Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCN(CC1)CC2.[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19].Cl>C(OCC)(=O)C>[OH:8][CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:18](=[CH2:19])[C:17]([O:21][CH3:22])=[O:20]
Reactant: C=CC(=O)OC
Reactant: O=Cc1ccccc1
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: CCOC(C)=O
Product: C=C(C(=O)OC)C(O)c1ccccc1
Yield: 87.3 %

Procedure:
106 g (1 mol) of benzaldehyde (available from Nakarai Tesk K. K.), 11.2 g (0.1 mol) of 1,4-diazabicyclo[2,2,2]octane (available from Nacalai Tesque Inc.), and 90 ml (1 mol) of methyl acrylate (available from Nacalai Tesque Inc.) were stirred at room temperature over 7 days. To the reaction solution were then added 200 ml of a 6N hydrochloric acid and 200 ml of ethyl acetate so that an organic phase was extracted. The resulting organic phase was washed with a 10% brine, and then dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was distilled under reduced pressure to obtain 167.8 g of the desired compound in the form of 99% purity colorless oily matter. When allowed to stand, the product was solidified. The product exhibited a melting point of from 34° to 36° C. (Yield: 87%)
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[C:10]([N:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:31])[CH2:24][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH2:19][CH2:18]3)[N:9]=2)[CH2:4][CH2:3]1.CCO.[NH4+].[Cl-].C([O-])(O)=O.[Na+]>[Fe].O>[NH2:14][C:13]1[C:8]([N:5]2[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]2)=[N:9][C:10]([N:17]2[CH2:18][CH2:19][N:20]([C:23](=[O:31])[CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH2:21][CH2:22]2)=[CH:11][CH:12]=1
Reactant: CC1CCN(c2nc(N3CCN(C(=O)CN4CCOCC4)CC3)ccc2[N+](=O)[O-])CC1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC1CCN(c2nc(N3CCN(C(=O)CN4CCOCC4)CC3)ccc2N)CC1
Temperature: 100 °C
Yield: 100 %

Procedure:
A solution of 1-[4-(4-methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl)-piperazin-1-yl]-2-morpholin-4-yl-ethanone (as prepared in the previous step, 0.16 g, 0.37 mmol) in 2:1 EtOH:water (3 mL) was treated with NH4Cl (0.20 g, 3.7 mmol) and iron powder (0.10 g, 1.8 mmol). The reaction was heated to 100° C. for 50 min then cooled to room temperature. The mixture was neutralized with saturated aqueous NaHCO3 and extracted with CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford the title compound (0.14 g, 100%), which was immediately used in the next reaction.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:3]=1[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[CH3:19][O:20][C:21]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC>[C:8]([O:7][C:6]([NH:5][CH2:4][C:3]1[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:2]=1[C:28]1[CH:29]=[CH:30][C:21]([O:20][CH3:19])=[C:22]([CH:27]=1)[C:23]([O:25][CH3:26])=[O:24])=[O:12])([CH3:11])([CH3:10])[CH3:9]
Reactant: COc1ccc(Br)c(CNC(=O)OC(C)(C)C)c1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)ccc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)c1cc(-c2ccc(OC)cc2CNC(=O)OC(C)(C)C)ccc1OC
Temperature: 80 °C
Yield: 112.5 %

