Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[CH3:18])[CH2:6]1)=[O:4].[Cl:19][C:20]1[CH:29]=[CH:28][C:23]2[NH:24][C:25](=[O:27])[O:26][C:22]=2[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:19][C:20]1[CH:29]=[CH:28][C:23]2[N:24]([CH2:2][C:3]([N:5]3[CH2:9][C:8](=[O:10])[N:7]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=4[CH3:18])[CH2:6]3)=[O:4])[C:25](=[O:27])[O:26][C:22]=2[CH:21]=1
Reactant: Cc1c(Cl)cccc1N1CN(C(=O)CCl)CC1=O
Reactant: O=c1[nH]c2ccc(Cl)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(Cl)cccc1N1CN(C(=O)Cn2c(=O)oc3cc(Cl)ccc32)CC1=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of (2-chloro-acetyl)-3-(3-chloro-2-methyl-phenyl)-imidazolidin-4-one (76) (28.6 mg, 1 equiv), 6-Chloro-3H-benzooxazol-2-one (16.9 mg, 1 equiv) and potassium carbonate (27 mg, 2 equiv) in DMF (2 ml) was stirred at 60° C. overnight, diluted with ethyl acetate, washed with water, purified with HPLC to give 6-chloro-3-{2-[3-(3-chloro-2-methyl-phenyl)-4-oxo-imidazolidin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (77): LCMS observed for (M+H)+: 421.2.
Reaction SMILES: [Si]([O:8][CH:9]1[C:16](=[O:17])[N:15]2[CH:11]([CH2:12][CH2:13][C:14]2=[O:18])[CH2:10]1)(C(C)(C)C)(C)C.O>C(O)(=O)C>[OH:8][CH:9]1[C:16](=[O:17])[N:15]2[CH:11]([CH2:12][CH2:13][C:14]2=[O:18])[CH2:10]1
Reactant: CC(C)(C)[Si](C)(C)OC1CC2CCC(=O)N2C1=O
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCC2CC(O)C(=O)N12

