Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH:21]2[O:23][CH:22]2[C:24]([O-:26])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[NH4+:28]>CC(C)=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C@@H:21]2[O:23][C@H:22]2[C:24]([NH2:28])=[O:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: O=C([O-])C1OC1c1ccccc1CCCCCCCCc1ccccc1
Agent: [OH-]
Solvent: CC(C)=O
Product: NC(=O)[C@@H]1O[C@H]1c1ccccc1CCCCCCCCc1ccccc1
Temperature: 25 °C
Yield: 86 %

Procedure:
The ester of Example 5c (2R-trans)-(2-napththalenyl) 3-[2-(8-phenyloctyl)phenyl]oxiranecarboxylate (462 g, 1 mol) was dissolved in acetone (5 L) and ammonium hydroxide (1 L). After stirring briefly at room temperature the reaction mixture was heated to reflux for 20 minutes, recooled to room temperature and concentrated to 1/3 of the original volume on the rotary evaporator. The solution was diluted with toluene (10 L) and washed with 10% aq. NaOH (3×5 L), water (1×5 L) and brine (1×5 L). The toluene solution was further evaporated to a volume of 2.5 L and n-hexane (7.5 L) was added. Upon cooling in the refrigerator (~12 h), the solid was collected and dried to yield the titled oxiranecarboxamide (302 g, 86%). Mp 81°-82° C.; [α]D +13.2° (c 1, CH2Cl2, 25° C.), [α] 546 +16.1.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]([CH3:27])[CH3:26])[CH2:20][CH2:19]1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:28].[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]([CH3:27])[CH3:26])[CH2:20][CH2:19]2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45]
Reactant: CN(C)C[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Cl)nc23)CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CN(C)C[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)nc23)CC1

Procedure:
Following general procedure II, (6-chloro-4-{trans-4-[(dimethylamino)methyl]-cyclohexyl amino}-1,5-naphthyridin-3-yl)(cyclopropyl)methanone (60 mg, 0.16 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (61 mg, 0.23 mmol) followed by formation of the dihydrochloride salt to afford the desired product (54 mg, 61%) as a light yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.41 (s, 1H), 8.45 (d, J=8.9 Hz, 1H), 8.34 (d, J=8.9 Hz, 1H), 8.02 (t, J=1.9 Hz, 1H), 7.88 (dd, J=11.6, 2.2 Hz, 1H), 5.73-5.64 (m, 1H), 3.09 (d, J=6.6 Hz, 2H), 2.94 (s, 6H), 2.93-2.83 (m, 1H), 2.48-2.40 (m, 2H), 2.10-1.96 (m, 3H), 1.73-1.61 (m, 2H), 1.46-1.34 (m, 2H), 1.34-1.18 (m, 4H). ESI MS m/z 497 [M+H]+; HPLC>99% (AUC), tR=10.26 min.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:23])[CH2:20][S:21][CH3:22])=[C:15]([NH:24][CH3:25])[CH:14]=1>ClCCl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:23])[CH2:20][S:21]([CH3:22])=[O:6])=[C:15]([NH:24][CH3:25])[CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CNc1cc(F)ccc1C(=O)CSC
Solvent: ClCCl
Product: CNc1cc(F)ccc1C(=O)CS(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-chloroperoxybenzoic acid (3.49 g) in dichloromethane (80 ml) was added to a stirred solution of 1-(4-fluoro-2-methylaminophenyl)-2-(methylthio)ethanone (4.3 g), prepared in a similar manner to that described in Example 2, in dichloromethane (75 ml) under nitrogen over 15 minutes whilst maintaining the temperature below 25°. The mixture was stirred for a further 2 hours at ambient temperature. The solution was washed with saturated aqueous sodium hydrogen carbonate solution (3×50 ml) and evaporated in vacuo to give a solid product. Crystallisation from toluene gave 1-(4-fluoro-2-methylaminophenyl)-2-methylsulphinylethanone, m.p. 137°-138°.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3([N:50]4[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]4)[C:46](=[O:47])[NH:45][C:44](=[O:48])[NH:43][C:42]3=[O:49])=[CH:37][CH:36]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.[CH2:56]([CH:61]=O)[CH2:57][C:58]([OH:60])=[O:59]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]3([N:50]4[CH2:55][CH2:54][N:53]([CH2:61][CH2:56][CH2:57][C:58]([OH:60])=[O:59])[CH2:52][CH2:51]4)[C:46](=[O:47])[NH:45][C:44](=[O:48])[NH:43][C:42]3=[O:49])=[CH:39][CH:40]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1
Reactant: O=CCCC(=O)O
Reactant: Cc1cc(COc2ccc(C3(N4CCNCC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(C3(N4CCN(CCCC(=O)O)CC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Yield: 45.1 %

