Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Cl.C(N1N=C(C2C=CC(OC)=C(OC)C=2)[C@H]2[C@H](CCCC2)C1=O)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[O:23][CH3:22])[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: COc1ccccc1CCl
Agent: COc1ccc(C2=NN(Cc3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccccc1CN1N=C(c2ccc(OC)c(OC)c2)[C@@H]2CCCC[C@@H]2C1=O

Procedure:
Prepared from compound 1 and 2-methoxybenzylchloride as described for compound 78. Purified by chromatography (dichloromethane). Crystallized from diethyl ether at -20° C. M.p. 96°-99° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)O)=[CH:4][CH:3]=1.[C:16]1([NH:22][C:23](=[O:25])[CH3:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(O)=O.OS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:19]2[CH:20]=[CH:21][C:16]([NH:22][C:23](=[O:25])[CH3:24])=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: OC(c1ccc(Cl)cc1)c1cccnc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C(c2ccc(Cl)cc2)c2cccnc2)cc1
Yield: 100 %

Procedure:
A mixture of α-(4-chlorophenyl)-3-pyridinemethanol (0.364 mol) and N-phenyl acetamide (0.364 mol) in HOAc (360 ml) and H2SO4 36N (38.6 ml) was stirred and refluxed for 6 days. The solvent was evaporated, yielding 122.6 g (±)-N-[4-[(4-chlorophenyl)(3-pyridinyl)methyl]phenyl]acetamide (compound 673).
Reaction SMILES: [C:1]([CH:4]1[NH:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1)(=[O:3])[NH2:2].C=O.[C:19](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[C:1]([CH:4]1[N:9]([CH3:19])[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1)(=[O:3])[NH2:2]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCNC(C(N)=O)C1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCN(C(=O)OC(C)(C)C)CC1C(N)=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 86.1 %

Procedure:
tert-Butyl 3-carbamoylpiperazine-1-carboxylate (340 mg, 1.48 mmol) was dissolved in methanol (10 mL) and cooled to 0° C. To the reaction mixture were added 35% formaline solution (185 mg) followed by sodium triacetoxyborohydride (0.95 g, 4.48 mmol). The reaction mixture was allowed to warm up to room temperature and further stirred for 4 h. The reaction mixture was quenched with 10% NaHCO3 solution. The reaction mixture was diluted with EtOAc and the organic layer was separated in separatory funnel. The organic layer was dried over anhydrous Na2SO4 and concentrated in reduced pressure to afford tert-butyl 3-carbamoyl-4-methylpiperazine-1-carboxylate (310 mg, yield 86%). 1H NMR (300 MHz, CDCl3) δ 6.51 (br s, 1H), 5.47 (br s, 1H), 4.21-4.15 (m, 1H), 4.03-3.97 (m, 1H), 2.93-2.81 (m, 3H), 2.64-2.59 (dd, J=10.6 Hz, 3.8 Hz, 1H), 2.31 (s, 3H), 2.24-2.19 (td, J=11.7 Hz, 3.3 Hz, 1H), 1.46 (s, 9H). MS (ESI) m/z: Calculated for C11H21N3O3: 243.16. found: 244.3 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH2:9])=[N:6][C:7]=1[CH3:8].[CH2:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])=O.[K+].C([O-])(O)=O.[Na+]>CN(C=O)C.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:8][C:7]1[N:6]=[C:5]([NH2:9])[CH:4]=[CH:3][C:2]=1[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1nc(N)ccc1Br
Reactant: C=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: Cc1nc(N)ccc1C=Cc1ccccc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 25.6 %

Procedure:
5-Bromo-6-methyl-pyridin-2-ylamine (0.5 g), styrene (0.28 g) and potassium formate (0.68 g) were dissolved in DMF (5 mL). Tetrabutylammonium chloride (0.74 g) and palladium(II)acetate (30 mg) were added and the mixture was stirred under argon at 60° C. for 18 hours; a black suspension was obtained. The mixture was poured into saturated NaHCO3 solution (75 mL) and extracted with ethyl acetate. The organic layers were washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica gel, gradient of ethyl acetate in heptane) to give 6-methyl-5-styryl-pyridin-2-ylamine (144 mg) as a 7:3 mixture of (E) and (Z) isomers as a white foam. MS (ESI): 211.3 (MH+). This material was contaminated with trace amounts of 6-methyl-5-phenethyl-pyridin-2-ylamine according to MS analysis.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]1(C)C=CC=CC=1.[CH3:18][O:19][CH2:20][O:21][C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[C:24]([O:29][CH2:30][O:31][CH3:32])[C:23]=1[C:33](=O)[C:34]([O:36][CH2:37][CH3:38])=[O:35]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:18][O:19][CH2:20][O:21][C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[C:24]([O:29][CH2:30][O:31][CH3:32])[C:23]=1[C:33](=[CH2:11])[C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: CCOC(=O)C(=O)c1c(OCOC)ccc(C)c1OCOC
Reactant: Cc1ccccc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C(C(=O)OCC)c1c(OCOC)ccc(C)c1OCOC
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 83.1 %

