Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]([CH3:15])[CH:9](C)[CH2:10][CH2:11][CH2:12][OH:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:16]1([CH3:26])[C:17]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl>[C:16]1([CH3:26])[C:17]([S:22]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:15])(=[O:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: CC(CCCO)N(C)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1S(=O)(=O)OCCCCN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.1 %

Procedure:
To a 500 mL round bottom flask, charged with 4.75 g (23.4 mmol) of N-BOC-N-methyl-4-aminopentanol (32) in 150 mL of methylene chloride, was added 5.25 g (27.5 mmol) of toluenesulfonyl chloride and 7.0 mL (49.6 mmol) of triethylamine. The mixture was stirred at room temperature for 24 h and then washed with 3×75 mL aliquots of 1 N aqueous HCl. The organic phase was dried over anhydrous magnesium sulfate, vacuum filtered, and concentrated via rotary evaporation. The residue was chromatographed on silica gel, eluting first with 20% ethyl acetate/hexane and then with 30% ethyl acetate/hexane. The fractions containing product (33) were combined and concentrated via rotary evaporation to afford 6.95 g of the product as a very pale yellow oil (83%): 1H-NMR (CDCl3) d 7.78 (2H, d), 7.31 (2H, d), 4.03 (2H, t), 3.15 (2H, t), 2.86 (3H, s), 2.42 (3H, s), 1.73-1.47 (4H, m), and 1.41 (9H, s) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[C:15]1([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([C:21]2[S:22][C:23]([C:7]([C:6]3[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[C:11]([F:14])([F:13])[F:12])=[O:9])=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc(-c2cccs2)cc1
Reactant: O=C(O)c1cc(Br)ccc1C(F)(F)F
Product: O=C(c1ccc(-c2ccccc2)s1)c1cc(Br)ccc1C(F)(F)F

Procedure:
To a solution of the above methyl 5-bromo-2-iodobenzoate (4.65 g) in N-methyl-2-pyrrolydinone (20 ml) were added copper (I) bromide (235 mg) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (2.6 ml), and the mixture was stirred under heating at 120° C. for 1.5 hours. The reaction mixture was cooled, and added thereto were 10% aqueous hydrochloric acid solution and ethyl acetate. Insoluble materials were filtered off, and an organic layer of the filtrate was washed with water for 4 times, and subsequently washed with a saturated aqueous sodium hydrogen carbonate solution and brine. The filtrate was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexan:ethyl acetate=80:1) to give methyl 5-bromo-2-trifluoromethylbenzoate (3.55 g) as colorless oil. (3) The above methyl 5-bromo-2-trifluoromethylbenzoate was treated in a manner similar to Reference Example 4-(1) to give 5-bromo-2-trifluoromethylbenzoic acid as pale brown crystals. ESI-Mass m/Z 267/269 (M−H). (4) The above 5-bromo-2-trifluoromethylbenzoic acid and 2-phenylthiophene were treated in a manner similar to Reference Example 5-(1) to give 5-bromo-2-trifluoromethylphenyl 5-phenyl-2-thienyl ketone as pale yellow crystals. APCI-Mass m/Z 411/413 (M+H). (5) To a mixed solution of the above 5-bromo-2-trifluoromethylphenyl 5-phenyl-2-thienyl ketone (670 mg) in methanol (20 ml)-tetrahydrofuran (10 ml) was added sodium borohydride (62 mg), and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in chloroform (10 ml)acetonitrile (20 ml). Thereto was added triethylsilane (0.78 ml), and the mixture was cooled to 0° C. Thereto was added dropwise boron trifluoride•diethyl ether complex (0.52 ml). The mixture was stirred at room temperature for 45 minutes, and added thereto was a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane) to give the desired 5-bromo-1-(5-phenyl-2-thienylmethyl)-2-trifluoromethylbenzene (565 mg) as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O-:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O:20][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CCS[C@H]12)c1csc(N)n1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCC(=O)OC(C)(C)C)=CCS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.1 %

Procedure:
To a solution of sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 5.0 g) in N,N-dimethylformamide (100 ml) was added tert-butyl bromoacetate (2.9 g), and the solution was stirred for 3 hours at ambient temperature. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and water in turn, and dried over anhydrous magnesium sulfate. The solution was evaporated in vacuo to give tert-butoxycarbonylmethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 3.2 g), mp 188°-190° C. (dec.).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]([CH2:17][CH2:18][CH2:19][OH:20])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1>>[CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]([CH2:17][CH2:18][CH2:19][O:20][C:27]1[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=1)[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:14])([F:15])[F:16])[CH:6]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)(C)CN(CCCO)c1ccc(C#N)c(C(F)(F)F)c1
Product: CC(C)(C)CN(CCCOc1ccc(F)cc1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in Example 1C from 4-[(2,2-dimethylpropyl)(3-hydroxypropyl)amino]-2-(trifluoromethyl)benzonitrile and 4-fluorophenol: MS (ESI) m/z 409 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][CH2:33][OH:34])[N:18]=[C:17]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:42].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OCC)(=O)C>CN(C)C=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[N:16]=[C:17]([N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)[N:18]=[C:19]([O:30][CH2:31][CH2:32][C:33]([OH:42])=[O:34])[C:20]=2[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCCO
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCC(=O)O
Yield: 15.6 %

