Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:4])[CH:2]=[CH2:3].C1CC=CC=1.[CH2:15]1[CH:19]2[CH:20]3C=CC([CH:18]2C=[CH:16]1)C3>>[CH2:6]([O:5][C:1]([CH:2]1[CH2:18][CH:19]2[CH2:20][CH:3]1[CH:16]=[CH:15]2)=[O:4])[CH2:7][CH2:8][CH3:9]
Reactant: C1=CC2C3C=CC(C3)C2C1
Reactant: C=CC(=O)OCCCC
Agent: C1=CCC=C1
Product: CCCCOC(=O)C1CC2C=CC1C2
Reaction time: 1 h
Yield: 93 %

Procedure:
A mixture of butyl acrylate (41.62 g, 0.032 mol) and cyclopentadiene (31.76 g, 0.48 mol, freshly prepared from dicyclopentadiene) was stirred in a flask with cooling in a cold water bath. After 1 hour, the mixture was stirred at 55° C. for 30 minutes. The mixture was then distilled under reduced pressure (60-65° C. @0.4 mmHg) to give the product as a colorless oil (yield 70.29 g, 93%).
Reaction SMILES: [Li+].[F:2][C:3]([F:23])([F:22])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]([O-])=[O:20])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[CH3:58][S:59]([C:62]1[CH:67]=[CH:66][C:65]([NH:68][CH:69]2[CH2:74][CH2:73][NH:72][CH2:71][CH2:70]2)=[CH:64][C:63]=1[C:75]([F:78])([F:77])[F:76])(=[O:61])=[O:60]>CN(C)C=O.ClCCl.O1CCCC1>[CH3:58][S:59]([C:62]1[CH:67]=[CH:66][C:65]([NH:68][CH:69]2[CH2:70][CH2:71][N:72]([C:19](=[O:20])[CH2:18][CH2:17][CH2:16][N:13]3[CH2:12][CH2:11][N:10]([C:7]4[CH:6]=[CH:5][C:4]([C:3]([F:22])([F:23])[F:2])=[CH:9][CH:8]=4)[CH2:15][CH2:14]3)[CH2:73][CH2:74]2)=[CH:64][C:63]=1[C:75]([F:78])([F:76])[F:77])(=[O:61])=[O:60]
Reactant: CS(=O)(=O)c1ccc(NC2CCNCC2)cc1C(F)(F)F
Reactant: O=C([O-])CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(NC2CCN(C(=O)CCCN3CCN(c4ccc(C(F)(F)F)cc4)CC3)CC2)cc1C(F)(F)F
Reaction time: 0.08 h

Procedure:
4-[4-(4-Trifluoromethyl-phenyl)-piperazin-1-yl]-butyric acid lithium salt (120 mg; 0.38 mmol, prepared in accordance with Example 3), diisopropylethyl amine (174 μL; 1.00 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (121 mg; 0.28 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (1.5 mL) and the resulting solution is stirred for 5 minutes. A solution (4-methanesulfonyl-3-trifluoromethyl-phenyl)-piperidin-4-yl-amine hydrochloride (103 mg; 0.32 mmol, prepared in accordance with Example 29) in dimethylformamide (0.5 mL) is added and the reaction is then stirred for 2 hours at room temperature. Following dilution with dichloromethane (10 mL), the organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (5 mL), is dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is finally purified by preparative HPLC to deliver the desired product in pure form (36 mg; 0.06 mmol). The structure was confirmed using Protocol I-B. Calculated mass=621; observed mass=621; HPLC retention time=4.39 min.
Reaction SMILES: [CH:1]([C:9]1[C:10]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:11][NH:12][CH:13]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:20]SC1C(C2C=NC=CC=2)=NNC=1>>[CH:1]([C:9]1[C:10]([C:14]2[CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][CH:19]=2)=[N:11][NH:12][CH:13]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CSc1c[nH]nc1-c1cccnc1
Reactant: CCCCCCC=Cc1c[nH]nc1-c1cccnc1
Product: CCCCCCC=Cc1c[nH]nc1C1=CCCN(C)C1