Procedure:
To a suspension of methyltriphenylphosphonium bromide (8.78 g, 24.6 mmol) in dry tetrahydrofuran (50 ml) at 0° C. KHMDS 0.5M solution in toluene (44.22 ml, 22.11 mmol) was slowly added and the reaction mixture was stirred for 15 minutes at 0° C. and for 45 minutes at room temperature. The reaction mixture was cooled to 0° C. and it was slowly added to a solution of ethyl 2-[2,6-bis(methoxymethoxy)-3-methyl-phenyl]-2-oxo-acetate (Intermediate 8, 4.6 g, 14.74 mmol) in dry tetrahydrofuran (25 mL) at 0° C. and the reaction mixture was stirred for 2 hours at 0° C. The reaction was quenched with water (50 ml), diluted with brine (50 ml) and extracted with ethyl acetate (2×100 ml). The organic layer was dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography (Biotage system) on silica gel using a 100 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 8:2 as eluents affording the title compound (3.8 g) as a colourless oil.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([C:22]([OH:24])=[O:23])=[CH:20][N:19]=[C:18]([Cl:25])[C:17]=2[F:26])=[C:11]([F:27])[CH:10]=1.C1COCC1>CO>[CH3:1][O:23][C:22](=[O:24])[C:21]1[C:16]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([Br:8])=[CH:10][C:11]=2[F:27])=[C:17]([F:26])[C:18]([Cl:25])=[N:19][CH:20]=1
Reactant: O=C(O)c1cnc(Cl)c(F)c1Nc1ccc(Br)cc1F
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cnc(Cl)c(F)c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
A hexanes solution of TMSCH2N2 (9.46 mL, 18.9 mmol) was added to 4-(4-bromo-2-fluorophenylamino)-6-chloro-5-fluoro-nicotinic acid (4.59 g, 12.62 mmol) in a solution of 3:1 THF:MeOH (48 mL) at 0° C. The reaction mixture was warmed to room temperature and stirred for 1 hour. After quenching with AcOH, the reaction mixture was diluted with ethyl acetate and water. The layers were separated and the organic layer was washed with water, saturated NaHCO3 solution and brine. The organic layer was dried (MgSO4) and concentrated to give 4.40 g (92%) clean desired product.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH2:9]([O:11][C:12](=[O:22])[C:13]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])[CH3:10].S(=O)(=O)(O)O>C(=S)=S>[CH2:9]([O:11][C:12](=[O:22])[C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:5](=[O:7])[CH3:6])=[CH:17][CH:16]=1)([CH3:21])[CH3:14])[CH3:10]
Reactant: CCOC(=O)C(C)(C)c1ccccc1
Reactant: CC(=O)Cl
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCOC(=O)C(C)(C)c1ccc(C(C)=O)cc1
Yield: 46.8 %

Procedure:
Ex-77A: To a mixture of aluminum chloride (2.8 g, 20.8 mmol) in carbon disulfide (50 mL) was added acetyl chloride (0.74 mL, 10.4 mmol) followed by addition of 2-methyl-2-phenyl-propionic acid ethyl ester (1.0 g, 5.2 mmol). The reaction mixture was refluxed for 2 hours and then poured into ice containing sulfuric acid (6M). The mixture was partitioned. The aqueous layer was extracted with ethyl acetate. The solution of ethyl acetate was washed with hydrochloric acid (0.5M), saturated solution of sodium bicarbonate and brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography. Elution with ethyl acetate (33%, v/v, in hexane) gave 2-(4-acetyl-phenyl)-2-methyl-propionic acid ethyl ester (0.57 g, 47%). 1H NMR (CDCl3) δ 7.92 (d, J=7.6 Hz, 2H), 7.42 (d, J=7.6 Hz, 2H), 4.13 (q, J=7.2 Hz, 2H), 2.59 (s, 3H), 1.61 (s, 3H), 1.59 (s, 3H), 1.18 (t, J=7.2 Hz, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:15]2[N:16]([CH3:41])[C:17]3[C:22]([N:23]=2)=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:20]=[C:19]([N:30]2[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[N:32]=[C:31]2[CH2:39][CH3:40])[N:18]=3)([OH:14])[CH2:9]1)=O)(C)(C)C.[ClH:42].CCOCC>C(Cl)Cl.CO.O1CCOCC1>[ClH:42].[ClH:42].[CH2:39]([C:31]1[N:30]([C:19]2[N:18]=[C:17]3[C:22]([N:23]=[C:15]([C:10]4([OH:14])[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]4)[N:16]3[CH3:41])=[C:21]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[N:20]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=1)[CH3:40]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCCN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCCNC3)n(C)c2n1
Yield: 92 %

