Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH2:5][CH2:4][C:3](=O)[CH2:2]1.C(N(CC)CC)C.[C:14](#[N:22])[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[NH2:17]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[S:1]1[C:2]2[C:3](=[N:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[C:14]=2[NH2:22])[CH2:4][CH2:5]1
Reactant: O=C1CCSC1
Reactant: N#Cc1ccccc1N
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1c2c(nc3ccccc13)CCS2
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
To a stirred solution of tetrahydrothiophen-3-one (1.1 g, 11 mmole) in methylene chloride (10 ml) at -78° C., a 1M solution of titanium (IV) chloride in methylene chloride (11 ml) was added. A mixture of triethylamine (2.2 g, 22 mmole) and anthranilonitrile (1.2 gms, 10.0 mmole) in methylene chloride (30 ml) was then added to the reaction mixture over a period of 5 minutes. The reaction mixture was then slowly warmed to room temperature and stirred for 2 hours. Tetrahydrothiophen-3-one (1 ml) and titanium(IV) chloride (1.0 ml) was then added to the reaction mixture and the mixture was stirred at 25° C. for 16 hours. Thereafter, the reaction mixture was quenched with 12% aqueous NaOH (100 ml) and the reaction mixture was then stirred vigorously with additional methylene chloride (300 ml). The reaction mixture was then filtered through diatomaceous earth (Celite (trademark)) and the organic phase was separated. The organic solvents were removed under vacuum to afford a residue which was loaded on a flash chromatography column. Elution with 5% methanol in methylene chloride containing 1% triethylamine, afforded the title compound (1.3 gms, 64%) which was crystallized from chloroform (560 mg, 32%, m.p. 208°-210° C.). 1H-NMR (CDCl3, 300 MHz, δ): 4H, m, 3.4-3.56 ppm; 2H, bs, 4.51 ppm; 1H, dt, 7.37 ppm (J=7.0, 1.0 Hz); 1H, dt, 7.52 ppm (J=7.0, 1.10 ppm); 1H, dd, 7.61 ppm (J=7.0, 1.0 ppm); 1H, dd, 7.61 ppm (J=7.0, 1.0 ppm), 1H, dd, 7.86 ppm (J=7.0, 1.0 ppm). HRMS: Calculated--202.0575; Found--202.0545.
Reaction SMILES: [I:1][C:2]#[C:3][C:4]1[CH:8]=[CH:7][S:6][CH:5]=1.[CH2:9]([N:16]=[N+:17]=[N-:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[I:1][C:2]1[N:16]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:17]=[N:18][C:3]=1[C:4]1[CH:8]=[CH:7][S:6][CH:5]=1
Reactant: IC#Cc1ccsc1
Reactant: [N-]=[N+]=NCc1ccccc1
Product: Ic1c(-c2ccsc2)nnn1Cc1ccccc1

Procedure:
Synthesized from 3-(iodoethynyl)thiophene and benzylazide using one-pot/two-step general procedure, 1.24 g, 3.38 mmol, 81%; mp=125-127° C. (dec.); IR (υ[cm−1]) 3025, 1496, 1455, 1354, 1318, 1230, 1211, 1072, 1008, 783, 717; 1H NMR (600 MHz, CDCl3) δ=7.94 (d, J=1.6, 1H), 7.75 (d, J=4.7, 1H), 7.39 (dd, J=4.7, 3.0, 1H), 7.36-7.29 (m, 3H), 7.29-7.25 (m, 2H), 5.64 (s, 2H); 13C NMR (151 MHz, CDCl3) δ=147.3, 134.5, 131.2, 129.1, 128.7, 127.9, 126.8, 126.1, 122.9, 76.0, 54.5; HRMS (ESI-TOF) (m/z): [M+H]+ calcd for C13H11IN3S, 367.9713; found 367.9713.
Reaction SMILES: [CH3:1][O:2][C:3]([O:6][CH3:7])([CH3:5])[CH3:4].[Cl:8][CH:9](CO)[CH:10]([OH:13])CO.S(=O)(=O)(O)O.[OH-].[Ba+2].[OH-]>CC(C)=O.O>[Cl:8][CH:9]([CH:1]1[CH2:7][O:6][C:3]([CH3:5])([CH3:4])[O:2]1)[CH2:10][OH:13]
Reactant: COC(C)(C)OC
Reactant: OCC(O)C(Cl)CO
Agent: O=S(=O)(O)O
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)OCC(C(Cl)CO)O1
Reaction time: 2 h

