Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]1[C:20]([N+:21]([O-])=O)=[C:19]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:18]=[C:17]([CH3:31])[C:16]=1[CH3:32].C(O)C>O>[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]1[C:16]([CH3:32])=[C:17]([CH3:31])[N:18]=[C:19]([O:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:20]=1[NH2:21]
Reactant: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCCCl)c1C
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1nc(Oc2ccccc2)c(N)c(NCCCCCl)c1C
Reaction time: 1.5 h
Yield: 87.4 %

Procedure:
A solution of sodium dithionite (35.13 g, 171.5 mmol), available as approximately 85% pure sodium hydrosulfite, in water (130 mL) was added to a mixture of N-(4-chlorobutyl)-2,3-dimethyl-5-nitro-6-phenoxypyridin-4-amine (12 g, 34 mmol) and ethanol (340 mL). The mixture was stirred for 1.5 hours. Analysis by thin layer chromatography indicated that the reaction was not complete. Solid sodium dithionite (5 g) was added and the reaction was allowed to stir for an additional 3 hours. The reaction mixture was filtered to remove solids. The filtrate was concentrated under reduced pressure until ˜50 mL of solvent remained. The residue was diluted with dichloromethane (300 mL), washed sequentially with aqueous sodium bicarbonate, water and brine, dried over magnesium sulfate, filtered and then concentrated under reduced pressure to provide 9.5 g of N4-(4-chlorobutyl)-5,6-dimethyl-2-phenoxypyridine-3,4-diamine as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18](O)=[O:19])[CH:12]=2.[Br:21][C:22]1[N:27]=[C:26]2[S:28][C:29]([NH2:31])=[N:30][C:25]2=[CH:24][CH:23]=1>>[Br:21][C:22]1[N:27]=[C:26]2[S:28][C:29]([NH:31][C:18]([C:13]3[CH:12]=[C:11]4[C:16]([CH:17]=[C:9]([C:3]5[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=5[Cl:1])[NH:10]4)=[CH:15][CH:14]=3)=[O:19])=[N:30][C:25]2=[CH:24][CH:23]=1
Reactant: Nc1nc2ccc(Br)nc2s1
Reactant: O=C(O)c1ccc2cc(-c3c(Cl)cccc3Cl)[nH]c2c1
Product: O=C(Nc1nc2ccc(Br)nc2s1)c1ccc2cc(-c3c(Cl)cccc3Cl)[nH]c2c1

Procedure:
The title compound was prepared from 2-(2,6-dichlorophenyl)-1H-indole-6-carboxylic acid and 5-bromothiazolo[5,4-b]pyridin-2-ylamine (WO 2007041365) analogous to Example 3-11. 1H NMR (DMSO-d6, 400 MHz): δ 13.08 (s, broad, 1H), 12.01 (s, broad, 1H) 8.33 (s, 1H), 8.11 (d, J=8.5 Hz, 1H), 7.86 (dd, J=8.5, 1.5 Hz, 1H), 7.71 (m, 4H), 7.56 (m, 1H), 6.65 (d, J=1.3 Hz, 1H). MS (m/z) 518.9 (M+1), Retention time=1.58 min (Method 10). High Res. MS: theory 516.9292; measured 516.9277.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH2:10][C@H:9]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]3[C:21]([F:34])=[CH:22][C:23](Br)=[C:24]([N:26]4[C:30](=[O:31])[N:29]([CH3:32])[N:28]=[N:27]4)[CH:25]=3)[N:13]=2)[CH2:8][C@H:7]2[N:3]1[CH2:4][CH2:5][CH2:6]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(C(C)C)CC)(C)C.[CH2:64]([OH:67])[C:65]#[CH:66]>[Cu]I.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[CH3:1][C:2]1([CH3:35])[CH2:10][C@H:9]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]3[C:21]([F:34])=[CH:22][C:23]([C:66]#[C:65][CH2:64][OH:67])=[C:24]([N:26]4[C:30](=[O:31])[N:29]([CH3:32])[N:28]=[N:27]4)[CH:25]=3)[N:13]=2)[CH2:8][C@H:7]2[N:3]1[CH2:4][CH2:5][CH2:6]2
Reactant: Cn1nnn(-c2cc(Nc3ncc(F)c(N[C@@H]4C[C@@H]5CCCN5C(C)(C)C4)n3)c(F)cc2Br)c1=O
Reactant: C#CCO
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cn1nnn(-c2cc(Nc3ncc(F)c(N[C@@H]4C[C@@H]5CCCN5C(C)(C)C4)n3)c(F)cc2C#CCO)c1=O
Temperature: 110 °C
Yield: 29.1 %

