Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:15])[C:12]=1[CH2:13][OH:14].[H-].[Na+].Cl[C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][N:20]=1.O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:15])[C:12]=1[CH2:13][O:14][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][N:20]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Cn1nnc(-c2ccccc2F)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(OCc2c(-c3ccccc3F)nnn2C)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
A solution of (4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methanol (100 mg, 0.48 mmol) in THF (1.4 mL) was added dropwise at 0° C. to a suspension of NaH (60% in oil, 21 mg, 0.53 mmol) in THF (0.7 mL) and the reaction mixture was then stirred at room temperature for 30 min. Then a solution of methyl 6-chloronicotinate (91 mg, 0.53 mmol) in THF (1 mL) was added dropwise at 0° C. and the reaction mixture stirred at room temperature for 16 h. The mixture was then poured into water extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (110 mg, 67%) as a colourless gum. MS: m/e=343.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3](=[O:21])[O:4][C:5]([CH2:19][CH3:20])([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:6][C:7]=1[OH:8].[Cl:22][C:23]1[CH:35]=[CH:34][C:26]2[N:27]([CH:31]([CH3:33])[CH3:32])[C:28]([SH:30])=[N:29][C:25]=2[CH:24]=1>>[Cl:22][C:23]1[CH:35]=[CH:34][C:26]2[N:27]([CH:31]([CH3:33])[CH3:32])[C:28]([S:30][C:2]3[C:3](=[O:21])[O:4][C:5]([CH2:19][CH3:20])([CH2:9][CH2:10][C:11]4[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=4)[CH2:6][C:7]=3[OH:8])=[N:29][C:25]=2[CH:24]=1
Reactant: CCC1(CCc2ccc(OC)cc2)CC(O)=C(Cl)C(=O)O1
Reactant: CC(C)n1c(S)nc2cc(Cl)ccc21
Product: CCC1(CCc2ccc(OC)cc2)CC(O)=C(Sc2nc3cc(Cl)ccc3n2C(C)C)C(=O)O1

Procedure:
The title compound was prepared from 3-Chloro-6-ethyl-4-hydroxy-6-[2-(4-methoxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one from Step 1 and 5-Chloro-1-isopropyl-1H-benzoimidazole-2-thiol using the coupling method described in Example C(4), 1H NMR (CDCl3): δ 0.96 (t, 3H, J=7.5 Hz), 1.69 (d, 6H, J=7.0 Hz), 1.85 (m, 2H), 1.98 (m, 2H), 2.59 (m, 2H), 2.71 (s, 2H), 3.78 (s, 3H), 5.16 (m, 1H), 6.81 (d, 2H, J=8.5 Hz), 7.06 (d, 2H, J=8.5 Hz), 7.28 (d, 2H, J=8.9 Hz), 7.48 (d, 1H, J=8.9 Hz), 7.59 (s, 1H). ESIMS: MH+ 501.10, 503.10, MH− 4.99.10, 501.10.
Reaction SMILES: C1(P(=C=[CH:21][C:22]([O:24][CH3:25])=[O:23])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:26]([O:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[OH:37])[CH:32]=O)[CH3:27]>C1(C)C=CC=CC=1>[CH2:26]([O:28][C:29]1[CH:30]=[C:31](/[CH:32]=[CH:21]/[C:22]([O:24][CH3:25])=[O:23])[CH:34]=[CH:35][C:36]=1[OH:37])[CH3:27]
Reactant: CCOc1cc(C=O)ccc1O
Reactant: COC(=O)C=C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOc1cc(/C=C/C(=O)OC)ccc1O
Reaction time: 1 h

