Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[NH:8]1[C:15]2[N:11]([N:12]=[CH:13][CH:14]=2)[CH:10]=[CH:9]1>C(O)=O>[CH:5]([N:8]1[C:15]2[N:11]([N:12]=[CH:13][CH:14]=2)[CH:10]=[CH:9]1)=[O:7]
Reactant: c1cc2[nH]ccn2n1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=Cn1ccn2nccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of acetic anhydride (3.68 ml) and formic acid (3 ml) was stirred at room temperature for 1 hour. The solution was cooled in an ice-bath and 1H-imidazo-[1,2-b]pyrazole (2.1 g) was added thereto. The mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated and the residue was subjected to column chromatography on silica gel using a mixture of n-hexane and ethyl acetate (1:1) as an eluent. Fractions containing the object compound were combined and the solvent was evaporated to give 1-formyl-1H-imidazo[1,2-b]pyrazole (1.83 g). NMR (DMSO-d6, δ) : 6.20 and 6.28 (total 1H, each d, J=2Hz), 7.65-7.72 (1H, m), 7.71 (1H, d, J=2Hz), 7.87-7.92 (1H, m), 9.02 (1H, br s)
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:28][N:27]=[CH:26][C:25]=2[CH2:29][CH2:30][C:31](O)=[O:32])=[CH:20][CH:19]=1.ON1C2N=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O>[CH2:12]([O:11][P:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:31](=[O:32])[CH2:30][CH2:29][C:25]2[CH:26]=[N:27][O:28][C:24]=2[C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)=[CH:16][CH:15]=1)([O:8][CH2:9][CH3:10])=[O:14])[CH3:13]
Reactant: O=C(O)CCc1cnoc1-c1ccc(F)cc1
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1ccc(NC(=O)CCc2cnoc2-c2ccc(F)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
A mixture of diethyl 4-aminobenzylphosphonate (0.73 g), 3-[5-(4-fluorophenyl)-4-isoxazolyl]propionic acid (0.49 g), 1-hydroxy-7-aza-1H-1,2,3-benzotriazole (HOAT) (0.40 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSCI) (0.45 g) and N,N-dimethylformamide (5 ml) was stirred at room temperature overnight. The reaction mixture was poured into a 1N aqueous hydrochloric acid solution and extracted with ethyl acetate. The ethyl acetate layer was washed with 10% aqueous potassium carbonate solution, and then with saturated brine, dried (MgSO4) and concentrated. The obtained solid was recrystallized from ethyl acetate-hexane to give N-[4-(diethylphosphonomethyl)phenyl]-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide (0.67 g, yield 70%) as a colorless prism. melting point: 134–135° C.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([S:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[OH:27])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:28][C:29]1[C:34]([C:35]#[N:36])=[C:33](Cl)[N:32]=[CH:31][N:30]=1.C(N(CC)C(C)C)(C)C>C(O)(C)(C)C>[NH2:28][C:29]1[C:34]([C:35]#[N:36])=[C:33]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([S:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[OH:27])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:32]=[CH:31][N:30]=1
Reactant: C[C@H](N)c1nn2ccc(Sc3ccccc3O)c2c(=O)n1-c1ccccc1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nn2ccc(Sc3ccccc3O)c2c(=O)n1-c1ccccc1
Yield: 38.6 %

Procedure:
(S)-2-(1-Aminoethyl)-5-((2-hydroxyphenyl)thio)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (183 mg, 0.36 mmol) was treated with 4-amino-6-chloropyrimidine-5-carbonitrile (84 mg, 0.54 mmol), and N,N-diisopropylethylamine (380 μl, 2.18 mmol) in tert-butanol according to the method described in Example 17. The crude was purified by reverse phase using SP1® Purification System to give 69 mg (38% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.S(=O)(=O)(O)O.[CH3:16]O>>[CH3:1][C:2]1[C:3]([C:8]([O:10][CH3:16])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: CO
Reactant: Cc1nccnc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1nccnc1C
Temperature: 80 °C
Yield: 73 %

