Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1(=[O:8])(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][NH:2]1.[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1>CN(C=O)C>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([N:2]2[CH2:3][CH2:4][CH2:5][CH2:6][S:1]2(=[O:8])=[O:7])=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=S1(=O)CCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCCCS2(=O)=O)cc1
Reaction time: 0.25 h

Procedure:
500 mg (3.7 mmol) [1,2]thiazinane-1,1-dioxide, dissolved in 10 ml DMF, are added to a suspension of 163 mg sodium hydride dispersion in mineral oil (60%, 4.07 mmol) in 5 ml DMF. The mixture is stirred for 15 minutes, then a solution of 522 mg (3.7 mmol) 1-fluoro-4-nitrobenzene in 10 ml DMF is added dropwise. After two hours the reaction mixture is poured onto ice water. The solid is filtered off, washed with water and dried.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH2:21])[C:11]([NH2:20])=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[NH:21][C:22](=[O:23])[NH:20][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nc(-c2ccncc2)c(-c2cccc(F)c2)nc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]c2nc(-c3ccncc3)c(-c3cccc(F)c3)nc2[nH]1
Yield: 44 %

Procedure:
A mixture of 5-(3-fluorophenyl)-6-pyridin-4-ylpyrazine-2,3-diamine (Example 72, 200 mg, 0.71 mmol), 1,1′-carbonylbis-1H-imidazole (138 mg, 0.85 mmol) in THF (3 mL) was stirred and heated at reflux overnight. Solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The separated organic phase was dried (MgSO4) and evaporated to dryness. The residue was recrystallized from ethanol to give the title compound as a white solid (96 mg, 44%).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:11])([F:12])[F:13]
Reactant: Cc1ccc(C#N)cc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)c(C(F)(F)F)c1
Yield: 98.1 %

Procedure:
4-methyl-3-(trifluoromethyl)benzonitrile (10 g, 54 mmol) was dissolved in 200 mL of carbon tetrachloride and treated with N-bromosuccinimide (10.5 g, 59 mmol) and benzoyl peroxide (1.3 g, 0.54 mmol). The reaction mixture was heated to reflux temperature and stirred for one week. Then, 80 mL of water was added and the layers were separated. The aqueous layer was extracted with methylene chloride (2×50 mL). The combined organic layers were washed with water (2×50 mL), dried over magnesium sulfate, and concentrated to provide 4-(bromomethyl)-3-(trifluoromethyl)benzonitrile (14 g, 53 mmol) as a yellow oil which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([S:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:23])=[O:22])[CH:11]=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Clc1ccc(-c2ncc[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccnc1-c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
To a solution of 2-(4-chlorophenyl)-1H-imidazole (90 (20 mmol) in anhydrous THF (200 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 1.2 g, 30 mmol) and stirred for 30 min. Benzenesulfonyl chloride (2.82 mL, 22 mmol) was added and the reaction mixture was stirred overnight. After dilution by 100 mL of saturated NaHCO3 solution (aqueous), the reaction mixture was extracted by ethyl acetate (500 mL). The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (hexane:ethyl acetate 2:1) to give a pale solid. Yield: 54.9%. NMR (500 MHz, CDCl3) δ 7.65 (d, J=2.0 Hz, 1H), 7.58 (t, J=7.5 Hz, 1H), 7.43 (d, J=8.5 Hz, 2H), 7.38 (t, J=8.0 Hz, 2H), 7.34-7.36 (m, 4H), 7.12 (d, J=1.5 Hz, 1H). MS (ESI): calculated for C15H11ClN2O2S, 318.0. found 341.0 [M+Na]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][OH:9].[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.CCOCC>CCO>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:7][CH2:8][OH:9]
Reactant: OCCC1CCCCN1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CCOCC
Solvent: CCO
Product: OCC[C@@H]1CCCCN1
Temperature: 25 °C
Reaction time: 72 h
Yield: 6.2 %

