Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[CH2:12]([NH:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: NCCOCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(CNCCOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.7 %

Procedure:
2-(Benzyloxy)ethanamine (12.3146 g; manufactured by Bionet Co., Ltd.) was dissolved in CH2Cl2 (150 mL), and benzaldehyde (8.7219 g; manufactured by Kanto Chemical Co., Inc.) and anhydrous sodium sulfate (67.7879 g; manufactured by Wako Pure Chemical Industries, Ltd.) were added to the solution. The mixture was stirred overnight at room temperature. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in methanol (150 mL), and sodium borohydride (3.4129 g; manufactured by Kanto Chemical Co., Inc.) was added thereto. The mixture as stirred for 2 hours at room temperature. The reaction solution was concentrated under reduced pressure, water added thereto, and then the mixture was extracted two times with ethyl acetate. The organic layer was washed twice with water and once with brine, and was dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and thus the title compound (20.188 g) was obtained.
Reaction SMILES: [N:1]1([CH2:6][C@H:7]2[CH2:12][CH2:11][C@H:10]([NH:13]C(=O)OC(C)(C)C)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:21].O>C1COCC1>[ClH:21].[ClH:21].[N:1]1([CH2:6][C@H:7]2[CH2:8][CH2:9][C@H:10]([NH2:13])[CH2:11][CH2:12]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CN2CCCC2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: N[C@H]1CC[C@H](CN2CCCC2)CC1
Temperature: 65 °C

Procedure:
To a solution of tert-butyl (trans-4-(pyrrolidin-1-ylmethyl)cyclohexyl)carbamate (1.3 g, 4.5 mmol) in THF (15 mL) was added aqueous 6 N HCl (6 mL) and water (6 mL) and the reaction mixture was stirred with heat at 65° C. for 3 h. The reaction mixture was cooled to room temperature and concentrated to afford the desired product (1.2 g, >99%) as an off-white solid. ESI MS m/z 183 [C11H22FN2+H]+
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[C@H:8]2[CH2:9][O:10][CH2:11][C@H:7]2[O:6][N:5]=1>FC(F)(F)C(O)=O.O>[O:6]1[C@@H:7]2[CH2:11][O:10][CH2:9][C@@H:8]2[C:4]([CH:3]=[O:2])=[N:5]1
Reactant: COC(OC)C1=NO[C@@H]2COC[C@H]12
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=CC1=NO[C@@H]2COC[C@H]12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
A solution of (3aS,6aS)-rel-3-dimethoxymethyl-3a,4,6,6a-tetrahydro-furo[3,4-d]isoxazole (35.3 mmol) in trifluoroacetic acid (30 ml) was treated with water (1.3 ml). The mixture was stirred at room temperature for 30 minutes. For the workup, the reaction mixture was diluted with water (100 ml) and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulphate and evaporated. The crude product was purified by chromatography on silica gel using a 5:1-mixture of dichloromethane and heptane as the eluent. The (3aS,6aS)-rel-3a,4,6,6a-tetrahydro-furo[3,4-d]isoxazole-3-carbaldehyde (4.79 g, 96% yield) was obtained as a yellow oil. MS: m/z=144.0 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([O:16][C:17]([C:19]1[O:20][C:21]2[C:27](Br)=[CH:26][CH:25]=[CH:24][C:22]=2[CH:23]=1)=[O:18])[CH3:15]>>[CH2:14]([O:16][C:17]([C:19]1[O:20][C:21]2[C:27]([N:11]3[CH2:12][CH2:13][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:9][CH2:10]3)=[CH:26][CH:25]=[CH:24][C:22]=2[CH:23]=1)=[O:18])[CH3:15]
Reactant: CCOC(=O)c1cc2cccc(Br)c2o1
Reactant: c1ccc(CN2CCNCC2)cc1
Product: CCOC(=O)c1cc2cccc(N3CCN(Cc4ccccc4)CC3)c2o1

