Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@@H:8]([C:11](=O)[NH:12][CH2:13][C:14]2[C:19]([Cl:20])=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)=O.[OH-].[NH4+]>C(#N)C.CN(C)C=O>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@@H:8]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([Cl:20])[C:14]3=[CH:13][N:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@H](C(=O)NCc2nccnc2Cl)CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)O[C@H]1CC[C@@H](c2ncc3c(Cl)nccn32)CC1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To (cis)-4-((3-chloropyrazin-2-yl)methylcarbamoyl)cyclohexyl acetate (52.9 mmol, 16.5 g) in acetonitrile (150 ml) were added dropwise subsequently phosphorus oxychloride (159 mmol, 14.80 ml) and N,N-dimethylformamide (2.65 mmol, 0.206 ml). After addition the reaction mixture was stirred at 70° C. for one hour. The reaction mixture was cooled to room temperature and added dropwise to a mixture of 25% ammonium hydroxide (125 ml) and crushed ice (350 ml). This mixture was stirred for 30 minutes at room temperature and the off white solid was isolated by filteration and rinsed with water. The solids were dissolved in dichloromethane (200 ml) and washed with water (50 ml) and brine, dried (MgSO4), and concentrated in vacuo to give (cis)-4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexyl acetate (10.9 g). A second crop of material was obtained by extraction of the filtrate twice using dichloromethane/methanol (10/1, 275 mL). The organic layers were combined and washed with brine, dried (MgSO4) and concentrated in vacuo to give an additional amount of (cis)-4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexyl acetate (3.2 g).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]1[C@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]2[C@H:12]([N:20]2[CH:28]=[N:27][C:26]3[C:21]2=[N:22][CH:23]=[N:24][C:25]=3[CH2:29][CH2:30][O:31][CH3:32])[O:11]1)(C(C)(C)C)(C)C.F>C1COCC1.N1C=CC=CC=1.N1C=CC=CC=1>[CH3:32][O:31][CH2:30][CH2:29][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[C:26]=1[N:27]=[CH:28][N:20]2[C@H:12]1[C@@H:13]2[O:17][C:16]([CH3:18])([CH3:19])[O:15][C@@H:14]2[C@@H:10]([CH2:9][OH:8])[O:11]1
Reactant: COCCc1ncnc2c1ncn2[C@@H]1O[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]2OC(C)(C)O[C@H]21
Agent: F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COCCc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@H]2OC(C)(C)O[C@H]21
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To a solution of 9-[(3aR,4R,6R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-6-(2-methoxyethyl)-9H-purine (70 mg, 0.15 mmol) in THF/pyridine (1.5 mL, 1:1) was added hydrofluoric acid in pyridine (15 drops). The reaction was stirred overnight, quenched with saturated aq NaHCO3, extracted with EtOAc, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (0 to 50% DCM/EtOAc to furnish 37 mg (70%) of the title compound.
Reaction SMILES: [O:1]([CH:8](OC1C=CC=CC=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)C1C=CC=CC=1.S(=O)(=O)(O)O.O>O1CCOCC1>[O:15]([C:11]1[N:10]=[C:9]([CH:8]=[O:1])[CH:14]=[CH:13][CH:12]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(Oc2cccc(C(Oc3ccccc3)Oc3ccccc3)n2)cc1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1cccc(Oc2ccccc2)n1
Yield: 111.3 %

