Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]([CH2:25][C:26]([OH:28])=O)[C:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:17][C:16]([F:19])([F:18])[CH2:15]2)=[C:10]([O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)[N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN.[CH3:31][N:32](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CO>[C:1]([N:5]([CH2:25][C:26](=[O:28])[NH:32][CH3:31])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:17][C:16]([F:18])([F:19])[CH2:15]2)=[C:10]([O:20][CH2:21][CH:22]2[CH2:23][CH2:24]2)[N:9]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)N(CC(=O)O)C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)CN(C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(C)(C)C

Procedure:
In analogy to the procedure described in Example 47 b), {tert-butyl-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-amino}-acetic acid (Example 24) was reacted with a 2 M solution of methanamine (CAN 74-89-5) in MeOH in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=411.5 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[C:4]([NH:6][CH:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:13]=1)[C:8](O)=[O:9])=[O:5].C1C=CC2N(O)N=NC=2C=1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:22]([O:21][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[N+:18]([O-:20])=[O:19])[CH2:11][CH:7]1[NH:6][C:4](=[O:5])[C:3]2[CH:29]=[CH:30][CH:31]=[CH:32][C:2]=2[NH:1][C:8]1=[O:9])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccccc1C(=O)NC(Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C1NC(Cc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)C(=O)Nc2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the title I compound, 2-(2-amino-benzoylamino)-3-(3-benzyloxy-4-nitro-phenyl)-propionic acid (317 mg, 0.728 mmol) in CH2Cl2 (10 mL) is added HOBt (111.5 mg, 0.728 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC.HCl, 140 mg, 0,72 mmol) and the mixture is stirred at RT for 4 h and evaporated. The residue is partitioned between EtOAc and water and the organic solution is washed with 1N aqueous HCl, water, saturated aqueous NaHCO3 and brine, dried over anhydrous MgSO4, decolorized and evaporated to a small volume. The precipitated product is collected by filtration and dried to give 3-(3-benzyloxy-4-nitro-benzyl)-3,4-dihydro-1H-benzo[1,4]diazepine-2,5-dione: mp=243-245° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][C:13]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].N1C=CC(C2C=CC(C#N)=CC=2)=N1.BrC1C=CC(C(=O)CC)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>[Cu]I.OC1C=CC=C2C=1N=CC=C2.CN(C=O)C.O>[OH:4][CH:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=3)=[N:12]2)=[CH:9][CH:10]=1)[CH2:2][CH3:3]
Reactant: CCC(=O)c1ccc(-n2ccc(-c3ccc(C#N)cc3)n2)cc1
Agent: [Cu]I
Agent: CCC(=O)c1ccc(Br)cc1
Agent: N#Cc1ccc(-c2cc[nH]n2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCC(O)c1ccc(-n2ccc(-c3ccc(C#N)cc3)n2)cc1
Yield: 86 %

