Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:14](=[CH2:15])[C:13](=[O:16])[C@@H:12]2[C@H:10]1[C@H:11]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:33]=[C:34]([SH:39])[CH:35]=[CH:36][C:37]=1[F:38].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@:9]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:14]([CH2:15][S:39][C:34]2[CH:35]=[CH:36][C:37]([F:38])=[C:32]([F:31])[CH:33]=2)[C:13](=[O:16])[C@@H:12]2[C@H:10]1[C@H:11]2[C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(S)cc1F
Reactant: C=C1C(=O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]2[C@]1(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2C(=O)[C@H]1CSc1ccc(F)c(F)c1
Temperature: 80 °C
Yield: 141 %

Procedure:
A suspension of di-tert-butyl (1S,2R,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-methylidene-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylate (350.00 g, 826.43 mmol) in toluene (2.95 L) is treated with 3,4-difluorobenzenethiol (172.49 g, 1.18 mol) and triethylamine (205.61 mL, 149.28 g, 1.48 mol) at 25° C. The mixture is stirred at 80° C. After twelve hours, the reaction was cooled to room temperature, washed sequentially with 2N aqueous NaOH (pH=10) and aqueous. 1N HCl (pH=4), dried over MgSO4, and concentrated in vacuo to yield a residue. Triturate the residue with hexane (1 L) and remove the solvent to yield the title compound (664 g, 100% yield).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C@@H:12]([NH2:14])[CH3:13])=[CH:6][CH:5]=1.[CH2:17]([O:24][C:25]([NH:27][C@@H:28]([CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C:29](O)=[O:30])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:17]([O:24][C:25](=[O:26])[NH:27][C@H:28]([C:29](=[O:30])[NH:14][C@@H:12]([CH3:13])[CH2:11][NH:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:15])([F:16])[F:1])=[CH:9][CH:8]=1)[CH2:32][CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[C@H](N)CNc1ccc(OC(F)(F)F)cc1
Reactant: O=C(N[C@@H](CC1CCCCC1)C(=O)O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](CNc1ccc(OC(F)(F)F)cc1)NC(=O)[C@H](CC1CCCCC1)NC(=O)OCc1ccccc1
Reaction time: 1.5 h

Procedure:
(S)—N-(4-trifluoromethoxy-phenyl)-propane-1,2-diamine (76.7 mg, 0.328 mmol), (S)-2-benzyloxycarbonylamino-3-cyclohexyl-propionic acid (100 mg, 0.328 mmol) and HATU (125 mg, 0.328 mmol) were added to a round bottom flask with 20 mL of dry DCM. DIPEA (127 mg, 0.982 mmol) was added dropwise over three minutes with vigorous stirring. The resulting slurry was stirred for 1.5 hours. The solution was then washed with sodium bicarbonate, the organic layer was separated and partially concentrated and the concentrate was purified by flash chromatography. Yield 138 mg, 81%.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1([S:19]([C:22]2[C:23]([S:33][CH3:34])=[N:24][N:25]3[C:30](Cl)=[CH:29][C:28]([CH3:32])=[N:27][C:26]=23)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[C:13]1([S:19]([C:22]2[C:23]([S:33][CH3:34])=[N:24][N:25]3[C:30]([N:10]4[CH2:11][CH2:12][N:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[CH2:8][CH2:9]4)=[CH:29][C:28]([CH3:32])=[N:27][C:26]=23)(=[O:21])=[O:20])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccccc1
Solvent: CN(C)C=O
Product: CSc1nn2c(N3CCN(c4ccccc4)CC3)cc(C)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
0.16 g (1 mmol) of N-phenyl-piperazine was added to a solution of 0.17 g (0.5 mmol) of 3-benzenesulphonyl-7-chloro-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine in 3 ml of DMF and stirred at 60° for 2 hrs. The reaction solution was cooled to RT and evaporated in a high vacuum. The residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/MeOH 19:1) and crystallization from EtOH yielded 0.16 g (67%) of 3-benzenesulphonyl-5-methyl-2-methylsulphanyl-7-(4-phenyl-piperazin-1-yl)-pyrazolo[1,5-a]pyrimidine as colorless crystals, m.p. >230°.
Reaction SMILES: Cl[C:2](Cl)(Cl)[C:3]([N:5]=[C:6]=[O:7])=[O:4].[NH2:10][C:11]1[C:15]([CH3:16])=[CH:14][S:13]C=1C(OC)=O>C(#N)C>[CH3:16][C:15]1[C:11]2[NH:10][C:6](=[O:7])[NH:5][C:3](=[O:4])[C:2]=2[S:13][CH:14]=1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: COC(=O)c1scc(C)c1N
Solvent: CC#N
Product: Cc1csc2c(=O)[nH]c(=O)[nH]c12
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 57.8 %

