Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]([NH2:13])=[NH:12])[CH:6]=[CH:7][C:8]=1[NH2:9].Cl.[CH2:15]([O:17][C:18](=[O:25])[CH2:19][C:20](OCC)=N)[CH3:16]>C(O)(=O)C>[ClH:1].[NH:10]([C:5]1[CH:6]=[CH:7][C:8]2[NH:9][C:20]([CH2:19][C:18]([O:17][CH2:15][CH3:16])=[O:25])=[N:2][C:3]=2[CH:4]=1)[C:11]([NH2:13])=[NH:12]
Reactant: N=C(N)Nc1ccc(N)c(N)c1
Reactant: CCOC(=N)CC(=O)OCC
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)Cc1nc2cc(NC(=N)N)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.6 %

Procedure:
A mixture comprising N-(3,4-diaminophenyl)guanidine hydrochloride (9.9 g, 49 mmol), ethoxycarbonimidoylacetic acid ethyl ester hydrochloride (12.4 g, 59 mmol) and acetic acid (20 mL) was heated in an oil bath at 110° C. and stirred for 1.5 hours, cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethanol (15 mL) and then ethyl acetate (10 mL) was added to the solution to give a precipitate in suspension. The suspension was filtered and an excess of ethyl ether was added to the filtrate to give a second precipitate. The precipitate was collected by filtration, washed with additional ethyl ether and dried in vacuo to provide ethyl 5-guanidino-1H-benzoimidazol-2-ylacetate hydrochloride (14.1 g, 94% yield) as an off white solid; 1H-NMR (300 MHz, DMSO-d6): 10.2 (s), 7.8 (d), 7.7 (m), 7.3 (d), 4.5 (s), 4.2 (q), 1.2 (t).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[C:12](N1C=CN=C1)([N:14]1C=CN=[CH:15]1)=O.C(N(CC)CC)C.Cl.CNC>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:14]([CH3:15])[CH3:12])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: CNC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Cc1ccc(Br)cc1
Reaction time: 1 h
Yield: 63.4 %

Procedure:
A solution of 4-bromophenylacetic acid (960 mg, 4.49 mmol) in dichloromethane (30 ml) was treated in one portion with solid 1,1′-carbonyldiimidazole (730 mg, 4.5 mmol) at 20° C. with stirring under argon. This mixture was allowed to stir at room temperature for 15 minutes. Triethylamine (0.63 ml) was then added followed by dimethylamine hydrochloride (367 mg, 4.5 mmol) and the stirring continued for 1 hour. Most of the solvent was removed under reduced pressure and the residue added to a 20 g isolute silica sep-pak column and eluted from 0-50% ethyl acetate in petroleum ether to give the title compound as a colourless solid (689 mg, 64%).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]([CH:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:8][CH:7]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:6]1)=[O:4].[CH3:24][C:25]1[CH:26]=[C:27]([NH:31][C:32](=[O:38])[NH:33][CH2:34][C:35](O)=[O:36])[CH:28]=[CH:29][CH:30]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[CH3:1][N:2]([CH3:23])[C:3]([CH:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:8]([C:35](=[O:36])[CH2:34][NH:33][C:32]([NH:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([CH3:24])[CH:26]=2)=[O:38])[CH:7]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:6]1)=[O:4]
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Reactant: CN(C)C(=O)C1CC(C(=O)OC(C)(C)C)NC1c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: Cc1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CC(C(=O)N(C)C)C2c2ccccc2)c1
Yield: 81 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 2B but from 1.7 g of tert-butyl (2RS,4RS,5SR)-4-dimethylcarbamoyl-5-phenylpyrrolidine-2-carboxylate, 1.15 g of 2-[3-(3-methylphenyl)ureido]acetic acid and 1.15 g of N,N'-dicyclohexylcarbodiimide in 50 cm3 of acetonitrile. After treatment, there are obtained 2.2 g of tert-butyl (2RS,4RS,5SR)-4-dimethylcarbamoyl-1-{2-[3-(3-methylphenyl)ureido]acetyl}-5-phenylpyrrolidine-2-carboxylate, melting at 199° C.
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[F:15][C:16]1[C:23]([F:24])=[CH:22][CH:21]=[C:20]([O:25][CH3:26])[C:17]=1[CH:18]=[O:19]>O1CCCC1>[Cl:8][C:5]1[N:4]=[C:3]([Cl:9])[C:2]([CH:18]([C:17]2[C:20]([O:25][CH3:26])=[CH:21][CH:22]=[C:23]([F:24])[C:16]=2[F:15])[OH:19])=[CH:7][N:6]=1
Reactant: COc1ccc(F)c(F)c1C=O
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1ccc(F)c(F)c1C(O)c1cnc(Cl)nc1Cl
Temperature: -30 °C
Reaction time: 0.33 h
Yield: 85.1 %

