Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[Cl:7][C:8]1[CH:43]=[CH:42][CH:41]=[CH:40][C:9]=1[CH2:10][N:11]1[C:19]2[C:18](=[O:20])[N:17]([CH3:21])[C:16](=[O:22])[N:15]([CH3:23])[C:14]=2[C:13]([C:24]#[N:25])=[C:12]1[N:26]1[CH2:31][CH2:30][CH2:29][C@@H:28]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:27]1.S([O-])(O)(=O)=O.[K+]>CN(C)C=O>[Cl:7][C:8]1[CH:43]=[CH:42][CH:41]=[CH:40][C:9]=1[CH2:10][N:11]1[C:19]2[C:18](=[O:20])[N:17]([CH3:21])[C:16](=[O:22])[N:15]([CH3:23])[C:14]=2[C:13]([C:24]2[NH:25][N:3]=[N:2][N:1]=2)=[C:12]1[N:26]1[CH2:31][CH2:30][CH2:29][C@@H:28]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])[CH2:27]1
Reactant: Cn1c(=O)c2c(c(C#N)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)([O-])O
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(c(-c3nnn[nH]3)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Temperature: 150 °C
Reaction time: 8 h
Yield: 8.5 %

Procedure:
Sodium azide (154 mg) and ammonium chloride (125 mg) were added to a solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-cyano-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (250 mg) in N,N-dimethylformamide (4 ml), and the resulting mixture was stirred at 150° C. for 8 hours. Sodium azide (154 mg) and ammonium chloride (125 mg) were further added thereto and stirred for another 6 hours. After the reaction solution was cooled to 25° C., a 10% aqueous potassium hydrogensulfate solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by HPLC to obtain the title compound (23 mg) as a white solid.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1.[F:11][C:12]([F:25])([F:24])[CH2:13][O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1>>[Cl:10][C:4]1[CH:3]=[C:2]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH2:13][C:12]([F:11])([F:24])[F:25])[CH:16]=2)[CH:8]=[C:7]([F:9])[C:5]=1[NH2:6]
Reactant: Nc1c(F)cc(Br)cc1Cl
Reactant: OB(O)c1cccc(OCC(F)(F)F)c1
Product: Nc1c(F)cc(-c2cccc(OCC(F)(F)F)c2)cc1Cl
Yield: 60.4 %

Procedure:
The title compound (85 mg) was prepared from 4-bromo-2-chloro-6-fluoroaniline (100 mg, 0.44 mmol) and 3-(2,2,2-trifluoroethoxy)phenylboronic acid (127 mg, 0.57 mmol) as a white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.53-7.44 (m, 2H), 7.38-7.26 (m, 3H), 6.94 (d, J 7, 1H), 5.55 (s, 2H), 4.83 (q, J 8.9, 2H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:39][CH3:40])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][NH:21][C:22]2[N:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:24][N:23]=2)[CH:9]=1)([CH3:3])[CH3:2].[Cl:41][C:42]1[CH:47]=[C:46]([CH2:48]Cl)[CH:45]=[C:44]([Cl:50])[CH:43]=1.[H-].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[Cl:41][C:42]1[CH:47]=[C:46]([CH:45]=[C:44]([Cl:50])[CH:43]=1)[CH2:48][N:21]([CH2:20][C:11]1[CH:12]=[C:13]([C:16]([F:19])([F:17])[F:18])[CH:14]=[CH:15][C:10]=1[C:8]1[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[CH:6][C:7]=1[O:39][CH3:40])[C:22]1[N:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:26][N:27]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNc1ncc(OCCCC(=O)OC(C)(C)C)cn1
Reactant: ClCc1cc(Cl)cc(Cl)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(Cl)cc(Cl)c1)c1ncc(OCCCC(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.6 %

Procedure:
Tert-butyl 4-{2-[(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (180 mg) is dissolved in N,N-dimethylformamide (1.0 ml), and thereto is added 1,3-dichloro-5-chloromethyl-benzene (252 mg), followed by an addition of sodium hydride (60%) (34 mg) under ice-cooling and the mixture is stirred at room temperature for 3 hours. To the reaction solution are added a saturated brine, and the mixture is extracted with ethyl acetate, and the organic layer is dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→9:1) to give tert-butyl 4-{2-[(3,5-dichloro-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (184 mg). MS (m/z): 720/718 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:32][CH3:33])[CH:3]=1.C([BH3-])#N.[Na+].[CH3:38][C:39]([CH3:41])=O>>[NH2:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH:39]([CH3:41])[CH3:38])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:32][CH3:33])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2ccccc2)CC1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN(Cc2ccccc2)C(C)C)CC1

