Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:4])(O)=[O:2].[Na+].[F:6][C@H:7]1[C@H:11]([OH:12])[C@@H:10]([CH2:13][OH:14])[O:9][C@H:8]1[C:15]1[N:23]=[C:22]2[C:18](=[N:19][CH:20]=[N:21]2)[C:17]([O:25][CH3:26])([NH2:24])[N:16]=1>O.[Pt]>[F:6][C@H:7]1[C@H:11]([OH:12])[C@@H:10]([CH:13]([C:1]([OH:4])=[O:2])[OH:14])[O:9][C@H:8]1[C:15]1[N:23]=[C:22]2[C:18](=[N:19][CH:20]=[N:21]2)[C:17]([O:25][CH3:26])([NH2:24])[N:16]=1
Reactant: O=C([O-])O
Reactant: COC1(N)N=C([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2F)N=C2N=CN=C21
Agent: [Pt]
Agent: [Na+]
Solvent: O
Product: COC1(N)N=C([C@@H]2O[C@H](C(O)C(=O)O)[C@@H](O)[C@@H]2F)N=C2N=CN=C21
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 40.6 %

Procedure:
A mixture of Pt/C (10%, 15 g (20-30% mol equiv.) as a water slurry) and NaHCO3 (1.5 g, 17.94 mmol) in H2O (500 mL) was stirred at 65° C. under H2 for 0.5 h. The reaction mixture was then allowed to cool, placed under a vacuum and flushed with N2 several times to completely remove all H2. Compound 4 (5.1 g, 17.94 mmol) was then added at room temperature. The reaction mixture was stirred at 65° C. under O2 (balloon) until the reaction was complete by LC-MS (typically 24-72 h). The mixture was cooled to room temperature and filtered. The Pt/C was washed with H2O extensively. The combined filtrates were concentrated to ˜30 mL, and acidified (pH 4) by the addition of HCl (4N) at 0° C. A black solid precipitated out which was collected by filtration. The crude product was dissolved in a minimum amount of Methanol and filtered through a pad of silica gel (eluting with Methanol). The filtrate was concentrated and crystallized from water to give compound 5 (2.5 g) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[I-].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]([CH3:34])[C:26](N2C=C[N+](C)=C2)=[O:27])=[CH:21][CH:20]=1>ClCCl>[Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:26](=[O:27])[N:25]([C:22]3[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=3)[CH3:34])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccc(Cl)cc1
Agent: [I-]
Solvent: ClCCl
Product: CN(C(=O)Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared from 4-(3,5-dichloro-pyridin-2-yloxy)-phenol and 3-[(4-chlorophenyl)-methyl-carbamoyl]-1-methyl-3H-imidazol-1-ium iodide. The crude product was subjected to flash chromatography (Quad flash 12, dichlormethane (67%). HPLC-MS m/z=422.9 (M+1), Rt: 5.5 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[NH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(N(CC)CC)C>C(#N)C>[Cl:8][C:4]1[N:3]=[C:2]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CCOC(=O)CN
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1cncc(Cl)n1
Temperature: 80 °C
Yield: 48.8 %

Procedure:
To 2,6-dichloropyrazine (50 g, 336 mmol) and ethyl 2-aminoacetate (34.6 g, 336 mmol) was added triethylamine (140 mL, 1007 mmol) and acetonitrile (350 mL). The reaction was heated at 80° C. for 3 d. Precipitated triethylamine salts were removed by filtration and washed with ethyl acetate and hexane (1:1) multiple times. The filtrate and wash solvent were combined and concentrated. The resulting white-yellow precipitate was filtered and washed with 20% ethyl acetate in hexane to afford an off-white solid. The filtrate was subjected