Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]([CH3:11])[C:6](OCC)=[O:7].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]([CH3:11])[CH:6]=[O:7]
Reactant: CCOC(=O)C(C)Oc1ccc(F)cc1Br
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C=O)Oc1ccc(F)cc1Br
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 102.6 %

Procedure:
A solution of 19.4 gm (66.7 mMol) ethyl 2-(2-bromo-4-fluorophenoxy)propionate in 400 mL toluene was cooled to −78° C. at which point 100 mL (100 mMol) diisobutylaluminum hydride (1 M in toluene) were added dropwise over 35 minutes. The reaction mixture was stirred at −78° C. for an additional 20 minutes after the addition was complete and then the reaction was quenched by the addition of methanol. The reaction mixture was warmed to room temperature and then treated with saturated aqueous sodium potassium carbonate. The mixture was stirred for 30 minutes and was then extracted well with ethyl acetate. The organic phases were combined, dried over sodium sulfate, and concentrated under reduced pressure to provide 16.9 gm of crude desired compound.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][C:10]([O:13][C:14]([NH:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20]2)=[O:15])([CH3:12])[CH3:11].CO>ClCCl>[Cl:1][C:20]1[C:19]2[C:23](=[CH:24][CH:25]=[C:17]([NH:16][C:14]([O:13][C:10]([CH3:9])([CH3:11])[CH3:12])=[O:15])[CH:18]=2)[NH:22][C:21]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1cc2cc(NC(=O)OC(C)(C)C)ccc2[nH]1
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1[nH]c2ccc(NC(=O)OC(C)(C)C)cc2c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
N-Chlorosuccinimide (0.044 g, 0.329 mmol) to a suspension of ethyl 5-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1H-indole-2-carboxylate (0.100 g, 0.329 mmol) in dichloromethane (5 mL). Methanol (2 mL) was added to complete solution. The mixture was stirred at room temperature overnight. The solvent was evaporated, the residue was dissolved in ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (hexane:ethyl acetate) to give the title compound (0.082 g, 74%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.93 (s, 1H), 9.31 (br. s., 1H), 7.80 (br. s., 1H), 7.28-7.32 (m, 2H), 4.31 (q, 2H), 1.44 (s, 9H), 1.25-1.35 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.CCCCCC.CCOC(C)=O>CN(C)C=O>[C:15]1([CH2:14][O:10][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][CH:7]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: BrCc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc(OCc2cccc3ccccc23)c1
Reaction time: 0.17 h

Procedure:
To a solution of 3-nitrophenol (200 mg) in 4.0 mL of dimethylformamide at 0° C. was added NaH. After 10 minutes, 1-bromomethylnaphthalene (480 mg) was added, and the cold bath was removed. After ca. 15 h, the solution was quenched by the addition of sat. NH4Cl solution, and concentrated to dryness in vacuo. The residue was diluted with ethyl acetate and washed with water, sat. aq. NaHCO3 solution, and brine. The solution was dried (MgSO4), filtered, and concentrated in vacuo to provide the crude product. Trituration with 9:1 hexane/EtOAc provided the titled compound as a light brown solid.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH:31]4[CH2:33][CH2:32]4)[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl.ClCCl.CO>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH:31]4[CH2:32][CH2:33]4)[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC4CC4)c4ccc(OC(F)F)cc34)nc12
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(CC4CC4)c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.9 %

