Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:36]2[CH2:48][CH2:47][N:39]3[C:40]4[CH2:41][CH2:42][CH2:43][CH2:44][C:45]=4[CH:46]=[C:38]3[C:37]2=[O:49])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][OH:33])[CH2:27][CH2:26]3)=[CH:21][N:20]=2)[C:15](=[O:34])[N:14]([CH3:35])[CH:13]=1)(=O)C.[Li+].[OH-]>CC(O)C.C1COCC1.O>[OH:33][CH2:32][CH2:31][N:28]1[CH2:29][CH2:30][N:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:16]3[C:15](=[O:34])[N:14]([CH3:35])[CH:13]=[C:12]([C:11]4[CH:10]=[CH:9][N:8]=[C:7]([N:36]5[CH2:48][CH2:47][N:39]6[C:40]7[CH2:41][CH2:42][CH2:43][CH2:44][C:45]=7[CH:46]=[C:38]6[C:37]5=[O:49])[C:6]=4[CH2:5][OH:4])[CH:17]=3)=[N:20][CH:21]=2)[CH2:26][CH2:27]1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(CCO)CC4)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2ccc(N3CCN(CCO)CC3)cn2)c1=O
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 22.9 %

Procedure:
A mixture of 123d (187 mg, 0.28 mmol) and LiOH (235 mg, 5.6 mmol) in iPrOH/THF (1:1, 3.5 mL) and H2O (0.5 mL) was stirred at 35° C. for 0.5 h. It was then evaporated in vacuo and the residue was extracted with EtOAc (5 mL×2). The combined EtOAc extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 123 (40 mg, 31%) as a yellow solid. MS: [M+H]+ 625.4. 1H NMR (500 MHz, CDCl3) δ 8.63 (d, J=2.5, 1H), 8.49 (d, J=5.0, 1H), 7.92 (d, J=2.5, 1H), 7.82 (d, J=2.0, 1H), 7.78 (s, 1H), 7.36 (d, J=5.5, 1H), 7.27-7.25 (m, 1H), 6.89 (s, 1H), 6.81 (d, J=9.5, 1H), 5.04-5.02 (m, 1H), 4.62 (d, J=10, 1H), 4.50-4.47 (m, 1H), 4.34-4.29 (m, 1H), 4.12-4.09 (m, 2H), 3.89-3.85 (m, 1H), 3.71-3.67 (m, 5H), 3.15-3.12 (m, 4H), 2.74-2.54 (m, 10H), 1.92-1.87 (m, 2H), 1.79-1.78 (m, 3H)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:62])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:58]([CH3:61])[CH2:59][CH3:60])[C@H:25]([O:56][CH3:57])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:54][CH3:55])[C@@H:35]([CH3:53])[C:36]([NH:38][C@@H:39]([CH2:43][C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[NH:46][CH:45]=1)[C:40]([NH2:42])=[O:41])=[O:37])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11].C(=O)([O-])O.[Na+].[O:68]=[C:69]1[CH:73]=[CH:72][C:71](=[O:74])N1C(OC)=O>O1CCOCC1>[O:68]=[C:69]1[CH:73]=[CH:72][C:71](=[O:74])[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:62])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:58]([CH3:61])[CH2:59][CH3:60])[C@H:25]([O:56][CH3:57])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:54][CH3:55])[C@@H:35]([CH3:53])[C:36]([NH:38][C@@H:39]([CH2:43][C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[NH:46][CH:45]=1)[C:40]([NH2:42])=[O:41])=[O:37])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:18])[CH3:19])=[O:14])[CH:10]([CH3:12])[CH3:11]
Reactant: COC(=O)N1C(=O)C=CC1=O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(N)=O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCCN)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(N)=O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCCN1C(=O)C=CC1=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
14 mg (16 μmol) of N-(6-aminohexyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 88) were taken up in 750 μl of dioxane and admixed with 1.5 ml of saturated sodium hydrogencarbonate solution and then with 3.2 mg (21 μmol) of methyl 2,5-dioxo-2,5-dihydro-1H-pyrrole-1-carboxylate. The reaction mixture was stirred at RT for 1 h and then concentrated under reduced pressure. The remaining residue was purified by means of preparative HPLC. After lyophilization, 5.5 mg (36% of theory) of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:20])[C:5]2[N:6]=[CH:7][N:8]([C@H]3[C@@H](O)[C@@H](O)[C@H](CO)O3)[C:9]=2[N:10]=1.[CH2:21](Br)[CH:22]=[CH2:23].Cl.[OH-].[Na+]>CS(C)=O.O>[CH2:23]([N:6]1[C:5]2[C:4](=[O:20])[NH:3][C:2]([NH2:1])=[N:10][C:9]=2[N:8]=[CH:7]1)[CH:22]=[CH2:21]
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@@H](CO)[C@H](O)[C@@H]2O)c(=O)[nH]1
Reactant: C=CCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: C=CCn1cnc2nc(N)[nH]c(=O)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
