Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([CH2:15][OH:16])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CS(C)=O.C(N(CC)CC)C>O>[CH2:1]([C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:15]=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cc(CO)ccc1OC
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCc1cc(C=O)ccc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A crude product of (3-hexyl-4methoxyphenyl)methanol, dimethyl sulfoxide (DMSO, 1.5 ml) and triethylamine (0.46 ml, 3.3 mmol) were mixed in a stream of argon. To this solution was added sulfur trioxide-pyridine complex (159 mg, 1 mmol) under ice-cooling, and the mire was stirred at room temperature for 1 hour. This reaction mixture was poured into water (20 ml) to stop the reaction. The aqueous layer was extracted 3 times with ethyl acetate (20 ml). The organic layer was washed successively with 2N hydrochloric acid (20 ml), water (20 ml) and saturated brine (30 ml). This solution was dried over anhydrous magnesium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (hexane/ethyl acetate=1/1) to give 3-hexyl-4-methoxybenzaldehyde (75.4 mg, 92% in 2 steps) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])([O-:3])=[O:2].CN(C)C=O>C1(C)C=CC=CC=1>[C:6]([O:14][C:13](=[O:15])[C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[CH:7]=1)([CH3:13])([CH3:7])[CH3:5]
Reactant: O=C(O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Reaction time: 0.75 h
Yield: 248.8 %

Procedure:
To a suspension of 5-nitro-isophthalic acid (5.0 g, 23.7 mmol) in dry toluene (100 ml) at 110° C. was added dimethylformamid di-t-butylacetale (3.4 ml, 71 mmol) drop wise over 60 min. Heating was continued for 45 min and the reaction mixture was left at Rt over night. The precipitated starting material was removed by filtration. The filtrate was concentrated to give a yellow oil (7.88 g). This was purified by flash chromatography using EtOAc/Hept 1:2 and EtOAc/Hept 1:2+5% AcOH in two portions to give the title compound in 38% yield (2.38 g)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]([OH:13])=O.[NH2:14][C@@H:15]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:17]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:16]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]([NH:14][C@@H:15]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[C@H:17]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:16]1)=[O:13]
Reactant: O=C(O)c1n[nH]c2ccc(F)cc12
Reactant: COC(=O)C[C@@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Product: COC(=O)C[C@@H]1C[C@H](NC(=O)c2n[nH]c3ccc(F)cc23)CN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 7 from 5-fluoro-1H-indazole-3-carboxylic acid (J. Heterocyclic Chem. 1964, 1, 239) and tert-butyl (2S,4S)-4-amino-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate (step 4 of Example 9).
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]3[S:16][CH:15]=[C:14]([CH2:17][C:18]4[CH:22]=[CH:21][S:20][CH:19]=4)[C:11]=3[S:12][CH:13]=2)=[CH:4]1.[CH2:23](Br)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].O>C1COCC1>[S:20]1[CH:21]=[CH:22][C:18]([C:17]([C:14]2[C:11]3[S:12][CH:13]=[C:9]([C:8]([C:5]4[CH:6]=[CH:7][S:3][CH:4]=4)([CH2:7][CH2:6][CH2:5][CH2:8][CH2:9][CH2:10][CH2:11][CH3:14])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:10]=3[S:16][CH:15]=2)([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19]1
Reactant: CCCCCCCCBr
Reactant: c1cc(Cc2csc3c(Cc4ccsc4)csc23)cs1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCC(CCCCCCCC)(c1ccsc1)c1csc2c(C(CCCCCCCC)(CCCCCCCC)c3ccsc3)csc12

Procedure:
To a suspension of sodium hydride in THF is added a THF solution of 3,6-bis(thiophen-3-ylmethyl)thieno[3,2-b]thiophene. Octyl bromide is then added and the mixture is refluxed until reaction completion, as determined by TLC. The reaction is then poured into cold water, extracted with MTBE and combined organic phases are washed with water. After drying the organic phase with magnesium sulfate and filtering through Buchner the solvent is evaporated. The resulting product can be purified by column chromatography.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:11](Br)[CH3:12].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH2:11]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1)[CH3:12]
Reactant: Oc1ccc2cc[nH]c2c1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOc1ccc2cc[nH]c2c1
Reaction time: 18 h