Procedure:
4-[1-(4-Propionyl-phenyl)-1H-pyrazol-3-yl]-benzonitrile. 4-(1H-Pyrazol-3-yl)-benzonitrile (100 mg, 0.591 mmol), 1-(4-bromophenyl)-propan-1-one (126 mg, 0.591 mmol), Cs2CO3 (770 mg, 2.364 mmol), CuI (4 mg, 0.018 mmol), 8-hydroxyquinoline (3 mg, 0.018 mmol), and DMF/H2O (2 mL; 10:1 solution) were combined in a 10 mL CEM Microwave reaction vessel fitted with magnetic stir bar and subjected to microwave irradiation at 150° C. for 30 min. The contents were then filtered and concentrated to dryness affording the nitrile (158 mg, 0.508 mmol, 86%).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:9]=[N:8][C:7]2[N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:11]=[CH:12][C:6]=2[C:5]=1O.FC(F)(F)S(N(C1C=CC=CC=1)S(C(F)(F)F)(=O)=O)(=O)=O.[N:44]1([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.[NH4+].[Cl-]>CN(C=O)C>[I:3][C:4]1[C:5]([N:47]2[CH2:46][CH2:45][N:44]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:49][CH2:48]2)=[C:6]2[CH:12]=[N:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:7]2=[N:8][CH:9]=1
Reactant: COc1ccc(Cn2ncc3c(O)c(I)cnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ncc3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(I)cnc32)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Sodium hydride (0.0881 g, 2.20 mmol) in DMF (5 mL) was added dropwise to 5-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (0.70 g, 1.84 mmol) in DMF (5 mL). Then the reaction mixture was warmed to 40° C. and stirred for 30 minutes. After cooling to room temperature, 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (0.787 g, 2.20 mmol) was added and stirred at room temperature for 1 hour. tert-Butyl piperazine-1-carboxylate (0.787 g, 4.22 mmol) was then added, and the mixture was stirred at 80° C. for 1 hour. Saturated NH4Cl (20 mL) was added, and the reaction was extracted with ethyl acetate and dried over sodium sulfate. After removal of the solvent, the resulting residue was purified by column chromatography (hexane:ethyl acetate, 5:1) to give tert-butyl 4-(5-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.94 g, 93%) as a solid. MS ESI (+) m/z 550.3 detected. 1H NMR (400 Hz, DMSO-d6) δ 8.64 (s, 1H), 8.31 (s, 1H), 7.20 (d, J=7.6 Hz, 2H), 6.82 (d, J=7.6 Hz, 2H), 5.52 (s, 2H), 3.69 (s, 3H), 3.56 (m, 4H), 3.46 (m, 4H), 1.44 (s, 9H).
Reaction SMILES: [Br:1][CH:2]([CH3:8])[C:3](=[O:7])[C:4]([OH:6])=[O:5].[C:9](OC(=NC(C)C)NC(C)C)([CH3:12])([CH3:11])[CH3:10]>C(Cl)Cl>[Br:1][CH:2]([CH3:8])[C:3](=[O:7])[C:4]([O:6][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:5]
Reactant: CC(C)N=C(NC(C)C)OC(C)(C)C
Reactant: CC(Br)C(=O)C(=O)O
Solvent: ClCCl
Product: CC(Br)C(=O)C(=O)OC(C)(C)C
Yield: 47.7 %

Procedure:
A solution of 1.6 g (8.85 mmol) of 3-bromo-2-ketobutyric acid and 7 g (4 equivalents) of O-t-butyl-N,N'-diisopropylpseudourea in 14 ml methylene chloride is stirred overnight at room temperature. After filtration, the solution is washed with NaHCO3 and brine, dried and evaporated to an oil which is chromatographed on silica gel with benzene as eluant to give 1 g (45%) of t-butyl 3-bromo-2-ketobutyrate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[S:27]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(O)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:29]4[CH:30]=[CH:31][S:27][CH:28]=4)=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1
Reactant: COC(=O)CCN1CCN(c2ccc(Oc3ccc(I)cc3)cc2)CC1
Reactant: OB(O)c1ccsc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: COC(=O)CCN1CCN(c2ccc(Oc3ccc(-c4ccsc4)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
To a mixture of the compound from step 1 (140 mg, 0.3 mmol), thiophene-3-boronic acid (70 mg, 055 mmol), palladium(II) acetate (20 mg, 0.09 mmol) and triphenyl phosphine (40 mg, 0.18 mmol) in DME (5 mL) was added potassium carbonate (140 mg, 1 mmol), ethanol (0.5 mL) and water (0.5 mL). The mixture was stir at rt under Ar for 30 min and then was heated to 80° C. for 16 h. After cooling to rt temperature, the mixture was poured onto 20 mL ice-water, followed by extraction with EtOAc (3×10 mL). The combined organic layers were washed with water (2×10 mL), brine (10 mL) and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to obtain the crude product, which was purified by silica gel flash chromatography (1% MeOH in CH2Cl2) to afford the title product (45 mg, 35%): MS (ESI) m/z 423 (M+H); 1H NMR (400 MHz, CDCl3) δ 2.56 (t, J=7.2 Hz, 2H), 2.64 (t, J=4.8 Hz, 4H), 2.77 (t, J=7.2 Hz, 2H), 3.16 (t, J=4.8 Hz, 4H), 3.70 (s, 3H), 6.90-6.99 (m, 6H), 7.34-7.37 (m, 3H), 7.51 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[O:6][C:5]([C:7]([OH:12])([CH2:10][CH3:11])[CH2:8][CH3:9])=[N:4][N:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([CH:30]=O)=[CH:27][CH:28]=3)[O:23][C:22](=[O:32])[CH:21]=2)=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[CH2:8]([C:7]([C:5]1[O:6][C:2]([NH:1][CH2:30][C:26]2[CH:25]=[C:24]3[C:29]([C:20]([C:17]4[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=4)=[CH:21][C:22](=[O:32])[O:23]3)=[CH:28][CH:27]=2)=[N:3][N:4]=1)([OH:12])[CH2:10][CH3:11])[CH3:9]
Reactant: CCC(O)(CC)c1nnc(N)o1
Reactant: O=Cc1ccc2c(-c3ccc(F)cc3)cc(=O)oc2c1
Solvent: Cc1ccccc1
Product: CCC(O)(CC)c1nnc(NCc2ccc3c(-c4ccc(F)cc4)cc(=O)oc3c2)o1
Temperature: 25 °C

