Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[C:4]([N+:26]([O-])=O)[CH:3]=1.O.NN>C(O)C.[Ni]>[NH2:26][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]=1[NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:15][CH2:14]1
Reactant: CC(C)Oc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])cc1Cl
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)Oc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)cc1Cl
Temperature: 45 °C
Yield: 82.7 %

Procedure:
A solution of 1,1-dimethylethyl 4-({4-chloro-5-[(1-methylethyl)oxy]-2-nitrophenyl}amino)-1-piperidinecarboxylate (D84, 260 mg, 0.63 mmol) in ethanol (40 ml) was treated with Raney Nickel followed by dropwise addition over 10 minutes of a solution of hydrazine hydrate (0.315 ml, 6.3 mmol) in ethanol. The mixture was heated at 45° C. for 1 hr, then the Raney Nickel was filtered off washing with ethanol and the filtrate concentrated under vacuum to afford the title compound as a purple coloured oil (200 mg, 83%).
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[F:9][C:10]([F:20])([F:19])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]([F:19])([F:20])[F:9])=[CH:16][C:15]=1[C:21](=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C(F)(F)F)cc1
Agent: O=S(=O)(O)C(F)(F)F
Product: COc1ccc(C(F)(F)F)cc1C(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.7 %

Procedure:
2′-methoxy-5′-trifluoromethyl-acetophenone was prepared as follow (US2003/0109574): In a water bath at room temperature, to a solution of trifluoromethane sulfonic acid (5 ml, 56.7 mmol) under argon was slowly added a solution of 4-trifluoromethyl-anisol (2.0 g, 11.35 mmol) in acetic anhydride (2.15 ml, 22.7 mmol). The resulting dark mixture was stirred for 3 hours at room temperature then poured onto ice water (26 ml). The product was extracted several times with ether. The ethereal layer was washed with a 10% solution of sodium hydrogenocarbonate, water, dried over sodium sulfate and concentrated to dryness. The residue was purified by flash chromatography over silica gel (gradient cyclohexane/dichloromethane: 0-50%) to yield 2′-methoxy-5′-trifluoromethyl-acetophenone (1.7 g, 67%) as a white solid.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[CH:10]=[C:9]([N:11]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[CH3:22])[C:12]2=[O:23])[CH:8]=[CH:7][N:6]=1.CO>O1CCOCC1.C(Cl)(Cl)Cl>[CH3:1][O:2][C:5]1[CH:10]=[C:9]([N:11]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[CH3:22])[C:12]2=[O:23])[CH:8]=[CH:7][N:6]=1
Reactant: Cc1ccncc1N1CCN(c2ccnc(Cl)c2)C1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1cc(N2CCN(c3cnccc3C)C2=O)ccn1
Temperature: 110 °C
Yield: 28.2 %

Procedure:
Sodium methoxide (225 mg, 4.165 mmol) was added dropwise to a stirred solution of 1-(2-chloro-pyridin-4-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (58A: 100 mg, 0.374 mmol) in 1,4-dioxane (20 mL) over a period of 10 minutes. The resulting mixture was heated to 110° C. and maintained at the same temperature for 4 days. The reaction was monitored by TLC (10% MeOH in CHCl3). The solvent was distilled from the reaction mixture and the concentrate was partitioned between water and ethylacetate. The organic layer was dried over Na2SO4 to afford the crude product. Purification by column preparative HPLC afforded 30 mg of the product (30.61% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH2:9]([O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)[CH2:10][CH2:11][CH3:12]>>[CH2:9]([O:13][C:14]1[CH:19]=[C:18]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:17]=[CH:16][CH:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCOc1cccc(B(O)O)c1
Reactant: Clc1ccnc(Cl)n1
Product: CCCCOc1cccc(-c2ccnc(Cl)n2)c1

