Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]([CH2:35][C@H:36]([OH:58])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([O:45]CC2C=CC=CC=2)=[C:41]([NH:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH:40]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:34]=[CH:33][C:18]([C:19]([NH:21][C@H:22]([C:30]([OH:32])=[O:31])[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:58][C@H:36]([CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[C:41]([NH:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH:40]=1)[CH2:35][NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]2[CH:34]=[CH:33][C:18]([C:19]([NH:21][C@H:22]([C:30]([OH:32])=[O:31])[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:20])=[CH:17][CH:16]=2)[CH2:13][CH2:14]1
Reactant: CS(=O)(=O)Nc1cc(OC[C@@H](O)CN(Cc2ccccc2)[C@H]2CC[C@H](c3ccc(C(=O)N[C@@H](Cc4ccccc4)C(=O)O)cc3)CC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CS(=O)(=O)Nc1cc(OC[C@@H](O)CN[C@H]2CC[C@H](c3ccc(C(=O)N[C@@H](Cc4ccccc4)C(=O)O)cc3)CC2)ccc1O
Reaction time: 3 h

Procedure:
A mixture of 0.2 g of trans-N-(4-{4-[benzyl((2S)-3-{4-(benzyloxy)-3-[(methylsulfonyl)-amino]phenoxy}-2-hydroxypropyl)amino]cyclohexyl}-benzoyl)-L-phenylalanine (0.248 mmol) and of 0.1 g of 10% palladium-on-charcoal (50% in water) in ethanol (15 ml) is placed under hydrogen atmosphere and stirred for 3 h. The reaction mixture is filtered through celite. The solvents are evaporated under reduced pressure and trans-N-(4-{4-[((2S)-2-hydroxy-3-{4-hydroxy-3-[(methylsulfonyl)amino]phenoxy}propyl)amino]cyclohexyl}benzoyl)-L-phenylalanine is obtained in the form of a white solid (0.049 g, 31%) after purification on C18-grafted silica (eluent: water/acetonitrile, 95/5 to 5/95 gradient in 15 min).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:10][C:11]([CH3:16])=[CH:12][C:13](Cl)=[O:14].O>C1COCC1>[CH3:10][C:11]([CH3:16])=[CH:12][C:13]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:14]
Reactant: Nc1ccccc1
Reactant: CC(C)=CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=CC(=O)Nc1ccccc1
Reaction time: 0.5 h
Yield: 47 %

Procedure:
In a 100 mL round bottom flask was placed NaH (1.93 g, 0.05 mol). After washing with dry hexane (2×10 mL dry THF (15 mL) was added), to this tan solid. Then, the resulting suspension was added to a solution of aniline (Compound 36, 4.89 mL, 0.054 mol) in dry THF (7 mL) at 0° C. After stirring for 30 min, 3,3-dimethylacryloyl chloride (Compound 35, 6.56 mL, 0.059 mol) was added dropwise to the above solution. The reaction mixture was stirred under N2 for overnight followed by a slow addition of water. The mixture was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with NH4Cl (sat.) and NaCl (sat.), dried over MgSO4 and concentrated to give the title compound as a tan solid (4.45 g, 51%). 1H NMR d 1.87 (s, 3H), 2.21 (s, 3H), 5.72 (s, 1H), 7.29-7.56 (m, 5H).
Reaction SMILES: [CH3:1][CH:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:32])[C:18]2[CH:23]=[CH:22][C:21]([O:24]CC3C=CC=CC=3)=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>C(OCC)(=O)C.C(O)C>[CH3:1][CH:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:32])[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)Oc1ccc(OC(=O)c2ccc(OCc3ccccc3)cc2)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCCCC(C)Oc1ccc(OC(=O)c2ccc(O)cc2)cc1
Yield: 90.9 %

Procedure:
Optically active p-benzyloxybenzoic acid p-(1-methylheptyloxy)phenyl ester (69.0 g, 0.16 mol) prepared above in (iv) was dissolved in a mixed solvent (2:1) (1,000 ml) of ethyl acetate-ethanol, followed by reducing it in the presence of 5% PdC (5.0 g) to obtain optically active p-hydroxybenzoic acid p-(1-methyl-heptyloxy)phenyl ester (49.8 g).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:14]([NH2:16])=O)[C:10](=O)[NH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:10]1[N:11]=[N:12][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][C:9]=1[C:14]#[N:16]
Reactant: NC(=O)c1cc(-c2ccccc2)n[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: N#Cc1cc(-c2ccccc2)nnc1Cl
Temperature: 80 °C

