Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:22]=[CH:21][N:20]=[CH:19][C:7]=3[CH2:8][N+:9]([O-])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.P(Cl)(Cl)Cl.[OH-].[NH4+]>C(Cl)Cl>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:22]=[CH:21][N:20]=[CH:19][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: [O-][N+]1=C(c2ccccc2F)c2cc(Cl)ccc2-c2ncncc2C1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClP(Cl)Cl
Product: Fc1ccccc1C1=NCc2cncnc2-c2ccc(Cl)cc21

Procedure:
A mixture of 0.5 g (1.5 mmol) of 9-chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine-6-oxide, and 1.0 mol (10 mmol) of phosphorous trichloride in 20 ml of methylene chloride was heated at reflux for 2 hr. The mixture was poured over ice, basified with ammonium hydroxide and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue was crystallized from ether to give off-white crystals, mp 122°-124° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[C:6]([O:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[N:5]=[CH:4][N:3]=1.[CH:22]([C:25]1[N:29]=[C:28]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[O:27][N:26]=1)([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:22]([C:25]1[N:29]=[C:28]([CH:30]2[CH2:35][CH2:34][N:33]([C:2]3[C:7]([C:8](=[O:10])[CH3:9])=[C:6]([O:11][C:12]4[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=4)[N:5]=[CH:4][N:3]=3)[CH2:32][CH2:31]2)[O:27][N:26]=1)([CH3:24])[CH3:23]
Reactant: CC(C)c1noc(C2CCNCC2)n1
Reactant: CC(=O)c1c(Cl)ncnc1Oc1ccc(S(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1c(Oc2ccc(S(C)(=O)=O)cc2)ncnc1N1CCC(c2nc(C(C)C)no2)CC1
Yield: 19.6 %

Procedure:
To a solution of 1-[4-chloro-6-(4-methanesulfonyl-phenoxy)-pyrimidin-5-yl]-ethanone (0.21 mmol, 70 mg) and 4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidine (0.21 mmol, 49 mg) in N,N-dimethyl formamide (500 uL) was added potassium carbonate (0.21 mmol, 29 mg). The mixture was microwaved at 100° C. for 150 seconds. Its progress was monitored by thin layer chromatography and LCMS. The reaction was treated with water and the desired compound was extracted in ethyl acetate. Organic layer was evaporated in vacuo. Purification by HPLC provided Compound A165 as a white solid (20 mg, 20%). 1H-NMR (400 MHz, CDCl3) δ(ppm): 8.24 (s, 1H); 8.01 (d, 2H); 7.32 (d, 2H); 4.02 (m, 2H); 3.22 (m, 3H); 3.10 (m, 1H); 3.08 (s, 3H); 2.69 (s, 3H), 2.18 (m, 2H), 2.02 (m, 2H); 1.35 (d, 6H). LCMS (ESI), m/z 486.3 (M+H+, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[O:9][CH3:10].[F:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[C:16]([F:18])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]2[CH:13]=[C:12]([F:11])[CH:17]=[C:16]([F:18])[CH:15]=2)=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: COc1cc(I)ccc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: COc1cc(-c2cc(F)cc(F)c2)ccc1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A round-bottom flask was charged with 1-bromo-4-iodo-2-methoxybenzene (Combi-Blocks, Inc., San Diego, Calif., 6.25 g, 19.97 mmol), (3,5-difluorophenyl)boronic acid (3.47 g, 21.97 mmol), potassium carbonate (8.28 g, 59.9 mmol), and PdCl2(dppf)-CH2Cl2 (0.816 g, 0.999 mmol). The flask was flushed with Ar (g), then 1,4-dioxane (30.0 ml) and water (9.99 ml) were added in sequence. The mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was taken up in DCM and loaded onto a pre-equilibrated 340-g SNAP Ultra column. The column was eluted with 0-10% EtOAc/Heptane containing 5% DCM. Fractions containing the desired product were combined and concentrated. The residue was taken up in heptane and filtered. The collected solid was washed with heptane (3×), then dried under a stream of N2 (g). The process was repeated with the filtrate to give a second crop of material. The two crops were dried under vacuum to give 4-bromo-3′,5′-difluoro-3-methoxy-1,1′-biphenyl as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=7.66 (d, J=8.2 Hz, 1H), 7.58-7.49 (m, 2H), 7.40 (d, J=1.9 Hz, 1H), 7.33-7.20 (m, 2H), 3.96 (s, 3H). m/z (ESI) 301.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[NH2:27][CH:28]1[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]1.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([NH:27][CH:28]1[CH2:29][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31]1)=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CNC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of commercially available 2-(((benzyloxy)carbonyl)amino)acetic acid (6.70 g, 32.0 mmol) and EDCI (8.42 g, 43.9 mmol) was stirred in anhydrous DCM for 15 minutes and then added to a solution of commercially available tert-butyl 3-aminoazetidine-1-carboxylate (5.02 g, 29.1 mmol) and HOBt (4.45 g, 29.0 mmol, mono hydrate). The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with saturated ammonium chloride solution, 1 N NaOH solution, brine and the organic layer dried over Na2SO4. After concentration in vacuo, the residue was purified by flash chromatography (silica gel, 0%-5% MeOH/EtOAc) to give a white solid after drying under high vacuum.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:5][C:6]1([OH:19])[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1.[ClH:24].C(O)C>C(O)C>[ClH:24].[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:5][C:6]1([OH:19])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(Cc2ccc(F)c(F)c2)CC1
Agent: Cl
Solvent: CCO
Product: OC1(Cc2ccc(F)c(F)c2)CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-(3,4-difluorobenzyl)-4-hydroxypiperidine-1-carboxylate (4.7 g) in ethanol (30 mL) was added 2.0 M HCl/ethanol solution (36 mL), and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the obtained solid was recrystallized from ethyl acetate/diisopropyl ether to give the title compound (3.5 g).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:23](O)[CH3:24]>>[C:1]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([O:14][CH2:23][CH3:24])=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=C(O)c1cccc(C(=O)c2ccccc2)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cccc(C(=O)c2ccccc2)c1
Temperature: 100 °C
Reaction time: 0.05 h