Procedure:
Piperidine-2-ethanol (127 g, 980 mmol) in 95% EtOH (260 mL) was added to (S)-(+)-camphorsulfonic acid (228.7 g, 1.0 eq.) in 95% EtOH (150 mL) and the resulting solution was warmed to reflux. To the warm solution was added Et2O (600 mL) and the solution cooled to room temperature and let stand 3 days. The resulting crystals were filtered and dried in vacuo (25 g): mp 173-173° C. (lit. 168° C.). The salt was then dissolved in NaOH (3M, 100 mL) and stirred 2 hours and the resulting solution was extracted with CH2Cl2 (5×100 mL). The combined organics were dried over Na2SO4, filtered, filtered and concentrated under reduced pressure to give (S)-piperidine-2-ethanol (7.8 g) a portion of which was recrystallized from Et2O: mp=69-70° C. (lit. 68-69° C.); [α]D=14.09° (CHCl3, c=0.2).
Reaction SMILES: [CH:1]1[N:9]2[C:4]([CH2:5][O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[N:3][C:2]=1[C:14]([O:16][CH3:17])=[O:15].S(=O)(=O)(O)O.[N+:23]([O-])([OH:25])=[O:24]>O>[N+:23]([C:11]1[CH:12]=[CH:13][C:7]2[O:6][CH2:5][C:4]3=[N:3][C:2]([C:14]([O:16][CH3:17])=[O:15])=[CH:1][N:9]3[C:8]=2[CH:10]=1)([O-:25])=[O:24]
Reactant: COC(=O)c1cn2c(n1)COc1ccccc1-2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1cn2c(n1)COc1ccc([N+](=O)[O-])cc1-2
Reaction time: 3 h
Yield: 79 %

Procedure:
8.0 g of methyl 4H-imidazo-[2,1-c][1,4]-benzoxazine-2-carboxylate were added to a stirred mixture of 25 ml of concentrated sulfuric acid and 25 ml of concentrated nitric acid at 10° C. The ester slowly went into solution with the solution turning yellow and after three hours at room temperature, thin layer chromatography indicated no starting material remained. 500 ml of water were then added and the yellow product thus formed was filtered off, washed well with water and then dried over P2O5 to obtain 7.5 g (79% yield) of methyl 8-nitro-4H-imidazo-[2,1-c][1,4]-benzoxazine-2-carboxylate with a melting point of 270°-2° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH:15]([NH:18][C:19]([CH:21]4[CH2:24][CH2:23][CH2:22]4)=[O:20])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:25][C:26]1[NH:27][C:28]2[C:33]([CH:34]=1)=[CH:32][C:31]([NH2:35])=[CH:30][CH:29]=2>>[CH3:25][C:26]1[NH:27][C:28]2[C:33]([CH:34]=1)=[CH:32][C:31]([NH:35][C:2]1[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]([N:13]4[CH2:17][CH2:16][CH:15]([NH:18][C:19]([CH:21]5[CH2:24][CH2:23][CH2:22]5)=[O:20])[CH2:14]4)=[O:12])[S:10][C:3]=13)=[CH:30][CH:29]=2
Reactant: O=C(NC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1)C1CCC1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N5CCC(NC(=O)C6CCC6)C5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from (+/−)-cyclobutanecarboxylic acid {1-[7-chloro-thieno[3,2-b]pyridine-2-carbonyl]-pyrrolidin-3-yl}-amide and 2-methyl-1H-indol-5-ylamine by a procedure analogous to Example 1C. MS: 474 (MH+); HPLC Rf: 4.37 min.; HPLC purity 97%.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11])=[O:4].[S-:12][C:13]#[N:14].[K+].O>C(O)C>[F:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][S:12][C:13]#[N:14]
Reactant: N#C[S-]
Reactant: O=C(CBr)c1ccccc1F
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CSCC(=O)c1ccccc1F
Temperature: 25 °C
Yield: 95.5 %