Procedure:
3-(4-Oct-1-enyl-1H-pyrazol-3-yl)-pyridine was converted to the title compound 47C, using the methodology described for the conversion of 21A to 22A (see Scheme 3). Yield: 95% (amorphous). 1H-NMR (400 MHz, CDCl3): δ 7.58 (s, 1H), 6.24 (bd, J=16 Hz, 1H), 6.07-6.02 (m, 1H), 5.98-5.89 (m, 1H), 3.29-3.25 (m, 2H), 2.63 (bt, J=7 Hz, 2H), 2.46 (s, 3H), 2.44-2.38 (m, 2H), 2.18-2.12 (m, 2H), 1.46-1.38 (m, 2H), 1.38-1.24 (m, 6H), 0.91 (t, J=7 Hz, 3H).
Reaction SMILES: O1C2(CCCC(=O)CC2)OCC1.C(=O)([O-])[O-].[Na+].[Na+].ClC(OCC1C=CC=CC=1)=O.C(OC([NH:40][C:41]1([C:52]([OH:54])=[O:53])[CH2:51][CH2:50][CH2:49][C:44]2([O:48][CH2:47][CH2:46][O:45]2)[CH2:43][CH2:42]1)=O)C1C=CC=CC=1.C(OC(NC1(C(O)=O)CCCC(=O)CC1)=O)C1C=CC=CC=1>O1CCOCC1.O>[NH2:40][C:41]1([C:52]([OH:54])=[O:53])[CH2:51][CH2:50][CH2:49][C:44]2([O:48][CH2:47][CH2:46][O:45]2)[CH2:43][CH2:42]1
Reactant: O=C(NC1(C(=O)O)CCCC2(CC1)OCCO2)OCc1ccccc1
Agent: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=C1CCCC(NC(=O)OCc2ccccc2)(C(=O)O)CC1
Solvent: O
Solvent: C1COCCO1
Product: NC1(C(=O)O)CCCC2(CC1)OCCO2
Reaction time: 4 h

Procedure:
8-Amino-1,4-dioxa-spiro[4.6]undecane-8-carboxylic acid was synthesized from 1,4-dioxa-spiro[4.6]undecan-8-one (F. Alonso et al., Tetrahedron 51 (1995), 10259-10280) via the Bucherer-Bergs route in analogy to the procedure described in J. W. Tsang et al., J. Med. Chem. 27 (1984), 1663-1668. The intermediate was suspended in dioxane/water (2.5 ml/5 ml), sodium carbonate (0.732 g, 6.90 mmol) was added, the mixture was cooled in an ice bath and benzyl chloroformate (0.392 ml, dissolved in 2.5 ml of dioxane) was added with stirring. After 4 h, the mixture was partitioned between 2 N hydrochloric acid and EA, the aqueous phase was extracted with EA, the combined organic phrases were washed with water, dried over sodium sulfate and evaporated to dryness to yield a mixture of 8-benzyloxycarbonylamino-1,4-dioxa-spiro[4.6]undecane-8-carboxylic acid and 1-benzyloxycarbonylamino-4-oxo-cycloheptanecarboxylic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:15][CH2:16][C:17]([OH:19])=[O:18]>>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([N:15]([CH2:16][C:17]([OH:19])=[O:18])[C:10](=[O:11])[C:5]=12)=[O:9])([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: NCC(=O)O
Product: O=C(O)CN1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Yield: 79.9 %

Procedure:
3-nitrophthalic anhydride (0.5 g, 0.0026 mol) and glycine (0.19 g, 0.0026 mol) were refluxed as above overnight. The clear solution was concentrated under vacuum with a rotary evaporator and the crude material triturated with hot 1,4-dioxane. Undissolved material was filtered through a Buchner funnel and washed twice with 1 ml hot 1,4-dioxane. The filtrate was diluted with water. A white solid appeared which was filtered through a Buchner and washed three times with 3-5 ml water. The product was dried in air for a short time and then in vacuo for 48-72 hours to afford 0.52 g (81%) 120 as off white crystals: mp=200-202° C.; Rf0.73 (A): Rf0.77 (C): Rf0.23 (D): IR (cm−1): 2800-3200 (OH), 3096 (C═CH), 2652 (C—H), 1779 (C═O), 1724 (C═O), 1690 (C═O), 1648 (C═C), 1544 (N═O), 1470 (C═C), 1448 (C═C), 1412 (C—O), 1368 (N═O), 1260 (C—O), 722 (C═CH); MS m/z (rel intensity) 250 (15), 249 (100), 205 (89).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][C:25](Cl)=[O:26]>C1COCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:25](=[O:26])[CH2:24][C:20]1[S:19][CH:23]=[CH:22][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cc1cccs1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(Cc1cccs1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 52.9 %

