Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[Na].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([SiH2:22][CH2:23]Cl)[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1>CN(C)C=O.O>[F:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]([SiH2:22][CH2:23][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:12][CH:13]=1
Reactant: Fc1ccc(C([SiH2]CCl)c2ccc(F)cc2)cc1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(C([SiH2]Cn2cncn2)c2ccc(F)cc2)cc1
Temperature: 25 °C

Procedure:
In this preparation 1.0 g of sodium 1,2,4-triazole is added to a solution of 3.1 g of bis(4-fluorophenyl)methylsilylmethyl chloride in 15 mL of dimethylformamide. The mixture is heated at about 80°-90° C. for two hours and then cooled to room temperature. The mixture is then diluted with 60 ml of water and extracted three times with 50 ml portions of ethyl ether. The extracts are combined, washed twice with 80 ml of water, then with 80 ml of aqueous saturated sodium chloride solution and dried over magnesium sulfate. The ethyl ether solvent is evaporated off affording an oil which is then purified by chromatography over silica gel solution with ethyl acetate, hexane, and mixture thereof.
Reaction SMILES: [BrH:1].[CH2:2]([N:9]1[CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:20]C)=[C:14]([O:18]C)[CH:15]=2)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[BrH:1].[CH2:2]([N:9]1[CH2:10][C:11]2[C:16](=[CH:15][C:14]([OH:18])=[C:13]([OH:20])[CH:12]=2)[CH2:17]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cc2c(cc1OC)CN(Cc1ccccc1)C2
Agent: Br
Product: Oc1cc2c(cc1O)CN(Cc1ccccc1)C2
Yield: 96.5 %

Procedure:
3.54 ml of 48% hydrobromic acid was added to 500 mg (1.86 mmol) of 2-benzyl-5,6-dimethoxyisoindoline, and the mixture was refluxed for 3 hours under stirring. The precipitated crystals were collected from the reaction solution, and washed with water and acetone to obtain 578 mg (yield: 96.5%) of the above identified compound as colorless prism crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH:24]([OH:27])[CH:25]=[CH2:26])[N:12]=2)=[N:4][NH:5][C:6]=1[CH:7]1[CH2:9][CH2:8]1.[C:28](Cl)(=[O:30])[CH3:29]>C1COCC1>[Br:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH:24]([OH:27])[CH:25]=[CH2:26])[N:12]=2)=[N:4][N:5]([C:28](=[O:30])[CH3:29])[C:6]=1[CH:7]1[CH2:9][CH2:8]1
Reactant: CC(=O)Cl
Reactant: C=CC(O)c1ccccc1-c1ncc(Cl)c(Nc2n[nH]c(C3CC3)c2Br)n1
Solvent: C1CCOC1
Product: C=CC(O)c1ccccc1-c1ncc(Cl)c(Nc2nn(C(C)=O)c(C3CC3)c2Br)n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 52.9 %

Procedure:
To a mixture of 1-(2-(4-(4-bromo-5-cyclopropyl-1H-pyrazol-3-ylamino)-5-chloropyrimidin-2-yl)phenyl)prop-2-en-1-ol (550 mg, 1.2 mmol, 1.0 eq) in THF (20 mL), a solution of acetyl chloride (966 mg, 12 mmol, 10 eq) in THF (2 mL) was added. The mixture was stirred at 0° C. for 4 h, then, partitioned between EtOAc and water. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to provide 1-(4-bromo-3-(5-chloro-2-(2-(1-hydroxyallyl)phenyl)pyrimidin-4-ylamino)-5-cyclopropyl-1H-pyrazol-1-yl)ethanone (310 mg, 52%). LC-MS (m/z)=488.0, 490.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[C:34]([OH:36])=O)=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[N:46]1([CH2:52][CH2:53][NH2:54])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C1C=CC2N(O)N=NC=2C=1>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[C:34](=[O:36])[NH:54][CH2:53][CH2:52][N:46]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(/C=C/C(=O)O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: NCCN1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2csc3c(/C=C/C(=O)NCCN4CCCCC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.3 %