Procedure:
To a stirred solution of N-tert-butyl-2-(1-(cyclopropylmethyl)-5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (140 mg, 239 μmol) in dichloromethane (10 mL) under Ar, trifluoroacetic acid (744 mg, 0.50 mL, 6.53 mmol) was added at 25° C. After 18 h, the reaction was concentrated in vacuo to give a light brown residue. The residue was dissolved in a mixture of dichloromethane/methanol/NH3OH (3:2:0.25, 10.5 mL) and stirred at 25° C. After 2.5 h, the reaction was concentrated to give a yellow solid and dried in vacuo (200 mTorr, 25° C.). The solid was dissolved in ethanol (4.5 mL, 200 proof) and cooled to 4° C. After 18 h, the precipitated solid was isolated by filtration and dried in vacuo (200 mTorr, 40° C.) to give N-tert-butyl-2-(1-(cyclopropylmethyl)-5-(difluoromethoxy)-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (72.8 mg, 160 μmol, 66.9%) as a yellow solid. MS (M)'=455; 1H NMR (DMSO-d6) δ: 9.09 (s, 1H), 8.39 (s, 1H), 8.21 (d, J=2.3 Hz, 1H), 7.93 (d, J=9.0 Hz, 1H), 7.88 (s, 1H), 7.40 (dd, J=2.3, 9.0 Hz, 1H), 7.20 (t, J=74.3 Hz, 1H), 5.86 (m, 1H), 5.08 (dd, J=1.5, 17.3 Hz, 2H), 4.63 (t, J=7.0 Hz, 2H), 2.71 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: [CH2:1]([C@@:4]1(C)[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:31][CH3:32])[CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:5]1=[O:33])C=C.C(#N)C.I([O-])(=O)(=O)=O.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.CC[O:59][C:60]([CH3:62])=[O:61]>O.O.[Ru](Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Cl:16][C:12]1[CH:11]=[C:10]([C@@H:8]2[C@@H:7]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:6]([C@@H:24]([CH2:31][CH3:32])[CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:5](=[O:33])[C@:4]([CH2:62][C:60]([OH:59])=[O:61])([CH3:1])[CH2:9]2)[CH:15]=[CH:14][CH:13]=1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNS(C)(=O)=O)C1=O
Reactant: CCOC(C)=O
Agent: Cl[Ru](Cl)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC[C@@H](CNS(C)(=O)=O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reaction time: 20 h

Procedure:
To a rapidly stirring solution of N-((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)methanesulfonamide (34 mg, 0.064 mmol; Example 91, Step C) in a mixture of water (0.55 mL), acetonitrile (0.37 mL), and CCl4 (0.37 mL) was added sodium periodate (55 mg, 0.26 mmol) and ruthenium(III) chloride hydrate (1.5 mg, 6.5 μmol). After being stirred vigorously for 20 h, the reaction was acidified (10% citric acid) and diluted with EtOAc. The insoluble material was removed by filtering through a pad of Celite® (J. T. Baker, Phillipsberg, N.J., diatomaceous earth). The filtrate was extracted (2×EtOAc) and washed (sat. aq. NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification by RP-HPLC (40 to 70% MeCN/H2O (0.1% TFA), a gradient elution) provided the title compound as a white foam.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1([C:10](=[O:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8]1.[F:17][C:18]([F:31])([F:30])[O:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1/[C:22](=[N:24]/O)/Cl>C1COCC1.O>[CH:7]1([C:10]2[O:16][N:24]=[C:22]([C:21]3[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=3[O:19][C:18]([F:17])([F:30])[F:31])[C:11]=2[C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8]1
Reactant: O/N=C(\Cl)c1ccccc1OC(F)(F)F
Reactant: COC(=O)CC(=O)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2ccccc2OC(F)(F)F)noc1C1CC1

Procedure:
Potassium carbonate (11 g, 79.7 mmol, 1.09 equiv) was suspended in THF (100 mL) and the mixture was stirred. A solution of methyl 3-cyclopropyl-3-oxopropanoate (11 g, 77.5 mmol, 1.06 equiv) in 50 ml THF was added to the above stirred mixture and stirred fo(30 min at −10°C. To this reaction mixture was added a solution of (Z)-2-(trifluoromethoxy)benzoyl chloride oxime (17.6 g, 73.3 mmol, 1.00 equiv) in THF (50 mL) at −5°C. and then allowed to stir fo(6 h at 35°C. The reaction mixture was diluted with 200 mL of H2O, extracted with ethyl acetate (2×300 mL). The organic layer was washed with brine (2×200 mL), dried over anhydrous sodium sulfate, concentrated under vacuum, and then purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:100-1:20) eluent to afford methyl 5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole-4-carboxylate as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:40])[CH2:6][CH2:5][CH:4]([CH3:7])[CH:3]1[O:8][C:9](=[O:39])[C@@H:10]([CH2:37][OH:38])[NH:11][C:12](=[O:36])[C@H:13]([CH:25](CC1C=CC=CC=1)[C:26](=[O:28])[OH:27])[NH:14]C(OCC1C=CC=CC=1)=O>CO.[Pd]>[CH3:40][C:2]1([CH3:1])[CH2:6][CH2:5][CH:4]([CH3:7])[CH:3]1[O:8][C:9](=[O:39])[C@@H:10]([CH2:37][OH:38])[NH:11][C:12](=[O:36])[C@H:13]([CH2:25][C:26](=[O:27])[OH:28])[NH2:14]
Reactant: CC1CCC(C)(C)C1OC(=O)[C@@H](CO)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Cc1ccccc1)C(=O)O
Agent: [Pd]
Solvent: CO
Product: CC1CCC(C)(C)C1OC(=O)[C@@H](CO)NC(=O)[C@@H](N)CC(=O)O

