Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C@@H:6]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5][CH2:4][N:3]1[C@H:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][C@H:19]1[CH2:25][CH2:26][CH3:27].[C:28]([NH2:32])([CH3:31])([CH3:30])[CH3:29].CO.[BH4-].[Na+]>C(Cl)Cl.[OH-].[Na+].CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[C:28]([NH:32][CH:21]1[CH2:22][CH2:23][C@H:18]([N:3]2[CH2:4][CH2:5][C@H:6]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:2]2=[O:1])[C@H:19]([CH2:25][CH2:26][CH3:27])[CH2:20]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CCC[C@@H]1CC(=O)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Reactant: CC(C)(C)N
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCC[C@@H]1CC(NC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Examples 2t and 2u, Step 6: A sample of benzyl (S)-2-oxo-1-((1S,2R)-4-oxo-2-propylcyclohexyl)pyrrolidin-3-ylcarbamate (114 mg) was dissolved in Ti(OiPr)4 (1.5 mL, 5.0 mmol) and tert-butylamine (0.14 mL, 1.8 mmol). The resultant solution was stirred at RT for 3 h before being cooled to 0° C. and charged successively with MeOH (2 mL) and NaBH4 (22.8 mg, 0.6 mmol). The mixture was stirred for 90 min while the solution slowly warmed to RT. The solution was diluted with methylene chloride (10 mL) and 0.5 N NaOH was added. The resultant suspension was filtered through a pad of Celite with EtOAc washings and the filtrate was dried, filtered, and concentrated in vacuo to afford benzyl (S)-1-((1S,2R,4R/S)-4-(tert-butylamino)-2-propylcyclohexyl)-2-oxopyrrolidin-3-ylcarbamate as an inseparable mixture of diastereomers. MS found: (M+H)+=430.5.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[S:8][C:4]=2[CH:3]=1.C1C(=O)N([Br:24])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.C(Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[Br:24][CH2:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[S:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc2nc(-c3ccccc3)sc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2nc(-c3ccccc3)sc2c1
Temperature: 25 °C
Yield: 67.1 %

Procedure:
Combine 6-methyl-2-phenyl-benzothiazole (0.2 g, 0.98 mmol), NBS (0.2 g, 1.02 mmol), AIBN (20 mg, 0.10 mmol), carbon tetrachloride (5 mL) and reflux for 3 h. Cool the reaction mixture to ambient temperature, dilute with chloroform and wash with water. Dry the organic extracts over anhydrous Na2SO4, concentrate and purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 9:1, 8:2 and 7:3) to obtain the title compound as a white solid (0.2 g, 69%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[SH:12].[H-].[Na+].F[C:16]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[S:12][C:16]1[C:23]([C:24]([F:25])([F:27])[F:26])=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: Nc1cc(C(F)(F)F)ccc1S
Reactant: N#Cc1cccc(C(F)(F)F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(C(F)(F)F)c1Sc1ccc(C(F)(F)F)cc1N
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
2-Amino-4-trifluoromethylthiophenol (5.74 g, 25 mmol) was added to a mixture of sodium hydride (2.0 g of 60% oil dispersion, 50 mmol) in DMF (100 ml) at 0° under nitrogen. After stirring for 30 minutes at 0°, 2-fluoro-3-trifluoromethylbenzonitrile (4.73 g, 25 mmol) in DMF (20 ml) was added and the mixture kept at room temperature overnight. The reaction mixture was evaporated and azeotroped with toluene, then the residue was partitioned between chloroform and water and the layers separated. Drying (magnesium sulphate) and evaporation of the organic layer gave a residue which was purified by chromatography on silica gel, eluting with dichloromethane. Recrystallisation from cyclohexane afforded the product as colourless needles (6.44 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:11]([OH:14])[C:12]#[CH:13].C([Mg]Cl)#C.COC1C(OC)=CC=CC=1C=O.Br[C:32]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:33]=1/[C:34](=[CH:42]/[C:43]1[NH:44][CH:45]=[CH:46][C:47]=1[O:48][CH3:49])/[C:35](=[O:41])[NH:36]2>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:11]([OH:14])[C:12]#[C:13][C:32]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:33]=1/[C:34](=[CH:42]/[C:43]1[NH:44][CH:45]=[CH:46][C:47]=1[O:48][CH3:49])/[C:35](=[O:41])[NH:36]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CC(O)c1cccc(OC)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#C[Mg]Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3cccc(OC)c3OC)c21

