Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17](=[O:26])[C:18]([CH3:25])([S:20][C:21]([F:24])([F:23])[F:22])[CH3:19]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][C:17](=[O:26])[C:18]([CH3:25])([S:20][C:21]([F:24])([F:23])[F:22])[CH3:19])=[CH:4][CH:3]=1
Reactant: CC(C)(SC(F)(F)F)C(=O)CBr
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(SC(F)(F)F)C(=O)COc1ccc(Cl)cc1
Yield: 72.4 %

Procedure:
26 g (0.21 mol) of 4-chlorophenol and 42 g (0.3 mol) of potassium carbonate were introduced into 250 ml of acetone. 53 g (0.2 mol) of 1-bromo-3-methyl-3-trifluoromethylthio-butan-2-one in 50 ml of acetone were slowly added dropwise to the mixture, under reflux. After the end of the addition, the mixture was stirred under reflux for 12 hours and was filtered, and the filtrate was concentrated. The residue was taken up in 500 ml of methylene chloride, the solution was extracted by shaking with water and sodium bicarbonate solution, and the organic phase was dried over sodium sulphate and concentrated. The residue was distilled in vacuo. 45.3 g (73% of theory) of 1-(4-chlorophenoxy)-3-methyl-3-trifluoromethylthio-butan-2-one of boiling point 105° C./0.4 mbar were obtained. ##STR14##
Reaction SMILES: [CH:1]([O:4][S:5]([CH2:8][CH3:9])(=[O:7])=[O:6])([CH3:3])[CH3:2].C([Li])CCC.[P:15](Cl)([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16].Cl>O1CCCC1>[CH:1]([O:4][S:5]([CH:8]([P:15]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16])[CH3:9])(=[O:7])=[O:6])([CH3:3])[CH3:2]
Reactant: CCS(=O)(=O)OC(C)C
Reactant: CCOP(=O)(Cl)OCC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(C)S(=O)(=O)OC(C)C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 58.3 %

Procedure:
A solution of ethanesulfonic acid isopropyl ester (1.0 g, 6.6 mmol) in tetrahydrofuran (15 mL) was cooled to −78° C., and n-butyllithium (1.57 M, 4.6 mL, 7.2 mmol) was added. After stirring at −78° C. for 20 minutes, diethyl chlorophosphate (0.52 mL, 3.6 mmol) was added to the reaction mixture, and the mixture was further stirred for 30 minutes. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=40/60) to give the title compound (0.61 g, 2.1 mmol, 58%).
Reaction SMILES: [CH3:1][NH2:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:10][C:11]1[N:15]([CH3:16])[N:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1>CC(C)=O>[CH3:1][NH:2][CH2:10][C:11]1[N:15]([CH3:16])[N:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1
Reactant: Cn1nc([N+](=O)[O-])cc1CBr
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CNCc1cc([N+](=O)[O-])nn1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a stirred solution of MeNH2 (30% wt in H2O) (2.5 g, 20 mmol) in acetone (10 mL) at 0° C. (ice bath) was added K2CO3 (415 mg, 3 mmol), followed by the dropwise addition of a solution of 5-(bromomethyl)-1-methyl-3-nitro-1H-pyrazole (220 mg, 1 mmol) in acetone (5 mL). The reaction mixture was then warmed to room temperature and stirred for 3 h. The solvent was removed and the residue was extracted with methylene chloride (15 mL×3), dried over Na2SO4 and concentrated to afford 320a as a yellow oil (170 mg, 99%), which was used in the next step without additional purification. LCMS: (M+H)+ 171
Reaction SMILES: [C:1]([C:3]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=2)[CH2:6][CH2:5][CH2:4]1)#[N:2].Cl.[CH3:15][C:16]1[N:17]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=2)[CH:18]=[CH:19][N:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([C:3]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:25][C:24]3[CH:23]=[CH:22][C:21]([N:17]4[CH:18]=[CH:19][N:20]=[C:16]4[CH3:15])=[CH:28][CH:27]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4]1)#[N:2]
Reactant: Cc1nccn1-c1ccc(CCl)cc1
Reactant: N#CC1(c2cccc(O)c2)CCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nccn1-c1ccc(COc2cccc(C3(C#N)CCC3)c2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 84.4 %