Procedure:
Trichloroacetyl isocyanate (2.0 g) was added to a solution of methyl 3-amino-4-methylthiophene-2-carboxylate (1.3 g) in acetonitrile (10 mL) and the resulting mixture was stirred for 15 minutes. The solid, which crashed out, was collected by filtration and suspended in methanol (5 mL), a solution of ammonia in methanol (7 M, 5 mL) was then added and the resulting mixture was heated at 70° C. for 15 minutes. The reaction mixture was cooled, the solid formed was collected by filtration, dried under reduced pressure to give 0.8 g of 7-methyl-1H-thieno[3,2-d]pyrimidine-2,4-dione.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[OH:16].C(N(C(C)C)CC)(C)C.[CH3:26][O:27][CH2:28]Cl>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].C(Cl)Cl>[CH3:26][O:27][CH2:28][C:2]1([Br:1])[CH:7]=[C:6]([C:8]([CH3:9])([CH3:10])[CH3:11])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]1[OH:16]
Reactant: COCCl
Reactant: CC(C)(C)c1cc(Br)c(O)c(C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCC1(Br)C=C(C(C)(C)C)C=C(C(C)(C)C)C1O
Temperature: 45 °C
Yield: 94.8 %

Procedure:
To a solution of 2-bromo-4,6-di-t-butylphenol (Compound D 2.54 g, 8.88 mmol) and catalytic amount of Bu4NI in 20 ml of dry CH2Cl2 at 0° C. was added diisopropylethylamine (9.51 ml, 53 mmol), followed by methoxymethyl chloride (2.02 ml, 26.6 mmol). The reaction mixture was heated to 45° C. for 12 hours. The reaction mixture was then washed with 10% citric acid, then NaHCO3 (sat.), brine, and dried over MgSO4. After filtration and removal of the solvent under reduced pressure, the residue was purified by column chromatography (pure hexane) to yield the title compound (2.79 g) as a colorless oil. 1H NMR δ 7.40 (d, J=2.44 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 5.22 (s, 2H), 3.70 (s, 3H), 1.43 (s, 9H), 1.29 (s, 9H).
Reaction SMILES: [CH3:1][O:2]/[CH:3]=[C:4](\[N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1)/[C:5]([O:7][CH3:8])=[O:6].P(Cl)(Cl)(Cl)=O.CN([CH:22]=[O:23])C.C([O-])(=O)C.[Na+]>ClCCCl>[CH3:1][O:2]/[CH:3]=[C:4](\[N:9]1[CH:10]=[CH:11][CH:12]=[C:13]1[CH:22]=[O:23])/[C:5]([O:7][CH3:8])=[O:6]
Reactant: CO/C=C(/C(=O)OC)n1cccc1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CO/C=C(/C(=O)OC)n1cccc1C=O
Temperature: 25 °C
Yield: 49.5 %