Procedure:
In a 2-L flask, 3-methylpyrazine-2-carboxylic acid (Matrix, 19.95 g, 144 mmol) was suspended in MeOH (500 mL). The suspension was cooled in an ice-water bath, and concentrated sulfuric acid (Fluka, 27.3 mL, 506 mmol) was added over a time period of 5 min. The reaction mixture was heated to 80° C. for 5 h. The reaction mixture was concentrated under reduced pressure and the residue was taken up in DCM (750 mL). The excess acid was neutralized carefully with aqueous NaOH (5M, 200 mL). The aqueous layer was separated and extracted with DCM (250 mL). The combined organic layers were combined, dried over MgSO4 and concentrated to afford the title compound (16.15 g, 106 mmol, 73%). MS m/z=153 (M+H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[C:11]1([NH:17][CH:18]=O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:3]1([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:17]=[CH:18]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: O=[N+]([O-])c1ccccc1I
Reactant: O=CNc1ccccc1
Product: c1ccc(-n2cnc3ccccc32)cc1
Yield: 72.1 %

Procedure:
The title compound was prepared with the analogous procedure described in example 1 using 1-Iodo-2-nitrobenzene (124 mg, 0.5 mmol) and N-Phenyl-formamide (73 mg, 0.6 mmol) as starting materials to yield the title compound as a yellow solid (70 mg, 72%). 1H NMR (DMSO) δ 7.28-7.33 (m, 2 H), 7.49 (d, J=7.3 Hz, 1 H), 7.59-7.68 (m, 5 H), 7.79 (d, J=6.9 Hz, 1 H), 8.56 (br s, 1 H); 13C NMR δ 110.6, 119.9, 122.4, 123.6, 123.9, 127.6, 130.0, 133.1, 135.9, 143.8.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][C:11]=2[F:20])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:22]1[C:23]([CH2:28][N:29]2[CH2:33][CH2:32][CH2:31][C:30]2=[O:34])=[N:24][CH:25]=[CH:26][CH:27]=1>>[F:20][C:11]1[CH:12]=[C:13]([C:16]([OH:19])([CH3:17])[CH3:18])[CH:14]=[CH:15][C:10]=1[C:4]1[S:3][C:2]([NH:1][C:25]2[CH:26]=[CH:27][CH:22]=[C:23]([CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][C:30]3=[O:34])[N:24]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: O=C1CCCN1Cc1ncccc1Br
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(CN4CCCC4=O)n3)s2)c(F)c1

Procedure:
The title compound was prepared by using the procedure listed in Example 1 with 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.14 g, 0.48 mmol) and 1-[(bromopyridin-2-yl)methyl]pyrrolidin-2-one (0.12 g, 0.47 mmol) as starting materials.
Reaction SMILES: [CH2:1]([N:5]1[C:12]([NH2:13])=[CH:11][C:9](=[O:10])[NH:8][C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].[N:14]([O-])=[O:15].[Na+].C(O)(=O)C>O>[CH2:1]([N:5]1[C:12]([NH2:13])=[C:11]([N:14]=[O:15])[C:9](=[O:10])[NH:8][C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(N)cc(=O)[nH]c1=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCn1c(N)c(N=O)c(=O)[nH]c1=O
Yield: 84.8 %

Procedure:
91.5 g (0.5 mole) of 1-butyl-6-aminouracil are suspended in 1 liter of water in a reactor equipped with a magnetic stirrer. A solution of 38 g of sodium nitrite in 250 ml of water is added to the suspension. 65 ml of acetic acid are then run in dropwise with stirring, after which the mixture is stirred for 18 hours at ambient temperature. After cooling in an ice bath, the precipitate is filtered, giving 90 g of violet-coloured crystals.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[O:27][C@H:28]([CH3:33])[C:29](OC)=[O:30])[N:20]=[CH:19][N:18]=3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.[CH2:34]([CH2:36][NH2:37])[OH:35]>>[OH:35][CH2:34][CH2:36][NH:37][C:29](=[O:30])[C@H:28]([O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:12]1[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[N:8]=[CH:9]3)=[N:18][CH:19]=[N:20]2)[CH3:33]
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12
Reactant: NCCO
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12)C(=O)NCCO
Yield: 82.2 %