Procedure:
1-(5-(4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-5-fluoropyrimidin-2-ylamino)-2-bromo-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-one (304.5 mg, 0.55 mmol) was weighed out and added to a reaction tube with magnetic stir bar. Triphenylphosphine (43.5 mg, 0.17 mmol) and copper(I) iodide (12.9 mg, 0.068 mmol) were then weighed out and added. 11 mL dioxane was added, followed by diisopropylethylamine (0.65 mL, 3.73 mmol) and propargyl alcohol (0.054 mL, 0.93 mmol). The reaction was subjected to vigorous sub-surface nitrogen sparge and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (40.5 mg, 0.055 mmol) was weighed out and added, and the reaction was sealed under nitrogen. The reaction was heated overnight at 110° C. The reaction solution was then combined with a 0.186 mmol pilot reaction run under the same conditions, concentrated directly onto silica, and purified by column chromatography. Pure fractions were combined, concentrated, and dried under high vacuum to give 84.0 mg of the title compound (22% total).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C[O:9][C:10](=[O:49])[C@@H:11]([NH:18][C:19]([C@H:21]1[C@H:25]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=2[F:33])[C@:24]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=2[F:43])([C:34]#[N:35])[C@H:23]([CH2:44][C:45]([CH3:48])([CH3:47])[CH3:46])[NH:22]1)=[O:20])[CH2:12][C:13]1[N:14]=[CH:15][S:16][CH:17]=1.[Li+].[OH-]>C1COCC1.CO.O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:32][C:28]1[C:27]([F:33])=[C:26]([C@@H:25]2[C@:24]([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=3[F:43])([C:34]#[N:35])[C@H:23]([CH2:44][C:45]([CH3:48])([CH3:47])[CH3:46])[NH:22][C@H:21]2[C:19]([NH:18][C@@H:11]([CH2:12][C:13]2[N:14]=[CH:15][S:16][CH:17]=2)[C:10]([OH:49])=[O:9])=[O:20])[CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)[C@H](Cc1cscn1)NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)N[C@@H](Cc2cscn2)C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.7 %

Procedure:
A mixture of chiral (S)-2-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-thiazol-4-yl-propionic acid methyl ester trifluoroacetate salt (112 mg, 0.176 mmol) was dissolved in THF (3 mL) and methanol (1 mL), then 2N LiOH (1 mL) was added and stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with ethyl acetate (2×), the organic phase was separated then concentrated under reduced pressure to afford the crude product that was purified by RP-HPLC (20-95% acetonitrile/water). The solvent was evaporated under reduced pressure to afford chiral (S)-2-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-thiazol-4-yl-propionic acid trifluoroacetate salt as a white powder (41 mg, 37.9%). HRMS (ES+) m/z Calcd for C29H28Cl2F2N4O3S+H [(M+H)+]: 621.1300. found: 621.1298.
Reaction SMILES: N([O-])=O.[Na+].Cl.[CH:6]1([C:11]2[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=2)N)[CH2:10][CH2:9][CH2:8][CH2:7]1.[I-:18].[K+].[OH-].[Na+]>O.Cl>[CH:6]1([C:11]2[CH:17]=[CH:16][CH:15]=[C:13]([I:18])[CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: [I-]
Reactant: Nc1cccc(C2CCCC2)c1
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: Ic1cccc(C2CCCC2)c1
Temperature: 70 °C
Reaction time: 0.83 h
Yield: 60 %