Procedure:
A solution of (Z)-methyl 3-methoxy-2-(pyrrol-1-yl)acrylate (10 g, 0.055 mol) in 1,2-dichloroethane (25 ml) was added dropwise with stirring at room temperature to the mixture resulting from adding phosphoryl chloride (5.6 ml, 0.06 mol) to DMF (4.7 ml, 0.06 mol) while cooling in ice. After stirring for 3 hours at room temperature, a saturated aqueous solution of sodium acetate (100 ml) was added and the resulting mixture was heated at reflux for 30 minutes. The mixture was cooled then extracted with dichloromethane (2×150 ml). The extracts were washed with water, dried and concentrated to give a clear oil (11.7 g, of a mixture of the 2 and 3-formylated pyrrole) which was purified by HPLC on silica gel using diethyl ether as the eluant to give (Z)-methyl 3-methoxy-2-(2-formylpyrrol-1-yl)acrylate (5.7 g, 45%) as a white crystalline solid, m.p. 58°-9° C., proton n.m.r. (CDCl3) delta: 3.74 (3) s, 3.88 (3) s, 6.35 (1) m, 6.87 (1) m, 7.04 (1) m, 7.55 (1) s, 9.30 (1) d.
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1.[C:11]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][C:22](Cl)=[O:23])[CH2:16][CH2:15]1)(=[O:13])[CH3:12].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[C:11]([N:14]1[CH2:15][CH2:16][CH:17]([CH2:20][CH2:21][C:22]([C:9]2[CH:8]=[CH:7][C:6]3[S:1][CH2:2][CH2:3][CH2:4][C:5]=3[CH:10]=2)=[O:23])[CH2:18][CH2:19]1)(=[O:13])[CH3:12]
Reactant: c1ccc2c(c1)CCCS2
Reactant: CC(=O)N1CCC(CCC(=O)Cl)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)N1CCC(CCC(=O)c2ccc3c(c2)CCCS3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
To a mixture of 3,4-dihydro-2H-1-benzothiopyran (1.5 g) and 3-(1-acetylpiperidin-4-yl)propionyl chloride (2.18 g) in 1,2-dichloroethane (20ml) was added aluminum chloride (3.2 g) portionwise at 10°-15° C. The mixture was stirred at room temperature for 2 hours then refluxed for additional 2 hours, and poured into icewater. The mixture was extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate. The solvent was distilled off. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate) to obtain 2.7 g of the title compound as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:35]I)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:35][O:14][C:11]2[CH:12]=[N:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccccc2OC)C1
Reactant: Oc1ccc(-c2ccc(Cl)cc2)nc1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(Cl)cc3)nc2)CCN(C(=O)c2ccccc2OC)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 6-(4-chloro-phenyl)-pyridin-3-ol (Preparation 23) and 3-iodomethyl-1-(2-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 15) to afford the racemate as a white solid (116 mg, 47.7%)
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:10][CH:9]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30]Br>CN(C=O)C.CCOC(C)=O>[F:21][C:18]([F:19])([F:20])[CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:2]([C:3]2([C:4]([O:6][CH3:7])=[O:5])[CH2:30][CH2:29]2)=[O:1])=[CH:9][CH:10]=1
Reactant: COC(=O)CC(=O)c1ccc(OCCCC(F)(F)F)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1(C(=O)c2ccc(OCCCC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64.5 %

Procedure:
To a solution of Intermediate 14A (6.0 g, 19.7 mmol) in DMF (197 mL) was added K2CO3 (8.18 g, 59.2 mmol) followed by 1,2-dibromoethane (2.6 mL, 30 mmol). The reaction mixture was stirred at rt for 2 days. The reaction was reduced in volume in vacuo, then diluted with EtOAc, washed with a 1:1 solution of sat'd aq NaCl and water, dried over anhydrous MgSO4, filtered and concentrated. The product was isolated by silica gel chromatography (220 g silica gel, eluted with EtOAc in hexanes) to provide Intermediate 14B (4.2 g, 61%) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 1.45-1.49 (m, 2H), 1.56-1.61 (m, 2H), 2.03-2.14 (m, 2H), 2.26-2.39 (m, 2H), 3.60 (s, 3H), 4.09 (t, J=6.05 Hz, 2H), 6.90-6.94 (m, 2H), 7.86-7.93 (m, 2H).
Reaction SMILES: [C:1]1([CH:7]([CH2:11][CH3:12])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:17]O>C(OCC)C>[C:1]1([CH:7]([CH2:11][CH3:12])[C:8]([O:10][CH3:17])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(C(=O)O)c1ccccc1
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: CCC(C(=O)OC)c1ccccc1
Reaction time: 8 h

