Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH:2]=1.Br[C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[CH2:19]([O:18][C:16](=[O:17])[C:15]([CH3:22])([O:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:8]=1)[CH3:21])[CH3:20]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1cccc(-c2cccnc2)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1cccc(-c2cccnc2)c1
Temperature: 95 °C
Reaction time: 0.25 h
Yield: 78.3 %

Procedure:
A mixture of 3-pyridin-3-yl-phenol (5.14 g, 30.0 mmol), ethyl 2-bromoisobutyrate (26.3 g, 135.0 mmol), and K2CO3 (18.7 g, 135.0 mmol) in anhydrous DMF (60 mL) was heated at 95° C. under nitrogen for 5 h. After cooling, brine (200 mL) was added and the mixture was extracted with ethyl acetate (250 mL). The separated organic layer was washed with brine, filtered, and concentrated. The oil residue was taken up in 80 mL of 3 M HCl, stirred for 15 min, diluted with brine (100 mL), and extracted with ethyl acetate (2×150 mL). The separated aqueous layer was cooled in ice/water bath, adjusted to pH 10 with solid Na2CO3, and extracted with ethyl acetate (2×200 mL). The organic extract was dried over sodium sulfate and concentrated to afford 6.70 g (78%) of 2-methyl-2-(3-pyridin-3-yl-phenoxy)-propionic acid ethyl ester as a light brown oil: 1H NMR (CDCl3) δ 1.22 (t, 3H), 1.61 (s, 6H), 4.22 (q, 2H), 6.82 (dd, 1H), 7.08 (s, 1H), 7.20 (dd, 1H), 7.38 (m, 2H), 7.81 (dd, 1H), 8.59 (br s, 1H), 8.80 (br s, 1H); MS m/z (relative intensity) 285 (M+, 11), 212 (22), 171 (100).
Reaction SMILES: [NH2:1][C:2]1[C:5](=[O:6])[C:4](=[O:7])[C:3]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19]O)[CH:14]=1.S(Cl)([Cl:23])=O>>[NH2:1][C:2]1[C:5](=[O:6])[C:4](=[O:7])[C:3]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][Cl:23])[CH:14]=1
Reactant: Nc1c(NCCCOc2cccc(CO)c2)c(=O)c1=O
Reactant: O=S(Cl)Cl
Product: Nc1c(NCCCOc2cccc(CCl)c2)c(=O)c1=O

Procedure:
When 1-amino-2-[3-(3-hydroxymethyl-phenoxy)propylamino]-1-cyclobutene-3,4-dione is treated with at least one equivalent of thionyl chloride, there is thereby produced the title compound.
Reaction SMILES: [O:1]=[C:2]([CH2:8][C:9](=[O:33])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:22]=[CH:21][S:20][CH:19]=2)=[CH:12][C:11]=1[O:23][CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32])[CH3:25])[C:3]([O:5]CC)=[O:4]>[OH-].[K+]>[O:1]=[C:2]([CH2:8][C:9](=[O:33])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:22]=[CH:21][S:20][CH:19]=2)=[CH:12][C:11]=1[O:23][CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32])[CH3:25])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(OCc2ccsc2)cc1OC(C)c1ccccc1C
Agent: [K+]
Agent: [OH-]
Product: Cc1ccccc1C(C)Oc1cc(OCc2ccsc2)ccc1C(=O)CC(=O)C(=O)O
Yield: 9.8 %

Procedure:
A solution of ethyl (RS)-2,4-dioxo-4-[2-(1-(2-methylphenyl)ethoxy)-4-(3-thienylmethoxy)phenyl]butanoate (0.38 g) in 15% methanolic potassium hydroxide (25 mL) is stirred at reflux for 1 hour before being cooled and concentrated under reduced pressure. The residue is dissolved in water, acidified to pH 1 with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer is dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is recrystallised from cyclohexane to give (RS)-2,4-dioxo-4-[2-(1-(2-methylphenyl)ethoxy)-4-(3-thienylmethoxy)-phenyl]butanoic acid (35 mg) as a yellow solid, m.p. 124-6° C. [Elemental analysis:- C, 65.82; H, 5.03%; Calculated for C24H22O6S:- C, 65.74; H, 5.06%].
