Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]([CH2:20][C:21](O)=[O:22])[S:10]([C:13]2[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[CH2:24]([NH:26][CH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1)[CH3:25]>>[C:32]([C:31]1[CH:34]=[CH:35][C:28]([CH2:27][N:26]([CH2:24][CH3:25])[C:21](=[O:22])[CH2:20][N:9]([C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[S:10]([C:13]2[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:11])=[O:12])=[CH:29][CH:30]=1)#[N:33]
Reactant: CCNCc1ccc(C#N)cc1
Reactant: COc1ccc(N(CC(=O)O)S(=O)(=O)c2ccccc2C)cn1
Product: CCN(Cc1ccc(C#N)cc1)C(=O)CN(c1ccc(OC)nc1)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-acetic acid with 4-ethylaminomethyl-benzonitrile
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][C:6]([F:15])=[C:7]([F:14])[CH:8]=2)[N:3]=1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18].N1C=CC=CC=1>ClCCl>[F:15][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][C:7]=1[F:14])[N:10]=[C:11]([O:12][CH3:13])[C:2]([NH:1][C:17](=[O:18])[O:19][CH2:20][CH3:21])=[N:3]2
Reactant: CCOC(=O)Cl
Reactant: COc1nc2cc(F)c(F)cc2nc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1nc2cc(F)c(F)cc2nc1OC
Temperature: 25 °C
Reaction time: 13 h
Yield: 59.8 %

Procedure:
2-Amino-6,7-di fluoro-3-methoxyquinoxaline (550 mg, 2.60 mmol) and ethyl chloroformate (564 mg, 5.20 mmol) were dissolved in dichloromethane (50 ml) at room temperature and thereto pyridine (411 mg, 5.20 mmol) was added. The mixture was stirred at room temperature for 13 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (3:1) mixture and concentration gave 440 mg of the titled compound (yield, 60%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:23]=[CH:22][C:8]2[N:9]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=4)[N:12]=[C:10]3[S:11][C:7]=2[CH:6]=1.[C:24]([C:28]1[O:32][N:31]=[C:30]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[C:24]([C:28]1[O:32][N:31]=[C:30]([NH:33][C:34]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([C:13]3[N:12]=[C:10]4[N:9]([CH:14]=3)[C:8]3[CH:22]=[CH:23][C:5]([O:4][CH2:3][CH2:2][Cl:1])=[CH:6][C:7]=3[S:11]4)=[CH:16][CH:17]=2)=[O:35])[CH:29]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)no1
Reactant: Nc1ccc(-c2cn3c(n2)sc2cc(OCCCl)ccc23)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OCCCl)ccc34)cc2)no1

Procedure:
A mixture of 7-(2-chloro-ethoxy)-2-(4-amino-phenyl)-benzo[d]imidazo[2,1-b]thiazole (1 equivalent) and phenyl 5-tert-butylisoxazol-3-ylcarbamate, prepared as described in WO 2006/082404 A1 (1 equivalent) in anhydrous THF is stirred at selected temperatures between rt and 50° C. until the reaction is substantially complete as monitored by LCMS or TLC. The mixture is concentrated under reduced pressure and the residue is partitioned between water and either dichloromethane or a mixture of dichloromethane and isopropanol. The separated aqueous layer is further extracted with dichloromethane or a mixture of isopropanol and dichloromethane, and the combined organic layers are dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel flash chromatography to afford 1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[7-(2-chloro-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[N:21][N:22]4[CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29]3)=[O:16])=[CH:13][N:14]=[C:8]2[CH:7]=1.[ClH:41]>C(Cl)Cl.O1CCOCC1>[ClH:41].[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[N:21][N:22]4[CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]3)=[O:16])=[CH:13][N:14]=[C:8]2[CH:7]=1
