Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH2:23][C:24]5[NH:25][CH:26]=[CH:27][N:28]=5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.[N:36]1([S:41](Cl)(=[O:43])=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH2:23][C:24]5[N:25]([S:41]([N:36]6[CH2:40][CH2:39][CH2:38][CH2:37]6)(=[O:43])=[O:42])[CH:26]=[CH:27][N:28]=5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1
Reactant: O=S(=O)(Cl)N1CCCC1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1Cc1ncc[nH]1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1Cc1nccn1S(=O)(=O)N1CCCC1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{[1-(pyrrolidin-1-ylsulfonyl)-1H-imidazol-2-yl]methyl}-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(1H-imidazol-2-ylmethyl)-1,3-thiazolidine-2,4-dione (from Example 403) and 1-pyrrolidinesulfonyl chloride following General Procedure U.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:15][C@@H:14]([CH2:16][CH2:17][OH:18])[CH2:13][CH2:12][C@@H:11]1[CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:29].[Na+]>C(#N)C.C(Cl)(Cl)(Cl)Cl.O.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C@@H:10]1[C@@H:11]([CH2:19][NH:20][C:21]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:27])[CH2:12][CH2:13][C@H:14]([CH2:16][C:17]([OH:29])=[O:18])[CH2:15]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CCO)C[C@@H]1CNC(=O)OC(C)(C)C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CC(=O)O)C[C@@H]1CNC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 49.2 %

Procedure:
To a solution of (racemic)-tert-butyl N-[[(1S,2S,4S)-2-[(tert-butoxycarbonylamino)methyl]-4-(2-hydroxyethyl)cyclohexyl]methyl]carbamate (772 mg, 2 mmol) in acetonitrile (3 mL), carbon tetrachloride (3 mL) and water (4.5 mL) is added sodium periodate (1.28 g, 6 mmol) followed by RuCl3.H2O (21 mg, 0.1 mmol). The resulting mixture is stirred for 2 hr then diluted with EtOAc, washed with brine, dried over MgSO4 and concentrated. The residue is taken up in saturated sodium carbonate solution and extracted with EtOAc. The aqueous phase is acidified with HCl (2M aqueous) and extracted with EtOAc. The organic extract is washed with brine, dried over MgSO4 and concentrated. This residue is purified by silica chromatography (eluting with ethyl acetate) to give the title compound (394 mg) as a viscous oil. 1H NMR (DMSO-d6) δ 0.7-1.0 (m, 1H), 1.0-1.9 (m, 9H), 1.39 (s, 18H), 2.0-2.3 (m, 2H), 2.6-3.18 (m, 4H), 6.6-6.8 (bm, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14](=O)[C:15]([F:18])([F:17])[F:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1CCN(Cc2ccccc2)C1)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: FC(F)(F)CNC1CCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 2.64 g sample of the compound from step 447a was added dropwise to a suspension of 1.11 g of LAH in ether stirred under N2 at 0° C. After one hour, the reaction was stirred at room temperature for 6 hours. The reaction was quenched by sequential addition of 1.2 mL of water, 1.2 mL of 15% NaOH and 2.4 mL of water. The mixture was filtered, and the filtrate was concentrated to give 2.39 of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH2:12][CH3:13])=[CH:4][C:3]=1F.Cl.[CH3:16][S:17]([CH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(=[O:19])=[O:18].C([O-])([O-])=O.[K+].[K+].CS(C)=O>CCOC(C)=O.C(Cl)Cl>[CH2:12]([O:11][C:5]1[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]([CH3:1])=[C:3]([N:25]2[CH2:26][CH2:27][CH:22]([CH2:21][CH2:20][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:23][CH2:24]2)[CH:4]=1)[CH3:13]
Reactant: CS(=O)(=O)CCC1CCNCC1
Reactant: CCOc1cc(F)c(C)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(C)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 66.2 %

