Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:36])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([CH2:34]O)[CH:29]=4)=[CH:24][CH:23]=3)[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.[CH3:38][NH:39][CH3:40].C(=O)([O-])[O-].[K+].[K+]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:16][CH2:17][N:18]([C:21](=[O:36])[C:22]3[CH:23]=[CH:24][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([CH2:34][N:39]([CH3:40])[CH3:38])[CH:29]=4)=[CH:26][CH:27]=3)[CH2:19][CH2:20]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(c1ccc(-c2ccnc(CO)c2)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN(C)Cc1cc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)ccn1
Reaction time: 24 h
Yield: 44 %

Procedure:
In the same manner as in Referential Example 178, the corresponding brome compound was obtained using 1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[4-(2-hydroxymethylpyridin-4-yl)benzoyl]piperazine (300 mg). To the resulting compound, dimethylamine hydrochloride (469 mg) and potassium carbonate (795 mg) were added, followed by stirring for 24 hours. The solvent was then distilled off under reduced pressure. Ethyl acetate and water were added to the residue to separate the organic layer. The organic layer thus obtained was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (3 to 5% methanol—dichloromethane). Hydrochloric acid in ethanol was added and the resulting mixture was concentrated. Ethyl acetate was added to the concentrate. The colorless powder thus obtained was collected by filtration and dried, whereby the title compound (74 mg, 21%) was obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[CH:21][C:22](=[O:25])[NH:23][N:24]=2)=[CH:15][CH:14]=1.Cl.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1>C(OCC)(=O)C.O1CCCC1>[N:30]1[CH:31]=[CH:32][CH:33]=[C:28]([C:27]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:20]=[CH:21][C:22](=[O:25])[NH:23][N:24]=3)=[CH:17][CH:18]=2)=[O:34])[CH:29]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: NCCCCc1ccc(-c2ccc(=O)[nH]n2)cc1
Agent: Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NCCCCc1ccc(-c2ccc(=O)[nH]n2)cc1)c1cccnc1
Reaction time: 3 h
Yield: 60.2 %

Procedure:
An aqueous solution (25 ml) containing 4.30 g of anhydrous potassium carbonate was added to a suspension in which 2.01 g of 6-[4-(4-aminobutyl)phenyl]pyridazin-3(2H)-one hydrobromide was suspended in ethyl acetate (40 ml) and tetrahydrofuran (10 ml). Under ice cooling, 2.23 g of nicotinic acid chloride hydrochloride was added thereto, and the mixture was stirred for 3 hours. Precipitated crystal was collected by filtration, washed with water, dried and then recrystallized from methanol to obtain 1.30 g of 6-[4-(4-(pyridin-3-ylcarbonylamino)butyl)phenyl]pyridazin-3(2H)-one.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=1.COC(C1C=NC(OC2C=CC3CCN(C4CCC4)CCC=3C=2)=CN=1)=O>>[CH3:27][O:26][C:24]([C:21]1[CH:22]=[N:23][C:18]([O:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[CH:19][CH:20]=1)=[O:25]
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Agent: COC(=O)c1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1
Product: COC(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1

Procedure:
The title compound was prepared from 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and methyl 6-chloro-3-pyridine carboxylate in an analogous manner to that described for E122; MS (ES+) m/e 353 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12])=O.[NH2:14][C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1>CC(C)=O>[N+:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]1[N:14]=[C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]2[CH:2]=1)([O-:13])=[O:12]
Reactant: Nc1ncccn1
Reactant: O=C(CBr)c1ccccc1[N+](=O)[O-]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccccc1-c1cn2cccnc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.6 %