Procedure:
A mixture of 3-(5-amino-1,3,4-oxadiazol-2-yl)pentan-3-ol (0.446 g, 2.6 mmol) and 4-(4-fluorophenyl)-2-oxo-2H-chromene-7-carbaldehyde (0.350 g, 1.3 mmol) in 5 mL of toluene was refluxed with a Dean-Stark trap overnight. After cooling to rt the solvent was removed and the crude imine diluted in ethanol (8 ml) at 0° C. Solid NaBH4 (49 mg) was added to the solution and after 30 min of stirring aqueous NH4Cl was added to destroy the excess hydride. After dilution with EtOAc-brine, the organic phase was dried with MgSO4. Purification on silica gel with toluene-EtOAc (2:8) gave the title compound. 1H NMR (400 MHz, acetone-d6): δ 7.67 (m, 2H), 7.48 (m, 2H), 7.37 (m, 3H), 7.19 (bt, 1H), 6.33 (s, 1H), 4.66 (m, 2H), 4.31 (s, 1H), 1.85 (m, 4H), 0.85 (t, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][N:8]2[CH2:16][C:15]3[C:14]([OH:17])=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][N:26]([CH3:30])[C:27](Cl)=[O:28].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH3:25][N:26]([CH3:30])[C:27](=[O:28])[O:17][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH2:16][N:8]([NH:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)[CH2:9]2
Reactant: Oc1cccc2c1CN(Nc1ccncc1)C2
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)Oc1cccc2c1CN(Nc1ccncc1)C2
Temperature: 25 °C
Yield: 60.5 %

Procedure:
To a mixture of 2,3-dihydro-2-(4-pyridinylamino)-1H-isoindol-4-ol (1.20 g), triethylamine (1.18 g) and chloroform (35 ml), was added dimethylcarbamyl chloride (0.68 g) with stirring, at ambient temperature, under nitrogen. The reaction mixture was heated under reflux for 3 hrs, poured into dilute sodium bicarbonate solution (100 ml), and the layers were separated. The aqueous phase was extracted with chloroform, and the combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was chromatographed on silica, eluting with 10-15% methanol/dichloromethane. The appropriate fractions were collected and concentrated to give 953 mg (60%) of product. Recrystallization from dichloromethane-heptane gave the analytical sample, mp 183-185° C.
Reaction SMILES: O[C:2]1([C:12]#[C:13]/[C:14](/[CH3:18])=[CH:15]\[CH2:16][OH:17])[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=[O:10])[CH2:4][CH:3]1[CH3:11].[C:19](OC(=O)C)(=[O:21])[CH3:20].OS([O-])(=O)=O.[K+].C([O-])(O)=O.[Na+]>CCCCCC.C(O)(=O)C>[C:19]([O:17]/[CH:16]=[CH:15]\[CH:14]([CH3:18])[C:13]#[C:12][C:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=[O:10])[CH2:4][C:3]=1[CH3:11])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: C/C(C#CC1(O)C(C)CC(=O)CC1(C)C)=C/CO
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CC(=O)O/C=C\C(C)C#CC1=C(C)CC(=O)CC1(C)C
Temperature: 70 °C

