Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([NH2:13])=[CH:6][C:5]=1[O:14][CH3:15]>O1CCCC1.[Ni]>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:13])=[CH:6][C:5]=1[O:14][CH3:15]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)cc1OC
Agent: [Ni]
Solvent: C1CCOC1
Product: COC(=O)c1cc(N)c(N)cc1OC

Procedure:
To a mixture of 29.0 g (0.16 mole) of methyl-4-amino-2-methoxybenzoate, 0.5 g of 4-dimethylaminopyridine, and 16.0 gm (0.16 mole) of triethylamine in 500 ml of dichloromethane was added in batches 22 ml (ca. 0.23 mole) of acetic acid. After two hours the reaction mixture was neutralized with sodium bicarbonate (in solution and as a solid). The organic phase was washed successively with aqueous sodium bicarbonate. The organic phase was washed successively with aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Recrystallization from toluene gave 30 g of methyl-4-acetamido-2-methoxybenzoate. To 100 ml of fuming nitric acid, stirred at −40° C., was slowly added 22.3 g (0.10 mole)of the acetylated intermediate. After about twenty minutes the mixture was warmed to 0° C. and stirred for another twenty minutes. The mixture was poured onto one liter of ice and the resultant precipitate was collected. Recrystallization from toluene/ethanol gave 14.2 g of the nitrated and deacetylated compound, methyl-4-amino-2-methoxy-5-nitrobenzoate. (Under similar conditions in which the acetyl group is not removed, saponification with methanolic sodium hydroxide gives the same product.) Hydrogenation of the nitro intermediate in tetrahydrofuran using Raney nickel as catalyst gave methyl-4,5-diamino-2-methoxybenzoate. A mixture of 4.83 g (24.6 mmole) of the diamine and 7.08 g (49.2 mmole) of potassium ethylxanthate was heated at reflux under argon in 40 ml of water. The resultant product mixture was chromatographed on silica gel to give 1.5 g of methyl-2-mercapto-5-methoxy-1H-benzimidazole-6-carboxylate. (Analysis. Calc'd. for C10H10N2O3S: C, 50.41; H, 4.23; N, 11.76; S, 13.46. Found: C, 50.30; H, 4.19; N, 11.71; S, 13.12.) The title compound was then prepared by the method of Example 1 using 1.19 g (5.0 mmole) of methyl-2-mercapto-5-methoxy-1H-benzimidazole-6-carboxylate instead of 2-mercaptobenzimidazole and 0.97 g (5.5 mmole)of 2-(chloromethyl)aniline hydrochloride instead of 2-(chloromethyl)-N,N-dimethylaniline. Analysis. Calc'd. for C17H17N3O3S*2HCl: C, 49.05; H,4.60; N, 10.09; S, 7.70; C1, 17.03. Found: C, 49.37; H, 4.77; N, 9.72; S, 7.43; C1, 16.77.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[F:25][C:26]1[CH:27]=[C:28]([NH:38][C:39]([NH2:41])=[NH:40])[CH:29]=[CH:30][C:31]=1[N:32]1[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:41]=[C:39]([NH:38][C:28]3[CH:29]=[CH:30][C:31]([N:32]4[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]4)=[C:26]([F:25])[CH:27]=3)[N:40]=2)=[CH:4][CH:3]=1
Reactant: Cc1cn(-c2ccc(NC(=N)N)cc2F)cn1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)cc1
Solvent: O=[N+]([O-])O
Product: Cc1cn(-c2ccc(Nc3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)cc2F)cn1