Procedure:
1.5 g of the product obtained in Example 1 are dissolved in 20 ml of phosphorus oxychloride and the solution is then heated at 80° C. for 5 hours. The mixture is poured into 50 ml of water. A precipitate appears, which is filtered off and dried.
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:11]=[CH:10][S:9][C:8]=1[C:12]([O:14]C)=[O:13])(=[O:5])[CH2:2][CH2:3][CH3:4].[OH-].[K+].Cl>CCO.O>[C:1]([NH:6][C:7]1[CH:11]=[CH:10][S:9][C:8]=1[C:12]([OH:14])=[O:13])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Nc1ccsc1C(=O)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCC(=O)Nc1ccsc1C(=O)O
Temperature: 80 °C
Reaction time: 12 h

Procedure:
Methyl 3-(butyrylamino)thiophene-2-carboxylate (1-2, 2.70 g, 11.9 mmol) was dissolved in 1: 1 EtOH/H2O (10 mL) and treated with KOH pellets (2.00 g, 35.6 mmol). The resulting solution was stirred 12 h at 80° C., poured into 1N HCl and cooled to 0° C. The precipitate was filtered, washed with cold Et2O and dried under vacuum to provide 3-(butyrylamino)thiophene-2-carboxylic acid (1-3). MS 214 found 213.2 required.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][C:6]1[CH:7]=[C:8]([C:15](=[O:17])[CH3:16])[CH:9]=[CH:10][C:11]=1[N+:12]([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:12][C:11]1[CH:10]=[CH:9][C:8]([C:15](=[O:17])[CH3:16])=[CH:7][C:6]=1[O:5][C:4]1[CH:18]=[CH:19][CH:20]=[C:2]([Cl:1])[CH:3]=1
Reactant: CC(=O)c1ccc([N+](=O)[O-])c(Oc2cccc(Cl)c2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(=O)c1ccc(N)c(Oc2cccc(Cl)c2)c1
Reaction time: 1 h
Yield: 106.8 %

Procedure:
A mixture of 3'-(3-chlorophenoxy)-4'-nitroacetophenone (2.4 g), iron powder (2.4 g) and ammonium chloride (0.24 g) in ethanol (32 ml) and water (16 ml) was refluxed with stirring for 1 hour. The insoluble was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30 ml), washed with water (20 ml), dried, and concentrated to give an oil of 4'-amino-3'-(3-chlorophenoxy)acetophenone (2.3 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11]S(C3C=CC=CC=3)(=O)=O)[CH:9]=2)[C:4]([C:21]2[C:22](=[O:37])[NH:23][C:24](=[O:36])[C:25]=2[C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]([CH3:35])[CH:27]=2)=[CH:3]1.[OH-].[Na+].CO.Cl>O>[OH:11][C:8]1[CH:9]=[C:10]2[C:5]([C:4]([C:21]3[C:22](=[O:37])[NH:23][C:24](=[O:36])[C:25]=3[C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]([CH3:35])[CH:27]=3)=[CH:3][N:2]2[CH3:1])=[CH:6][CH:7]=1
Reactant: Cn1cc(C2=C(c3cn(C)c4cc(OS(=O)(=O)c5ccccc5)ccc34)C(=O)NC2=O)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1cc(C2=C(c3cn(C)c4cc(O)ccc34)C(=O)NC2=O)c2ccccc21
Temperature: 25 °C

Procedure:
3-(6-hydroxy-1-methyl-1H-indol-3-yl)-4-(1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione was prepared by treating Benzenesulfonic acid 1-methyl-3-[4-(1-methyl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-1H-indol-6-yl ester (141 mg 0.28 mm) with 4N NaOH (0.5 mL, 2 mmol) and CH3OH (4 mL) and heating to reflux temperature for 6 hours. After cooling to room temperature, the reaction mixture was diluted with H2O, acidified with 2N HCl, and extracted with EtOAc. The organic phase was washed with saturated NaCl solution, dried over MgSO4, filtered and evaporated to afford, after purification by flash column chromatography 3-(6-hydroxy-1-methyl-1H-indol-3-yl)-4-(1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione (15 mg); mp=279°-282° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:9][C:10]=1[CH3:11])=[O:4].C([Sn](CCCC)(CCCC)[C:24]#[C:25][CH2:26][O:27][CH3:28])CCC>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([C:24]#[C:25][CH2:26][O:27][CH3:28])=[N:7][C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:9][C:10]=1[CH3:11])=[O:4]
Reactant: COC(=O)c1c(C)cc(N2CCOCC2)nc1Cl
Reactant: CCCC[Sn](C#CCOC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: COCC#Cc1nc(N2CCOCC2)cc(C)c1C(=O)OC
Temperature: 100 °C
Yield: 63.1 %

