Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:7]1[C:12]([F:13])=[CH:11][C:10]([O:14][CH2:15][CH3:16])=[CH:9][C:8]=1[F:17])[OH:6])[CH3:2].I[CH3:20]>C1(C)C=CC=CC=1.[Ag-]=O>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:7]1[C:12]([F:13])=[CH:11][C:10]([O:14][CH2:15][CH3:16])=[CH:9][C:8]=1[F:17])[O:6][CH3:20])[CH3:2]
Reactant: CCOC(=O)C(O)c1c(F)cc(OCC)cc1F
Reactant: CI
Agent: O=[Ag-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(OC)c1c(F)cc(OCC)cc1F
Temperature: 60 °C
Yield: 97.3 %

Procedure:
To a solution of (4-ethoxy-2,6-difluoro-phenyl)-hydroxy-acetic acid ethyl ester (4.0 g, 15.37 mmol, 1.0 equiv) in toluene (50 mL) was added iodo-methane (21.82 g, 9.78 mL, 153.70 mmol, 10.0 equiv) and silver(I) oxide (7.12 g, 30.74 mmol, 2.0 equiv) and the reaction mixture heated to 60° C. for 18 h. The reaction mixture was filtered, the filtrate poured into ice water and then extracted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4 and concentrated by evaporation under reduced pressure yielding 4.1 g (97%) of the title compound. 1H NMR (300 MHz, CDCl3): 1.25 (t, J=7.5 Hz, 3H), 1.41 (t, J=7.5 Hz, 3H), 3.43 (s, 3H), 4.01 (q, J=7.5 Hz, 2H), 4.26 (q, J=7.5 Hz, 2H), 5.05 (s, 1H), 6.43-6.48 (m, 2H). MS (ISP): 292.3 [M+NH4]+.
Reaction SMILES: C(O[CH:4]([O:36]CC)[CH2:5][CH:6]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:7]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:11][CH:10]=1)[OH:8])C.S(=O)(=O)(O)O.O.[OH-].[Na+]>O1CCCC1>[OH:36][CH:4]1[O:8][C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[CH:13][CH:14]=2)[CH:6]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:5]1
Reactant: CCOC(CC(c1ccccc1)C(O)(c1ccccc1)c1ccc(OCCN2CCOCC2)cc1)OCC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: OC1CC(c2ccccc2)C(c2ccccc2)(c2ccc(OCCN3CCOCC3)cc2)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The evaporation residue obtained in step (a) is dissolved in a mixture containing 19.5 g of concentrated sulfuric acid, 150 ml of water and 400 ml of tetrahydrofuran. The mixture is stirred for 3 h at room temperature. The solution is neutralized with 2M sodium hydroxide solution and the solvent is evaporated. The product is extracted in toluene containing ethyl acetate. The solution is dried over sodium sulfate. The solvent is evaporated, and the residue is recrystallized from toluene. The yield is 12.0 g (27% from desoxybenzoin) of a product having m.p. 150°-3° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.F[C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH:22]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])=[O:21])=[CH:16][CH:15]=1.[C:37](C1C=CC(C(N(OC)C)=O)=CC=1)([CH3:40])([CH3:39])[CH3:38]>C1COCC1>[C:37]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH:22]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[O:23][Si:24]([C:27]([CH3:29])([CH3:30])[CH3:28])([CH3:25])[CH3:26])=[O:21])=[CH:16][CH:15]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)[Si](C)(C)OC(C(=O)c1ccc(F)cc1)c1ccncc1
Reactant: CON(C)C(=O)c1ccc(C(C)(C)C)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(=O)C(O[Si](C)(C)C(C)(C)C)c2ccncc2)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
To a cooled solution of diisopropylamine (183 mg, 1.81 mmol) in dry THF (0.35 mL) at -20° C. was added a solution of n-butyllithium in hexanes (0.83 mL of a 2.5M solution, 2.08 mmol). Stirred at -20° C. for 1 hr and then added a solution of 4-pyridyl-t-butydimethylsilyloxymethyl 4-fluorophenyl ketone from Step B (383 mg, 1.72 mmol) in THF (0.45 mL). Stirred at -20° C. for 45 min, resulting in a thick yellow-brown solution. A solution of 4-t-butyl-N-methoxy-N-methyl-benzamide (400 mg, 1.81 mmol) in THF (0.5 mL) was added and the solution stirred at -20° to 0° C. for 5 h. The reaction was cooled to -20° C. and quenched by the addition of a saturated ammonium chloride solution. The reaction mixture was then extracted with ethyl acetate (3 times) and the combined extracts washed successively with water (2 times) and saturated salt solution and dried over anhydrous sodium sulfate. The mixture was filtered and the solvent removed by rotoevaporation. The residue was purified by flash column chromatography on silica gel eluted with 5-10% ethyl acetate in hexanes to yield the title compound as a yellow oil (341 mg, 49% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=O)[CH:2]=1.[NH2:14][N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH2:20][O:21][CH3:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)C>[CH3:22][O:21][CH2:20][C@@H:16]1[CH2:17][CH2:18][CH2:19][N:15]1[N:14]=[C:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: COC[C@@H]1CCCN1N
Reactant: O=C1CCCCC1c1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC[C@@H]1CCCN1N=C1CCCCC1c1cccnc1