Reactant: COCCOc1ccn2c(C(=O)Nc3cccc4c3cnn4CC3CCCN(C(=O)OC(C)(C)C)C3)cnc2c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COCCOc1ccn2c(C(=O)Nc3cccc4c3cnn4CC3CCCNC3)cnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
A solution of tert-butyl 3-((4-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)piperidine-1-carboxylate (0.056 g, 0.10 mmol) in DCM (1 mL) was treated with 4N hydrochloric acid in dioxane (1 mL) at ambient temperature. The mixture was stirred at ambient temperature overnight, concentrated to afford 7-(2-methoxyethoxy)-N-(1-(piperidin-3-ylmethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide hydrochloride (0.0046 g, 93% yield) as a brown oil. MS (APCI) m/z=449 (M+H).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([O:21]C)=[O:20])=[CH:17][C:18]=4[N:9]3[CH2:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.CNCC(N1CCOCC1)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH-].[Na+].Cl>CN(C=O)C.O.C1COCC1.CO.C(N(CC)CC)C>[CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[CH:17][C:18]=4[N:9]3[CH2:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNCC(=O)N1CCOCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 7H-indolo[2,1-a][2]benzazepine-10-carboxylate, 13-cyclohexyl, 6-carboxylic acid, 3-methoxy (200 mg, 0.45 mmol), 2-(methylamino)-1-morpholinoethanone (86 mg, 0.54 mmol) and triethylamine (0.19 mL) in DMF (3 mL) was added HATU (205 mg, 0.54 mmol). The reaction mixture was stirred at rt for 2 h, diluted with H2O (˜12 mL) and the resulting solids were collected by filtration, washed with H2O and dried on the filter with aspirator vacuum for 1 h. The solids were dissolved into THF/MeOH (1:1, 4 mL) and 1M NaOH (aq.) (1.0 mL, 1.0 mmol). The reaction mixture was heated in a sealed tube with microwave irradiation at 85° C. for 20 min. The reaction was cooled, neutralized with 1M HCl (aq.) (1.0 mL, 1.0 mmol) and concentrated. The residue was slurried with H2O and the solids were collected by filtration, flushed with H2O, dried and purified by preparative HPLC (MeOH/H2O with an NH4OAc buffer) to yield 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-3-methoxy-6-[[methyl[2-(4-morpholinyl)-2-oxoethyl]amino]carbonyl]- (163 mg, 0.29 mmol, 63%) as a yellow solid and 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 6-[[(carboxymethyl)methylamino]carbonyl]-13-cyclohexyl-3-methoxy- (13 mg, 0.03 mmol, 6%) as a yellow solid. Data for 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-3-methoxy-6-[[methyl[2-(4-morpholinyl)-2-oxoethyl]amino]carbonyl]-: 1HNMR (300 MHz, CDCl3) δ 8.26 (br s. 1H), 7.85 (d, J=8.4 Hz, 1H), 7.74 (dd, J=1.1, 8.4 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.03 (dd, J=2.7, 8.8 Hz, 1H), 7.00-6.92 (m, 1H), 6.89 (br s, 1H), 5.23-5.06 (m, 1H), 4.47-4.31 (m, 1H), 3.87 (s, 3H), 3.78-3.37 (m, 6H), 3.05-2.73 (m, 5H), 2.13-1.69 (m, 6H), 2.08 (s, 3H), 1.46-1.13 (m, 4H). LCMS: m/e 570 (M−H)−, ret time 1.38 min, column A, 2 minute gradient. Data for 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 6-[[(carboxymethyl)methylamino]carbonyl]-13-cyclohexyl-3-methoxy-. 1HNMR (300 MHz, DMSO-d6) δ 8.09 (s. 1H), 7.82 (d, J=9.5 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.47 (d, J=9.5 Hz, 1H), 7.24-6.95 (m, 3H), 5.20-5.02 (m, 1H), 4.23-4.04 (m, 1H), 3.86 (s, 3H), 3.86-3.74 (m, 2H), 2.85 (s, 3H), 2.82-2.71 (m, 1H), 2.12-1.12 (m, 10H). LCMS: m/e 503 (M+H)+, ret time 2.83 min, column B, 3 minute gradient.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[CH:17](I)([CH3:19])[CH3:18]>C(#N)C>[CH:17]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)([CH3:19])[CH3:18]