Procedure:
A mixture of 1-cyano-1-(3-hydroxyphenyl)cyclobutane (1.76 g, 10 mmol), 4-(2-methylimidazol-1-yl)benzylchloride hydrochloride (2.10 g, 10 mmol) and potassium carbonate (6.90 g, 50 mmol) in DMF (80 ml) were stirred together at 80° C. for 3 hrs. Water (200 ml) was added and the mixture extracted with ethyl acetate/benzene (2/1, 100 ml×2), washed with water (100 ml×2), brine (100 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 150 g; dichloromethane/methanol (20/1)) to afford 2.90 g (84%) of the titled compound as a clear yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=O)=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)C.N1CCCCC1>[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:13][C:12]2=[O:18])=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Reactant: Cc1cc(C(=O)NCCN2CCCC2)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cccc(-c2cccc3c2C(=Cc2[nH]c(C)cc2C(=O)NCCN2CCCC2)C(=O)N3)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 34 %

Procedure:
To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 2-Formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (64.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(3-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (40 mg, 34%).
Reaction SMILES: [CH2:1]([CH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])[C:10]=2[O:9][C:8]1=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-:25].[K+].CO>>[OH:9][C:10]1[C:15]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[CH:14][CH:13]=[CH:12][C:11]=1[CH:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8]([OH:24])=[O:25]
Reactant: [OH-]
Reactant: CCCCCCC1C(=O)Oc2c(Sc3ccccc3C)cccc21
Agent: [K+]
Solvent: CO
Product: CCCCCCC(C(=O)O)c1cccc(Sc2ccccc2C)c1O

Procedure:
3-n-Hexyl-7-(o-tolylthio)-2,3-dihydrobenzofuran-2-one was hydrolyzed by treating with potassium hydroxide-methanol to give 2-[2-hydroxy-3-(o-tolylthio)phenyl]octanoic acid, mp. 90°-91° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:8]2)=[CH:4][CH:3]=1.ClS([N:21]=[C:22]=O)(=O)=O.CN(C=O)C>ClCCl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:22]#[N:21])=[C:7]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Fc1ccc2cc(-c3cccnc3)[nH]c2c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1c(-c2cccnc2)[nH]c2cc(F)ccc12
Reaction time: 8 h

Procedure:
To a solution of 6-fluoro-2-pyridin-3-yl-1H-indole (Example 89, 212 mg, 1.0 mmol) in dichloromethane (90 mL) at ambient temperature is added chlorosulfonyl isocyanate (0.71 g, 5 mmol) and the mixture is stirred overnight. Anhydrous DMF (1 mL) is added. After 1 h, the solvent is removed in vacuo and the residue purified by HPLC using an Xbridge C18 with a gradient of acetonitrile in 0.1% NH4OH to give 6-fluoro-2-pyridin-3-yl-1H-indole-3-carbonitrile as a white solid. 1H NMR (400 MHz, DMSO-d6) d ppm 7.12-7.21 (m, 1H), 7.39 (dd, J=9.5, 2.4 Hz, 1H), 7.64-7.74 (m, 2H), 8.27-8.35 (m, 1H), 8.73 (dd, J=4.9, 1.6 Hz, 1H), 9.14 (d, J=1.8 Hz, 1H), 12.89 (s, 1H). MS (ESI) m/z 238.0 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[C@@H:10]([C@@H:21]([OH:23])[CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][N:28]=1>CN(C=O)C>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[C@@H:10]([C@@H:21]([O:23][C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][N:28]=2)[CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: C[C@H](O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](Oc1ccc(C#N)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
To a stirred solution of 84 mg (0.26 mmol) of (S)-1-[(3R,4S)-1-benzyl-4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethanol in DMF (10 mL) was added NaH (19 mg, 0.40 mmol). The reaction mixture was stirred at RT for 30 minutes, and then at 50° C. for 20 minutes. A solution of 6-chloro-nicotinonitrile (45 mg, 0.32 mmol) in DMF (2 mL) was added dropwise and stirring was continued 3 hours at 50° C. The reaction mixture was concentrated under vacuo. Extraction with EtOAc/H2O, followed by column chromatography (SiO2, EtOAc/H, 1:3) yielded 66 mg (60%) of the title compound as a colorless oil. ES-MS m/e: 420.3 (M+H+).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:6]=[CH:7][O:8][C:9]=1[CH3:10])=O.N1C=CC=CC=1.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[C:38]([NH:40][NH2:41])=O)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>ClCCl>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[C:38]2[N:2]([CH3:1])[C:3]([C:5]3[N:6]=[CH:7][O:8][C:9]=3[CH3:10])=[N:41][N:40]=2)(=[O:28])=[O:29])=[CH:23][CH:22]=1)([CH3:18])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)NN)cc1
Reactant: CNC(=O)c1ncoc1C
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ocnc1-c1nnc(-c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1C
Temperature: -40 °C
Reaction time: 2 h