Procedure:
To 1-(ethyloxy)-5-fluoro-4-methyl-2-nitrobenzene (Example 215, step A) (13.1 g, 65.9 mmol), 4-[2-(methylsulfonyl)ethyl]piperidine hydrochloride (15.0 g, 65.9 mmol) and K2CO3 (31.9 g, 231 mmol) was added DMSO (300 mL). The reaction mixture was heated at 100° C. overnight. The reaction was cooled to rt and diluted with EtOAc and DCM. The organic layer was washed with H2O and the aqueous layer was backextracted with DCM. The combined organic layers were dried (MgSO4), filtered and rotovapped down. Purification by flash chromatography provided the title compound of Step F (16.2 g, 43.6 mmol, 66% yield). This reaction was carried out in duplicate to provide an overall amount of 33.2 g, 89.4 mmol of the title compound of Step F. 1H NMR (400 MHz, DMSO-d6) δ 7.79 (s, 1H), 6.56-6.73 (m, 1H), 4.16 (q, J=7.0 Hz, 2H), 3.30 (d, J=12.2 Hz, 2H), 3.04-3.15 (m, 2H), 2.95 (s, 3H), 2.74 (t, J=11.5 Hz, 2H), 2.26 (s, 3H), 1.81-1.97 (m, 4H), 1.42-1.74 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][CH:18]=2)=[C:4]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[N:3]=1.I[CH2:26][CH2:27][CH2:28][OH:29]>>[NH2:1][C:2]1[N:3]=[C:4]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[N:17]([CH2:26][CH2:27][CH2:28][OH:29])[CH:18]=2)=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: OCCCI
Reactant: Nc1nc(-c2ccco2)c(-c2ccc(=O)[nH]c2)c(-c2ccco2)n1
Product: Nc1nc(-c2ccco2)c(-c2ccc(=O)n(CCCO)c2)c(-c2ccco2)n1

