Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH3:17])[S:4]([C:7]1[CH:8]=[N:9][C:10]([Sn](C)(C)C)=[CH:11][CH:12]=1)(=[O:6])=[O:5])[CH3:2].[NH2:18][C:19]1[C:24]([C:25]2[S:33][C:28]3[C:29](=[O:32])[NH:30][CH2:31][C:27]=3[CH:26]=2)=[CH:23][C:22](Br)=[CH:21][N:20]=1>>[NH2:18][C:19]1[N:20]=[CH:21][C:22]([C:10]2[CH:11]=[CH:12][C:7]([S:4]([N:3]([CH2:1][CH3:2])[CH3:17])(=[O:6])=[O:5])=[CH:8][N:9]=2)=[CH:23][C:24]=1[C:25]1[S:33][C:28]2[C:29](=[O:32])[NH:30][CH2:31][C:27]=2[CH:26]=1
Reactant: Nc1ncc(Br)cc1-c1cc2c(s1)C(=O)NC2
Reactant: CCN(C)S(=O)(=O)c1ccc([Sn](C)(C)C)nc1
Product: CCN(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3cc4c(s3)C(=O)NC4)c2)nc1
Yield: 36.5 %

Procedure:
General method D was applied to N-ethyl-N-methyl-6-(trimethylstannyl)pyridine-3-sulfonamide (218 mg, 0.6 mmol) and 2-(2-amino-5-bromopyridin-3-yl)-4H-thieno[2,3-c]pyrrol-6(5H)-one (186 mg, 0.6 mmol) to give 6′-amino-N-ethyl-N-methyl-5′-(6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)-[2,3′-bipyridine]-5-sulfonamide as a yellow solid (94 mg, 38% yield) after purification by preparatory reverse phase HPLC. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.91 (d, J=1.5 Hz, 1H), 8.87 (d, J=2.3 Hz, 1H), 8.44 (s, 1H), 8.26 (d, J=2.3 Hz, 1H), 8.10-8.20 (m, 2H), 7.43 (s, 1H), 6.65 (s, 2H), 4.35 (s, 2H), 3.30 (s, 4H), 3.09 (dd, J=14.3, 7.0 Hz, 2H), 2.72 (s, 3H), 1.06 (t, J=7.0 Hz, 3H); MS (EI) m/z=430 [M+1]+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[N:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4].Br[CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>>[CH2:1]([C:5]1[N:6]=[N:7][C:8]2[C:13]([C:14]=1[O:15][CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc2ccccc2c1O
Reactant: N#Cc1ccc(CBr)cc1
Product: CCCCc1nnc2ccccc2c1OCc1ccc(C#N)cc1

Procedure:
Using the procedure of Example 6, the product of Step B of Example 13 and 4-(bromomethyl)benzonitrile were reacted to obtain the desired product.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:19]=[CH:18][C:8]([CH2:9][N:10]2[C:14](=O)[CH:13]([CH3:16])[NH:12][C:11]2=[O:17])=[CH:7][CH:6]=1.CO.Cl>O1CCCC1>[CH3:3][O:4][C:5]1[CH:19]=[CH:18][C:8]([CH2:9][N:10]2[CH2:14][CH:13]([CH3:16])[NH:12][C:11]2=[O:17])=[CH:7][CH:6]=1
Reactant: COc1ccc(CN2C(=O)NC(C)C2=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CN2CC(C)NC2=O)cc1
Reaction time: 0.25 h
Yield: 61.7 %

Procedure:
Under a nitrogen stream, sodium borohydride (0.65 g) was suspended in tetrahydrofuran (25 mL), boron trifluoride diethyl ether complex (2.63 mL) was added dropwise under ice-cooling, and the mixture was stirred at the same temperature for 15 min. Then, a solution of 3-(4-methoxybenzyl)-5-methylimidazolidine-2,4-dione (2.00 g) described in Preparation Example 51 in tetrahydrofuran (25 ml) was added under ice-cooling, and the mixture was stirred at the same temperature for 30 min and at room temperature overnight. To the reaction mixture were added dropwise methanol and 0.5N hydrochloric acid, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated from the reaction mixture, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water and saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (1.16 g).
Reaction SMILES: [OH:1][CH:2]1[C:7]([O:10][CH3:11])([O:8][CH3:9])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1.[H-].[Na+].I[CH2:22][CH3:23]>CN(C=O)C>[CH2:22]([O:1][CH:2]1[C:7]([O:8][CH3:9])([O:10][CH3:11])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1)[CH3:23]
Reactant: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC1CN(C(=O)OC(C)(C)C)CCC1(OC)OC
Yield: 84.7 %