Procedure:
A solution of 2-bromo-1-(2-fluorophenyl)ethanone (5.00 g, 23.0 mmol) and potassium thiocyanate (2.24 g, 23.0 mmol) in ethanol (50 ml) was stirred at 80° C. for 2 hours. After cooling to room temperature, water (60 ml) was poured into the reaction solution, and the mixture was extracted with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the desired product (4.29 g, 95.5%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:19][CH2:20][CH3:21])[N:6]2[CH2:13]/[C:14](=[N:17]/[H])/[NH:15][OH:16].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[CH3:40][N:41]1[C:45]([C:46](O)=O)=[CH:44][C:43]([CH3:49])=[N:42]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:19][CH2:20][CH3:21])[N:6]2[CH2:13][C:14]1[N:17]=[C:46]([C:45]2[N:41]([CH3:40])[N:42]=[C:43]([CH3:49])[CH:44]=2)[O:16][N:15]=1
Reactant: Cc1cc(C(=O)O)n(C)n1
Reactant: [H]/N=C(/Cn1c(CCC)cc2c(Cl)c(C#N)ccc21)NO
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCc1cc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2cc(C)nn2C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Synthesized as described in Example 32A and Example 33 using (1Z)-2-(4-chloro-5-cyano-2-propyl-1H-indol-1-yl)-N-hydroxyethanimidamide (0.030 g, 0.1 mmol) in anhydrous THF (5 mL) with propanephosphonic acid cyclic anhydride (T3P) (0.034 g, 0.12 mmol), 1,3-dimethyl-1H-pyrazole-5-carboxylic acid (0.014 g, 0.1 mmol) and DIEA (0.016 g, 0.12 mmol) and stirred at rt for 1 h and then heated at 120° C. for 2 h in the microwave: 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.46 (d, J=8.5 Hz, 1H), 6.71 (s, 1H), 5.44 (s, 2H), 4.12 (s, 3H), 2.97 (t, 2H), 2.30 (s, 3H), 1.80-1.72 (m, 2H), 1.04 (t, 3H); MS (ES) m/z 395 (M+1).
Reaction SMILES: [ClH:1].CO[N:4]=[C:5]1[CH2:24][CH2:23][C:8]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:9]2)[CH2:7][CH2:6]1.C(O)(=O)C.[H][H].Cl.CCOCC>CCOCC>[ClH:1].[NH2:4][CH:5]1[CH2:6][CH2:7][C:8]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[O:9]2)[CH2:23][CH2:24]1
Reactant: CON=C1CCC2(CC1)OC(c1ccccc1)c1ccccc12
Reactant: [H][H]
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)O
Product: NC1CCC2(CC1)OC(C1CCCCC1)c1ccccc12
Yield: 66 %

Procedure:
A mixture of 1.50 of 4-methoxyimino-3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]hydrochloride, 150 ml of acetic acid and 0.5 g of platinujm oxide is hydrogen at 50 psi and room temperature for 41/2 hours. After filtration and removing the solvent, the oily product is dissolved in 100 ml of dichloromethane and washed with 5% sodium hydroxide solution and water. After drying over anhydrous sodium sulfate, the solvent is removed in vacuo to give an oil. The oil is dissolved in 10 ml of methaol and the solution is made acidic using hydrogen chloride/ether. After addition of 50 ml of ether, the preceipitate is suction filtered, washed with ether and dried to give 66.0% of product, mp 220°-224° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][C@:11]([CH3:18])([CH2:16][CH3:17])[C:12]([O:14]C)=[O:13])=[CH:8][CH:7]=1.[Cl:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1O)[O:28][C:27]([CH3:34])([CH3:33])[CH2:26][CH2:25]2>>[Cl:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][C@:11]([CH3:18])([CH2:16][CH3:17])[C:12]([OH:14])=[O:13])=[CH:8][CH:7]=1)[O:28][C:27]([CH3:34])([CH3:33])[CH2:26][CH2:25]2
Reactant: CC1(C)CCc2cc(Cl)c(O)cc2O1
Reactant: CC[C@@](C)(Oc1ccc(OCCCO)cc1)C(=O)OC
Product: CC[C@@](C)(Oc1ccc(OCCCOc2cc3c(cc2Cl)CCC(C)(C)O3)cc1)C(=O)O