Procedure:
2,4 dichloropyrimidine was coupled with 3-butoxyphenylboronic acid following procedure A. LC-MS showed the product had the expected M+H+ of 263.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@@H:13]2[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@@H:12]2[C@@H:11]([C:19]([OH:21])=O)[O:10]1)C1C=CC=CC=1.[NH3:22].C(OCC)(=O)C>CO.CS(O)(=O)=O>[CH3:1][O:8][C@H:9]1[C@@H:13]2[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@@H:12]2[C@@H:11]([C:19]([NH2:22])=[O:21])[O:10]1
Reactant: N
Reactant: CC1(C)O[C@H]2[C@H](OCc3ccccc3)O[C@H](C(=O)O)[C@H]2O1
Agent: CS(=O)(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: CO[C@@H]1O[C@H](C(N)=O)[C@H]2OC(C)(C)O[C@@H]12
Temperature: 60 °C
Yield: 64.2 %

Procedure:
To a solution of (3aS, 4S, 6R, 6aR)-6-benzyloxy-2,2-dimethyltetrahydro-furo[3,4-d][1,3]dioxole-4-carboxylic acid (588.6 mg, 2 mmol) in methanol (8.8 mL) was added methanesulfonic acid (0.007 mL, 0.1 mmol), and the mixture was stirred with heating to 60° C. for 24 hours. After the solution was dried under reduced pressure, ethyl acetate (2.9 mL) and 2,2-dimethoxypropane (0.17 mL, 1.4 mmoL) were added to the resulting oil, and the mixture was stirring at ambient temperature for 2 hours. Aqueous 7% sodium hydrogen carbonate solution (0.5 mL) was added for layer separation, and the resulting organic layer was concentrated under reduced pressure, to which was added aqueous 28% ammonia (1.2 mL, 20 mmol), and the mixture was stirred at ambient temperature for 14 hours. To the resulting solution was added ethyl acetate (3 mL) for layer separation, and the organic layer was concentrated under reduced pressure. To the resulting solid was added a hexane/ethyl acetate (3:1) solution (3 mL) for rinsing as a slurry at ambient temperature for 2 hours. Subsequently, the solid was filtered and rinsed in a hexane/ethyl acetate (3:1) solution (0.5 mL). The solid was dried under reduced pressure to recover (3aS, 4S, 6R, 6aR)-6-methoxy-2,2-dimethyltetrahydro-furo[3,4-d][1,3]dioxol-4-carboxylic acid amide (278.7 mg; yield of 64.2%) as a white solid. Melting point: 136° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:12](=[O:23])[C:11]2[C:6]1=[C:7]([O:27][CH2:28][CH2:29][CH3:30])[CH:8]=[C:9]1[CH2:26][CH2:25][CH2:24][C:10]1=2.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(OCC)(=O)C.O.CN(C)C=O>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[C:12](=[O:23])[C:11]3[C:6](=[C:7]([O:27][CH2:28][CH2:29][CH3:30])[CH:8]=[C:9]4[CH2:26][CH2:25][CH2:24][C:10]4=3)[N:5]([CH2:4][CH2:3][CH2:2][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:14]=2)=[CH:20][CH:19]=1
Reactant: CCCOc1cc2c(c3c(=O)c(-c4ccc(OC)cc4)cn(CCCCl)c13)CCC2
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1cc2c(c3c(=O)c(-c4ccc(OC)cc4)cn(CCCN4CCOCC4)c13)CCC2
Temperature: 60 °C
Reaction time: 7 h
Yield: 37.7 %

Procedure:
A mixture containing 6-(3-chloropropyl)-8-(4-methoxyphenyl)-5-propoxy-1,2,3,6-tetrahydro-6-aza-cyclopenta[a]naphthalen-9-one (700 mg, 1.64 mmol), morpholine (165 mg, 1.90 mmol), potassium carbonate (341 mg, 2.47 mmol), sodium iodide (295 mg, 1.97 mmol) and dimethyl formamide (3 ml) was stirred at 60° C. for 7 hours. Water and ethyl acetate were added to the reaction mixture, followed by separation. The thus-obtained organic layer was washed with an aqueous saturated sodium chloride solution twice and then concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane:methanol=70:1→50:1). The purified product was concentrated under reduced pressure to recrystallize the residue from ethyl acetate-n-hexane, giving a white powder of 8-(4-methoxyphenyl)-6-(3-morpholin-4-ylpropyl)-5-propoxy-1,2,3,6-tetrahydro-6-aza-cyclopenta[a]naphthalen-9-one (295 mg, yield: 38%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])=[CH:9][C:4]=2[CH:3]=[CH:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)CCOCCc1ccc2sccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)CCOCCc1ccc2sccc2c1
Yield: 85.4 %