Procedure:
A 100-mL round bottom flask was charged with of 3-benzoylbenzoic acid (2.20 g, 9.7 mmol), ethanol (40 mL), and sulfuric acid (3 mL). The reaction mixture was heated at 100° C. for 15 h, poured into ice water and extracted twice with Et2O. The combined organic phase was washed with satd aq NaHCO3 and dried over K2CO3. The crude ethyl 3-benzoylbenzoate was used in the next step without further purification. LC-MS (3 min) tR=1.87 min in 3 min chromatography, m/z 255 (MH+). 1H NMR (400 MHz, CDCl3) δ 8.45-8.44 (m, 1H), 8.28-8.25 (m, 1H), 8.00-7.97 (m, 1H), 7.82-7.79 (m, 2H), 7.64-7.48 (m, 4H), 4.40 (q, J=7.1 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H).
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[CH:12]=[C:11]([SH:13])[CH:10]=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=1[OH:18])([CH3:6])([CH3:5])[CH3:4].Br[CH:20]([CH2:24][CH2:25][CH2:26][CH3:27])[C:21]([OH:23])=[O:22].Cl>O.C(O)C>[C:3]([C:7]1[CH:12]=[C:11]([S:13][CH:20]([CH2:24][CH2:25][CH2:26][CH3:27])[C:21]([OH:23])=[O:22])[CH:10]=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=1[OH:18])([CH3:6])([CH3:5])[CH3:4]
Reactant: CCCCC(Br)C(=O)O
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCC(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A base solution (22 grams of NaOH in 41 milliliters (ml) of water) was added to a solution of 2,6-di-t-butyl-4-mercaptophenol (64.3 grams; 0.27 mole) in 540 ml. of absolute ethanol with stirring while cooling the reaction mixture under nitrogen. Following the base addition, a solution of 2-bromohexanoic acid (52.8 grams; 0.27 mole) in 27 ml. of ethanol was added and the resulting reaction mixture was stirred at room temperature for about 6 hours and left standing overnight. The reaction mixture was then diluted with about 400 ml. of water and acidified with cold 6N HCl. The yellow brown precipitate resulting from the acidification was obtained by filtration, washed with water and recrystallized from a methylene chloride-hexane mixture. As a result of these operations, the desired 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)hexanoic acid compound was obtained as a white crystalline solid having a melting point of 140°-142° C. Analysis calculated for C20H32O3S: C, 68.15; H, 9.14; S, 9.10. Found: C, 68.14; H, 9.34; S, 8.86.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]=[C:5]2[CH:13]1[CH2:15][CH2:14]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Cl)=[CH:30][CH:29]=1>CN(C=O)C.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:32][C:31]1[CH:34]=[CH:35][C:28]([O:27][CH3:26])=[CH:29][CH:30]=1)[C:7](=[O:12])[N:6]=[C:5]2[CH:13]1[CH2:15][CH2:14]1
Reactant: COc1ccc(CCl)cc1
Reactant: O=c1nc(C2CC2)c2cc(Cl)ccc2[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)nc(C3CC3)c3cc(Cl)ccc32)cc1
Reaction time: 8 h
Yield: 51.3 %