to the same process to give an additional batch of off-yellow solid. The batches were combined to afford the title compound (35.5 g, 164 mmol, 49% yield). MS (ESI) m/z 216.1 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[CH:7][CH:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O[NH:50][C:51]([C:53]1[C:54]2[CH:55]=[CH:56][N:57]=[CH:58][C:59]=2[CH:60]=[CH:61][CH:62]=1)=[NH:52]>CN(C=O)C>[F:14][C:2]([F:1])([F:15])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([C:11]2[O:13][N:52]=[C:51]([C:53]3[CH:62]=[CH:61][CH:60]=[C:59]4[C:54]=3[CH:55]=[CH:56][N:57]=[CH:58]4)[N:50]=2)=[CH:7][CH:6]=1
Reactant: N=C(NO)c1cccc2cnccc12
Reactant: O=C(O)c1ccc(OCC(F)(F)F)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: FC(F)(F)COc1ccc(-c2nc(-c3cccc4cnccc34)no2)cn1
Temperature: 120 °C
Yield: 14.1 %

Procedure:
6-[(2,2,2-Trifluoroethyl)oxy]-3-pyridinecarboxylic acid (Fluorochem; 130 mg, 0.642 mmol) was stirred in DMF (1 ml) with HATU (244 mg, 0.642 mmol) and DIPEA (0.28 ml, 1.605 mmol) at room temperature for 30 mins before adding a solution of N-hydroxy-5-isoquinolinecarboximidamide (D1, 100 mg, 0.535 mmol) in DMF (1 ml). The resulting mixture was heated to 120° C. for 30 mins in a Biotage Initiator microwave. The solvent was removed under vacuum, and the residue was purified by column chromatography on silica, eluting with 0-60% ethyl acetate in cyclohexane. The relevant fractions were combined and concentrated under vacuum to give the title compound as a white solid (28 mg).
Reaction SMILES: Cl.C([SiH2][O:7][C:8](C)(C)[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[CH:19]=[N:20][N:21]3[CH:26]=[CH:25][CH:24]=[N:23][C:22]=23)=[O:17])=[C:11]([O:27][CH3:28])[CH:10]=1)(C)(C)C.O.[OH-].[Na+]>ClCCl>[OH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[CH:19]=[N:20][N:21]3[CH:26]=[CH:25][CH:24]=[N:23][C:22]=23)=[O:17])=[C:11]([O:27][CH3:28])[CH:10]=1
Reactant: COc1cc(C(C)(C)O[SiH2]C(C)(C)C)ccc1NC(=O)c1cnn2cccnc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1cc(CO)ccc1NC(=O)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of hydrochloric acid (1 M in Et2O, 3 mL) was added to a solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [4-(tert-butyl-dimethyl-silanyloxymethyl)-2-methoxy-phenyl]-amide (150 mg, 0.364 mmol) in dichloromethane (20 mL) and the resulting mixture was stirred at room temperature for 2 hours. Ice and water were then added and the pH of the mixture was neutralized by addition of an aqueous solution of sodium hydroxide (5%). The resulting mixture was extracted 3 times with dichloromethane. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography and by preparative TLC to give a yellow solid which was washed with water, methanol, dichloromethane, hexane and diethyl ether to give after drying pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (4-hydroxymethyl-2-methoxy-phenyl)-amide as a light yellow solid. MS=299 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[CH:3]1[C:8]([CH2:9][C@@H:10]([NH2:14])[C:11](O)=[O:12])=[CH:7][CH:6]=[C:5]([F:15])[CH:4]=1.II.CO>C1COCC1>[F:15][C:5]1[CH:4]=[CH:3][C:8]([CH2:9][C@@H:10]([NH2:14])[CH2:11][OH:12])=[CH:7][CH:6]=1
Reactant: N[C@H](Cc1ccc(F)cc1)C(=O)O
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: N[C@@H](CO)Cc1ccc(F)cc1
Temperature: 0 °C