Procedure:
570 mg of t-butyl N-(2-bromo-5-methoxybenzyl)carbamate, 440 mg of methyl 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate, 86 mg of dichlorobistriphenyl phosphinoferrocene palladium and 1.0 g of potassium carbonate were dissolved in 15 ml of dimethoxyethane, and the mixture was heated at 80° C. for 24 hours in a nitrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was evaporated. The residue was purified by silica gel column, to give 680 mg of the title compound in the 3:1 hexane-ethyl acetate fraction.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=S)[CH2:15][C:16]2[N:17]=[CH:18][N:19]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][CH2:14][CH2:15][C:16]2[N:17]=[CH:18][N:19]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=S)Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](NCCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-N-[1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-2-[1-(triphenylmethyl)-1H-imidazol-4-yl]thioacetamide, as described above in Step D, 1.29 g, 2.33 mmol) in TBF (65 mL) and MeOH (65 mL), was added NiCl2.6H2O (2.22 g, 9.33 mmol). The mixture was cooled to 0° C. and NaBH4 (2 M in THF, 4.7 mL, 9.33 mmol) was slowly added. After 30 min, the solvent was partially removed in vacuo, and the residual mixture was partitioned between saturated aqueous Na2CO3 containing NH4OH and Et2O. The organic layer was removed and the aqueous layer was further extracted with EtOAc (2×). The combined organic extracts were combined, dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with a gradient of CH2Cl2—1% to 10% MeOH—0.1% to 1% NH4OH, to yield the above-titled compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].[Br:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[C:15]([F:20])=[C:14]([F:21])[C:13]=1[S:22](Cl)(=[O:24])=[O:23]>>[Br:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[C:15]([F:20])=[C:14]([F:21])[C:13]=1[S:22]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:2]([OH:1])[CH:3]=1)(=[O:24])=[O:23]
Reactant: COc1ccc(N)cc1O
Reactant: O=S(=O)(Cl)c1c(F)c(F)c(F)c(F)c1Br
Product: COc1ccc(NS(=O)(=O)c2c(F)c(F)c(F)c(F)c2Br)cc1O

Procedure:
The title compound was prepared in a manner similar to that described in Example 1 by replacing p-anisidine with 3-hydroxy-4-methoxyaniline and replacing 4-fluoro-3-nitrophenylsulfonyl chloride with 2-bromo-3,4,5,6-tetrafluorophenylsulfonyl chloride (Example F). 1H-NMR (CDCl3): δ 7.28 (br s, 1H), 6.69 (m, 3H), 5.72 (s, 1H), 3.82 (s, 3H). MS (EI): 431 (20), 429 (20), 138 (100). Anal. Calcd. for C13H8BrF4NO4S: C, 36.30; H, 1.87; N, 3.26; S, 7.45. Found: C, 36.20; H, 1.90; N, 3.31; S, 7.39.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[C:4]([CH3:11])[CH:3]=1.[O:12]=[S:13]1(=[O:30])[CH2:18][CH2:17][N:16]2[CH2:19][CH2:20][CH2:21][C@@H:22]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:15]2=[N:14]1.N1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N.C(O[Cu]OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:29][C:26]2[CH:25]=[CH:24][C:23]([C@H:22]3[C:15]4=[N:14][S:13](=[O:30])(=[O:12])[CH2:18][CH2:17][N:16]4[CH2:19][CH2:20][CH2:21]3)=[CH:28][CH:27]=2)=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1B(O)O
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(O)cc3)C2=N1
Agent: CC(=O)O[Cu]OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1cc(Cl)ccc1Oc1ccc([C@@H]2CCCN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.1 %

Procedure:
A mixture of (4-chloro-2-methylphenyl)boronic acid (912 mg), 4-[(9S)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenol (500 mg), pyridine (3.60 ml), cesium carbonate (581 mg), diacetoxycopper (648 mg) and powdered 4A MS (5.00 g) in MeCN (18 ml) was stirred at room temperature overnight. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (37.0 mg) as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C(=O)([O-])[O-:13].[Na+].[Na+].O.[Mn]([O-])(=O)(=O)=O.[K+]>C(O)(=O)C>[N:7]1[C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[NH:4][C:3]=1[C:2]([OH:13])=[O:1]
Reactant: O=C([O-])[O-]
Reactant: OCc1nc2ccccc2[nH]1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1nc2ccccc2[nH]1