Procedure:
The same operation as in Example (90a) was performed using tert-butyl 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylate (5.2 g, 20 mmol), sodium hydride (55% content, 1.31 g, 30 mmol), 1-iodoethane (6.24 g, 40 mmol) and DMF (50 mL). The residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=10/1, 4/1, 2/1) to obtain 4.90 g of the title compound as a colorless oily substance (85%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([I:10])[C:3]=1[NH2:4].Cl[C:12](Cl)([O:14]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCOCC1>[F:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([I:10])[C:3]=1[N:4]=[C:12]=[O:14]
Reactant: Cc1cc(F)c(N)c(I)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: Cc1cc(F)c(N=C=O)c(I)c1

Procedure:
A mixture of 2-fluoro-6-iodo-4-methylaniline (D1) (370 mg, 1.5 mmol), triphosgene (150 mg, 0.05 mmol), and dioxan (3 ml) was heated at reflux for 1 h 15 min then cooled and evaporated to give the crude title compound.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1CCN.C(OCC)(=O)C>CN(C)C=O>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]1[NH:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[S:12]
Reactant: S=C(Nc1nc2ccccc2[nH]1)n1ccnc1
Reactant: COc1ccccc1CCN
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccccc1CCNC(=S)Nc1nc2ccccc2[nH]1
Temperature: 25 °C
Yield: 38 %

Procedure:
A solution of 1-[(2-benzimidazolyl)thiocarbamoyl]imidazole (1.22 g, 5.0 mmol) and 2-(2-methoxyphenyl)ethylamine (0.82 g, 5.0 mmol) in N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.62 g (38%) of the titled product as a white solid:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:22])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:4][CH:3]=1.[CH2:23]([O:25][C:26](=[O:46])[CH2:27][C:28]1([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)[CH2:30][CH2:29]1)[CH3:24]>>[CH2:23]([O:25][C:26](=[O:46])[CH2:27][C:28]1([C:31]2[CH:36]=[CH:35][C:34]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:22])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:4][CH:3]=3)=[CH:33][CH:32]=2)[CH2:30][CH2:29]1)[CH3:24]
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: CC(C)=CCCC(C)Nc1c(C)noc1-c1ccc(Br)cc1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCC=C(C)C)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(1,5-dimethyl-hex-4-enyl)-amine and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[C@@H:18]([OH:19])[C@H:17]([OH:20])[C@@H:16]([OH:21])[C@H:15]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([CH2:29][C:30]4[S:31][C:32]([C:35]5[O:36][CH:37]=[CH:38][CH:39]=5)=[CH:33][N:34]=4)[CH:23]=3)[O:14]2)(=O)=O)=CC=1.[F-:40].[K+].O>C(O)CO>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C@H:15]2[C@H:16]([OH:21])[C@@H:17]([OH:20])[C@H:18]([OH:19])[C@@H:13]([CH2:12][F:40])[O:14]2)=[CH:23][C:24]=1[CH2:29][C:30]1[S:31][C:32]([C:35]2[O:36][CH:37]=[CH:38][CH:39]=2)=[CH:33][N:34]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H](c3ccc(Cl)c(Cc4ncc(-c5ccco5)s4)c3)[C@H](O)[C@@H](O)[C@@H]2O)cc1
Reactant: [F-]
Agent: [K+]
Solvent: O
Solvent: OCCO
Product: O[C@@H]1[C@@H](O)[C@H](c2ccc(Cl)c(Cc3ncc(-c4ccco4)s3)c2)O[C@H](CF)[C@H]1O
Yield: 10.7 %

Procedure:
The solution of toluenesulfonate 90 (200 mg, 0.34 mmol) and potassium fluoride (23.5 mg 0.41 mmol) in ethylene glycol (3.5 mL) was stirred at 100° C. for 20 h. H2O was added to the reaction mixture and then extracted with CH2Cl2. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by prep HPLC (C18) to afford the titled compound 94 (16 mg, 11%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].I[C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[NH2:20])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: Nc1ccccc1I
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Nc1ccccc1-c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 68.8 %

