Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O-])=[O:2].[Na+].[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:33])[C:12]2[O:18][C:17]3[C:19]([Cl:29])=[CH:20][C:21]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[CH:22][C:16]=3[CH2:15][S:14](=[O:31])(=[O:30])[C:13]=2[CH:32]=1)=[O:8].O>C(O)=O>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:33])[C:12]2[O:18][C:17]3[C:19]([Cl:29])=[CH:20][C:21]([N:23]4[CH2:24][CH2:25][N:26]([CH:1]=[O:2])[CH2:27][CH2:28]4)=[CH:22][C:16]=3[CH2:15][S:14](=[O:30])(=[O:31])[C:13]=2[CH:32]=1)=[O:8]
Reactant: O=C[O-]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCNCC3)cc(Cl)c1O2
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(C=O)CC3)cc(Cl)c1O2
Temperature: 90 °C
Reaction time: 15 h

Procedure:
Sodium formate (0.1 g, 1.37 mmol) was added to a solution of 4-chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid methyl ester (free base of example 16, 0.3 g, 0.68 mmol) in formic acid (85%, 5 mL), and stirred at 90° C. for 15 h. The reaction mixture was diluted using water (10 mL), extracted using ethyl acetate, washed with water and brine. Solvent was removed and the crude product was purified by column chromatography (silica gel, 1.5% methanol in chloroform) to obtain the title compound. Yield: 0.11 g, (35%); 1H NMR (DMSO-d6, 300 MHz): δ 2.62 (s, 3H, CH3), 3.17-3.24 (m, 4H, 2CH2), 3.47 (s, 4H, 2CH2), 3.85 (s, 3H, OCH3), 5.15 (s, 2H, CH2), 7.13 (s, 1H, Ar), 7.17 (s, 1H, Ar), 8.06 (s, 1H, CHO), 8.08 (t, 1H, Ar), 8.14 (d, 1H, Ar); MS: m/e (ES+) 465 (M+1); analysis: C21H21ClN2O6S.0.5H2O requires C, 53.23; H, 4.64; N, 5.91; Cl, 7.49; S, 6.75. found: C, 53.82; H, 4.48; N, 5.42; Cl, 8.07; S, 7.17%.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[CH2:10]([S:14]CCCC)[CH2:11][CH2:12][CH3:13]>>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[S:14][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCSCCCC
Reactant: COc1ccccc1I
Product: CCCCSc1ccccc1OC

Procedure:
The general procedure was used to convert 2-iodoanisole and n-butyl sulfide to the title product. Purification by flash chromatography (hexane as the eluent) gave the analytically pure product as a light yellow oil (329 mg, 84% yield). 1H NMR (300 MHz, CDCl3) δ 7.18–6.75 (m, 4H; Hb, Hc, Hd, He); 3.82 (s, 3H; Hj), 2.84–2.79 (t, J=7.3, 2H; Hf), 1.60–1.52 (m, 2H; Hg), 1.43–1.36 (m, 2H; Hh) 0.87–0.82 (t, J=7.3, 3H; Hi). 13C NMR (75 MHz, CDCl3) δ 156.98 (C6), 128.56 (C2), 126.54 (C4), 125.22 (C1), 120.98 (C3), 110.28 (C5), 55.73 (C11), 31.49 (C7), 30.94 (C8), 22.06 (C9), 13.66 (C10). Anal. Calcd. for C11H160S: C, 67.30; H, 8.22; S, 16.33; Found C, 67.43; H, 8.28; S, 16.10.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([S:8][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: N#Cc1ccc(SCc2ccccc2)cc1
Yield: 68.2 %