Procedure:
Using a procedure analogous to Example 15, the product from example 14 (100 mg, 0.125 mmol) was treated with succinic semialdehyde (76.6 mg, 6.0 eq) to provide the title barbituric acid (50.0 mg, 45%). MS found: (M+H)+=546.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[C:18]([OH:25])[CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[CH:13][N:14]=[C:8]2[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:37][CH:38]1[O:43][CH2:42][CH2:41][N:40]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:39]1)(=O)=O.O>CC(N(C)C)=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[C:18]([O:25][CH2:37][CH:38]5[O:43][CH2:42][CH2:41][N:40]([C:44]([O:46][C:47]([CH3:48])([CH3:50])[CH3:49])=[O:45])[CH2:39]5)[CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[CH:13][N:14]=[C:8]2[CH:7]=1
Reactant: COCCOc1ccn2c(-c3ccc4cccc(O)c4n3)cnc2c1
Reactant: CC(C)(C)OC(=O)N1CCOC(COS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COCCOc1ccn2c(-c3ccc4cccc(OCC5CN(C(=O)OC(C)(C)C)CCO5)c4n3)cnc2c1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-ol [prepared as in Example 3, Step C; 50 mg, 0.15 mmol] in anhydrous DMA (2 mL) was added cesium carbonate (150 mg, 0.45 mmol) followed by tert-butyl 2-((methylsulfonyloxy)methyl)morpholine-4-carboxylate (130 mg, 0.45 mmol). The heterogeneous mixture was stirred at 100° C. for 16 hours and allowed to cool. The mixture was treated with water (20 mL) and extracted with EtOAc. The combined organic phases were washed with water and brine, then dried over Na2SO4, filtered and concentrated. The residue was purified via flash column chromatography using gradient elution (CH2Cl2 to 1% MeOH/CH2Cl2 to 2% MeOH/CH2Cl2) to afford tert-butyl 2-((2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-yloxy)methyl)morpholine-4-carboxylate as a gum. This was dissolved in CH2Cl2 (4 mL) and treated with TFA (1 mL). After stirring for 2 hours at ambient temperature the mixture was concentrated. The residue was triturated with ether, filtered and dried in vacuo to provide 29.1 mg (76%) of desired product as its di-TFA salt as a powder. MS ESI (+) m/z 435.3 (M+1) detected.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5](Cl)[C:6]([CH3:12])=[N:7]2.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>CC#N.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6]([CH3:12])=[N:7]2
Reactant: Cc1nc2cccc(Br)c2nc1Cl
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1nc2cccc(Br)c2nc1-c1ccccc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 89.4 %

Procedure:
A suspension of 5-bromo-3-chloro-2-methylquinoxaline (126e; 327 mg, 1.270 mmol), phenylboronic acid (Aldrich; 155 mg, 1.270 mmol), Na2CO3 (673 mg, 6.35 mmol), and Pd(PPh3)4 (Strem Chemicals, Inc.; 73.4 mg, 0.063 mmol) in a mixture of CH3CN (9.00 mL) and water (3 mL) was stirred under argon at 80° C. for 16 h. The reaction was cooled to RT and concentrated onto silica gel. Chromatographic purification (silica gel, 0-40% EtOAc/hexanes) furnished 5-bromo-2-methyl-3-phenylquinoxaline (340.0 mg, 1.136 mmol, 89% yield) as a peach-colored solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.03 (2H, d, J=7.8 Hz), 7.77 (2H, dd, J=7.9, 1.7 Hz), 7.60 (1H, d, J=7.8 Hz), 7.48-7.57 (3H, m), 2.85 (3H, s). m/z (ESI, +ve) 298.9/300.8 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13]CC)=[O:12])=[C:5]2[CH3:16].[OH-].[K+].Cl>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[C:5]2[CH3:16]
Reactant: CCOC(=O)c1[nH]c2ccc(F)cc2c1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(C(=O)O)[nH]c2ccc(F)cc12