Procedure:
Using the same procedure as in Example 26, methyl (2R)-2-[(4-{[1-(1,3-thiazol-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (210 mg, 0.46 mmol) was reacted with ethanolamine (0.17 ml, 2.7 mmol) to give the title compound as a solid (185 mg, 83%), except that the mixture was heated at 65° C. for 2 hours. NMR Spectrum 1.65 (d, 3H), 3.21-3.25 (m, 2H), 3.42-3.46 (m, 2H), 4.75 (t, 1H), 5.23 (q, 1H), 6.04 (s, 2H), 7.02 (d, 1H), 7.37 (d, 1H), 7.66 (s, 1H), 7.73 (t, 1H), 7.77-7.79 (m, 3H) 8.21 (s, 1H), 8.48 (m, 1H), 8.54 (s, 1H), 8.57 (s, 1H), 10.75 (br s, 1H); Mass spectrum MH+ 490.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([O:19][C@H:20]2[C@@H:25]([O:26][CH3:27])[C@@H:24]([NH:28][C:29]3[C:46](=[O:47])[C:45]4[CH:44]=[C:43]5[C:34]([C:35](=[O:63])[C@@:36]6([O:61][CH3:62])[C@@:41]([OH:49])([C:42]5=[O:48])[C:40]5[C:50]([OH:59])=[C:51]([C:55]([O:57][CH3:58])=[O:56])[C:52]([CH3:54])=[CH:53][C:39]=5[CH2:38][C@H:37]6[OH:60])=[C:33]([OH:64])[C:32]=4[C:31](=[O:65])[CH:30]=3)[O:23][C@@H:22]([CH3:66])[C@@H:21]2[O:67][CH3:68])[O:7][C@@H:6]1[CH2:69][O:70]C(=O)C)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:27][O:26][C@@H:25]1[C@H:20]([O:19][C@H:8]2[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:69][OH:70])[O:7]2)[C@@H:21]([O:67][CH3:68])[C@H:22]([CH3:66])[O:23][C@@H:24]1[NH:28][C:29]1[C:46](=[O:47])[C:45]2[CH:44]=[C:43]3[C:34]([C:35](=[O:63])[C@@:36]4([O:61][CH3:62])[C@@:41]([OH:49])([C:42]3=[O:48])[C:40]3[C:50]([OH:59])=[C:51]([C:55]([O:57][CH3:58])=[O:56])[C:52]([CH3:54])=[CH:53][C:39]=3[CH2:38][C@H:37]4[OH:60])=[C:33]([OH:64])[C:32]=2[C:31](=[O:65])[CH:30]=1
Reactant: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O[C@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)[C@H]1OC)C4=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H]1OC)C4=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.7 %

Procedure:
A mixture of (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-((2S,3S,4R,5R,6S)-3,5-dimethoxy-2-methyl-6-((6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-6a-methoxy-2-(methoxycarbonyl)-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracen-11-ylamino)tetrahydro-2H-pyran-4-yloxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (44 mg, 0.043 mmol) and potassium carbonate (24 mg, 0.17 mmol) in methanol (4 mL) was stirred at room temperature under nitrogen for 4 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by semi-preparative HPLC (20:80 acetonitrile/water to 60:40 acetonitrile/water with 0.05% TFA over 30 min) to afford (6R,6aS,14aR)-methyl 11-((2S,3R,4R,5S,6S)-3,5-dimethoxy-6-methyl-4-((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)tetrahydro-2H-pyran-2-ylamino)-1,6,8,14a-tetrahydroxy-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (18 mg, 49%) as an orange-red solid: 1H NMR (500 MHz, CD3OD) δ 8.09 (s, 1H), 6.61 (s, 1H), 5.94 (s, 1H), 4.92 (s, 1H), 4.52 (d, J=8.0 Hz, 1H), 3.96-3.85 (m, 3H), 3.79 (s, 3H), 3.75 (s, 3H), 3.65-3.61 (m, 2H), 3.60 (s, 3H), 3.55-3.36 (m, 3H), 3.35 (s, 3H), 3.22-3.15 (m, 5H), 2.38 (s, 3H), 1.25 (d, J=6.0 Hz, 3H); MS (ESI+) m/z 860 (M+H); HPLC 97.6% (AUC), tR 10.95 min.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:19][CH:20]=2)=[CH:9][C:8]=1[CH2:27][O:28][C:29](=[O:37])[NH:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)C.[OH-].[Na+]>C(O)C>[CH:31]1([NH:30][C:29]([O:28][CH2:27][C:8]2[CH:9]=[C:10]([O:13][CH2:14][CH2:15][C:16]3[N:17]=[C:18]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[O:19][CH:20]=3)[CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]([OH:38])=[O:3])=[O:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CCOC(=O)CCc1ccc(OCCc2coc(-c3ccccc3)n2)cc1COC(=O)NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCc1ccc(OCCc2coc(-c3ccccc3)n2)cc1COC(=O)NC1CCCCC1
Temperature: 55 °C
Yield: 69.3 %

