Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:5]=[C:6]2[C:10]=1[N:9]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:8]=[CH:7]2.[C:22]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH3:22][O:1][C:2]1[CH:3]=[C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:5]=[C:6]2[C:10]=1[N:9]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:8]=[CH:7]2
Reactant: CCOC(=O)c1cc(O)c2c(cnn2C2CCCCO2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)c1cc(OC)c2c(cnn2C2CCCCO2)c1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a solution of ethyl 7-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylate (1.45 g, 5.0 mmol) in acetone (20 mL) containing K2CO3 (760 mg, 5.50 mmol) was added iodomethane (781 mg, 0.34 mL, 5.5 mmo). The mixture was heated at reflux under N2 overnight. The mixture was cooled to room temperature, filtered, evaporated and partitioned between EtOAc and water. The aqueous phase was extracted with additional EtOAc. The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated to provide crude product. The crude material was purified by chromatography (Isco, 0-40% EtOAc/heptane) to provide material which was dried under high vacuum overnight to afford ethyl 7-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylate (1.40 g, 92%).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH2:23][CH2:24][CH2:25][CH3:26])[C:3](=[O:22])[CH:4]=[CH:5][C@@H:6]1[CH2:10][CH2:9][C:8](=[O:11])[C@H:7]1[CH2:12][CH:13]=[CH:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19].[CH2:28](O)[CH2:29][OH:30].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:28]1[CH2:29][O:30][CH:9]2[CH:8]([CH:7]([CH2:12]/[CH:13]=[CH:14]/[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:6](/[CH:5]=[CH:4]\[CH:3]([OH:22])[C:2]([CH3:27])([CH3:1])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:10]2)[O:11]1
Reactant: CCCCC(C)(C)C(=O)C=C[C@@H]1CCC(=O)[C@H]1CC=CCCCC(=O)OC
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCCC(C)(C)C(O)/C=C\C1CC2OCCOC2C1C/C=C/CCCC(=O)OC
Reaction time: 0.5 h

Procedure:
A mixture of the compound of formula 3 in which L is the radical C, methyl trans-7-[2-(4,4-dimethyl-3-oxo-1-octenyl)-5-oxo-cyclopentyl]-5-heptenoate (2.5 g, γmaxfilm 1730-1725, 1667, 1620 cm-1), ethylene glycol (360 mg) and p-toluenesulfonic acid (35 mg) in 50 ml of benzene is heated at reflux for 2.5 hr. Thereafter the mixture is extracted with ether. The ether extract is washed with water, dried (MgSO4) and concentrated under reduced pressure. The residue containing methyl trans, cis-7-[2-(ethylenedioxy)-5-(4,4-dimethyl-3-oxo-1-octenyl)cyclopentyl-5-heptenoate, γmaxfilm 1730, 1667, 1620 cm-1, is taken up in 20 ml of methanol and treated with sodium borohydride (350 mg) in small portions with stirring which is continued for 30 minutes. The solvent is evaporated under reduced pressure, the residue taken up in ether, washed to neutrality with water, dried (MgSO4) and the solvent concentrated under reduced pressure. The residue is chromatographed on silica gel (140 g). Elution with ethyl acetate-benzene (4:1) and concentration of the eluant affords methyl trans,cis-7-[2-(ethylenedioxy)-5-(3-hydroxy-4,4-dimethyl-1-octenyl)cyclopentyl]-5-heptenoate, γmaxfilm 3460, 1740, 950 cm-1.