Procedure:
A mixture of 2-(pyrid-3-yl)cyclohexanone (20.6 g, 117.6 mmol), [S]-(-)-1-amino-2-(methoxymethyl)pyrrolidine (`SAMP`) (15.4 g, 118 mmol) and p-toluenesulphonic acid (316 mg) was refluxed in toluene (475 ml) for 4 hours. The toluene was removed in vacuo to afford an oil which was dissolved in diethyl ether (340ml) and washed with aqueous saturated sodium bicarbonate solution (2×170 ml). The organic phase was dried over magnesium sulphate then filtered and concentrated in vacuo to afford [2S]-2-(methoxymethyl)-1-[2-(pyrid-3-yl)cyclohexylidenamino]pyrrolidine (30.8 g, 113 mmol) as a 50:50 mixture of diastereoisomers;
Reaction SMILES: C1(C(N)=O)CC1.[C:7]([NH2:11])([CH3:10])([CH3:9])[CH3:8].[CH:12]1([C:15]2N(C)[C:18]([CH:21]=[O:22])=[CH:17][N:16]=2)[CH2:14][CH2:13]1>>[C:7]([N:11]1[C:18]([CH:21]=[O:22])=[CH:17][N:16]=[C:15]1[CH:12]1[CH2:14][CH2:13]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: Cn1c(C=O)cnc1C1CC1
Reactant: CC(C)(C)N
Agent: NC(=O)C1CC1
Product: CC(C)(C)n1c(C=O)cnc1C1CC1

Procedure:
3-tert-Butyl-2-cyclopropyl-3H-imidazole-4-carbaldehyde was prepared from cyclopropyl carboxamide and tert-butylamine in the same manner as 2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.[C:12]([C:16]1[CH:17]=[CH:18][C:19]([O:25][CH3:26])=[C:20]([CH:24]=1)[C:21](Cl)=[O:22])([CH3:15])([CH3:14])[CH3:13].Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([O:25][CH3:26])=[C:20]([CH:24]=1)[C:21]([NH:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:22])([CH3:15])([CH3:13])[CH3:14]
Reactant: COc1ccc(CCN)cc1
Reactant: COc1ccc(C(C)(C)C)cc1C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(CCNC(=O)c2cc(C(C)(C)C)ccc2OC)cc1

