Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:9]1)(=O)=O.[OH:22][C:23]1([C:29]2[CH:34]=[CH:33][C:32]3[O:35][CH2:36][O:37][C:31]=3[CH:30]=2)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:22][C:23]1([C:29]2[CH:34]=[CH:33][C:32]3[O:35][CH2:36][O:37][C:31]=3[CH:30]=2)[CH2:28][CH2:27][N:26]([CH2:6][CH2:7][CH:8]2[O:12][C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH2:9]2)[CH2:25][CH2:24]1
Reactant: COc1ccc(N2CC(CCOS(C)(=O)=O)OC2=O)cc1
Reactant: OC1(c2ccc3c(c2)OCO3)CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(N2CC(CCN3CCC(O)(c4ccc5c(c4)OCO5)CC3)OC2=O)cc1

Procedure:
4.10 g of 5-(2-methanesulfonyloxyethyl)-3-p-methoxyphenyloxazolidin-2-one [m.p. 61°-64°; obtainable by reaction of 3,4-epoxy-1-butanol with N-benzyl-p-methoxyaniline to give 1-(N-benzyl-p-methoxyanilino)butane-2,4-diol (resin), hydrogenolysis to give 1-p-methoxyanilinobutane-2,4-diol (resin), reaction with diethyl carbonate to give 5-(2-hydroxyethyl)-3-p-methoxyphenyloxazolidin-2-one (m.p. 77°-78°) and reaction with CH3SO2Cl] are boiled together with 3.13 g of 4-hydroxy-4-(3,4-methylenedioxyphenyl)piperidine ("M"), 2.16 g of potassium iodide and 1.8 g of potassium carbonate in 100 ml of acetonitrile for 16 hours, the mixture is cooled, worked up as usual, to give 5-[2-(4-hydroxy-4-(3,4-methylenedioxyphenyl)piperidino)ethyl]-3-p-methoxyphenyloxazolidin-2-one, m.p. 128°-130°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][Si](C=[N+]=[N-])(C)C>CO.C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:15])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)Cc1ccc(O)c([N+](=O)[O-])c1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
In methanol/toluene (1:10, 55 ml) was dissolved 4-hydroxy-3-nitrophenylacetic acid (2.0 g, 10.1 mmol). Trimethylsilyldiazomethane (2.0M hexane solution, 5.0 ml) was added dropwise to the resulting solution. After stirring at room temperature for 50 minutes, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was diluted with ethyl acetate. The ethyl acetate extract was then washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent, whereby the title compound (2.15 g, 100%) was obtained as a yellow solid (this compound was provided for the subsequent reaction without further purification).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[C:21]#[N:22])=[CH:4][C:5](=[O:13])[N:6]([CH:8]([CH3:12])[C:9]([OH:11])=O)[CH:7]=1.[F:23][C:24]([F:38])([F:37])[C:25]1[N:29]=[C:28]([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[NH:27][N:26]=1>>[Cl:1][C:2]1[C:3]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[C:21]#[N:22])=[CH:4][C:5](=[O:13])[N:6]([CH:8]([CH3:12])[C:9]([NH:34][C:33]2[CH:35]=[CH:36][C:30]([C:28]3[NH:27][N:26]=[C:25]([C:24]([F:38])([F:37])[F:23])[N:29]=3)=[CH:31][CH:32]=2)=[O:11])[CH:7]=1
Reactant: CC(C(=O)O)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: Nc1ccc(-c2nc(C(F)(F)F)n[nH]2)cc1
Product: CC(C(=O)Nc1ccc(-c2nc(C(F)(F)F)n[nH]2)cc1)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
126 mg (purity 66%, 0.25 mmol) of 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) (Example 12.1D) and 64 mg (0.27 mmol) of 4-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]aniline (Example 1.1C) were reacted according to General Method 1. Yield: 76 mg (57% of theory)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]([O:16][C:17]2[C:22]([CH:23]=CC)=[CH:21][CH:20]=[C:19]([F:26])[C:18]=2[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[CH3:34])[CH:14]=C)(=[O:10])=[O:9])=[CH:4][CH:3]=1>C(Cl)Cl.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH:14]=[CH:23][C:22]3[C:17](=[C:18]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=4[CH3:34])[C:19]([F:26])=[CH:20][CH:21]=3)[O:16]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: C=C[C@H](COS(=O)(=O)c1ccc(C)cc1)Oc1c(C=CC)ccc(F)c1-c1ccc(Cl)cc1C
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3ccc(F)c(-c4ccc(Cl)cc4C)c3O2)cc1
Yield: 40.5 %