Procedure:
A mixture of (Z)-4-hydroxy-4-(5-hydroxy-3-methylpent-3-en-1-ynyl)-3,5,5-trimethylcyclohexanone 795 mg, 3.1 mmol), glacial acetic acid (5 mL), acetic anhydride (5 mL), and KHSO4 (440 mg, 3.2 mmol) was heated to 70° C. under argon for 5 h. Then the mixture was cooled to room temperature and slowly added to a chilled (ice bath) and stirred mixture of hexane and saturated NaHCO3. More saturated NaHCO3 was added until the pH of the aqueous phase was about 6-7. The organic and aqueous layers were then separated, and the aqueous layer was extracted with hexane. The combined hexane layers were washed with saturated NaHCO3, H2O, and dried over anhydrous Na2SO4. Removal of solvent gave a yellow oil (737 mg) which on purification by flash column chromatography using 75% ether+25% hexane as solvent gave compound (3) (600 mg, 70%) as a yellow oil, ir: 1730 (strong, broad) cm-1; 1H nmr d: 5.77 (ddq, J=7.0, 7.0, 1.5 Hz, 1H, =CH), 4.76 (dd, J=7.0, 1.0 Hz, 2H CH2O), 2.90 (broad s, 2H, CH2), 2.39 (s, 2H, CH2), 2.03 (s, 3H, CH3COO), 1.94 and 1.93 (2m, 6H, 2 vinyl CH3), 1.16 (s, 6H, 2CH3); ms m/z: 274 (M+, 30), 214 (100).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[S:20][C:19]([CH2:21]O)=[CH:18][C:17]=3[CH2:23][CH3:24])[N:12]=2)=[CH:7][CH:6]=1.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:54]1[CH2:57][CH:56]([C:58]([O:60][CH3:61])=[O:59])[CH2:55]1.C(N(CC)C(C)C)(C)C>>[Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[S:20][C:19]([CH2:21][N:54]4[CH2:57][CH:56]([C:58]([O:60][CH3:61])=[O:59])[CH2:55]4)=[CH:18][C:17]=3[CH2:23][CH3:24])[N:12]=2)=[CH:7][CH:6]=1
Reactant: CCc1cc(CO)sc1-c1noc(-c2ccc(Oc3ccccc3Cl)cc2)n1
Reactant: COC(=O)C1CNC1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(CN2CC(C(=O)OC)C2)sc1-c1noc(-c2ccc(Oc3ccccc3Cl)cc2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1f) using (5-{5-[4-(2-chlorophenoxy)phenyl]-1,2,4-oxadiazol-3-yl}-4-ethyl-2-thienyl)methanol (0.19 g, 0.46 mmol) that was obtained in Example 19 (19b), carbon tetrabromide (0.18 g, 0.55 mmol), triphenylphosphine (0.14 g, 0.55 mmol), methyl 3-azetidinecarboxylate hydrochloride (0.10 g, 0.69 mmol), and N,N-diisopropylethylamine (0.16 mL, 0.92 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography using a mixed solvent of ethyl acetate and hexane (5:5) to afford the title compound (0.21 g) in a yield of 91% as a pale yellow oily product.
Reaction SMILES: [OH:1][CH:2]([C:6]1([OH:19])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)[CH2:3][CH2:4]O.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(N(CC)CC)C>ClCCl>[OH:1][CH:2]1[C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]2)[O:19][CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C(O)CCO)CC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)OCCC2O
Reaction time: 12 h