Procedure:
1.51 g (10.0 mmol) of 2-(4-methoxyphenyl)ethylamine were dissolved in 40 ml of pyridine and admixed with a spatula tip of 4-dimethylaminopyridine and then with a solution of 2.15 g (10.5 mmol) of 5-tert-butyl-2-methoxybenzoyl chloride. After the 2-(4-methoxyphenyl)ethylamine had been converted completely, the reaction mixture was poured into cold dilute hydrochloric acid, and the precipitated product was filtered off with suction and dried to give 5-tert-butyl-2-methoxy-N-[2-(4-methoxyphenyl)ethyl]benzamide as a colorless solid. The benzamide was introduced into cold chlorosulfonic acid. After the benzamide had been converted completely, the reaction mixture was poured onto ice and filtered off with suction, and the precipitate was dissolved in acetone. This solution was admixed with excess concentrated aqueous ammonia. After the exothermic reaction had subsided, the mixture was concentrated to a third of its original volume and the precipitate was filtered off with suction. The 5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-methoxybenzenesulfonamide was obtained in the form of colorless crystals of melting point 165-168° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].Cl[CH2:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([S:20]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)(=[O:22])=[O:21])[CH2:16][CH2:15]1)=[O:13].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:11][C:12]([N:14]1[CH2:15][CH2:16][N:17]([S:20]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)(=[O:21])=[O:22])[CH2:18][CH2:19]1)=[O:13]
Reactant: O=C(CCl)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(COc1ccc(F)cc1F)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Yield: 73.8 %

Procedure:
2,4-difluoro phenol (110 mg, 0.85 mmol), 2-chloro-1-(4-(naphthalen-2-ylsulfonyl)piperazin-1-yl)ethanone (compound 5, 0.3 g, 0.85 mmol) and anhydrous potassium carbonate (0.352 g, 2.55 mmol) were stirred for over night in dry acetonitrile (20 mL). The mixture was poured into a large volume of water and the solution extracted with ether. Un-reacted phenol was removed with cold 1N NaOH solution. The ether extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by re-crystallization to yield the title compound (280 mg, 73.87% yield) as an off-white solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]([CH3:20])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=2)[CH2:4][C@H:3]1[O:21][CH2:22][CH3:23].[Cl:24][C:25]1[N:26]=[C:27]([C:32](O)=[O:33])[NH:28][C:29]=1[CH2:30][CH3:31].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.ClCCl>[Cl:24][C:25]1[N:26]=[C:27]([C:32]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[O:9][C:10]([CH3:20])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=3)[CH2:4][C@H:3]2[O:21][CH2:22][CH3:23])=[O:33])[NH:28][C:29]=1[CH2:30][CH3:31]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](N)[C@H](OCC)C2)oc1C
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)oc1C
Yield: 43.6 %

Procedure:
The same operation as in Example (106d) was performed using butyl cis(±)-2-(4-amino-3-ethoxypiperidin-1-yl)-5-methyl-1,3-oxazole-4-carboxylate obtained in Example (112h) (0.66 g, 2.03 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (85% content, 0.2 g, 1 mmol), WSC hydrochloride (0.5 g, 2.5 mmol), HOBt (0.2 g, 1.5 mmol), dichloromethane (5 mL) and DMA (3 mL), to obtain 0.21 g of the title compound as a yellow amorphous solid (44%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[N+:12]([C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[Cl:22])[NH2:18])([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:16]=[C:17]([NH:18][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:19]=[CH:20][C:21]=1[Cl:22])([O-:14])=[O:13]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Product: O=C(O)Cc1ccccc1Nc1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3-nitro-4-chloroaniline to yield 2-[(3-nitro-4-chlorophenyl)amino]phenylacetic acid.
Reaction SMILES: [CH3:1][S:2]([N:5]([CH3:9])[C:6](Cl)=[O:7])(=[O:4])=[O:3].C(N(CC)CC)C.[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[Cl:25])[NH2:21]>O1CCCC1>[CH3:9][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[C:6]([NH:21][C:20]1[CH:22]=[CH:23][C:24]([Cl:25])=[C:18]([Cl:17])[CH:19]=1)=[O:7]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CN(C(=O)Cl)S(C)(=O)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)Nc1ccc(Cl)c(Cl)c1)S(C)(=O)=O
Reaction time: 3 h
Yield: 58.2 %

