Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([C:12]#[N:13])[CH:3]=1.[CH3:14][CH2:15][Mg+].[Br-]>CCOCC.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6](=[O:8])[NH:13][C:12]32[CH2:15][CH2:14]3)=[CH:10][CH:11]=1
Reactant: CC[Mg+]
Reactant: COC(=O)c1ccc(Cl)cc1C#N
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [Br-]
Solvent: CCOCC
Product: O=C1NC2(CC2)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 21 %

Procedure:
To a solution of methyl 4-chloro-2-cyanobenzoate (2.0 g, 10.2 mmol) in Et2O (40 mL) was added Ti(OiPr)4 (3.43 ml, 11.7 mmol). After cooling to 0° C., a 3.0 M solution of EtMgBr in Et2O (6.8 ml, 20.4 mmol) was added slowly. The reaction was warmed to room temperature and stirred for 3 h. Upon completion, the reaction was quenched with 1.0 M HCl (20 mL) then filtered over celite. The layers were separated and the aqueous layer was washed with EtOAc (2×20 mL). The combined organics were dried over Na2SO4, then filtered and concentrated. The crude product was purified by flash chromatography over silica gel (2-5% MeOH/DCM eluent) to provide 6′-chlorospiro[cyclopropane-1,1′-isoindolin]-3′-one (400 mg, 21% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (br. s., 1H), 7.66 (d, J=8.5 Hz, 1H), 7.40-7.54 (m, 2H), 1.47 (dt, J=11.2, 2.8 Hz, 4H); MS m/z C10H8ClNO [M+1]+=194.6.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.O>CS(C)=O>[N:15]1([CH2:14][CH2:13][CH2:12][NH:11][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=2)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: NCCCn1ccnc1
Reactant: O=[N+]([O-])c1cccc(F)c1
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cccc(NCCCn2ccnc2)c1
Temperature: 100 °C
Reaction time: 60 h

Procedure:
28.2 g 3-fluoronitrobenzene and 137.5 g 1-(3-aminopropyl)imidazole were dissolved in 300 ml dimethyl sulfoxide, and the batch was stirred for 60 h at 100° C. After cooling, the batch was poured into 1 l water. The precipitated product was suction-filtered and dried overnight under vacuum.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:3]=1[C:4](O)=[O:5].CO.Cl>O1CCCC1>[NH2:1][C:2]1[C:10]([Br:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Cc1cc(Br)c(N)c(C(=O)O)c1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Br)c(N)c(CO)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
The 2-amino-3-bromo-5-methylbenzoic acid (20.0 g, 86.0 mmol) was dissolved in tetrahydrofuran (200 ml) and cooled to 0° C. A solution of borane dimethylsulfide complex (15.6 mL, 156.0 mmol) was dissolved in tetrahydrofuran (40 mL) and added dropwise. The solution was kept at 0° C. for an additional 30 minutes, warmed to room temperature for 2 h and finally refluxed for 16 h. The solution was cooled to room temperature and methanol (10 mL) added slowly to control the gas evolution. The solution was stirred for 30 minutes at room temperature and 1 N hydrochloric acid added. The solution was stirred for 3 h and solvent removed to a volume of about 100 mL. Water (200 mL) was added and the solution extracted with diethylether (200 mL). The aqueous layer was collected, adjusted to pH=12 with 1N sodium hydroxide which formed a solid in the solution. The solid was collected, dissolved in ethyl acetate (100 mL), dried over sodium sulfate and solvent removed at reduced pressure. The (2-amino-3-bromo-5-methylphenyl)methanol (9.5 g, 43.9 mmol) was obtained as a off white solid. (51% yield): HRMS m/z 216.0047; calcd for M+H 216.0024.
