Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2S[CH2:11][CH2:10][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][C:7]=2[CH:17]=1.ClC1C=CC=C(C(OO)=O)C=1.[S:29]([O-:33])([O-])(=[O:31])=S.[Na+].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:29](=[O:33])(=[O:31])[CH2:11][CH2:10][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][C:7]=2[CH:17]=1
Reactant: COC(=O)C1=Cc2cc(OC)ccc2SCC1
Reactant: O=S([O-])([O-])=S
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1=Cc2cc(OC)ccc2S(=O)(=O)CC1

Procedure:
Into a solution of methyl 7-methoxy-2,3-dihydro-1-benzothiepine-4-carboxylate (3.00 g) in THF (30 ml) was added at 0° C. 70% 3-chloroperbenzoic acid (6.5 g), and the resulting mixture was stirred at 0° C. for 0.5 hour and at room temperature for one hour. The reaction mixture was mixed with an aqueous solution of sodium thiosulfate, was stirred for a few minutes and was then extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium bicarbonate (3 times) and an aqueous saturated solution of sodium chloride, and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain methyl 7-methoxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (3.15 g) as colorless crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>>[CH3:16][O:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:18][C:19]1[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=1)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(OC)ccc2[nH]1
Reactant: BrCc1cccc2ccccc12
Product: COc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc2ccccc12

Procedure:
Using general procedure B, 5-methoxy-1H-indole-2-carboxylic acid ethyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as white solid. MS: 330.0 ([M−H]−).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[Cl:11][C:12]1[CH:21]=[C:20]([CH:22]([NH2:24])[CH3:23])[C:19]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][O:33][CH3:34])[CH2:27][CH2:26]2)=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[N:17]2.C(N(CC)C(C)C)(C)C>C(O)C>[Cl:11][C:12]1[CH:21]=[C:20]([CH:22]([NH:24][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:23])[C:19]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][O:33][CH3:34])[CH2:27][CH2:26]2)=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[N:17]2
Reactant: COCCN1CCN(c2c(C(C)N)cc(Cl)c3cccnc23)CC1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COCCN1CCN(c2c(C(C)Nc3ncnc4[nH]cnc34)cc(Cl)c3cccnc23)CC1

Procedure:
A mixture of 6-bromo-9H-purine (0.0274 g, 0.138 mmol), 1-{5-chloro-8-[4-(2-methoxyethyl)piperazin-1-yl]quinolin-7-yl]ethanamine (0.024 g, 0.069 mmol), and N,N-diisopropylethylamine (0.02396 mL, 0.1376 mmol) in ethanol (0.2 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resultant residue was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/minute) to give the desired product as a tris-TFA salt. LCMS calculated for C23H28ClN8O(M+H)+: m/z=467.2; found: 467.1. 1H NMR (DMSO-d6, 400 MHz) δ 9.70 (1H, br s), 8.98 (1H, s), 8.50 (1H, d, J=8.0 Hz), 8.21 (2H, m), 8.02 (1H, s), 7.66 (1H, dd, J=8.4 and 4.4 Hz), 6.41 (1H, m), 4.42˜3.02 (12H, m), 3.33 (3H, s), 1.55 (3H, d, J=6.4 Hz) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[NH2:21][C:22]1[C:23](=[O:35])[N:24]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH:25]=[CH:26][CH:27]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CC#N.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([NH:21][C:22]3[C:23](=[O:35])[N:24]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH:25]=[CH:26][CH:27]=3)=[O:18])=[CH:19][CH:20]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1
Reactant: O=C(O)c1ccc(Nc2cc(Cl)nn3ccnc23)cc1
Reactant: Nc1cccn(-c2ccc(F)cc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C(Nc1cccn(-c2ccc(F)cc2)c1=O)c1ccc(Nc2cc(Cl)nn3ccnc23)cc1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
To a 2 dram vial was added 4-(6-chloroimidazo[1,2-b]pyridazin-8-ylamino)benzoic acid (0.050 g, 0.17 mmol, prepared as described in Example XIV, step 1b), 3-amino-1-(4-fluorophenyl)pyridin-2(1H)-one (0.053 g, 0.26) from 1a-1 and 1a-2 described below, EDCI (0.050 g, 0.26 mmol), HOBt (0.035 g, 0.26 mmol), TEA (0.07 ml, 0.51 mmol), DMF (0.8 ml) and CH3CN (0.8 ml). the reaction was allowed to stir at 50° C. for 12 hrs. Upon cooling, the solvent was removed in vacuo and diluted with methanol (2 ml). The solution was purified by HPLC (20-100% methanol gradient), which yielded 0.0.12 g of 4-(6-chloroimidazo[1,2-b]pyridazin-8-ylamino)-N-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridin-3-yl)benzamide.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)[CH3:2].C=O.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[C:18]1(O)C=CC=CC=1>C(#N)C.N1CCOCC1>[N:12]1([CH2:18][C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=2[OH:9])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CCc1cccc(O)c1
Reactant: Oc1ccccc1
Reactant: C1COCCN1
Agent: C=O
Solvent: CC#N
Product: CCc1ccc(CN2CCOCC2)c(O)c1
Temperature: 70 °C
Yield: 90 %