Procedure:
The title compound was prepared from 1-(4-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (125 mg, 0.5 mmol) and N-[3-fluoro-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (180 mg, 0.5 mmol) using in analogous manner the procedure described in example 29). Obtained as a pale-yellow solid (18 mg, 8%). Mp 248-250° C.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:17])=[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)=[O:4].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>C1COCC1>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9]1[N:10]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[S:7][C:8]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[O:17]
Reactant: O=C(CBr)Nc1nc(-c2ccco2)c(C(=O)c2ccccn2)s1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: O=C(CN1CCOCC1)Nc1nc(-c2ccco2)c(C(=O)c2ccccn2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
Compound 263 (196 mg, 0.49 mmol) was dissolved in THF (3.3 mL), morpholine (0.128 mL, 1.47 mmol) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was recrystallized from a mixed solvent (5:1) of hexane and acetone to afford the entitled Compound 264 (139 mg, 71%) as a pale yellow solid.
Reaction SMILES: [CH3:1][S:2](=[O:19])([CH:7]([C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1)[CH3:8])=[N:3][C:4]([NH2:6])=[S:5].Br[CH:21]1[CH2:29][CH2:28][C:24]2=[N:25][O:26][N:27]=[C:23]2[C:22]1=O>CCO>[CH3:1][S:2](=[N:3][C:4]1[S:5][C:29]2[CH2:21][CH2:22][C:23]3[C:24]([C:28]=2[N:6]=1)=[N:25][O:26][N:27]=3)(=[O:19])[CH:7]([C:9]1[CH:10]=[N:11][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:13][CH:14]=1)[CH3:8]
Reactant: CC(c1ccc(C(F)(F)F)nc1)S(C)(=O)=NC(N)=S
Reactant: O=C1c2nonc2CCC1Br
Solvent: CCO
Product: CC(c1ccc(C(F)(F)F)nc1)S(C)(=O)=Nc1nc2c(s1)CCc1nonc1-2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-(methyl(oxo){1-[6-(trifluoromethyl)-3-pyridinyl]ethyl}-λ6-sulfanylidene)thiourea (J) (100 mg, 0.321 mmol) and 5-bromo-6,7-dihydrobenzo[c][1,2,5]oxadiazol-4(5H)-one (76.6 mg, 0.353 mmol, 1.1 eq) were suspended in EtOH (1.6 mL). The reaction was stirred at room temperature for 2 h, and then heated to reflux for 1 h. The hot solution was filtered via a 0.45 μm nylon syringe filter and the filtrate was stored at −20° C. over night. 7-[(methyl(oxo){1-[6-(trifluoromethyl)-3-pyridinyl]ethyl}-λ6-sulfanylidene)amino]-4,5-dihydro[1,3]thiazolo[4,5-e][2,1,3]benzoxadiazole (65) was obtained in form of slightly yellow crystals (70 mg, 0.163 mmol, 51%) as a 1:1 mixture of diastereomers (racemate) that were isolated by filtration, washed with a small amount of cold ethanol, and dried in the high vacuum. 1H-NMR (DMSO-d6, 400 MHz): δ=1.87 (d, J=6.9 Hz, 1.5H, CHCH3, diastereomer 1); 1.89 (d, J=6.9 Hz, 1.5H, CHCH3, diastereomer 2); 3.06-3.27 (m, 4H, CH2—CH2, diastereomers 1, 2); 3.42 (s, 1.5H, S—CH3, diastereomer 1); 3.43 (s, 1.5H, S—CH3, diastereomer 2); 5.34 (q, J=6.9 Hz, 1H, CHCH3, diastereomers 1, 2); 7.96 (d, J=7.7 Hz, 0.5H, pyr-C3-H, diastereomer 1), 7.98 (d, J=7.8 Hz, 0.5H, pyr-C3-H, diastereomer 2); 8.21-8.26 (m, 1H, pyr-C4-H, diastereomers 1, 2); 8.85 (d, 0.5H4J=1.6 Hz, pyr-C6-H, diastereomer 1); 8.86 (d, 0.5H, 4J=1.6 Hz, pyr-C6-H, diastereomer 2). 13C-NMR (DMSO-d6, 100 MHz): δ=13.3, 13.6 (CHCH3, two diastereomers); 17.9 (double peak, CH2, two diastereomers); 20.4 (double peak, CH2, two diastereomers); 36.4, 36.5 (S—CH3, two diastereomers); 60.8, 60.9 (CHCH3, two diastereomers); 119.4, 119.5 (pyr-C, two diastereomers); 120.3 (q, 2J (C—F)=271.5 Hz, CF3, two diastereomers), 131.6, 131.9; (pyr-C, two diastereomers); 132.0, 132.1 (Ar, two diastereomers), 132.4, 132.5 (Ar, two diastereomers); 138.0, 138.1 (pyr-C, two diastereomers); 145.0 (double peak, Ar, two diastereomers); 145.0, 145.1 (Ar, two diastereomers); 149.9 (double peak, pyr-C, two diastereomers); 151.2 (double peak, Ar, two diastereomers); 166.3, 166.6 (thiazole, two diastereomers). UPLC-MS (ESI+): mass calc'd for C16H15F3N5O2S2 (M+H+): 430.1, found 430.1, UPLC-MS (ESI+) mass calc'd for C16H13F3N5O2S2 (M−H+): 428.1, found 428.1.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[N:7][C:8]#[N:9])[S:5][CH3:6])[CH3:2].[CH3:10][O:11]CCN.C(N)C>>[CH3:10][O:11][CH:1]([NH:3][C:4](=[N:7][C:8]#[N:9])[S:5][CH3:6])[CH3:2]
Reactant: COCCN
Reactant: CCNC(=NC#N)SC
Agent: CCN
Product: COC(C)NC(=NC#N)SC