Procedure:
A mixture of Example 271 (30.6 mg, 0.044 mmol), N,N-diisopropylethylamine (35 μL, 0.20 mmol), 2-piperidin-1-ylethylamine (14.3 μL, 0.10 mmol), and DMF (1 mL) was treated sequentially with 0.5M (0.09 mL) of HBTU in DMF and 0.5M (0.09 mL) of HOBT in DMF. The reaction was stirred for 24 hours at ambient temperature and partitioned between 1N NaOH and ethyl acetate. The combined extracts were dried (Na2SO4), filtered, and concentrated to provide the desired product (20.4 mg, 0.034 mmol). LCMS m/e 609.2; retention time: 2.93 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:46][O:47][C:48]1[CH:49]=[CH:50][CH:51]=[C:52]2[C:57]=1[CH2:56][CH:55]([NH:58][CH2:59][CH2:60][CH3:61])[CH2:54][CH2:53]2>CN(C=O)C>[CH3:46][O:47][C:48]1[CH:49]=[CH:50][CH:51]=[C:52]2[C:57]=1[CH2:56][CH:55]([N:58]([CH2:59][CH2:60][CH3:61])[C:10](=[O:12])[CH2:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1])[CH2:54][CH2:53]2
Reactant: CCCNC1CCc2cccc(OC)c2C1
Reactant: Cc1ccc(C)c(CC(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(C(=O)Cc1cc(C)ccc1C)C1CCc2cccc(OC)c2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 340 mg (2.1 mmol) 2,5-dimethylphenylacetic acid (A3-4: W═OH, Cy=2,5-dimethylphenyl) and 0.70 mL diisopropylethylamine (DIPEA) (4.24. mmol) in 10 mL of dry DMF was cooled in an ice-bath. After addition of 950 mg (2.5 mmol) O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) in 5.0 mL dry DMF a solution of 640 mg (2.9 mmol) of the free base of N-(8-methoxytetralin-2-yl)-N-propylamine (A2-1) in 8.0 mL dry DMF was added dropwise, the ice-bath was removed and the reaction mixture was stirred for 3 hrs at room temperature. The mixture was washed with a saturated solution of aqueous NaHCO3 for several times and the resulting aqueous layer was extracted with CH2Cl2. The organic layers were dried over MgSO4 and the solvent was evaporated in vacuo. Flash chromatography of the residue on silica gel with a mixture of hexane/ethyl acetate 60/10 gave the product N-(8-methoxytetralin-2-yl)-N-propyl-2-(2,5-dimethylphenyl)acetamide.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][CH3:13])=[CH:9][CH:10]=2)[C:5](=[O:14])[N:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1.[H-].[Na+].Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.O>CN(C=O)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:12]([CH3:13])[CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:9][CH:10]=2)[C:5](=[O:14])[N:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1
Reactant: CNc1ccc2c(Br)nn(C(C)C)c(=O)c2c1
Reactant: ClCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1nc(Br)c2ccc(N(C)CCN3CCOCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.3 %

Procedure:
4-Bromo-2-isopropyl-7-methylamino-2H-phthalazin-1-one (0.13 g, 0.44 mmol) was dissolved in DMF (5 ml). To this was added NaH (60%, 0.053 g, 1.3 mmol) as a suspension in DMF (2 ml). The mixture was stirred at RT for 30 min then 4-(2-chloro-ethyl)-morpholine (0.12 g, 0.66 mmol) was added in one portion as a solution in DMF (I ml) and the reaction mixture was heated to 70° C. for 24 hours. After this time, the reaction mixture was cooled to RT and water (10 ml) was added cautiously, the mixture was extracted with EtOAc (3×10 ml), the organic layers were combined, dried (MgSO4), filtered and concentrated under vacuum. Flash column chromatography (elution: 95% EtOAc, 5% MeOH) gave the title compound (0.051 g, 30% yield) as a white solid. 1H-NMR: (400 MHz, CDCl3), 7.72 (1H, d), 7.49 (1H, s), 7.16 (1 H, d), 5.42-5.29 (1H, m), 3.73-3.67 (4H, m), 3.66-3.59 (2H, t), 3.15 (3H, s), 2.61-2.54 (2H, m), 2.53-2.46 (4H, m), 1.41 (6H, d).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:24][CH2:25][S:26][CH3:27])[NH:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:9][C:8]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(Cl)(=O)[C:30](Cl)=[O:31]>ClC1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:24][CH2:25][S:26][CH3:27])[NH:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:16]=[C:30]=[O:31])(=[O:15])=[O:14])=[CH:9][C:8]=1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(S(N)(=O)=O)cc1-c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: Clc1ccccc1
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(S(=O)(=O)N=C=O)cc1-c1ccccc1

Procedure:
A mixture of the resultant sulfonamide from Example 119A in chlorobenzene is treated with with oxalyl chloride according to the procedure of Franz et al. (J. Org. Chem, 1964, 29, 2592) to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][NH:13][C:12]2=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C)C=O>[CH2:27]([N:13]1[C:12](=[O:22])[C:11]2([CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:24][CH2:23]2)[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(Cc1ccccc1)CN2c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94 %

