Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:3]=1.[C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)#[N:27]>>[CH3:1][C:2]1[N:7]=[C:6]([C:32]2[CH:33]=[C:28]([CH:29]=[CH:30][CH:31]=2)[C:26]#[N:27])[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(OS(=O)(=O)C(F)(F)F)n1
Reactant: N#Cc1cccc(B(O)O)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(C#N)c2)n1

Procedure:
The title compound was prepared trifluoro-methanesulfonic acid 6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl ester (example A.32) (5.00 g, 13 mmol) and commercially available 3-cyanophenylboronic acid (1.67 g, 14.3 mmol) according to the general procedure VI. Obtained as a white solid (3.00 g, 68%). MS (ISP) 339.1 [(M+H)+]; mp 140° C.
Reaction SMILES: [C:1](=[O:3])=[O:2].CC(C)=O.[Si]([N:15]1[C@@H:18]([S:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:17]([CH2:39]O)[C:16]1=[O:41])(C(C)(C)C)(C)C.[Li]CCCC>O1CCCC1>[CH:1]([O:3][CH2:39][C@H:17]1[C@H:18]([S:19][C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[NH:15][C:16]1=[O:41])=[O:2]
Reactant: O=C=O
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](CO)[C@@H]1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: O=COC[C@@H]1C(=O)N[C@H]1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.42 h
Yield: 60 %

Procedure:
To a cold (dry ice-acetone bath, -78° C.) solution of trans 1-(t-butyldimethylsilyl)-3-hydroxymethyl-4-tritylthio-2-azetidinone (4.89 g, 10 mmol) in tetrahydrofuran (15 ml) was added dropwise 1.6 M n-BuLi (8.2 mmol). The red solution was stirred in a cold bath for 25 min and then treated dropwise with a solution of paranitrobenzylchloroformate (2.6 g, 12 mmol). Stirring was continued for 2 h. The reaction mixture was partitioned between ammonium chloride and ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate (2×10 ml). The organic layers were combined and washed with brine, dried (MgSO4), and evaporated in vacuo. The residual oil was chromatographed on a silica gel column (70 g). Elution with benzene gave the title compound 4.0 g (60%) as an amorphous solid. ir νmax (CDCl3) 1750, 1610 cm-1 1 Hmr (CDCl3) δ: 8.40 (2H, d, J=9), 7.45 (17H, m), 5.22 (2H, s, benzyl), 4.4 (1H, d, J=1.5, H-4), 4.05 (1H, dd, J=14, J=4.5, H-1'), 3.28 (1H, m, H-3), 3.18 (1H, dd, J=14, J=4, H=1'), 0.95 (9H, s, t-Bu) and 0.32 ppm (6H, s, CH3).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CN(C=O)C>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH:22]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)Cc1csc(-c2cnn(C(C)(C)C)c2-c2ccc(F)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(Cc1ccccc1)c1csc(-c2cnn(C(C)(C)C)c2-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 25.4 %

