Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([CH2:21][O:22][CH:23]([CH3:29])[C:24]([O:26]CC)=[O:25])[N:17]=2)[CH2:11][C:12]([NH:14][OH:15])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+]>O1CCOCC1.O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([CH2:21][O:22][CH:23]([CH3:29])[C:24]([OH:26])=[O:25])[N:17]=2)[CH2:11][C:12]([NH:14][OH:15])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(C)OCc1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(OCc1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1)C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
A solution of ethyl 2-[(5-{(1R)-4-cyclohexyl-1 -[2-(hydroxyamino)-2-oxoethyl]butyl}-1,2,4-oxadiazol-3-yl)methoxy]propanoate (Example 51) (184 mg, 0.45 mmol) in 1,4-dioxan (4 ml) and water (2 ml) was cooled to 0° C. and treated with lithium hydroxide monohydrate (2 mg, 0.48 mmol) and stirred at 0° C. for 2 hours. The solvent was partially removed under reduced pressure and diluted with water and washed with diethylether (×2). The aqueous layer was acidified to pH 1 with hydrochloric acid (2M) and washed with ethyl acetate (×2). The combined organic layers were washed with brine, dries over anhydrous sodium sulphate, filtered and the solvent was removed under reduced pressure to afford the title compound as a colourless oil (160 mg).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[S:18](=[O:21])(=[O:20])[CH2:19][C:10]=3[C:9]([C:22](O)=[O:23])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>C(Cl)Cl.CN(C=O)C.Cl>[N:31]1([C:22]([C:9]2[C:10]3[CH2:19][S:18](=[O:20])(=[O:21])[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:11]=3[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)=[O:23])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: O=C(O)c1nn(-c2ccccc2)c2c1CS(=O)(=O)c1ccccc1-2
Reactant: C1COCCN1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(c1nn(-c2ccccc2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-phenyl-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid 5,5-dioxide (150.00 mg; 0.44 mmol; 1.00 Eq) is suspended in DCM (4.00 ml) and 2 drops of DMF and then Oxalyl chloride (3 mL) is added dropwise. The reaction mixture is stirred at room temperature for 30 min. The solution is evaporated to dryness. The residue is suspended in DCM (4.00 ml) and morpholine (350.00 μL; 4.02 mmol; 9.12 Eq) is added dropwise. The reaction mixture is stirred at rt for 30 min then diluted with aq. solution of HCl 0.05 M. The two layers are separated. The aqueous layer is extracted with DCM (2×). The organic layers are washed with a saturated solution of NaHCO3 and brine, dried over MgSO4 and evaporated to give foam. The foam is recrystallised in EtOH to the title compound as a white solid. 1H NMR (DMSO-d6, 300 MHz) δ 8.04-8.01 (m, 1H), 7.67-7.53 (m, 7H), 6.85-6.82 (m, 1H), 4.91 (s, 2H), 3.98-3.94 (m, 2H), 3.68-3.61 (m, 6H). UPLC/MS: (ES+): 410.1, (ES−): 408.1. HPLC (max plot) 100.0%; Rt 3.36 min.
Reaction SMILES: C(=S)=S.[Br:4]Br.O.[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15]>>[Br:4][C:12]1[CH:11]=[CH:10][C:9]([O:14][CH3:15])=[C:8]([F:7])[CH:13]=1
Reactant: COc1ccccc1F
Reactant: BrBr
Solvent: S=C=S
Solvent: O
Product: COc1ccc(Br)cc1F

Procedure:
To 50 ml of carbon disulfide in which 50 g of o-fluoroanisole was dissolved, a solution prepared by mixing 27 g of carbon dislufide with 63.8 g of bromine was slowly added dropwise at a temperature of -5° C. to 5° C. in 1 hour with stirring. After the dropping of the solution was finished, it was further stirred at 5° C. for 30 min, added with 125 ml of water, and subjected to extraction with chloroform. The chloroform layer was washed with an aqueous sodium thiosulfate (Na2S2O3) solution and an aqueous sodium hydrogencarbonate (NaHCO3) solution in turn. Then, the solvent was distilled off with an evaporator under a reduced pressure to obtain 70.9 of 4-bromo-2-fluoroanisole.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[C:5]1([CH2:11][CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:5]1([CH2:11][CH2:12][CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([C:1]([Cl:4])=[O:2])[CH2:18][CH2:19]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: c1ccc(CCCC2CCNCC2)cc1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(Cl)N1CCC(CCCc2ccccc2)CC1
Reaction time: 1 h