Procedure:
1-Methoxyethyl-2-methyl-3-cyanoisothiourea was prepared following the same procedure as for 1-ethyl-2-methyl-3-cyanoisothiourea (see EXAMPLE 250) except methoxyethylamine was used in lieu of ethylamine. 1H NMR (CDCl3) δ 2.53 (br s, 3H), 3.37 (s, 3H), 3.52 (m, 4H), 6.29 (br s, 1H).
Reaction SMILES: N#N.[Br:3][C:4]1[N:5]=[C:6]([CH2:9][OH:10])[S:7][CH:8]=1.CCN(CC)CC.[S:18](Cl)([CH3:21])(=[O:20])=[O:19]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:21][S:18]([O:10][CH2:9][C:6]1[S:7][CH:8]=[C:4]([Br:3])[N:5]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1nc(Br)cs1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1nc(Br)cs1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (4-bromo-thiazol-2-yl)-methanol (695 mg, 3.58 mmol) in dry CH2Cl2 (10 mL) was treated at 0° C. with Et3N (0.67 mL, 4.74 mmol) followed by DMAP (44 mg, 0.36 mmol) and Ms-Cl (0.36 mL, 4.65 mmol). After stirring at 0° C. for 1 h, the reaction was quenched with water (10 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (4-bromothiazol-2-yl)methyl methanesulfonate as a brown oil. The crude material was dissolved in dry DMF (6 mL) and treated with NaN3 (257 mg, 3.91 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 2-(azidomethyl)-4-bromothiazole as a yellow oil. LC-MS-conditions 01: tR=0.83 min.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[NH:34][C:33](=[O:35])[C:20]3([CH2:25][CH2:24][N:23](CC4C=CC=CC=4)[CH2:22][CH2:21]3)[N:19]=[C:18]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:17]=2[CH:42]=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[NH:34][C:33](=[O:35])[C:20]3([CH2:25][CH2:24][N:23]([C:2]([O:4][CH2:5][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=4)=[O:3])[CH2:22][CH2:21]3)[N:19]=[C:18]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:17]=2[CH:42]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=NC12CCN(Cc1ccccc1)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1CCC2(CC1)N=C(c1ccccc1)c1cc(Cl)ccc1NC2=O
Reaction time: 3 h

Procedure:
10 g (0.029 mole) of a 50% strength solution of benzyl chloroformate in toluene are added to a mixture of 4.0 g (0.0093 mole) of 7-chloro-5-phenyl-1'-benzyl-spiro[1H-1,4-benzodiazepine-3,4'-piperidin]-2-(3H)-one and 2.4 g (0.029 mole) of finely powdered NaHCO3 in 80 ml of absolute chloroform. The reaction mixture is boiled for 3 hours, with reflux cooling. It is then poured onto ice and the organic phase is separated off and washed twice with 10% strength NaHCO3 solution. After drying over Na2SO4, the mixture is filtered and the solvent is evaporated off. A pale brown-colored remains, and is crystallized with petroleum ether. The compound is filtered off with suction, washed with petroleum ether and dried at 60° C. in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:38]1[N:43]=[C:42]([C:44]#[N:45])[CH:41]=[N:40][CH:39]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:34])[CH3:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([C:38]4[N:43]=[C:42]([C:44]#[N:45])[CH:41]=[N:40][CH:39]=4)=[CH:21][CH:22]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: N#Cc1cncc(Cl)n1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(-c2cncc(C#N)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 6-chloropyrazine-2-carbonitrile following a procedure analogous to that described in Example 14. LC-MS Method 1 tR=1.61 min, m/z=497 (M+Na); 1H NMR (CDCl3) 8.98 (d, 2H), 7.87 (d, 2H), 7.26 (m, 1H), 7.18 (m, 3H), 7.04 (t, 2H), 5.72 (q, 1H), 2.99 (m, 1H), 1.59 (d, 3H), 1.14 (d, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH2:17]([O:19][C:20]([C:22]1[NH:23][C:24]([CH:33]=O)=[C:25]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:26]=1[CH3:27])=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([C:22]1[NH:23][C:24]([CH:33]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[NH:11][C:10]2=[O:16])=[C:25]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:26]=1[CH3:27])=[O:21])[CH3:18]
Reactant: CCOC(=O)c1[nH]c(C=O)c(CCC(=O)O)c1C
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Product: CCOC(=O)c1[nH]c(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)c(CCC(=O)O)c1C