Procedure:
To a magnetically stirred solution of 0.1 mole 2,2,5-trimethylcyclopentyl-D-serinate in 100 ml dry DMF at 0° C. under an argon atmosphere is added 1 equivalent of N-Cbz-L-aspartic acid β-benzyl ester followed by addition of 1 equivalent each of Cu(II) chloride and dicyclohexylcarbodiimide. After 18 hours the mixture is poured into 200 ml 0.1N HCl and extracted with 300 ml ethyl acetate which is successively washed with saturated NaHCO3, H2O, and dried over MgSO4. Filtration and evaporation yields N-Cbz-β-benzyl-L-aspartyl-D-serine 2,2,5-trimethylcyclopentyl ester. 2 g N-Cbz-β-benzyl-L-aspartyl-D-serine 2,2,5-trimethylcyclopentyl ester in 50 ml dry CH3OH is hydrogenated in a Paar apparatus over 5% Pd/C. Upon completion of the reaction, the mixture is filtered through Celite and concentrated to dryness to yield the final product.
Reaction SMILES: C(OC(=O)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[N:8]=[C:7]1[C@@H:19]([NH:24][C:25]([O:27]CC1C=CC=CC=1)=O)[CH2:20][CH2:21][CH2:22][CH3:23])C>CC(O)=O.[Pd]>[CH2:20]([C:19]1[C:7]2[N:6]([CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])[N:8]=2)[CH2:5][C:25](=[O:27])[N:24]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCC[C@H](NC(=O)OCc1ccccc1)c1nc(-c2ccccc2OC)cn1CC(=O)OCC
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCCC1=NC(=O)Cn2cc(-c3ccccc3OC)nc21
Temperature: 70 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
The product from Step 1.d. (compound v where R3 is n-butyl, R4 is 2-methoxyphenyl, and R5 and R6 are H) (11.5 g, 23.9 mmol) was dissolved in HOAc (100 ml) containing 10% Pd on carbon catalyst (500 mg) and hydrogenated under 50 psi of H2 for about 3 hours at room temperature. The catalyst was removed by filtration through a 3 cm pad of diatomaceous earth and the filtrate was warmed at about 70° C. for about 2 hours. The mixture was concentrated to a solid under reduced pressure, dissolved in CH2Cl2 (100 ml) and washed with saturated NaHCO3 solution (125 ml). The CH2Cl2 layer was dried over Na2SO4, filtered and 275 ml hexanes was added. Product was filtered off and dried to constant weight to yield 6.21 g (87%) of product, m.r.=200-202° C., NMR (300 MHz, DMSO-d6, 30° C.) 8.5-8.6 (1H s), 8.0-8.1 (1H, d), 7.4-7.6 (1H, s), 7.1-7.3 (1H, t), 7.0-7.1 (1H, d), 6.9-7.1 (1H, t), 4.55-4.8 (2H, q), 4.55-4.7 (1H, t), 3.8-4.0 (3H, s), 1.75-1.95 (2H, m), 1.1-1.5 (4H, m), 0.8-0.9 (3H, t).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH2:5][S:4][C:3]1=[S:8].[C:9]([O:12][C:13](=O)C)(=O)[CH3:10]>C([O-])([O-])OCC>[CH2:9]([O:12][CH:13]=[C:5]1[S:4][C:3](=[S:8])[N:2]([CH3:1])[C:6]1=[O:7])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: CN1C(=O)CSC1=S
Agent: CCOC([O-])[O-]
Product: CCOC=C1SC(=S)N(C)C1=O