Procedure:
Ethyl 5-fluoro-3-methyl-1H-indole-2-carboxylate (8.3 g, 37.5 mmol) and potassium hydroxide (6.3 g, 112.5 mmol) in a mixture of ethanol (20 mL) and water (15 mL) was heated at reflux for 1 hour. The volume was reduced to 10 mL under reduced pressure and the solution brought to an acidic pH with a 3N aqueous solution of hydrochloric acid. The resulting precipitate was filtered, washed with water (100 mL) and dried in vacuo at 80° C. overnight to afford 5-fluoro-3-methyl-1H-indole-2-carboxylic acid as a white solid. MS (ES) m/z 192.0
Reaction SMILES: [F:1][CH2:2][C:3]1[CH:4]=[C:5]([N:9]2CCN(C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C(N(C(C)C)CC)(C)C.[N:31]1([C:36](=[NH:38])[NH2:37])[CH:35]=[CH:34]C=N1>Cl.O1CCOCC1>[F:1][CH2:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:34][CH2:35][N:31]([C:36](=[NH:38])[NH2:37])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(CF)c2)CC1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N=C(N)N1CCN(c2cccc(CF)c2)CC1
Temperature: 25 °C

Procedure:
Tert-butyl 4-(3-(fluoromethyl)phenyl)piperazine-1-carboxylate (201.3 mg, mmol) was dissolved in a 4.0 M solution of HCl and dioxane (2 mL) and stirred at room temperature. After 45 min. the reaction mixture was concentrated and re-dissolved in ACN (2 mL). Diisopropylethylamine (22 μL, 1.51 mmol) and 1H-pyrazole-1-carboximidamide (110 mg, 0.75 mmol) were added to the stirring reaction mixture. The next day, the reaction mixture was concentrated to yield a crude oil, which was purified by HPLC using a Phenomenex Luna C-18 (2) column (10 250×21.2 mm, gradient method 0-100% B over 14 min., where B=90% ACN in water using 0.1% TFA as a modifier and A=water using 0.1% TFA as a modifier) with a flow rate of 20 ml/min to isolate 4-(3-(fluoromethyl)phenyl)piperazine-1-carboximidamide as a white solid (42.7 mg, 23% isolated yield over 4 steps). 1H NMR (300 MHz, DMSO-d6): δ 7.58 (br s, 3H), 7.28 (t, 1H, J=7.8 Hz), 7.01 (br s, 1H), 6.98 (br s, 1H), 6.87 (d, 1H, J=7.3 Hz), 5.35 (d, 2H, J=47.9 Hz), 3.58 (dd, 4H, J=5.4, 4.9 Hz), 3.26 (dd, 4H, J=5.4, 4.8 Hz); 13C NMR (75.5 MHz, DMSO-d6): δ 156.1, 150.3, 137.1 (136.8), 129.2, 118.8 (118.7), 115.9, 114.9 (114.8), 84.6 (83.4), 47.2, 44.7; HRMS calcd for C12H17FN4: 237.15100 found 237.1514.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].F[C:19](F)(F)[O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:20][CH3:19])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2cc(Br)ccc2sc1=O
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: COC(=O)c1c(O)c2cc(-c3ccccc3OC)ccc2sc1=O

