Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@@H:10]([N:11]2[CH2:15][CH2:14][C@H:13]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=4)[N:20]=[CH:19][N:18]=3)[C:12]2=[O:31])[CH2:9][CH2:8][C@@H:7]([NH:32]C(=O)OC(C)(C)C)[CH2:6]1)(=[O:3])[CH3:2].[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>ClCCl>[NH2:32][C@H:7]1[CH2:6][C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[C@@H:10]([N:11]2[CH2:15][CH2:14][C@H:13]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]([F:29])([F:30])[F:28])[CH:25]=4)[N:20]=[CH:19][N:18]=3)[C:12]2=[O:31])[CH2:9][CH2:8]1.[C:42]([OH:44])([C:41]([F:46])([F:45])[F:40])=[O:43]
Reactant: CC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N[C@@H]1C[C@H](N)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirring solution of tert-butyl (1R,3R,4S)-3-acetamido-4-((S)-2-oxo-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-1-yl)cyclohexylcarbamate (1.65 g, 3 mmol) in dichloromethane (8 mL) was charged with trifluoroacetic acid (4 mL). The reaction was stirred for 1 h at room temperature and concentrated in vacuo. The residue was dissolved in a mixture of 1 mL of methanol and 5 mL of dichloromethane. The resulting solution was added dropwise to 80 mL of t-butylmethylether with stirring. The solid formed was collected with filtration and dried to give the title compound as its TFA salt (1.75 g, 86%). LC/MS found [M+H]+=451. 1H-NMR (400 MHz, CD3OD), δ ppm: 8.82 (1H, s), 8.77 (1H, s), 8.20-8.27 (1H, m), 7.95 (1H, d, J=8.65 Hz), 5.32 (1H, t, J=9.92 Hz), 4.36 (1H, t, J=4.07 Hz), 4.16-4.23 (1H, m), 3.87 (1H, t, J=9.16 Hz), 3.70-3.79 (1H, m), 3.39 (1H, s), 2.54-2.67 (1H, m), 2.32-2.45 (1H, m), 2.08-2.23 (2H, m), 1.88-2.04 (6H, m), 1.73-1.87 (1H, m).
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].O.C(=O)([O-])[O-].[K+].[K+].Cl[C:12]1[C:22](Cl)=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]([CH3:24])[C:13]=1[C:25]1[O:29][N:28]=[C:27]([CH3:30])[CH:26]=1>CN(C=O)C>[CH2:1]([S:3][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]([CH3:24])[C:13]=1[C:25]1[O:29][N:28]=[C:27]([CH3:30])[CH:26]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(Cl)c(Cl)c(-c2cc(C)no2)c1C
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(SCC)c(-c2cc(C)no2)c1C
Temperature: 0 °C
Yield: 43.2 %

Procedure:
Into a 250-ml round-bottomed flask were placed 0.311 g of ethyl mercaptan, 0.018 g of water and 6 ml of DMF, and then 0.346 g of potassium carbonate and 0.314 g of ethyl 4,5-dichloro-2-methyl-3-(3-methylisoxazol-5-yl)benzoate were adder The resulting mixture was stirred with a magnetic stirrer at room temperature for 6 hours under the irradiation of 40W fluorescent light. The reaction solution was poured into 25 ml of ice-water, and extracted with 25 ml of diethyl ether. The organic layer was washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained crude product was purified on silica gel column chromatography (elution with n-hexane/ethyl acetate=95/5) to give 0.132 g of the title compound as white crystals. Melting point: 39-40° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.[CH:8]([N:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][N:30]=[C:29](S(C)(=O)=O)[N:28]=2)=[CH:23][C:22]1=[O:37])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CC(N(C)C)=O.O>[CH:8]([N:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([NH:7][CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[N:28]=2)=[CH:23][C:22]1=[O:37])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NC1CCOCC1
Reactant: CS(=O)(=O)c1nccc(-c2ccn(C(c3ccccc3)c3ccccc3)c(=O)c2)n1
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=c1cc(-c2ccnc(NC3CCOCC3)n2)ccn1C(c1ccccc1)c1ccccc1
Temperature: 120 °C
Yield: 55.2 %

