Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([Cl:16])[C:7]=2[C:8]=1[NH2:9])(=[O:3])[CH3:2].[CH:17]([C:20]1[S:21][C:22]([CH:25]=O)=[CH:23][N:24]=1)([CH3:19])[CH3:18].[OH-].[Na+]>C1COCC1>[NH2:9][C:8]1[C:7]2[C:10]([Cl:16])=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:6]=2[O:5][C:4]=1[C:1](=[O:3])/[CH:2]=[CH:25]/[C:22]1[S:21][C:20]([CH:17]([CH3:19])[CH3:18])=[N:24][CH:23]=1
Reactant: COc1ccc2oc(C(C)=O)c(N)c2c1Cl
Reactant: CC(C)c1ncc(C=O)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc2oc(C(=O)/C=C/c3cnc(C(C)C)s3)c(N)c2c1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
7G (3 g, 12.5 mmol) was dissolved in THF (tetrahydrofuran, 30 mL). To the solution was added 2-isopropyl-thiazole-5-carbaldehyde (2.33 g, 15 mmol, 1.2 eq), followed by crushed NaOH powder (1 g, 25 mmol, 2 eq). The reaction mixture was stirred at room temperature for 10 min. The solution became dark and some solids formed. The mixture was poured into ice-water under stirring.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH:11]=1)[CH2:7][CH2:8][CH3:9].CN(C)[CH:24]=[O:25]>ClCCl>[CH2:6]([C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH2:13][CH2:12][C:11]=1[CH:24]=[O:25])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCC1=CCCc2cc(OC)ccc21
Reactant: CN(C)C=O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCC1=C(C=O)CCc2cc(OC)ccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Phosphorus oxychloride (16.6 mL) was added dropwise with stirring to dimethylformamide (70 mL) at -5° C. After the addition was completed, the mixture was stirred at 0° C. for 15 minutes, then a solution of 1-butyl-3,4-dihydro-6-methoxy-naphthalene (34.9 g) in dimethylformamide (30 mL) was added slowly over 15 minutes while the reaction temperature was maintained at 0° C. The cooling bath was then withdrawn and after the mixture had stirred at room temperature for 1.5 hours, a few chips of ice were added, followed, after 5 minutes, by 10N sodium hydroxide (200 mL). The reaction was heated to 110° C. which caused the vigorous evolution of dimethylamine from the mixture and after 10 minutes the reaction was cooled, diluted with water (750 mL) and extracted with dichloromethane (1×500 mL; 2×300 mL). The organic layers were washed in turn with water (2×200 mL), then were combined, dried (MgSO4 ) and evaporated to furnish an amber oil which was passed through a short column of silica gel (200 g) in dichloromethane. The fractions containing the product were evaporated to yield 39.4 g of crude 1-butyl-3,4-dihydro-6-methoxy-2-naphthalene-carboxaldehyde as an oil.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([N+:14]([O-])=O)[CH:8]=2)[CH:3]=1>[Pd]>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[NH:5][N:6]=[C:2]([CH3:1])[CH:3]=2)=[CH:8][C:9]=1[NH2:14]
Reactant: Cc1cc(-c2ccc(C)c([N+](=O)[O-])c2)n[nH]1
Agent: [Pd]
Product: Cc1cc(-c2ccc(C)c(N)c2)[nH]n1
Reaction time: 5 h
Yield: 5.9 %

Procedure:
5-Methyl-3-(4-methyl-3-nitro-phenyl)-1H-pyrazole (8.2 g) was dissolved in ethanoland Palladium (10%) on activated carbon was added. The mixture was subject to barometric hydrogenation under balloon pressure for five hours at room temperature. The mixture was filtered and the filtrate was concentrated under reduced pressure to give 414 mg of crude 2-methyl-5-(5-methyl-2H-pyrazol-3-yl)-phenylamine as a white solid, which was used directly without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:10].[Cl-].[Mg+2].[Cl-].[CH2:14]=[O:15].Cl>ClCCCl.C(N(CC)CC)C>[Cl:1][C:2]1[C:3]([OH:10])=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[CH:14]=[O:15]
Reactant: COc1cccc(O)c1Cl
Reactant: C=O
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COc1ccc(C=O)c(O)c1Cl
Temperature: 70 °C
Reaction time: 4 h
Yield: 94.7 %