Procedure:
3-Methyl-4-oxo-thiazolidine-2-thione (403 g) and ethyl orthoformate (1370 ml) were added to acetic anhydride (775 ml), and the mixture was refluxed for 6 hours. The mixture was allowed to stand, and the resulting crystals were collected by filtration and washed with diisopropyl ether to give 342 g of 5-ethoxymethylene-3-methyl-4-oxo-thiazolidine-2-thione.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[C:3]([O:5][CH2:6][N:7]1[C:15]2[N:14]=[CH:13][NH:12][C:11]=2[C:10](=[O:16])[N:9]([CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:8]1=[O:25])=[O:4].Br[CH2:29][C:30]#[C:31][CH3:32].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:29]([N:12]1[C:11]2[C:10](=[O:16])[N:9]([CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:23])[CH3:22])[C:8](=[O:25])[N:7]([CH2:6][O:5][C:3](=[O:4])[C:2]([CH3:27])([CH3:26])[CH3:1])[C:15]=2[N:14]=[CH:13]1)[C:30]#[C:31][CH3:32]
Reactant: CC(C)(C)C(=O)OCn1c(=O)c2[nH]cnc2n(COC(=O)C(C)(C)C)c1=O
Reactant: CC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCn1cnc2c1c(=O)n(COC(=O)C(C)(C)C)c(=O)n2COC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2,2-dimethylpropionic acid [3-(2,2-dimethylpropionyloxymethyl)-2,6-dioxo-2,3,6,7-tetrahydropurin-1-yl]methyl ester (1.0 g), 1-bromo-2-butyne (0.28 ml), anhydrous potassium carbonate (0.73 g), and N,N-dimethylformamide (15 ml) was stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate-water, and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 20–30% ethyl acetate/hexane to give 1.06 g of 2,2-dimethylpropionic acid [7-(2-butynyl)-3-(2,2-dimethylpropionyloxymethyl)-2,6-dioxo-2,3,6,7-tetrahydropurin-1-yl]methyl ester.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[C:24]([C:26]5[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=5)[CH:23]=[CH:22][N:21]4[C:32]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.Cl.O1CCOCC1>CO.C(Cl)Cl>[C:33]1([C:32]2[N:21]3[CH:22]=[CH:23][C:24]([C:26]4[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=4)=[CH:25][C:20]3=[N:19][C:18]=2[C:15]2[CH:14]=[CH:13][C:12]([C:8]3([NH2:7])[CH2:11][CH2:10][CH2:9]3)=[CH:17][CH:16]=2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(-c5ccncc5)ccn4c3-c3ccccc3)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: NC1(c2ccc(-c3nc4cc(-c5ccncc5)ccn4c3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
To a solution of {1-[4-(3-phenyl-7-pyridin-4-yl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (60 mg, 0.12 mmol) in MeOH (0.5 mL) and CH2Cl2 (0.7 mL) was added a 4 molar solution of HCl in dioxane (0.6 mL, 2.3 mmol, 20 equiv) and the resulting solution was stirred at room temperature for 12 h. The resulting solution was added to ice water, and the resulting mixture was extracted with CH2Cl2 (3×25 mL). The combined organic phases were dried (Na2SO4 anh), and concentrated under reduced pressure. The remaining material was purified using MPLC (Biotage Isolera Flash NH2 Snap 10 reverse phase column; 100% CH2Cl2 for 4 min., gradient to 95% CH2Cl2: 5% MeOH over 1 min.; 95% CH2Cl2: 5% MeOH for 2.5 min., gradient to 90% CH2Cl2: 10% MeOH over 1 min., 90% CH2Cl2: 10% MeOH for 2.5 min., gradient to 80% CH2Cl2: 20% MeOH over 1.5 min., 80% CH2Cl2: 20% MeOH for 0.8 min., gradient to 74% CH2Cl2: 26% MeOH over 2.2 min., gradient to 70% CH2Cl2: 30% MeOH over 1.8 min., 70% CH2Cl2: 30% MeOH for 7.4 min.) to give 1-[4-(3-phenyl-7-pyridin-4-yl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine (40 mg, 83%): UPLC-MS (Method 2): RT=1.22 min; m/z (rel intensity) 417 (700, (M+H)+), 833 (40, (2M+H)+).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[Br:9][CH2:10][CH2:11][C:12](Cl)=[O:13]>[OH-].[Na+]>[Br:9][CH2:10][CH2:11][C:12]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])=[O:13]
Reactant: O=C(Cl)CCBr
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@@H]1CCCN1C(=O)CCBr
Reaction time: 1.5 h

