) and extracted with DCM (3×5 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The crude material was triturated with ether and the solid was filtered off to give the title compound as a white solid (0.065 g, 84% yield, 0.15 mmol) after drying under vacuum. MS m/z=423.0 [M+H]+. Calculated for C18H14F4N6O2: 422
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][N:10](CC3C=CC=CC=3)[CH2:9][CH:8]2[CH2:19][NH2:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].CO>[C:1]1([CH:7]2[CH2:11][NH:10][CH2:9][CH:8]2[CH2:19][NH2:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCC1CN(Cc2ccccc2)CC1c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NCC1CNCC1c1ccccc1
Yield: 86.4 %

Procedure:
A mixture of 4.79 g (0.018 mole) of 4-phenYl-1-(phenylmethyl)-3-pyrrolidinemethanamine, 0.7 g of 20% palladium on carbon, and 250 ml of methanol was shaken in an atmosphere of hydrogen at about 50 psi and at room temperature for 24 hours. The catalyst was filtered and the filtrate evaporated under reduced pressure to give 2.74 g of 4-phenyl-3-pyrrolidinemethanamine.
Reaction SMILES: [OH:1][CH:2]1[C:14]2[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[C:17]1([CH:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:24][CH2:25]O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[C:17]1([CH:23]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:24][CH2:25][O:1][CH:2]2[C:14]3[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=3[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]2=3)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCCC(c1ccccc1)c1ccccc1
Reactant: O=c1[nH]c2c([nH]c1=O)C(O)c1ccccc1-2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: O=c1[nH]c2c([nH]c1=O)C(OCCC(c1ccccc1)c1ccccc1)c1ccccc1-2
Yield: 12.5 %

Procedure:
A suspension of 9-hydroxy-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione. 1H2O (1.0 g, 4.26 mmol) in benzene (40 ml), 3,3-diphenyl-1-propanol (10 ml) and p-toluensulfonic acid (40 mg) was refluxed with water separation for 48 hours. The reaction mixture was evaporated in vacuo to dryness, the residue was suspended in ethanol (10 ml) and the precipitate was filtered off and washed with ethanol and dried to give 0.224 g (12.5%) of the title compound. M.p. 224°-228° C. 1H-NMR(DMSO-d6, δ): 2.14-2.32 (m, 2H), 3.0-3.22 (m, 2H), 4.13 (t, 1H), 5.22 (s, 1H), 7.0-7.5 (m, 14H), 12.12 (s, 1H), 12.26 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5](=[CH:9][C:10]=1[F:11])[C:6]([OH:8])=O.FC1C=C(C=CC=1F)N.Cl.NO.[O:25]=[CH:26]C(Cl)(Cl)Cl.S(=O)(=O)(O)O>>[F:11][C:10]1[CH:9]=[C:5]2[C:4](=[CH:3][C:2]=1[F:1])[NH:12][C:26](=[O:25])[C:6]2=[O:8]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Agent: Cl
Agent: NO
Agent: Nc1ccc(F)c(F)c1
Product: O=C1Nc2cc(F)c(F)cc2C1=O

Procedure:
U.S. Pat. No. 4,833,270 also relates to the synthesis of 4,5-difluoroanthranilic acid by, first, reacting 3,4-difluoroaniline with hydroxylamine hydrochloride in the presence of chloral. The resulting intermediate is then cyclyzed using sulfuric acid to form 5,6-difluoroisatin. The 4,5-difluoroanthranilic acid is produced by oxidation of the aforementioned isatin with hydrogen peroxide. As before, however, 3,4-difluoroaniline is expensive and difficult to obtain.
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:5]=1[O:6][CH2:7][C:8]([O:10]C)=[O:9])(=[O:3])[CH3:2].O.[OH-].[Na+]>O1CCCC1>[C:1]([C:4]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:5]=1[O:6][CH2:7][C:8]([OH:10])=[O:9])(=[O:3])[CH3:2]
Reactant: COC(=O)COc1cc(Br)ccc1C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccc(Br)cc1OCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
To a solution of methyl 2-(2-acetyl-5-bromophenoxy)acetate (1.35 g, 4.5 mmol) in tetrahydrofuran:water=3:1 (20 mL) was added sodium hydroxide (400 mg, 10 mmol). The mixture was stirred at room temperature for 2 hours. The suspension was concentrated in vacuum and quenched with aqueous 1N hydrochloric acid (5 mL). The residue was taken up with water (50 mL) and extracted with dichloromethane (50 mL). The combined extract was dried over sodium sulphate, evaporated and purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give the product 2-(2-acetyl-5-bromophenoxy)acetic acid (1.14 g, 91%) as pale solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Na+].[I-].Br[CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]([Br:20])[CH:17]=[CH:18][CH:19]=1.[Cl:21][C:22]1[C:43]([C:44]([F:47])([F:46])[F:45])=[CH:42][CH:41]=[CH:40][C:23]=1[CH2:24][NH:25][CH2:26][CH:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(#N)C>[Cl:21][C:22]1[C:43]([C:44]([F:45])([F:46])[F:47])=[CH:42][CH:41]=[CH:40][C:23]=1[CH2:24][N:25]([CH2:26][CH:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]([Br:20])[CH:17]=[CH:18][CH:19]=1
Reactant: BrCCCOc1cccc(Br)c1
Reactant: FC(F)(F)c1cccc(CNCC(c2ccccc2)c2ccccc2)c1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: FC(F)(F)c1cccc(CN(CCCOc2cccc(Br)c2)CC(c2ccccc2)c2ccccc2)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29 %

