Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([NH:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:7]([F:16])=[CH:6][C:3]=1[C:4]#[N:5].[NH2:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][C:28]=1[CH3:29])[C:21]([NH:23][O:24][CH3:25])=[O:22].[F-].[K+]>CS(C)=O>[C:4]([C:3]1[C:2]([NH:17][C:18]2[CH:19]=[C:20]([CH:26]=[CH:27][C:28]=2[CH3:29])[C:21]([NH:23][O:24][CH3:25])=[O:22])=[N:9][C:8]([NH:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:7]([F:16])[CH:6]=1)#[N:5]
Reactant: CONC(=O)c1ccc(C)c(N)c1
Reactant: CC(C)(C)CNc1nc(Cl)c(C#N)cc1F
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: CONC(=O)c1ccc(C)c(Nc2nc(NCC(C)(C)C)c(F)cc2C#N)c1
Temperature: 150 °C
Yield: 1 %

Procedure:
A mixture of 2-chloro-6-[(2,2-dimethyl-propyl)-amino]-5-fluoro-nicotinonitrile (150 mg, 0.62 mmol), 3-amino-N-methoxy-4-methyl-benzamide (150 mg, 0.83 mmol) and potassium fluoride (30 mg, 0.51 mmol) in DMSO (1 mL) was heated to 150° C. overnight. The reaction mixture was allowed to cool to room temp and then partitioned between water and ethyl acetate. The organic layer was dried (sodium sulfate) and concentrated under reduced pressure. The product (2.5 mg, 1%) was obtained after purification by silica gel chromatography with 30% EtOAc in hexane as eluent. C20H24FN5O2 MS m/e=386 (M+H).
Reaction SMILES: [C:1]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][CH:20]([F:22])[F:21])[N:14]=[CH:13][CH:12]=[C:11]2[Cl:23])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C:25]1[C:29]([CH3:30])=[C:28]([NH2:31])[NH:27][N:26]=1.CCO>Cl.CC#N>[ClH:23].[C:1]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][CH:20]([F:22])[F:21])[N:14]=[CH:13][CH:12]=[C:11]2[NH:31][C:28]1[NH:27][N:26]=[C:25]([CH3:24])[C:29]=1[CH3:30])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1n[nH]c(N)c1C
Reactant: CC(C)(C)S(=O)(=O)c1cc2c(Cl)ccnc2cc1OCC(F)F
Agent: Cl
Solvent: CCO
Solvent: CC#N
Product: Cc1n[nH]c(Nc2ccnc3cc(OCC(F)F)c(S(=O)(=O)C(C)(C)C)cc23)c1C
Temperature: 80 °C
Yield: 84.2 %

Procedure:
To 6-(tert-butylsulfonyl)-4-chloro-7-(2,2-difluoroethoxy)quinoline (85 mg, 0.234 mmol) and 3,4-dimethyl-1H-pyrazol-5-amine (33.8 mg, 0.304 mmol) in a microwave vial was added EtOH (779 μl) followed by 1 drop of 1N aq HCl (8.52 mg, 0.234 mmol). The vial was sealed and heated to 80° C. behind a blast shield overnight. LCMS showed full conversion to product. Concentrated reaction and triturated resulting residue with ˜2 mL of MeCN using ˜1 min of sonication. Filtered resulting solid, rinsing with MeCN, and dried under vacuum resulting in the product 6-(tert-butylsulfonyl)-7-(2,2-difluoroethoxy)-N-(3,4-dimethyl-1H-pyrazol-5-yl)quinolin-4-amine, hydrochloride (93.5 mg, 0.197 mmol, 84% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.70 (s, 1H), 11.25 (br. s., 1H), 9.26 (br. s., 1H), 8.51 (d, J=7.07 Hz, 1H), 7.57 (s, 1H), 6.67 (d, J=7.33 Hz, 1H), 6.47 (tt, J=3.28, 53.81 Hz, 1H), 4.63 (td, J=3.16, 14.46 Hz, 2H), 2.24 (s, 3H), 1.84 (s, 3H), 1.34 (s, 9H). MS: m/z: 439.3 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[S:11](=[O:13])(=[O:12])[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]([OH:14])=[C:3]1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16].Cl[CH:25]([O:27][C:28]([CH:30]1[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH:30]1([C:28]([O:27][CH:25]([O:14][C:4]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[S:11](=[O:13])(=[O:12])[N:2]([CH3:1])[C:3]=2[C:15]([NH:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=2)=[O:16])[CH3:26])=[O:29])[CH2:32][CH2:31]1
Reactant: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O
Reactant: CC(Cl)OC(=O)C1CC1
Product: CC(OC(=O)C1CC1)OC1=C(C(=O)Nc2ccccn2)N(C)S(=O)(=O)c2ccccc21