Procedure:
To a solution of ethyl 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetate (50 mg, 0.13 mmol) in DMF (2.0 mL) was added sodium hydride (60 wt % oil 6.19 mg, 0.15 mmol) at 0° C., and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added benzyl bromide (0.018 mL, 0.15 mmol) at 0° C., and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 0→10% ethyl acetate/hexane) to give ethyl 2-(2-(1-(tert-butyl)-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)-3-phenylpropanoate (15.9 mg, 0.033 mmol, 25.8%) as a colorless oil.
Reaction SMILES: O.NN.[N+]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=[CH:9][C:8]=1[CH:21]=[CH:22][N:23]1CCCC1)([O-])=O>CO.[Ni]>[CH2:14]([O:13][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:7]=1[NH:23][CH:22]=[CH:21]2)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1c(C=CN2CCCC2)cccc1OCc1ccccc1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: c1ccc(COc2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrazine hydrate (4.6 g, 92 mmol, 85% solution) was added to a mechanically stirred mixture of 1-[2-[2-nitro-3-(phenylmethoxy)phenyl]ethenyl]pyrrolidine and N-methyl-N-[2-[2-nitro-3-(phenylmethoxy)phenyl]ethenyl]methanamine (20 g, 61.8 mmol, crude product obtained as described in Step 2) and Raney-Nickel (5 g) in methanol (500 mL), care being taken to keep the temperature at 45°-50° C. Two additional portions of hydrazine hydrate (4.6 g each ) were added after 30 and 60 minutes, respectively. The temperature was maintained at 45°-50° C. for 5 hours. After stirring overnight at room temperature, the mixture was filtered off (Celite) and the filtrate was concentrated in vacuo. The residue (dark liquid) was purified by flash-chromatography (on silica Merck-60, dichloromethane-light petroleum ether 1:1) to yield pure 7-benzyloxyindole as an oil that solidifies upon standing (2.3-3.03 g, 17-22%, based upon different runs). A sample was recrystallized from petroleum ether as white needles, m.p. 62°-63° C. (Dictionary of Organic Compounds Vol III, p 3077, m.p. 67°-68° C., ligroin).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[N:10][C:9]([NH:12][C:13](=[O:37])[C@@H:14]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH:31]3[CH2:33][CH2:32]3)(=[O:30])=[O:29])=[C:24]([CH:34]3[CH2:36][CH2:35]3)[CH:23]=2)[CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:8][N:7]=1)(=O)C.[OH-].[Na+].Cl>CO>[CH:34]1([C:24]2[CH:23]=[C:22]([C@@H:14]([CH2:15][CH:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[C:13]([NH:12][C:9]3[CH:8]=[N:7][C:6]([CH2:5][OH:4])=[CH:11][N:10]=3)=[O:37])[CH:27]=[CH:26][C:25]=2[S:28]([CH:31]2[CH2:32][CH2:33]2)(=[O:29])=[O:30])[CH2:36][CH2:35]1
Reactant: CC(=O)OCc1cnc(NC(=O)[C@H](CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(Nc1cnc(CO)cn1)[C@H](CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)c(C2CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
To a solution of (5-{[(2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-(tetrahydro-2H-pyran-4-yl)propanoyl]amino}pyrazin-2-yl)methyl acetate (120 mg) in methanol (4 mL) was added 1 M aqueous sodium hydroxide solution (1 mL) at room temperature, followed by stirring at room temperature for 2 hours. 1 M Hydrochloric acid was added to adjust the pH to 3, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The crude product obtained by concentration was purified by silica gel column chromatography (wetting with hexane:ethyl acetate=1:1, chloroform:methanol=1:0-10:1) to obtain (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-[5-(hydroxymethyl)pyrazin-2-yl]-3-(tetrahydro-2H-pyran-4-yl)propanamide (93 mg) as a white amorphous substance.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][CH:13]2[CH:9]1[CH2:10][NH:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[Cs+].Cl[C:19]1[N:24]=[C:23]([NH2:25])[N:22]2[N:26]=[C:27]([C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)[N:28]=[C:21]2[CH:20]=1>CS(C)=O>[CH2:1]([N:8]1[CH2:15][CH2:14][CH:13]2[CH2:12][N:11]([C:19]3[N:24]=[C:23]([NH2:25])[N:22]4[N:26]=[C:27]([C:29]5[O:30][CH:31]=[CH:32][CH:33]=5)[N:28]=[C:21]4[CH:20]=3)[CH2:10][CH:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nc(Cl)cc2nc(-c3ccco3)nn12
Reactant: c1ccc(CN2CCC3CNCC32)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Product: Nc1nc(N2CC3CCN(Cc4ccccc4)C3C2)cc2nc(-c3ccco3)nn12
Temperature: 120 °C
Reaction time: 18 h

Procedure:
2-Benzyl-2,7-diazabicyclo[3.3.0]octane (1.2 mmol; see U.S. Pat. No. 5,071,999) was dissolved in 2 mL of DMSO along with 7-chloro-2-furan-2-yl-[1,2,4]triazolo[1,5-c]pyrimidin-5-ylamine (0.25 mmol; see U.S. Pat. No. 6,222,035 B1) and CsF (0.3 mmol). The reaction mixture was stirred at 120° C. for 18 hours. It was then cooled to room temperature and purified by preparative HPLC to afford the title compound. 1H NMR (400 Hz, DMSO-d6) 7.60 (d, J=1.0 Hz, 1H), 7.28 (br s, 2H), 7.22 (d, J=3.6 Hz, 1H), 7.0-7.2 (m, 5H), 6.68 (dd, J=3.6 Hz, 1.0 Hz, 1H) 5.4 (s, 1H), 3.8 (br s, 2H), 2.2-3.2 (m, 10H). MS: m/z: 402 [M+H]+.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[F:9][C:10]([F:20])([F:19])[CH2:11][I+]C1C=CC=CC=1.[CH2:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:22]>C(Cl)Cl>[CH2:21]([N:23]([CH2:11][C:10]([F:20])([F:19])[F:9])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:22]
Reactant: CCNc1ccccc1
Reactant: FC(F)(F)C[I+]c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: CCN(CC(F)(F)F)c1ccccc1
Yield: 98 %