Procedure:
Using Method D above, 3-(2,3-dimethoxyphenyl)-3-hydroxy-1-propyne (132 mg, 0.69 mmol) (prepared by the addition of ethynylmagnesium chloride (Aldrich) to 2,3-dimethoxybenzaldehyde (Aldrich) according to Method A above) was coupled to (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 1) (98 mg, 0.31 mmol) using (Ph3P)2PdCl2 (38 mg) (Aldrich) and CuI (17 mg) (Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 17 h, yielding rac-(Z)-1,3-dihydro-4-[3-(2,3-dimethoxyphenyl)-3-hydroxy-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 98 mg, 71%).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][C:6]=2[C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.OS(O)(=O)=O.[CH3:22]O>>[CH:1]1([NH:4][C:5]2[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][C:6]=2[C:7]([O:9][CH3:22])=[O:8])[CH2:2][CH2:3]1
Reactant: CO
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1NC1CC1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc([N+](=O)[O-])c1NC1CC1

Procedure:
The crude 2-(cyclopropylamino)-3-nitrobenzoic acid (0.90 g, 4.1 mmol) was dissolved in MeOH (15 mL), and 2 mL H2SO4 (98%) was added. The mixture was heated to reflux for 18 h. The mixture was cooled, concentrated in vacuo, and purified by column chromatography on a silica gel column using DCM as eluent to give methyl 2-(cyclopropylamino)-3-nitrobenzoate: LC-MS (ESI) m/z 237.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:9](=O)[CH2:8][CH2:7][C:6]2([CH3:16])[CH3:15].[CH3:17][CH2:18][Mg+].[Br-]>>[CH2:17]([C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([CH3:13])[CH:11]=2)[C:6]([CH3:16])([CH3:15])[CH2:7][CH:8]=1)[CH3:18]
Reactant: COc1cc2c(cc1C)C(=O)CCC2(C)C
Reactant: CC[Mg+]
Agent: [Br-]
Product: CCC1=CCC(C)(C)c2cc(OC)c(C)cc21
Yield: 39.6 %

Procedure:
Following General Procedure F, 6-methoxy-4,4,7-trimethyl-3,4-dihydro-2H-naphthalen-1-one (compound 30, 1.0 g, 4.6 mmol) was reacted with a solution of 3M EtMgBr (8 mL, 23.0 mmol), and the crude product was purified by flash column (hexane:ethyl acetate=96:4) to give 0.42 g (40%) of the title compound as a clear oil. PNMR (300 MHz, CDCl3) δ 1.36 (t, 3H, J=6.0 Hz), 1.46 (s, 6H), 2.35 (d, 2H, J=4.5 Hz), 2.42 (s, 3H), 2.65 (q, 2H, J=7.5 Hz), 4.03 (s, 3H), 5.82 (t, 1H, J=2.5 Hz), 7.02 (s, 1H), 7.28 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18](=[O:26])[C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)[C:6]=2[C:5](=[O:27])[NH:4][C:3]1=[O:28].C(=O)([O-])[O-].[K+].[K+].[CH2:35](I)[CH2:36][CH2:37][CH3:38]>CN(C=O)C.O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([C:15]2[CH:14]=[CH:13][C:12]([CH2:11][N:7]3[C:6]4[C:5](=[O:27])[N:4]([CH2:35][CH2:36][CH2:37][CH3:38])[C:3](=[O:28])[N:2]([CH3:1])[C:10]=4[N:9]=[CH:8]3)=[CH:17][CH:16]=2)=[O:26])=[CH:20][CH:21]=1
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)n(C)c1=O
Yield: 21 %