Procedure:
A solution of sodium nitrite (558 mg, 8.1 mmol) in water (10 ml) was added over 5 minutes to a cooled (5° C.) solution of 3-cyclopentyl-aniline hydrochloride (1 g, 5.1 mmol) in 6N HCl (25 ml). After 50 minutes, a solution of potassium iodide (2.02 g, 12.2 mmol) in water (10 ml) was added over 5 minutes. The mixture was then heated for 1 h at 70° C. After cooling down to room temperature, the pH was set over 11 with 6N NaOH, and the mixture was extracted three times with CH2Cl2 (3×100 ml). The combined organic layers were washed with sodium thiosulfate (75 ml) then brine (75 ml) and dried over MgSO4. The solvent was removed under reduced pressure to give 1.23 g of crude material (HPLC: 67%) which was purified by chromatography over silica gel (eluent:cyclohexane) to yield the above titled compound as an oil: 825 mg, yield: 60%.
Reaction SMILES: [CH2:1]([C@H:8]1[C@H:12]([CH2:13][CH:14]([NH:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:15][C:16]2[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=2)[O:11][C:10]([CH3:35])([CH3:34])[N:9]1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:43][C:44]1[CH:45]=[CH:46][C:47]([Sn](CCCC)(CCCC)CCCC)=[N:48][CH:49]=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C@H:8]1[C@H:12]([CH2:13][CH:14]([NH:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:47]3[CH:46]=[CH:45][C:44]([CH3:43])=[CH:49][N:48]=3)=[CH:18][CH:17]=2)[O:11][C:10]([CH3:35])([CH3:34])[N:9]1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cn1
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccccc2)[C@H](CC(Cc2ccc(Br)cc2)NC(=O)OCc2ccccc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc(CC(C[C@@H]3OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]3Cc3ccccc3)NC(=O)OCc3ccccc3)cc2)nc1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
A solution containing the product from Example 128B (0.50 g, 0.78 mmol) in DMF (8 mL) was treated with dichlorobis(triphenylphosphine)palladium(II) (0.165 g, 0.235 mmol), and the product from Example 74A (0.60 g, 1.63 mmol), stirred at 100° C. for 6 hours, cooled to 25° C., filtered through celite®, and partitioned between ethyl acetate and water. The organic was washed with brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-15% ethyl acetate in chloroform to give the product (0.322 g, 63% yield).
Reaction SMILES: C([O:3][C:4]([C@@:6]1([CH3:19])[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7]1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[CH2:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@@:6]([CH2:4][OH:3])([CH3:19])[CH2:7]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)[C@@]1(C)CCCN(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@]1(CO)CCCN(Cc2ccccc2)C1
Yield: 93.4 %

Procedure:
(S)-1-Benzyl-3-methylpiperidine-3-carboxylic acid ethyl ester (1.64 g, 6.3 mmol) in dry THF (20 ml) was slowly added to a stirred suspension of LiAlH4 (0.71 g, 18.8 mmol) in dry THF (20 ml) under nitrogen atmosphere. After the addition the mixture was refluxed for 1.5 h. The solution was cooled with an ice bath, stirred vigorously and 2.5 M NaOH was added carefully drop by drop until no reaction occurred and a white precipitate was formed. The solvent was decanted and the solid washed with EtOAc (2×20 ml). The combined organic phases were dried, filtered and evaporated to dryness to give 1.29 g of the alcohol product as a white powder.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9](CC3C=CC(OC)=CC=3OC)[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]2[NH:31]C(=O)OC(C)(C)C)[N:3]=1.[CH3:39][C:40]1[N:41]=[CH:42][NH:43][CH:44]=1.C([O-])([O-])=O.[K+].[K+].[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]>C(#N)C>[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52].[NH2:31][C@H:26]1[CH2:27][CH2:28][CH2:29][CH2:30][C@H:25]1[NH:24][C:4]1[N:3]=[C:2]([N:43]2[CH:44]=[C:40]([CH3:39])[N:41]=[CH:42]2)[C:7]2[C:8](=[O:22])[NH:9][CH2:10][C:6]=2[C:5]=1[F:23]
Reactant: Cc1c[nH]cn1
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(Cl)c3C2=O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1cn(-c2nc(N[C@@H]3CCCC[C@@H]3N)c(F)c3c2C(=O)NC3)cn1
Temperature: 80 °C
Yield: 23 %