Procedure:
Tetrahydro-2H-pyran-4-amine (0.20 g, 2.0 mmol) was added to 1-benzhydryl-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one (0.12 g, 0.29 mmol) in DMA (3 mL) in a microwave vial. The mixture was heated at 120° C. for 1 hour in a microwave. The reaction mixture was diluted with water and extracted with EtOAc. The EtOAc was washed with water, twice with brine, dried over MgSO4, filtered, and evaporated to yield a crude product (0.09 g) as a film. This was chromatographed on a 10 g Biotage SNAP column with EtOAc. Fractions 9-20 contained a film (0.0764 g). This was triturated with water, dried, then triturated with hexane and dried to afford the desired 1-benzhydryl-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.072 g, 0.16 mmol, 57% yield) as a film. 1H NMR (400 MHz, CDCl3) δ 8.38 (d, 1H), 7.52 (s, 1H), 7.40-7.15 (m, 9H), 6.91 (d, 1H), 6.76-6.72 (m, 1H), 5.25-5.21 (m, 1H), 4.15-4.06 (m, 1H), 4.02-3.96 (m, 2H), 3.59-3.51 (m, 2H), 2.09-2.03 (m, 2H), 1.62-1.52 (m, 2H); m/z (APCI-pos) M+1=439.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:12]=[CH2:13])=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2.[H][H]>CN(C=O)C.[Pd]>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][CH3:13])=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2
Reactant: [H][H]
Reactant: C=Cc1ccc(N)c2c1CNC2=O
Agent: [Pd]
Solvent: CN(C)C=O
Product: CCc1ccc(N)c2c1CNC2=O
Yield: 102.8 %

Procedure:
7-Amino-4-vinylisoindolinone (50.0 mg, 0.287 mmol) was dissolved in DMF (2.5 mL), and the solution was added with 10% Pd—C (10 mg) followed by stirring at room temperature for 1.8 hours under normal pressure and hydrogen atmosphere. The reaction mixture was filtered using Celite and the solvent of the filtrate was evaporated under reduced pressure to obtain 7-amino-4-ethylisoindolinone (52.0 mg, quantitative).
Reaction SMILES: [C:1]([CH:5]1[CH2:14][C:13]2[C:8](=[C:9]([O:17]C)[CH:10]=[CH:11][C:12]=2[O:15]C)[CH2:7][S:6]1)([O:3][CH3:4])=[O:2]>CC#N.O>[C:1]([CH:5]1[CH2:14][C:13]2[C:12](=[O:15])[CH:11]=[CH:10][C:9](=[O:17])[C:8]=2[CH2:7][S:6]1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C1Cc2c(OC)ccc(OC)c2CS1
Solvent: CC#N
Solvent: O
Product: COC(=O)C1CC2=C(CS1)C(=O)C=CC2=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
To a stirred solution of isothiochroman from step 1 above (253 mg, 0.94 mmol) in 3 ml of CH3CN was added dropwise a solution of ceric ammonium nitrate (1.550 g, 283 mmol) in 3 ml of H2O. The reaction mixture was stirred at 0° C. for 10 minutes and then at room temperature for 10 minutes, followed by extraction with CH2Cl2 (10 ml×3). The combined organic layers were washed with brine and water, dried over MgSO4, and then concentrated to a yellow residue (213 mg, 0.89 mmol) in 95% yield, which was found to be pure by H1NMR. 1H NMR (300 MHz, CDCl3) d:2.90 (m, 2H, HCHa,eCHC=O), 3.56 (m, 2H, HCHae--S), 3.73 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 3.75 (m, 1H, HC--S), 6.75 (m, 2H, ArH). 13C NMR (75.44 MHz, CDCl3) δ:22.2, 26.0, 37.4, 52.8, 136.2, 137.0, 140.0, 140.5, 172.0 (CO ester), 185.8, 187.0 (CO quinones). IR: (neat) 2956, 1736, 1658, 1607, 1442, 1409 cm-1.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[N:20]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:21]3[C:26]([N:27]=2)=[CH:25][N:24]=[CH:23][N:22]=3)[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][N:12]2[CH2:13][CH2:14][CH:15]([NH:18][C:19]3[N:20]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[C:21]4[C:26]([N:27]=3)=[CH:25][N:24]=[CH:23][N:22]=4)[CH2:16][CH2:17]2)=[CH:5][CH:6]=1
Reactant: c1ccc(Cn2c(NC3CCNCC3)nc3cncnc32)nc1
Reactant: COc1ccc(CCCl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CCN2CCC(Nc3nc4cncnc4n3Cc3ccccn3)CC2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A mixture of 2 parts of 1-(2-chloroethyl)-4-methoxybenzene, 3.1 parts of N-(4-piperidinyl)-9-(2-pyridinylmethyl)-9H-purin-8-amine, 1.5 parts of sodium carbonate and 45 parts of N,N-dimethylformamide was stirred overnight at 70° C. The reaction mixture was poured into water. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 2.2 parts (50%) of N-[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]-9-(2-pyridinylmethyl)-9H-purin-8-amine; mp. 144.5° C. (compound 74).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Cu](C#N)[C:10]#[N:11]>CN(C)C=O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]#[N:11])=[N:3][CH:4]=1
Reactant: Cc1ccc(Br)nc1
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Product: Cc1ccc(C#N)nc1
Temperature: 50 °C