Procedure:
2.1 g (6.32 mmol) of methyl (triphenylphosphoranylidene)acrylate are added, at room temperature, to a solution of 1.0 g (6.01 mmol) of 3-ethoxy-4-hydroxybenzaldehyde and 10 ml of toluene. The reaction is then allowed to continue for 1 hour at room temperature, the reaction suspension is clarified by filtration over a silica gel bed and the filtrate is evaporated down. Chromatography of the residue over silica gel using toluene/ethyl acetate gives methyl 3(E)-(3-ethoxy-4-hydroxyphenyl)acrylate.
Reaction SMILES: CO.[OH-].[K+].[OH:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:18])[CH2:11][C:12]([CH3:17])([CH3:16])[O:13]2)=[CH:8][CH:7]=1.[CH2:19]1[O:22][CH:20]1[CH3:21]>O>[OH:22][CH:20]([CH3:21])[CH2:19][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:18])[CH2:11][C:12]([CH3:16])([CH3:17])[O:13]2)=[CH:8][CH:7]=1
Reactant: CC1CO1
Reactant: CC1(C)CC(=O)c2ccc(O)cc2O1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(O)COc1ccc2c(c1)OC(C)(C)CC2=O
Yield: 79.9 %

Procedure:
To a mixture of 40 ml of methanol, 5 ml of water 1.1 g (20 millimoles) of potassium hydroxide and 3.8 g (20 millimoles) of 7-hydroxy-2,2-dimethyl-4-chromanone under stirring 11.6 g (14 ml, 0.2 mole) of propene oxide are added and the reaction mixture is refluxed for 5 hours. The reaction mixture is diluted with 200 ml of water and worked up according to Example 12. Thus 4.0 g of the desired compound are obtained, yield 80%. Mp.: 111°-113° C.
Reaction SMILES: [Se](=O)=[O:2].[C:4]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[CH3:12])(=[O:6])[CH3:5]>O1CCOCC1.O>[CH3:12][C:11]1[CH:10]=[CH:9][S:8][C:7]=1[C:4](=[O:6])[CH:5]=[O:2]
Reactant: O=[Se]=O
Reactant: CC(=O)c1sccc1C
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccsc1C(=O)C=O

Procedure:
A 34.9 g portion of selenium dioxide was dissolved in a mixture of 85 ml of dioxane and 10 ml of water with stirring and heating to 55°-60° C. A 40 g portion of -acetyl-3-methylthiophene was added and the mixture was refluxed for 6 hours, then cooled, diluted with dioxane, filtered and evaporated to dryness. The residue was dissolved in ether and the crystals which formed collected, giving 12.03 g of 3-methyl-α-oxo-2-thiopheneacetaldehyde.
Reaction SMILES: [O:1]=[C:2]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:14][C:15]([OH:17])=[O:16].S(=O)(=O)(O)O.[OH-].[Na+].[CH3:25]O>[O-]S([O-])(=O)=O.[Na+].[Na+]>[CH3:25][O:16][C:15](=[O:17])[CH2:14][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:2]1=[O:1]
Reactant: O=C(O)CC1CCCCCCCCCCC1=O
Reactant: CO
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: COC(=O)CC1CCCCCCCCCCC1=O
Yield: 97 %

Procedure:
One hundred seventy-five grams (0.73 mol) of the ketomono acid from step 3 and 440 ml of methanol were refluxed with agitation for 3 hours with the addition of 7.3 gm of concentrated sulfuric acid. The cooled solution was neutralized with 50% sodium hydroxide solution and then methanol and water were completely removed. The residue contained, in addition to small amounts of salt (approximately 10 gm of Na2SO4), approximately 180 gm of ketomonoester (IX) (97% yield), which was further reacted in that form.
Reaction SMILES: [C:1]([NH:11][C@@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:17][O:18][C:19](=[O:25])[C@@H:20]1[CH2:24][CH2:23][CH2:22][NH:21]1.Cl.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.O>[CH3:17][O:18][C:19](=[O:25])[C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:14](=[O:16])[C@@H:12]([CH3:13])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of N-CBZ-D-alanine (28.1 g, 0.149 mol) in DMF (250 mL) at 0° C., was added L-proline-methylester.HCl (24.6 g, 0.149 mmol), 1-hydroxybenzotriazole hydrate (22.2 g, 0.164 mmol), ethyl-3-(3-dimethylamino)-propyl carbodiimide.HCl (31.4 g, 0.164 mmol) and 4-methylmorpholine (22.6 g, 0.224 mmol). The reaction mixture was stirred for 12 h while allowing the reaction to warm to room temperature. The reaction mixture was poured in water (750 mL) and extracted with ethyl acetate (2×150 mL). The combined organic extracts were washed as follows: KHSO4 (0.25M, 2×50 mL), water (1×50 mL), saturated aqueous NaHCO3 (2×50 mL) and saturated NaCl (1×50 mL). The organic layer was dried over MgSO4, filtered and the solvent removed in vacuo to give the title compound, 41.16 g (92%), as an oil. MS (M+H)+ =301+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[N:17]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[N:17]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: Nc1nc(-c2ccc(Cl)c(Cl)c2)cs1
Product: O=C(Nc1nc(-c2ccc(Cl)c(Cl)c2)cs1)c1cc(Cl)ccc1O
Yield: 15.1 %