Procedure:
Add 4-bromophenyl boronic acid (5.0 g, 24.82 mmol), tetrakis(triphenylphosphine) palladium (0) (0.717 g, 0.620 mmol) and 2 M Na2CO3 (10 mL) to a solution of 2-iodoaniline (4.5 g, 20.69 mmol) in toluene (2 mL):ethanol (20 mL), deoxygenate and heat at 80° C. under nitrogen. After 4 h, add water and extract with EtOAc. Combine the organic layers, dry over sodium sulfate, filter and concentrate under reduced pressure to give a residue. Purify the residue by flash chromatography (Silica gel-EtOAc/hexane 1:12), to provide 4′-bromo-biphenyl-2-ylamine (3.53 g, 69%). MS (m/e): 248 (M+1); 249 (M+2).
Reaction SMILES: [C:1]([S:4][CH2:5][C:6]1[NH:7][C:8]([CH3:32])=[C:9]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([F:26])([F:25])[F:24])[C:11]=1C(OCC)=O)(=[O:3])C.Cl>C(O)C>[CH3:32][C:8]1[NH:7][C:6]2[CH2:5][S:4][C:1](=[O:3])[C:11]=2[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([F:26])([F:25])[F:24])[C:9]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)C1=C(C)NC(CSC(C)=O)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC2=C(C(=O)SC2)C1c1ccccc1C(F)(F)F

Procedure:
10 mmol of diethyl 2 -acetylthiomethyl-6-methyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylate, dissolved in 40 ml of ethanol, are boiled with 6 ml of saturated ethanolic HCl for 2 hours and the product is precipitated with water and then recrystallized from ethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])[C:7]2=[O:12].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[CH:22][C:21]=1[F:30].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CN(C)C=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:16]([NH:15][CH2:14][CH2:13][N:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:27](=[O:28])[CH2:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[C:21]([F:30])[CH:22]=2)[C:7]1=[O:12])(=[O:18])[CH3:17]
Reactant: O=C(O)Cc1ccc(Cl)c(F)c1
Reactant: CC(=O)NCCn1ccc2c(N)cccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)NCCn1ccc2c(NC(=O)Cc3ccc(Cl)c(F)c3)cccc2c1=O
Temperature: 50 °C

Procedure:
Into a 20 ml reaction vial was combined N-(2-(5-amino-1-oxoisoquinolin-2(1H)-yl)ethyl)acetamide (20 mg, 0.00008 mol), 2-(4-chloro-3-fluorophenyl)acetic acid (30.55 mg, 0.0001620 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (72.66 mg, 0.0001911 mol) N,N-diisopropylethylamine (61.6 μL, 0.000353 mol), and N,N-dimethylformamide (1 mL, 0.02 mol). The mixture was heated at 50° C. for two hours, allowed to cool and poured onto sat sodium bicarbonate (200 ml). The mixture was extraced with methylene chloride (3×100 ml). The combined extracts were dried over sodium sulfate and reduced in vacuo. The mixture was purified by reverse phase prep HPLC using an acetonitrile:water gradient at pH 10. The combined pure fractions were reduced in vacuo to yield the compound as an off white solid.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:29]=[CH:30][CH:31]=3)[O:23][CH2:24][C:25]([O:27]C)=[O:26])[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:29]=[CH:30][CH:31]=3)[O:23][CH2:24][C:25]([OH:27])=[O:26])[S:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)COc1cccc(CCc2nc(-c3ccccc3)c(-c3ccccc3)s2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)COc1cccc(CCc2nc(-c3ccccc3)c(-c3ccccc3)s2)c1
Reaction time: 0.33 h
Yield: 79 %