Procedure:
A mixture of 37.2 g of benzylmercaptan, 36.3 g of 4-fluorobenzonitrile and 42 g of potassium carbonate in 700 ml of butan-2-one is held under reflux for 7 hours. The solvent is evaporated in vacuo, the residue is taken up into water and petroleum ether. The crystals formed are filtered off, washed with water and petroleum ether to give 46 g of 4-benzylthiobenzonitrile as crystals with a melting point of 85° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:12])[CH:3]=1.[CH:13]1([C:16]#[CH:17])[CH2:15][CH2:14]1.CN(C=O)C>C1(C)C=CC=CC=1.CCN(CC)CC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:12][C:4]1[CH:3]=[C:2]([C:17]#[C:16][CH:13]2[CH2:15][CH2:14]2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: C#CC1CC1
Reactant: COC(=O)c1ccc(Br)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#CC2CC2)cc1Cl
Yield: 75.8 %

Procedure:
A mixture of methyl 4-bromo-2-chlorobenzoate (450 mg, 0.0018 mol), copper(I) iodide (34 mg, 0.00018 mol), 70% solution of cyclopropylacetylene (0.26 g, 0.0027 mol) in toluene and bis(triphenylphosphine)palladium(II) chloride (130 mg, 0.00018 mol) in Et3N (5 mL) and DMF (3 mL) was heated at 100° C. in a 50 mL sealed reaction vessel for 36 hours. After cooling, the mixture was filtered through Celite® and the filter cake was washed repeatedly with ethyl acetate. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel to give the product (320 mg, 76%) as a brown oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][N+:17]([O-])=[CH:16][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[Si]([C:34]#[N:35])(C)C.CN(C)C(Cl)=O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Si:1]([O:8][CH2:9][CH:10]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:34]#[N:35])[CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)(C)[Si](C)(C)OCC(CCCc1cc[n+]([O-])cc1)CO[Si](C)(C)C(C)(C)C
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)OCC(CCCc1ccnc(C#N)c1)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 87 %

Procedure:
To a solution of the crude 4-[5-(tert-butyldimethylsilanyloxy)-4-(tert-butyldimethylsilanyloxy-methyl)-pentyl]pyridine 1-oxide (0.43 g) prepared in (5) in chloroform (5 mL) were added trimethylsilyl cyanide (0.17 mL) and N,N-dimethylcarbamoyl chloride (0.12 mL). The reaction mixture was stirred at RT for 12 hr. Saturated aqueous NaHCO3 was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was dried over Na2SO4. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (Developing solvent: hexane/ethyl acetate=9/1) to give the title compound (0.40 g, 87%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([O:19][CH3:20])[CH:15]=[CH:14]2)C1C=CC=CC=1>CCO.[Pd]>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]2[C:18](=[C:9]([OH:8])[CH:10]=[CH:11][CH:12]=2)[N:17]=1
Reactant: COc1ccc2cccc(OCc3ccccc3)c2n1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2cccc(O)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.5 %

Procedure:
To a solution of 8-(benzyloxy)-2-methoxyquinoline (2.2 g, 8.3 mmol) in EtOH (40 mL) was added Pd/C (230 mg). The mixture was stirred at 25° C. for 16 h under an atmosphere of H2. The mixture was filtered, and the filtrate was evaporated to give the desired compound (1.2 g, 83%). 1HNMR (CDCl3, 400 MHz) δ: 7.91 (d, J=8.8 Hz, 1H), 7.52 (br. s., 1H), 7.23-7.15 (m, 2H), 7.07 (dd, J=1.4, 7.2 Hz, 1H), 6.85 (d, J=8.8 Hz, 1H), 3.99 (s, 3H).
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([N:16]1[C:22](=[O:23])[CH2:21][CH2:20][N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[CH2:18][CH2:17]1)[CH2:5][CH2:6][N:7]1[CH2:14][CH2:13][C:10]2([CH2:12][CH2:11]2)[C@H:9]([OH:15])[CH2:8]1.[Li+].[BH4-]>>[Cl:30][C:26]1[CH:25]=[C:24]([N:19]2[CH2:20][CH2:21][C:22](=[O:23])[N:16]([C@H:4]([CH2:3][OH:2])[CH2:5][CH2:6][N:7]3[CH2:14][CH2:13][C:10]4([CH2:12][CH2:11]4)[C@H:9]([OH:15])[CH2:8]3)[CH2:17][CH2:18]2)[CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1CCN(c2cccc(Cl)c2)CCC1=O
Agent: [BH4-]
Agent: [Li+]
Product: O=C1CCN(c2cccc(Cl)c2)CCN1[C@H](CO)CCN1CCC2(CC2)[C@H](O)C1
Yield: 77 %