Procedure:
Using 5-chlorosalicylic acid and 2-amino-4-(3,4-dichlorophenyl)thiazole as the raw materials, the same operation as the Example 16 gave the title compound.
Reaction SMILES: [OH-].[Na+].C1(S([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([C:21]3[N:22]=[C:23]([N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[C:24]4[N:29]=[C:28]([CH2:30][N:31]5[CH2:34][CH:33]([N:35]6[CH2:40][CH2:39][O:38][CH2:37][CH2:36]6)[CH2:32]5)[S:27][C:25]=4[N:26]=3)=[CH:13]2)(=O)=O)C=CC=CC=1>O1CCOCC1>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]2[N:22]=[C:23]([N:41]3[CH2:42][CH2:43][O:44][CH2:45][CH2:46]3)[C:24]3[N:29]=[C:28]([CH2:30][N:31]4[CH2:32][CH:33]([N:35]5[CH2:36][CH2:37][O:38][CH2:39][CH2:40]5)[CH2:34]4)[S:27][C:25]=3[N:26]=2)=[CH:13]1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2nc(N3CCOCC3)c3nc(CN4CC(N5CCOCC5)C4)sc3n2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: c1ccc2c(-c3nc(N4CCOCC4)c4nc(CN5CC(N6CCOCC6)C5)sc4n3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
A degassed solution of 5-chloro-7-morpholin-4-yl-2-(3-morpholin-4-yl-azetidin-1-ylmethyl)thiazolo[5,4-c]pyrimidine (210 mg, 0.51 mmol), 1-(phenylsulfonyl)-3-indoleboronic acid (231 mg, 0.77 mmol), Pd(PPh3)4 (60 mg, 0.052 mmol) and Cs2CO3 (332 mg, 1.03 mmol) in a mixture of 1,4-dioxane (8 mL) and water (4 mL) was subjected to microwave irradiation at 150° C. for 30 min. The reaction mixture was cooled to ambient temperature and loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The eluent was collected and concentrated to give 5-(1-benzenesulfonyl-1H-indol-3-yl)-7-morpholin-4-yl-2-(3-morpholin-4-yl-azetidin-1-ylmethyl)-thiazolo[5,4-c]pyrimidine as a crude oil. Aqueous NaOH (12.5 M, 0.6 mL) was added to a solution 5-(1-benzenesulfonyl-1H-indol-3-yl)-7-morpholin-4-yl-2-(3-morpholin-4-yl-azetidin-1-ylmethyl)thiazolo[5,4-d]pyrimidine in 1,4-dioxane (6 mL) and IMS (6 mL). The reaction mixture was stirred at ambient temperature for 1 h, then concentrated in vacuo. The resultant residue was dissolved in MeOH then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The eluent was collected and concentrated to afford a sticky solid. The solid was purified by flash chromatography (Si-PPC, DCM: MeOH, 100:0 to 98:2 to 95:5) followed by trituration from hot MeOH to afford 117 as a tan solid (117 mg, 47%). LCMS (Method E): RT=7.47 min, [M+H]+ 492.2. 1H NMR (CDCl3, 400 MHz): δ 8.65-8.60 (m, 1H); 8.44 (s, 1H); 8.13 (d, J=2.8 Hz, 1H); 7.44-7.39 (m, 1H); 7.31-7.25 (m, 2H); 4.43 (t, J=4.6 Hz, 4H); 3.99 (s, 2H); 3.91 (t, J=4.7 Hz, 4H); 3.73 (t, J=4.5 Hz, 4H); 3.66 (t, J=5.8 Hz, 2H); 3.18-3.07 (m, 3H); 2.40-2.31 (m, 4H)
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([OH:13])=O.[O:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][NH2:24])[CH2:17][CH2:16]1>>[CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([NH:24][CH2:23][CH2:22][CH2:21][N:18]1[CH2:19][CH2:20][O:15][CH2:16][CH2:17]1)=[O:13]
Reactant: Cc1[nH]c2c(c1C(=O)O)CCCC2=O
Reactant: NCCCN1CCOCC1
Product: Cc1[nH]c2c(c1C(=O)NCCCN1CCOCC1)CCCC2=O
Yield: 84.5 %