Procedure:
To 102 g. of 2-phenylbutyric acid dissolved in 1 liter of methanol was added 2 ml of thionyl chloride. The solution was allowed to stand at room temperature overnight. The solvent was removed in vacuo to yield an oil which was dissolved in diethyl ether, washed successively with dilute sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous potassium carbonate, and concentrated in vacuo. Distillation yielded 101 g of the title compound as a water-white oil, b.p. 62°-65°/0.5 mm, having the following elemental analysis:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([OH:9])=[C:4]([CH2:10][CH3:11])[N:3]=1.O.[OH-].[Li+].Br[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][C:28]([O:30]C)=[O:29]>CN(C=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[C:4]([CH2:10][CH3:11])[N:3]=1
Reactant: COC(=O)CCc1ccccc1OCCCBr
Reactant: CCc1nc(N)nc(N)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc(N)nc(N)c1OCCCOc1ccccc1CCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
2,4-Diamino-6-ethyl-5-hydroxypyrimidine (0.4625 g, 3 mmol) was added to a stirred solution of lithium hydroxide monohydrate (0.4406 g, 10.5 mmol) in DMF (4 mL) and the reaction mixture was stirred at 25° C. for 1 hour. A solution of methyl 3-(2-(3-bromopropoxy)phenyl)propanoate (0.9035 g, 3 mmol) in DMF (1 mL) was added and the reaction mixture was left stirring at 25° C. overnight. DMF was partially removed under reduced pressure to give residue. The residue was diluted with water followed by extraction with dichloromethane. The aqueous layer was neutralized with dil. HCl to give white solid. Recrystallization from acetone afforded the desired diaminopyrimidine as white solid (0.6271 g, 58%, m.p. 155.5-157.5° C.). 1H NMR (400 MHz, DMSO-d6): 1.04 (3H, t, J=7.6 Hz), 2.19 (2H, m), 2.39 (2H, q, J=7.5 Hz), 2.46 (2H, t, J=7.5 Hz), 2.78 (2H, t, J=7.7 Hz), 3.83 (2H, t, J=6.1 Hz), 4.15 (2H, t, J=5.9 Hz), 6.29 (2H, bs), 6.85 (1H, t, J=7.4 Hz), 6.96 (2H, bs), 6.98 (1H, d, J=8.1 Hz), 7.14-7.19 (2H, m).
Reaction SMILES: C([N:9]1[C:17]2[C:12](=[C:13]3[CH:20]([CH2:21][Cl:22])[CH2:19][N:18]([C:23]([O:25]C(C)(C)C)=O)[C:14]3=[CH:15][CH:16]=2)[CH:11]=[C:10]1[C:30]([O:32][CH2:33][CH3:34])=[O:31])(=O)C1C=CC=CC=1.Cl.C(Cl)CCl.[CH3:40][O:41][C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[NH:47][C:46](C(O)=O)=[CH:45]2>C(OCC)(=O)C>[Cl:22][CH2:21][CH:20]1[C:13]2=[C:12]3[C:17](=[CH:16][CH:15]=[C:14]2[N:18]([C:23]([C:46]2[NH:47][C:48]4[C:44]([CH:45]=2)=[CH:43][C:42]([O:41][CH3:40])=[CH:50][CH:49]=4)=[O:25])[CH2:19]1)[NH:9][C:10]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:11]3
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: CCOC(=O)c1cc2c3c(ccc2n1C(=O)c1ccccc1)N(C(=O)OC(C)(C)C)CC3CCl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCOC(=O)c1cc2c3c(ccc2[nH]1)N(C(=O)c1cc2cc(OC)ccc2[nH]1)CC3CCl
Reaction time: 0.5 h
Yield: 105.4 %