Procedure:
In analogy to the procedure described in example 2, (S)-2-[4-(3-chloro-phenyl)-7-oxo-[1,4]diazepan-1-yl]-4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-butyric acid methyl ester and LiBH4 gave the title compound in 77% yield as a white foam. MS: 421.2 (MH+, 1Cl).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18]N1C(=O)CCC1=O>C(O)(=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]([C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:9][Cl:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(N)C(=O)c1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N(NCl)C(=O)c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of a benzoylhydrazinecarboxylic acid tert-butyl ester (Example 7) in acetic acid (5 mL) is added N-chlorosuccinimide (1.2 eq.). After 1 hour, the reaction mixture is diluted with ethyl acetate and washed with saturated NaHCO3, water, and brine. The organic layer is dried over MgSO4 and filtered. The filtrate is concentrated under vacuum and purified via flash column chromatography (ethyl acetate/hexanes) to afford the corresponding chloro-benzoylhydrazinecarboxylic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[N:9][N:10]=2)[CH:7]=1.[C:11]([O:15][CH3:16])(=[O:14])[C:12]#[CH:13].N1C(C)=CC=CC=1C.O>O1CCCC1.CS(C)=O.[Cu]I>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:13]=[C:12]([C:11]([O:15][CH3:16])=[O:14])[N:8]=[N:9]2)=[N:6][CH:7]=1
Reactant: C#CC(=O)OC
Reactant: Brc1ccc2nnnn2c1
Agent: [Cu]I
Solvent: Cc1cccc(C)n1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cn(-c2ccc(Br)cn2)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
In a 10 ml round-bottomed flask, 6-bromotetrazolo[1,5-a]pyridine (209 mg, 1.05 mmol) was dissolved in a mixture of tetrahydrofuran (3.5 ml) and dimethylsulfoxide (0.06 ml) to give an orange solution. Methyl propiolate (265 mg, 276 μl, 3.15 mmol), copper (I) iodide (200 mg, 1.05 mmol) and 2,6-lutidine (225 mg, 245 μl, 2.1 mmol) were added and the reaction mixture was stirred at room temperature overnight. Water was added and the layers were separated using ethyl acetate. The organic layer was washed with 1 N hydrochloric acid and brine, dried over magnesium sulphate and filtered. The filtrate was concentrated under vacuum to yield a brown solid (300 mg), which was adsorbed on silica gel. Purification by flash chromatography (Silica gel, 20 g, 10 to 30% EtOAc in heptane) yielded a light grey solid (255 mg, 86%). MS (ISP): 283.4 ({79Br} [M+H]+), 285.4 ({81Br} [M+H]+).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH2:7]([N:14]1[C:19](=[O:20])[C:18]2=[C:21]([Cl:24])[CH:22]=[CH:23][N:17]2[N:16]=[C:15]1[CH:25]=CN(C)C)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([N:14]1[C:19](=[O:20])[C:18]2=[C:21]([Cl:24])[CH:22]=[CH:23][N:17]2[N:16]=[C:15]1[CH:25]=[O:2])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN(C)C=Cc1nn2ccc(Cl)c2c(=O)n1Cc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1nn2ccc(Cl)c2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.3 %