Yield: 78.4 %

Procedure:
To the solution of sodium borohydride (0.48 g, 13.1 mmol) in THF (10 mL) was added D-4-fluorophenylalanine (1.0 g, 5.5 mmol). After cooling to 0° C., the solution of iodine (1.4 g, 5.5 mmol) in THF (10 mL) was added dropwisely. The mixture was stirred at reflux for 18 h. after cooling to the room temperature, methanol (7 mL) was added to stop the reaction. After removal of solvent, 20% potassium hydroxide (50 mL) was added. The mixture was stirred for 4 h and extracted with methylene chloride (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 0%-10% methanol in methylene chloride in 30 min afforded (R)-2-(4-fluoro-phenyl)-1-hydroxymethyl-ethylamine (0.73 g, 79%).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15][O:16][C:17](=[O:25])[NH:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][OH:24])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1COCC1.[Cl:33][CH2:34][CH2:35][CH2:36][CH2:37]I>CCCCCCC.C(OCC)(=O)C>[CH:11]1[C:12]2[C:7](=[CH:6][C:5]3[C:14]([C:13]=2[CH2:15][O:16][C:17](=[O:25])[NH:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:37][CH2:36][CH2:35][CH2:34][Cl:33])=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(NCCOCCO)OCc1c2ccccc2cc2ccccc12
Reactant: ClCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=C(NCCOCCOCCCCCl)OCc1c2ccccc2cc2ccccc12
Reaction time: 0.08 h
Yield: 31.4 %

Procedure:
A 50 ml round bottom flask was charged with [2-(2-Hydroxyethoxy)-ethyl]-carbamic acid anthracen-9-ylmethyl ester (0.25 g, 0.74 mmol) and fresh sodium hydride, 60% dispersion in mineral oil (150 mg, 3.75 mmol) under inert atmosphere. 10 ml anhydrous THF was added and the reaction allowed to stir for 5 minutes. After this point, 1-chloro-4-Iodobutane (180 μl, 1.5 mmol) is added via syringe. The reaction is stirred at room temperature for 24 hours. Silica gel 60 is co-absorbed onto the reaction mixture with loss of solvent under reduced pressure. Silica gel column chromatography takes place initially with heptane as eluent, followed by 10%, 20%, and 30% ethyl acetate. A total of 0.1 g (32% yield) of product is isolated from appropriate fractions: 1H NMR (CDCl3) δ 8.50 (s, H-10), 8.40 (d, H-1, 8), 8.03 (d, H-4, 5), 7.53 (dt, H-2,3,6,7), 6.15 (s, CH2-anth), 5.19 (m, exchangeable, NH), 3.93-3.32 (m, 12H) 1.69-1.25 (m, 4H). Mass spectrum, m/e Calcd for C24H28ClNO4.H2O: 447.18 (100.0%); 448.18 (27.1%). Found: 447.17; 448.41.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:18])([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[C:8]([NH:10][C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH:7]=[CH:6][C:5]=1[O:18][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])([O-:3])=[O:2]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
A solution of 5-1 (5 g, 19.7 mmol) in DMF (125 mL) was treated with cesium carbonate (3.17 g, 9.73 mmol), stirred for 10 minutes and treated with ethyl bromoacetate (2.2 mL, 19.8 mmol) at room temperature. After 1.5 hours the solution was concentrated under high vacuum and the residue was absorbed to silica gel and chromatographed in a gradient of 20 to 30% EtOAc/hexanes to give 5-2 as a bright yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([NH:10][C:11]2[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13]3[C:19]4[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[CH:22][C:20]=4[S:21][C:12]=23)=[C:4]([CH3:29])[CH:3]=1.[Cl-].[NH4+]>CO.[Fe]>[NH2:26][C:24]1[CH:23]=[CH:22][C:20]2[S:21][C:12]3[C:13](=[N:14][CH:15]=[C:16]([C:17]#[N:18])[C:11]=3[NH:10][C:5]3[CH:6]=[C:7]([O:8][CH3:9])[C:2]([Cl:1])=[CH:3][C:4]=3[CH3:29])[C:19]=2[CH:25]=1