Procedure:
2-Bromo-2′-nitroacetophenone (5.0 g, 20.4 mmol) and 2-aminopyrimidine (1.94 g, 20.4 mmol) were dissolved in acetone (50 ml) and brought to reflux. After 60 minutes a light white precipitate developed. Refluxing was continued for 5.5 hours and cooled to room temperature. The volume was reduced 1 by evaporation and the intermediate solids were collected by filtration, washed with acetone (20 ml) and air dried (2.84 g of intermediate). A second crop was collected by concentration of the combined mother liquors, and refluxing the residue in fresh acetone (20 ml) for 1.5 hours. Upon cooling, and reducing the volume by 1 by evaporation, 3.11 g of solids were collected. The combined solid intermediate (5.95 g) was dissolved in MeOH (70 ml) with 5 drops of conc. HBr and refluxed for 2 hours. After cooling the volume was reduced by ½, water (40 ml) was added solution was made basic (pH=10) with 1N NaOH. Roto-evaporation to remove methanol resulted in the product crystallizing. The product was filtered, washed with water and air dried to obtain 5.03g of the desired product. (MS, M++H=241.0)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7](=[N:9][OH:10])[NH2:8].[Cl:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17](Cl)=O>>[Cl:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17]1[O:10][N:9]=[C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[N:8]=1
Reactant: O=C(Cl)c1sccc1Cl
Reactant: NC(=NO)c1cnccn1
Product: Clc1ccsc1-c1nc(-c2cnccn2)no1

Procedure:
The title compound was prepared from pyrazine-2-amidoxime (42.2 mg, 0.306 mmol) and 3-chloro-thiophene-2-carbonyl chloride (55 mg, 0.30 mmol) similar to Example 16, and yielded 67.4 mg (84%) of white solid. 1H NMR (CDCl3): 9.45 (d, J=1.37 Hz, 1H), 8.81 (dd, J=2.48, 1.65 Hz, 1H), 8.77 (d, J=2.47 Hz, 1H), 7.66 (d, J=4.95 Hz, 1H), 7.16 (d, J=5.50 Hz, 1H).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[N:8]2[C:16]([CH2:19][CH2:20][C:21]3[O:22][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[N:24][N:25]=3)=[N:17][N:18]=[C:7]12)[CH2:2][CH2:3][CH2:4][CH3:5].[Br:32]N1C(=O)CCC1=O>C1COCC1>[Br:32][C:12]1[NH:11][C:10]2[C:9](=[O:15])[N:8]3[C:16]([CH2:19][CH2:20][C:21]4[O:22][C:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)=[N:24][N:25]=4)=[N:17][N:18]=[C:7]3[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]=2[N:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(CCc3nnc(-c4ccccc4)o3)nnc12
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(CCc3nnc(-c4ccccc4)o3)nnc12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
The mixture of 9-pentyl-3-[2-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl]-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (53 mg, 0.13 mmol) and N-bromosuccinimide (34 mg, 0.19 mmol) in THF (20 mL) was stirred at 70° C. for 1 hour. The reaction mixture was concentrated and the residue was purified by preparative LCMS to give the desired product. LCMS calculated for C21H22BrN8O2(M+H): 497.1; found: 497.1.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[C:12]([NH:14][C:15](=[N:18][CH3:19])SC)#[N:13]>C(#N)C>[C:12]([NH:14][C:15]([NH:18][CH3:19])=[N:11][CH2:10][CH2:9][S:8][CH2:7][C:6]1[N:5]=[CH:4][NH:3][C:2]=1[CH3:1])#[N:13]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CN=C(NC#N)SC
Solvent: CC#N
Product: CNC(=NCCSCc1nc[nH]c1C)NC#N