Procedure:
To a solution of 700 mg (2.6 mmol) 2-chloro-4-methyl-6-morpholino-pyridine-3-carboxylic acid methylester and 1.39 g (3.9 mmol) tributyl(3-methoxyprop-1-ynyl)stannane in dioxane (10 ml) was added 273 mg (0.39 mmol) PdCl2(PPh3)2. Then the reaction solution was heated at 100° C. for 16 h. After cooling to RT the mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc and washed with water. The organic layer was dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (5% KF-silica, hexane/EtOAc 19:1) provided 500 mg (1.64 mmol, 63%) 2-(3-methoxyprop-1-ynyl)-4-methyl-6-morpholino-pyridine-3-carboxylic acid methylester.
Reaction SMILES: [CH:1]12[N:8]([C:9]([C:11]3[S:12][CH:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)[N:15]=3)=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2.[Br:23]N1C(=O)CCC1=O.O>CN(C=O)C>[CH:5]12[N:8]([C:9]([C:11]3[S:12][C:13]([Br:23])=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)[N:15]=3)=[O:10])[CH:1]([CH2:7][CH2:6]1)[CH2:2][O:3][CH2:4]2
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(c1nc(-c2ccc(Cl)cc2)cs1)N1C2CCC1COC2
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1nc(-c2ccc(Cl)cc2)c(Br)s1)N1C2CCC1COC2
Temperature: 52.5 °C
Reaction time: 4 h
Yield: 48.3 %

Procedure:
To a stirred solution 3-oxa-8-azabicyclo[3.2.1]octan-8-yl(4-(4-chlorophenyl)thiazol-2-yl)methanone (Step-2 of compound 68, 0.2 g, 0.60 mmol) in DMF (10 ml) at 0° C. was added N-bromosuccinimide (0.10 g, 0.60 mmol) in a portionwise manner. The resulting reaction mixture was stirred at 50-55° C. for 4 hrs. The progress of reaction was monitored by TLC. The reaction mixture was cooled to room temperature, water (40 ml) was added slowly and aqueous layer was extracted with ethyl acetate (2×50 ml). The organic layer was washed with water (1×30 ml). Combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain a crude product; which was purified by flash column chromatography using 20% ethyl acetate in hexanes as an eluent to obtain the title compound (0.12 g, 48.6%). MS: m/z 414 (M+1).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[C:13]([O:16][C:17]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:18]=1[C:19]([OH:21])=O)(=[O:15])[CH3:14].[NH2:27][C@@H:28]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:29]([NH:31][C:32]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=1)=[O:30].ON1C2C=CC=CC=2N=N1.Cl>CN(C)C=O>[C:13]([O:16][C:17]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:18]=1[C:19]([NH:27][C@H:28]([C:29](=[O:30])[NH:31][C:32]1[CH:37]=[C:36]([C:38]([F:40])([F:41])[F:39])[CH:35]=[C:34]([C:42]([F:43])([F:44])[F:45])[CH:33]=1)[CH2:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)=[O:21])(=[O:15])[CH3:14]
Reactant: N[C@@H](Cc1ccccc1)C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(=O)Oc1ccc(Cl)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(Cl)cc1C(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.4 %

Procedure:
WSC.HCl (184 mg, 0.96 mmol) was added to a solution of 2-acetoxy-5-chlorobenzoic acid (104 mg, 0.48 mmol), (S)-2-amino-3-phenyl-N-[3,5-bis(trifluoromethyl)phenyl]propionamide (0.20 g, 0.48 mmol) and 1-hydroxybenzotriazole (71.4 mg, 0.53 mmol) in N,N-dimethylformamide (4 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:1→2:1) to give the title compound (141.4 mg, 51.4%) as a white crystal.
Reaction SMILES: [CH2:1]([N:4]([CH2:27][CH2:28][CH3:29])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH3:26])[C:10](=[O:25])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH:18][CH2:19][C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)=[CH:13][CH:12]=1)[CH2:2][CH3:3].[CH3:30][N:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH:36]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:27]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH3:26])[C:10](=[O:25])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]([CH2:19][C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)[CH2:36][C:32]2[N:31]([CH3:30])[CH:35]=[CH:34][N:33]=2)=[CH:13][CH:12]=1)[CH2:28][CH3:29]
Reactant: Cn1ccnc1C=O
Reactant: CCCN(CCC)CCCCN(C)C(=O)c1ccc(CNCc2ncc[nH]2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCCN(C)C(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The compound (266.9 mg) obtained in Example 111-1 was dissolved in anhydrous methanol (11 ml) and then added with 1-methyl-2-imidazole carboxaldehyde (110.1 mg) and sodium cyanoborohydride (84.2 mg). Then, the solution was adjusted to pH 5 with acetic acid, followed by stirring at room temperature for 3 days. After the reaction, the solvent was distilled off. The residue was added with a 1 mol/l sodium hydroxide aqueous solution (1.0 ml) and extracted with chloroform. The extract was dried with magnesium sulfate. The solvent was distilled off. Then, the residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (234.9 mg) of the subject compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)=[N:4][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.Br[CH2:33][C:34]([NH2:36])=[O:35].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)=[N:4][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:33][C:34]([NH2:36])=[O:35])[CH2:21][CH2:20]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3ccc(C4CCNCC4)c4ccccc34)ncc2Cl)n[nH]1
Reactant: NC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(Nc3ccc(C4CCN(CC(N)=O)CC4)c4ccccc34)ncc2Cl)n[nH]1
Temperature: 130 °C

