Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][NH2:17])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1>ClCCl.O>[C:1]([O:5][C:6](=[O:18])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][NH:17][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:20]([Br:19])=[CH:21][CH:22]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CN)cs1
Reactant: O=C(O)c1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CNC(=O)c2ccc(Br)cc2)cs1
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.4 %

Procedure:
2-{[4-(Aminomethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (3.0 g) synthesized in Example 13 and 4-bromobenzoic acid (2.51 g) was dissolved in dichloromethane (50 mL), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) hydrochloride (2.99 g) and hydroxybenzotriazole (HOBT) monohydrate (2.39 g) were successively added thereto, and the mixture was stirred at room temperature for 12 hr. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1) to give the title compound (3.5 g) as a white solid.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][N:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39]([C:41]1[CH:46]=[N:45][CH:44]=[CH:43][N:42]=1)=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([C:39]([C:41]2[CH:46]=[N:45][CH:44]=[CH:43][N:42]=2)=[O:40])[C:23]([F:35])=[C:24]([Cl:34])[C:25]=1[N:26]1[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)c1cnccn1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ncc(F)c2Cl)C[C@H](C)O1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc(C(=O)c3cnccn3)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting material: (2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine (Intermediate 45) and N-methoxy-N-methylpyrazine-2-carboxamide.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].C([Li])CCC.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>C1COCC1.CCOCC>[CH2:23]([Sn:18]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:19][CH2:20][CH2:21][CH3:22])[C:2]#[C:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: C#Cc1ccccn1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC[Sn](C#Cc1ccccn1)(CCCC)CCCC
Reaction time: 0.25 h

Procedure:
Dissolve 2-ethynylpyridine (7.14 g, 69.23 mmol) in THF (350 mL) and cool the solution to −10° C. (ice/methanol) under nitrogen. Add n-butyllithium (1.6 M in hexanes, 47.6 mL, 76.16 mmol) dropwise and stir the mixture. After 15 minutes, add tributyltin chloride (20.7 mL, 76.2 mL) dropwise. Warn the mixture to room temperature overnight. Quench the reaction with water, dilute with ether, and wash with saturated ammonium chloride, then brine. Dry over sodium sulfate, filter and concentrate. No further purification necessary to give the title compound: 1H NMR (CDCl3) δ 8.50-8.54 (m, 1H), 7.51-7.59 (m, 1H), 7.35-7.43 (m, 1H), 7.11-7.18 (m, 1H), 1.59-1.64 (m, 6H), 1.32-1.42 (m, 6H), 1.05-1.10 (m, 6H), 0.88-0.94 (m, 9H).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH2:8]([C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[CH3:9]>N1C=CC=CC=1>[CH2:8]([C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:5](=[O:7])[CH3:6])=[CH:12][CH:11]=1)[CH3:9]
Reactant: CCc1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCc1ccc(NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
Acetic anhydride (4.3 mL, 45.45 mmol) was added to a mixture of 4-ethylaniline (5.0 g, 41.32 mmol) and pyridine (20 mL) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned between dichloromethane and an aqueous solution of hydrochloric acid. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 6.857 g of N-(4-ethyl-phenyl)-acetamide as a brown solid without further purifications.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[OH-].[K+].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([O:22][CH3:23])[CH:14]=1>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[CH3:23][O:22][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[N+:19]([O-:21])=[O:20])[O:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: OCCN1CCOCC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [K+]
Product: COc1cc(OCCN2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 57 %

