Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.[CH3:19][C:20]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22].[C:28]([O:32][C:33]([N:35]1[CH2:48][CH2:47][C@@H:46]2[C@@H:38]([N:39]([CH2:51][C:52](O)=[O:53])[C:40]3[CH:41]=[CH:42][C:43]([Cl:50])=[C:44]([Cl:49])[C:45]=32)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>C1COCC1>[Cl:50][C:43]1[CH:42]=[CH:41][C:40]2[N:39]([CH2:51][C:52]([NH:22][C:21]3[CH:23]=[CH:24][CH:25]=[C:26]([CH3:27])[C:20]=3[CH3:19])=[O:53])[C@H:38]3[CH2:37][CH2:36][N:35]([C:33]([O:32][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:34])[CH2:48][CH2:47][C@H:46]3[C:45]=2[C:44]=1[Cl:49]
Reactant: Cc1cccc(N)c1C
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2c3c(ccc(Cl)c3Cl)N(CC(=O)O)[C@H]2CC1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)CN2c3ccc(Cl)c(Cl)c3[C@@H]3CCN(C(=O)OC(C)(C)C)CC[C@@H]32)c1C
Temperature: 50 °C

Procedure:
EEDQ (0.57 g, 2.3 mmol) and 2,3-dimethylaniline (0.28 g, 2.3 mmol) were added to a solution of [3-(tert-butoxycarbonyl) (5aS*,10bS*)-9,10-dichloro-2,3,4,5,5a,10b-hexahydroazepino[4,5-b]indol-6(1H)-yl]acetic acid (0.80 g, 1.9 mmol) in THF (20 mL). The reaction was heated to 50° C., cooled to rt after 6 h, and concentrated. The crude product was purified via column chromatography (Biotage, 40 M) with CH2Cl2/MeOH (99: 1) followed by crystallization from EtOAc/heptane to give a white solid: mp 145.5-146.0° C.; 1H NMR (CDCl3, 300 MHz) δ 68.49 (br s, 1H), 7.31 (m, 1H), 7.21 (d, J=8.3Hz, 1H), 7.13 (m, 1H), 7.00 (d, J=7.5 Hz, 1H), 6.37 (d, J=8.4Hz, 1H), 3.89 (m, 2H), 3.78 (m, 2H), 3.66 (m, 1H), 3.58 (m, 1H), 3.33 (m, 2H), 2.34 (m, 1H), 2.27(s, 3H), 2.17 (m, 1H), 2.02 (s, 3H), 1.90 (m, 2H), 1.45 (s, 9H); IR (diffuse reflectance) 1692, 1661, 1596, 1517, 1499, 1465, 1428, 1365, 1329, 1265, 1252, 1241, 1177, 1142, 795 cm−1; MS (EI) m/z 517 (M+), 519, 315, 313, 269, 228, 226, 57, 56, 55; Anal. Calcd for C27H33Cl2N3O3: C, 62.55; H, 6.41; N, 8.10; found: C, 62.53; H, 6.43; N, 8.08.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH:14](C=O)[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:28]([CH:33]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:30][CH2:31][CH3:32])=[O:29].[CH:53]1C=CC=CC=1>>[C:1]([O:5][C:6]([CH:8]1[CH:14]([CH:53]=[CH:33][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: c1ccccc1
Reactant: COc1ccc(S(=O)(=O)N2CCCCC(C=O)C2C(=O)OC(C)(C)C)cc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)C=CC1CCCCN(S(=O)(=O)c2ccc(OC)cc2)C1C(=O)OC(C)(C)C
Reaction time: 72 h

Procedure:
To a solution of 3-Formyl-1-(4-methoxy-benzenesulfonyl)-azepane-2-carboxylic acid tert-butyl ester (310 mg, 0.78 mmoL) in 8.1 mL benzene was added (Carboethoxymethylene) triphenylphosphorane (408 mg, 1.17 mmoL) at ambient temperature. An additional 310 mg was added after 24 hours, after which the reaction was allowed to proceed for 72 hours. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph (silica: 18% to 25% ethyl acetate in hexanes) to yield 3-(2-Ethoxycarbonyl-vinyl)-1-(4-methoxy-benzenesulfonyl)-azepane-2-carboxylic acid tert-butyl ester; MS: (M+H)+ =468, (M+NHY4)- =485.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[Cl:10][C:11]1[N:16]=[C:15]([O:17][CH3:18])[C:14]([CH:19]=[O:20])=[CH:13][CH:12]=1.CO.[OH-].[K+]>ClCCl>[Cl:10][C:11]1[N:16]=[C:15]([O:17][CH3:18])[C:14]([CH:19]([C:3]2[C:4]3[C:9](=[N:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[OH:20])=[CH:13][CH:12]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: COc1nc(Cl)ccc1C=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COc1nc(Cl)ccc1C(O)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