Procedure:
A solution of 5-bromo-2,4-dichloropyrimidine (18.8 g, 82.5 mmol, Aldrich) in tetrahydrofuran (50 mL) was chilled to −30° C. and isopropylmagnesium chloride (41.25 mL, 82.5 mmol, 2M in tetrahydrofuran, Aldrich) was added. The mixture was stirred at −30° C. for 20 minutes and a solution of 2,3-difluoro-6-methoxybenzaldehyde (12.91 g, 75 mmol, Apollo) in tetrahydrofuran (40 mL) was added slowly at this temperature. The mixture was then stirred at 0° C. for one hour and quenched with aqueous ammonium chloride. Extraction with ethyl acetate and crystallization from ethyl ether/hexanes gave 20.5 g of rac-(2,4-dichloro-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanol as a light yellow solid, MP 99-101° C. MS(ES) MH+322
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][N:2]1[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([S:13]([NH2:16])(=[O:15])=[O:14])=[C:8]([OH:17])[C:7]=1[N+:18]([O-])=O.[H][H]>[Pd]>[O:1]1[CH2:5][CH2:4][CH2:3][N:2]1[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([S:13]([NH2:16])(=[O:14])=[O:15])=[C:8]([OH:17])[C:7]=1[NH2:18]
Reactant: NS(=O)(=O)c1c(Cl)cc(N2CCCO2)c([N+](=O)[O-])c1O
Reactant: [H][H]
Agent: [Pd]
Product: Nc1c(N2CCCO2)cc(Cl)c(S(N)(=O)=O)c1O
Yield: 94.6 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, (N-isoxazolidinyl)-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (0.84 g, 2.7 mmol) was reduced with hydrogen and 10% Pd/C (0.84 g) to form the desired product (0.75 g crude). LC-MS m/z 279(M+).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:38][N:39]([CH3:44])[S:40](Cl)(=[O:42])=[O:41]>CN(C)C=O>[CH3:38][N:39]([CH3:44])[S:40]([N:26]1[CH2:25][CH2:24][N:23]([S:20]([C:17]2[CH:16]=[CH:15][C:14]([NH:13][C:7]3[C:6]4[C:11](=[CH:12][C:3]([C:2]([F:29])([F:1])[F:30])=[CH:4][CH:5]=4)[N:10]=[CH:9][CH:8]=3)=[CH:19][CH:18]=2)(=[O:22])=[O:21])[CH2:28][CH2:27]1)(=[O:42])=[O:41]
Reactant: O=S(=O)(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)N1CCN(S(=O)(=O)c2ccc(Nc3ccnc4cc(C(F)(F)F)ccc34)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of [[4-[(7-trifluoromethyl-4-quinolinyl)amino]phenyl]sulfonyl]piperazine (prepared as in Example 9, part D) and triethylamine, in dimethyl formamide, is added dropwise an equimolar quantity of dimethylsulfamoyl chloride. The reaction mixture is stirred at room temperature for 15 to 25 hours and is then partitioned with methylene chloride-aqueous sodium carbonate. The organic phase is dried over sodium sulfate and is concentrated and purified by conventional methods to give 1-(dimethylaminosulfonyl)-4-[[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]phenyl]sulfonyl]piperazine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][C:5]=1[OH:15])([O-])=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)C.O>[NH2:1][C:4]1[CH:9]=[C:8]([O:10][C:11]([F:12])([F:13])[F:14])[CH:7]=[CH:6][C:5]=1[OH:15]