Procedure:
L-proline (5.75 g.) is dissolved in N sodium hydroxide with stirring in an ice bath. To this 50 ml. of N sodium hydroxide is added followed immediately by 3-bromopropanoyl chloride (8.5 g.). The pH is about 8 and the bath is removed. After 1.5 hours an additional 2.5 ml. of 2 N sodium hydroxide is added to bring the pH to 7. The reaction mixture is extracted twice with ether, the aqueous portion is acidified with concentrated hydrochloric acid and extracted into ethyl acetate. Yield 7.7 g. The 1-(3-bromo-1-oxopropyl)-L-proline is converted with dicyclohexylamine in ethyl acetate to the dicyclohexylamine salt, m.p. 284°-286°. This salt is then converted to the free acid with 10% potassium bisulfate in ethyl acetate. This product is recrystallized from ethyl acetate:hexane and recrystallized from ethyl acetate, m.p. 83°-85°.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[C:14]3[S:21][CH:20]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][C:23]=4[F:32])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:8][CH2:7]1.C([O-])([O-])=O.[K+].[K+].I[CH:40]([CH3:42])[CH3:41]>CNC=O.CC(C)=O>[F:32][C:23]1[CH:24]=[C:25]([S:28]([CH3:31])(=[O:29])=[O:30])[CH:26]=[CH:27][C:22]=1[C:19]1[C:15]2[N:16]=[CH:17][N:18]=[C:13]([O:12][CH:9]3[CH2:10][CH2:11][N:6]([C:5]4[N:1]=[N:2][N:3]([CH:40]([CH3:42])[CH3:41])[N:4]=4)[CH2:7][CH2:8]3)[C:14]=2[S:21][CH:20]=1
Reactant: CS(=O)(=O)c1ccc(-c2csc3c(OC4CCN(c5nn[nH]n5)CC4)ncnc23)c(F)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CNC=O
Solvent: CC(C)=O
Product: CC(C)n1nnc(N2CCC(Oc3ncnc4c(-c5ccc(S(C)(=O)=O)cc5F)csc34)CC2)n1
Temperature: 25 °C

Procedure:
700 mg of 4-(1-(2H-tetrazol-5-yl)piperidin-4-yloxy)-7-(2-fluoro-4-methanesulfonyl-phenyl)thieno[3,2-d]pyrimidine obtained in step 94-1 and 41 mf of K2CO3 were added in a mixture of methylformamide and acetone, and 44 μl of 2-iodopropane was dropwise added with stirring. The resulting mixture was stirred at 50° C. for 12 hr, cooled to room temperature and extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under a reduced pressure to obtain 51 mg of the title compound.
Reaction SMILES: [OH-].[NH4+:2].[O-][N+:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2[N:14]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][C:15]3=[N:16][C:6]=2[CH:5]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[NH2:2][C:5]1[C:6]2[N:16]=[C:15]3[CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20][N:14]3[C:7]=2[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c(nc3c[n+]([O-])c4ccccc4c32)C1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCn2c(nc3c(N)nc4ccccc4c32)C1