Reactant: COc1cc(Nc2c(C#N)cnc3c2sc2ccc([N+](=O)[O-])cc23)c(C)cc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COc1cc(Nc2c(C#N)cnc3c2sc2ccc(N)cc23)c(C)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
A mixture of 476 mg (1.12 mmol) of 4-(4-chloro-5-methoxy-2-methylphenylamino)-8-nitrobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile, 180 mg (3.22 mmol) of iron powder and 180 mg (3.36 mmol) of ammonium chloride in 20 mL of 50% aqueous methanol is heated at reflux temperature for 2 hours. An additional 80 mg (1.42 mmol) of iron powder and 100 mg (1.87 mmol) of ammonium chloride are added and the reaction mixture is heated at reflux temperature for 2 hours, then stirred at room temperature overnight. The reaction mixture is heated at reflux for 4 hours then cooled slightly and filtered. The solid residue is extracted with several portions of hot ethyl acetate followed by hot methanol. All the organic layers are combined and washed with water. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography eluting with a gradient of 1:1 hexane/ethyl acetate to only ethyl acetate to give 165 mg (37%) of a tan solid, mp 266-268° C. dec.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:17]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:18]=1.C(O)C.[N+](C(OCC)=O)(C(OCC)=O)=[N-]>C(OCC)(=O)C>[CH2:17]([O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:18]
Reactant: N#Cc1ccc(O)c(Oc2ccccc2)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOc1ccc(C#N)cc1Oc1ccccc1
Yield: 88.6 %

Procedure:
To a stirred solution of the product of step 2 (0.742 g, 3.51 mmol), triphenylphosphine (1.01 g, 3.85 mmol) and ethanol (0.25 mL, 4.29 mmol) in ethyl acetate (12 mL) was added, dropwise, diethyl diazodicarboxylate (0.61 mL, 3.87 mmol). After 4 hours the reaction solution was diluted with ethyl acetate and washed with aqueous sodium bicarbonate solution. The organic layer was dried (sodium sulfate) and concentrated. The resulting gum was purified by flash chromatography over silica (hexanes/ethyl acetate) to afford 0.744 g (89%) of product as a white solid: 1H NMR (CDCl3) δ7.40 (dd, J=8.4, 2.0 Hz, 1H), 7.37-7.31 (m, 2H), 7.17 (d, J=2.0 Hz, 1H), 7.13 (t, J=7.4 Hz, 1H), 7.03-6.92 (m, 3H), 4.13 (q, J=7.1 Hz, 2H), 1.37 (t, J=7.1 Hz, 3H) ppm.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([N:11]3[CH2:19][C:18]4[C:13](=[C:14]([Cl:20])[CH:15]=[CH:16][CH:17]=4)[C:12]3=[O:21])=[CH:9][N:8]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:49]2[CH:54]=[CH:53][C:52]([S:55]([CH:58]3[CH2:63][CH2:62][N:61]([C:64]([O:66]C(C)(C)C)=[O:65])[CH2:60][CH2:59]3)(=[O:57])=[O:56])=[CH:51][CH:50]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[Cl:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[C:12](=[O:21])[N:11]([C:10]1[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:49]4[CH:50]=[CH:51][C:52]([S:55]([CH:58]5[CH2:59][CH2:60][N:61]([C:64]([O:66][C:13]([CH3:18])([CH3:14])[CH3:12])=[O:65])[CH2:62][CH2:63]5)(=[O:56])=[O:57])=[CH:53][CH:54]=4)[N:3]=3)[N:8]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:9]=1)[CH2:19]2