Procedure:
To a solution of 2-chloro-3-methoxyphenol (19.3 g) in 1,2-dichloroethane (150 mL) were added triethylamine (73.7 g), magnesium chloride (57.8 g) and paraformaldehyde (36.5 g), and the mixture was stirred at 70° C. for 4 hr under nitrogen atmosphere. The reaction mixture was poured into 1N hydrochloric acid, and the precipitate was removed by filtration, and washed with dichloromethane. The organic layer was washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (21.5 g).
Reaction SMILES: C([C@@H:6]([C@H:8]([C:10]([O:12][CH2:13]C)=O)[OH:9])O)(OCC)=O.C(OO)(C)(C)C.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1C(=C)[C@@H](O)C.[OH-].[Na+].[Na+].[Cl-].[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C@:10]1([O:12][CH2:13]1)[C@@H:8]([OH:9])[CH3:6]
Reactant: C=C(c1ccc(F)cc1F)[C@H](C)O
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Agent: [Ti+4]
Agent: CC(C)(C)OO
Agent: CC(C)[O-]
Solvent: ClCCl
Product: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Temperature: -5 °C
Reaction time: 0.42 h
Yield: 43 %

Procedure:
To a solution of diethyl L(+)-tartrate (2.43 g, 0.0118 mole) in 470 ml of dry CH2Cl2 were added activated 3A° molecular sieve powder (6 g) and cooled the mixture to -5° C. Added a solution of titanium (IV) isopropoxide (7.2 g, 0.0253 mole) in 38 ml of CH2Cl2 followed by t-butyl hydroperoxide (11.2 g, 0.124 mole) in 75 ml of CH2Cl2 and continue to stir at -5° C. for 25 minutes. To this mixture, a solution of compound 6a, (2S)-3-(2,4-Difluorophenyl)-3-buten-2-ol, (7.5 g, 0.041 mole) in 38 ml of CH2Cl2 was added and stirred for 12 hours at 5° C. Cooled the reaction mixture to -40° C., added 20 ml of 30% aq. NaOH solution saturated with NaCl and the mixture was allowed to warm to 10° C. 20 g of MgSO4, 6 g of celite was added to the mixture and continued to stir at 10° C. for 30 minutes. The mixture was suction-filtered over celite. To the filtrate 280 ml of toluene, 225 ml of ether were added and insoluble material removed by filtration. The filtrate was evaporated in vacuo, the residue was dissolved in 200 ml of ether and suction filtered to remove the insoluble material. The filtrate was passed through a bed of silica gel and washed the pad of silica gel with 20 ml of ether. The filtrate was concentrated under reduced pressure to give yellow oil, which was chromatographed on silica gel. Elution with CHCl3 gave title compound 7a as an oil (3.5 g, 43%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@@H:3]1[C:11]([OH:13])=O.[NH2:15][C:16]1[S:17][C:18]([CH3:21])=[CH:19][N:20]=1>>[CH3:14][C:2]1([CH3:1])[C@@H:4]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@H:3]1[C:11]([NH:15][C:16]1[S:17][C:18]([CH3:21])=[CH:19][N:20]=1)=[O:13]
Reactant: Cc1cnc(N)s1
Reactant: CC1(C)[C@@H](C(=O)O)[C@@H]1c1ccccc1
Product: Cc1cnc(NC(=O)[C@H]2[C@H](c3ccccc3)C2(C)C)s1
Yield: 61.8 %