Reaction SMILES: C([O:3][C:4]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([C:37]2[NH:41][N:40]=[N:39][N:38]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[C:25]([OH:27])[C:24]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[CH:23][C:22]=2[CH2:35][CH3:36])=[CH:10][CH:9]=1)=[O:5])C.C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)C>[C:4]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([C:37]2[NH:41][N:40]=[N:39][N:38]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[C:25]([OH:27])[C:24]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)=[CH:23][C:22]=2[CH2:35][CH3:36])=[CH:10][CH:9]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)COc1ccc(C(CCCCCOc2cc(O)c(-c3ccc(F)cc3)cc2CC)c2nnn[nH]2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCc1cc(-c2ccc(F)cc2)c(O)cc1OCCCCCC(c1ccc(OCC(=O)O)cc1)c1nnn[nH]1

Procedure:
Crude 1-(4-(ethoxycarbonylmethoxy)phenyl)-1-(1H-tetrazol-5-yl)-6-(2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy)hexane (50 mg) was dissolved in ethanol (20 mL). 1M Aqueous sodium carbonate solution was added and the resultant solution stirred at room temperature for 3 hours. The pH of the solution was then adjusted to 2 using 1M hydrochloric acid and the solution extracted 5 times with chloroform. The combined chloroform extracts were dried with magnesium sulfate and evaporated to an oil which was purified on a reverse phase HPLC C18 column eluting with methanol/water (85:15) and 0.1% acetic acid. On removal of the solvent 9.7 mg of the title compound was obtained as a colorless oil. MS, NMR.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[S:7]1[C:11]([CH2:12][CH2:13][NH2:14])=[CH:10][C:9]2[CH:15]=[CH:16][CH:17]=[CH:18][C:8]1=2>C(Cl)(Cl)Cl.C(N(CC)CC)C>[S:7]1[C:11]([CH2:12][CH2:13][NH:14][C:2](=[O:3])[O:4][CH2:5][CH3:6])=[CH:10][C:9]2[CH:15]=[CH:16][CH:17]=[CH:18][C:8]1=2
Reactant: NCCc1cc2ccccc2s1
Reactant: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)NCCc1cc2ccccc2s1
Reaction time: 0.5 h

Procedure:
Ethyl chloroformate (0.18 ml) was added dropwise to a stirred, ice-cooled solution of benzo[b]thiophene-2-ethanamine (300 mg) in a mixture of chloroform (8 ml) and triethylamine (0.28 ml) under nitrogen and stirring was continued at 0° for 30 min. The solution was evaporated, the residue was treated with water (10 ml), extracted with dichloromethane (3×10 ml) and the combined, dried organic extracts were evaporated to give an oily solid. This was purified by FCC eluting with System B (1:2) to give the title compound (313 mg), m.p. 65°-66°.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH:23]2[CH2:25][CH2:26][CH:20]1[CH2:21][CH2:22]2>C1(C)C=CC=CC=1>[C:1]1([C:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)([CH2:17][CH2:18][N:19]2[CH2:24][CH:23]3[CH2:25][CH2:26][CH:20]2[CH2:21][CH2:22]3)[C:8]#[N:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCCN1CC2CCC1CC2
Reactant: N#CC(c1ccccc1)c1cccnc1
Solvent: Cc1ccccc1
Product: N#CC(CCN1CC2CCC1CC2)(c1ccccc1)c1cccnc1

Procedure:
α-Phenyl-3-pyridylacetonitrile (U.S. Pat. No. 3,225,054) is reacted with 2-(2-chloroethyl)-2-azabicyclo[2.2.2]octane in toluene to provide 2-phenyl-2-(3-pyridyl)-4-(2-azabicyclo[2.2.2]oct-2-yl)butyronitrile. This nitrile is reacted with sodium azide in DMF containing lithium chloride to provide 5-[1-phenyl-1-(3-pyridyl)-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-1H-tetrazole. Reaction this tetrazole with acetic anhydride in pyridine provides 5-[1-phenyl-1-(3-pyridyl)-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-2-methyl-1,3,4-oxadiazole, the oxalate salt melts at 171°-172° C.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([N:13]1[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15][CH2:14]1)=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][CH2:35][CH2:36][C:37](O)=[O:38].C(Cl)CCl.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][CH2:35][CH2:36][C:37]([NH:1][C@H:2]([C:11]([N:13]1[CH2:14][CH2:15][CH:16]([O:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:18]1)=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)=[O:38]
Reactant: O=C(O)CCNc1ccccn1
Reactant: CC(C)(C)OC(=O)COC1CCN(C(=O)[C@@H](N)Cc2ccc(O)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)COC1CCN(C(=O)[C@H](Cc2ccc(O)cc2)NC(=O)CCNc2ccccn2)CC1

Procedure:
A mixture of tert-butyl [(1-tyrosyl-4-piperidinyl)oxy]acetate, Alig, et. al., EP 372486, (1 mmol), N-(2-pyridinyl)-β-alanine, Chowdhary, et. al., Indian J. Chem., 1990, 29A, 280-284, (1 mmol), EDC (1.5 mmol), and DIEA (3 mmol) in DMF (25 mL) is stirred at RT. The mixture is poured into 5% NaHCO3 and extracted with EtOAc. The combined orgainic phase is washed with H2O, dried (MgSO4) and concentrated. The residue is chromatographed (silica gel) to give the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:5]([C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=2)=[O:17])=[CH:4][C:3]=1[F:28]>CCO.[Pd]>[F:28][C:3]1[CH:4]=[C:5]([C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=2)=[O:17])[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)=[N:7][CH:2]=1
Reactant: CC(C)c1ccc(NC(=O)c2cc(F)c(Cl)nc2NCc2ccncc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1ccc(NC(=O)c2cc(F)cnc2NCc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
{6-Chloro-5-fluoro-2-[(4-pyridylmethyl)amino](3-pyridyl)}-N-[4-(methylethyl)phenyl]carboxamide (50 mg, 0.125 mmol, from Example 66) dissolved in EtOH (10 mL) with TEA (0.5 mL) and suspended with Pd/C (10%, 5 mg). The mixture was stirred at RT under a H2 balloon for 45 min. The mixture was filtered through a layer of Celite® and the filtrate was concentrated in vacuo. The residue was partitioned between CH2Cl2 and aq. NaHCO3 (sat.). The organic solution was dried over Na2SO4 and concentrated in vacuo to give the title compound. MS: 365 (M+1). Calc'd. for C21H21FN4O—364.42.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([CH2:18][S:19](Cl)(=[O:21])=[O:20])([CH2:7][N:8]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[N:10]([CH3:16])[C:9]2=[O:17])[C:4](=[O:23])[NH:3]1.[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[N:29][CH:30]=1>>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][CH:32]2[CH2:37][CH2:36][N:35]([S:19]([CH2:18][C:5]3([CH2:7][N:8]4[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[N:10]([CH3:16])[C:9]4=[O:17])[NH:6][C:2](=[O:1])[NH:3][C:4]3=[O:23])(=[O:21])=[O:20])[CH2:34][CH2:33]2)=[N:29][CH:30]=1
Reactant: CN1C(=O)N(CC2(CS(=O)(=O)Cl)NC(=O)NC2=O)C(=O)C1(C)C
Reactant: Clc1ccc(OC2CCNCC2)nc1
Product: CN1C(=O)N(CC2(CS(=O)(=O)N3CCC(Oc4ccc(Cl)cn4)CC3)NC(=O)NC2=O)C(=O)C1(C)C

Procedure:
The title compound was prepared as described in Example 12 from racemic {2,5-dioxo-4-[(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)methyl]imidazolidin-4-yl}methanesulfonyl chloride and 5-chloro-2-(piperidin-4-yloxy)-pyridine.
