Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34][CH:35]([CH3:37])[CH3:36])[CH2:24][CH:23]2[OH:38])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].C(N(CC)CC)C.CS(C)=[O:48]>C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34]([CH:35]([CH3:36])[CH3:37])=[O:48])[CH2:24][C:23]2=[O:38])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: CC(C)Sc1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Reactant: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)S(=O)c1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(=O)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To the solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(2-isopropylthiophenyl)piperidin-3-ol (60 mg) obtained in Step 1 in 5 ml of dimethyl sulfoxide (DMSO), was added 0.093 ml of triethylamine (0.66 mmol). The reaction mixture was cooled to 0° C. Pyridine-SO3 complex (103 mg, 0.66 mmol) was added to the reaction mixture, which was then stirred for about 2 hours at room temperature. The reaction mixture was diluted with 100 ml of ethyl acetate, washed with brine. The resulting organic layer was dried on sodium sulfate. The resulting residue was purified with column chromatography to give 50 mg of the titled compound.
Reaction SMILES: [CH:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH2:6]([SH:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>C(N(CC)CC)C>[CH2:6]([S:18][CH:3]([CH3:4])[CH2:2][CH:1]=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCS
Reactant: C/C=C/C=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCSC(C)CC=O
Reaction time: 1.5 h

Procedure:
14.02 Grams of crotonaldehyde (0.20 mole) is added dropwise over a 40-minute period at 60° to 65° C. to a solution of 41.2 grams of n-dodecyl mercaptan (0.20 moles) and 0.66 grams of triethylamine after which heating and stirring are continued at 85° C. for 1.5 hours. Analysis of the reaction mixture indicates that the reaction is then substantially complete. The product is isolated as a light yellow liquid by stripping off the volatiles.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:9]([CH3:16])[C:10]([O:12]C(C)C)=[O:11])[C:3]([O:5]C(C)C)=[O:4].[OH-].[K+]>C1COCC1.O>[OH:1][C@@H:2]([C@@H:9]([CH3:16])[C:10]([OH:12])=[O:11])[C:3]([OH:5])=[O:4]
Reactant: CC(C)OC(=O)[C@@H](O)[C@@H](C)C(=O)OC(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](C(=O)O)[C@H](O)C(=O)O
Temperature: 0 °C
Reaction time: 48 h

Procedure:
Diisopropyl (2S,3R)-2-hydroxy-3-methylsuccinate (3.70 g; 15.93 mmol; 1.0 eq.) was taken in THF (55 mL), cooled to 0° C. and treated with KOH (5.36 g, 96 mmol) in water (18.5 mL). The resulting mixture was stirred at RT for 48 h. THF was removed and the residue was taken in water. The aqueous layer was washed with Et2O (100 mL) and was acidified with an aqueous solution of HCl (1.5 N), then was extracted with EtOAc (continuous extraction during 20 hours). The organic phase was dried over Na2SO4 and then concentrated to give the title product (mixture of diastereoisomers) as pale yellow oil (2.4 g, quant.).
Reaction SMILES: Br[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.[OH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=1>C1(C)C=CC=CC=1>[C:2]12([C:16]3[CH:17]=[C:18]([C:2]45[CH2:11][CH:6]6[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]6)[CH2:3]4)[CH2:9]5)[C:13]([OH:12])=[CH:14][C:15]=3[OH:19])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: BrC12CC3CC(CC(C3)C1)C2
Reactant: Oc1cccc(O)c1
Solvent: Cc1ccccc1
Product: Oc1cc(O)c(C23CC4CC(CC(C4)C2)C3)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 130 °C
Reaction time: 24 h
Yield: 69.8 %

Procedure:
75.0 g of 1-bromoadamantane (349 mmol), 9.58 g of 1,3-dihydroxybenzene (87.0 mmol), 25 mL of toluene and stirrer were charged in a 300 mL recovery flask and heated and agitated at 130° C. for 24 hours under nitrogen flow. A solvent was removed under reduced pressure to obtain a solid. The obtained solid was purified by column chromatography, thus obtaining 23.0 g of 4,6-di(1-adamantyl)-1,3-dihydroxybenzene (60.8 mmol; the yield was 69.9%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCN(c3ccccn3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)N2CCN(c3ccccn3)CC2)cc1
Yield: 81.3 %

