Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[C:28]1([S:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[CH:41]=O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+]>CCOCC>[C:28]1([S:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[CH:41]=[CH2:2])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=Cc1ccccc1Sc1ccccc1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCOCC
Product: C=Cc1ccccc1Sc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Methyl triphenylphosphonium iodide (1.57 g, 3.88 mmol) was dissolved in 25 mL ether in a 50 mL round-bottomed flask under dry nitrogen. To the mixture was added in one portion at 0° C. potassium tert-butoxide (0.47 g, 4.19 mmol) and it was stirred for 10 min at room temperature. 2-(phenylsulfanyl)benzenecarbaldehyde (2.77 mmol) was added in one portion at 0° C. and the reaction mixture was stirred until complete disappearance of the reactants (17 hr) at room temperature (followed by TLC). The mixture was added, to 50 mL of saturated sodium bicarbonate solution, followed by extraction with 3×50 mL portions of ether. The extracts were dried with magnesium sulfate and evaporated. The crude product was further purified by chromatography on silica gel using petroleum ether 60-80 as eluent. Yield: 0.53 g, 91%, colorless oil. 1H NMR (200 MHz, CDCl3): δ 5.33 (dd, J1=10.9, J2=1.2, 1H), 5.74 (dd, J1=17.4, J2=1.2, 1H), 7.16-7.65 (m, 10H) ppm.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:15][C:16]([NH:18][CH3:19])=[O:17].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:15][C:16]([NH:18][CH3:19])=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)CCl
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)CN1CCN(Cc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 18 h
Yield: 82.7 %

Procedure:
A mixture of 1-benzyl-piperazine (1.0 g, 5.67 mmol), 2-chloro-N-methylacetamide (671.2 mg, 6.24 mmol, 1.1 eq.), and potassium carbonate (941 mg, 6.81 mmol, 1.2 eq.) in anhydrous THF (23 mL) was stirred at 60° C. under N2 for 18 h. The mixture was cooled to rt and poured into EtOAc. The organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by MPLC (Biotage®, gradient elution 1:4:5 v/v MeOH:Acetone:DCM) to give 1.16 g (83%) of the product as a white solid. 1H-NMR (300 MHz, DMSO-d6) 7.62 to 7.56 (broad d, 1H), 7.33 to 7.20 (m, 5H), 3.45 (s, 2H), 2.85 (s, 2H), 2.58 (d, 3H), 2.44 to 2.33 (broad s, 8H); ES-MS m/z 248.2 [M+H]+, RT (min) 0.33.
Reaction SMILES: [NH:1]1[CH2:6][C:5](=[O:7])[CH2:4][CH2:3][C:2]1=[O:8].CC1(C2C=CC=CC=2)NC(=O)N([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:34]=[CH:33][C:23]3[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[N:25][O:26][C:22]=3[C:21]=2[CH2:35][CH2:36][CH3:37])C1=O>>[CH2:35]([C:21]1[C:22]2[O:26][N:25]=[C:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:23]=2[CH:33]=[CH:34][C:20]=1[O:19][CH2:18][CH2:17][CH2:16][N:1]1[CH2:6][C:5](=[O:7])[CH2:4][CH2:3][C:2]1=[O:8])[CH2:36][CH3:37]
Reactant: O=C1CCC(=O)NC1
Reactant: CCCc1c(OCCCN2C(=O)NC(C)(c3ccccc3)C2=O)ccc2c(-c3ccccc3)noc12
Product: CCCc1c(OCCCN2CC(=O)CCC2=O)ccc2c(-c3ccccc3)noc12

Procedure:
1-(3-{[7-Propyl-3-(phenyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperidin-2,5-dione was prepared as for Example 10 from piperidin-2,5-dione and the bromide from Example 27. After aqueous work-up and silica gel chromatography, the title compound was obtained.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)[N:3]=1.FC(F)(F)C(O)=O.[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21]([NH:28][C:29]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:30])=[N:20]1.C(N(CC)CC)C.O>CN(C)C=O>[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21]([NH:28][C:29]([N:31]2[CH2:36][CH2:35][N:34]([C:2]3[S:6][N:5]=[C:4]([C:7]4[CH:11]=[CH:10][S:9][CH:8]=4)[N:3]=3)[CH2:33][CH2:32]2)=[O:30])=[N:20]1
Reactant: O=C(Nc1noc2ccccc12)N1CCNCC1
Reactant: Clc1nc(-c2ccsc2)ns1
Solvent: O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1noc2ccccc12)N1CCN(c2nc(-c3ccsc3)ns2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
To a solution of 5-chloro-3-(3-thienyl)-1,2,4-thiadiazole (119 mg, 0.555 mmol) and N-1,2-benzisoxazol-3-ylpiperazine-1-carboxamide trifluoroacetate (200 mg, 0.555 mmol) in N,N-dimethylformamide (2 ml) was added triethylamine (0.389 ml, 2.78 mmol) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured to water, and the precipitated solid was separated by filtration, which was recrystallized from a mixed solvent of ethyl acetate and tetrahydrofuran to give 100 mg (43.7%) of the desired product.
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21](OC2C=CC([N+]([O-])=O)=CC=2)=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2].[CH:45]1([NH2:48])[CH2:47][CH2:46]1>C(#N)C>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21]([NH:48][CH:45]2[CH2:47][CH2:46]2)=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:43])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2]
Reactant: NC1CC1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Solvent: CC#N
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)NC2CC2)C(=O)N1c1cccc(C(F)(F)F)c1

