Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH:4]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[N:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:15]=1)[O:5][P:6]([CH:9]([NH2:13])[CH:10]([CH3:12])[CH3:11])([OH:8])=[O:7].CCN(C(C)C)C(C)C.[C:48]1([CH:54]=[CH:55][S:56](Cl)(=[O:58])=[O:57])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C(Cl)Cl>[C:26]([O:25][C:23]([N:22]=[C:21]([NH:30][C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[NH:20][C:16]1[CH:15]=[C:14]([CH:4]([O:5][P:6]([CH:9]([NH:13][S:56]([CH:55]=[CH:54][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)(=[O:58])=[O:57])[CH:10]([CH3:12])[CH3:11])([OH:8])=[O:7])[C:3]([O:2][CH3:1])=[O:38])[CH:19]=[CH:18][CH:17]=1)=[O:24])([CH3:28])([CH3:29])[CH3:27]
Reactant: COC(=O)C(OP(=O)(O)C(N)C(C)C)c1cccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Reactant: O=S(=O)(Cl)C=Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(OP(=O)(O)C(NS(=O)(=O)C=Cc1ccccc1)C(C)C)c1cccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Temperature: 0 °C
Yield: 57.3 %

Procedure:
To a solution of 2-(3-(N′,N″-di(t-butoxycarbonyl)guanidino)phenyl)-2-((1-amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid methyl ester (300 mg, 0.53 mmol) in 8 mL methylene chloride was added DIEA (0.44 mL, 1.06 mmol), which was cooled to 0° C. by an ice-water bath. Then a solution of 2-phenylethenylsulfonyl chloride (120 mg, 0.59 mmol) in 1 mL methylene chloride was added dropwise. The resulting mixture was stirred at ambient temperature for thirty minutes. The mixture was washed with water, 2N NaHSO4, and brine. The organic phase was dried over sodium sulfate and concentrated to afford a yellow solid. Purification by chromatograph on silica gel afforded a yellow solid, 2-(3-(N′,N″-di(t-butoxycarbonyl)guanidino)phenyl)-2-((1-(2-phenylethenylsulfonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid, methyl ester, (220 mg).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([S:17]([Cl:20])(=[O:19])=[O:18])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[N+:21]([O-])([OH:23])=[O:22]>>[C:1]([O:4][CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[C:12]([N+:21]([O-:23])=[O:22])[CH:13]=[CH:14][CH:15]=2)[C:10]([S:17]([Cl:20])(=[O:18])=[O:19])=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)OCCc1ccc(S(=O)(=O)Cl)c2ccccc12
Product: CC(=O)OCCc1ccc(S(=O)(=O)Cl)c2c([N+](=O)[O-])cccc12
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 47.6 %

Procedure:
4-(2-acetoxy-ethyl)-naphthalene-1-sulfonyl chloride (76.96 g, 246 mmol) was added portionwise over 12 minutes to 90% nitric acid (154 mL, 3.278 mol) cooled in an ice-methanol bath (-20° C.). After the addition was complete, the reaction mixture was stirred at -20° C. for an additional 15 minutes. The reaction mixture was partitioned between ice water (800 mL) and chloroform (800 mL). The aqueous layer was extracted with chloroform (100 mL). The combined organic layers were washed with brine (400 mL, 200 mL), then dried over magnesium sulfate, filtered, and evaporated to a golden oil. Diethyl ether (300 mL) was added to the crude product and the mixure was shaken vigorously to afford an off-white solid. The solid was collected by filtration, washed with ether (2×50 mL), and dried under vacuum to afford 4-(2-acetoxy-ethyl)-8-nitro-naphthalene-1-sulfonyl chloride (41.85 g) as an off-white solid.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O>>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-c1nnc(N)nc1-c1ccccc1
Yield: 48.5 %

Procedure:
6-(2-Methoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine (108 mg, 48%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.80 mmol) and 2-methoxyphenyl boronic acid (0.137 g, 0.90 mmol) according to the general procedure of Example 1.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([Cl:15])[CH:9]=1>C(OCC)C>[CH3:5][O:6][C:7](=[O:16])[C:8]1[CH:13]=[C:12]([N+:1]([O-:4])=[O:2])[C:11]([OH:14])=[C:10]([Cl:15])[CH:9]=1
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Solvent: CCOCC
Product: COC(=O)c1cc(Cl)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.5 %