Procedure:
4-Amino-N-((1-(5-benzylaminopentyl)piperidin-4-yl)methyl)-5-chloro-2-methoxybenzamide (2.0 g) as starting compound, acetone (0.3 ml) and sodium cyanoborohydride (0.35 g) were reacted and treated in the same manner as in Example 136 to give 0.43 g of 4-amino-5-chloro-N-((1-(5-(N-isopropyl-N-benzylamino)pentyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:34]=[CH:33][C:17]([CH2:18][N:19]2[C:23]3=[N:24][CH:25]=[CH:26][CH:27]=[C:22]3[C:21]([CH2:28][C:29]([O:31]C)=[O:30])=[N:20]2)=[CH:16][CH:15]=1)=[O:12].O.[OH-].[Li+].Cl>O1CCCC1.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][N:19]2[C:23]3=[N:24][CH:25]=[CH:26][CH:27]=[C:22]3[C:21]([CH2:28][C:29]([OH:31])=[O:30])=[N:20]2)=[CH:33][CH:34]=1)=[O:12]
Reactant: COC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ncccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1nn(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ncccc12
Yield: 49.3 %

Procedure:
Methyl 2-[1-[4-(2-naphthamido)benzyl]-1H-pyrazolo[3,4-b]pyridin-3-yl]acetate (60 mg, 0.13 mmol) and lithium hydroxide monohydrate (10 mg, 0.24 mmol) were added into a mixed solution of tetrahydrofuran (5 mL) and water (20 mL), and reacted at room temperature for 2 hours. Tetrahydrofuran was rotate evaporated. The pH was adjusted to 3 with 1 mol/L hydrochloric acid. It was extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The organic phase was rotate evaporated to dryness to obtain a light brown solid 28 mg, at a yield of 49.3%.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:28][C:29]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=1[CH3:37].C(=O)(O)[O-].[Na+]>C1COCC1>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:28][C:29]2[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:37])[N:8]=1)=[O:5]
Reactant: COc1cccc(C)c1CBr
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(C)c1Cn1ccc(NC(=O)c2c(F)cccc2F)n1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2,6-difluoro-N-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 9)(50 mg, 0.224 mmol) in dry THF (1.75 ml) under nitrogen was added 1.0 lithium bis(trimethylsilyl)amide in THF (0.2 ml, 0.2 mmol) dropwise and the solution stirred for 30 min. To the solution was added a solution of 2-(bromomethyl)-1-methyl-3-(methyloxy)benzene (for a preparation see intermediate 57)(48 mg, 0.224 mmol) in THF (1.75 ml). The solution was stirred for 1.5 h and then allowed to stand overnight. The solvent was blown down using a stream of nitrogen and aqueous sodium bicarbonate added to the residue. The aqueous phase was then extracted with chloroform. The organic extract was removed in vacuo to give a gum (84 mg). The residue was purified on MDAP (Method B). The solvent was removed and the residue dried at −45° C. under high vacuum to give the title compound as a white solid; LCMS (System 4) MH+=358, tRET=2.77 min.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[CH2:11]([C@H:13]1[CH2:18][C@H:17]2[C@H:19]3[C@H:28]([CH2:29][CH2:30][C@:15]2([CH3:16])[C@H:14]1[O:32][C:33](=[O:36])[CH2:34]Br)[C@@H:27]1[C:22](=[CH:23][C:24](=[O:31])[CH2:25][CH2:26]1)[CH2:21][CH2:20]3)[CH3:12].CN(C=O)C>CC(C)=O>[CH2:11]([C@H:13]1[CH2:18][C@H:17]2[C@H:19]3[C@H:28]([CH2:29][CH2:30][C@:15]2([CH3:16])[C@H:14]1[O:32][C:33](=[O:36])[CH2:34][O:5][C:4](=[O:6])[CH2:3][C:2]([CH3:8])([CH3:7])[CH3:1])[C@@H:27]1[C:22](=[CH:23][C:24](=[O:31])[CH2:25][CH2:26]1)[CH2:21][CH2:20]3)[CH3:12]
Reactant: CC(C)(C)CC(=O)O
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)CC(C)(C)C
Yield: 61 %

