Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][NH:12][C:11]=3[C:10](=[O:17])[N:9]2[C:18]2[CH:23]=[C:22]([CH3:24])[C:21](=[O:25])[N:20]([CH3:26])[CH:19]=2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH:30]1[CH2:33][O:32][CH2:31]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([CH:30]4[CH2:33][O:32][CH2:31]4)[C:11]=3[C:10](=[O:17])[N:9]2[C:18]2[CH:23]=[C:22]([CH3:24])[C:21](=[O:25])[N:20]([CH3:26])[CH:19]=2)=[CH:4][CH:3]=1
Reactant: IC1COC1
Reactant: Cc1n[nH]c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c(=O)n(C)c1)C2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn(C2COC2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c(=O)n(C)c1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.4 %

Procedure:
To a stirred solution of 4-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Example 27) (100 mg, 0.271 mmol) in DMF (3 mL) was added under Ar NaH (13.01 mg, 0.325 mmol) at 0° C. The reaction mixture was stirred for 30 min at rt. 3-Iodooxetane (0.030 mL, 0.352 mmol) was added. The reaction mixture was stirred for 30 min at rt, quenched with a saturated aqueous solution of sodium bicarbonate (75 mL), and extracted with EtOAc (2×75 mL). The combined organic layers were washed with a saturated aqueous solution of sodium bicarbonate (75 mL), dried on Na2SO4 and evaporated. The residue was purified by silica gel column chromatography (CH2Cl2/MeOH 1-4%), followed by preparative achiral SFC (column: PPU, 250×30 mm, 5 μm, 100 A, Princeton; eluent: MeOH/scCO2; gradient: 1 min 20% MeOH, 20-25% MeOH in 6 min, 25-50% MeOH in 1 min, 1.5 min 50% MeOH; flow: 100 mL/min) to afford 27 mg of 4-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-methyl-1-(oxetan-3-yl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Example 135) and ten fractions containing the impure title compound. These fractions were collected and evaporated to afford after a second SFC purification 16 mg of 4-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-methyl-2-(oxetan-3-yl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(2H)-one (title compound). tR: 0.81 min (LC-MS 2); ESI-MS: 425.1 [M+H]+ (LC-MS 2); Rf=0.25 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.92 (s, 3H) 2.02 (s, 3H) 3.36 (s, 3H) 4.84-5.03 (m, 4H) 5.56-5.69 (m, 1H) 6.12 (s, 1H) 7.14-7.29 (m, 2H) 7.31-7.38 (m, 2H) 7.39-7.42 (m, 1H) 7.73 (d, J=2.74 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-].[C:10]([NH2:14])([CH3:13])([CH3:12])[CH3:11].C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1>C(Cl)Cl.FC1C(F)=C(F)C=CC=1>[Br:1][C:2]1[N:3]=[C:4]([NH:14][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)N
Reactant: [O-][n+]1cccc(F)c1Br
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Agent: Fc1cccc(F)c1F
Solvent: ClCCl
Product: CC(C)(C)Nc1ccc(F)c(Br)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 4.5 %

Procedure:
To a solution of 2-bromo-3-fluoropyridine 1-oxide (511 mg, 2.7 mmol) in DCM (10 mL) and trifluorobenzene (4 mL) at 50° C. were added tert-butylamine (2.5 mL, 23.9 mmol) and p-toluenesulfonic anhydride (3.7 g, 11.4 mmol) portion-wise. The reaction mixture was stirred at 50° C. for 2 hours and then filtered. The filtrate was concentrated to give a residue that was purified by flash chromatography (Si—PPC, Et2O:pentane, gradient 0:100 to 5:95) to give (6-Bromo-5-fluoropyridin-2-yl)-tert-butylamine as a colourless oil (30 mg, 5%). 1H NMR (400 MHz, CHCl3-d): δ 7.13 (dd, J=8.8, 7.3 Hz, 1 H); 6.29 (dd, J=8.8, 2.5 Hz, 1 H); 4.49 (s, 1 H); 1.40 (s, 9 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[CH2:7][C:8](=O)[NH:9][N:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)[C:5]=2[CH:4]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:25].C(OCC)(=O)C.CCCCCC>N1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[CH2:7][C:8](=[S:25])[NH:9][N:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C(c1ccc([N+](=O)[O-])cc1)=NNC(=O)C2
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc2c(c1)C(c1ccc([N+](=O)[O-])cc1)=NNC(=S)C2
Temperature: 100 °C
Reaction time: 2 h
Yield: 172.8 %