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]2[NH:11][C:12](=[O:25])[C:13]3[C:14](=[C:16]([C:20]4[O:21][CH:22]=[CH:23][CH:24]=4)[N:17]([CH3:19])[N:18]=3)[N:15]=2)=[CH:8][C:7]([S:26]([N:29]2[CH2:34][CH2:33][N:32]([CH2:35][CH3:36])[CH2:31][CH2:30]2)(=[O:28])=[O:27])=[CH:6][N:5]=1)[CH3:2]>[Pd].C(O)C.O>[CH2:1]([O:3][C:4]1[C:9]([C:10]2[NH:11][C:12](=[O:25])[C:13]3[C:14](=[C:16]([CH:20]4[CH2:24][CH2:23][CH2:22][O:21]4)[N:17]([CH3:19])[N:18]=3)[N:15]=2)=[CH:8][C:7]([S:26]([N:29]2[CH2:34][CH2:33][N:32]([CH2:35][CH3:36])[CH2:31][CH2:30]2)(=[O:27])=[O:28])=[CH:6][N:5]=1)[CH3:2]
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(-c3ccco3)n(C)nc2c(=O)[nH]1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(C3CCCO3)n(C)nc2c(=O)[nH]1
Reaction time: 18 h
Yield: 32.6 %

Procedure:
A mixture of the title compound from example 61 (80 mg, 0.16 mmol) and 10% palladium on charcoal (10 mg) in ethanol (4.5 ml) and water (0.5 ml) was hydrogenated at 60 psi (414 kPa) and 40° C. for 18 hours. The reaction mixture was filtered through Celite®, and the filtrate evaporated under reduced pressure to afford the title compound, (27 mg, 32%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[O:6][CH:7]=1.C(N(C(C)C)CC)(C)C.CS(Cl)(=O)=O.[N:34]1([CH2:39][CH2:40][CH2:41][CH2:42][C:43]2[CH:48]=[CH:47][C:46](O)=[CH:45][CH:44]=2)[CH:38]=[CH:37][N:36]=[N:35]1.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[F:17][C:16]([F:19])([F:18])[C:13]1[CH:14]=[CH:15][C:10](/[CH:9]=[CH:8]/[C:5]2[O:6][CH:7]=[C:3]([CH2:2][O:1][C:46]3[CH:45]=[CH:44][C:43]([CH2:42][CH2:41][CH2:40][CH2:39][N:34]4[CH:38]=[CH:37][N:36]=[N:35]4)=[CH:48][CH:47]=3)[N:4]=2)=[CH:11][CH:12]=1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: OCc1coc(/C=C/c2ccc(C(F)(F)F)cc2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)Cl
Agent: [Br-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(/C=C/c2nc(COc3ccc(CCCCn4ccnn4)cc3)co2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
The obtained 4-(hydroxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole (1.00 g, 3.71 mmol) and diisopropylethylamine (0.95 mL, 5.44 mmol) were added to THF (tetrahydrofuran) (15 ml). Methanesulfonyl chloride (0.45 mL, 5.81 mmol) was added dropwise under ice-cooling. The mixture was stirred at the same temperature for 1 hour. 4-[4-(1H-1,2,3-Triazol-1-yl)butyl]phenol (900 mg, 4.14 mmol) and tetra(n-butyl)ammonium bromide (60 mg, 0.19 mmol) were added at the same temperature. A 2N aquous sodium hydroxide solution (7.5 mL, 15.0 mmol) was added dropwise at not more than 15° C. and the mixture was stirred with reflux for 1 hour. After allowing to cool to room temperature and stirring, the organic layer was concentrated under reduced pressure. Ethanol (20 ml) was added to the residue, and the mixture was stirred with reflux. Water (20 ml) was added dropwise at the same temperature. After allowing to cool to room temperature and stirring, the mixture was ice-cooled. The precipitated crystals were collected by filtration, washed with water (20 ml) and dried under reduced pressure to give 1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole (1.61 g, 3.44 mmol, yield 88%).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[C:23]([CH3:30])[CH:22]=1>>[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]4[CH:18]=[N:17][C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:10]=4)[CH2:3]3)[CH2:6]2)=[O:26])=[C:23]([CH3:30])[CH:22]=1
Reactant: COc1ccc(C(=O)O)c(C)c1
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Product: COc1ccc(C(=O)N2CC3CN(c4cnc5ccccc5n4)CC3C2)c(C)c1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and 4-methoxy-2-methyl-benzoic acid. MS (ESI): mass calculated for C23H24N4O2, 388.47; m/z found 389.2 [M+H]+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](CCCCCCCC)[CH:6]=[C:5]2CN(C)C.F[C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)N(CCCCCCCC)C=[C:27]2CN1CCCCC1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:26]1([CH3:27])[CH:30]=[CH:31][CH:32]=[C:24]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)[CH:25]=1