Procedure:
Phosgene is passed into 150 ml. of dry toluene at 0° C. until 17 g. of gas has been absorbed. The cooling bath is removed, and to the phosgene solution is added, dropwise, with stirring, during 1 hour, a solution prepared from 27.6. g. of 4-(3-phenylpropyl)piperidine, and 12.3 ml. of pyridine and 100 ml. of toluene. After the end of the addition, the reaction mixture is stored at ambient temperature for 16 hours. At this point, the reaction mixture is filtered, and the filtrate is evaporated in vacuo, leaving 39 g. of the title compound in crude state. The product is contaminated with toluene, but it is sufficiently pure for coupling with alkenesulfonamides.
Reaction SMILES: Cl.Cl.[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([C:16]([NH2:18])=[NH:17])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:25][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][C:35]=1[F:36])[C:29](=O)[CH2:30]Br>CN(C)C=O.C(OCC)(=O)C>[CH2:3]([N:10]1[CH2:11][CH2:12][CH:13]([C:16]2[NH:18][C:29]([C:28]3[CH:33]=[CH:34][C:35]([F:36])=[C:26]([Cl:25])[CH:27]=3)=[CH:30][N:17]=2)[CH2:14][CH2:15]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(CBr)c1ccc(F)c(Cl)c1
Reactant: N=C(N)C1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1ccc(-c2cnc(C3CCN(Cc4ccccc4)CC3)[nH]2)cc1Cl
Temperature: 45 °C
Reaction time: 0.08 h
Yield: 77.6 %

Procedure:
Dissolve 1-benzyl-piperidine-4-carboxamidine dihydrochloride (2 g; 1.00 equiv; 6.89 mmoles) in dimethylformamide (90 mL). Add powdered potassium carbonate (4 equiv; 27.56 mmoles; 3.8095 g) and warm to ˜45° C. Add 3-chloro-4-fluoro-phenacyl bromide (2.00 equiv; 13.782 mmoles; 3.5366 g) in 8 mL with DMF dropwise over 40 minutes. Dilute with 50 mL ethyl acetate, stir 5 min and filter. Evaporate and partition with ethyl acetate/sat. sodium bicarbonate, wash organic layer with water, then saturated aqueous sodium chloride. Dry with MgSO4, filter and evaporate to red foam. Purify over flash silica gel with 0-10% MeOH/ACN. Pool fractions to give 1.9772 g (5.346 mmol, 78%) 1-Benzyl-4-[5-(3-chloro-4-fluoro-phenyl)-1H-imidazol-2-yl]-piperidine.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:21]>ClCCl.CCOCC>[ClH:21].[ClH:21].[O:17]1[CH2:16][CH2:15][N:14]([C@H:11]2[CH2:10][CH2:9][C@H:8]([NH2:7])[CH2:13][CH2:12]2)[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N2CCOCC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: N[C@H]1CC[C@H](N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of trans-tert-butyl-4-morpholinocyclohexylcarbamate (19.2 g, 67.5 mmol) in dichloromethane (100 ml) was added HCl (100 ml, 400 mmol) (4M in dioxane) and the reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was diluted with ether and solid salt was filtered off, and dried in an oven.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:29][C:30]1[CH:31]=[N:32][C:33]2[C:38]([CH:39]=1)=[CH:37][CH:36]=[C:35]([OH:40])[CH:34]=2>CN(C=O)C>[F:29][C:30]1[CH:31]=[N:32][C:33]2[C:38]([CH:39]=1)=[CH:37][CH:36]=[C:35]([O:40][C:2]1[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=1)[CH:34]=2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Reactant: Oc1ccc2cc(F)cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4cc(F)cnc4c3)ncnc2cc1OCCCN1CCCC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 28.2 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (218 mg, 0.68 mmol), (prepared as described for the starting material in Example 9), potassium carbonate (138 mg, 1.13 mmol) and 3-fluoro-7-hydroxyquinoline (117 mg, 0.72 mmol), (prepared as described for the starting material in Example 157), in DMF (4.5 ml) was stirred at 100° C. for 4 hours and then allowed to cool to ambient temperature. The reaction mixture was evaporated to dryness and the residue taken up in dichloromethane, washed with water, brine and dried (MgSO4). The organic fractions were evaporated to dryness and the residue recrystallised from acetonitrile to give 4-(3-fluoro-quinolin-7-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (86 mg, 28%).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]=2[N+:19]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1CCCCC=1>C(O)C.[Pd]>[NH2:19][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:8]=1[NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CCOC(=O)c1ccc(NC2CCCCC2)c(N)c1
Temperature: 83 °C
Yield: 85.1 %

