Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[C:4]([N:11]([CH3:13])[CH3:12])[N:3]=1.[Br:14]Br.[OH-].[Na+]>C(O)(=O)C.O>[Br:14][C:5]1[C:6]([CH3:10])=[C:7]([C:8]#[N:9])[C:2]([Cl:1])=[N:3][C:4]=1[N:11]([CH3:12])[CH3:13]
Reactant: Cc1cc(N(C)C)nc(Cl)c1C#N
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(Br)c(N(C)C)nc(Cl)c1C#N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.9 %

Procedure:
To a suspension of 2-chloro-3-cyano-6-(N,N-dimethylamino)-4-methylpyridine (0.98 g) in acetic acid (10 mL) was added bromine (0.9 g) in acetic acid (1 mL). The reaction mixture was stirred at room temperature for 20 minutes and then warmed to 60° C. for 5 minutes. After cooling to room temperature the mixture was poured into a solution of sodium hydroxide (8 g) in water (100 mL). The mixture was extracted with chloroform (3×30 mL). The combined organic phase was washed, dried, and evaporated to give 1.36 g of the title compound, suitable for use in the next reaction.
Reaction SMILES: [Br-].[Br:2][CH2:3][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[CH2:29]1[CH2:42][O:41][C:31]([CH3:40])([CH2:32][CH:33]=[CH:34][C:35]([CH3:39])=[CH:36][CH:37]=O)[O:30]1.O>O1CCCC1>[CH2:29]1[CH2:42][O:41][C:31]([CH3:40])([CH2:32][CH:33]=[CH:34][C:35]([CH3:39])=[CH:36][CH:37]=[CH:3][Br:2])[O:30]1
Reactant: BrC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C=CCC1(C)OCCO1)=CC=O
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C=CCC1(C)OCCO1)=CC=CBr
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
Anhydrous tetrahydrofuran (22 cc) and bromomethyltriphenylphosphonium bromide (1.7 g, 3.9 mmol) are introduced into a 50-cc round-bottomed flask. This is cooled to -70° C. and potassium tert-butylate (0.44 g) is then added over 10 minutes. The mixture is stirred for 1 hour 30 minutes and 7,7-ethylenedioxy-3-methyl-2,4-octadienal (0.5 g) is then added in solution in tetrahydrofuran (3 cc) over 10 minutes. The temperature is allowed to rise to 10° C. and stirring is then performed for 2 hours 20 minutes. Water (12 cc) is quickly added and stirring is then performed for 15 minutes. After extraction, the organic phases are dried over magnesium sulphate. After evaporation of the solvents, the product obtained is placed in a mortar and is taken up with petroleum ether; the triphenylphosphine oxide which precipitates is ground until white and is then separated by filtration. After evaporation of the petroleum ether, 8,8-ethylenedioxy-1-bromo-4-methyl-1,3,5-nonatriene (0.49 g) is obtained, its characteristics being as follows:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Br[CH:13]([Cl:16])[CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(Cl)(Cl)Cl>[Cl:16][CH2:13][CH2:14][CH2:15][O:11][C:8]1[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=1
Reactant: CCC(Cl)Br
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(OCCCCl)cc1

Procedure:
A mixture of 4-acetamidophenol, 182.2 g (1.2 mole), bromochloropropane, 157.4 g (1.0 mole), and potassium carbonate, 145.0 g (1.05 mole) was refluxed overnight in 700 ml of acetone. The acetone solution was refrigerated overnight and white crystals formed. This white solid was filtered and washed with acetone. The filtrate was stripped to dryness and the residue was dissolved in chloroform and extracted with 5% sodium hydroxide. Removal of chloroform gave an oil. The white solid was also dissolved in chloroform and extracted with 5% sodium hydroxide. Removal of chloroform gave a white solid. The white solid and oil were combined and placed in acetone in the refrigerator; white crystals were obtained. The white crystals were recrystallized twice from acetone. A 5 g sample of the white crystals was recrystallized from acetone. This furnished 1.76 g (after drying in vacuo overnight at 80° C.) (23%) of white crystalline product; m.p. 125°-127° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.[Cl:15]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:15][C:3]1[CH:4]=[CH:5][C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])=[N:7][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)C(=O)Nc1cccc(Cl)n1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)Nc1ccc(Cl)c(Cl)n1
Temperature: 25 °C
Yield: 66 %