Procedure:
6-Hydroxyindole (1.0 equivalents) is dissolved in dry, degassed acetone. EtBr (5.0 equivalents) and Cs2CO3 (2.5 equivalents) are added, and the resulting solution is stirred for 18 hours. The reaction mixture is filtered through a Celite plug. The solvent is evaporated, and the product is purified by flash chromatography (MeOH:CH2Cl2, 5:95) to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1[O:24][CH3:25])[C@H:13]1[NH:23][C@H:12]1[CH2:11]3.[OH-].[K+].C(=O)=O.[CH3:31][CH2:32]OCC>C(O)C=C.C(Cl)(Cl)Cl.CC(C)=O>[C:18](=[O:17])([OH:19])[NH2:20].[OH:17][CH2:16][CH:15]1[C:6]2[C:4](=[O:5])[C:3]([O:24][CH2:25][CH:31]=[CH2:32])=[C:2]([CH3:1])[C:8](=[O:9])[C:7]=2[N:10]2[CH2:11][CH:12]3[NH:23][CH:13]3[C:14]12[O:21][CH3:22]
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Reactant: CCOCC
Agent: O=C=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: C=CCO
Solvent: ClC(Cl)Cl
Product: C=CCOC1=C(C)C(=O)C2=C(C1=O)C(CO)C1(OC)C3NC3CN21
Product: NC(=O)O
Yield: 42 %