Procedure:
The compound was prepared according to the procedure disclosed in Example 1a starting from benzylpiperazine (16.1 mL, 92.6 mmol) and 7-bromo-benzofuran-2-carboxylic acid ethyl ester (16.6 g, 61.7 mmol). The product was purified by flash chromatography (SiO2; hexane/EtOAc, gradient 0-50%). Yield: 14 g (63%).
Reaction SMILES: Cl[CH:2]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH2:12][CH3:13].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=1>>[CH:14]1([CH:2]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=2)[C:3]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[O:5][C:4]=2[CH2:12][CH3:13])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: CCc1oc2ccccc2c1C(Cl)C1CCCCC1
Product: CCc1oc2ccccc2c1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Yield: 77.3 %

Procedure:
Using 3-[chloro(cyclohexyl)methyl]-2-ethyl-1-benzofuran (300 mg) synthesized in Example A26(2) and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (255 mg) synthesized in Example 1(2) and in the same manner as in Example A22(4), the title object compound (374 mg, 77%) was obtained as a pale-brown solid.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.[CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[CH2:20].CCN(C(C)C)C(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1/[CH:19]=[CH:20]/[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1
Reactant: O=Cc1ccc2c(I)nn(C3CCCCO3)c2c1
Reactant: C=Cc1ccccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=Cc1ccc2c(/C=C/c3ccccn3)nn(C3CCCCO3)c2c1
Temperature: 100 °C
Yield: 75.8 %

Procedure:
In a scintillation vial a solution of 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-carbaldehyde (24 mg, 0.0673 mmol), 2-vinylpyridine (9.4 uL, 0.0875 mmol), DIPEA (24 uL, 0.135 mmol) and DMF (1.0 mL) was purged with Ar for 20 min. Pd(OAc)2 (1.5 mg, 0.0067 mmol) and P(o-tolyl)3 (6.1 mg, 0.0202 mmol) were then added and the vial was capped and heated to 100° C. overnight. The solution was cooled to room temperature and extracted with EtOAc, washing with NH4Cl(sat.), H2O, and brine. The organic layer was dried over MgSO4, the solvent removed in vacuo, and the residue purified by column chromatography (silica gel, 96:4 CH2Cl2/MeOH) to give 17 mg, 77% of a yellow oil which was 70% pure by NMR. This crude material was used for the subsequent synthetic step. 1H NMR (400 MHz, CD3OD) δ 10.16 (s, 1H), 8.59 (s, 1H), 8.34 (s, 1H), 8.27 (d, J=8.4 Hz, 1H), 7.95-7.83 (m, 4H), 7.75 (m, 1H), 7.68 (d, J=16.0 Hz, 1H), 6.00 (d, J=9.6 Hz, 1H), 4.05-4.01 (m, 1H), 3.93-3.86 (m, 1H), 2.65-2.56 (m, 1H), 2.27-2.10 (m, 2H), 1.92-1.66 (m, 3H); MS ESI 334.1 [M+H]+, calcd for [C20H19N3O2+H]+ 334.16.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C@H:17]3[C@@H:24]4[C@@H:20]([CH2:21][NH:22][CH2:23]4)[CH2:19][CH2:18]3)[CH:11]=2)=[CH:6][CH:5]=1)[CH3:2].C(N(CC)C(C)C)(C)C.[C:34](=O)([O:42]C1C=CC([N+]([O-])=O)=CC=1)[O:35][CH2:36][C:37]1[N:38]=[CH:39][S:40][CH:41]=1.C1CCCCC1>C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C@H:17]3[C@@H:24]4[C@@H:20]([CH2:21][N:22]([C:34]([O:35][CH2:36][C:37]5[N:38]=[CH:39][S:40][CH:41]=5)=[O:42])[CH2:23]4)[CH2:19][CH2:18]3)[CH:11]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(-c2cccc(O[C@@H]3CC[C@@H]4CNC[C@@H]43)c2)cc1
Reactant: O=C(OCc1cscn1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCCCC1
Product: CCOc1ccc(-c2cccc(O[C@@H]3CC[C@@H]4CN(C(=O)OCc5cscn5)C[C@@H]43)c2)cc1
Yield: 62.3 %