To 1H-Pyrrolo[2,3-b]pyridine (1, 0.455 g, 3.85 mmol) and 6-chloro-2-methoxypyridine-3-carbaldehyde (26, 0.661 g, 3.85 mmol) was added methanol (10 mL) followed by potassium hydroxide (0.310 g, 5.52 mmol). The reaction was allowed to stir at room temperature overnight. The reaction was extracted with diethyl ether/ethyl acetate and water. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and volatiles were removed by rotary evaporation to provide a solid that was treated with dichloromethane and stored in a freezer overnight. The white solid was collected by vacuum filtration and dried in vacuo to give 613 mg of compound 27 (2.12 mmol, 55%). MS (ESI) [M+H+]+=290.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][N:8]([CH2:7][C:6]1[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[S:9]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=1)(=[O:11])=[O:10]
Reactant: Fc1cccc(CBr)c1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC)cc2)Cc2cccc(F)c2)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 79.9 %

Procedure:
Methyl 4-(N-(4-methoxybenzyl)sulfamoyl)benzoate (Example 5-10b) (500 mg, 1.49 mmol), 3-fluorobenzyl bromide (280 mg, 2.98 mmol), and cesium carbonate (971 mg, 2.98 mmol) were placed in DMF (12 mL) and stirred at 90° C. for 4 hours. The solution was cooled to ambient temperature, diluted with H2O (200 mL) and extracted with ethyl acetate (3×, 100 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (10-20% ethyl acetate in hexane) to afford methyl 4-(N-(3-fluorobenzyl)-N-(4-methoxybenzyl) sulfamoyl)benzoate (528 mg, 80%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:13])[C:5]([C:8]2([CH2:11][NH2:12])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(N(CC)CC)C.[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:23]=1[C:24](Cl)=[O:25].O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([Cl:13])[C:5]([C:8]2([CH2:11][NH:12][C:24](=[O:25])[C:23]3[C:22]([F:21])=[CH:30][CH:29]=[CH:28][C:27]=3[F:31])[CH2:9][CH2:10]2)=[N:6][CH:7]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: NCC1(c2ncc(Br)cc2Cl)CC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC1(c2ncc(Br)cc2Cl)CC1)c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
570 mg of C-[1-(5-bromo-3-chloro-pyridin-2-yl)-cyclopropyl]-methylamine (step 3) was dissolved in 8 ml of dichloromethane and cooled to 0° C. 441 mg of triethylamine was added, followed by dropwise addition of a solution of 385 mg of 2,6-difluorobenzoyl chloride in 2 ml of dichloromethane. The reaction mixture was stirred at ambient temperature for 1 hour. Water was added and the reaction mixture was extracted twice with dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated. 1095 mg of crude material was obtained as a pale brown sticky oil. This residue was purified by chromatography on silica gel with cyclohexane/ethyl acetate (3:1) as a eluent. Thus, 742 mg of N-[1-(5-bromo-3-chloro-pyridin-2-yl)-cyclopropylmethyl]-2,6-difluoro-benzamide was obtained as a yellow sticky oil. 1H-NMR (CDCl3): 8.47 ppm (s, 1H), 7.86 ppm (s, 1H), 7.33 ppm (m, 1H), 6.90 ppm (t, 2H), 6.30 ppm (s, 1H, broad), 3.71 ppm (d, 2H), 1.09 ppm (m, 4H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6](O)/[CH:7]=[CH:8]/[C@@H:9]1[C@H:13]2[CH2:14]/[C:15](/O[C@H:12]2[CH2:11][C@H:10]1[OH:24])=[CH:16]/[CH2:17][CH2:18][CH2:19][C:20](O)=O.C(O)C.C(O)(=O)CCC/C=C\C/C=C\C/C=C\C/C=C\CCCCC.CCCCC[C@H](O)/C=C/[C@H]1OC(O)C[C@H](O)[C@@H]1C/C=C\CCCC(O)=O>C(Cl)(Cl)Cl.CS(C)=O>[CH3:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]1[C@@H:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[O:24][CH2:10][CH2:11][CH2:12]1
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2C/C(=C/CCCC(=O)O)O[C@H]2C[C@H]1O