Procedure:
The title compound was synthesized in a similar manner to Example 66 using 5-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone and 3-iodopropanol.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14])#[N:2].[NH2:15][OH:16]>CCO>[NH2:2][C:1](=[N:15][OH:16])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14]
Reactant: NO
Reactant: COC(=O)c1ccc(C#N)c(OC)c1
Solvent: CCO
Product: COC(=O)c1ccc(C(N)=NO)c(OC)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a suspension of methyl 4-cyano-3-methoxybenzoate, obtained in step 1 (135 mg; 0.71 mmol; 1 eq.) in EtOH (1.35 mL) was added hydroxylamine (50% in water) (0.21 mL; 3.53 mmol; 5 eq.). The reaction mixture was stirred at 60° C. for 3 h. Solvent were removed to dryness, to afford the title compound as a white powder (191 mg; quantitative). 1H NMR (DMSO-d6, 300 MHz) δ 9.58 (br s, 1H), 7.56-7.51 (m, 3H), 5.71 (br s, 2H), 3.87-3.85 (m, 6H). HPLC (Method A), Rt 1.17 min (purity: 95.0%).
Reaction SMILES: [CH3:1]OCC(O)=O.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH2:43]([N:50]([CH2:56][CH:57]1[CH2:59][CH:58]1OC)[C:51](=O)[CH2:52][O:53][CH3:54])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.B.C1COCC1>ClCCl.C1COCC1>[CH2:43]([N:50]([CH2:56][CH:57]1[CH2:59][CH:58]1[CH3:1])[CH2:51][CH2:52][O:53][CH3:54])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: COCC(=O)N(Cc1ccccc1)CC1CC1OC
Reactant: COCC(=O)O
Agent: B
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCCN(Cc1ccccc1)CC1CC1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Coupling In a 500 mL flask methoxyacetic acid (2.24 g, 24.8 mmol), N-benzyl-1-(2-trans-methylcyclopropyl)methanamine hydrochloride (5.0 g, 23.6 mmol) and DIPEA (13.4 g, 104 mmol) were dissolved in 300 mL of dichloromethane. To this solution at rt BOP (11.0 g, 24.8 mmol) was added as a solid portionwise and stirred 15 minutes. The reaction mixture was evaporated ini vacuo. Purification by flash chromatography (25-35% ethyl acetate:hexanes) provided a mixture of cis and trans amides as a clear oil: ES MS (M+H)=248.1. Step B: Reduction A 500 mL flask charged with N-benzyl-2-methoxy-N-(2-methoxycyclopropyl)methyl acetamide (from step A, 7.75 g, 31.3 mmol) in THF (100 mL) was added BH3-THF (1.0 M, 94 mL, 94 mmol) dropwise via an addition funnel. Upon complete addition (10 min.) the mixture was refluxed for 14 h. The mixture was allowed to cool to rt and quenched carefully with MeOH (15 mL). The mixture was then treated with 15 mL concentrated HCl and heated to reflux for 5 h. The reaction was evaporated in vacuo and partitioned between ethyl acetate and 20% NaOH solution. The aqueous layer was washed with ethyl acetate (3×). The combined organics were dried over sodium sulfate, filtered and evaporated in vacuo. Purification by reverse phase LC gave N-benzyl-2-methoxy-N-(2-methylcyclopropyl)methylethanamine as a clear oil: 1H NMR (400 MHz, CDCl3) δ 7.28 (m, 5H), 3.70 (bq, J=13.5 Hz, 2H), 3.49 (bs, 2H), 3.31 (s, 3H), 2.75 (bm, 2H), 2.51 (m, 1H), 2.31 (m, 1H), 1.03 (d, J=5.86, 3H), 0.59 (m, 1H), 0.48 (m, 1H), 0.22 (m, 2H). ES MS (M+H)=234.2. Step C: Hydrogenation A degassed solution of N-benzyl-2-methoxy-N-(2-methylcyclopropyl)methylethanamine (4.89 g, 20.9 mmol) in 150 mL ethyl alcohol was treated with palladium hydroxide (20% on carbon, 0.29 g) and hydrogen chloride (5.24 mL of a 4M solution in dioxane, 21 mmol) then placed under a hydrogen atmosphere for 16 hours. The reaction mixture was degassed with nitrogen, filtered through celite, washed with methanol and evaporated in vacuo to give (2-methoxyethyl)[(2-methylcyclopropyl)methyl]amine hydrochloride as a pale yellow oil: 1H NMR (400 MHz, CD3OD) δ 3.65 (m, 2H), 3.41 (s, 3H), 3.21 (m, 2H), 2.92 (m, 2H), 1.09 (d, J=5.68 Hz, 3H), 0.80 (m, 2H), 0.57 (m, 1H), 0.46 (m, 1H).
Reaction SMILES: [C:1](OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:2].[NH2:16][C:17]1[CH:18]=[C:19]([CH2:25][CH:26]([O:32][CH:33]([CH3:35])[CH3:34])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24].S(=O)(=O)(O)O.C(#N)C>C(#N)C.CN(C)C1C=CN=CC=1>[N:16]([C:17]1[CH:18]=[C:19]([CH2:25][CH:26]([O:32][CH:33]([CH3:34])[CH3:35])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24])=[C:1]=[O:2]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CCOC(=O)C(Cc1ccc(OC)c(N)c1)OC(C)C
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(O)O
Solvent: CC#N
Product: CCOC(=O)C(Cc1ccc(OC)c(N=C=O)c1)OC(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.4 %

Procedure:
0.13 g of di-t-Butyl dicarbonate was dissolved in 2.5 ml of acetonitrile, and a solution containing 60 mg of 4-dimethylaminopyridine and 0.12 g of ethyl 3-(3-amino-4-methoxy-phenyl)-2-isopropoxypropanoate in acetonitrile were added thereto, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was cooled in ice, and 0.73 ml of 40% sulfuric acid-acetonitrile solution was added and stirring was continued at room temperature for 2 minutes, then the mixture was extracted with hexane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated, to give 28 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]2[NH:15][C:16]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[CH:25]=[C:24]([C:29]3[CH:34]=[CH:33][C:32]([C:35]5[NH:39][C:38]([CH:40]6[CH2:45][C@@H:44]7[C@@H:42]([CH2:43]7)[N:41]6C(OCC6C=CC=CC=6)=O)=[N:37][CH:36]=5)=[CH:31][CH:30]=3)[CH:23]=[CH:22]4)=[CH:17][N:18]=2)[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C@@H:42]12[CH2:43][C@@H:44]1[CH2:45][C@@H:40]([C:38]1[NH:37][CH:36]=[C:35]([C:32]3[CH:33]=[CH:34][C:29]([C:24]4[CH:25]=[C:26]5[C:21](=[CH:22][CH:23]=4)[CH:20]=[C:19]([C:16]4[NH:15][C:14]([C@@H:13]6[CH2:12][C@@H:11]7[C@@H:9]([CH2:10]7)[N:8]6[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:18][CH:17]=4)[CH:28]=[CH:27]5)=[CH:30][CH:31]=3)[N:39]=1)[NH:41]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6C[C@H]7C[C@H]7N6C(=O)OCc6ccccc6)[nH]5)cc4)ccc3c2)[nH]1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5c[nH]c([C@@H]6C[C@H]7C[C@H]7N6)n5)cc4)ccc3c2)[nH]1
Reaction time: 3 h