Procedure:
2,2-Dimethyl-trans-3-phenylcyclopropanecarboxylic acid (250 mg, 1.32 mmol) and 2-amino-5-methylthiazole (150 mg, 1.31 mmol) were reacted as described under General Procedure D to furnish the title compound (232 mg, 61%) as a yellow foam. 1H NMR (300 MHz, CDCl3) δ 7.33-7.17 (m, 6H), 7.02 (s, 1H), 2.95 (d, J=5.6 Hz, 1H), 2.37 (s, 3H), 2.08 (d, J=5.6 Hz, 1H), 1.44 (s, 3H), 1.03 (s, 3H). mp 132-135° C. ESIMS m/z [M+H]+ 287.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH3:17])([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[O:30]1[C:34]([C:35]2[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=2)[NH2:38])=[CH:33][N:32]=[CH:31]1>ClCCCl.CN(C=O)C.C(OCC)(=O)C>[CH3:17][C:11]1([C:14](=[O:16])[NH:38][C:37]2[CH:39]=[CH:40][CH:41]=[C:35]([C:34]3[O:30][CH:31]=[N:32][CH:33]=3)[CH:36]=2)[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Reactant: Nc1cccc(-c2cnco2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(C)(C(=O)Nc2cccc(-c3cnco3)c2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (61.3 mg, 0.252 mmol) and pyridine (79.7 mg, 0.08 mL, 1.01 mmol) in 1,2-dichloroethane (2 mL) at 0° C. was added DMF (1-2 drops) followed by oxalyl chloride (31.9 mg, 0.022 mL, 0.252 mmol). The reaction was stirred for 0.5 hour, and 3-(oxazol-5-yl)aniline (40.4 mg, 0.252 mmol) was added. The reaction was allowed to stir for another 1.5 hours. The mixture was diluted with ethyl acetate (10 mL), and the organics were washed with 0.1 N HCl (2×10 mL), brine (4 mL), dried over MgSO4, filtered, and concentrated to give the title compound, which was used in the next step without further purification. MS (ES+) [M+H]+=386.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[N:21]([C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)=[C:22]=[O:23]>CN(C=O)C>[F:31][C:30]([F:32])([F:33])[C:27]1[CH:26]=[CH:25][C:24]([NH:21][C:22]([N:18]2[CH2:19][CH2:20][CH:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:23])=[CH:29][CH:28]=1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: CN(C)C=O
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(C(F)(F)F)cc4)CC3)c2cc1OC
Yield: 26.7 %

Procedure:
A solution of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (20 mg, 0.0733 mmol), as prepared in Example 1d, in DMF (1 mL) was treated with 1-isocyanato-4-trifluoromethyl-benzene (20 mg, 0.107 mmol) at RT overnight. The reaction was then partitioned between EtOAc (10 mL) and H2O (10 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. Purification by prep tlc (1:9 MeOH/DCM) afforded the title compound as a yellow solid (9.0 mg, 27%). 1H NMR (300 MHz, CDCl3) δ 9.10 (s, 1H), 7.54 (m, 2H), 7.39 (m, 1H), 7.28 (m, 2H), 6.69 (m, 1H), 6.63 (br s, NH), 4.33-4.29 (m, 2H), 4.09 (s, 6H), 3.65 (m, 1H), 3.22 (m, 2H), 2.17 (m, 2H), 2.06-2.01 (m, 2H); LC/MS (ESI) calcd mass 460.2, found 461.3 [M+1]+.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][C@@H:7]([CH2:9][OH:10])[C@@H:6]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:5]1)=[N+]=[N-].CCOC(C)=O>[Pd]>[NH2:1][C@@H:4]1[CH2:8][C@@H:7]([CH2:9][OH:10])[C@@H:6]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:14])[CH2:5]1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](N=[N+]=[N-])C[C@H]1CO
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](N)C[C@H]1CO
Reaction time: 8 h
Yield: 87.6 %