Procedure:
In a 10 mL sealed cap glass vial, tert-butyl (1S,2R)-2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (50 mg, 0.091 mmol), 4-methyl-1H-imidazole (22.43 mg, 0.273 mmol) and K2CO3 (50.3 mg, 0.364 mmol) were dissolved in ACN (2 mL). The cap was sealed and the mixture was reacted at 100° C. for 16 h. The reaction mixture was subsequently filtered through a Buchner funnel to remove un-dissolved solids. The solids were washed with ACN (2×5 mL) and the filtrate was evaporated to give a residue, which was treated with TFA (4 mL) and heated at 80° C. for 1 h to remove the protecting groups. Next, TFA was evaporated from the reaction mixture. The resulting residue was reconstituted in DMSO (5 mL) and purified via preparative HPLC eluting with water (0.05% TFA) and ACN (15-65% gradient, 0.035% TFA). The pure fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a white solid (7.2 mg, 23%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20-1.65 (m., 8H), 3.65-3.79 (m, 5H), 4.15 (s, 2H), 6.40 (d, 1H), 6.51 (d, 1H), 6.73 (m, 1H), 6.97 (d, 1H), 7.26 (d, 1H), 8.68 (br s, 1H). [M+H] calc'd for C17H21FN6O, 345. found, 345.
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](O)=[O:18])[CH2:8][C:7]2=1.C(N1C=CN=C1)([N:24]1C=CN=C1)=O>O1CCCC1>[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]([NH2:24])=[O:18])[CH2:8][C:7]2=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)C1CCc2[nH]c3ccc(OC(F)(F)F)cc3c2C1
Solvent: C1CCOC1
Product: NC(=O)C1CCc2[nH]c3ccc(OC(F)(F)F)cc3c2C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.6 %

Procedure:
A stirred solution of 6-(trifluoromethoxy)-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid of Step 2 (1.722 g, 5.75 mmol) in anhydrous tetrahydrofuran (37 mL) was treated under nitrogen with carbonyldiimidazole (1.37 g, 8.61 mmol). The yellow solution was stirred at room temperature for 5 hours and then anhydrous ammonia was bubbled through the solution for 30 minutes. The suspension was diluted with ethyl acetate and the organic phase was washed with 1:1 water/saturated aqueous sodium bicarbonate and 1:1 water/brine. The extracts were dried over anhydrous magnesium sulfate and evaporated to dryness to yield a pale yellow glass. The residue was purified by chromatography on silica gel Merck-60 using a 1% to 3% gradient of methanol in dichloromethane to provide the title compound (1.33 g, 77%) as an off white solid, m.p. 177-178° C. MS [(+)ES, m/z]: 299 [M+H]+. HRMS [(+)ESI, m/z]: 299.1004 [M+H]+. Calc'd for C14H14F3N2O2: 299.1007. HPLC: Chromolith Monolith column, 0.46×10 cm, gradient of acetonitrile in water (0.01% TFA), 4 mL/min, detection at 254 nm; Rt 1.8 min.
Reaction SMILES: [Br-].[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](=O)[CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[NH+:15]=3)Br)=[CH:10][C:5]=2[O:4][CH2:3]1.[NH2:22][C:23]([NH2:25])=[S:24].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:22]=[C:23]([NH2:25])[S:24][C:12]=3[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=3)=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: NC(N)=S
Reactant: Cc1cccc(C(Br)C(=O)c2ccc3c(c2)OCO3)[nH+]1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Product: Cc1cccc(-c2sc(N)nc2-c2ccc3c(c2)OCO3)n1
Temperature: 25 °C
Yield: 69.6 %

Procedure:
A solution of 2-(2-benzo[1,3]dioxol-5-yl-1-bromo-2-oxo-ethyl)-6-methyl-pyridinium bromide (30 mg, 0.072 mmol), thiourea (7.5 mg, 0.094 mmol, 1.3 equiv), and potassium carbonate (0.11 mmol, 1.5 equiv) in ethanol (1 mL) was heated to 80° C. overnight. The resulting reaction mixture was cooled to ambient temperature and concentrated in vacuo. Reverse phase high pressure liquid chromatography (a gradient from 5-30% acetonitrile in 0.1% aqueous formic acid) provided 4-Benzo[1,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-thiazol-2-ylamine (15.6 mg, 70%).[MS: M+H=312.0].
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH:14]=[O:15])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][Mg]Br>C1COCC1>[C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([CH:14]([OH:15])[CH3:17])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=O)CC1
Solvent: C1CCOC1
Product: CC(O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reaction time: 0.33 h