Procedure:
In 22.8 mL of toluene was dissolved 7.60 g of tert-butyl 3-[2-(1-benzothiophen-5-yl) ethoxy]propionate, and 94 mg of p-toluenesulfonic acid monohydrate was added thereto, after which the resulting mixture was refluxed for 6 hours. After the reaction mixture was cooled, water and ethyl acetate were added thereto and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was crystallized from a toluene-cyclohexane mixture (1:4, 23 mL) to obtain 5.30 g of 3-[2-(1-benzothiophen-5-yl)ethoxy]propionic acid as light-red crystals.
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[N:24]=[CH:23][N:22]=[C:21]3[C:17]=2[N:18]=[C:19]([C:31]2[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=[CH:33][CH:32]=2)[N:20]3C2CCCCO2)[CH2:11]1)(C(C)(C)C)(C)C.O.CC(O)=O>C1COCC1>[C:31]1([C:19]2[NH:20][C:21]3[C:17]([N:18]=2)=[C:16]([O:15][C@H:12]2[CH2:13][CH2:14][C@H:10]([CH2:9][OH:8])[CH2:11]2)[N:24]=[CH:23][N:22]=3)[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CC[C@H](Oc2ncnc3c2nc(-c2cccc4ccccc24)n3C2CCCCO2)C1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: OC[C@H]1CC[C@H](Oc2ncnc3[nH]c(-c4cccc5ccccc45)nc23)C1
Reaction time: 7 h
Yield: 84.7 %

Procedure:
To a stirred solution of 6-{[(1S,3S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-cyclopentyl]oxy}-8-(1-naphthyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (156.9 mg, 0.0002808 mol) in THF (3.8 mL) was added water (3.8 mL) and AcOH (7.6 mL), and the reaction mixture was stirred for 7 hours. The reaction mixture was quenched by the slow addition of saturated NaHCO3, and the resulting mixture was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (0 to 5% MeOH/CH2Cl2) to obtain 85.7 mg (85%) of the title compound as a white solid. LC/MS: Rt=1.51 min, ES+ 361 (FA standard).
Reaction SMILES: C(O[C:4](=[N:19][NH:20][CH:21]=O)[C:5]1[S:6][C:7]([S:17][CH3:18])=[C:8]2[C:13](=[O:14])[CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10][C:9]=12)C.[CH3:23][NH2:24]>C(O)C>[CH3:15][C:11]1([CH3:16])[CH2:10][C:9]2=[C:5]([C:4]3[N:24]([CH3:23])[CH:21]=[N:20][N:19]=3)[S:6][C:7]([S:17][CH3:18])=[C:8]2[C:13](=[O:14])[CH2:12]1
Reactant: CN
Reactant: CCOC(=NNC=O)c1sc(SC)c2c1CC(C)(C)CC2=O
Solvent: CCO
Product: CSc1sc(-c2nncn2C)c2c1C(=O)CC(C)(C)C2
Temperature: 60 °C

Procedure:
Formic acid[ethoxy-(6,6-dimethyl-3-methylthio-4-oxo-4,5,6,7-tetrahydrobenzo[c]thiophen-1-yl)methylene]hydrazide (150 mg, 0.49 mmol) was dissolved in a solution of methylamine in ethanol (30%, 10 mL) and the mixture heated at 60° C. More methylamine solution (10 mL) was added periodically over 8 h. The solution was evaporated to dryness and the residue purified by chromatographed on silica gel, eluting with methanol:dichloromethane (5:95). The title compound was obtained as a white powder (60 mg, 44%). mp 178-180° C. Found: C, 52.50; H, 5.43; N, 12.73%. C14H17N3OS2.0.8 (H2O) requires: C, 52.25; H, 5.83; N, 13.06%. 1HNMR (360 MHz, CDCl3)δ 1.05 (6H, s), 2.44 (2H, s), 2.62 (3H, s), 2.79 (2H, s), 3.75 (3H, s), 8.28 (1H, s). MS (ES+) 308 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].Cl[CH2:14][C:15]1[C:16]([F:21])=[N:17][CH:18]=[CH:19][CH:20]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:14][C:15]1[C:16]([F:21])=[N:17][CH:18]=[CH:19][CH:20]=1)[CH:6]=[CH:5]2
Reactant: Fc1ncccc1CCl
Reactant: Clc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ncccc1Cn1ccc2cc(Cl)ccc21
Reaction time: 0.3 h
Yield: 59 %

