Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)[C:10](I)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([Zn]CC)[CH3:22].CO.ClCCl>O1CCOCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:21][CH3:22])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[Zn]CC
Reactant: O=[N+]([O-])c1cccc2c1c(I)nn2Cc1ccccc1
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: CCc1nn(Cc2ccccc2)c2cccc([N+](=O)[O-])c12
Reaction time: 0.5 h
Yield: 20.4 %

Procedure:
To a mixture of 1-benzyl-3-iodo-4-nitro-1H-indazole (304 mg, 0.802 mmol) (prepared as in Example 1, steps E-F) and 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (196 mg, 0.241 mmol) in dioxane (4.0 mL) under an atmosphere of dry nitrogen was added a solution of diethylzinc (1.6 mL, 1.60 mmol; 1 molar in hexane) with magnetic stirring. The mixture was heated at reflux for 2 hours. After allowing to cool methanol (1 mL) was added followed by dichloromethane (30 mL) and the mixture was stirred for 30 minutes. The mixture was transferred to a separatory funnel and washed with water (30 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated under vacuum. The crude product was purified by column chromatography on silica, eluting with 15-20% ethyl acetate in hexanes. Fractions containing product were concentrated under reduced pressure to give 1-benzyl-3-ethyl-4-nitro-1H-indazole (46 mg).
Reaction SMILES: [C-:1]#[N:2].[K+].CN(C)[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[N+:16]([O-:18])=[O:17])[NH:9][CH:8]=1>O.CN(C=O)C>[N+:16]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[C:7]([CH2:6][C:1]#[N:2])=[CH:8][NH:9]2)([O-:18])=[O:17]
Reactant: CN(C)Cc1c[nH]c2cccc([N+](=O)[O-])c12
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1c[nH]c2cccc([N+](=O)[O-])c12
Temperature: 25 °C

Procedure:
Potassium cyanide (9.20 g, 141 mmol) in H2O (80 mL) was added to a solution of N,N-dimethyl-1-(4-nitro-1H-indol-3-yl)methanamine from Step A (3.10 g, 14.1 mmol) in DMF (80 mL) and the mixture was heated at reflux for 1 h, then cooled to ambient temperature and partitioned between H2O (200 mL) and EtOAc (400 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=265 (M+Na+CH3CN).
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[I:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[I:10][C:11]1[CH:16]=[CH:15][C:14]([O:1][CH:2]2[CH:7]3[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]3)[CH2:3]2)=[CH:13][CH:12]=1
Reactant: Ic1ccc(I)cc1
Reactant: OC1CN2CCC1CC2
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Ic1ccc(OC2CN3CCC2CC3)cc1
Temperature: 110 °C
Reaction time: 40 h

Procedure:
Under N2, the mixture of 3-hydroxy quinuclidine (Aldrich, 2.54 g, 20 mmol), 1,4-diiodobenzene (Aldrich, 7.9 g, 24 mmol), Cul (Strem Chemicals, 0.38 g, 2 mmol) and 1,10-phenanthroline (Aldrich, 0.72 g, 4 mmol) in toluene (anhydrous, Aldrich, 50 mL) was stirred at 110° C. for 40 h. After the reaction went to completion, the reaction mixture was diluted with chloroform (100 mL) and washed with water (2×10 mL). The organic solution was concentrated and the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.20) as oil (3.7 g, yield, 56%). 1H NMR (300 MHz, CD3OD) δ 1.40-1.56 (m, 1H), 1.64-1.80 (m, 2H), 1.90-2.08 (m, 1H), 2.10-2.21 (m, 1H), 2.60-3.00 (m, 5H), 3.34-3.40 (m, 1H), 4.46 (m, 1H), 6.73 (d, J=8.8 Hz, 2H), 7.56 (d, J=8.8, Hz, 2H), ppm. MS (DCI/NH3) m/z 330 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:13]3[N:14]=[C:15]([NH2:17])[S:16][C:12]=3[CH:11]=2)=[N:6][CH:7]=1.[Br:20]Br.Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.C(OCC)(=O)C.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[CH:19]=[C:18]([Br:20])[C:13]3[N:14]=[C:15]([NH2:17])[S:16][C:12]=3[CH:11]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(CCc2ccc3nc(N)sc3c2)nc1
Reactant: BrBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(CCc2cc(Br)c3nc(N)sc3c2)nc1
Yield: 51.6 %