Procedure:
By the procedure of Example 6, piroxicam (3.00 g, 9.1 mmol) and cyclopropanecarboxylic acid alpha-chloroethyl ester (4.03 g, 27.2 mmol) were converted to title product, 3.51 g white foam (7.0 mmol, 87.3%) which gave 1.90 g white crystals from toluene; mp 176°-177° C.; IR (KBr) 1735, 1680 cm-1 ; 1H NMR (CDCl3) delta 0.70-0.97 (m, 4H), 1.37-1.50 (m, 1H), 1.72 (d, J=6 Hz, 3H), 3.11 (s, 3H), 6.40 (q, J=6 Hz, 1H), 7.07-7.17 (m, 1H), 7.63.7.97 (m, 5H), 8.29-8.42 (m, 2H), 9.54 (br s, 1H); precise mass calcd for C21H22N3O6S m/e (P+ +H) 444.1235, found 444.1013.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([CH:19]=O)=[C:12]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([CH2:19][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[C:12]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)Nc1nc(-c2ccco2)c(C=O)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)Nc1nc(-c2ccco2)c(CN2CCOCC2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
Compound 92 (1.58 g, 5.37 mmol) and morpholine (0.64 mL, 10.7 mmol) were dissolved in 1,2-dichloroethane (26 mL), and sodium triacetoxyborohydride (3.41 g, 16.1 mmol) was added thereto, followed by stirring overnight at room temperature. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=30:1) to afford the entitled Compound 93 (1.15 g, 57%).
Reaction SMILES: [I-].[CH:2]1([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:16]1COCC1>>[CH:2]1([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH2:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C1CCOC1
Reactant: O=C(c1ccccc1)C1CCCCC1
Agent: [I-]
Product: C=C(c1ccccc1)C1CCCCC1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
To a suspension of methylbiphenylphosphonium iodide in dry THF cooled at 0° C. was added NaNH2. After stirring for 15 h at ambient temperature, cyclohexylphenyl ketone Was added. The reaction mixture was stirred for 8 h at ambient temperature and then quenched with aqueous ammonium chloride and extracted with ethyl acetate. The combined organic phases were washed (brine), dried (Na2SO4) and concentrated. Silica gel column chromatography of the crude product using petroleum ether:EtOAc (49:1) as eluent gave α-cyclohexylstyrene as a colorless oil.
Reaction SMILES: C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[CH:23]2.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].[OH-].[Na+]>ClCCCl>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([NH:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][CH:24]=[CH:23]3)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccc2[nH]ccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc3[nH]ccc3c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.4 %