Procedure:
In a 50 ml, three-necked flask fitted with a magnetic stirrer under inert atmosphere, 5-chloro-1H-indole x70 (1.13 g, 7.43 mmol) is dissolved in dry DMF (20 ml). At 0° C., NaH (327 mg, 8.18 mmol, 60% in mineral oil) is added and the mixture is stirred at this temperature for 0.3 h. A solution of 3-(chloromethyl)-2-fluoropyridine x71 (obtained from (2-fluoropyridin-3-yl)methanol and SOCl2 (1.3 g, 8.92 mmol)) in DMF (5 ml) is then added and stirring is continued for 0.5 h at 0° C. The reaction mixture is poured on ice and the aqueous phase is extracted three times with AcOEt. The combined organic phases are dried over MgSO4, filtered and concentrated. Purification by chromatography on silicagel (Hexane/AcOEt: 9/1 (v/v)) affords 5-chloro-1-[(2-fluoropyridin-3-yl)methyl]-1H-indole x72 as a solid (1.13 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[BH4-].[Na+]>ClCCCl.CO>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[OH:11])=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(F)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Product: OC1CCc2ccc(F)cc21
Yield: 97.6 %

Procedure:
To a solution of 6-fluoro-indan-1-one (0.50 g, 3.3 mmol) in DCE (10 mL) and MeOH (10 mL) was added NaBH4 (0.25 g, 6.6 mmol). After 30 min the reaction was quenched with H2O (10 mL) and extracted with CH2Cl2 (3×20 mL). The organic layers were combined and dried to give the title compound (0.49 g, 97%). MS (ESI): mass calcd. for C9H7FO, 150.1; m/z found, 151.4 [M+H]+. 1H NMR (CDCl3): 7.23-7.13 (m, 1H), 7.09 (dd, J=8.6, 2.5 Hz, 1H), 6.99-6.90 (m, 1H), 5.21 (t, J=6.3 Hz, 1H), 3.13-2.91 (m, 1H), 2.85-2.68 (m, 1H), 2.63-2.44 (m, 1H), 2.09-1.74 (m, 2H).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:25][CH:24]=3)(=[O:22])=[O:21])=[CH:13][CH:12]=2)[S:6]1(=[O:37])=[O:36])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+].[Cl-].[NH4+]>O1CCCC1>[C:1]([N:5]1[C:9](=[O:10])[CH2:8][CH:7]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][NH:19][S:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:27][CH:28]=3)(=[O:21])=[O:22])=[CH:15][CH:16]=2)[S:6]1(=[O:37])=[O:36])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N1C(=O)C=C(c2ccc(CCNS(=O)(=O)c3ccc(Oc4ccccc4)cc3)cc2)S1(=O)=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)N1C(=O)CC(c2ccc(CCNS(=O)(=O)c3ccc(Oc4ccccc4)cc3)cc2)S1(=O)=O
Reaction time: 0.17 h
Yield: 72.8 %

