Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.C(=O)([O-])O.[Na+]>S(Cl)(Cl)=O.C(#N)C.CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(O)c2ccc(C)cc2)cc1
Reactant: C1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: CC#N
Product: Cc1ccc(C(c2ccc(C)cc2)N2CCCC2)cc1
Temperature: 25 °C
Yield: 85.5 %

Procedure:
Compound 14 (0.30 g, 1.41 mmol) was dissolved in thionyl chloride (1 mL) (Wako Pure Chemical Industries, Ltd.), and the mixture was refluxed for 2 hours. The reaction solution was concentrated under reduced pressure, to thereby obtain a residue. The residue was dissolved in acetonitrile (5 mL) (Wako Pure Chemical Industries, Ltd.), and pyrrolidine (0.50 g, 7.03 mmol) was added thereto, and the mixture was refluxed for 2 hours and then allowed to cool to room temperature. A saturated aqueous solution of sodium hydrogen carbonate (Wako Pure Chemical Industries, Ltd.) was added to the reaction solution, and then mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform (Wako Pure Chemical Industries, Ltd.):methanol (Wako Pure Chemical Industries, Ltd.)=99:1 as an eluent), to thereby obtain the title compound (0.32 g, 84% yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[C:22]([N:24]2[CH2:38][C:27]3=[C:28]4[N:33]([N:34]=[C:26]3[CH2:25]2)[C:32]([CH3:35])=[C:31]([Cl:36])[C:30]([CH3:37])=[N:29]4)=[O:23])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:39].O1CCOCC1>O.[OH-].[Na+].C(Cl)Cl.CCOCC>[ClH:36].[ClH:39].[Cl:36][C:31]1[C:30]([CH3:37])=[N:29][C:28]2[N:33]([N:34]=[C:26]3[CH2:25][N:24]([C:22]([C:16]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=4[CH2:14][N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[O:23])[CH2:38][C:27]3=2)[C:32]=1[CH3:35]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1CN1CCN(C(=O)OC(C)(C)C)CC1)C3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1CN1CCNCC1)C3
Temperature: 25 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
4-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-5-fluoro-benzyl]-piperazine-1-carboxylic acid tert-butyl ester (133 mg, 0.21 mmol) was added into a mixture of a 4N solution of HCl in dioxane (2 mL, 8.0 mmol) and water (0.4 mL). After 1 hour of stirring at RT, the reaction mixture was diluted with a 1N aqueous solution of NaOH (15 mL) and extracted with DCM (3×25 mL). The organic layers were combined, dried (Na2SO4) and concentrated under vacuum. After purification by flash chromatography (silica, DCM/EtOH/28% aqueous ammonia), the parent compound was obtained as a white solid. The solid was dissolved in DCM (2 ml), then a 2N solution of HCl in Et2O (0.5 mL) was added, followed by Et2O (2 mL). The precipitate was filtered off, washed with Et2O (3×) and dried under vacuum to give the title compound as a white powder (34 mg, 32%). 1H NMR (D2O) δ 7.76-7.67 (m, 1H), 7.47-7.34 (m, 2H), 5.01 (s, 1H), 4.98 (s, 1H), 4.72 (s, 1H), 4.67 (s, 1H), 4.15 (s, 2H), 3.40-3.21 (m, 8H), 2.80 (s, 1.5H), 2.76 (s, 1.5H), 2.63 (s, 1.5H), 2.57 (s, 1.5H). HPLC (max plot) 99.9%, Rt 2.39 min. UPLC/MS: (MS+) 443.4 ([M+H]+), (MS−) 441.4 ([M−H]−).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C1C=CC=CC=1.[OH2:17]>[Cl-].C([N+](C)(C)C)CCCCCCCCCCC.O.O.[Cu](Cl)Cl.[Ru](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2](=[O:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C=CCCCCCCCC
Reactant: O
Agent: Cl[Cu]Cl
Agent: Cl[Ru]Cl
Agent: CCCCCCCCCCCC[N+](C)(C)C
Solvent: c1ccccc1
Product: CCCCCCCCC(C)=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
A mixture of copper (11) chloride dihydrate [10 mmol] and tris (triphenylphosphine) ruthenium (11) chloride [1.0 mmol] in water [10 ml] was stirred for 10 minutes at room temperature. Then 1-decene [3.51 g, 25 mmol] was added followed by benzene [15 ml] and dodecyltrimethylammonium chloride [2.0 mmol]. Oxygen was bubbled through the solution at 80° C. for 48 hours. After cooling to room temperature, ethyl acetate (15 ml) was added and the solution was filtered. The filtrate was dried using anhydrous magnesium sulphate, and then distilled to provide pure 2-decanone in 64% yield.
Reaction SMILES: [NH:1]1[C:9](=O)[C:8]2[NH:7][CH:6]=[N:5][C:4]=2[N:3]=[CH:2]1.CN(C)C1C=CC=CC=1.[CH3:20][S:21]([OH:24])(=[O:23])=[O:22].P(Cl)(Cl)([Cl:27])=O>>[CH3:20][S:21]([OH:24])(=[O:23])=[O:22].[Cl:27][C:9]1[N:1]=[CH:2][N:3]=[C:4]2[C:8]=1[NH:7][CH:6]=[N:5]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2nc[nH]c12
Agent: CS(=O)(=O)O
Solvent: CN(C)c1ccccc1
Product: Clc1ncnc2nc[nH]c12
Reaction time: 1 h
Yield: 78 %