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][C@@H:12]2[O:16][C:15](=[O:17])[CH2:14][CH2:13]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25]([C:27]([C:46]1[CH:51]=[CH:50][C:49](O)=[C:48]([CH3:53])[CH:47]=1)([C:30]1[CH:35]=[CH:34][C:33]([B:36]2[O:40][C:39]([CH3:42])([CH3:41])[C:38]([CH3:44])([CH3:43])[O:37]2)=[C:32]([CH3:45])[CH:31]=1)[CH2:28][CH3:29])[CH3:26].C(OCC)(=O)C>CN(C)C=O>[CH2:25]([C:27]([C:46]1[CH:51]=[CH:50][C:49]([O:10][CH2:11][C@@H:12]2[O:16][C:15](=[O:17])[CH2:14][CH2:13]2)=[C:48]([CH3:53])[CH:47]=1)([C:30]1[CH:35]=[CH:34][C:33]([B:36]2[O:40][C:39]([CH3:41])([CH3:42])[C:38]([CH3:43])([CH3:44])[O:37]2)=[C:32]([CH3:45])[CH:31]=1)[CH2:28][CH3:29])[CH3:26]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCC(=O)O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(CC)(c1ccc(OC[C@H]2CCC(=O)O2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
(R)-(−)-Dihydro-5-(p-tolyl-sulfonyloxymethyl)-2(3H)-furanone (293 mg, 1.084 mmol) and potassium carbonate (180 mg, 1.301 mmol) were added to a solution of 4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenol (Example 15-(2); 171 mg, 0.434 mmol) in N,N-dimethylformamide (1.5 mL) at room temperature, and the mixture was stirred at 110° C. for one hour. Ethyl acetate was added to the reaction solution. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=80/20 to ethyl acetate only) to give the title compound (164 mg, 76.8%).
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].C(N(C(C)C)CC)(C)C.O([CH2:42][CH:43]([F:45])[F:44])S(C(F)(F)F)(=O)=O>C1COCC1>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][N:11]2[CH2:42][CH:43]([F:45])[F:44])=[O:9])[CH2:6][CH2:5]1)#[N:3]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2CC(F)F)CC1
Reaction time: 24 h

Procedure:
To a suspension of (2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride (0.13 mmole) from experiment K4 in THF (2 ml) was added at 22° C. diisopropyl ethyl amine (0.75 mmole) and 2,2-difluoroethyl triflate (0.60 mmole) and stirring was continued at 60° C. for 24 h. The mixture was quenched with methanol, acidified with acetic acid and subjected to prep. HPLC (RP-18) using a mixture of acetonitrile and water to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(2,2-difluoro-ethyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless oil. MS: 418.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[N:9])[N:3]=1.[O-:10][CH2:11][CH3:12].[Na+]>O1CCCC1>[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:10][CH2:11][CH3:12])[N:3]=1)#[N:9]
Reactant: CC[O-]
Reactant: N#Cc1cccc(Cl)n1
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1cccc(C#N)n1
Yield: 14.1 %

Procedure:
A mixture of 2-chloro-6-cyanopyridine (1.00 g, 7.2 mmol), sodium ethoxide (0.54 g, 7.9 mmol) and tetrahydrofuran (100 ml) was refluxed for 18 hrs. The reaction mixture was concentrated under reduced pressure, diluted with ice-water and extracted with ethyl acetate. The extract was washed with saturated brine and dried. The solvent was evaporated under reduced pressure. The residue was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (5:1, v/v) to give the titled compound (0.15 g, 14%).
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9](Cl)=[O:10])[CH2:5][CH2:4]1)#[N:2].[NH2:15][C:16]1[CH:17]=[C:18]([CH:35]=[CH:36][CH:37]=1)[O:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([N:26]=[C:27]([NH:29][C:30]([CH:32]3[CH2:34][CH2:33]3)=[O:31])[N:28]=2)[CH:25]=1>CN(C)C(=O)C.C(OCC)(=O)C>[C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([NH:15][C:16]2[CH:37]=[CH:36][CH:35]=[C:18]([O:19][C:20]3[CH:21]=[CH:22][C:23]4[N:24]([N:26]=[C:27]([NH:29][C:30]([CH:32]5[CH2:33][CH2:34]5)=[O:31])[N:28]=4)[CH:25]=3)[CH:17]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: N#CC1(c2cccc(C(=O)Cl)c2)CC1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)C6CC6)nn5c4)c3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of 3-(1-cyanocyclopropyl)benzoyl chloride synthesized above in N,N-dimethylacetamide (5.0 mL) was added N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (150 mg, 0.485 mmol) produced in Example B2(vii), and the mixture was stirred at room temperature for 8 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=60/40→0/100), and the obtained oil was triturated with ethyl acetate, toluene and diisopropyl ether to give the title compound (175 mg, 63%) as a colorless powder.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH:21]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH:22]([F:24])[F:23])=[C:17]([CH2:19]O)[CH:18]=1.C1C=CC(P([N:48]=[N+:49]=[N-:50])(C2C=CC=CC=2)=O)=CC=1>C1COCC1>[N:48]([CH2:19][C:17]1[CH:18]=[C:13]([Cl:12])[CH:14]=[CH:15][C:16]=1[CH:21]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[CH:22]([F:24])[F:23])=[N+:49]=[N-:50]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(NC(c2ccc(Cl)cc2CO)C(F)F)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc(NC(c2ccc(Cl)cc2CN=[N+]=[N-])C(F)F)cc1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