Reaction SMILES: Cl[CH2:2][C:3](=[O:21])[C@@H:4]([NH:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.[NH2:23][C@H:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH3:25].C(=O)(O)[O-].[Na+].[I-].[Na+]>CN(C)C=O.CCOCC>[C:13]([NH:12][CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](=[O:21])[CH2:2][NH:23][C@H:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH3:25])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)CCl)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C[C@H](NCC(=O)C(Cc1ccccc1)NC(=O)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of (S)-N-[3-chloro-2-oxo-1-(phenylmethyl)propyl]benzamide 10.0 g., 33.1 mmole) in dimethylformamide (80 ml.) is added L-alanine, 1,1-dimethylethyl ester, hydrochloride (6.0 g., 33.1 mmole), sodium bicarbonate (6.1 g., 72 mmole) and sodium iodide (4.9 g., 33.1 mmole). The resulting solution is stirred overnight at room temperature, poured into ether and washed with water (twice) and 10% sodium bicarbonate. The ether solution is extracted with 1N hydrochloric acid (3×), the combined extracts are made basic by the addition of solid sodium bicarbonate and extracted with ethyl acetate (4×). The organic extracts are combined, dried (MgSO4) and concentrated to give 8.9 g. of pale yellow solid. A portion of this material is recrystallized from ethyl acetate to give (S)-N-[3-(benzoylamino)-2-oxo-4-phenylbutyl]-L-alanine, 1,1-dimethylethyl ester as a white solid; m.p. 106.5°-110°.
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.[CH2:19]([O:26][C:27]([C:29]1([NH:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(Br)C=C>O1CCCC1>[CH2:19]([O:26][C:27]([C:29]1([NH:35][CH:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:3][CH:1]=[CH2:2])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:28])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)CNC1(C(=O)OCc2ccccc2)CCCCC1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C=CCBr
Solvent: CCCCCC
Product: C=CCC(NC1(C(=O)OCc2ccccc2)CCCCC1)C(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
To a solution of diisopropylamine (3.03 mL, 21.6 mmol) in dry tetrahydrofuran (75 mL) at -78° C. was added a 2.38M solution of n-butyllithium in hexane (9.07 mL, 21.6 mmol). After 10 minutes, a solution of 1-(tert-butoxycarbonylmethylamino)cyclohexanecarboxylic acid benzyl ester (5.0 g, 14.4 mmol) in tetrahydrofuran (25 mL) was added and the resulting mixture was allowed to warm to -40° C. over 2.5 hours. The mixture was again cooled to -78° C. and allyl bromide was added. The mixture was allowed to warm to 0° C. over 4 hours while stirring and was quenched by addition of a saturated aqueous solution of ammonium chloride. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate and evaporated under vacuum to afford an oil. The oil was chromatographed on silica gel eluting with 1% ethyl acetate in methylene chloride to give 1-(1-tert-butoxycarbonylbut-3-enylamino)cyclohexanecarboxylic acid benzyl ester as an oil, 2.0 g (36%).
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:3]=1[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:19][C@@H:18]([C:20]2[CH:31]=[CH:30][C:23]3[O:24][C:25]([CH3:29])([CH3:28])[O:26][CH2:27][C:22]=3[CH:21]=2)[O:17]C1=O.C[Si](C)(C)[O-].[K+]>C1COCC1>[Cl:1][C:2]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:3]=1[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:19][C@@H:18]([C:20]1[CH:31]=[CH:30][C:23]2[O:24][C:25]([CH3:28])([CH3:29])[O:26][CH2:27][C:22]=2[CH:21]=1)[OH:17]
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4c(Cl)cccc4Cl)C(=O)O3)ccc2O1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCOCc3c(Cl)cccc3Cl)ccc2O1
Reaction time: 3 h
Yield: 97.4 %

Procedure:
A solution of (5R)-3-(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (140 mg) in THF (7 ml) under nitrogen was treated with potassium trimethylsilanolate (130 mg) and the mixture was heated (oil bath temperature 80°) with stirring for 3 h. The mixture was cooled to 20° and was partitioned between phosphate buffer solution (20 ml, pH6.5) and EtOAc (20 ml). The organic phase was separated, dried (NaSO4) and the solvent evaporated in vacuo to give the title compound (130 mg). LCMS RT=3.00 min.
