Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([CH2:18][C:19]([OH:21])=[O:20])[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.[C:33](=[O:36])([O-])[O-:34].[Na+].[Na+]>C1C=CC=CC=1>[C:33]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:20][C:19](=[O:21])[CH2:18][C:10]1[C:9]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[N:8][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([OH:34])=[O:36]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)Cc1c(-c2ccccc2)nn(-c2ccccc2)c1-c1ccccc1
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(Cc1c(-c2ccccc2)nn(-c2ccccc2)c1-c1ccccc1)Oc1ccccc1C(=O)O
Reaction time: 0.42 h
Yield: 54 %

Procedure:
7.0 grams 1,3,5-triphenyl-pyrazol-4-acetic acid, 3.1 grams phosphorus oxychloride and 40 milliliters benzene were mixed and the mixture was heated to the boiling temperature under reflux for 2 hours. The reaction mixture was then poured on ice, the pH adjusted to 6 by the addition of dilute aqueous sodium carbonate solution. The benzene solution was separated, washed with water, dried over anhydrous magnesium sulfate, and evaporated. The residue, consisting of 1,3,5-triphenyl-pyrazol-4-acetylchloride was taken up in 40 milliliters absolute ether. The ether solution was then added dropwise at 0°-3° C. and within 20 minutes to a solution of 2.8 grams salicyclic acid in a mixture of 20 milliliters ether and 4.2 grams pyridine. The mixture was after stirred for 25 minutes and thereafter poured on a mixture of ice and concentrated aqueous hydrochloric acid. The acid solution was separated, extracted with water, and the ether evaporated. The residue was recrystallized from ethanol. 5.1 grams 1,3,5-triphenyl-pyrazol-4-acetic acid-(2-carboxyphenyl)-ester, melting at 190°-191° C., were obtained representing a yield of 54%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][C:8]3[CH:14]=[C:13]([CH2:15][C:16](=[O:18])[CH3:17])[CH:12]=[CH:11][C:9]=3[O:10][C:2]=12.C1(C)C=CC(S(O[CH2:29][CH2:30][O:31][CH3:32])(=O)=O)=CC=1>[Na].C(O)(C)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][C:8]3[CH:14]=[C:13]([CH:15]([CH2:29][CH2:30][O:31][CH3:32])[C:16](=[O:18])[CH3:17])[CH:12]=[CH:11][C:9]=3[O:10][C:2]=12
Reactant: CC(=O)Cc1ccc2c(c1)Cc1cccnc1O2
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Agent: [Na]
Solvent: CC(C)O
Product: COCCC(C(C)=O)c1ccc2c(c1)Cc1cccnc1O2
Temperature: 40 °C
Yield: 53.6 %

Procedure:
3 g of 5H-[1]benzopyrano[ 2,3-b]pyridin-7-yl-acetone is dissolved in a solution of 0.32 g of metallic sodium in 15 ml of absolute isopropyl alcohol by warming to 50°-60°C. The solution is cooled to 40°C, 3.5 g of 2-methoxyethyl p-toluenesulfonate is added, and the mixture is stirred under reflux for 1.5 hours. The reaction mixture is concentrated, chloroform and water are added to the residue, and the mixture is stirred. The chloroform layer is separated, dried over anhydrous magnesium sulfate and concentrated. The oily residue is column chromatographed over silica gel (100 g) with a mixture of chloroform and ethyl acetate (10:1) as eluent to give 2.0 g of 3-(5H-[1]benzopyrano[ 2,3-b]pyridin-7-yl)-5-methoxy-2-pentanone as a pale yellow transparent oil. nD28 = 1.5764
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([C:11]3([OH:21])[CH2:19][CH2:18][CH2:17][C:16]4[N:15]([CH3:20])[N:14]=[CH:13][C:12]3=4)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.C1C(=O)N([Br:29])C(=O)C1>CN(C=O)C.O>[Br:29][C:10]1[N:9]=[C:8]([C:11]2([OH:21])[CH2:19][CH2:18][CH2:17][C:16]3[N:15]([CH3:20])[N:14]=[CH:13][C:12]2=3)[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=12
Reactant: Cn1ncc2c1CCCC2(O)c1ncc2c(Cl)nccn12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc2c1CCCC2(O)c1nc(Br)c2c(Cl)nccn12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
To a solution of 4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-indazol-4-ol (1 g, 3.3 mmol) in DMF (8 ml) was added NBS (584 mg, 3.3 mmol) portionwise at 0° C. After the addition was complete, the reaction mixture was stirred at 0° C. for 30 minutes. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC to give 4-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-indazol-4-ol (860 mg, 68%). MS-ESI (m/z): 382 (M+1)+ (Acq Method: 10-80AB_2 min; Rt: 1.01 min)
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[C:11]([O:12][CH3:13])=[C:10]([OH:14])[C:9]([CH3:15])=[CH:8][C:6]=1[OH:7]>C(Cl)(Cl)Cl>[CH3:3][O:4][C:5]1[C:11]([O:12][CH3:13])=[C:10]([OH:14])[C:9]([CH3:15])=[C:8]([Br:1])[C:6]=1[OH:7]
Reactant: COc1c(O)cc(C)c(O)c1OC
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COc1c(O)c(C)c(Br)c(O)c1OC
Reaction time: 3 h
Yield: 100.7 %