Procedure:
4-(2-Hydroxyethyl)morpholine (0.98 g, 9.0 mmol) was added to a mixture of powdered KOH (0.50 g, 9.0 mmol) and Aliquat 336 (0.36 g, 0.9 mmol) and the resulting mixture was stirred for 5 minutes at 80° C. Then 4-fluoro-2-methoxy-1-nitrobenzene (1.28 g, 7.5 mmol) was added, and stirring proceeded at this temperature for 30 minutes. The mixture was cooled and partitioned between methylene chloride (80 mL) and dilute aqueous HCl (50 mL), and the organic layer was extracted with dilute aqueous HCl (2×50 mL). The combined aqueous phases were washed with methylene chloride (3×75 mL), basified (3N NaOH), and extracted with methylene chloride (3×75 mL). The combined organic extracts were washed with water (3×100 mL), dried (MgSO4), and evaporated, providing 1.2 g as a yellow oil, in 57% yield: 1H NMR (CDCl3) δ 2.58 (t, J=4.6 Hz, 6H), 2.83 (t, J=5.6 Hz, 2H), 3.74 (t, J=4.6 Hz, 4H), 3.94 (s, 3H), 4.17 (t, J=5.6 Hz, 2H), 6.51 (dd, J=9.1 Hz, J=2.4 Hz, 1H), 6.56 (d, J=2.4 Hz, 1H), 8.00 (d, J=9.1 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10](/[CH:12]=[CH:13]/[C:14]2[CH:19]=[C:18]([CH3:20])[C:17]([O:21][CH2:22][O:23][CH3:24])=[C:16]([CH3:25])[CH:15]=2)[CH:11]=1)[C:6]([OH:8])=[O:7].C1CCC(N=C=NC2CCCCC2)CC1.[F:42][C:43]1[CH:48]=[CH:47][C:46](O)=[CH:45][CH:44]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:26][N:2]([CH3:1])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10](/[CH:12]=[CH:13]/[C:14]2[CH:15]=[C:16]([CH3:25])[C:17]([O:21][CH2:22][O:23][CH3:24])=[C:18]([CH3:20])[CH:19]=2)[CH:11]=1)[C:6]([O:8][C:46]1[CH:47]=[CH:48][C:43]([F:42])=[CH:44][CH:45]=1)=[O:7]
Reactant: Oc1ccc(F)cc1
Reactant: COCOc1c(C)cc(/C=C/c2cc(C(=O)O)cc(N(C)C)c2)cc1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COCOc1c(C)cc(/C=C/c2cc(C(=O)Oc3ccc(F)cc3)cc(N(C)C)c2)cc1C
Reaction time: 18 h

Procedure:
To a solution of Compound 5 (80 mg, 0.225 mmol) in DCM (3 mL) were added DCC (70 mg, 0.338 mmol), DMAP (5.5 mg, 0.045 mmol), and 4-fluorophenol (61.5 mg, 0.450 mmol) at room temperature. The reaction mixture was stirred overnight (about 18 hours) and filtered through Celite. The filtrate was washed with brine, and dried with Na2SO4. The solution was filtered and concentrated. The residue was subjected to chromatography over silica gel (Hexanes/EtOAc=8/1) to give (E)-4-fluorophenyl 3-(dimethylamino)-5-(4-(methoxymethoxy)-3,5-dimethyl-styryl)benzoate.
Reaction SMILES: C(NC1C=C([N+]([O-])=O)C=C(NC(=O)CC)C=1)(=[O:4])CC.[C:20]([C:23]1[C:28](=[O:29])[O:27][C:26](=[O:30])[C:25](=[C:31](NC2C=C(NC(=O)CC)C=C(NC(=O)CC)C=2)[CH3:32])[C:24]=1[OH:50])(=[O:22])[CH3:21]>>[C:31]([C:25]1[C:26](=[O:30])[O:27][C:28]([OH:29])=[C:23]([C:20](=[O:22])[CH3:21])[C:24]=1[OH:50])(=[O:4])[CH3:32]
Reactant: CCC(=O)Nc1cc(NC(=O)CC)cc(NC(C)=C2C(=O)OC(=O)C(C(C)=O)=C2O)c1
Reactant: CCC(=O)Nc1cc(NC(=O)CC)cc([N+](=O)[O-])c1
Product: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O