Procedure:
4.3 g of 8-methoxy-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepin-4-one is mixed in 48 ml of pyridine with 2.46 g of diphosphorus pentasulfide and stirred under argon and with exclusion of moisture for 2 hours at a bath temperature of 100° C. It is diluted with water, and the precipitated product is suctioned off. After chromatography on silica gel first with ethyl acetate:hexane=1:1 and later with ethyl acetate, a total of 3.13 g of 8-methoxy-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine-4-thione is obtained.
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2].[OH-].[Ca+2:7].[OH-]>>[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Ca+2:7].[Ca+2:7].[Ca+2:7].[P:1]([O-:5])([O-:4])([O-:3])=[O:2]
Reactant: O=P(O)(O)O
Agent: [Ca+2]
Agent: [OH-]
Product: O=P([O-])([O-])[O-]

Procedure:
A hydrated gel of tricalcium phosphate is prepared by slowly adding a solution of phosphoric acid (85% by weight) to a solution of calcium hydroxide (2.0% by weight) and reacted for 30 minutes. A translucent, hydrated precipitate of tricalcium phosphate is formed, which is concentrated by centrifugation. The concentrated gel of tricalcium phosphate is then added to the slurry of soy isolate. The slurry, following addition of the gel has a solids level of 14% by weight and a pH of 7.0±0.05. The gel is added in an amount sufficient to provide a calcium level of 2.6% by weight of the protein solids on a dry basis and the fortified slurry was allowed to equilibrate for 1 hour.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11]C=[N:9][C:8]=2[C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1.Cl.O1CCOCC1>CO>[ClH:1].[NH2:9][CH:8]([C:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:11])[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ncoc1-c1ccc(Cl)s1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)C(N)C(=O)c1ccc(Cl)s1
Temperature: 70 °C
Reaction time: 8 h
Yield: 199 %

Procedure:
To a solution of methyl 5-(5-chlorothiophen-2-yl)oxazol-4-carboxylate (12.6 g) in methanol (150 ml) was added 4N hydrogen chloride-dioxane solution (100 ml) under argon atmosphere, and the mixture was stirred at 70° C. for overnight. The reaction mixture was cooled and the solvent was removed under reduced pressure, and the resulting residue was triturated with acetone to obtain methyl 2-amino-3-(5-chlorothiophen-2-yl)-3-oxo-propionate hydrochloride (13.9 g) as colorless powder.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[C:14]([F:20])=[C:15](F)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.CS(O)(=O)=O.CS(O)(=O)=O.[NH2:37][CH:38]1[CH2:41][NH:40][CH2:39]1>>[NH2:37][CH:38]1[CH2:41][N:40]([C:15]2[C:16]([F:18])=[CH:17][C:10]3[C:11]([C:14]=2[F:20])=[N:12][C:13]2[N:4]([CH:1]4[CH2:2][CH2:3]4)[CH:5]=[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:7](=[O:21])[C:8]=2[CH:9]=3)[CH2:39]1
Reactant: NC1CNC1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Agent: CS(=O)(=O)O
Product: CCOC(=O)c1cn(C2CC2)c2nc3c(F)c(N4CC(N)C4)c(F)cc3cc2c1=O
Yield: 53.8 %

Procedure:
8-(3-Amino-1-azetidinyl)-1-cyclopropyl-3-ethoxycarbonyl-7,9-difluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 2, but starting with 1.3 g of 1-cyclopropyl-3-ethoxycarbonyl-7,8,9-trifluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine and 1.32 g of 3-aminoazetidine dimethanesulphonate. After recrystallization in 50 cm3 of ethanol, 0.8 g of 8-(3-amino-1-azetidinyl)-1-cyclopropyl-3-ethoxycarbonyl-7,9-difluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine is obtained in the form of a yellow solid, melting point 236°-238° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:19]=[C:18]([NH:20]/[C:21](/[NH:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[N:22]\[C:23](=[O:34])[C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[NH:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:36]([NH:35]/[C:21](/[NH:20][C:18]1[NH:17][N:16]=[C:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=2)[CH:19]=1)=[N:22]/[C:23](=[O:34])[C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=1)([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)N/C(=N/C(=O)c1ccc(C(F)(F)F)cc1)Nc1cc(-c2cccc(OCc3ccccc3)c2)n[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)N/C(=N/C(=O)c1ccc(C(F)(F)F)cc1)Nc1cc(-c2cccc(O)c2)n[nH]1
Yield: 54.5 %