Procedure:
A mixture of 5 g (0.0368 mole) of hypoxanthine, 12.5 ml of N,N-dimethylaniline and 150 ml of phosphorus oxychloride was refluxed for 40 minutes. Excess phosphorus oxychloride was removed by vacuum distillation with an external oil bath having a temperature below 70° C. and 200 ml of methylene chloride were added to the oily residue. The red methylene chloride solution was cooled in an ice bath and 6 g (0.063 mole) of methanesulfonic acid were added slowly. The mixture was left in an ice bath with stirring for 1 hour and then filtered to give 7.20 g (78% yield) of 6-chloropurine methanesulfonate as a light yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])=O)(C)(C)C.C([O-])(O)=O.[Na+].[OH-].[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[N+:21]([C:19]1[CH:18]=[CH:17][C:16]([C:24]([F:30])([F:29])[C:25]([F:26])([F:27])[F:28])=[C:15]([CH:20]=1)[O:14][CH2:13][C@@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)([O-:23])=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cc([N+](=O)[O-])ccc1C(F)(F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(OC[C@@H]2CCCN2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-(5-nitro-2-pentafluoroethyl-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester in CH2Cl2 (5 mL), TFA (2.5 mL) was added and stirred at RT for 1 h. The mixture was diluted with CH2Cl2 (20 mL) and neutralized with sat NaHCO3 and then 2N NaOH. The mixture was transferred to a seperatory funnel and the layers separated. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with MgSO4, filtered and concentrated in vacuo to yield the title compound as a yellow solid.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:15]([C:19]([F:22])([F:21])[F:20])[O:16]3)=[CH:11][CH:10]=2)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCO.[Pd]>[C:1]1([CH:7]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:15]([C:19]([F:21])([F:22])[F:20])[O:16]3)=[CH:11][CH:10]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(c1ccccc1)c1ccc2c(c1)OC(C(F)(F)F)C(C(=O)OCC)=C2
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1=Cc2ccc(C(C)c3ccccc3)cc2OC1C(F)(F)F
Reaction time: 3 h
Yield: 75 %

Procedure:
A mixture of ethyl 7-(1-phenylvinyl)-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 50a, step 4 (2.13 g, 5.69 mmole) and 10% Pd/C (150 mg) in absolute EtOH (30 mL) was hydrogenated at 30 psi for 3 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. Purification of the crude product by silica chromatography (92.5 hexanes:EtOAc) gave 1.62 g (75% yield) of the product as a colorless oil: EIHRMS m/z 376.1279 (M+, C21H19F3O3, Calc'd 376.1286).
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]([C:13]1[CH:17]=[CH:16][O:15][CH:14]=1)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[C:1]([NH:9][CH:10]([C:11]([C:13]1[CH:17]=[CH:16][O:15][CH:14]=1)=[O:12])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CNC(=O)c1ccccc1)c1ccoc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(NC(=O)c1ccccc1)C(=O)c1ccoc1
Yield: 85.7 %