Procedure:
A suspension of ((1S,2S,4R)-4-azido-2-{[tert-butyl(dimethyl)silyl]oxy}-cyclopentyl)methanol (0.211 g, 0.000777 mol) and 10% Pd/C (0.047 g, 0.000044 mol) in EtOAc (6 mL, 0.06 mol) was stirred under an atmosphere of Hydrogen overnight. The reaction was purged with nitrogen and filtered the mixture through celite with DCM. The filtrate was concentrated to obtain 167 mg (87.5%) of the title compound.
Reaction SMILES: C(O)(=O)C.[C:5]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:10]=[CH:9][C:8]([CH:11]=[N:12][NH:13][C:14]2[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:18](=[O:29])[N:17]([CH3:30])[C:16](=[O:31])[CH:15]=2)=[CH:7][CH:6]=1.N1CCCCC1.[C:44]1([CH2:50][CH:51]=O)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C=O)C>[CH2:50]([C:51]1[N:12]([CH2:11][C:8]2[CH:7]=[CH:6][C:5]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:10][CH:9]=2)[N:13]=[C:14]2[C:15]=1[C:16](=[O:31])[N:17]([CH3:30])[C:18](=[O:29])[N:19]2[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=CCc1ccccc1
Reactant: COc1ccc(Cn2c(NN=Cc3ccc(-c4ccccc4)cc3)cc(=O)n(C)c2=O)cc1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: COc1ccc(Cn2c(=O)n(C)c(=O)c3c(Cc4ccccc4)n(Cc4ccc(-c5ccccc5)cc4)nc32)cc1
Temperature: 42.5 °C
Reaction time: 36 h
Yield: 31.2 %

Procedure:
Acetic acid (4.4 mL) is added in to a solution of 6-(2-(Biphenyl-4-ylmethylene)hydrazinyl)-1-(4-methoxybenzyl)-3-methylpyrimidine-2,4(1H,3H)-dione (3.2 g, 7.26 mmol) in DMF (50 mL) and ButOH (25 mL) at 50° C. Piperidine (8.7 mL) is mixed with a solution of 2-phenylacetaldehyde (8.5 mL, 72.6 mmol) in DMF (20 mL), and the resulting greenish solution is added in to the above solution. The reaction mixture is stirred at 40-45° C. for 36 hours under argon, and the solvent is evaporated under high vacuum. The residue is treated with MeOH (200 mL) to precipitate out 1.23 g product as sandy solids (Yield: 31.4%). MS (FAB) m/z 543.4 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][F:4].[CH2:5]([C:7]1[C:8]([NH:27][C@@H:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30][C@@H:29]2[OH:37])=[N:9][C:10]([CH2:25][CH3:26])=[C:11]([C:13]2[C:22]([O:23][CH3:24])=[CH:21][C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[CH:14]=2)[N:12]=1)[CH3:6]>>[CH2:5]([C:7]1[C:8]([NH:27][C@@H:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30][C@@H:29]2[O:37][CH2:2][CH2:3][F:4])=[N:9][C:10]([CH2:25][CH3:26])=[C:11]([C:13]2[C:22]([O:23][CH3:24])=[CH:21][C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[CH:14]=2)[N:12]=1)[CH3:6]
Reactant: CCc1nc(-c2cc3c(cc2OC)CCCC3)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: FCCBr
Product: CCc1nc(-c2cc3c(cc2OC)CCCC3)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1OCCF
Yield: 65 %

Procedure:
Following the general procedure of Example 13 Step 3 and making non-critical variations but substituting iodoethane with 1-bromo-2-fluoroethane and substituting (2S)-2-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]butan-1-ol with (1R,2S)-1-{[3,6-diethyl-5-(3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)pyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol (240 mg, 0.54 mmol) gave 260 mg of a crude yellow paste. This material was purified by Biotage MPLC (40 g column, 25% ethyl acetate in heptane) to give 203 mg (65%) of 3,6-diethyl-N-[(1R,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl]-5-(3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)pyrazin-2-amine as an ivory foam. Rf 0.20 (25% ethyl acetate in heptane). IR (diffuse reflectance) 2966, 2932, 2875, 2857, 1562, 1551, 1482, 1389, 1309, 1248, 1232, 1203, 1183, 1118, 1033 cm−1. OAMS supporting ions at: ESI+490.2. Anal. Calcd for C30H36FN3O2: C, 73.59; H, 7.41; N, 8.58; F, 3.88. Found: C, 73.57; H, 7.65; N, 8.41.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:19][O:20][CH2:21]Cl>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][O:9][CH2:19][O:20][CH3:21])[N:7]=1
Reactant: OCc1cccc(Br)n1
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 98.4 %