Procedure:
To a solution of 0.5 g of 2-[bis-(phenoxy)methyl]-6-(phenoxy)pyridine in 15 ml of 1,4-dioxane was added dropwise, 5 percent sulfuric acid until the mixture just became turbid. The mixture was heated over a steam bath at 80°-90° C. for about 10 minutes. The reaction mixture was poured into 20 ml of water, producing a yellowish emulsion and then extracted with 50 ml of ethyl ether. The extract was washed with 50 ml of a 5 percent aqueous sodium hydroxide solution and thrice with 50 ml portions of water and then with 50 ml of a saturated sodium chloride solution. The extract was then dried over sodium sulfate and the solvent removed by evaporation under reduced pressure. The residue was a yellow-orange oil which solidified partially on cooling to yield 0.3 g of the desired product. The product was confirmed by Infrared and Nuclear Magnetic resonance analysis.
Reaction SMILES: Br[C:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[CH:9][CH:8]=1)([CH3:6])[CH2:3][CH2:4][OH:5].FC1C=C(F)C=CC=1C1C=CC(C(C)CCO)=CC=1.[C:40]([O-:43])(=[O:42])[CH3:41].[K+]>>[C:40]([O:43][C:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[CH:9][CH:8]=1)([CH3:6])[CH2:3][CH2:4][OH:5])(=[O:42])[CH3:41]
Reactant: CC(Br)(CCO)c1ccc(-c2ccc(F)cc2F)cc1
Reactant: CC(=O)[O-]
Agent: CC(CCO)c1ccc(-c2ccc(F)cc2F)cc1
Agent: [K+]
Product: CC(=O)OC(C)(CCO)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
Analogously to Example 25 (a), 3-bromo-3-(2',4'-difluoro-4-biphenylyl)butan-1-ol, obtained by brominating 3-(2',4'-difluoro-4-biphenylyl)butan-1-ol, and potassium acetate are reacted to give 3-acetoxy-3-(2',4'-difluoro-4-biphenylyl)butan-1-ol.
Reaction SMILES: C[C:2]1([N:8]2[C:12]([C:13]3[S:25][C:16]4[N:17]=[CH:18][N:19]=[C:20]([S:21]([CH3:24])(=[O:23])=[O:22])[C:15]=4[CH:14]=3)=[CH:11][N:10]=[CH:9]2)C=CC=CC1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31](C2N=CN(C)C=2C2SC3N=CN=C(SC)C=3C=2)=[CH:30][CH:29]=1>>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:11]2[N:10]=[CH:9][N:8]([CH3:2])[C:12]=2[C:13]2[S:25][C:16]3[N:17]=[CH:18][N:19]=[C:20]([S:21]([CH3:24])(=[O:22])=[O:23])[C:15]=3[CH:14]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(-c2ncn(C)c2-c2cc3c(SC)ncnc3s2)cc1
Reactant: CC1(n2cncc2-c2cc3c(S(C)(=O)=O)ncnc3s2)C=CC=CC1
Product: COc1ccc(-c2ncn(C)c2-c2cc3c(S(C)(=O)=O)ncnc3s2)cc1

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 17 but using 6-[4-(4-methoxyphenyl)-1-methyl-1H-imidazol-5-yl]-4-(methylthio)thieno[2,3-d]pyrimidine (Intermediate 105) in place of 6-(1-methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylthio)thieno[2,3-d]pyrimidine (Example 7). Brown gum (3.13 g, 100%);
Reaction SMILES: [CH3:1][C:2]([O:13][C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([C:21](=[O:39])[N:22]([C@@H:26]2[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]2)[CH:23]([CH3:25])[CH3:24])=[CH:16][C:15]=1[N+:40]([O-])=O)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3](OCC)=[O:4]>C(O)(=O)C.[Fe]>[CH3:1][C:2]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3](=[O:4])[NH:40][C:15]2[CH:16]=[C:17]([C:21](=[O:39])[N:22]([C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[O:33])[CH2:27]3)[CH:23]([CH3:24])[CH3:25])[C:18]([CH3:20])=[CH:19][C:14]=2[O:13]1
Reactant: CCOC(=O)C(C)(Oc1cc(C)c(C(=O)N(C(C)C)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)cc1[N+](=O)[O-])C(=O)OCC
Agent: [Fe]
Solvent: CC(=O)O
Product: CCOC(=O)C1(C)Oc2cc(C)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc2NC1=O
Temperature: 25 °C
Yield: 57.1 %