Procedure:
To a 0° C. solution of 9.0 g (0.04 1 mol) of 6-chloro-4-cyclopropylquinazolin-2(1H)-one in 150 mL of dry DMF (Aldrich Sure-Seal) under Ar was added 42.5 mL of a 1.0M solution of lithium bis(trimethylsilyl)amide in hexane dropwise. After the addition, 8.14 mL (0.06 mol) of p-methoxybenzyl chloride (Aldrich) was added in one portion, and the flask immersed in an oil bath maintained at 55°-60° C. The reaction was heated for 12.5 h, then allowed to stand at room temperature overnight. The solvents were removed by rotovap at reduced pressure and the residue partitioned between CHCl3 and cold 1M citric acid. The aqueous layer was extracted with CHCl3 and the combined organic layers washed with 10% Na2CO3, dried over MgSO4. After removal of the solvents by rotovap at reduced pressure, the residue was triturated with ether to give 10.5 g (75%) of the title compound as a light yellow solid.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)C1C=CC=CC=1.[H-].[Na+].[CH3:16][O:17][CH2:18]Cl.[OH-].[Na+]>C1COCC1.O>[CH3:16][O:17][CH2:18][O:13][C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: O[C@H]1CCN(Cc2ccccc2)C1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COCO[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 13 h
Yield: 178.7 %

Procedure:
To a stirred solution of N-benzyl-3-(S)-hydroxypyrrolidine (4.785 g, 27 mmol) in THF (50 ml) was added sodium hydride (60% oil suspension, 1.12 g, 28 mmol) by portions under nitrogen at room temperature. The suspension mixture was then refluxed for 1 h. To this reaction mixture was added chloromethyl methyl ether (2.3 ml, 30 mmol) and refluxing was continued for 13 h. After cooling down to room temperature, water (10 ml) was added to the reaction mixture to give a solution mixture, which was basified with 1N NaOH aqueous solution, extracted with ethyl acetate (30 ml×3), and dried (Na2SO4). Evaporation of the solvent gave 6.33 g of brown oil, which was purified by column chromatography (silica gel: 150 g, CH2Cl2 /MeOH: 20/1 as eluent) to afford 5.09 g (85%) of clear brown oil. A suspension mixture of this oil (5.09 g, 23 mmol) and Pearlman's catalyst (2.00 g) in MeOH (100 ml) was stirred under hydrogen atmosphere at room temperature for 15 h. After removal of the catalyst by Celite filtration, the filtrate was concentrated to give an oil and water mixture, which was dried in vacuo to afford 2.76 g (91.4%) of orange color oil.
Reaction SMILES: [F:1][CH:2]([F:10])[O:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.C([O:14][B:15](OC(C)C)[O:16]C(C)C)(C)C.C([Li])CCC.Cl>O1CCCC1>[F:1][CH:2]([F:10])[O:3][C:4]1[CH:9]=[C:8]([B:15]([OH:16])[OH:14])[CH:7]=[CH:6][CH:5]=1
Reactant: FC(F)Oc1ccccc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cccc(OC(F)F)c1
Reaction time: 0.17 h
Yield: 57.6 %