Reaction SMILES: [BrH:1].[NH2:2][NH:3][C:4]([NH:6][N:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1)=[NH:5].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1>>[BrH:1].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[N:2][NH:3][C:4]([NH:6][N:7]=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)=[NH:5])=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: N=C(NN)NN=Cc1ccc(Cl)c(Cl)c1
Agent: Br
Product: N=C(NN=Cc1ccc(Cl)cc1)NN=Cc1ccc(Cl)c(Cl)c1

Procedure:
In a similar manner the reaction of 1-amino-3-(4-bromobenzylideneamino)guanidine methosulfate with 4-chlorobenzaldehyde gives the methosulfate salt of the subject compound. The reaction of 1-amino-3-(4-cyanobenzylideneamino)guanidine hydroiodide with 4-chlorobenzaldehyde gives 1-(4-chlorobenzylideneamino)-3-(4-cyanobenzylideneamino)guanidine hydroiodide; the reaction of 1-amino-3-(4-chlorobenzylideneamino)guanidinehydrochloride with 4-cyanobenzaldehyde affords the corresponding hydrochloride salt which melts at 297°-298° C. The reaction of 1-amino-3-(3,4-dichlorobenzylideneamino)guanidine hydrobromide and 4-chlorobenzaldehyde gives 1-(4-chlorobenzylidene-amino)-3-(3,4-dichlorobenzylideneamino)guanidine hydrobromide; the reaction of 1-amino-3-(4-chlorobenzylideneamino)guanidine hydrochloride with 3,4-dichlorobenzaldehyde gives the corresponding hydrochloride salt which melts at 288° C.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:8]2[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].[NH2:25][NH2:26]>CO>[CH2:12]([O:11][C:10]1[C:9](=[O:19])[N:8]2[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:7]2=[N:6][C:5]=1[C:3]([NH:25][NH2:26])=[O:4])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1nc2ccc(C)cn2c(=O)c1OCc1ccccc1
Reactant: NN
Solvent: CO
Product: Cc1ccc2nc(C(=O)NN)c(OCc3ccccc3)c(=O)n2c1
Temperature: 45 °C
Yield: 78 %

Procedure:
To a stirred solution of the product from Example 8.1 (800 mg, 2.56 mmol) in methanol (30 mL), was added hydrazine (6.0 eq) at room temperature. The mixture was then heated at 45° C. for 4 h then partially concentrated in vacuo (not to dryness), then cooled to room temperature. The resulting solid was filtered, washed with water and dried under vacuum to afford the desired compound (650 mg, yield 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][CH:10]=O)=[CH:7][CH:6]=[CH:5][N:4]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=1)[CH2:16][NH:17][C:18](=[O:26])[CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][NH:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.C(O)(=O)C>[F:12][C:13]1[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=1)[CH2:16][NH:17][C:18](=[O:26])[CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]1[CH2:10][CH2:9][C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ncccc1CC=O
Reactant: O=C(CC1CCCCN1)NCc1cccc(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ncccc1CCN1CCCCC1CC(=O)NCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
200 mg of 2-(2-methoxy-3-pyridyl)acetaldehyde, 400 mg of N1-(3-fluorobenzyl)-2-(2-piperidyl)acetamide, 440 mg of sodium triacetoxyborohydride and 0.12 ml of acetic acid were suspended in THF, followed by stirring at room temperature for 1 hour. An aqueous sodium bicarbonate was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate. After filtering off the drying agent, the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=8:1, subsequently 4:1), to give 370 mg of a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:18][CH:19]2[CH2:21][CH2:20]2)[CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])=[CH:5][C:4]=1[C:22]([F:25])([F:24])[F:23])#[N:2].C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:18][CH:19]2[CH2:20][CH2:21]2)[CH2:10][C:11]([OH:13])=[O:12])=[CH:5][C:4]=1[C:22]([F:23])([F:25])[F:24])#[N:2]