Procedure:
A reaction mixture of (1R,5R)-benzyl 3-(5-(4-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (0.305 g, 0.416 mmol) and NaHCO2 (0.070 g, 0.832 mmol) in MeOH (15 mL) was charged with 10% Pd/C (0.022 g, 0.021 mmol). The resulting suspension was vacuum flushed with N2 (3×) and placed under 1 atm of H2 (balloon) for 3 h at room temperature. The mixture was then filtered though a pad of diatomaceous earth (CELITE®) and concentrated under vacuum. An off-white solid corresponding to (1R,3S,5R)-tert-butyl 3-(5-(6-(4-(2-((1R,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (0.235 g) was recovered and used without further purification. LC-MS [M+H]+=599; Rt=1.96 min is product. Column Luna 3u C18 2×50 mm; start % B: 0, final % B: 100 Solvent A: 10% Acetonitrile/90% H2O+1% TFA; Solvent B: 90% Acetonitrile/10% H2O+1% TFA; flow rate 4 ml/min. Run time: 5 min. Purity=94%. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.00 (2H, br. s.), 8.11-8.32 (3H, m), 7.88-8.02 (5H, m), 7.72-7.88 (9H, m), 7.63 (4H, br. s.), 4.64 (2H, br. s.), 4.42 (1H, t, J=7.93 Hz), 3.97-4.18 (1H, m), 3.45 (1H, br. s.), 3.17 (3H, s), 2.96 (1H, dd, J=13.43, 6.71 Hz), 2.08-2.43 (6H, m), 1.66 (2H, br. s.), 1.07-1.50 (20H, m), 0.81-0.89 (3H, m), 0.77 (1H, br. s.), 0.45-0.61 (3H, m), 0.30 (1H, br. s.).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[CH3:14][NH:15][CH3:16]>CS(C)=O.CCOC(C)=O>[CH3:14][N:15]([CH3:16])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11]
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Reactant: CNC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CN(C)c1ccc(C#N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-Fluoro-3-(trifluoromethyl)benzonitrile (240 mg, 1.27 mmol) was dissolved in DMSO (1 ml) together with dimethylamine (1 ml, 40% aq). The mixture was stirred at r.t. for 18 hours followed by 4 hours at 50° C. The reaction was cooled, diluted with EtOAc (10 ml), washed with H2O (2*20 ml), dried over MgSO4 and evaporated to give 253 mg (93%) of the title substance as a greenish oil.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:21])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]3O)[C:6]=2[N:7]=1.Cl[C@@]1(O[C@H](COC(C2C=CC(C)=CC=2)=O)[C@@H](OC(C2C=CC(C)=CC=2)=O)C1)O>>[NH2:1][C:2]1[NH:3][C:4](=[O:21])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[CH2:13]3)[C:6]=2[N:7]=1
Reactant: Nc1nc2c(sc(=O)n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: Cc1ccc(C(=O)OC[C@H]2O[C@@](O)(Cl)C[C@@H]2OC(=O)c2ccc(C)cc2)cc1
Product: Nc1nc2c(sc(=O)n2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1