Procedure:
According to the General Procedure 1, 4-nitrophenyl (6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate (80.0 mg, 0.128 mmol; Example 6A) was reacted with cyclopropylamine (21.9 mg, 0.384 mmol) in acetonitrile (1 ml) to give the target compound (45 mg, 65% of theory).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.C(O)(C)C.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[C:25]([C:32]1[CH:33]=[N:34][N:35]([CH2:37][CH3:38])[CH:36]=1)[N:26]2[CH3:31]>C(N(CC)CC)C>[CH2:37]([N:35]1[CH:36]=[C:32]([C:25]2[N:26]([CH3:31])[C:27]3[C:23]([N:24]=2)=[C:22]([N:1]2[CH2:2][CH2:3][CH:4]([N:7]4[C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=5[NH:9][C:8]4=[O:16])[CH2:5][CH2:6]2)[N:30]=[CH:29][N:28]=3)[CH:33]=[N:34]1)[CH3:38]
Reactant: CCn1cc(-c2nc3c(Cl)ncnc3n2C)cn1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCn1cc(-c2nc3c(N4CCC(n5c(=O)[nH]c6ccccc65)CC4)ncnc3n2C)cn1
Temperature: 80 °C
Yield: 96.5 %

Procedure:
To a solution of 1-piperidin-4-yl-1,3-dihydro-2H-benzimidazol-2-one (0.1 g, 0.33 mmol) in an anhydrous isopropanol (8 mL) and triethylamine (0.2 mL) was added 6-chloro-8-(1-ethyl-1H-pyrazol-4-yl)-9-methyl-9H-purine (65 mg, 0.25 mmol). The reaction mixture was heated to 80° C. for 16 hours, and cooled to room temperature. The resulting precipitates were collected by vacuum filtration, and triturated with 15 mL of ethanol at 75° C. for 30 min. The solids were collected by vacuum filtration to give 107 mg (97% yield) of the title compound. 1H-NMR (400 MHz, DMSO-d6): δ 10.86 (s, 1H), 8.44 (s, 1H), 8.25 (s, 1H), 8.03 (d, 1H), 7.13 (dd, 1H), 6.93 (m, 3H), 5.61 (s, 2H), 4.53 (dd, 1H), 4.22 (q, 2H), 3.84 (s, 3H), 3.18 (s, 2H), 2.33 (m, 2H), 1.82 (d, 2H), 1.40 (t, 3H); MS (EI) for C23H25N9O: 444.3 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>C(OCC)(=O)C>[CH3:24][S:25]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:15][CH:16]=1)(=[O:27])=[O:26]
Reactant: CCOC(=O)COc1ccc(CCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(CCOS(C)(=O)=O)cc1
Temperature: 25 °C