To a solution of 2-amino-9-((2R,3S,4R,5S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H-purin-6(9H)-one (50 g, 176.7 mmol) in DMSO (150 mL) was added allyl bromide (36 mL, 420 mmol), the mixture was stirred at room temperature overnight under nitrogen atmosphere. The reaction was chilled to 0° C. concentrated HCl (100 mL) was added and the reaction was stirred at 70° C. for 4 h. The reaction was cooled to room temperature, poured into water (800 mL), and neutralized with 6N sodium hydroxide to pH 7-8. The solids that formed were collected and the filter cake was washed with water and ethanol, then dried under vacuum to give 7-allyl-2-amino-1H-purin-6(7H)-one (20 g, 59.2% yield) as yellow solid. LCMS retention time 0.330 min; LCMS MH+ 192.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:13]=[C:12]([S:14][CH3:15])[C:8]([C:9]([OH:11])=O)=[C:7]([S:16][CH3:17])[CH:6]=2)[CH2:3][CH2:2]1.[CH3:18][C:19]([CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)([S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)(=[O:23])=[O:22])[CH3:20].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C.CN(C)C=O>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([S:16][CH3:17])[C:8]([C:9]([N:37]3[CH2:38][CH2:39][CH:34]([C:19]([CH3:20])([S:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=4)(=[O:22])=[O:23])[CH3:18])[CH2:35][CH2:36]3)=[O:11])=[C:12]([S:14][CH3:15])[CH:13]=2)[CH2:2][CH2:3]1
Reactant: CSc1cc(OC2CC2)cc(SC)c1C(=O)O
Reactant: CC(C)(C1CCNCC1)S(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1cc(OC2CC2)cc(SC)c1C(=O)N1CCC(C(C)(C)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 16 ml vial was added 4-(cyclopropyloxy)-2,6-bis(methylthio)benzoic acid (375 mg, 1.39 mmol), 4-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)piperdine (465 mg, 1.39 mmol), Bop reagent (675 mg, 1.53 mmol), diisopropylethyl amine (1.21 ml, 6.93 mmol) and 4 ml dimethylformamide. The resulting solution was stirred at room temperature for 1 hour. It was diluted with 30 ml ethyl acetate, washed sequencially with 20 ml 1N HCl, 20 ml 5% KOH and 20 ml brine. The organics were dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel column eluted with 1:2 to 1:1 ethyl acetate/hexane to give desired product as sticky material.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[C:4](=[O:6])[CH3:5])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[C:17]([CH2:19][C@@H:20]([OH:27])[CH2:21][C:22](OCC)=[O:23])#[N:18].Cl>O1CCCC1.O1CCCC1.CCCCCCC>[C:17]([CH2:19][C@@H:20]([OH:27])[CH2:21][C:22](=[O:23])[CH2:5][C:4]([N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])=[O:6])#[N:18]
Reactant: CCOC(=O)C[C@H](O)CC#N
Reactant: CCN(CC)C(C)=O
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CCN(CC)C(=O)CC(=O)C[C@H](O)CC#N
Reaction time: 0.5 h

Procedure:
To a stirred -10° C. solution of N,N-diethylacetamide (prepared from N,N-diethylamine and acetyl chloride by refluxing for 2 hours in toluene) (28.75 g, 0.25 mol) in tetrahydrofuran (0.25 L) is slowly added a solution of lithium diisopropylamide in tetrahydrofuran-heptane (0.125 L of 2M) while maintaining the temperature between -10° C. to -50° C., and the mixture is stirred at -20° C. to 0° C. for 30 minutes. (R)-4-cyano-3-hydroxybutyric acid, ethyl ester (Brower, supra) (10 g, 0.06 mol) as a solution in 200 mL of tetrahydrofuran is added to the previously prepared mixture. The reaction mixture is stirred for 30 minutes at -5° C. to -20° C., and transferred to a 2.2N aqueous hydrochloric acid solution (0.25 L). The aqueous layer is extracted with 300 mL of ethyl acetate, the aqueous layer is separated and reextracted with 50 mL of ethyl acetate, the extracts are combined and concentrated in vacuo to afford crude (R)-6-cyano-N,N-diethyl-5-hydroxy-3-oxohexanamide as an oil;
Reaction SMILES: Cl.[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@H:25]4[CH3:30])[C:18]4[CH2:23][NH:22][CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])[CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:40]([O:42][CH2:43][CH3:44])=[O:41]>CN(C=O)C>[CH:2]1([NH:5][C:6](=[O:7])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@H:25]4[CH3:30])[C:18]4[CH2:23][N:22]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)[CH2:3][CH2:4]1
Reactant: C[C@@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CNC2
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)N1Cc2nc(-c3ccc(NC(=O)NC4CC4)cc3F)nc(N3CCOC[C@H]3C)c2C1
Reaction time: 8 h
Yield: 26.8 %