Reactant: CCCCCCCCn1cc(CN(C)C)c2cc(F)ccc21
Reactant: CCCCCCCCn1cc(CN2CCCCC2)c2cc(F)ccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cccc(-c2ccc3[nH]ccc3c2)c1
Reaction time: 0.25 h
Yield: 55 %

Procedure:
To the mixture of 5-bromo-1H-indole (1, 5 mmol, 1 equiv.), 3-tolylboronic acid (2, 5.5 mmol, 1.1 equiv.) and Pd(dppf)Cl2 (0.25 mmol, 0.05 equiv.) in 12 mL 1,4-dioxane was added 4 mL aqueous solution of K2CO3 (15 mmol, 3 equiv.). The mixture was stirred under argon for about 15 min then stirred under microwave in 130□ for about 25 min twice. On cooling, the solvent was evaporated and the resulting residue was extracted with CH2Cl2 (20 mL×3), the dichloromethane layer was washed with brine, dried (Na2SO4) and filtered. The residue obtained on removal of the solvent was purified by column chromatography on silica gel with EtOAc/hexane as eluting solvents to give the target compound 5-m-tolyl-1H-indole (3). Yield: 55.0%. 1H NMR (300 MHz, CDCl3): δ 2.31 (s, 3 H), 6.47 (s, 1 H), 6.92-7.12 (m, 2 H), 7.18-7.23 (m, 1 H), 7.29-7.35 (m, 4H), 7.74 (s, 1 H), 7.99 (br, 1H). 13C NMR (75 MHz, CDCl3) δ 21.5, 102.9, 111.1, 119.2, 121.9, 124.4, 124.8, 127.0, 128.2, 128.3, 128.5, 133.4, 135.2, 138.1, 142.5.
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.O1CCCC1.[O:18]=[C:19]1[C:25]2[CH:26]=[CH:27][C:28]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:29][C:24]=2[CH:23]=[CH:22][C:21]2[CH:35]=[CH:36][CH:37]=[CH:38][C:20]1=2>CCCCCC.CN(C)P(=O)(N(C)C)N(C)C>[O:18]=[C:19]1[C:25]2[CH:26]=[CH:27][C:28]([C:30](=[CH2:1])[C:31]([O:33][CH3:34])=[O:32])=[CH:29][C:24]=2[CH:23]=[CH:22][C:21]2[CH:35]=[CH:36][CH:37]=[CH:38][C:20]1=2
Reactant: COC(=O)Cc1ccc2c(=O)c3ccccc3ccc2c1
Reactant: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C(C(=O)OC)c1ccc2c(=O)c3ccccc3ccc2c1
Temperature: -80 °C
Reaction time: 0.17 h

Procedure:
1.25 Ml. of 1.6 molar n-butyllithium in hexane is added to a solution of 0.280 ml. of diisopropylamine in 30 ml. of tetrahydrofuran. The solution is cooled to -80° C and 0.556 g. of methyl (5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)acetate is added. After 10 minutes 0.38 ml. of hexamethylphosphoric triamide is added. The cooling bath is removed and formaldehyde vapor, entrained in nitrogen, is passed over the solution until it becomes colorless. Water and ether are then added and the organic layer is washed with dilute hydrochloric acid, saturated sodium chloride solution, then dried and evaporated. The residue is chromatographed on 10 g. of silica gel, eluting with hexane:ethyl acetate (5:1) to isolate methyl 2-(5-oxo-5H-dibenzo-[a,d]cyclohepten-2-yl)acrylate. 0.02 G. of this compound is refluxed under nitrogen in 5 ml. of water, 2 ml. of ethanol and 0.5 ml. of saturated sodium carbonate solution for 4 hours. The mixture is cooled, washed with ether and acidified with dilute hydrochloric acid, then extracted with ethyl acetate and the extract dried and evaporated to yield 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)acrylic acid.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:33])[C@@H:4]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:5][C@H:6]([CH2:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[N:16][N:17]2[CH2:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:13][CH:12]=1)[CH:7]([CH3:9])[CH3:8].[CH3:34][C:35]([CH3:43])([CH2:39][CH2:40][CH2:41][CH3:42])[C:36](O)=[O:37].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:34][C:35]([CH3:43])([CH2:39][CH2:40][CH2:41][CH3:42])[C:36]([NH:1][CH2:2][C@H:3]([OH:33])[C@@H:4]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:5][C@H:6]([CH2:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[N:16][N:17]2[CH2:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:13][CH:12]=1)[CH:7]([CH3:8])[CH3:9])=[O:37]
