Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]2[C:7](=[O:19])[C:8]([CH3:18])([CH3:17])[CH:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1.[N:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]2[C:4]3[CH:3]=[C:2]([C:23]4[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=4)[S:6][C:5]=3[C:7](=[O:19])[C:8]2([CH3:18])[CH3:17])=[CH:11][CH:12]=1
Reactant: OB(O)c1ccncc1
Reactant: CC1(C)C(=O)c2sc(Br)cc2C1c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)C(=O)c2sc(-c3ccncc3)cc2C1c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a 20 mL vial was added a solution of 2-bromo-4-(4-chlorophenyl)-5,5-dimethyl-4,5-dihydro-6H-cyclopenta[b]thiophen-6-one (0.0434 g, 0.122 mmol) and pyridine-4-boronic acid (0.02802 g, 0.2280 mmol) in 1,4-dioxane (2 mL) and water (0.200 mL). Cesium carbonate (0.1193 g, 0.3661 mmol) was added followed by [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride (0.0120 g, 0.0146 mmol). The reaction mixture was heated to 90° C. and allowed to stir for 18 hr. The reaction was cooled to ambient temperature and quenched by the addition of a saturated aqueous solution of sodium bicarbonate (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified and the enantiomers were separated on a Chiralpak IC 20×250 column using 90/10/01% Hexane/EtOH/DEA, 1.0 mL/minute for 40 minutes. Peak 1 RT=23.9 minutes (0.0050 g, 11%) and Peak 2 RT=39.4 minutes (0.0048 g, 11%) were both isolated as white solids. Absolute configuration of the obtained enantiomers is unknown. LC/MS (AA) ES+ 354, 356, 357, 358. 1H NMR (DMSO-d6, 400 MHz): δ 8.67-8.65 (2H, m), 7.88 (1H, s), 7.80-7.79 (2H, m), 7.43-7.42 (2H, m), 7.16-7.14 (2H, m), 4.48 (1H, s), 1.34 (3H, s), 0.63 (3H, s).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[C:24]([C:28](Cl)=[O:29])[CH:23]=1>C1(C)C=CC=CC=1>[CH3:31][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[C:28]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)=[O:29]
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cccc(C(=O)OC2CCN(Cc3ccccc3)CC2)c1
Yield: 65 %

Procedure:
1.0 g (0.00532 mol) of 1-benzyl-4-hydroxypiperidine and 0.72 ml (0.00532 mol) of triethylamine were dissolved in 50 ml of toluene and treated with 0.7 ml (0.00532 mol) of m-toluoyl chloride. The mixture was boiled at reflux for 2 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:3→1:2). 1.07 g (65%) of 1-benzyl-piperidin-4-yl 3-methyl-benzoate were obtained as a yellow solid: m.p. 45°-46°.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:7]=1[CH2:8][NH:9][C:10]([C@:12]1([CH:18]([CH3:20])[CH3:19])[CH2:16][C:15](=[O:17])[CH:14]=[CH:13]1)=[O:11])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]1[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][C:7]=1[CH2:8][NH:9][C:10]([C@@:12]1([CH:18]([CH3:20])[CH3:19])[CH2:13][CH2:14][C:15](=[O:17])[CH2:16]1)=[O:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)[C@]1(C(=O)NCc2cc(C(F)(F)F)ccc2OC(C)(C)C)C=CC(=O)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@]1(C(=O)NCc2cc(C(F)(F)F)ccc2OC(C)(C)C)CCC(=O)C1

Procedure:
(1S)—N-[2-tert-butoxy-5-(trifluoromethyl)benzyl]-1-isopropyl-4-oxocyclopent-2-ene-1-carboxamide (32 g, 80.6 mmol) was dissolved in MeOH and was hydrogenated for 18 hr with a hydrogen balloon in the presence of a catalytic amount of 10% palladium on carbon. The palladium was filtered through a celite plug. The filtrate was evaporated to dryness to give (1S)—N-[2-tert-butoxy-5-(trifluoromethyl)benzyl]-1-isopropyl-3-oxocyclopentanecarboxamide as a yellow solid.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][CH2:16]Br>CN(C)C=O>[C:1]([C:3]1([C:4]([O:6][CH3:7])=[O:5])[CH2:16][CH2:15]1)#[N:2]
Reactant: BrCCBr
Reactant: COC(=O)CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1(C#N)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.4 %