Procedure:
N-2-[4-(2-tert-Butyl-1,1-dioxido-3-oxo-2,3-dihydroisothiazol-5-yl)phenyl]ethyl-4-phenoxybenzenesulfonamide (26.0 mg, 0.0481 mmol) was dissolved in tetrahydrofuran (0.25 mL) and 2 M lithium tetrahydroborate in tetrahydrofuran (18 μL) was added to the reaction via syringe. After 10 minutes, 2 M lithium tetrahydroborate in tetrahydrofuran (18 μL) was added. After an additional 10 minutes, the reaction was added to 1 mL of saturated aqueous ammonium chloride and stirred vigorously. The reaction was chromatographed on a 21.2 mm Luna C 18 column using a 10–90% acetonitrile in water gradient with 0.05% trifluoroacetic acid at 12.5 mL per minute over a 15 minute period. The major fraction was evaporated to give a light orange solid (19 mg, 75%). 1H NMR (500 MHz, CDCl3): δ 7.77 (d, J=8.8 Hz, 2H), 7.42 (t, J=8.3 Hz, 2H), 7.34 (d, J=8.3 Hz, 2H), 7.23 (t, J=7.8 Hz, 1H), 7.13 (d, J=7.8 Hz, 2H), 7.07 (d, J=7.9 Hz, 2H), 7.03 (d, J=8.8 Hz, 2H), 4.65 (m, 1H), 4.29 (m, 1H), 3.95 (m, 1H), 3.75 (m, 1H) 3.40 (m, 1H), 2.60 (m, 1H), 2.24 (m, 1H), 1.31 (s, 9H); LCMS found for C27H34N3O6S2 (M+NH4)+: m/z 560.2.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CN(C=O)C.[NH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1.N1C=CC=CC=1.[CH3:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:30]=1[NH2:36].C(N)CN>C(Cl)Cl>[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:36][C:30]2[C:31]([CH3:35])=[CH:32][CH:33]=[CH:34][C:29]=2[CH3:28])=[O:19])=[CH:20][CH:21]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: Cc1cccc(C)c1N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1cccc(C)c1NC(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
Oxalyl chloride (1.9 mL, 22 mmol) was added dropwise to a solution of DMF (1.7 mL, 22 mmol) and DCM (22 mL) that was kept at 0° C. The resulting foamy white suspension was stirred for 30 min and allowed to warm to room temperature, then cooled again to 0° C. 4-Aminobenzoic acid (1.50 g, 10.9 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The flask was again cooled to 0° C. and DCM (11 mL) and pyridine (2.6 mL, 33 mmol) were added. Stirring was continued for 50 min and 2,6-dimethyl-phenylamine (1.33 g, 10.9 mmol) was then added. The reaction mixture was stirred at room temperature for 1.5 h and concentrated to dryness. The residue was dissolved in ethanol (30 mL) and 1,2-ethylenediamine (3.3 mL, 49 mmol) was added. The reaction mixture was heated at reflux for 2 h, allowed to cool to room temperature, stirred for 2 d, and concentrated. Water (50 mL) was added to the residue and the precipitate was collected, rinsed well with water, and dried to yield the titled compound (1.904 g, 70% yield). MS (ESI/Cl): mass calcd. for C15H16N2O, 240.1; m/z found, 241.1 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.76 (d, J=8.8 Hz, 2H), 7.10 (s, 3H), 6.72 (d, J=8.8 Hz, 2H), 2.24 (s, 6H).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C:8]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:12][CH2:11][CH2:10][O:9]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:13]1([C:8]2([CH2:7][OH:6])[O:12][CH2:11][CH2:10][O:9]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)[Si](C)(C)OCC1(c2ccccc2)OCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCC1(c2ccccc2)OCCO1
Temperature: 25 °C
Reaction time: 12 h
Yield: 45.5 %

Procedure:
To a solution of tert-butyldimethyl-(2-phenyl-[1,3]dioxolan-2-yl-methoxy)silane (5.5 g, 18.7 mmol) in tetrahydrofuran (50 ml) was added tetrabutylammonium fluoride (1M in tetrahydrofuran, 56 ml) at room temperature. The mixture was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=3/1) to give (2-phenyl-[1,3]dioxolan-2-yl)methanol (1.54 g, 8.5 mmol, 45%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:10][CH2:11]Br)[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:13][S-:14].[Na+].O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1([CH2:10][CH2:11][S:14][CH3:13])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(CCBr)CCCC1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1(CCSC)CCCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.5 %