Reactant: COCCCn1ncc2ccc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN)C(C)C)cc21
Reactant: CCCCC(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCC(C)(C)C(=O)NC[C@H](O)[C@H](C[C@H](Cc1ccc2cnn(CCCOC)c2c1)C(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 5 h
Yield: 74.9 %

Procedure:
To a solution of tert-butyl (2S,3S,5S)-1-amino-2-hydroxy-5-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-6-methylheptan-3-ylcarbamate (350 mg, 0.76 mmol) in CH2Cl2 (15 mL), 2,2-dimethylhexanoic acid (176 mg, 1.22 mmol), HOBt (290 mg, 2.1 mmol) and EDCl (400 mg, 2.1 mmol) were added. The mixture cooled to 0° C. and DIEA (700 mg, 5.4 mmol) was added. The resulting mixture was allowed to warm to rt and stirred for 5 h. The reaction mixture was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to give tert-butyl (2S,3S,5S)-1-(2,2-dimethylhexanamido)-2-hydroxy-5-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-6-methylheptan-3-ylcarbamate (335 mg, 75%). 1H NMR (400 MHz, CDCl3): 0.86 (m, 3H), 0.92 (m, 3H), 0.99 (m, 3H), 1.13 (s, 6H), 1.16 (m, 2H), 1.27 (m, 3H), 1.49 (m, 2H), 1.70 (m, 3H), 1.88 (m, 1H), 2.11 (m, 2H), 2.62 (m, 1H), 2.85 (m, 1H), 2.97 (m, 1H), 3.10 (m, 1H), 3.28 (s, 3H), 3.36 (m, 1H), 3.62 (m, 1H), 4.48 (m, 2H), 7.06 (m, 1H), 7.39 (s, 1H), 7.67 (m, 1H), 7.99 (s, 1H); MS: 588 (M++1)
Reaction SMILES: [CH2:1]([N:5]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[C:8]([O:14][CH3:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:20]([C:22]1[C:23](=[C:38]([C:41]#[N:42])[C:39]#[N:40])[O:24][C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:28]([F:31])([F:30])[F:29])[C:26]=1[CH3:27])#[N:21]>C(O)C>[CH2:1]([N:5]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH:27][C:26]2[C:25]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)([C:28]([F:31])([F:29])[F:30])[O:24][C:23](=[C:38]([C:41]#[N:42])[C:39]#[N:40])[C:22]=2[C:20]#[N:21])=[C:8]([O:14][CH3:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(c1ccccc1)C(F)(F)F
Reactant: CCCCN(CCCC)c1ccc(C=O)c(OC)c1
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=CC2=C(C#N)C(=C(C#N)C#N)OC2(c2ccccc2)C(F)(F)F)c(OC)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
In 5 ml of ethanol were dissolved 150 mg (0.57 mmol) of 4-dibutylamino-2-methoxybenzaldehyde and 197 mg (0.63 mmol) of 2-(3-cyano-4-methyl-5-phenyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. After the mixture was stirred at 50° C. for 2 hours, ethanol was evaporated off. The residue was purified by silica gel column chromatography to give 272 mg of a dark brown crystal (yield: 85.2%; mp: 191-194° C.)
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH2:8])=[CH:6][C:5]([CH2:9][C:10](=O)[N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:4]1)[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH2:1]([N:3]1[C:7]([NH2:8])=[CH:6][C:5]([CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)=[N:4]1)[CH3:2]
Reactant: CCn1nc(CC(=O)N2CCCC2)cc1N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCn1nc(CCN2CCCC2)cc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
To a solution of 1-ethyl-3-[2-oxo-2-(1-pyrrolidinyl)ethyl]-1H-pyrazol-5-amine (600 mg, 1.784 mmol) in tetrahydrofuran (8 mL) cooled with water-ice bath was added a solution of 2M LAH (1.0 mL, 2.00 mmol) solution dropwise, and the reaction mixture was stirred for 5 h at rt and 30 min at 50 degree. The reaction mixture was carefully quenched with methanol followed by water and concentrated. The residue was washed with DCM/methanol 5 times. The extract was concentrated and the residue was purified using HPLC under the basic conditions to give 220 mg of product. MS: (M+H)+=208.7. 1H NMR (400 MHz, CHLOROFORM-d) ppm 1.37 (t, J=7.2 Hz, 3H), 1.79 (m, 4H), 2.56 (m, 4H), 2.71 (m, 2H), 3.42 (m, 2H), 3.94 (q, J=7.2 Hz, 2H), 5.40 (s, 1H).