Procedure:
Under a stream of argon, (6-bromopyridine-2-yl)methanol (10 g; 53.2 mmol) was dissolved in methylene chloride (50 mL). Diisopropylethylamine (9.6 g; 74.5 mmol) and chloromethyl methyl ether (5.35 g; 66.5 mmol) were added to the reaction mixture in an ice bath, and further, the reaction mixture was stirred at room temperature for 17 hours. The reaction solution was poured into ice water and extracted with chloroform. The organic layer was washed with water, dried over sodium sulfate, and then evaporated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (SiO2, 200 g) (toluene/ethyl acetate=10/1) to give 12.15 g (yield: 98%) of the title compound (11).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.C(=O)([O-])[O-].[K+].[K+].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][O:13][C:5]1[CH:4]=[CH:3][C:2]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:12])[NH:10]2
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(Br)c2c1CCC(=O)N2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(-c2ccccc2)c2c1CCC(=O)N2
Yield: 83.9 %

Procedure:
8-Bromo-5-methoxy-3,4-dihydro-1H-quinolin-2-one (10.0 g), tetrakis(triphenylphosphine)palladium (0.45 g) and potassium carbonate (5.4 g) were suspended in dioxane (100 ml), and phenylboronic acid (5.24 g) was added, followed by heating under reflux in an argon atmosphere for 2 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the resulting mixture was subjected to extraction with ethyl acetate. The extract was washed twice with water, washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from an ethyl acetate-n-hexane mixed solvent to thereby obtain 8.3 g (yield: 84%) of 5-methoxy-8-phenyl-3,4-dihydro-1H-quinolin-2-one as a light yellow powder.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([OH:14])=O)[NH:9]2)=[CH:5][C:4]=1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1.[Cl-].[Li+].[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([C:12]([C:8]2[NH:9][C:10]3[C:6]([CH:7]=2)=[CH:5][C:4]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]2)=[C:3]([Cl:2])[CH:11]=3)=[O:14])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)O)[nH]c3cc2Cl)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)[nH]c3cc2Cl)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 57 %

