Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1.[OH-].[K+]>C1(C)C(C)=CC=CC=1.CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1
Reactant: CCCCCCCC(=O)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: CO
Product: CCCCCCCC(O)c1ccc(C)cc1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
Tris(triphenylphosphine)ruthenium (II) chloride (1.9 mg, 2 μmol, 0.5 mol %) and a chiral ligand (M=Ru, R=t-Bu, Ar=C6H5—, 1.3 μmol, 0.33 mol %) were dissolved in xylene (3 mL) under nitrogen atmosphere, and then heated and stirred for 2 h at 140° C. After the mixture was cooled to room temperature, p-methyloctanophenone (0.8 mmol), xylene (2 mL) and a solution of potassium hydroxide in methanol (0.8 mL, 0.2 M) were added thereto. Thereafter, the reaction system was placed in an autoclave, and stirred for 6 h under H2 (10 atm) at 50° C. The solvent was removed under reduced pressure, and the resultants were separated by column chromatography (silica gel column; eluent:ethyl acetate/petroleum ether=1/5). Accordingly, pure 1-(p-methylphenyl) octanol was obtained and the ee value (ee=99.0%) was measured by GC analysis.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[CH2:41]([NH2:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C)C=O.ClCCl>[NH2:1][C:2]1[S:3][C:4]([C:8]([NH:48][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: NCc1ccccc1
Reactant: Cc1nc(N)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(N)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.8 %

Procedure:
To a solution of 2-amino-4-methylthiazole-5-carboxylic acid (0.86 g, 5.44 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added 1-hydroxy-benzotriazole (0.96 g, 7.07 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (1.36 g, 7.07 mmol), N,N-diisopropylethylamine (2.46 mL, 14.14 mmol) and benzylamine (0.71 mL, 6.53 mmol). The reaction mixture was stirred at ambient temperature for 18 hours, diluted with dichloromethane (30 mL) and washed with saturated aqueous sodium bicarbonate (15 mL) and brine (15 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (20-35% ethyl acetate in hexanes) to afford the title compound as a white solid (1.02 g, 76%): 1H NMR (300 MHz, DMSO-d6) δ 8.01 (t, J=6.0 Hz, 1H), 7.36-71.9 (m, 7H), 4.34 (d, J=6.0 Hz, 2H), 2.34 (s, 3H); MS (ES+) m/z 248.2 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.Cl[CH2:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19]>C1COCC1>[I:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:17][C:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(I)cc3c2C1
Reactant: O=C(CCl)N1CCCCC1
Solvent: C1CCOC1
Product: CN1CCc2c(c3cc(I)ccc3n2CC(=O)N2CCCCC2)C1
Reaction time: 0.5 h

Procedure:
Sodium hydride was washed with hexane for removal of oil and dried under vacuum. Then sodium hydride was taken in THF. To this solution 8-iodo-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.32 mmol) in THF was added drop wise at 0° C. Then reaction mixture stirred for 0.5 h. The solution of 2-chloro-1-(piperidin-1-yl)ethanone in THF was added drop wise in reaction mixture. Then reaction mixture stirred at rt for 2 h. Reaction monitored by TLC, after completion of reaction, reaction mixture quench with ice-water. THF was evaporated and aqueous layer was extracted with ethyl acetate. Organic layer was dried over anhydrous sodium sulphate. The crude compound was purified by column chromatography to gives 25 mg of desired compound. Out of that 5 mg was stirred with ethanolic HCl to give HCl salt of 2-(8-iodo-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(piperidin-1-yl)ethanone.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:16])[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:5]([F:17])=[C:4](Cl)[N:3]=1.O.[NH2:20][NH2:21]>CS(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:16])[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:5]([F:17])=[C:4]([NH:20][NH2:21])[N:3]=1
Reactant: CN(Cc1ccncc1)c1nc(Cl)nc(Cl)c1F
Reactant: NN
Solvent: O
Solvent: CS(C)=O
Product: CN(Cc1ccncc1)c1nc(Cl)nc(NN)c1F
Temperature: 50 °C
Yield: 23.1 %