Procedure:
A solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole (17.0 g) and N-cyano-N',S-dimethylisothiourea (11.2 g) in acetonitrile (500 ml) was heated under reflux for 24 hours. Following concentration, the residue was chromatographed on a column of silica gel with acetonitrile as eluant and the product obtained was finally recrystallised from acetonitrile-ether to yield N-cyano-N'-methyl-N"-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]guanidine, m.p. 141°-142°.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][C:19]([F:24])([F:23])[CH:20]([F:22])[F:21])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27].O.C(O)(=O)C>N1C=CC=CC=1>[C:12]1([C:11]2[N:10]=[C:9]([S:18][C:19]([F:23])([F:24])[CH:20]([F:22])[F:21])[N:8]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: FC(F)C(F)(F)Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: CCOC(=O)Cl
Solvent: CC(=O)O
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)n1c(SC(F)(F)C(F)F)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.76 g (5 mmole) 4,5-diphenyl-2-(1,1,2,2-tetrafluoroethylthio)imidazole, 1.1 g (10 mmole) of ethyl chloroformate in 10 ml pyridine was stirred at RT overnight. TLC showed some starting material, so another 0.6 g (5 mmole) of ethyl chloroformate was added and stirring was continued another 24 hours. The mixture was poured into water, neutralized with acetic acid and extracted three times with ether. The ether extracts were backwashed three times with water, then dried and concentrated. The last traces of pyridine were removed by pumping at 50° (0.5 mm). The residue was chromatographed on 150 g SilicAR CC-7, eluting with toluene to give, after recrystallization from hexane, 1.05 g (55%) of white product, mp 126.5°-127°.
Reaction SMILES: [Na+:1].[Na+].[Na+].[CH2:4]([NH:12][C:13]1[CH:14]=[C:15]([C:25]([O-:27])=[O:26])[C:16]([C:22]([O-:24])=[O:23])=[C:17]([C:19]([O-:21])=[O:20])[CH:18]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Na+].[Na+].[Na+].[CH2:31](NC1C=C(C([O-])=O)C(C([O-])=O)=C(C([O-])=O)C=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]C.[Na+].[Na+].[Na+].C(NC1C=C(C([O-])=O)C(C([O-])=O)=C(C([O-])=O)C=1)CCCCCCCCC.[Na+].[Na+].[Na+].C(NC1C=C(C([O-])=O)C(C([O-])=O)=C(C([O-])=O)C=1)CCCCCCCCCC.[Na+].[Na+].[Na+].CC(NC1C=C(C([O-])=O)C(C([O-])=O)=C(C([O-])=O)C=1)CCCCCCCCCC.[Na+].[Na+].[Na+].C(NC1C=C(C([O-])=O)C(C([O-])=O)=C(C([O-])=O)C=1)CCCCCCCCCCC.[Na+].[Na+].[Na+].C(NC1C=C(C([O-])=O)C(C([O-])=O)=C(C([O-])=O)C=1)CCCCCCCCCCCC.[Na+].[Na+].[Na+].C(NC1C=C(C([O-])=O)C(C([O-])=O)=C(C([O-])=O)C=1)CCCCCCCCCCCCC.[Na+].[Na+].[Na+].C(NC1C=C(C([O-])=O)C(C([O-])=O)=C(C([O-])=O)C=1)CCCCCCCCCCCCCC.[Na+].[Na+].[Na+].CC(C)CCCCCCCCCCCCCNC1C=C(C([O-])=O)C(C([O-])=O)=C(C([O-])=O)C=1.[Na+].[Na+].[Na+].C(NC1C=C(C([O-])=O)C(C([O-])=O)=C(C([O-])=O)C=1)CCCCCCCCCCCCCCCC.[Na+].[Na+].[Na+].C(NC1C=C(C([O-])=O)C(C([O-])=O)=C(C([O-])=O)C=1)CCCCCCCCCCCCCCCCC.[Na+].[Na+].[Na+].C(NC1C=C(C([O-])=O)C(C([O-])=O)=C(C([O-])=O)C=1)CCCCCCCCCCCCCCCCCC>>[Na+:1].[Na+:1].[Na+:1].[CH2:4]([NH:12][C:13]1[CH:18]=[C:17]([C:19]([O-:21])=[O:20])[C:16]([C:22]([O-:24])=[O:23])=[C:15]([C:25]([O-:27])=[O:26])[CH:14]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCNc1cc(C(=O)[O-])c(C(=O)[O-])c(C(=O)[O-])c1
Reactant: CCCCCCCCCNc1cc(C(=O)[O-])c(C(=O)[O-])c(C(=O)[O-])c1
Agent: CC(C)CCCCCCCCCCCCCNc1cc(C(=O)[O-])c(C(=O)[O-])c(C(=O)[O-])c1
Agent: CCCCCCCCCCC(C)Nc1cc(C(=O)[O-])c(C(=O)[O-])c(C(=O)[O-])c1
Agent: CCCCCCCCCCCCCCCCCCCNc1cc(C(=O)[O-])c(C(=O)[O-])c(C(=O)[O-])c1
Product: CCCCCCCCCCCCCCCCNc1cc(C(=O)[O-])c(C(=O)[O-])c(C(=O)[O-])c1