Procedure:
Subsequently, to a suspension of iron (110 g) in acetic acid (500 ml) was added dropwise a solution of the obtained diethyl methyl(5-methyl-4-{[(3R)-1-{[(2-methyl-2-propanyl)oxy]carbonyl}-3-piperidinyl](2-propanyl)carbamoyl}-2-nitrophenoxy)propanedioate (205 g) in acetic acid (200 ml) slowly at 90° C. Ten hours later, the mixture was allowed to cool to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure. To the obtained residue was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography to give the title compound (102 g).
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Li]CCCC.C([O:21][C:22](=O)[C:23]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([Cl:36])[CH:30]=2)[C:26]([O:37][CH2:38][CH2:39][OH:40])=[C:25]([Br:41])[CH:24]=1)C>C1COCC1.O.Cl>[CH2:1]([NH:13][C:22](=[O:21])[C:23]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([Cl:36])[CH:30]=2)[C:26]([O:37][CH2:38][CH2:39][OH:40])=[C:25]([Br:41])[CH:24]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN
Reactant: CCOC(=O)c1cc(Br)c(OCCO)c(-c2ccc(F)c(Cl)c2)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCO)c(-c2ccc(F)c(Cl)c2)c1
Temperature: 25 °C
Yield: 56.3 %

Procedure:
Into a flamed dried round bottom flask charged with n-dodecylamine (586 mg, 3.16 mmol) in 7 mL THF at −20° C. was added n-BuLi (1.8 mL, 3.6 mmol) as a solution in hexanes. After the addition, the reaction was warmed up to room temperature and stirred for one-half hour. Then the solution was cooled to −20° C. and was added to a solution of 3-bromo-4-(2-hydroxyethoxy)-5-(3-chloro-4-fluorophenyl)benzoic acid ethyl ester (400 mg, 0.957 mmol) in 8 mL THF that had been previously cooled to −40° C. The resulting mixture was stirred at 40° C. for 5 min after which point the reaction mixture was allowed to warm up to room temperature. The reaction was diluted with water and 2N HCl then extracted with EtOAc three times. The combined organic extracts were washed with sat NaHCO3 then dried over Na2SO4. After filtering and removal of solvent in vacuo, there yielded a yellow oil that was subjected to column chromatography on silica gel (10% EtOAc:90% Hexanes followed by 25% EtOAc:75% Hexanes). There resulted 300 mg, 58% of the amide as a yellow oil. 1H NMR (CDCl3) 0.868 (t, J=8.13 Hz, t); 1.20-1.40 (m, 18H); 1.48-1.67 (m, 2H); 1.895-2.00 (bs, 1H); 3.427 (q, J=8.13 Hz, 2H); 3.636-7.71 (m, 4H); 6.014 (m, 1H); 7.20-7.24 (m, 1H); 7.40-7.454 (m, 1H); 7.586-7.668 (m, 2H); 7.868 (d, J=2.04 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:22][C:23]1[C:35]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:34][C:26]2[O:27][CH:28]([C:31](O)=[O:32])[CH2:29][O:30][C:25]=2[CH:24]=1>>[OH:22][C:23]1[C:35]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:34][C:26]2[O:27][CH:28]([C:31]([N:12]3[CH2:11][CH2:10][N:9]([CH:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)[CH2:14][CH2:13]3)=[O:32])[CH2:29][O:30][C:25]=2[CH:24]=1
Reactant: CC(C)(C)c1cc2c(cc1O)OCC(C(=O)O)O2
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Product: CC(C)(C)c1cc2c(cc1O)OCC(C(=O)N1CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC1)O2
Yield: 74 %

Procedure:
That compound is obtained in a yield of 74% starting from 1-[bis(4-fluorophenyl) methyl]piperazine and 6-hydroxy-7-tert-butyl-2,3-dihydro-1,4-benzodioxin-2-carboxylic acid.
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7]([N:9]1[CH2:16][C:15](=[O:17])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=[O:3])[CH3:2].[N+](=[CH2:20])=[N-]>CCOCC>[C:1]([S:4][CH2:5][CH2:6][C:7]([N:9]1[CH2:16][C:15](=[O:17])[CH2:14][C@H:10]1[C:11]([O:13][CH3:20])=[O:12])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCCC(=O)N1CC(=O)C[C@H]1C(=O)O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)[C@@H]1CC(=O)CN1C(=O)CCSC(C)=O
Reaction time: 2 h