Procedure:
Potassium carbonate (140 mg, 1.0 mmol) and NaI (82 mg, 0.34 mmol) were added to a solution of 3-(3-bromopropoxy)bromobenzene (100 mg, 0.34 mmol), (2-chloro-3-trifluoromethylbenzyl)(2,2-diphenylethyl)amine and acetonitrile (3 mL). The mixture was heated at reflux for 16 h. The mixture was allowed to cool to RT and concentrated in vacuo. The residue was partitioned between methylene chloride and 10% NaHCO3 aq. solution and layers separated. The aqueous layer was extracted with methylene chloride (2×10 mL). The organic layers were combined, dried (MgSO4) and concentrated in vacuo. The residue was purified by preparative HPLC (YMC CombiPrep ODS-A, 50×20 mm, 20 mL/min, A: 0.1% trifluoroacetic acid in acetonitrile B: 0.1% aqueous trifluoroacetic acid, A: 10 to 90% during 10 min, UV detection at 254 nm) to give 52 mg (29%) of the title compound as an oil. MS (ESI) 639.2 [M+H]+.
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[O:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]#[CH:11])[CH2:6][CH2:5]1.[CH2:14]([CH:19]1[CH2:24][CH2:23][CH:22]([CH2:25][CH:26]=[O:27])[CH2:21][CH2:20]1)[CH2:15][CH2:16][CH2:17][CH3:18].Cl>C1COCC1>[CH3:1][Si:2]([CH3:12])([CH3:13])[O:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]#[C:11][CH:26]([OH:27])[CH2:25][CH:22]2[CH2:23][CH2:24][CH:19]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:20][CH2:21]2)[CH2:6][CH2:5]1
Reactant: C#CC1CCC(O[Si](C)(C)C)CC1
Reactant: CCCCCC1CCC(CC=O)CC1
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCC1CCC(CC(O)C#CC2CCC(O[Si](C)(C)C)CC2)CC1
Temperature: 25 °C
Yield: 63.7 %

Procedure:
4-Trimethylsilyloxycyclohexylacetylene (20 mmol) was dissolved in THF (20 ml), followed by dropwise adding a n-butyllithium-hexane solution (1.61M, 12.4 ml) while stirring the above solution under ice cooling, stirring the reaction solution under ice cooling for 30 minutes, dropwise adding a solution of 2-(4-pentylcyclohexyl)acetaldehyde (4.0 g) in THF (10 ml), raising the temperature of the reaction solution up to room temperature after completion of the dropwise addition, stirring it for 5 hours, adding dilute hydrochloric acid (5 ml) to the resulting raw solution, extracting the mixture with ethyl acetate (150 ml), washing the organic phase with water, drying over anhydrous MgSO4, concentrating under reduced pressure to obtain a brown oil, which is recrystallized from a mixed solution of ethyl acetate-heptane, to obtain 1-(4-trimethylsilyloxycyclohexyl)-4-(4-pentylcyclohexyl)-1-butyn-3-ol (5.0 g) (white crystal).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])[CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:34]=[C:35]([OH:39])[CH:36]=[CH:37][CH:38]=1>C1COCC1>[OH:39][C:35]1[CH:34]=[C:33]([NH:32][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]4[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]5[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])=[CH:16][CH:15]=4)=[O:13])[CH:10]=3)[NH:5][C:4]2=[O:31])[CH:38]=[CH:37][CH:36]=1
Reactant: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)C(=CO)C(=O)N3)cc1
Reactant: Nc1cccc(O)c1
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)C(=CNc2cccc(O)c2)C(=O)N3)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 24.6 %