Procedure:
A solution of 39.5 g of bromine in 70 ml of chloroform was added dropwise at about 5° C. to a solution of 46.0 g of 2,3-dimethoxy-5-methylhydroquinone in 500 ml of chloroform, under a nitrogen atmosphere. Stirring was continued at the same temperature for 3 hours, and then the reaction mixture was washed with water until the washings were colorless. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to provide 65.5 g of 2,3-dimethoxy-5-methyl-6-bromohydroquinone.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[CH2:12](Br)[CH:13]=[CH2:14].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCCCCC>[CH2:14]([O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)[CH:13]=[CH2:12]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: C=CCOc1cccc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a suspension of 3-trifluoromethyl phenol (4.05 g, 0.025 mol) and allyl bromide in acetone (50 mL) was added K2CO3 (3.5 g, 0.025 mol). The mixture was stirred overnight at 60° C. and was diluted with n-hexane. The solution was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography to 1-alkyloxy-3-trifluoromethyl-benzene (4.0 mg, 79%).
Reaction SMILES: C([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]1[CH:27]=[CH:26][C:16]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])=[O:18])=[C:15]([Cl:28])[CH:14]=1)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.C(O)C(F)(F)F>[Cl:28][C:15]1[CH:14]=[C:13]([NH:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[OH:5])[CH:27]=[CH:26][C:16]=1[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25])=[O:18]
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2OC(C)(C)C)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: OCC(F)(F)F
Solvent: ClCCl
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2O)cc1Cl
Temperature: -5 °C
Reaction time: 1 h

Procedure:
A solution of 4-(2-tert-butoxy-phenylamino)-2-chloro-2′-methylbenzophenone (Compound 107) (1.33 g, 3.4 mmol) in a mixture of CH2Cl2 (5 ml) and trifluoroethanol (20 ml) was cooled to −5° C. under argron. Trifluoroacetic acid (423 mg, 3.7 mmol) was added dropwise and the reaction mixture was allowed to come to room temperature over 1 h. After 23 h at room temperature the reaction mixture was poured into saturated NaHCO3 and then extracted with EtOAc and CH2Cl2. The organic phases was collected, dried (MgSO4), filtered, and concentrated in vacuo to give the crude product. This was further purified by flash chromatography using EtOAc/pentane 1:4 as eluant.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([N:23](CC)CC)C>C(Cl)Cl>[C:11]1([S:17]([NH:23][NH:10][C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][CH:2]=2)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCN(CC)CC
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Product: N#Cc1ccc(NNS(=O)(=O)c2ccccc2)cc1
Reaction time: 0.08 h