Procedure:
A vial was charged with 5-methyl-oxazole-4-carboxylic acid methylamide (71 mg, 0.5 mmol), pyridine (0.12 mL, 1.5 mmol), and anhydrous dichloromethane (2.5 mL). The reaction vessel was cooled to −40° C. and trifluoromethanesulfonyl anhydride (0.11 mL, 0.65 mmol) was added. The reaction was subsequently warmed to −10° C. over 2.5 h and then 4-tert-butyl-N-(4-chloro-2-hydrazinocarbonyl-phenyl)-benzenesulfonamide (191 mg, 0.5 mmol) was added. The reaction was warmed to room temperature stirred an additional 2 h. The solvent was concentrated in vacuo and ethanol (5 mL) and diisopropylamine (0.5 mL) were added and the solution stirred at 90° C. overnight. The following day, the reaction was concentrated in vacuo and the crude material was purified by flash column chromatography (10-100% ethyl acetate and hexane), followed by preparative HPLC (10-90% gradient of MeCN-water) to yield the title compound: MS (ES) M+H expected 486.1, found 486.0.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]([CH3:20])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH:18][NH2:19])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:22][CH2:23][C:24](OC(=O)CCl)=O>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]([CH3:20])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][C:24]([CH2:23][Cl:22])=[N:19][N:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(C(=O)NN)ncn2-c2cccc(Cl)c2C1=O
Reactant: O=C(CCl)OC(=O)CCl
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3nnc(CCl)o3)ncn2-c2cccc(Cl)c2C1=O
Temperature: 25 °C
Yield: 53.3 %

Procedure:
15.3 g (50 mmol) of 7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-3-carboxylic acid hydrazide were stirred at room temperature overnight in 160 ml of N,N-dimethylformamide with 9.41 g (55 mmol) of chloroacetic anhydride. After evaporating the solvent the residue was stirred at room temperature over the weekend with 100 ml of a 10% solution of phosphorus pentoxide in methanesulphonic acid. The reaction mixture was treated with ice, made alkaline with conc. sodium hydroxide solution and extracted four times with methylene chloride. By drying the organic phase over magnesium sulfate, evaporation of the solvent and chromatography of the residue on silica gel while eluting with ethyl acetate there were obtained 9.7 g (53%) of 7-chloro-3-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of m.p. 201°-203°.
Reaction SMILES: [C:1]1([CH3:26])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][C:10]1[S:11][C:12]2[C:18]([C:19]([O:21]C)=[O:20])=[CH:17][C:16]([N+:23]([O-:25])=[O:24])=[CH:15][C:13]=2[N:14]=1.[OH-].[Na+]>CO.C1COCC1>[C:1]1([CH3:26])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][C:10]1[S:11][C:12]2[C:18]([C:19]([OH:21])=[O:20])=[CH:17][C:16]([N+:23]([O-:25])=[O:24])=[CH:15][C:13]=2[N:14]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])cc2nc(Nc3c(C)cc(C)cc3C)sc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C)c(Nc2nc3cc([N+](=O)[O-])cc(C(=O)O)c3s2)c(C)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
To a mixture of methyl 2-mesitylamino-5-nitro-1,3-benzothiazole-7-carboxylate (230 mg, 0.619 mmol) (prepared in example 19) in methanol (5 ml) and THF (5 ml) was added 1 N NaOH solution (2.48 ml, 2.48 mmol). The mixture was stirred at 50° C. for 3 h. The solvent was evaporated under vacuum and the aqueous residue was neutralized with 1N HCl solution. The resulting precipitate was collected by filtration and dried under vacuum to afford 177 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[N:12][C:11]([NH:14][NH2:15])=[N:10][CH:9]=1.[C:16]([O-])([O-])(OCC)[CH3:17]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([C:16]([CH3:17])=[N:15][N:14]=2)[N:13]=1
Reactant: NNc1ncc(-c2ccccc2F)nn1
Reactant: CCOC(C)([O-])[O-]
Product: Cc1nnc2ncc(-c3ccccc3F)nn12

Procedure:
A mixture of 3.8 g. of 6-(o-fluorophenyl)-3-hydrazino-1,2,4-triazine and 40 ml. of ethyl orthoacetate is refluxed for 4 hours, cooled and the solid is collected by filtration and washed with hexane, giving the desired product as a yellow solid, m.p. 199.5°-203.5° C.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li:18])CCC.CCCCCC>C1COCC1>[C:1]1([Li:18])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: [Li]CCCC
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Solvent: CCCCCC
Solvent: C1CCOC1
Product: [Li]c1cccc2c1Cc1ccccc1-2