Procedure:
36 g (209 mmol) 2-Bromo-5-methylpyridine and 37.5 g (418 mmol) copper cyanide are refluxed for two hours in 500 ml dimethylformamide. After cooling down to 50° C., 10% aqueous armnoia solution (500 ml) is added with stirring. The product is extracted with dichloromethane, the organic phase is dried over magnesium sulfate, and the solvent is removed in vacuo. The product is purified by column chromatography (silica, eluent cyclohexane/ethyl acetate 9:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:11]([C:21]3[CH:26]=[CH:25][C:24]([S:27](C)(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[NH3:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:11]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:31])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2cccc(Cl)c2)c1=O
Reactant: N
Product: CC(C)CCOc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2cccc(Cl)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(3-chlorophenyl)-4-(3-methylbutoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 339) in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 0.575 g, 18%). mp 137-139° C. 1H NMR (300 MHz, DMSO d6) δ 0.81 (d, J=7 Hz, 6H), 1.49 (m, 2H), 1.57 (m, 1H), 4.42 (t, J=7 Hz, 2H), 7.44-7.65 (m, 5H), 7.76 (m, 1H), 7.84 (m, 2H), 7.94 (m, 2H), 8.20 (s, 1H). MS (DCI/NH3) m/z 448 (M+H)+, 465 (M+NH4)+. Anal. calc. for C21H22ClN3O4S: C, 56.31; H, 4.95; N, 9.38. Found C, 56.02; H, 4.82; N, 9.31.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:40]2[N:41]=[N:42][NH:43][N:44]=2)=[C:33]2[C:37]=1[C:36](=[O:38])[N:35]([CH3:39])[CH2:34]2>>[CH3:39][N:35]1[C:36](=[O:38])[C:37]2[C:33](=[C:32]([C:40]3[N:44]=[N:43][NH:42][N:41]=3)[CH:31]=[CH:30][C:29]=2[NH:28][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([CH2:17][P:18](=[O:25])([O:19][CH2:20][CH3:21])[O:22][CH2:23][CH3:24])=[CH:26][CH:27]=3)[N:3]=2)[CH2:34]1
Reactant: CN1Cc2c(-c3nn[nH]n3)ccc(N)c2C1=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4nn[nH]n4)c4c3C(=O)N(C)C4)n2)cc1)OCC

Procedure:
The title product was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate and 7-amino-2-methyl-4-(2H-tetrazol-5-yl)-2,3-dihydro-1H-isoindol-1-one (Compound 181A). MS (ES+): m/z 618.33 (100) [MH+]; HPLC: tR=1.13 min (UPLC, purity).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6].[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6]
Reactant: N#Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc([N+](=O)[O-])c(Oc2ccccc2Br)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.5 %

Procedure:
To a solution of 3-fluoro-4-nitrobenzonitrile (6.3 g; 37.93 mmol) and 2-bromophenol (4.4 mL; 37.94 mmol) in DMF (50 mL) was added potassium carbonate (6.29 g; 45.51 mmol). The mixture was stirred for 5 h at rt. Water (100 mL) was added, and a precipitate formed. The solid was separated via filtration, washed with water, and dried to yield 11.20 g (92.5%) of 3-(2-bromo-phenoxy)-4-nitrobenzonitrile, 1a.
Reaction SMILES: C(OC([CH2:8][NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([C@@H:23]([OH:32])[C@H:24]([O:29][CH2:30][CH3:31])[C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1)=O)(C)(C)C.C([SiH](CC)CC)C.C(OCC)(=O)C.[OH-].[Na+]>FC(F)(F)C(O)=O>[CH2:30]([O:29][C@@H:24]([C@H:23]([OH:32])[C:20]1[CH:21]=[CH:22][C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][NH:9][CH3:8])[CH:12]=2)=[CH:18][CH:19]=1)[C:25]([O:27][CH3:28])=[O:26])[CH3:31]
Reactant: CCO[C@H](C(=O)OC)[C@H](O)c1ccc(-c2cccc(CNCC(=O)OC(C)(C)C)c2)cc1
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCO[C@H](C(=O)OC)[C@H](O)c1ccc(-c2cccc(CNC)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 120.7 %