Procedure:
A solution of 2-t-butyldimethylsilyloxy-dihydro-1H-pyrrolizine-3,5(2H,6H)-dione (2.1 g) in acetic acid:water, 3:1 (18 ml) is stirred at 60° C. for six hours. The solution is cooled, concentrated, toluene added and the solution reconcentrated. The oil is triturated with anhydrous ethyl ether and filtered to yield 2-hydroxy-dihydro-1H-pyrrolizine-3,5(2H,6H)-dione as a white solid with mp 135°-140° C. NMR (CDCl3) and 5.48 (m, 1H), 4.47 (m, 1H), 4.10 (b.s., 1H), 2.93-1.36 (m, 6H). IR 3310, 2860, 1770, 1710, 1655, 1410, 1372, 1307, 1275.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([CH3:12])=[CH:5]2.[N+:13]([O-])([O-:15])=[O:14].[K+].N.ClCCl.CCCCC>OS(O)(=O)=O>[Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([CH3:12])=[CH:5]2
Reactant: Cc1cc2cc(Cl)ccc2cn1
Reactant: O=[N+]([O-])[O-]
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCCCC
Solvent: ClCCl
Product: Cc1cc2c([N+](=O)[O-])c(Cl)ccc2cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
To a solution of 6-chloro-3-methylisoquinoline (10.0 g, 57.5 mmol) in concentrated H2SO4 (100 mL) was added dropwise during 10 min. a solution of KNO3 (6.05 g, 60 mmol) in concentrated H2SO4 (50 mL) at 5° C. Care was taken that the temperature of the reaction mixture did not rise above 10° C. The reaction mixture was stirred for 3 h at room temperature, poured onto ice (200 g) and rendered basic (pH=10) with a 33% aqueous ammonia solution. A dark yellow precipitate was formed, which was filtered off, thoroughly rinsed with water and taken up in dichloromethane. The organic phase was washed with water and brine, dried over Na2SO4, filtered and dried in vacuo to afford a pale brown solid. Re-crystallization from dichloromethane/pentane afforded the title compound as pale brown crystals (9.2, 41.4 mmol, 72%). MS (ES+): 223 (M(C10H735ClN2O2)+H)+.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[C:7]([N:10]2[CH2:13][CH:12]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11]2)[S:8][CH:9]=1)=[N+]=[N-].[O:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[C:37](Cl)=[O:38].C(N(CC)CC)C>CO.[OH-].[Pd+2].[OH-]>[Si:15]([O:14][CH:12]1[CH2:13][N:10]([C:7]2[S:8][CH:9]=[C:5]([CH2:4][NH:1][C:37]([C:33]3[O:32][CH:36]=[CH:35][CH:34]=3)=[O:38])[N:6]=2)[CH2:11]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(CN=[N+]=[N-])cs2)C1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)c1ccco1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OC1CN(c2nc(CNC(=O)c3ccco3)cs2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
1-(4-Azidomethyl-1,3-thiazol-2-yl)-3-t-butyldiphenylsilyloxyazetidine (2.47 g, 5.50 mmol) (obtained as described in Reference Example 62(1)) in methanol (120 ml) was subjected to catalytic reduction in the presence of 20% palladium hydroxide (2.47 g) at room temperature. After checking the completion of the reaction, the reaction mixture was filtered in order to remove the catalyst and the filtrate concentrated under reduced pressure. The residue was dissolved in methylene chloride (115 ml). To the mixture were added 2-furoyl chloride (0.65 ml, 6.60 mmol) and triethylamine (0.92 ml, 6.60 mmol), and the mixture was stirred at room temperature for 1 hour. After checking the completion of the reaction, the mixture was distilled under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-[4-(furan-2-carbonylamino)methyl-1,3-thiazol-2-yl]azetidine (1.60 g, yield 60%) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:25])[CH2:23][NH2:24])[CH3:21])[C:14]=3[Cl:26])[C:5]2=[N:4][C:3]=1[CH3:27].[C:28](O)(=[O:33])[CH2:29][CH2:30][CH:31]=[CH2:32].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:25])[CH2:23][NH:24][C:28](=[O:33])[CH2:29][CH2:30][CH:31]=[CH2:32])[CH3:21])[C:14]=3[Cl:26])[C:5]2=[N:4][C:3]=1[CH3:27]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccn2c1Br
Reactant: C=CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: C=CCCC(=O)NCC(=O)N(C)c1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
A mixture of 3-bromo-8-[2,6-dichloro-3-(N-glycyl-N-methylamino)benzyloxy]-2-methylimidazo[1,2-a]pyridine (150 mg), 4-pentenoic acid (33 mg), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (77 mg), 1-hydroxybenzotriazole (64 mg) and N,N-dimethylformamide (1.5 ml) was stirred for 2 hours at ambient temperature. Water was added thereto, and the mixture was extracted with methylene chloride three times. The organic layers were combined, washed with water four times and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (methylene chloride:methanol=30:1, V/V) to give 3-bromo-8-[2,6-dichloro-3-[N-(4-pentenoylglycyl)-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (172 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][NH2:11])=[N:7][C:6]=2[CH:12]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][NH:11][S:21]([CH3:20])(=[O:23])=[O:22])=[N:7][C:6]=2[CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCc1nc2cc(Br)ccc2s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCc1nc2cc(Br)ccc2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.7 %

Procedure:
To a stirred solution of C-(5-Bromo-benzothiazol-2-yl)-methylamine (0.780 g, 3.209 mmol) in CH2Cl2 (12 mL) is added triethylamine (1.2 mL, 8.024 mmol). To above solution is added drop wise methane sulfonyl chloride (0.5 mL, 6.419 mmol) at 0° C. then stirred at room temperature for 3 hours. The reaction mixture is concentrated in vacuo and the crude material is diluted with water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, concentrated and purified by combiflash using 50% ethyl acetate in hexane as an eluent to afford the title compound (0.45 g). 1HNMR (400 MHz, DMSO-d6) δ: 3.03 (s, 3H), 4.60 (d, J=5.72 Hz, 2H), 7.64-7.67 (dd, J1=1.88 Hz, J2=8.72 Hz, 1H), 7.88 (d, J=8.68 Hz, 1H), 8.21 (t, J=6 Hz, 1H), 8.40 (d, J=1.88 Hz, 1H). LC-MS (m/z): [M−H]=320.8.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([NH:11][CH3:12])=[O:10])=[C:4]([F:14])[CH:3]=1.CC1(C)C(C)(C)OB([C:23]2[CH:24]=[N:25][C:26]([NH2:29])=[N:27][CH:28]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O1CCOCC1.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>[NH2:29][C:26]1[N:27]=[CH:28][C:23]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([NH:11][CH3:12])=[O:10])=[C:4]([F:14])[CH:3]=2)=[CH:24][N:25]=1
Reactant: CNC(=O)C(O)c1ccc(Br)cc1F
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
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: [K+]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CNC(=O)C(O)c1ccc(-c2cnc(N)nc2)cc1F
Temperature: 100 °C