Procedure:
Treatment of (2R)-2-(4′-chloro-6-fluoro-2′-methyl-3-(prop-1-enyl)biphenyl-2-yloxy)but-3-enyl 4-methylbenzenesulfonate (1.35 g, 2.69 mmol) with benzylidene-bis(tricyclohexylphosphine)dichlororuthenium (0.70 g, 0.85 mmol) in methylene chloride (30 mL) according to the procedure described for Example 69, Step 7 provided 0.5 g (41%) of ((2R)-8-(4-chloro-2-methylphenyl)-7-fluoro-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate as a brown oil.
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:20])[N:11]([CH3:19])[C:12](=[O:18])[N:13]([CH3:17])[C:14]=1[CH2:15]Br)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.C(N(CC)CC)C.[NH2:31][CH2:32][C@H:33]([OH:35])[CH3:34]>C(Cl)Cl.O>[OH:35][C@H:33]([CH3:34])[CH2:32][N:31]1[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:9]2[C:14]([N:13]([CH3:17])[C:12](=[O:18])[N:11]([CH3:19])[C:10]2=[O:20])=[CH:15]1
Reactant: C[C@@H](O)CN
Reactant: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: C[C@@H](O)Cn1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C
Temperature: 100 °C

Procedure:
5-Benzoyl-6-(bromomethyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (Intermediate C) (1 g 2.97 mmol) was added to a microwave vial (10-25 mL) equipped with a stirrer bar. To the vial was added ethanol (10 ml) followed by triethylamine (0.41 ml, 2.97 mmol) and (R)-1-aminopropan-2-ol (commercial). (223 mg, 2.97 mmol) The vial was heated to 100° C. in a microwave reactor for 1 h. The ethanol was removed in vacuo to yield a solid. The solid was dissolved in DCM and water added. The DCM water mixture was separated and the aqueous extracted with DCM (×2). The organics were combined, washed with water and passed through a hydrophobic frit. The solvent was removed in vacuo to yield the title compound as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:7]=1[CH2:8][CH3:9].[CH:16]([N-]C(C)C)(C)C.[Li+].CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C.CI>C1COCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:7]=1[CH:8]([CH3:16])[CH3:9]
Reactant: CCc1cc(-c2ccccc2)nnc1Cl
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CI
Product: CC(C)c1cc(-c2ccccc2)nnc1Cl
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A RBF was charged with 3-chloro-4-ethyl-6-phenylpyridazine (250 mg, 1.143 mmol) and 5.7 mL of THF, and the mixture was cooled to −78° C. under nitrogen. Lithium diisopropylamide, 2.0 M solution in heptane/tetrahydrofuran/ethylbenzene (0.686 mL, 1.372 mmol) was added, and the mixture was stirred for 5 min at −78° C., followed by 1 h at room temperature. The mixture was cooled back down to −78° C., and methyl iodide (195 mg, 1.372 mmol) that had been passed through a plug of basic alumina prior to use was added dropwise. The reaction was stirred at this temperature for 5 min, followed by RT for 0.5 h. After quenching with water, the solution was diluted with CH2Cl2 and the layers were separated. The aqueous portion was extracted with additional CH2Cl2 and the combined organics were dried with MgSO4, filtered and concentrated. The crude material was purified by silica gel chromatography (CH2Cl2— 10% MeOH/CH2Cl2) to provide 3-chloro-4-isopropyl-6-phenylpyridazine as a colorless oil, which crystallized upon standing. MS m/z=233 [M+H]+. Calc'd for C13H13ClN2: 232.71.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][C:4]#[CH:5].I[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14]>C(NCC)C>[CH3:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]#[C:4][CH2:3][CH2:2][CH2:1][OH:6]
Reactant: Cc1ccccc1I
Reactant: C#CCCCO
Solvent: CCNCC
Product: Cc1ccccc1C#CCCCO
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.4 %