Procedure:
7.8 g of N-benzoyl-(3-furylcarbonyl)methylamine, 1.6 g of 61% sodium hydride and 6.3 g of ethyl bromoacetate are treated in the same manner as described in Preparation 1-(2). 9.2 g of ethyl 3-benzoylamino-3-(3-furylcarbonyl)propionate are thereby obtained. Yield: 86.0%
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[F:16])=[C:6](Cl)[N:5]2[N:18]=[CH:19][N:20]=[C:4]2[N:3]=1.[F:21][C:22]([F:26])([F:25])[CH2:23][NH2:24].C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[F:16])=[C:6]([NH:24][CH2:23][C:22]([F:26])([F:25])[F:21])[N:5]2[N:18]=[CH:19][N:20]=[C:4]2[N:3]=1
Reactant: Fc1cc(F)c(-c2c(Cl)nc3ncnn3c2Cl)c(F)c1
Reactant: NCC(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cc(F)c(-c2c(Cl)nc3ncnn3c2NCC(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
A mixture of 5,7-dichloro-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine (3.19 g, 10 mmol), 2,2,2-trifluoroethylamine (3.0 g, 30 mmol), and triethylamine (3.0 g, 30 mmol) in 30 mL of N,N-dimethylformamide is stirred at room temperature under nitrogen atmosphere for 1 h. The reaction mixture is diluted with ethyl acetate. The organic layer is washed with saturated sodium chloride (×3), dried over magnesium sulfate, and concentrated. The residue is filtered through hydrous magnesium silicate. Concentration provides 5-chloro-6-(2,4,6-trifluorophenyl)-N-(2,2,2-trifluoroethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine as a light yellow solid (3.70 g). MS: m/z 381.9 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:37])[CH2:34][O:35][CH3:36])[NH:28][C:27](=[O:38])[CH2:26]2>>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:37])[CH2:34][O:35][CH3:36])[NH:28][C:27](=[O:38])[C:26]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: COCC(=O)Nc1cc2c(cc1F)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Product: COCC(=O)Nc1cc2c(cc1F)C(=Cc1[nH]c3c(c1C)C(=O)N(CCN1CCOCC1)CC3)C(=O)N2
Yield: 84.4 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-methoxy-acetamide as starting materials to give N-{5-fluoro-3-[3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-methoxy-acetamide (70 mg, 84.4%) as a brown solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:12]2[CH:11]=[CH:10]N=[N:8][C:7]=2[O:6][CH2:5]1.[Cl:13][C:14]1N=C2OCC(=O)C2=CC=1>>[CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[N:8][C:14]([Cl:13])=[CH:10][CH:11]=2)[O:6][CH2:5]1
Reactant: O=C1COc2nc(Cl)ccc21
Reactant: CON=C1COc2nnccc21
Product: CON=C1COc2nc(Cl)ccc21

Procedure:
This compound was prepared using a method analogous to that of furo[2,3-c]pyridazin-5(6H)-one O-methyl oxime (A.2.3.3), 6-chlorofuro[2,3-b]pyridin-3(2H)-one replacing furo[2,3-c]pyridazin-5(6H)-one;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([O:30]C)=[O:29])=[CH:24][N:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH:10](Cl)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>CO.Cl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][N:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(CSc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3Cl)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(C(=O)O)cn3)c2CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
Dissolve 3-tert-butoxycarbonyl-7-chloro-6-(5-methoxycarbonyl-pyridin-2-ylmethylthio)-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.86 g, 4.03 mmol) in methanol (25 mL). Add 1M aqueous lithium hydroxide (12 mL) and stir at ambient temperature overnight. Remove methanol in vacuo, and dilute the mixture with cold 0.5M aqueous HCl to pH 4. Add brine and extract three times with EtOAc. Dry over anhydrous Na2SO4, and concentrate in vacuo to give the title compound as an off-white solid (1.78 g, 95%). MS (APCI+) m/z 449 (M+H)+, 349 (M+H−Boc)+.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]3([NH:24][C:25](=[O:27])[CH3:26])[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)=[O:2].[C:28]1([CH3:36])[CH:33]=[CH:32][C:31]([Mg]Br)=[CH:30][CH:29]=1.[Cl-].[NH4+]>O1CCCC1>[OH:2][CH:1]([C:31]1[CH:32]=[CH:33][C:28]([CH3:36])=[CH:29][CH:30]=1)[C:3]1[S:7][C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]3([NH:24][C:25](=[O:27])[CH3:26])[CH2:17][O:18][C:19]([CH3:22])([CH3:23])[O:20][CH2:21]3)=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: CC(=O)NC1(CCc2ccc(-c3ccc(C=O)s3)cc2)COC(C)(C)OC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)NC1(CCc2ccc(-c3ccc(C(O)c4ccc(C)cc4)s3)cc2)COC(C)(C)OC1
Reaction time: 1 h