Procedure:
A mixture of 5-chloro-N4-(5-methyl-1H-pyrazol-3-yl)-N2-(4-(piperidin-4-yl)naphthalene-1-yl)pyrimidine-2,4-diamine (30.8 mg, 0.07 mmol), 2-bromoacetamide (19.6 mg, 0.14 mmol) and triethylamine (30.0 μL, 0.21 mmol) in 2 mL of DMF was heated at 130° C. in a microwave reactor for 20 min. The crude product was purified by RP-HPLC to afford 2-(4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)naphthalene-1-yl)piperidin-1-yl)acetamide; ESMS m/z 491.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Li]CCCC.[C:15]1([C:21]2[S:25][C:24]([CH:26]=[O:27])=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:26]([C:24]2[S:25][C:21]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:22][CH:23]=2)[OH:27])=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(-c2ccccc2)s1
Reactant: COc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2ccc(-c3ccccc3)s2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
To a solution of 4-bromoanisole (0.6 g, 3.2 mmol) in THF was added n-BuLi (2.5M in hexane, 1.5 mL, 3.5 mmol) at −78° C., and continued to stir for 30 min. The product of step 1 (0.48 g, 2.6 mmol) was added. After it was stirred at −78° C. for 30 min, the reaction was allowed to warm to room temperature and stirred for an additional 1 h. The reaction was quenched with water, extracted with EtOAc, washed with brine and dried over Na2SO4. After the solvent was removed, the residue was purified by a column chromatography on silica gel to yield the title compound (0.6 g, 68%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14](O)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:2].CCN(S(F)(F)[F:25])CC>ClCCl>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([F:25])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N2CCC(O)CC2)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N2CCC(F)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
To a solution of 4-(4-hydroxy-piperidin-1-yl)benzoic acid ethyl ester (1.25 g. 5 mmoles) in dry dichloromethane (30 ml) at room temperature under an inert atmosphere, it was slowly added DAST (0.97 g, 6 mmoles) in dichloromethane (5 ml). The reaction mixture was stirred at room temperature for 1 hour and then quenched with aqueous NaHCO3. The organic layer was washed with brine, dried and evaporated. The residue was purified by flash chromatography on silica gel using hexane/EtOAc (70/30) as eluent to give the title compound as a white solid (0.7 g, 56%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[CH:23]1(/[CH:28]=[CH:29]/[C:30]([O:32][CH3:33])=[O:31])[CH2:27][CH2:26][CH2:25][CH2:24]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH:23]1([CH:28]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]4[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=4[N:9]=[CH:10][N:11]=3)[CH:3]=[N:2]2)[CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COC(=O)/C=C/C1CCCC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)CC(C1CCCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reaction time: 96 h
Yield: 63.2 %

Procedure:
To a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (2.9 g, 9.2 mmol) and methyl (2E)-3-cyclopentylacrylate (1.70 g, 11.0 mmol) in ACN (100 mL), was added DBU (2.7 mL, 18 mmol). The resulting mixture was stirred for 96 hours. The ACN was removed in vacuo, and the resulting residue was dissolved in ethyl acetate. This solution was washed with 1.0 N HCl, followed by brine, and then dried over sodium sulfate, and the solvent removed in vacuo. Flash column chromatography (eluting with a gradient from 0-70% ethyl acetate in hexanes) afforded the product (2.73 g, 63%).
Reaction SMILES: [I-].[K+].[N+]([O-])(O)=O.O=O.[CH2:9]=[CH2:10].[C:11]([OH:14])(=[O:13])[CH3:12]>>[CH3:12][C:11]([O:14][CH2:9][CH2:10][O:14][C:11]([CH3:12])=[O:13])=[O:13]
Reactant: C=C
Reactant: CC(=O)O
Agent: O=O
Agent: [I-]
Agent: [K+]
Solvent: O=[N+]([O-])O
Product: CC(=O)OCCOC(C)=O
Temperature: 65 °C