Procedure:
To a solution of N-(6-chloropyridin-2-yl)pivalamide, synthesized as in J. Org. Chem. 2005, 70, 1771, (1.02 g, 4.80 mmol) in chloroform (25 mL) was added 1-chloropyrrolidine-2,5-dione (0.62 g, 4.67 mmol) and the mixture was refluxed in an oil bath for 3 hrs. It was allowed to cool to room temperature overnight. The reaction mixture was evaporated in vacuo and re-dissolved in DMF (15 mL). Another 480 mg 1-chloropyrrolidine-2,5-dione was added and the resulting solution was heated overnight in an oil bath at 95-100°, then cooled again to room temperature. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The aqueous phase was washed twice more with ethyl acetate and the combined organic phases were washed with brine, dried over magnesium sulfate, and evaporated in vacuo. TLC (10% ethyl acetate/hexane) showed a robust spot at Rf 0.6 with smaller spots at Rf 0.4 and 0.2. The material was subjected to the Biotage in 5-10% ethyl acetate/hexane, collecting the Rf 0.6 fraction to give 790 mg (66%) white solid, N-(5,6-dichloropyridin-2-yl)pivalamide. 1H NMR (500 MHz, CDCl3) δ ppm 8.17 (s, 1H), 7.96 (s, 1H), 7.72 (s, 1H), 1.31 (s, 10H). MS (LC/MS) R.T.=1.85; [M+H]+=248.8.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH:4]([Cl:8])[C:5]([CH3:7])=[O:6].[H-].[Na+].[Li]CCCC.[Cl:17][C:18]1[CH:19]=[C:20]([CH2:26][CH2:27][C:28]([CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:29])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].BrC1C=CC(OC)=C(Cl)C=1.BrC1C=CC=CN=1>C1COCC1>[CH3:1][O:2][C:3](=[O:9])[CH:4]([Cl:8])[C:5](=[O:6])[CH2:7][C:28]([CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)([OH:29])[CH2:27][CH2:26][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]([Cl:17])[CH:19]=1
Reactant: COC(=O)C(Cl)C(C)=O
Reactant: COc1ccc(CCC(=O)C2CCCC2)cc1Cl
Agent: Brc1ccccn1
Agent: COc1ccc(Br)cc1Cl
Agent: [H-]
Solvent: C1CCOC1
Product: COC(=O)C(Cl)C(=O)CC(O)(CCc1ccc(OC)c(Cl)c1)C1CCCC1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Methyl-2-chloroacetoacetate (2.5 g, 16.9 mmol) was added to a cooled 0° C. suspension of NaH (0.68 g, 16.9 mmol, 60% dispersion in mineral oil) in THF (30 ml). After 15 min the solution was cooled to −40° C. and n-BuLi (10.6 mL, 16.9 mmol, 1.6M in hexanes) was added. The resulting dianion was stirred for an additional 30 min and then treated with a solution of 3-(3-Chloro-4-methoxy-phenyl)-1-cyclopentyl-propan-1-one (1.5 g, 5.6 mmol, compound was prepared analogously to Step 1 of Example A(82), where 4-bromo-2-chloro-1-methoxybenzene was substituted in place of 2-Bromopyridine) in THF (10 ml). After stirring for 1 h at −40° C., the reaction mixture was quenched with saturated NH4Cl and extracted with EtOAc. The organic layers were washed with brine, dried with Na2SO4 and concentrated to an orange oil that was used without further purification.
Reaction SMILES: [OH-].[Na+].[CH2:3]([CH:5]([C:11]([CH3:13])=[O:12])[C:6]([O:8]CC)=[O:7])[CH3:4]>O>[CH2:3]([CH:5]([C:11]([CH3:13])=[O:12])[C:6]([OH:8])=[O:7])[CH3:4]
Reactant: CCOC(=O)C(CC)C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(C(C)=O)C(=O)O
Temperature: 25 °C