Procedure:
To a solution of 3-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (1.0 g, 1.78 mmol) in DCM (5 mL) and MeOH (1 mL) was added 4M HCl in dioxane (5 mL). The resulting mixture was allowed to stir for 2 h at r.t. before Et2O was added. The resulting precipitate was collected by filtration, washed with Et2O and dried in vacuo affording 3-[2-(2-Ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]piperidin-3-ol dihydrochloride (870 mg, 92%). LCMS (method H): RT 1.84 min [M+H]+ 463.3
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:10]=[C:9]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([Cl:30])[CH:23]=2)[N:8]=1)C.[OH-].[Na+]>CO>[Cl:30][C:24]1[CH:23]=[C:22]([NH:21][C:9]2[N:8]=[C:7]([O:6][CH2:5][C:4]([OH:31])=[O:3])[CH:12]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[N:10]=2)[CH:27]=[CH:26][C:25]=1[O:28][CH3:29]
Reactant: CCOC(=O)COc1cc(-c2ccc(OC)cc2)nc(Nc2ccc(OC)c(Cl)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-c2cc(OCC(=O)O)nc(Nc3ccc(OC)c(Cl)c3)n2)cc1
Temperature: 30 °C
Reaction time: 3 h

Procedure:
To a solution of [2-(3-chloro-4-methoxyphenylamino)-6-(4-methoxyphenyl)pyrimidin-4-yloxy]acetic acid ethyl ester (0.15 g, 0.33 mmol) in MeOH (5 mL) was added aqueous NaOH (prepared by adding NaOH in 2 mL of water) and the mixture was stirred for 3 hours at refluxing temperature. The mixture was then cooled to temperature in the range of 20-40° C., concentrated under vacuum, diluted with water (5 mL) and washed with ethyl acetate (2 x 2 mL). The aqueous layer was neutralized with 2N HCl. The solid precipitated was filtered off and dried to give the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.[C:12](Cl)(=O)C(Cl)=O>CO>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CO
Product: COC(=O)c1ccc(Br)cc1F
Temperature: 60 °C
Yield: 88.2 %

Procedure:
To a solution of 4-bromo-2-fluorobenzoic acid (4 g, 18 mmol) in methanol (10 mL) was added dropwise oxalyl dichloride (4.6 g, 36 mmol). The reaction was heated to 60° C. overnight and added slowly into ice water, and extracted with DCM (50 mL×2). The combined extracts were washed with brine, dried over Na2SO4 and concentrated to give the desired product (3.7 g, 88%) as brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[N:55]=[C:54]2[N:56]=[C:57]([CH:59]([NH2:61])[CH3:60])[NH:58][C:53]2=[CH:52][CH:51]=1.ClCl>CN(C)C=O.ClCCl.C(O)C>[Cl:49][C:50]1[N:55]=[C:54]2[N:56]=[C:57]([CH:59]([NH:61][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH3:60])[NH:58][C:53]2=[CH:52][CH:51]=1
Reactant: CC(N)c1nc2nc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NC(C)c2nc3nc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 42 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and 1-(5-chloro-1H-imidazo[4,5-b]pyridin-2-yl)ethylamine in dimethylformamide. Yield: 42%; Rf value: 0.45 (silica gel; dichloromethane/ethanol=9:1); C21H22ClN5O2 (411.89); mass spectrum: (M+H)+=410/412 (chlorine isotope).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:26])[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[C:22]([F:25])([F:24])[F:23])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:27]>O1CCOCC1>[ClH:27].[F:21][C:19]1[CH:18]=[CH:17][C:16]([C:22]([F:25])([F:23])[F:24])=[C:15]([C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:26])[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(c1cc(F)ccc1C(F)(F)F)N1CCNCC1
Reaction time: 0.25 h
Yield: 89 %