Procedure:
4-Hydroxy-6-(2-methoxy-phenyl)-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 6-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester under conditions analogous to Example 7(a) using 4-trifluoromethoxy-phenylboronic acid. 1H NMR (200 MHz, CDCl3): δ (ppm)=8.534 (s, 1H), 7.782 (d, 1H), 7.639 (d, 2H), 7.444 (d, 1H), 7.320 (d, 2H), 4.026 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][C:9]1([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][O:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:33]4=[N:40][N:41]=[C:42]([C:43]5[CH:47]=[C:46]([CH3:48])[O:45][N:44]=5)[N:32]4[N:31]=3)=[CH:24][N:23]=2)[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1>C(Cl)Cl>[CH3:48][C:46]1[O:45][N:44]=[C:43]([C:42]2[N:32]3[N:31]=[C:30]([O:29][CH2:28][C:25]4[CH:26]=[CH:27][C:22]([C:9]5([OH:8])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]5)=[N:23][CH:24]=4)[C:39]4[C:34]([C:33]3=[N:40][N:41]=2)=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:47]=1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccc(C5(O)CCN(C(=O)OC(C)(C)C)CC5)nc4)nn23)no1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccc(C5(O)CCNCC5)nc4)nn23)no1
Reaction time: 6 h
Yield: 62.1 %

Procedure:
Trifluoroacetic acid (3 ml) was added to a stirred solution of 1,1-dimethylethyl 4-hydroxy-4-[5-({[3-(5-methylisoxazol-3-yl){1,2,4]triazolo[3,4-α]phthalazin-6-yl]oxy}methyl)pyridin-2-yl]-1-piperidine carboxylate(707 mg, 1.27 mmol) in CH2Cl2 (30 ml) at room temperature and the reaction stirred for 6 h. The reaction mixture was concentrated under reduced pressure, 2N NaOH solution (30 ml) was added and the resulting precipitate was filtered off. After dissolving in MeOH/CH2Cl2 (60 ml) and dry loading onto alumina, the crude residue was purified by column chromatography on alumina using 5-7% MeOH/CH2Cl2 containing 1% NH3 to yield the desired phthalazine (361 mg, 62%). 1H NMR (360 MHz, d6-DMSO) δ 8.80 (1H, s), 8.55 (1H, d, J=7.1 Hz), 8.23 (1H, d, J=7.1 Hz), 8.15-8.03 (2H, m), 7.93 (1H, t, J=7.1 Hz), 7.71 (1H, d, J=7.4 Hz), 7.07 (1H, s), 5.67 (2H, s), 5.06 (2H, s), 2.91 (2H, t, J=11.2 Hz), 2.74 (2H, d, J=11.2 Hz), 2.60 (3H, s), 2.04 (2H, td, J=12.4, 4.0 Hz), 1.44 (2H, d, J=12.4 Hz). m/z (ES+) 458 (M+H+).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([OH:15])[C:8](=[CH:13][CH:14]=1)[C:9]([O:11][CH3:12])=[O:10]>C(Cl)Cl>[Br:1][C:14]1[CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]([OH:15])=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: COC(=O)c1ccc(OC)cc1O
Reactant: BrBr
Solvent: ClCCl
Product: COC(=O)c1cc(Br)c(OC)cc1O
Reaction time: 5 h
Yield: 97 %

Procedure:
A solution of 9.0 g (56.5 mmol) of bromine in 5 ml of CH2Cl2 is added dropwise to a 0° C. solution of 10.0 g (54.9 mmol) of methyl 4-methoxysalicylate in 90 ml of CH2Cl2. The reaction is stirred at 0° C. to 25° C. over five hours and then concentrated in vacuo to give 13.9 g of methyl 5-bromo-4-methoxysalicylate as a white solid: mp 141°-143° C.) (lit mp 143°-144° C.), Cresp, T. M.; Sargent, M. V.; Elix, J. A.; Murphy, D. P. H., J. Chem. Soc., Perkin Trans., 1, 1973, 340). The material is sufficiently pure to be used in the subsequent reaction.
Reaction SMILES: [N+](=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[N-].[S:13]1[C@H:24]2[CH2:25][C@@H:26]([OH:37])[C@H:27](/[CH:28]=[CH:29]/[C@@H:30]([OH:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C@H:23]2[CH2:22][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20].CO>C(Cl)Cl>[CH2:3]([O:21][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[S:13][C@H:24]2[CH2:25][C@@H:26]([OH:37])[C@H:27](/[CH:28]=[CH:29]/[C@@H:30]([OH:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C@H:23]2[CH2:22]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCC=[N+]=[N-]
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2CC(CCCCC(=O)O)S[C@H]2C[C@H]1O
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCCCCOC(=O)CCCCC1C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]2S1