Procedure:
Within 2 hours, 258 ml of 2,2-dimethoxypropane is added dropwise to a stirred and water-cooled solution of 272 g of 3-chloro-1,2,4-butanetriol and 0.5 ml of concentrated sulfuric acid in 1 liter of acetone. The reaction is completed after another 4 hours. The solution is neutralized by the addition of 3.8 g of barium hydroxide, stirred for 30 minutes, filtered off from the solid matter, and concentrated to dryness under vacuum, yielding 2-chloro-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[NH2:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[N:29][CH:28]=[CH:27]2>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH:30]1[C:31]2[C:26](=[CH:25][C:24]([NH:23][C:11](=[O:13])[CH:10]([C:14]3[CH:18]=[CH:17][S:16][CH:15]=3)[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:33][CH:32]=2)[CH:27]=[CH:28][N:29]=1
Reactant: Nc1ccc2cnccc2c1
Reactant: CC(C)(C)OC(=O)NCC(C(=O)O)c1ccsc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccsc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(tert-butoxycarbonylamino)-2-(thiophen-3-yl)propanoic acid (E431) in pyridine was added was added EDC, DMAP, and 6-aminoisoquinoline, and the solution was stirred overnight at room temperature. The mixture was poured into NaHCO3(sat) and extracted with EtOAc. The organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 3% MeOH/CH2Cl2) gave pure tert-butyl 3-(isoquinolin-6-ylamino)-3-oxo-2-(thiophen-3-yl)propylcarbamate (E432).
Reaction SMILES: N1C=CC(N2CCC([CH2:13][NH:14][C:15]3[C:20]([C:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][N:16]=3)CC2)=CC=1.[NH4+].C(Cl)(Cl)=[O:26]>O1CCOCC1>[C:20]12[C:15](=[N:16][CH:17]=[CH:18][CH:19]=1)[NH:14][C:13](=[O:26])[O:23][C:21]2=[O:22]
Reactant: O=C(Cl)Cl
Reactant: O=C([O-])c1cccnc1NCC1CCN(c2ccncc2)CC1
Agent: [NH4+]
Solvent: C1COCCO1
Product: O=c1[nH]c2ncccc2c(=O)o1
Reaction time: 2 h