Procedure:
To a solution of ethyl 2-[4-(2-hydroxyethyl)-phenoxy]acetate (7.3 g) in ethyl acetate (22 mL) was added triethylamine (5.9 mL) at room temperature under a nitrogen atmosphere, and the mixture was stirred. Methanesulfonyl chloride (2.8 mL) was added dropwise to the mixture at 0-15° C. of internal temperature, and the mixture was stirred at room temperature for 30 minutes. After water was added to the reaction mixture, the aqueous layer was separated and extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution and brine, and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, ethyl acetate (8.6 mL) and 2-propanol (23 mL) were added to the residue, and the mixture was heated to dissolve. After cooling to room temperature, the resulting crystals were collected by filtration to give ethyl 2-[4-(2-methanesulfonyloxyethyl)-phenoxy]acetate (7.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][CH:17]=[C:18]([Cl:20])[Cl:19])[CH:5]=[C:6]([Cl:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12]Br.[CH3:21][NH2:22].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>CN(C)C=O.CO>[Cl:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][CH:17]=[C:18]([Cl:20])[Cl:19])[CH:5]=[C:6]([Cl:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:22][CH3:21]
Reactant: ClC(Cl)=CCOc1cc(Cl)c(OCCCCBr)c(Cl)c1
Reactant: CN
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: CNCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
A mixture of 1.0 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-bromobutyloxy)benzene, 4 ml of 40% methanol solution of methylamine, 0.33 g of potassium carbonate and N,N-dimethylformamide was stirred at room temperature for 24 hours. To the reaction mixture was added 100 ml of saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with 100 ml of ethyl acetate. The ethyl acetate layer was successively washed with 100 ml of saturated sodium hydrogen carbonate and saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated, which afforded 0.80 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-(methylamino)butyloxy)benzene (89% yield), nD26.0 1.5545.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:24]5[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=5)[CH:22]=4)[NH:17][C:16]=3[OH:30])=[N+:12]([O-])[CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.P(Cl)(Cl)Cl>C(OCC)(=O)C>[N:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:24]5[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=5)[CH:22]=4)[NH:17][C:16]=3[OH:30])=[N:12][CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: [O-][n+]1cc(CN2CCOCC2)ccc1-c1c(O)[nH]c2ccc(-c3cccnc3)cc12
Solvent: ClP(Cl)Cl
Solvent: CCOC(C)=O
Product: Oc1[nH]c2ccc(-c3cccnc3)cc2c1-c1ccc(CN2CCOCC2)cn1
Yield: 2.6 %

Procedure:
To a solution of 3-[5-(morpholin-4-ylmethyl)-1-oxidopyridin-2-yl]-5-pyridin-3-yl-1H-indol-2-ol (200 mg, 0.6 mmol) in ethyl acetate (60 mL) was added phosphorus trichloride (0.4 mL). A yellow precipitate was formed and the mixture was refluxed for 3 h, and then diluted with ethyl acetate and washed with an aqueous saturated NaHCO3 solution. The aqueos layer was extracted with two portions of ethyl acetate and one portion of chloroform. The organic- layers were combined, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by preparative HPLC (column: Xterra, 19×300 mm, eluent: water/acetonitrile, (0:100 to 100:0), gradient) affording 6 mg (3% yield) of the title compound as a yellow solid: 1H NMR (DMSO-d6, 400 MHz) δ 10.50 (br s, 1 H), 8.92 (d, J=2 Hz, 1 H), 8.49 (dd, J=4, 1 Hz, 1 H), 8.12-8.06 (m, 1 H), 8.02 (s, 1 H), 7.90-7.71 (m, 1 H), 7.71-7.67 (m, 2 H), 7.43 (dd, J=8, 5 Hz, 1 H), 7.20 (d, J=8 Hz, 1 H), 6.98 (d, J=8 Hz, 1 H), 3.63-3.53 (m, 4 H), 3.40-3.24 (m, 2 H), 2.42-2.34 (m, 4 H); MS (ES) m/z 388 (M++1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]([NH2:15])=[N:11][CH:12]=[CH:13][CH:14]=1.[Br:16]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:16][C:13]1[CH:14]=[C:9]([O:8][C:7]2[CH:6]=[CH:5][N:4]=[N:3][C:2]=2[CH3:1])[C:10]([NH2:15])=[N:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nnccc1Oc1cccnc1N
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nnccc1Oc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93.9 %

Procedure:
3-(3-Methylpyridazin-4-yloxy)pyridin-2-amine (0.50 g, 2.5 mmol) was dissolved in DMF (7 mL). N-Bromosuccinimide (0.46 g, 2.6 mmol) was added and the solution stirred at ambient temperature for 5 minutes. The solution was diluted with water and filtered through celite (rinsing with chloroform). The solution was extracted with chloroform, dried (Na2SO4), filtered and concentrated. Flash chromatography gave 5-bromo-3-(3-methylpyridazin-4-yloxy)pyridin-2-amine (0.66 g, 95%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[CH2:19]([N:26]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:27][CH2:28]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[C:5](=[C:6]([O:10][CH2:28][CH2:27][N:26]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:7]=[CH:8][CH:9]=1)[OH:11]
Reactant: COC(=O)c1cccc(O)c1O
Reactant: ClCCN(Cc1ccccc1)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cccc(OCCN(Cc2ccccc2)Cc2ccccc2)c1O