Procedure:
Following the procedures outlined in Example 2, this nitrobenzene was hydrogenated to the 3,5-bis-propionamidoaniline and the latter (2.15 g., 0.0084 mol) was reacted with 1.75 g. (0.0084 mol) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one to furnish 5-acetyl-4-hydroxy-3-[1-(3,5-bis-propionamidophenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 239°-241° (dec.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:31][C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][C:33]=1[O:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:31][C:32]2[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][C:33]=2[O:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: COc1ccc(COc2ccc(C)cc2CI)cc1
Product: COc1ccc(COc2ccc(C)cc2Cc2ccc(N3CC(=O)N(CC[Si](C)(C)C)S3(=O)=O)c(OCc3ccccc3)c2)cc1

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and 2-iodomethyl-1-(4-methoxybenzyloxy)-4-methylbenzene analogous to Example 57, step B.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Cl)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].[C:38]([C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1)#[N:39]>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:44]3[CH:43]=[CH:42][CH:41]=[C:40]([C:38]#[N:39])[CH:45]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(Cl)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: N#Cc1cccc(B(O)O)c1
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(-c4cccc(C#N)c4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-methylbenzene 57 obtained in Example 120-(1) and 3-cyanophenylboronic acid were used and treated in a manner similar to Example 120-(2) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3-cyano phenyl)-2-thienylmethyl)-4-methylbenzene. APCI-Mass m/Z 637 (M+NH4).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[CH3:10][NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1.C(N(CC)CC)C>ClCCl.C1(C)C=CC=CC=1>[CH3:23][O:22][C:16]1[CH:15]=[C:14]([CH2:13][CH2:12][N:11]([CH3:10])[C:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])=[O:8])[CH:19]=[CH:18][C:17]=1[O:20][CH3:21]
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: O=C(Cl)CCCCCBr
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CCN(C)C(=O)CCCCCBr)cc1OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
10 ml of 6-bromohexanoyl chloride were dissolved in a mixture of 100 ml of absolute dichloromethane and 100 ml of absolute toluene. A solution of 13.6 g of N-methyl-N-[2-(3,4-dimethoxyphenyl)-ethyl]-amine and 9.5 ml of triethylamine in 25 ml of absolute toluene was added dropwise to the solution with ice cooling. The reaction mixture was subsequently stirred at room temperature for 12 hours. In order to work it up, the precipitated salts were filtered out and washed with toluene. The filtrate was washed first with 1 molar citric acid solution and then with sodium bicarbonate solution, dried with magnesium sulfate and concentrated. 19.3 g of 5-{N-[2-(3,4-dimethoxyphenyl)-ethyl]-N-methylaminocarbonyl}-pentyl bromide were obtained as an oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH:7]1[CH2:9][CH:8]1[C:10]([OH:13])([CH3:12])[CH3:11].Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH:22]2[CH2:27][C:26]([CH3:29])([CH3:28])[NH:25][C:24]([CH3:31])([CH3:30])[CH2:23]2)[N:16]=1>>[CH3:28][C:26]1([CH3:29])[CH2:27][CH:22]([NH:21][C:17]2[N:16]=[C:15]([C:5]3[S:1][C:2]([CH2:6][CH:7]4[CH2:9][CH:8]4[C:10]([OH:13])([CH3:11])[CH3:12])=[CH:3][CH:4]=3)[CH:20]=[CH:19][N:18]=2)[CH2:23][C:24]([CH3:31])([CH3:30])[NH:25]1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: CC(C)(O)C1CC1Cc1cccs1
Product: CC1(C)CC(Nc2nccc(-c3ccc(CC4CC4C(C)(C)O)s3)n2)CC(C)(C)N1
Yield: 20 %