Reactant: CC(C)I
Reactant: Oc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)Oc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.4 %

Procedure:
To a solution of 5-hydroxyindole 23 (2.0 g, 0.015 mol) in 20 ml of acetonitrile, anhydrous potassium carbonate (4 grams, 0.028 mol) was added and stirred vigorously before isopropyl iodide (3 grams, 0.018 mol) was added. The reaction was stirred for 2 days at room temperature and the solid was washed with acetonitrile. The filtrate was concentrated and purified with flash-chromatography (80% n-hexane/20% ethyl acetate) to give the desired product 24 as a light-yellowish oil (1.72 g, 83%; M+1=176.1).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Si:14]([CH3:17])([CH3:16])[CH3:15].C(O[B:22]1[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]1)(C)C.C(=O)=O.CC(C)=O.Cl>O1CCCC1.O>[F:6][C:7]1[C:12]([F:13])=[C:11]([B:22]2[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]2)[CH:10]=[CH:9][C:8]=1[Si:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: C[Si](C)(C)c1cccc(F)c1F
Agent: Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc([Si](C)(C)C)c(F)c2F)OC1(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
A 2.5 M solution of n-butyl lithium (9.5 mL, 24 mmol, 1.1 equiv) was added to a stirred solution of (2,3-difluorophenyl)trimethylsilane (4.0 g, 21 mmol, 1.0 equiv) in tetrahydrofuran (86 mL) at −78° C. The resulting very pale yellow solution was stirred at −78° C. for 1 h. 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.8 mL, 24 mmol, 1.1 equiv) was added and the pale yellow solution was allowed to slowly warm to 23° C., by allowing the dry ice/acetone bath to melt, and stirred for 20 h. The reaction mixture was diluted with water (200 mL), adjusted to approximately pH 4 using 1M hydrochloric acid, and extracted with dichloromethane (3×100 mL). The combined organic layers were dried (magnesium sulfate), gravity filtered, and concentrated by rotary evaporation to afford the title compound as a white powder (6.4 g, 96%): 1H NMR (400 MHz, CDCl3) δ 7.42 (ddd, J=7.5, 4.5, 0.5 Hz, 1H), 7.09 (ddd, J=7.5, 4, 1 Hz, 1H), 1.34 (s, 12H), 0.29 (d, J=1 Hz, 9H).
Reaction SMILES: [C:1]([C:4]1([NH:10][S:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)(=O)=O)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)(=O)[CH3:2].[H-].[Na+].O>CN(C=O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[S:11][NH:10][C:4]3([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]3)[C:1]=2[CH3:2])=[CH:16][CH:17]=1
Reactant: CC(=O)C1(NS(=O)(=O)Cc2ccc(Cl)cc2)CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1=C(c2ccc(Cl)cc2)SNC12CCCCC2
Temperature: 120 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