Procedure:
Sodium hydroxide (1.92 g) was dissolved in water (10 mL) and ethyl 2-ethylacetoacetate (6.32 g: made by Wako Pure Chemical Industries) was added while stirring at room temperature, and this was further stirred for 30 minutes. The ethanol was subsequently removed with a rotary evaporator, and the remaining aqueous layer was washed with ether. To this was added ether (20 mL), and then, while stirring and chilling with ice, a solution of concentrated sulfuric acid 2.35 g dissolved in water 8 mL was added dropwise. The ether layer was fractioned off, and the aqueous layer was salt precipitated and extracted with ether. The ether layers were combined to yield an ether solution of α-ethylacetoacetic acid.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([CH3:13])[C:7](=[O:14])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([O:25][C@H:26]2[CH2:30][CH2:29][O:28][CH2:27]2)[CH:24]=1)[C:19](O)=[O:20].N1C=CC=CC=1.[NH2:37][C:38]1[CH:42]=[CH:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[N:39]=1>C(Cl)Cl>[Cl:1][C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([CH3:13])[C:7](=[O:14])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][C:16]1[CH:17]=[C:18]([C:19]([NH:37][C:38]2[CH:42]=[CH:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[N:39]=2)=[O:20])[CH:22]=[C:23]([O:25][C@H:26]2[CH2:30][CH2:29][O:28][CH2:27]2)[CH:24]=1
Reactant: CC(C)(C)OC(=O)n1ccc(N)n1
Reactant: CN1CCOc2c(ccc(Oc3cc(O[C@H]4CCOC4)cc(C(=O)O)c3)c2Cl)C1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN1CCOc2c(ccc(Oc3cc(O[C@H]4CCOC4)cc(C(=O)Nc4ccn(C(=O)OC(C)(C)C)n4)c3)c2Cl)C1=O
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 52.5 %

Procedure:
1-Chloro-N,N-2-trimethylpropenylamine (0.09 mL, 0.37 mmol) was added to a solution of 3-[(9-chloro-4-methyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepin-8-yl)oxy]-5-[(3S)-tetrahydrofuran-3-yloxy]benzoic acid (145 mg, 0.34 mmol) in DCM (5 mL) and the reaction stirred at RT for 30-40 minutes. Pyridine (0.055 mL, 0.67 mmol) and 1,1-dimethylethyl 3-amino-1H-pyrazole-1-carboxylate (123 mg, 0.67 mmol) were added and the reaction stirred for 2 hours at RT. The reaction mixture was evaporated in vacuo and water (20 mL) added. The mixture was extracted with ethyl acetate (3×20 mL), washed with 1N hydrochloric acid (20 mL), a saturated solution of sodium hydrogen carbonate (20 mL), brine (20 mL), dried (MgSO4) and evaporated in vacuo. The crude product was chromatographed on silica, eluting with a gradient of 0-5% methanol in DCM, to give the desired compound as a pale yellow oil (107 mg). m/z 611 (M−H)−
Reaction SMILES: ClC1C(C2C=CC=CC=2)=NN=C2N(CC(O)=O)N=C(C3C=CC=CC=3)C=12.[Cl:27][C:28]1[C:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:32][N:31]=[C:30]2[N:40]([CH2:49][C:50]([N:52]3C[CH2:56][N:55]([CH3:58])[CH2:54][CH2:53]3)=[O:51])[N:41]=[C:42]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:29]=12.CNCCNC>>[Cl:27][C:28]1[C:33]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[N:32][N:31]=[C:30]2[N:40]([CH2:49][C:50]([NH:52][CH2:53][CH2:54][N:55]([CH3:58])[CH3:56])=[O:51])[N:41]=[C:42]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:29]=12
Reactant: CN1CCN(C(=O)Cn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)CC1
Agent: CNCCNC
Agent: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Product: CN(C)CCNC(=O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21

