Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:18][C:17]=2[N+:29]([O-:31])=[O:30])[CH2:11][CH2:10]1)=O)(C)(C)C.CO.C(Cl)Cl>O1CCOCC1>[C:25]([O:24][C:22](=[O:23])[C:19]1[CH:20]=[CH:21][C:16]([NH:15][CH:12]2[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]2)=[C:17]([N+:29]([O-:31])=[O:30])[CH:18]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(NC2CCNCC2)c([N+](=O)[O-])c1
Reaction time: 12 h

Procedure:
Hydrogen chloride (1 mL, 4M in 1,4-dioxane) was added to a solution of (43) (0.1 g, 0.24 mmol) in 1,4-dioxane (5 mL) at 25° C. After 12 h, the reaction mixture was evaporated to a bright yellow solid residue which was basicified with NaOH(aq). The aqueous solution was extracted with EtOAc (3×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to give a yellow oily residue which was used in the next reaction without further purification (0.045 g, 59%): TLC (Rf =0.20; 15% MeOH/CH2Cl2); 1H NMR (CDCl3) δ 8.74 (s, 1H), 8.33 (d, 1H, J=5.4), 7.94 (d, 1H, J=8.8), 6.82 (d, 1H, J=8.8), 3.60 (m, 1H), 3.12 (d, 2H, J=11.3), 2.74 (t, 2H, J=11.7), 2.21 (s, 2H), 2.05 (d, 2H, J=12.5), 1.53 (s, 9H); 13C NMR (CDCl3) δ 164.2, 146.3, 136.2, 131.1, 129.4, 118.9, 113.4, 81.2, 49.8, 44.8, 32.9, 28.2; HRMS (FAB) m/z 322.1750 (M+H)+ (C16H23N3O4 requires 322.1761); Anal. (C16H23N3O4 ·1HCl·1CH3OH) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].I[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[Cu]Br>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:6]=[CH:5]2
Reactant: Ic1ccccc1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Brc1ccc2c(ccn2-c2ccccc2)c1
Temperature: 100 °C
Reaction time: 9 h
Yield: 33.1 %

Procedure:
A mixture of 5-bromoindole (10 g), potassium carbonate (27 g), copper (I) bromide (0.73 g) and iodobenzene (135 g) was heated to 100° C., then was removed once from the oil bath, sodium hydroxide (1.58 g) and copper (II) acetate (50 mg) were added and the mixture was stirred at 140° C. for 9 hours. From the reaction solution, the insolubles were filtered off, the filtrate was distilled off in vacuo, and the residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=19:1 to 3:2) to afford the above-identified compound (4.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)[CH2:11][O:10]1.S(=O)(=O)(O)[OH:19].N>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:19])([CH2:11][OH:10])[CH2:12][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: O=S(=O)(O)O
Reactant: Clc1ccc(C2(Cn3ccnc3)CO2)c(Cl)c1
Agent: N
Solvent: CCOC(C)=O
Product: OCC(O)(Cn1ccnc1)c1ccc(Cl)cc1Cl
Reaction time: 1 h

Procedure:
A mixture of 2-(2,4-dichlorophenyl)-2-(imidazol-1-yl)methyloxirane (170.4 g; Japanese Patent Publications (unexamined) Nos. 12372/1981 and 106666/1982) and a 25% aqueous sulfuric acid solution (1193 g) was stirred at 80°-85° C. for 5 hours. To the reaction mixture, ethyl acetate (405 ml) and a 28% aqueous ammonia solution (520 ml) were added dropwise at 0°-10° C., and then the mixture was stirred for 1 hour at the same temperature. The resulting precipitate was collected by filtration and dried at 80° C. (10 mmHg) for 5 hours to give 2-(2,4-dichlorophenyl)-1-(imidazol-1-yl)-2,3-propanediol. Yield, 146 g; 80.3%. M.P., 123.5°-124.5° C.
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([O:8][C:9]1[CH:20]=[CH:19][CH2:18][C:17]2[C:10]=1[CH:11]=[C:12]1[C:16]=2[CH:15]=[N:14][N:13]1[CH2:21][C@@H:22](O)[CH3:23])[CH3:7].C(N(CC)CC)C.[N-:32]=[N+:33]=[N-:34].[Na+].[Cl-].[Na+]>ClCCl.CN(C)C=O>[N:32]([C@H:22]([CH3:23])[CH2:21][N:13]1[C:12]2=[CH:11][C:10]3[C:17]([CH2:18][CH:19]=[CH:20][C:9]=3[O:8][CH2:6][CH3:7])=[C:16]2[CH:15]=[N:14]1)=[N+:33]=[N-:34]
Reactant: CCOC1=C2C=c3c(cnn3C[C@H](C)O)=C2CC=C1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC1=C2C=c3c(cnn3C[C@@H](C)N=[N+]=[N-])=C2CC=C1
Yield: 92.7 %