Procedure:
A mixture of 4-pentyn-1-ol (1 g, 12.1 mmol), 2-iodotoluene (2.53 g, 11.6 mmol), dry diethylamine (20 ml), bis-triphenyl-phosphine palladium (II) chloride (150 mg) and cuprous iodide (60 mg) was stirred at room temperature under dry nitrogen for 24 hours. The solvent was removed and the residue extracted with ether. The organic phase was washed with brine and dried and the solvent removed. The crude product was purified by dry column chromatography (alumina, 9:1 hexane:ether 1:1 hexane:ether) to give 1.2 g (60% of theory) of 5-(2'-methylphenyl)-4-pentyn-1-ol as a brown oil.
Reaction SMILES: C(=O)([O-])O.[Na+].Cl.[NH2:7][OH:8].[C:9]([CH2:11][C@H:12]1[C@H:18]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[O:17][CH2:16][CH2:15][N:14]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:13]1)#[N:10].O>CS(C)=O>[NH2:10][C:9](=[N:7][OH:8])[CH2:11][C@H:12]1[C@H:18]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[O:17][CH2:16][CH2:15][N:14]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:13]1
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CC#N)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CC(N)=NO)C1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 108.1 %

Procedure:
Sodium hydrogen carbonate (872 mg, 10.38 mmol) was added to a suspension of hydroxylamine monohydrochloride (721 mg, 10.38 mmol) in DMSO (3 mL), and the mixture was stirred at 80° C. for 15 min. The precipitate was filtered off, and a solution of tert-butyl (6R,7R)-6-(cyanomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (500 mg, 1.30 mmol) in DMSO (4 mL) was added to the filtrate. The reaction mixture was stirred at 80° C. overnight. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (588 mg). This compound was used for the next reaction without purification.
Reaction SMILES: [C:1](=[O:19])([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[C:10]([OH:18])[CH:9]=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].[CH:20]1([CH2:23]O)[CH2:22][CH2:21]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1](=[O:19])([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[C:10]([O:18][CH2:23][CH:20]2[CH2:22][CH2:21]2)[CH:9]=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: OCC1CC1
Reactant: CC(C)(C)OC(=O)Oc1ccc(C(C)(C)C)c(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)Oc1ccc(C(C)(C)C)c(OCC2CC2)c1
Yield: 79.1 %

Procedure:
Tert-butyl 4-tert-butyl-3-hydroxyphenyl carbonate (1.5 g, 5.6 mmol), cyclopropylmethanol (0.5 mL, 6.2 mmol), triphenylphosphine (1.6 g, 6.2 mmol) and diethyl azodicarboxylate (DEAD) (1.0 mL, 6.2 mmol) were treated in the same procedure described in Example 31(a). The crude residue was applied to a silica gel chromatography column and eluted with a volume mixture of hexane and ethyl acetate (19/1 to 9/1) to furnish 1.42 g (79% yield) of the title compound as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:17]2[C@@H:12]([C:13]3[C:21]([OH:22])=[CH:20][CH:19]=[CH:18][C:14]=3[CH2:15][CH2:16]2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:24]1[N:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN1CCCC1=O>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C@@H:17]2[C@@H:12]([C:13]3[C:21]([O:22][C:24]4[N:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=4)=[CH:20][CH:19]=[CH:18][C:14]=3[CH2:15][CH2:16]2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(Cl)nn1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]2c3c(O)cccc3CC[C@@H]21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1ccc(Oc2cccc3c2[C@H]2CCCN(C(=O)OC(C)(C)C)[C@H]2CC3)nn1
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
A mixture of cis-10-hydroxy-2,3,4a,5,6,10b-hexahydro-1H-benzo[f]quinoline-4-carboxylic acid tert-butyl ester (0.40 g), 3-chloro-6-methyl-pyridazine (0.13 g), cesium carbonate (0.35 g), and N-methylpyrrolidinone (5 mL) is stirred at 150° C. for 1.5 h. After cooling to room temperature, the mixture is diluted with ethyl acetate and washed with water and brine and dried (Na2SO4). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 3:1→1:2) to give the title compound. Yield: 0.14 g (impure); LC (method 1): tR=4.19 min; Mass spectrum (ESI+): m/z=396 [M+H]+.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C=O)C.O>[Si:22]([C@@:3]1([OH:4])[C@@H:5]([CH2:6][O:7][Si:22]([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23])[O:8][C@@H:1]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2]1)([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cn([C@H]2C[C@@](O)([Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of thymidine (5.00 g, 20.64 mmol) and imidiazole (9.0 g, 132.1 mmol) in anhydrous DMF (11 mL), a solution of TBSCl (9.96 g, 66.05 mmol) in DMF (11 mL) was added dropwise, and the mixture was stirred at room temperature overnight under a N2 atmosphere. After the mixture was diluted with water (100 mL), the formed precipitate was filtered and dissolved in ethyl ether (125 mL). The ether solution was washed twice with water (25 mL each) and once with brine (25 mL), dried over Na2SO4, and concentrated under reduced pressure to a waxy solid, which was re-crystallized from hexane/ethyl either (10:1) to yield 3′,5′-O-bis-tert-butyldimethylsilyl-thymidine dT.04 (10.64 g, 90%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(OCC)C>N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[O:15][S:17]([CH3:16])(=[O:19])=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@@H]1OS(C)(=O)=O
Reaction time: 5 h
Yield: 71.6 %