DBU (0.20 mL, 1.34 mmol) was added to a stirred solution of (5-chloro-2-{2,2-difluoro-1-[(4-methoxyphenyl)amino]ethyl}phenyl)methanol (0.439 g, 1.34 mmol) and DPPA (0.29 mL, 1.34 mmol) in THF (1.7 mL) at 0° C. and the mixture was warmed to ambient temperature. After 3 h the solution was partitioned between EtOAc (20 mL) and water (10 mL). The EtOAc layer was washed with 1M NaOH (10 mL) and brine (10 mL), dried (Na2SO4) and reduced in vacuo to give N-{1-[2-(azidomethyl)-4-chlorophenyl]-2,2-difluoroethyl}-N-(4-methoxyphenyl)amine (0.463 g) as an oil: MS 353.5 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[F:25].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].C(OCC)(=O)C>C(Cl)(Cl)Cl>[CH2:1]([O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[F:25])[C:32]1[CH:31]=[CH:30][CH:35]=[CH:34][CH:33]=1
Reactant: COc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2cc1OC
Reactant: CCCCCC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 27 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoro-nitrobenzene (4.3 g) was dissolved in chloroform (200 ml) to prepare a solution. Aluminium chloride (10 g) was added to the solution, and the mixture was heated under reflux for 2 hr. The solvent was removed by evaporation before water (200 ml) was carefully added to the residue. The precipitated crude crystal (6.5 g) was collected by filtration. This crude crystal was dissolved in dimethylformamide (150 ml). Potassium carbonate (9.0 g) and benzyl chloride (4.5 g) were added to the solution, and the mixture was stirred at room temperature for 5 hr. The mixture was extracted with ethyl acetate. The extract was then washed with saturated brine and was dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under the reduced pressure. The residue was purified by column chromatography on silica gel, and the title compound (1.4 g, yield 27%) was obtained from the fraction of n-hexane:ethyl acetate (1:4).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=O.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=1.O>CN(C)C=O>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=3)[N:19]=2)[CH:18]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(-c2cn3cc(Cl)ccc3n2)cc1
Yield: 8.8 %

Procedure:
2-Bromo-1-(4-chlorophenyl)ethanone (9.08 g, 39 mmol) was added to a solution of 5-chloro-2-pyridinamine (5.0 g, 39 mmol) in dimethylformamide (100 mL) and the mixture was heated under reflux for 20 h. The mixture was cooled and poured into water (400 mL) and the solid was collected. The solid was dissolved in dichloromethane (300 mL), washed with water (50 mL) and brine (50 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was recrystallised from ethanol/water and the solid was collected and dried in vacuo to give the title compound (0.9 g, 9%). 1H NMR (360 MHz, CDCl3) δ 8.17 (1H, d, J 2.0 Hz), 7.87 (2H, d, J 8.9 Hz), 7.81 (1H, s), 7.56 (1H, d, J 9.5 Hz), 7.41 (2H, d, J 8.9 Hz), and 7.16 (1H, dd, J 9.5, 2.0 Hz). n/z (ES+) 263, 265 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([C:23]4[C:24](=[O:30])[NH:25][CH:26]=[CH:27][C:28]=4Cl)[NH:20]3)=[C:16]([CH3:31])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.[NH2:40][CH2:41][C@H:42]([C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([Cl:50])[CH:45]=1)[OH:43]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([C:23]4[C:24](=[O:30])[NH:25][CH:26]=[CH:27][C:28]=4[NH:40][CH2:41][C@H:42]([C:44]4[CH:49]=[CH:48][CH:47]=[C:46]([Cl:50])[CH:45]=4)[OH:43])[NH:20]3)=[C:16]([CH3:31])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)nc2[nH]c(-c3c(Cl)cc[nH]c3=O)nc12
Reactant: NC[C@@H](O)c1cccc(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)nc2[nH]c(-c3c(NC[C@@H](O)c4cccc(Cl)c4)cc[nH]c3=O)nc12