Procedure:
tert-Butyl 4-(1,3-dihydroxypropyl)-4-hydroxypiperidine-1-carboxylate (from step (ii) above; 480 mg) was dissolved in dichloromethane and p-toluenesulfonyl chloride was added followed by triethylamine (0.49 mL) and the mixture was stirred for 12 h. An additional aliquot of triethylamine was added (0.49 mL) and the mixture stirred for 48 h. This mixture was concentrated in vacuo. The crude product was purified by chromatography on silica using 50-95% ethyl acetate in iso-hexane as eluant to afford the product (300 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:32])[C@@H:13]([O:21][P:22]([OH:31])(CC2C=CC=CC=2)=[O:23])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)[CH3:2].[Ca]>>[CH2:1]([O:3][C:4](=[O:33])[C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:32])[C@@H:13]([O:21][P:22]([O:31][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:23])[CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(NC(=O)[C@H](Cc2ccccc2)OP(=O)(O)Cc2ccccc2)cc1
Agent: [Ca]
Product: CCOC(=O)c1ccc(NC(=O)[C@H](Cc2ccccc2)OP(=O)(OCc2ccccc2)OCc2ccccc2)cc1

Procedure:
4-[[(S)2-[[hydroxy(phenylmethyl)phosphinyl]oxy]-1-oxo-3-phenylpropyl]amino]benzoic acid ethyl ester, calcium thereof;
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH2:6]([CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH2:10]1)[C:7]#[CH:8]>CC(C)=O.CCOCC.[O-2].[O-2].[O-2].[Cr+6]>[CH2:6]([CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:2])=[O:16])[CH2:11][CH2:10]1)[C:7]#[CH:8]
Reactant: C#CCC1CCC(CO)CC1
Reactant: O=S(=O)(O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CCOCC
Solvent: CC(C)=O
Product: C#CCC1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of chromium trioxide (1.1 g, 11 mmol) in 1.5 M sulfuric acid (40 mL, 27 mmol) was maintained at 0° C. while 5.3 (0.46 g, 3 mmol) in 80 mL of acetone was added over 2 hours. The reaction was then stirred for an additional 2 hours at room temperature. The reaction mixture was diluted with ether (200 mL) and extracted 2 times with water. The organics were dried with sodium sulfate. The solvent was removed under reduced pressure and the product was purified by chromatography on silica gel column eluting with acetone-dichloromethane (70:30) to give 5.4 (75%). 1H NMR (300 MHz, CDCl3) δ 2.24 (dt, J=3.66, 12.1 Hz, 1 H), 2.10 (dd, J=2.7, 6.5 Hz, 2 H), 2.04-1.89 (m, 5 H), 1.76 (d, J=2.3 Hz, 1 H), 1.43 (dq, J=3.28, 13.1 Hz, 2 H), 1.03 (dq, J=3.28, 13.1 Hz, 2 H). 13C NMR (300 MHz, CDCl3) δ 183.2, 83.3, 69.9, 43.4, 36.7, 31.8, 28.9, 26.3.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:30]=[CH:29][C:10]([O:11][C:12]2[CH:13]=[CH:14][C:15]3[S:21](=[O:23])(=[O:22])[CH2:20][CH2:19][C:18]([C:24]([O:26]C)=[O:25])=[CH:17][C:16]=3[CH:28]=2)=[CH:9][CH:8]=1)[CH3:2].CO.[OH-].[Na+]>C1COCC1>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:11][C:12]2[CH:13]=[CH:14][C:15]3[S:21](=[O:22])(=[O:23])[CH2:20][CH2:19][C:18]([C:24]([OH:26])=[O:25])=[CH:17][C:16]=3[CH:28]=2)=[CH:29][CH:30]=1)[CH3:2]
Reactant: CCOCCCc1ccc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOCCCc1ccc(Oc2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Temperature: 70 °C
Reaction time: 5 h
Yield: 44.3 %

Procedure:
To methyl 7-[4-(3-ethoxypropyl)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.28 g) dissolved methanol (5 ml) and THF (10 ml) was added a 1 N aqueous solution of sodium hydroxide (0.6 ml), and the resulting mixture was stirred at 70° C. for 5 hours. The reaction mixture was concentrated, was then neutralized with 1 N hydrochloric acid and was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, and was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain 7-[4-(3-ethoxypropyl)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (0.12 g) as colorless crystals.
Reaction SMILES: CN1CCOCC1.[CH3:8][S:9](Cl)(=[O:11])=[O:10].ClCCl.Cl.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH:27]([C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=2[F:39])[CH2:28][CH2:29][CH2:30][NH2:31])(=[O:26])=[O:25])=[CH:20][CH:19]=1>C(OCC)(=O)C.CCCCCC.CCCCCC>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([CH:27]([C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=2[F:39])[CH2:28][CH2:29][CH2:30][NH:31][S:9]([CH3:8])(=[O:11])=[O:10])(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCCCCC
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.7 %