Procedure:
The 2'-deoxyerythropentofuranosyl, the xylofuranosyl and the arabinofuranosyl analogs of compound 7 can be prepared in a manner similar to that described for compound 7 (scheme VI). Thus reacting 4 with 1-chloro-2-deoxy-3,5-di-O-(p-toluoyl)-α-D-erythropentofuranose followed by deblocking yields 5-amino-3-(2-deoxy-β-D-erythropentofuranosyl)thiazolo[4,5-d]pyrimidine-2,7(3H,6H)-dione (36). Likewise after deblocking of the respective intermediates, 4 and 1,2,3,5-tetra-O-acetyl-D-xylofuranose will yield 5-amino-3-(β-D-xylofuranosyl)thiazolo[4,5-d]pyrimidine-2,7(3H,6H)-dione (38) and 4 and 1-chloro-2,3,5-tri-O-benzyl-α-D-arabinofuranose will yield 5-amino-3-(β-D-arabinofuranosyl)thiazolo[4,5-d]pyrimidine-2,7(3H,6H)-dione (40). The tri-O-acetyl (40) prodrug form of compound 7 is prepared from 4 and 1,2,3,5-tetra-O-acetyl-D-ribofuranose and the 2,3-di-O-isopropylidene derivative (42) is prepared directly from 7 (scheme VI).
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH2:4][CH:5]2[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH:6]2[CH:20]=1.Br[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.N>>[N:26]1[CH:27]=[CH:28][CH:29]=[C:24]([C:3]2[CH2:4][CH:5]3[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[O:11])[CH:6]3[CH:20]=2)[CH:25]=1
Reactant: C[Sn](C)(C)C1=CC2C(CCN2C(=O)OCc2ccccc2)C1
Reactant: Brc1cccnc1
Agent: N
Product: O=C(OCc1ccccc1)N1CCC2CC(c3cccnc3)=CC21

Procedure:
The mixture of Example 38C (140 mg, 0.332 mmol) and 3-bromopyridine (0.042 mL, 0.43 mmol) were processed as described in Example 4C. Purification by chromatography (SiO2, 30% EtOAc/hexane) provided 90 mg (85%) of a 4:1 mixture of the title compounds. MS (DCI/NH3) m/z 321 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(#N)C>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:3]([CH:6]=1)[C:4]#[N:5])([O-:12])=[O:11]
Reactant: C1CCNCC1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Solvent: CC#N
Product: N#Cc1cc([N+](=O)[O-])ccc1N1CCCCC1
Reaction time: 1 h
Yield: 67.1 %

Procedure:
2-Chloro-5-nitrobenzonitrile (20 g) and piperidine (9.34 g) were added to acetonitrile (100 ml) and the mixture was stirred at the refluxing temperature for 1 hr. The solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization and the crystals were recrystallized from methanol to give 5-nitro-2-piperidinobenzonitrile (17 g). Subsequently, ammonium chloride (1.6 g) and iron powder (8.4 g) were added to a mixed solvent of water (40 ml) and ethanol (120 ml) and the mixture was heated to 65° C. 5-Nitro-2-piperidinobenzonitrile (10 g) was added by portions over 20 min and the mixture was stirred at the refluxing temperature for 30 min. The reaction mixture was ice-cooled and the reaction solution was filtrated. The solvent was evaporated under reduced pressure. An aqueous sodium hydroxide solution was added and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization and the crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (8.3 g). melting point: 148-149° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH2:11][CH2:10][CH:9]([C:17]([NH2:19])=O)[CH2:8][C:7]2=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:21][C:2]([F:1])([F:20])[O:3][C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH2:11][CH2:10][CH:9]([CH2:17][NH2:19])[CH2:8][C:7]2=1
Reactant: NC(=O)C1CCc2[nH]c3ccc(OC(F)(F)F)cc3c2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC1CCc2[nH]c3ccc(OC(F)(F)F)cc3c2C1
Temperature: 70 °C
Yield: 81.4 %