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-amide (as prepared in Example 7, 70 mg, 0.168 mmol) and THF (2 mL). To the resulting solution was added 3-aminophenol (20.2 mg, 0.184 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 25% (21 mg, 0.0414 mmol) of the title compound.
Reaction SMILES: [N+:1]1([O-])[C:2]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:3][CH:4]=[CH:5][CH:6]=1.C[Si]([C:18]#[N:19])(C)C.CN(C)C(Cl)=O>[N+](CC)([O-])=O>[C:18]([C:6]1[N:1]=[C:2]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:3]=[CH:4][CH:5]=1)#[N:19]
Reactant: [O-][n+]1ccccc1-c1ccccn1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Solvent: CC[N+](=O)[O-]
Product: N#Cc1cccc(-c2ccccn2)n1
Temperature: 25 °C
Reaction time: 36 h
Yield: 41.4 %

Procedure:
2,2′-Bipyridyl N-oxide (2.8 g, 16 mmol) was dissolved in nitroethane (50 ml), and trimethylsilyl cyanide (6.4 g, 65 mmol) and N,N-dimethylcarbamoyl chloride (3.7 g, 35 mmol) were added thereto. The mixture was stirred at room temperature for 36 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with hexane-ethyl acetate (3:1, v/v) were collected, concentrated and recrystallized from hexane-ethyl acetate to give the titled compound (1.2 g, 43%) as white crystals.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=[O:12].[K+].[K+]>CS(C)=O>[C:8]([OH:10])(=[O:9])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:12]
Reactant: O=C(O)Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)C(O)c1ccccc1
Temperature: 60 °C
Yield: 74 %

Procedure:
Phenyl acetic acid (1.82 Kg, 8.89 mol, 1.1 eq) and nitrile (1.62 Kg, 8.08 mol, 1.0 eq) were dissolved in DMSO (8 L) at 25° C. To this solution was added K2CO3 (2.46 Kg, 17.8 mol, 2.2 eq) in portions to control off gassing. The purple slurry was heated to 60° C. and aged overnight. Upon reaction completion the reaction mixture was inversely quenched in to a mixture of (16 L) of MTBE, (12.9 L) DI water and (3.5 L) methane sulfonic acid slowly. After mixing for 30 minutes the aqueous layer was removed and the organic layer was washed with 16 L of DI water and concentrated to dryness. MeOH (4 L) was added and the solution concentrated to dryness twice, until the residual MTBE was <5% by GC. To the product, MeOH (22 L) and 8.3 mL of methane sulfonic acid were charged, and the batch was heated to 63° C. over 15 hours, until 99% conversion. The reaction was cooled by ramping to 20° C. and the resulting suspension was filtered and washed with MeOH (2×3 L). The solid cake was dried under N2 to provide 74% yield with 101.8 wt % potency and 99.5 A % purity. Chloroisomer content was 2.16 A %. A second recrystallization using 23.6 L of MeOH and heating to 68° C. obtained the desired product in 67% with 100 wt % potency, 99.7 A % purity and 0.74 A % chloroisomer content. Recrystallization process was repeated until <0.5 A % of chloroisomer content was achieved.
Reaction SMILES: [ClH:1].[C:2]1([CH2:8][C:9]([NH2:11])=[NH:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[O-].[Na+].[Cl-].[Na+]>O>[Cl:1][NH:10][C:9](=[NH:11])[CH2:8][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl
Reactant: N=C(N)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Product: N=C(Cc1ccccc1)NCl
Temperature: 0 °C
Reaction time: 1 h
Yield: 11.9 %

