Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:24][C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:29]3[CH:30]=[CH:31][C:26]([NH2:25])=[N:27][CH:28]=3)[N:7]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(Cl)n2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3ccc(N)nc3)n2)n1

Procedure:
The title compound was prepared from 2-chloro-4-[6-methyl-4-(4-trifluoromethylphenyl)-pyridin-2-yl]-pyrimidine (example E.83) (0.40 g, 1.14 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.302 g, 1.37 mmol) according to the general procedure VI. Obtained as an off-white solid (0.050 g, 10%). MS (ISP) 408.3 [(M+H)+]; mp 191° C.
Reaction SMILES: [N+](C1C=CC(C([O:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=2[NH:20][C:21](=[O:31])[C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=O)=CC=1)([O-])=O.[OH-].[Na+].C(OCC)(=O)C>O>[OH:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[NH:20][C:21](=[O:31])[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1
Reactant: Cc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2)c(OC(=O)c2ccc([N+](=O)[O-])cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2)c(O)c1
Reaction time: 3 h
Yield: 48.3 %

Procedure:
To a suspension of N-[2-(4-nitrophenylcarbonyloxy)-4-methylphenyl]-4-nitrobenzamide (12.5 g) was added 1N sodium hydroxide (20 ml) at ambient temperature. After 3 hours, ethyl acetate (100 ml) and water (200 ml) was added to this solution and resulting solid was filtered and washed with water and diethyl ether to give N-(2-hydroxy-4-methylphenyl)-4-nitrobenzamide (3.9 g) as yellow crystal.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[CH2:9]([S:11](Cl)(=[O:13])=[O:12])[CH3:10].C(OCC)C>ClCCl>[CH2:9]([S:11]([NH:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)(=[O:13])=[O:12])[CH3:10]
Reactant: NCc1cccnc1
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CCS(=O)(=O)NCc1cccnc1
Reaction time: 18 h

Procedure:
3-Aminomethylpyridine (2.15 g, 19.88 mmol) was dissolved in 40 ml dichloromethane. Ethanesulfonyl chloride (2.56 g, 19.9 mmol) was added to the mixture and stirred for 18 h. To the resultant precipitate was added 40 ml diethyl ether and decanted from the solid. The solid was partitioned between a mixture of 100 ml dichloromethane/20 ml isopropyl alcohol and 20 ml of a saturated sodium bicarbonate solution. The organic layer was separated and the aqueous phase extracted twice with the 80/20 mixture of dichloromethane/isopropyl alcohol. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound. 1H NMR: 8.67 (s,1H), 8.60 (d,1H,J=4 Hz), 7.90 (m,1H), 7.42 (m,1H), 5.77 (t,1H,J=6 Hz), 4.38 (d,2H,J=6 Hz), 3.07 (t,2H,J=8 Hz), 1.38 (t,3H,J=8 Hz). MS calcd. 200.2; MS (M+1) 201.1.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[Cl:26][C:27]1[CH:28]=[C:29]([Mg]Br)[CH:30]=[CH:31][C:32]=1[Cl:33]>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:29]3[CH:30]=[CH:31][C:32]([Cl:33])=[C:27]([Cl:26])[CH:28]=3)=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: Clc1ccc([Mg]Br)cc1Cl
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)c(Cl)c1)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 90 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 0.98 mL 0.5M 3,4-dichlorophenylmagnesium bromide. Yield: 64 mg of a white solid. LC-MSD, m/z for C22H13BrCl2N2O2 [M+H]+=487.0, 489.0, 491.0; HPLC retention time: 2.9 min.
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[NH2:17][C:18]1[C:19]([Cl:33])=[C:20]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:21][NH:22][C:23](=[O:28])[C:24]([CH3:27])([F:26])[CH3:25]>O.O1CCOCC1>[Cl:33][C:19]1[C:18]([N:17]=[C:1]=[S:2])=[C:31]([Cl:32])[CH:30]=[CH:29][C:20]=1[CH2:21][NH:22][C:23](=[O:28])[C:24]([CH3:25])([F:26])[CH3:27]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: CC(C)(F)C(=O)NCc1ccc(Cl)c(N)c1Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(F)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl

Procedure:
1,1′-Thiocarbonyldi-2-pyridone (1.21 g, 5.2 mmol) is added to a mixture of N-(3-amino-2,4-dichloro-benzyl)-2-methyl-2-fluoro-propionamide (1.32 g, 4.7 mmol) and dioxane (25 mL) and it is stirred at reflux for 2 d. The mixture is diluted with water, most of the dioxane is removed under reduced pressure and the resulting precipitate is collected by filtration, washed with water and dried.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])[CH:11]=2)[C:6](=[C:20](OCC)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]1=[O:30])(=O)C.[NH2:31][C:32]1[CH:42]=[CH:41][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:34][CH:33]=1>>[CH2:39]([O:38][C:36]([C:35]1[CH:34]=[CH:33][C:32]([NH:31]/[C:20](=[C:6]2\[C:5](=[O:30])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH:11]=3)/[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:42][CH:41]=1)=[O:37])[CH3:40]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(-c3ccccc3C)ccc21)c1ccccc1
Product: CCOC(=O)c1ccc(N/C(=C2\C(=O)Nc3cc(-c4ccccc4C)ccc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-(2-tolyl)-2-indolinone and ethyl 4-aminobenzoate
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[N:15][C:16]([NH:27][C:28](=[O:32])[NH:29][CH2:30][CH3:31])=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:12])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[C:33]([O:37][CH2:38][CH3:39])(=[O:36])[C:34]#[CH:35]>CN(C=O)C>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:18]2[CH:17]=[C:16]([NH:27][C:28](=[O:32])[NH:29][CH2:30][CH3:31])[N:15]=[CH:14][C:13]=2[C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([N:1]3[CH:35]=[C:34]([C:33]([O:37][CH2:38][CH3:39])=[O:36])[N:3]=[N:2]3)=[CH:9][CH:8]=2)=[O:12])=[CH:21][CH:22]=1
Reactant: CCNC(=O)Nc1cc(Nc2ccc(Cl)cc2)c(C(=O)Nc2ccc(N=[N+]=[N-])cc2)cn1
Reactant: C#CC(=O)OCC
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1cc(Nc2ccc(Cl)cc2)c(C(=O)Nc2ccc(-n3cc(C(=O)OCC)nn3)cc2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.3 %

Procedure:
To a solution of Compound 132 (50 mg, 0.11 mmol) in DMF (1.8 mL) was added ethyl prop-2-ynoate (21 mg, 0.2218 mmol), followed by ethyl-diiopropylamine (0.023 mL, 0.13 mmol) and cuprous iodide (3.8 mg, 0.020 mmol) at 0° C. The ice bath was removed and the mixture stirred at RT for 2 hours. Water was added and the mixture extracted with EtOAc (4 times). The organic fractions were combined and concentrated in vacuo to give a residue that was purified by medium pressure chromatography (C18 column), eluting with ACN gradient in water, to give target product. The product was triturated with EtOAc to give Compound 133 (5 mg). 1H NMR (400 MHz, DMSO) δ 10.55 (s, 1H), 9.82 (5, 1H), 9.43 (s, 1H), 9.12 (s, 1H), 8.62 (s, 1H), 7.94 (t, J=6.4 Hz, 5H), 7.44 (d, J=8.5 Hz, 2H), 7.31 (d, J=8.5 Hz, 2H), 7.26 (s, 1H), 4.37 (q, J=7.1 Hz, 2H), 3.20-3.11 (m, 2H), 1.35 (t, J=7.1 Hz, 3H), 1.07 (t, J=7.2 Hz, 3H), [M+H]+ m/z=549.03.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[C:13]2[CH:14]=[C:15]([C:31]([OH:33])=O)[CH:16]=[C:17]3[C:22]=2[O:21][C:20]([N:23]2[CH2:28][CH2:27][O:26][C@H:25]([CH3:29])[CH2:24]2)=[CH:19][C:18]3=[O:30])[CH:5]=[CH:6][CH:7]=1.[CH3:34][NH:35][CH3:36]>>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[C:13]2[CH:14]=[C:15]([C:31]([N:35]([CH3:36])[CH3:34])=[O:33])[CH:16]=[C:17]3[C:22]=2[O:21][C:20]([N:23]2[CH2:28][CH2:27][O:26][C@H:25]([CH3:29])[CH2:24]2)=[CH:19][C:18]3=[O:30])[CH:5]=[CH:6][CH:7]=1
Reactant: CNC
Reactant: C[C@@H]1CN(c2cc(=O)c3cc(C(=O)O)cc(C4CCCN4c4cccc(F)c4)c3o2)CCO1
Product: C[C@@H]1CN(c2cc(=O)c3cc(C(=O)N(C)C)cc(C4CCCN4c4cccc(F)c4)c3o2)CCO1
Yield: 46.2 %