Procedure:
The process is performed according to the procedure described in Example 1, step 1.3. Starting with 0.053 g (0.19 mmol) of (3aR,4R,6aS)-4-[(4′-ethoxybiphenyl-3-yl)oxy]octahydrocyclopenta[c]pyrrole, obtained in step 14.3., 0.04 mL (0.23 mmol) of N,N-diisopropylethylamine and 0.068 g (0.21 mmol) of thiazol-4-ylmethyl 4-nitrophenyl carbonate (WO 2008/013 834), and after chromatography on silica gel, eluting with a 95/5 and then a 90/10 mixture of cyclohexane and ethyl acetate, 0.055 g (63%) of expected product is obtained in the form of an oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][NH:5][CH:6]=1.N12CCCN=C1CCCCC2.[C:23]([CH:25]=[C:26]1[CH2:29][N:28]([C:30]2[C:44]([F:45])=[CH:43][C:33]([C:34]([NH:36][C@@H:37]([CH3:42])[C:38]([F:41])([F:40])[F:39])=[O:35])=[C:32]([F:46])[CH:31]=2)[CH2:27]1)#[N:24]>C(O)(C)C>[Br:1][C:2]1[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][N:5]([C:26]2([CH2:25][C:23]#[N:24])[CH2:29][N:28]([C:30]3[CH:31]=[C:32]([F:46])[C:33]([C:34]([NH:36][C@@H:37]([CH3:42])[C:38]([F:39])([F:41])[F:40])=[O:35])=[CH:43][C:44]=3[F:45])[CH2:27]2)[CH:6]=1
Reactant: CCOC(=O)c1n[nH]cc1Br
Reactant: C[C@H](NC(=O)c1cc(F)c(N2CC(=CC#N)C2)cc1F)C(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)O
Product: CCOC(=O)c1nn(C2(CC#N)CN(c3cc(F)c(C(=O)N[C@@H](C)C(F)(F)F)cc3F)C2)cc1Br
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a microwave vial was added isopropyl alcohol (10 mL), ethyl 4-bromo-1H-pyrazole-3-carboxylate (from ChemBridge) (788 mg, 3.60 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (48.9 μL, 0.327 mmol) and 4-[3-(cyanomethylene)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide (from Example 4 step 4, 1.13 g, 3.27 mmol). The reaction mixture was stirred at 80° C. for 2 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was purified with flash chromatography (eluting with 0-35% ethyl acetate in hexanes) to give the desired product as white foam. 1H NMR (500 MHz, DMSO) δ 8.61 (s, 1H), 8.47 (d, J=8.7 Hz, 1H), 7.34 (dd, J=12.5 and 6.3 Hz, 1H), 6.62 (dd, J=11.9 and 7.3 Hz, 1H), 4.76 (dt, J=15.5 and 7.8 Hz, 1H), 4.61 (d, J=9.2 Hz, 2H), 4.39 (d, J=8.0 Hz, 2H), 4.32 (q, J=7.1 Hz, 2H), 3.68 (s, 2H), 1.31 (m, 6H) ppm. LCMS calculated for C21H20BrF5N5O3 (M+H)+: m/z=564.1. Found: 563.8.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][CH2:8][N:9]1[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]1=[O:11])(=O)C.O(C)[Na].Cl>CO>[OH:4][CH2:5][CH2:6][O:7][CH2:8][N:9]1[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]1=[O:11]
Reactant: CC(=O)OCCOCn1cc(C)c(=O)[nH]c1=O
Agent: CO[Na]
Agent: Cl
Solvent: CO
Product: Cc1cn(COCCO)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of 1-[(2-acetoxyethoxy)methyl]thymine (4 g, 16 mmol) in CH3OH (100 mL) was added NaOCH3 in CH3OH (20 mL, 1N). After 2 hours of stirring at room temperature, 1N HCl was added to adjust the pH to 4.0. Methanol and water were removed under vacuum to obtain a solid. The solid was dissolved in CH3OH and crystallized by dropwise addition of CHCl3; it was used in the next reaction without further purification. Yield 76%; Wt. 2.5 g; mp 154°-156° C.; 1H NMR (DMSO-d6) 1.75 (s, CH3 C5 thymine), 3.55-3.75 (A2B2 pattern, O CH2 CH2 O), 5.10 (s, O CH2 N), 7.55 (s, H C6 thymine), 11.3 (s, HN thymine).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:7].C1COCC1.[Cl-].[NH4+].O>CO.[Zn]>[CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:7]
Reactant: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=S)C1(CCCCS(C)(=O)=O)CCCC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=S)C1(CCCCS(C)(=O)=O)CCCC1
Reaction time: 1 h
Yield: 98.4 %