Procedure:
To the stirred solution of (trans)-(4-formyl-cyclohexyl)-carbamic acid tert-butyl ester (4.55 g, 20 mmol) in THF (250 ml) was added methylmagnesium bromide (3M in diethyl ether) (6.67 ml, 20 mmol) during 2 min at −70° C. Stirring was continued for 20 min at −70° C. and then quenched with 1M NH4Cl (200 ml). The mixture was extracted with TBME (2×). The organic phases were washed with brine and dried over Na2SO4, filtered and evaporated to dryness. Purification of the residue by normal phase column chromatography, eluting with EtOAc-heptane 1:1, gave the title compound after crystallization (diisopropyl ether-heptane) as a white solid (1.72 g, 7.0 mmol, 35%). TLC (EtOAc-heptane 1:1) Rf=0.37; 1H NMR (600 MHz, DMSO-d6): 0.86-1.81 (m, 9H), 0.99 (d, 3H), 1.36 (s, 9H), 3.09 (m, 1H), 3.32 (m, 1H), 4.27 (d, 1H), 6.67 (d, 1H)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[CH:7][C:8]([OH:10])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl-].[Mg+2].[Cl-].[K+].[C:27]([O:33][CH3:34])(=[O:32])[CH2:28]C([O-])=O.Cl>CN(C=O)C>[O:10]=[C:8]([CH:7]=[CH:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[CH2:28][C:27]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)CC(=O)[O-]
Reactant: O=C(O)C=Cc1nccs1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COC(=O)CC(=O)C=Cc1nccs1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97 %

Procedure:
Methyl 3-oxo-5-(1,3-thiazole-2-yl)-4-pentenoate was prepared from 3-(1,3-thazol-2-yl)-2-propenic acid (Bull. Chem. Soc. Jap. 1974, 47, 151.) according to the literature procedure (Heterocycles 1994, 38, 751.). To a stirred solution of 3-(1,3-thiazol-2-yl)-2-propenoic acid (100.0 g, 644.4 mmol) in DMF (1000 ml) was added 1,1′-carbonyldiimidazole (115.0 g, 708.9 mmol) in small portions. After stirring at room temperature for 5 h, to the reaction mixture were added anhydrous magnesium chloride (73.6 g, 773.0 mmol) and monomethyl malonate potassium salt (120.8 g, 773.0 mmol). The resulting suspension was heated at 55° C. with stirring for 14 h. After cooling to room temperature, the reaction mixture was poured into 1500 ml of 2 N HCl, and extracted with a mixture of EtOAc (1500 ml) and toluene (500 ml). The organic phase was separated and the aqueous phase was extracted with a 3:1 mixture of EtOAc and toluene (2000 ml). The combined organic phase was washed with H2O (1000 ml) and brine (1000 ml), dried (Na2SO4) and evaporated to afford 132.0 g of methyl 3-oxo-5-(1,3-thiazole-2-yl)-4-pentenoate (½ of keto/enol form)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:29])[CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[NH:21][C:20]2=[O:28])[CH2:15][CH2:14]1)([O-])=O>CN(C=O)C.CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:29])[CH2:12][N:13]1[CH2:14][CH2:15][CH:16]([N:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[NH:21][C:20]2=[O:28])[CH2:17][CH2:18]1
Reactant: O=C(CN1CCC(n2c(=O)[nH]c3ccccc32)CC1)Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)CN1CCC(n2c(=O)[nH]c3ccccc32)CC1