Procedure:
In a 250 mL round bottom flask ethyl 4-(cyclohexylamino)-3-nitrobenzoate (3.01 g, 0.0103 mol) was dissolved in ethanol (40 mL) and 1 gram of 5% palladium on carbon (54.62% water) was added. Cyclohexene (7 mL, 0.07 mol) was then added and the reaction heated at 83° C. for 3 hours. The reaction mixture was filtered through celite and the filter cake washed with ethanol. The combined filtrates were concentrated to give 2.3 g title compound as a brownish tan solid.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1>O.CC(C)=O>[C:10]1([CH3:9])[CH:16]=[CH:15][C:13]([NH:14][C:5]2[C:4]([NH:14][C:13]3[CH:15]=[CH:16][C:10]([CH3:9])=[CH:11][CH:12]=3)=[N:3][C:2](=[O:1])[C:7](=[O:8])[CH:6]=2)=[CH:12][CH:11]=1
Reactant: Oc1cccnc1O
Reactant: Cc1ccc(N)cc1
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(NC2=CC(=O)C(=O)N=C2Nc2ccc(C)cc2)cc1
Reaction time: 2 h
Yield: 32 %

Procedure:
2,3-dihydroxypyridine (0.0027 mol), p-methylaniline (0.0054 mol), and NaIO3 (0.0009 mol) were dissolved in 160 ml water/acetone (80:1, v/v) solvent. The reaction mixture was stirred for 2 hours; and maintained still overnight. It was then filtered and recrystallized with chloroform. The final product was 5,6-di(p-tolylamino)-2,3-pyridindione in a red powder. The yield was 32%-54%.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[S:14][CH:15]=[C:16]([Br:18])[CH:17]=2)[C:11]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[F:28])([C:19]#[N:20])[CH:10]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:9]1)=[O:7])(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[Br:18][C:16]1[CH:17]=[C:13]([CH:12]2[C:11]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[F:28])([C:19]#[N:20])[CH:10]([CH2:29][C:30]([CH3:31])([CH3:32])[CH3:33])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[S:14][CH:15]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cc(Br)cs2)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cc(Br)cs2)C1(C#N)c1ccc(Cl)cc1F
Yield: 92 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(4-bromo-thiophen-2-yl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 70b (0.9 g, 1.6 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(4-bromo-thiophen-2-yl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a light blue solid (0.9 g, 92%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:15]C(=O)OC(C)(C)C)[CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])=[CH:5][CH:4]=1>C(Cl)Cl.CO>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([NH2:15])[CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])=[CH:7][CH:8]=1
Reactant: CN(C)CCC(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CN(C)CCC(N)c1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
Hydrogen chloride (4M in dioxane, 1.132 mL, 32.61 mmol) was added to tert-butyl 1-(4-chlorophenyl)-3-(dimethylamino)propylcarbamate (Intermediate 32) (0.051 g, 0.16 mmol) in a mixture of DCM (5 mL) and methanol (2 mL) at 22° C. The resulting solution was stirred at 22° C. for 4 hours. The mixture was concentrated and the residue was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 2M NH3/MeOH and pure fractions were evaporated to dryness to afford 1-(4-chlorophenyl)-N3,N3-dimethylpropane-1,3-diamine (0.032 g, 92%) as a colourless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[CH2:23][CH2:24][NH2:25].[OH-].[NH4+]>O>[F:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[NH:25][CH2:24][CH2:23][C:14]1[CH:15]=[CH:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=1
Reactant: NCCc1ccc2ccccc2c1
Reactant: Fc1cccc2c(Cl)ccnc12
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Fc1cccc2c(NCCc3ccc4ccccc4c3)ccnc12
Yield: 40.2 %