Agent: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Agent: CCCCC[C@H](O)/C=C/[C@H]1OC(O)C[C@H](O)[C@@H]1C/C=C\CCCC(=O)O
Solvent: CS(C)=O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC

Procedure:
After addition of prostacyclin, human thrombocytes were isolated from platelet-rich plasma and suspended in Tyrode-Hepes buffer of pH 7.4 at 2×108 cells/ml. One ml aliquots of cells were incubated either with a compound according to the invention (0.1 to 100 μM) or a solvent (ethanol and/or dimethyl sulfoxide) at 37° C. for 3 minutes and thereafter with radioactively labelled arachidonic acid (3.5 μM) for 5 minutes. The reaction was stopped and the metabolites of arachidonic acid were extracted by adding methanol, chloroform and formic acid. After evaporation of the chloroform-containing layer to dryness under nitrogen, the residue obtained was resuspended in 50 μl chloroform and analyzed by thin layer chromatography. The distribution of the radioactivity of the different metabolites of arachidonic acid was measured using a TLC linear analyzer. By correlating the percentages of the amount of TXB2 formed under the action of thromboxane synthase in the presence of solvent and in the presence of different concentrations of compounds according to the invention, the following IC50 -values were determined graphically from semilogarithmic diagrams.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:13][CH2:14][NH:15][CH2:16][CH2:17][OH:18])[N:8]=[C:7]3[C:19]4[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=4[S:21][C:5]=1[C:6]=23)([O-:3])=[O:2].[C:26]([O-:29])(=O)[CH3:27].[Na+].O.[CH3:32][C:33](OC(C)=O)=[O:34]>>[C:33]([O:18][CH2:17][CH2:16][N:15]([CH2:14][CH2:13][N:9]1[C:10]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[C:5]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[C:7]([C:6]=23)=[N:8]1)[C:26](=[O:29])[CH3:27])(=[O:34])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)[O-]
Reactant: O=[N+]([O-])c1ccc2c3c(nn2CCNCCO)-c2ccccc2Sc13
Agent: [Na+]
Solvent: O
Product: CC(=O)OCCN(CCn1nc2c3c(c([N+](=O)[O-])ccc31)Sc1ccccc1-2)C(C)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 1.0 g (0.0025 mol) of 2-[[2-(5-nitro-2H[1]benzothiopyrano[4,3,2-cd]indazol-2-yl)-ethyl]amino]ethanol and 0.5 g (0.0053 mol) of sodium acetate in 50 ml of Ac2O was stirred at 25° C. for 24 hours and poured into 500 ml of H2O. The precipitate that accumulated was collected and dried to give 1.0 g of product, mp 113°-116° C.
Reaction SMILES: [CH3:1]C(C[AlH]CC(C)C)C.[CH3:10][C:11]1([CH3:24])[CH2:15][CH2:14][C:13](=[O:16])[N:12]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CCOCC.CO>[CH3:1][O:16][CH:13]1[N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:11]([CH3:24])([CH3:10])[CH2:15][CH2:14]1
Reactant: CC(C)C[AlH]CC(C)C
Reactant: CC(C)(C)OC(=O)N1C(=O)CCC1(C)C
Solvent: CCOCC
Solvent: CO
Product: COC1CCC(C)(C)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
DIBAL-H (73.65 mL, 110.5 mmol, 1.5M in toluene) was added portionwise to a solution of tert-butyl 2,2-dimethyl-5-oxopyrrolidine-1-carboxylate (23.10 g, 108.3 mmol) in dry Et2O (200 mL) cooled to −78° C. The reaction was stirred for 1 hour at −78° C. and then allowed to warm to room temperature and stirred overnight. The reaction was quenched with NH4OH (50 mL) and stirred for 20 minutes. The reaction was then diluted with EtOAc (200 mL), 0.5M Rochelle's Salt (100 mL) was added, and the layers were separated. The organic fraction was washed with 0.5M Rochelle's Salt (2×100 mL), brine (100 mL), dried (MgSO4) and concentrated to an oil. The oil was taken up in a solution of p-TsOH monohydrate (2.06 g, 10.8 mmol) in MeOH (200 mL) and stirred overnight at room temperature. The reaction was then concentrated, taken up in EtOAc (200 mL), washed with saturated Na2CO3 (2×100 mL), brine (50 mL), dried (MgSO4) and concentrated to give tert-butyl 5-methoxy-2,2-dimethylpyrrolidine-1-carboxylate (24.07 g, 96.9% yield) as an oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].CCN(C(C)C)C(C)C.[N:24]([C:27]([CH3:33])([CH3:32])[CH2:28][C:29](Cl)=[O:30])=[N+:25]=[N-:26]>C(Cl)Cl>[N:24]([C:27]([CH3:33])([CH3:32])[CH2:28][C:29]([N:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:1])=[O:30])=[N+:25]=[N-:26]