Procedure:
(1S,2S)-2-tert-Butoxycarbonylamino-1-cyclohexanol (646 mg) was dissolved in pyridine (4 ml), methane-sulfonyl chloride (378 mg) was added with ice cooling, and the mixture was stirred for 5 hours. After diethyl ether was added to the reaction mixture and washed 5 times with water, the resultant organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (630 mg) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.CN1CCN(C)C1=O.[CH3:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=1)=[O:22].C(N(CC)CC)C>CCCCCC.C(OCC)(=O)C.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:22][C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=2)=[CH2:20])=[O:8])=[CH:5][CH:4]=1
Reactant: CC(=O)c1ccc(C(C)(C)C)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CN1CCN(C)C1=O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: C=C(OC(=O)c1ccc(OC)cc1)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 7 %

Procedure:
4-methoxybenzoyl chloride (2.35 g, 13.8 mmol), 0.65 g of cuprous chloride and 5.6 mL of 1,3-dimethyl-2-imidazolidinone were added to crude 4-tert-butylacetophenone trimethylsilylenol (6.7 mmol). After stirring the solution for 20 hours at room temperature, 1.4 mL of triethylamine and 10 mL of chloroform were added. Then the solution was chromatographied through flash silica column (hexane/ethyl acetate 10:1). The first collected fraction was purified twice by flash chromatography (hexane/dichloromethane 3:2 and next, hexane/dichloromethane 4:1) giving 0.14 g of an uncolored oil corresponding to 1-(4-tert-butylphenyl)-vinyl 4-methoxybenzoate. Yield 7%.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][N:19]3[C:23]4=[N:24][CH:25]=[C:26]([C:28]([O:30]C)=[O:29])[CH:27]=[C:22]4[N:21]=[CH:20]3)[CH:15]=[CH:14][C:12]=2[N:13]=1.Cl>C1COCC1.[Li+].[OH-]>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][N:19]3[C:23]4=[N:24][CH:25]=[C:26]([C:28]([OH:30])=[O:29])[CH:27]=[C:22]4[N:21]=[CH:20]3)[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: COC(=O)c1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.2 %

Procedure:
A mixture of methyl 3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate (210 mg, 0.48 mmol) from Example 79 in THF (5 mL) and 1 M aq LiOH (5 mL) was stirred at rt for 3 h. The reaction mixture was acidified to pH˜1.0 with 2 M aq HCl, and the mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford 3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (37 mg, 18%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 13.15 (br s, 1H), 8.96 (d, J=1.7 Hz, 1H), 8.74 (s, 1H), 8.52 (d, J=1.9 Hz, 1H), 7.98 (d, J=7.3 Hz, 1H), 7.67 (d, J=1.1 Hz, 1H), 7.19-7.33 (m, 2H), 5.53 (s, 2H), 4.75 (br s, 1H), 3.51 (m, 1H), 3.33 (m, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.55-1.68 (m, 2H), 1.09-1.35 (m, 4H). LCMS (ESI) m/z 424 (M+H)+.
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.[CH3:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O>[CH3:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH:22][C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2[C:3]=1[N:11]=[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:9]=2
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: Cc1ccccc1CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: Cc1nc(NCc2ccccc2C)c2nc(-c3ccccc3)cc-2[nH]1
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 36.5 %