Procedure:
(Z)—N-(((3-(3-(Benzyloxy)phenyl)-1H-pyrazol-5-yl)amino)(tert-butylamino)methylene)-4-(trifluoromethyl)benzamide (170 mg) was dissolved in methanol (10 mL) and the solution was degassed with nitrogen. To the solution was added 10% palladium on carbon (34 mg, 0.1 equiv). The mixture was then subjected to hydrogen gas at 30 psi pressure in a Parr shaker. The reaction was checked periodically for completion. Upon completion, the reaction mixture was filtered through celite, and the filtrate was concentrated in vacuo to provide the crude product, which was purified by silica chromatography (9:1 to 55:45 hexanes:EtOAc) to provide the title compound (77 mg, 54% yield). 1HNMR (400 MHz, DMSO-d6) δ 13.18 (s, 1H), 12.79 (s, 1H), 9.63 (s, 1H), 9.02 (s, 1H), 8.28 (d, 2H), 7.82 (d, 2H), 7.23 (m, 1H), 7.18 (m, 1H), 7.09 (m, 1H), 6.79 (m, 1H), 6.49 (s, 1H), 3.98 (m, 1H), 1.95 (s, 1H), 1.56 (s, 9H), 1.12 (m, 1H), 0.82 (m, 1H); MS (EI+) m/z: 445.94, 467.97; HPLC (Method B): 6.08 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].Br[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[O:17]([CH2:16][CH2:15][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:13]=2)[CH:9]=[CH:10]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCCOc1ccccc1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccn(CCOc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.6 %

Procedure:
To a solution of 1H-indole-6-carboxylic acid methyl ester (0.5 g, 2.9 mmol) and 1-(2-bromoethoxy)benzene (0.74 g, 3.7 mmol) in DMF (15 mL) was added K2CO3 (1.2 g, 8.6 mmol). After stirring at room temperature for 16 hr, the mixture was heated to 55° C. for 5 hr then cooled to room temperature and diluted with ethyl acetate (100 ml) and washed with water (3×50 ml). The organic layer was dried (MgSO4), filtered and concentrated. The remaining residue was subjected to flash chromatography (20% ethyl acetate/hexane, then ethyl acetate) to provide 0.63 g (75%) of methyl 1-(2-phenoxyethyl)-1H-indole-6-carboxylate. 1H NMR (300 MHz, DMSO) δ 8.26 (d, 1H, J=1.0 Hz), 7.67-7.62 (m, 3H), 7.23 (td, 2H, J=7.6 Hz, J=1.0 Hz), 6.92-6.84 (m, 3H), 6.55 (dd, 1H, J=3.0 Hz, J=0.6 Hz), 4.66 (t, 2H, J=4.9 Hz), 4.28 (t, 2H, J=4.9 Hz), 3.86 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C:13]2[C:14]([CH2:22][CH3:23])=[N:15][N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=23)[CH2:6][CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.FC1C([I:31])=C(F)C(F)=C(F)C=1F.O.C1COCC1>O1CCCC1>[CH:1]1([CH2:4][N:5]([C:13]2[C:14]([CH2:22][CH3:23])=[N:15][N:16]3[C:21]([I:31])=[CH:20][CH:19]=[CH:18][C:17]=23)[CH2:6][CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1
Reactant: CCc1nn2ccccc2c1N(CC1CCOCC1)CC1CC1
Reactant: Fc1c(F)c(F)c(I)c(F)c1F
Solvent: C1CCOC1
Solvent: O
Product: CCc1nn2c(I)cccc2c1N(CC1CCOCC1)CC1CC1
Reaction time: 0.33 h
Yield: 87.2 %