Procedure:
To a 15 mL round bottomed flask was charged with 3-{2-cyclohexylcarbamoyloxymethyl-4-[2-(2-phenyloxazol-4-yl)ethoxy]phenyl}propionic acid ethyl ester (0.10 g, 0.17 mmol), ethanol (2 mL), and then 2N NaOH (0.48 mL, 0.96 mmol). The solution was heated at 55° C. for 2 h. The mixture was concentrated, acidified using 5% H2SO4 (1.5 mL), and partitioned between CH2Cl2 (15 mL) and brine (15 mL). The organic layer was dried (Na2SO4), filtered, and concentrated and was concentrated. The crude residue was submitted for mass-directed HPLC purification to give a white solid (0.058 g, 63%). MS (ES) m/e 537 (M+1).
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[C:9]2[S:24][C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:26][C:8]=2[C:7]=1[OH:33])=[O:5])C.[NH2:34][CH2:35][C:36]([OH:38])=[O:37]>C[O-].[Na+].CO>[OH:33][C:7]1[C:8]2[N:26]=[C:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[S:24][C:9]=2[C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[CH:14][CH:13]=2)=[N:11][C:6]=1[C:4]([NH:34][CH2:35][C:36]([OH:38])=[O:37])=[O:5]
Reactant: CCOC(=O)c1nc(-c2ccc(N3CCOCC3)cc2)c2sc(-c3ccccc3)nc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1nc(-c2ccc(N3CCOCC3)cc2)c2sc(-c3ccccc3)nc2c1O
Temperature: 25 °C
Yield: 74.7 %

Procedure:
A mixture of 7-Hydroxy-4-(4-morpholin-4-yl-phenyl)-2-phenyl-thiazolo[5,4-c]pyridine-6-carboxylic acid ethyl ester (56 mg, 0.12 mmole) and glycine (182 mg, 2.43 mmole) in 0.5 M sodium methoxide/methanol (4.4 ml) was refluxed for 5 days before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (120 ml) and extracted with dichloromethane. The remaining aqueous layer was acidified to pH=3 with 1N HCl (5 ml). The resulting suspension was extracted with ethyl acetate, washed with brine and dried in vacuo to give the title compound as a yellow solid (44 mg). 1H NMR (DMSO-d6, 200 MHz): δ=13.1 (br s, 1H), 9.37 (t, 1H), 8.15 (m, 2H), 8.04 (m, 2H), 7.62 (m, 3H), 7.10 (m, 2H), 4.06 (d, 2H, J=5.8 Hz), 3.77 (m, 4H); MS: (+) m/z 491.22 (M+1).
Reaction SMILES: [OH-].[CH3:2][O:3][C:4]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Br)=[CH:8][CH:7]=1)=[O:5].[F:14][C:15]1[C:16](=[O:49])[NH:17][C:18](=[O:48])[N:19]([CH:47]=1)[C@@H:20]1[O:46][C@H:24]([CH2:25][O:26]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C@@H:22]([OH:23])[CH2:21]1>O1CCOCC1>[F:14][C:15]1[C:16](=[O:49])[NH:17][C:18](=[O:48])[N:19]([CH:47]=1)[C@@H:20]1[O:46][C@H:24]([CH2:25][OH:26])[C@@H:22]([O:23][CH2:10][C:9]2[CH:12]=[CH:13][C:6]([C:4]([O:3][CH3:2])=[O:5])=[CH:7][CH:8]=2)[CH2:21]1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)cc1F
Agent: [OH-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(CO[C@H]2C[C@H](n3cc(F)c(=O)[nH]c3=O)O[C@@H]2CO)cc1
Temperature: 25 °C