Procedure:
A solution of (R)-1-cyclopropyl-3-(3-fluoro-4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride (intermediate 33) (121 mg, 0.270 mmol) and triethylamine (75 μL, 0.534 mmol) in anhydrous DMF (2 ml) was stirred at RT for 40 minutes. After this time, ethyl chloroformate (30 μl, 0.322 mmol) was added and stirring was continued at RT overnight. The reaction was partitioned between H2O and EtOAc and the aqueous phase was extracted into EtOAc. The organic extracts were combined, dried over magnesium sulphate and concentrated in vacuo. The sample was then purified via preparative HPLC at low pH to yield the title compound (35 mg, 27%).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[C:16]1([NH:15][C:13]([C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[O:14])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccccc1)[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 55.3 %

Procedure:
To a solution of (S)-(+)-N-Boc-2-phenylaminocarbonylpyrrolidine (1.1 g, 3.8 mmol) in 5 mL of CH2Cl2 at 0° C. was added 5 mL of TFA dropwise over 1 hour. The solution was warmed to room temperature and stirred for 1.5 hours. To the reaction mixture was added 100 mL of water and the aqueous layer was washed with EtOAc. The aqueous layer was then made basic with 30 mL of 10% NaOH and extracted therein with 20 mL EtOAc. The organic layer was then dried over Na2SO4, filtered and concentrated under reduced pressure to give a white solid (0.40 g, 56%). ES (+) MS m/e=191 (M+H).
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])=[N:9][C:7]=2[N:8]=1.C[O-:25].[Na+].Cl>CO.O>[O:25]=[C:3]1[NH:8][C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]=2[N:5]=[N:4]1
Reactant: CCCOc1ccccc1-c1nc2nc(SC)nnc2c(=O)[nH]1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCOc1ccccc1-c1nc2[nH]c(=O)nnc2c(=O)[nH]1
Yield: 92.4 %

Procedure:
A stirred mixture of 3-methylthio-8-oxo-6-(2-propoxyphenyl)-7,8-dihydropyrimido[4,5-e][1,2,4]triazine (0.5 g) and sodium methoxide (prepared from sodium, 0.17 g, and methanol) in methanol (50 ml) was heated under reflux for 3 hours. The cooled reaction mixture was evaporated under reduced pressure to afford a yellow solid which was dissolved in water and acidified with 2 Normal hydrochloric acid to yield a yellow solid (420 mg) which was recrystallised from dimethylformamide to afford the title compound, 0.16 g, m.p. 298°-299° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].ClC(OCC)=O.[OH-].[NH4+:23]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([NH2:23])=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: [NH4+]
Reactant: COc1ccc(CCC(=O)O)cc1OC
Agent: CCOC(=O)Cl
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(CCC(N)=O)cc1OC
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a stirred solution of 3-(3,4-dimethoxy-phenyl)-propionic acid (10.0 g, 47.56 mmol) in dry THF (175 ml), under nitrogen, was added TEA (7.3 ml, 52.44 mmol), and the resulting mixture was cooled to −10° C. before ethyl chloroformate (5 ml, 52.47 mmol) was added dropwise. After stirring at −10° C. (20 min), ammonium hydroxide (25% in water, 105 ml) in THF (105 ml) was added and the mixture was stirred at −15° C. for 30 min and then at RT for 1.5 h. The reaction mixture was concentrated in vacuo, extracted three times with CH2Cl2 and the combined organic extracts were washed with saturated aqueous NaHCO3 and brine. The organic phase was dried over anhydrous MgSO4, filtered and concentrated to give the title compound (9.73 g, 46.50 mmol, 97%) as a colorless solid. No further purification of the crude amide was necessary.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].Cl[CH2:13][CH2:14][CH2:15][C:16](Cl)=O.C(N(CC)CC)C>O1CCCC1.[OH-].[Na+]>[O:10]=[S:8]1(=[O:9])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]2[CH2:13][CH2:14][CH2:15][C:16]2=[N:11]1
Reactant: O=C(Cl)CCCCl
Reactant: Nc1ccccc1S(N)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S1(=O)N=C2CCCN2c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5.8 mmol of 2-aminobenzenesulfonamide are dissolved in tetrahydrofuran (THF) at room temperature. This solution is cooled on an ice bath, and 6 mmol of 4-chlorobutanoyl chloride and 6 mmol of triethylamine are successively added. The mixture is stirred for 16 hours at room temperature, filtered and evaporated. The yellow solid obtained is taken up in 40 ml of 1N sodium hydroxide and stirred at room temperature. After complete dissolution, a white precipitate appears; it is filtered off and gives the expected product after crystallization from an ethanol/water (4/1) mixture.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Cl[CH2:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:25][C:21]1[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH2:15][N:7]2[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:6]2)[CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1n[nH]cc1[N+](=O)[O-]
Reactant: O=C(CCl)Nc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(CC(=O)Nc2cccc(F)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 73.9 %