Procedure:
8-(1-(3-fluorophenyl)pyrrolidin-2-yl)-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylic acid (102 mg, 0.23 mmol) was reacted with dimethylamine (2N in THF) (0.169 ml, 0.34 mmol) as described in Example 3.02 to give 8-(1-(3-fluorophenyl)pyrrolidin-2-yl)-N,N-dimethyl-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxamide (51 mg, 47%) as a pale yellow foam.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C:10](=[CH:11][O:12]CC)[CH2:9][C@H:8]2[C@H:15]3[C@H:24]([CH2:25][CH2:26][C@:6]12[CH3:7])[C:23]1[CH:22]=[CH:21][C:20]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:19][C:18]=1[CH2:17][CH2:16]3)(=[O:3])[CH3:2].C([O-])(O)=O.[Na+]>C1COCC1.Cl.O>[C:1]([O:4][C@H:5]1[C@H:10]([CH:11]=[O:12])[CH2:9][C@H:8]2[C@H:15]3[C@H:24]([CH2:25][CH2:26][C@:6]12[CH3:7])[C:23]1[CH:22]=[CH:21][C:20]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:19][C:18]=1[CH2:17][CH2:16]3)(=[O:3])[CH3:2]
Reactant: CCOC=C1C[C@H]2[C@@H]3CCc4cc(OCc5ccccc5)ccc4[C@H]3CC[C@]2(C)[C@H]1OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)O[C@H]1[C@H](C=O)C[C@H]2[C@@H]3CCc4cc(OCc5ccccc5)ccc4[C@H]3CC[C@@]21C
Yield: 56.4 %

Procedure:
A solution of 183 mg (0.397 mmol) of 4 in THF (1.5 mL) with 4 drops of 10% aqueous HCl and 2 drops of H2O was stirred at rt for 6 h. Reaction was poured into saturated aqueous NaHCO3 (100 mL) and extracted with CH2Cl2 (3×, 75 mL). Combined organic extracts were dried over Na2SO4 and concentrated in vacuo. Purification of the residue by repeated (3×) flash chromatography on a 2×15 cm column of silica gel using hexanes/acetone (6:1) as eluent gave 96.9 mg (56%) of 5 as a white solid. Data for 5: TLC, T-3, Rf0.22. 1H NMR (500 MHz, CDCl3) δ 0.91 (s, 3H, H-18), 2.10 (s, 3H, OAc), 4.86 (d, 1H, J=8.1 Hz, H-17), 5.04 (s, 2H, benzylic), 6.73 (d, 1H, J=2.7 Hz, H-4), 6.79 (dd, 1H, J=8.5, 2.7 Hz, H-2), 7.19 (d, 1H, J=8.5 Hz, H-1), 7.31-7.44 (m, 5H, Ar—H), 9.83 (d, 1H, J=3.1 Hz, O═CH); HRMS (ES) calcd for C28H32O4Na (M+Na+) m/e 455.2198, found m/e 455.2205.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[S:9][C:10]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:5][CH:4]=1.Cl.[CH2:21]1[CH:25]2[CH2:26][NH:27][CH2:28][CH:24]2[CH2:23][N:22]1[C:29]([NH2:31])=[O:30].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([O:7][C:6]3[CH:18]=[CH:19][C:3]([CH2:2][N:27]4[CH2:26][CH:25]5[CH2:21][N:22]([C:29]([NH2:31])=[O:30])[CH2:23][CH:24]5[CH2:28]4)=[CH:4][CH:5]=3)[S:9][C:10]=2[CH:16]=1
Reactant: NC(=O)N1CC2CNCC2C1
Reactant: Fc1ccc2nc(Oc3ccc(CCl)cc3)sc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC(=O)N1CC2CN(Cc3ccc(Oc4nc5ccc(F)cc5s4)cc3)CC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
To a suspension of 2-(4-chloromethyl-phenoxy)-6-fluoro-benzothiazole (152 mg, 0.52 mmol), hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid amide, hydrochloride (110 mg, 0.57 mmol) and Cs2CO3 (676 mg, 2.08 mmol) in DMF (1 mL) was stirred at rt overnight. The resultant mixture was filtered and the residue purified via preparative reverse phase HPLC to afford the title compound (15 mg, 7%). MS (ESI): Mass calcd for C21H21N4O2SF, 412.1; m/z found, 413.1 [M+H]+; 1H NMR (400 MHz, CD3OD): 7.64 (dd, J=8.9, 4.7 Hz, 1H), 7.58 (dd, J=8.4, 2.6 Hz, 1H), 7.47 (d, J=8.5 Hz, 2H), 7.33 (d, J=8.5 Hz, 2H), 7.19 (dt, J=9.0, 8.9, 2.6 Hz, 1H), 3.66 (s, 2H), 3.59-3.40 (m, 2H), 3.29-3.27 (m, 2H), 2.97-2.83 (m, 2H), 2.77 (d, J=9.3, 6.8 Hz, 2H), 2.46 (d, J=9.3, 3.6 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[OH-].[K+].[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br.[Br-]>CS(C)=O.O>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Reactant: Clc1ccccc1CBr
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C1CCCc2nc3ccccc3c(NCc3ccccc3Cl)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.2 %