To N-(1-acetylcyclohexyl)-(4-chlorophenyl)methane-sulfonamide (612 mg, 1.86 mmol), from Example 1, in dry DMF (6 mL) was added NaH (60%, 2.2 eq.) under Ar. The mixture was stirred overnight at 120° C., water was added and the solution was extracted with ethyl acetate. The organic layer was washed with NaCl solution and water, dried (Na2SO4) and concentrated. Recrystallization from ethyl acetate yielded 0.37 g (64%) of 3-(4-chlorophenyl)-4-methyl-2-thia-1-azaspiro[4.5]dec-3-ene, 2,2-dioxide, shown below as a solid. MS (IS): 312 [MH]+
Reaction SMILES: [F:1][CH:2]([F:19])[C@:3]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[NH:8][C:7](=[O:9])[CH2:6][CH2:5][C:4]1([F:11])[F:10].OS(O)(=O)=O.[N+:25]([O-])([OH:27])=[O:26].[OH-].[Na+]>FC(F)(F)C(O)=O>[F:19][CH:2]([F:1])[C@:3]1([C:12]2[CH:17]=[C:16]([N+:25]([O-:27])=[O:26])[CH:15]=[CH:14][C:13]=2[F:18])[NH:8][C:7](=[O:9])[CH2:6][CH2:5][C:4]1([F:11])[F:10]
Reactant: O=[N+]([O-])O
Reactant: O=C1CCC(F)(F)[C@](c2ccccc2F)(C(F)F)N1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCC(F)(F)[C@](c2cc([N+](=O)[O-])ccc2F)(C(F)F)N1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
(S)-6-(difluoromethyl)-5,5-difluoro-6-(2-fluorophenyl)piperidin-2-one (880 mg, 3.15 mmol) was suspended in trifluoroacetic acid (2.55 mL). The mixture was cooled to 0° C. and concentrated H2SO4 (2.46 g, 24.3 mmol) was added. Then, HNO3 (661.61 mg, 6.30 mmol) was added dropwise. After 2 hours of stirring at 25° C., the reaction mixture was poured onto 100 g ice and basified to pH>11 using 5 M NaOH (aq). The suspension was extracted with ethyl acetate (150 mL). The phases were separated and the aqueous layer was extracted with ethyl acetate (2×70 mL). The combined organic phases were washed with a solution of saturated aqueous NH4Cl (30 mL) and water (30 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to afford (S)-6-(difluoromethyl)-5,5-difluoro-6-(2-fluoro-5-nitrophenyl)piperidin-2-one (1.00 g, crude).
Reaction SMILES: Cl[Si](C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:12]([P:19]([CH2:27][C:28]12O[C:29]1([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][P:42]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH:30]=[CH:31][CH:32]1O[CH:33]12)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[CH2:50]([P:42]([CH2:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][P:19]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: C1=CC2(c3ccccc3CP(Cc3ccccc3)Cc3ccccc3)OC2(CP(Cc2ccccc2)Cc2ccccc2)C2OC12
Agent: C[Si](C)(C)Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: c1ccc(CP(Cc2ccccc2)Cc2ccccc2-c2ccccc2CP(Cc2ccccc2)Cc2ccccc2)cc1
Temperature: -35 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
Chlorotrimethylsilane (4.1 ml, 32.2 mmol) was added to lithium aluminum hydride (1.22 grams, 32.2 mmol) in THF (20 ml) at -72° C. The mixture was removed from the cold bath, stirred two hours, and then cooled again at -35° C. A suspension of the above 2,2'-bis(dibenzylphosphinomethyl)-1,1'-biphenyl dioxide (3.40 grams, 5.32 mmol) in THF (45 ml) was added by cannula. The mixture was stirred 0.5 hour at -30° C., then overnight at room temperature. The reaction mixture was cooled in an ice bath and quenched by the successive, dropwise addition of water (1.2 ml), 15% aqueous NaOH (1.2 ml) and water (3.6 ml). The resulting mixture was filtered, and the solid was washed with diethyl ether. The filtrate was evaporated on the steam bath under a stream of nitrogen. The residual solid was heated in