Procedure:
4-t-Butyl-N-[6-(3-hydroxypropyloxy)-5-(2-methoxyphenoxy)-2-morpholino-4-pyrimidinyl]-benzenesulfonamide (800 mg) was dissolved in dimethylformamide (40 ml). Pyridinium dichromate (2.63 g) was added to the solution, and the resultant mixture was stirred for 14 hours at room temperature. Ethyl acetate was added to the reaction mixture, followed by successive washing with 0.5N-HCl, water, and brine. The organic layer was dried over anhydrous sodium sulfate and, evaporated. The residue was purified by silica gel column chromatography (chloroform:methanol=25:1), to thereby obtain 128 mg (yield: 16%) of the title compound as a white powder.
Reaction SMILES: Cl[C:2]([O:4][C:5]([CH3:7])=[CH2:6])=[O:3].[CH:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[C:10]([OH:17])[CH:9]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:2](=[O:3])([O:17][C:10]1[CH:11]=[CH:12][C:13]([N+:14]([O-:16])=[O:15])=[CH:8][CH:9]=1)[O:4][C:5]([CH3:7])=[CH2:6]
Reactant: C=C(C)OC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: C=C(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Isopropenyl chloroformate (5.0 g) was added to an ice cold suspension of p-nitrophenol in chloroform (100 mL). To the stirred reaction mixture, pyridine (3.32 g) was added dropwise over 20 minutes. After stirring at ice bath temperature for 15 minutes, the reaction mixture was allowed to warm up and stirred at room temperature overnight. The reaction mixture was washed with water, IN HCl, ice-cold 1% aqueous sodium hydroxide, water and brine. The organic layer was dried over sodium sulfate and evaporated. The solid residue weighed at 8.7 g. It was crystallized from benzene-hexane m.p. 71-72° . 1H NMR (CDCl3) δ 2.05 (3H, s), 4.82 (2H, s), 7.44 (2H, d) and 8.01 (2H, d); 13C NMR (CDCl3) δ19.59, 102.49, 128.25, 128.79, 131.29, 139.8, 153.07 and 163.84; 1R (KBr) 1770, 1521, 1352, 1266, 1207, 859 cm-1.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.F[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[CH3:11][C:10]1[O:9][N:8]=[C:7]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:6]=1[C:4]1[N:3]=[CH:2][N:1]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:5]=1
Reactant: Fc1ccccn1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccccn2)cn1
Yield: 23 %

Procedure:
As described for Example 12, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (100 mg, 0.44 mmol) using 2-fluoropyridine instead of 4-fluoroacetophenone was converted to the title compound (31 mg, 23%) which was obtained as an off-white solid. MS: m/e=303.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:17][O:18]C(Cl)Cl.Cl>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH:17]([C:6]1[C:7]2[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:10][C:11]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:18]
Reactant: COC(Cl)Cl
Reactant: CCOC(=O)c1cc2cccc(OC)c2o1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(C=O)ccc(OC)c2o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 7-methoxybenzofuran-2-carboxylate (10 g) was dissolved in anhydrous methylene chloride (200 ml), to which were dropwise added dichloromethyl methyl ether (8.2 ml) and titanium tetrachloride (10 ml) with cooling with ice, and directly stirred for 30 minutes. After being allowed to stand for heating to the room temperature, the mixture was stirred for 1.5 hours, to which was dropwise added an aqueous HCl (1 mol/liter) solution to decompose the remaining titanium tetrachloride. Then, this was extracted with chloroform. The organic layer was washed with an aqueous NaOH (1 mol/liter) solution and a saturated saline solution, and dried over sodium sulfate, and the solvent was evaporated. The residue was suspended in ether and taken out through filtration to obtain Compound IIcc-a (8.9 g, 79%) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40](Cl)=[O:41]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[C:40](=[O:41])[C:39]3[CH:43]=[CH:44][CH:45]=[C:37]([O:36][CH3:35])[CH:38]=3)=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Product: COc1cccc(C(=O)N(Cc2ccc3ccc(C#N)cc3c2)c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2)c1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, 3-methoxybenzoyl chloride.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]2[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:3]1=2.[Cl-].[NH4+].[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C)C=O>[NH:20]1[C:16]([C:14]2[CH:13]=[CH:12][C:4]3[O:5][C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:11]4[C:2](=[O:1])[C:3]=3[CH:15]=2)=[N:17][N:22]=[N:21]1
Reactant: N#Cc1ccc2oc3ncccc3c(=O)c2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2cc(-c3nnn[nH]3)ccc2oc2ncccc12
Reaction time: 20 h
Yield: 71.5 %