Procedure:
To a solution of (S)-(-)-4-benzyl-2-oxazolidinone (350 mg, 2.00 mmol) in dry THF (10 mL) at -30° C. was added dropwise n-butyllithium (2.59 M in hexanes, 0.8 mL). The mixture was cooled to -78° C. and treated with 2-thiopheneacetyl chloride (0.25 mL, 2 mmol). After stirring at -78° C. for 45 minutes, the mixture was allowed to warm to ambient temperature and stir for 1 hour. The mixture was diluted with hexanes (10 mL), quenched with 1M pH 7 phosphate buffer, and stirred for 45 minutes. The layers of the resultant biphasic mixture were separated and the aqueousueous phase extracted with EtOAc. The combined organic layers were washed with 0.5N aqueous HCl two times, saturated aqueous NaHCO3 two times, and brine, dried over Na2SO4, and concentrated to provide a crude residue which was purified via flash column chromatography with 20% EtOAc/hex as eluant to yield 319 mg (53%) of 4(S)-benzyl-3-(2-thien-2-yl-acetyl)-2-oxazolidinone as a tan solid, mp 56-9° C. 1H NMR: δ 7.34-7.26 (m, 5H), 7.17-7.14 (m, 2H), 7.02-6.98 (m, 1H), 4.72-4.67 (m, 1H), 4.57, 4.48 (AB quartet, 2H, J=16.8 Hz), 4.26-4.17 (m, 2H), 3.29 (dd, 1H, J=3.2, 13.4 Hz), 2.78 (dd, 1H, J=9.5, 13.4 Hz). Anal. Calculated for C16H15NO3S: C, 63.77; H, 5.02; N, 4.65; S, 10.64. Found: C, 63.87; H, 5.04; N, 4.71; S, 10.74.
Reaction SMILES: [C:1]([CH:4]1[CH2:8][C:7](=[O:9])[O:6][CH:5]1[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][CH2:20][CH3:21])[CH:14]=[C:13]2[CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]=1[O:33][CH3:34])([OH:3])=[O:2].C(N(CC)CC)C.[CH2:42]([NH2:45])[CH2:43][CH3:44]>C(Cl)Cl.C(OCC)(=O)C>[C:1]([CH:4]([CH2:8][C:7](=[O:9])[NH:45][CH2:42][CH2:43][CH3:44])[CH:5]([C:10]1[CH:11]=[C:12]2[C:19](=[CH:20][CH:21]=1)[N:15]([CH2:16][CH2:17][CH3:18])[CH:14]=[C:13]2[CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]=1[O:33][CH3:34])[OH:6])([OH:3])=[O:2]
Reactant: CCCN
Reactant: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(C3OC(=O)CC3C(=O)O)ccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCNC(=O)CC(C(=O)O)C(O)c1ccc2c(c1)c(Cc1ccc(C(=O)OC)cc1OC)cn2CCC

Procedure:
A solution of methyl 4-[5-(3-carboxy-2,3,4,5-tetrahydro-5-oxofuran-2-yl)-1-propylindol-3-ylmethyl]-3-methoxybenzoate (0.89 g), triethylamine (2.1 g), and propylamine (1.5 g) in methylene chloride (15 ml) was stirred and heated under reflux for 22 hr. The cooled mixture was diluted with ethyl acetate, washed (1M hydrochloric acid (twice), water (3 times), brine), dried (MgSO4), and evaporated to give methyl 4-[5-(2-carboxy-1-hydroxy-3-(propylcarbamoyl)propyl]-1-propylindol-3-ylmethyl]-3-methoxybenzoate (0.82 g, 82%, as a mixture of diastereomers) as an off-white foam: partial NMR (300 MHz, DMSO-d6): 0.80(m, 6H, 2×CH3, both isomers), 3.83(s, 3H, OCH3, both isomers), 3.92(s, 3H, OCH3, both isomers), 4.71(d, 0.5H, CHOH, isomer A), 5.05(d, 0.5H, CHOH, isomer B), 7.64(t, 0.5H, NH isomer A/B), 7.75(t, 0.5H, NH isomer B/A).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([NH2:7])[S:4][N:3]=1.N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16].O>O1CCCC1>[CH3:1][C:2]1[N:6]=[C:5]([NH:7][C:15](=[O:16])[O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])[S:4][N:3]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cc1nsc(N)n1
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: Cc1nsc(NC(=O)OCC(Cl)(Cl)Cl)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
To a solution of 3-methyl-1,2,4-thiadiazol-5-amine (1.00 g, 8.68 mmol) and pyridine (0.850 ml, 10.4 mmol) in tetrahydrofuran (30 ml) was added 2,2,2-trichloroethyl chloroformate (1.44 ml, 10.4 mmol) with ice-cooling and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. Hexane was poured to the residue and a solid was collected by filtration to obtain the desired product (1.84 g, 72.8%).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.Cl.[NH2:13][OH:14].C([O-])(=O)C.[Na+].O>C(O)C>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:13][OH:14])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN(C)c1ccc(C=NO)cc1
Temperature: 25 °C
Yield: 47.8 %