Procedure:
A solution of 3,4 diamino benzonitrile (10.7 g, 0.08 mol) in methylene chloride was treated with phenyl sulfonyl chloride (2 eq, 0.16 mol) and triethyl amine (2 eq, 0.16 mol) for 18 hours at 23° C. The reaction mixture was partitioned between water and methylene chloride. The organic layer was separated and dried over sodium sulfate. The solution was filtered and concentrated to 50 mL and a solid was precipitated out with hexanes. This solid was dissolved in tetrahydrofuran and treated with 25% NaOMe in methanol. The reaction was complete after 5 minutes. The reaction mixture was acidified to pH 7 with ammonium chloride solution, then it was extracted with methylene chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated to 50 mL. Hexanes were added to precipitate desired as a white solid (19.7 grams).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][O:8][C:9](=[O:10])[C:2]=12.[Li+].CC([N-]C(C)C)C.CS([C:23]1[N:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[N:24]=1)(=O)=O.Cl>C1COCC1>[CH3:32][O:31][C:25]1[CH:26]=[C:27]([O:29][CH3:30])[N:28]=[C:23]([CH:7]2[C:3]3[C:2](=[N:1][CH:6]=[CH:5][CH:4]=3)[C:9](=[O:10])[O:8]2)[N:24]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: O=C1OCc2cccnc21
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(OC)nc(C2OC(=O)c3ncccc32)n1
Temperature: 25 °C

Procedure:
A solution of 1.3 g (0.0096 mols) of furo [3,4-b]pyridine-7(5H)-one in 50 ml of dry THF is cooled to -75° C. and 8 ml (0.0192 mols) of 2.5M LDA added dropwise over 5 minutes. The mixture is allowed to react for 1 hr at -750° C. and 2.1 g (0.0096 mol) of 2-methylsulfonyl-4,6-dimethoxypyrimidine in 30 ml of dry THF added dropwise over 10 minutes. The mixture is allowed to warm to RT, 1.6 ml of HCl added and the THF evaporated off. The residue is dissolved in 75 ml of CH2Cl2, washed with water (2×50 ml) and the organic phase concentrated to give a yellowish white gummy solid. This is chromatographed on a silica gel column using 50/50 hexane/ethyl acetate (500 ml), ethyl acetate (500 ml) and 80/20 acetone/methanol (1000 ml) (30 fractions). The crystalline residue (fractions 18-21) of the title product has m.p. of 167°-168° C.
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][O:12][C:13]2[CH:26]=[CH:25][C:16]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:24])=[CH:15][CH:14]=2)=[N:8][CH:9]=1)[CH3:3].[C:27]([OH:36])(=[O:35])[C@@H:28]([C@H:30]([C:32]([OH:34])=[O:33])[OH:31])[OH:29].O>CO>[C:32]([C@@H:30]([C@H:28]([C:27]([OH:36])=[O:35])[OH:29])[OH:31])([OH:34])=[O:33].[CH2:2]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][O:12][C:13]2[CH:26]=[CH:25][C:16]([CH2:17][C@H:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:24])=[CH:15][CH:14]=2)=[N:8][CH:9]=1)[CH3:3]
Reactant: CCc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)nc1
Agent: Cl
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CO
Solvent: O
Product: CCc1ccc(CCOc2ccc(C[C@H]3SC(=O)NC3=O)cc2)nc1
Reaction time: 96 h

Procedure:
5-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-1,3-thiazolidine-2,4-dione hydrochloride (100 mg) in MeOH (2 mL) was stirred for 5 min. using brief sonication to give a clear solution. L-tartaric acid (38 mg, 1 eq) was added followed by dropwise addition of water until a haziness persisted (up to 2 mL used). The reaction was stirred in closed vial for 96 h, the precipitated solid was collected on a filter cup and washed with H2O-MeOH (2:1, 3 ml) and then dried under vacuum (42 mg). (Method 13) 48.30%, Rt 9.62 min.; 51.60%, Rt 14.30 min.; d.e. 3.3%. 1H NMR (400 MHz, DMSO-d6): δ 8.34-8.29 (1H, d, J 1.9), 7.55-7.49 (1H, dd, J 2.2, 7.9), 7.24-7.20 (1H, d, J 7.8), 7.12-7.05 (2H, d, J 8.6), 6.84-6.77 (2H, d, J 8.6), 4.78-4.71 (1H, dd, J 4.3, 9.1), 4.30-4.19 (1H, d, J 4.3), 3.24-3.18 (2H, d), 3.11-3.03 (2H, t, J 6.6), 3.00-2.92 (1H, dd, J 9.2, 14.2), 2.59-2.50 (2H, q, J 7.6), 1.17-1.09 (3H, t, J 7.7).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1)#[N:2].[Cl:32][C:33]1[CH:40]=[C:39]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:38]=[CH:37][C:34]=1[CH2:35]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:41]([C:39]1[CH:38]=[CH:37][C:34]([CH2:35][O:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2/[CH:24]=[CH:23]/[CH:11]([CH2:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)=[C:33]([Cl:32])[CH:40]=1)([CH3:44])([CH3:42])[CH3:43]
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2O)CCc2ccc(C#N)cc2)cc1
Reactant: CC(C)(C)c1ccc(CBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2Cl)CCc2ccc(C#N)cc2)cc1