Procedure:
Compound 3.7(100 mg, 0.21 mmol) was treated with a solution of hydrochloric acid in ethyl acetate (4M, 500 μL). After 30 min, the solvent was concentrated and DMF (1 mL) was added. The solution was treated with EDC (120 mg, 0.63 mmol) and 5-methoxyindole-2-carboxylic acid (120 mg, 0.63 mmol). After 16 h, the solvent was removed under reduced pressure and the residue (the 6N-benzoyl protected precursor of compound 3.8) was dissolved in CH3OH (1 mL). A solution of NaOCH3 in CH3OH (2M, 100 μL) was then added and the solution stirred for 10 minutes. The solvent was removed and chromatography (SiO2, 10% ethyl acetate/hexanes) gave the product (3.8) (100 mg, 86%). FABMS (NBA/NaI) m/z 557 (M+H+ expected 557).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)[N:9]=[C:10](I)[C:3]=12.[CH3:21][O:22][C:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][C:24]=1[NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.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>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)[N:9]=[C:10]([C:27]3[CH:26]=[CH:25][C:24]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[C:23]([O:22][CH3:21])[CH:28]=3)[C:3]=12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OC(C)(C)C
Reactant: Nc1ncnc2c1c(I)nn2-c1ccc([N+](=O)[O-])cc1
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: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(-c2nn(-c3ccc([N+](=O)[O-])cc3)c3ncnc(N)c23)ccc1NC(=O)OC(C)(C)C
Temperature: 85 °C
Reaction time: 26 h
Yield: 63 %

Procedure:
A suspension of 4-amino-1-[4-nitrophenyl]-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (0.500 g, 1.31 mmol) in dimethylformamide (8 mL) was treated with tert-butyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (0.915 g, 2.62 mmol), tetrakis(triphenylphosphine)palladium (0.091 g, 0.06 mmol), and a solution of sodium carbonate (0.333 g, 3.14 mmol) in water (4 mL). The reaction mixture stirred at 85° C. for 26 h under a nitrogen atmosphere. Water was added to the reaction mixture. The precipitate was filtered and washed with water. The solid was triturated with diethyl ether to give 0.431 g, (63%) of tert-butyl N-(4-{4-amino-1-[4-nitrophenyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)carbamate. 1H NMR (DMSO-d6, 400 MHz) δ 8.6862-8.6634 (d, 2H, J=9.12 Hz), 8.4897-8.4423 (m, 3H), 8.1117 (s, 1H), 8.0074-7.9872 (d, 1H, J=8.08 Hz), 7.3743-7.3293 (m, 2H), 3.9189 (s, 3H), 1.4959 (s, 9H); LCMS (Perkin Elmer, Pecosphere C18 column, 3 um particle size, 33×4.6 mm; 100% 50 mM ammonium Acetate in Water to 100% Acetonitrile over 5 min, 3.0 to 3.5 mil/min) tR=4.38 min M+ 478.1.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].Br[CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12]>>[CH2:11]([CH:10]([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1)[CH2:13][CH3:14])[CH3:12]
Reactant: CCC(Br)CC
Reactant: O=[N+]([O-])c1c[nH]cn1
Product: CCC(CC)n1cnc([N+](=O)[O-])c1