Procedure:
8-(tert-Butoxycarbonyl)-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one (1.441 g) was dissolved in N,N-dimethylformamide (28 ml), added with sodium hydride (60%, in oil, 521 mg) and stirred at room temperature for 1.5 hours. The reaction mixture was added with benzyl bromide (1.81 ml) with ice cooling and further stirred at room temperature for 1 hour. The reaction mixture was added with water (50 ml) and extracted twice with dichloromethane (70 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=5:1 →4:1) to obtain 1.710 g of the title compound. Yield: 94%.
Reaction SMILES: [CH2:1]([S:4]([NH:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1)(=[O:6])=[O:5])[CH2:2][CH3:3].O=S(Cl)[Cl:19]>>[CH2:1]([S:4]([NH:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([Cl:19])=[O:13])=[CH:10][CH:9]=1)(=[O:6])=[O:5])[CH2:2][CH3:3]
Reactant: CCCS(=O)(=O)Nc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: CCCS(=O)(=O)Nc1ccc(C(=O)Cl)cc1

Procedure:
In a manner similar to Preparation 10 react 4-[(1-propylsulfonyl)amino]benzoic acid with SOCl2 to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])[C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:7])=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[C:27]=1[NH:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20]([N:28]([CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]2[C:37]([CH3:41])=[CH:38][CH:39]=[CH:40][C:26]=2[CH3:25])=[O:21])[C:9]2[C:10]([CH3:16])=[CH:11][CH:12]=[CH:13][C:14]=2[CH3:15])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1cccc(C)c1N(CCCC(=O)O)C(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)CCCNc1c(C)cccc1C
Product: CCOC(=O)CCCN(C(=O)CCCN(C(=O)c1ccc(Cl)cc1)c1c(C)cccc1C)c1c(C)cccc1C

Procedure:
Analogously to Example 1, using equivalent quantities, reacting N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyric acid and ethyl 4-(2,6-dimethylanilino)butyrate and suitable processing produces ethyl N-[N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyryl]-4-(2,6-dimethylanilino)butyrate (M.P. 95° to 97°), the saponification of which and the processing of the reaction product yields N-[N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyryl]-4-(2,6-dimethylanilino)butyric acid (M.P. 129° to 131°).
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][C:7]2[O:11][C:10]([NH:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:26][CH2:25][CH:24]([CH2:27][C:28]([O:30]CC)=[O:29])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[O:14])=[N:9][N:8]=2)=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.CO.O>[F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][C:7]2[O:11][C:10]([NH:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:22][CH2:23][CH:24]([CH2:27][C:28]([OH:30])=[O:29])[CH2:25][CH2:26]4)=[CH:17][CH:16]=3)=[O:14])=[N:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC1CCC(c2ccc(C(=O)Nc3nnc(Cc4ccc(F)cc4)o3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)CC1CCC(c2ccc(C(=O)Nc3nnc(Cc4ccc(F)cc4)o3)cc2)CC1
Temperature: 4 °C
Reaction time: 4 h
Yield: 54.4 %

Procedure:
0.1 g of ethyl (4-{4-[5-(4-fluorobenzyl)[1,3,4]oxadiazol-2-ylcarbamoyl]phenyl}cyclohexyl)acetate (0.21 mmol, 1 eq.) and 0.036 g of lithium hydroxide hydrate (0.86 mmol, 4 eq.) are dissolved in 4 mL of a 2/1/1 mixture of tetrahydrofuran/methanol/water cooled to 4° C. using an ice bath. The reaction medium is stirred for 4 hours at room temperature. The solvents are evaporated off and an aqueous solution of SO2 is added. The solid obtained is filtered off, washed with water and dried to give 0.05 g of (4-{4-[5-(4-fluorobenzyl)[1.3.4]oxadiazol-2-ylcarbamoyl]phenyl}cyclohexyl)acetic acid.
Reaction SMILES: C(N)=O.C(N(CC)CC)C.[O-:11][P:12]([O:15][P:16]([O-])([O-:18])=[O:17])(=[O:14])[O-:13].C(N(CCCC)CCCC)CCC.[P:33]([O:37][CH2:38][C@H:39]1[O:43][C@@H:42]([N:44]2[CH:51]=[CH:50][C:48](=[O:49])[NH:47][C:45]2=[O:46])[C@H:41]([OH:52])[C@@H:40]1[OH:53])([OH:36])([OH:35])=[O:34]>O1CCOCC1.CC(N(C)C)=O.N1C=CC=CC=1>[CH:50]1[C:48](=[O:49])[NH:47][C:45](=[O:46])[N:44]([C@@H:42]2[O:43][C@H:39]([CH2:38][O:37][P:33]([O:35][P:16]([O:15][P:12]([OH:14])([OH:13])=[O:11])([OH:18])=[O:17])([OH:36])=[O:34])[C@@H:40]([OH:53])[C@H:41]2[OH:52])[CH:51]=1
Reactant: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: O=P([O-])([O-])OP(=O)([O-])[O-]
Solvent: CCCCN(CCCC)CCCC
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1