Procedure:
A solution of 16 g of N-methylsulfonyl-N-methyl-carbamoyl chloride in 100 ml of tetrahydrofuran was slowly added at less than 10° C. to a mixture of 150 ml of tetrahydrofuran, 9.4 g of triethylamine and 15 g of 3,4-dichloroaniline and after stirring for 3 hours, the insolubles were removed by filtration, and the filtrate was concentrated to dryness under reduced pressure to obtain 16 g of N-methyl-N-methylsulfonyl-N'-(3,4-dichlorophenyl)-urea melting at 140° C. Crystallization from ethanol gave an unchanged melting point.
Reaction SMILES: C(NC(C1SC(N2C(O)CN(CC3C=CC(F)=CC=3)C2=O)=NC=1C)=O)C1C=CC=CC=1.[F:32][C:33]1[CH:62]=[CH:61][C:36]([CH2:37][N:38]2[CH2:42][CH:41](O)[N:40]([C:44]3[S:45][C:46]([C:50]([NH:52][CH2:53][C:54]4[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=4)=[O:51])=[C:47]([CH3:49])[N:48]=3)[C:39]2=[O:60])=[CH:35][CH:34]=1>>[F:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:37][N:38]2[CH:42]=[CH:41][N:40]([C:44]3[S:45][C:46]([C:50]([NH:52][CH2:53][C:54]4[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=4)=[O:51])=[C:47]([CH3:49])[N:48]=3)[C:39]2=[O:60])=[CH:61][CH:62]=1
Reactant: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)CC2O)sc1C(=O)NCc1cccnc1
Agent: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)CC2O)sc1C(=O)NCc1ccccc1
Product: Cc1nc(-n2ccn(Cc3ccc(F)cc3)c2=O)sc1C(=O)NCc1cccnc1
Yield: 81 %

Procedure:
Following the procedure as described in Example 17, making variations as required to replace N-benzyl-2-(3-(4-fluorobenzyl)-5-hydroxy-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxamide with 2-(3-(4-fluorobenzyl)-5-hydroxy-2-oxoimidazolidin-1-yl)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide, the title compound was obtained as a colorless solid in 81% yield: mp 158-159° C. (ethyl acetate/hexanes): 1H NMR (300 MHz, CDCl3) δ 8.58 (d, J=1.5 Hz, 1H), 8.49 (dd, J=4.5, 1.5 Hz, 1H), 7.69-7.65 (m, 1H), 7.26-7.16 (m, 4H), 7.04-6.97 (m, 2H), 6.47 (t, J=5.7 Hz, 1H), 6.29 (d, J=3.3 Hz, 1H), 4.78 (s, 2H), 4.58 (d, J=5.7 Hz, 2H), 2.62 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.6, 162.2, 153.5, 150.5, 149.2, 149.0, 135.6, 133.7, 131.3, 129.8, 123.6, 119.5, 116.1, 115.8, 113.1, 107.6, 46.7, 41.5, 17.2; MS (ES+) m/z 424.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10][OH:11])[CH:9]=1)=[O:4].[I:13][C:14]1[CH:19]=[CH:18][C:17](O)=[CH:16][N:15]=1>>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10][O:11][C:17]2[CH:16]=[N:15][C:14]([I:13])=[CH:19][CH:18]=2)[CH:9]=1)=[O:4]
Reactant: Oc1ccc(I)nc1
Reactant: COC(=O)c1cc(CO)c(C)o1
Product: COC(=O)c1cc(COc2ccc(I)nc2)c(C)o1

Procedure:
Compound (54) was prepared from compound (16) and 2-iodo-5-hydroxy-pyridine in a manner analagous to that described in Example 5(a). LC/MS System A: Rt=3.52 mins, m/z=374 (M+H) for C13H12INO4)
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[O:12])=[C:3]1[CH2:35][C:36]([O:38]CC)=[O:37].[OH-].[Na+]>CO.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[O:12])=[C:3]1[CH2:35][C:36]([OH:38])=[O:37]
Reactant: CCOC(=O)Cc1c(C(=O)N2CCN(c3ccc(OCCCN4CCCCC4)cc3)CC2)c2ccccc2n1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1c(CC(=O)O)c(C(=O)N2CCN(c3ccc(OCCCN4CCCCC4)cc3)CC2)c2ccccc21
Yield: 39 %