Procedure:
A solution of the product of Example 1 in ether is treated with a slight excess of diazomethane. After standing at room temperature for two hours, the solvent is evaporated to give 1-[3-(acetylthio)-1-oxopropyl]-4-oxo-L-proline, methyl ester.
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[CH2:4]Cl.[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13]>COCCOC.C(O)C>[Cl:1][CH2:2][C:3]1[N:13]=[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]2[CH:4]=1
Reactant: Nc1ccccn1
Reactant: O=C(CCl)CCl
Solvent: CCO
Solvent: COCCOC
Product: ClCc1cn2ccccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a solution of 1,3-dichloropropan-2-one (1.40 g, 11 mmol) in 1,2-dimethoxyethane (5 mL), pyridin-2-amine (0.94 g 10 mmol) was added. The solid dissolved immediately and a white precipitate was observed. The mixture was stirred at room temperature for 1 h, and then was cooled to 0° C. for 20 min. The resulting mixture was filtered to give a white solid. The precipitate was suspended in ethanol (EtOH) (40 mL) and heated at reflux to render a clear solution. After refluxing for 2 h, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in water and saturated aqueous NaHCO3 solution was added to adjust the pH to ˜7.0. A white suspension formed during the course of addition. The resulting mixture was stirred for 20 min and then filtered to give the title compound as a white solid (0.5 g, 30% yield). ESI MS: m/z 167 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J=6.8 Hz, 1H), 7.97 (s, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.23 (t, J=7.6 Hz, 1H), 6.88 (t, J=6.4 Hz, 1H), 4.82 (s, 2H).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:10]=[C:11]([OH:19])[CH:12]=[C:13]2[C:18]=1[CH:17]=[N:16][CH:15]=[CH:14]2.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>ClCCl>[CH3:30][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:19][C:11]2[CH:12]=[C:13]3[C:18](=[C:9]([Br:8])[CH:10]=2)[CH:17]=[N:16][CH:15]=[CH:14]3)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Oc1cc(Br)c2cnccc2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2cc(Br)c3cnccc3c2)cc1
Reaction time: 15 h
Yield: 70.9 %

Procedure:
Triethylamine (0.137 mL) was added to a dichloromethane (5 mL) solution of Intermediate 7 (100 mg) and p-toluenesulfonic acid chloride (66 mg; WAKO) at room temperature and the resulting mixture was stirred as it was for 15 hours. The resulting mixture was diluted with dichloromethane and washed with water, the organic layer was dried, then the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (Yamazen; n-hexane/ethyl acetate) to give the title compound (92.9 mg).
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[OH:1][C:2]1([C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)[CH2:7][CH2:6][CH:5]([N:15]2[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=3)=[O:21])[CH2:16]2)[CH2:4][CH2:3]1
Reactant: Cc1csc(C2(O)CCC(=O)CC2)n1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: Cc1csc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)n1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-(4-methyl-thiazol-2-yl)-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[NH2:6].[CH2:12](O)[CH2:13][CH2:14][CH2:15]C.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:2][C:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[NH2:6])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCO
Reactant: COC(=O)c1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCOC(=O)c1ccccc1N
Reaction time: 8 h
Yield: 95 %

Procedure:
450 parts of anthranilic acid methyl ester, 500 parts of n-pentanol and 10 parts of potassium carbonate are reacted as described in Example 1. The reaction lasts for about 8 hours. There are obtained 588 parts of anthranilic acid n-pentyl ester (boiling point 132°-135° C. under 0.3-0.4 mm Hg; nD25 1.538; purity according to gas chromatography 99%, below 0.2% of anthranilic acid methyl ester). Yield: 95% of the theory.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].Cl[C:20]1[N:25]=[N:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=1.[H-].[Na+].[NH4+].[Cl-].Cl>C1COCC1>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:20]3[N:25]=[N:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Reactant: N#Cc1ccc(Cl)nn1
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCOC(=O)CC1OB(O)c2cc(Oc3ccc(C#N)nn3)cc(C)c21
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.5 %