Procedure:
A mixture of ethyl 4-nitro-1H-pyrazole-3-carboxylate (0.685 g, 3.7 mmol) and 2-chloro-N-(3-fluorophenyl) acetamide (0.694 g, 3.7 mmol) and potassium carbonate (0.613 g, 4.44 mmol) in dimethyl formamide (10 ml) was stirred at room temperature for 20 hours. The mixture was evaporated and the residue was purified by silica gel chromatography eluting with a 8 to 10% mixture of ethyl acetate in dichloromethane to give ethyl 1-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-4-nitro-1H-pyrazole-3-carboxylate (0.920 g, 74% yield):
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:23])[CH2:3][CH2:2]1.Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.[I-].[K+]>[CH2:29]([O:28][C:26]([CH2:25][N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:23])[CH2:5][CH2:6]1)=[O:27])[CH3:30]
Reactant: O=C1Nc2ccccc2C(c2ccccc2)N1C1CCNCC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Product: CCOC(=O)CN1CCC(N2C(=O)Nc3ccccc3C2c2ccccc2)CC1
Yield: 89.5 %

Procedure:
To a solution of 1.5 g (4.88 mmol) of 3-(piperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone in 30 mL of isopropanol were added 896 mg (5.37 mmol) of ethyl bromoacetate, 853 mg (96.18 mmol) of potassium carbonate and 20 mg of potassium iodide, and the mixture was heated under reflux for 3 hours. The hot solution was subjected to filtration, and the solid matter was washed with 200 mL of hot isopropanol. The filtrate was concentrated in vacuo, and the residue was purified by means of column chromatography (silica gel, 1:9 :90 aqueous ammonia:methanol:chloroform) to give 1.88 g (4.37 mmol) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:16])=[C:8]2[C:14]([CH3:15])=[N:13][O:12][C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:23](I)[CH3:24].C(OC(C1C=NC2=NOC(C)=C2C=1OCC)=O)C>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:16][CH2:23][CH3:24])=[C:8]2[C:14]([CH3:15])=[N:13][O:12][C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2onc(C)c2c1O
Reactant: CCI
Agent: CCOC(=O)c1cnc2noc(C)c2c1OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cnc2onc(C)c2c1OCC
Reaction time: 6 h