Procedure:
203 mg (0.465 mmol) of (2,2,2-trifluoroethyl)phenyliodonium trifluoromethanesulfonate, 113 mg (0.931 mmol) of N-ethylaniline and 5 ml of methylene chloride were treated and worked up in the same manner as described in Reference Example 4 to obtain 92.6 mg of N-ethyl-N-(2,2,2-trifluoroethyl)aniline as an oily substance. Yield, 98%.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]1([CH3:22])[NH:20][C:19](=O)[CH2:18][CH2:17]1.P(Cl)(Cl)(Cl)=O>>[CH3:15][C:16]1([CH3:22])[N:20]=[C:19]([N:13]2[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[O:6][C:7]3[C:12]2=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:18][CH2:17]1
Reactant: c1ccc2c(c1)Nc1ccccc1O2
Reactant: CC1(C)CCC(=O)N1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)CCC(N2c3ccccc3Oc3ccccc32)=N1

Procedure:
Reaction of phenoxazine, 5,5-dimethyl-2-pyrrolidinone and phosphorus oxychloride according to the procedure of Example 1 provides the free base 10-(5,5-DIMETHYL-1-PYRROLIN-2-YL)PHENOXAZINE, m.p. 148°-150° C. Conversion of the free base to the hydrochloride salt affords 10-(5,5-DIMETHYL-1-PYRROLIN-2-YL)PHENOXAZINE HYDROCHLORIDE, m.p. 239°-242.5° C. (corr.), in a 48% overall yield.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.C([Li])CCC.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19].II>O1CCCC1.C(OCC)(=O)C>[Cl:11][C:9]1[C:10]2[C:2]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:3][NH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CCOC(=O)Cl
Reactant: Clc1ncnc2[nH]cc(Br)c12
Agent: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c[nH]c2ncnc(Cl)c12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (40.0 g, 173 mmol) in dry tetrahydrofuran (700 mL) at −78° C. was added n-butyl lithium (195 mL, 2.5 M solution in hexane, 487 mmol) over the period of 2 hours. The reaction mixture was stirred for another 30 minutes at −78° C., after which ethyl chloroformate (17.8 mL, 186 mmol) was added over 30 minutes. The reaction mixture was stirred for 2 hours at −60° C. and then the temperature was slowly increased to 30° C. The reaction mixture was allowed to stir for 12 hours at 30° C. The progress of the reaction was monitored by TLC using 25% ethyl acetate in petroleum ether using iodine and 254 nm UV light to visualize the spot. The reaction mixture was then quenched with saturated solution of ammonium chloride (200 mL) at 0° C. and the reaction mixture was extracted with ethyl acetate (×3). The combined organic layers were washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford a crude reaction mixture. The residue was purified by chromatography on silica eluting with 5-100% ethyl acetate/petroleum ether to afford ethyl 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate as pale yellow solid. LRMS (ESI) calc'd for C9H7ClN3O2 [M−H]+: 224. found 224. 1H NMR (400 MHz, DMSO-D6): δ 13.28 (s, 1H), 8.70 (s, 1H), 8.39 (s, 1H), 4.31 (q, J=7.2, 6.8 Hz, 2H), 1.34 (t, J=7.6, 6.8 Hz, 3H).
Reaction SMILES: ClCCl.Cl.[NH2:5][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:7]O.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(N(CC)CC)C>[C:14]1([C:13]([NH:5][C:6](=[CH2:7])[C:9]([O:11][CH3:12])=[O:10])=[O:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(NC(=O)c1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To dichloromethane (400 mL) were added methyl serinate hydrochloride (45.0 g) and triethylamine (132 mL), and benzoyl chloride (77.0 mL) was added dropwise. After stirring at room temperature overnight, the reaction system was washed twice with saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (300 mL), and 2,3,4,6,7,8,9,10-octahydroprimido[1,2-a]azepine (52.0 g) was added. The mixture was stirred at room temperature for 4 hr, and the reaction system was washed twice with water and saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give a crude product (67.0 g) of the title compound as a brown oil.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][C@H:12]2[NH:11][C:10]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:24][CH2:25][C:26](Br)=[O:27]>C(OCC)(=O)C.CCCCCC>[CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][C@H:12]2[N:11]([C:26](=[O:27])[CH2:25][Br:24])[C:10]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1[C@H]2CCC[C@H]2Nc2ccc(Cl)cc2N1Cc1ccccc1
Reactant: O=C(Br)CBr
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1[C@H]2CCC[C@H]2N(C(=O)CBr)c2ccc(Cl)cc2N1Cc1ccccc1
Yield: 50 %