Procedure:
To a mixture of methyl cyanoacetate (21.6 ml, 244.0 mmol) and potassium carbonate (52.9 g, 383.0 mmol) in N,N-dimethylformamide (200 ml) was added 1,2-dibromoethane (15.0 ml, 174.0 mmol). The reaction mixture was stirred at room temperature for 16 h and then filtered. The filtrate was partitioned between diethyl ether and brine and the organic phase was separated, washed with brine, dried (MgSO4) and concentrated in vacuo to give the title compound (15.1 g).
Reaction SMILES: O.NN.O=C1C2C(=CC=CC=2)C(=O)[N:6]1[CH2:15][C:16]([P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])([F:18])[F:17]>C(Cl)Cl>[NH2:6][CH2:15][C:16]([P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])([F:17])[F:18]
Reactant: CCOP(=O)(OCC)C(F)(F)CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: ClCCl
Solvent: O
Product: CCOP(=O)(OCC)C(F)(F)CN
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Hydrazine monohydrate was added to a methylene chloride solution of diethyl [2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1,1-difluoroethyl]phosphonate, for stirring at ambient temperature for one hour, to obtain diethyl (2-amino-1,1-difluoroethyl)phosphonate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH:14]=1)([O-])=O>N.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Agent: [Pd]
Agent: N
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reaction time: 8 h
Yield: 100.2 %

Procedure:
A solution of compound 85 (0.5 g, 1.456 mmol) in 2 M NH3 in methanol (15 mL) was treated with Pd—C (0.05 g) and purged with hydrogen gas. The reaction was stirred under hydrogen atm. for overnight. The solution was filtered through a celite bed and washed with methanol: CH2Cl2 (1:1, 2×20 mL). The combined organic layer was evaporated to obtain compound 86 (0.46 g, quantitative) as a solid. mp 205-207° C.; 1H NMR (DMSO-d6) δ 1.41-1.53 (m, 11H), 1.87-1.91 (m, 2H), 2.73-2.85 (m, 3H), 4.03-4.07 (m, 2H), 4.43 (s, 2H), 6.45 (dd, 1H, J=1.8, 8.4 Hz), 6.69 (d, 1H, J=1.5 Hz), 6.90 (d, 1H, J=2.4 Hz), 7.01 (d, 1H, J=8.4 Hz), 10.28 (s, 1H); ESI-MS m/z (%): 338 (M.Na+, 23), 316 (MH+,11), 216 (100).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([SH:7])[NH:4][N:3]=1.[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1>[OH-].[Na+].C(O)C>[NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:13][C:12]2[CH:15]=[CH:16][C:9]([Cl:8])=[CH:10][CH:11]=2)[NH:4][N:3]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: Nc1n[nH]c(S)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1n[nH]c(SCc2ccc(Cl)cc2)n1
Reaction time: 0.5 h