Procedure:
To a solution of N-(5-{2-[4-(5-formyl-2-thienyl)phenyl]ethyl}-2,2-dimethyl-1,3-dioxan-5-yl)acetamide (0.25 g) in tetrahydrofuran (20 mL) was added dropwise a solution (1 mol/L, 1.36 mL) of p-tolylmagnesium bromide in tetrahydrofuran at 0° C. under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 1 hr. 0.5M Aqueous ammonium chloride solution (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.35 g) as a brown oil.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[I:14]I.C(Cl)(Cl)Cl>CC(O)=O.CCOC(C)=O.[Hg](OC(C)=O)OC(C)=O>[N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([I:14])[C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: II
Reactant: Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Nc1c(I)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 12 h
Yield: 81.3 %

Procedure:
To a solution of 2,4-dinitroaniline (3.0 g, 16 mmol) and Hg(OAc)2 (6.8 g, 21 mmol) in 40 ml of AcOH was added 5.0 g (19 mmol) of I2 in 100 ml of AcOH dropwise and reaction mixture was stirred for 12 h. The reaction mixture was concentrated in vacuo, yielding a dark residue which was diluted with EtOAc and washed with aqueous NaHCO3. Organic layer was dried over MgSO4 and concentrated in vacuo to produce dark residue which was subjected to column chromatography (CHCl3, neat) to provide 4.1 g (13 mmol, 81%) of 2,4-dinitro-6-iodoaniline.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=O)[O:7][C:8](=O)[C:9]3[C:10]=2[C:11]=1[CH:12]=[CH:13][CH:14]=3.[BH4-].[Na+].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][O:7][CH2:8][C:9]3[C:10]=2[C:11]=1[CH:12]=[CH:13][CH:14]=3
Reactant: O=C1OC(=O)c2ccc(Br)c3cccc1c23
Agent: CC[SiH](CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: Brc1ccc2c3c(cccc13)COC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 6-bromo-1H,3H-naphtho[1,8-cd]pyran-1,3-dione (1.5 g, 5.4 mmol) in ethanol (10 mL) was added sodium borohydride (0.41 g, 10.8 mmol) and the mixture stirred at room temperature for 1 h. The reaction was quenched with 3M hydrochloric acid and extracted into dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in dichloromethane and trifluoroacetic acid (1.05 mL, 13.53 mmol) and triethylsilane (4.3 mL, 27 mmol) added. After stirring for 5 min at room temperature, the solvent was removed in vacuo and the residue purified by column chromatography on silica gel, eluting with dichloromethane, to yield 6-bromo-1H,3H-naphtho[1,8-cd]pyran as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH3:18][N:19](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[C:18]([C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:19]
Reactant: CN(C)C=O
Reactant: CCOC(=O)Cc1cc([N+](=O)[O-])c(F)cc1Br
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cc([N+](=O)[O-])c(F)cc1C#N
Temperature: 160 °C
Yield: 37 %