Procedure:
To a stirred solution of (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (1.0 g, 3.9 mmol) and 6-chloro-pyridazine-3-carbonitrile (1.12 g, 7.9 mmol) in THF (50 mL) at 0° C. was added NaH (0.38 g) in portions. The reaction mixture was allowed to warm to room temperature and stirred for 12 hours. Saturated NH4Cl (10 mL) was added at 0° C. and the solution acidified to pH˜4 with 1N HCl. The mixture was extracted with EtOAc (2×15 mL) and the organic extracts washed with water (10 mL), dried and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (DCM:MeOH 95:5) to give [6-(6-cyano-pyridazin-3-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.75 g, 53%). 1H NMR (400 MHz, CDCl3): δ 9.27 (s, 1H), 8.36 (d, J=9.2 Hz, 1H), 7.71 (d, J=9.2 Hz, 1H), 7.33 (d, J=2.0 Hz, 1H), 7.18 (d, J=1.6 Hz, 1H), 5.55 (dd, J=2.4, 9.2 Hz, 1H), 4.04 (q, J=6.8 Hz, 2H), 3.14 (dd, J=2.4, 15.6 Hz, 1H), 2.36-2.32 (m, 1H), 2.31 (s, 3H), 1.13 (t, J=6.8 Hz, 3H). MS (ESI) m/z=354 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[C:35]([F:38])([F:37])[F:36].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O>[Cl:8][C:6]1[CH:7]=[C:2]([C:31]2[CH:32]=[CH:33][C:34]([C:35]([F:37])([F:38])[F:36])=[C:29]([Cl:28])[CH:30]=2)[N:3]=[CH:4][N:5]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OB(O)c1ccc(C(F)(F)F)c(Cl)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.7 %

Procedure:
To a solution of CH3CN and water (75:25 mL) that has been degassed by bubbling N2 into the solvent were added 4,6-dichloro-pyrimidine (3.63 g, 22.7 mmol) and Ph3P (840 mg, 2.2 mmol). De-gassing was continued for an additional 15 min before adding 3-chloro-4-trifluoromethylphenyl boronic acid (5 g, 22 mmol), Pd (OAc)2 (250 mg, 1.11 mmol) and K3PO4 (9.4 g, 44.3 mmol). The resulting mixture was stirred at rt for 2 h before diluting with water and extracting with EtOAc. The organic layer was dried (Na2SO4), and concentrated. The crude residue was purified (FCC) to give the title compound (2.3 g, 35%).
Reaction SMILES: COC1C=C(C2OC3C=CC=CC=3N=2)C=CC=1CN1C=CN=N1.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:33][C:34]3[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=3[N:36]=2)=[CH:28][C:27]=1[O:41][CH3:42].[Br:43][C:44]1[N:45]=[CH:46][NH:47][CH:48]=1>>[Br:43][C:44]1[N:45]=[CH:46][N:47]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[O:33][C:34]4[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=4[N:36]=3)=[CH:28][C:27]=2[O:41][CH3:42])[CH:48]=1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1CBr
Reactant: Brc1c[nH]cn1
Agent: COc1cc(-c2nc3ccccc3o2)ccc1Cn1ccnn1
Product: COc1cc(-c2nc3ccccc3o2)ccc1Cn1cnc(Br)c1