Procedure:
Similarly, the 5-alkylamino-1,2,3-benzenetricarboxylic acids described in Example 6 give, respectively, 5-octylamino-1,2,3-benzenetricarboxylic acid trisodium salt, 5-nonylamino-1,2,3-benzenetricarboxylic acid trisodium salt, 5-decylamino-1,2,3-benzenetricarboxylic acid trisodium salt, 5-undecylamino-1,2,3-benzenetricarboxylic acid trisodium salt, 5-(1-methylundecyl)amino-1,2,3-benzenetricarboxylic acid trisodium salt, 5-dodecylamino-1,2,3-benzenetricarboxylic acid trisodium salt, 5-tridecylamino-1,2,3-benzenetricarboxylic acid trisodium salt, 5-tetradecylamino-1,2,3-benzenetricarboxylic acid trisodium salt, 5-pentadecylamino-1,2,3-benzenetricarboxylic acid trisodium salt, 5-(14-methylpentadecyl)amino-1,2,3-benzenetricarboxylic acid trisodium salt, 5-heptadecylamino-1,2,3-benzenetricarboxylic acid trisodium salt, 5-octadecylamino-1,2,3-benzenetricarboxylic acid trisodium salt, and 5-nonadecylamino-1,2,3-benzenetricarboxylic acid trisodium salt.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[S:46][CH:47]=[CH:48][CH:49]=3)[C:19]2=[O:50])=[N:9]1)=O)(C)(C)C.Cl.CCOCC>O1CCOCC1>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[S:46][CH:47]=[CH:48][CH:49]=3)[C:19]2=[O:50])=[N:9]1
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(C(=O)OC(C)(C)C)c4ccccc34)C(=O)N(c3cccs3)c3ccccc32)C(C)C)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3n[nH]c4ccccc34)C(=O)N(c3cccs3)c3ccccc32)C(C)C)cc1
Reaction time: 3 h
Yield: 10 %