Procedure:
Under a nitrogen atmosphere, N-methylmorpholine (51.0 μl, 0.465 mmol) and methanesulfonyl chloride (18.8 μl, 0.242 mmol) were added to a dichloromethane solution (4 ml) of the 4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)butylamine hydrochloride (80.0 mg, 0.202 mmol) obtained in Example 227. After stirring at room temperature for 15 hours, N-methylmorpholine (156 μl, 1.42 mmol) and methanesulfonyl chloride (10.0 μl, 0.129 mmol) were added. The resulting mixture was stirred at room temperature for 2 hours. After dilution with dichloromethane, the mixture was successively washed with a saturated aqueous solution of ammonium chloride, water, and brine, dried over magnesium sulfate and then, concentrated. The residue thus obtained was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate=1:1 eluate was concentrated. The solid thus obtained was recrystallized from ethyl acetate-hexane, whereby the title compound (71.5 mg, 0.163 mmol, 81%) was obtained as colorless plate crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[NH:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=5)[S:23][C:16]=34)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1>>[NH:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:31]=[CH:30][C:27]([CH2:28][NH:1][CH2:2][CH2:3][OH:4])=[CH:26][CH:25]=5)[S:23][C:16]=34)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1
Reactant: O=Cc1ccc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Reactant: NCCO
Product: OCCNCc1ccc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from 2-aminoethanol and 4-[7-(1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-benzaldehyde by a procedure analogous to example 17. LC-MS: 415 (MH+); HPLC RT: 3.40 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:38])(=[N:29][C:30]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[O:31])=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1.[C:39](Cl)(=[O:41])[CH3:40]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:22]=[CH:23][C:24]([S:27]([CH3:38])(=[N:29][C:30]([CH:32]3[CH2:37][CH2:36][N:35]([C:39](=[O:41])[CH3:40])[CH2:34][CH2:33]3)=[O:31])=[O:28])=[CH:25][CH:26]=2)=[O:20])=[O:10])=[N:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: CS(=O)(=NC(=O)C1CCNCC1)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Product: CC(=O)N1CCC(C(=O)N=S(C)(=O)c2ccc(C(=O)Nc3ccc(Cl)cc3C(=O)Nc3ccc(Cl)cn3)cc2)CC1
Yield: 87 %

Procedure:
Product of Example 25 was acetylated using standard N-acetylating procedure with acetyl chloride to give titled compound in 87% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.ClC(OCC(C)C)=O.[N:22]1([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[NH:33][C:32](=[O:37])[CH2:31]3)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([N:25]1[CH2:26][CH2:27][N:22]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[NH:33][C:32](=[O:37])[CH2:31]3)[CH2:23][CH2:24]1)=[O:8]
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: O=C1Cc2cc(N3CCNCC3)ccc2N1
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CC(=O)N4)CC2)cc1OC
Yield: 42.2 %

Procedure:
3,4-Dimethoxybenzoic acid (2.6 g) and 1.65 g of 1,8-diazabicyclo[5,4,0]undecene-7 were added to 100 ml of DMF and to the mixture was added dropwise 1.5 ml of isobutyl chloroformate with ice-cooling externally with stirring. After completion of addition, the mixture was stirred for 30 minutes. To the mixture was added 40 ml of DMF solution containing 2.16 g of 5-(1-piperazinyl)oxindol and the mixture was stirred at room temperature for 5 hours. After completion of reaction, the solvent was removed by distillation. The residue was extracted with 300 ml of chloroform and the extract was washed with a diluted aqueous solution of sodium hydrogencarbonate, water, diluted hydrochloric acid and water, successively. Chloroform was removed by distillation and the residue was recrystallized from methanol to give 1.6 g of 5-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]oxindol.