Procedure:
To a solution of 10.38 g (62.5 mmol) of fluorene in 250 ml of THF at 0° C. was added dropwise a 1.6 molar solution of butyllithium in hexane (39.05 ml, 62.5 mmol) in order to produce fluorenyllithium. The solution was stirred for 3 h at room temperature and then added dropwise over a period of 2 h via a cannula to 125 ml (1.45 mol) of 1,2-dibromoethane. The solution was stirred overnight at room temperature. After hydrolysis with 125 ml aqueous NH4Cl, the organic layer was separated. The aqueous layer was extracted twice with ether. The combined organic layers were dried on MgSO4, filtered and the solvents were removed. The excess 1,2-dibromoethane was recovered by trap to trap distillation at 0.5 mm Hg with gentle heating by a warm water bath. A chilled receiving flask was used. The resulting yellow residue was dissolved in pentane, filtered, concentrated and cooled to -20° C. to give 1-(9-fluorenyl)-2-bromoethane (10.25 g, 60%) as a yellow solid; melting point: 48-49° C. 1H NMR data was consistent with that reported in literature.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](Cl)(=[O:19])=[O:18]>N1C=CC=CC=1>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][S:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH3:10])(=[O:19])=[O:18])[C:3]([Cl:9])=[N:4][CH:5]=1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: Nc1cc(Br)cnc1Cl
Solvent: c1ccncc1
Product: Cc1ccccc1S(=O)(=O)Nc1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Amino-5-bromo-2-chloropyridine (767 mg) in dry pyridine (8 ml) was treated with 2-methylbenzenesulfonyl chloride (641 μl) then stirred at RT overnight. The reaction was purified by prep-HPLC. Desired fractions were combined, diluted with saturated sodium bicarbonate (aq) and brine and extracted into EtOAc. The solvent was dried over sodium sulfate and evaporated to give title compound (500 mg).
Reaction SMILES: C(N(CC)CC)C.[CH:8]1[C:16]2[C:15]3[CH2:17][CH2:18][CH2:19][CH2:20][C:14]=3[O:13][C:12]=2[CH:11]=[CH:10][C:9]=1[NH2:21].[CH3:22][C:23]([CH3:28])([CH3:27])[C:24](Cl)=[O:25]>>[CH3:22][C:23]([CH3:28])([CH3:27])[C:24]([NH:21][C:9]1[CH:10]=[CH:11][C:12]2[O:13][C:14]3[CH2:20][CH2:19][CH2:18][CH2:17][C:15]=3[C:16]=2[CH:8]=1)=[O:25]
Reactant: Nc1ccc2oc3c(c2c1)CCCC3
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc2oc3c(c2c1)CCCC3
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.1 %

Procedure:
Triethylamine (2.0 mL, 14 mmol) was added to a cooled (0° C.) solution of 6,7,8,9-tetrahydro-dibenzofuran-2-ylamine (0.86 g, 4.6 mmol). The reaction mixture was stirred for 10 minutes at 0° C. and then trimethylacetyl chloride (0.60 mL, 4.8 mmol) was added. The ice bath was removed and the reaction mixture was stirred for 30 min and then concentrated. The crude material was dissolved in chloroform and washed with 10% aqueous ammonium hydroxide, water, and brine, dried (Na2SO4) and concentrated. The crude material was recrystallized from acetonitrile to provide 2,2-dimethyl-N-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-propionamide (0.80 g). Mp 210-211° C.; Anal. Calcd. for C17H21NO2: C, 75.25; H, 7.80; N, 5.16; Found: C, 75.33; H, 7.64; N, 5.07.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[N:12]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C[O-].[Na+].C(O)(=O)C>CO>[CH3:23][O:22][C:20]([C:19]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]2[C:4]([C:3]=1[OH:2])=[CH:9][C:8]([O:10][CH3:11])=[CH:7][CH:6]=2)=[O:21]
Reactant: COC(=O)CN(c1ccccc1)c1ccc(OC)cc1C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1c(O)c2cc(OC)ccc2n1-c1ccccc1
Temperature: 20 °C
Yield: 82 %

Procedure:
A mixture of 1.7 kg (5.2 mole) of 5-methoxy-2-[(2-methoxy-2-oxoethyl)phenylamino]benzoic acid methyl ester, and 303 g (5.6 mole) of sodium methoxide in 10.0 l of anhydrous methanol was stirred at reflux for 90 minutes. The mixture was cooled to 20° C., filtered, and treated with 336 g (320 ml, 5.6 mole) of glacial acetic acid. The mixture was cooled in ice, and the precipitated crude product was filtered and washed with cold methanol followed by hexane. There was obtained 1267 g (82% yield) of the indole product of analytical purity, mp 114°-116° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH2:11]([SH:14])[CH2:12][SH:13]>CCCCCC>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]2[S:14][CH2:11][CH2:12][S:13]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: SCCS
Solvent: CCCCCC
Product: COc1ccc(C2SCCS2)cc1
Yield: 99.5 %