Procedure:
A solution of 3-(difluoromethoxy)benzene (3.0 g) and triisopropoxyborane (2.78 g) in tetrahydrofuran (15 ml) was cooled to −78° C. under argon atmosphere, and thereto was added a solution of n-butyl lithium (1.59 M hexane solution, 9.3 ml). The mixture was stirred at same temperature for 10 minutes, warmed, and further stirred at room temperature overnight. Thereto was added 3N aqueous hydrochloric acid solution (10 ml), and the mixture was stirred at room temperature for 5 minutes. The mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was crystallized from hexane to give 3-difluoromethoxybenzene-boronic acid (1.6 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].[F:34][CH:35]1[CH2:40][CH2:39][CH2:38][N:37]([CH2:41][CH2:42][NH2:43])[CH2:36]1>>[F:34][CH:35]1[CH2:40][CH2:39][CH2:38][N:37]([CH2:41][CH2:42][NH:43][C:30]([C:26]2[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:31])[CH2:36]1
Reactant: NCCN1CCCC(F)C1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCN1CCCC(F)C1

Procedure:
5-[5-(2,6-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid was coupled with 2-(3-fluoro-piperidin-1-yl)-ethylamine to give the titled compound.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Br:27][CH2:28][Br:29].[O:30]1[CH2:35][CH2:34][CH:33]([C:36](OC)=[O:37])[CH2:32][CH2:31]1.Cl>C(OC)(C)(C)C>[Br:27][CH:28]([Br:29])[C:36]([CH:33]1[CH2:34][CH2:35][O:30][CH2:31][CH2:32]1)=[O:37]
Reactant: BrCBr
Reactant: COC(=O)C1CCOCC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: O=C(C(Br)Br)C1CCOCC1
Temperature: 5 °C
Reaction time: 0.75 h
Yield: 57 %

Procedure:
Prepare lithium diisopropyl amide (LDA) as follows: Charge diisopropylamine (316.8 g, 2.5 equiv) and methyl tert-butyl ether (1.25 L) to a reactor and cool the reaction vessel to −10° C. to 0° C. Add n-butyl lithium in hexane (748 g, 2.2 equiv) while maintaining the temperature between −10° C. and 0° C. Stir the mixture for 30-60 min. In a separate vessel, add methyl tert-butyl ether (1.8 L), dibromomethane (471.6 g, 2.2 equiv) and methyl tetrahydro-2H-pyran-4-carboxylate (180 g) and cool to −90° C. to −70° C. Slowly add the LDA solution while maintaining the temperature between −90° C. and −70° C. After 30-90 min, transfer the reaction mixture to a solution of 1 N HCl (5.58 kg) maintained at 0-10° C. Upon completion of the addition, allow the mixture to warm to 15° C. to 25° C. and stir at this temperature for 15-20 min. Separate and discard the aqueous layer. Wash the organic layer with water (1.8 L) until the water layer registers a pH of 6-7, and concentrate the organic layer in vacuo to ˜2.2-2.5 volumes below 35° C. Add n-heptanes (720 mL), cool to −10° C. to −5° C. and stir for 1-2 h. Filter, rinse the filter cake with cold heptanes (90 mL) and dry under vacuum to give 2,2-dibromo-1-(tetrahydro-2H-pyran-4-yl)ethanone as a pale yellow solid (203.6 g, 55%). 1H NMR (400 MHz, CDCl3) δ 5.87 (s, 1H), 4.02 (m, 2H), 3.48 (m, 2H), 3.34 (m, 1H), 1.86 (m, 4H).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:30]=[CH:29][C:28]([NH:31]C(=O)C)=[CH:27][C:15]=4[C:16](=[O:26])[C:17]=3[O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl>C(O)C>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][C:15]=4[C:16](=[O:26])[C:17]=3[O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(=O)Nc1ccc2oc(-c3ccc(-n4ccnc4)cc3)c(OCc3ccccc3)c(=O)c2c1
Agent: Cl
Solvent: CCO
Product: Nc1ccc2oc(-c3ccc(-n4ccnc4)cc3)c(OCc3ccccc3)c(=O)c2c1