Procedure:
To a solution of 6-[2-(5-methyl-2-pyridyl)ethyl]-2-aminobenzothiazole (1.35 g) in acetic acid (15 ml) was dropwise added a solution of bromine (0.8 g) in acetic acid (2 ml) at 20° to 22° C. under stirring and the resultant mixture was stirred at ambient temperature for 5 hours. The reaction mixture was poured into a mixture of water and ethyl acetate and the mixture was acidified to pH 1.0 with 10% hydrochloric acid. The separated aqueous layer was adjusted to pH 8.0 with aqueous 20% potassium carbonate and extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and residue was recrystallized from a mixture of ethyl acetate and tetrahydrofuran to give 6-[2-(5-methyl-2-pyridyl)ethyl]-2-amino-4-bromobenzothiazole (0.9 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[O:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:24](=[O:31])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:7][CH:6]=3)=[CH:9][O:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: Nc1ccc(-c2coc3ncnc(N)c23)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Nc1ncnc2occ(-c3ccc(NC(=O)c4ccccc4)cc3)c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.2 %

Procedure:
A 0° C. suspension of Example 13E (74 mg, 0.33 mmol) in dichloromethane (3 mL) was treated with pyridine (0.032 mL, 0.4 mmol) and benzoyl chloride (0.040 mL, 0.34 mmol), stirred at 0° C. for 1 hour, warmed to room temperature, and stirred overnight. The mixture was triturated with hexanes and the precipitate was collected by vacuum filtration, washed with dichloromethane and water, and purified by flash column chromatography on silica gel with ethyl acetate to provide 46 mg (42%) of the desired product. MS (ESI(+)) m/e 331 (M+H)+; 1H NMR (DMSO-d6) δ 10.41 (s, 1H), 8.26 (s, 1H), 7.99-7.94 (m, 5H), 7.62-7.50 (m, 5H), 6.50 (br s, 2H); Anal. Calcd. for C19H14N4O2.0.25H2O: C, 68.15; H, 4.36; N, 16.73. Found: C, 68.20; H, 4.21; N, 19.78.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].[H][H].F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1>CN(C)C=O>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]([O:8][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: [H][H]
Reactant: CN1CCC(O)(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC(Oc2ccc([N+](=O)[O-])cc2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
A solution of 54 g of 1-methyl-4-phenylpiperidin-4-ol in 200 ml of absolute dimethylformamide is added dropwise to a suspension of 12.6 g of sodium hydride (80% strength in oil) in 200 ml of absolute dimethylformamide at a temperature of 45° C., while stirring and with exclusion of moisture. During this addition, evolution of hydrogen occurs. When the addition has ended, the mixture is stirred at 50° C. for a further 2 hours and allowed to cool to room temperature. A solution of 49.4 g of 4-fluoronitrobenzene in 100 ml of absolute dimethylformamide is then added dropwise thereto. Stirring is continued for a further 2 hours, and the reaction mixture is then poured onto 800 ml of ice-water. The precipitate which forms is filtered off and washed with water. Recrystallization from 250 ml of ethanol yields 52 g of the title compound of m.p. 135° to 137° C.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9]Cl)=[O:7])=[CH:4][CH:3]=1.[Na+].[I-:14]>CC(C)=O>[F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][I:14])=[O:7])=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: O=C(OCCl)c1ccc(F)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(OCI)c1ccc(F)cc1
Reaction time: 8 h