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 4-[8-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-methyl-9H-purin-2-yl]-piperazine-1-carboxylic acid t-butyl ester (200 mg, 0.448 mmol) in acetonitrile (10 mL) was added triethylamine (125 μl, 0.896 mmol) and (S)-2-amino-1-(3-chlorophenyl)-ethanol hydrochloride (99 mg, 0.493 mmol). The reaction mixture was stirred at 80° C. for 18 hours in a sealed tube and concentrated. The residue was dissolved in CH2Cl2 (50 mL) washed with H2O (2×30 mL), dried over MgSO4 and concentrated. The crude material was purified by crystallization in hot MeOH (35 mL) to give the title compound as a beige solid. (0.197 g, 76%). HPLC 98%; LCMS (+ESI, M+H+) m/z 581; IR (KBr, cm−1) 3419, 3271, 2975, 1696, 1496, 1232; 1H NMR (400 MHz, DMSO+D2O) δ 10.79 (br s, 1H), 7.59–7.32 (m, 5H), 6.22 (d, J=7.6 Hz, 1H), 5.00 (br t, 1H), 3.73 (br s, 4H, 3.60 (m, 1H), 3.44 (br s, 4H), 2.58 (s, 3H); HRMS calcd for C28H33ClN8O4: 581.2391; found 581.2389.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1[C:14](=[O:22])[NH:15][C:16]([CH2:19][CH2:20][CH3:21])=[CH:17][CH:18]=1>O1CCOCC1.[OH-].[Na+].O.C(=O)(O)[O-].[Na+]>[CH2:5]([O:4][C:2]([NH:12][C:13]1[C:14](=[O:22])[NH:15][C:16]([CH2:19][CH2:20][CH3:21])=[CH:17][CH:18]=1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCCc1ccc(N)c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCc1ccc(NC(=O)OCc2ccccc2)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
Benzyl chloroform ate (1.8 ml; 12.6 mmol) was added to a solution of 3-amino-6-propyl-2-(1H)-pyridinone (1.63 g, 10.8 mmol) in a mixture of dioxane (25 ml) and 1N NaOH at 0° C. Within minutes a white precipitate formed. The reaction mixture was stirred at the same temperature for 1 hr then at room temperature for an additional hour. The reaction mixture was diluted with water and extracted with ethyl acetate then methylene chloride. Each extract was washed with brine then combined and dried over magnesium sulfate. Removal of the solvents in vacuo gave a yellow semi-solid which was a mixture of starting material and product. This was redissolved in a mixture of dioxane (24 ml) and 10% aqueous sodium bicarbonate (12 ml) and cooled to 0° C. Benzyl chloroformate (1.5 ml, 10.5 mmol) was once again added and after stirring for 30 min, the reaction mixture was allowed to stir at room temperature for 3 h. After dilution with water, the precipitate was filtered off and washed thoroughly, first with water and then with ether. Drying gave 2.64 g of the title compound as a white powder: 1H NMR (CDCl3) δ 0.96 (t, J=7.3 Hz, 3 H), 1.68 (m, 2 H), 2.52 (t, J=7.5 Hz, 2 H), 5.22 (s, 2 H), 6.07 (d, J=7.5 Hz, 1 H), 7.34-7.43 (m, 4 H), 7.68 (s, 1 H), 8.05 (br d, J=5.3 Hz, 1 H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[N+](=CP(=O)(OC)OC)=[N-].[CH3:16][O:17][C:18]1([O:40][CH3:41])[CH2:23][CH2:22][C:21]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[CH:27]=2)([CH:24]=O)[CH2:20][CH2:19]1.C(O)(=O)C>O1CCCC1>[CH3:41][O:40][C:18]1([O:17][CH3:16])[CH2:19][CH2:20][C:21]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH:35]3[CH2:36][CH2:37][CH2:38][CH2:39]3)[CH:27]=2)([C:24]#[CH:1])[CH2:22][CH2:23]1
Reactant: COc1ccc(C2(C=O)CCC(OC)(OC)CC2)cc1OC1CCCC1
Reactant: CC(C)(C)[O-]
Agent: COP(=O)(C=[N+]=[N-])OC
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCC(OC)(OC)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 31.5 %

Procedure:
To a solution of potassium t-butoxide (0.155 g, 1.38 mmol) in dry tetrahydrofuran (5 mL) under an argon atmosphere at -78° C. was added a solution of dimethyl (diazomethyl)phosphonate (ca. 88% pure, 0.24 g, 1.38 mmol). After 0.25 h, a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-formylcyclohexan-1-one dimethyl ketal (0.42 g, 1.15 mmol) in dry tetrahydrofuran (5 mL) was added dropwise and the mixture was allowed to stir at -78° C. under an argon atmosphere for 5 h. Aqueous acetic acid was added, the mixture was concentrated, partitioned between methylene chloride and water and extracted twice. The organic extract was dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 3:1 hexanes/ethyl acetate, provided an oil (0.13 g, 32%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.CN([CH:27]=[O:28])C.Cl>C1COCC1>[CH3:11][C:8]1([CH3:12])[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([CH:27]=[O:28])[CH:10]=2)[CH2:6][O:7]1
Reactant: CC1(C)OCc2ccc(Br)cc21
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)OCc2ccc(C=O)cc21
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 6-bromo-1,1-dimethyl-1,3-dihydro-isobenzofuran (1.41 g, 6.3 mmol) in anhydrous THF (10 mL) was added under Argon at −78° C. 2.5 M nBuLi in hexane (2.7 mL, 6.6 mmol) and after stirring for 0.5 h at −78° C. DMF (0.98 mL, 12.5 mmol) was added. After stirring for 2 h at −78° C. the reaction mixture was added to 0.5 N cold aq. HCl and extracted with Et2O. Combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated. The title compound was obtained after chromatographic purification (Combi-Flash, 40 g silicagel, hexane-EtOAc 95:5 to 50:50) as a light yellow oil: TLC (hexane-EtOAc 1:1) Rf=0.50; HPLC RtA=1.43 min; 1H NMR (400 MHz, CDCl3): δ10.02 (s, 1H), 7.78 (d, 1H), 7.65 (s, 1H), 7.36 (d, 1H), 5.11 (s, 2H), 1.53 (s, 6H).