Procedure:
A solution of 4-(dimethylamino)benzaldehyde (5.0 g), hydroxylamine hydrochloride (2.3 g), and sodium acetate (2.7 g) in ethanol (61 mL)/water (11 mL) is heated at reflux temperature for 1 hour. The mixture is cooled to ambient temperature and partitioned between diethyl ether and water. The aqueous layer is back-extracted with diethyl ether and the combined organic extracts are washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2.6 g pure white solid as the product. MS: m/z 165 (M+H)+.
Reaction SMILES: [S:1]1[C:5]23[CH:13]=[CH:12][CH:11]=[CH:10][C:6]2=[N:7][CH:8]=[CH:9][C:4]3=[C:3]([C:14]([OH:16])=O)[CH2:2]1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[S:1]1[C:5]23[CH:13]=[CH:12][CH:11]=[CH:10][C:6]2=[N:7][CH:8]=[CH:9][C:4]3=[C:3]([C:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])[CH2:2]1
Reactant: C1CCNCC1
Reactant: O=C(O)C1=C2C=CN=C3C=CC=CC32SC1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(C1=C2C=CN=C3C=CC=CC32SC1)N1CCCCC1
Yield: 38.9 %

Procedure:
In 5 ml of dimethylformamide were dissolved 458 mg of benzo[b]thieno[2,3-c]pyridine-3-carboxylic acid and 170 mg of piperidine, and 660 mg of DPPA (diphenylphosphorylazide) was added dropwise to the solution under ice-cooling. Then, 335 μl of triethylamine was added to the mixture and the resultant mixture was stirred overnight at room temperature. After the reaction was over, the reaction mixture was diluted with ethyl acetate and the solution was washed with an aqueous 5% citric acid solution, an aqueous 5% sodium hydrogencarbonate solution, and then a saturated aqueous sodium chloride solution and thereafter dried with sodium sulfate. The ethyl acetate layer was concentrated under reduced pressure and the residue was purified by silica gel thin layer chromatography (solvent: chloroform) and then recrystallized from a mixture of chloroform and ether to provide 230 mg (yield of 85%) of 1-(benzo[b]thieno[2,3-c]pyridine-3-carbonyl)-piperidine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:12]([C:13]([OH:15])=O)[C:11]=1[C:19]([OH:21])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:23][C:24]1([CH3:32])[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]1=[O:31]>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:12]2[C:11]=1[C:19](=[O:21])[N:23]([C:24]1([CH3:32])[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]1=[O:31])[C:13]2=[O:15])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(=O)O)c1C(=O)O
Reactant: CC1(N)CCC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCc1cccc2c1C(=O)N(C1(C)CCC(=O)NC1=O)C2=O
Yield: 51.2 %

Procedure:
A mixture of 3-(t-butoxycarbonylamino-methyl)-phthalic acid (3.3 g, 11.2 mmol) and 3-amino-3-methyl-piperidine-2,6-dione hydrochloride (2.0 g, 11.2 mmol) in pyridine (40 mL) was refluxed for 17 hours. The mixture was cooled and concentrated. The residue was dissolved in EtOAc (200 mL) and water (50 mL). The organic layer was washed with water (40 mL), Sat. NaHCO3 (40 mL), water (40 mL), and brine (40 mL), and dried (MgSO4). Solvent was removed, and the residue was purified by chromatography (Silica gel) to give [2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-carbamic acid t-butyl ester (2.3 g, 51%): 1H NMR (CDCl3) δ 1.43 (s, 9H, 3(CH3)), 2.08 (s, 3H, CH3), 2.10-2.15 (m, 1H), 2.69-2.84 (m, 3H), 4.62 (d, J=6.5 Hz, 2H, CH2), 5.46 (m, 1H, NH), 7.64-7.76 (m, 3H, Ar), 8.15 (s, 1H, NH).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[O:23][CH3:24])(=[O:14])=[O:13])[C:7](=[O:25])[C:6]2([NH:35][C:36](=O)[O:37]C1C=CC=CC=1)[C:26]1[C:27]([O:32][CH2:33][CH3:34])=[N:28][CH:29]=[CH:30][CH:31]=1)#[N:2].[NH:45]1[CH2:50][CH2:49][CH:48]([N:51]2[CH2:56][CH2:55][N:54]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:53][CH2:52]2)[CH2:47][CH2:46]1.C(#N)C.O.C(O)(C(F)(F)F)=O>O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[O:23][CH3:24])(=[O:13])=[O:14])[C:7](=[O:25])[C:6]2([NH:35][C:36]([N:45]1[CH2:50][CH2:49][CH:48]([N:51]2[CH2:52][CH2:53][N:54]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:55][CH2:56]2)[CH2:47][CH2:46]1)=[O:37])[C:26]1[C:27]([O:32][CH2:33][CH3:34])=[N:28][CH:29]=[CH:30][CH:31]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCNCC2)CC1
Reactant: CCOc1ncccc1C1(NC(=O)Oc2ccccc2)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(C#N)cc21
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ncccc1C1(NC(=O)N2CCC(N3CCN(C(=O)OC(C)(C)C)CC3)CC2)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.7 %