Reactant: O=[N+]([O-])c1cc(OC(F)(F)F)ccc1O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cc(OC(F)(F)F)ccc1O
Temperature: 80 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
To a mixture of 2-nitro-4-(trifluoromethoxy)phenol (2 g, 0.0089 mol) in ethanol (50 mL) and water (25 mL) was added sodium thiosulfate (6.2 g, 0.0356 mol) at room temperature. The heterogeneous mixture was stirred at 80° C. under an atmosphere of nitrogen for 1 hour. The reaction mixture was cooled to room temperature, and ethanol was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (3×70 mL), and the organic layer was washed with brine and dried under sodium sulfate. The solvent was removed under reduced pressure to give yellow solid of 2-amino-4-(trifluoromethoxy)phenol (0.9 g, 0.005 mol). TLC (methanol/dichloromethane=5:95) Rf 0.29 MS: MH+: 194.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:10])[CH2:7][CH2:8][CH2:9][C:2]1=2.O.[Br:12]Br>C(O)(=O)C>[Br:12][C:5]1[S:1][C:2]2[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[C:3]=2[CH:4]=1
Reactant: BrBr
Reactant: O=C1CCCc2sccc21
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCCc2sc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
In a 500 mL round bottomed flask was placed 6,7-dihydro-4-benzo[b]thiophenone (8.3 g, 54 mmol) and then dissolved in acetic acid (30 mL). To the mixture was added water (30 mL) and the solution was stirred for 30 min at rt. To the mixture was dropwise added freshly prepared solution of bromine (9.4 g, 59 mmol) in acetic acid (50 mL) over 10 min. After addition of the Br2, the mixture was stirred for 1.5 h at the same temperature. The mixture was concentrated under reduced pressure and the residue was diluted with ether (150 mL), which was washed with 1N NaOH aq (100 mL). The aqueous phase was extracted with ether (100 mL) and the combined organic phase was washed with brine (100 mL), dried over anhydrous MgSO4 and then decolorized with activated carbon. Insoluble materials were removed by filtration through Celite pad and the filtrate was concentrated under reduced pressure. The residue was suspended in 50 mL of MeOH and then stirred for 15 min for washing. The precipitate was collected by filtration to obtain the title compound (5.65 g; 45%) as a yellowish crystalline solid. From the mother liquid, 2nd crop of the title compound (6.66 g; 53%) has been obtained. LCMS: (FA) ES+ 231, 233. 1H NMR (300 MHz, d1-chloroform) δ: 7.35 (s, 1H), 2.95 (t, 2H), 2.52-2.56 (m, 2H), 2.17-2.25 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[C:14]([CH3:18])[CH:13]=[C:12]([CH3:19])[C:11]=2[C:10](=O)[CH2:9]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[C:14]([CH3:18])[CH:13]=[C:12]([CH3:19])[C:11]=2[C:10](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:9]1
Reactant: N=C(N)NN
Reactant: Cc1cc(C)c2c(n1)CC(c1ccccc1Cl)CC2=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c2c(n1)CC(c1ccccc1Cl)CC2=NNC(=N)N
Yield: 83.1 %