Procedure:
1.01 ml (13.4 mmol) of methanesulfonyl chloride were added dropwise while stirring to a solution, cooled to 0°, of 1.73 g (6.7 mmol) of (S)-1-(7-ethoxy-1,4-dihydro-indeno[2,1-c]pyrazol-1-yl)-propan-2-ol and 3.72 ml (26.8 mmol) of triethylamine in 50 ml of dichloromethane and the mixture was stirred at this temperature for a further 90 minutes. The reaction mixture was subsequently diluted with 130 ml of dichloromethane, washed twice with 70 ml 70 of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The yellowish solid obtained was dissolved in 50 ml of anhydrous dimethylformamide, treated with 0.86 g (13.4 mmol) of sodium azide and the reaction mixture was heated to 90° for 16 hours while stirring. After cooling, the solution was poured into 80 ml of semi-saturated sodium chloride solution and extracted twice with 100 ml of diethyl ether each time. The combined organic phases were washed once with 80 ml of water and once with 80 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The yellow oil obtained was purified by column chromatography on silica gel (ethyl acetate). 1.76 g (93%) of (R)-1-(2-azido-propyl)-7-ethoxy-1,4-dihydro-indeno[2,1-c]pyrazole were obtained as a light yellow solid.
Reaction SMILES: [ClH:1].[CH:2]1([NH:8][C:9]2[C:14]([C:15]3[CH2:19][C:18]4([CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)[O:17][N:16]=3)=[CH:13][N:12]=[C:11]3[N:32]([CH2:35][CH3:36])[N:33]=[CH:34][C:10]=23)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>>[ClH:1].[CH:2]1([NH:8][C:9]2[C:10]3[CH:34]=[N:33][N:32]([CH2:35][CH3:36])[C:11]=3[N:12]=[CH:13][C:14]=2[C:15]2[CH2:19][C:18]3([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[O:17][N:16]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CCn1ncc2c(NC3CCCCC3)c(C3=NOC4(CCN(C(=O)OC(C)(C)C)CC4)C3)cnc21
Agent: Cl
Product: CCn1ncc2c(NC3CCCCC3)c(C3=NOC4(CCNCC4)C3)cnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethanolic hydrochloric acid (25 ml) was added to tert-butyl 3-[4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl]-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-8-carboxylate (700 mg, 0.00148 mole) (example 9) The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. White solid precipitated, which was dried under vacuum.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[C:5]#[N:6].[CH3:11][S-:12].[Na+].C(N(CC)C(C)C)(C)C.Cl>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Cl:10][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([S:12][CH3:11])[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(Cl)cc(Br)c1
Reactant: C[S-]
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CSc1cc(Cl)cc(C#N)c1
Yield: 76.6 %