Procedure:
Glacial acetic acid (1.3 mL, 22.7 mmol) and sodium triacetoxyborohydride (6.73 g, 31.7 mmol) were added to a solution of 5-aminoindole (3 g, 22.7 mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (4.52 g, 22.7 mmol) in 1,2-dichloroethane (100 mL). The reaction mixture was stirred for 4 hours at room temperature; an aqueous solution of NaOH (1 M, 100 mL) was then added. The organic layer was separated, dried over MgSO4, filtered and evaporated under reduced pressure to give 6.9 g (96% yield) of 4-(1H-indol-5-ylamino)-piperidine-1-carboxylic acid tert-butyl ester as a black foam; this material was used without further purifications for the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1)([O-:3])=[O:2]
Reactant: BrCc1ccc(-c2ccccc2)cc1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cccc(OCc2ccc(-c3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 3-Nitro-phenol (3.5 g, 25 mmole), 4-Bromomethyl-biphenyl (4.94 g, 20 mmole) and Potassium carbonate (3.8 g, 30 mmole) in 75 mL of acetone is stirred for 16 hr at room temperature. After removal of the solvent, the residue is taken up in ethyl acetate, washed with 1 N NaOH and brine, dried over Na2SO4, and concentrated to yield a solid. The solid is washed with methanol and dried under vacuum to afford 4-(3-Nitro-phenoxymethyl)-biphenyl.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:21]/[O:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])/[C:8]([O:10]CC2C=CC([N+]([O-])=O)=CC=2)=[O:9])[N:6]=1.[H][H]>O1CCCC1.[Pd]>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:21]/[O:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)CO/N=C(\C(=O)OCc1ccc([N+](=O)[O-])cc1)c1csc(N)n1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CO/N=C(\C(=O)O)c1csc(N)n1
Temperature: 5 °C
Yield: 80.3 %

Procedure:
In 1.2 l of tetrahydrofuran is dissolved 20 g (45.9 mmol) of p-nitrobenzyl (Z)-2-(2-amino-4-thiazolyl)-2-(t-butoxycarbonylmethoxyimino)acetate and, after addition of 20 g of 10% palladium-on-carbon, hydrogen gas is bubbled into the solution. After completion of the reaction, the catalyst is filtered off, and the filtrate is poured into 300 ml of water. The mixture is adjusted to about pH 8 with 5% aqueous sodium bicarbonate and washed with three 200-ml portions of ethyl acetate. The aqueous layer is adjusted to pH about 2 with 10% HCl and cooled to 5° C. or lower. The resulting crystalline precipitate is collected by filtration, washed with water and dried under reduced pressure to give 11.1 g of (Z)-2-(2-amino-4-thiazolyl)-2-(t-butoxycarbonylmethoxyimino)acetic acid.
Reaction SMILES: [OH:1][CH:2]([CH3:15])[CH:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11]([O:13]C)=[O:12])[N:10]=1)[CH3:4].[OH-].[Li+]>C1COCC1.O>[OH:1][CH:2]([CH3:15])[CH:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11]([OH:13])=[O:12])[N:10]=1)[CH3:4]
Reactant: COC(=O)c1csc(NC(C)C(C)O)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)C(C)Nc1nc(C(=O)O)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 2-(3-hydroxybutan-2-ylamino)thiazole-4-carboxylate (1.092 g, 4.75 mmol) was dissolved in THF/water (9:1) mixture and 1M lithium hydroxide (9.49 ml, 9.49 mmol) was added slowly. The reaction mixture was stirred at RT for 1 h and evaporated to dryness. DCM and water was added and pH was adjusted to 2. Acidic water phase was washed twice with DCM and evaporated to dryness. Evaporation residue was dissolved in ethanol, a precipitation was filtered and the filtrate was evaporated to dryness to give a crude product. m/z [216.3+1].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH2:7][OH:8].N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH2:7][O:8][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(Br)cc1CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc(Br)cc1CO[Si](C)(C)C(C)(C)C
Reaction time: 4 h
Yield: 95.8 %