Procedure:
To a solution of 1-(2-bromoethyl)cyclopentane carboxylic acid methyl ester (2.0 mmol, 472 mg) in DMF (5 mL) was added sodium thiomethoxide (2.65 mmol, 186 mg). The reaction mixture was stirred for 15 h at room temperature and was poured into water (30 mL). The organic compound was extracted into diethyl ether (2×20 mL). The combined extracts were washed with a saturated solution of sodium chloride (50 mL) and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the solution was concentrated under vacuum and the resulting residue was purified by silica gel column chromatography to afford 334 mg (82%) of a colorless oil. HR MS C10H18O2S): Obs mass, 202.1024. Calcd mass, 202.1028 (M+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12]([N:14]1[C@H:18]([CH:19]=[CH:20][CH2:21][CH2:22][C:23](OCC)=[O:24])[CH2:17][O:16][C:15]1([CH3:29])[CH3:28])=[O:13])([CH3:10])([CH3:9])[CH3:8].S([O-])(O)(=O)=O.[K+]>C(OCC)C.O>[C:7]([O:11][C:12]([N:14]1[C@H:18]([CH:19]=[CH:20][CH2:21][CH2:22][CH2:23][OH:24])[CH2:17][O:16][C:15]1([CH3:29])[CH3:28])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CCOC(=O)CCC=C[C@@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1[C@H](C=CCCCO)COC1(C)C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
2.7 g of lithium aluminium hydride are added in portions at 0°-2° to a solution of 23.5 g of 2 according to b) in 550 ml of absolute diethyl ether. After stirring at 0°-2° for 3 hours, a solution of 25 g of potassium hydrogen sulphate in 250 ml of water is added dropwise with cooling. The mixture is filtered through Celite® and washed thoroughly with diethyl ether. The organic phase is washed twice with 200 ml of 1 N hydrochloric acid each time and twice with 250 ml of 10% sodium bicarbonate solution each time. The aqueous phases are extracted twice with 100 ml of ether each time. The organic phases are washed with 20% sodium chloride solution, dried over sodium sulphate and concentrated by evaporation. Chromatography on silica gel using ethyl acetate as eluant yields 18.6 g of 3, [α]D =-10.1° (c=1.4, CHCl3); C 15 H27NO4 ; calculated: 63.13%, H 9.54%, N 4.91%; found: C 63.0%, H 9.5%, N 5.0%.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:10])[CH2:4][CH:5]=[CH:6][C:7](O)=[O:8].CCN(CC)CC.C(OC(Cl)=O)C(C)C.[I:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:37])[NH:32][C:31](=[O:38])[C:30]2=[CH:39][NH:40][C:41]1[CH:46]=[CH:45][C:44]([CH:47]2[CH2:51][CH2:50][CH2:49][NH:48]2)=[CH:43][CH:42]=1>CN(C)C=O>[CH3:2][N:3]([CH3:10])[CH2:4][CH:5]=[CH:6][C:7]([N:48]1[CH2:49][CH2:50][CH2:51][CH:47]1[C:44]1[CH:45]=[CH:46][C:41]([NH:40][CH:39]=[C:30]2[C:29]3[C:34](=[CH:35][CH:36]=[C:27]([I:26])[CH:28]=3)[C:33](=[O:37])[NH:32][C:31]2=[O:38])=[CH:42][CH:43]=1)=[O:8]
Reactant: CN(C)CC=CC(=O)O
Reactant: O=C1NC(=O)c2ccc(I)cc2C1=CNc1ccc(C2CCCN2)cc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)CC=CC(=O)N1CCCC1c1ccc(NC=C2C(=O)NC(=O)c3ccc(I)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.6 %

Procedure:
4-Dimethylamino-but-2-enoic acid hydrochloride salt (66 mg, 0.40 mmol) in N,N-dimethylformamide (1 mL) is treated with Et3N (0.06 mL) at 0° C. To the mixture is then added isobutylchloroformate (0.05 mL). The mixture is then stirred at this temperature for 30 min before addition of 6-Iodo-4-[(4-pyrrolidin-2-yl-phenylamino)-methylene]-4H-isoquinoline-1,3-dione (80 mg, 0.17 mmol) in N,N-dimethylformamide (3 mL) dropwisely and the reaction is allowed to stir at room temperature overnight. After an aqueous workup, the final residue is purified with prep-TLC to afford the title compound (20 mg, 21%). 1H NMR (400 MHz, DMSO) δ12.52 (1H, d, J=12.4 Hz), 11.39-11.41 (1H, m), 8.90-8.94 (1H, m), 8.59 (1H, m), 7.21-7.75 (6H, m), 6.48-6.59 (1.4H, m), 6.01-6.05 (0.6H, m), 5.1-5.24 (1H, m), 3.57-3.91 (2H, m), 3.06-3.07 (1H, m), 2.82-2.84 (1H, m), 2.1-2.39 (2H, m), 2.18 (3H, s), 1.96 (3H, s), 1.77-1.95 (2H, m). MS (ESI): 571.0 (M+1)+1.