Procedure:
Pottasium hydroxide (4.30 g) and 1.70 g of 4-methoxycarbonylbenzyl bromide were added to a solution of 3.00 g of 2'-deoxy-5-fluoro-5'-O-trityluridine in 200 ml of dioxane. The mixture was stirred at room temperature for a day. The reaction mixture was concentrated under a reduced pressure. To the concentrate was added 200 ml of ethyl acetate for extraction. The extract was washed with water, dried over magnesium sulfate and concentrated. The concentrate was dissolved in 20 ml of a 80% aqueous solution of acetic acid.
Reaction SMILES: [CH2:1]([N:3]([CH:10]=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1>>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]=[CH:10][N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCN(C=O)c1ccccc1
Reactant: Nc1ccccn1
Product: CCN(C=Nc1ccccn1)c1ccccc1

Procedure:
Prepared following the procedure of Example 1 from N-ethylformanilide and 2-aminopyridine. Vacuum distillation of the crude product gave pure 4 as a pale yellow oil: bp 164° C. @ 0.5 mm Hg. 1H-NMR (CDCl3) 8.83 (S, 1H), 8.30 (m, 1H), 7.5-6.9 (m, 8H), 4.09 (q, 2H, J=7 Hz) 1.26 (t, 3H, J=7 Hz); IR(neat) 2990, 1620, 1570, 1500, 1460, 1440, 1390, 1230, 1130; MS (m/e) 225 (M+), 78 (base).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=2)[CH:3]=1.[C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)#[N:22]>>[C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=3)[CH:3]=2)=[CH:25][CH:24]=1)#[N:22]
Reactant: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(Br)c2c1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: N#Cc1ccc(-c2cc(-c3ccc(O)c(F)c3)nc3ccc(O)cc23)cc1
Yield: 52 %

Procedure:
This compound was prepared from 6b using 4-cyanophenylboronic acid according to method P. Yellow powder; Yield: 52%; mp 266-267° C.; 1H-NMR (400 MHz, DMSO-d6) δ 6.97 (d, J=2.7 Hz, 1H), 7.07 (t, J=8.8 Hz, 1H), 7.34 (dd, J=9.0, 2.6 Hz, 1H), 7.82 (d, J=8.5 Hz, 2H), 7.92 (s, 1H), 7.95-8.00 (m, 2H), 8.07-8.10 (m, 3H), 10.00 (s, 1H), 10.21 (s, 1H); MS (ESI) m/z 355 ([M−H]−), 357 ([M+H]+); Anal. Calcd for C22H13FN2O2: C, 74.15; H, 3.68; N, 7.86. Found: C, 73.69; H, 3.53; N, 7.86.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH:14]=[N:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])C.[OH-].[K+].Cl>CO.O.O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([N:12]2[C:8]3[CH:9]=[N:10][CH:11]=[C:6]([C:4]([OH:5])=[O:3])[C:7]=3[CH:14]=[N:13]2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1cncc2c1cnn2-c1ccc(F)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cncc2c1cnn2-c1ccc(F)cc1
Reaction time: 8 h

Procedure:
A mixture of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid ethyl ester (2.75 g, 9.64 mmol) and 85% potassium hydroxide pellets (6.4 g, 84 mmol) in methanol-water was warmed at reflux for 15 minutes and then stirred overnight. The mixture was then diluted with water (300 mL) and then a dilute solution of aqueous HCl (1 equivalent based on mass of KOH) was added in several portions (final pH=5). The resulting solid was collected by filtration and dried by pulling vacuum through the filter cake to afford 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17](=O)[CH2:18]Br>CN1C(=O)CCC1.C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:15]=[C:16]([C:17]2[N:10]=[C:8]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=3)[O:9][CH:18]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: NC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(CBr)c1cccc(Cl)c1
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(-c2nc(-c3cccc(Cl)c3)co2)cc1
Temperature: 135 °C
Reaction time: 2.5 h
Yield: 43.4 %