ethanol, then cooled and filtered to give 2.00 grams (62% yield) of white solid, melting point 163° to 167° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([S:15]C(CCCCC3C=CC=CC=3)CC(NO)=O)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].CO>O1CCCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([SH:15])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(SC(CCCCc2ccccc2)CC(=O)NO)cc1OC1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(S)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 138.4 %

Procedure:
A suspension of 3,3′-dicyclopentyloxy-4,4′-dimethoxyphenyldisulfide (15 g, Reference Example 3) and sodium borohydride (3.18 g) in anhydrous tetrahydrofuran (150 ml) at reflux was treated dropwise with anhydrous methanol (15 ml) over 1 hour. The cloudy yellow solution was stirred at reflux for 30 minutes then cooled to room temperature and stirring was continued for 18 hours. The reaction mixture was partitioned between hydrochloric acid (400 ml, 1N) and diethyl ether (400 ml). The aqueous layer was extracted three times with diethyl ether (200 ml). The combined organic phases were washed with hydrochloric acid (100 ml), then with water (100 ml) and then extracted three times with sodium hydroxide solution (200 ml, 0.2N) and once with water (200 ml). The combined aqueous extracts were acidified by addition of hydrochloric acid (1N) and then extracted five times with diethyl ether (200 ml). The combined ether extracts were washed with water (200 ml) then with brine (200 ml), then dried over magnesium sulphate and then evaporated to give the title compound (10.5 g) as a pale yellow oil. NMR (CDCl3): δ1.60 (m,2H), 1.80-2.00 (m,6H), 3.40 (s,1H), 3.80 (s,3H), 4.73 (m,1 H), 6.74 (d,1H), 6.88 (dd,2H). Mass spectrum (FAB): m/z 224 (M)+.
Reaction SMILES: [NH2:1][C@H:2]([C:12](=[O:20])[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][S:8][C:9](=[O:11])[CH3:10].FC(F)(F)C([O-])=O.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[O:70]=[C:71]1[C@H:75]([C:76](O)=[O:77])[C@@H:74]([C:79]2[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=2)[CH2:73][NH:72]1>C(Cl)Cl.CN(C=O)C>[O:70]=[C:71]1[CH:75]([C:76]([NH:1][C@H:2]([C:12](=[O:20])[NH:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][S:8][C:9](=[O:11])[CH3:10])=[O:77])[CH:74]([C:79]2[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=2)[CH2:73][NH:72]1
Reactant: O=C(O)[C@H]1C(=O)NC[C@@H]1c1ccccc1
Reactant: CC(=O)SCCCCC[C@H](N)C(=O)Nc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])C(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)SCCCCC[C@H](NC(=O)C1C(=O)NCC1c1ccccc1)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thioacetic acid S—((S)-6-amino-6-phenylcarbamoyl-hexyl) ester-trifluoroacetate (1.03 mmol), DIPEA (3.08 mmol) and PyBOP (1.03 mmol) were added to a solution of (3R*,4S*)-2-oxo-4-phenyl-pyrrolidine-3-carboxylic acid in DCM/DMF: 5/9. The resulting reaction mixture was stirred at RT overnight. After removal of the solvent under reduced pressure, the resulting solid was poured into water and extracted twice with AcOEt. The organic layer was then washed with NaHCO3, water and brine before being dried over Na2SO4 and concentrated under reduced pressure to yield an oil. The latter was partially purified by silica gel chromatography and then subjected to HPLC purification.