Procedure:
A mixture of 7-(2-chlorophenyl)-2,4-dimethyl-5,6,7,8-tetrahydroquinolin-5-one (0.20 g), aminoguanidine hydrochloride (0.081 g), concentrated hydrochloric acid (0.1 ml), water (0.1 ml) and ethanol (20 ml) was refluxed for 13.5 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol to give 7-(2-chlorophenyl)-5-guanidinoimino-2,4-dimethyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 86) (0.11 g) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.[C:25]([O:28][CH:29]([CH3:33])[C:30](Cl)=[O:31])(=[O:27])[CH3:26]>CN(C=O)C>[C:25]([O:28][CH:29]([CH3:33])[C:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:6][CH:7]=1)=[O:31])(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)C(=O)Cl
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Solvent: CN(C)c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)OC(C)C(=O)Nc1ccc(C2=NNC(=O)NC2C)cc1
Yield: 72.5 %

Procedure:
To a stirred mixture of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (1.0 g) and N,N-dimethylaniline (0.93 ml) in DMF (10 ml) was added dropwise 2-acetoxypropionyl chloride (0.98 g) under ice cooling. The stirring was continued for one night at ambient temperature. The mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate after addition of saline solution. The extract was washed successively with 1N hydrochloric acid, water and saline solution, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (170 ml) with a mixture of chloroform and methanol (10:1) as an eluent. The eluates containing the object compound were evaporated in vacuo to give 1.13 g of 6-[4-(2-acetoxypropionylamino)phenyl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one.
Reaction SMILES: N[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:18]2([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][C:3]=1[O:28][CH2:29][C:30]([F:33])([F:32])[F:31].N([O-])=O.[Na+].CC#N.O.[ClH:42]>O.Cl[Cu]>[Cl:42][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:18]2([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][C:3]=1[O:28][CH2:29][C:30]([F:33])([F:32])[F:31]
Reactant: CCOC(=O)C1(c2cc(OCC(F)(F)F)c(N)c(-c3ccc(C(F)(F)F)cc3)c2)CCCC1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C1(c2cc(OCC(F)(F)F)c(Cl)c(-c3ccc(C(F)(F)F)cc3)c2)CCCC1
Temperature: 90 °C
Reaction time: 0.67 h

Procedure:
Ethyl 1-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate (1 g, 2.2 mmol) was dissolved in a mixture of MeCN/H2O/HCl 30 mL/30 mL/2 mL at 0° C. A solution of NaNO2 (0.200 g, 2.9 mmol) in water (10 mL) was added drop wise at 0° C., and the reaction mixture was stirred for 40 min, at the same temperature. A solution of CuCl (1.1 g, 11.1 mmol) in water (10 mL) was added drop wise at 0° C. The reaction mixture was heated to 90° C. for 2.0 h and the solvent was evaporated. The reaction mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with water (50 mL) followed by brine (50 mL). The solution was dried over Na2SO4, filtered and concentrated under reduced pressure to give an oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give the ethyl 1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentane carboxylate (1.1 g) as yellow oil.
Reaction SMILES: [C:1]1([C:7]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[S:10][C:9](=S)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CCCCCC.[CH3:27][O:28][C:29](=[O:32])[CH2:30]Br>CN(C)P(=O)(N(C)C)N(C)C>[CH3:27][O:28][C:29]([CH2:30][C:9]1[S:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1)=[O:32]
Reactant: COC(=O)CBr
Reactant: S=C1N=C(c2ccccc2)C(c2ccccc2)S1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Product: COC(=O)Cc1nc(-c2ccccc2)c(-c2ccccc2)s1
Temperature: 0 °C

Procedure:
The starting material can be produced, for example, in the following manner: 6 g of 4,5-bis-phenylthiazoline-2-thione are dissolved in 50 ml of hexamethylphosphoric acid triamide, the solution is cooled to 5° and, while stirring, sodium hydride (0.89 g of a 50% strength suspension in mineral oil, de-oiled with hexane) is added. The mixture is stirred for 30 minutes at room temperature, 3.57 g of bromoacetic acid methyl ester are slowly added dropwise, the mixture is then stirred for 1 hour at room temperature, poured into 500 ml of ice-water, extracted by shaking twice with 300 ml of ethyl acetate each time, washed with water, dried over magnesium sulphate and concentrated to dryness by evaporation under reduced pressure. The remaining oil is dissolved in toluene and purified by chromatography over 50 g of silica gel. The eluate with toluene/ethyl acetate (95:5) is concentrated by evaporation under reduced pressure. 2-Methoxycarbonylmethyl-4,5-bis-phenylthiazole having a melting point of 65°-67° is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][C@H:13]1[C:26](=[S:28])[NH2:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:30][C:31](=O)[CH2:32][CH3:33]>C1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][C@H:13]1[C:26]1[S:28][CH:30]=[C:31]([CH2:32][CH3:33])[N:27]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)CCl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](C(N)=S)C1
Solvent: c1ccccc1
Product: CCc1csc([C@@H]2C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]2NC(=O)OCc2ccccc2)n1
Temperature: 75 °C
Yield: 36.3 %