Procedure:
The poorly soluble N-[[1-[4-(methylsulfonyl)butyl]cyclopentyl]thioxomethyl]-4-nitro-L-phenylalanine methyl ester (19.3 mmol, 9.07 g) was dissolved in methanol (150 mL) and THF (20 mL) by gentle heating with a heat gun. To this solution, zinc dust (325 mesh, 193 mmol, 12.62 g, 10 equiv.) and ammonium chloride (289.5 mmol, 15.5 g, 15 equiv.) were added followed by water (75 mL) at room temperature. After the addition of water, an exothermic reaction ensued and the temperature rose to 45 to 50° C. The suspension was stirred for 1 h, at which time TLC analysis of the mixture indicated the absence of starting material. The reaction mixture was filtered and the filter cake was washed with methanol (200 mL) and THF (100 mL). The volatiles were removed under vacuum and the organic residue was extracted into ethyl acetate (2×200 mL). The combined extracts were washed brine (250 mL) then were dried (MgSO4), filtered and evaporated to dryness to give 8.37 g (98%) of 4-amino-N-[[1-[4-(methylsulfonyl)butyl]cyclopentyl]thioxomethyl]-L-phenylalanine methyl ester as a colorless gum which was used directly for next step. HRMS: Obs. mass, 441.1884. Calcd. mass, 441.1882 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:20]([CH3:21])=[C:19]([N+:22]([O-:24])=[O:23])[CH:18]=[C:17]([Br:25])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=[O:11].[CH3:26][Al](C)C.C1(C)C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[C:20]([CH3:21])=[C:19]([N+:22]([O-:24])=[O:23])[CH:18]=[C:17]([Br:25])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:14]([CH3:15])[CH3:16])[C:8]([OH:13])=[C:9]([CH:10]([OH:11])[CH3:26])[CH:12]=1
Reactant: C[Al](C)C
Reactant: Cc1c([N+](=O)[O-])cc(Br)c(Oc2cc(C=O)c(O)c(C(C)C)c2)c1Br
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1c([N+](=O)[O-])cc(Br)c(Oc2cc(C(C)C)c(O)c(C(C)O)c2)c1Br
Temperature: 4 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
5-(2,6-Dibromo-3-methyl-4-nitrophenoxy)-2-hydroxy-3-isopropylbenzaldehyde of Part 8D (210 mg, 0.44 mmol) was dissolved in CH2Cl2 (5 mL) and cooled to 4° C. Me3Al in toluene (0.355 mL, 0.67 mmol, 2N) was added to the mixture and the reaction was stirred for 16 hours at room temperature. The reaction mixture was quenched with ice water and extracted with EtOAc. The organic phase was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Filtration through a pad of silica gave 195 mg (93%) of 4-(2,6-dibromo-3-methyl-4-nitrophenoxy)-2-(1-hydroxyethyl)-6-isopropylphenol as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:26]=[CH:25][C:16]([O:17][CH2:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:15]([CH3:27])[CH:14]=2)([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:28].[Cl:29][CH2:30][CH2:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>>[CH3:21][C:20]([CH3:22])([CH3:23])[C:19](=[O:24])[CH2:18][O:17][C:16]1[CH:25]=[CH:26][C:13]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:32]([CH2:31][CH2:30][Cl:29])(=[O:34])=[O:33])=[C:3]([CH3:28])[CH:4]=2)([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:14][C:15]=1[CH3:27]
Reactant: CCC(CC)(c1ccc(N)c(C)c1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Reactant: O=S(=O)(Cl)CCCl
Solvent: CCN(CC)CC
Product: CCC(CC)(c1ccc(NS(=O)(=O)CCCl)c(C)c1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Yield: 98.4 %