Procedure:
A mixture of 10.62 g (0.0305 m) of 1-[(p-nitrophenyl)sulfonyl]-4-(2-pyridinyl)piperazine, 1.5 g of 5% palladium on charcoal, and 150 ml of absolute ethanol is shaken under hydrogen on a Parr hydrogenator. After the theoretical amount of hydrogen has been taken up, the catalyst is filtered off and the filtrate is taken to dryness. The product, 1-[(p-aminophenyl)sulfonyl]-4-(2-pyridinyl)piperazine, is crystallized from methanol/methylene chloride to give 7.89 g (81%) of 1-[(p-aminophenyl)sulfonyl]-4-(2-pyridinyl)piperazine of melting point 208°-210° C.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[OH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[C:4]([O:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:16]1)(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: OCCCN1CCC(c2ccccc2)CC1
Reactant: C=C1CC(=O)O1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)OCCCN1CCC(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 70 h

Procedure:
Diketene (0.95 mL, 12 mmol, 1.3 equiv) was added to a solution of 1-(3-hydroxypropyl)-4-phenylpiperidine (2.08 g, 9.48 mmol, 1.0 equiv) in toluene (30 mL), and the mixture was stirred under argon for 70 hours at room temperature. Removal of solvent gave 2.88 g (100%) of light brown, viscous oil, which was characterized spectroscopically and used for the next reaction without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([N+:17]([O-])=O)[CH:13]=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.C(OCC)(=O)C>C(O)C.[Pt](=O)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=3[CH:10]=[N:9]2)=[CH:20][CH:21]=1
Reactant: COc1ccc(Cn2ncc3c([N+](=O)[O-])cccc32)cc1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(Cn2ncc3c(N)cccc32)cc1
Reaction time: 2 h
Yield: 99.8 %

Procedure:
A suspension of 1-(4-methoxybenzyl)-4-nitro-1H-indazole (9 g, 31.77 mmol) and platinum(IV) oxide (0.433 g, 1.91 mmol) in ethanol (150 mL)/ethyl acetate (10 mL) was hydrogenated under 40 psi at 25° C. for 2 hours. The resulting mixture was filtered and the filtrate was concentrated to dryness to afford 1-(4-methoxybenzyl)-1H-indazol-4-amine (8.03 g, 100%) as a yellow-orange solid. Mass spectrum: MH+ 254.
Reaction SMILES: CC([N:5]([C@H:9]([CH3:29])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:28]=[CH:27][C:23]3[CH2:24][O:25][CH2:26][C:22]=3[CH:21]=2)=[CH:15][CH:14]=1)=[O:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:24]1[C:23]2[CH:27]=[CH:28][C:20]([O:19][C:16]3[CH:15]=[CH:14][C:13]([NH:12][C:10](=[O:11])[C@@H:9]([CH3:29])[NH2:5])=[CH:18][CH:17]=3)=[CH:21][C:22]=2[CH2:26][O:25]1
Reactant: C[C@H](C(=O)Nc1ccc(Oc2ccc3c(c2)COC3)cc1)N(C(=O)[O-])C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](N)C(=O)Nc1ccc(Oc2ccc3c(c2)COC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
A solution of 1,1-dimethylethyl((1R)-2-{[4-(1,3-dihydro-2-benzofuran-5-yloxy)phenyl]amino}-1-methyl-2-oxoethyl)carbamate (Intermediate 76, 130 mg, 0.326 mmol) and TFA (1 ml) in dichloromethane (4 ml) was stirred under argon at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated and the residue was purified by SCX to afford the title compound (94 mg), which was directly used in the next step.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[C:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:19]=[O:20]>>[CH:19]([C:5]1[NH:6][C:2]([CH3:1])=[CH:3][C:4]=1[CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:20]
Reactant: Cc1cc(CCC(=O)O)c[nH]1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(CCC(=O)O)c(C=O)[nH]1