Procedure:
The title compound was prepared analogous to Method C, starting from 2-(2-thiophen-2-ylmethyl-cyclopropyl)-propan-2-ol and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine. Yield: 20%.
Reaction SMILES: [NH2:1][CH:2]([CH2:4][CH2:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([CH2:17][CH3:18])[CH:11]=1)([CH3:9])[CH3:8])[CH3:3].Cl.[H][H]>>[NH2:1][CH:2]([CH2:4][CH2:5][CH2:6][C:7]([CH:10]1[CH2:15][CH2:14][CH:13]([NH2:16])[CH:12]([CH2:17][CH3:18])[CH2:11]1)([CH3:8])[CH3:9])[CH3:3]
Reactant: CCc1cc(C(C)(C)CCCC(C)N)ccc1N
Reactant: [H][H]
Agent: Cl
Product: CCC1CC(C(C)(C)CCCC(C)N)CCC1N

Procedure:
10.0 Parts of 2-amino-6-(4-amino-3-ethylphenyl)-6-methylheptane in 120 parts of 1 N aqueous hydrochloric acid were shaken with hydrogen at room temperature and atmospheric pressure with 1.0 parts Nishimura catalyst. After 46% of theory hydrogen had been taken up in 8 hours a further 1.0 parts of catalyst was added and 96% of theory hydrogen uptake was reached in the next 15 hours. The hydrogenation which ceased at 110% theory during the next 24 hours following a final 1.0 part catalyst addition, was worked up according to Example VI, and gave on distillation 8.8 parts of 2-amino-6-(4-amino-3-ethylcyclohexyl)-6-methylheptane, boiling point 176°-80° C. at 12 mbar with the following percentage composition by weight.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][O:4][CH2:3]1.C(NC(C)C)(C)C.[Li].[N:15]1([C:19]2[C:28]3[C:23](=[N:24][C:25](Cl)=[C:26]([Cl:29])[N:27]=3)[N:22]=[C:21]([Cl:31])[N:20]=2)[CH2:18][CH2:17][CH2:16]1.O>O1CCCC1>[N:15]1([C:19]2[C:28]3[C:23](=[N:24][C:25]([O:1][C@@H:2]4[CH2:6][CH2:5][O:4][CH2:3]4)=[C:26]([Cl:29])[N:27]=3)[N:22]=[C:21]([Cl:31])[N:20]=2)[CH2:18][CH2:17][CH2:16]1
Reactant: O[C@@H]1CCOC1
Reactant: Clc1nc(N2CCC2)c2nc(Cl)c(Cl)nc2n1
Agent: [Li]
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Clc1nc(N2CCC2)c2nc(Cl)c(O[C@@H]3CCOC3)nc2n1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
a)+b) 111 μl (1.38 mmol) (R)-3-hydroxytetrahydrofuran are dissolved in 5 ml of tetrahydrofuran and under protective gas at −10° C. mixed with 688 μl (1.38 mmol) of a 2 molar solution of lithium diisopropylamine in tetrahydrofuran. The mixture is stirred for 30 minutes at −10° C., then for one hour at ambient temperature. The mixture is cooled to −10° C. again and combined with a suspension of 400 mg (1.38 mmol) 4-azetidin-1-yl-2,6,7-trichloro-pteridine in 10 ml of tetrahydrofuran. The mixture is stirred for one hour at −10° C., slowly allowed to come up to ambient temperature and stirred for approx. another 16 hours. The reaction mixture is mixed with water and extracted with dichloromethane. The organic phase is dried on sodium sulphate and the solvent is eliminated in vacuo. The residue is stirred with diethyl ether, the precipitated solid is suction filtered, washed with diethyl ether and dried. 290 mg (R)-4-azetidin-1-yl-2,6-dichloro-7-(tetrahydrofuran-3-yl-oxy)-pteridine is obtained, which is dissolved in 13 ml dioxane and slowly added dropwise to a solution of 365 mg (4.24 mmol) piperazine in 12 ml dioxane at a temperature of 80° C. The mixture is stirred for approx. another 16 hours at 80° C., cooled to ambient temperature and water is added to the reaction mixture. It is extracted with dichloromethane, the organic phase is dried on sodium sulphate and purified by chromatography. Yield 170 mg (51% of theoretical)
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([CH2:13][C:14]([OH:16])=[O:15])[CH2:10][C@@H:9]1[C@H:17]1[O:21]C(C)(C)[N:19]([C:24](=[O:26])[CH3:25])[C@H:18]1[CH2:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=1)=O)(C)(C)C.[ClH:36]>>[ClH:36].[C:24]([NH:19][C@@H:18]([CH2:27][C:28]1[CH:29]=[C:30]([F:35])[CH:31]=[C:32]([F:34])[CH:33]=1)[C@@H:17]([CH:9]1[NH:8][CH2:12][C@@H:11]([CH2:13][C:14]([OH:16])=[O:15])[CH2:10]1)[OH:21])(=[O:26])[CH3:25]
Reactant: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2CC(CC(=O)O)CN2C(=O)OC(C)(C)C)OC1(C)C
Agent: Cl
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)C1C[C@H](CC(=O)O)CN1
Reaction time: 8 h
Yield: 105.9 %