Procedure:
A mixture of 2-(4-bromo-2-fluorophenyl)-2-hydroxy-N-methylacetamide (0.4 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (0.11 g, 0.48 mmol), tetrakis(triphenylphosphine)palladium (0.01 g, 0.01 mmol) and potassium carbonate (0.16 g, 1.2 mmol) in toluene (0.6 mL) and 1,4-dioxane (0.6 mL) was heated at 100° C. for 1.5 h. After cooling to RT, the mixture was filtered through a pad of silica gel, washed with 10% methanol in dichloromethane. The filtrate was concentrated under reduced pressure and the residue purified by chromatography on silica gel with 10% methanol in dichloromethane to afford the desired product. LCMS: (M+H)=277.0.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:16]2[NH:15][C:14](=[O:17])[O:13][C:12]([CH3:19])([CH3:18])[C:11]=2[CH:10]=[CH:9][CH:8]=1.[CH3:20][C:21]1[CH:22]=[C:23]([SH:28])[CH:24]=[CH:25][C:26]=1[CH3:27]>>[CH3:20][C:21]1[CH:22]=[C:23]([S:28][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[C:16]3[NH:15][C:14](=[O:17])[O:13][C:12]([CH3:19])([CH3:18])[C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH:24]=[CH:25][C:26]=1[CH3:27]
Reactant: Cc1ccc(S)cc1C
Reactant: CC1(C)OC(=O)Nc2c(OCCCCCl)cccc21
Product: Cc1ccc(SCCCCOc2cccc3c2NC(=O)OC3(C)C)cc1C