Procedure:
To a solution of tert-butyl (1R,3R,4S)-4-((benzyloxycarbonyl)amino)-3-carbamothioylcyclohexylcarbamate (0.5 g, 0.0012 mol, see Example 12f, Step 2) in dry benzene (20 ml) under nitrogen was added 1-chloro-butan-2-one (0.42 g, 0.0039 mol) of and the reaction mixture was heated at 75° C. for over night. Benzene was removed under vaccum and the crude product was extracted with ethyl acetate. The organic layer was washed with brine, concentrated, and purified by recrystallization from ether to give 0.2 g (35%) of tert-butyl (1R,3R,4S)-4-((benzyloxycarbonyl)amino)-3-(4-ethylthiazol-2-yl)cyclohexylcarbamate as a white solid obtained. 1H NMR (400 MHz, CDCl3) δ 1.27 (t, 3H), 1.44 (s, 9H), 1.62 (m, 2H), 1.81 (m, 3 H), 2.22 (m, 2H), 2.78 (q, 2H), 3.50 (bs, 1H), 3.72 (bs, 1H), 4.12 (bs, 1H), 5.04 (s, 2H), 5.40 (bs, 1H), 5.74 (s, 1H), 7.33 (m, 5H); 13H NMR (400 MHz, CDCl3) 13.45, 24.7, 28.0, 28.24, 28.4, 33.3, 42.3, 47.0, 50.4, 61.0, 66.5, 79.0, 111.6, 127.9, 128.0, 128.4, 136.5, 155.2, 155.8, 158.8, 169.8. MS found: (M+H)+=460.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][C:11]1[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][C:12]=1[NH2:13].C(N(C(C)C)CC)(C)C>C(O)C>[C:18]([C:15]1[CH:16]=[CH:17][C:11]([CH3:10])=[C:12]([NH:13][C:6]2[C:5]([F:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:14]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Cc1ccc(C(C)(C)C)cc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccc(C(C)(C)C)cc1Nc1nc(Cl)ncc1F
Temperature: 25 °C
Yield: 68.3 %

Procedure:
A solution of 2,4-dichloro-5-fluoropyrimidine (307 mg, 1.84 mmol), 2-methyl-5-t-butylaniline (300 mg, 1.84 mmol) and diisopropylethylamine (2 mL) in ethanol (2 mL) was heated at 80° C. for 16 h in an oil bath. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel Biotage 40M, eluting with EtOAc/hexane to afford the product (369 mg, 68%) as a solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:22]=[CH:21][C:9]([O:10][CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])=[CH:8][CH:7]=1.C(N(CC)CC)C.I.[NH2:31][C:32]1[C:33]([C:40]([NH:42][C:43](=[NH:46])SC)=[O:41])=[N:34][C:35]([Cl:39])=[C:36]([NH2:38])[N:37]=1>C(O)C>[NH2:31][C:32]1[C:33]([C:40]([N:42]=[C:43]([NH2:46])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:22]=[CH:21][C:9]([O:10][CH2:11][C:12]([NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:13])=[CH:8][CH:7]=2)=[O:41])=[N:34][C:35]([Cl:39])=[C:36]([NH2:38])[N:37]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: NCCCCc1ccc(OCC(=O)Nc2ccccc2)cc1
Agent: I
Solvent: CCO
Solvent: CCN(CC)CC
Product: NC(=NC(=O)c1nc(Cl)c(N)nc1N)NCCCCc1ccc(OCC(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.1 %