Reactant: CC(C)(C)OC(=O)CN(CC1CC1)c1ccc(C#N)c(C(F)(F)F)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(N(CC(=O)O)CC2CC2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
A mixture of 1,1-dimethylethyl N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(cyclopropylmethyl)glycinate (5.01 g, 14.1 mmol), TFA (50 mL), and triethylsilane (5 mL) in CH2Cl2 (50 mL) was stirred at ambient temperature for 3 h. When the TLC indicated no remaining starting material, the solvents were removed under reduced pressure, and the residue was stirred in hexane (50 mL) for 12 hours. The solid precipitate was filtered and dried to obtain 2.9 g (71%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J=8.8 Hz, 1H), 6.97 (d, J=2.8 Hz, 1H), 6.78 (dd, J=8.8, 2.8 Hz, 1H), 4.29 (s, 2H), 3.34 (d, J=6.4 Hz, 2H), 1.37 (m, 1H), 0.64 (m, 2H), 0.27 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](C)=[CH:9][NH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].Br[CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[C:29]([F:31])[C:28]([O:32][CH2:33][C:34]([F:37])([F:36])[F:35])=[C:27]([Cl:38])[CH:26]=2)[N:24]=1)=[O:18].[H-].[Na+]>CN(C=O)C>[Cl:38][C:27]1[CH:26]=[C:25]([C:23]2[N:24]=[C:20]([NH:19][C:17](=[O:18])[CH2:16][N:10]3[C:6]4[C:5](=[O:12])[N:4]([CH3:13])[C:3](=[O:14])[N:2]([CH3:1])[C:7]=4[CH:8]=[CH:9]3)[S:21][CH:22]=2)[CH:30]=[C:29]([F:31])[C:28]=1[O:32][CH2:33][C:34]([F:35])([F:36])[F:37]
Reactant: O=C(CBr)Nc1nc(-c2cc(F)c(OCC(F)(F)F)c(Cl)c2)cs1
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ccn2CC(=O)Nc2nc(-c3cc(F)c(OCC(F)(F)F)c(Cl)c3)cs2)n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (33 mg, 0.184 mmol) with 2-bromo-N-{4-[3-chloro-5-fluoro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl}acetamide (70 mg, 0.156 mmol) in the presence of NaH (11 mg, 0.458 mmol) in dry DMF (5.0 mL) to give 11 mg of the product as an off-white solid; 1H NMR (δ ppm, DMSO-d6, 300 MHz) 3.17 (s, 3H), 3.39 (s, 3H), 4.84 (q, J=8.7 Hz, 2H), 5.32 (s, 2H), 6.23 (s, 1H), 7.35 (s, 1H), 7.82-7.91 (m, 3H), 12.71 (br s, 1H); APCI-MS (m/z) 546.03 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][N:22]=1.Cl>[OH-].[K+].C(O)C.C(#N)C>[Cl:20][C:21]1[N:22]=[CH:23][C:24]([C:25]([NH:1][C@H:2]([C:4]([N:6]2[CH2:13][CH2:12][CH2:11][C@H:7]2[C:8]([OH:10])=[O:9])=[O:5])[CH3:3])=[O:26])=[CH:28][CH:29]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: C[C@H](NC(=O)c1ccc(Cl)nc1)C(=O)N1CCC[C@H]1C(=O)O
Yield: 39.8 %

Procedure:
L-Alanyl-L-proline (1.0 g, 5.4 mmol) is dissolved in a mixture of 10.8 ml of 0.5 N potassium hydroxide and 750 mg (5.4 mmol) of anhydrous potassium carbonate, and 10 ml of acetonitrile are added. After cooling in an ice bath, a concentrated acetonitrile solution of 1.2 g of 6-chloronicotinoyl chloride is added dropwise while stirring and keeping the pH of the mixture at 12 to 13 with 1N potassium hydroxide, as necessary. Stirring is continued for 2 additional hours at room temperature, then the solution is neutralized to pH 6 with aqueous hydrochloric acid, and the solvent is distilled off under reduced pressure. The residue thus obtained is suspended in 50 ml of absolute ethanol, the remaining potassium chloride is separated by centrifugation, and the solvent of the clear solution is distilled off under reduced pressure. The crude product is purified through silica gel column chromatography, using absolute ethanol as eluant, to isolate 700 mg of the desired product (yield: 40%).