Procedure:
Formamide (2.5 ml) and pyridine (7.6 ml) were added to a dehydrated triethylamine salt (10 mmol) of pyrophosphate (TEA-PPi), followed by stirring the resultant mixture. To a dehydrated tributylamine salt of uridine 5′-monophosphate (UMP-TBA) (10 mmol) placed in another vessel, DMAC (3.6 ml), dioxane (3.2 ml), and tributylamine (3.3 ml) were added and stirred, and DPC (2.3 ml) was added dropwise thereto. The mixture was stirred at room temperature for one hour, to thereby form UMP-DPP, which was added to the aforementioned dehydrated solution of TEA-PPi prepared in advance. The reaction mixture was stirred at room temperature for one hour, forming UTP. DMAC (7.2 ml) was added to a tributylamine salt of 2′-deoxycytidine 5′-monophosphate (TBA-dCMP) (4.9 g, 10 mmol) placed in another vessel, to thereby form a suspension, and DPC (2.2 ml, 1.1 equivalents) was added to the suspension. The resultant mixture was stirred for 40 minutes, and tributylamine (TBA) (9.5 ml) was added to the mixture. Another 20 minutes stirring was carrier out, to thereby prepare dCMP-DPP. The thus-prepared dCMP-DPP solution was added to the aforementioned synthesized UTP solution prepared in advance, and the mixture was stirred at room temperature for 56 hours. Reaction was terminated by adding water, and the pH of the reaction mixture was adjusted to 11 by adding a 30% aqueous sodium hydroxide solution. After the solvent was removed by concentration, the pH was adjusted to 7.0 by adding a 6 mol/L hydrochloric acid. The mixture was partitioned with ethyl acetate. The aqueous layer formed by partitioning was subjected to HPLC analysis (272 nm), revealing that the synthesis yield of dCP4U was 37.7%.
Reaction SMILES: C1(P(CC)C2C=CC=CC=2)C=CC=CC=1.[CH3:16][C:17]1([CH3:24])[C:21]([CH3:23])([CH3:22])[O:20][BH:19][O:18]1.[C:25]([NH:28][C:29]([C:54](=[O:60])[NH:55][C:56]([CH3:59])([CH3:58])[CH3:57])([CH2:49][CH2:50][CH2:51][CH:52]=C)[CH2:30][CH2:31][CH:32]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][N:33]1[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])(=[O:27])[CH3:26]>ClCCl>[C:25]([NH:28][C:29]([C:54](=[O:60])[NH:55][C:56]([CH3:59])([CH3:58])[CH3:57])([CH2:49][CH2:50][CH2:51][CH2:52][B:19]1[O:20][C:21]([CH3:23])([CH3:22])[C:17]([CH3:24])([CH3:16])[O:18]1)[CH2:30][CH2:31][CH:32]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][N:33]1[C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])(=[O:27])[CH3:26]
Reactant: CC1(C)OBOC1(C)C
Reactant: C=CCCCC(CCC1Cc2ccccc2CN1C(=O)OC(C)(C)C)(NC(C)=O)C(=O)NC(C)(C)C
Agent: CCP(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(CCC1Cc2ccccc2CN1C(=O)OC(C)(C)C)C(=O)NC(C)(C)C
Reaction time: 4 h
Yield: 91.6 %

Procedure:
While under an atmosphere of argon, a solution of bis(1,5-dicyclooctadiene)diiridium(I) dichloride (54 mg, 3% mol), diphenylphosphinoethane (64 mg, 6% mol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 mL, 10.7 mmol) in dry dichloromethane (20 mL) was cooled to 0° C. A second solution of tert-butyl 3-(3-acetamido-3-(tert-butylcarbamoyl)oct-7-enyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.5 g, 2.67 mmol) in dry dichloromethane (20 mL) was added in one portion. After 4 h LCMS indicated all the starting olefin was consumed and the reaction was washed successively with water, sat'd aq sodium chloride, dried over MgSO4, filtered and concentrated. Purification by flash chromatography (20-35% ethyl acetate in hexanes) gave tert-butyl 3-(3-acetamido-3-(tert-butylcarbamoyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)heptyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate as a yellow oil (1.5 g, 93%). ESI MS found for C34H56BN3O6 m/z [614.7 (M+1), 633.7 (M+23)].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH2:12]([NH2:14])[CH3:13].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>ClCCl.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:14][CH2:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCNC(=O)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37 %