Procedure:
The crude 2-phenyl-acetamidine hydrochloride (1.32 g, 7.74 mmol) was dissolved in water (10 mL) and cooled to 0° C. A ˜1.7 M solution of sodium hypochlorite in water (3.68 mL, 6.26 mmol) was added dropwise. The reaction mixture was stirred 1 h, then solid sodium chloride was added to saturate the aqueous phase, which was extracted with ethyl acetate (2×25 mL). The combined organic phases were filtered through sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 33% ethyl acetate/hexanes) to afford N-chloro-2-phenyl-acetamidine (155 mg, 9% over two steps) as an off-white semi-solid: H1-NMR (400 MHz, CDCl3) δ=3.67 (2H, s), 5.13 (2H, br), 7.31 (5H, m).
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][NH2:23])=[C:18]([OH:24])[CH:17]=1)(=[O:14])[CH3:13].C(OC1C=CC(N)=C(O)C=1)(=O)C.[Cl:37][CH:38]([C:42](=O)[CH3:43])[C:39](=O)[CH3:40]>>[C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:42]([CH3:43])=[C:38]([Cl:37])[C:39]([CH3:40])=[N:23]2)=[C:18]([OH:24])[CH:17]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)C(Cl)C(C)=O
Reactant: CC(=O)Oc1ccc(NN)c(O)c1
Agent: CC(=O)Oc1ccc(N)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(=O)Oc1ccc(-n2nc(C)c(Cl)c2C)c(O)c1
Yield: 4.2 %

Procedure:
30 mg of the title compound was prepared in a manner similar to Example 54b) by using 4-hydrazinyl-3-hydroxyphenyl acetate 4-methylbenzenesulfonate (0.9 g), which was prepared from 4-amino-3-hydroxyphenyl acetate (1.0 g) in a manner similar to Example 54a), and 3-chloropentane-2,4-dione (1.2 g).
Reaction SMILES: Br.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([NH2:16])[S:14][CH:15]=2)=[CH:7][CH:6]=1)([O-:4])=[O:3].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.Cl>N1C=CC=CC=1>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:16][C:13]2[S:14][CH:15]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=3)[N:12]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(-c2ccc([N+](=O)[O-])cc2)cs1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3ccc([N+](=O)[O-])cc3)cs2)cc1
Yield: 16.1 %

Procedure:
A mixture of 0.5 g of 4-(4-nitro-phenyl)-thiazol-2-ylamine hydrobromide with 0.35 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and the mixture was extracted three times with 100 ml of ethyl acetate each time. The organic phases were combined, dried with magnesium sulphate and the solvent was removed on a rotary evaporator. The residue was chromatographed on 60 g of Kieselgel 60 with diethyl ether/ethyl acetate (1:1) as the eluent. The product-containing fractions were concentrated and the residue was digested with a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. The product separated upon neutralization of the filtrate with concentrated hydrochloric acid. Recrystallization from 50 ml of 60% ethanol yielded 0.10 g of 4-methyl-N-[4-(4-nitro-phenyl)-thiazol-2-yl]-benzenesulfonamide as yellowish crystals.
Reaction SMILES: C[Li].[CH2:3]([C:9]1[C:10](=O)[CH2:11][CH2:12][CH:13]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].BrCBr.C([Mg]Cl)(C)(C)C.C([O:26][CH2:27][CH3:28])C>>[CH2:3]([C@@:4]12[CH2:5][C@@H:6]1[CH2:7][CH2:8][C:27]2([CH3:28])[OH:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCOCC
Reactant: CCCCCCC1=CCCC1=O
Agent: CC(C)(C)[Mg]Cl
Agent: [Li]C
Solvent: BrCBr
Product: CCCCCC[C@@]12C[C@@H]1CCC2(C)O
Yield: 60 %

Procedure:
Methyl lithium 1.6 M in diethyl ether (4 ml, 7 mmol) is added dropwise to 2-hexylcyclopent-2-enone (Isojasmone B11) (1 g, 6 mmol) in diethylether (4 ml) at −78° C. At 0°-5° C. dibromomethane (3×0.6 ml, 24 mmol) and tert-butyl magnesium chloride 2M in diethyl ether (3×4 ml, 24 mmol) are added. Work-up after 18 h at 25° C. (as described in example 1) and bulb-to-bulb distillation gives 0.7 g (60%) of a colorless oil (cisltrans=93:7). 1H NMR (CDCl3): δ 0.3 (m, 1H), 0.7 (m, 1H), 0.9 (t, 3H), 1.05 (m, 1H), 1.2-2 (15H), 1.3 (s, 3H) ppm. 13C-NMR (CDCl3): δ 11.0 (t), 14.0 (q), 22.6 (t), 23.4 (d), 24.7 (t), 25.15 (q), 27.5 (t), 29.9 (t), 31.2 (t), 31.8 (t), 34.3 (s), 37.9 (t), 81.05 (s). cis-configuration assigned by COSY, HMBC, HSQC, NOESY in CDCl3. MS (EI): m/z (%) 196 (M+, 2), 181 ([M-15]+, 14), 155 (24), 138 (15), 135 (27), 125 (32), 110 (34), 107 (38), 93 (92), 79 (50), 57 (14), 43 (100).