Procedure:
4 g (10.12 mmol) of 1-[2-(2-nitrophenyl)amino-2-oxoethyl]-4-(2-oxo-1-benzimidazolinyl)piperidine are dissolved in 40 ml of DMF. After addition of 400 mg of 10% Pd/C (Aldrich), the mixture is hydrogenated at 3 bar until reaction is complete (TLC). The catalyst is filtered off and all solvent is stripped off in a high vacuum. The crude product is coevaporated several times with methanol. The crystals obtained are stirred in methanol, filtered off with suction and dried at 30° C. in a high vacuum.
Reaction SMILES: C([O:9][CH2:10][C@@H:11]1[CH2:15][C@@H:14]([CH2:16][C:17]([CH3:19])=[CH2:18])[C@H:13]([N:20]2[C:24]3[N:25]=[C:26]([NH2:30])[NH:27][C:28](=[O:29])[C:23]=3[S:22][C:21]2=[O:31])[O:12]1)(=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CO>[NH2:30][C:26]1[NH:27][C:28](=[O:29])[C:23]2[S:22][C:21](=[O:31])[N:20]([C@H:13]3[C@H:14]([CH2:16][C:17]([CH3:19])=[CH2:18])[CH2:15][C@@H:11]([CH2:10][OH:9])[O:12]3)[C:24]=2[N:25]=1
Reactant: C=C(C)C[C@@H]1C[C@@H](COC(=O)c2ccccc2)O[C@H]1n1c(=O)sc2c(=O)[nH]c(N)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C=C(C)C[C@@H]1C[C@@H](CO)O[C@H]1n1c(=O)sc2c(=O)[nH]c(N)nc21
Yield: 29.6 %

Procedure:
A solution of [(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-(2-methylallyl)tetrahydrofuran-2-yl]methyl benzoate (compound 41b, 180 mg, 0.41 mmol) in methanol was stirred with K2CO3 (150 mg, 1.09 mmol) at room temperature for 4 hours. The reaction was quenched by addition of acetic acid and the resulting mixture was concentrated in vacuo. The residue was purified by preparative HPLC to afford 41 mg of 3-[(2R,3R,5S)-3-allyl-5-(hydroxymethyl)tetrahydrofuran-2-yl]-5-amino-6H-thiazolo[4,5-d]pyrimidine-2,7-dione (Example 41) as a white powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](Cl)=[O:15])[CH:5]=[CH:4][C:3]1=2.[OH:18][C:19]1[CH:28]=[C:27]([C:29]#[C:30][Si](C)(C)C)[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22]>>[OH:18][C:19]1[CH:28]=[C:27]([C:29]#[C:30][C:14](=[O:15])[C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:17])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=3[CH:7]=2)[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)Cl)ccc21
Reactant: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1O
Product: COC(=O)c1ccc(C#CC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1O

Procedure:
Following the basic procedure of Example 1(b), by reacting 2.4 g (0.01 mol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoyl chloride with 2.5 g (0.01 mol) of methyl 2-hydroxy-4-trimethylsilylethynylbenzoate, 2.9 g (74%) of the expected ester, with a melting point of 189°-190° C., were recovered.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]2[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)=[N:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].N([O-])=O.[Na+].[N-:32]=[N+:33]=[N-].[Na+].C(OCC)C>FC(F)(F)C(O)=O>[N:1]([C:2]1[C:3]([C:20]2[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)=[N:4][C:5]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)nc(-c2ccc(OC)nc2)c1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: COC(=O)c1cc(-c2ccc(OC)cc2)nc(-c2ccc(OC)nc2)c1N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
Methyl 3-amino-6′-methoxy-6-(4-methoxyphenyl)-2,3′-bipyridine-4-carboxylate (120 mg, 0.33 mmol) was dissolved in trifluoroacetic acid (1.6 mL) and the solution was cooled in an ice bath. Sodium nitrite (45 mg, 0.66 mmol) was added with stirring to give a dark red suspension. After 30 min, sodium azide (214 mg, 3.3 mmol) was added followed immediately by diethyl ether (1.6 mL). This was stirred in the ice bath for 30 min. and then partially concentrated on the rotary evaporator. The residue was partitioned between ethyl acetate and sufficient saturated aqueous sodium bicarbonate solution (gas evolution) to neutralize the mixture. The organic phase was separated, washed with brine, dried with sodium sulfate, and the solvent removed to leave methyl 3-azido-6′-methoxy-6-(4-methoxyphenyl)-2,3′-bipyridine-4-carboxylate (122 mg, 95% yield) as a yellow solid. MS (ESI) m/z 392.1 (M+H). 1H NMR (CDCl3) δ ppm 8.74 (1H, d, J=2.52 Hz), 8.13 (1H, dd, J=8.69, 2.39 Hz), 8.01 (2H, d, J=9.07 Hz), 7.98 (1H, s), 6.97 (2H, d, J=8.81 Hz), 6.85 (1H, d, J=8.81 Hz), 4.03 (3H, s), 4.01 (4H, s), 3.85 (3H, s).