Procedure:
Combine (R)-2-[(4S,5S)-3-Acetyl-4-(3,5-difluoro-benzyl)-2,2-dimethyl-oxazolidin-5-yl]-4-carboxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.05 g, 0.101 mmol) and HCl (4M in dioxane, 1.88 mL, 7.55 mmol). Stir overnight. Concentrate under reduced pressure to provide the title compound (0.042 g, 92%).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[CH:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)[CH:22]=[C:21]([C:35]([F:38])([F:37])[F:36])[N:20]=3)[CH:18]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[F:38][C:35]([F:36])([F:37])[C:21]1[N:20]=[C:19]([N:17]2[CH:18]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=3)[N:15]=[CH:16]2)[CH:24]=[C:23]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:30]=2)[CH:22]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)s1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2cn(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 23 °C
Reaction time: 16 h
Yield: 94.2 %

Procedure:
To 5-{1-[6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butylamide (example 301) (0.200 g, 0.348 mmol) was added TFA (5 mL) and the reaction mixture was stirred at 23° C. for 16 h. The mixture was evaporated to dryness and partitioned between TBME and saturated NaHCO3 solution, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left a crude product which was triturated with diethyl ether to give the title compound as a white solid (0.170 g, 94%). MS (ISP) 519.2 [(M+H)+]; mp 237° C. (dec.).
Reaction SMILES: Cl.C(OC([NH:9][C:10]1[C:15](B(O)O)=[CH:14][CH:13]=[CH:12][N:11]=1)=O)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+].Br[C:26]1[C:27]([C:37]#[N:38])=[N:28][N:29]([CH2:35][CH3:36])[C:30]=1[CH2:31][CH:32]([CH3:34])[CH3:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(O)CC.C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:35]([N:29]1[C:30]([CH2:31][CH:32]([CH3:34])[CH3:33])=[C:26]2[C:27]([C:37]([NH2:38])=[N:9][C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:15]=32)=[N:28]1)[CH3:36]
Reactant: CC(C)(C)OC(=O)Nc1ncccc1B(O)O
Reactant: CCn1nc(C#N)c(Br)c1CC(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCCO
Product: CCn1nc2c(N)nc3ncccc3c2c1CC(C)C
Temperature: 80 °C
Yield: 9.1 %