Procedure:
(Step 1) A mixture of 3-bromo-5-chlorobenzonitrile (4.0 g), sodium methanethiolate (1.42 g), Pd2(dba)3 (84 mg), Xantphos (106 mg) and N,N-diisopropylethylamine (4.78 g) was stirred in toluene (100 ml) at 90° C. for 9 hr. The reaction mixture was treated with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:20) to give 3-chloro-5-(methylsulfanyl)benzonitrile (2.6 g) as a solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](Cl)=[O:11].[NH:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1>ClCCCl>[Cl:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([C:14]1[NH:13][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: O=C(Cl)CCCCCl
Reactant: c1cc[nH]c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(CCCCCl)c1ccc[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 26.7 g (0.200 mol) of aluminium chloride and 31 g (0.200 mol) of 5-chlorovaleryl chloride in 200 ml of 1,2-dichloroethane is added slowly to a solution of 13.4 g (0.200 mol) of pyrrole in 250 ml of 1,2-dichloroethane. The reaction medium is stirred for 2 h at room temperature and is poured onto ice-cold hydrochloric acid. After extraction with methylene chloride, a red-brown oil is obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(CN2CCN(C3SC(C(O)=O)=C(C)N=3)C2=O)CCCCC1.[NH2:45][CH2:46][C:47]1[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=1>>[CH:2]1([CH2:1][N:8]2[CH2:12][CH2:11][N:10]([C:13]3[S:14][C:15]([C:19]([NH:45][CH2:46][C:47]4[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=4)=[O:21])=[C:16]([CH3:18])[N:17]=3)[C:9]2=[O:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1nc(N2CCN(CC3CCCCC3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(CC3CCCCC3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 52 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(cyclohexylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a white powder in 52% yield: mp 134-136° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.57-8.47 (m, 2H), 7.68 (d, J=7.2 Hz, 1H), 7.27 (s, 1H), 6.31 (br s, 1H), 4.55 (d, J=5.7 Hz, 2H), 4.11-4.03 (m, 2H), 3.57 (m, 2H), 3.09 (d, J=7.2 Hz, 2H), 2.57 (s, 3H), 1.84-1.56 (m, 5H), 1.24-0.84 (m 6H); 13C NMR (75 MHz, CDCl3) δ 162.7, 157.5, 155.6, 153.6, 148.9, 148.5, 135.9, 134.2, 123.7, 116.5, 50.3, 43.0, 42.0, 41.3, 36.0, 30.7, 26.2, 25.6, 17.2; MS (ES+) m/z 414.3 (M+1).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[CH:20][CH:21]=4)[NH:16][CH:15]=3)[CH:11]=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23]C([O-])(C)C.[K+].CI>C1COCC1>[CH:1]1([NH:7][C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH3:23])[CH:15]=3)[CH:11]=[CH:10][N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)[O-]
Reactant: c1cnc2[nH]cc(-c3ccnc(NC4CCCCC4)n3)c2c1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1cc(-c2ccnc(NC3CCCCC3)n2)c2cccnc21
Reaction time: 1 h
Yield: 82 %

Procedure:
Compound 13 (24 mg) was dissolved in THF (1 mL) and KOtBu (1 M in THF, 82 μL) was added. The mixture was stirred for 1 hr, followed by addition of methyl iodide (5.1 μL). The stirring was continued for additional 1 hr, then the solution was concentrated and the residue was purified by flash chromatography [silica gel, EtOAc] to afford 16 mg (82%) of the desired product. 1H NMR (400 MHz, CDCl3) δ 8.65 (d, 1 H), 8.32 (d, 1 H), 8.13 (d, 1 H), 7.75 (s, 1 H), 7.15 (dd, 1 H), 6.71 (d, 1 H), 5.0 (m, 1 H), 3.90 (s, 3 H), 3.88 (m, 1 H), 2.10 (m, 2 H), 1.70 (m, 2 H), 1.60 (m, 2 H), 1.40 (m, 2 H), 1.20 (m, 2 H). MS (ESI) m/z: 308 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([O:7][CH2:8][CH2:9][N:10]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:11][CH2:12]OS(C)(=O)=O)=[CH:5][CH:4]=1)#[N:2].[Br-:24].[Li+]>CC(C)=O>[Br:24][CH2:12][CH2:11][N:10]([CH2:9][CH2:8][O:7][C:6]1[CH:22]=[CH:23][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[S:18]([CH3:21])(=[O:20])=[O:19]
Reactant: [Br-]
Reactant: CS(=O)(=O)OCCN(CCOc1ccc(C#N)cc1)S(C)(=O)=O
Agent: [Li+]
Solvent: CC(C)=O
Product: CS(=O)(=O)N(CCBr)CCOc1ccc(C#N)cc1

Procedure:
To a solution of methanesulfonic acid 2-{[2-(4-cyanophenoxy)ethyl]-methanesulfonylamino}ethyl ester (10 g, 0.028 mol; see step (iii) above) in dry acetone (100 mL), was added lithium bromide (4.8 g, 0.055 mol). The reaction mixture was added refluxed overnight under a nitrogen atmosphere, before being filtered and concentrated to give the title compound. Yield: 10 g (97%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:23]([NH2:25])=[O:24])[C:5]2[NH:6][C:7]3[CH:8]=[C:9]([C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[O:16])[CH:10]=[CH:11][C:12]=3[C:13]=2[N:14]=1.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[CH:36][CH:35]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[N:17]1([C:15]([C:9]2[CH:10]=[CH:11][C:12]3[C:13]4[N:14]=[C:2]([C:34]5[CH:35]=[CH:36][C:37]([N:40]6[CH2:41][CH2:42][O:43][CH2:44][CH2:45]6)=[CH:38][CH:39]=5)[CH:3]=[C:4]([C:23]([NH2:25])=[O:24])[C:5]=4[NH:6][C:7]=3[CH:8]=2)=[O:16])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: NC(=O)c1cc(Br)nc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: NC(=O)c1cc(-c2ccc(N3CCOCC3)cc2)nc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Temperature: 100 °C