Procedure:
Similar procedure as Example 2, 2-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (S4) 0.2 g (1.0 mmol) and 3-morpholinopropan-1-amine 0.30 g (2.1 mmol) was reacted to give 0.27 g (85%) of the titled compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]4([C:28]([O:30]C)=[O:29])[CH2:27][CH2:26][CH2:25]4)[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]4([C:28]([OH:30])=[O:29])[CH2:27][CH2:26][CH2:25]4)[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)C1(Oc2ccc(Cl)cc2C2CC(=O)NC(c3cc(F)ccc3C)C23C(=O)Nc2cc(Cl)ccc23)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC2(C(=O)O)CCC2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 70 °C
Yield: 90.9 %

Procedure:
To a mixture of racemic (2′R,3R,4′S)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-cyclobutoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (200 mg, 0.33 mmol) in methanol (4 mL) was added a solution of NaOH (40 mg, 1 mmol) in water (2 mL). The mixture was heated at 70° C. for 2 h, evaporated to remove methanol, cooled to room temperature, and acidified to “pH” 1 with HCl aq. The precipitate was collected, washed with water and dried to give the title compound as a white solid (175 mg).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH:15]([O:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][C:30]([O:32]CC[Si](C)(C)C)=[O:31])=[CH:23][CH:22]=3)[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:40][C:2]([F:1])([F:39])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[C:13]([CH:15]([O:20][C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:25][CH:26]=3)[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCCCC(Oc1ccc(CCCC(=O)OCC[Si](C)(C)C)cc1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCCC(Oc1ccc(CCCC(=O)O)cc1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 17.5 h
Yield: 19.4 %

Procedure:
To a stirred solution of 2-(trimethylsilyl)ethyl 4-{4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}butanoate (42 mg, 0.07 mmol) in THF at rt was added, drop-wise, TBAF (70 μL of a 1.0M solution in THF, 0.07 mmol) and the mixture stirred at rt for 1.5 hours. Additional TBAF (35 μL of a 1.0M solution in THF, 0.04 mmol) was then added and the mixture left to stir at rt for 17.5 hours. The mixture was then concentrated under vacuum and the residue purified by SPE (silica, 1 g Cartridge) eluting with cyclohexane:EtOAc (gradient 25:1 to 0:1), then EtOAc:MeOH (gradient 10:1 to 0:1) to give a crude product which was purified further by mass directed auto-prep HPLC to give the title compound (6.4 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([C:12]2[N:16]=[CH:15][N:14](/[CH:17]=[CH:18]\[C:19]([O:21]C(C)C)=[O:20])[N:13]=2)=[CH:4][C:3]=1[C:25]([F:28])([F:27])[F:26].C1COCC1.[Li+].[OH-].Cl>O>[Cl:1][C:2]1[C:7]([C:8]([F:9])([F:11])[F:10])=[CH:6][C:5]([C:12]2[N:16]=[CH:15][N:14](/[CH:17]=[CH:18]\[C:19]([OH:21])=[O:20])[N:13]=2)=[CH:4][C:3]=1[C:25]([F:26])([F:27])[F:28]
Reactant: CC(C)OC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)c(Cl)c(C(F)(F)F)c2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)c(Cl)c(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.7 %