Procedure:
A solution of N-cyclopropylmethyl-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-tetrahydro-2H-4-pyranylmethylamine (180 g, 574 mmol) in tetrahydrofuran (1620 mL) was cooled with dry ice-ethanol bath. A 1.6M n-butyllithium-hexane solution (538 mL, 854 mmol) was added dropwise to the solution at an internal temperature of from −73° C. to −64.5° C. After stirring the reaction mixture for 1 hour at the same temperature, pentafluoroiodobenzene (115 mL, 861 mmol) was added dropwise. The reaction mixture was additionally stirred for 1 hour and 20 minutes, and then water/THF (1/1, v/v, 360 mL) was added thereto. Cooling was terminated, and then water (3600 mL) and heptane (3600 mL) were added to the reaction mixture, the aqueous layer was removed and the organic extract was washed with water (3600 mL). A 5N aqueous hydrochloric acid solution (1800 mL) was then added to the organic layer and the aqueous layer was separated off. After cooling the aqueous layer in an ice bath and adding a 5N aqueous sodium hydroxide solution (1620 mL), toluene (3600 mL) was further added to the reaction mixture and the organic layer was separated off. The aqueous layer was extracted with toluene (3600 mL), and both organic extracts were combined and concentrated to afford 220 g of the title compound as a dark green oil (87.3% yield)
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH2:15][C:16]1[N:21]=[CH:20][N:19]=[C:18]2[N:22]([CH:26]([C:28]3[CH:35]=[C:34]([CH3:36])[C:31]([C:32]#[N:33])=[C:30]([CH:37]4[CH2:40][NH:39][CH2:38]4)[C:29]=3[O:41][CH3:42])[CH3:27])[N:23]=[C:24]([CH3:25])[C:17]=12.CCN(C(C)C)C(C)C.[CH3:52][C@H:53]1[CH2:55][O:54]1>C(O)C>[NH2:15][C:16]1[N:21]=[CH:20][N:19]=[C:18]2[N:22]([CH:26]([C:28]3[CH:35]=[C:34]([CH3:36])[C:31]([C:32]#[N:33])=[C:30]([CH:37]4[CH2:40][N:39]([CH2:52][C@@H:53]([OH:54])[CH3:55])[CH2:38]4)[C:29]=3[O:41][CH3:42])[CH3:27])[N:23]=[C:24]([CH3:25])[C:17]=12
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(C)c(C#N)c1C1CNC1
Reactant: C[C@H]1CO1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(C)c(C#N)c1C1CN(C[C@H](C)O)C1
Temperature: 90 °C
Yield: 41.3 %

Procedure:
The 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-3-methoxy-6-methylbenzonitrile bis(trifluoroacetate) (0.074 g, 0.10 mmol) was dissolved in ethanol (3.0 mL) and DIPEA (0.071 mL, 0.41 mmol) and the (S)-(−)-methyloxirane (0.0071 g, 0.12 mmol) was added. The reaction was heated in a sealed tube to 90° C. and monitored by LC/MS. After heating for 6 hrs the reaction was purified without workup by prep HPLC on a C-18 column eluting water:acetonitrile gradient buffered pH 10 to give the title compound as a white amorphous solid (0.018 g, 40%). The product was isolated as a single enantiomer. LCMS calculated for C23H30N7O2(M+H)+: m/z=436.2; found: 436.3. 1H NMR (300 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.21 (s, 1H), 6.22 (q, J=7.1 Hz, 1H), 4.34 (d, J=4.5 Hz, 1H), 4.09-3.83 (m, 3H), 3.60 (s, 3H), 3.58-3.51 (m, 1H), 3.12-2.95 (m, 2H), 2.55 (s, 3H), 2.33 (s, 3H), 2.27 (d, J=5.9 Hz, 2H), 1.71 (d, J=7.1 Hz, 3H), 1.00 (d, J=6.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][OH:26])=[CH:20][CH:19]=3)[C:11]3[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][CH:25]=[O:26])=[CH:22][CH:23]=3)[C:11]3[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCCc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CCc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.3 %