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][CH3:7])C.[CH3:24][C:25]1[O:29][C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)[CH:31]=2)=[N:27][C:26]=1[CH2:41][CH2:42]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C(O)C>[CH3:24][C:25]1[O:29][C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)[CH:31]=2)=[N:27][C:26]=1[CH2:41][CH2:42][O:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][C:5]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)([CH2:6][CH3:7])[C:4]([OH:3])=[O:23])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4cccs4)c3)oc2C)cc1
Reactant: CCOC(=O)C(CC)(Cc1ccc(O)cc1)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: CCC(Cc1ccc(OCCc2nc(-c3cccc(-c4cccs4)c3)oc2C)cc1)(Oc1ccccc1)C(=O)O

Procedure:
A mixture of 2-(4-hydroxybenzyl)-2-phenoxybutyric acid ethyl ester (0.030 mmol) (see Ex. 40, Part C), toluene-4-sulfonic acid 2-[5-methyl-2-(3-thiophen-2-ylphenyl)oxazol-4-yl]ethyl ester (0.030 mmol) (see Ex. 5, Part B) and 325 mesh K2CO3 (0.084 g, 0.60 mmol) in ethanol (2 mL) was heated to reflux for 24 h under N2. Aqueous 5N NaOH (0.5 mL) and additional ethanol (1 mL) was added to the reaction mixture and it was heated at reflux for an additional 2 h. The reaction was cooled and the solvent removed in vacuo. The residue was acidified with aqueous 1 N HCl (5 mL), extracted with water and CH2Cl2 and the organic layer dried by passing it through a Varian Chem Elut 1003 cartridge. The solvent was removed in vacuo to give 2-(4-{2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-benzyl)-2-phenoxy-butyric acid. 1H NMR (400 MHz, CDCl3) δ 8.22–8.21 (m, 1H), 7.89–7.85 (m, 1H), 7.66–7.62 (m, 1H), 7.45–7.40 (m, 2H), 7.32–7.25 (m, 3H), 7.11–6.97 (m, 6H), 6.77 (d, 2H, J=8.4 Hz), 4.20 (t, 2H, J=6.4 Hz), 3.29 (s, 2H), 2.98 (t, 2H, J=6.4 Hz), 2.39 (s, 3H), 2.14 (qd, 1H, J=14.6, 7.6 Hz), 2.07 (qd, 1H, J=14.6, 7.6 Hz), 0.91 (t, 3H, J=7.6 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:23]([O:25][CH3:26])=[O:24])=[N:11][N:12]2[CH:17]([C:18](O)=[O:19])[CH2:16][N:15]([CH3:21])[C:14](=[O:22])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1>[CH2:1]([O:8][C:9]1[C:10]([C:23]([O:25][CH3:26])=[O:24])=[N:11][N:12]2[CH:17]([CH2:18][OH:19])[CH2:16][N:15]([CH3:21])[C:14](=[O:22])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2C(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-benzyloxy-2-methoxycarbonyl-5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-7-carboxylic acid (183 mg, 0.509 mmol) in anhydrous THF under an atmosphere of nitrogen was added 1M borane-THF complex (6.11 mL, 6.11 mmol). The reaction was stirred at room temperature for 1 hour and quenched with aqueous 6N HCl. The solvent was removed in vacuo, and the resulting residue was purified by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA). Collection and concentration of the appropriate fractions afforded the alcohol as a sticky, clear oil. 1H NMR (400 MHz, d6-DMSO) δ 7.49-7.47 (m, 2H), 7.39-7.30 (m, 3H), 5.18 (s, 2H), 4.50-4.47 (m, 1H), 4.27 (br s, 1H), 4.07 (dd, J=5.2, 13.6 Hz, 1H), 3.91 (dd, J=5.2, 13.2 Hz, 1H), 3.79 (s, 3H), 3.78-3.71 (m, 2H), 3.03 (s, 3H); ES MS (M+H)=346.