Procedure:
A solution of 3-methyl-7-[4-(4-chlorobenzoyl)-benzyl]xanthine (612 mg), potassium carbonate (228 mg) and butyl iodide (430 mg) in DMF (10 ml) was stirred at 60° C. for 5 hours. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate =1:1) and recrystallized from ethyl acetate to provide the title compound as colorless solid (147 mg).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][CH:5]=[C:6]([C:22]([NH2:24])=O)[C:7]=2[C:10]2[C:11]([C:19]([NH2:21])=O)=[CH:12][CH:13]=[C:14]3[O:18][CH2:17][O:16][C:15]=23)[O:2]1>P(Cl)(Cl)(Cl)=O>[CH2:1]1[O:9][C:8]2[C:3](=[CH:4][CH:5]=[C:6]([C:22]#[N:24])[C:7]=2[C:10]2[C:11]([C:19]#[N:21])=[CH:12][CH:13]=[C:14]3[O:18][CH2:17][O:16][C:15]=23)[O:2]1
Reactant: NC(=O)c1ccc2c(c1-c1c(C(N)=O)ccc3c1OCO3)OCO2
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc2c(c1-c1c(C#N)ccc3c1OCO3)OCO2
Temperature: 0 °C
Yield: 91.3 %

Procedure:
5,6-Methylenedioxy-5',6'-methylenedioxy-2,2'-biphenyldicarboxamide (8 g) is refluxed in phosphorus oxychloride (70 ml) for 4 hours. The reaction mixture is cooled and then poured into ice water. The precipitated crystals are separated by filtration and dissolved in chloroform. The solution is washed with water, dried and distilled to remove the solvent to give 5,6-methylenedioxy-5',6'-methylenedioxy-2,2'-biphenyldicarbonitrile (6.5 g) as colorless crystal. M.p. 213°-215° C.
Reaction SMILES: C(OC(N(C)[C@H](C(O)=O)C)=O)(C)(C)C.C(O[C:20](=O)[N:21]([C@H:23]([C:25](=[O:45])[NH:26][CH2:27][CH2:28][CH2:29][CH:30]([C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1)[C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)[CH3:24])C)(C)(C)C>CO.C(Cl)Cl>[F:37][C:34]1[CH:33]=[CH:32][C:31]([CH:30]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[CH2:29][CH2:28][CH2:27][NH:26][C:25](=[O:45])[C@H:23]([NH:21][CH3:20])[CH3:24])=[CH:36][CH:35]=1
Reactant: C[C@@H](C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1)N(C)C(=O)OC(C)(C)C
Agent: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CO
Product: CN[C@H](C)C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
(R)-N-[4,4-Bis-(4-fluoro-phenyl)-butyl]-2-methylamino-propionamide was prepared in accordance with the methods of Example 12, except that: N-tert-butoxycarbonyl-N-methyl-L-alanine was used instead of N-tert-butoxycarbonyl-N-methyl-L-leucine in Step A, and (S){1-[4,4-Bis-(4-fluoro-phenyl)-butylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester was used instead of (S){1-[4,4-bis-(4-fluoro-phenyl)-butylcarbamoyl]-3-methyl-butyl}-methyl-carbamic acid tert-butyl ester in Step B. MS: 347 (M+1 for C20H24N2F2O1); an oil; Rf 0.3 (5% MeOH/CH2Cl2).
Reaction SMILES: [CH3:1][NH:2][CH3:3].C[Al](C)C.[N:8]([CH2:11][CH2:12][CH2:13][C:14]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:18]([C:19]2[S:20][CH:21]=[C:22]([C:24]([O:26]CC)=O)[N:23]=2)[N:17]=[C:16]([C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=2[F:36])[S:15]1)=[N+:9]=[N-:10].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1>[N:8]([CH2:11][CH2:12][CH2:13][C:14]1([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[N:18]([C:19]2[S:20][CH:21]=[C:22]([C:24]([N:2]([CH3:3])[CH3:1])=[O:26])[N:23]=2)[N:17]=[C:16]([C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=2[F:36])[S:15]1)=[N+:9]=[N-:10]
Reactant: CNC
Reactant: CCOC(=O)c1csc(N2N=C(c3cc(F)ccc3F)SC2(CCCN=[N+]=[N-])c2ccccc2)n1
Agent: C[Al](C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)C(=O)c1csc(N2N=C(c3cc(F)ccc3F)SC2(CCCN=[N+]=[N-])c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of dimethylamine (0.102 mL, 2.0 M, 0.2 mmol) in 1 mL of anhydrous THF was added trimethylaluminum (0.102 mL, 2.0 M, 0.2 mmol). The solution was stirred at room temperature for 15 minutes, then treated with a solution of ethyl 2-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)thiazole-4-carboxylate (0.035 g, 0.07 mmol) in 0.5 mL of anhydrous THF. After stirring at room temperature for 16 hours the mixture was treated with 0.5 N aqueous Rochelle's salt solution (10 mL), then partitioned between saturated NH4Cl (10 mL) and EtOAc (10 mL). The aqueous layer was extracted with EtOAc (2×10 mL) and the combined organic phases were washed with brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (20-35% ethyl acetate/hexanes) to afford the desired product as a yellow gum, 0.026 g, 74%.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10](O)=[O:11])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.C(Cl)(=O)C([Cl:24])=O>CN(C=O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([Cl:24])=[O:11])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: O=C(O)c1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Yield: 103.7 %