Procedure:
65% aq. nitric acid solution (2.4 mL, 54 mmol) and fuming nitric acid (2.2 mL, 54 mmol) were added at −10° C. to a solution of 3-chloro-4-hydroxy-benzoic acid methyl ester (5.00 g, 26.8 mmol) in diethyl ether (65 mL). The ice bath was removed and the reaction mixture was stirred at room temperature for 16 h, then partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated to afford 3-chloro-4-hydroxy-5-nitro-benzoic acid methyl ester (6.24 g, 100%). Yellow solid, MS (ISP)=230.3 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[C:13]([F:15])([F:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[Cl:21][C:22]1[N:27]=[N:26][C:25]([C:28](O)=[O:29])=[CH:24][CH:23]=1>>[NH2:18][C:10]1[O:11][C:12]([CH3:16])([CH3:17])[C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28]([C:25]3[N:26]=[N:27][C:22]([Cl:21])=[CH:23][CH:24]=3)=[O:29])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: CC1(C)OC(N)=N[C@](C)(c2cc(N)ccc2F)C1(F)F
Reactant: O=C(O)c1ccc(Cl)nn1
Product: CC1(C)OC(N)=N[C@](C)(c2cc(NC(=O)c3ccc(Cl)nn3)ccc2F)C1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-2) and 6-chloro-pyridazine-3-carboxylic acid following procedure I yielded the 6-chloro-pyridazine-3-carboxylic acid [3-((R)-2-amino-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenyl]-amide which, after treatment with hydrochloric acid in dioxane (4N), evaporation and trituration with diethylether, gave the title compound as a white solid. MS (ISP): m/z=428.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:4]=1[NH2:5].[CH:16]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH2:17]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:17][CH2:16][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:4]=1[NH2:5]
Reactant: C=CS(C)(=O)=O
Reactant: COc1cc(C2CCNCC2)ccc1N
Solvent: ClCCl
Product: COc1cc(C2CCN(CCS(C)(=O)=O)CC2)ccc1N
Reaction time: 8 h
Yield: 58.3 %

Procedure:
To 2-(methyloxy)-4-(4-piperidinyl)aniline (0.50 g, 2.4 mmol) in DCM (5 mL) was added methyl vinyl sulfone (0.25 g, 2.4 mmol). The mixture was stirred in a sealed tube overnight. Silica gel was added, the solvent was removed under vacuum, and the material was purified by silica gel chromatography. The desired fractions were combined and rotovaped to give the title compound of step B (0.45 g, 1.4 mmol, 58%) as an oil. 1H NMR (400 MHz, CDCl3) 6 1H NMR (400 MHz, d6-DMSO) δ 6.63-6.57 (m, 3H), 3.79 (s, 3H), 3.71 (br s, 2H), 3.13 (t, J=6.6 Hz, 2H), 3.01 (s, 3H), 2.97 (d, J=11.4 Hz, 2H), 2.83 (t, J=6.6 Hz, 2H), 2.42-2.32 (m, 1H), 2.15-2.04 (m, 2H), 1.80 (d, J=12.1 Hz, 2H), 1.69-1.57 (m, 2H).
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>O>[S:22]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][O:13][S:22](=[O:24])(=[O:23])[CH3:21])(=[O:24])(=[O:23])[CH3:21]
Reactant: OCCOCCOCCOCCO
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOCCOCCOCCOS(C)(=O)=O
Temperature: 5 °C
Yield: 89.5 %