Procedure:
To 280 mg (0.40 mmol) of crude 2-[3-(1-tert-butoxycarbonyl-1H-indazol-3-ylmethyl)-2,4-dioxo-5-thiophen-2-yl-2,3,4,5-tetrahydro-benzo [b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Intermediate 60, is added 10 mL of 4N HCl in dioxane at RT. The resulting solution is stirred 3 h and 100 mL of Et2O is added. The Et2O is decanted away from the gum. The gum is washed with Et2O and purified by RP-HPLC (30-60% acetonitrile/H2O over 30 min) to afford 23.7 mg of the title compound: 1H NMR (CDCl3, 300 MHz) δ7.83 (d, 1H, J=8.0), 7.45-7.06 (m, 11H), 6.96-6.79 (m, 4H), 4.97 (m, 1H), 4.31 (d, 1H, J=16.6), 4.20 (m, 1H), 4.08 (d, 1H, J=16.6), 3.81 (s, 3H), 3.73 (m, 2H), 1.05 (d, 3H, J=6.8), 1.02 (d, 3H, J=6.8); low resolution MS (FAB) m/e 594 (MH+); RP-HPLC Tr =22.0 min (30-60% acetonitrile/ H2O).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[S:15][CH:16]=[C:17]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[N:30][N:29]=[N:28]4)=[CH:23][CH:22]=3)[N:18]=2)[CH2:9]1)=O)(C)(C)C.[ClH:32]>ClCCl.CO.O1CCOCC1>[N:27]1([C:24]2[CH:23]=[CH:22][C:21]([O:20][CH2:19][C:17]3[N:18]=[C:14]([CH:10]4[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]4)[S:15][CH:16]=3)=[CH:26][CH:25]=2)[CH:31]=[N:30][N:29]=[N:28]1.[ClH:32]
Reactant: CC(C)(C)OC(=O)N1CCCC(c2nc(COc3ccc(-n4cnnn4)cc3)cs2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: c1cc(-n2cnnn2)ccc1OCc1csc(C2CCCNC2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.13 mmol) in dichloromethane (10 mL) and methanol (2 mL) were treated with 2 mL of 4N HCl in dioxane. The resulting solution was stirred at room temperature for 30 minutes. The solvents were removed in vacuo to afford the desired product as an HCl salt.
Reaction SMILES: Br[CH2:2][CH2:3]C.[CH2:5]([O:12][C@@H:13]1[CH2:18][CH2:17][C@H:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1COCC1>[CH2:5]([O:12][C@@H:13]1[CH2:18][CH2:17][C@H:16]([C:19](=[O:21])[CH2:20][CH2:2][CH3:3])[CH2:15][CH2:14]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCCBr
Reactant: CC(=O)[C@H]1CC[C@@H](OCc2ccccc2)CC1
Solvent: C1CCOC1
Product: CCCC(=O)[C@H]1CC[C@@H](OCc2ccccc2)CC1
Temperature: 25 °C

Procedure:
To a suspension of Mg (0.51 g, 21.6 mmol, 5.0 eq.) in dry THF (15 mL) under N2 was added 1-bromopropane (0.51 g, 2 mL, 5.0 eq.) dropwise and stirred at room temperature until Mg disappeared, then 1-(cis-4-(benzyloxy)cyclohexyl)ethanone (1.2 g, 4.3 mmol, 1.0 eq.) was added to the reaction mixture in an ice bath. The reaction mixture was warmed to r.t and stirred for 3 h., extracted (EtOAc), washed (brine), dried (Na2SO4), filtered and concentrated. The crude was then purified by silica gel chromatography eluting with EtOAc/Petroleum ether (10:1) to give the title compound (0.6 g, 50%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.34-7.24 (m, 5H), 4.49 (s, 2H), 3.62-3.60 (m, 1H), 2.44-2.40 (m, 2H), 2.34-2.33 (m, 1H), 1.98-1.80 (m, 4H), 1.64-1.46 (m, 6H), 0.89 (t, 3H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.Br[CH:17]([CH2:22][CH3:23])[C:18]([O:20][CH3:21])=[O:19]>>[C:12]([C:11]1[C:3]([C:2]([F:14])([F:1])[F:15])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:17]([CH2:22][CH3:23])[C:18]([O:20][CH3:21])=[O:19])[CH:6]=[CH:5]2)#[N:13]
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Reactant: CCC(Br)C(=O)OC
Product: CCC(C(=O)OC)n1ccc2c(C(F)(F)F)c(C#N)ccc21