Procedure:
Sodium periodate (17.3 g, 80.7 mmol) was added to a pH 7.0 buffered solution (75 mL) of 3-benzyl-5-chloro-2-(2-dimethylamino-vinyl)-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (5.3 g, 16.1 mmol) in THF (150 mL) at room temperature. The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was filtered through Celite® and the solids washed with CHCl3 (100 ml). The filtrate was wash with saturated NaCl (2×50 mL), dried (Na2SO4), filtered and concentrated in vacuo. The solid was azeotroped with toluene (2×50 mL) to afford the title compound as a solid (4.6 g, 100%): TLC, Rf=0.5 (2/1 hexane/EtOAc, UV); 1H NMR (CDCl3) δ 9.34 (s, 1H), 7.33 (m, 1H), 7.16–7.27 (m, 5H), 6.60 (m, 1H), 5.62 (s, 2H).
Reaction SMILES: [NH3:1].[NH:2]1[CH:6]=[N:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[N:3]1>C1COCC1>[NH:2]1[CH:6]=[N:5][C:4]([S:7]([NH2:1])(=[O:9])=[O:8])=[N:3]1
Reactant: O=S(=O)(Cl)c1nc[nH]n1
Reactant: N
Solvent: C1CCOC1
Product: NS(=O)(=O)c1nc[nH]n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 54.3 %

Procedure:
Liquid ammonia was added dropwise via a CO2/acetone condenser to a solution of 1H-1,2,4-triazole-3-sulfonyl chloride (500 mg, 2.98 mmol) in THF (5 mL) at −78° C. until the volume had approximately doubled (˜15 min). The reaction was stirred at −78° C. for 1 h and then allowed to slowly warm to rt. The reaction was concentrated to dryness and the residue was diluted with DCM. The slurry was filtered to remove the solids and the solution was concentrated to yield 1H-1,2,4-triazole-3-sulfonamide (240 mg, 1.620 mmol, 54.3% yield) as an off white solid. 1H NMR (300 MHz, CD3OD) δ ppm 8.60 (br s, 1H). LC-MS retention time 0.19 min; m/z 147 (MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][CH:8]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[ClH:24].O1CCOCC1>CO>[ClH:24].[F:1][C:2]1[C:10]2[O:9][CH:8]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cccc(F)c3O2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Fc1cccc2c1OC(C1CCNCC1)C2
Temperature: 25 °C
Reaction time: 5 h
Yield: 97 %

Procedure:
To a solution of tert-butyl 4-(7-fluoro-2,3-dihydrobenzofuran-2-yl)piperidine-1-carboxylate (2.36 g, 7.34 mmol) in MeOH (43.2 mL) was added HCl in dioxane (4 M, 26.8 mL, 107 mmol). Upon completion of addition, the mixture was stirred at room temperature for 5 h. After this time, the solvent was removed under reduced pressure to afford Compound 3D as a yellow oil (1.826 g, 97% yield), which was used in the next reaction without further purification. LC/MS (m/z)=222 (M+H)+.
Reaction SMILES: [Si]([N:8]1[C:11](=[O:12])[CH2:10][CH:9]1[CH2:13][CH:14]=[CH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])(C(C)(C)C)(C)C.Cl.C(=O)(O)[O-].[Na+]>CO>[O:12]=[C:11]1[NH:8][CH:9]([CH2:13][CH:14]=[CH:15][C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[CH2:10]1
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC=CC(=O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=C1CC(CC=CC(=O)OCc2ccccc2)N1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 97.7 %