Procedure:
21 g (47.3 mmol) of methyl (2S,3R)-3-{3′-[(tert-butoxycarbonylmethylamino)methyl]biphenyl-4-yl}-2-ethoxy-3-hydroxypropionate, 8.76 ml (54.9 mmol) of triethylsilane in 300 ml of trifluoroacetic acid are introduced into a round-bottomed flask and under a nitrogen stream. The reaction medium is stirred for 4 hours at room temperature. Ethyl acetate is then added and the mixture is neutralized with sodium hydroxide. The organic phase is washed with a saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and evaporated off. 19.6 g (100%) of the expected crude product are obtained.
Reaction SMILES: I[C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:24]#[N:25])[C:8]=2[NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH:3]=1.[CH:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)=[O:27].O>C(=O)(O)[O-].[Na+].COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:26]([C:28]1[CH:33]=[CH:32][C:31]([C:2]2[S:10][C:9]3[C:4](=[N:5][CH:6]=[C:7]([C:24]#[N:25])[C:8]=3[NH:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)[CH:3]=2)=[CH:30][CH:29]=1)=[O:27]
Reactant: COc1cc(Nc2c(C#N)cnc3cc(I)sc23)cc(OC)c1OC
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4ccc(C=O)cc4)sc23)cc(OC)c1OC
Yield: 93.8 %

Procedure:
A mixture of 2-iodo-7-[(3,4,5-trimethoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile (500 mg, 1.07 mmol), 4-formylphenylboronic acid (240.7 mg, 1.61 mmol), tetrakis(triphenylphosphine)palladium(0) (61.8 mg, 0.054 mmol) in 16 mL of saturated aqueous sodium bicarbonate and 20 mL of ethylene glycol dimethyl ether is heated at reflux for 3 h. After cooling, the mixture is treated with water. The precipitate is filtered, washed with water, ethyl acetate, and ether, then dried in vacuo to provide 447.2 mg of 2-(4-formylphenyl)-7-[(3,4,5-trimethoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile as a yellow solid, mp 268–270° C.; 1H NMR (DMSO-d6) δ 3.73 (s, 3H), 3.75 (s, 6H), 6.69 (s, 2H), 7.94 (d, J=8 Hz, 2H), 8.00 (d, J=8 Hz, 2H), 8.10 (s, 1H), 8.64 (s, 1H), 9.64 (s, 1H), 10.00 (s, 1H); HRMS 446.11691 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:9])[CH2:5][CH:6]([CH3:8])[CH3:7])C.[Li+].CC([N-]C(C)C)C.Cl[CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[CH3:7][CH:6]([CH3:8])[CH:5]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:4]([OH:9])=[O:3]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)CC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)C(COCC[Si](C)(C)C)C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-methylbutyric acid ethyl ester (1.3 g, 10 mmol) in THF (50 mL) is added dropwise LDA solution (2 M in THF/hexane/ethylbenzene, 6 mmol) at −78° C., and the mixture is stirred at −78° C. After 0.5 h, to the reaction mixture is added (2-chloromethoxyethyl)trimethylsilane (2.65 mL, 15 mmol) at −78° C. The reaction mixture is allowed to warm to 0° C. 2 h and then quenched by addition of 100 mL of 5% aqueous KHSO4 and extracted with Et2O (200 mL). The organic phase is successively washed with 5% aqueous KHSO4, 5% aqueous NaHCO3, H2O, and brine, then dried over Na2SO4 and concentrated in reduced pressure. A mixture of the residue and 1M aqueous NaOH in MeOH is stirred at 70° C. After 5 h at 70° C., the reaction mixture is quenched by 5% aqueous KHSO4 (100 mL) and extracted with Et2O (200 mL). The organic phase is successively washed with H2O, and brine, then dried over Na2SO4. The solution is filtered and the solvent is evaporated in vacuo to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=3)[CH:9]=2)=[C:4]([O:24][CH3:25])[CH:3]=1>C1COCC1.CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=3)[CH:9]=2)=[C:4]([O:24][CH3:25])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1ccnc(Nc2cccc([N+](=O)[O-])c2)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(F)ccc1-c1ccnc(Nc2cccc(N)c2)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of C2 (98 mg, 0.29 mmol) in THF/MeOH 1:1 (20 mL) was added Pd/C (10% w/w, 46 mg). The reaction mixture was stirred under hydrogen atmosphere (1 atm) at RT for 15 hours. The suspension was filtered through a pad of Celite® and the solvent was removed in vacuo to leave the desired product I1 as a brown solid (89 mg, 99%). MS (ES) C18H16FN3O requires: 309. found: 310 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:11]=2)[C:6](=[O:33])[C:5]([C:34]([O:36]C)=[O:35])=[N:4]1)[CH3:2].O.[K]>CO>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:10]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH:11]=2)[C:6](=[O:33])[C:5]([C:34]([OH:36])=[O:35])=[N:4]1)[CH3:2]
Reactant: CCn1nc(C(=O)OC)c(=O)c2cc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Agent: [K]
Solvent: O
Solvent: CO
Product: CCn1nc(C(=O)O)c(=O)c2cc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a suspension of methyl 1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydrocinnoline-3-carboxylate (3 g, 5.95 mmol) in a mixed solvent of water (25.00 mL) and methanol (75 mL) was added potassium hydtoxide (1.668 g, 29.7 mmol). The mixture was stirred at room temperature for 0.5 h and then heated to reflux for 1 h when the yellow suspension turned into a clear yellow solution. LCMS indicated completion of the reaction. The mixture was cooled to room temperature and concentrated. The residue was dissolved in water (100 mL), and was then acidified to ˜pH 1 using aq. 6N hydrochloric acid. The white precipitates were collected by filtration, and the filtrate was extracted with ethyl acetate (2×100 mL). The combined organic layers were concentrated to provide more white solids that were combined with previous white precipitates and dried under high vacuum to afford 1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydrocinnoline-3-carboxylic acid (2.8 g, 5.71 mmol, 96% yield). LCMS: (M+H)+: 491.4.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH:17]([C:19]1[NH:20][C:21]([CH3:29])=[CH:22][C:23]=1[CH2:24][CH2:25][C:26]([OH:28])=[O:27])=O>>[CH3:29][C:21]1[NH:20][C:19]([CH:17]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[NH:11][C:10]2=[O:16])=[C:23]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH:22]=1
Reactant: Cc1cc(CCC(=O)O)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Product: Cc1cc(CCC(=O)O)c(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)[nH]1