Procedure:
2,6-Dichloro-5-fluoro-N-methyl-N-(4-pyridinylmethyl)-4-pyrimidinamine (0.3516 g, 1.23 mmol) was dissolved in 5 mL of DMSO and hydrazine monohydrate (0.36 mL, 7.4229 mmol). The reaction vessel was pressure sealed and heated to 50° C. for 2.5 hours. The reaction mixture was then purified by RP-HPLC to provide 2-chloro-5-fluoro-6-hydrazino-N-methyl-N-(4-pyridinylmethyl)-4-pyrimidinamine as a wine colored solid (0.0803 g, 23%). LCMS: (M+H)+=283.0.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][CH:46]=1)[CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]([N:13]([CH2:20][CH2:21][N:22]([CH2:30][CH2:31][C:32]1[C:37]2[O:38][CH2:39][C:40](=[O:42])[NH:41][C:36]=2[C:35]([OH:43])=[CH:34][CH:33]=1)[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12])#N.O.[PH2]([O-])=[O:49].[Na+]>N1C=CC=CC=1.C(O)(=O)C.O.[Ni]>[CH:14]1([N:13]([CH2:20][CH2:21][N:22]([CH2:30][CH2:31][C:32]2[C:37]3[O:38][CH2:39][C:40](=[O:42])[NH:41][C:36]=3[C:35]([OH:43])=[CH:34][CH:33]=2)[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[C:11](=[O:12])[CH2:10][CH2:9][O:8][CH2:7][CH2:6][C:5]2[CH:44]=[CH:45][CH:46]=[C:3]([CH:1]=[O:49])[CH:4]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(O)c2c1OCC(=O)N2)CCN(C(=O)CCOCCc1cccc(C#N)c1)C1CCCCC1
Reactant: O=[PH2][O-]
Agent: [Ni]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)N(CCc1ccc(O)c2c1OCC(=O)N2)CCN(C(=O)CCOCCc1cccc(C=O)c1)C1CCCCC1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a stirred solution of tert-butyl 2-(3-(3-cyanophenethoxy)-N-cyclohexylpropanamido)ethyl(2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethyl)carbamate [Examples 81-175, step e] (7.3 g) in pyridine (115 mL), acetic acid (58 mL) and water (58 mL), pre-cooled in ice-water under nitrogen, was added sodium hypophosphite monohydrate (14.6 g) followed by Raney® nickel (50% in water, 3.0 g). The reaction mixture was stirred at 45° C. for 8 hours, then allowed to cool and stand over a weekend. Celite was added and the suspension was filtered through a pad of Celite, washing the residue well with acetic acid and ethyl acetate. The filtrate was washed three times with water, once with brine, then dried (MgSO4), filtered and concentrated in-vacuo. The residue was azeotroped twice with toluene to afford the subtitled compound as a pale yellow foam. Yield 6.6 g.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:13][C:12]2[O:22][CH2:23][O:24][C:11]=2[CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=[O:27])C.OO.[OH2:31]>[NH4+].[NH4+].[O-][Mo]([O-])(=O)=O>[C:7]([NH:8][C:9]1[CH:10]=[C:11]2[O:24][CH2:23][O:22][C:12]2=[CH:13][C:14]=1[C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:27])(=[O:31])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O
Reactant: CC(=O)O
Reactant: c1ccc(-c2[nH]c3cc4c(cc3c2-c2ccccc2)OCO4)cc1
Agent: O=[Mo](=O)([O-])[O-]
Agent: OO
Agent: [NH4+]
Product: O=C(Nc1cc2c(cc1C(=O)c1ccccc1)OCO2)c1ccccc1

Procedure:
To a flask equipped with a stirrer, condenser, dropping funnel and thermometer are charged 31.3 g. of 2,3-diphenyl-5,6-methylenedioxy indole, 600 ml. of acetic acid and 0.30 g. of ammonium molybdate dissolved in 30 ml. of water. The stirred mixture is heated to 60°-65°C. and then treated dropwise (about 15 minutes) with 30 ml. of 40% hydrogen peroxide. The mixture is maintained at 65° for about 2 hours and then treated with 150 ml. water. The resultant solid is filtered off and recrystallized from chloroform to give 2-benzoylamino-4,5-methylenedioxybenzophenone, m.p. 195°-197°C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.CCN(CC)CC.Br[CH2:44][C:45]([NH2:47])=[O:46]>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:45]([CH2:44][N:23]1[CH2:22][CH2:21][CH:20]([C:18]2[CH:17]=[CH:16][C:15]([NH:26][C:27]([C:29]3[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=3)=[O:28])=[C:14]([C:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=3)[CH:19]=2)[CH2:25][CH2:24]1)(=[O:46])[NH2:47]
Reactant: NC(=O)CBr
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(CC(N)=O)CC3)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.8 %