Procedure:
To a solution of benzyl 4-[(2RS)-1-(tert-butyldimethylsilyl)-4-oxoazetidin-2-yl]but-2-enoate (45 mg) in methanol was added 1 N hydrochloric acid (0.1 ml) at 0°. After stirring at room temperature for 2.5 hours, the reaction mixture was neutrallized to pH 7 with saturated aqueous sodium bicarbonate. The resultant solution was concentrated, taken up into ethyl acetate (15 ml), and washed in turn with water and brine. Drying over magnesium sulfate and removal of the solvent left an oil, which was chromatographed on a silica gel plate (developing solvent: 6% methanol in dichloromethane) to give benzyl 4-[(2RS)-4-oxoazetidin-2-yl]but-2-enoate (30 mg) as a crystalline solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)[CH3:2].[CH3:13][C:14]1[CH:18]=[C:17]([NH2:19])[N:16]([C:20]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[N:25]3)[N:15]=1.ClCCl>N1C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:19][C:17]2[N:16]([C:20]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:21]=3[CH:22]=[CH:23][CH:24]=[N:25]4)[N:15]=[C:14]([CH3:13])[CH:18]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(N)n(-c2cccc3ncccc23)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1ccc(S(=O)(=O)Nc2cc(C)nn2-c2cccc3ncccc23)cc1
Temperature: 80 °C
Yield: 37.7 %

Procedure:
A mixture of 4-ethylbenzenesulfonyl chloride (0.033 g, 0.16 mmol) and 3-methyl-1-(quinolin-5-yl)-1H-pyrazol-5-amine (prepared from Example 4 step b, 0.030 g, 0.13 mmol) in pyridine (1.0 mL) was heated at 80° C. for 2 h with stirring. After cooling to room temperature, dichloromethane was added to the reaction mixture and washed with 1 M aqueous sodium hydrogen sulfate (1 mL). The aqueous layer was further extracted with dichloromethane (2×5 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.019 g, 0.049 mmol, 38%). 1H NMR (400 MHz, CDCl3) δ 8.86 (dd, J=2.0, 4.0 Hz, 1H), 8.12 (d, J=8.8 Hz, 1H), 7.60 (dd, J=7.2, 8.4 Hz, 1H), 7.51-7.46 (m, 3H), 7.27-7.23 (m, 1H), 7.15 (s, 1H), 7.13 (s, 1H), 7.06 (d, J=7.6 Hz, 1H), 6.27 (s, 1H), 2.68 (q, J=7.6 Hz, 2H), 2.34 (s, 3H), 1.27 (t, J=7.6 Hz, 3H); MS: (ES) m/z calculated for C21H21N4O2S [M+H]+ 393.2. found 393.2
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[C:32](=[O:40])[C:33](=[O:39])[C:34]=2[O:35][CH:36]([CH3:38])[CH3:37])=[CH:21][CH:20]=1>CN(C)C=O>[CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[C:32](=[O:40])[C:33](=[O:39])[C:34]=3[O:35][CH:36]([CH3:38])[CH3:37])=[CH:23][CH:24]=2)[C:7]([C:11]([O:13][CH3:14])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)Oc1c(-c2ccccc2-c2ccc(CBr)cc2)c(=O)c1=O
Reactant: CCCCc1nc(Cl)c(C(=O)OC)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2c(OC(C)C)c(=O)c2=O)cc1
Reaction time: 0.5 h

Procedure:
Methyl 2-butyl-4-chloro-1H-imidazole-5-carboxylate (0.19 g) was added to a stirring suspension of sodium hydride (60% dispersion in mineral oil; 35 mg) in dry dimethylformamide (2 ml) at ambient temperature under a nitrogen atmosphere and stirring was continued for 30 minutes. A solution of 3-(4'-bromomethylbiphenyl-2-yl)-4-isopropoxycyclobut-3-ene-1,2-dione (0.64 g; preparable as in Example 1(c)) in dry dimethyl formamide (3 ml) was added and stirring was continued for 24 hours. The reaction mixture was partitioned between water (20 ml) and diethyl ether (20 ml), and the aqueous layer was separated and extracted with diethyl ether (20 ml). The combined ether solutions were dried over magnesium sulphate and the solvent was evaporated in vacuo. The residue obtained was purified by flash chromatography on silica gel (eluting with 20% ethyl acetate in petroleum ether (b.p. 40°-60° C.)) to give methyl 2-butyl-4-chloro-1-[2'-(2-isopropoxy-3,4-dioxocyclobut-1-en-1-yl)biphenyl-4-ylmethyl]-1H-imidazole-5-carboxylate, an active compound of the present invention, as a yellow oil (0.17 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:25][CH2:24][C@@H:23](O)[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[C:14]([O:18][C:19]([N:21]1[CH2:25][CH2:24][C@H:23]([O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=2)[CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CCOC(=O)Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Reaction time: 42 h