Procedure:
The 2-hydroxymethylbenzimidazole from Part A (4 gms.) was refluxed in a small amount of saturated sodium carbonate solution with addition of sufficient boiling water to dissolve it. A hot, dilute solution of 6.67 gms. of potassium permanganate then was added slowly with stirring. Upon completion of the addition, the resulting suspension was refluxed for 30 minutes. The resulting hot liquid was separated by filtration from manganese dioxide which had formed. The filtrate then was cooled and rendered acidic (pH 5.0) by addition of acetic acid. The resulting yellow precipitate was filtered, dried, and recrystallized from hot water to obtain 1.98 gms. of the title compound as fine yellow needles.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][C:11]([CH2:15][O:16][C:17]3[CH:28]=[CH:27][C:20]([C:21]([NH:23][CH2:24][CH2:25]O)=[O:22])=[CH:19][CH:18]=3)(O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O>C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH:12]=[C:11]([CH2:15][O:16][C:17]3[CH:28]=[CH:27][C:20]([C:21]4[O:22][CH2:25][CH2:24][N:23]=4)=[CH:19][CH:18]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(NCCO)c1ccc(OCC2(O)CCN(c3ccc(Cl)nn3)CC2)cc1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: Clc1ccc(N2CC=C(COc3ccc(C4=NCCO4)cc3)CC2)nn1
Reaction time: 8 h
Yield: 10.7 %

Procedure:
To a stirred and cooled mixture of 10 parts of 4-[[1-(6-chloro-3-pyridazinyl)-4-hydroxy-4-piperidinyl]methoxy]-N-(2-hydroxyethyl)benzamide and 228 parts of ethyl acetate were added dropwise 8.4 parts of thionyl chloride. Upon complete addition, stirring was continued first overnight at room temperature and then for 1 hour at 60° C. The reaction mixture was evaporated and the residue was dissolved in a solution of 20 parts of sodium hydrogen carbonate in 160 parts of ethanol. The whole was stirred overnight at reflux temperature. After evaporation, the residue was taken up in water. The precipitated product was filtered off and purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 1 part (10.7%) of 3-chloro-6-[4-[[4-(4,5-dihydro-2-oxazolyl)phenoxy]methyl]-3,6-dihydro-1(2H)-pyridinyl]pyridazine; mp. 176.0° C. (comp. 168).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([Cl:13])=[C:11]([CH2:14][O:15][CH3:16])[N:10]=[C:9]([S:17][CH3:18])[N:8]=1)(=O)=O.[CH3:21]B1OB(C)OB(C)O1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:12]1[C:11]([CH2:14][O:15][CH3:16])=[N:10][C:9]([S:17][CH3:18])=[N:8][C:7]=1[CH3:21]
Reactant: COCc1nc(SC)nc(OS(=O)(=O)C(F)(F)F)c1Cl
Reactant: CB1OB(C)OB(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COCc1nc(SC)nc(C)c1Cl
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A mixture of the title compound from Step B (1.00 g, 2.83 mmol), trimethyl boroxine (1.78 g, 14.18 mmol), Cs2CO3 (0.92 g, 2.83 mmol), and catalytic amount Pd(PPh3)4 was stirred at 140° C. under microwave for 1 h. The solvent was removed. CH2Cl2 and water were added. The organic was extracted with CH2Cl2 (3×10 mL), washed with brine and dried over Na2SO4. The residue was purified by column chromatography on silica gel Biotage 40M, eluting with EtOAc/hexane (1/9) to give as a colorless oil. 1H NMR (CDCl3, 500 MHz) δ 4.61 (s, 2H), 3.55 (s, 3H), 2.60 (s, 3H), 2.58 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH:18]([F:20])[F:19])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][NH:11][C:10](=[O:16])[CH:9]=2)[CH:7]=1.Br[CH:22]([CH3:26])[C:23]([OH:25])=[O:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH:18]([F:20])[F:19])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:22]([CH3:26])[C:23]([OH:25])=[O:24])[C:10](=[O:16])[CH:9]=2)[CH:7]=1
Reactant: CC(Br)C(=O)O
Reactant: COc1c[nH]c(=O)cc1-c1cc(Cl)ccc1OC(F)F
Product: COc1cn(C(C)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1OC(F)F