Procedure:
A mixture of methyl [3-[2-(4,5-diphenyl-2-thiazolyl)ethyl]phenoxy]acetate (2.70 g, 6mmol), 5N NaOH solution (3.77mL, 18mmol) and methanol (40 mL) was heated to reflux on a steam bath. After 20 minutes, the mixture was cooled, the methanol removed and the residue diluted with water and 2N HCl solution. The precipitate was filtered off, washed with water and dried in air. Recrystallization from a mixture of CH2Cl2 and hexanes provide [3-[2-(4,5-diphenyl-2-thiazolyl)ethyl)phenoxy]acetic acid (1.97 g, 75%), mp 118°-120° C.
Reaction SMILES: C([O:5][C:6](=[O:31])[CH2:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([NH:27][C:28]([NH2:30])=[O:29])=[C:12]([CH2:25][CH3:26])[N:13]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:25]([C:12]1[N:13]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:14]2[C:10]([C:11]=1[NH:27][C:28]([NH2:30])=[O:29])=[C:9]([O:8][CH2:7][C:6]([OH:31])=[O:5])[CH:17]=[CH:16][CH:15]=2)[CH3:26]
Reactant: CCc1c(NC(N)=O)c2c(OCC(=O)OC(C)(C)C)cccc2n1Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1c(NC(N)=O)c2c(OCC(=O)O)cccc2n1Cc1ccccc1
Yield: 46.1 %

Procedure:
A solution of [[2-ethyl-1-(phenylmethyl)-3-ureido-1H-indol-4-yl]oxy]acetic acid tert-butyl ester (0.2 g) and trifluoroacetic acid (0.3 mL) in 5 mL of methylene chloride was stirred at room temperature for 18 hours. After concentrating to dryness, the resulting solid was slurried in ether, filtered and air dried to give 0.08 g of titled compound. Mass spectrum: 368.
Reaction SMILES: [CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[S:20][C:19]=2[CH2:29][CH3:30])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31][NH:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36]>>[CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[S:20][C:19]=2[CH2:29][CH3:30])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([N:32]([CH3:31])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:14])=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCc1sc(C2CCCCC2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CCOC(=O)CCNC
Product: CCc1sc(C2CCCCC2)cc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 42.9 %

Procedure:
An operation similar to that in Example 69 (9) was performed using 4-[cyclohexyl(5-cyclohexyl-2-ethylthiophen-3-yl)methoxy]benzoic acid (200 mg) synthesized in Example 77 (4) and ethyl 3-(methylamino)propanoate (73.8 mg) to give the title compound (103 mg, 43%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:13]([O-])=O)[C:11]=1[CH3:12])[N:8]=[CH:7][NH:6][C:5]2=[O:16]>CCO>[NH2:13][C:10]1[C:11]([CH3:12])=[CH:2][CH:3]=[C:4]2[C:9]=1[N:8]=[CH:7][NH:6][C:5]2=[O:16]
Reactant: Cc1c(Br)cc2c(=O)[nH]cnc2c1[N+](=O)[O-]
Solvent: CCO
Product: Cc1ccc2c(=O)[nH]cnc2c1N
Reaction time: 96 h

Procedure:
6-Bromo-7-methyl-8-nitroquinazolin-4(3H)-one (4.8 g, 17 mmol) was suspended in EtOH (500 ml) and degassed using a vacuum line. The mixture was then evacuated with nitrogen and 10% Pd/C (1.4 g) was added under a positive flow of nitrogen. The reaction was then placed under a hydrogen atmosphere with a large balloon while stirring. After 4 days, the reaction was filtered through a pad of celite. The filtrate was reduced under vacuum and the residue was triturated with ether to give 8-amino-7-methylquinazolin-4(3H)-one as an off white solid. MS Found: (ESI pos. ion) m/z 176 (M+H+).
Reaction SMILES: OO.[OH:3][N:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][C:7](=[O:12])[CH2:6][C:5]1([CH3:14])[CH3:13].CS(O)(=O)=O.[CH2:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2].CO>[CH:20]1([O:3][N:4]2[C:9]([CH3:10])([CH3:11])[CH2:8][C:7](=[O:12])[CH2:6][C:5]2([CH3:14])[CH3:13])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C1CCCCC1
Reactant: CC1(C)CC(=O)CC(C)(C)N1O
Agent: [Fe+2]
Agent: CS(=O)(=O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CO
Product: CC1(C)CC(=O)CC(C)(C)N1OC1CCCCC1
Yield: 35 %