Procedure:
To a reactor similar to that described in Example 1 were added 3.3 g (20 millimoles) of potassium iodide, 1 ml (10 millimoles) of nitric acid, 0.5 g of activated carbon prepared from coconut shells (manufactured by Dai-ichi Carbon Industries Company) and 80 ml of acetic acid. The flask was set up in an oil bath maintained at 65° C. A gas mixture comprising by volume 8.5% of oxygen, 80% of nitrogen and 11.5% of ethylene was fed through the reaction mixture at a rate of 1.15 standard liters per hour with continuous stirring of the reaction mixture. At the conclusion of the one hour reaction period, the conversion of ethylene was 90%. The combined yields of EGDA and EGMA were 95% based on the reacted ethylene. Trace amounts of EDA and AcH were detected as by-products.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]#[N:11])=[CH:2]1.[CH2:12]([O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18](I)[CH:17]=1)[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CS(C)=O.[Cu](I)I>[CH2:12]([O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]#[N:11])=[CH:2]2)[CH:17]=1)[CH3:13]
Reactant: N#Cc1c[nH]c2ccccc12
Reactant: CCOC(=O)c1cccc(I)c1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(-n2cc(C#N)c3ccccc32)c1
Temperature: 75 °C
Reaction time: 72 h
Yield: 66.5 %

Procedure:
To a solution of 1H-indole-3-carbonitrile (0.28 g) in dimethyl sulfoxide (3 mL) were added 3-iodobenzoic acid ethyl ester (0.61 g), cesium carbonate (0.65 g), copper iodide (0.038 g) and N,N-dimethyl grycine (0.041 g), this mixture was stirred at 75° C. for 3 days. To this reaction mixture was added ethyl acetate, the insoluble material was removed by filtration and this filtrate was concentrated under reduced pressure. To this residue was added water, the precipitated solid was collected by filtration, and washed with water and n-hexane, and dried under reduced pressure at 40° C. to give the title compound (0.38 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17](Cl)=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1[NH:22][CH:23]=[CH:24][N:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.[Cu](I)I>[CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:22]3[CH:23]=[CH:24][N:25]=[C:21]3[CH3:20])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ncc[nH]1
Reactant: Clc1cnc2c(n1)OCCN(Cc1ccccc1)C2
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nccn1-c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Yield: 15.4 %

Procedure:
A solution of 8-benzyl-3-chloro-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (100 mg), 2-methyl-1H-imidazole (42 mg), copper iodide (14 mg) and cesium carbonate (236 mg) in DMF (2 mL) was stirred at 100° C. overnight. The reaction mixture was filtered, water (10 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 50→100% ethyl acetate/hexane) to give the title compound (18 mg, 15%) as a pale-yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C:14]2[C:10](=[N:11][NH:12][C:13]=2[NH2:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:17][CH:18]([C:22](=O)[CH3:23])[C:19](=O)[CH3:20]>CC(O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:15][C:14]2=[C:13]3[N:12]([N:11]=[C:10]2[CH2:9]1)[C:22]([CH3:23])=[C:18]([F:17])[C:19]([CH3:20])=[N:16]3)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2n[nH]c(N)c2C1
Reactant: CC(=O)C(F)C(C)=O
Solvent: CC(=O)O
Product: Cc1nc2c3c(nn2c(C)c1F)CN(C(=O)OC(C)(C)C)C3
Reaction time: 1 h
Yield: 51 %

Procedure:
A solution of 3-amino-2,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester (4.3 g; 19.2 mmol; 1 eq.) and 3-fluoropentane-2,4-dione (2.49 g; 21.1 mmol; 1.1 eq.) in AcOH (40 mL) was stirred at room temperature for 18 hours. 3-fluoropentane-2,4-dione (0.45 g; 3.83 mmol; 0.2 eq.) was added and the reaction mixture was stirred for one hour then concentrated in vacuo. The residue was partitioned between EA and 1M NaOH and the aqueous layer extracted with EA. The combined organic phase was dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (10 to 40% EA in cyclohexane) afforded the title compound (3 g, 58%) as a white solid. HPLC (max plot) 99.4%; Rt 3.83 min. UPLC/MS: (MS+) 307.2 ([M+H]+).