Procedure:
A 5,000 mL, 3-necked flask equipped with a mechanical stirrer, thermometer and 500 mL addition funnel was charged with tetraethylene glycol (388 g, 2.0 mol) dichloromethane (1,500 mL) and triethylamine (445 g, 4.40 mol). The mixture was stirred and cooled to ca. 5° C., and methanesulfonyl chloride (470 g, 4.1 mol) was added dropwise over 3 hours. The reaction mixture was stirred an additional 3 hours while warming to 25° C., then water (1,000 mL) was added and the phases were separated. The organic layer was washed with ice-cold 6N HCl (2×1,000 mL) and then washed with 5% Na2CO3, saturated aqueous NaCl, dried, filtered and evaporated in vacuo to yield 627 g (90%) of tetraethylene glycol dimesylate, i.e.,
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:28]=[CH:27][C:8]([NH:9]/[C:10](=[C:13]2\[C:14](=[O:26])[NH:15][C:16]3[C:21]\2=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)/[CH2:11][CH3:12])=[CH:7][CH:6]=1)([OH:3])=O.[NH4+].O[N:31]1C(=O)CCC1=O>>[NH2:31][C:1]([CH2:4][C:5]1[CH:28]=[CH:27][C:8]([NH:9]/[C:10](=[C:13]2\[C:14](=[O:26])[NH:15][C:16]3[C:21]\2=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)/[CH2:11][CH3:12])=[CH:7][CH:6]=1)=[O:3]
Reactant: CC/C(Nc1ccc(CC(=O)O)cc1)=C1/C(=O)Nc2cc(OC)c(OC)cc21
Reactant: O=C1CCC(=O)N1O
Agent: [NH4+]
Product: CC/C(Nc1ccc(CC(N)=O)cc1)=C1/C(=O)Nc2cc(OC)c(OC)cc21

Procedure:
Prepared from 3-(Z)-{1-[4-(carboxymethyl)-anilino]-1-ethyl-methylidene}-5,6-dimethoxy-2-indolinone and N-hydroxy-succinimide-ammonium salt
Reaction SMILES: [CH3:1][Mg]Cl.[CH3:4][N:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8](=[O:15])[N:7]([C:16]2[CH:17]=[CH:18][C:19]3[S:23][N:22]=[C:21]([CH:24]=[O:25])[C:20]=3[CH:26]=2)[C:6]1=[O:27]>O1CCCC1>[OH:25][CH:24]([C:21]1[C:20]2[CH:26]=[C:16]([N:7]3[C:8](=[O:15])[CH:9]=[C:10]([C:11]([F:12])([F:13])[F:14])[N:5]([CH3:4])[C:6]3=[O:27])[CH:17]=[CH:18][C:19]=2[S:23][N:22]=1)[CH3:1]
Reactant: C[Mg]Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C=O)c3c2)c1=O
Solvent: C1CCOC1
Product: CC(O)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Temperature: 25 °C
Yield: 711.3 %

Procedure:
Methyl magnesium chloride (14.1 ml, 0.0422 mol) is added dropwise to a solution of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-carboxaldehyde (6.00 g, 0.00170 mol) in tetrahydrofuran at -78° C. over 15 minutes. The resultant mixture is stirred at -78° C. for 30 minutes, quenched with saturated ammonium chloride and allowed to warm to room temperature. After dilution with ethyl acetate, the mixture is washed with saturated ammonium chloride, water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to a solid. The solid is chromatographed on silica gel with hexanes/ethyl acetate to give the title compound as a white crystalline solid (4.49 g, 71.1%) which is identified by NMR spectral analysis.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.I[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].N1CCC[C@H]1C(O)=O>CS(C)=O.[Cu]I.O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCOc1ccc(I)cc1
Reactant: Brc1ccc2cc[nH]c2c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: O
Product: CCOc1ccc(-n2ccc3ccc(Br)cc32)cc1
Temperature: 25 °C
Yield: 56.4 %

Procedure:
A solution of 1.0 g (5 mmol) of 6-bromo-1H-indole, 1.06 g (4.15 mmol) of 4-iodophenetole, 1.45 g of potassium carbonate, 38.1 mg of copper(I) iodide and 42 mg of L-proline in 15 ml of dimethyl sulfoxide is heated at 120° C. for 15 hours. The reaction mixture is then cooled to room temperature, 30 ml of water are added, and the mixture is extracted three times with 20 ml of ethyl acetate each time. After the combined organic phases have been dried over sodium sulfate, the solvent is stripped off in a rotary evaporator, and the crude product is purified by column chromatography on silica gel (n-heptane/ethyl acetate 98:2), giving 0.74 g of 6-bromo-1-(4-ethoxyphenyl)-1H-indole as brownish resin; LC/MS: 317 (M+H).
Reaction SMILES: [CH:1]1([C:6]2([CH3:19])[CH2:14][C:13]3[C:8](=[C:9]([Cl:17])[C:10]([CH3:16])=[C:11]([OH:15])[CH:12]=3)[C:7]2=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>O1CCCC1>[CH:1]1([C:6]2([CH3:19])[CH2:14][C:13]3[C:8](=[C:9]([Cl:17])[C:10]([CH3:16])=[C:11]([OH:15])[CH:12]=3)[CH:7]2[OH:18])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1c(O)cc2c(c1Cl)C(=O)C(C)(C1CCCC1)C2
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(O)cc2c(c1Cl)C(O)C(C)(C1CCCC1)C2