Procedure:
The title compound was prepared following the procedure described in Example 1, Steps F-G employing (2R)-methyl 2-(4-(3-hydroxypropoxy)phenoxy)-2-methylbutanoate and 6-Chloro-2,2-dimethylchroman-7-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:10][C:11]([NH:14][NH2:15])=[N:12][CH:13]=1.[F:23][C:24]([F:36])([F:35])[C:25]1[N:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27][CH:26]=1.ClC1C=CC=CC=1C1N=NC(NNC(=O)CC2C=CC(C(F)(F)F)=CC=2)=CC=1C1C=CC(Cl)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:10][C:11]([NH:14][NH:15][C:32](=[O:33])[CH2:31][C:28]2[CH:29]=[N:30][C:25]([C:24]([F:23])([F:36])[F:35])=[CH:26][CH:27]=2)=[N:12][CH:13]=1
Reactant: NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)cn1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)nc1
Agent: O=C(Cc1ccc(C(F)(F)F)cc1)NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nn1
Product: O=C(Cc1ccc(C(F)(F)F)nc1)NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)cn1
Yield: 103.1 %

Procedure:
The title compound (40 mg, 100%) as a white solid was prepared from 5-(2-chlorophenyl)-4-(4-chlorophenyl)-2-hydrazinylpyridine (25 mg, 0.075 mmol) and 2-(6-(trifluoromethyl)pyridin-3-yl)acetic acid (23 mg, 0.113 mmol) in a manner analogous to that in which N′-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3-yl)-2-(4-(trifluoromethyl)phenyl)acetohydrazide (Example 11A) was prepared. HPLC/MS: retention time=3.53 min, [M+H]+=517.1.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH:13]1(Br)[CH2:17][CH2:16][CH2:15][CH2:14]1.CCCCCCC=CCCC>CN(C)C=O>[CH:13]1([O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: BrC1CCCC1
Agent: CCCC=CCCCCCC
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1OC1CCCC1
Temperature: 55 °C
Reaction time: 1.5 h
Yield: 80.2 %

Procedure:
A mixture of N-hydroxypthalimide (10.00 g, 61.3 mmol), cyclopentylbromide (8.21 mL, 76.63 mmol), and 1,8-diazabicyclo)5.4.0]undec-7-ene (13.75 mL, 76.6 mmol) were combined under an Argon atmosphere in dimethylformamide (50 mL). The mixture was heated to 55° C. and stirred vigorously for 1.5 hours. After cooling to ambient temperature, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and 1N hydrochloric acid. After separating the phases, the aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with 5% w/v potassium carbonate, saturated aqueous brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was triturated with hexane, filtered, and dried under high vacuum to provide 2-(cyclopentyloxy)-1H-isoindole-1,3(2H)-dione (11.37 g, 80%). HL-NMR (chloroform-D3): 1.61 (m, 2H), 1.77 (m, 2H), 1.97 (m, 4H), 4.91 (m, 1H), 7.73 (m, 2H), 7.82 (m, 2H). MS(ESI): 254 (M+Na).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[CH2:23]([N:25]=[C:26]=[O:27])[CH3:24]>CC#N>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:26]([NH:25][CH2:23][CH3:24])=[O:27])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CCN=C=O
Agent: Cl
Solvent: CC#N
Product: CCNC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 30.2 %

Procedure:
(0.29 g, 1.90 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.60 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, ethyl isocyanate (0.16 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 ml). The CH2Cl2 solution was washed with 1N HCL (30 ml), H2O (30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:CH3CN 6:4) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(ethylamino)carboxamide (0.2 g, 30%) as a white solid: mp 173-175° C.; 1H NMR (DMSO-d6) δ d 11.13 (s, 1H), 7.86-7.69 (m, 3H), 6.44 (t, J=6.1 Hz, 1H), 6.11 (t, J=5.55 Hz, 1H), 5.18-5.11 (dd, J=5.4 and 12.6 Hz, 1H), 4.63 (d, J=6.1 Hz, 2H), 3.07-2.83 (m, 3H), 2.64-2.49 (m, 2H), 2.08-2.04 (m, 1H), 0.99 (t, J=7.1 Hz, 3H); 13C NMR (DMSO-d6) δ d 172.73, 169.80, 167.58, 167.03, 157.93, 141.15, 134.61, 133.37, 131.49, 126.96, 121.61, 48.83, 38.71, 34.17, 30.92, 21.98, 15.58; Anal. Calcd. For C17H18N4O5+0.14H2O: C, 56.58; H, 5.11; N, 15.53. Found: C, 56.56; H, 5.05; N, 15.28.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][O:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]([CH3:31])([CH3:30])[CH2:13][CH2:14][C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]#[N:17])[CH2:8]1.[OH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O>>[OH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:2]1[CH:34]=[CH:33][CH:32]=[C:4]([CH2:5][O:6][C@H:7]2[CH2:11][CH2:10][N:9]([C:12]([CH3:30])([CH3:31])[CH2:13][CH2:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:16]#[N:17])[CH2:8]2)[CH:3]=1
Reactant: CC(C)(CCC(C#N)(c1ccccc1)c1ccccc1)N1CC[C@H](OCc2cccc(Br)c2)C1
Reactant: OB(O)c1ccccc1O
Product: CC(C)(CCC(C#N)(c1ccccc1)c1ccccc1)N1CC[C@H](OCc2cccc(-c3ccccc3O)c2)C1