Procedure:
Prepared analogously to Example 1 from 8-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 3,4-dimethyl-thiophenol.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:17][CH2:16][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([CH3:29])[CH2:28][O:27]2)=[CH:22][CH:21]=1>CN(C=O)C>[CH3:3][N:4]1[CH2:17][CH2:16][C:7]2[N:8]([CH2:29][C:26]([C:23]3[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=3)([OH:27])[CH3:28])[C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1
Reactant: COc1ccc(C2(C)CO2)cc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(C)(O)Cn2c3c(c4cc(C)ccc42)CN(C)CC3)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A flask was charged with sodium hydride 60% (0.803 mg, 20.12 mmol) in DMF and stirred at RT for 10 min. 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.28 g, 6.4 mmol) was added and the mixture stirred at RT for 1 h. 2-(4-Methoxyphenyl)-2-methyloxirane (1.5 g, 9.14 mmol) was added and the mixture stirred at RT overnight. Ice water was added and the mixture extracted with ethyl acetate (3×). The combined organic layers were washed with water (4×) and concentrated, followed by purification of the product on silica gel (#100-200 mesh) using 0-5% MeOH:DCM as eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:9]2[CH2:14][CH2:13][NH:12][C:11](=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.Br[CH2:24][C:25]([O:27][CH3:28])=[O:26].[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:9]2[CH2:14][CH2:13][N:12]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:11](=[O:15])[CH2:10]2)=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: O=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CCN1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CN1CCN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To a solution of 4-(bis(4-chlorophenyl)methyl)piperazin-2-one (180 mg, 537 μmol) in 10 mL of dry THF was added methyl 2-bromoacetate (60 μl, 644 μmol), followed by sodium hydride, 60% dispersion in mineral oil (16 μl, 644 μmol). After stirring rt overnight, the solvent was evaporated to dryness and was directly submitted to column chromatography (SiO2, hexane to hexane/EtOAc=100:5 to 100:10 to 100:20 to 100:30) to give methyl 2-(4-(bis(4-chlorophenyl)methyl)-2-oxopiperazin-1-yl)acetate (160 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9]O)=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.CS([Cl:22])(=O)=O>C(Cl)Cl>[Cl:22][CH2:9][C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ncccc1CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ncccc1CCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2-methoxy-pyridin-3-yl)-methanol (0.38 g, 2.74 mmol) from example 42 step A and triethylamine (0.5 mL, 3.56 mmol) in 6 mL of CH2Cl2 was added methanesulfonyl chloride (0.26 mL, 3.29 mmol) at 0° C. After 1 hr, the reaction was warmed to room temperature and stirred overnight. The reaction mixture was brought to the usual work-up to give the crude product, which was purified by chromatography (silica gel, 25% EtOAc/hexanes). 1H NMR (300 MHz, CDCl3) 8.15 (m, 1H), 7.67 (m, 1H), 6.91 (m, 1H), 4.60 (s, 2H), 4.02 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[S:4][C:3]=1/[CH:8]=[CH:9]/[C:10](N(C)C)=O.[N+]([O-])(O)=O.[NH:19]([C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=1)[CH2:26][NH:27][C:28](=[O:30])[CH3:29])[C:20]([NH2:22])=[NH:21]>CC#N>[CH3:7][C:5]1[S:4][C:3]([C:8]2[CH:9]=[CH:10][N:22]=[C:20]([NH:19][C:23]3[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=3)[CH2:26][NH:27][C:28](=[O:30])[CH3:29])[N:21]=2)=[C:2]([CH3:1])[N:6]=1
Reactant: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Reactant: CC(=O)NCc1cccc(NC(=N)N)c1
Solvent: O=[N+]([O-])O
Solvent: CC#N
Product: CC(=O)NCc1cccc(Nc2nccc(-c3sc(C)nc3C)n2)c1

Procedure:
By treatment of 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone and N-(3-guanidino-benzyl)-acetamide nitrate. Yellow solid. Mp 206-207° C. Anal. RP-HPLC: tR=13.6 min (0-60% MeCN, purity>95%). 1H-NMR (DMSO-D6) δ: 1.99 (s, 3H, CH3), 2.65 (s, 3H, CH3), 2.68 (s, 3H, CH3), 4.38 (s, 2H, CH2), 6.94 (d, 1H, J=7.5 Hz, Ph-H), 7.01 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 7.26 (d, 1H, J=8.0 Hz, Ph-H), 7.56 (d, 1H, J=7.5 Hz, Ph-H), 7.70 (s, 1H, Ph-H), 8.40 (d, 1H, J=5.5 Hz, pyrimidinyl-H). MS (ESI+) m/z 345.42 [M+H]+ (C18H19N5OS requires 353.44).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([Cl:15])[CH:9]=2)[N:5]=[C:4]2[CH2:16][CH2:17][CH2:18][C:3]=12.[CH2:19]([O:21][C:22](=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1)[CH3:20]>>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[C:4]3[CH2:16][CH2:17][CH2:18][C:3]3=[C:2]([NH:30][C:27]3[CH:26]=[CH:25][C:24]([CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:31])=[CH:29][CH:28]=3)[CH:7]=2)[CH:13]=[C:12]([F:14])[CH:11]=1
Reactant: Fc1cc(Cl)cc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Product: CCOC(=O)Cc1ccc(Nc2cc(-c3cc(F)cc(Cl)c3)nc3c2CCC3)cc1
Yield: 56.2 %