Procedure:
2,3-dihydroxybenzoic acid methyl ester is reacted in the presence of potassium carbonate in acetonitrile with 1.1 equivalents of 1-dibenzylamino-2-chloroethane for 18 hours at 82°. The crude 3-(2-dibenzylaminoethoxy)-salicylic acid methyl ester obtained after working up is put to further use without further purification.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.[S:14](N)([NH2:17])(=[O:16])=[O:15]>O1CCOCC1>[NH2:17][S:14]([N:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]1)(=[O:16])=[O:15]
Reactant: NS(N)(=O)=O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(S(N)(=O)=O)C1
Temperature: 110 °C

Procedure:
To a solution of tert-butyl (3S)-pyrrolidin-3-ylcarbamate (1.3 g) in dioxane (50 ml) was added sulfamide (1.55 g) and the reaction was heated at 110° C. for 18 h. The reaction mixture was then partitioned between DCM (150 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with DCM (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a pale yellow solid. Yield: 1.44 g
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([N+:8]([O-:10])=[O:9])[N:3]=1.[CH2:11]([O:13][C@@H:14]([CH2:19][C:20]1[CH:25]=[CH:24][C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16])[CH3:12]>>[CH2:11]([O:13][C@@H:14]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[N:6]([CH3:7])[N:5]=[C:4]([N+:8]([O-:10])=[O:9])[N:3]=2)=[CH:22][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16])[CH3:12]
Reactant: CCO[C@@H](Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)OC
Reactant: Cn1nc([N+](=O)[O-])nc1Br
Product: CCO[C@@H](Cc1ccc(-c2nc([N+](=O)[O-])nn2C)cc1)C(=O)OC
Yield: 61.9 %

Procedure:
In a manner similar to that of Example 9(e), starting with 0.9 g (4.35 mmol) of 5-bromo-1-methyl-3-nitro-1H-[1,2,4]triazole and 1.9 g (6.5 mmol) of methyl 2(S)-ethoxy-3-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]propanoate, 0.9 g (62%) of methyl 2(S)-ethoxy-3-[4-(2-methyl-5-nitro-2H[1,2,4]triazol-3-yl)phenyl]propanoate is obtained in the form of a white solid with a melting point of 119° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:12][CH2:13][Cl:14].[CH2:15]([NH2:19])[CH2:16][CH2:17][CH3:18]>>[CH2:15]([NH:19][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:12][CH2:13][NH:19][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:16][CH2:17][CH3:18].[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:12][CH2:13][Cl:14]
Reactant: CCCCN
Agent: ClCCOc1ccccc1OCCCl
Product: CCCCNCCOc1ccccc1OCCNCCCC

Procedure:
14.70 grams (0.0477 mol) 1,2-bis(2-n-butylaminoethoxy)benzene [obtained from the reaction of 1,2-bis(2-chloroethoxy)benzene and n-butylamine] and 11.21 grams (0.0477 mol) 1,2-bis(2-chloroethoxy)benzene were dissolved in 120 ml of N-methylpyrrolidone. The solution was heated under nitrogen at 120-125° C. for 1 hour and then 5 grams anhydrous sodium carbonate was added and the solution was further heated at 120-125° C. for 16 hours. Three portions of sodium carbonate (3 grams each) were then added at one hour intervals for a total heating time of 20 hours. The solvent was removed under vacuum, and the residue dissolved in toluene and the solution washed with water. The toluene solution was evaporated to leave a semi-solid which was triturated with ethanol. The crystalline precipitate which was obtained was filtered and recrystallized from cyclohexane to give the crown ether of formula XV where R is n-butyl in an amount equal to 8.19 grams (36.7% yield). The melting point of this product was 151-152° C. The structure of this crown ether compound was established by the analyses for the elements which were as follows:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=1[C:14]([NH:16][C:17]1[CH:21]=[CH:20][NH:19][N:18]=1)=[O:15].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[C:36]([F:39])([F:38])[F:37]>C1COCC1.CS(C)=O>[F:11][C:12]1[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=1[C:14]([NH:16][C:17]1[CH:21]=[CH:20][N:19]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[C:36]([F:37])([F:38])[F:39])[N:18]=1)=[O:15]
Reactant: COc1ccc(CBr)c(C(F)(F)F)c1
Reactant: O=C(Nc1cc[nH]n1)c1ccccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COc1ccc(Cn2ccc(NC(=O)c3ccccc3F)n2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.0 M lithium bis(trimethylsilyl)amide (100 μl, 0.1 mmol, Aldrich) was slowly added to a solution of 2-fluoro-N-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 43) (20.5 mg, 0.1 mmol) in THF (400 μl). The resulting solution was then transferred to a solution of 1-(bromomethyl)-4-(methyloxy)-2-(trifluoromethyl)benzene 24.7 mg, 0.1 mmol, JRD Fluorochemicals Ltd) in THF (200 μl) and stirred for 2 h under nitrogen at ambient temperature. The mixture was diluted with DMSO (0.6 ml) and purified by MDAP using the Sunfire C18 column (Method D) using Acetonitrile-Water with a TFA modifier. The solvent was removed under a stream of nitrogen to give the title compound (27 mg). LCMS (System 4)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=1.[Br:23]N1C(=O)CCC1=O>CN(C)C=O>[Br:23][C:10]1[N:9]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[N:12][C:11]=1[C:13]([OH:15])=[O:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(O)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Solvent: CN(C)C=O
Product: O=C(O)c1nc(-c2ccccc2Cl)n(-c2ccc(Cl)cc2)c1Br
Yield: 49.7 %