Procedure:
Synthesized in a manner similar to Example 1 using 4-(trifluoromethyl)-1H-indole-5-carbonitrile and methyl 2-bromobutanoate: MS (ESI): m/z 311 (MH+).
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[C:7]([CH3:23])[CH:8]=[C:9]([C:13]([C:15]3[CH:16]=[N:17][N:18]([CH2:21][CH3:22])[C:19]=3[OH:20])=[O:14])[C:10]=2[CH3:12])[S:5](=[O:25])(=[O:24])[CH2:4][CH2:3]1.O.C(=O)([O-])[O-].[K+].[K+].[C:33]1([CH3:43])[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>ClCCl.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH3:1][CH:2]1[C:11]2[C:6](=[C:7]([CH3:23])[CH:8]=[C:9]([C:13]([C:15]3[CH:16]=[N:17][N:18]([CH2:21][CH3:22])[C:19]=3[O:20][S:39]([C:36]3[CH:37]=[CH:38][C:33]([CH3:43])=[CH:34][CH:35]=3)(=[O:41])=[O:40])=[O:14])[C:10]=2[CH3:12])[S:5](=[O:25])(=[O:24])[CH2:4][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCn1ncc(C(=O)c2cc(C)c3c(c2C)C(C)CCS3(=O)=O)c1O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCn1ncc(C(=O)c2cc(C)c3c(c2C)C(C)CCS3(=O)=O)c1OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 77.4 %

Procedure:
A 30-ml eggplant type flask was charged with 0.18 g (0.50 mmol) of 4,5,8-trimethyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide, 5 ml of dichloromethane, 5 ml of water and 0.07 g (0.50 mmol, 1 equivalent) of potassium carbonate, and a solution of 0.10 g (0.55 mmol, 1.1 equivalents) of p-toluenesulfonyl chloride in 1 ml of dichloromethane was dropwise added with stirring at room temperature. 5 mg of benzyltriethylammonium chloride (BTEAC) was added, and the mixture was allowed to react at the above temperature for 2 hours and then liquid-separated. An aqueous layer was extracted with dichloromethane. An organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. The solvent was distilled off to give 0.30 g of a crude product, which was then recrystalized from ethanol to give 0.20 g (yield 77%) of 4,5,8-trimethyl-6-(1-ethyl-5-p-toluenesulfonyloxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide (Compound No. 52).
Reaction SMILES: [CH2:1]([CH:10]1[CH2:14][CH2:13][CH2:12][NH:11]1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:15]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]C1>>[CH2:1]([CH:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:19]([CH:15]1[CH2:18][CH2:17]1)=[O:20])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)C1CCC1
Reactant: C(=Cc1ccccc1)CC1CCCN1
Product: O=C(C1CC1)N1CCCC1C/C=C/c1ccccc1

Procedure:
Stage a) According to the method of Example 1.1, Stage a), from 2-(cinnamyl)pyrrolidine and cyclobutanecarboxylic acid chloride there is obtained, with a yield of 95%, 2-cinnamyl-1-cyclobutanecarbonylpyrrolidine (formula II; Ar=C6H5, m=1, n=1, R=cyclobutyl), which is introduced in the next stage without further treatment.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([C:16]2[CH:21]=[C:20]([O:22][CH2:23][CH3:24])[CH:19]=[CH:18][C:17]=2[O:25][CH2:26][C:27](=[O:29])[NH2:28])[C:12]([O:14]C)=[O:13])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[Li+].[OH-]>C1COCC1>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([C:16]2[CH:21]=[C:20]([O:22][CH2:23][CH3:24])[CH:19]=[CH:18][C:17]=2[O:25][CH2:26][C:27](=[O:29])[NH2:28])[C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1)(=[NH:2])[NH2:3]
Reactant: CCOc1ccc(OCC(N)=O)c(C(Nc2ccc(C(=N)N)cc2)C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1ccc(OCC(N)=O)c(C(Nc2ccc(C(=N)N)cc2)C(=O)O)c1