Procedure:
In 10 ml of acetone is dissolved 1.16 g of 3,3-dimethylbutyric acid, and 5.0 ml of 2N-NaOH is added, followed by addition of 1.15 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one and 20 ml of DMF. The mixture is refluxed for 5 hours, and thereafter treated in the same manner as Example 26. The reaction mixture is chromatographed on a silica gel column. Following passage of 200 ml of n-hexanediisopropyl ether (3:7), elution is carried out with a 1:1 mixture of the same solvents. The eluate is evaporated under reduced pressure to remove the solvent, giving 0.76 g of the above-identified compound as a colorless viscous oil.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.Cl.[NH2:28][CH2:29][C@H:30]([N:35]1[CH2:40][CH2:39][N:38]([S:41]([CH3:44])(=[O:43])=[O:42])[CH2:37][CH2:36]1)[C:31]([O:33][CH3:34])=[O:32].O>ClCCl>[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:28][CH2:29][C@H:30]([N:35]2[CH2:40][CH2:39][N:38]([S:41]([CH3:44])(=[O:43])=[O:42])[CH2:37][CH2:36]2)[C:31]([O:33][CH3:34])=[O:32])(=[O:24])=[O:23])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)[C@H](CN)N1CCN(S(C)(=O)=O)CC1
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CNS(=O)(=O)c1ccc(OCc2ccccc2)cc1)N1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.1 ml (7.8 mmol) of triethylamine and then 730 mg (2.6 mmol) of 4-benzyloxybenzenesulfonyl chloride in 8 ml of dichloromethane are added to a solution of 800 mg (2.4 mmol) of methyl (S)-3-amino-2-(4-methanesulfonylpiperazin-1-yl)propanoate dihydrochloride in 20 ml of dichloromethane and the reaction medium is stirred at ambient temperature for 3 h. After the addition of water, the product is extracted with dichloromethane. The organic phase is washed with water, dried over magnesium sulfate, filtered and concentrated.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:22][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[CH:24][N:25]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Xe](F)[F:33].C(=O)([O-])O.[Na+]>C(#N)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:22][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[C:24]([F:33])[N:25]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:2][CH2:3]1
Reactant: F[Xe]F
Reactant: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ncc(-c3ccccn3)[nH]2)cc1)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2nc(F)c(-c3ccccn3)[nH]2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1 %

Procedure:
To a solution of 2-(2-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-imidazol-5-yl)pyridine (0.750 g) in acetonitrile (20 mL) was added xenon difluoride (434 mg), and the mixture was stirred at room temperature for 30 min, and at 0° C. for 63 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-100:0, volume ratio) and preparative thin layer chromatography to give the title compound (0.008 g, yield 1%) as a yellow oil. MS: 456 (MH+).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH2:25])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1.[C:28]([O:31][C:32](=O)[CH:33](C1C=CC=CC=1)[OH:34])(=[O:30])[CH3:29].C(N(CC)CC)C>O1CCOCC1>[F:27][C:2]([F:26])([F:1])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH:25][C:33]([CH2:32][O:31][C:28](=[O:30])[CH3:29])=[O:34])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)OC(=O)C(O)c1ccccc1
Reactant: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1

Procedure:
This material was prepared according to the procedure described in Example 78(a) using 4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine, (Example 65), (0.36 g, 0.9 mmol), O-acetyl mandelic acid (0.41 mL, 1.8 mmol, Heico Chemicals, Inc.) and triethylamine (0.25 mL, 1.8 mmol) in dioxane (3 mL). Purification by silica gel chromatography (3:1 hexanes: EtOAc) provided the title compound as a light-yellow foam. MS (ESI, pos. ion) m/z: 565 (M+1). Mp: 118.6–138.4° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].CN1C=CN=C1.[C:20]([O:28][CH2:29][C@@H:30]([OH:46])[C@@H:31]([O:37][C:38](=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:32][CH:33]=[N:34][O:35][CH3:36])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OCC)(=O)C>C(#N)C.O>[C:20]([O:28][CH2:29][C@@H:30]([O:46][S:10]([C:3]1[CH:4]=[C:5]([Cl:9])[C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])(=[O:12])=[O:11])[C@@H:31]([O:37][C:38](=[O:45])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH2:32][CH:33]=[N:34][O:35][CH3:36])(=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)cc1Cl
Reactant: CON=CC[C@H](OC(=O)c1ccccc1)[C@H](O)COC(=O)c1ccccc1
Agent: Cn1ccnc1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CON=CC[C@H](OC(=O)c1ccccc1)[C@@H](COC(=O)c1ccccc1)OS(=O)(=O)c1cc(Cl)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
5.51 g of 2,4,5-trichlorobenzenesulfonyl chloride and 2.14 mL of 1-methylimidazole were added to a solution of 6.65 g of (2R,3S)-2-hydroxy-5-(methoxyimino)pentane-1,3-diyl dibenzoate in 67 mL of acetonitrile at room temperature, and the obtained mixture was then stirred at room temperature for 2 hours. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. 20 mL of ethyl acetate and 30 mL of hexane were added to the obtained residue, and a solid was then removed by filtration. After that, the solvent was distilled away under reduced pressure, so as to obtain 8.97 g of (2R,3S)-5-(methoxyimino)-2-(((2,4,5-trichlorophenyl)sulfonyl)oxy)pentane-1,3-diyl dibenzoate in the form of a colorless oily product.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][C:18](F)=[CH:17][CH:16]=1)=[O:14].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][C:18]1[CH:19]=[CH:20][C:15]([C:13](=[O:14])[CH3:12])=[CH:16][CH:17]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(=O)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 0 °C