Reactant: CCCCCCCCCCCCNC
Reactant: CC(C)(CC(=O)Cl)N=[N+]=[N-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCCN(C)C(=O)CC(C)(C)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
To a stirred ice cold solution of N-methyldodecanamine (5.0 g, 25.1 mmol) and DIEA (5.70 mL, 1.3 equiv, 32.6 mmol) in anhydrous DCM (150 mL) was added 3-azido-3-methylbutanoyl chloride (4.05 g, 1 equiv, 25.1 mmol) in small portions. The ice bath was removed and the reaction was stirred and left at room temperature for 3 h. The content of the reaction was poured into a separatory funnel. The organic layer was washed with 1 M HCl (3×100 mL) and saturated NaHCO3 (2×100 mL). It was dried over anhydrous MgSO4, filtered, concentrated and dried under high vacuum to give a crude oil (8.08 g, quant). This material was purified on an ISCO flash chromatography system with a gradient from 10-40% ethyl acetate and hexanes as eluent. The desired fractions were collected and concentrated to give a pale yellow oil (7.28 g, 89.3%). 1H NMR (CDCl3, 400 MHz): δ 0.88-0.94 (m, 3H), 1.26-1.35 (m, 6H), 1.47-1.48 (d, J=4, 6H), 1.50-1.59 (m, 2H), 2.51 (s, 2H), 2.94-3.04 (d, J=40, 3H), 3.30-3.40 (m, 2H). LRMS (ESI+) for C18H36N4O (324.3); Found: 325 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:21]3[C:20](=O)[CH2:19][CH2:18][CH2:17][C:16]=3[NH:15][C:14]3[CH2:13][CH2:12][CH2:11][C:10](=[O:23])[C:9]2=3)[CH:5]=[CH:6][CH:7]=1.C(O)C.[BH4-].[Na+]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:9]3[C:10](=[O:23])[CH2:11][CH2:12][CH2:13][C:14]=3[NH:15][C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:21]2=3)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCC2=C1C(c1cccc(Br)c1)C1=C(CCCC1=O)N2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccncc1
Product: O=C1CCCC2=C1C(c1cccc(Br)c1)C1=C(CCCC1)N2
Yield: 99.7 %

Procedure:
To a stirred 70° C. mixture of 9-(3-bromophenyl)-3,4,6,7,9,10-hexahydro-1,8(2H,5H)-acridinedione (5.0 g, 13.4), ethanol (120 mL) and pyridine (40 mL) was added sodium borohydride (7.5 g) in three portions over six hours. The solvent was removed; the resulting yellow solid washed well with water and air dried to provide the title compound (4.8 g). Recrystallization from ethanol/hexane returned analytically pure yellow solid, mp 258°-260° C.; NMR: 1.41-1.51 (m,3, CH2), 1.60-1.88 (m,5, CH2), 2.09-2.15 (m,4, CH2), 2.39-2.45 (m,2, CH2), 4.17 (s,1, CH), 7.16-7.21 (m,2, Ar), 7.26-7.29 (m,2, Ar), 8.44 (s,1, NH); (CI, CH4) MS: m/z=360(M+1). Analysis for C19H20BrNO: Calculated C, 63.69; H, 5.59; N, 3.91; Found: C, 63.73; H, 5.69; N, 3.94.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[NH:32]1[CH:39]=[CH:38][C:36]([NH2:37])=[N:35][C:33]1=[O:34]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:37][C:36]3[NH:35][C:33](=[O:34])[N:32]=[CH:39][CH:38]=3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Nc1cc[nH]c(=O)n1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Product: Cc1cc(F)ccc1-c1nc(Nc2ccnc(=O)[nH]2)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