Procedure:
A solution of 2-[4-(4-aminobutyl)phenoxy]-N-phenylacetamide 19 (100 mg, 0.35 mmol) and triethylamine (0.14 mL, 1.00 mmol) in absolute ethanol (2 mL) was stirred at 60° C. for 30 min, after which 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methyl-isothiourea hydriodide (140 mg, 0.37 mmol) was added in one portion. The reaction mixture was stirred at that temperature for 4 h, cooled to room temperature, and concentrated by rotary evaporation. The crude residue was triturated with water and filtered. The filter cake was purified by flash silica gel column chromatography eluting with dichloromethane/methanol/concentrated ammonium hydroxide (500:10:0, 500:10:1, 200:10:1, v/v) to give 2-(4-{4-[N′-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)guanidino]butyl}phenoxy)-N-phenylacetamide (20, PSA 17482) as a yellow solid (120 mg, 67% yield). mp 168-170° C. 1H NMR (300 MHz, DMSO-d6) δ 6 1.55 (m, 4H), 2.55 (m, 2H), 3.16 (m, 2H), 4.65 (s, 2H), 6.60 (br s, 2H), 6.90 (d, 2H), 7.08 (m, 2H), 7.15 (d, 2H), 7.30 (m, 5H), 7.60 (d, 2H), 9.00 (br s, 1H), 10.00 (br s, 1H). m/z (ESI): 511 [C24H27ClN8O3+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1.C(OB([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)O)CCC>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:44]3[CH:43]=[CH:42][C:41]([CH:6]([CH2:7][CH3:8])[CH3:11])=[CH:46][CH:45]=3)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)CNc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1
Reactant: CCCCOB(O)c1ccccc1
Product: CCC(C)c1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(NCC(=O)OC)cc3)cc2)cc1

Procedure:
{-4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester (1.8 g, 3.3 mmol) was coupled with 4-sec butyl-phenyl boronic acid (750 mg, 4.0 mmol) according to general procedure G to give {-4-[2-(4′-sec-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:6]([C:7](OC)=[O:8])[C:5]([OH:12])=[CH:4][CH:3]=1.[NH2:13][OH:14]>O1CCOCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([NH:13][OH:14])=[O:8]
Reactant: NO
Reactant: COC(=O)c1cc(Br)ccc1O
Solvent: C1COCCO1
Solvent: O
Product: O=C(NO)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Methyl 5-bromosalicylate (5 g, 21.6 mmol) was dissolved in 90 mL 1,4-dioxane and 10 mL water. 10 mL 50% aqueous hydroxylamine solution was added and the mixture was stirred at ambient temperature for 24 hours. After concentrating the mixture under vacuum, water was added. The formed precipitate was filtered, washed with water and dried yielding 5-bromo-N,2-dihydroxybenzamide (4.12 g, 17.76 mmol) as off-white solid.
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH3:6])[CH2:3][CH2:4][OH:5].[N+:8]([C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([N+]([O-])=O)[C:12]=1[C:13]#[N:14])([O-:10])=[O:9]>>[OH:7][C:2]([CH3:6])([CH3:1])[CH2:3][CH2:4][O:5][C:15]1[CH:16]=[CH:17][CH:18]=[C:11]([N+:8]([O-:10])=[O:9])[C:12]=1[C:13]#[N:14]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CC(C)(O)CCO
Product: CC(C)(O)CCOc1cccc([N+](=O)[O-])c1C#N
Yield: 81 %

Procedure:
Prepared as in Example 215c from 3-methylbutane-1,3-diol and 2,6-dinitrobenzonitrile in 81% yield. MS 251 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH3:15])[C:5](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[CH3:21]O>>[Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH3:15])[C:5](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:6]([O:8][CH3:21])=[O:7]
Reactant: COc1cc(Cl)c([N+](=O)[O-])cc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(Cl)cc1OC
Temperature: 0 °C

Procedure:
To a solution of 3.1 g of 4-chloro-5-nitro-o-anisic acid in methanol (100 ml) was added a catalytic amount of sulfuric acid and the resulting mixture was heated under reflux for 3 hours. Then the reaction mixture was poured into ice/water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, 3.3 g of methyl 4-chloro-5-nitro-o-anisate was obtained as pale yellow crystals.