Procedure:
A stirred mixture of 90.6 g of 3-(trifluoromethyl)phenol, 55.2 g of 4-fluoroacetophenone and 400 ml of dry dimethylacetamide was treated under argon with 71.9 g of anhydrous potassium carbonate in portions. The mixture was stirred and refluxed at 155°-160° C. on an oil bath for 18 hours. The mixture was cooled, poured into 1.5 Kg of ice and extracted with three portions of ether. The extracts were combined, washed successively with water, three 100 ml. portions of cold 1N sodium hydroxide, water and then brine, dried and evaporated to an oil. This oil was distilled at 105°-120° C., 0.15-0.20 mm Hg, giving the desired intermediate as an oil, bp 130°-142° C. (0.2 mm).
Reaction SMILES: Br[CH:2]([CH2:15][CH2:16][CH2:17][CH2:18]Br)[C:3]([O:5][CH:6]([CH3:14])[C:7](=[O:13])[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:4].[Na+].[I-].C(N(CC)CC)C.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1>[CH2:29]([N:36]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:2]1[C:3]([O:5][C@@H:6]([CH3:14])[C:7](=[O:13])[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:4])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCc1ccccc1
Reactant: CC(OC(=O)C(Br)CCCCBr)C(=O)N1CCCC1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H](OC(=O)C1CCCCN1Cc1ccccc1)C(=O)N1CCCC1
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
To 1-methyl-2-oxo-2-tetrahydro-1-H-1-pyrrolylethyl 2,6-dibromohexanoate (295 mg, 0.75 mmol), NaI (225 mg, 1.5 mmol) and tetrahydrofuran (4 mL) were added. The mixture was stirred at 40° C. for 1.5 hours. Next, triethylamine (84 mg, 0.83 mmol), benzylamine (97 mg, 0.90 mmol) and tetrahydrofuran (4 mL) were added thereto. The mixture was stirred at 20° C. for 15 hours. It was confirmed with NMR analysis of the reaction solution that the conversion ration was 83% and the diastereo ratio calculated from the NMR analysis was 79:21.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:26]([NH:28][CH2:29][CH:30]5[O:35][CH2:34][CH2:33][NH:32][CH2:31]5)=[O:27])=[C:21]5[C:25]=4[O:24][CH2:23][CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:36])[C:8](=[O:37])[C@H:7]2[CH2:38][CH3:39])[CH2:5][CH2:4][CH2:3][CH2:2]1.C=O.[C:42](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(#N)C.O>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:26]([NH:28][CH2:29][CH:30]5[O:35][CH2:34][CH2:33][N:32]([CH3:42])[CH2:31]5)=[O:27])=[C:21]5[C:25]=4[O:24][CH2:23][CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:36])[C:8](=[O:37])[C@H:7]2[CH2:38][CH3:39])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)NCC4CNCCO4)c4c3OCC4)nc2N1C1CCCC1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)NCC4CN(C)CCO4)c4c3OCC4)nc2N1C1CCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 37.6 %