Procedure:
The product from Example 168a (2.0 g. 6.8 mmol) was treated with oxalyl chloride (9.0 g, 13.6 mmol) and catalytic DMF at 60° C. for 5 h. The excess oxalyl chloride was removed under vacuum. The residue was chased with benzene to give the desired product (2.2 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7]C)=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH:21]1[CH2:23][CH2:22]1>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:20][CH:21]1[CH2:23][CH2:22]1)[C:5]([OH:7])=[O:6]
Reactant: BrCC1CC1
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(OCC2CC2)c(Cl)c1
Temperature: 70 °C

Procedure:
To a solution of methyl 3-chloro-4-hydroxybenzoate (10.0 g) in DMF (100 mL) were added potassium carbonate (14.8 g) and (bromomethyl)cyclopropane (7.80 mL), and the mixture was stirred with heating at 70° C. for 1 hr. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, and washed with saturated brine. The obtained organic layer was subjected to silica gel column chromatography (NH, ethyl acetate), and the solvent was evaporated. To a solution of the obtained residue in a mixed solvent of THF (50 mL) and methanol (50 mL) was added 2 M aqueous sodium hydroxide solution (54 mL), and the mixture was stirred with heating at 50° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, and neutralized with 6 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid was washed with ethyl acetate to give the title compound (11.7 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[C:7](Cl)(=[O:9])[CH3:8]>CCOCC>[C:7]([N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]1)(=[O:9])[CH3:8]
Reactant: Cc1c[nH]cn1
Reactant: CC(=O)Cl
Solvent: CCOCC
Product: CC(=O)n1cnc(C)c1
Yield: 30.7 %

Procedure:
50 g (0.6 mol) of 4-methylimidazole are dissolved in 500 ml of absolute ether. After dropwise addition of 23.6 g (0.3 mol) of acetyl chloride in 75 ml of absolute ether at room temperature, the mixture is heated under reflux for 11 hours. The residue is removed by filtration, and the solution is evaporated in vacuo. 11.45 g (31%) of 1-acetyl-4-methylimidazole are obtained as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)=[O:19])=[N:6][CH:5]=1)([O-])=O.[Sn](Cl)(Cl)(Cl)Cl.N1C=CC=CC=1.[CH3:39][O:40][C:41](Cl)=[O:42]>C1COCC1.Cl>[CH3:39][O:40][C:41](=[O:42])[NH:1][C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7]([C:18](=[O:19])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)=[N:6][CH:5]=1
Reactant: COC(=O)Cl
Reactant: COc1cccc(C(=O)c2ncc([N+](=O)[O-])c3cc(OC)c(OC)cc23)c1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)Nc1cnc(C(=O)c2cccc(OC)c2)c2cc(OC)c(OC)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.9 %