Procedure:
Using a procedure analogous to Example 17, 1-{4-[1-(4-amino-3-methyl-phenyl)-1-ethyl-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-one (382 mg, 1 mmol), 2-chloro-ethanesulfonyl chloride (0.1 mL, 1 mmol) and triethylamine (0.14 mL, 1 mmol) give the title compound as a oil (500 mg, quant.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])=[O:10])=[CH:4][CH:3]=1.[Br:19]Br.ClCCl>C1C=CC=CC=1>[Br:19][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])=[O:10]
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Reactant: BrBr
Solvent: ClCCl
Solvent: c1ccccc1
Product: O=C(c1ccc(Cl)cc1Cl)C(Br)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.7 %

Procedure:
Part B: To a solution of 2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)ethanone (2.82 gram, 9.42 mmol) in benzene (25 mL) is added bromine (0.48 mL, 1.49 gram, 9.31 mmol) and the resulting solution is stirred at room temperature for two hours. Dichloromethane is added and the resulting solution is washed with aqueous NaHCO3 solution. The organic layer is dried over MgSO4, filtered and evaporated in vacuo to give 3.55 gram (quantitative yield) of 2-bromo-2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)ethanone as a yellow oil (purity˜95% according to HPLC analysis). 1H-NMR (200 MHz, CDCl3): δ 7.00-7.50 (m, 7H), 6.16 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][CH2:6][CH:7](Br)[CH:8]1[O:37][C@H:11]2[CH2:12][C@@H:13]([O:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[C@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:10]2[CH2:9]1.C1CCN2C(=NCCC2)CC1.Cl.[OH2:52]>>[CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:52])[CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[CH2:12][C@@H:11]1[OH:37]
Reactant: CCCCC[C@@H](/C=C/[C@@H]1[C@H]2CC(C(Br)CCCC(=O)OC)O[C@H]2C[C@H]1OC1CCCCO1)OC1CCCCO1
Reactant: O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCC[C@@H](/C=C/[C@@H]1[C@@H](CC(=O)CCCCC(=O)OC)[C@@H](O)C[C@H]1OC1CCCCO1)OC1CCCCO1
Temperature: 0 °C

Procedure:
Under an atmosphere of nitrogen, a solution of 970 mg of (13E)-(5RS,6RS,9α,11α,15S)-5-bromo-6,9-epoxy-11,15-bis(tetrahydropyran-2-yloxy)prost-13-enoic acid methyl ester (prepared as described in Reference Example 1) and 2 ml of DBU was stirred at room temperature overnight, and then cooled to 0° C. 6 ml of water was added to the reaction mixture, which was then acidified to pH 1 with 1 N hydrochloric acid at 0° C., and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure to give the crude title compound having the following physical characteristic:
Reaction SMILES: [CH2:1]([N:5]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]#[N:32])=[CH:21][CH:20]=1)[C:6](=[O:17])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([OH:16])=[O:15])[CH2:2][CH2:3][CH3:4].C([Sn]([N:46]=[N+:47]=[N-:48])(CCCC)CCCC)CCC.[OH-].[Na+].C(Cl)Cl.CO>C1(C)C(C)=CC=CC=1>[CH2:1]([N:5]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[NH:48][N:47]=[N:46][N:32]=2)=[CH:23][CH:24]=1)[C:6](=[O:17])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([OH:16])=[O:15])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CCCCN(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)Cc1ccccc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: Cc1ccccc1C
Product: CCCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)Cc1ccccc1C(=O)O