Procedure:
A solution of 20.1 g (0.295 mol) of 50% aqueous hydrogen peroxide is added over 6 hours at 60° C. to a mixture of 8.51 g (50.0 mmol) of 1-oxyl-2,2,6,6-tetramethylpiperid-4-one, 0.70 g (2.5 mmol) of iron(II) sulfate heptahydrate, 0.3 ml (5 mmol) of methanesulfonic acid, 11 ml of cyclohexane, and 90 ml of methanol. Shortly after the addition is completed, the reaction mixture tests negative for hydrogen peroxide. The reaction mixture is concentrated to afford 4.4 g (35% yield) of the title compound, isolated as a yellow oil. Structure is confirmed by mass spectrometry and NMR analysis.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].CI.[CH3:19]C(C)=O>O>[CH3:19][O:1][C:2]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: CC(C)=O
Reactant: Cc1ccc(O)c(C(=O)c2ccccc2)c1
Solvent: CI
Solvent: O
Product: COc1ccc(C)cc1C(=O)c1ccccc1
Yield: 71.5 %

Procedure:
To a solution of 5.00 g (23.5 mmole) 2-hydroxy-5-methyl-benzophenone and 6.67 g (47.1 mmole) methyliodide in 50 ml abs. acetone 4.50 g (32.6 mmole) potassium carbonate are added. The reaction mixture is then heated for 5 hours with recycling. Following cooling, 50 ml water and 50 ml petroleum ether (30/60) are added to the suspension. The organic phase is separated off, the aqueous phase is extracted twice with 75 ml petroleum ether (30/60) and the purified organic phase is washed twice with 50 ml 10% NaOH solution. The organic phase is then dried through magnesium sulphate and the solvent is removed. 3.80 g (16.8 mmole, 71%) 2-methoxy-5-methyl-benzophenone are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([CH3:20])=[CH:17][CH:18]=3)[C:13]([CH:21]=[O:22])=[CH:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:23]([O-:25])=[O:24].[BH4-].[Na+].Cl>CO.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([CH3:20])=[CH:17][CH:18]=3)[C:13]([CH2:21][OH:22])=[CH:12]2)(=[O:9])=[O:10])=[CH:4][C:3]=1[N+:23]([O-:25])=[O:24]
Reactant: Cc1ccc2c(c1)c(C=O)cn2S(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)c(CO)cn2S(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reaction time: 0.5 h

Procedure:
To the solution of 1-(4-chloro-3-nitro-benzenesulfonyl)-5-methyl-1H-indole-3-carbaldehyde (284.10 mg, 0.75 mmol) in the mixture of methanol/THF (1:1, 20 mL), NaBH4(32 mg, 0.825 mmol) was added slowly at 0° C. After addition, the reaction was stirred for additional 30 min at same temperature. 1.0 ml of 1N HCl was added after reaction was completed, as determined by checking using thin layer chromatography (TLC). The resulting reaction mixture was concentrated, and the residue was diluted with water (20 ml) and extracted with ethyl acetate (3×10 ml). The combined organic layers was washed with water, 10% NaHCO3, and brine, dried with MgSO4, filtered and concentrated. The residue was purified with column chromatography to give pure product, OSU-A9M (248.5 mg, 87%) as off white solid.
Reaction SMILES: N[C:2]1C=C2C(C=CC(S(O)(=O)=O)=C2)=CC=1.[Na:16].[H-].[Na+].[C:19]([NH:29][C:30]1[CH:39]=[C:38]2[C:33]([CH:34]=[CH:35][C:36]([S:40]([OH:43])(=[O:42])=[O:41])=[CH:37]2)=[CH:32][CH:31]=1)([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].CI>CN(C=O)C>[C:19]([NH:29][C:30]1[CH:39]=[C:38]2[C:33]([CH:34]=[CH:35][C:36]([S:40]([OH:43])(=[O:42])=[O:41])=[CH:37]2)=[CH:32][CH:31]=1)([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20].[C:19]([N:29]([CH3:2])[C:30]1[CH:39]=[C:38]2[C:33]([CH:34]=[CH:35][C:36]([S:40]([OH:43])(=[O:42])=[O:41])=[CH:37]2)=[CH:32][CH:31]=1)([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20].[Na:16]
Reactant: Nc1ccc2ccc(S(=O)(=O)O)cc2c1
Agent: O=C(Nc1ccc2ccc(S(=O)(=O)O)cc2c1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C(=O)OCc1ccccc1)c1ccc2ccc(S(=O)(=O)O)cc2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
N-Cbz-7-Aminonaphthalene-2-sulfonic acid, sodium salt is prepared as described in EXAMPLE 39, Part A using 7-aminonaphthalene-2-sulfonic acid, sodium salt (3 g, 12.2 mmol) in place of 6-aminonaphthalene-2-sulfonic acid, sodium salt. A 60% dispersion of sodium hydride (0.21 g, 5.27 mmol) in mineral oil is washed with hexanes twice, suspended in 20 mL of DMF and the resulting suspension is cooled to 0° C. To this mixture is added the crude N-Cbz-7-aminonaphthalene-2-sulfonic acid, sodium salt (1 g, 2.64 mmol) in 15 mL of DMF. The reaction mixture is stirred for 10 min at 0° C. and then treated with methyl iodide (0.49 mL, 7.92 mmol). The resulting mixture is allowed to warm to room temperature with stirring overnight. The reaction mixture is worked up according to the similar procedure used in EXAMPLE 32, Part A to yield the crude N-Cbz-7-methylaminonaphthalene-2-sulfonic acid, sodium salt (0.88 g) as a beige solid. A mixture of the sulfonic acid, sodium salt (0.88 g, 2.23 mmol) is chlorinated as described in EXAMPLE 32, Part A. The crude product is purified by column chromatography in a gradient of 10% EtOAc/hexanes to 30% EtOAc/hexanes to afford the title compound (0.38 g, 0.97 mmol) as a beige solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=S)[CH2:11][CH2:10]3)[CH:2]=1.[CH:18]([NH:20][NH2:21])=O.C1(O)CCCCC1.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>CS(C)=O>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]2[CH:18]=[N:20][N:21]=[C:12]2[CH2:11][CH2:10]3)[CH:2]=1
Reactant: NNC=O
Reactant: S=C1CCc2cc(-c3cccnc3)ccc2N1
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: OC1CCCCC1
Product: c1cncc(-c2ccc3c(c2)CCc2nncn2-3)c1
Temperature: 25 °C