Procedure:
2.22 g. of 4-Hydroxy-3-methylisoxazolo[5,4-b]pyridine-5-carboxylic acid ethyl ester (0.1 mol.) are dissolved in 150 ml. of ethanol and 28 g. of potassium carbonate (0.2 mol.). 31 g. of ethyl iodide (0.2 mol.) are added. The mixture is heated with stirring for 6 hours. The hot solution is filtered and the solvent evaporated. The oily residue yields on crystallization with methanol 18.2 g. of 4-ethoxy-3-methylisoxazolo-[3,4-b]pyridine-5-carboxylic acid ethyl ester (73%), m.p. 62°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[CH3:28][O:29][CH:30]([O:38][CH3:39])[C:31]1[N:32]=[CH:33][C:34]([NH2:37])=[N:35][CH:36]=1.N1C=CC=CC=1>C(Cl)Cl.C1(C)C=CC=CC=1.CN(C)C=O.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:37][C:34]2[CH:33]=[N:32][C:31]([CH:30]([O:38][CH3:39])[O:29][CH3:28])=[CH:36][N:35]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: COC(OC)c1cnc(N)cn1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(OC)c1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 883 mg, 2.67 mmol) and oxalyl chloride (677 mg, 5.34 mmol) in methylene chloride/toluene (1:1, 5 mL) was treated with N,N-dimethylformamide (2 drops) at 25° C. The reaction mixture was stirred at 25° C. for 2 h. The solution was concentrated in vacuo, and the residue was concentrated three times from toluene (5 mL). The residue was suspended in tetrahydrofuran (5 mL) at 0° C. and then treated with a mixture of 5-dimethoxymethyl-pyrazin-2-ylamine (451 mg, 2.67 mmol) and pyridine (0.216 mL, 2.67 mmol) in tetrahydrofuran (5 mL) over 5 min. At this time, the reaction was allowed to warm to 25° C. where it stirred for 18 h. The resulting mixture was partitioned between ethyl acetate (50 mL) and a dilute aqueous ammonium chloride solution (50 mL). The aqueous layer was separated. The organic layer was sequentially washed with water (1×25 mL), a saturated aqueous sodium bicarbonate solution (1×25 mL), water (1×25 mL), an aqueous copper(II) sulfate solution (1×25 mL), and a saturated aqueous sodium chloride solution (1×25 mL). The organic layer was then dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 2/3 ethyl acetate/hexanes) afforded the 2-(R)-(3-chloro-4-methanesulfonylphenyl)-3-cyclopentyl-N-(5-dimethoxymethylpyrazin-2-yl)-propionamide (890 mg, 69%) as a pale yellow foam: (ES)+-HRMS m/e calcd for C22H28ClN3O5S (M+H)+ 424.0729, found 424.0733.
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH:18][C:19]3[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[F:27][C:25]([F:26])([F:28])[C:22]1[N:21]=[CH:20][C:19]([NH:18][C:14]2[C:15]3[CH2:16][CH2:17][NH:8][CH2:9][C:10]=3[N:11]=[CH:12][N:13]=2)=[CH:24][CH:23]=1
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CCN(Cc2ccccc2)C3)cn1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: FC(F)(F)c1ccc(Nc2ncnc3c2CCNC3)cn1
Reaction time: 24 h

Procedure:
7-Benzyl-N-(6-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (1.7 g, 4.4 mmol) was dissolved in methanol (25 mL) and palladium hydroxide was added (0.2 g, 20% wt). The mixture was shaken on a Parr Shaker under H2(g) atmosphere (60 PSI) for 1 day. The mixture was filtered through celite and evaporated to give 1.3 g (quant.) as an orange oil, which was used as such for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[NH:11][C:12]([C:14]2[CH:36]=[CH:35][C:17]([O:18][C:19]3[CH:28]=[C:27]4[C:22]([CH:23]([C:29]([O:31]C)=[O:30])[CH2:24][CH2:25][O:26]4)=[CH:21][C:20]=3[C:33]#[N:34])=[CH:16][CH:15]=2)=[O:13])=[CH:4][CH:3]=1.O[Li].O.Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([O:18][C:19]3[CH:28]=[C:27]4[C:22]([CH:23]([C:29]([OH:31])=[O:30])[CH2:24][CH2:25][O:26]4)=[CH:21][C:20]=3[C:33]#[N:34])=[CH:35][CH:36]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CC4c4ccc(Cl)cc4)cc3)c(C#N)cc21
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc2c(cc1Oc1ccc(C(=O)NC3CC3c3ccc(Cl)cc3)cc1)OCCC2C(=O)O
Temperature: 25 °C
Reaction time: 17 h
Yield: 95.2 %

Procedure:
methyl 7-(4-((2-(4-chlorophenyl)cyclopropyl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylate (50.7 mg, 0.101 mmol) was dissolved in THF (3 ml). A 1M solution of LiOH—H2O (0.202 ml, 0.202 mmol) was added and the mixture was stirred for 17 hours at ambient temperature. HCl (4M in dioxane) (0.0756 ml, 0.302 mmol) was added to the mixture. The solution was stirred additional 30 minutes and concentrated. The residue was purified on silica gel (MeOH in dichloromethane with 1% acetic acid gradient) to provide 47 mg of the title compound as a solid (95%). MS (apci) m/z=486.7 (M−H).