Procedure:
To a stirred solution of 244.0 grams (1.78 moles--1.0 equiv.) of 89.1% pure m-ethylphenol in 320 mL (%Wt/Vol. Phenol to Solvent--76.3%) of acetonitrile was added 67.6 grams (2.14 moles--1.2 equiv.) of paraformaldehyde. Upon completion of addition, the mixture was stirred for ten minutes and then heated to 65° C. where 179.5 grams (2.06 moles--1.16 equiv.) of morpholine was added during a one hour period at a rate to maintain the reaction temperature below 70-75° C. Upon completion of addition, the reaction mixture was heated to 70° C. where it stirred for two hours. At this point, the reaction mixture was analyzed by GC, which indicated that 2% of the phenol starting material remained. An additional 3.5 grams (0.04 mole--0.02 equiv.) of morpholine was added. Upon completion addition, the reaction mixture was stirred at 70° C. until GC analysis indicated that 1.1% of the phenol starting material remained. The acetonitrile was removed under vacuum, yielding 446.6 grams of 89.1% pure 2-(morpholin-4-ylmethyl)-5-ethylphenol (90% yield).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]1[C:15]1[S:16][CH:17]=[CH:18][N:19]=1.[NH2:20][C:21]1[N:26]=[C:25]2[CH2:27][C:28]3([CH2:38][C:24]2=[CH:23][CH:22]=1)[C:36]1[C:31](=[N:32][CH:33]=[CH:34][CH:35]=1)[NH:30][C:29]3=[O:37].C1CN(C(Cl)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1>[O:37]=[C:29]1[NH:30][C:31]2=[N:32][CH:33]=[CH:34][CH:35]=[C:36]2[C:28]21[CH2:27][C:25]1=[N:26][C:21]([NH:20][C:8](=[O:10])[CH2:7][N:6]3[C:5]4[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=4[N:3]([C:15]4[S:16][CH:17]=[CH:18][N:19]=4)[C:2]3=[O:1])=[CH:22][CH:23]=[C:24]1[CH2:38]2
Reactant: Nc1ccc2c(n1)CC1(C2)C(=O)Nc2ncccc21
Reactant: O=C(O)Cn1c(=O)n(-c2nccs2)c2ccccc21
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Cn1c(=O)n(-c2nccs2)c2ccccc21)Nc1ccc2c(n1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of [2-oxo-3-(1,3-thiazol-2-yl)-2,3-dihydro-1H-benzimidazol-1-yl]acetic acid (62 mg, 0.23 mmol, described in Intermediate 33), (±)-2-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (71 mg, 0.28 mmol, described in Intermediate 5), N,N,N′,N′-bis(tetramethylene)chloroformamidinium hexafluorophosphate (153 mg, 0.46 mmol), and N,N-diisopropylethylamine (0.20 mL, 1.15 mmol) in THF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (3×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@H:11]1[NH:15][C:14](=[O:16])[C@H:13](OS(C)(=O)=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][SH:29])=[CH:26][CH:25]=1.C1CCN2C(=NCCC2)CC1.C(OCC)(=O)C>CN(C=O)C>[CH2:1]([O:8][C:9]([C@H:11]1[NH:15][C:14](=[O:16])[CH:13]([S:29][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)OCc2ccccc2)NC1=O
Reactant: COc1ccc(CS)cc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: COc1ccc(CSC2C[C@@H](C(=O)OCc3ccccc3)NC2=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 111.6 %