Procedure:
127 mg (0.42 mmol) of 4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxypyridin-2(1H)-one and 1.5 eq. of 2-bromopropanoic acid (racemate) were reacted according to General Method 4A at 90° C. Yield: 220 mg of crude product which was reacted in the next step without further purification
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1.C(N(CC)CC)C>C(O)CCC>[CH3:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)[N:3]=1
Reactant: COc1cccc(N)c1
Reactant: Cc1nc(Cl)c2[nH]cnc2n1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: COc1cccc(Nc2nc(C)nc3nc[nH]c23)c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a suspension of 2-methyl-6-chloropurine (1.69 g; 0.01 mol) and m-anisidine (1.23 g; 0.01 mol) in n-butanol (20 ml), triethylamine (3.5 ml; 0.025 mol) was added. The resulting thick suspension was stirred at 110° C. for 3 hours, when TLC showed the absence of starting material and the presence of desired product. The reaction mixture was then cooled to room temperature. The white precipitate was filtered off, rinsed with n-butanol (2×10 ml) and water (3×10 ml) and dried into constant weight. Yield: 1.92 g (75%). The crude product was purified as hydrochloride salt by the crystallization from 2.5 M methanolic hydrochloric acid. TLC (chloroform-methanol-NH4OH; 4:1:0.05): one single spot, free of starting material. HPLC purity: 99+%.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([Cl:10])=[CH:5][C:4]=1[NH2:11].O=[C:13]1[CH2:17][S:16][CH2:15][CH:14]1[C:18]([O:20]C)=O>C1(C)C=CC=CC=1>[Cl:9][C:7]1[C:6]([Cl:10])=[CH:5][C:4]2[NH:11][C:18](=[O:20])[C:14]3[CH2:15][S:16][CH2:17][C:13]=3[N:2]([CH3:1])[C:3]=2[CH:8]=1
Reactant: CNc1cc(Cl)c(Cl)cc1N
Reactant: COC(=O)C1CSCC1=O
Solvent: Cc1ccccc1
Product: CN1C2=C(CSC2)C(=O)Nc2cc(Cl)c(Cl)cc21