Procedure:
2-[(4-(imidazol-1-yl)-phenyl]-3-benzyloxy-6-acetamido-4H-1-benzopyran-4-one (7 g; 15.5 mmol) was suspended in ethanol (250 mL), HCl 4N (16 mL; 62 mmol) was added and the mixture refluxed for 24 hours. After cooling, the reaction was concentrated and the precipitate was filtered off. The crude was suspended in diisopropyl ether, filtered and dried to give the titled compound as light yellow solid. 1H-NMR (d6-DMSO): 9.91 (s, 1H); 8.44 (d, 1H); 8.22 (d, 2H); 7.90 (d, 3H); 7.78 (d, 2H); 7.33 (d, 1H); 7.32 (m, 6H); 5.16 (s, 2H); MS (EI) 410 (M+1), 319 (M-91).
Reaction SMILES: [OH:1][C@H:2]([C@H:10]1[O:15][CH2:14][CH2:13][N:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[C:11]1=[O:26])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:27][C:28](OC(C)=O)=[O:29].N1C=CC=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:28]([O:1][C@H:2]([C@H:10]1[O:15][CH2:14][CH2:13][N:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:18][CH:17]=2)[C:11]1=[O:26])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])(=[O:29])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)[C@H](O)[C@H]1OCCN(c2ccc(C(F)(F)F)cc2)C1=O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O[C@@H](C(=O)OC(C)(C)C)[C@H]1OCCN(c2ccc(C(F)(F)F)cc2)C1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Compound 93-1 (350 mg, 0.932 mmol) was dissolved in CH2Cl2 (4.66 ml) and cooled to 0° C., Ac2O (0.176 ml, 2 eq), pyridine (0.151 ml, 2 eq), and DMAP (11 mg, 0.1 eq) was added. The mixture was stirred for 2 hours, diluted with EtOAc, washed with CuSO4 solution, water, dried and concentrated to give 370 mg of compound 93-2.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[CH:31]1[CH2:33][CH:32]1[CH:34]=O.C([BH3-])#N.[Na+]>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[CH:31]1[CH2:33][CH:32]1[CH2:34][NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:22])[CH2:4][CH2:3]1
Reactant: N#Cc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CO2
Reactant: O=CC1CC1c1cc(F)ccc1F
Agent: [BH3-]C#N
Agent: [Na+]
Product: N#Cc1ccc2c(c1)N(CCN1CCC(NCC3CC3c3cc(F)ccc3F)CC1)C(=O)CO2
Yield: 42 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile (Intermediate 58) (1 mmol), 2-(2,5-difluorophenyl)cyclopropanecarbaldehyde (Intermediate 68) (200 mg, 1.1 mmol) and sodium cyanoborohydride (125 mg, 2 mmol) were reacted as described under Example 21 to give 196 mg (42%) product as a gum.
Reaction SMILES: N1(CC(N)=O)C=CC=N1.[C:10]1([C:16]2[CH:17]=[N:18][N:19]([CH2:27][C:28]([O:30]CC)=O)[C:20]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH2:33][CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.C(N(C(C)C)CC)(C)C>>[C:10]1([C:16]2[CH:17]=[N:18][N:19]([CH2:27][C:28]([NH:33][CH2:34][CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[O:30])[C:20]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCCN1CCCC1
Reactant: CCOC(=O)Cn1ncc(-c2ccccc2)c1-c1ccccc1
Agent: NC(=O)Cn1cccn1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cn1ncc(-c2ccccc2)c1-c1ccccc1)NCCN1CCCC1