Procedure:
A solution of 2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carboxylic acid (50 mg, 0.15 mmol) and N-bromosuccinimide (88 mg, 0.49 mmol) in dimethylformamide (5 mL) was stirred at 75° C. for 3 days. The solution was purified by preparative HPLC to give 5-bromo-2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carboxylic acid as a white solid (30.7 mg, 50%). LC-MS m/z 411.2 (MH+), retention time 2.70 min (method 2).
Reaction SMILES: [CH:1]1([CH2:8][CH2:9][NH:10][C:11](=[O:42])[C@H:12]([CH3:41])[C@H:13]([C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](=[O:40])[CH2:22][C@@H:23]([O:38][CH3:39])[C@@H:24]([N:29]([CH3:37])[C:30](=[O:36])[C@H:31]([CH:33]([CH3:35])[CH3:34])[NH2:32])[C@@H:25]([CH3:28])[CH2:26][CH3:27])[O:14][CH3:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=[CH:2]1.[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][CH2:53][CH2:52][C@:51]1([CH3:59])[C:56](O)=[O:57])=[O:49])([CH3:46])([CH3:45])[CH3:44].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[CH:1]1([CH2:8][CH2:9][NH:10][C:11](=[O:42])[C@H:12]([CH3:41])[C@H:13]([C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](=[O:40])[CH2:22][C@@H:23]([O:38][CH3:39])[C@@H:24]([N:29]([CH3:37])[C:30](=[O:36])[C@@H:31]([NH:32][C:56]([C@@:51]2([CH3:59])[CH2:52][CH2:53][CH2:54][CH2:55][N:50]2[C:48]([O:47][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:49])=[O:57])[CH:33]([CH3:34])[CH3:35])[C@@H:25]([CH3:28])[CH2:26][CH3:27])[O:14][CH3:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@]1(C)C(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCC1C=CC=CC=C1)OC)N(C)C(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCC1C=CC=CC=C1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@]1(C)CCCCN1C(=O)OC(C)(C)C)C(C)C

Procedure:
According to the general procedure D, from #176 (100 mg, 0.170 mmol, 1 eq.), #157 (53.8 mg, 0.221 mmol, 1.3 eq.), dichloromethane (4.5 mL), HATU (84.9 mg, 0.221 mmol, 1.3 eq.) and N,N-diisopropylethylamine (0.123 mL, 0.697 mmol, 4.1 eq.), was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0 to 100% ethyl acetate in heptane) to afford #179 (155 mg, assume quantitative yield) as a white solid. LC-MS (Protocol Q1): m/z 814.7 [M+H+], retention time=1.14 minutes.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[C:11](=[O:20])[NH:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][N:15]=2)=[C:4]([F:21])[CH:3]=1.[C:22](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[C:11](=[O:20])[N:12]([CH3:22])[C:13]([C:16]([F:19])([F:17])[F:18])=[CH:14][N:15]=2)=[C:4]([F:21])[CH:3]=1
Reactant: COc1cc(-c2ncc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 100 °C
Reaction time: 48 h
Yield: 54.2 %

Procedure:
First, 3.61 g of 3-(4-chloro-2-fluoro-5-methoxyphenyl)-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (compound 1-1008) was dissolved in 16 ml of N,N-dimethylformamide, to which 2.35 g of potassium carbonate and 1.39 ml of methyl iodide were added, and the mixture was stirred at 100° C. for 2 days. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluent, hexane/ethyl acetate=5:1), which afforded 2.04 g (yield, 55%) of 3-(4-chloro-2-fluoro-5-methoxyphenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-144; m.p., 108.7° C.).