Procedure:
Utilizing the general procedure outlined for 2-[3-methoxy-4-(1H-1,2,3-triazol-1-ylmethyl)phenyl]-1,3-benzoxazole, reaction of 2-[4-(bromomethyl)-3-methoxyphenyl]-1,3-benzoxazole (300 mg, 1.0 mmol) and 4-bromo-1H-imidazole (150 mg, 1.0 mmol) afforded the desired 2-{4-[(4-bromo-1H-imidazol-1-yl)methyl]-3-methoxyphenyl}-1,3-benzoxazole as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 7.94–7.99 (m, 3H), 7.85–7.87 (m, 1H), 7.75–7.78 (m, 1H), 7.65–7.68 (m, 1H), 7.43–7.49 (m, 2H), 7.20 (s, 1H), 5.55 (s, 2H), 4.09 (s, 3H). MS (ESI) 384 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[C:20]([CH2:21][C@@H:22]5[CH2:26][CH2:25][N:24]([C:27]([CH:29]6[CH2:31][CH2:30]6)=[O:28])[CH2:23]5)=[N:19][NH:18][C:17]4=[O:32])=[CH:12][CH:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:40][C:41]([NH2:43])=[O:42]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[CH:12][C:13]([N:16]4[C:17](=[O:32])[N:18]([CH2:40][C:41]([NH2:43])=[O:42])[N:19]=[C:20]4[CH2:21][C@@H:22]4[CH2:26][CH2:25][N:24]([C:27]([CH:29]5[CH2:30][CH2:31]5)=[O:28])[CH2:23]4)=[CH:14][CH:15]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: NC(=O)CCl
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4occc4c3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)Cn1nc(C[C@@H]2CCN(C(=O)C3CC3)C2)n(-c2ccc(-c3ccc4occc4c3)cc2)c1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
To a solution of 4-[4-(1-benzofuran-5-yl)phenyl]-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (50 mg, 0.117 mmol) in N,N-dimethylformamide (1 mL) in a 5 mL microwaveable vial was added potassium carbonate (50 mg, 0.362 mmol, 3.1 eq) and 2-chloroacetamide (16 mg, 0.175 mmol, 1.5 eq). The vial was capped and purged with nitrogen gas, and the reaction mixture was stirred for 16 h at 80° C. Analysis by LC/MS displayed the reaction had gone to completion. The reaction mixture was cooled to room temperature and poured into a mixture of dichloromethane and water. The organic layer was separated. The aqueous layer was washed with dichloromethane. The organic extractions were combined and washed 3× with a dilute brine solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by reverse phase HPLC (LUNA C-18: 30×50 mm column; 20-50% acetonitrile w/0.1% TFA/water w/0.1% TFA). The product fractions were neutralized with the addition of saturated aq sodium bicarbonate, combined, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (25 mg, 44%). MS(ES)+ m/e 486.2 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[Cl:18])[C@@H:14]([C:19]([OH:21])=O)[CH2:13][CH2:12]2.[N:22]1([CH2:27][C@@H:28]2[CH2:33][S:32][CH2:31][CH2:30][NH:29]2)[CH2:26][CH2:25][CH2:24][CH2:23]1.C(P(=O)(OCC)OCC)#N>O1CCCC1>[N:22]1([CH2:27][C@@H:28]2[CH2:33][S:32][CH2:31][CH2:30][N:29]2[C:19]([C@@H:14]2[C:15]3[C:11](=[CH:10][C:9]([Cl:8])=[C:17]([Cl:18])[CH:16]=3)[CH2:12][CH2:13]2)=[O:21])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: O=C(O)[C@H]1CCc2cc(Cl)c(Cl)cc21
Reactant: C1CCN(C[C@@H]2CSCCN2)C1
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C([C@H]1CCc2cc(Cl)c(Cl)cc21)N1CCSC[C@H]1CN1CCCC1
Reaction time: 0.17 h
Yield: 56.1 %

Procedure:
9.0 ml of triethylamine were added dropwise to a solution of 14.7 g of (S)-5,6-dichloroindanecarboxylic acid in 200 ml of tetrahydrofuran at -25° to -20° C. under a stream of nitrogen and then a solution of 10.9 g of (R)-3-(1-pyrrolidinylmethyl)thiomorpholine in 50 ml of tetrahydrofuran was added dropwise thereto at the same temperature. After the solution was stirred for 10 minutes, a solution of 10.5 g of diethyl cyanophosphonate in 50 ml of tetrahydrofuran was added dropwise to the above solution and stirred at the same temperature for 30 minutes and then at 0° to 5° C. for an hour. After the tetrahydrofuran was distilled off, an aqueous solution of sodium hydrogencarbonate was added to the residue and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. After the organic solvent was distilled off, the residue was recrystallized from a mixture of ethyl acetate and hexane to give 13.1 g of the title compound. m.p.: 123°-124° C.