Procedure:
A mixture of 34 g of 5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-7-carbonitrile, 460 ml of dimethylformamide, 10.5 g of ammonium chloride and 13.1 g of sodium azide is heated with stirring at 110° C to 120° C for 20 hours. After cooling, crystals are filtered off and added to a dilute hydrochloric acid, and the mixture is stirred. The crystals are filtered off, washed with water and recrystallized from dimethylformamide to give 29 g of 7-(5-1H-tetrazolyl)-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine melting at above 300° C.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.[F-].[K+]>C1(C)C=CC=CC=1>[CH3:12][C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=[C:7]([CH3:8])[C:2]=1[C:18]1[CH:19]=[CH:20][C:15]([C:14]([F:25])([F:24])[F:13])=[CH:16][CH:17]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Br
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc([N+](=O)[O-])cc(C)c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 53.6 %

Procedure:
To a solution of 2-bromo-1,3-dimethyl-5-nitro-benzene (1 g, 4.3 mmol) in toluene (20 mL) is added palladium tetrakis triphenylphosphine (0.5 g, 0.43 mmol), 4-trifluoromethyl phenyl boronic acid (1.65 g, 8.7 mmol), and potassium fluoride (0.75 g, 12.9 mmol). The reaction is purged with nitrogen three times and heated to reflux under nitrogen. At the reflux temperature, water (5 mL) is added to the reaction and the reaction is allowed to reflux under nitrogen. The reaction is monitored by HPLC, and upon completion, allowed to cool to room temperature. The reaction is diluted with ethyl acetate and Celite® is added, followed by water. This mixture is then filtered through a pad of Celite®. The solution is poured into a separatory funnel and the organic layer is washed with water and brine. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue is purified by flash column chromatography eluting with ethyl acetate/hexanes to afford 0.68 g of the titled compound as a yellow solid. 1H-NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([CH:9]=1)[C:7]#[N:8].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)=[O:19]>>[NH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:9]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1
Reactant: O=C(CBr)c1cccc(Cl)c1
Reactant: CCOC(=O)Nc1ccc(Cl)cc1C#N
Product: CCOC(=O)n1c(C(=O)c2cccc(Cl)c2)c(N)c2cc(Cl)ccc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 5-chloro-2-[(ethoxycarbonyl)amino]benzonitrile (K. O. Geolotte et al, J. Heterocyclic Chem., 1990, 27, 1549) and 2-bromo-3′-chloroacetophenone (M. Kihara et al., Tetrahedron, 1992, 48, 67-78).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[C:26](Cl)(=[O:28])[CH3:27].C(N(CC)CC)C>ClCCl>[CH3:1][N:2]([CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1)[C:26](=[O:28])[CH3:27]
Reactant: CNC1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(C)C1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
A mixture of compound 7B (15 mg, 0.044 mmol), acetyl chloride (2.8 μL, 1.1 eq), triethylamine (15 μL, 3.0 eq) and dichloromethane (1 mL) was stirred at room temperature for 2 h. The clear solution was directly loaded on silica gel column and eluted with 0.5% ammonium hydroxide and 5% methanol in dichloromethane to give the desired product (10.5 mg, 78% yield)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][C:26]1[C:27]([C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][N:36]=2)=[O:33])=[N:28][CH:29]=[CH:30][CH:31]=1>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:13]=1[C:14]([NH:25][C:26]1[C:27]([C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][N:36]=2)=[O:33])=[N:28][CH:29]=[CH:30][CH:31]=1)=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCOc1cc(S(C)(=O)=O)ccc1C(=O)O
Reactant: Nc1cccnc1C(=O)Nc1ccc(Cl)cn1
Product: CC(C)(C)OC(=O)NCCOc1cc(S(C)(=O)=O)ccc1C(=O)Nc1cccnc1C(=O)Nc1ccc(Cl)cn1
Yield: 84 %

Procedure:
Using a procedure analogous to Example 1-G, 2-(2-t-butoxycarbonylaminoethoxy)-4-methylsulfonylbenzoic acid and 3-amino-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide gave the desired product as a solid (4.0 g, 84%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9].[CH2:32]([N:34]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1)[CH3:33]>>[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH:40][CH:37]4[CH2:38][CH2:39][N:34]([CH2:32][CH3:33])[CH2:35][CH2:36]4)=[O:28])=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CCN1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCN1CCC(NC(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4C)c3O)nc2)CC1