Procedure:
To a suspension of 9-amino-3,4-dihydroacridin-1(2H)-one (8.0 g) in 75 ml of dimethyl sulfoxide was added pulverized potassium hydroxide (6.2 g). This was stirred for 0.5 hour at ambient temperature. To this solution was added 2-chlorobenzyl bromide (9.4 g). After 1 hour, an additional 1 ml of the bromide was added. This was stirred for an additional hour. At this time, 200 ml of water was added, and the precipitate was filtered and washed with water. The solid was taken up in dichloromethane and dried over anhydrous magnesium sulfate. The compound was purified via flash chromatography to yield 6.75 g of solid, mp 150°-161° C. A portion of this was recrystallized from methanol to give analytically pure needles, mp 162°-165° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:19][CH:20]1[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]1.[Cl:29][C:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[CH:32][N:31]=1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[O:12])[N:8]2[C:34]2[CH:33]=[CH:32][N:31]=[C:30]([Cl:29])[CH:35]=2)=[CH:4][C:3]=1[O:19][CH:20]1[CH2:21][CH2:22][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:24][CH2:25]1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCOCC4)[nH]c3cc2Br)CC1
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCOCC4)n(-c4ccnc(Cl)c4)c3cc2Br)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from [6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-morpholin-4-yl-methanone (example 41, step 6) and 2-chloropyridine-4-boronic acid. The title compound was obtained in 12% yield as light yellow oil. MS (m/e): 561.4 (MH+, 100%).
Reaction SMILES: [H-].[Na+].[Cl-].[CH2:4]([O:11][C:12]1[CH:37]=[CH:36][C:15]([CH2:16][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[O:38]1[C:42]2([CH2:47][CH2:46][C:45](=O)[CH2:44][CH2:43]2)[O:41][CH2:40][CH2:39]1>CN(C)C=O.CCCCC>[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH:16]=[C:45]2[CH2:46][CH2:47][C:42]3([O:41][CH2:40][CH2:39][O:38]3)[CH2:43][CH2:44]2)=[CH:36][CH:37]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: c1ccc(COc2ccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc2)cc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: C(=C1CCC2(CC1)OCCO2)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 47.6 %