Procedure:
Compound 2 was synthesised from 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid following a similar procedure outlined in Example 17 (Compound 1), using N,N′-dimethylethylenediamine instead of N-methylpiperazine in the final step.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH:16]=[C:17]([C:20]#[N:21])[C:18]#[N:19])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[C-:22]#[N:23].[Na+].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>CN(C)C=O.O.C(Cl)(Cl)Cl>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([C:22]#[N:23])=[C:17]([C:18]#[N:19])[C:20]#[N:21])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: [C-]#N
Reactant: CCn1c2ccccc2c2cc(C=C(C#N)C#N)ccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [Pb+4]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCn1c2ccccc2c2cc(C(C#N)=C(C#N)C#N)ccc21
Reaction time: 0.17 h
Yield: 13.5 %

Procedure:
10.2 g (37.5 mmol) of N-ethyl-3-(2,2-dicyanoethenyl)carbazole and 100 ml of N,N-dimethylformamide as solvent were placed in a 500 ml four-necked flask with a mechanical stirrer and bulb-shaped cooler. To this was added an aqueous solution of 1.84 g (37.5 mmol) of sodium cyanide and 4.3 ml of water, which was stirred for 10 minutes. Further, 16.6 g of lead tetraacetate was added. The resultant product was subjected to the reaction for 30 minutes. After the reaction was completed, 200 ml of chloroform was added. To the resultant aqueous solution was added 100 ml of water. The resultant liquid was washed in a separatory funnel. To the washed liquid was added sodium sulfate, which was left to stand for 30 minutes and dehydrated. The dehydrated solution was concentrated in an evaporator and dried under vacuum to obtain a red solid, which was recrystallized in the presence of benzene to obtain 1.5 g of a red crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]2[C:11]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:22](O)=[O:23])[CH:18]=4)[N:13]=3)=[CH:10][C:9]([C:25]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:26])=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:67]([O:69][C:70](=[O:85])[C:71]1[CH:76]=[CH:75][C:74]([NH:77][CH:78]2[CH2:83][CH2:82][CH2:81][CH2:80][CH2:79]2)=[C:73]([NH2:84])[CH:72]=1)[CH3:68]>CN(C=O)C>[CH2:67]([O:69][C:70](=[O:85])[C:71]1[CH:76]=[CH:75][C:74]([NH:77][CH:78]2[CH2:79][CH2:80][CH2:81][CH2:82][CH2:83]2)=[C:73]([NH:84][C:22]([C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([C:11]2[C:6]([C:5]4[CH:32]=[CH:33][C:2]([Cl:1])=[CH:3][CH:4]=4)=[CH:7][CH:8]=[C:9]([C:25]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[O:26])[CH:10]=2)[CH:21]=[CH:20]3)=[O:23])[CH:72]=1)[CH3:68]
Reactant: O=C(O)c1ccc2nc(-c3cc(C(=O)N4CCCC4)ccc3-c3ccc(Cl)cc3)ccc2c1
Reactant: CCOC(=O)c1ccc(NC2CCCCC2)c(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC2CCCCC2)c(NC(=O)c2ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4-c4ccc(Cl)cc4)ccc3c2)c1
Reaction time: 8 h

Procedure:
Compound 24 (270 mg, 0.59 mmol) in 4 mL of DMF was activated with 246.6 mg (0.65 mmol) of HATU and 226 μL (1.30 mmol) of DIEA at room temperature for 15 minutes. Compound 11 (170 mg, 0.65 mmol) was added as solid and the mixture was stirred overnight. The DMF was evaporated; the remaining oil was solidified by trituration with water. The solid Compound 25 was filtered off, dried and used without further purification. MS: 701.34 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:25]([NH:28][CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:28]([CH2:29][CH2:30][CH3:31])[CH2:25][CH2:26][CH3:27])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2cccc(Cl)c2C1=O
Reactant: CCCNCCC
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1nc(-c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)no1
Yield: 90.1 %