Procedure:
To a solution of 2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)phenyl)ethanol (0.175 g, 0.48 mmol) in methylene chloride (10 mL) was added Dess-Martin periodinate (0.304 g, 0.72 mmol). The mixture stirred at rt for 16 h. After this time, the reaction was quenched with water and a saturated solution of Na2S2O3 and then extracted with ethyl acetate. The organic layer were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.114 g, 65%) as an orange oil. MW=363.84. 1H NMR (CDCl3, 500 MHz) δ 9.78 (t, J=2.3 Hz, 1H), 8.40-8.37 (m, 1H), 8.29-8.25 (m, 1H), 7.71 (d, J=8.5 Hz, 2H), 7.41-7.36 (m, 2H), 7.27-7.23 (m, 2H), 6.33 (s, 1H), 3.71 (d, J=2.3 Hz, 2H), 3.04 (t, J=7.5 Hz, 2H), 2.81 (t, J=7.5 Hz, 2H), 2.21 (quin, J=7.5 Hz, 2H); APCI MS m/z 364 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2/[C:12](=[CH:15]/[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)/[C:13]#[N:14].C(=O)=O.C(O)C.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2/[C:12](=[CH:15]/[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)/[C:13]#[N:14]
Reactant: COc1ccc2[nH]cc(/C(C#N)=C/c3cccnc3)c2c1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: CCO
Product: N#C/C(=C\c1cccnc1)c1c[nH]c2ccc(O)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.7 %

Procedure:
To a mixture of (Z)-2-(5-methoxy-1H-indol-3-yl)-3-pyridin-3-yl-acrylonitrile (compound of example 4) (175 mg, 0.6 mmol, 1.0 eq.) in anhydrous dichloromethane (2 mL) cooled to −78° C. (dry ice/ethanol bath) was added, under an argon atmosphere, a 1M boron tribromide solution in dichloromethane (2 mL, 2.0 mmol, 3.2 eq.). The reaction mixture was stirred at ambient temperature for 18 hours and then quenched with ethanol. The solvent was removed under reduced pressure and the residue purified by silica gel flash-column chromatography (eluent: CH2Cl2/MeOH, 95:5 to 93:7) to afford (Z)-2-(5-hydroxy-1H-indol-3-yl)-3-pyridin-3-yl-acrylonitrile as a yellow powder (150 mg, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:29]3[C:28]4[CH2:27][CH2:26][NH:25][CH2:24][C:23]=4[S:22][C:21]=3[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[O:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[O:36][CH2:37][CH2:38][CH:39]=[CH:40][C:41](O)=[O:42].C(N(C(C)C)CC)(C)C>ClCCl.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:29]3[C:28]4[CH2:27][CH2:26][N:25]([C:41](=[O:42])[CH:40]=[CH:39][CH2:38][CH2:37][O:36][CH:31]5[CH2:32][CH2:33][CH2:34][CH2:35][O:30]5)[CH2:24][C:23]=4[S:22][C:21]=3[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: Clc1cc(Nc2ncnc3sc4c(c23)CCNC4)ccc1OCc1ccccn1
Reactant: O=C(O)C=CCCOC1CCCCO1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(C=CCCOC1CCCCO1)N1CCc2c(sc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.2 %

Procedure:
In a 100 ml rb flask were placed [3-chloro-4-(pyridine-2-ylmethoxy)-phenyl]-(5,6,7,8-tetrahydro-9-thia-1,3,7-triaza-fluoren-4-yl)-amine (2.0, 4.71 mmol), 5-(tetrahydro-pyran-2-yloxy)-pent-2-enoic acid (0.94 g, 4.71 mmol) and O-(Benzotriazol-1-yl)-N,N,N′,N′-tetrafluorobonate (1.81 g, 5.66 mmol) in anhydrous dichloromethane/THF (15 ml/15 ml) and cooled at 0° C. To this cooled suspension was slowly added diisopropylethylamine (1.83 g, 14.15 mmol) (2.5 ml) during 15 minute. Then the reaction mixture was warmed to room temperature and stirred at room temperature for 12 hours. The reaction mixture was concentrated at room temperature (no heating) to remove dichloromethane. To the residue was added water and precipitated grey-white solid was filtered and washed with water. The grey-white solid was further suspended in methyl alcohol, sonicated, filtered and dried to provide 2.26 g of grey-white solid. (80.0%). It will be carried to next step reaction without any purification. 1H-NMR (DMSO-d6) δ 8.593-8.575 (m, 1H), 8.391 (s, 1H), 8.191 (s, 1H), 7.872-7.868 (m, 1H), 7.769 (s, 1H) 7.571-7.498 (m, 2H), 7.369-7.329 (m, 1H), 7.236-7.214 (d, 1H), 6.779-6.607 (m, 2H), 5.274 (s, 2H), 4.946-4.835 (d, 2H), 4.572 (s, 1H), 3.928-3.730 (m, 2H), 3.504-3.402 (m, 2H), 3.313-3.204 (m, 4H), 1.673-1.434 (m, 8H). MS m/e 605.9 (M+H), RT=3.02 min
Reaction SMILES: N[C@H:2]([C:8]([OH:10])=O)[CH2:3][CH2:4][C:5]([OH:7])=O.C[CH2:12][O:13]C(C)=O>>[C:8]1([CH:2]=[CH:3][CH:4]=[C:5]([OH:7])[C:12]=1[OH:13])[OH:10]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: CCOC(C)=O
Product: Oc1cccc(O)c1O