Procedure:
A solution of ammonium 2-[[1-(4-pyridinyl)piperidin-4-ylmethyl]amino]pyridine-3-carboxylate (3.0 g, 9.12 mmol) in dioxane (45 mL) was treated with phosgene (1.9 M in toluene, 9.50 mL, 18.2 mmol), and the resulting mixture was heated at reflux. After 2 h, the mixture was concentrated yielding the corresponding aza-isatoic anhydride which was used without further purification. A solution of the crude anhydride (300 mg, 0.648 mmol) in tetrahydrofuran (2 mL) at 0° C. was treated with the magnesium salt of 2-amino-5-chloropyridine [2.60 mmol; freshly prepared by addition of methyl magnesium bromide (3.0 M in THF, 0.865 mL, 2.60 mmol) to 2-amino-5-chloropyridine (900 mg, 3.89 mmol) in THF (10 mL) at 0° C.]. After 17 h, the mixture was treated with a saturated aqueous solution of ammonium chloride and then partitioned between EtOAc and water. The aqueous layer was washed with EtOAc (3×) and the combined extracts were washed with water (1×), dried with sodium sulfate, and concentrated. The residue was purified by RPHPLC yielding 29 mg (9%) of the title compound as a hydrochloride salt.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH2:38]([NH2:42])[CH:39]([CH3:41])[CH3:40]>>[F:36][C:30]1[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:29]=1[S:26]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:9]2[N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][CH2:38][CH:39]([CH3:41])[CH3:40])[N:7]=2)[C:20]=1[F:37])(=[O:28])=[O:27]
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1cc(F)ccc1F
Reactant: CC(C)CN
Product: CC(C)CNc1nccc(-c2sc(C3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.150 g, 0.265 mmol) and isobutylamine (1.052 mL, 10.58 mmol) the title compound was obtained as an off-white solid (108 mg, 0.166 mmol, 62.9% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.77 (s, 1H), 8.02 (d, J=5.1 Hz, 1H), 7.44-7.64 (m, 3H), 7.31-7.44 (m, 3H), 7.27 (t, J=7.8 Hz, 1H), 5.68-6.07 (m, 1H), 3.83-3.96 (m, 2H), 3.38-3.55 (m, 2H), 3.21-3.32 (m, 1H), 2.87-3.18 (m, 2H), 1.92-2.06 (m, 2H), 1.61-1.92 (m, 3H), 0.74-0.99 (m, 6H). MS (ESI): 604.20 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:7]=[CH:6][CH:5]=2.[CH3:17][SiH:18]([N:20](Cl)[C:21]([CH3:24])([CH3:23])[CH3:22])[CH3:19]>C1COCC1>[CH3:1][C:2]1[CH:3]([Si:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:17])[C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:7]=[CH:6][CH:5]=2
Reactant: C[SiH](C)N(Cl)C(C)(C)C
Reactant: CC1=Cc2c(cccc2-c2ccccc2)C1
Solvent: C1CCOC1
Product: CC1=Cc2c(-c3ccccc3)cccc2C1[Si](C)(C)NC(C)(C)C
Reaction time: 16 h
Yield: 82 %

Procedure:
2-methyl-4-phenylindene (synthesized substantially according to the technique reported in U.S. Pat. No. 5,329.033) (3.00 g, 0.014 moles) in THF (10 mL) was added dropwise to a stirring solution of KH (0.601 g, 0.0150 moles) in THF (50 mL). This mixture was allowed to stir for 16 hours. The solution was then filtered and added dropwise to a solution of dimethylsilyl(t-butylamino)chloride (2.41 g, 0.0145 moles) in THF (75 mL). This mixture was allowed to stir for 16 hours. After the reaction period the volatiles were removed and the residue extracted and filtered using hexane. Removal of the volatiles resulted in the isolation of the desired product as a light yellow oil (4.00 g, 82.0 percent).
Reaction SMILES: [C:1]1([CH:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:8]2[CH:12]([NH2:13])[CH:11]([CH2:14][CH2:15][C:16](=[O:21])[NH:17][N:18]([CH3:20])[CH3:19])[CH2:10][NH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:34][C:31]=1[CH:32]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:22]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]2[CH:12]([NH:13][CH2:32][C:31]3[CH:34]=[C:35]([CH:38]([CH3:40])[CH3:39])[CH:36]=[CH:37][C:30]=3[O:29][CH3:28])[CH:11]([CH2:14][CH2:15][C:16](=[O:21])[NH:17][N:18]([CH3:20])[CH3:19])[CH2:10][NH:9]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CN(C)NC(=O)CCC1CNC(C(c2ccccc2)c2ccccc2)C1N
Reactant: COc1ccc(C(C)C)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COc1ccc(C(C)C)cc1CNC1C(CCC(=O)NN(C)C)CNC1C(c1ccccc1)c1ccccc1
Reaction time: 18 h
Yield: 62 %