Procedure:
To a solution of chloromethyl 4-fluorobenzoate (3.0g, 15.9 mmol) in 50 mL of dry acetone, NaI (4.8 g, 31.8 mmol) was added and the mixture was stirred overnight. The solvent was removed and Et2O (150 mL) was added to the solid residues and the mixture was stirred for 10 min. After filtration the filtrate was washed with 5% NaHSO3 (aq) (2×25 mL) followed by brine. The organic solution was concentrated by rotary evaporation and purified by silica gel chromatography to give a light yellow oil. Yield 3.7 g (85%). 1H NMR (300 MHz, CDCl3): δ 6.16 (s, 2H), 7.17 (m, 2H), 8.08 (m, 2H).
Reaction SMILES: O1CCCC1.C(N(CC)CC)C.[C:13]([CH:16]([N:20]1[CH2:23][CH:22]([NH:24][C:25](=[O:33])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]1=[O:34])[CH:17]([CH3:19])[CH3:18])(O)=[O:14].ClC(OCC)=O.[N-:41]=[N+:42]=[N-:43].[Na+]>O>[N:41]([C:13]([CH:16]([N:20]1[CH2:23][CH:22]([NH:24][C:25](=[O:33])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]1=[O:34])[CH:17]([CH3:19])[CH3:18])=[O:14])=[N+:42]=[N-:43]
Reactant: CC(C)C(C(=O)O)N1CC(NC(=O)Cc2ccccc2)C1=O
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)C(C(=O)N=[N+]=[N-])N1CC(NC(=O)Cc2ccccc2)C1=O
Temperature: 0 °C
Yield: 91.2 %

Procedure:
A tetrahydrofuran solution (5 ml) containing triethylamine (1.02 g) was added to a tetrahydrofuran solution (40 ml) containing 1-(1-carboxy-2-methylpropyl)-3-(2-phenylacetamido)-2-azetidinone (3.04 g) at -20° C. with stirring. To this solution, there was dropwise added a tetrahydrofuran solution (5 ml) containing ethyl chloroformate (1.14 g) at -10° C. in the course of 5 minutes, whereafter the mixture was stirred at -10° to 0° C. for 2 hours. To the resultant mixture, there was all at once added water (8 ml), in which sodium azide (1.23 g) was dissolved at the same temperature, and the stirring was continued for additional half an hour. The reaction mixture was poured into ice-water (200 ml) and the resultant mixture was extracted with three portions of 100 ml methylene chloride. The extracts were washed with three portions of 100 ml water and dried over calcium chloride. The solution was evaporated to dryness under reduced pressure to give oily 1-(1-azidocarbonyl-2-methylpropyl)-3-(2-phenylacetamido)-2-azetidinone (3.0 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17](O)=[O:18])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:20]1[CH:21]=[CH:22][C:23]([Cl:30])=[C:24]2[C:28]=1[C:27](=[O:29])[NH:26][CH2:25]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[C:53]([O:57][C:58]([N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)=[O:59])([CH3:56])([CH3:55])[CH3:54]>CN(C=O)C.O>[Cl:30][C:23]1[CH:22]=[CH:21][C:20]([C:9]2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:16]3[C:11]([CH:10]=2)=[CH:12][C:13]([C:17]([N:63]2[CH2:62][CH2:61][N:60]([C:58]([O:57][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:59])[CH2:65][CH2:64]2)=[O:18])=[CH:14][CH:15]=3)=[C:28]2[C:24]=1[CH2:25][NH:26][C:27]2=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C(=O)O)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc3c(c2)cc(-c2ccc(Cl)c4c2C(=O)NC4)n3C(=O)OC(C)(C)C)CC1
Yield: 82.5 %

Procedure:
In a similar manner to Example 20, 7-[1-(tert-butoxycarbonyl)-5-carboxyindol-2-yl]-4-chloroisoindolinone (37.8 mg, 0.0886 mmol) was dissolved in DMF (1 mL), and the solution was treated with EDCI (34 mg, 0.18 mmol), HOBT monohydrate (12 mg, 0.089 mmol) and 1-(tert-butoxycarbonyl)piperazine (66 mg, 0.35 mmol). The mixture was added with water and the precipitated solid was collected by filtration, washed with water and then dried under reduced pressure to obtain 4-chloro-7-(1-(tert-butoxycarbonyl)-5-[-4-(tert-butoxycarbonyl)piperazin-1-ylcarbonyl]indol-2-yl)isoindolinone (43.5 mg, yield 83%).
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][C:21]1[CH:22]=[C:23]([NH:27][C:28](=[O:34])[NH:29][CH2:30][C:31](O)=[O:32])[CH:24]=[CH:25][CH:26]=1.C1(N=C=NC2CCCCC2)CCCCC1.[K+].[Br-]>CCCCCCC.CN(C=O)C>[CH3:20][C:21]1[CH:22]=[C:23]([NH:27][C:28](=[O:34])[NH:29][CH2:30][C:31]([N:9]2[C@H:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:12][S:11][C@@H:10]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[O:32])[CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CSC(c2ccccc2F)N1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCCC
Product: Cc1cccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3F)SC[C@H]2C(=O)OC(C)(C)C)c1
Yield: 20.1 %