Procedure:
Following the general procedure as in Example 1, 25 gm (0.184 moles) of 4-methoxybenzaldehyde and 17.3 gm (0.184 moles) of 1,2-ethanedithiol gave, after crystallization from hexane, 39.3 gm (0.183 moles) of a white colored solid (96% yield) m.p. 62°-63° C. Elemental analysis for C10H12OS2 :
Reaction SMILES: [C:1]1([O:11][CH2:12][CH:13]2[CH2:15][O:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(O)C>[CH2:16]([N:23]1[CH2:24][CH2:25][N:26]([CH2:15][CH:13]([OH:14])[CH2:12][O:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH2:27][CH2:28]1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: c1ccc2c(OCC3CO3)cccc2c1
Reactant: CCCCCCCN1CCNCC1
Solvent: CCO
Product: CCCCCCCN1CCN(CC(O)COc2cccc3ccccc23)CC1
Yield: 92.2 %

Procedure:
To a solution of 2-((1-naphthyloxy)methyl)oxirane (106 mg, 0.53 mmol) in ethanol (1 mL) was added 4-heptylpiperazine (118 mg, 0.64 mmol) at room temperature. The mixture was stirred under reflux for 1 hr. The reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give HUHS1018 (188 mg, 93%).
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:9])[NH:2]2.[H-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[CH2:12]([N:2]1[C:3](=[O:9])[CH:4]2[CH2:7][CH2:8][CH:1]1[CH2:6][CH2:5]2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1NC2CCC1CC2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1C2CCC(CC2)N1Cc1ccccc1
Reaction time: 0.25 h
Yield: 47.5 %

Procedure:
Compound 2-azabicyclo[2.2.2]octan-3-one (1.1 g, 8.8 mmol) in THF (10 ml) was added to a stirred suspension of sodium hydride (0.42 g, 10.6 mmol, 60%) in THF (10 ml) at 0° C. and stirred for 15 min. Benzyl bromide (1.05 ml, 8.80 mmol) was added to the reaction mixture at 0° C. and stirred for 4 h at room temperature. The reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the crude compound. The crude compound was triturated with n-pentane to afford 900 mg (47.6%) of 2-benzyl-2-aza-bicyclo[2.2.2]octan-3-one as solid.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:18][CH2:19][CH3:20].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].[H-].[Na+]>CN(C=O)C>[CH3:32][O:31][C:29](=[O:30])[CH2:28][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([CH2:18][CH2:19][CH3:20])[N:8]2[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)CBr
Reactant: CCCc1cc2c(O)cccc2n1Cc1ccccc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1cc2c(OCC(=O)OC)cccc2n1Cc1ccccc1-c1ccccc1
Yield: 56 %

Procedure:
1-([1,1'-Biphenyl]-2-ylmethyl)-4-hydroxy-2-propyl-1H-indole (794 mg, 2.8 mmol) was alkylated by treating with 0.22 mL (2.3 mmol) of methyl bromoacetate and 93 mg (2.3 mmol) of 60% NaH/mineral oil in DMF as described in Example 1, Part E. The product was purified by chromatography over silica gel eluting with 20% EtOAc/hexane, to give 533 mg (56% yield) of [[1-([1,1'-biphenyl]-2-ylmethyl)-2-propyl-1H-indol-4-yl]oxy]acetic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH2:11]Br)[C:6]=2[C:5]([F:13])=[C:4]([F:14])[CH:3]=1.C([O-])(=[O:17])C.[K+].CO.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH2:11][OH:17])[C:6]=2[C:5]([F:13])=[C:4]([F:14])[CH:3]=1
Reactant: CC(=O)[O-]
Reactant: Fc1cc(Br)c2occ(CBr)c2c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: OCc1coc2c(Br)cc(F)c(F)c12
Temperature: 60 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
The compound (1.47 g, 4.51 mmol) obtained in Step 1 was dissolved in acetonitrile (50 mL), and potassium acetate (660 mg, 6.76 mmol) was added thereto, and stirred at 60° C. for 3 hours. After cooling, the solvent was distilled away, and to the resulting residue, methanol (20 mL) and potassium carbonate (1.56 g, 11.28 mmol) were added, and stirred at room temperature for 2 hours. The solvent was distilled away. After diluted with ethyl acetate, the resultant was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away, and the resulting residue was purified by silica gel chromatography (hexane/ethyl acetate) to thus obtain the title compound.