Procedure:
A flask was charged with 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (50 mg, 0.10 mmol) (as prepared in Example 14, step (b)), NEt3 (32 μL, 0.23 mmol), 2-bromoacetamide (16 mg, 0.12 mmol), and 0.5 mL of DCM and stirred for 4 h at 25° C. The reaction was concentrated and the title compound was purified by RP-HPLC (C18), eluting with 30-50% CH3CN in 0.1% TFA/H2O over 12 min to give 42 mg (75%) of a white solid. 1H-NMR (400 MHz, DMSO-d6): δ 14.28 (br s, 1H), 9.78 (s, 1H), 9.50 (br s, 1H), 8.34 (s, 1H), 8.00 (s, 1H), 7.88 (d, 1H), 7.72 (s, 1H), 7.18 (dd, 1H), 7.10 (d, 1H), 5.76 (m, 1H), 3.94 (s, 2H), 3.58 (m, 2H), 3.12 (m, 2H), 2.80 (m, 1H), 2.20 (m, 4H), 1.98 (m, 4H), 1.80 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C24H28N6O2, 433.2 (M+H). found 433.2.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[Cl:5][CH2:6][C:7]([N:9]([CH3:11])[CH3:10])=[O:8]>>[Cl-:5].[CH3:10][N:9]([CH3:11])[C:7]([CH2:6][S:3][C:2]([NH2:4])=[NH2+:1])=[O:8]
Reactant: NC(N)=S
Reactant: CN(C)C(=O)CCl
Product: CN(C)C(=O)CSC(N)=[NH2+]
Product: [Cl-]
Yield: 89 %

Procedure:
Example 1 was repeated with thiourea and 2-chloro-N,N-dimethylacetamide, affording the title compound ina yield of 89%.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[O:8][CH2:9][C:10]([OH:12])=O)(=[O:3])[CH3:2].[NH2:16][CH2:17][CH:18]([OH:30])[CH2:19][N:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[O:8][CH2:9][C:10]([NH:16][CH2:17][CH:18]([OH:30])[CH2:19][N:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)=[O:12])(=[O:3])[CH3:2]
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: CC(=O)Nc1cccc(OCC(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1cccc(OCC(=O)NCC(O)CN2CCc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.8 %

Procedure:
To a stirred mixture of 2-(3-acetamidophenoxy) acetic acid (85 mg, 0.41 mmol) in DCM (5 mL) was added TEA (0.5 mL), 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (83.8 mg, 0.41 mmol) and HATU (171 mg, 0.451 mmol). The mixture was stirred at 25° C. for 3 hours. The reaction mixture was quenched by addition of water (20 mL) and extracted with DCM (3×20 mL) and the combined extracts washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-HPLC to afford the title product (55 mg, Yield 35%). 1H NMR (400 MHz, MeOD) δ=7.36 (s, 1H), 7.27-7.17 (m, 1H), 7.19-7.01 (m, 6H), 6.68-6.66 (m, 1H), 4.53 (s, 2H), 4.03-4.00 (m, 1H), 3.71-3.62 (m, 2H), 3.50-3.35 (m, 2H), 2.95-2.85 (m, 2H), 2.83-2.74 (m, 2H), 2.56 (d, J=6.3 Hz, 2H), 2.12 (s, 3H). LCMS (m/z): 398.1 (M+1).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:5]=1[CH2:11]Br.[NH3:14]>>[Br:10][C:7]1[CH:6]=[C:5]2[C:4](=[CH:9][CH:8]=1)[C:3](=[O:2])[NH:14][CH2:11]2
Reactant: N
Reactant: COC(=O)c1ccc(Br)cc1CBr
Product: O=C1NCc2cc(Br)ccc21
Temperature: 25 °C
Yield: 65 %

Procedure:
4-Bromo-2-bromomethyl-benzoic acid methyl ester (0.5 g, 16.2 mmol) is treated with methanolic ammonia (10 mL, 7 N NH3 in MeOH) for 5 minutes at 90° C. After cooling to room temperature a precipitate is formed, collected by filtration and washed with a small amount of methanol to afford the title compound as a colourless solid (224 mg, 65%). 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 4.41 (2H, s), 7.64 (1H, d), 7.70 (1H, d), 7.87 (1H, s), 8.67 (1H, br s). LCMS: Rt 2.49 min, (99.6%), m/z (APCI) 212 (M+H+).
Reaction SMILES: [CH2:1]([CH:3]([CH2:9][CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.Br[CH2:32][C:33]#[N:34]>C1COCC1>[C:33]([CH2:32][C:3]([CH2:9][CH3:10])([CH2:1][CH3:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:34]
Reactant: N#CCBr
Reactant: CCOC(=O)C(CC)CC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(CC)(CC)CC#N
Temperature: -78 °C
Reaction time: 1 h
Yield: 101 %