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 3-(2-formyl-5-methyl-1H-pyrrol-3-yl)-propionic acid to give the title compound.
Reaction SMILES: [S:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18]OS(C)(=O)=O)[O:15][C:14]3=[O:24])=[CH:9][C:8]=2[F:25])[CH2:3][CH2:2]1.[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C)C=O.C(OCC)(=O)C>[S:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][N:26]=[N+:27]=[N-:28])[O:15][C:14]3=[O:24])=[CH:9][C:8]=2[F:25])[CH2:3][CH2:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(C3=CCSCC3)c(F)c2)C(=O)O1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC[C@H]1CN(c2ccc(C3=CCSCC3)c(F)c2)C(=O)O1
Temperature: 25 °C

Procedure:
Methanesulfonic acid (5R)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl ester (8 g, 19.7 mmol) and sodium azide (4 g, 61.5 mmol) were heated in N,N-dimethylformamide (75 ml) at 80° C. for 2 hours. It was cooled to room temperature, diluted with ethyl acetate, washed with potassium phosphate buffer (pH 7) and with water and dried over sodium sulfate. After evaporation of the solvent the title product was obtained as a brown oil (˜7 g, crude).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([OH:19])[C:12]([C:20]2[C:24]([F:25])=[C:23]([Si](C)(C)C)[O:22][C:21]=2[CH2:30][O:31][Si](C(C)(C)C)(C)C)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([OH:19])[C:12]([C:20]2[C:24]([F:25])=[CH:23][O:22][C:21]=2[CH2:30][OH:31])=[CH:11][CH:10]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc(-c2c(CO[Si](C)(C)C(C)(C)C)oc([Si](C)(C)C)c2F)c1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc(-c2c(F)coc2CO)c1O
Yield: 78.8 %

Procedure:
A solution of methyl 6-bis-(tert-butoxycarbonyl)amino-3-[2-(-tert-butyldimethylsilanyloxymethyl)-4-fluoro-5-trimethylsilanylfuran-3-yl]-2-hydroxybenzoate (Intermediate 100, 3.66 g) in a 1M solution of tetrabutylammonium fluoride in THF (30 mL) was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate and washed with water, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 10-50% to give methyl 6-bis-(tert-butoxycarbonyl)amino-3-(4-fluoro-2-hydroxymethylfuran-3-yl)-2-hydroxybenzoate (2.08 g) as a white solid.