Procedure:
2-Bromo-7-(morpholine-4-carbonyl)-5H-pyrido[3,2-b]indole-4-carboxamide (60 mg, 0.149 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine (86 mg, 0.298 mmol), PdCl2(dppf)-CH2Cl2 adduct (12.15 mg, 0.015 mmol), and Na2CO3 (2M) (0.223 mL, 0.446 mmol) were mixed with DME (4 mL) in a sealed microwave vial. The mixture was flushed with N2 and heated at 100° C. in an oil bath for 4 hrs. The mixture was concentrated and purified using preparative HPLC to give titled product. MS (ESI) m/z 486.13 (M+H)+. 1H NMR (DMSO-d6) δ ppm 11.65 (s, 1H), 8.63 (s, 1H), 8.4 (s, 1H), 8.29 (d, 1H, J=7.9), 8.20 (d, 2H, J=8.9), 7.9 (s, 1H), 7.79 (s, 1H), 7.29(dd, 1H, J=8.0, 1.5), 7.11 (d, 2H, J=9.2), 3.79 (t, 4H, J=4.9), 3.65-3.45 (bm, 8H), 3.23 (t, 4H, J=4.9).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[C:4]2[CH:14]=[C:15]([C:17]([OH:19])=O)[S:16][C:3]1=2.O=S(Cl)Cl.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.Cl.N1CCOCC1>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[C:4]2[CH:14]=[C:15]([C:17]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:19])[S:16][C:3]1=2
Reactant: C1COCCN1
Reactant: Cn1c2ccc([N+](=O)[O-])cc2c2cc(C(=O)O)sc21
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cn1c2ccc([N+](=O)[O-])cc2c2cc(C(=O)N3CCOCC3)sc21
Reaction time: 1 h

Procedure:
280 mg of (68) was added to 25 ml of THF, 0.5 ml of SOCl2 was added, and the reaction left with stirring for 1 hour. 1 ml of morpholine was added in portions, and stirring continued . The precipitated morpholine hydrochloride was filtrered off, and the solvent evaporated. The residue was purified by column chromatography on silica gel, using MeOH in CH2Cl2, 1+9 as the eluent. MeOH was added to the pooled fractions to precipitate the product, giving after filtration and drying 50 mg of (69). M.p. 250°-2° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:16]([F:19])([F:18])[F:17])=[N:11][CH:12]=[C:13](Br)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)[O:24][B:23](B2OC(C)(C)C(C)(C)O2)[O:22]1.C([O-])(=O)C.[K+].Cl>O1CCOCC1.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]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([B:23]([OH:24])[OH:22])[CH:12]=[N:11][C:10]=1[C:16]([F:19])([F:18])[F:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ncc(Br)cc1OCc1ccccc1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: OB(O)c1cnc(C(F)(F)F)c(OCc2ccccc2)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a solution of 3-(benzyloxy)-5-bromo-2-(trifluoromethyl)pyridine (Intermediate G25.2, 521 mg, 1.569 mmol) in dry 1,4 dioxane (10 ml), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (438 mg, 1.726 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (344 mg, 0.471 mmol) and potassium acetate (462 mg, 4.71 mmol) were added and the suspension was stirred at 90° C. overnight. Then, HCl 4 N was added (10 mL) and the solution was stirred overnight. The solvent was removed under reduced pressure and crude was purified by C18 flash chromatography Snap 30 g eluent ((H2O/ACN)) 95:5+0.1% HCOOH}:{(ACN/H2O) 95:5+HCOOH 0.1%} from 95:5 to 0:100 affording the title compound (400 mg, 1.347 mmol, 86% yield) a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:35])([C:31]([F:34])([F:33])[F:32])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](=[O:30])[NH:28][CH:27]=[N:26]2)=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:28]1[CH:27]=[N:26][N:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]([F:15])([F:35])[C:31]([F:33])([F:34])[F:32])=[CH:24][CH:23]=2)[C:29]1=[O:30])[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]cnn1-c1ccc(OCC(F)(F)C(F)(F)F)cc1
Product: C[C@@H](n1cnn(-c2ccc(OCC(F)(F)C(F)(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 53.4 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.98 g of (1S)-[(2R)-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.04 g of 2-[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone, 0.882 g of 4-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-2-[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone was obtained as colorless prisms.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:10]([CH2:19][CH2:20][CH:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[OH:22])[C:9]2=[O:30])=[CH:4][CH:3]=1.[Br:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][C:42]([CH2:45]Br)=[CH:41][CH:40]=2)=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>>[Br:31][CH2:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]2[CH:44]=[CH:43][C:42]([CH2:45][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH:11]4[N:8]([C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)[C:9](=[O:30])[CH:10]4[CH2:19][CH2:20][CH:21]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)[OH:22])=[CH:17][CH:16]=3)=[CH:41][CH:40]=2)=[CH:37][CH:38]=1
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(O)cc2)N1c1ccc(F)cc1
Reactant: BrCc1ccc(-c2ccc(CBr)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCc3ccc(-c4ccc(CBr)cc4)cc3)cc2)N1c1ccc(F)cc1