Procedure:
3-(5-Methyl-1H-pyrrole-3-yl)propionic acid was formylated using phosphorus oxycloride (POCl3) and N,N-dimethylformamide (DMF) to give 3-(2-formyl-5-methyl-1H-pyrrole-3-yl)propionic acid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.C([Li])CCC.C([Li])(CC)C.[O:22]1CCC[CH2:23]1>CN(C)C=O>[O:9]=[C:7]1[NH:6][C:5]2[CH:10]=[CH:11][C:2]([CH:23]=[O:22])=[CH:3][C:4]=2[O:8]1
Reactant: O=c1[nH]c2ccc(Br)cc2o1
Reactant: C1CCOC1
Agent: [Li]C(C)CC
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: O=Cc1ccc2[nH]c(=O)oc2c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of 6-bromo-3H-benzooxazol-2-one (0.9236 g, 4.31 micromoles) in anhydrous tetrahydrofuran (25 mL) and dimethylformamide (3 mL) under nitrogen was cooled to −78° C. before addition of n-butyllithium (2.5M in hexane) (3.8 mL, 2.2 equiv). After stirring for 10 min at −78° C., 24 mL of sec-butyllithium (1.4 M in cyclohexane, 8 equiv) was added. The reaction was stirred while slowly warming to −40° C. When this temperature was reached, the reaction was quenched by addition of methanol. The reaction mixture was concentrated in vacuo and water was added. The aqueous layer was acidified with 1N HCl (ca. pH 5) and extracted with ethyl acetate (3×50 mL), dried over sodium sulfate, filtered and concentrated to give the product, 0.6402 g (91%). MS (ESI) 164 (MH)+. 1H NMR (400 MHz, DMSO-d6) δ 9.90 (1H, s), 7.79 (1H, d, J=8.0 Hz), 7.74 (1H, s), 7.28 (1H, d, J=8.0 Hz).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].I[CH2:15][CH2:16][C:17]([F:29])([F:28])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21].O>O1CCCC1>[F:28][C:17]([F:29])([C:18]([F:26])([F:27])[C:19]([F:24])([F:25])[C:20]([F:21])([F:23])[F:22])[CH2:16][CH2:15][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
Anhydrous tetrahydrofuran (200 ml) was added to 60% sodium hydride (2.78 g, 69.52 mmol) and the resulting mixture was cooled to 0° C. Diethyl malonate (12.18 ml, 80.22 mmol) was slowly added dropwise to this mixture, which was then stirred for 1 hour at room temperature. A solution of 1-iodo-3,3,4,4,5,5,6,6,6-nonafluorohexane (20.0 g, 53.48 mmol) in anhydrous tetrahydrofuran (50 ml) was then slowly added dropwise to the mixture, followed by stirring for 12 hours at room temperature. Water was added to the reaction mixture, which was then extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/50) to give diethyl 2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)malonate (19.4 g, Yield 89%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3]1.[H-].[Na+].I[CH3:24]>C1COCC1>[CH3:24][N:3]1[C:4]2[CH:20]=[CH:19][CH:18]=[CH:17][C:5]=2[N:6]([CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:2]1=[O:1]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCCn1c(=O)[nH]c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCNC(=O)OC(C)(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 50 %

Procedure:
To a solution of tert-butyl (2-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl)carbamate (190 mg, 0.69 mmol) in THF (10 mL) was added sodium hydride (34.5 mg, 0.86 mmol, 60% in mineral oil) at 0° C. under nitrogen in a sealed tube. After the resulting reaction mixture was stirred at room temperature for 20 min, iodomethane (112 mg, 0.79 mmol) in THF (2 mL) was added at 0° C. under nitrogen. The reaction was stirred at room temperature for 4 h. The reaction was quenched with saturated aqueous ammonium chloride solution and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. Concentration under vacuum gave the crude product, which was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether) to afford the title compound (100 mg, 0.345 mmol, 50% yield). MS (ESI) m/z 292.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C1C(=O)N([Cl:20])C(=O)C1>CN(C=O)C>[NH2:1][C:2]1[C:3]([CH3:12])=[C:4]([C:9]([Cl:20])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(N)c1C
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: COC(=O)c1c(Cl)ccc(N)c1C
Yield: 40.7 %