Reaction SMILES: F.F.F.C(N(CC)CC)C.C(N(CC)CC)C.[B-](F)(F)(F)F.CCN([S+](F)[F:29])CC.[CH:31]([N:44]1[CH2:47][C:46]([C:49]2[CH:54]=[CH:53][C:52]([C:55]3[CH2:59][C:58]([C:64]4[CH:69]=[C:68]([Cl:70])[C:67]([Cl:71])=[C:66]([Cl:72])[CH:65]=4)([C:60]([F:63])([F:62])[F:61])[O:57][N:56]=3)=[CH:51][C:50]=2[Br:73])(O)[CH2:45]1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl>[CH:31]([N:44]1[CH2:45][C:46]([C:49]2[CH:54]=[CH:53][C:52]([C:55]3[CH2:59][C:58]([C:64]4[CH:69]=[C:68]([Cl:70])[C:67]([Cl:71])=[C:66]([Cl:72])[CH:65]=4)([C:60]([F:63])([F:62])[F:61])[O:57][N:56]=3)=[CH:51][C:50]=2[Br:73])([F:29])[CH2:47]1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: OC1(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2Br)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CCN(CC)[S+](F)F
Agent: F
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: FC1(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2Br)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: -78 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
Triethylamine trihydrofluoride (0.3 mL, 1.7 mmol) and triethylamine (0.11 mL, 0.8 mL) were dissolved in dichloromethane (30 mL) and cooled to −78° C. To the cooled mixture was added XtalFluor-E (310 mg, 1.4 mmol) and then 1-benzhydryl-3-(2-bromo-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidin-3-ol (Preparation 28, 600 mg, 0.8 mmol). Cooling was removed and the mixture was allowed to warm to room temperature with stirring for 2 hours. The reaction was poured into saturated aqueous sodium carbonate solution (100 mL) and the organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. Crude material was chromatographed (40 G Redi-Sep Column) eluting from 100% heptane to 20:80 EtOAc:heptane to afford the intermediate (523 mg, 87%) as a glass. 1HNMR (CDCl3) δ ppm: 7.90 (1H), 7.69-7.66 (3H), 7.47-7.21 (11H), 4.46 (1H), 4.08 (1H), 3.90-3.66 (5H); m/z (Cl) 713 ([M+H]+.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[CH:37]=[C:36]([CH:41]=O)[CH:35]=[CH:34]2>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:41][C:36]3[CH:35]=[CH:34][C:33]4[C:38](=[CH:39][CH:40]=[C:31]([O:30][CH3:29])[CH:32]=4)[CH:37]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2cc(C=O)ccc2c1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: COc1ccc2cc(CNc3cccc(-c4c(Cc5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)ccc2c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 6-methoxy-naphthalene-2-carbaldehyde. MS (ESI) m/z 549.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.[C:16]([Mg]Br)([CH3:18])=[CH2:17]>>[CH3:18][C:16]1[NH:1][C:4]2=[C:5]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:6]=[CH:7][CH:8]=[C:9]2[CH:17]=1
Reactant: C=C(C)[Mg]Br
Reactant: O=[N+]([O-])c1cccnc1-c1ccccc1
Product: Cc1cc2ccnc(-c3ccccc3)c2[nH]1
Yield: 37 %

Procedure:
In accordance with the same procedures as in Example 242, except for using 3-nitro-2-phenylpyridine prepared in Preparation 15 and isopropenylmagnesium bromide, the titled compound was obtained as a white solid. (Yield: 37%)