Procedure:
A mixture of 2.0 g of 4-chloro-8-fluoroquinoline and 3.8 g of 2-(2-naphthyl)ethyl amine was heated under nitrogen to 160°-165° C. for one hour. Then 200 mL of a 50:50 mixture of ammonium hydroxide in water was added. The product was extracted from the mixture into CH2Cl2, which was then concentrated to dryness. The residue was recrystallized from pentane/ethyl acetate to give 1.4 g of the title product. Yield 41.2%. M.P. 173°-174° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:23][C:24]1[CH:25]=[C:26]([C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[C:36]([OH:38])=O)[CH:27]=[CH:28][CH:29]=1.[C@H:39]12[CH2:44][C@H:43]1[CH2:42][C@@H:41]([CH2:45][NH:46][C:47](=[O:52])[C:48]([F:51])([F:50])[F:49])[NH:40]2.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:51][C:48]([F:49])([F:50])[C:47]([NH:46][CH2:45][C@@H:41]1[CH2:42][C@H:43]2[C@H:39]([CH2:44]2)[N:40]1[C:36]([C:31]1[N:32]=[C:33]([CH3:35])[S:34][C:30]=1[C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([F:23])[CH:25]=1)=[O:38])=[O:52]
Reactant: Cc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)C(F)(F)F)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
TBTU (3.22 mmol, 1.05 eq) is added to a solution of 5-(3-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (3.07 mmol, 1.0 eq), N-[(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-2,2,2-trifluoro-acetamide (3.07 mmol, 1.0 eq) and DIPEA (9.20 mmol, 3.0 eq) in DCM (15 mL). After 2 h the mixture is washed twice with water, once with sat. aqueous NaHCO3 solution, once with hydrochloric acid (0.2 M) and three times with water. The organic layer is dried over Na2SO4, the solvents are removed in vacuo and the residue is purified by flash chromatography (gradient: DCM to DCM/MeOH 19/1) and preparative TLC (DCM/MeOH 19/1) to give the desired product as an orange foam. LC-MS (acidic): tR=0.97 min; [M+H]+=428.1.
Reaction SMILES: [NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:19](O)=[O:20])[CH3:18])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:32][C@H:33]([C:42]([CH2:44][Cl:45])=[O:43])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1.Cl.N(C(OCC1C=CC=CC=1)=O)[C@H](C(NCC(N[C@H](C(N[C@H](C(CCl)=O)CC(C)C)=O)CC(C)C)=O)=O)CC1C=CC=CC=1>>[NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:19]([NH:32][C@H:33]([C:42]([CH2:44][Cl:45])=[O:43])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1)=[O:20])[CH3:18])=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)CCl
Reactant: C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)CCl
Agent: Cl
Product: C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)CCl

Procedure:
Z-Phe-Gly-Ala-OH (0.77 g, 1.80 mmoles) was coupled to H-TyrCH2Cl.HCl by a mixed anhydride coupling procedure substantially similar to that used for the preparation of Z-Phe-Gly-Leu-LeuCH2Cl in Procedure E. Product was crystallized from ethyl acetate to yield 0.73 g of Z-Phe-Gly-Ala-TyrCH2Cl, which slowly decomposed from 140°-160° and melted with complete decomposition at 160°-160.5°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[CH3:25][O:26][C:27](=[O:37])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][CH:30]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>CN(C=O)C>[CH3:25][O:26][C:27](=[O:37])[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:7]3[C:6]4[C:11](=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=4)[N:10]=[N:9][C:8]=3[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:19]=2)=[CH:33][CH:34]=1
Reactant: COC(=O)Cc1ccc(C=O)cc1
Reactant: Cc1cccc2c(-c3cccc(N)c3)c(-c3ccccc3)nnc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(CNc2cccc(-c3c(-c4ccccc4)nnc4c(C)cccc34)c2)cc1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
3-(8-Methyl-3-phenyl-cinnolin-4-yl)-phenylamine (0.031 g, 0.1 mmol) and (4-formyl-phenyl)-acetic acid methyl ester (0.07 g, 0.4 mmol) were mixed in DMF (4 mL) and then treated with NaBH(OAc)3 (0.43 g, 2.0 mml) and acetic acid (0.4 mL). After stirring at 40° C. for 4 hours the mixture was quenched with water and then extracted with ethyl acetate. The organic residue was purified by silica gel chromatography using 5-50% EtOAc/hexanes as eluent to provide (4-{[3-(8-methyl-3-phenyl-cinnolin-4-yl)-phenylamino]-methyl}-phenyl)-acetic acid methyl ester as a gum which was used for the next reaction. MS (EI) m/z 474;
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[C:10]([CH3:15])[N:9]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:23][CH2:24][C:25](Cl)=[O:26]>C1COCC1>[Cl:23][CH2:24][C:25]([NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[C:10]([CH3:15])[N:9]=2)=[CH:4][CH:3]=1)=[O:26]
Reactant: O=C(Cl)CCl
Reactant: Cc1cc(O)nc(-c2ccc(N)cn2)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(O)nc(-c2ccc(NC(=O)CCl)cn2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound of example 13 (0.10 g, 0.49 mmol) in THF (5 mL) was added triethylamine (0.075 g, 0.742 mmol) and chloroacetylchloride (0.0559 g, 0.495 mmol), and the reaction mixture was stirred at room temperature for 2 hours. THF was removed under reduced pressure, and the reaction mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by crystallization from ethyl acetate and petroleum ether to obtain the title compound.
Reaction SMILES: CO.[CH3:3][C:4]([CH3:6])=O.[ClH:7].Cl.Cl.[OH:10][C:11]1[CH:32]=[CH:31][C:14]([CH2:15][NH:16][C:17]([NH:19][C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[NH:21])=[NH:18])=[CH:13][CH:12]=1>C(#N)C>[ClH:7].[CH2:23]([NH:22][C:20]1[NH:19][C:17]([NH:16][CH2:15][C:14]2[CH:13]=[CH:12][C:11]([OH:10])=[CH:32][CH:31]=2)=[N:18][C:4]([CH3:6])([CH3:3])[N:21]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CC(C)=O
Reactant: CCCCCCCCNC(=N)NC(=N)NCc1ccc(O)cc1
Agent: Cl
Solvent: CC#N
Solvent: CO
Product: CCCCCCCCNC1=NC(C)(C)N=C(NCc2ccc(O)cc2)N1
Temperature: 40 °C
Reaction time: 63 h