Procedure:
A solution of 450 mg (1.09 mmol) of methyl 4-[(3E)-2-[2-(4-cyanophenyl)ethyl]-4-(2-hydroxyphenyl)but-3-en-1-yl)benzoate in 10 ml of dry acetonitrile is mixed with 825.2 mg (1.64 mmol) of 2-chloro-4-(tert-butyl)benzyl bromide and 453.4 mg (3.28 mmol) of anhydrous potassium carbonate and heated under reflux for 12 h. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The organic phase is concentrated. The resulting crude product is purified by preparative HPLC. 518 mg (0.87 mmol, 73.9% of theory) of a colorless foam are obtained.
Reaction SMILES: [C-:1]#[N:2].[K+].[Br:4][C:5]1[CH:29]=[CH:28][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C-:12]([CH:19]([C:25]#[N:26])[C:20](OCC)=[O:21])[C:11]2=[O:27])=[C:7]([F:30])[CH:6]=1.Cl.C[OH:33]>C(OCC)(=O)C>[Br:4][C:5]1[CH:29]=[CH:28][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]3([CH:19]([C:25]#[N:26])[C:20](=[O:21])[NH:2][C:1]3=[O:33])[C:11]2=[O:27])=[C:7]([F:30])[CH:6]=1
Reactant: [C-]#N
Reactant: CO
Reactant: CCOC(=O)C(C#N)[c-]1c(=O)n(Cc2ccc(Br)cc2F)c2ccccc21
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Product: N#CC1C(=O)NC(=O)C12C(=O)N(Cc1ccc(Br)cc1F)c1ccccc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Potassium cyanide (5.85 g.) was added to a solution of ethyl 2-[1-(4-bromo 2-fluorobenzyl)-2-oxo3-indolinidyl]-2-cyanoacetate (D) (35.0 g.) in methanol (80 ml.). The mixture was stirred for 2 hours, cooled to 0° C. and then saturated with dry hydrogen chloride at 0°-1O° C. The solution obtained was left overnight at ambient temperature, heated at 50°-55° C. for 1 hour and then under reflux for 4 hours. The cooled reaction solution deposited a solid which was collected; washed with water, air dried and then heated under reflux in acetic acid (85 ml.) for 12 hours. This mixture was cooled and the solid residue removed by filtration. The filtrate was evaporated, residual acetic acid being removed by azeotropic evaporation with toluene (3×150 ml.). The oily residue obtained was dissolved in ethyl acetate (100 ml.) and absorbed onto chromatographic silica gel (30 g.) by evaporation of the solvent. The residue was added to a column of silica gel (300 g.) made up in toluene. Elution with an increasing concentration of ethyl acetate in toluene (up to 25% v/v) and combination and evaporation of those fractions containing the major component (relative flow value 0.6), gave 1'-(4-bromo-2-flurobenzyl)-4-cyano-spiro[pyrrolidine3,3'-indoline]-2,2',5-trione (5.5 g.), m.p. 208°-210° C., after recrystallisation from ethyl acetate/petrol 60-80.
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=2)[C:30]([O:32][CH3:33])=[O:31])=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.BrC1C=C(C=CC=1)C(OC)=O>>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([C:22]2[O:23][C:24]([C:27]3[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=3)[C:30]([O:32][CH3:33])=[O:31])=[CH:25][N:26]=2)=[O:8])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1cccc(-c2cnc(C(CCCCCCc3ccccc3)O[Si](C)(C)C(C)(C)C)o2)c1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: COC(=O)c1cccc(Br)c1
Product: COC(=O)c1cccc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)c1
Yield: 76 %