Procedure:
A solution of ethyl (1-methyl-3-{[4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-1-piperazinyl]carbonyl}-1H-indol-2-yl)acetate (E60) [54 mg] in methanol [6 ml] and water [0.8 ml] was treated with 2N sodium hydroxide [0.46 ml] and was heated under reflux for 2 h. The reaction mixture was quenched with hydrochloric acid [10 ml] at room temperature. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and water. The organic phase was dried and concentrated in vacuo to give the title compound (20 mg). LCMS RT=2.35 min, 518 (M+H)+
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:17]=[CH:16][C:11]3[B:12]([OH:15])[O:13][CH2:14][C:10]=3[CH:9]=2)=[CH:5][CH:4]=1.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.CCN(CC)CC>C(Cl)Cl>[OH:15][B:12]1[C:11]2[CH:16]=[CH:17][C:8]([O:7][C:6]3[CH:18]=[CH:19][C:3]([CH2:2][NH:1][S:27]([C:24]4[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=4)(=[O:29])=[O:28])=[CH:4][CH:5]=3)=[CH:9][C:10]=2[CH2:14][O:13]1
Reactant: NCc1ccc(Oc2ccc3c(c2)COB3O)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NCc2ccc(Oc3ccc4c(c3)COB4O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 20 mL scintillation vial containing 5-(4-aminomethyl-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol (144 mg, 0.56 mmol, 1.1 eq.), 4-methyl-benzenesulfonyl chloride (118.4 mg, 0.62 mmol, 1.1 eq.) in DCM (10.0 mL) was added Et3N (160 μL, 1.12 mmol, 2.0 eq.) drop wise. The mixture was stirred at room temperature overnight. The mixture was carefully treated with aqu. NH4Cl (10 mL) and the layers were separated. The aqueous was extracted with DCM (2×5 mL), combined organic phase was washed with H2O (10 mL), brine (10 mL), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The residue was applied to silica chromatography eluting with EtOAc/Heptanes (0:100 to 80:20) to give N-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-4-methyl-benzenesulfonamide as a white solid. LCMS (m/z) 432 (M+23); 1H NMR (400 MHz, DMSO-d6) δ ppm 1H NMR (DMSO-d6) δ: 9.11 (s, 1H), 8.08 (t, J=6.3 Hz, 1H), 7.65-7.74 (m, 3H), 7.38 (d, J=8.0 Hz, 2H), 7.23-7.31 (m, J=8.6 Hz, 2H), 6.95-7.00 (m, 2H), 6.89-6.95 (m, 2H), 4.92 (s, 2H), 3.95 (d, J=6.3 Hz, 2H), 2.38 (s, 3H).
Reaction SMILES: Cl[CH2:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1>C(#N)C>[N:11]1([CH2:2][O:3][C:4]2[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=2)[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: ClCOc1ccc(Cl)cc1
Reactant: c1nc[nH]n1
Solvent: CC#N
Product: Clc1ccc(OCn2cncn2)cc1
Temperature: 25 °C

Procedure:
α-Chloro-p-chloroanisole (10.6 g) and 1,2,4-triazole (12.4 g) in acetonitrile (120 ml) were refluxed for 48 hours. After cooling to room temperature, triazole hydrochloride was filtered off and acetonitrile removed at reduced pressure to give a sticky gum which was extracted with hot petroleum ether (80°-100°) and allowed to cool slowly to give colourless prisms of the title compound.
Reaction SMILES: [OH:1][C:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH2:24][C:25]([CH3:27])=[CH2:26])[CH2:3][CH2:4][N:5]([C:10]([C:13]1[N:14]=[N:15][N:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=1)([CH3:12])[CH3:11])[C:6](=O)[O:7]C.[H-].[Na+]>C1COCC1.Cl.CO>[CH3:27][C:25](=[CH2:26])[CH2:24][C:2]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:1][C:6](=[O:7])[N:5]([C:10]([C:13]2[N:14]=[N:15][N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=2)([CH3:11])[CH3:12])[CH2:4][CH2:3]1
Reactant: C=C(C)CC(O)(CCN(C(=O)OC)C(C)(C)c1cn(-c2ccccc2)nn1)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C=C(C)CC1(c2ccccc2)CCN(C(C)(C)c2cn(-c3ccccc3)nn2)C(=O)O1
Yield: 67.4 %