Procedure:
1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-azetidin-2-one (11) was reacted with 4,4′-bisbromomethylbiphenyl and potassium carbonate analogously to Example IV, giving a colorless solid (21) of molecular weight 668.54 (C38H32BrF2NO3); MS (ESI): 668.1 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.[CH3:11][NH2:12]>CS(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:12][CH3:11])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: CN
Solvent: CS(C)=O
Product: CNC(=O)c1ccc(Br)nc1
Reaction time: 24 h
Yield: 59 %

Procedure:
N,N′-Carbonyldiimidazole (480 mg, 2.96 mmol) was added to a solution of 6-bromonicotinic acid (480 mg, 2.96 mmol) in dimethylsulfoxide (2 mL) and the mixture was stirred for 24 hours. Methylamine (2M in THF, 6 mL, 12 mmol) was then added and the mixture was stirred for a further 18 hours. The reaction mixture was evaporated under reduced pressure and the residue was diluted with water (25 mL) and extracted with dichloromethane (3×10 mL). The combined organic extracts were dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate to afford the title compound as a colourless solid in 59% yield, 300 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1.[Cl:18]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:18][C:13]1[CH:14]=[N:15][N:16]([CH3:17])[C:12]=1[C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc([N+](=O)[O-])cc1-c1ccnn1C
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1-c1c(Cl)cnn1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
5-(2-Methoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole (2.37 g, 10.17 mmol) was dissolved in DMF (100 mL). The solution was then heated to 80° C. N-Chlorosuccinimide (1.49 g, 11.1 mmol) was added at 80° C. under Argon gas. After two hours of continuous stirring, the reaction was checked by TLC and LCMS, and found to be incomplete. An additional aliquot of NCS (0.5 g, 3.7 mmol) was added, bringing the reaction to completion after 1.5 hours. While stirring, a portion of water (200 mL) was added to force the product to precipitate out of solution. After the precipitation was complete, the flask containing the solid was cooled in an ice water bath for 10 minutes. The solid was then filtered under vacuum and rinsed with water, yielding 2.4 g (89%) of 4-chloro-5-(2-methoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole. This material was used in the next step without purification. LCMS m/z (%)=267 (M+H, 100). 1H NMR (400 MHz, CDCl3) δ: 8.41 (dd, J1=8 Hz, J2=4 Hz, 1H), 8.22 (d, J=4 Hz, 1H), 7.53 (s, 1H), 7.14 (d, J=12 Hz, 1H), 3.97 (s, 3H), 3.72 (s, 3H).
Reaction SMILES: C1(C[O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])C=CC=CC=1.Cl>CO.[Pd]>[OH:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][NH:26][C:27](=[O:32])[C:28]([F:30])([F:31])[F:29]
Reactant: O=C(NCCOCCOCCOCCOCCOCCOCc1ccccc1)C(F)(F)F
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=C(NCCOCCOCCOCCOCCOCCO)C(F)(F)F
Reaction time: 17 h

Procedure:
672 mg of compound 14 were dissolved in 5 ml of MeOH, and the solution was adjusted to a pH of 3 with HCl and, following addition of 76 mg of Pd on carbon (10%), was hydrogenated under atmospheric pressure for 17 h. The suspension was filtered over Celite, concentrated, and coevaporated twice with toluene. Solvent residues were removed overnight under an oil pump vacuum. Yield: 480 mg of colourless oil.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]1([N:26]=[C:27]=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([NH:26][C:27](=[O:28])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][C:10]3([CH3:19])[CH3:18])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C=NC1CCCCC1
Reactant: CC1(C)CN(Cc2ccccc2)c2ccc(O)cc21
Product: CC1(C)CN(Cc2ccccc2)c2ccc(OC(=O)NC3CCCCC3)cc21

Procedure:
The title compound was synthesized from 1-benzyl-3,3-dimethylindolin-5-ol (20.0 mg, 0.09 mmol) using the same procedure employed for Example 2 (2), but with cyclohexylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (12.2 mg, 41%) having the following characteristics.