Procedure:
A mixture of 3-amino-5-mercapto-s-triazole (Compound 5) [4.64g; 40 mmoles] in 40 ml. of IN sodium hydroxide was stirred at room temperature while solution of p-chlorobenzylchloride [7.55g; 48 mmoles] in 80 ml of absolute ethanol was added. The mixture was then warmed to 70°-75° and stirred for 30 minutes. The amber colored solution was then evaporated to 40 ml at reduced pressure, diluted with 50 ml of water and chilled overnight. The crude product was separated by filtration, air dried, and recrystallized two times from chloroform to afford 4.3g (45%) of analytically pure product that had a melting point of 107°-8°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=2)=[CH:5][CH:4]=1.C([Li])CCC.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH:26]=[O:27].O>O1CCCC1.CCCCCC.C(OCC)(=O)C>[OH:27][CH:26]([C:25]1[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:23]([O:22][CH3:21])[CH:24]=1)[C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[C:9]1[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: COc1ccc(C2=NC(C)(C)CO2)cc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C2=NC(C)(C)CO2)c(C(O)c2cc(OC)c(OC)c(OC)c2)c1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
A solution of 2-(4-methoxyphenyl)-4,4-dimethyl-2-oxazoline (11.0 g) in tetrahydrofuran (50 ml) is cooled to −50° C., and thereto is added dropwise a 1.6 M solution of n-butyl lithium in hexane (36.8 ml) over a period of 20 minutes. The mixture is stirred at 40° C. for 30 minutes, and thereto is added dropwise a solution of 3,4,5-trimethoxybenzaldehyde (10.5 g) in tetrahydrofuran (30 ml) at the same temperature over a period of 10 minutes. After reaction at −30T for one hour, to the mixture are added water and ethyl acetate. The ethyl acetate layer is separated, washed, dried, and concentrated under reduced pressure. The residue is crystallized from diethyl ether to give 2-{2-[hydroxy-(3,4,5trimethoxyphenyl)methyl]-4-methoxyphenyl}-4,4-dimethyl-2-oxazoline (16.2 g) as listed in Table 53.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH3:42])[CH2:4][CH2:5][CH2:6][C:7]([CH3:41])=[CH:8][CH2:9][CH:10]([O:20][C:21](=[O:40])[CH2:22][C@H:23]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[C:24]([CH3:31])([CH3:30])[C:25](=[O:29])[CH:26]([Br:28])[CH3:27])[C:11]([CH3:19])=[CH:12][C:13]1[N:14]=[C:15]([CH3:18])[S:16][CH:17]=1.CS(C)=O.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)C>[CH3:41][C:7]([CH2:6][CH2:5][CH2:4][CH:3]([CH3:42])[CH:2]=[O:1])=[CH:8][CH2:9][CH:10]([O:20][C:21](=[O:40])[CH2:22][C@H:23]([O:32][Si:33]([C:36]([CH3:37])([CH3:38])[CH3:39])([CH3:35])[CH3:34])[C:24]([CH3:30])([CH3:31])[C:25](=[O:29])[CH:26]([Br:28])[CH3:27])[C:11]([CH3:19])=[CH:12][C:13]1[N:14]=[C:15]([CH3:18])[S:16][CH:17]=1
Reactant: CC(=CCC(OC(=O)C[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)C(=O)C(C)Br)C(C)=Cc1csc(C)n1)CCCC(C)CO
Solvent: CS(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=CCC(OC(=O)C[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)C(=O)C(C)Br)C(C)=Cc1csc(C)n1)CCCC(C)C=O

Procedure:
180 mg (0.262 mmol) (3S)-6-bromo-3-(tert-butyl-dimethyl-silanyloxy)-4,4-dimethyl-5-oxo-heptanoic acid 9-hydroxy-4,8-dimethyl-1-[1-methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-non-3-enyl ester (277b) were dissolved in 5.30 mL CH2Cl2 and 1.72 mL DMSO at 0° C. and 212 μl (155 mg, 1.53 mmol) triethylamine were added. After addition of 195 mg (1.223 mmol) SO3.Pyridine—complex the mixture was stirred 60 min at 0° C. Dilution with 40 mL diethylether was followed by twofold washing with 10 mL demi water and with brine (2×10 mL). The organic layer was the dried over Na2SO4, filtered and concentrated in vacuo to give a slightly yellow oil which was used in the following reaction step without further purification.
Reaction SMILES: [C:1]([NH:9][CH:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30](O)[C:31]#[CH:32]>>[C:1]([NH:9][CH:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)[C:11]([O:13][CH2:32][C:31]#[CH:30])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC(Cc1ccc(OC(=O)c2ccccc2)cc1)C(=O)O)c1ccccc1
Reactant: C#CCO
Product: C#CCOC(=O)C(Cc1ccc(OC(=O)c2ccccc2)cc1)NC(=O)c1ccccc1