Reaction SMILES: [O:1]=[C:2]([NH:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21]1[N:29]=[C:28]([NH:30][C@H:31]3[CH2:36][CH2:35][C@H:34]([NH:37]C(OC(C)(C)C)=O)[CH2:33][CH2:32]3)[N:27]=[C:26]3[C:22]=1[N:23]=[CH:24][N:25]3C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl>CO>[NH2:37][C@H:34]1[CH2:33][CH2:32][C@H:31]([NH:30][C:28]2[N:27]=[C:26]3[C:22]([N:23]=[CH:24][NH:25]3)=[C:21]([N:17]3[C:18]4[C:14](=[CH:13][C:12]([NH:11][C:2](=[O:1])[CH2:3][CH2:4][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=5)=[CH:20][CH:19]=4)[CH2:15][CH2:16]3)[N:29]=2)[CH2:36][CH2:35]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(N3CCc4cc(NC(=O)CCc5ccccc5)ccc43)c3ncn(C(=O)OC(C)(C)C)c3n2)CC1
Agent: Cl
Solvent: CO
Product: N[C@H]1CC[C@H](Nc2nc(N3CCc4cc(NC(=O)CCc5ccccc5)ccc43)c3nc[nH]c3n2)CC1
Reaction time: 48 h

Procedure:
The product obtained in stage 1 is dissolved in 2 ml of methanol. 2 ml of a 2N solution of hydrochloric acid in methanol are added. Stirring is carried out for 48 hours at ambient temperature, followed by evaporation to dryness. The residue is chromatographed on an Xterra LCMSprep column, eluting with acetonitrile/ammonium hydrogen carbonate buffer at 0.2% at a gradient. 4 mg of expected product, example 42, are thus recovered.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[OH:28][C:29]1([C:32](O)=[O:33])[CH2:31][CH2:30]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32]([C:29]5([OH:28])[CH2:31][CH2:30]5)=[O:33])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)C1(O)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)C1(O)CC1

Procedure:
The title compound, off-white solid (41 mg, 40%), MS (ISP) m/z=415.4 [(M+H)+], mp 174.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 1-hydroxy-cyclopropanecarboxylic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[N:15]3)[S:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.C1(/C=C/B(O)O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].C(COC)OC>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.O>[C:4]1([C:8]2[N:9]=[C:10]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[N:15]3)[S:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cccc(Br)c3)cs2)c1
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: OB(O)/C=C/c1ccccc1
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1cnn(Cc2nc(-c3ccccc3)cs2)c1
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 15.3 %

Procedure:
Under an argon atmosphere, a mixture of the compound (400 mg, 1.02 mmol) obtained in Example 27a, [(E)-2-phenylethenyl]boronic acid (200 mg, 1.33 mmol), tetrakistriphenylphosphinepalladium (118 mg, 0.10 mmol), potassium carbonate (282 mg, 2.04 mmol), dimethoxyethane (5 mL) and water (1 mL) was stirred under microwave conditions at 150° C. for 10 min. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by column chromatography (hexane-hexane/ethyl acetate=70/30) to give a compound (49 mg, 12%) shown in Example 27b as a pale-yellow oil and a compound (85 mg, 27%) shown in Example 27c as a pale-red oil.
Reaction SMILES: Cl.[NH2:2][OH:3].N1C=CC=CC=1.[CH2:10]([CH:26]1[CH2:31][C:30](=[O:32])[O:29][C:27]1=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]C>C(#N)C>[OH:3][NH:2][C:30](=[O:32])[CH2:31][CH:26]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:27]([OH:29])=[O:28]
Reactant: NO
Reactant: CCCCCCCCCCCCCCCCC1CC(=O)OC1=O
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(CC(=O)NO)C(=O)O

Procedure:
HA-4 (2-[2-(hydroxyamino)-2-oxoethl]heptadecanoic acid) was prepared as follows. Hydroxylamine hydrochloride (18.07 g, 0.26 moles) was dissolved in pyridine (18.49 g, 0.26 moles) by stirring the mixture for one-half hour at 26° C. n-Hexadecyl succinic anhydride (88.14 g, 0.27 moles, available from Tokyo Kasei Kogyo Co. Ltd., Tokyo, Japan) was added to the solution followed by the addition of acetonitrile (about 50 ml). The resulting mixture was refluxed for two hours, cooled, and the solvent removed under reduced pressure using a rotary evaporator. Hydrochloric acid (10%) in water (100 ml) was added to the resulting residue and the mixture filtered to recover the suspended solids. The filtrate was dispersed in water to dissolve the pyridinium hydrochloride by-product of the reaction and the dispersion filtered and the solid retained. The process of washing with water and filtering was repeated several times, yielding 2-[2-(hydroxyamino)-2-oxoethyl]heptadecanoic acid as a solid.