Procedure:
A 25-mL, 3-necked, round-bottomed flask was charged with a solution of (Z)-isopropyl 3-(3-(4-chloro-3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylate (1.33 g) in 1:1 THF:water (26 mL). The solution was treated with solid LiOH (0.53 g, 4 eq.) and stirred at room temperature for 4 h before being diluted with 400 ml water, acidified to pH=2-3 with dilute aqueous HCl, and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 0.8 g of crude compound (yield: 66%).
Reaction SMILES: C([C:5]1([C:18]([NH2:20])=[O:19])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][NH:6]1)=[CH:16][CH:15]=[CH:14][CH:13]=3)(C)(C)C.[CH2:21]([O:28][C:29]([NH:31][C@@H:32]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@@H:33]1[O:35][CH2:34]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([O:28][C:29]([NH:31][C@@H:32]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:33]([OH:35])[CH2:34][N:6]1[CH2:7][CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:5]1[C:18]([NH:20][C:9]([CH3:17])([CH3:10])[CH3:8])=[O:19])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)C1(C(N)=O)NCCc2c1[nH]c1ccccc21
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H]1CO1)OCc1ccccc1
Product: CC(C)(C)NC(=O)C1c2[nH]c3ccccc3c2CCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1

Procedure:
A solution of 0.60 g of tert.butyl 1,2,3,4-tetrahydropyrido[3,4-b]indole-1-carboxamide and 0.66 g of 3(S)-(benzyloxyformamido)-1,2(S)-epoxy-4-phenylbutane in 20 ml of methanolwas heated at reflux under argon for 16 hours and then evaporated to give aclear oil. The two diastereomeric products were separated by flash chromatography on silica gel using n-hexane/ethyl acetate (3:1) for the elution. There were obtained 268 mg of isomer A of 2-[3(S)-(benzyloxyformamido)-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-1,2,3,4-tetrahydropyrido[3,4-b]indole-1-carboxamide, MS: m/e 569 [M+H]+ and 65 mg of isomer B of the same compound; MS: m/e 569 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1.Cl.N>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][NH:20]4)=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)cn1
Agent: Cl
Agent: N
Product: COc1ccc(Nc2ncccc2-c2ncnc3[nH]cnc23)cn1
Reaction time: 8 h
Yield: 80.1 %

Procedure:
A solution of 6-methoxy-N-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)pyridin-3-amine (190 mg, 471 μmol) in 2N aqueous HCl (2.0 mL, 4 mmol) was heated briefly at 100° C. in an oil bath, and then the heater was turned off and the mixture allowed to slowly cool and stand overnight. An essentially clean conversion was observed. The solution was neutralized with aqueous ammonia, and the precipitated product was collected by filtration washing with a small volume of water and dried under vacuum. N-(6-Methoxypyridin-3-yl)-3-(9H-purin-6-yl)pyridin-2-amine (120.4 mg, 80.1% yield) was obtained as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ 13.80 (br. s., 1H); 12.33 (br. s., 1H); 9.73 (br. s., 1H); 9.10 (s, 1H); 8.70 (s, 1H); 8.50-8.58 (m, 1H); 8.25-8.34 (m, 1H); 8.08-8.20 (m, 1H); 6.95-7.07 (m, 1H); 6.79-6.90 (m, 1H); 3.85 (s, 3H). m/z (ESI, +ve) 320.0 (M+H)+.
Reaction SMILES: C[Li].Br[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[N:13][N:14]=2)=[CH:6][CH:5]=1.C([Li])CCC.C([O:23][B:24](OC(C)C)[O:25]C(C)C)(C)C>O1CCCC1.O.C(O)(=O)C>[O:11]1[CH:12]=[N:13][N:14]=[C:10]1[C:7]1[CH:8]=[CH:9][C:4]([B:24]([OH:25])[OH:23])=[CH:5][CH:6]=1
Reactant: Brc1ccc(-c2nnco2)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]C
Agent: [Li]CCCC
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: OB(O)c1ccc(-c2nnco2)cc1
Temperature: -65 °C
Yield: 82 %