Procedure:
A solution of ethyl 2-ethylbutyrate (21.60 g, 150 mmol) in THF (25 mL) was added dropwise to a solution of lithium diisopropylamide prepared by treating diisopropylamine (16.67 g, 165 mmol) in dry THF (150 mL) with butyllithium in hexanes (2.5M, 66 mL, 165 mmol) at -78° C. for 1 h in a nitrogen atmosphere. The resulting mixture was stirred at -78° C. for 1 h, then a solution of bromoacetonitrile (21.60 g, 180 mmol) in THF (50 mL) was introduced slowly over a period of 30 minutes (the reaction mixture starts getting darker as the addition progresses). The resulting dark mixture was stirred overnight (ca. 16 h) and allowed to warm from -78° C. to room temperature. The reaction was quenched by addition of HCl (1N, 250 mL) at 0° C. The layers were separated, and the aqueous phase was further extracted with ether (3×100 mL). The combined organic extract was washed sequentially with 75 mL portions of saturated NaHCO3, water (several times), and brine, and dried over MgSO4. The solvent was removed in vacuo to give 27.77 g of dark colored liquid. After two vacuum distillations, the nitrile (12.35 g, 45%) was obtained as a colorless liquid: bp 84°-85° C. (1.3 mmHg). Analytical sample was prepared by column chromatography over silica gel (hexanes-EtOAc, 19:1) followed by bulb-to-bulb distillation (pot temp. 80° C. (1 mmHg)).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[OH:11].Cl[C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[C:16]([C:23]3[NH:31][C:30]4[CH2:29][CH2:28][NH:27][C:26](=[O:32])[C:25]=4[CH:24]=3)[CH:17]=[CH:18][CH:19]=2)[N:14]=1.C(O)(C(F)(F)F)=O>CN(C=O)C.CS(C)=O>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[O:11][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[C:16]([C:23]3[NH:31][C:30]4[CH2:29][CH2:28][NH:27][C:26](=[O:32])[C:25]=4[CH:24]=3)[CH:17]=[CH:18][CH:19]=2)[N:14]=1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Reactant: Oc1c(F)cccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Oc5c(F)cccc5Cl)nc34)cc21
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 29.4 %

Procedure:
To NaH (60 wt % in mineral oil; 0.071 g, 1.763 mmol) in 1 mL DMF was added 2-chloro-6-fluorophenol (0.258 g, 1.763 mmol). After 10 min, a clear/colorless solution resulted. 2-(2-Chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 0.075 g, 0.252 mmol) was added and the reaction became dark red. The reaction was heated at 70° C. for 1 h, then at 90° C. for 2 h, then at 110° C. for 14 h. The reaction was cooled to 0° C. and quenched with TFA (0.136 ml, 1.763 mmol), diluted with 1 mL DMSO, filtered, and purified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 15-100% ACN/H2O with 0.1% TFA); product-containing fractions were concentrated in vacuo then treated with saturated aq. NaHCO3 and DCM. The organic layer was separated and the aq. layer was extracted 3×DCM. The combined organic extracts were then dried over Na2SO4, filtered, and concentrated in vacuo to give 2-(2-(2-chloro-6-fluorophenoxy)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.030 g, 0.074 mmol, 29% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 10.91 (1H, br. s), 8.57 (1H, d, J=8.8 Hz), 8.05-8.15 (1H, m), 7.84 (1H, dt, J=7.7, 0.8 Hz), 7.38-7.69 (5H, m), 6.87-6.91 (1H, m), 6.85 (1H, d, J=2.3 Hz), 3.32-3.38 (2H, m), 2.54-2.50 (2H, m). m/z (ESI, +ve) 408.2 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]2[N:13]=[CH:14][S:15][CH:16]=2)=[CH:6][C:5]=1[OH:17])([CH3:3])[CH3:2].Br[CH2:19][C:20]#[N:21].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]2[N:13]=[CH:14][S:15][CH:16]=2)=[CH:6][C:5]=1[O:17][CH2:19][C:20]#[N:21])([CH3:3])[CH3:2]
Reactant: N#CCBr
Reactant: COc1cc(C(C)C)c(O)cc1-c1cscn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(C)C)c(OCC#N)cc1-c1cscn1
Yield: 72 %