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: O=C1c2c(Cl)cccc2CN1c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12
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: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(-c3cnc4c(n3)c(N3Cc5cccc(Cl)c5C3=O)cn4C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)CC1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
2-(2-bromo-5-trityl-pyrrolo[2,3-b]pyrazin-7-yl)-7-chloro-isoindolin-1-one (150 mg, 0.2476 mmol), tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfonylpiperidine-1-carboxylate (112 mg, 0.2476 mmol) and Na2CO3 (371 μL of a 2.0 M aqueous solution, 0.7428 mmol) combined in 1,4-dioxane (3 mL) under N2. Mixture de-gassed (×3 vacuum-N2 cycles) then Pd(PPh3)4 (14 mg, 0.01238 mmol) added. Reaction mixture de-gassed (×3 cycles) and stirred overnight at 110° C. Reaction cooled and partitioned between DCM and water. Aqueous phase extracted with DCM and combined organics dried and concentrated. Residue purified by chromatography (silica, 0-100% EtOAc-petroleum ether gradient elution). Title compound obtained as a yellow solid (186 mg, 88%), taken directly on to deprotection reaction; MS (ES+) 850.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[CH:18]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH2:19]>CC(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:19][CH2:18][S:20]([CH3:23])(=[O:22])=[O:21])[CH2:14][CH2:13]1
Reactant: C=CS(C)(=O)=O
Reactant: COc1ccc([N+](=O)[O-])cc1N1CCNCC1
Solvent: CC(C)O
Product: COc1ccc([N+](=O)[O-])cc1N1CCN(CCS(C)(=O)=O)CC1
Temperature: 25 °C
Yield: 69 %

Procedure:
The compound was synthesized by heating a solution of 1-[2-(methyloxy)-5-nitrophenyl]piperazine (0.5 g, 2.11 mmol) and methyl vinyl sulfone (0.336 g, 3.16 mmol) in iPrOH (25 mL) to reflux overnight. Reaction was cooled to rt and dried directly onto silica gel. Purified by silica gel chromatography 0-20% MeOH/NH4OH in EtOAc to obtain 0.5 g (69% yield) of the desired compound as a solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 2.6 (m, 4H) 2.7 (t, J=6.8 Hz, 2H) 3.0 (m, 8H) 3.9 (s, 3H) 7.1 (d, J=9.0 Hz, 1H) 7.6 (d, J=2.7 Hz, 1H) 7.9 (dd, J=9.1, 2.8 Hz, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)=[CH:13][C:12]3=[O:26])=[CH:7][N:6]2[C:27]=1[CH3:28].C[Si]([C:33]#[N:34])(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([C:8]3[CH:9]=[CH:10][C:5]4[N:6]([C:27]([CH3:28])=[C:3]([CH2:2][C:33]#[N:34])[N:4]=4)[CH:7]=3)[C:12](=[O:26])[CH:13]=2)=[CH:20][CH:21]=1
Reactant: C[Si](C)(C)C#N
Reactant: Cc1c(CCl)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(CC#N)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cn12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 1-(2-(chloromethyl)-3-methylimidazo[1,2-a]pyridin-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (150 mg) in THF (5 ml) were added trimethylsilyl cyanide (115 μl) and TBAF (1 M in THF, 1.13 ml) at room temperature, and the resulting mixture was stirred at room temperature for 4 h. The reaction mixture was then quenched with saturated FeSO4, and the organic layer was extracted with DCM. The extract was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (60 mg) as a white solid.