Procedure:
The above [4-nitro-6,7-dimethoxy-isoquinolin-1-yl]-(3-methoxy-phenyl)-methanone (150 mg, 0.407 mmol) was treated with tin chloride (459 mg, 2.03 mmol) in THF (30 mL) and 6N HCl (19 mL) at room temperature overnight. The reaction mixture was treated with ice-cold saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and dried to a crude solid. 75 mg (0.203 mmol) of this crude solid was dissolved in dry THF (5 mL) and treated with pyridine (24.6 uL, 0.364 mmol) and methylchloroformate (18.7 uL, 0.243 mmol) under argon at 0° C. The reaction was stirred at room temperature overnight. The reaction mixture was poured into ice water and extracted with ethyl acetate. The combined ethyl acetate layers were dried over magnesium sulfate, filtered, and evaporated to crude product. Preparative HPLC purification yielded 23 mg of [6,7-dimethoxy-1-(3-methoxy-benzoyl)-isoquinolin-4-yl]-carbamic acid methyl ester; trifluoro-acetic acid salt as an off-white solid: APCI-MS (M+H+) m/e calcd for C21H20N2O6 397.4, found 397.4; 1H NMR (300 MHz) compatible.
Reaction SMILES: [CH2:1]([CH:3]([CH2:28][CH3:29])[CH:4]([NH:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=1)[C:5]1[O:6][C:7]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:2].O1CCCC1.[OH-].[Na+]>C(O)C>[CH2:28]([CH:3]([CH2:1][CH3:2])[CH:4]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:26][CH:27]=1)[C:5]1[O:6][C:7]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:29]
Reactant: CCC(CC)C(Nc1ccc(C(=O)OC)cc1)c1oc2ccc(OC)cc2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCC(CC)C(Nc1ccc(C(=O)O)cc1)c1oc2ccc(OC)cc2c1C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To a mixture of methyl 4-{[2-ethyl-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)butyl]amino}benzoate (718 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (5.00 mL), and the mixture was stirred overnight with heating under reflux, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (5.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (574 mg, 83%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:6][C:5]([F:16])=[CH:4][N:3]=1.[NH2:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([F:24])[CH:23]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:16][C:5]1[CH:6]=[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)[C:2]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[C:22]([F:24])[CH:23]=2)=[N:3][CH:4]=1
Reactant: Nc1cncc(F)c1
Reactant: Cc1nc(N)nc(-c2cc(F)cnc2Cl)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(N)nc(-c2cc(F)cnc2Nc2cncc(F)c2)n1
Reaction time: 0.08 h
Yield: 16.1 %

Procedure:
A solution of 4-(2-chloro-5-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (85 mg, 0.355 mmol) and 3-amino-5-fluoropyridine (118 mg, 1.053 mmol) in THF (3 mL) was cooled in an ice bath under nitrogen. After 5 min, a solution of LiHMDS (1 M in THF, 2500 μL, 2.500 mmol) was added. After 10 min, the cooling bath was removed. After 2 h, HCl (5 N, 0.5 mL) was added. EtOAc (10 mL) and saturated NH4Cl (10 mL) were added. The mixture was vigorously stirred for 15 min. The resulting emulsion was filtered through a glass frit. The collected solid was dissolved in warm DMSO and purified by prep HPLC (30-75% MeCN/water/w 0.1% TFA over 20min). The collected product fractions were concentrated to dryness. Saturated NaHCO3 (10 mL) was added. The mixture was neutralized with HCl (5 N) and filtered. The filtrate was extracted with iPrOH (5%) in CHCl3 (3×5 mL). The combined organic layers were dried over Na2SO4 and concentrated to a yellow solid which was filtered as a suspension in ether to give the product as a yellow powder (18 mg). LCMS (ES, pos.): calcd for C14H11F2N7: 315.1; found: 316.1 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.18 (s, 1H); 8.82 (s, 1H); 8.62 (dd, J=9.78, 3.13 Hz, 1H); 8.44-8.53 (m, 2H); 8.18 (d, J=2.54 Hz, 1H); 8.04 (br. s., 1H); 7.90 (br. s., 1H); 2.46 (s, 3H). 19F NMR (377 MHz, d6-DMSO) δ −139.21 (s, 1 F); −127.41 (s, 1 F).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9]([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Reactant: Oc1ccccc1Cl
Product: COc1ccccc1Cl