Following the general procedure outlined in Example 217, the product of Example 48 (100 mg, 0.22 mmol) and cytosine (124 mg, 1.12 mmol) were reacted to give the crude material. Preparative HPLC afforded the title compound, 27 mg (20%). LC-MS: 477.2 (MH+, m/z), 1.77 (Rt, min).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[F:28])[NH2:16]>CC(O)C>[ClH:1].[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[F:28])[NH:16][C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1csc2ncnc(Cl)c12
Reactant: Nc1ccc(OCc2ccccc2F)c(Cl)c1
Solvent: CC(C)O
Product: Cc1csc2ncnc(Nc3ccc(OCc4ccccc4F)c(Cl)c3)c12
Product: Cl

Procedure:
4-Chloro-5-methylthieno[2,3-d]pyrimidine (commercially available from Maybridge Chemical Co. Ltd.) (0.092 g, 0.50 mmol) and 3-chloro-4-(2-fluorobenzyloxy)aniline (prepared according to the published method: WO 96/09294) (0.164 g, 0.65 mmol) were reacted in 2-propanol (3.5 ml) for 4 hours, according to Procedure A. The product was obtained as cream plates (0.156 g, 72%) with m.p. 193-196° C.; (Found: C, 55.17; H, 3.77; N, 9.56. C20H15ClFN3OS.HCl requires: C, 55.05; H, 3.70; N, 9.63%); δH [2H6]-DMSO 8.39 (1H, s, 2-H), 8.37 (1H, br s, N—H), 7.75 (1H, d, J 4, 2′-H), 7.49-7.59 (2H, m), 7.34-7.44 (1H, m), 7.15-7.32 (4H, m) (6-H, 5′-H, 6′-H, 3″-H, 4″-H, 5″-H, 6″-H), 5.19 (2H, s, CH2), 2.69 (3H, s, 5-CH3); m/z 400 (M+1+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:11].[H-].[Na+].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH:28]([CH3:33])[C:29]([F:32])([F:31])[F:30])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=1.O>CN(C=O)C.C(OCC)(=O)C>[F:30][C:29]([F:31])([F:32])[CH:28]([CH3:33])[CH:22]([C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:5]2[CH2:4][C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])[C:6]2=[O:11])=[CH:21][CH:20]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: O=C1NCc2c(F)cccc21
Reactant: CCOC(=O)C(c1ccc(CBr)cc1)C(C)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(c1ccc(CN2Cc3c(F)cccc3C2=O)cc1)C(C)C(F)(F)F
Reaction time: 0.5 h

Procedure:
At 0° C., 645 mg (4.27 mmol) of 4-fluoro-2,3-dihydro-1H-isoindol-1-one were added to 170.7 mg (4.27 mmol, 60% pure) of sodium hydride in 4 ml of DMF. The mixture was stirred for 30 min, and 2.11 g (5.98 mmol) of ethyl 2-[4-(bromomethyl)phenyl]-4,4,4-trifluoro-3-methylbutanoate were then added at 0° C. The reaction mixture was stirred for a further 2 h, and water and ethyl acetate were then added. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 40:1 to 3:1). This gave 856 mg (33.9% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]1[CH:15]=[C:14]([N:16]2[C:20]3[CH:21]=[N:22][CH:23]=[CH:24][C:19]=3[N:18]=[CH:17]2)[S:13][C:12]=1[C:25]([O:27]C)=O)[CH3:9].[NH3:29]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]1[CH:15]=[C:14]([N:16]2[C:20]3[CH:21]=[N:22][CH:23]=[CH:24][C:19]=3[N:18]=[CH:17]2)[S:13][C:12]=1[C:25]([NH2:29])=[O:27])[CH3:9]
Reactant: COC(=O)c1sc(-n2cnc3ccncc32)cc1OC(C)c1ccccc1Cl
Reactant: N
Solvent: CO
Product: CC(Oc1cc(-n2cnc3ccncc32)sc1C(N)=O)c1ccccc1Cl
Temperature: 125 °C
Reaction time: 4 h

Procedure:
A mixture of 49 mg of the above-synthesized methyl 3-[1-(2-chlorophenyl)ethoxy]-5-(3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate and 5 ml of a saturated solution of ammonia in methanol was stirred in a microwave vial at 125° C. for 4 h in the microwave cavity. The reaction mixture was allowed to cool down to room temperature, then another 5 ml of a saturated solution of ammonia in methanol were added and the procedure was repeated as described above. The solvent was removed under vacuum and the residue was purified by flash chromatography to yield the title compound.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([O:13][C:14]2[CH:19]=[C:18]([F:20])[C:17]([C:21]([F:24])([F:23])[F:22])=[C:16]([Cl:25])[CH:15]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-])=O.[OH:26][C:27]1[CH:39]=[CH:38][C:30]([O:31][CH:32]([CH3:37])[C:33]([O:35][CH3:36])=[O:34])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.C(Cl)Cl>[Cl:25][C:16]1[CH:15]=[C:14]([O:13][C:6]2[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:4]([CH:5]=2)[O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH:32]([CH3:37])[C:33]([O:35][CH3:36])=[O:34])=[CH:38][CH:39]=2)[CH:19]=[C:18]([F:20])[C:17]=1[C:21]([F:22])([F:23])[F:24]