Procedure:
To a suspension of sodium hydride (729 mg 60% in mineral oil) in N,N-dimethylformamide containing one drop of pentane is added (4-benzyloxybenzyl)triphenylphosphonium chloride (7.52 g). The mixture is stirred for 40 min, then 1,4-dioxaspiro[4.5]decan-8-one (2.37 g) is added. The mixture is stirred for one hour at room temperature, the suspension turning from red to green. The mixture is poured into ice (250 g) and extracted with ethyl acetate (4 times 100 mL). The organic extracts are pooled, washed with saturated aqueous solution of sodium chloride (3 times 50 mL), dried over magnesium sulfate, concentrated under reduced pressure and purified by column chromatography over silica gel using a gradient heptane/ethyl acetate from 90/10 to 60/40 to give 2.43 g of 8-(4-benzyloxybenzylidene)-1,4-dioxaspiro[4.5]decane as a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1ccn2Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 91.6 %

Procedure:
To a solution of methyl indole-4-carboxylate (10.0 g, 57.14 mmol) was added sodium hydride (60% dispersion in mineral oil (5.71 g, 142.8 mmol) in DMF (200 mL) in portions. The mixture was stirred under an atmosphere of nitrogen for 20 minutes. To this was added benzyl bromide (8.48 mL, 74.4 mmol) and the mixture continued to stir for 16 hours. The mixture was poured into an ice/water mixture and extracted with diethyl ether (3×500 mL). The combined organic layers were washed with brine (3×200 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by column chromatography (silica gel, 5 to 15% ethyl acetate in hexanes) afforded methyl 1-benzyl-1H-indole-4-carboxylate (A1b, 13.89 g, 92%) as a pale yellow oil, which crystallized upon standing: 1H NMR (500 MHz, CDCl3) δ 7.90 (d, J=7.5 Hz, 1H), 7.46 (d, J=7.5 Hz, 1H), 7.30-7.25 (m, 4H), 7.20-7.16 (m, 2H), 7.10-7.05 (m, 2H), 5.36 (s, 2H), 3.98 (s, 3H); MS (ESI+) m/z 266 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]3[CH2:13][C:12](=[CH:14][O:15]C)[CH2:11]3)[NH:7][C:6]=2[CH:17]=1.Cl.[CH3:19]C#N>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]3[CH2:13][CH:12]([CH:14]=[O:15])[CH2:11]3)[N:7]([CH3:19])[C:6]=2[CH:17]=1
Reactant: COC=C1CC(c2nc3ccc(Br)cc3[nH]2)C1
Reactant: CC#N
Agent: Cl
Product: Cn1c(C2CC(C=O)C2)nc2ccc(Br)cc21
Reaction time: 16 h

Procedure:
To a solution of 6-bromo-2-(3-(methoxymethylidene)cyclobutyl)-1H-benzimidazole (850 mg) in CH3CN (20 ml) was added 2 M HCl (4.2 ml), and the resulting mixture was stirred at same temperature for 16 h. The reaction mixture was then quenched with saturated NaHCO3 solution, and extracted with DCM. The extract was washed with brine, dried over Na2SO4, concentrated in vacuo and purified by column chromatography (hexane/EtOAc) to afford two isomers of the title compound (Less polar isomer: 200 mg, polar isomer: 300 mg) as yellow sticky solids.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:7][CH:8]=1)([O-])=O.[H-].[Na+].[CH2:16](I)[CH3:17].O>CN(C)C=O>[NH2:1][C:4]1[CH:5]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:7]([CH2:16][CH3:17])[CH:8]=1
Reactant: CCI
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(N)cn1CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a solution of ethyl 4-nitro-1H-pyrrol-2-carboxylate (10 g) in N,N-dimethylformamide (100 mL) was slowly added sodium hydride (60%, oily, 2.4 g) at 0° C., and the mixture was stirred at room temperature for 30 min. Ethyl iodide (4.8 mL) was slowly added to the reaction mixture, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. A mixture of the residue and 10% palladium-carbon (50% containing water, 1.0 g) in tetrahydrofuran (20 mL)-ethanol (20 mL) was stirred at room temperature for 12 hr under a hydrogen atmosphere. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to give ethyl 4- amino-1-ethyl-1H-pyrrole-2-carboxylate (7.1 g, yield 78%) as a brown oil from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [CH:1]1[C:6]2[C:7]([C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)=[N:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C.C1COCC1.[Pt](=O)=O>[CH:1]1[C:6]2[CH:7]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=3)[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(C2=Nc3ccccc3Oc3ccccc32)cc1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C2Nc3ccccc3Oc3ccccc32)cc1
Yield: 67 %