Procedure:
A 2 mM solution of 2-chlorophenol containing 1.23 mM chloromethane and buffered at pH 4.0 with 20 mM citrate buffer was incubated with 0.035 g of fungal mycelium (Phellinus pomaceus, NCWRF. FPRL 33A or CBS 137.42) at 25° C. for 12 h. 2-chloroanisole was formed at a rate of 16 nanomoles/g fungal mycelium/hour.
Reaction SMILES: [OH:1][CH:2]([C:7]1[N:12]([CH3:13])[C:11](=[O:14])[C:10]2[N:15](CC3C=CC(OC)=CC=3)[CH:16]=[CH:17][C:9]=2[C:8]=1[C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)[C:3]([O:5][CH3:6])=[O:4].OS(O)(=O)=O.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[OH:1][CH:2]([C:7]1[N:12]([CH3:13])[C:11](=[O:14])[C:10]2[NH:15][CH:16]=[CH:17][C:9]=2[C:8]=1[C:27]1[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(O)c1c(-c2ccc(C)cc2)c2ccn(Cc3ccc(OC)cc3)c2c(=O)n1C
Agent: O=S(=O)(O)O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(O)c1c(-c2ccc(C)cc2)c2cc[nH]c2c(=O)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
An ice cold solution of methyl 2-hydroxy-2-(1-(4-methoxybenzyl)-6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (266 mg, 0.596 mmol) in Trifluoroacetic acid (TFA) (2.5 mL) was treated with conc. H2SO4 (185 μl, 3.47 mmol), and anisole (370 μl, 3.39 mmol). After stirring for 1 hour, the reaction was warmed to rt for 2 hours, and then quenched with sat. NaHCO3 until neutral. The mixture was extracted with EtOAc, washed with Brine, dried with Na2SO4, filtered, and concentrated. Purification with column chromatography (0-100% EtOAc/Hexane) afforded methyl 2-hydroxy-2-(6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (130.1 mg, 0.399 mmol, 66.9% yield) as off-white solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 10.94 (br. s., 1H), 7.36 (dd, J=7.3, 12.5 Hz, 2H), 7.30-7.20 (m, 3H), 6.12-6.03 (m, 1H), 5.42 (s, 1H), 3.82-3.73 (m, 4H), 3.67 (s, 3H), 2.42 (s, 3H); LCMS (m/z) ES+=327 (M+1).
Reaction SMILES: [Cl-:1].[NH2:2][N:3]1[CH:7]=[CH:6][N+:5]([N:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)=[C:4]1[CH2:19][CH3:20]>C(O)C.[Pd]>[Cl-:1].[NH2:2][N:3]1[CH:7]=[CH:6][N+:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)=[C:4]1[CH2:19][CH3:20]
Reactant: CCc1n(N)cc[n+]1N=Cc1ccc(N(C)C)cc1
Agent: [Pd]
Agent: [Cl-]
Solvent: CCO
Product: CCc1n(N)cc[n+]1NCc1ccc(N(C)C)cc1

Procedure:
293 mg (1 mmol) of 3-amino-1-[[p-(dimethylamino)-benzylidene]amino]-2-ethylimidazolium chloride are dissolved in 40 ml of ethanol, whereupon the solution is hydrogenated at room temperature over 50 mg of palladium (5 percent on carbon). After crystallization from ethanol/ether there is obtained 3-amino-1-[[p-(dimethylamino)benzyl]amino]-2-ethylimidazolium chloride of melting point 153°-154°.