Procedure:
A solution of 100 mg (0.272 mmol) [(2SR, 3SR, 4RS)-2-diphenylmethyl-3-amino-4-(2-dimethylaminocarbamoylethyl)pyrrolidine](the product of Example 26B) in 25 ml of dichloroethane was treated with 48 mg (0.272 mmol) of 2-methoxy-5isopropylbenzaldehyde and 81 mg (0.381 mmol) of sodium triacetoxyborohydride. The reaction mixture was stirred for 18 hours and then quenched with 15 ml of saturated aqueous sodium bicarbonate. The reaction mixture was extracted with methylene chloride and the organic phase was washed with brine, dried and evaporated. The residue was chromatographed on silica gel eluting with 97/2/1 (methylene chloride/methanol/ammonia) to afford 89 mg (62%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1C=CC(S(OCCC#C)(=O)=O)=[CH:4][CH:3]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(N(C(C)C)CC)(C)C>ClCCCl>[CH2:4]([N:25]1[CH2:24][CH2:23][N:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=2)[CH2:27][CH2:26]1)[CH2:3][C:2]#[CH:1]
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: C#CCCN1CCN(c2ccccn2)CC1
Yield: 48.4 %

Procedure:
A solution of but-3-ynyl 4-methylbenzenesulfonate (1.27 g), 1-(pyridin-2-yl)piperazine (1.17 g) and diisoproylethylamine (1.37 mL) in 1,2-dichloroethane (7 mL) was heated to reflux overnight. The mixture was concentrated, diluted with sat. aq. NaHCO3 (5 mL) and extracted with DCM (2×50 mL). Drying (Na2SO4) and silica gel flash chromatography (EtOAc/hexane 1:1→1:0) afforded 1-(but-3-ynyl)-4-(pyridin-2-yl)piperazine (0.59 g)
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=1)=[O:6].[C:17]([NH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].Cl>>[C:17]([NH:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=2)=[O:6])[CH2:28][CH2:27]1)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)c1ccc(C(=O)CCCCl)cc1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)c1ccc(C(=O)CCCN2CCC(NC(=O)c3ccccc3)CC2)cc1
Yield: 57.4 %

Procedure:
4-Chloro-4'-tert-butylbutyrophenone (3.58 g.), 4-benzamidopiperidine (3.06 g.) and anhydrous potassium carbonate 2.67 g.) were reacted together in the manner of Example 68 to give the title compound (3.495 g.) as the hydrochloride, colourless microcrystals, m.p. 268.0°. Analysis: Found: C, 70.50; H, 8.14; N, 6.29. C26H34N2O2.HCl requires C, 70.48; H, 7.96; N, 6.32%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH:9]=[CH2:10])=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[ClH:19]>O1CCCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][Cl:19])=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cl
Reactant: C=CC(O)c1ccc(F)c(Oc2ccccc2)c1
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(/C=C/CCl)cc1Oc1ccccc1
Reaction time: 2 h

Procedure:
1-(4-Fluoro-3-phenoxyphenyl)prop-2-en-1-ol (38 g) was dissolved in tetrahydrofuran (400 cm3) and concentrated hydrochloric acid (180 cm3) was added with vigorous stirring. Stirring was continued for a further 2 hours, after which time, analysis of a withdrawn sample by gas liquid chromatography showed no starting material remaining. The mixture was diluted with water and the products extracted into ethyl acetate. The combined organic layers were washed with water (4 times), then dried over anhydrous magnesium sulphate. Evaporation of the solvent under reduced pressure gave E-3-(4-fluoro-3-phenoxyphenyl)-1-chloroprop-2-ene (44 g) as a viscous oil, 98% pure by gas liquid chromatographic analysis.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[F:16][C:17]1([F:32])[CH2:22][CH2:21][N:20]([C:23]2[N:28]=[CH:27][C:26]([CH2:29][NH2:30])=[CH:25][C:24]=2[CH3:31])[CH2:19][CH2:18]1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:30]([CH2:29][C:26]3[CH:27]=[N:28][C:23]([N:20]4[CH2:19][CH2:18][C:17]([F:32])([F:16])[CH2:22][CH2:21]4)=[C:24]([CH3:31])[CH:25]=3)[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(CN)cnc1N1CCC(F)(F)CC1
Agent: Cl
Product: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)cnc1N1CCC(F)(F)CC1
Yield: 76 %