Procedure:
Synthesis of pyrogallol subsequently switched to a strategy where gallic acid solutions containing PCA contamination were added to the culture medium of RB791serA::aroB/pSK6.234, which carried plasmid-localized aroY and utilized the same system for plasmid maintenance as KL7/pSK6.161. It was unlear whether protocatechuate decarboxylase expressed in RB791serA::aroB/pSK6.234 would have access to the gallic acid added to the culture medium although this strategy, from the outset, benefited from the knowledge that stationary phase E. coli are more tolerant of catechol's toxicity (Draths, K. M. et al., J. Am. Chem. Soc. 117:2395 (1995)). Accordingly, RB791serA::aroB/pSK6.234 was cultured under fermentor conditions to stationary phase. Gallic acid and PCA were added to the culture medium to give conentrations of 115 mM and 4.5 mM, respectively, followed by termination of glucose addition. Airflow was also terminated and the fermentor was sparged with a continuous flow of N2. Within 14 h (FIG. 8), gallic acid and PCA were converted into a solution containing 112 mM pyrogallol (97%) and 4 mM catechol. Repetition of the decarboxylation with culture supernatant produced by KL7/pSK6.161 resulted in a 93% yield of pyrogallol. The concentrations of DHS, DAH, and glutamic acid remained unchanged. Pyrogallol was isolated from cell-free culture supernatants by extraction with EtOAc. Removal of solvent from the charcoal-decolorized organic layer followed by heating under vacuum to remove catechol contamination afforded pyrogallol as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[N:5][CH:4]=[N:3]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[CH3:16][S:17]([O:8][CH2:7][C:6]1[N:2]([CH3:1])[N:3]=[CH:4][N:5]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1ncnc1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1ncnc1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (1-methyl-1H-1,2,4-triazol-5-yl)methanol (53 mg, 0.47 mmol) in 2 mL of dichloromethane was added triethylamine (0.13 mL, 0.94 mmol), followed by methanesulfonyl chloride (0.044 mL, 0.56 mmol). The mixture was stirred at room temperature for 3 hours, then partitioned between EtOAc and water. The organic layer was washed with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the title product. ESI+MS: 192.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[C:4]([CH3:9])[CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.CN(C)C(=O)N(C)C.CN1CCCC1=O>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH3:10])[CH:13]=2)=[C:4]([CH3:9])[CH:3]=1
Reactant: COc1cccc(O)c1
Reactant: Cc1ccc(Br)c(C)c1
Solvent: CN(C)C(=O)N(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cccc(Oc2ccc(C)cc2C)c1

Procedure:
A mixture of 1,3-dimethyl-4-bromobenzene, 10.5 g. of m-methoxyphenol, 4.65 g. of cuprous oxide, 40 ml. of tetramethylurea, and 75 ml. of N-methylpyrrolidone is stirred at 165° for 96 hours. The resultant mixture is diluted with water and extracted with methylene chloride. The methylene chloride extracts are chromatographed on 300 g. of alumina with gradient elution using hexane:ether to give 1,3-dimethyl-4-(m-methoxyphenyloxy)-benzene.