Procedure:
By a procedure substantially similar to that of Example 18, 6.67 g of 4,5-diphenyl-N-2-(1-pyrrolidinyl)ethyl-]1H-pyrazole-1-acetamide, mp 80°-84° C., was prepared from 15 g (0.049 mol) of ethyl 4,5-diphenyl-1H-pyrazole-1-acetate of Example 1, 9 mL (0.072 mol) of N-(2-aminoethyl)pyrrolidine and 62 mL (0.36 mol) of diisopropylethylamine.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[S:16][C:17]([CH3:21])=[C:18]([CH3:20])[N:19]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:20][C:18]1[N:19]=[C:15]([NH:14][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([NH2:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)[S:16][C:17]=1[CH3:21]
Reactant: Cc1nc(N)sc1C
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cc1nc(NC(=O)c2ccc(N)c([N+](=O)[O-])c2)sc1C

Procedure:
Prepared analogously to example 3c with 4-amino-3-nitro-benzoic acid and 2-amino-4,5-dimethyl-thiazole using TBTU and TEA in DMF.
Reaction SMILES: B(C1C=CC(CCCC(O)=O)=CC=1)(O)O.[C:16]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:48])[CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([B:40]3[O:45]CC(C)(C)C[O:41]3)=[CH:36][CH:35]=2)=[CH:25][C:24]=1[C:49]#[N:50])(=[O:22])=[O:21])([CH3:19])([CH3:18])[CH3:17].[OH-].[Na+]>>[C:16]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:48])[CH2:31][CH2:32][CH2:33][C:34]2[CH:35]=[CH:36][C:37]([B:40]([OH:41])[OH:45])=[CH:38][CH:39]=2)=[CH:25][C:24]=1[C:49]#[N:50])(=[O:22])=[O:21])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC1(C)COB(c2ccc(CCCC(=O)Nc3ccc(S(=O)(=O)C(C)(C)C)c(C#N)c3)cc2)OC1
Agent: O=C(O)CCCc1ccc(B(O)O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)S(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Yield: 70.7 %

Procedure:
Using a procedure analogous to that used to prepare 2B, 10D (431 mg, 0.869 mmol) was reacted with NaOH to give 10E (263 mg, 71%) as a brown solid. 1H NMR (400 MHz, THF-d8) δ 1.34 (s, 9 H), 1.96-2.07 (m, 2 H), 2.35 (t, J=7.25 Hz, 2 H), 2.69 (t, J=7.25 Hz, 2 H), 7.09 (s, 1 H), 7.16 (d, J=7.91 Hz, 2 H), 7.71 (d, J=8.35 Hz, 2 H), 7.92-7.96 (m, 1 H), 8.01 (dd, J=2.20 Hz, 1 H), 8.23 (d, J=2.20 Hz, 1 H), 9.69-9.77 (m, 1 H).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].N1C=CC=CC=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C(Cl)Cl>[CH3:22][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O:5][CH2:1][CH2:2][C:3]#[CH:4])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C#CCCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: C#CCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.7 %

Procedure:
To a mixture of 3-butyn-1-ol (0.5 g, 8.3 mmol) in CH2Cl2 (20 mL) and pyridine (1.7 mL, 33.2 mmol) was added p-toluenesulfonyl chloride (1.7 g, 8.7 mmol). This mixture was stirred at ambient temperature for 16 h then diluted with CH2Cl2 (20 mL) and quenched with aqueous 1% HCl (5 mL). The layers were separated and the organic layer was washed with aqueous 1% HCl (5 mL) and brine (5 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified via column chromatography (4:1 hexanes:EtOAc) to provide the title compound (0.30 g, 1.3 mmol, 16% yield). MS (DCI/NH3) m/z 242 (M+NH4)+.