Procedure:
The crude compound 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-N-(morpholin-2-ylmethyl)-2,3-dihydrobenzofuran-4-carboxamide 2f (163 mg, 0.30 mmol) was dissolved in 60 mL of the mixture solvent of acetonitrile and water (V/V=1:1) in an ice-water bath, the reaction solution was cooled down to 0° C. followed by the addition of formaldehyde (18 mg, 0.60 mmol) and sodium triacetoxyborohydride (191 mg, 0.90 mmol), warmed up slowly to room temperature and stirred for 2 hours. The resulting mixture was added dropwise with saturated sodium bicarbonate solution to adjust pH to 9 to 10, extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL×3), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-N-[(4-methylmorpholin-2-yl)methyl]-2,3-dihydrobenzofuran-4-carboxamide 2 (62 mg, yield: 38.0%) as a white solid.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:19])[NH:6][C:7]1[CH:8]=[N:9][N:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:11]=1.[CH:22]([C:25]1[N:29]2[CH:30]=[C:31]([O:34][C@@H:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[C@@H:38]([NH2:45])[CH2:37][CH2:36]3)[CH:32]=[CH:33][C:28]2=[N:27][N:26]=1)([CH3:24])[CH3:23].CCN(C(C)C)C(C)C>CN(C=O)C>[CH:22]([C:25]1[N:29]2[CH:30]=[C:31]([O:34][C@@H:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[C@@H:38]([NH:45][C:5]([NH:6][C:7]4[CH:8]=[N:9][N:10]([C:12]5[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=5)[CH:11]=4)=[O:19])[CH2:37][CH2:36]3)[CH:32]=[CH:33][C:28]2=[N:27][N:26]=1)([CH3:24])[CH3:23]
Reactant: Cc1ccc(-n2cc(NC(=O)OCC(Cl)(Cl)Cl)cn2)cc1
Reactant: CC(C)c1nnc2ccc(O[C@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-n2cc(NC(=O)N[C@H]3CC[C@H](Oc4ccc5nnc(C(C)C)n5c4)c4ccccc43)cn2)cc1
Yield: 77.9 %

Procedure:
A solution of Intermediate 6c (65.0 mg, 0.19 mmol), Intermediate 5c (50.0 mg, 0.155 mmol), and DIPEA (0.127 mL, 0.8 mmol) in DMF (1 mL) was heated at 110° C. for 75 min and 50° C. for 64 h. After cooling, the mixture was concentrated to dryness and the residue purified by FCC, eluting with 0-10% MeOH in DCM, to give the impure product (63 mg). Further purification by HPLC (Method 6) gave the title compound as a white solid (45 mg, 56%). LCMS (Method 5): Rt 4.06 min, m/z 522.1 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.36-1.41 (6H, m), 1.76-1.85 (1H, m), 1.98-2.08 (1H, m), 2.13-2.28 (2H, m), 2.33 (3H, s), 3.59 (1H, quintet, J 6.8), 4.96-5.03 (1H, m), 5.62 (1H, t, J 4.6), 6.74 (1H, d, J 8.5), 7.24 (1H, dd, J 9.9, 2.1), 7.26-7.46 (6H, m), 7.62-7.66 (2H, m), 7.68 (1H, s), 7.70 (1H, dd, J 9.9, 0.8), 8.24 (1H, br d), 8.26 (1H, s), 8.31 (1H, s).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([NH:7][NH2:8])=[O:6].NN.[C:15](OCC)(OCC)(OCC)[CH3:16]>C1(C)C(C)=CC=CC=1>[CH3:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]2[O:6][C:15]([CH3:16])=[N:8][N:7]=2)=[CH:3][C:2]=1[OH:1]
Reactant: Cc1ccc(C(=O)NN)cc1O
Reactant: CCOC(C)(OCC)OCC
Agent: NN
Solvent: Cc1ccccc1C
Product: Cc1nnc(-c2ccc(C)c(O)c2)o1
Temperature: 150 °C

Procedure:
A suspension of ethyl 3-hydroxy-4-methylbenzoate (3.60 g, 20 mmol) (from Example 6 supra) in anhydrous hydrazine (10 mL, 318 mmol) (Aldrich) was heated at reflux (150° C. bath temperature) for 3 hours. After cooling to room temperature, mixture was concentrated under reduced pressure to give a dry solid. This was suspended in xylene (50 mL) and concentrated under reduced pressure. Resulting solid was suspended in triethyl ortho-aceate (35 mL, 191 mmol) (Aldrich) and heated at reflux (150° C. bath temperature) for 20 hours with removal of ethanol. After cooling, dichloromethane was added and solid was collected by filtration to give 2-methyl-5-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenol as an off-white crystalline material. (Yield 2.28 g, 60.0%).