Procedure:
The operation is carried out in a fashion similar to that described in Example 33, but starting from 3.5 g of tert-butyl-(2RS,4R)-2-(2-fluorophenyl)-4-thiazolidinecarboxylate, 2.3 g of 2-[3-(3-methylphenyl)ureido]acetic acid and 2.3 g of N,N'-dicyclohexylcarbodiimide. After vigorous stirring in heptane, 1.05 g of tert-butyl (2R,4R)-3-{2-[3-(3-methylphenyl)ureido]acetyl}-2-(2-fluorophenyl)-4-thiazolidinecarboxylate are thus obtained in the form of a white solid, melting at 107° C. ([α]D20 =+61.8°±1.5° (C=0.66%; DMF)) [proton NMR (200 MHz, DMSO D6, δ in ppm), 2 rotamers at room temperature, peak coalescence at 120° C., characteristic chemical shifts at 120° C.: 2.2 (bs, 3H, CH3); 6.7 (bd, 1H, N--C6H4 --C in position 4 or 6); 7.1 to 7.40 (m, 6H, aromatic); 7.9 (bm, 1H, C6H4F in position 3). Infrared spectrum (KBr), characteristics bands in cm-1 : 3370, 2975, 2925, 1735, 1645, 1615, 1590, 1560, 1490, 1460, 1370, 1150, 775, 760, 690].
Reaction SMILES: Cl.[CH3:2][C:3]1([OH:8])[CH2:7][CH2:6][NH:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:20][CH2:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=O)=O>C(#N)C>[C:23]1([CH:22]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:21][CH2:20][N:5]2[CH2:6][CH2:7][C:3]([CH3:2])([OH:8])[CH2:4]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC1(O)CCNC1
Reactant: CS(=O)(=O)OCCC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(O)CCN(CCC(c2ccccc2)c2ccccc2)C1
Reaction time: 12 h
Yield: 56.9 %

Procedure:
To a 10 L reaction flask were added 3-methylpyrrolidin-3-ol hydrochloride (616 g, 4.48 mol), anhydrous potassium carbonate (1186 g, 8.6 mol) and acetonitrile (5 L). To the resulting mixture was slowly added a solution of 3,3-diphenylpropyl methanesulfonate (1000 g, 3.45 mol) in acetonitrile dropwisely at 85° C. The reaction was conducted for 12 hours. After the completion of reaction monitored by TLC, the reaction solution was evaporated under reduced pressure to remove acetonitrile. A mixed solution of dichloromethane and water was added for extraction. The organic phase was dried over anhydrous sodium sulfate, and evaporated to remove the solvent to produce a crude product, which was purified by column chromatography (silica gel column, eluted with petroleum ether: ethyl acetate=50:1 (volumetric ratio)) to produce 1-(3,3-diphenylpropyl)-3-methylpyrrolidin-3-ol (580 g) in a yield of 57%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].C([O-])([O-])=O.[Cs+].[Cs+].[C:28]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([SH:38])=[CH:34][CH:33]=1)(=[O:30])[CH3:29]>CN1C(=O)CCC1.O>[C:14]([C:8]1([C:4]2[CH:3]=[C:2]([S:38][C:35]3[CH:34]=[CH:33][C:32]([NH:31][C:28](=[O:30])[CH3:29])=[CH:37][CH:36]=3)[CH:7]=[CH:6][CH:5]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:15]
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: N#CC1(c2cccc(Br)c2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1ccc(Sc2cccc(C3(C#N)CCOCC3)c2)cc1
Temperature: 130 °C
Yield: 79.5 %