Procedure:
2-Cyclopentyl-2,6-dimethyl-7-chloroindan-1,5-diol is prepared following substantially the same procedure described in Example 4, Step E, using the following substances: 2-cyclopentyl-2,6-dimethyl-5-hydroxy-7-chloro-1-indanone (8.37 g., 0.03 mole); sodium bis-(2-methoxyethoxy)-aluminum hydride (70% in [10 ml.]); and tetrahydrofuran (100 ml.).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:25])[C@@H:8]([NH2:24])[CH2:9][NH:10][C:11]([C:13]1[S:14][C:15]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:17]=1)=[O:12])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[F:33][C:34]([F:46])([F:45])[C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1>ClCCl>[C:2]([O:6][C:7](=[O:25])[C@@H:8]([NH:24][S:41]([C:38]1[CH:37]=[CH:36][C:35]([C:34]([F:33])([F:45])[F:46])=[CH:40][CH:39]=1)(=[O:43])=[O:42])[CH2:9][NH:10][C:11]([C:13]1[S:14][C:15]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:17]=1)=[O:12])([CH3:5])([CH3:3])[CH3:4]
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](N)C(=O)OC(C)(C)C)s1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccc(C(F)(F)F)cc2)C(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
A solution of 0.197 g (0.5 mmol) of (2S)-2-amino-3-((5-(2-methoxycarbonyl-ethyl)-thiophene-2-carbonyl)-amino)-propionic acid tert-butyl ester hydrochloride (example 15, step a) and triethylamine (0.14 ml, 1 mmol) in dichloromethane (5 ml) was cooled to 0° C. in an ice bath and a solution of 0.250 g (1 mmol) of 4-trifluoromethylphenylsulfonyl chloride in dichloromethane (5 ml) was added. Then the reaction mixture was stirred for 3 hours at room temperature. After removal of the solvent in vacuo the residue was absorbed onto silica gel and chromatographed with ethyl acetate/cyclohexane (1/1) to yield 0.127 g (45%) of the title compound as a white amorphous solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]=[C:4]2[CH:15]=[CH:16][S:17][C:3]=12.[NH:18]1[CH2:26][CH2:25][CH:21]([C:22]([NH2:24])=[O:23])[CH2:20][CH2:19]1.C([O-])(=O)C.[Na+]>CN1CCCC1=O.C(OCC)(=O)C>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[C:4]3[CH:15]=[CH:16][S:17][C:3]3=[C:2]([N:18]3[CH2:26][CH2:25][CH:21]([C:22]([NH2:24])=[O:23])[CH2:20][CH2:19]3)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: Fc1ccc(-c2cc(Cl)c3sccc3n2)cc1
Reactant: NC(=O)C1CCNCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: NC(=O)C1CCN(c2cc(-c3ccc(F)cc3)nc3ccsc23)CC1
Temperature: 160 °C
Yield: 59.5 %

Procedure:
A mixture of 7-chloro-5-(4-fluorophenyl)thieno[3,2-b]pyridine (68 mg, 0.26 mmole), isonipecotamide (66 mg, 0.52 mmole), and sodium acetate (21 mg, 0.26 mmole) in 1-methyl-2-pyrrolidone (3 mL) is stirred and heated in an oil bath at 160° C. for about 4 hours. The reaction mixture is then cooled, diluted with ethyl acetate (15 mL) and washed with water (3×15 mL). The organic layer is dried over sodium sulfate, filtered, and concentrated. The residue is recrystalized with ethyl acetate to give 1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)piperidine-4-carboxamide (55 mg, 60% yield) as a white solid product (m.p. 251° C.-253° C.).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([CH3:21])[CH:14]=2)(=[O:12])=[O:11])[C:3]=1[C:4]#[N:5].[NH3:22]>C(O)C.C1COCC1>[NH2:22][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([CH3:21])[CH:14]=2)(=[O:12])=[O:11])[C:3]=1[C:4]#[N:5]
Reactant: N
Reactant: COc1cc(C)cc(S(=O)(=O)c2cccc(F)c2C#N)c1
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(C)cc(S(=O)(=O)c2cccc(N)c2C#N)c1
Temperature: 130 °C
Yield: 34 %