Procedure:
The title compound is prepared in 76% yield (228 mg, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (212 mg, 0.76 mmol, Step-1 of Intermediate-1) and (6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methanamine hydrochloride (211 mg, 0.76 mmol, Amine-82) in a similar manner to Intermediate-2.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[NH2:7].C(N(CC)CC)C.[F:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([F:29])[C:24]=1[O:25][CH2:26][C:27]#[CH:28])[C:19](Cl)=[O:20]>C(OCC)(=O)C>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][C:19](=[O:20])[C:18]1[CH:22]=[C:23]([F:29])[C:24]([O:25][CH2:26][C:27]#[CH:28])=[C:16]([F:15])[CH:17]=1
Reactant: CC1CCCC1N
Reactant: C#CCOc1c(F)cc(C(=O)Cl)cc1F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C#CCOc1c(F)cc(C(=O)NC2CCCC2C)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 23.9 %

Procedure:
A mixture of 0.12 g of 2-methylcyclopentylamine, 0.2 ml of triethylamine and 1 ml of ethyl acetate was added dropwise under ice cooling to a mixture of 1 ml of ethyl acetate and 0.23 g of 3,5-difluoro-4-(2-propynyloxy)benzoyl chloride. The mixture obtained was stirred at room temperature for 12 hours. Then, the reaction mixture was subjected to silica gel column chromatography to obtain 0.07 g of N-(2-methylcyclopentyl)-3,5-difluoro-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 54 of the present invention) represented by the formula:
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[C:23]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].[H-].[Na+].CN(C)P(N(C)C)(N(C)C)=O>O1CCCC1>[CH3:6][O:5][C:3](=[O:4])[CH:2]([O:33][C:30]1[CH:31]=[CH:32][C:27]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:28][CH:29]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)C(Br)c1ccc(OCOc2ccc(Cl)cc2)cc1
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C(Oc1ccc(C(C)(C)C)cc1)c1ccc(OCOc2ccc(Cl)cc2)cc1
Yield: 105.3 %

Procedure:
As described in Example 3, 8.92 g of methyl bromo{p-[(p-chlorophenoxy)methoxy]phenyl}acetate, 3,45 g of p-tert.-butylphenol and 9.17 g of 60% sodium hydride-oil dispersion are reacted in 75 ml of tetrahydrofuran containing 1 ml of hexamethylphosphoramide and worked-up to give 11 g of product as an oil. Chromatography over silica gel with dichloromethane as eluent gives 7.1 g of gum which is crystallized from methanol to give 4.9 g of white crystals. Recrystallization gives white crystals, mp 64°-65° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([S:11]([N:14]([O:16][CH3:17])[CH3:15])(=[O:13])=[O:12])[S:10][C:3]=12.[F:18][C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1[OH:28].C([O-])([O-])=O.[K+].[K+]>C1(OC2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl>[F:18][C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1[O:28][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([S:11]([N:14]([O:16][CH3:17])[CH3:15])(=[O:13])=[O:12])[S:10][C:3]=12
Reactant: CON(C)S(=O)(=O)c1cc2nccc(Cl)c2s1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CON(C)S(=O)(=O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 25 °C
Yield: 39.7 %