Procedure:
Hydrochloric acid (15 mL of 1M) was added to a solution of 2-tert-butoxycarbonylamino-3-pyridylboronic acid (3.31 g, 13.9 mmol), prepared as described in Parts A and B of Example 15, in 1-propanol (15 mL), and the resulting mixture was heated at 80° C. for one hour and allowed to cool to ambient temperature. Solid sodium carbonate (2.69 g, 25.4 mmol) was added with stirring followed by a solution of 4-bromo-1-ethyl-5-(2-methylpropyl)-1H-pyrazole-3-carbonitrile (1.78 g, 6.95 mmol), prepared as described in Example 2, in 1-propanol (4 mL). Triphenylphosphine (109 mg, 0.42 mmol) was added, and the reaction was evacuated and backfilled with nitrogen three times and stirred for five minutes. A solution of palladium (II) acetate (31 mg, 0.14 mmol) in warm toluene (0.5 mL) was added. The reaction was twice evacuated and backfilled with nitrogen and then heated at 100° C. overnight. An analysis by HPLC indicated the reaction was incomplete, and additional triphenylphosphine (109 mg, 0.42 mmol) and palladium (II) acetate (31 mg, 0.14 mmol) were added. The reaction was twice evacuated and backfilled with nitrogen at heated at reflux for three days. The 1-propanol was removed under reduced pressure, and the residue was dissolved in chloroform (100 mL). The resulting solution was washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on a HORIZON HPFC system as described in Example 15. The resulting solid (200 mg) was recrystallized from acetonitrile (20 mL) after hot filtration, isolated by filtration, washed with cold acetonitrile, and dried overnight in a vacuum oven at 60° C. to provide 0.17 g of 2-ethyl-1-(2-methylpropyl)-2H-pyrazolo[3,4-c][1,8]naphthyridin-4-amine as off-white needles, mp 273-276° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[C:17]([CH3:24])([CH3:23])[C:18](OCC)=[O:19]>CC(C)=O>[Br:9][C:5]1[CH:4]=[N:3][C:2]2[NH:1][C:18](=[O:19])[C:17]([CH3:24])([CH3:23])[O:8][C:7]=2[CH:6]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Nc1ncc(Br)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)Oc2cc(Br)cnc2NC1=O
Reaction time: 18 h
Yield: 84 %

Procedure:
To a mixture of 2-amino-5-bromopyridin-3-ol (0.500 g, 2.64 mmol) and K2CO3 (1.09 g, 7.93 mmol) in acetone (11.0 mL) was added ethyl bromoisobutyrate (0.50 mL, 3.4 mmol). The solution was stirred under N2 for 18 h and then heated to reflux. After 18 h, the solution was cooled and concentrated. The light-pink, sweet-smelling solid was dissolved in CH2Cl2 (50 mL) and MeOH (5 mL). The solution was diluted with H2O (150 mL) and then washed with CH2Cl2 (3×75 mL). The combined organic layers were washed with brine (2×100 mL), dried (Na2SO4) and concentrated to yield the title compound (0.57 g, 84%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 11.39 (s, 1H), 8.03 (d, J=1.2 Hz, 1H), 7.66 (d, 0.9 Hz, 1H), 1.43 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([NH2:24])=[C:20]([NH2:23])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:25][C:26](=O)[C:27](=O)[CH3:28]>O.C(O)C.C(=O)([O-])O.[Na+]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3=[C:19]4[C:20](=[CH:21][CH:22]=[C:16]3[O:15][CH2:14]2)[N:23]=[C:27]([CH3:28])[C:26]([CH3:25])=[N:24]4)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(=O)C(C)=O
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(N)c(N)c3O2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4nc(C)c(C)nc4c3O2)cc1
Temperature: 60 °C

Procedure:
To a solution of [(2R)-7,8-diamino-2,3-dihydro-1,4-benzodioxin-2-yl]-methyl 4-methylbenzenesulfonate (2.170 g, 5.126 mmole) in water (50 mL) was added a solution of 2,3-butanedione (0.552 g, 6.408 mmole) in ethyl alcohol (50 mL) and the reaction mixture was heated at 60° C. for 3 hours. The reaction mixture was allowed to cool to room temperature and was diluted with aqueous sodium hydrogen carbonate (250 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with water (100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 7:3) gave 1.525 g (74%) of the (R)-enantiomer of the title compound as a white crystalline solid. Rf=0.50 (silica, ethyl acetate:hexanes 7:3); mp 153–155° C.