Procedure:
A solution of 0.3 g (0.00098 mol) of 2-fluoro-6-[(3-methyl-5-methoxyphenyl)sulfonyl]benzonitrile (Example 25) in 10 mL of absolute ethanol and ca. 2 mL of THF was saturated with ammonia. The resultant solution was sealed in a glass-lined Parr bomb and heated to 130° C. for 4 h. The solvent was removed in vacuo. 20 mL of 1 NaOH was added. This aqueous solution was extracted with 3×50 mL of EtOAc. The EtOAc solution was dried over MgSO4. After solvent removal, the crude product was recrystallized from absolute ethanol to give 0.1 g (34%) of 2-amino-6-[(3-methyl-5-methoxyphenyl)sulfonyl]benzonitrile: mp 166°-168° C.; NMR (Me2SO-d6, 200 MHz δ 2.4 (s, 3H), 3.87 (s, 3H), 6.7 (br s, 2H), 7.13 (apparent d, 1H), 7.2 (unresolved s, 1H), 7.3-7.5 (m, 2H), 7.57 (apparent t, 1H). Anal. Calc. for C15H14N2O3S: C, 59.59; H, 4.67;N, 9.27; S, 10.6. Found: C, 59.67;H, 4.71;N, 9.25; S, 10.51.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:28]=[CH:27][C:12]([S:13][CH:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)=[CH:11][CH:10]=1>ClCCl>[Br:8][C:9]1[CH:28]=[CH:27][C:12]([S:13][CH:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Sc2ccc(Br)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccc(SC2CCNCC2)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Trifluoroacetic acid (7.5 ml) was added in portions to a stirred, ice-cooled solution of 4-(4-bromothiophenoxy)-1-t-butoxycarbonylpiperidine (2.6 g) in dry dichloromethane (5 ml) under an atmosphere of argon so that the temperature of the mixture was maintained between 5 and 10° C. The solution was stirred at 5° C. for 1 hour, then at ambient temperature for 2 hours. The solution was evaporated. The residual oil was treated with a saturated aqueous solution of sodium carbonate and extracted with ethyl acetate (3×70 ml). The ethyl acetate extracts were combined, dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography on silica gel, using a mixture of 95:5:3, ethyl acetate:methanol:aqueous ammonia (density 0.88 g/cm3) as eluent, to give 4-(4-bromothiophenoxy)piperidine (1.9 g) as an off-white solid;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[O:15])[N:11]=[C:10]2[NH:16][C:17]([NH:19][CH:20]([CH3:22])[CH3:21])=[NH:18])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:24]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[O:15])[NH:11][C:10]2=[N:16][C:17]([NH:19][CH:20]([CH3:22])[CH3:21])=[N:18][C:24]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:25])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)NC(=N)NC1=NC(=O)C(=O)N1c1ccc(Cl)c(Cl)c1
Reactant: CCCCCCOC(=O)Cl
Product: CCCCCCOC(=O)N=C(N=C1NC(=O)C(=O)N1c1ccc(Cl)c(Cl)c1)NC(C)C