Procedure:
Methyl 3-(2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)oxazol-5-yl)benzoate. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (188 mg, 0.284 mmol) and methyl 3-bromobenzoate following General Procedure A. Flash chromatography (2-10% EtOAc/hexanes) yielded the title compound as a clear oil (110 mg, 76%): 1H NMR (CDCl3, 500 MHz) δ 8.40 (m, 1H), 8.07 (d, 1H, J=8.0 Hz), 7.90 (d, 1H, J=8.0 Hz), 7.58 (t, 1H, J=7.6 Hz), 7.44 (s, 1H), 7.35-7.32 (m, 2H), 7.25-7.23 (m, 3H), 4.93 (t, 1H, J=6.0 Hz), 4.03 (s, 3H), 2.67 (t, 2H, J=7.4 Hz), 2.04-1.99 (m, 2H), 1.75-1.68 (m, 2H), 1.45-1.37 (m, 6H), 1.00 (s, 9H), 0.20 (s, 3H), 0.10 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 166.9, 165.7, 150.6, 143.1, 131.4, 129.7, 129.5, 128.9, 128.8, 128.6, 128.6, 126.1, 125.8, 123.5, 69.1, 52.7, 36.8, 36.4, 31.8, 29.6, 29.6, 26.2, 25.6, 14.1, −4.5, −4.6.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:11])([CH2:9][CH3:10])[C:4](=[O:8])[CH:5](Cl)[Cl:6].C.C(O)C>C(OCC)(=O)C.[Pd]>[ClH:6].[NH2:2][C:3]([CH3:11])([CH2:9][CH3:10])[C:4](=[O:8])[CH2:5][Cl:6]
Reactant: CCC(C)(N)C(=O)C(Cl)Cl
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCC(C)(N)C(=O)CCl
Reaction time: 3 h
Yield: 196.6 %

Procedure:
In a 2 L Parr bottle were placed 41 g of 3-amino-1,1-dichloro-3-methyl-2-pentanone hydrochloride, 0.8 g of 10% palladium over charcoal and 400 ml of ethanol (200 proof). The resulting mixture was shaken in a Parr apparatus at 50 psi for 3 hours. The crude reaction mixture was filtered through Celite™ filter agent and evaporated in vacuo. A viscous oil resulted, which was taken up in approximately 400 ml of ethyl acetate and stirred at room temperature for several hours. The expected 3-amino-1-chloro-3-methyl-2-pentanone hydrochloride crystallized as a white solid. To the resulting suspension were added 300 ml of hexane. Filtration yielded 34 g (98%) of the expected 3-amino-1-chloro-3-methyl-2-pentanone hydrochloride (Compound 14).
Reaction SMILES: C(OO)(=[O:3])C.[C:6]1([CH:12]=[CH:13][C:14]2[S:15][C:16]3[C:25]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[N:19]=[CH:18][C:17]=3[N:26]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(O)C>C(OC)(=O)C>[C:6]1([CH:12]=[CH:13][C:14]2[S:15][C:16]3[C:25]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[N+:19]([O-:3])=[CH:18][C:17]=3[N:26]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C(=Cc1nc2cnc3ccccc3c2s1)c1ccccc1
Reactant: CC(=O)OO
Solvent: COC(C)=O
Solvent: CCO
Product: [O-][n+]1cc2nc(C=Cc3ccccc3)sc2c2ccccc21
Temperature: 25 °C

Procedure:
Peracetic acid (1.32 mL of 32% in acetic acid) was added to a suspension of 2-(2-phenyl-1-ethenyl)thiazolo[4,5-c]quinoline (1.20 g) in methyl acetate (50 mL). A precipitate formed. Ethanol was added to the reaction mixture until all of the precipitate was dissolved. The reaction mixture was heated at reflux overnight and then cooled to ambient temperature. The resulting precipitate was isolated by filtration, dried and then recrystallized from methanol/dichloromethane to provide 2-(2-phenyl-1-ethenyl)thiazolo[4,5-c]quinoline-5-oxide as a yellow solid, m.p. 268-270° C. Analysis: Calculated for: C18H12N2OS: % C, 71.03; % H, 3.97; % N, 9.20; Found: % C, 69.94; % H, 3.87; % N, 9.05.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:7][C:6]=1[F:16])([CH3:4])([CH3:3])[CH3:2].[Cl-].ClC1N(C)CC[NH+]1C.FC(F)(F)[C:28](O)=[O:29].[NH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])=[CH:37][C:36]=1OC>C(N(CC)CC)C>[C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([NH:33][CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH:41][S:42]([CH3:45])(=[O:43])=[O:44])=[C:39]([O:29][CH3:28])[CH:40]=2)=[O:13])=[CH:7][C:6]=1[F:16])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc(NS(C)(=O)=O)ccc1CN
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1F
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: COc1cc(CNC(=O)COc2ccc(C(C)(C)C)c(F)c2)ccc1NS(C)(=O)=O
Yield: 19.6 %