Procedure:
4-nitroimidazole was alkylated with 3-bromopentane to provide the title compound: 1H NMR (400 MHz, CDCl3) 0.84-0.90 (m, 6H), 1.71-1.82 (m, 2H), 1.86-1.96 (m, 2H), 3.79 (p, 1H, J=4.8 Hz), 7.41 (d, 1H, J=1.6 Hz), 7.73 (d, 1H, J=1.3 Hz); MS 184.2 m/z (M+1).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:15][O:16][CH2:17][O:18][C:19]1[CH:35]=[CH:34][C:22]2[CH2:23][C:24]([C:27]3[N:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)([CH3:26])[O:25][C:21]=2[CH:20]=1.O[CH2:37][C@@H:38]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH3:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:15][O:16][CH2:17][O:18][C:19]1[CH:35]=[CH:34][C:22]2[CH2:23][C:24]([C:27]3[N:32]=[CH:31][C:30]([O:33][CH2:39][C@@H:38]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:44])([CH3:46])[CH3:45])[CH3:37])=[CH:29][CH:28]=3)([CH3:26])[O:25][C:21]=2[CH:20]=1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: COCOc1ccc2c(c1)OC(C)(c1ccc(O)cn1)C2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COCOc1ccc2c(c1)OC(C)(c1ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cn1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
A solution of diisopropyl azodicarboxylate (1.9 M in toluene, 2.20 mL) was added dropwise to a solution of diastereomer of 6-(6-(methoxymethoxy)-2-methyl-2,3-dihydrobenzofuran-2-yl)pyridin-3-ol (shorter retention time, 800 mg), (S)-tert-butyl (1-hydroxypropan-2-yl)carbamate (976 mg), and triphenylphosphine (1100 mg) in toluene (20 mL) at ambient temperature. The mixture was stirred at room temperature for 2 hr. The mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The separated organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (hexane/ethyl acetate) to give the title compound (1100 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[CH:30][N:29]=[C:28]3[CH3:32])=[CH:23][CH:22]=2)[CH:5]=[C:6]([C:8]2([C:14]([O:16]CC)=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.[OH-].[Li+].CO.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[CH:30][N:29]=[C:28]3[CH3:32])=[CH:23][CH:22]=2)[CH:5]=[C:6]([C:8]2([C:14]([OH:16])=[O:15])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:7]=1
Reactant: CCOC(=O)C1(c2cc(F)cc(OCc3ccc(-n4ccnc4C)cc3)c2)CCOCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nccn1-c1ccc(COc2cc(F)cc(C3(C(=O)O)CCOCC3)c2)cc1
Temperature: 0 °C
Yield: 9.6 %

Procedure:
A stirred mixture of ethyl 4-[5-fluoro-3-[4-(2-methylimidazol-1-yl)benzyloxy]phenyl]-3,4,5,6-tetrahydro-2H-pyran-4-carboxylate (Example 2) (1.10 g, 25 mmol), an aqueous solution of lithium hydroxide (0.13 g, 30 mmol, 5 ml), methanol (15 ml) and THF (15 ml) was refluxed for 24 hr. The reaction mixture was neutralized with 1N hydrogen chloride. Volatiles were removed by evaporation under reduced pressure. The residue was suspended into a mixture of water (20 ml) and phosphate buffer (pH=7, 5 ml) and heated to reflux for 30 min. After cooling to 0° C., solids were collected by filtration, washed with water and then with ether and dried to constant weight under vacuum at 80° C. for 14 hr to afford the titled compound as white solids (0.98 g, 96%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1.[CH3:16][C:17]([CH3:19])=[O:18].CO.[OH-].[K+]>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11](/[CH:14]=[CH:16]/[C:17](=[O:18])[CH3:19])=[CH:12][CH:13]=1
Reactant: CC(C)=O
Reactant: O=Cc1ccc(-c2ccccc2F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)/C=C/c1ccc(-c2ccccc2F)cc1

Procedure:
200.2 Gm (1.0 mol) of 2'-fluoro-4-biphenyl-carboxaldehyde, 3500 gm (60.3 mols) of acetone and 200 ml of methanol were charged into a 6-liter three-neck-flask equipped with a stirrer, a dropping funnel and an internal thermometer. While thoroughly stirring the contents of the flask, a solution of 2.805 gm (0.05 mol) of potassium hydroxide in 16 ml of water was added dropwise thereto while maintaining a reaction temperature of 20° to 25°C, and the resulting mixture was stirred for three hours more. Thereafter, the precipitated solid side product was filtered off, the filtrate was made neutral by dropwise addition of glacial acetic acid, and the neutral solution was evaporated in vacuo. The residue was recrystallized three times from diisopropyl ether and then once from a mixture of ethyl acetate and diisopropyl ether (volumetric ratio 1:1) in the presence of activated charcoal, yielding 101.2 gm (42% of theory) of the fallow crystalline compound of the formula ##SPC20##