Procedure:
100 mg (0.16 mmol) of phenyl [5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carbamate (prepared according to Example 1, process steps 1a) to 1f)) were initially charged in 8 ml of anhydrous tetrahydrofuran (dried over molecular sieve), and 65.8 mg (0.24 mmol) of tert-butyl 4-piperidin-4-ylpiperazine-1-carboxylate were added. The mixture was then stirred at room temperature overnight. The progress of the reaction was monitored by TLC (silica gel, CH2Cl21MeOH 9:1) and LCMS (RP, mobile phases acetonitrile/water and 0.01% TFA). The solvent was removed under reduced pressure, and the residue was taken up in dichloromethane and extracted with 2 N aqueous sodium hydroxide solution (1×). The combined organic phases were dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The crude mixture was purified by column chromatography (5 g NP-SiO2 cartridge, Chromabond) using dichloromethane/methanol in a ratio of 98:2 as mobile phase. This gave 55.3 mg (0.07 mmol, 43%) of the desired product, which was directly used in the next reaction step for Boc deprotection.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[Br:15][C:16]1[CH:26]=[C:25]2[O:27][CH2:28][O:29][C:24]2=[CH:23][C:17]=1[CH:18]=[CH:19][C:20](O)=O>>[Br:15][C:16]1[CH:26]=[C:25]2[O:27][CH2:28][O:29][C:24]2=[CH:23][C:17]=1/[CH:18]=[CH:19]/[C:20]1[NH:1][C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=2[N:8]=1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: O=C(O)C=Cc1cc2c(cc1Br)OCO2
Product: CCn1c(=O)c2[nH]c(/C=C/c3cc4c(cc3Br)OCO4)nc2n(CC)c1=O
Yield: 36.8 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 2.50 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 3.77 g (13.9 mmol) of 2-bromo-4,5-methylenedioxycinnamic acid. Then, the resultant crude crystals were recrystallized from dimethylsulfoxide/water to give 2.01 g (yield 38%) of Compound 165 as a yellow powder.
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1.BrC1C=CC(C(O)=O)=CC=1.ONC(=O)CCC(N)=O.[NH:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[CH2:42][N:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1>O1CCCC1>[Br:16][C:13]1[CH:12]=[CH:11][C:10]([C:9]([N:37]2[CH2:41][CH2:40][CH2:39][C@H:38]2[CH2:42][N:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)=[O:17])=[CH:15][CH:14]=1
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: O=C(ON1C(=O)CCC1=O)c1ccc(Br)cc1
Agent: NC(=O)CCC(=O)NO
Agent: O=C(O)c1ccc(Br)cc1
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)cc1)N1CCC[C@H]1CN1CCCC1
Yield: 93 %