Procedure:
4-(3-Bromo-phenyl)-tetrahydro-pyran-4-carbonitrile (1.33 g) was mixed with Na2CO3 (1.59 g), Cs2CO3 (0.651 g) and 4-acetamidothiophenol (1 g) in N-methyl pyrrolidinone (15 mL). The reaction mixture was heated at 130° C. overnight. After cooling, the mixture was poured into iced water. The product precipitated out as a solid, was collected by suction filtration. The solid was recrystallized from a mixture of EtOAc and hexanes to provide N-{4-[3-(4-Cyano-tetrahydro-pyran-4-yl)-phenyl sulfanyl]-phenyl}acetamide(1.4 g, 80% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[OH-].[K+].[CH3:12][O:13][CH2:14]Cl>N1C=CC=CC=1>[F:1][CH:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]1([CH2:12][O:13][CH3:14])[OH:9]
Reactant: COCCl
Reactant: Oc1ccc(F)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Product: COCC1(O)C=CC(F)=CC1F
Yield: 71 %

Procedure:
To a reaction mixture containing 2,4-difluorophenol (25, 2 g, 15.37 mmol) in 30 mL of dry pyridine was added powdered KOH (0.854 g, 15.25 mmol) and methoxymethyl chloride (1.6 g, 19.37 mmol) and this reaction mixture was heated under reflux for 3.5 hours (FIG. 2E). The reaction was cooled and partitioned between 1 M NaOH and ethyl ether (2×30 mL). The organic solution was washed with 1 M HCl (2×20 mL), water, and then dried (MgSO4), filtered, and the solvent removed under vacuo to afford a oily residue. The crude product was purified by column chromatography (EtOAc:hexanes; 5:95) to afford the desired product as a pale yellow oil in 71% yield. 1H NMR (CDCl3) δ 7.1-7.16 (m, 1H, ArH), 6.78-6.88 (m, 2H, ArH), 5.15 (s, 2H, CH2), 3.52 (s, 3H, CH3).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]1[C:20]([F:21])=[C:19]([C:22]([F:25])([F:24])[F:23])[C:18]([F:26])=[C:17]([F:27])[C:14]=1[CH2:15]Br>CN(C=O)C>[Cl:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:15][C:14]2[C:17]([F:27])=[C:18]([F:26])[C:19]([C:22]([F:23])([F:25])[F:24])=[C:20]([F:21])[C:13]=2[F:12])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Reactant: Fc1c(F)c(C(F)(F)F)c(F)c(F)c1CBr
Solvent: CN(C)C=O
Product: O=C(O)c1cc(NCc2c(F)c(F)c(C(F)(F)F)c(F)c2F)ccc1Cl
Yield: 85.5 %

Procedure:
According to the similar procedure in Synthesis Example 1, by using 5-amino-2-chlorobenzoic acid (1.02 g, 5.94 mmole) (ACROS, 32525-5000), DMF (50 ml) and 2,3,5,6-tetrafluoro-4-trifluoromethylbenzyl bromide (1.16 g, 6.99 mmole), 2.04 g (85.5% yield) of 2-chloro-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid was obtained as a pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][C:5]([S:17]([N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)(=[O:19])=[O:18])=[C:4]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33])[CH:3]=1.Br[C:35]1[C:40]([C:41]#[N:42])=[CH:39][C:38]([C:43]([F:46])([F:45])[F:44])=[N:37][CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:7]([C:35]2[CH:36]=[N:37][C:38]([C:43]([F:45])([F:46])[F:44])=[CH:39][C:40]=2[C:41]#[N:42])=[CH:6][C:5]([S:17]([N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)(=[O:19])=[O:18])=[C:4]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33])[CH:3]=1
Reactant: N#Cc1cc(C(F)(F)F)ncc1Br
Reactant: CN(c1ccccn1)S(=O)(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(Cl)cc1OCCCCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN(c1ccccn1)S(=O)(=O)c1cc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)cc1OCCCCO
Temperature: 90 °C
Yield: 37.5 %