Procedure:
An ethereal solution of diazodecane was added dropwise to a solution of 100 mg of (13E)-(6RS,9α,11α,15S)-6,9-epithio-11,15-dihydroxyprost-13-enoic acid (prepared as described in Example 2) in 5 ml of methylene chloride at room temperature with stirring until the starting material was not detected by thin layer chromatography on silica gel using a 2% v/v solution of methanol in ethyl acetate as developing solvent. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (1:1) as eluent to give 109 mg of the title compound having the following physical characteristics:
Reaction SMILES: C1(C[O:8][C@@H:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[NH:14][C:15]2[N:23]=[CH:22][N:21]=[C:20]3[C:16]=2[N:17]=[CH:18][N:19]3[CH:24]2[C@H:28]([OH:29])[C@H:27]([OH:30])[C@@H:26]([CH2:31][Cl:32])[O:25]2)C=CC=CC=1>C(O)C.C1CCCCC1.[OH-].[Pd+2].[OH-]>[OH:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH:24]1[C@H:28]([OH:29])[C@H:27]([OH:30])[C@@H:26]([CH2:31][Cl:32])[O:25]1
Reactant: O[C@@H]1[C@@H](CCl)OC(n2cnc3c(N[C@@H]4CCC[C@H]4OCc4ccccc4)ncnc32)[C@@H]1O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCCCC1
Product: O[C@@H]1[C@@H](CCl)OC(n2cnc3c(N[C@@H]4CCC[C@H]4O)ncnc32)[C@@H]1O
Reaction time: 6 h