Procedure:
A mixture of 82 (400 mg, 1.37 mmol), 2-fluoro-4-nitrophenol (321 mg, 2.05 mmol) and K2CO3 (756 mg, 5.48 mmol) were heated to 190° C. in diphenyl ether (55 ml) for 3 hrs. The mixture was cooled to room temperature, diluted with DCM and filtered. The filtrate was concentrated and purified by column chromatography (eluent EtOAc:hexane, 1:1) to afford title compound 83 (225 mg, 40% yield). MS (m/z) 414.0 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][C:5]1[C:6]([CH3:19])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[C:9]=1[CH3:10].C(N(CC)CC)C.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[C:28]1([S:34]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([CH2:11][N:8]3[C:9]([CH3:10])=[C:5]([CH2:4][C:3]([OH:2])=[O:20])[C:6]([CH3:19])=[N:7]3)=[CH:13][CH:14]=2)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc(N)cc2)c1C
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nn(Cc2ccc(NS(=O)(=O)c3ccccc3)cc2)c(C)c1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sulfonamide formation: To a solution of [1-(4-amino-benzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-acetic acid methyl ester (intermediate 1.1.3, 54 mg, 0.20 mmol) in dichloromethane (1 mL) was added triethylamine (72 μL, 0.51 mmol) and phenylsulfonyl chloride (36 μL, 0.25 mmol). The reaction mixture was stirred for 1 h at room temperature. The reaction mixture was filtered over Alox B, eluting with 10% methanol in dichloromethane. Saponification: After removing the volatiles under reduced pressure, the remaining residue was dissolved in methanol (0.5 mL) and treated with aqueous LiOH solution (1 M, 0.4 mL). After 1.5 h, the mixture was neutralized and purified via preparative reversed phase HPLC (gradient of methanol in water+0.1% trifluoroacetic acid).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([OH:15])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].Br[CH2:17][CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1.[H-].[Na+]>CN(C=O)C.CC(=O)OCC>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([O:15][CH2:17][CH2:18][CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(O)cc(C(C)(C)C)c1
Reactant: BrCCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCCCOC2CCCCO2)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
Methyl 3-tert-butyl-5-hydroxybenzoate (O6.043; 3.22 g) and 2-(3-bromopropoxy)-tetrahydropyran (4.14 g) were dissolved in DMF (30 ml), and sodium hydride (445 mg) was added. After stirring at RT for 3 h, the mixture was left to stand overnight. Then the DMF was drawn off and the residue was taken up in EA, washed with water, dried, filtered and concentrated. 5.37 g of product were obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[N:8]1([C:14]([C:16]2[CH:28]=[C:27]3[C:19]([C:20]4[CH:21]=[C:22](B5OC(C)(C)C(C)(C)O5)[CH:23]=[C:24]([C:29]([NH2:31])=[O:30])[C:25]=4[NH:26]3)=[CH:18][CH:17]=2)=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>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.CO>[N:8]1([C:14]([C:16]2[CH:28]=[C:27]3[C:19]([C:20]4[CH:21]=[C:22]([C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=5)[CH:23]=[C:24]([C:29]([NH2:31])=[O:30])[C:25]=4[NH:26]3)=[CH:18][CH:17]=2)=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CC1(C)OB(c2cc(C(N)=O)c3[nH]c4cc(C(=O)N5CCOCC5)ccc4c3c2)OC1(C)C
Reactant: Brc1ccccn1
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: Cc1ccccc1
Solvent: CO
Product: NC(=O)c1cc(-c2ccccn2)cc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Temperature: 100 °C

Procedure:
2-Bromopyridine (0.1 mL, 1.025 mmol), 7-(morpholine-4-carbonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazole-1-carboxamide 429A (140 mg, 0.125 mmol), Pd(Ph3P)4 (76 mg, 0.066 mmol) and Na2CO3 (2M) (0.8 mL, 1.600 mmol) were mixed with toluene (2 mL) and MeOH (1 mL) in a sealed microwave tube. The mixture was degassed and heated at 100° C. for 12 hrs. The mixture was concentrated and purified using preparative HPLC to give titled product. MS (ESI) m/z 401.16 (M+H)+. 1H NMR (DMSO-d6) δ ppm 11.66 (s, 1H), 9.13 (d, 1H, J=1.5), 8.73 (d, 1H, J=4.8), 8.71 (d, 1H, J=1.5), 8.40 (s, 1H), 8.33 (d, 1H, J=8.0), 8.21 (d, 1H, J=8.0), 7.95 (td, 1H, J=7.8, 1.8), 7.83 (s, 1H), 7.57 (s, 1H), 7.37 (m, 1H), 7.27(dd, 1H, J=8.1, 1.5), 3.7-3.5 (bm, 8 H).