Procedure:
16.3 g (52.1 mmol) of (3R,5S)-5-benzyloxycarbonyl-3-mesyloxypyrrolidin-2-one was dissolved in 82 ml of DMF, and 7.95 ml (57.3 mmol) of p-methoxybenzylmercaptan was added to the solution under cooling with ice, then 8.48 ml (56.7 mmol) of DBU was added dropwise thereto. The mixture was stirred for 15 minutes at room temperature. Ethyl acetate was added to the reaction mixture, which was washed sequentially with water, 1 N HCl, a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution. The ethyl acetate solution was dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain 21.6 g of (3RS,5S)-5-benzyloxycarbonyl-3-p-methoxybenzylthiopyrrolidin-2-one as an oily substance. This oily substance was dissolved in 122 ml of methanol, and 36.5 ml of 2N NaOH was added thereto under cooling with ice, and then the mixture was stirred for 1 hour at the same temperature. After the reaction mixture was washed twice with ethyl acetate, the aqueous layer was adjusted to pH 2.0 with 2N HCl, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was triturated with isopropyl ether to obtain 10.6 g of (3RS,5S)-3-p-methoxybenzylthio-2-oxopyrrolidin-5-carboxylic acid. This was dissolved in 348 ml of THF, and 6.17 g (75.7 mmol) of dimethylamine hydrochloride and 11.5 g (94.3 mmol) of 4-dimethylaminopyridine were added thereto under cooling with ice. And then, a solution of 11.7 g (56.8 mmol) of DCC in 37 ml of THF was added dropwise thereto. The mixture was stirred for 3 hours at the same temperature, and then for 1 day at room temperature. After the precipitate was filtered off, ethyl acetate was added to the filtrate, which was washed with lN HCl. The solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (Wakogel® C-300, elution with 1-2% methanol-chloroform) to obtain 5.33 g (yield: 28.4%) of (3S,5S)-5-dimethylcarbamoyl-3-p-methoxybenzylthiopyrrolidin-2-one as an oil and 4.41 g (yield: 23.5%) of (3R,5S)-5-dimethylcarbamoyl-3-p-methoxybenzylthiopyrrolidin-2-one as a powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([NH:16][C:17]([C:19]4[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=4)=[O:18])[CH:14]=3)[NH:9][N:8]=2)=[CH:3][CH:2]=1.O.[OH-].[Li+]>O1CCCC1>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([NH:16][C:17]([C:19]4[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=4)=[O:18])[CH:14]=3)[NH:9][N:8]=2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc3[nH]nc(-c4ccncc4)c3c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(C(=O)Nc2ccc3[nH]nc(-c4ccncc4)c3c2)cc1
Yield: 70.5 %

Procedure:
The title compound was prepared using methyl 4-[N-(3-(4-pyridyl)-1H-indazol-5-yl)carbamoyl]benzoate (0.129 g, 0.35 mmol) and lithium hydroxide mono hydrate (0.075 g, 1.8 mmol) in tetrahydrofuran (5 mL). The compound was isolated as a beige powder that was washed with small portions of diethyl ether (5 mL). (0.091 g, 70.5% yield) 1H NMR (DMSO-d6) 10.2 (s, 1H), 8.5 (m, 3H), 7.9–7.8 (m, 6H), 7.6 (s, 2H); ES-MS (m/z) 359 [M+1]+.
Reaction SMILES: [Si]([O:18][C:19]1[CH:56]=[CH:55][C:22]([O:23][CH2:24][C@@H:25]([OH:54])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:53]=[CH:52][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([C:43]4[C:51]5[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=5)[NH:45][CH:44]=4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[OH:54][C@H:25]([CH2:24][O:23][C:22]1[CH:21]=[CH:20][C:19]([OH:18])=[CH:56][CH:55]=1)[CH2:26][NH:27][CH2:28][CH2:29][C:30]1[CH:53]=[CH:52][C:33]([NH:34][CH:35]2[CH2:40][CH2:39][N:38]([C:41]([C:43]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[NH:45][CH:44]=3)=[O:42])[CH2:37][CH2:36]2)=[CH:32][CH:31]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)c4c[nH]c5ccccc45)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(c1c[nH]c2ccccc12)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 83 %