Procedure:
The 2-(6-{[(1R,2R)-2-(phenylmethoxy)cyclopentyl]amino}purin-9-yl)(4S,5S,3R)-5-(chloromethyl)oxolane-3,4-diol obtained in Example 11 (22 g) was dissolved in ethanol (450 mL) and cyclohexane (200 mL). To this solution was added palladium hydroxide (20 mole %, 1 gram added initially, 1 gram after 6 hours, and 1 gram after 14 hours), and the reaction mixture was refluxed for 18 hours. The reaction mixture was filtered thru celite while still hot, and solvent removed from the filtrate under reduced pressure. The product was triturated with ethanol (20 mL), filtered, and washed with ethanol, to afford 2-{6-[((1R,2R)-2-hydroxycyclopentyl)amino]purin-9-yl}(4S,5S,3R)-5-(chloromethyl)oxolane-3,4-diol as a white powder).
Reaction SMILES: O.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([N+:10]([O-])=O)=[CH:5][C:4]=1[C:13]1[C:14](=[O:24])[N:15]([CH3:23])[C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:18]=1>C(O)(=O)C.[Fe]>[NH2:10][C:6]1[C:7]([Cl:9])=[CH:8][C:3]([Cl:2])=[C:4]([C:13]2[C:14](=[O:24])[N:15]([CH3:23])[C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:18]=2)[CH:5]=1
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc([N+](=O)[O-])c(Cl)cc2Cl)c1=O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(C(F)(F)F)cnc(-c2cc(N)c(Cl)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
Then, 0.59 g of iron powder was added to a mixture of 5.3 ml of acetic acid and 3.2 ml of water, to which a solution of 0.65 g of 3-(2,4-dichloro-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-333) in 1.6 ml of acetic acid was slowly added dropwise, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was poured into ice water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium hydrogencarbonate solution, water, and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated, which afforded 0.49 g (yield, 82%) of 3-(5-amino-2,4-dichlorophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-334; m.p., 188.7° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)N(C2CC2)CCC3(C)C)=[CH:7][CH:6]=1)[CH3:2].[CH2:29]([O:31][C:32](=O)[C:33]1[CH:38]=CC(I)=CC=1)C>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:29][O:31][C:32]1([C:20]2[CH:15]=[CH:14][C:13]([C:12]#[C:11][C:8]3[CH:9]=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:28])=[CH:6][CH:7]=3)=[CH:22][CH:21]=2)[CH2:33][CH2:38]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCN3C2CC2)cc1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OC)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-methoxycyclopropyl)benzene (Intermediate 61, 100.0 mg, 0.47 mmol) and ethyl-4-iodo benzoate (Reagent A, 141.0 mg, 0.51 mmol) in triethyl amine (6 mL) was treated with copper(I)iodide (30.0 mg, 0.16 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (109 mg, 0.16 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-5% EtOAc-hexanes) afforded 135.0 mg (90%) of the title compound as an orange solid.
Reaction SMILES: CN(C)CCN(C)C.Br[C:10]1[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][CH:11]=1.[F:18][C:19]1[CH:43]=[CH:42][C:22]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([N:31]3[C:39]4[C:34](=[CH:35][CH:36]=[C:37]([CH:40]=[O:41])[CH:38]=4)[CH2:33][CH2:32]3)[CH2:27][CH2:26]2)=[CH:21][CH:20]=1>C(OCC)C>[F:18][C:19]1[CH:43]=[CH:42][C:22]([CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][CH:28]([N:31]3[C:39]4[C:34](=[CH:35][CH:36]=[C:37]([CH:40]([OH:41])[C:10]5[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][CH:11]=5)[CH:38]=4)[CH2:33][CH2:32]3)[CH2:29][CH2:30]2)=[CH:21][CH:20]=1
Reactant: O=Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Reactant: COc1cccc(Br)n1
Agent: CN(C)CCN(C)C
Solvent: CCOCC
Product: COc1cccc(C(O)c2ccc3c(c2)N(C2CCN(CCc4ccc(F)cc4)CC2)CC3)n1
Yield: 76.5 %

Procedure:
Tetramethylethylenediamine (0.26 ml) was added to 6-bromo-2-methoxypyridine (0.32 g) synthesized in accordance with the method described in Tetrahedron, 1373 (1985). and 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-formylindoline (0.4 g) and diethyl ether was employed as the solvent. The resultant mixture was treated as in Example 93 to give the title compound (0.401 g) as colorless crystals (yield: 76.5%).
Reaction SMILES: [C:1]1([S:7]([C:10]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=2)=[C:11](Cl)Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][NH2:24]>O1CCCC1>[C:1]1([S:7]([C:10]2[N:14]=[C:15]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[O:22][C:11]=2[CH2:23][NH2:24])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NC(=C(Cl)Cl)S(=O)(=O)c1ccccc1)c1cccnc1
Reactant: CN
Solvent: C1CCOC1
Product: NCc1oc(-c2cccnc2)nc1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(1-Phenylsulfonyl-2,2-dichlorovinyl)nicotinamide (0.4 g, 1.120 mmol) is dissolved in tetrahydrofuran, mixed with methylamine (2.607 ml, 2M in tetrahydrofuran, 4.480 mmol) and stirred overnight at room temperature. The resulting precipitate was filtered off with suction and discarded, the mother liquor was concentrated in a rotary evaporator and the residue was crystallized using a small amount of isopropanol, filtered off with suction and dried in air.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:14])=O>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:14])=[O:11])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccc(I)cc1
Product: O=C(Cl)Cc1ccc(I)cc1
Temperature: 100 °C

Procedure:
Under an argon atmosphere, to 4-iodophenylacetic acid (11) (prepared by the process described in Chen, Q.-H. et al., Bioorg. Med. Chem., 14, 7898-7909 (2006)) (1.06 g, 4.05 mmol) was added thionyl chloride (5.00 mL, 68.6 mmol) and heated to reflux (100° C.) for 1.5 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to give 4-iodophenylacetyl chloride (12) as a brown oily crude product.