Procedure:
A solution of mitomycin A (100 mg or 0.286 mmole) in 4 ml of allyl alcohol was stirred at room temperature and under nitrogen for 45 minutes with 500 mg of a 1.6% solution of potassium hydroxide (KOH) in allyl alcohol. The reaction mixture was decomposed with excess dry ice while immersing the flask into a water bath at room temperature. It was then isolated on a silica gel plate using ether, which elutes the allyl alcohol to the top of the plate (the plate was developed several times), followed by CHCl3 -acetone 1:1 which elutes the product. This procedure gives 45 mg (42%) of the title compound, having a melting point of 106°-111° C. (decomposition) and providing the following analysis:
Reaction SMILES: [F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29](=[S:31])[NH2:30])[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2.CCO.Br[CH2:36][C:37](=O)[C:38]([O:40][CH2:41][CH3:42])=[O:39]>CN(C=O)C>[F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29]3[S:31][CH:36]=[C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:30]=3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2
Reactant: C[C@@H]1CN2c3c(cc4c(C(N)=S)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)c1csc(-c2noc3c(F)c4c(cc23)CC2(C(=O)NC(=O)NC2=O)[C@H]2[C@H](C)O[C@H](C)CN42)n1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To a stirred solution of (2R,4S,4aS)-rel-11-fluoro-2,4-dimethyl-2′,4′,6′-trioxo-1,1′,2,3′,4,4′,4a,6′-octahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-8-carbothioamide (Intermediate 575, 54 mg, 0.128 mmol) in mixture of EtOH:DMF (1 mL: 0.5 mL) were added ethyl bromopyruvate (47 mg, 0.24 mmol) and molecular sieves, and the mixture was stirred at 100° C. for 12 hours. The reaction mixture was concentrated, the residue was purified by silica gel column chromatography to give product as solid. Yield: 13 mg (20%).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3([OH:20])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[NH:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=2)=[O:23])=[CH:4][CH2:3]1.[C:32]([O:36]C)(=[O:35])[CH2:33]O.C(O)(C(F)(F)F)=O.[OH-].[K+]>C(Cl)Cl>[C:29]([C:26]1[NH:25][C:24]([C:22]([NH:21][C:9]2[CH:10]=[CH:11][C:12]([C:14]3([O:20][CH2:33][C:32]([OH:36])=[O:35])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:13][C:8]=2[C:5]2[CH2:6][CH2:7][C:2]([CH3:31])([CH3:1])[CH2:3][CH:4]=2)=[O:23])=[N:28][CH:27]=1)#[N:30]
Reactant: CC1(C)CC=C(c2cc(C3(O)CCOCC3)ccc2NC(=O)c2ncc(C#N)[nH]2)CC1
Reactant: COC(=O)CO
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CC=C(c2cc(C3(OCC(=O)O)CCOCC3)ccc2NC(=O)c2ncc(C#N)[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
To a suspension of 5-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(4-hydroxy-tetrahydro-pyran-4-yl)-phenyl]-amide (48.0 mg, 0.114 mmol)(prepared in Example 1, step (h)) in 1 mL of DCM was added methyl glycolate (0.215 mL, 2.78 mmol), TFA (0.036 mL, 0.464 mmol), and the mixture was stirred for 8 h at RT. The mixture was concentrated and the methyl ester of the title compound was eluted from a 10-g SPE column with 50% EtOAc/hexanes. The resulting ester was dissolved in 1 mL of MeOH, 2N KOH (0.30 mL, 0.60 mmol) was added and the mixture stirred for 8 h at RT. The title compound was purified by RP-HPLC on a C18 column eluting with a linear gradient of 30-60% CH3CN in 0.1% TFA/H2O over 12 min to give 13 mg (30%) of a white solid. 1H-NMR (400 MHz, CD3OD): δ 8.34 (d, J=8.6 Hz, 1H), 7.85 (s, 1H), 7.60 (s, 1H), 7.37 (dd, J=8.6, 2.2 Hz, 1H), 7.28 (d, J=2.2 Hz, 1H), 5.79 (m, 1H), 4.03-3.94 (m, 2H), 3.88-3.80 (m, 2H), 3.72 (s, 2H), 2.35-2.27 (m, 2H), 2.13-2.06 (m, 4H), 1.60 (t, J=6.3 Hz, 2H), 1.11 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C26H30N4O5, 477.2 (M−H). found 477.2.
Reaction SMILES: Cl.O1CCOCC1.[F:8][C:9]1[CH:10]=[C:11]([C@@H:33]([NH:35][S@@](C(C)(C)C)=O)[CH3:34])[CH:12]=[CH:13][C:14]=1[C:15]1[S:16][C:17]2[C:22]([N:23]=1)=[CH:21][CH:20]=[C:19]([C:24]1([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:26][CH2:25]1)[N:18]=2>CO>[F:8][C:9]1[CH:10]=[C:11]([C@@H:33]([NH2:35])[CH3:34])[CH:12]=[CH:13][C:14]=1[C:15]1[S:16][C:17]2[C:22]([N:23]=1)=[CH:21][CH:20]=[C:19]([C:24]1([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:25][CH2:26]1)[N:18]=2
Reactant: C[C@H](N[S@](=O)C(C)(C)C)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@H](N)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Hydrogen chloride, 4.0 M solution in 1,4-dioxane (0.63 mL, 2.5 mmol) was added to a suspension of (R)-N-((S)-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide. (0.413 g, 0.84 mmol)) in methanol (60.00 mL). The yellow reaction mixture was allowed to stir at ambient temperature for 4 h. The crude reaction mixture was concentrated in vacuo and purified by silica gel chromatography to afford (S)-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)ethanamine. MS (ESI) m/z: calculated: 389.1; Observed: 390.1 (M++1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[S:21](=[O:23])(=[O:22])[CH2:20][CH2:19][CH2:18][C:9]=2[N:10]=[C:11]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:12]=1)(=O)=O.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][OH:35])=[CH:29][CH:28]=1>>[CH:13]1([C:11]2[N:12]=[C:7]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][OH:35])=[CH:29][CH:28]=3)[C:8]3[S:21](=[O:23])(=[O:22])[CH2:20][CH2:19][CH2:18][C:9]=3[N:10]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Nc1ccc(CCO)cc1
Reactant: O=S1(=O)CCCc2nc(C3CCCC3)nc(OS(=O)(=O)C(F)(F)F)c21
Product: O=S1(=O)CCCc2nc(C3CCCC3)nc(Nc3ccc(CCO)cc3)c21
Yield: 41.3 %

Procedure:
Following general procedure H, 2-cyclopentyl-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl trifluoromethanesulfonate (0.200 g, crude) was reacted with 2-(4-aminophenyl)ethanol (0.034 g, 0.25 mmol) to afford the title compound (0.040 g, 20%) as a white solid. MW=387.50. 1H NMR (DMSO-d6, 500 MHz) δ 8.57 (s, 1H), 7.52 (d, J=8.5 Hz, 2H), 7.21 (d, J=8.5 Hz, 2H), 4.62 (t, J=5.5 Hz, 1H), 3.70-3.65 (m, 2H), 3.63-3.57 (m, 2H), 3.09 (quin, J=8.0 Hz, 1H), 2.93 (t, J=6.5 Hz, 2H), 2.71 (t, J=7.0 Hz, 2H), 2.37-2.29 (m, 2H), 1.99-1.90 (m, 2H), 1.83-1.54 (m, 6H); APCI MS m/z 388 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[N:10][N:9]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:17](Cl)(=[O:19])[CH3:18].Cl>C(Cl)Cl>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:17](=[O:19])[CH3:18])=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[N:10][N:9]=1
Reactant: CC(=O)Cl
Reactant: Oc1ccccc1-c1nnn[nH]1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(O)c(-c2nnn[nH]2)c1
Yield: 39.2 %