Procedure:
A stirred solution of 4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester (295 mg, 0.78 mmol) in dioxane was cooled to 0° C. and dioxane.HCl (1 mL) was added. The reaction mixture was stirred for 15 minutes, then concentrated. The resulting solid was washed with diethyl ether and dried to afford 220 mg (89%) of (5-fluoro-2-trifluoromethyl-phenyl)-piperazin-1-yl methanone hydrochloride, LCMS: 313.07 (M+1)+, 97.2%. Intermediate-3
Reaction SMILES: [C:1]([C:5]1[CH:45]=[CH:44][C:8]([C:9]([NH:11][C@@H:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([NH:26][NH:27][C:28](=O)[C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:31][CH:30]=3)=[O:25])=[CH:20][CH:19]=2)[C:13]([O:15][CH3:16])=[O:14])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].ClC1N(C)CC[NH+]1C>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:1]([C:5]1[CH:45]=[CH:44][C:8]([C:9]([NH:11][C@@H:12]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[O:25][C:28]([C:29]4[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:31][CH:30]=4)=[N:27][N:26]=3)=[CH:22][CH:23]=2)[C:13]([O:15][CH3:16])=[O:14])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCOc1ccc(C(=O)NNC(=O)c2ccc(C[C@H](NC(=O)c3ccc(C(C)(C)C)cc3)C(=O)OC)cc2)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCCOc1ccc(-c2nnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)OC)cc3)o2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
To a stirring solution (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(2-(4-(heptyloxy)benzoyl)hydrazinecarbonyl)phenyl)propanoate INT-3 (127 mg, 0.21 mmol) and TEA (0.09 mL, 0.62 mmol) in DCM (4 mL) was added 2-chloro-1,3-dimethylimidazolidinium chloride (41.8 mg, 0.25 mmol). The reaction mixture was stirred at room temperature for 18 h then warmed to 40° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with NaHCO3 (15 mL), shaken, split through a hydrophobic frit and evaporated to afford 120 mg (95%) of (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,3,4-oxadiazol-2-yl)phenyl)propanoate as a white solid. LCMS-ESI (m/z) calculated for C36H43N3O5: 597.8. found 598.0 [M+H]+, tR=3.25 min. (Method 4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH:3]=1.S1C=CC=C1B(O)O.[Br:21]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:21][C:9]1[S:10][CH:11]=[CH:12][C:8]=1[C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=1
Reactant: Clc1ccnc(-c2ccsc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: OB(O)c1cccs1
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccnc(-c2ccsc2Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-chloro-2-thiophen-3-yl-pyridine (755 mg, 3.9 mmol), prepared from 2-thiopheneboronic acid via the method outlined in Example 26, Step A, and N-bromosuccinimide (712 mg, 4 mmol) in DMF (6 mL) was stirred at room temperature for 8 h. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was dried and concentrated to yield a residue. The residue was recrystallized from EtOH to yield 2-(2-bromo-thiophen-3-yl)-4-chloro-pyridine as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][CH3:14].[CH:15]1(Br)[CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:15]1([O:1][C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=2[O:13][CH3:14])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: BrC1CCCC1
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(OC2CCCC2)c(OC)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 4-hydroxy-3-methoxybenzoate (7.17 g), cyclopentyl bromide (4.7 ml) and potassium carbonate (7.6 g) in N,N-dimethylformamide (70 ml) was stirred at 80° C. for 3 hours. Then the mixture was poured into water and extracted with ethyl acetate twice. The combined organic solution was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column (hexane-ethyl acetate, 4:1) to give ethyl 4-cyclopentyloxy-3-methoxybenzoate (8.58 g) as an oil.
Reaction SMILES: C(=O)([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[C:10]([O:18][CH2:19][CH:20]2[CH2:22][CH2:21]2)[CH:9]=1)OC(C)(C)C>O1CCOCC1>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([OH:7])=[CH:9][C:10]=1[O:18][CH2:19][CH:20]1[CH2:21][CH2:22]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)Oc1ccc(C(C)(C)C)c(OCC2CC2)c1
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(O)cc1OCC1CC1
Yield: 46 %