Procedure:
The title compound was prepared from the product of example 55 and 2-hydroxyphenylboronic acid, using the same method as that described for example 56. The crude compound was purified by column chromatography on silica gel, eluting with ethyl acetate followed by dichloromethane:methanol, 95:5, to afford the desired product as pale brown foam in 61% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6](/[CH:8]=[C:9](\[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])/[C:10]([O:12][CH3:13])=[O:11])[CH:7]=1.[H][H]>C(O)C.O1CCOCC1>[Br:1][C:2]1[CH:7]=[C:6]([C:5]([F:22])=[CH:4][CH:3]=1)[CH2:8][C@@H:9]([C:10]([O:12][CH3:13])=[O:11])[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: COC(=O)/C(=C/c1cc(Br)ccc1F)NC(=O)OC(C)(C)C
Reactant: [H][H]
Solvent: C1COCCO1
Solvent: CCO
Product: COC(=O)[C@H](Cc1cc(Br)ccc1F)NC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
20 g (53.45 mmol) of methyl (2Z)-3-(5-bromo-2-fluorophenyl)-2-[(tert-butoxycarbonyl)amino]acrylate (Example 4O) are dissolved in 300 ml of ethanol/dioxane (3:1). Under an argon atmosphere, 200 mg of (+)-1,2-bis((2S,5S)-2,5-diethylphospolano)benzene(cyclooctadiene)rhodium(I)trifluoromethanesulfonate are added, and argon is passed through the solution for 30 min. The mixture is then hydrogenated under a pressure of 3.5 bar of hydrogen for 3 days. The solvent is removed on a rotary evaporator, and the crude product is purified by column chromatography on silica gel (mobile phase: cyclohexane:ethyl acetate 2:2).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=2)=[N:5][S:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[F:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[CH:25]=[C:26]([F:29])[C:27]=1O>>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([C:4]2[C:3]([CH2:2][O:1][C:27]3[C:26]([F:29])=[CH:25][C:24]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:23][C:22]=3[F:21])=[C:7]([C:8]([F:11])([F:9])[F:10])[S:6][N:5]=2)=[CH:13][CH:14]=1)(=[O:20])[CH3:19]
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Reactant: CC(=O)c1ccc(-c2nsc(C(F)(F)F)c2CO)cc1
Product: CC(=O)c1ccc(-c2nsc(C(F)(F)F)c2COc2c(F)cc(CCC(=O)O)cc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling 1-(4-(4-(hydroxymethyl)-5-(trifluoromethyl)isothiazol-3-yl)phenyl)ethanone and ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ: 8.08 (d, J=7.2 Hz, 2H), 7.87 (d, J=7.2 Hz, 2H), 6.78-6.85 (m, 2H), 5.19 (s, 2H), 2.80-2.85 (m, 2H), 2.64 (s, 3H), 2.53-2.58 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C22H16F5NO4S, 484.1 (M−H). found 484.1.
Reaction SMILES: [C@@H:1]12[C:10](=[O:11])[O:9][C:7](=O)[C@@H:2]1[CH2:3][CH:4]=[CH:5][CH2:6]2.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[N:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH2:19][CH2:18]1.C(O)CCC.[ClH:34]>C(O)(C)C>[ClH:34].[N:24]1[CH:25]=[CH:26][CH:27]=[N:28][C:23]=1[N:20]1[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[C:10](=[O:11])[CH:1]3[CH2:6][CH:5]=[CH:4][CH2:3][CH:2]3[C:7]2=[O:9])[CH2:18][CH2:19]1
Reactant: O=C1OC(=O)[C@@H]2CC=CC[C@H]12
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Agent: Cl
Solvent: CCCCO
Solvent: CC(C)O
Product: O=C1C2CC=CCC2C(=O)N1CCCCN1CCN(c2ncccn2)CC1