Procedure:
(4-[4-(2-{[(2S)-3-(4-([tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxy-propyl]amino}ethyl)anilino]-1-piperidinyl}(1H-indol-3-yl)methanone (0.148 g, 0.182 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol) to give the title compound (0.087 g, 0.151 mmol).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[C:10]([N:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[OH:28])([CH3:21])[CH3:20])[C:13]3=[O:29])[C:9]([CH3:30])=[C:8]([F:31])[CH:7]=2)[CH2:3][CH2:2]1.[N+](C1C=C(S(O[CH2:46][C@H:47]2[CH2:49][O:48]2)(=O)=O)C=CC=1)([O-])=O>>[CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[C:10]([N:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([CH3:20])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH2:46][C@H:47]4[CH2:49][O:48]4)[CH3:21])[C:13]3=[O:29])[C:9]([CH3:30])=[C:8]([F:31])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2O)c1=O
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OC[C@H]2CO2)c1=O

Procedure:
Prepared from N-cyclopropyl-3-fluoro-5-[3-[[1-(2-hydroxyphenyl)-1-methylethyl]amino]-2-oxo-1(2H)pyrazinyl]-4-methyl-benzamide (Example 252j) and (R)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate, using a similar method to that described in Example 299a.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([CH:27]5[CH2:31][CH2:30][N:29]([CH3:32])[C:28]5=[O:33])=[O:26])=[CH:20][C:19]=4[F:34])=[C:11]3[C:10]([CH3:35])=[N:9]2)=CC=1.FC(F)(F)C(O)=O>>[F:34][C:19]1[CH:20]=[C:21]([NH:24][C:25]([CH:27]2[CH2:31][CH2:30][N:29]([CH3:32])[C:28]2=[O:33])=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:8][N:9]=[C:10]([CH3:35])[C:11]=12
Reactant: COc1ccc(Cn2nc(C)c3c(Oc4ccc(NC(=O)C5CCN(C)C5=O)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]c2nccc(Oc3ccc(NC(=O)C4CCN(C)C4=O)cc3F)c12
Temperature: 60 °C
Yield: 90.5 %

Procedure:
A 100 mL round-bottomed flask was charged with N-(4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-1-methyl-2-oxopyrrolidine-3-carboxamide (14.8 mg, 0.0294 mmol) and 2,2,2-trifluoroacetic acid (335 mg, 2.94 mmol). The reaction mixture was stirred at 60° C. until LC-MS showed that the starting material was consumed. The CF3COOH was removed under reduced pressure and purified the resulting residue was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to give the desired product (10.2 mg, 90.5%). LRMS (APCI neg) m/e 382 (M−1). 1H NMR (400 MHz, CD3OD) δ 8.25 (d, J=6.0 Hz, 1H), 7.85 (dd, J=12.8, 2.4 Hz, 1H), 7.42 (m, 1H), 7.37 (m, 1H), 6.25 (m, 1H), 3.44-3.59 (m, 2H), 3.31 (m, 1H), 2.90 (s, 3H), 2.71 (s, 3H), 2.44-2.49 (m, 1H), 2.30-2.37 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@H:4]([F:28])[CH:5]([NH:20]C(OC(C)(C)C)=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:9][CH:8]=1.Cl>O1CCOCC1>[ClH:19].[CH3:1][O:2][C:3](=[O:29])[C@H:4]([F:28])[CH:5]([NH2:20])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:11][CH:12]=1
Reactant: COC(=O)[C@H](F)C(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@H](F)C(N)Cc1ccc(-c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-3-tert-butoxycarbonylamino-4-(3′-chloro-biphenyl-4-yl)-2-fluoro-butyric acid methyl ester (60 mg, 0.142 mmol) is treated with 4M HCl in dioxane (1.5 mL). After being stirred at room temperature for 1 h, the reaction mixture is concentrated. The residue is used for a next step without further purification. HPLC retention time=0.88 minutes (condition B): MS (m+1)=322.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:14][C@H:13]3[N:10]([C:11](=[O:18])[C@@H:12]3[C@H:15]([OH:17])[CH3:16])[C:9]=2[C:19]([O:21][CH2:22][O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[O:20])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:39](Cl)(=[O:41])[CH3:40]>ClCCl>[C:39]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:14][C@H:13]3[N:10]([C:11](=[O:18])[C@@H:12]3[C@H:15]([OH:17])[CH3:16])[C:9]=2[C:19]([O:21][CH2:22][O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[O:20])=[CH:4][CH:3]=1)(=[O:41])[CH3:40]
Reactant: CC(=O)Cl
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(c3ccc(N)cc3)C[C@H]12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C2=C(C(=O)OCOC(=O)C(C)(C)C)N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Temperature: 0 °C