Procedure:
A flask containing the title compound from Example 1 Step B (20 mg, 0.08 mmol), formic hydrazide (6.0 mg, 0.10 mmol) and cyclohexanol (0.50 ml, 0.08 mmol) was heated to reflux for 6 hours. The reaction was cooled to room temperature, diluted with dimethylsulfoxide, acidified with trifluoroacetic acid and passed through a syringe filter. Purification by reverse phase HPLC (C18 column, 10 to 100% acetonitrile/water, both 0.1% v/v trifluoroacetic acid) provided the title compound: LCMS m/z 249.16 [M+H]+; 1H NMR (500 MHz, CD3OD) δ 9.90 (s, 1H), 9.30 (d, J=2.0 Hz, 1H), 9.01 (ddd, J=1.5, 1.9, 8.2 Hz, 1H), 8.93 (d, J=5.6 Hz, 1H), 8.23 (dd, J=5.8, 8.2 Hz, 1H), 8.10-8.07 (m, 2H), 8.02 (dd, J=1.9, 8.4 Hz, 1H), 3.46-3.43 (m, 2H), 3.38-3.35 (m, 2H).
Reaction SMILES: [CH:1]([NH:3][CH:4]1[C:15](=[O:16])[N:6]2[CH:7]([C:12]([OH:14])=[O:13])[C:8](=[CH2:11])[CH2:9][S:10][C@H:5]12)=[O:2].[C:17]1([C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N+]=[N-])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)(=O)C>[CH:1]([NH:3][CH:4]1[C:15](=[O:16])[N:6]2[CH:7]([C:12]([O:14][CH:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:13])[C:8](=[CH2:11])[CH2:9][S:10][C@H:5]12)=[O:2]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: C=C1CS[C@@H]2C(NC=O)C(=O)N2C1C(=O)O
Solvent: CCOC(C)=O
Product: C=C1CS[C@@H]2C(NC=O)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
7-Formamido-3-methylenecepham-4-carboxylic acid (1.570 g) was added to a solution (0.93M, 8.36 l) of diphenyldiazomethane in ethyl acetate by portions. The mixture was stirred at 45° C. for 1 hour and evaporated in vacuo. The residue was triturated with diisopropyl ether to give benzhydryl 7-formamido-3-methylenecepham-4-carboxylate (2.337 g).