Procedure:
Proceeding in a similar manner, but substituting for 2-(benzoylamino)-3-(4-benzoyloxyphenyl)propanoic acid, and using propargyl alcohol or another appropriate acetylenic alcohol, the mono-acids prepared by Example 1 and 2 may be converted to the corresponding ester, to obtain, for example:
Reaction SMILES: [CH3:1][C:2]1[NH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:3]=1[CH2:4][CH2:5][NH2:6].[CH3:14][O:15][C:16](=[O:27])/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][CH:20]=1.[BH4-].[Na+].[ClH:30]>CO.O>[ClH:30].[CH3:14][O:15][C:16](=[O:27])/[CH:17]=[CH:18]/[C:19]1[CH:20]=[CH:21][C:22]([CH2:25][NH:6][CH2:5][CH2:4][C:3]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:13][C:2]=2[CH3:1])=[CH:23][CH:24]=1
Reactant: COC(=O)/C=C/c1ccc(C=O)cc1
Reactant: Cc1[nH]c2ccccc2c1CCN
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)/C=C/c1ccc(CNCCc2c(C)[nH]c3ccccc23)cc1
Temperature: 22.5 °C
Reaction time: 1 h

Procedure:
2-Methyltryptamine (50 g, 287 mmole) and (E)-3-(4-formyl-phenyl)-acrylic acid methyl ester (54.6 g, 287 mmole) are suspended in methanol (514 g). The solution is stirred for 1 hour at 20-25° C., to allow the formation of the imine intermediate. The solution is cooled to −15° C. within ca. 20 minutes. Sodium borohydride (5.43 g, 143.5 mmole) is added in several portions during ca. 1 hour while maintaining the temperature at −15° C. to −10° C. The reaction mixture is stirred for additional 30 minutes at this temperature and the temperature is raised to 20-25° C. within ca. 25 minutes. The reaction mixture is stirred for 30 minutes at 20-25° C. and water (80 g) is slowly added while maintaining the temperature at 20-25° C. The pH of the reaction mixture is adjusted to 8.5 by slow addition of an aqueous hydrochloric acid solution (ca. 37.3 g of a 21.6 m/m % solution in water) at 20-25° C., until the pH of the solution reaches 8.5. The addition needs ca. 30 minutes in this case. After completion of the addition, the reaction mixture is stirred for one hour at 20-25° C. to allow crystallization. At this stage, the solution can be seeded with crystals of (E)-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl]-phenyl)-acrylic acid methyl ester hydrochloride salt to accelerate the crystallization. A suspension is obtained. A second portion of aqueous hydrochloric acid (36 g of a 21.6% m/m HCl solution in water) is added to the suspension during 30 minutes at 20-25° C., followed by the addition of a third portion of aqueous hydrochloric acid (167.7 g of a 21.6% m/m HCl solution in water) during 30 minutes at 20-25° C. The suspension is heated to 65° C. Then, the suspension is cooled to −15° C. and stirred for 30 minutes at −10 to −15° C. to complete the crystallization. The product is isolated by filtration and the wet filter cake is washed with pre-cooled (−15° C.) methanol (2×150 g). The wet product is dried at 50° C. under reduced pressure to obtain pure (E)-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl]-phenyl)-acrylic acid methyl ester hydrochloride salt as product. The product has usually >99 area % purity according to HPLC. IR, NMR and HR-MS confirmed the proposed structure. Melting point: decomposition starting at 251-252° C.
Reaction SMILES: OCCN1CCNCC1.COC1C=CC(C[N:17](CC2C=CC(OC)=CC=2)[C:18]2[N:23]=[CH:22][C:21]([C:24]3[C:25]4[CH2:38][CH2:37][N:36]([C:39]5[S:40][CH:41]=[C:42]([C:44]([N:46]6[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][OH:54])[CH2:48][CH2:47]6)=[O:45])[N:43]=5)[C:26]=4[N:27]=[C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[N:29]=3)=[CH:20][N:19]=2)=CC=1>>[NH2:17][C:18]1[N:19]=[CH:20][C:21]([C:24]2[C:25]3[CH2:38][CH2:37][N:36]([C:39]4[S:40][CH:41]=[C:42]([C:44]([N:46]5[CH2:47][CH2:48][N:49]([CH2:52][CH2:53][OH:54])[CH2:50][CH2:51]5)=[O:45])[N:43]=4)[C:26]=3[N:27]=[C:28]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[N:29]=2)=[CH:22][N:23]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3nc(C(=O)N4CCN(CCO)CC4)cs3)cn2)cc1
Agent: OCCN1CCNCC1
Product: Nc1ncc(-c2nc(N3CCOCC3)nc3c2CCN3c2nc(C(=O)N3CCN(CCO)CC3)cs2)cn1
Yield: 29 %