Procedure:
Following General Procedure B2, 4-chloro-2-(3-chloro-5-fluorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.100 g, 0.36 mmol) was reacted with 4-aminophenylacetic acid ethyl ester (0.096 g, 0.53 mmol) to afford the title compound (0.086 g, 87%) as a yellow oil. MW=424.90. 1H NMR (CD3OD, 300 MHz) δ 7.54 (s, 1H), 7.43-7.34 (m, 1H), 7.31 (s, 1H), 7.28 (s, 1H), 7.25-7.13 (m, 3H), 7.10-7.06 (m, 1H), 5.48 (s, 1H), 4.21-4.07 (m, 2H), 3.69 (s, 2H), 2.98 (t, J=7.6 Hz, 2H), 2.86 (t, J=7.6 Hz, 2H), 2.17 (quin, J=7.6, 2H), 1.37-1.17 (m, 3H); APCI MS m/z 425 [M+H]+.
Reaction SMILES: [C:1]12([O:11][C:12]3[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Li]CCCC.Cl[CH2:25][CH2:26][O:27][CH2:28][CH2:29]Cl>C1COCC1.CCCCCC>[C:1]12([O:11][C:12]3[CH:13]=[CH:14][C:15]([N:16]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:17][CH:18]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: ClCCOCCCl
Reactant: Nc1ccc(OC23CC4CC(CC(C4)C2)C3)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: c1cc(N2CCOCC2)ccc1OC12CC3CC(CC(C3)C1)C2
Reaction time: 1 h

Procedure:
To 12.2 g (0.050 mole) of 4-(1-adamantyloxy)aniline dissolved in 200 ml of THF cooled in an ice bath was added dropwise with stirring 47 ml of a 1.07 M solution of n-BuLi in hexane. During the addition 100 ml of THF was added to the reaction mixture, and the mixture was stirred for one hour. 7.16 g (0.050 mole) of bis(2-chloroethyl)ether was added (as a solution in THF) and the mixture was refluxed for nineteen hours and allowed to cool. An additional 47 ml of the 1.07 M solution of n-BuLi in hexane was added dropwise with stirring to the reaction mixture cooled in an ice bath, and the mixture was stirred for one hour at room temperature and refluxed for twenty-three hours.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=O)[CH2:7][CH:8]([CH3:11])[CH:9]=O)=[CH:4][CH:3]=1.[S:15]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)(=[O:18])(=[O:17])[NH2:16]>>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]2[N:23]([C:22]3[CH:24]=[CH:25][C:19]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:20][CH:21]=3)[CH:9]=[C:8]([CH3:11])[CH:7]=2)=[CH:4][CH:3]=1
Reactant: CC(C=O)CC(=O)c1ccc(Cl)cc1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Product: Cc1cc(-c2ccc(Cl)cc2)n(-c2ccc(S(N)(=O)=O)cc2)c1

Procedure:
Following a procedure similar to that described in Example 64(iii), but using 2-(4-chlorophenacyl)propionaldehyde [prepared as described in step (ii) above] and 4-sulfamoylaniline as starting materials, the title compound was obtained as a pale brown powder (yield 35%), melting at 196-198° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH-:8].[N+:9]([C:12]1[CH:24]=[C:23]2[C:15]([C:16]3[C:17]([C:26](O)=O)=[CH:18][CH:19]=[CH:20][C:21]=3[C:22]2=[O:25])=[CH:14][CH:13]=1)([O-:11])=[O:10]>C(O)(=O)C>[NH:1]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]=[C:26]1[C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[C:15]1[CH:14]=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:24][C:23]=1[C:22]2=[O:25]
Reactant: [NH-]c1ccccc1N
Reactant: O=C(O)c1cccc2c1-c1ccc([N+](=O)[O-])cc1C2=O
Solvent: CC(=O)O
Product: O=C1c2cc([N+](=O)[O-])ccc2-c2c1cccc2-c1nc2ccccc2[nH]1
Temperature: 130 °C