Procedure:
1.09 g (3 mmol) of 7-chloro-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at room temperature for 4.5 hours with 1.02 g (10 mmol) of dipropylamine and 15 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there were obtained 1.16 g (90%) of 7-chloro-3-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, which was converted into the hydrochloride of m.p. 212°-215°.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:25])[N:14]([CH3:24])[N:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:17]=1[S:18][CH3:19])[CH3:2].C(=O)([O-])[OH:27].[Na+].ClC1C=C(C=CC=1)C(O)=O.S([O-])([O-])=O.[Na+].[Na+]>O.C(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:25])[N:14]([CH3:24])[N:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:17]=1[S:18]([CH3:19])=[O:27])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1-c1c(SC)c(C(F)(F)F)nn(C)c1=O
Reactant: O=C([O-])O
Agent: O=C(O)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCc1cc(C)cc(CC)c1-c1c(S(C)=O)c(C(F)(F)F)nn(C)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
To a 50 ml volume three-necked flask, 4-(2,6-diethyl-4-methylphenyl)-2-methyl-5-methylsulfanyl-6-trifluoromethyl-2,3-dihydro-3-pyridazinone ((2-46)-(1)-39) (0.51 g) and chloroform (12.5 ml) were added at room temperature. Sodium hydrogen carbonate (0.46 g) and meta-chlorobenzoic acid (0.48 g) was added and the resulting mixture was stirred at room temperature for 3 hours. Then, the reaction mixture was poured into water (20 ml), added sodium sulfite (0.3 g), and extracted with t-butyl methyl ether (40 ml) 2 times. Then, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (hexane:ethyl acetate=3:1 to hexane:ethyl acetate=1:1) to give 0.461 g of 4-(2,6-diethyl-4-methylphenyl)-2-methyl-5-methylsulfinyl-6-trifluoromethyl-2,3-dihydro-3-pyridazinone ((2-49)-(1)-39).
Reaction SMILES: [F:1][C:2]([F:17])([C:13]([F:16])([F:15])[F:14])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[S:5](F)(=[O:7])=[O:6].CCN(CC)CC.[CH2:25]([CH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([OH:41])[CH:39]=2)[C:34](=[O:42])[NH:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[F:9][C:4]([F:10])([S:5]([O:41][C:38]1[CH:39]=[C:40]2[C:35](=[CH:36][CH:37]=1)[C:34](=[O:42])[NH:33][CH:32]2[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:7])=[O:6])[C:3]([F:12])([F:11])[C:2]([F:17])([F:1])[C:13]([F:16])([F:15])[F:14]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=C1NC(Cc2ccccc2)c2cc(O)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1NC(Cc2ccccc2)c2cc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution of nonafluorobutanesulfonyl fluoride (712 mg, 2.36 mmol) and NEt3 (0.49 mL, 3.54 mmol) in 3 mL of dichloromethane was added 3-benzyl-5-hydroxyisoindolin-1-one (example 1.4, 282 mg, 1.18 mmol) in 2 mL of dichloromethane slowly. This reaction mixture was stirred at room temperature for overnight. TLC showed complete conversion, the solvent was evaporated. The residue was purified by flash-chromatography on silica gel with 30-80% ethyl acetate in hexane, 474 mg (77%) of the product was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:21]#[N:22])[C:5]2[CH:6]=[N:7][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH:33]=[CH:34][NH:35]3)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[NH:35]1[C:36]2[C:32](=[C:31]([C:2]3[CH:3]=[C:4]([C:21]#[N:22])[C:5]4[CH:6]=[N:7][N:8]([S:11]([C:14]5[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=5)(=[O:12])=[O:13])[C:9]=4[CH:10]=3)[CH:39]=[CH:38][CH:37]=2)[CH:33]=[CH:34]1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(C#N)cc(Br)cc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ncc3c(C#N)cc(-c4cccc5[nH]ccc45)cc32)cc1
Temperature: 80 °C

Procedure:
To a suspension of 6-bromo-1-[(4-methylphenyl)sulfonyl]-1H-indazole-4-carbonitrile in 1,4-dioxane (100 ml) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (4.79 g, 10.72 mmol, available from Frontier Scientific Europe), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (2.061 g, 2.82 mmol) and potassium phosphate tribasic (8.97 g, 42.3 mmol). Water (20 ml) was added and the reaction mixture heated to 80° C. for 1 h. The solvent was removed and the residue partitioned between water (50 ml) and ethyl acetate (100 ml). The layers were filtered and the filtrate partitioned and concentrated, then purified by column chromatography, on a silica cartridge (300 g), eluting with a gradient of cyclohexane and ethyl acetate to give the title compound as a pale yellow solid (2.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([OH:14])=O)[CH:5]=[C:6]([Br:10])[C:7]=1[O:8][CH3:9].C(Cl)(=O)C([Cl:18])=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([Cl:18])=[O:14])[CH:5]=[C:6]([Br:10])[C:7]=1[O:8][CH3:9]
Reactant: COc1c(Br)cc(CC(=O)O)cc1Br
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Product: COc1c(Br)cc(CC(=O)Cl)cc1Br
Yield: 100 %