Procedure:
Ethyl 2-(2-bromo-4-fluoro-5-nitrophenyl)acetate (1.0 g, 3.27 mmol) and zinc cyanide (0.77 g, 6.54 mmol) were combined in DMF (8 mL), de-gassed under vacuum and backfilled with argon (4×). Palladium tetrakis(triphenylphosphine) (380 mg, 0.32 mmol) was added and the reaction was heated at 160° C. under microwave for 30 min. The solution was diluted with EtOAc and then the solid was filtered. The filtrate was washed with brine (3×) and dried (Na2SO4), concentrated in vacuo and the residue was purified by silica gel column chromatography to obtain ethyl 2-(2-cyano-4-fluoro-5-nitrophenyl)acetate (0.3 g, 37% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][CH2:15][C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:41][N:42]([C@@H:59]([C:67](=[O:70])[NH:68][CH3:69])[CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:43](=[O:58])[C@H:44]([NH:56][CH3:57])[CH2:45][C:46]1[CH:55]=[CH:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=1.C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][CH2:15][C:16](=[O:18])[N:56]([CH3:57])[C@@H:44]([C:43](=[O:58])[N:42]([CH3:41])[C@@H:59]([C:67](=[O:70])[NH:68][CH3:69])[CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[CH2:45][C:46]1[CH:55]=[CH:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COCC(=O)O
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)NC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)COC[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
To a solution of (2S)-2-(((carboxy)methoxy)methyl)-pyrrolidin-1-carboxylic acid tert-butylester (1.2 g, 4.5 mmol) in dichloromethane (20 ml) were added 1-hydroxy-7-azabenzotriazole (612 mg, 4.5 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (950 mg, 4.95 mmol) and the mixture was stirred for 30 min. (2R)-N-Methyl-2-methylamino-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(2-naphthyl)propionamide (605 mg, 1.5 mmol) in dichloromethane (10 mL) was added followed by diisopropylethylamine (0.33 ml, 2.0 mmol) and the mixture was stirred for 2 hours at room temperature. The mixture was washed with water (10 ml), aqueous sodium bicarbonate (10 ml), water (2×10 ml), brine (10 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed on silica (40 g) with ethyl acetate/heptane 4:1 to give 760 mg of (2S)-2-([N-methyl-N{(1R)-1-(N-methyl-N-[(1R)-1-(methylcarbamoyl)-2-phenylethyl]carbamoyl)-2-(2-naphthyl)ethyl}carbamoyl]methoxymethyl)pyrrolidine-1-carboxylic acid tert-butylester. The obtained product was taken up in 50% trifluoroacetic acid in methylene chloride (5 ml) and stirred for 10 min. Then saturated sodium bicarbonate was added until pH 8 and the phases were separated. The aqueous phase was extracted with dichloromethane (2×10 ml) and the combined organic phases were washed with brine (5 ml), dried over magnesium sulfate and concentrated in vacuo. The product was redissolved in water (30 ml) and acetic acid (2 ml) was added and the mixture was liophilized to give 720 mg of the acetate salt of the title compound as an amorphous powder.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:26])=[CH:7][CH:6]=1.[Si:27]([O:34][C@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].C(N(C(C)C)C(C)C)C.CN(C=O)C>O>[Si:27]([O:34][C@H:35]1[CH2:39][CH2:38][N:37]([CH2:2][CH2:3][O: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]([Cl:25])=[CH:21][N:20]=4)=[CH:13][C:12]3=[O:26])=[CH:7][CH:6]=2)[CH2:36]1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: O=c1cc(OCc2ccc(Cl)cn2)ccn1-c1ccc(OCCBr)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCN(CCOc2ccc(-n3ccc(OCc4ccc(Cl)cn4)cc3=O)cc2)C1
Temperature: 60 °C
Reaction time: 14 h
Yield: 72.1 %

Procedure:
A mixture of 1-[4(2-bromoethoxy)phenyl]-4-[(5-chloro-2-pyridinyl)methoxy]-1H-pyridin-2-one (300.7 mg, 0.69 mmol), (3S)-3-{[tert-butyl(dimethyl)silyl]oxy}pyrrolidine (417 mg, 2.1 mmols), ethyl (diisopropyl)amine (0.132 mL, 0.76 mmol) and DMF (3.5 mL) was stirred at 60° C. for 14 hours. Adding water, the reaction liquid was filtered. Thus obtained crude title compound was purified on silica gel column chromatography (KP-Sil FLASH 25+M, chloroform:methanol=1:0→10:1) to provide the title compound (276.6 mg, 72%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18]Cl>O1CCCC1>[Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:21])([CH3:20])[CH3:13])[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc2[nH]ccc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)nccc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-chloro-1H-pyrrolo[3,2-c]pyridine (98%, 2.0 g, 13 mmol) and tetrahydrofuran (20 mL) was cooled to 0° C. Sodium hydride (60% in oil, 1.03 g, 25.8 mmol) was added portion-wise over 5 minutes, and the reaction mixture was allowed to stir at 0° C. for 10 minutes. 2-(Trimethylsilyl)ethoxymethyl chloride (3.40 mL, 19.3 mmol) was then added drop-wise over 5 minutes, and stirring was continued at 0° C. for 15 minutes. The reaction mixture was quenched with saturated aqueous ammonium chloride solution; the aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 10% to 20% ethyl acetate in heptane) afforded the product as a colorless oil. Yield: 2.64 g, 9.33 mmol, 72%. LCMS m/z 283.0 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J=5.8 Hz, 1H), 7.34 (dd, J=5.8, 0.7 Hz, 1H), 7.25 (d, J=3.3 Hz, 1H), 6.69 (dd, J=3.3, 0.7 Hz, 1H), 5.48 (s, 2H), 3.46 (dd, J=8.2, 8.1 Hz, 2H), 0.89 (dd, J=8.2, 8.1 Hz, 2H), −0.05 (s, 9H).