Procedure:
A mixture of 6-chloro-5-(1-isopropyl-piperidin-4-yloxy)-1H-indole-2-carboxylic acid hydrochloride salt with 1 eq. lithium chloride (760 mg, 1.0 eq.), tert-butyl-1-piperazinecarboxylate (467 mg, 1.25 eq.), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (838 mg, 1.25 eq.) and N,N-diisopropylethylamine (2.43 mL, 7 eq.) in N,N-dimethylformamide (9 mL) was stirred at room temperature for 20 h. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous sodium hydrogencarbonate solution. The organic layer was separated and washed with water and brine, and dried over sodium sulfate, filtered and the solvents were removed in vacuo. The residue was purified by flash chromatography on silica gel with a 19:1:0 to 90:9:1 gradient of dichloromethane/methanol/ammonia as eluant, to afford 577 mg (57%) of the title compound as a light-yellow solid.
Reaction SMILES: S=C1[N:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:20])[CH3:19])=[C:13]([O:21][CH3:22])[CH:12]=2)=[O:8])[CH2:5][CH2:4]S1.C(N)C[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[C:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][O:9][C:7](=[O:8])[NH:6][CH2:5][CH2:4][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:12][C:13]=1[O:21][CH3:22])(=[O:20])[CH3:19]
Reactant: COc1cc(COC(=O)N2CCSC2=S)ccc1OC(C)=O
Reactant: NCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(COC(=O)NCCc2ccccc2)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
To a stirred yellow solution of VII (362.5 mg, 1.062 mmol) in anhydrous THF (10 mL) was added phenethylamine (142 mg, 147 μL, 1.1×1.062 mmol) and then, dropwise, triethylamine (118 mg, 164 μL, 1.1×1.062 mmol). The solution was stirred for 1 hour at room temperature. The colorless solution was then diluted with CH2Cl2 and washed with 1N HCl, distilled water, and saturated NaCl. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated. The crude product was purified by column chromatography on silica gel using hexanes/ethyl acetate (1:1, v/v) to yield 203 mg (56%) of 12 as a clear light yellow oil: Rf=0.45 (hexanes/ethyl acetate, 1:1, v/v); 1HNMR (CDCl3) δ 7.28 (td, 3J=7.4 Hz, 2H), 7.20 (tt, 3J=7.4 Hz, 1H), 7.16 (d, 3J=7.3 Hz, 2H), 6.98 (d, 3J=8.0 Hz, 1H), 6.93 (d, 1H), 6.90 (dd, 3J=8.0 Hz, 1H), 5.04 (s, 2H, CH2O), 4.73 (bs, 1H, NH), 3.81 (s, 3H, OCH3), 3.45 (q, 3J=6.6 Hz, 2H, NCH2), 2.80 (t, 3J=6.9 Hz, 2H, PhCH2) and 2.29 (s, 3H). Exact mass (ESI) calculated for C19H22NO5 [M+H]=344.1492. found 344.1496.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=3)[C:14]2=[O:30])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[H-].C([Al+]CC(C)C)C(C)C.C(OCC)(=O)C.[Cl-].[NH4+]>O1CCCC1.C1(C)C=CC=CC=1>[CH3:29][O:28][C:20]1[CH:19]=[C:18]([CH:15]2[CH2:16][CH2:17][CH:13]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)[CH:14]2[OH:30])[CH:23]=[C:22]([O:24][CH3:25])[C:21]=1[O:26][CH3:27]
Reactant: COc1cc(C2CCC(c3cc(OC)c(OC)c(OC)c3)C2=O)cc(OC)c1OC
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cc(C2CCC(c3cc(OC)c(OC)c(OC)c3)C2O)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 2.26 g of the compound of Example 2 in 54 ml of tetrahydrofuran which was cooled to -78° C. was added 14.5 ml of a 1.5M solution of diisobutylaluminum hydride in toluene. The reaction mixture was then stirred for 2 hours, while maintaining the temperature at -78° C., after which time it was warmed to room temperature. The mixture was then stirred for an additional 22 hours, after which time it was poured into a mixture of 100 ml of ethyl acetate and 100 ml of a saturated aqueous ammonium chloride solution. The resultant mixture was then filtered through Celite and the filtrate was extracted with a mixture of ethyl acetate and water. The organic layers were then combined, dried and evaporated to afford the crude residue which was chromatographed on silica gel employing a mixture of hexane and isopropyl alcohol in a ratio of 3:1 as the eluent to yield the 1α, 2α, 5β and 1α, 2α, 5α isomers of the title compound, the former of which had a m.p. of 126°-128° C., and the latter of which had a m.p. of 138°-140° C.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].N12CCCN=C1CCCCC2.[C@@H:16]1([N:25]2[C:34]3[N:33]=[CH:32][N:31]=[C:29]([OH:30])[C:28]=3[N:27]=[CH:26]2)[O:24][C@H:21]([CH2:22][OH:23])[C@@H:19]([OH:20])[C@H:17]1[OH:18]>>[CH2:1]([N:31]1[CH:32]=[N:33][C:34]2[N:25]([C@@H:16]3[O:24][C@H:21]([CH2:22][OH:23])[C@@H:19]([OH:20])[C@H:17]3[OH:18])[CH:26]=[N:27][C:28]=2[C:29]1=[O:30])[C:2]#[CH:3]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Reactant: C#CCBr
Solvent: C1CCC2=NCCCN2CC1
Product: C#CCn1cnc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1=O

Procedure:
reacting propargyl bromide, 1,8-diazabicyclo[5.4.0]undec-7-ene, and inosine to produce 1-propargylinosine;