Procedure:
The crude 2-Isopropyl-4-methoxy-5-thiazol-4-yl-phenol from step 4 and bromoacetonitrile (0.33 g, 2.72 mmol) together with K2CO3 (0.94 g, 6.81 mmol) in anhydrous actonitrile (30 ml) was heated at 60° C. for 3 hrs. The reaction mixture was partitioned between EtOAc and water. The combined organic extract was dried over Na2SO4, filtered and concentrated. Flash chromatography on silica (10 to 20%% EtOAc in Hexanes) gave (2-Isopropyl-4-methoxy-5-thiazol-4-yl-phenoxy)-acetonitrile (0.47 g, 72%) as an oil.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:18])C=1.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([C:3]1[C:4]([CH3:9])=[N+:5]([O-:18])[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCc1cccnc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1ccc[n+]([O-])c1C
Temperature: 25 °C
Reaction time: 90 h
Yield: 89.6 %

Procedure:
First, 3-ethyl-2-methylpyridine (7.25 g, 59.8 mmol) was dissolved in dichloromethane (dehydrated) (100 ml) and 3-chloroperbenzoic acid (19.0 g, 71.6 mmol, as the content was regarded as 65%) was added in a nitrogen atmosphere at ice-cooling temperature. The mixture was stirred at room temperature for 90 hours. To the reaction mixture, a saturated aqueous sodium hydrogen carbonate solution was added. The aqueous layer was extracted twice with dichloromethane and three times with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, filtrated and concentrated. The residue was purified by silica gel column chromatography (silica gel: 100 g, elution solvent: heptane, ethyl acetate/methanol=10/1) to obtain the title compound (7.35 g, yield: 89.6%) as a reddish solid.
Reaction SMILES: [CH2:1](/[C:3](/[C:11]#[C:12][C:13]1([OH:28])[C:24]([CH3:26])([CH3:25])[CH2:23][C:16]2(OC(C)C(C)[O:17]2)[CH:15]=[C:14]1[CH3:27])=[CH:4]/[C:5]([NH:7][CH2:8][CH2:9][CH3:10])=[O:6])[CH3:2].Cl.O>CC(C)=O>[CH2:1](/[C:3](/[C:11]#[C:12][C:13]1([OH:28])[C:24]([CH3:26])([CH3:25])[CH2:23][C:16](=[O:17])[CH:15]=[C:14]1[CH3:27])=[CH:4]/[C:5]([NH:7][CH2:8][CH2:9][CH3:10])=[O:6])[CH3:2]
Reactant: CCCNC(=O)/C=C(\C#CC1(O)C(C)=CC2(CC1(C)C)OC(C)C(C)O2)CC
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CCCNC(=O)/C=C(\C#CC1(O)C(C)=CC(=O)CC1(C)C)CC
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 87.5 %