Procedure:
To a solution of 5-bromo-2-methoxybenzyl alcohol (1.0 g, 4.6 mmol) and imidazole (470 mg, 7.01 mmol) in DMF (15 ml) was added tert-butyldimethylsilyl chloride (1.04 g, 6.91 mmol). The mixture was allowed to stir for 4 h, poured onto water (100 ml) and extracted with ether (3×30 ml). The combined organic phases were washed with water (50 ml), brine (50 ml), dried over sodium sulfate and evaporated under reduced pressure to leave a pale yellow oil. This was purified by chromatography (SiO2, 5% ether/petrol), to give the title compound (1.46 g, 96%) as a colourless oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:22]=[N:23][CH:24]=[C:25]([C:27]#[N:28])[CH:26]=3)[CH:16]=2)([CH3:14])[N:13]=1)(C)(C)C.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>ClCCl>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[NH2:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:16]=[C:17]([C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:26]=3)[C:27]#[N:28])[CH:18]=[CH:19][CH:20]=2)([CH3:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=NC(C)(c2cccc(-c3cncc(C#N)c3)c2)COC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(c2cccc(-c3cncc(C#N)c3)c2)COCC(N)=N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (RS)-{5-[3-(5-cyano-pyridin-3-yl)-phenyl]-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl}-carbamic acid tert-butyl ester (49 mg, 0.13 mmol) in dichloromethane (1.5 ml) was treated with trifluoroacetic acid (1.03 ml, 13.3 mmol). The orange colored solution was stirred at room temperature for 30 minutes. For the workup, the solution was evaporated at high vacuum. Heptane was added to the oily residue, and the resulting suspension was evaporated at reduced pressure. After drying at high vacuum the title compound was obtained as a brown solid (49 mg, 98% of theory). MS (ISP): m/z=293.1 [M+H]+.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24]2[C:26]([C:29]([O:31]CC)=O)=[N:27][O:28][C:23]2=[C:22]([Cl:34])[C:21]=1[N:35]1[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:43][NH2:44]>C1COCC1>[Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24]2[C:26]([C:29]([NH:44][CH3:43])=[O:31])=[N:27][O:28][C:23]2=[C:22]([Cl:34])[C:21]=1[N:35]1[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]1)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: CCOC(=O)c1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc12
Solvent: C1CCOC1
Product: CNC(=O)c1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc12

Procedure:
Starting materials: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-7-chloro-6-((2R,6S)-2,6-dimethylmorpholino)isoxazolo[4,5-b]pyridine-3-carboxylate (Intermediate 211) and methylamine, 2M in THF.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>>[NH2:8][C:9]1[C:14]([C:15](=[O:16])[C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:28][CH2:29][N:30]([C:33](=[O:36])[CH2:34][CH3:35])[CH2:31][CH2:32]2)[N:10]=1
Reactant: CCC(=O)Cl
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N1CCC(Nc2ncc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
The same procedure as described in Example 60 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 59, and propionyl chloride (Aldrich) to give 1-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-propan-1-one. MS (M+H)+, 402.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>C(#N)C>[O:32]=[C:26]1[CH:25]([N:18]2[CH2:17][C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:36]([CH:33]3[CH2:35][CH2:34]3)=[O:37])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2Cc3c(CNC(=O)C4CC4)cccc3C2=O)C(=O)N1
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.7 g, 4.62 mmol) was added to a stirred suspension of 3-[4-(aminomethyl)-1-oxoisoindolin-2-yl]piperidine-2,6-dione hydrochloride (0.65 g, 2.10 mmol) in acetonitrile (50 mL). After stirring for 30 min, cyclopropanecarbonyl chloride (0.24 g, 2.31 mmol) was added. The mixture was stirred at room temperature for 17 hours. The mixture was filtered and the solid was recrystallized from methanol (100 mL) to afford N-{[2-(2,6-dioxo(3-piperidyl))-1-oxoisoindolin-4-yl]methyl}cyclopropylcarboxamide (0.36 g, 50%) as a white solid: mp 262-264° C.; 1H NMR (DMSO-d6) δ 11.02 (s, 1H), 8.63 (t, J=5.7 Hz, 1H), 7.65-7.47 (m, 3H), 5.18-5.11 (dd, J=5.0 and 13.2 Hz, 1H), 4.46 (d, J=17.3 Hz, 1H), 4.38-4.31 (m, 3H), 3.00-2.85 (m, 1H), 2.65-2.30 (m, 2H), 2.04-1.99 (m, 1H), 1.64-1.54 (m, 1H), 0.69-0.65 (m, 4H); 13C NMR (DMSO-d6) δ 172.82, 172.69, 170.96, 168.03, 140.08, 134.76, 131.66, 130.70, 128.30, 121.64, 51.54, 46.15, 31.16, 22.59, 13.47, 6.27; Anal. Calcd. For C18H19N3O4: C, 63.33; H, 5.61; N, 12.31. Found: C, 62.97; H, 5.55; N, 12.33.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=4)[CH:17]=3)=[C:11]([C:27]([F:30])([F:29])[F:28])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:31][Mg]Br>C1COCC1.Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([OH:26])([CH3:31])[CH3:25])=[CH:20][CH:19]=4)[CH:17]=3)=[C:11]([C:27]([F:30])([F:28])[F:29])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)cc1
Reaction time: 18 h
Yield: 48.3 %