Procedure:
A solution of methyllithium (8% w/w in diethoxymethane) (65 ml) was added to a suspension of 2-(4-bromophenyl)-1,3,4-oxadiazole (40 g) in tetrahydrofuran (THF) (415 ml) at −65° C. After an hour a solution of n-butyllithium (2.5M in hexanes) (78 ml) was then added at −65° C. After an hour, triisopropylborate (90 ml)) was then added maintaining the reaction mixture at −65° C. The reaction mixture was held at −65° C. for an hour and then warmed to −20° C. and drowned out into a mixture of acetic acid (28 ml) in water (222 ml). The resultant solid was isolated, washed with THF and water, and dried to yield the title compound (28.96 g@ 95.1% w/w, 82%); 400 MHz NMR Spectrum: (DMSOd6) 8.00 (s, 4H), 8.31 (s, 2H), 9.35 (s, 1H); Mass Spectrum MH+ 191.0628 (calc. using 11-B) Found 191.0633.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+]>O.CCOC(C)=O>[CH3:8][C:6]1[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]2=[C:2]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:7]=1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(N2CCNCC2)c2nc(-c3ccccc3)cc-2[nH]1
Temperature: 25 °C
Yield: 29.1 %

Procedure:
This compound was prepared according to the method described in Example 26 by employing 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (0.10 g, 0.41 mmol), piperazine (Aldrich Chemical Company) (0.382 g, 4.43 mmol) and K2CO3 (0.34 g, 2.50 mmol) in H2O (2.5 mL) to give crude pink solids. These solids were taken up in hot EtOAc, cooled to room temperature, and the impurities were removed by filtration. The filtrate was concentrated to give 0.035 g (29%) of the title compound as an off-white solid. Mp: 236° C. 1H NMR (DMSO-d6; 500 MHz): δ 2.42 (s, 3), 2.85 (t, 4, J=5.2), 3.62 (t, 4, J=5.2), 6.77 (s, 1), 7.36 (m, 1), 7.45 (t, 2, J=7.8), 7.95 (d, 2, J=7.6), 10.96 (s, 1); MS m/z: 294 (M+1). Anal. Calcd for C17H19N5O.0.5 H2O: C 67.53, H 6.67, N 23.16. Found: C 67.35, H 6.59, N 23.01.
Reaction SMILES: [C:1]([O:9][CH:10]([C@@H:13]1[CH2:17][C@@H:16](OC(OC2C=CC=CC=2)=S)[C@H:15]([N:28]2[C:32]3[N:33]=[C:34]([NH2:38])[NH:35][C:36](=[O:37])[C:31]=3[S:30][C:29]2=[O:39])[O:14]1)[CH2:11][CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(C(C)(C)C#N)=N[C:42](C)([CH3:45])[C:43]#N.C([Sn](CCCC)(CCCC)CCCC)C=C>C1(C)C=CC=CC=1>[C:1]([O:9][CH:10]([C@@H:13]1[CH2:17][C@@H:16]([CH2:45][CH:42]=[CH2:43])[C@H:15]([N:28]2[C:32]3[N:33]=[C:34]([NH2:38])[NH:35][C:36](=[O:37])[C:31]=3[S:30][C:29]2=[O:39])[O:14]1)[CH2:11][CH3:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Reactant: CCC(OC(=O)c1ccccc1)[C@@H]1C[C@@H](OC(=S)Oc2ccccc2)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Agent: C=CC[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=CC[C@@H]1C[C@@H](C(CC)OC(=O)c2ccccc2)O[C@H]1n1c(=O)sc2c(=O)[nH]c(N)nc21
Temperature: 80 °C
Reaction time: 4 h
Yield: 179.6 %

Procedure:
A mixture of 1-[(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-phenoxycarbothioyloxy-tetrahydrofuran-2-yl]propyl benzoate (compound 26e, 1.14 g, 2.0 mmol), 2,2′-azobisisobutyronitrile (168 mg, 1 mmol) and allyl(tributyl)stannane (3.08 mL, 10 mmol) in anhydrous toluene (15 mL) was degassed with argon and then heated with stirring at 80° C. for 4 hours. The resulting mixture was stirred with saturated aqueous NH4F at room temperature for 2 hours and extracted with DCM twice. The combined organic layers were dried over Na2SO4, concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 1:3 EtOAc in petroleum ether) to afford 820 mg of 1-[(2S,4R,5R)-4-allyl-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-2-yl]propyl benzoate (compound 26f) as a brown solid. MS obsd. (ESI+) [(M+H)+]: 457.