Procedure:
Compound 4e was prepared by the same method for preparation of 4b, using pure compound 4 (0.800 g, 2.34 mmol) and hexyl chloroformate as starting materials to yield compound 4e as a white color crystal (0.354 g, 32%). 1H NMR (300 MHz, CDCl3) δ 12.45 (s, 1H), 7.57–7.54 (m, 2H), 7.31–7.27 (dd, J=8.5 and 2.4 Hz, 1H), 4.25 (t, J=6.8 Hz, 2H), 4.12 (m, 1H),1.74 (m, 2H), 1.35 (m, 6H), 1.25 (d, J=6.6 Hz, 6H), 0.93 (t, J=6.4 Hz, 3H); 13C NMR: δ170.78, 168.50, 159.20, 155.93, 154.15, 132.56, 132.18, 131.50, 130.41, 128.62, 125.61, 31.31, 28.38, 25.32, 22.49, 22.30, 14.00. MS m/z 470 (M+), 418, 416, 368, 342, 314, 272, 230, 174.
Reaction SMILES: [SH:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[H-].[Na+].ClN1C(=O)CCC1=O.[CH3:17][C:18]1[N:19]=[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]2[CH:26]=1>CN(C)C=O>[CH3:17][C:18]1[N:19]=[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]2[C:26]=1[S:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1
Reactant: Cc1cn2ccccc2n1
Reactant: Sc1nc[nH]n1
Agent: O=C1CCC(=O)N1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2ccccn2c1Sc1nc[nH]n1
Reaction time: 0.25 h
Yield: 27.4 %

Procedure:
To a mixture of 3-mercapto-1H-1,2,4-triazole (1.15 g) and N,N-dimethylformamide (15 ml) was added 60% sodium hydride (450 mg). After foaming was completed, N-chlorosuccinimide in small portions was added to the mixture on an ice bath, and stirred at this temperature for 15 minutes. 2-methylimidazo[1,2-a]pyridine (1.0 g) was then added, and the reaction mixture was heated and stirred at room temperature for 1 hour, and then for 3 hours on an oil bath at 70° C. The reaction solution was concentrated under reduced pressure. The residue was washed twice with diethyl ether, and methanol was added to the residue to remove undissolved materials. The filtrate was concentrated, and then crystals precipitated by the addition of water were collected by filtration, washed with water, followed by diethyl ether, and dried to yield the title compound (480 mg).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C@H:10]1[CH2:14][CH2:13][C@@H:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24]C)=[O:23])=[CH:18][CH:17]=2)[N:11]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].[OH-]>CO>[C:29]([O:28][C:26]([N:11]1[C@@H:10]([C@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:14][CH2:13][C@H:12]1[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([OH:24])=[O:23])=[CH:20][CH:21]=1)=[O:27])([CH3:30])([CH3:31])[CH3:32]
Reactant: COC(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3ccccc3)N2C(=O)OC(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)O)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of the title compound from Step E (800 mg, 1.48 mmol) in MeOH (7.5 ml) was added 1 N LiOH (7.41 ml, 7.41 mmol) and the mixture was stirred at RT overnight. LC-MS showed no more starting material left. The mixture was evaporated to remove MeOH, extracted the aqueous layer with ether 3×50 ml, the aqueous layer was adjusted to PH=4.5 with 1N HCl, then extracted with ethyl acetate 3×50 ml. The combined organic layers was washed with brine (saturated, 1×50 mL), dried (Na2SO4), filtered and the solvent evaporated under reduced pressure to afford title compound (i-5). Yield is 99%. LC-MS: m/z (E/S) 526.2 (MH)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:13]2=[O:30])=[CH:4][C:5]2[O:9][N:8]=[C:7]([CH3:10])[C:6]=2[CH:11]=1.[C:31]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12]3([C:3]4=[CH:4][C:5]5[O:9][N:8]=[C:7]([CH3:10])[C:6]=5[CH:11]=[C:2]4[O:1][CH2:31]3)[C:13]2=[O:30])=[CH:27][CH:26]=1
Reactant: COc1ccc(CN2C(=O)C(c3cc4onc(C)c4cc3O)c3ccccc32)cc1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: COc1ccc(CN2C(=O)C3(COc4cc5c(C)noc5cc43)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 3-(5-hydroxy-3-methyl-1,2-benzisoxazol-6-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(4-methoxybenzyl)-3-methylspiro[furo[2,3-f][1,2]benzisoxazole-7,3′-indol]-2′(1′H)-one was obtained (17%): mp 183-184° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.29-7.21 (m, 3H), 7.13-7.10 (m, 1H), 7.05 (s, 1H), 7.03-6.98 (m, 1H), 6.89-6.86 (m, 3H), 6.82 (s, 1H), 5.07-5.00 (m, 2H), 4.79-4.74 (m, 2H), 3.78 (s, 3H), 2.51 (s, 3H); MS (ES+) m/z 412.8 (M+1).