Procedure:
To a solution of 1-(4-{4-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-yl]-imidazol-1-yl}-phenyl)-ethanone (50 mg, 0.12 mmol) in dry THF (2 mL) was added methylmagnesium bromide (3 M, 44 μL, 0.13 mmol) under nitrogen at room temperature and the resulting mixture stirred for 18 h, after which time methylmagnesium bromide (3 M, 40 μL, 0.12 mmol) was added and the resulting mixture stirred for 19 h. The mixture was then diluted with HCl (0.1 N) and then extracted with ethyl acetate. The combined organic extracts were then dried over sodium sulphate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=1:3 to 0:100) afforded the title compound (25 mg, 48%) which was obtained as a white solid. MS: m/e=432.3 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]([C:8]1[S:12][C:11]2[CH2:13][CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17](=[O:18])[C:10]=2[CH:9]=1)=[O:7].[OH-].[K+].Cl>O1CCOCC1.O>[O:18]=[C:17]1[C:10]2[CH:9]=[C:8]([C:6](=[O:7])[CH2:5][CH2:4][C:3]([OH:23])=[O:2])[S:12][C:11]=2[CH2:13][CH2:14][C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]1=2
Reactant: COC(=O)CCC(=O)c1cc2c(s1)CCc1ccccc1C2=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCC(=O)c1cc2c(s1)CCc1ccccc1C2=O

Procedure:
A solution of 3.0 g of 4-(9,10-dihydro-4- oxo-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-2-yl)-4- oxobutyric acid methyl ester and 1.5 g of potassium hydroxide in 60 cc of dioxane and 30 cc of water is stirred at room temperature for 3 hours, dilution is effected with 200 cc of water and the pH of the solution is adjusted to 1 with concentrated hydrochloric acid at 10°-15°. The resulting title compound is extracted with methylene chloride, the organic solution is washed with water, dried over magnesium sulphate, concentrated by evaporation, and the title compound is recrystallized from dimethyl formamide/acetone. M.P. 167°-168°.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:11]=[C:12]([OH:27])[C:13]2[C:18]3[CH:19]=[C:20]([O:23]C)[CH:21]=[CH:22][C:17]=3[C:16](=[O:25])[O:15][C:14]=2[CH:26]=1)([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].B(Br)(Br)Br.O>ClCCl>[CH3:9][C:2]([C:10]1[CH:11]=[C:12]([OH:27])[C:13]2[C:18]3[CH:19]=[C:20]([OH:23])[CH:21]=[CH:22][C:17]=3[C:16](=[O:25])[O:15][C:14]=2[CH:26]=1)([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)(C)c1cc(O)c2c(c1)oc(=O)c1ccc(OC)cc12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCCCCCC(C)(C)c1cc(O)c2c(c1)oc(=O)c1ccc(O)cc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 78.4 %