Procedure:
Title compound 4 was dissolved in ethanol (25 mL) and THF (5 mL). Platinum (IV) oxide (0.075 g, 10% wt) was added. The mixture was stirred at room temperature for 3 h under 1 atmosphere of hydrogen. The catalyst was filtered and the filtrate was concentrated under reduced pressure to one third volume. The precipitate was filtered to afford title compound 5 (510 mg, 67%) as a white solid. LRMS (ESI): (calc) 345.14 (found) 346.3 (MH)+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.88 (d, J=8.4 Hz, 2H), 7.48 (dd, J=7.5, 1.7 Hz, 1H), 7.39 (d, J=8.0 Hz, 2H), 7.33 (td, J=7.7, 1.8 Hz, 1H), 7.19 (td, J=7.4, 1.2 Hz, 1H), 7.11 (dd, J=8.0, 1.2 Hz, 1H), 6.90-6.83 (m, 3H), 6.77 (dd, J=7.9, 1.4 Hz, 1H), 6.50 (td, J=7.3, 1.6 Hz, 1H), 5.55 (d, J=6.1 Hz, 1H), 4.28 (q, J=7.0 Hz, 2H), 1.28 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]2[O:9][C:10]3[C:15]([C:16]([O:18][CH2:19][C:4]=2[CH:3]=1)=[O:17])=[C:14]([O:20][CH3:21])[C:13]([C@@H:22](O)[CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:12][CH:11]=3.S(Cl)([Cl:30])=O>O1CCOCC1>[Cl:30][CH:22]([C:13]1[CH:12]=[CH:11][C:10]2[O:9][C:5]3[C:6]([OH:8])=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=3[CH2:19][O:18][C:16](=[O:17])[C:15]=2[C:14]=1[O:20][CH3:21])[CH2:23][CH:24]([CH3:26])[CH3:25]
Reactant: O=S(Cl)Cl
Reactant: COc1c([C@@H](O)CC(C)C)ccc2c1C(=O)OCc1cc(C)cc(O)c1O2
Solvent: C1COCCO1
Product: COc1c(C(Cl)CC(C)C)ccc2c1C(=O)OCc1cc(C)cc(O)c1O2

Procedure:
200 mg (0.54 mmol) of penicillide (Ib) are heated under reflux for 5 h (exclusion of moisture) in 1 ml of dioxane and 0.38 ml (5.2 mmol) of thionyl chloride. After evaporating in vacuo, the residue is taken up in methylene chloride, and the solution is washed with aqueous bicarbonate, then with water, dried and evaporated. Chromatography on silica gel Si60 in ether/petroleum ether=2:1 yields 187 mg (93% of theory) of colorless solid.
Reaction SMILES: Cl.[CH2:2]([C:4]1[N:5]=[C:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[O:12])[NH:7][C:8]=1[CH3:9])[CH3:3].C[O-].[Na+].[C:23](OC)(=[O:26])[C:24]#[CH:25]>>[CH2:2]([C:4]1[NH:5][C:6]2[N:7]([C:8]=1[CH3:9])[C:23](=[O:26])[CH:24]=[CH:25][C:10]=2[C:11](=[O:12])[C:13]1[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=1)[CH3:3]
Reactant: C#CC(=O)OC
Reactant: CCc1nc(CC(=O)c2ccc(F)cc2)[nH]c1C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: CCc1[nH]c2c(C(=O)c3ccc(F)cc3)ccc(=O)n2c1C

Procedure:
The compound is prepared as described in example 20 with 200 mg (0.71 mmol) of 2-(4-Ethyl-5-methyl-1H-imidazol-2-yl)-1-(4-fluorophenyl)ethanone hydrochloride (example XVIII), 50 mg (0.92 mmol) of sodium methylate and 59.5 mg (0.71 mmol) methyl propiolate.