Procedure:
A solution of 2.7 g. of N-methyl-4,5-dichloro-o-phenylenediamine and 1.85 g. of methyl tetrahydro-4-oxo-3-thiophenecarboxylate in 150 ml. of toluene is heated under reflux for 3 hours during which 100 ml. of distillate is collected in a Dean-Stark trap. The solution is cooled and the solid which separates is recrystallized from ethyl acetate to give yellow crystals, m.p. 281°-283°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:21][C:20]([O:22][C@@H:23]3[CH2:27][O:26][C@@H:25]4[C@H:28]([O:31][Si](C(C)(C)C)(C)C)[CH2:29][O:30][C@H:24]34)=[N:19][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:21][C:20]([O:22][C@H:23]3[C@H:24]4[O:30][CH2:29][C@@H:28]([OH:31])[C@H:25]4[O:26][CH2:27]3)=[N:19][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(N4CCCC4)cc3)c(Cl)cc2[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(N4CCCC4)cc3)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
[(3R,3aR,6R,6aS)-3-[[6-chloro-5-(4-pyrrolidin-1-ylphenyl)-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy-tert-butyl-dimethyl-silane (31.8 mg, 0.057 mmol) and tetrabutylammonium fluoride 1.0 M in THF (0.6 ml, 0.600 mmol) were combined in a vial. The reaction mixture was a light amber solution that was stirred at room temperature. After 3.5 hours, the reaction mixture was partitioned between EtOAc (40 ml) and water (40 ml). The aqueous layer was extracted with EtOAc (2×20 ml) and a few milliliters of brine. The organic layers were combined, washed with brine (1×20 ml), dried over MgSO4, filtered, and evaporated under reduced pressure to give a pale yellow residue. The residue (loaded in DMSO/MeOH) was purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting (20 ml/min) with a 17 minute 20%-80% acetonitrile/water+0.05% TFA gradient followed by a 2 minute 80% acetonitrile/water+0.05% TFA flush. The product fractions were combined, frozen, and lyophilized to give the title compound as a yellow solid. LC-MS: calculated for C22H23ClN4O4 442.14 observed m/e: 443.19 (M+H)+ (Rt 1.09/2 min); 1H NMR δ (ppm) (500 MHz CD3OD): 8.01 (s, 1H), 7.54-7.56 (m, 2H), 6.72-6.74 (m, 2H), 5.59 (q, J=5.4 Hz, 1H), 4.97 (t, J=5.3 Hz, 1H), 4.48 (t, J=5.0 Hz, 1H), 4.27-4.31 (m, 1H), 4.13-4.19 (m, 2H), 3.88-3.91 (m, 1H), 3.60 (dd, J=9.1, 7.6 Hz, 1H), 3.37-3.40 (m, 4H), 2.08-2.10 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:20])[C:9]([NH:11][C:12]([CH3:19])([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=[O:14])=O)=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:9]2[O:14][C:13](=[O:15])[C:12]([CH:16]([CH3:18])[CH3:17])([CH3:19])[N:11]=2)[CH3:20])=[CH:4][CH:3]=1
Reactant: CC(C(=O)NC(C)(C(=O)O)C(C)C)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(C1=NC(C)(C(C)C)C(=O)O1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.5 %

Procedure:
3.7 g (12.5 mmol) of 2-[2-(4-chlorophenyl)-propanoylamino]-2,3-dimethylbutanoic acid was suspended in 50 ml of toluene. Thereto was added 2 g (19.6 mmol) of acetic anhydride. The mixture was refluxed with heating, to give rise to a reaction. The reaction was complete in 20 minutes. The reaction mixture was cooled to room temperature. 50 ml of water was added and phase separation was allowed to take place. The separated organic layer was washed with 30 ml of water and 30 ml of a saturated aqueous sodium bicarbonate solution, and then concentrated to obtain 3.2 g (yield=97%) of 2-[1-(4-chlorophenyl)ethyl]-4-isopropyl-4-methyl-1,3-oxazol-5-one.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=O)[CH2:9]1.Cl.[NH2:17][CH2:18][C:19]#[C:20][CH3:21].O1CCCC1>C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:9][C:10]2[N:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:11]=2[C:12](=[O:14])[CH2:13]1
Reactant: CC#CCN
Reactant: O=C1CC(=O)CC(c2ccccc2Br)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccnc2c1C(=O)CC(c1ccccc1Br)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.4 %