Procedure:
To a stirring solution of 4-bromobenzoic acid-2,5-dioxo-pyrrolidin-1-yl ester (3.5 g, 11.7 mmol), [which can be prepared from 4-bromobenzoic acid and N-hydroxy succinamide by the method of C. Mitsos, Chem Pharm Bull 48(2), 211-214 (2000), or purchased from Ambinter, CAS# 80586-82-9], in tetrahydrofuran (0.15 M), add (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine and heat to reflux for 4 h. After this time, remove the heat and wash the reaction with water while extracting with 10% isopropanol/dichloromethane. Dry the organic portion with sodium sulfate, filter and concentrate in vacuo. Purify the resulting residue on a silica column eluting with 2 M ammonia in methanol and dichloromethane to give (4-bromo-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-yl)methanone (93% yield with 80% purity). MS (m/e): 337.1 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.COC[O:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[C:34]3[N:35]=[C:36]([NH:38][C:39](=[O:41])[CH3:40])[S:37][C:33]=3[CH:32]=[CH:31][CH:30]=2)[CH:23]=1>ClCCl>[OH:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:15]=[CH:14][C:13]=1[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[C:34]3[N:35]=[C:36]([NH:38][C:39](=[O:41])[CH3:40])[S:37][C:33]=3[CH:32]=[CH:31][CH:30]=2)[CH:23]=1
Reactant: COCOc1cc(C(F)(F)F)ccc1-c1cc(Oc2cccc3sc(NC(C)=O)nc23)ncn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4O)ncn3)cccc2s1

Procedure:
Trifluoroacetic acid (0.10 mL, 1.3 mmol, Aldrich) was added dropwise to a solution of N-{4-[6-(2-methoxymethoxy-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide, (Example 136(b)), (0.50 g, 1.0 mmol) in dichloromethane (10 mL) with stirring and cooling in an ice bath. The reaction mixture was stirred for 16 h at room temperature, diluted with dichloromethane (5 mL) and quenched with satd sodium bicarbonate solution. The reaction mixture was diluted with water (100 mL), extracted with dichloromethane (2×100 mL), and the combined organic extracts were concentrated in vacuum. The resulting white solid was suspended in MeOH (50 mL), collected by filtration, and dried under vacuum to obtain the title compound as a white solid. Mp: 302–304° C. MS (ESI, pos. ion.) m/z: 445 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([N+]([O-])=O)[CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-])=O.C1(P(=[CH:34][C:35](OCC)=[O:36])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)(=O)C.C(O)C>C([O-])(=O)C=C>[NH:1]1[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:34][C:35]1=[O:36]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C=CC(=O)[O-]
Solvent: CC(=O)O
Solvent: CCO
Product: O=c1ccc2ccccc2[nH]1

Procedure:
Synthesis of intermediates containing A2-77 (V═O) is shown in Scheme 54. Utilizing the procedure published by Doherty et. al (see WO 03/0999284), Wittig homologation of commercially available 2,4-dinitrobenzaldehyde (251) with ethyl (triphenylphosphoranylidene)-acetate results in propenoate 252. Catalytic hydrogenation in the presence of glacial acetic acid and ethanol results in the target 1H-quinolin-2-one 253 which, utilizing the same oxidation/reduction sequence as shown in Scheme 53 results in hydrazine 254 (R15, V═O) and iodide (255). At the conclusion of the synthesis that utilizes 254 or 255, reduction of the amide with LAH under standard conditions provides an optional synthesis of intermediates containing A2-77 (V═H2).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][C:10]1([CH3:27])[CH2:19][C:18](=O)[C:17]2[C:12](=[CH:13][C:14]([O:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[CH:15][CH:16]=2)[O:11]1.Cl>C1COCC1.CCOCC>[CH3:9][C:10]1([CH3:27])[CH:19]=[C:18]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:17]2[C:12](=[CH:13][C:14]([O:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[CH:15][CH:16]=2)[O:11]1
Reactant: Br[Mg]c1ccccc1
Reactant: CN(C)CCOc1ccc2c(c1)OC(C)(C)CC2=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)CCOc1ccc2c(c1)OC(C)(C)C=C2c1ccccc1

Procedure:
To a stirred solution of phenylmagnesium bromide [from bromobenzene and magnesium in dry tetrahydrofuran] was added 2,2-dimethyl-7-(2-dimethylaminoethoxy)-chroman-4-one in dry THF and the resulting solution was boiled under reflux for 2 weeks. The cooled reaction mixture was decomposed with 2.5 N hydrochloric acid and the organic layer separated and dried (magnesium sulphate). Removal of the solvent gave a yellow oil which was chromatograhed on silica in 3% ether-97% light petroleum (b.p. 60°-80°) gave the title compound as a colourless oil. Dissolution in dry ether and passage of dry hydrogen chloride through the solution gave the hydrochloride salt, m.p. 186.5°-187.5°. An analogous procedure yielded 7-(2-N-benzyl-N-methyl-aminoethoxy)-4-(4-fluorophenyl)-2,2-dimethyl-2H-chromene as a colourless oil.