Procedure:
Using (3aR*,10aS*)-9-benzyl-7-chloro-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]-diazepin-10(1H)-one and bromoacetyl bromide, the titled compound was synthesized in substantially the same manner as in Working Example 122 in a yield of 50%, m.p. 163°-164° C. (ethyl acetate-hexane).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[NH2:13][C:14]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:15]=1[C:16](O)=[O:17].Cl[Si](C)(C)C.Cl>CCOCC.C1COCC1>[NH2:13][C:14]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:15]=1[C:16]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:17]
Reactant: Brc1ccccn1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Nc1ccc(Cl)cc1C(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.1 %

Procedure:
To a solution of 2-bromopyridine (5 ml, 52 mmol) in Et2O (60 ml) was added 40 ml of a n-butyllithium (1.6M in hexane, 64 mmol) drop wise at −40° C. over 30 min under a nitrogen atmosphere. The resulting yellow solution was stirred for a further 1 hr at −50° C. to −30° C. In a separate flask, a solution of 2-amino-5-chlorobenzoic acid (2.05 g, 12 mmol) in dry THF (90 ml), under nitrogen atmosphere and with ice-cooling, was added in one portion to the solution prepared as described above. The reaction mixture was stirred for 2 hrs at 0° C. and then chlorotrimethylsilane (30 ml) was added at 0° C. with stirring. The reaction mixture was allowed to warm to room temperature and 1 N HCl aq (100 ml) was added. The resulting two-phase system was separated. The aqueous phase was adjusted to pH 12 with 6N NaOH solution and extracted with ethyl acetate (2×150 ml). The combined organic extractions were dried over Na2SO4. After removal of solvent, the residue was purified by the flash chromatography using ethyl acetate/hexane (1:4) as eluent. Crystallization of the product from Et2O/hexane mixture gave 1.26 g (45%) of desired product as yellow solid. 1H-NMR (DMSO-d6, 500 MHz): δ 6.90 (1H, d, J=9 Hz), 7.31 (1H, dd, J=9 and 2.5 Hz), 7.40 (2H, br), 7.53 (1H, d, J=2.5 Hz), 7.61 (1H, m), 7.79 (1H, d, J=8 Hz), 8.03 (1H, m), 8.69 (1H, m). MS: (ESI+): 233.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])(C)(C)C.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][C:16]=1[S:23]([NH2:26])(=[O:25])=[O:24]>O1CCCC1>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:6]2[CH:5]=[CH:4][C:3]([F:8])=[CH:2][CH:7]=2)[OH:22])=[CH:17][C:16]=1[S:23]([NH2:26])(=[O:25])=[O:24]
Reactant: NS(=O)(=O)c1cc(C=O)ccc1Cl
Reactant: Fc1ccccc1Br
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cc(C(O)c2ccc(F)cc2)ccc1Cl
Temperature: -78 °C
Reaction time: 2 h
Yield: 18.5 %

Procedure:
A solution of 590 mg of 1-bromofluorobenzene (1.11 mmol, 3 equivalent) in 10 mL of anhydrous tetrahydrofuran is stirred at −78° C. as 3.9 mL of tert-butyllithium (1.7 M in cyclohexane, 6.66 mmol, 6 equivalent) is added drop-wise. The reaction mixture is stirred at −78° C. for 2 h, then is transferred to a previously prepared a solution of 243 mg of 2 chloro-5-formyl-benzenesulfonamide (1.11 mmol, 1 equivalent) and 0.65 mL of tert-butyllithium (1.7 M in cyclohexane, 1 equivalent) in 10 mL of anhydrous tetrahydrofuran. The reaction is allowed to warm to room temperature and stirred at room temperature for 18 h. The reaction is quenched with 0.1 N HCl and then extracted several times with ethyl acetate. The combined organic extracts are dried over sodium sulfate, and concentrated in vacuo to give 65 mg of the title compound which is carried on without further purification.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)(=[O:13])=[O:12])[CH2:7][CH2:6]1)=[O:4].[CH3:24][O:25][C:26]([C:28]1[CH:38]=[CH:37][C:31]([O:32]CC(O)=O)=[CH:30][CH:29]=1)=[O:27].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[S:11]([N:8]1[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][O:32][C:31]2[CH:30]=[CH:29][C:28]([C:26]([O:25][CH3:24])=[O:27])=[CH:38][CH:37]=2)[CH2:6][CH2:7]1)(=[O:13])=[O:12]
Reactant: O=C(CCl)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Reactant: COC(=O)c1ccc(OCC(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(OCC(=O)N2CCN(S(=O)(=O)c3ccc4ccccc4c3)CC2)cc1
Reaction time: 8 h
Yield: 63 %