Procedure:
A mixture of 4-chloro-2-(4-hydroxy-butoxy)-N-methyl-N-pyridin-2-yl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonamide (150 mg, 0.34 mmol), 5-bromo-2-trifluoromethyl-isonicotinonitrile (111 mg, 0.44 mmol), Pd(Ph3P)4 (40 mg, 0.034 mmol) and Na2CO3 (217 mg, 2.1 mmol) in dioxane (2 mL) and water (0.2 mL) was degassed with N2 for 5 min. The reaction vessel was sealed and then heated at 90° C. for 16 hrs. The mixture was absorbed onto silica gel and purified by chromatography on silica gel eluting with 20-25% acetone in hexanes to give 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(4-hydroxy-butoxy)-N-methyl-N-pyridin-2-yl-benzenesulfonamide as an oil (69 mg). A small sample was also purified by prep. LCMS. MS: 541.1 (M+H)+; tR=7.59 min (method 2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:4][CH:3]=1.[Br:13][CH2:14][CH2:15][CH3:16]>C1COCC1>[Br-:13].[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:8]2[CH:12]=[CH:11][N:10]([CH2:14][CH2:15][CH3:16])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCCBr
Reactant: Fc1ccc(-n2ccnc2)cc1
Solvent: C1CCOC1
Product: CCCn1cc[n+](-c2ccc(F)cc2)c1
Product: [Br-]

Procedure:
According to the general synthesis procedure, 3.09 mmol (0.50 g) 1-(4-fluorophenyl)imidazole and 3.09 mmol (0.380 g) 1-bromopropane are dissolved in 5 ml THF and heated for 12 h to 120° C.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)C[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl.Cl.NC1CCN(CCN2CCC([OH:54])CC2)CC1>>[OH:54][CH:4]1[CH2:5][CH2:6][N:1]([CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:14][CH2:15]2)[CH2:2][CH2:3]1
Reactant: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(Oc3ccc(F)cc3)cccc2[nH]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCC(O)CC2)CC1)c1cc2c(Oc3ccc(F)cc3)cccc2[nH]1

Procedure:
This compound is synthesized analogously to Example 1 from 4-(4-fluoro-phenoxy)-1H-indole-2-carboxylic acid 145 (see example 120) and amine 21.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][S:11]([O-:14])(=O)=[O:12])=[N:2]1.[Na+].P(Cl)(Cl)(Cl)=O.[NH3:21]>ClCCCl.C(N(CC)CC)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][S:11]([NH2:21])(=[O:14])=[O:12])=[N:2]1
Reactant: N
Reactant: O=S(=O)([O-])Cc1noc2ccccc12
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Product: NS(=O)(=O)Cc1noc2ccccc12
Reaction time: 1.5 h

Procedure:
Water is removed by distillation from the above mixture of 1,2-benzisoxazole-3-acetic acid and 1,2-dichloroethane, and thereto is added dropwise chlorosulfonic acid (15.5 g) while the internal temperature is kept at 63° C.-79° C. After the addition, the mixture is stirred for 90 minutes while the reaction temperature is kept at 63° C.-79° C. After cooling, a 25% aqueous sodium hydroxide solution is added to the reaction mixture so as to adjust the pH value thereof to pH 11 or above. Water is removed by distillation from the reaction mixture to give a mixture of sodium 1,2-benzisoxazole-3-methanesulfonate and 1,2-dichloroethane. Triethylamine (2.4 g) and phosphoryl chloride (17.5 g) are added to this mixture, and the mixture is stirred at a temperature of 77° C.-83° C. for 6 hours. After cooling, to the reaction mixture is added 1,2-dichloroethane (80 ml), and ammonia gas is blown into the mixture until saturated while the reaction temperature is kept at 30° C.-60° C. The reaction mixture is concentrated, and water is added thereto. The mixture is stirred, and the precipitated crystals are collected by filtration, and washed with water to give crude crystals of 1,2-benzisoxazole-3-methanesulfonamide. The purity of the crude crystals is 96%.