Procedure:
3-(1,1-Dimethylheptyl)-1-hydroxy-9-methoxy-6H-dibenzo[b,d]pyran-6-one (4b) (200 mg, 0.54 mmol) was dissolved in 12 mL of dry dichloromethane, 2 mL of a 1M solution of boron tribromide in dichloromethane (2 mmol) was added and the resulting mixture was stirred at room temperature for 3 days. Water was added and the mixture was extracted with diethyl ether. The organic extract was dried and rotary evaporated. The residue was chromatographed on silica gel (50% ethyl ether-petroleum ether) to afford 150 mg of a flaky off-white foam: m.p. 103-108° C.; Rf; 0.28 (50% diethyl ether-petroleum ether); 1H NMR δ 8.60 (m, 1H), 8.35 (d, 1H), 7.05 (d, 1H), 6.90 (s, 1H), 6.73 (s, 1H), 6.10 (br s, 2H), 1.70-0.98 (series of m, 10H), 1.27 (s, 6H), 0.82 (t, J=6.6 Hz, 3H); Anal. calcd. for C23H28O4 74.55% C, 7.39% H. Found 72.70% C, 7.25% H.
Reaction SMILES: [OH:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:29]1([C:39](Cl)=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[C:29]1([C:39]([O:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:12]=3)[CH2:7][CH2:6]2)=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](O)c3ccccc3)CC2)c1
Reactant: O=C(Cl)c1cccc2ccccc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](OC(=O)c3cccc4ccccc34)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.2 %

Procedure:
Into a 25-mL RB-flask was added N-(3-{1-[(3S)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 1-naphthalenecarbonyl chloride (100 mg), diisopropylethylamine (0.30 mL) in THF (0.50 mL) at room temperature. After stirring for 16 hrs at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified using preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (4.70 mg, 71.3% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 8.90 (d, 1H, J=8.9 Hz), 8.28 (apparent dd, 1H, J=1.5, 7.2 Hz), 8.03 (d, 1H, J=8.7 Hz), 7.88 (dm, 2H, J=8.7 Hz), 7.60-7.48 (m, 7H), 7.40-7.32 (m, 3H), 7.25 (m, 1H), 6.90 (apparent d, 1H, J=7.4 Hz), 6.18 (apparent dd, 1H, J=5.7, 7.8 Hz), 3.42 (m, 2H), 2.84 (m, 2H), 2.53 (m, 2H), 2.44 (apparent sept, partially hidden, 4H, J=7.5 Hz), 2.30-2.10 (m, 2H), 1.82 (m, 2H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 535.6 (M+H)+.
Reaction SMILES: [ClH:1].CC1C2COC(=O)C=2C=CC=1[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.Br[C:22]1[CH:31]=[CH:30][C:25]2[C:26](=[O:29])[O:27][CH2:28][C:24]=2[C:23]=1[C:32]([F:35])([F:34])[F:33]>>[ClH:1].[N:15]1([CH2:14][CH2:13][C:22]2[CH:31]=[CH:30][C:25]3[C:26](=[O:29])[O:27][CH2:28][C:24]=3[C:23]=2[C:32]([F:35])([F:34])[F:33])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: O=C1OCc2c1ccc(Br)c2C(F)(F)F
Reactant: Cc1c(CCN2CCNCC2)ccc2c1COC2=O
Agent: Cl
Product: O=C1OCc2c1ccc(CCN1CCNCC1)c2C(F)(F)F

Procedure:
5-[2-(piperazin-1-yl)ethyl]-4-(trifluoromethyl)-2-benzofuran-1(3H)-one hydrochloride was prepared in an analogous fashion to that described for the synthesis of 4-methyl-5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one hydrochloride above starting from 5-bromo-4-(trifluoromethyl)-2-benzofuran-1(3H)-one. LC-MS (IE, m/z): 315 [M+1]+;