Procedure:
To a stirred solution of methyl 3-hydroxy-5-methyl-3-phenylhex-5-enyl(2-(1-phenyl-1H-1,2,3-triazol-4-yl)propan-2-yl)carbamate (14 mg, 0.031 mmol) in dry THF (1 mL) was added 60% NaH in oil (10 mg, 0.25 mmol). The mixture was heated at 50 C in an oil bath for 1.5 h, cooled, diluted with 5% aq HCl (0.5 mL) and MeOH (0.5 mL) and purified by prep HPLC to afford the title compound (8.7 mg, 67%) as an oil. LC-MS Method 1 tR=1.90 min, m/z=417; 1H NMR (CDCl3) 1.58 (s, 3H), 1.76 (s, 6H), 2.25 (m, 1H), 2.36 (m, 1H), 2.56 (dd, 2H), 3.03 (m, 1H), 3.52 (m, 1H), 4.58 (s, 1H), 4.81 (s, 1H), 7.25-7.80 (11H).
Reaction SMILES: CS(C)=O.[CH3:5][C:6]([O:9][C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11])([CH3:8])[CH3:7].F[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>O>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([N:16]2[CH2:15][CH2:14][CH:13]([NH:12][C:10](=[O:11])[O:9][C:6]([CH3:5])([CH3:7])[CH3:8])[CH2:18][CH2:17]2)=[CH:21][CH:22]=1)#[N:25]
Reactant: N#Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(C#N)cc2)CC1
Temperature: 100 °C
Yield: 85 %

Procedure:
A DMSO (25 mL, 0.1M) solution containing 4-N—BOC-aminopiperidine (500 mg, 2.5 mmol, 1.0 eq), 4-fluorobenzonitrile (303 mg, 2.5 mmol, 1.0 eq), and potassium carbonate (691 mg, 5.0 mmol, 2.0 eq) was heated to 100° C. for 18 h. The resulting mixture was cooled to RT, poured in H2O (ca 50 mL), and extracted (3×) with EtOAc. The combined extracts were washed (2×) with H2O, dried over MgSO4, and concentrated in vacuo. The resulting solid was used in the next step without further purification. Isolated 642 mg (2.13 mmol, 85% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6](Cl)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Cu](C#N)[C:23]#[N:24]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:23]#[N:24])=[CH:4][CH:3]=1
Reactant: Clc1ccc(C(Cl)(c2ccccc2)c2ccccc2)cc1
Reactant: N#C[Cu]C#N
Solvent: Cc1ccccc1
Product: N#CC(c1ccccc1)(c1ccccc1)c1ccc(Cl)cc1
Temperature: 150 °C

Procedure:
2-(4-Chlorophenyl) 2,2-diphenylacetonitrile was synthesized by carefully triturating 1.50 g (4.8 mmol) of 4-chlorotrityl chloride with 1.00 g (11 mmol) of copper cyanide and the resulting mixture was heated for 4 hours at 150° C. without a solvent. After cooling 50 ml of toluene was added, the mixture was filtered and the filtrate was concentrated in vacuo. The resulting residue was recrystallized from petroleum ether (40-60° C.) to give 0.66 g (45%) of the triarylmethyl acetonitrile derivative.
Reaction SMILES: [CH3:1][C:2]1[N:41]=[C:5]2[N:6]([C@H:29]3[CH2:34][CH2:33][C@H:32]([O:35][CH2:36][C:37]4([CH3:40])[CH2:39][O:38]4)[CH2:31][CH2:30]3)[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[FH:59].F.[F-]>ClC1C=CC=CC=1>[F:59][CH2:39][C:37]([OH:38])([CH3:40])[CH2:36][O:35][C@H:32]1[CH2:33][CH2:34][C@H:29]([N:6]2[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:18][CH:19]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]3[N:3]=[C:2]([CH3:1])[N:41]=[C:5]23)[CH2:30][CH2:31]1
Reactant: F
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3(C)CO3)CC2)c2nc(C)nn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: Clc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(O)CF)CC2)c2nc(C)nn12
Temperature: 120 °C
Reaction time: 20 h

Procedure:
A mixture of 4′-[(2-methyl-4-{trans-4-[(2-methyloxiran-2-yl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.19 g), tetra-n-butylammonium dihydrogentrifluoride (0.65 g) and chlorobenzene (0.5 mL) was stirred at 120° C. for 20 hr. The reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.094 g, 46%).