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[C:34]1[S:35][CH:36]=[C:37]([C:39](O)=[O:40])[N:38]=1>>[NH2:9][C@H:8]1[C@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:39]([C:37]2[N:38]=[C:34]([C:28]3[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=3[F:26])[S:35][CH:36]=2)=[O:40])[CH2:6][CH2:7]1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: O=C(O)c1csc(-c2ccc(F)cc2F)n1
Product: Cn1ncc(NC(=O)c2csc(-c3ccc(F)cc3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 2-(2,4-difluorophenyl)thiazole-4-carboxylic acid (see US2008/76771) gave 325. 1H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.56-8.46 (m, 2H), 7.88 (s, 1H), 7.59-7.50 (m, 1H), 7.32-7.24 (m, 1H), 4.87 (dd, J=10.4, 3.5 Hz, 1H), 4.57-4.38 (m, 1H), 4.38-4.23 (m, 1H), 4.18-3.98 (m, 1H), 3.78 (s, 3H), 2.14-2.02 (m, 1H), 1.88-1.66 (m, 4H). LCMS (ES+) m/z 452 (M+1).
Reaction SMILES: [Na].[Cl:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[C:5]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:14]=[CH:13]2)[N:4]=1.[C:29]1([CH3:55])[CH:34]=[CH:33][C:32]([C:35]([O:37][C@@H:38]2[C@@H:42]([CH2:43][O:44][C:45]([C:47]3[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=3)=[O:46])[O:41][C@H:40](Cl)[CH2:39]2)=[O:36])=[CH:31][CH:30]=1>CC#N.C(Cl)Cl>[Cl:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@@H:40]2[O:41][C@H:42]([CH2:43][O:44][C:45]([C:47]3[CH:48]=[CH:49][C:50]([CH3:53])=[CH:51][CH:52]=3)=[O:46])[C@@H:38]([O:37][C:35]([C:32]3[CH:31]=[CH:30][C:29]([CH3:55])=[CH:34][CH:33]=3)=[O:36])[CH2:39]2)=[C:5]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:15]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:14]=[CH:13]2)[N:4]=1
Reactant: Clc1nc(-n2cnc(-c3ccccc3)c2-c2ccccc2)c2[nH]cnc2n1
Reactant: Cc1ccc(C(=O)OC[C@H]2O[C@H](Cl)C[C@@H]2OC(=O)c2ccc(C)cc2)cc1
Agent: [Na]
Solvent: ClCCl
Solvent: CC#N
Product: Cc1ccc(C(=O)OC[C@H]2O[C@@H](n3cnc4c(-n5cnc(-c6ccccc6)c5-c5ccccc5)nc(Cl)nc43)C[C@@H]2OC(=O)c2ccc(C)cc2)cc1

Procedure:
The sodium salt of 2-chloro-6-(4,5-diphenylimidazol-1-yl)purine (94 mg, 0.25 mmol) in dried CH3CN (10 mL) was treated with 2-deoxy-3,5-di-O-(p-toluoyl)-α-D-erythro-pentofuranosyl chloride (0.334 g, 0.86 mmol) in CH2Cl2 (10 mL) by general method 2. Sampling of the reaction mixture showed no α-nucleoside by 1H NMR (500 MHz). Volatiles were evaporated in vacuo, and the residue was chromatographed (25 g silica gel, EtOAc/hexanes, 3:7→1:1) to give the β-anomer (quantitative). Recrystallization (EtOAc/hexanes) gave 2-chloro-9-[2-deoxy-3,5-di-O-(p-toluoyl)-β-D-erythro-pentofuranosyl]-6-(4,5-diphenylimidazol-1-yl)purine: UV (MeOH) max 240, 275 nm (∈ 53 400, 19 300), min 223, 270 nm (∈ 42 000, 19 100); 1H NMR (500 MHz, CDCl3) δ 8.97 (s, 1H), 8.25 (s, 1H), 7.97 (d, J=7.9 Hz, 2H), 7.86 (d, J=7.9 Hz, 2H), 7.55 (d, J=8.2 Hz, 2H), 7.19-7.40 (m, 13H), 6.56 (t, J=7.0 Hz, 1H), 5.77-5.78 (m, 1H), 4.76-4.79 (m, 1H), 4.65-4.69 (m, 2H), 2.92-2.96 (m, 2H), 2.45 (s, 3H), 2.40 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 166.06, 165.94, 154.03, 153.17, 147.13, 144.71, 144.45, 142.81, 140.38, 139.24, 133.50, 131.02, 129.85, 129.55, 129.37, 129.34, 128.25, 128.17, 127.47, 127.17, 126.41, 126.18, 124.00, 85.11, 83.52, 74.85, 63.84, 38.57, 21.78, 21.71; HRMS m/z 747.2100 (MNa+[C41H33ClN6O5Na]=747.2099).