Procedure:
A suspension of 16.2 g (0.1 mol) of 5-(2-hydroxyphenyl)-1H-tetrazole in 300 ml of dry methylene chloride is cooled in an ice bath, 39.9 g (0.3 mol) of anhydrous aluminum chloride are added and acetyl chloride 8.1 g (0.1 mol) is added via dropwise addition over a period of 5 minutes. The mixture is refluxed for 3.5 hours, cooled, and 200 ml of 2N HCl is added dropwise with stirring. The resulting precipitate is collected, washed with 2N HCl, water and recrystallized from an isopropanol-water mixture to yield 8.0 g of 1-[4-hydroxy-3-(1H-tetrazol-5-yl)phenyl]ethanone, m.pt. 260°-261° C. (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[C:12]([O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH2:22]1)(=[O:17])[CH2:13][C:14]([CH3:16])=O.[NH2:40]/[C:41](/[CH3:47])=[CH:42]\[C:43]([O:45][CH3:46])=[O:44].[ClH:48]>C(O)(C)C>[OH2:2].[ClH:48].[ClH:48].[CH3:16][C:14]1[NH:40][C:41]([CH3:47])=[C:42]([C:43]([O:45][CH3:46])=[O:44])[CH:6]([C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N+:1]([O-:3])=[O:2])[C:13]=1[C:12]([O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([CH:27]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:23][CH2:22]1)=[O:17]
Reactant: COC(=O)/C=C(/C)N
Reactant: CC(=O)CC(=O)OCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)C1c1ccccc1[N+](=O)[O-]
Product: O
Yield: 11.4 %

Procedure:
A mixture of o-nitrobenzaldehyde, 2-(4-benzhydryl-1-piperazinyl)ethyl acetoacetate and methyl 3-aminocrotonate was worked up in isopropyl alcohol in the same manner as Example 1 and the product was further treated with methanolic hydrogen chloride to give 2-(4-benzhydryl-1-piperazinyl)ethyl methyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate dihydrochloride monohydrate as light yellow crystals, m.p. 162°-164° C. Yield 11.4%.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([OH:12])[CH:5]=[CH:4][C:3]1=2.[H-].[Na+].Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>O1CCCC1>[CH3:1][C:2]1([CH3:13])[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCCc2cc(O)ccc21
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COc1ccc2c(c1)CCCC2(C)C
Yield: 85.3 %

Procedure:
A mixture of 5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-2-ol (2.0 g, 11.3 mmol), 60% sodium hydride (542 mg, 13.2 mmol), tert-butyl bromoacetate (3.3 g, 17 mmol) and tetrahydrofuran (THF) (10 ml) was treated in the same procedure described in Example 3(a) to furnish 2.8 g of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]([S:14]([CH3:17])(=[O:16])=[O:15])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([Cl:12])=[C:7]([Cl:13])[CH:6]=2.C(=O)([O-])[O-].[Cs+].[Cs+].[C:24]1([NH:30][C:31](=[O:34])[NH:32][NH2:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[Cl:13][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][C:8]=1[Cl:12])[N:11]=[C:2]([N:32]([C:31]([NH:30][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:34])[NH2:33])[C:3]([S:14]([CH3:17])(=[O:16])=[O:15])=[N:4]2
Reactant: NNC(=O)Nc1ccccc1
Reactant: CS(=O)(=O)c1nc2cc(Cl)c(Cl)cc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1nc2cc(Cl)c(Cl)cc2nc1N(N)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,6,7-trichloro-2-(methylsulfonyl)quinoxaline (312 mg, 1.0 mmol) in DMF (10 ml) was added caesium carbonate (489 mg, 1.5 mmol) followed by 4-phenylsemicarbazide (182 mg, 1.2 mmol). The reaction was stirred overnight at room temperature. The product was purified by flash column chromatography using ethyl acetate:hexane 1:1 obtaining the title compound as a solid.
Reaction SMILES: C1C(/C=C/C(O)=O)=CC=C(O)C=1.C1C([C@H]2OC3C=C(O)C=C(O)C=3C(=O)C2)=CC=C(O)C=1.[CH:33]1[C:38]([C@H:39]2[O:49][C:48]3[CH:47]=[C:46]([OH:50])[CH:45]=[C:44]([OH:51])[C:43]=3[C:41](=[O:42])[C@@H:40]2[OH:52])=[CH:37][CH:36]=[C:35]([OH:53])[CH:34]=1>>[CH:33]1[C:38]([C:39]2[O:49][C:48]3[CH:47]=[C:46]([OH:50])[CH:45]=[C:44]([OH:51])[C:43]=3[C:41](=[O:42])[C:40]=2[OH:52])=[CH:37][CH:36]=[C:35]([OH:53])[CH:34]=1
Reactant: O=C1c2c(O)cc(O)cc2O[C@H](c2ccc(O)cc2)[C@H]1O
Agent: O=C(O)/C=C/c1ccc(O)cc1
Agent: O=C1C[C@@H](c2ccc(O)cc2)Oc2cc(O)cc(O)c21
Product: O=c1c(O)c(-c2ccc(O)cc2)oc2cc(O)cc(O)c12