Procedure:
(2Z)-3-Ethyl-5-(8-hydroxy-2,3,7,9,9-pentamethyl-1,4-dioxaspiro[4.5]dec-6-en-8-yl)-N-propylpent-2-en-4-ynamide (280 mg, 0.72 mmol) was dissolved in acetone (4 ml) under argon in a round-bottom flask, and 10% strength hydrochloric acid was added. The resulting reaction solution was stirred at room temperature for 50 minutes, and water was then added. After removing acetone under reduced pressure, the aqueous phase was extracted repeatedly with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By final column chromatography purification of the resulting crude product (ethyl acetate/heptane gradient), it was possible to obtain (2Z)-3-ethyl-5-(1-hydroxy-2,6,6-trimethyl-4-oxocyclohex-2-en-1-yl)-N-propylpent-2-en-4-ynamide (200 mg, 88% of theory) in the form of a colorless solid. 1H-NMR (400 MHz, CDCl3 δ, ppm) 6.08 (br. t, 1H, NH), 6.00 (s, 1H), 5.87 (s, 1H), 3.54 (br. s, 1H, OH), 3.27 (m, 2H), 2.53 (d, 1H), 2.42 (d, 1H), 2.27 (q, 2H), 2.17 (s, 3H), 1.56 (sext, 2H), 1.22 (s, 3H), 1.13 (s, 3H), 1.11 (t, 3H), 0.93 (t, 3H).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[N:8]=1)=O.[OH:27][CH2:28][CH2:29][NH:30][NH2:31]>CO>[OH:27][CH2:28][CH2:29][N:30]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:18][CH:19]=3)[N:8]=2)=[CH:4][CH:3]=[N:31]1
Reactant: CN(C)C=CC(=O)c1nn(-c2ccc(N3CCOCC3)cc2)ccc1=O
Reactant: NNCCO
Solvent: CO
Product: O=c1ccn(-c2ccc(N3CCOCC3)cc2)nc1-c1ccnn1CCO
Yield: 7.3 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-(4-morpholin-4-ylphenyl)pyridazin-4(1H)-one (476 mg, 1.34 mmol) in 20 mL of methanol, 2-hydroxyethylhydrazine (414 mg, 5.36 mmol) was added, the resulting mixture was refluxed for 4 hours, and then concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1 M acetic acid aqueous solution and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (36 mg, 7.3% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3): δ 3.20-3.22 (4H, m), 3.87-3.89 (4H, m), 4.03-4.05 (2H, m), 4.33-4.36 (2H, m), 6.69 (1H, d, J=7.6 Hz), 6.98 (2H, dd, J=6.8, 2.0 Hz), 7.34 (1H, d, J=2.4 Hz), 7.51-7.53 (3H, m), 8.14 (1H, d, J=7.6 Hz); LCMS (mobile phase: from 95% water and 5% CH3CN to 5% water and 95% CH3CN in 6 min, finally under these conditions for 0.5 min.) purity is >95%, Rt=2.770 min; MS Calcd.: 367, MS Found: 368 [M+H]+.
Reaction SMILES: CS[C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH:9]([O:16][CH3:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]=1.Cl[C:19]1C=CC=C(C(OO)=O)C=1.[S:29]([O-:33])([O-])(=[O:31])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:17][O:16][CH:9]([C:5]1[CH:4]=[C:3]([S:29]([CH3:19])(=[O:33])=[O:31])[N:8]=[CH:7][N:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(c1ccccc1)c1cc(SC)ncn1
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(c1ccccc1)c1cc(S(C)(=O)=O)ncn1
Temperature: 0 °C
Reaction time: 10 h

Procedure:
To 2 ml of chloroform were added 0.17 g of 6-methylthio-4-(α-methoxybenzyl)pyrimidine and 0.43 g of m-chloroperbenzoic acid (>65%), followed by stirring at 0° C. for 10 hours. The reaction mixture was then poured into a saturated aqueous sodium thiosulfate solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.2 g of 4-(α-methoxybenzyl)-6-methanesulfonylpyrimidine.
Reaction SMILES: [C:1]([C@@:18]1([N:26]2[C:36]3[N:35]=[C:33]([NH2:34])[NH:32][C:30](=[O:31])[C:29]=3[N:28]=[CH:27]2)[O:25][C@H:22]([CH2:23][OH:24])[C@@H:20]([OH:21])[CH2:19]1)(=[O:17])[CH2:2][CH2:3][CH2:4]CCCCCCCCCCCC.C(Cl)(=O)CCC.C(Cl)(=O)CCCCCCCCCCCCCCC>>[C:1]([C@@:18]1([N:26]2[C:36]3[N:35]=[C:33]([NH2:34])[NH:32][C:30](=[O:31])[C:29]=3[N:28]=[CH:27]2)[O:25][C@H:22]([CH2:23][OH:24])[C@@H:20]([OH:21])[CH2:19]1)(=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCCCCCCCCCC(=O)[C@]1(n2cnc3c(=O)[nH]c(N)nc32)C[C@H](O)[C@@H](CO)O1
Agent: CCCC(=O)Cl
Agent: CCCCCCCCCCCCCCCC(=O)Cl
Product: CCCC(=O)[C@]1(n2cnc3c(=O)[nH]c(N)nc32)C[C@H](O)[C@@H](CO)O1

Procedure:
This compound was prepared using the procedure for palmitoyl-2'-deoxyguanosine, substituting the appropriate amount of butyryl chloride for palmitoyl chloride, and isolating as follows: evaporating the solvent after 72 hours, triturating the resulting material in 1:1 diethyl ether-ethyl acetate, and recovering the product by filtration.