Procedure:
To a dioxane (10 mL) solution of tert-butyl 4-tert-butyl-3-(cyclopropylmethoxy)phenyl carbonate. (1.42 g, 4.43 mmol) was added 2M hydrochrolic acid (12 ml) at ambient temperature. The stirred mixture was refluxed for 18 hours. The reaction mixture was then quenched with saturated aqueous solution of sodium bicarbonate and then crude products were extracted with ethyl acetate. The organic layer was then washed with brine, dried over sodium sulfate. After filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with hexane and ethyl acetate (9/1) to furnish 0.44 g (46% yield) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Cl)=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1OCCOCCOCCOCCOCCOC1.[OH:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1.[K]>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:37][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(CCl)cc1-c1ccccc1
Reactant: Oc1cccnc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 50.2 %

Procedure:
To a solution of 11.1 g (42.3 mmol) of 4-chloromethyl-2-phenylbenzoic acid methyl ester, prepared as in Example 187A, in 150 mL of toluene was added 1.7 g (6.4 mmol) of 18-Crown-6, and 8.40 g (63.1 mmol) of 3-hydroxypyridine, potassium salt. The reaction was stirred at ambient temperature for 20 minutes, then heated to reflux under N2. After 3 hours, the mixture was poured into 100 mL of water. The layers were separated, then the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers were back extracted with 2M aqueous NaOH (2×30 mL), brine (1×100 mL), dried over magnesium sulfate, filtered, and concentrated to an oil which slowly crystallized. The product was recrystallized from 50 mL of 2-propanol to give 6.78 g of a tan solid. The supernatant was concentrated and purified via silica gel chromatography (50:50 hexanes:ethyl acetate) to give another 2.18 g of product, for a total yield of 8.96 g (66%). 1H NMR (300 MHz, d6-DMSO) δ 3.60 (s, 3H), 5.33 (s, 2H), 7.28-7.54 (m, 8H), 7.57 (dd, J=1.5, 9.0 Hz, 1H), 7.78 (d, J=9 Hz, 1H), 8.18 (dd, J=1.0, 5.5 Hz, 1H), 8.38 (d, J=3.0 Hz, 1H).
Reaction SMILES: OC(C1C=CC=C(C2C=C3[C:20]([C:21]4C=C[CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[CH:19][N:18](S(C4C=CC(C)=CC=4)(=O)=O)C3=NC=2)C=1)C(O)=O.CNCC1CCC[O:43]1.C(N(C(C)C)CC)(C)C>C1COCC1.C(OCC)(=O)C>[O:27]1[CH2:28][CH2:24][CH2:23][CH:22]1[CH2:21][CH2:20][C:19]([NH2:18])=[O:43]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cccc(C(O)C(=O)O)c3)cc12
Reactant: CNCC1CCCO1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)CCC1CCCO1
Temperature: 60 °C
Yield: 93.7 %

Procedure:
A mixture of hydroxyl-{3-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenyl}-acetic acid (0.2 g, 0.38 mmol), methyl-(tetrahydro-furan-2-ylmethyl)-amine (0.7 g, 0.57 mmol), diisopropylethylamine (DIEA, 200 μl, 1.14 mmol), N,N,N′N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU, 216 mg, 0.57 mmol) in THF (5 ml) was stirred at 60° C. until no solid remained. The reaction mixture was taken up in 10 ml ethyl acetate and subsequently extracted with 1N HCl, saturated NaHCO3, brine, dried with Na2SO4, concentrated to dryness. The crude was purified by silica chromatography. The resulting material was dissolved in 3 ml of methanol and aqueous NaOH (1 ml, 2 N in H2O) was added and the mixture stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue neutralized with 500 μl of 1N HCl. The resulting crude was directly purified by mass-triggered reverse phase HPLC to afford 2-hydroxyl-2{3-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-N-methyl-N-(tetrahydro-furan-2-ylmethyl-acetamide as an off-white powder (51 mg, 28% yield). 1H NMR (500 MHz, DMSO-d6) δ 1.35-1.45 (m, 1H), 1.61-1.79 (m, 3H), 2.89-2.92 (d, 3H), 3.14-3.68 (m, 4H), 3.84 (s, 3H), 3.92-3.98 (m, 1H), 5.47 (d, 1H), 7.05 (m, 1H, 7.15 (d, 1H), 7.31 (m, 1H), 7.36 (m, 1H), 7.45-7.48 (m, 1H), 7.56-7.59 (m, 1H), 7.63-7.70 (m, 2H), 7.73 (m, 1H), 8.14 (m, 1H), 8.52 (m, 1H). MS: m/z 472.2 (M+H+).