Procedure:
The title compound, as a TFA salt, was prepared in a manner similar to Example 74 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-ethylpiperidin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.31 (m, 3H) 1.71-1.88 (m, 2H) 1.91-2.20 (m, 2H) 2.44 (s, 3H) 3.01-3.18 (m, 3H) 3.23-3.43 (m, 1H) 3.55 (d, J=12.13 Hz, 2H) 3.99-4.28 (m, 1H) 7.67 (d, J=7.83 Hz, 1H) 7.70-7.86 (m, 2H) 8.07-8.31 (m, 1H) 8.32-8.64 (m, 2H) 8.73 (d, J=6.32 Hz, 1H) 8.84-8.99 (m, 1H) 9.24 (br. s., 1H) 12.78-13.45 (m, 1H). MS m/z [M+H]+ 431.2.
Reaction SMILES: [CH3:1][C:2]1[C:11]2([CH2:13][CH2:12]2)[C@:10]([OH:15])([CH3:14])[C:8](=[O:9])[C:7]2[C:3]=1[C@@H:4]([OH:18])[C:5]([CH3:17])([CH3:16])[CH:6]=2.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl.C(OCC)C>[CH3:1][C:2]1[C:11]2([CH2:12][CH2:13]2)[C@:10]([OH:15])([CH3:14])[C:8](=[O:9])[C:7]2=[CH:6][C:5]([CH3:16])([CH3:17])[C:4](=[O:18])[C:3]=12
Reactant: CC1=C2C(=CC(C)(C)[C@@H]2O)C(=O)[C@](C)(O)C12CC2
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC1=C2C(=O)C(C)(C)C=C2C(=O)[C@](C)(O)C12CC2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of illudin M (200 mg) and pyridinium dichromate (1 g) in dry dichloromethane (60 ml) was stirred at room temperature in a flask equipped with a rubber septum so that an atmosphere of argon could be maintained. After 20 hours, the reaction mixture was diluted with diethyl ether (20 ml) and filtered through a short column of silica gel. The column was further eluted with more diethyl ether and the combined filtrate was concentrated, giving a residue which was chromatographed on silica gel with hexane-ethyl acetate (10:1 ) as eluent. The desired compound was obtained in early fractions from the chromatography. The yield was 140 mg of white crystals melting at 64°-65° C.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[N:20][NH:21]4)=[CH:15][N:16]=[C:11]2[N:10]([C:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:45]C([O-])(C)C.[K+].IC>C1COCC1>[C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[N:20][N:21]4[CH3:45])=[CH:15][N:16]=[C:11]2[N:10]([C:26]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3cccc4[nH]ncc34)nc12
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1ncc2c(-c3cnc4c(n3)c(C(=O)NC(C)(C)C)cn4C(c3ccccc3)(c3ccccc3)c3ccccc3)cccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.1 %

Procedure:
To a solution of N-tert-butyl-2-(1H-indazol-4-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (375 mg, 0.65 mmol) in dry THF (20 mL) was added potassium 2-methylpropan-2-olate (109 mg, 0.975 mmol) at 0° C. After stirring for 30 minutes, iodomethane (138 mg, 0.975 mmol) was added at 0° C. Then it was warmed to room temperature and stirred for 1 hour. Reaction mixture was quenched by the addition of water (2 mL), extracted with ethyl acetate (100 mL), then organic phase washed with water (3×10 mL) and brine (2×10 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, 200-300 mesh, eluting with EtOAc: petroleum ether=1:3) to afford N-tert-butyl-2-(1-methyl-1H-indazol-4-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (154 mg, 40%) as a white solid. LCMS: (M+H)+=591; 1H NMR (300 MHz, CDCl3): δ 8.54 (s, 1H), 8.50 (s, 1H), 8.40 (s, 1H), 8.35 (s, 1H), 7.53-7.47 (m, 3H), 7.32-7.27 (m, 9H), 7.24-7.19 (m, 6H), 4.14 (s, 3H), 1.52 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[CH3:11][C:12]([C:14]1[C:19]([NH2:20])=[CH:18][C:17]2[O:21][CH2:22][O:23][C:16]=2[CH:15]=1)=[O:13]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:20][C:19]2[CH:18]=[C:17]3[O:21][CH2:22][O:23][C:16]3=[CH:15][C:14]=2[C:12]([CH3:11])=[O:13])=[O:7])=[CH:9][CH:10]=1
Reactant: CC(=O)c1cc2c(cc1N)OCO2
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: CC(=O)c1cc2c(cc1NC(=O)c1ccc(Cl)nc1)OCO2

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 2-amino-4,5-methylenedioxyacetophenone as a light grey-yellow solid as described in Example 1. 1H NMR (CDCl3): 9.09-9.08 (m, 1H), 8.55 (s, 1H), 8.30-8.27 (m, 1H), 7.50-7.47 (m, 1H), 7.35 (s, 1H), 6.10 (s, 2H), 2.64 (s, 3H).