Procedure:
We also performed the shake flask experiments in LB medium, under the same conditions as described for the M9 medium. When p-coumaric acid was used as a precursor, naringenin (0.39 mg/lt) and dihydrokaempferol (1.29 mg/lt) accumulated in the fermentation broth but no kaempferol was produced. When caffeic acid was used as a precursor, eriodictyol accumulated at a lower concentration compared to the M9 medium (7.5 μg/lt), while no dihydroquercetin or quercetin was detected. Finally, when cinnamic acid was used, pinocembrin accumulated at a concentration of 0.245 mg/lt and no dihydroflavonol or flavonol was detected.
Reaction SMILES: [OH:1][CH:2]([C:4]1[NH:9][C:8](=[O:10])[C:7]2=[CH:11][N:12]=[C:13]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:6]2[N:5]=1)[CH3:3]>C(Cl)Cl.O=[Mn]=O>[C:2]([C:4]1[NH:9][C:8](=[O:10])[C:7]2=[CH:11][N:12]=[C:13]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:6]2[N:5]=1)(=[O:1])[CH3:3]
Reactant: CC(O)c1nn2c(C3CCOCC3)ncc2c(=O)[nH]1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(=O)c1nn2c(C3CCOCC3)ncc2c(=O)[nH]1
Temperature: 50 °C
Yield: 88.2 %

Procedure:
To a solution of compound 14 (400 mg, 1.6 mmol) in CH2Cl2 (50 mL) was added MnO2 (520 mg, 6 mmol). The mixture was heated at 50° C. overnight. The reaction mixture was filtered and washed with ethyl acetate. The filtrate was concentrated in vacuo to afford compound 15 (370 mg, 86% yield) as a white solid. LC-MS: m/z 263 [M+H]+. 1H NMR (300 MHz, CDCl3): δ 8.99 (br. s, 1H), 7.93 (s, 1H), 4.16˜4.12 (m, 2H), 3.67˜3.59 (m, 2H), 3.54˜3.48 (m, 1H), 2.72 (s, 3H), 2.19˜2.11 (m, 2H), 2.00˜1.96 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[NH:15]C(=O)C)[CH3:3].CC(C)=O.[ClH:23]>>[ClH:23].[ClH:23].[ClH:23].[CH3:1][N:2]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[NH2:15])[CH3:3]
Reactant: CC(=O)Nc1cc(N)ccc1OCCCN(C)C
Agent: Cl
Solvent: CC(C)=O
Product: CN(C)CCCOc1ccc(N)cc1N