Procedure:
25 ml of methanol, 40 ml of acetone and 0.1 ml of concentrated hydrochloric acid were added to 16 g (4.6 mmol) of N1-(4-hydroxybenzyl)-N5-octyl-biguanide dihydrochloride, and the mixture was stirred at 40° C. for 63 hours, and refluxed for 8 hours. The solvent was distilled off under reduced pressure, to give a residue, which was dissolved in 80% aqueous acetonitrile. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution with a mixture of chloroform and methanol (8:2)) to obtain 16 g of a colorless resinous solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[Br:13]N1C(=O)CCC1=O>CN(C)C=O>[Br:13][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([F:1])[CH:3]=1)[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CCc2cccc(F)c2N1
Solvent: CN(C)C=O
Product: O=C1CCc2cc(Br)cc(F)c2N1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 8-fluoro-3,4-dihydroquinolin-2(1H)-one (109-2; 7 g, 0.0424 mol) in N,N-dimethylformamide (30 mL) was added N-bromosuccinimide (9.06 g, 0.050 mol) portion wise at 0° C. Reaction mixture was allowed to stir at room temperature for 12 h. The reaction mixture was concentrated and diluted with ice cold water (150 mL) with constant stirring and the solid residue was filtered and dried to obtain the title compound. MS (M+1): 245.1
Reaction SMILES: [OH-].[Na+].[C:3]([NH:6][CH2:7][C:8]1[N:13]=[C:12]([C:14]2[N:15]=[C:16]([NH:19][C:20]([NH:22]C(=O)C3C=CC=CC=3)=[S:21])[S:17][CH:18]=2)[CH:11]=[CH:10][CH:9]=1)(=[O:5])[CH3:4]>O.CO>[C:3]([NH:6][CH2:7][C:8]1[N:13]=[C:12]([C:14]2[N:15]=[C:16]([NH:19][C:20]([NH2:22])=[S:21])[S:17][CH:18]=2)[CH:11]=[CH:10][CH:9]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)NCc1cccc(-c2csc(NC(=S)NC(=O)c3ccccc3)n2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)NCc1cccc(-c2csc(NC(N)=S)n2)n1
Reaction time: 1 h
Yield: 91 %

Procedure:
A solution of sodium hydroxide (0.8 g) in water (8 ml) was added to a suspension of 4-(6-acetylaminomethylpyridin-2-yl)-2-(3-benzoylthioureido)thiazole (8.0 g) in methanol (80 ml) and the mixture was stirred at 50°-60° C. for 1 hour. Following evaporation in vacuo, the residue was mixed with water and the mixture was adjusted to pH 7.5 with 6N-hydrochloric acid. The mixture was extracted with the mixture of tetrahydrofuran and ethyl acetate and extract layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give 4-(6-acetylaminomethylpyridin-2-yl)-2-thioureidothiazole (5.44 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39].[O:47]1[CH:51]=[CH:50][CH:49]=[C:48]1[C:52](Cl)=[O:53]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][N:43]([C:52]([C:48]2[O:47][CH:51]=[CH:50][CH:49]=2)=[O:53])[CH2:42][CH2:41]1)=[O:39]
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCNCC1
Reactant: O=C(Cl)c1ccco1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCN(C(=O)c2ccco2)CC1
Yield: 16 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and 2-furancarbonyl chloride as starting materials in 16% yield. LCMS for C29H28ClN6O3 (M+H)+: m/z=543.2.