Procedure:
A mixture of 4-chlorophenyl acetic acid (1 g, 5.88 mmol), ethylamine (2M in tetrahydrofuran, 5.88 mL, 11.76 mmol), 1-hydroxybenzotriazole hydrate (90 mg, 5.88 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.13 g, 5.88 mmol), and triethylamine 1.78 g, 17.64 mmol) in dichloromethane (30 mL) was stirred at room temperature for 18 hours. The mixture was then diluted with 1M sodium hydroxide solution (30 mL) and the aqueous layer was extracted with dichloromethane (30 mL). The combined organic solution was washed with 1M hydrochloric acid and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol, 100:0 to 90:10, to afford the title compound as a colourless solid in 37% yield, 443 mg. 1H NMR (400 MHz, CDCl3) δ: 7.31-7.28 (2H, m), 7.27-7.24 (2H, m), 3.45 (2H, s), 3.18 (2H, m), 1.08 (3H, t) ppm; LRMS APCI m/z 198 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)=[N:9][CH:10]=1.[ClH:28].O1CCOCC1>O1CCOCC1>[ClH:28].[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)=[N:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Oc3ccccc3F)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Fc1ccccc1Oc1cnc(N2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-(5-(2-fluorophenoxyl)pyrimidin-2-yl)piperazine-1-carboxylate (50 mg, 0.13 mmol) in dioxane (3 mL) was added 4 M HCl/dioxane (3 mL). The reaction mixture was stirred at room temperature overnight and then concentrated to dryness. The residue (50 mg, yellow solid) was directly used in the next reaction.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:10]=2)[N:5]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:4][CH2:3]1.[CH3:33][Mg+].[Br-].[Cl-].[NH4+]>C1COCC1>[OH:1][C:2]1([CH3:33])[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=3)[N:10]=2)[N:5]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:4][CH2:3]1
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(C(=O)OC(C)(C)C)CCC3=O)cc1
Reactant: C[Mg+]
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)C(C)(O)CCN3C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 8-oxo-2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazine-5(6H)-carboxylate (step 2) (591 mg, 1.376 mmol) in THF (20 ml) at 0° C. was added 1M MeMgBr in THF (5.50 ml, 5.50 mmol). The mixture was left to stir at 0° C. for 30 mins under an atmosphere of nitrogen and then warmed to room temperature. After 1.5 hours, the reaction mixture was poured into a saturated ammonium chloride solution (30 ml). The product was extracted with ethyl acetate (2×30 ml) and the combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give the crude product as an oil. Purification of the oil by chromatography on silica eluting with EtOAc in iso-hexane afforded the titled compound;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([NH:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:8][CH2:7][CH2:6]2.[C:18]([S:21][CH2:22][CH:23]([CH3:27])[C:24](Cl)=[O:25])(=[O:20])[CH3:19].O>CC(N(C)C)=O>[C:18]([S:21][CH2:22][CH:23]([CH3:27])[C:24]([N:13]([CH:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH2:6][CH2:7][CH2:8]1)[CH2:14][C:15]([OH:17])=[O:16])=[O:25])(=[O:20])[CH3:19]
Reactant: CC(=O)SCC(C)C(=O)Cl
Reactant: COc1ccc2c(c1)CCCC2NCC(=O)O
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc2c(c1)CCCC2N(CC(=O)O)C(=O)C(C)CSC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.3 %

Procedure:
N-(6-Methoxy-1,2,3,4-tetrahydro-1-naphthyl)glycine (3.0 g) is suspended in 30 ml of dimethylacetamide, then 3.3 g of 3-acetylthio-2-methylpropionyl chloride is added dropwise with stirring at room temperature, and thereafter stirring is continued at room temperature for 2 hours. The reaction mixture is poured into 200 ml of water, and extracted with 200 ml of ethyl acetate. The extract is washed with 20 ml of 10% hydrochloric acid and with water, and dried over anhydrous sodium sulfate. Ethyl acetate is distilled off under reduced pressure, 10 ml of ethyl ether is added to the residue, and the mixture is allowed to stand at room temperature. Collection of the resulting crystalline precipitate by filtration gives 1.9 g of N-(3-acetylthio-2-methylpropionyl)-N-(6-methoxy-1,2,3,4-tetrahydro-1-naphthyl)glycine as colorless needles. Melting point: 158°-161° C.