Reaction SMILES: [CH2:1]1[C:11]2[C:6](=[C:7]([OH:13])[CH:8]=[C:9]([OH:12])[CH:10]=2)[C:4](=[O:5])[CH2:3][C@H:2]1[OH:14].OC1C2C(=CC=CC=2O)C=C(O)C=1.C(SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(O)(=O)OP(O)(=O)OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1OP(O)(O)=O)(=O)CC(O)=O>>[OH:5][C:4]1[C:6]2[C:11](=[CH:10][C:9]([OH:12])=[CH:8][C:7]=2[OH:13])[CH:1]=[C:2]([OH:14])[CH:3]=1
Reactant: O=C1C[C@@H](O)Cc2cc(O)cc(O)c21
Agent: CC(C)(COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)CC(=O)O
Agent: Oc1cc(O)c2c(O)cccc2c1
Product: Oc1cc(O)c2c(O)cc(O)cc2c1

Procedure:
Biosynthesis of DHN melanin is synthesized by a polyketide pathway, through the genes encoding Polyketide synthase (PKS), Scytalone dehydratase (SCD), and 1,3,8-trihydroxynaphthalene reductase (THN). It started with a PKS using malonyl-CoA as a substrate to produce 1,3,6,8-tetrahydroxynaphthalene, 1,3,6,8-THN (Fujii et al., 2000), followed by reducatse catalysis to produce scytalone, dehydration by SCD to yield 1,3,8-trihydroxynaphthalene (1,3,8-THN), reduction by THN to yield vermelone, dehydration to produce melanin precursor 1,8-dihydroxynaphthalene (1,8-DHN), and then oxidation and polymerization to yield melanin.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I.CCOC(C)=O.O>[I:8][C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]2=[O:9])=[CH:3][CH:4]=1
Reactant: Oc1ccccn1
Reactant: Ic1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=c1ccccn1-c1ccc(I)cc1
Temperature: 130 °C
Yield: 36.2 %

Procedure:
A mixture of 1,4-diiodobenzene 1-1 (4.00 g, 12.1 mmol), 2-hydroxypyridine 1-7 (1.15 g, 12.1 mmol), 8-hydroxyquinoline (176 mg, 1.21 mmol) and K2CO3 (1.74 g, 12.6 mmol) in DMSO (16 mL) was degassed with Ar before being charged with CuI (230 mg, 1.21 mmol). The mixture in a sealed tube was heated at 130° C. overnight. After being cooled to room temperature, H2O and EtOAc were added. It was filtered through celite. The organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel column, eluted with EtOAc in hexanes (0-70% EtOAc) to give 1-(4-iodophenyl)pyridin-2(1H)-one (1.30 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].F[C:16](F)(F)[C:17]([OH:19])=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[CH:30][CH:31]=[C:32]([CH:51]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.C(Cl)(=O)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:17]([N:48]1[CH2:49][CH2:50][N:45]([CH2:44][C:36]2[CH:37]=[CH:38][C:39]3[NH:40][C:41]4[N:42]=[C:26]([NH:27][C:28]5[CH:29]=[CH:30][CH:31]=[C:32]([CH:51]=5)[CH2:33][CH2:34][C:35]=2[CH:43]=3)[N:25]=[CH:24][C:23]=4[Cl:22])[CH2:46][CH2:47]1)(=[O:19])[CH3:16]
Reactant: Clc1cnc2nc1Nc1ccc(CN3CCNCC3)c(c1)CCc1cccc(c1)N2
Solvent: CC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCN(Cc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 52 %

Procedure:
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-12-(piperazin-1-ylmethyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and acetyl chloride as the starting materials in 52% yield. LCMS for C25H28ClN6O (M+H)+: m/z=463.2.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH:16]1([C:21]([OH:23])=O)[CH2:20][CH2:19][CH2:18][CH2:17]1.C([O:31][C:32](=[O:42])[C@H:33]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[NH2:34])C1C=CC=CC=1.C(N1CCOCC1)C>ClCCl.CN(C=O)C>[CH:16]1([C:21]([NH:34][C@H:33]([C:32]([OH:42])=[O:31])[CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:23])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: O=C(O)C1CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)C1CCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A cool solution of 2.06 gm of dicyclohexylcarbodiimide in 10 ml of dichloromethane was added to a solution of 1.4114 gm of cyclopentanecarboxylic acid in 5 ml of dichloromethane at -5° C. It was followed by the addition of 4.28 gm of phenylalanine benzyl ester touluenesulfonate salt in 10 ml of DMF which was neutralized with 1.36 ml of N-ethyl morpholine. The reaction mixture was stirred at 0° C. for one hour and then at room temperature for three hours. Dicyclohexylurea was removed by filtration and 50 ml of ethyl acetate was added to the filtrate. The organic phase was washed until neutral, dried over anhydrous MgSO4 and filtered. The solvent was removed with a rotary evaporator. The residue was crystallized from isopropanol and hexane yielding 2.35 gm of white crystals having a melting point of 88°-89° C. Elemental analysis of these crystals yielded the following.