Procedure:
To a mixture of 5-(2-bromophenyl)cyclohexane-1,3-dione (1.5 g), 1-amino-2-butyne hydrochloride (0.59 g) and tetrahydrofuran (30 ml) was added triethylamine (0.57 g). The mixture was stirred at room temperature for 1 hour, refluxed for 13 hours and cooled, and insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated, and to the residue was added diphenylether. The mixture was stirred at 250° C. for 12 hours and cooled, and to the mixture was added diethylether. The mixture was extracted with 1N hydrochloric acid, and the aqueous layer was washed with diethylether, neutralized with 1N sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give crystals of 7-(2-bromophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.52 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(Cl)(Cl)Cl.C[C:21](C)([O-:23])C.[K+].C(=O)(O)[O-].[Na+]>CN(C=O)C.C1COCC1.CO.C(#N)C.O.FC(F)(F)S([O-])(=O)=O.[Ag+].C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:8][C:9]=1[CH:21]=[O:23])([O-:3])=[O:2]
Reactant: CC(C)(C)[O-]
Reactant: O=[N+]([O-])c1cccc(-c2ccccc2)c1
Agent: [Ag+]
Agent: O=C([O-])O
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: O=Cc1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
3-Nitrobiphenyl (3.0 g, 15 mmol), was dissolved in DMF (7.5 ml) and dry chloroform (16.5 mmol). This mixture was added dropwise to a stirred precooled mixture of potassium tert-butoxide (7.2 mg, 60 mmol) in DMF (20 ml) and THF (25 ml), at such a rate that the temperature was maintained between −69 and −73° C. When the addition was complete, the mixture was stirred for a further 1 minute then treated with acetic acid (1.5 ml) in methanol (5 ml) and allowed to warm to room temperature. The mixture was treated with saturated aqueous sodium bicarbonate (50 ml) and extracted with dichloromethane (3×5 ml), the combined organic phase dried (MgSO4), filtered and evaporated, then the residue purified by flash chromatography (ether-hexane). This gave a yellow material which consisted of between 30 and 50% of dichloromethylsubstituted 3-nitrobiphenyl and starting material. The mixture was dissolved in acetonitrile (10 ml) and treated with a solution of silver trifluoromethanesulphonate (15 mmol, 3.84 g) in water (5 ml). The mixture was heated to reflux for 16 h in the dark then cooled, the mixture concentrated in vacuo, filtered and the filtrate extracted with ether (3×50 ml). The combined organic phase was evaporated and purified by flash chromatography to give 3-nitrobiphenyl-4-carbaldehyde;
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].F[C:11]1[CH:12]=[CH:13][C:14]([N+:20]([O-:22])=[O:21])=[C:15]([CH:19]=1)[C:16]([OH:18])=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C>[N+:20]([C:14]1[CH:13]=[CH:12][C:11]([O:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:19][C:15]=1[C:16]([OH:18])=[O:17])([O-:22])=[O:21]
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: Oc1ccc(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(O)c1cc(Oc2ccc(F)cc2F)ccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 70.4 %

Procedure:
The mixture of 2,4-difluorophenol 4 (20 g, 153.9 mmol), 5-fluoro-2nitrobenzoic acid 5, (28.5 g, 153.9 mmol), and cesium carbonate (100 g, 307.7 mmol) in DMF (310 mL) was heated in a 100° C. oil bath for 10 hrs. At the completion of the reaction, the mixture was cooled down to room temperature and was treated with 1 N HCl solution to bring pH to acidic, and was extracted with ethyl acetate. The organic layer was washed three times with 300 mL of water, dried, and concentrated to yield 32 g of 2-nitro-5-(2,4-difluorophenoxy)benzoic acid 6 as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C(=O)([O-])[O-].[K+].[K+].I[CH2:16][CH3:17].CCOCC>CN(C)C=O>[CH2:16]([S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[CH3:17]
Reactant: CCI
Reactant: Sc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCSc1ccccc1Br
Temperature: 57.5 °C
Reaction time: 12 h

Procedure:
To a suspension of 1.00 g (5.3 mmol) of 2-bromo-benzenethiol and 1.47 g (10.6 mmol) of potassium carbonate in 15 ml of N,N-dimethylformamide was added 1.65 g (10.6 mmol) of iodoethane at 0° C. The reaction mixture was stirred at 55-60° C. for 12 h and was poured into 200 ml of ether. It was washed with water (20 ml×3), dried over MgSO4 and concentrated to afford 1-ethylmercapto-2-bromobenzene as a colorless oil.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:29][CH2:30][CH3:31]>>[NH2:27][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:29][CH2:30][CH3:31])[CH2:20]1
Reactant: CCCI
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCCNC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCC3CCCN(CCC)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[4-(3-piperidinyl)butyl]-9H-purin-6-amine and 1-iodopropane.