Procedure:
This compound was prepared in a manner analogous to Step C, Example 1. Here, 29.9 grams (0.181 mole) of methyl 3-amino-2-methylbenzoate was combined with 27.8 grams (0.208 mole) of NCS in 800 mL of DMF. The reaction product was purified by column chromatography on silica gel using mixtures of EtOAc and hexane as eluants. The fractions containing product were combined and concentrated under reduced pressure, yielding 14.7 grams of subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([C:5]1[O:6][CH2:7][C:8](=[O:40])[N:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[C:19]([NH:21][C:22]3[CH:30]=[CH:29][CH:28]=[C:27]4[C:23]=3[CH2:24][CH:25]([C:31]([O:33]C)=[O:32])[CH2:26]4)=[O:20])=[CH:14][CH:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>O1CCOCC1.O>[C:1]([C:5]1[O:6][CH2:7][C:8](=[O:40])[N:9]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([CH:18]([CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[C:19]([NH:21][C:22]3[CH:30]=[CH:29][CH:28]=[C:27]4[C:23]=3[CH2:24][CH:25]([C:31]([OH:33])=[O:32])[CH2:26]4)=[O:20])=[CH:16][CH:17]=2)[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1Cc2cccc(NC(=O)C(c3ccc(CN4N=C(C(C)(C)C)OCC4=O)cc3)C3CCCC3)c2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)C1=NN(Cc2ccc(C(C(=O)Nc3cccc4c3CC(C(=O)O)C4)C3CCCC3)cc2)C(=O)CO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
167 mg (0.306 mmol) of methyl 4-{[{4-[(2-tert-butyl-5-oxo-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}(cyclopentyl)acetyl]amino}-2,3-dihydro-1H-indene-2-carboxylate (Example 108A) were dissolved in 14 ml of dioxane/water (3:1 v/v), and 0.46 ml of 1 N aqueous sodium hydroxide solution was added. The mixture was stirred at room temperature overnight. The mixture was then acidified with 1 N hydrochloric acid and extracted repeatedly with dichloromethane, and the combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC. This gave 68 mg (42% of theory) of the title compound as a mixture of diastereomers.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:9])[C:6](Cl)=[O:7])(=[O:3])[CH3:2].[Cl:10][C:11]1[CH:12]=[C:13]2[C:19]3([CH2:23][CH2:22][NH:21][CH2:20]3)[CH2:18][N:17]([C:24]([NH:26][C:27]3[S:28][C:29]([Cl:32])=[CH:30][N:31]=3)=[O:25])[C:14]2=[CH:15][CH:16]=1>>[C:1]([O:4][C@H:5]([CH3:9])[C:6]([N:21]1[CH2:22][CH2:23][C:19]2([C:13]3[C:14](=[CH:15][CH:16]=[C:11]([Cl:10])[CH:12]=3)[N:17]([C:24](=[O:25])[NH:26][C:27]3[S:28][C:29]([Cl:32])=[CH:30][N:31]=3)[CH2:18]2)[CH2:20]1)=[O:7])(=[O:3])[CH3:2]
Reactant: O=C(Nc1ncc(Cl)s1)N1CC2(CCNC2)c2cc(Cl)ccc21
Reactant: CC(=O)O[C@H](C)C(=O)Cl
Product: CC(=O)O[C@H](C)C(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Cl)cc12

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Step 1 of Example 17, with the exceptions that (R)-2-acetoxypropionic acid chloride was used instead of acetoxyacetic acid chloride, and that 5-chloro-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide was used instead of 5-bromo-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide.
Reaction SMILES: C(OC([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][N:24]([C:33]([O:35][C:36]2[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=2[C:38]([OH:40])=[O:39])=[O:34])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.Cl.O1CCOCC1>O1CCOCC1>[C:11]1([C@H:9]([NH:8][CH2:21][C@@H:22]2[C@@H:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][N:24]([C:33]([O:35][C:36]3[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=3[C:38]([OH:40])=[O:39])=[O:34])[CH2:23]2)[CH3:10])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)Oc2ccccc2C(=O)O)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](NC[C@H]1CN(C(=O)Oc2ccccc2C(=O)O)C[C@@H]1c1ccccc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
A 2.0 ml 1,4-dioxane solution of 145 mg of 2-({[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin 1-yl]carbonyl}oxy)benzoic acid was mixed with 1.0 ml of 4 M hydrogen chloride/1,4-dioxane at room temperature and stirred overnight at room temperature. The reaction solution was concentrated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography (chloroform-methanol) to obtain 39 mg of 2-({[(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}oxy)benzoic acid as a colorless amorphous substance.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[C:10]=1[NH:16][CH2:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21].[C:23](Cl)(=O)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>ClCCl>[Cl:8][C:9]1[C:10]2[N:16]([CH2:17][CH2:18][CH2:19][N:20]([CH3:21])[CH3:22])[C:40]([CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23])=[N:15][C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CN(C)CCCNc1c(N)cccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCc1nc2cccc(Cl)c2n1CCCN(C)C
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 55.3 %