Procedure:
To a mixture of 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (85.0 mg, 0.35 mmol) and 2-methylbenzyl amine (Aldrich Chemical Company) (2.2 mL, 17.4 mmol) was added a solution of K2CO3 (0.35 g, 2.54 mmol) in H2O (2.5 mL). This mixture was stirred at 140° C. in a closed-capped Wheaton vial for 1.5 h. After cooling, CH2Cl2 (10 mL) and H2O (10 mL) were added. The organic solution was removed and the aqueous solution washed with CH2Cl2 (10 mL). The combined organic solutions were washed with saturated NaCl (15 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (3% MeOH:CHCl3 on silica gel) and then recrystallized from MeOH/CH2Cl2 to give 42 mg (35%) of the title compound as a white solid. Mp: 277-281° C. MS m/z: 329 (M+1). 1H NMR (DMSO-d6; 400 MHz): δ 2.38 (s, 3), 2.42 (s, 3), 4.69 (d, 2, J=4.8), 6.75 (s, 1), 6.98 (br t, 1), 7.19-7.25 (m, 3), 7.35-7.42 (m, 2), 7.49 (t, 2, J=7.8), 7.76 (d, 2, J=7.8), 11.27 (s, 1). Anal. Calcd for C21H20N4: C, 76.83; H, 6.10; N, 17.07. Found: C, 76.58; H, 6.20; N, 16.94.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12](O)=[O:13])=[CH:9][CH:10]=2)[N:5]([CH2:15][CH3:16])[CH:4]=1)#[N:2].C(Cl)(=O)C([Cl:20])=O>C(Cl)Cl.CN(C=O)C>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([Cl:20])=[O:13])=[CH:9][CH:10]=2)[N:5]([CH2:15][CH3:16])[CH:4]=1)#[N:2]
Reactant: CCn1cc(C#N)c2ccc(C(=O)O)cc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCn1cc(C#N)c2ccc(C(=O)Cl)cc21
Temperature: 0 °C
Yield: 100.9 %

Procedure:
A suspension of 3-cyano-1-ethyl-1H-indole-6-carboxylic acid (0.42 g, 1.96 mmol) in CH2Cl2 (15 mL) is cooled to 0° C. The suspension is treated with DMF (2 drops) and then oxalyl chloride (0.34 mL, 3.92 mmol) is added via syringe during 2 minutes after which the ice bath is removed and the reaction mixture is allowed to warm to ambient temperature during 1.5 h during which time the reaction became a yellow solution. The solution is then concentrated in vacuo to afford 0.46 g (quantitative yield) of 3-cyano-1-ethyl-1H-indole-6-carbonyl chloride as a yellow solid.
Reaction SMILES: C(OC(=O)C[C@@H](NC(OC(C)(C)C)=O)C(N[C@H](C(=O)NC)C(C)(C)C)=O)C1C=CC=CC=1.[NH2:33][C@H:34]([C:39]1[NH:40][CH:41]=[CH:42][N:43]=1)[CH2:35][CH:36]([CH3:38])[CH3:37].Cl.[CH2:45]([O:52][C:53](=[O:76])[CH2:54][C@@H:55]([N:59]1[CH:63]=[CH:62][C:61]([C:64]2[CH:69]=[CH:68][C:67]([C:70]3[CH:75]=[CH:74][N:73]=[CH:72][CH:71]=3)=[CH:66][CH:65]=2)=[CH:60]1)[C:56](O)=[O:57])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[CH2:45]([O:52][C:53](=[O:76])[CH2:54][C@@H:55]([N:59]1[CH:63]=[CH:62][C:61]([C:64]2[CH:65]=[CH:66][C:67]([C:70]3[CH:75]=[CH:74][N:73]=[CH:72][CH:71]=3)=[CH:68][CH:69]=2)=[CH:60]1)[C:56]([NH:33][C@H:34]([C:39]1[NH:43][CH:42]=[CH:41][N:40]=1)[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:57])[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: O=C(C[C@H](C(=O)O)n1ccc(-c2ccc(-c3ccncc3)cc2)c1)OCc1ccccc1
Reactant: CC(C)C[C@H](N)c1ncc[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Agent: Cl
Product: CC(C)C[C@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccncc3)cc2)c1)c1ncc[nH]1
Yield: 41 %

Procedure:
According to the procedure described in Example 1(b) for the preparation of 3(R)-t-butyloxycarbonylamino-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester, 2-(1(S)-amino-3-methyl-butyl)-imidazole (See Chen, J. J.; Zhang, Y.; Hammond, S.; Dewdney, N.: Ho, T.; Browner, M. F.; Castelhano, A. L., submitted for publication; and Abel-Meguid, S. S.; Metcalf B. W.; Caw, T. J.; DeMarsh, P.; Des Jarlais, R. L.; Fisher, S.; Green, D. W.; et al. Biochemistry, 1994, 33, 11671-11677) and 2(R)-[3-(4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinic acid 4-benzyl ester hydrochloride (prepared as described in Example 7(a)) were coupled with TBTU. Flash column chromatography with 0-5% MeOH/CH2Cl2 gradient eluant and recrystallization from EtOAc gave in 41% yield N-[1(S)-(1H-imidazol-2-yl)-3-methylbutyl]-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid benzyl ester as white crystals, mp 179-81° C. (d).