Procedure:
A solution of 3,5-dibromo-4-methoxy-phenylacetic acid (30.29 g, 0.093 mol) and oxalyl chloride (118.7 g, 81.6 ml, 0.93 mol) in 300 mL of benzene was refluxed for 6 h. The solution was evaporated with benzene 3 times and dried in vacuum. Yield 100%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[C@H:10]([CH2:11]2)[C@H:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:16]1[C:20]2=[CH:21][CH:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:19]2[CH2:18][CH2:17]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[C@H:10]([CH2:11]2)[C@H:9]1[CH2:14][NH:15][C:25]([C:24]1[CH:23]=[CH:22][CH:21]=[C:20]2[O:16][CH2:17][CH2:18][C:19]=12)=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1cccc2c1CCO2
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CN
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CNC(=O)c1cccc2c1CCO2

Procedure:
prepared by reaction of (1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester with 2,3-Dihydro-benzofuran-4-carboxylic acid.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][O:24][C:25](=[O:45])[C:26]1[CH:31]=[C:30]([CH:32]([OH:36])[CH2:33][CH2:34][CH3:35])[C:29]([C:37]([F:40])([F:39])[F:38])=[CH:28][C:27]=1[NH:41][C:42](=[O:44])[CH3:43].O.[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl.CCOC(C)=O>[CH3:23][O:24][C:25](=[O:45])[C:26]1[CH:31]=[C:30]([C:32](=[O:36])[CH2:33][CH2:34][CH3:35])[C:29]([C:37]([F:38])([F:40])[F:39])=[CH:28][C:27]=1[NH:41][C:42](=[O:44])[CH3:43]
Reactant: CCCC(O)c1cc(C(=O)OC)c(NC(C)=O)cc1C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CCCC(=O)c1cc(C(=O)OC)c(NC(C)=O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a solution of Dess-Martin periodinane (514 mg, 1.18 mmol) in DCM (2.5 mL) at r.t. was added 2-acetylamino-5-(1-hydroxy-butyl)-4-trifluoromethyl-benzoic acid methyl ester (245 mg, 0.735 mmol). The reaction was stirred at r.t. for 1 h then diluted with EtOAc and poured onto 1:1 mixture water/sat. aq Na2SO3. The organic phase was washed twice with aq KHCO3, brine, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo to give the title compound (237 mg, 97% yield) as a beige product. ESI-MS: m/z 332 [M+H]+, m/z 330 [M−H]−.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][NH:6][C:7]1[S:8][C:9]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:10]([CH2:12]O)[N:11]=1>C(Cl)(Cl)Cl>[CH3:5][NH:6][C:7]1[S:8][C:9]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:10]([CH2:12][Cl:3])[N:11]=1
Reactant: O=S(Cl)Cl
Reactant: CNc1nc(CO)c(-c2ccncc2)s1
Solvent: ClC(Cl)Cl
Product: CNc1nc(CCl)c(-c2ccncc2)s1
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
A solution of thionylchloride (1.06 g) in chloroform (5 ml) was dropwise added to a solution of 2-methylamino-4-hydroxymethyl-5-(4-pyridyl)thiazole (1.0 g) in chloroform (20 ml) at ambient temperature for a period of 5 minutes with stirring, which was continued under the same condition for 90 minutes and at 50° C. for 30 minutes. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture of water (50 ml) and ethyl acetate (30 ml). The solution was adjusted to pH 6.5 with 30% aqueous potassium carbonate and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off to give yellow powder of 2-methylamino-4-chloromethyl-5-(4-pyridyl)thiazole (0.9 g).