Procedure:
under an N2 atmosphere, 4-nitrobenzamide (5.3 g, 32 mmol) and 3-chlorophenacyl bromide (4.9 g, 21 mmol) were combined in NMP (3.0 mL) and heated to 135° C. After 2.5 hours at 135° C., the reaction was diluted with 20 mL of toluene and allowed to cool to room temperature. The solid was removed by filtration and the filtrate was concentrated in vacuo. The resulting solid from concentration of the filtrate was triturated with ethyl acetate. The solid was collected by filtration and afforded 4-(3-chlorophenyl)-2-(4-nitrophenyl)oxazole (2.74 g, 43% yield). ESI m/z=301.0 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([CH3:14])[NH:11][CH2:10][CH:9]1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](OC(N1CC(C)(C)NCC1C)=O)(C)(C)C>>[CH2:1]([N:8]1[CH2:13][CH:12]([CH3:14])[NH:11][CH2:10][C:9]1([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CNC(C)(C)CN1C(=O)OC(C)(C)C
Reactant: CC1CN(Cc2ccccc2)C(C)CN1
Product: CC1CN(Cc2ccccc2)C(C)(C)CN1

Procedure:
1-Benzyl-2,2,5-trimethyl-piperazine was prepared in analogy to the preparation of benzyl-2,5-dimethyl-piperazine (see above) starting form 2,5,5-trimethyl-piperazine-1-carbox ylic acid tert-butyl ester.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@:20]1([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([Cl:46])[CH:40]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:38])[C:26]2[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=2)[CH2:21]1)(=O)=O.C(#N)C>>[Cl:46][C:41]1[CH:40]=[C:39]([C@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][CH:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:38])[C:26]3[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=3)[CH2:21]2)[CH:44]=[CH:43][C:42]=1[Cl:45]
Reactant: COc1cc(C(=O)N2CC[C@](CCOS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: CC#N
Product: COc1cc(C(=O)N2CC[C@@](CCN3CCC(N4CCCCC4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
In 30 ml of acetonitrile (S)-3-(2-methanesulfonyloxyethyl)-3-(3,4-dichlorophenyl)-1-(3,4,5-trimethoxybenzoyl)pyrrolidine (3.17 g), prepared essentially as described, supra, is mixed with an equimolar amount of 4-(piperidin-1-yl)piperidine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum and the residue is taken up in methylene chloride and washed with a 3N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.
Reaction SMILES: N[C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[CH3:12][C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15]>N1C=CC=CC=1>[C:14]([C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1)(=[O:15])[C:13]([CH3:18])([CH3:17])[CH3:12]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1nc(Cl)c2cc[nH]c2n1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)c1nc(Cl)c2cc[nH]c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
To a 100 ml round bottom flask was charged 4.0 g (23.8 mmol) of 2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidine dissolved in 50 ml of anhydrous pyridine. To this solution was added 10.2 ml (83 mmol) of trimethylacetyl chloride, and after several minutes a precipitate began forming. The reaction was stirred at RT under a nitrogen atmosphere for 30 min. The volatiles were removed in vacuo, and the residue was dissolved in 1 L of CHCl3, washed twice with 0.1 N HCl, dried over Na2SO4, and removed in vacuo. The crude residue was flash chromatographed on silica gel eluting with a gradient of 100% CHCl3 to 2% MeOH/CHCl3. After collecting the correct fractions, the solvents were removed in vacuo to give 4.4 g (73%) of 2-pivaloyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidine as an off-white solid.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([C:10](O)=[O:11])=[C:4]2[CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[O:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([CH2:10][OH:11])=[C:4]2[CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc2c1CCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cccc2c1CCO2

Procedure:
A solution of Part A 2,3-dihydrobenzofuran-4-carboxylic acid (10 g, 61 mmol) in THF (100 mL) was stirred as LAH (4.64 g, 122 mmol) was slowly added. The mixture was heated to reflux for 30 min. The mixture was cooled and quenched cautiously with ethyl acetate and then with 1N HCl (150 mL). The mixture was then made acidic with 12N HCl until all the inorganic precipitate dissolved. The organic layer was separated, and the inorganic layer was extracted twice with ethyl acetate. The organic layers were combined, washed twice with brine, and then concentrated in vacuo. This oil was distilled to give 2,3-dihydrobenzofuran-4-methanol as a clear oil that crystallized upon cooling (8.53 g, 87.6%).