Procedure:
To a stirred solution of 2-chloro-1-(4-(naphthalen-2-yl-sulfonyl)piperazin-1-yl)ethanone (compound 4, 0.2 g, 0.64 mmol) and 2-(4-(methoxycarbonyl)phenoxy)acetic acid (134 mg, 0.64 mmol) taken in dry DCM (20 mL), DIPEA (495 mg, 3.86 mmol) followed by HATU (486 mg, 1.27 mmol) was added at room temperature and stirred overnight. The mixture was then diluted with DCM washed with water (2×10 mL) and brine (2×10 mL) The organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield the title compound (0.189 g, 63.21%) as an off-white solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:8]([OH:10])=[O:9])=[O:4].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1>CN(C)C=O>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][CH2:2][C:3]([NH:5][C:6]2[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8]([OH:10])=[O:9])=[O:4])=[CH:17][CH:18]=1
Reactant: O=C(CCl)Nc1ccccc1C(=O)O
Reactant: Cc1ccc(N)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(NCC(=O)Nc2ccccc2C(=O)O)cc1
Temperature: 90 °C
Yield: 182.9 %

Procedure:
N(chloroacetyl)anthranilic acid 3.2 g (0.02 mol) and p-toluidine 3.4 g (0.005 mol) were dissolved in 4 ml of dimethylformamide and heated at 90° C. for 3 hours. The reaction solution was poured into ice water and deposited crystals were collected by filtration. These crystals were washed with ether and recrystallized from ethanol to obtain N-[(4-methylphenylamino)acetyl]anthranilic acid 2.6 g (yield: 70%).
Reaction SMILES: [NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:5]([NH:7]N)=[O:6])[CH2:3][OH:4].N(OCCC(C)C)=O.C(N(CC)CC)C.N[C@H:35]([C:40]([NH:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])=[O:41])[CH2:36][CH:37]([CH3:39])[CH3:38]>CN(C)C=O>[NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:5]([NH:7][C@H:35]([C:40]([NH:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])=[O:41])[CH2:36][CH:37]([CH3:39])[CH3:38])=[O:6])[CH2:3][OH:4]
Reactant: NNC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Reactant: CCOC(=O)CNC(=O)[C@@H](N)CC(C)C
Agent: CC(C)CCON=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Reaction time: 0.08 h

Procedure:
2.48 Grams of Z-Ser-NHNH2 was dissolved in 20 ml of dimethylformamide and 4.89 ml of N-hydrochloric acid/dioxane, after cooled the reaction mixture to -15° C., then 1.31 ml of isoamyl nitrite was added thereto and stirred for 5 minutes. Then 4.11 ml of triethylamine was added to the reaction mixture to neutralize the mixture. This reaction mixture was added into 10 ml of a dimethylformamide solution containing the above-mentioned H-Leu-Gly-OC2H5 and 1.24 ml of triethylamine and stirred at 4° C. for 20 hours. After removal of dimethylformamide by distillation, the residue thus obtained was extracted with ethyl acetate, and the extract was washed with 1N-citric acid and a saturated aqueous solution of sodium chloride in this order, then the extract was dried with anhydrous magnesium sulfate. After removal of ethyl acetate, reprecipitated from ethyl acetate to obtain 2.64 g of Z-Ser-Leu-Gly-OC2H5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[CH2:5][NH:6][NH2:7].C([O:17][C:18](=O)[CH:19]=[C:20]([NH2:24])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:24][C:20]1[NH:7][N:6]([CH2:5][C:4]2[CH:8]=[CH:9][C:10]([C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:3]=2)[C:18](=[O:17])[CH:19]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: NNCc1ccc(C(F)(F)F)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2ccc(C(F)(F)F)c(Cl)c2)[nH]1
Reaction time: 8 h

Procedure:
33 g of 3-chloro-4-trifluoromethylbenzylhydrazine were added dropwise, under nitrogen, to a solution of 23.5 g of β-amino-β-ethoxyacrylic acid ethyl ester and a pinch of p-toluenesulphonic acid in 100 ml of ethanol. After stirring overnight, the product which had precipitated was filtered off and recrystallised from ethanol. Melting point: 83°, 24 g (56%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[NH:13]1.[CH:21]1(Br)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:17][CH2:18][CH2:19][CH2:20]2)[N:13]1[CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: BrC1CCCCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCC2(CCCC2)N1C1CCCCC1

Procedure:
1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was sequentially reacted with SOCl2 and 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclohexyl bromide according to Method D2e to give 2-(2-methyl-4-nitrophenylimino)-1-cyclohexyl-3-thia-1-azaspiro[4.4]nonane.