Procedure:
A solution of 2.50 g of 2-carboxy-phenylacetic acid N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amide and 6.50 g of tributyltin azide in 50 ml of xylene is heated under reflux for 15 hours. When cool, the mixture is stirred with 50 ml of 2N sodium hydroxide solution at room temperature for 30 minutes. The aqueous phase is acidified and extracted three times with 50 ml of CH2C2 each time. After customary treatment, the combined dichloromethane phases yield a crude product that, after chromatography on silica gel 60 (40-63 μm) using CH2Cl2 /CH3OH (97:3)) as eluant, yields 2-carboxy-phenylacetic acid N-butyl-N-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amide that has an Rf value of 0.37 [CH2Cl2 /CH3OH (4:1)]. ##STR11##
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O.Cl.[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[Cl:5][C:6]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:7]=1[C:8]([C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:7]=1)=[O:10]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C(c1ccccc1)c1ccc([N+](=O)[O-])cc1Cl
Temperature: 80 °C

Procedure:
Thionyl chloride (35.8 grams, 0.305 mole) was added to a benzene solution of 2-chloro-4-nitrobenzoic acid (60.3 grams, 0.3 mole) and the mixture heated to reflux during 5 hours until the evolution of hydrogen chloride had ceased. Aluminum chloride (100 grams, 0.72 mole) was added slowly to the stirred solution during a 3.5 hour period and the temperature rose to 48° C. After the addition, the mixture was warmed to 80° C. for 2 hours, cooled, poured onto ice-water (one liter), concentrated hydrochloric acid (90 ml.) added and the mixture warmed at 40° C. for 3 hours. Benzene extraction followed by successive treatment with 5% aqueous sodium hydroxide, water and calcium chloride yielded, after removal of benzene, a reddish black residue purified by filtration. The pale yellow solid so obtained was further characterized as having a melting point equal to 95.5° - 96.5° C. in 44% yields.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24](=S)[NH:23][CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:36](O)[CH3:37]>[Ni]>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[CH2:24][N:23]([CH2:36][CH3:37])[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=S)NCC4)cc2)CCC1
Reactant: CCO
Agent: [Ni]
Product: CCN1CCc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2C1
Temperature: 25 °C
Yield: 74 %

Procedure:
To a solution of tert-butyl(1-(4-(3-phenyl-5-thioxo-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)phenyl)cyclobutyl)carbamate (41 mg, 0.08 mmol) in dry ethanol (1 mL) was added Raney Nickel (1 mL) under nitrogen. The resulting mixture was heated under reflux for 4 h. After cooled down to room temperature, the mixture was filtered on celite (rinse few times with ethanol) and concentrated to dryness under reduced pressure to give the title compound (28 mg, 74%). 1H NMR (500 MHz, CDCl3): 7.29 (1H, s), 7.22-7.18 (4H, m), 7.15-7.14 (3H, m), 7.07-7.06 (2H, m), 4.98 (1H, br s), 3.64 (2H, S), 3.09 (2H, t), 2.83 (2H, t), 2.58 (2H, q), 2.50-2.20 (4H, m), 2.00-1.91 (1H, m), 1.74-1.66 (1H, m), 1.40-1.10 (9H, br), 1.15 (3H, t).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[CH:6]1[CH2:10][CH:9]=[CH:8]C=1.[CH2:11](OCC)C>>[CH:3]12[CH2:11][CH:10]([CH:9]=[CH:8]1)[CH2:6][CH:2]2[C:1]([OH:5])=[O:4]
Reactant: C=CC(=O)O
Reactant: CCOCC
Reactant: C1=CCC=C1
Product: O=C(O)C1CC2C=CC1C2
Yield: 82 %

Procedure:
49.5 g of acrylic acid was added to 49.9 g of cyclopentadiene and 40 ml of diethyl ether, and a reaction was allowed to react at room temperature for 2 hr with stirring. After the completion of the reaction, the reaction mixture was concentrated and purified by distillation to give 78.0 g (yield: 82%) of an intended product.