Reactant: O=[N+]([O-])c1ccc(Oc2cc(F)c(C(F)(F)F)c(Cl)c2)cc1[N+](=O)[O-]
Reactant: COC(=O)C(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(C)Oc1ccc(Oc2cc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)ccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 23.2 %

Procedure:
A mixture of 2-chloro-α,α,α,6-tetrafluoro-p-tolyl 3,4-dinitrophenyl ether (5.0 g, 0.013 mol), methyl 2-(p-hydroxyphenoxy)propionate (5.15 g, 0.026 mol) and potassium carbonate (3.6 g, 0.026 mol) in acetonitrile is refluxed for 18 hours, cooled to room temperature, poured into water and extracted with ether. The organic extract is washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue. Column chromatography of the residue using silica gel and methylene chloride gives an oil. A solution of the oil in ether is washed sequentially with saturated sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the title product as a yellow oil (1.6 g) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C1CCCCC1.[CH3:19][O:20][C:21](=[O:36])[CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1.[H-].[Na+].[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=[O:47])[C:41]=1[NH:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51]>O1CCCC1>[F:39][C:40]1[C:41]([NH:48][C:49](=[O:54])[C:50]([CH3:52])([CH3:51])[CH3:53])=[C:42]([CH:46]([OH:47])[CH:22]([CH:23]2[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:27][CH2:28]2)[C:21]([O:20][CH3:19])=[O:36])[CH:43]=[CH:44][CH:45]=1
Reactant: CC(C)(C)C(=O)Nc1c(F)cccc1C=O
Reactant: COC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(C1CCN(C(=O)OC(C)(C)C)CC1)C(O)c1cccc(F)c1NC(=O)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 81 %

Procedure:
Diisopropylamine (24.2 mmol, 3.40 mL) was dissolved in tetrahydrofuran (70 mL). The mixture was cooled to −78° C. 2N Butyllithium in cyclohexane (24.40 mmoles, 12.20 mL) was added drop-wise to the reaction. The mixture was held at −78° C. with stirring on and held for 20 minutes. A solution of tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (20.21 mmoles, 5.20 g) in 15 mL tetrahydrofuran was added to the mixture drop-wise. The mixture was held at −78° C. with stirring on and held for 45 min. In a seperate flask, 60% Sodium hydride in mineral oil (24.25 mmoles, 970.00 mg) was washed with hexanes then suspended in tetrahydrofuran (50.00 mL). The mixture was cooled to 0° C. A solution of N-(2-Fluoro-6-formylphenyl)pivalamide (20.16 mmoles, 4.50 g) in 20 mL tetrahydrofuran was added to the mixture drop-wise. The mixture was held at 0° C. with stirring on and held for 1 hr. Aldehyde mixture was added to the ester mixture drop-wise over 1.25 hours. The mixture was held at −78° C. with stirring on and held for 1 hr. The reaction was quenched with aq. ammonium chloride. Mixture was warmed to room temperature then diluted with water. The mixture was extracted 2 times with ethyl acetate and the aqueous phase was discarded. The material was dried (magnesium sulfate), filtered, and concentrated to dryness. Silica gel chromatography gave the title compound as white foam in 81% yield. MS m/e (M-C4H8O2+H)+=381.2.