Procedure:
(4-tert-Butyl-3-fluorophenoxy)acetic acid (113 mg, 0.5 mmol), 2-chloro-1,3-dimethylimidazolinium chloride (CDI) (89 mg, 0.55 mmol), triethylamine (0.33 ml) and N-[4-(aminomethyl)-3-methoxyphenyl]methanesulfonamide trifluoroacetic acid (258 mg, 0.75 mmol) were treated in the same procedure described in Example 2(b). The crude residue was applied to a silica gel chromatography column and eluted with a volume mixture of hexane and ethyl acetate (3/1 to 1/1) to furnish 43 mg (20% yield) of the title compound as a white solid.
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:12][O:13][CH2:14][C:15]1([N:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22](=[O:25])[CH2:23][CH3:24])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CC(NC(C)C)C>CC(C)CC(=O)C>[C:3]([CH:2]([N:18]1[CH2:19][CH2:20][C:15]([N:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22](=[O:25])[CH2:23][CH3:24])([CH2:14][O:13][CH3:12])[CH2:16][CH2:17]1)[CH3:11])(=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCC(=O)N(c1ccccc1)C1(COC)CCNCC1
Reactant: CC(Br)C(=O)c1ccccc1
Solvent: CC(C)NC(C)C
Solvent: CC(=O)CC(C)C
Product: CCC(=O)N(c1ccccc1)C1(COC)CCN(C(C)C(=O)c2ccccc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 3.6 parts of 2-bromo-1-phenyl-1-propanone, 4.1 parts of N-[4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide, 3.5 parts of N-(1-methylethyl)-2-propanamine and 80 parts of 4-methyl-2-pentanone is stirred and refluxed for 16 hours. The reaction mixture is cooled to room temperature and the precipitate is filtered off. The filtrate is evaporated. The oily residue is purified by column-chromatography over silica gel, using a mixture of trichloromethane and 3% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue solidifies on triturating in petroleumether. The product is filtered off and crystallized from 2,2'-oxybispropane. It is filtered off again and dried, yielding N-[1-(1-benzoylethyl)-4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide; mp. 123° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][C:23]=1[F:24])[C:16](OCC)=[O:17])(=[O:11])=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:35][C:36]1[N:41]=[C:40]([CH3:42])[CH:39]=[CH:38][N:37]=1>C1COCC1>[Cl:35][C:36]1[N:41]=[C:40]([CH2:42][C:16]([C:15]2[CH:21]=[CH:22][C:23]([F:24])=[C:13]([NH:12][S:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])(=[O:11])=[O:10])[CH:14]=2)=[O:17])[CH:39]=[CH:38][N:37]=1
Reactant: CCOC(=O)c1ccc(F)c(NS(=O)(=O)c2c(F)cccc2F)c1
Reactant: Cc1ccnc(Cl)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1ccnc(Cl)n1)c1ccc(F)c(NS(=O)(=O)c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of ethyl 3-{[(2,6-difluorophenyl)sulfonyl]amino}-4-fluorobenzoate (5.0 g, 13.9 mmol) in THF (100 mL) was added 1.0 M LiHMDS in THF (34.8 mL, 34.8 mmol). A solution of 2-chloro-4-methylpyrimidine (2.7 g, 20.9 mmol) in THF (100 mL) was added dropwise over 30 min, and the reaction was stirred overnight at rt. The reaction was quenched with 10 mL of MeOH and concentrated, and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layer was extracted with 2×50 mL EtOAc, and the combined organic layers were passed through a pad of silica gel, concentrated, and adsorbed onto silica gel. The crude product was purified via flash chromatography with 0-100% EtOAc/DCM to generate 3.07 g (50% yield) of the title compound as a white powder. MS (ESI): 443 (M+H).