Procedure:
The methyl (RS)-(4-carbamimidoyl-phenylamino)-(2-carbamoylmethoxy-5-ethoxy-phenyl)-acetate was saponified in THF with 1N LiOH to give (RS)-(4-carbamimidoyl-phenylamino)-(2-carbamoylmethoxy-5-ethoxy-phenyl)-acetic acid and purified by trituration in water and dilute ammonia; m.p. 266° C., MS: 387 (M+H)+.
Reaction SMILES: [CH:1]([CH:15]1[CH2:20][C:19](=[O:21])[O:18][C:16]1=[O:17])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(N(CC)CC)C.[F:29][C:30]1[CH:51]=[CH:50][CH:49]=[CH:48][C:31]=1[CH:32]=[C:33]1[C:38](=[O:39])[C:37](=[CH:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[F:47])[CH2:36][NH:35][CH2:34]1.CO>C(Cl)Cl.C(Cl)(Cl)Cl>[F:47][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[CH:40]=[C:37]1[C:38](=[O:39])[C:33](=[CH:32][C:31]2[CH:48]=[CH:49][CH:50]=[CH:51][C:30]=2[F:29])[CH2:34][N:35]([C:16]([CH:15]([CH:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:20][C:19]([OH:18])=[O:21])=[O:17])[CH2:36]1
Reactant: CCCCCCCCCCCCC=CC1CC(=O)OC1=O
Reactant: O=C1C(=Cc2ccccc2F)CNCC1=Cc1ccccc1F
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCC=CC(CC(=O)O)C(=O)N1CC(=Cc2ccccc2F)C(=O)C(=Cc2ccccc2F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tetradecenyl succinic anhydride (198 mg, 0.67 mmol) and triethylamine (0.18 ml, 1.29 mmol) were added to a solution of compound 1 (200 mg, 0.64 mmol) in methylene chloride. The reaction mixture was stirred at room temperature for 2 h. The crude compound was passed through silica column, and using 10% methanol:chloroform as eluant, compound 27 was obtained as yellow thick syrup (357 mg, 92% yield). Rf (10:90 methanol:chloroform)=0.31. 1H NMR (300 MHz, CDCl3): δ 7.90-7.80 (m, 3H, 2C═CH, vinyl-H), 7.45-7.00 (m, 9H, Ar—H, vinyl-H), 5.40-4.50 (m, 9H), 2.70-1.70 (m, 9H), 1.40-1.20 (m, 12H), 0.93 (t, 3H, J=6.6, CH3). 13C NMR (75 MHz, CDCl3): δ 186.10, 174.03, 170.76, 162.6 (d, J=51.2), 133.75, 133.55, 132.36, 130.75, 126.68, 124.22 (d, J=9.8), 115.98 (d, J=21.2), 44.75, 32.46, 31.90, 22.67, 14.12. ESI Mass calculated for C37H45F2NNaO4 (M+Na)+628.32. found 628.27.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:16][CH:17]2[CH2:24][CH:20]3[CH2:21][NH:22][CH2:23][CH:19]3[CH2:18]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[N:6][CH:7]=1.[C:25]([CH2:27][C:28](O)=[O:29])#[N:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:16][CH:17]2[CH2:24][CH:20]3[CH2:21][N:22]([C:28](=[O:29])[CH2:27][C:25]#[N:26])[CH2:23][CH:19]3[CH2:18]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[N:6][CH:7]=1
Reactant: Cc1c(Nc2ncc(Cl)c(NC3CC4CNCC4C3)n2)cnn1C
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(Nc2ncc(Cl)c(NC3CC4CN(C(=O)CC#N)CC4C3)n2)cnn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
To a solution of 5-chloro-N2-(1,5-dimethyl-1H-pyrazol-4-yl)-N4-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine (58.4 mg, 0.17 mmol) and 2-cyanoacetic acid (23.1 mg, 0.27 mmol) in mixture of DCM (8 mL) and DMF (2 mL) were added HATU (109.8 mg, 0.29 mmol) and Et3N (45.7 mg, 0.45 mmol). The reaction mixture was stirred at rt for 1 h, quenched with H2O (30 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/50) to give the title compound as a beige solid (46.5 mg, 66.7%).