Procedure:
A mixture of cis-4-cyclohexene-1,2-dicarboxylic anhydride (633 mg; 4.25 mmol), 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine (1 g; 4.25 mmol) and n-butanol (10 ml) was heated under reflux for 6 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography to give an oily substance. The oily substance was treated with a mixture of 3% hydrogen chloride in isopropanol, and the precipitate was recrystallized from isopropanol to give N-[4-{4-(2-pyrimidinyl)-1-piperazinyl}butyl]-4-cyclohexene-1,2-dicarboximide hydrochloride. M.P., 177°-179° C.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:21]=[C:20]2[N:8]([CH2:9][C:10]3[C:11]2=[N:12][C:13]2[C:18]([CH:19]=3)=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7](=[O:22])[C:6]=1[CH3:23])[CH2:3][CH3:4].[CH3:24][C:25]([CH3:45])([O:27][C:28]([NH:30][CH2:31][CH2:32][C:33](OC1C=CC([N+]([O-])=O)=CC=1)=[O:34])=[O:29])[CH3:26].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCCl>[CH3:23][C:6]1[C:7](=[O:22])[N:8]2[C:20](=[CH:21][C:5]=1[CH:2]([O:1][C:33](=[O:34])[CH2:32][CH2:31][NH:30][C:28]([O:27][C:25]([CH3:26])([CH3:24])[CH3:45])=[O:29])[CH2:3][CH3:4])[C:11]1=[N:12][C:13]3[C:18]([CH:19]=[C:10]1[CH2:9]2)=[CH:17][CH:16]=[CH:15][CH:14]=3
Reactant: CCC(O)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Reactant: CC(C)(C)OC(=O)NCCC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCC(OC(=O)CCNC(=O)OC(C)(C)C)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Reaction time: 312 h

Procedure:
A mixture containing (±)-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one (61.2 mg, 0.20 mmol), 4-dimethylaminopyridine (7.4 mg, 0.06 mmol), 4-nitrophenyl 3-[[(1,1-dimethylethoxy)carbonyl]amino]propionate (248 mg, 0.80 mmol) and dry triethylamine (222 mL, 1.60 mmol) in 1,2-dichloroethane (5 mL) under an argon atmosphere was heated at reflux for 5 d. Thin layer chromatographic analysis at this time indicated that the reaction was incomplete, so the mixture was transferred to a pressure bottle and heated at 90°-95° C. for 1 d. Afterwards, additional 4-nitrophenyl 3-[[(1,1-dimethylethoxy)carbonyl]amino]propionate (248 mg, 0.80 mmol) and dry triethylamine (222 mL, 1.60 mmol) were added, and heating was continued for 13 d. The mixture was then purified by flash chromatography eluting with a solvent gradient of 0-3% MeOH/CH2Cl2. The material that was isolated was recrystallized from Et2O and dried in vacuo to afford the title compound, mp 155°-8° C. 1H NMR (CDCl3) d 8.35 (s, 1H), 8.22 (d, J=8.6 Hz, 1H), 7.91 (d, J=7.2 Hz, 1H), 7.81 (m, 1H), 7.63 (m, 1H), 7.32 (s, 1H), 5.90 (dd, J=7.7, 6.1 Hz, 1H), 5.26 (s, 2H), 5.02 (br s, 1H), 3.44 (m, 2H), 2.66 (q, J=5.8 Hz, 2H), 2.02-1.80 (m, 2H), 1.38 (s, 9H), 0.98 (t, J=7.4 Hz, 3H). Anal. Calcd for C27H31N3O5.1/5 H2O: C, 67.40; H, 6.58; N, 8.73. Found: C, 67.78; H, 6.48; N, 8.35.