Procedure:
Using N-2-hydroxyethylpiperazine instead of N-ethylpiperazine in Step B in Example 1-D-120, in the same manner as Step B in Example 1-D-120, a crude product of [2-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-thiazol-4-yl]-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone was obtained, and then the PMB groups were removed according to Deprotection method 1, to obtain the desired compound (D-121) as an ivory powder (20 mg, 29%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].[CH:12](O)=[O:13]>>[C:12](=[N:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11])=[O:13]
Reactant: O=CO
Reactant: Nc1ccc(C(=O)O)cc1O
Product: O=C=Nc1ccc(C(=O)O)cc1O
Temperature: 25 °C

Procedure:
A solution of 4-amino-3-hydroxybenzoic acid (10.0 g) in 85% formic acid (60 mL) was heated at reflux for 3 h and then cooled to room temperature. The precipitated solid was filtered, washed with methanol, and dried under vacuum to produce 4-carbonylamino-3-hydroxybenzoic acid. A portion of this material (1.00 g) and zinc chloride (3.76 g) were suspended in m-xylene (135 L), and treated with 2 drops of concentrated sulfuric acid. The reaction mixture was azeotroped for 8 h, cooled to room temperature, and treated with water (20 mL). The resulting solid was collected by filtration, washed with water, and dried under high vacuum to afford benzoxazole-6-carboxylic acid. A portion of this material (0.80 g) was suspended in anhydrous dichloromethane (30 mL) under a nitrogen atmosphere and treated with oxalyl chloride (12.3 mL of a 2M solution in dichloromethane) and 1 drop of DMF. This suspension was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure. The residue was suspended in dichloromethane (20 mL) and poured into an ice-cold 2M solution of ammonia in methanol (122 mL). The mixture was stirred at 0° C. for 1 h, and concentrated under reduced pressure. The solid residue was washed with dichloromethane and water, and dried under high vacuum to afford benzoxazole-6-carboxamide. A portion of this material (80 mg) was dried by azeotropic distillation with toluene (5.3 mL) and treated with 3-chlorophenyl isocyanate (83.3 mg). The mixture was heated at reflux for 6 h, allowed to cool to room temperature, and treated with methanol (5 mL). The precipitated solid was collected by filtration, washed with methanol and dichloromethane, and dried under high vacuum to yield the title compound. 1H NMR (DMSO-d6) δ 7.18 (d, 1H, J=8.0 Hz), 7.39 (t, 1H, J=8.0 Hz), 7.49 (d, 1H, J=8.0 Hz), 7.86 (d, 1H, J=1.6 Hz), 7.97 (d, 1H, J=8.4 Hz), 8.09 (dd, 1H, J=8.4, 1.6 Hz), 8.50 (s, 1H), 8.98 (s, 1H), 10.90 (s, 1H), 11.24 (s, 1H). MS (ESI) m/z 314, 316.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][CH3:18])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=1.C(N(CC)CC)C.[I-].C[N+]1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][CH3:18])[C:13]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][CH:26]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CCCC(NS(=O)(=O)c1ccc(Cl)cc1)C(=O)O
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCC(NS(=O)(=O)c1ccc(Cl)cc1)C(=O)Nc1ccc(CC(=O)OCC)cc1
Yield: 27.7 %