Procedure:
A mixture of [(2,2-dimethylpropanoyl)oxy]methyl (5R,6S)-3-(4-aminophenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate prepared by example 26, diisopropylethylamine and dichloromethane was cooled at 0° C., and thereto was dropped acetyl chloride. After stirring, the reaction mixture was poured into ice water. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution in the order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography, to give [(2,2-dimethylpropanoyl)oxymethyl (5R,6S)-3-[4-(acetylamino)phenyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]([CH2:14][C:15]2[CH:16]=[C:17]([CH:34]=[CH:35][C:36]=2[O:37][CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:18][NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[C:22]([F:33])[CH:21]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].Cl>C(OCC)(=O)C.O1CCCC1>[C:1]([C:5]1[CH:9]=[C:8]([C:10]([CH3:11])([CH3:13])[CH3:12])[N:7]([CH2:14][C:15]2[CH:16]=[C:17]([CH:34]=[CH:35][C:36]=2[O:37][CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:18][NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[C:22]([F:33])[CH:21]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)CCc1ccc(NCc2ccc(OCC(C)C)c(Cn3nc(C(C)(C)C)cc3C(C)(C)C)c2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)COc1ccc(CNc2ccc(CCC(=O)O)c(F)c2)cc1Cn1nc(C(C)(C)C)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
To a mixture of ethyl 3-[4-({3-[(3,5-di-tert-butyl-1H-pyrazol-1-yl)methyl]-4-isobutoxybenzyl}amino)-2-fluorophenyl]propanoate (0.62 g, 1.16 mmol), methanol (6 mL) and tetrahydrofuran (12 mL) was added 1 M aqueous sodium hydroxide solution (2.32 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was neutralized with 1M hydrochloric acid, and diluted with ethyl acetate, and the organic layer was washed with saturated brine, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1-hexane/ethyl acetate=1/4) to give the title compound (0.52 g, yield 83%) as colorless crystals.
Reaction SMILES: [CH:1]1([N:7]([CH3:36])[C:8](=[O:35])[CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]([NH:23][C:24](=[O:26])[CH3:25])[N:17]([CH2:27][C:28]([O:30][C:31](C)(C)[CH3:32])=[O:29])[CH2:16]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br>C(OCC)(=O)C.C(O)C.C(O)(=O)C>[CH:1]1([N:7]([CH3:36])[C:8](=[O:35])[CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]([NH:23][C:24](=[O:26])[CH3:25])[N:17]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:16]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)NC1=Nc2ccc(OCCCC(=O)N(C)C3CCCCC3)cc2CN1CC(=O)OC(C)(C)C
Agent: Br
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1Cc2cc(OCCCC(=O)N(C)C3CCCCC3)ccc2N=C1NC(C)=O
Reaction time: 8 h

Procedure:
A solution of N-cyclohexyl-N-methyl-4-[2-acetamido-3-tert-butyloxycarbonylmethyl-3,4-dihydroquinazolin-6-yl]oxybutyramide (13.7 g, 25 mmol) was dissolved in a mixture of ethyl acetate and ethanol (10 mL each), and to the mixture was added saturated HBr in acetic acid. After stirring overnight, the mixture was concentrated, dissolved in ethyl acetate and the organic layer was washed with half-saturated sodium bicarbonate and brine, otherwise dried, filtered and evaporated. Column chromatography over silica gel (3:1 dichloromethane-ethyl acetate) afforded the title compound as an amorphous foam which crystalled from cold ether, mp 96°-7° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH:22]1([NH:25][S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Cl)(=[O:28])=[O:27])[CH2:24][CH2:23]1>C(N(C(C)C)C(C)C)C>[CH:22]1([NH:25][S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:12]2[CH2:11][CH2:10][N:9]([CH:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:14][CH2:13]2)(=[O:28])=[O:27])[CH2:24][CH2:23]1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: O=S(=O)(CCCCCCCl)NC1CC1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCCN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)NC1CC1
Yield: 94.7 %

Procedure:
1-[Bis(4-fluorophenyl)methyl]piperazine (8.92 g, 30.0 mmol) and N-cyclopropyl-6-chlorohexanesulfonamide (7.91 g, 33.0 mmol) were refluxed in N-ethyldiisopropylamine (20 ml) for 8 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (50:3), to give N-cyclopropyl-6-[4-[bis(4-fluorophenyl)methyl]1-piperazinyl]hexanesulfonamide (13.97 g) as a crystalline substance (yield based on 1-[bis(4-fluorophenyl)methyl]piperazine: 94.7%).