Procedure:
57 g of 2-acetylamino-4-aminophenyl γN,N-dimethylaminopropyl ether in 112 ml of hydrochloric acid (d=1.19) are heated for 75 minutes in a boiling water bath. The reaction medium is cooled and 75 ml of acetone are then added. The expected product precipitates in the form of the trihydrochloride, which melts at 236° C. with decomposition.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[H-].[Na+].[Cl:15][C:16]1[C:21]([N:22]([CH3:37])[C:23](=[O:36])[CH2:24][N:25]2[C:29](=[O:30])[C:28]3=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]3[C:26]2=[O:35])=[CH:20][CH:19]=[C:18]([Cl:38])[C:17]=1OS(C)(=O)=O.O.[CH3:45]N(C)C=O>>[Cl:15][C:16]1[C:21]([N:22]([CH3:37])[C:23](=[O:36])[CH2:24][N:25]2[C:29](=[O:30])[C:28]3=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]3[C:26]2=[O:35])=[CH:20][CH:19]=[C:18]([Cl:38])[C:17]=1[CH2:45][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2
Reactant: CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)c(OS(C)(=O)=O)c1Cl
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN4C(=O)c5ccccc5C4=O)c3Cl)c2n1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 8-hydroxy-2-methylquinoline (17.8 g) in N,N-dimethylformamide (89 ml) was added sodium hydride (40% in oil, 4.48 g) under ice-bath cooling, and the mixture was stirred for 40 minutes at ambient temperature. A solution of 2,6-dichloro-1-methylsulfonyloxy-3-[N-methyl-N-(phthalimidoacetyl)amino]benzene (56.1 g) in N,N-dimethylformamide (200 ml) was added thereto under ice-bath cooling, and the mixture was stirred for 70 minutes at ambient temperature. Water (290 ml) was dropwise added thereto, and the resulting precipitate was collected by filtration to give 8-[2,6-dichloro-3-[N-methyl-N-(phthalimidoacetyl)amino]benzyloxy]-2-methylquinoline (57.07 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:12][O-:13].[Na+]>O1CCOCC1.CO.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5]([O:13][CH3:12])=[CH:6][CH:7]=1
Reactant: C[O-]
Reactant: O=C(O)c1nc(Cl)ccc1Cl
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(Cl)c(C(=O)O)n1
Temperature: 85 °C
Reaction time: 14 h

Procedure:
To a solution of 3,6-dichloropyridine-2-carboxylic acid (7.10 mmol 1.36 g) in dioxane (15 mL) was added sodium methoxide (21.31 mmol 1.15 g) in methanol dropwise. The mixture was stirred at 85° C. for 14 h, cooled to rt, and diluted with ethyl acetate and aqueous HCl. The organic layer was washed with water and brine, and dried (MgSO4). Removal of the solvent provided 3-chloro-6-methoxypyridine-2-carboxylic acid which was used in the next step without further purification.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:12][CH:11]([C:13]2[CH:18]=[C:17]([Cl:19])[C:16]([C:20]3[S:21][C:22]4[C:23]([NH:29][C:30]5[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32][N:31]=5)=[N:24][CH:25]=[CH:26][C:27]=4[N:28]=3)=[C:15]([Cl:37])[CH:14]=2)[CH2:10]1)=O)(C)(C)C>>[NH:9]1[CH2:10][CH:11]([C:13]2[CH:18]=[C:17]([Cl:19])[C:16]([C:20]3[S:21][C:22]4[C:23]([NH:29][C:30]5[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32][N:31]=5)=[N:24][CH:25]=[CH:26][C:27]=4[N:28]=3)=[C:15]([Cl:37])[CH:14]=2)[CH2:12]1
Reactant: Cc1cc(Nc2nccc3nc(-c4c(Cl)cc(C5CN(C(=O)OC(C)(C)C)C5)cc4Cl)sc23)ncn1
Agent: Cl
Product: Cc1cc(Nc2nccc3nc(-c4c(Cl)cc(C5CNC5)cc4Cl)sc23)ncn1
Temperature: 40 °C
Yield: 39.6 %

Procedure:
HCl (4N in dioxane, 5 mL) was added to 3-{3,5-dichloro-4-[4-(6-methylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-phenyl}-azetidine-1-carboxylic acid tert-butyl ester (0.062 g, 0.114 mmol). The suspension was heated at 40° C. for 1 hour and then cooled to room temperature. The volatiles were removed under reduced pressure and the resultant residue was triturated with a mixture of EtOAc/DCM and then purified by column chromatography on silica gel eluting with 0-5% 2N NH3/MeOH in DCM to afford the title compound as an off-white solid (20 mg, 40% yield). 1H NMR (400 MHz, CDCl3): δ 8.65 (d, J=1.2 Hz, 1H), 8.46 (d, J=5.6 Hz, 1H), 7.84 (d, J=5.6 Hz, 1H), 7.75 (s, 2H), 7.63 (s, 1H), 3.99-3.90 (m, 1H), 3.85 (t, J=7.6 Hz, 2H), 3.61 (t, J=6.9 Hz, 2H), 2.41 (s, 3H). LCMS (Method C): RT=2.21 min, m/z: 443 [M+H+].