Procedure:
The procedure used in Example 68 is followed. In a 100 ml round-bottomed flask under an argon atmosphere, heat, at 130° C. for 4 hours, a suspension of 1.6 g of (2-aminophenyl)amide of 7-nitro-9-oxo-9H -fluorene-4-carboxylic acid, obtained in the previous stage, in 30 ml of acetic acid. After cooling, the insoluble material that formed is filtered off, and washed successively with water, with a saturated aqueous solution of sodium hydrogen carbonate and then with water. After purification by flash chromatography on silica gel (40-63 μm), eluting with a mixture of dichloromethane and 7N ammoniacal methanol (9/1 by volume), then formation of a paste in diisopropyl ether, in this way we obtain 550 mg of 5-(1H-benzimidazol-2-yl)-2-nitro-9H-fluoren-9-one, in the form of a yellow powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Li]C(C)(C)C.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1>C1COCC1>[S:1]1[C:5]([CH:20]([OH:21])[C:19]2[CH:22]=[CH:23][C:16]([Cl:15])=[CH:17][CH:18]=2)=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: c1ccc2sccc2c1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)cc1)c1cc2ccccc2s1

Procedure:
a-(2-benzo[b]thienyl)-4-chlorobenzyl alcohol was prepared by the method of Example 40A with benzo[b]thiophene (7.5 mmoles, 1.0 g), t-BuLi (1.7 m, 9.7 mmoles, 5.7 ml), 4-chlorobenzaldehyde (9.7 mmoles, 1.4 g) and THF (20 ml). The crude material (2.45 g) was taken forward without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=O)[C:8]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[Br:24]C1C=C2C(=CC=1OC)C(C)(C)C(=O)CC2>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:13]2[C:14]=1[C:6]1[CH2:7][C:8]3[CH:20]=[C:19]([Br:24])[C:18]([O:21][CH3:22])=[CH:17][C:9]=3[C:10]([CH3:15])([CH3:16])[C:11]=1[NH:12]2
Reactant: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(Br)ccc3c1C2=O
Reactant: COc1cc2c(cc1Br)CCC(=O)C2(C)C
Product: COc1cc2c(cc1Br)Cc1c([nH]c3cccc(Br)c13)C2(C)C

Procedure:
Under the same conditions as the method for synthesizing Compound A4, the title compound was prepared (as a mixture) from Compound E1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:25][CH:26]([NH2:29])[CH2:27][OH:28]>>[OH:28][CH2:27][CH:26]([NH:29][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:22])[CH3:25]
Reactant: CC(N)CO
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)O)n(C)n1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)NC(C)CO)n(C)n1
Yield: 66 %

Procedure:
As described for example 55, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (200 mg, 0.6 mmol) was converted, using DL-2-amino-1-propanol instead of 2-amino-2-methyl-1-propanol, to the title compound (155 mg, 66%) which was obtained as a white solid. MS: m/e=389.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][O:4][CH2:5][C:6]([O:8]C)=[O:7].[OH-].[Na+].S(=O)(=O)(O)O>CO.CCOCC>[F:1][C:2]([F:11])([F:10])[CH2:3][O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: COC(=O)COCC(F)(F)F
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: O=C(O)COCC(F)(F)F
Temperature: 0 °C
Reaction time: 18 h
Yield: 94.3 %

Procedure:
To a solution of methyl 2-(2,2,2-trifluoroethoxy)acetate (8.26 g, 47.98 mmol) and methanol (16 mL) was added sodium hydroxide (1.92 g, 47.98 mmol) in methanol (16 mL). After stirring for 18 hours, the reaction was concentrated and ether (170 mL) was added. The mixture was cooled to 0° C. and concentrated sulfuric acid (2.15 g, 43.9 mmol) in ether (7.5 mL) was slowly added. The resulting mixture was stirred for 18 hours, filtered and concentrated to give the title compound as a colorless oil (7.15 g, 94%), MS(CI): 159(M+H); H-NMR (300 MHz, DMSO-d6): 4.14(q, J=9.3 Hz, 2H), 4.21(s, 2H), 12.92(s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:5]#[N:6]
Reactant: N#Cc1ccc(F)c(Cl)c1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(N2CCNCC2)c(Cl)c1

Procedure:
A solution of 3-chloro-4-fluoro-benzonitrile (236 mg, 1.52 mmoles), piperazine (784 mg, 9.1 mmoles) and potassium carbonate (276 mg, 2 mmoles) in acetonitrile (5 mL) was heated to 100° C. overnight. The mixture was cooled, filtered and the filtrate concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 0-5% 2N methanolic ammonia in DCM) to provide the title compound. MS(APCI+) m/z 222 (M+H)+.