Procedure:
Concentrated ammonium hydroxide (160 mL) was added with vigorous stirring to a solution of tert-butyl 5-oxido-10,11-dihydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(8H)-carboxylate (28.49 g, 83.7 mmol) in dichloromethane (300 mL). p-Toluenesulfonyl chloride (15.96 g, 83.7 mmol) was added in small portions over a period of five minutes, after which an analysis by HPLC indicated that the reaction was complete. The aqueous layer was then extracted with dichloromethane (3×150 mL), and the combined organic fractions were washed with 1% aqueous sodium carbonate (2×150 mL). The combined aqueous washings were extracted with dichloromethane (200 mL), and all organic fractions were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide tert-butyl 6-amino-10,11-dihydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(8H)-carboxylate as a yellow solid.
Reaction SMILES: [NH:1]1[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:11]=3[CH:21]=2)=[N:4][N:3]=[N:2]1.C(Cl)(Cl)Cl.[Br:26]Br>O1CCOCC1>[Br:26][C:13]1[O:14][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C:5]3[NH:1][N:2]=[N:3][N:4]=3)=[CH:21][C:11]=2[C:12]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrBr
Reactant: c1ccc(-c2coc3ccc(Cc4nnn[nH]4)cc23)cc1
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: Brc1oc2ccc(Cc3nnn[nH]3)cc2c1-c1ccccc1
Temperature: 0 °C

Procedure:
To a stirred solution of 2.8 g. (0.01 mole) of 5-tetrazolylmethyl-3-phenylbenzofuran in 100 ml. of chloroform and 20 ml. of dioxane is added dropwise 1.6 g. (0.01 mole) of bromine. After 45 minutes the mixture is cooled to 0° C., then the product is separated by filtration and washed with chloroform. Recrystallization from aqueous ethanol provides 2-bromo-3-phenyl-5-(1H-tetrazol-5yl)methylbenzofuran m.p. 215°-217° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([OH:17])=[CH:5][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7]2.C([O-])([O-])=O.[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-]>[CH2:24]([O:17][C:4]1[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[Br:1])[CH:7]=[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc(O)c2c(Br)cccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(OCc2ccccc2)c2c(Br)cccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Naphthol 7 (3.20 g, 11.0 mmol) was dissolved in anhydrous DMF (78 mL). K2CO3 (3.05 g, 22.0 mmol), benzyl bromide (1.59 mL, 13.2 mmol), and Bu4NI (163 mg, 0.440 mmol) were added. The solution was stirred at 25° C. for 16 h. The reaction mixture was poured into H2O and extracted with ethyl acetate (3×). The organic extracts were combined, dried over Na2SO4, and concentrated under reduced pressure. The solid was recrystallized with 5% EtOAc/hexanes and the mother liquor was further purified by flash chromatography (SiO2, 6×15 cm, 10-20% EtOAc/hexanes gradient elution) affording additional 8 (3.30 g combined, 77%) as a brown crystalline solid. 1H NMR (CDCl3 500 MHz) δ 8.17 (s, 1H), 7.87 (d, J=7.5 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.61 (d, J=7.5 Hz, 2H), 7.57 (s, 1H), 7.40 (t, J=7.5 Hz, 2H), 7.35-7.32 (m, 1H), 7.29 (t, J=7.5 Hz, 1H), 5.30 (s, 2H), 4.43 (q, J=7.0 Hz, 2H), 1.44 (t, J=7.0 Hz, 3H). 13C NMR (CDCl3, 125 MHz) δ 166.0, 154.5, 136.1, 136.0, 135.0, 129.3, 128.3, 128.0 (2C), 127.8, 126.8, 125.8, 124.1, 116.7, 106.9, 71.2, 61.1. IR (film) νmax 2980, 1712, 1413, 1236 cm−1. ESI-TOF HRMS m/z 385.0433 (M+H+, C20H17BrO3 requires 385.0434).
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH:11]1([NH2:14])[CH2:13][CH2:12]1>>[CH:11]1([NH:14][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([F:10])[C:2]=2[F:1])[CH2:13][CH2:12]1
Reactant: NC1CC1
Reactant: O=Cc1cccc(F)c1F
Product: Fc1cccc(CNC2CC2)c1F

Procedure:
Synthesized according to typical procedure J from 2,3-difluorobenzaldehyde and cyclopropylamine.