Procedure:
The procedure described in Example 177 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)pentanoic acid (1 g) and ethyl 4-aminophenylacetate hydrochloride (665 mg) were condensed in chloroform (30 ml) in the presence of triethylamine (1.9 ml) and 1-methyl-2-chloropyridinium iodide (1.05 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)pentanamide (387 mg).
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H](CC1C=CC=CC=1)C(O)=O)[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C@@H:26]1[C:32](=[O:33])[N:31]2[C@H:34]([C:38]([O:40][CH3:41])=[O:39])[CH2:35][CH2:36][CH2:37][C@@H:30]2[CH2:29][CH2:28][CH2:27]1>>[CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([NH:25][C@@H:26]1[C:32](=[O:33])[N:31]2[C@H:34]([C:38]([O:40][CH3:41])=[O:39])[CH2:35][CH2:36][CH2:37][C@@H:30]2[CH2:29][CH2:28][CH2:27]1)=[O:10])[C:9]([NH:25][C@@H:26]1[C:32](=[O:33])[N:31]2[C@H:34]([C:38]([O:40][CH3:41])=[O:39])[CH2:35][CH2:36][CH2:37][C@@H:30]2[CH2:29][CH2:28][CH2:27]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@H](CC[C@H](Cc1ccccc1)C(=O)O)Cc1ccccc1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2CCC[C@H](N)C(=O)N21
Product: COC(=O)[C@@H]1CCC[C@@H]2CCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCC[C@H]4CCC[C@@H](C(=O)OC)N4C3=O)Cc3ccccc3)C(=O)N21

Procedure:
Dimethyl (4S,7S,10aS,4′S,7′S,10a′S)-7,7′-(((2R,5R)-2,5-dibenzyl-1,6-dioxo-1,6-hexanediyl)diimino)bis(6-oxodecahydropyrido[1,2-a]azepine-4-carboxylate) was synthesized as described in General Procedure F using Intermediate 3 (10 mg, 0.031 mmol) and (4S,7S,10aS)-methyl 7-amino-6-oxodecahydropyrido[1,2-a]azepine-4-carboxylate (16 mg, 0.067 mmol) to give a white solid (8.0 mg, 34% yield). Anal. Calcd. for C44H58N4O8 m/z 770.5. found: 771.5 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([O:6][CH2:7][CH2:8]P(OCC)(OCC)=O)(=[O:5])[CH3:4].[Br:17][C:18]1[N:23]=[C:22]([CH:24]=O)[CH:21]=[CH:20][CH:19]=1.C(OCC)C>C1COCC1>[Br:17][C:18]1[N:23]=[C:22]([CH:24]=[CH:4][C:3]([O:6][CH2:7][CH3:8])=[O:5])[CH:21]=[CH:20][CH:19]=1
Reactant: CCOP(=O)(CCOC(C)=O)OCC
Reactant: O=Cc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C=Cc1cccc(Br)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
In THF (10 ml) was suspended sodium hydride (60%, 440 mg, 11.0 mmol), and to the mixture was added at −30° C. a solution of diethylphosphonoethyl acetate (2.47 g, 11.0 mmol) in THF (10 ml). The mixture was stirred at the same temperature for 30 minutes, and to the mixture was added at −30° C. a solution of 6-bromo-2-pyridinecarbaldehyde (1.86 g, 10.0 mmol) in THF (10 ml). While warming the temperature of the mixture from −30° C. to −10° C., the mixture was stirred for 1.5 hours. To the mixture was added diethylether (40 ml), and the mixture was washed with water (20 ml, 5 ml×2) and saturated brine (5 ml). The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue was added hexane (10 ml), and the mixture was cooled to 0° C. The precipitated insoluble materials were filtered, which were washed with hexane cooled to 0° C., and dried under reduced pressure to give ethyl 6-bromo-2-pyridineacrylate (2.00 g, 7.81 mmol, 78%).