Procedure:
Triethylamine (0.587 g) was added to a solution containing 3-chloro-N2-[3-(dimethylamino)propyl]-1,2-benzenediamine (1.100 g) in dichloromethane (22 ml), and then stearoyl chloride (1.610 g) was added thereto while being cooled with ice. After being stirred for 4.5 hours at room temperature, the reaction mixture was diluted with dichloromethane, washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (4.0 ml) was added to a solution containing the residue (3.451 g) in ethanol (24 ml). After being stirred for 4 hours at 90° C., the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (2.95 g) was purified by silica gel column chromatography (silica gel 92 g, chloroform:methanol=1:0-100:1), thereby yielding the entitled compound (1.271 g) as pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([OH:11])=[C:7]([CH:10]=1)[CH:8]=O.C(=O)([O-])[O-].[K+].[K+].[CH:18]([CH:20]=[CH2:21])=[O:19]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:21][C:20]([CH:18]=[O:19])=[CH:8][C:7]=2[CH:10]=1
Reactant: COc1ccc(O)c(C=O)c1
Reactant: C=CC=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc2c(c1)C=C(C=O)CO2
Temperature: 100 °C

Procedure:
The starting material is prepared as follows: 5-Methoxy-2-hydroxybenzaldehyde (25 g, 0.16 mol) and potassium carbonate (22.7 g, 0.16 mol) are taken up in 300 ml of 1,4-dioxane and treated with acrolein (13.8 g, 0.25 mol). The mixture is heated at 100° C. for 1 hour, and allowed to cool. The mixture is diluted with water and extracted three times with ether. The combined ether extracts are dried (MgSO4) and evaporated. The residual oil is dissolved in a minimal amount of ethyl acetate (approx. 40 ml) and passed through 40 g of silica gel. The gel is successively washed with several portions of a hexane/ether mixture (3:1) until no further fluorescent material is eluted. The organic phase is evaporated and the residue is crystallized from ethyl acetate/hexane to give 6-methoxy-2H-1-benzopyran-3-carboxaldehyde as a yellow solid, m.p. 49°-50° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[S:25][C:24]4[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[N:22][C:21](Cl)=[N:20][C:19]=4[CH:18]=3)[CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:33][C:34]1[N:39]=[CH:38][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][N:35]=1>>[O:29]1[CH2:30][CH2:31][N:26]([C:23]2[C:24]3[S:25][C:17]([CH2:16][N:13]4[CH2:14][CH2:15][N:10]([S:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)(=[O:9])=[O:8])[CH2:11][CH2:12]4)=[CH:18][C:19]=3[N:20]=[C:21]([C:37]3[CH:36]=[N:35][C:34]([NH2:33])=[N:39][CH:38]=3)[N:22]=2)[CH2:27][CH2:28]1
Reactant: O=S(=O)(c1ccccc1)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(=O)(=O)c5ccccc5)CC4)cc3n2)cn1

Procedure:
6-(4-Benzenesulfonyl-piperazin-1-ylmethyl)-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 2-aminopyrimidine-5-boronic acid pinacol ester using General Procedure A. Purification on silica yielded 120. (400 MHz, CDCl3): 2.56-2.58 (4H, m, CH2), 3.04 (4H, m, CH2), 3.74 (2H, s, CH2), 3.76-3.79 (4H, m, CH2), 3.90-3.92 (4H, m, CH2), 7.18 (1H, s, ar), 7.47-7.51 (1H, d (J=7.36), ar), 7.55 (1H, d (J=7.36), ar), 7.71 (2H, d (J=7.07), ar), 9.19 (2H, s, ar). (M+H)+553.29
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:11]=2)=[CH:6][C:5]=1[OH:21])([O-])=O>O1CCCC1.[Ni]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:11]=2)=[CH:6][C:5]=1[OH:21]
Reactant: O=[N+]([O-])c1ccc(-c2nc(-c3cccnc3)no2)cc1O
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1ccc(-c2nc(-c3cccnc3)no2)cc1O

Procedure:
A solution of the product of Example 25 (284 mg, 1 mmol) in tetrahydrofuran (10 mL) was stirred with Raney®-nickel (Aldrich, 100 mg) under hydrogen at ambient temperature for 2 hours. The catalyst was then removed by filtration and the organic solution concentrated to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 5.67 (s, 2 H), 6.74 (d, J=8.1 Hz, 1 H), 7.41-7.50 (m, 2 H), 7.62 (dd, J=8.3, 4.6 Hz, 1 H), 8.39 (dt, J=8.2, 1.9, 1.7 Hz, 1 H), 8.78 (dd, J=4.7, 1.7 Hz, 1 H), 9.20 (d, J=1.7 Hz, 1 H), 9.74 (s (broad), 1 H) ppm; MS (DCI/NH3) m/z 255 (M+H)+.