Procedure:
6.0 g (33.3 mmol) of ethyl 4-hydroxyphenylacetate, 6.25 g (33.3 mmol) of (3R)-1-(t-butoxycarbonyl)-3-hydroxypyrrolidine and 10.5 g (40 mmol) of triphenylphosphine were dissolved in 125 ml of tetrahydrofuran. 6.3 ml (40 mmol) of diethyl azodicarboxylate was added to the solution at room temperature, and they were stirred for 42 hours. After the same isolation process as that of step 1 in Example 1 with ethyl acetate as the extractant, the crude product was obtained. The crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]2[NH:10][C:9](=[O:14])[N:8]3[CH2:15][CH2:16][N:17]=[C:7]3[C:6]=2[CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[N+:1]([C:4]1[CH:13]=[CH:12][C:11]2[N:10]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:9](=[O:14])[N:8]3[CH2:15][CH2:16][N:17]=[C:7]3[C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: BrCc1ccccc1
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2C2=NCCN12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C1N2CCN=C2c2cc([N+](=O)[O-])ccc2N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
11.5 g (0.05 mol) of 9-nitro-5-oxo-2,3,5,6-tetrahydroimidazo-[1,2-c]-quinazoline and 6.4 g (0.02 mol) of tetra-n-butylammonium bromide were suspended in 250 ml of 10% strength sodium hydroxide solution. 17.815 g (0.15 mol) of benzyl bromide in 150 ml of methylene chloride were added to the mixture, and the latter was stirred for 2 hours at room temperature.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][Cl:19])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(I)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: ClCCc1ccc(I)cc1
Yield: 98.6 %

Procedure:
To a 500 mL round-bottomed flask equipped with dropping funnel, condenser and N2 inlet were added 307 g (124 mmol) 2-(4-iodophenyl)ethanol, 200 mL chloroform, and 10.0 mL (124 mmol) pyridine. A solution of 13.5 mL (186 mmol) thionyl chloride in 50 mL chloroform was added dropwise over 15 min, and the reaction then heated at reflux for 2 hr. The reaction was cooled, the solvent evaporated, and the residue taken up in ethyl acetate, washed with 1 N hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and brine, dried, and evaporated. The resulting oil was chromatographed on silica gel using 20% ethyl acetate in hexane as eluant to afford 32.6 g (99%) of the product as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]2[C:10]=1[C:11]([CH3:40])=[C:12]([CH2:24][C:25]1[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=1)[C:13]([O:20][CH:21]([F:23])[F:22])=[N:14]2)([CH3:4])([CH3:3])[CH3:2].[Cl:42][C:43]1[CH:44]=[N:45][NH:46][CH:47]=1>>[C:1]([O:5][C:6](=[O:41])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]2[C:10]=1[C:11]([CH3:40])=[C:12]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([N:45]3[CH:44]=[C:43]([Cl:42])[CH:47]=[N:46]3)=[CH:29][CH:30]=1)[C:13]([O:20][CH:21]([F:23])[F:22])=[N:14]2)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)OC(C)(C)C)c12
Reactant: Clc1cn[nH]c1
Product: Cc1c(Cc2ccc(-n3cc(Cl)cn3)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)OC(C)(C)C)c12

Procedure:
The title compound was prepared by the method of Preparation 18a using {8-chloro-2-difluoromethoxy-4-methyl-3-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzyl]quinolin-5-yloxy}acetic acid tert-butyl ester and 4-chloro-1H-pyrazole.