Procedure:
To a stirred solution of 6-(trifluoromethoxy)-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide of Step 3 (1.22 g, 4.09 mmol) in anhydrous tetrahydrofuran kept under nitrogen, was added via syringe a 1M solution of lithium aluminum hydride in terahydrofuran (8.18 mmol). The pale yellow suspension was heated at 70° C. for 1 hour, allowed to cool to room temperature and then placed in an ice water bath. Under vigorous stirring the mixture was quenched with ethyl acetate, followed by a saturated aqueous solution of Rochelle salt. The slurry was extracted with ethyl acetate, the extracts were washed with brine and dried over anhydrous magnesium sulfate. Removal of the solvent provided a solid residue that was purified by chromatography over silica Merck 60 using a 2% to 10% gradient of methanolic ammonia in dichloromethane to provide the title compound as a white solid (0.946 g, 81.6%), m.p. 148-150° C. MS [(+)ES, m/z]: 285.1 [M+H]+. MS [(−)ES, m/z]: 283.1 [M−H]−. HRMS [(+)ESI, m/z]: 285.1212 [M+H]+. Calc'd for C14H16F3N2O: 285.1214. HPLC: Chromolith Monolith column, 0.46×10 cm, gradient of acetonitrile in water (0.01% TFA), 4 mL/min, detection at 280 nm; Rt 1.6 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[OH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1>CCN(CC)CC>[Cl:8][C:4]1[N:3]=[C:2]([O:9][CH:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)[CH:7]=[N:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1cncc(Cl)n1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(Oc2cncc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.1 %

Procedure:
A mixture of 2,6-dichloropyrazine (5.00 g, 33.6 mmol), tert-butyl 4-hydroxy-1-piperidinecarboxylate (6.76 g, 33.6 mmol) and K-t-BuO (1 M in tert-butanol; 35 mL, 35 mmol) in Et3N (200 mL) was stirred at room temperature for 12 h. The reaction was quenched with water (50 mL) and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with saturated aqueous KH2PO4, dried (MgSO4), and concentrated in vacuo. The residue was recrystallized from ethanol/water to give 9.50 g (90%) of the title compound as a white solid: mp 86-87° C.; MS m/z 313 (M)+. Anal. (C14H20ClN3O3) C, H, N.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([O:9][CH2:10][C:11]3[N:12]=[N:13][N:14]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18](I)[CH:17]=4)[N:15]=3)=[N:7][N:6]=[C:5]2[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH2:3][CH2:2]1.[CH3:29][N:30](C=O)C>[C-]#N.[Zn+2].[C-]#N>[CH:1]1([N:4]2[C:5]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[N:6][N:7]=[C:8]2[O:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=3)[C:29]#[N:30])[N:15]=2)[CH2:3][CH2:2]1
Reactant: CN(C)C=O
Reactant: Ic1cccc(-n2nnc(COc3nnc(-c4ccncc4)n3C3CC3)n2)c1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cccc(-n2nnc(COc3nnc(-c4ccncc4)n3C3CC3)n2)c1

Procedure:
The title compound is prepared from 4-{4-cyclopropyl-5-[2-(3-iodo-phenyl)-2H-tetrazol-5-ylmethoxy]-4H-[1,2,4]triazol-3-yl}-pyridine (1 mmol), zinc cyanide (1.1 mmol), palladium (0) tetrakis-triphenylphosphine (0.05 mmol) in DMF (5 mL) at 80° C. overnight.
Reaction SMILES: C([NH:7][C:8]1[C:13]([C:14](O)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:15][C:16](OC(C)(C)C)=[O:17])=[CH:12][CH:11]=[CH:10][N:9]=1)(=O)C(C)(C)C.C(=O)(O)[O-].[Na+]>Cl.O1CCOCC1>[C:23]1([C:14]2[C:13]3[C:8](=[N:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:16](=[O:17])[CH:15]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)CC(O)(c1ccccc1)c1cccnc1NC(=O)C(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=c1cc(-c2ccccc2)c2cccnc2[nH]1
Temperature: 25 °C
Yield: 51.4 %

Procedure:
Tert-butyl 2-pivaloylamino-β-hydroxy-β-phenyl-3-pyridinepropanoate (2.09 g, 5.25 mmol) was dissolved in a mixed solvent of 3N hydrochloric acid aqueous solution (10 ml) and dioxane (10 ml), and the solution was heated under reflux for 3 days. After cooling to room temperature, saturated sodium bicarbonate aqueous solution was added for neutralization. The reaction mixture was filtered, and the resulting crystals were thoroughly washed with water and recrystallized from acetonitrile to give 4-phenyl-1,8-naphthyridin-2(1H)-one (600 mg, 51%).