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 4-(2-carboxyethyl)-5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester to give the title compound.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:34]C(=O)C)([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:30]=[C:29]([CH2:31][CH2:32][CH3:33])[O:28][N:27]=3)=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[CH2:7][O:8]C(=O)C)(=O)C.[Li+].[OH-]>C1COCC1.O>[NH2:34][C:6]([CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:30]=[C:29]([CH2:31][CH2:32][CH3:33])[O:28][N:27]=3)=[CH:22][CH:21]=2)=[CH:18][CH:19]=1)([CH2:7][OH:8])[CH2:5][OH:4]
Reactant: CCCc1cc(-c2ccc(-c3ccc(CCC(COC(C)=O)(COC(C)=O)NC(C)=O)cc3)cc2)no1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1cc(-c2ccc(-c3ccc(CCC(N)(CO)CO)cc3)cc2)no1

Procedure:
Acetic acid 2-acetoxymethyl-2-acetylamino-4-[4′-(5-propyl-isoxazol-3-yl)-biphenyl-4-yl]butyl ester (0.1 mmol) is dissolved in THF (1 mL) and treated with 2 N LiOH aqueous solution (0.5 mL). The resulting mixture is stirred at reflux for 1 h and diluted with H2O (10 mL). It is then extracted with EtOAc (3×5 mL) and the combined organic phase is washed with brine and dried over Na2SO4. After concentrated, the crude product is purified with LC-MS to give the desired product as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.86 (d, J=8.4 Hz, 2H), 7.70 (d, J=8.4 Hz, 2H), 7.58 (d, J=8.2 Hz, 2H), 7.33 (d, J=8.2 Hz, 2H), 3.53 (q, J=11.0 Hz, 4H), 2.81 (t, J=7.4 Hz, 2H), 2.71 (m, 2H), 1.79 (m, 4H), 1.04 (t, J=7.4 Hz, 3H). MS: (ES+): 381.2 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:42])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[S:27](=[O:37])(=[O:36])[NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:17][CH:16]=3)[C:10]([CH2:38][CH2:39][CH2:40][CH3:41])=[N:9]2)[CH:7]=1.[C:43](Cl)(=[O:48])[CH2:44][CH2:45][CH2:46][CH3:47]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:32]([O:31][C:29]([NH:28][S:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:11]2[C:10]([CH2:38][CH2:39][CH2:40][CH3:41])=[N:9][N:8]([C:6]3[CH:7]=[C:2]([NH:1][C:43](=[O:48])[CH2:44][CH2:45][CH2:46][CH3:47])[CH:3]=[CH:4][C:5]=3[Cl:42])[C:12]2=[O:13])=[CH:20][CH:19]=1)(=[O:37])=[O:36])=[O:30])([CH3:34])([CH3:35])[CH3:33]
Reactant: CCCCc1nn(-c2cc(N)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1
Reactant: CCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCCCC(=O)Nc1ccc(Cl)c(-n2nc(CCCC)n(Cc3ccc(-c4ccccc4S(=O)(=O)NC(=O)OC(C)(C)C)cc3)c2=O)c1
Yield: 46 %

Procedure:
A solution of 78 mg (0.128 mmol) of 2-(5-amino-2-chlorophenyl)-4-[[2'-[N-(t-butoxycarbonyl)sulfamoyl]biphenyl-4-yl]methyl]-5-n-butyl-2,4-dihydro-3H-1,2,4-triazol-3-one (from Example 25), 76 μL (77 mg, 0.64 mmol) of valeryl chloride, and 15.6 mg (0.128 mmol) of 4-(dimethylamino)pyridine (DMAP) in 1 mL of dry pyridine was stirred overnight at room temperature. The mixture was quenched by addition of water and extracted twice with ethyl acetate. The combined organic fractions were washed twice with water, then with brine, and dried over Na2SO4. The filtered solution was concentrated, and the residue was flash chromatographed twice on silica gel (gradient elution with 0.5-3% methanol in CH2Cl2) to provide 41 mg (46%) of the title compound as a white solid, mp 177°-179° C.; homogeneous by TLC (9:1 CH2Cl2 --MeOH).
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:25]3[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=3[NH:23][C:22]2=[O:31])[CH2:17][CH2:16]1>C(O)C>[Cl:30][C:28]1[CH:27]=[CH:26][C:25]2[N:21]([CH:18]3[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][CH2:12][N:11]4[C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[NH:4][C:1]4=[S:3])[CH2:16][CH2:17]3)[C:22](=[O:31])[NH:23][C:24]=2[CH:29]=1
Reactant: S=C=S
Reactant: Nc1ccccc1NCCCN1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1
Solvent: CCO
Product: O=c1[nH]c2cc(Cl)ccc2n1C1CCN(CCCn2c(=S)[nH]c3ccccc32)CC1
Yield: 45.5 %

Procedure:
A mixture of 38 parts of carbon disulfide, 6 parts of 1-[1-{3-[N-(2-aminophenyl)amino]propyl}-4-piperidinyl]-5-chloro-1,3-dihydro-2H-benzimidazol-2-one and 32 parts of ethanol is stirred and refluxed for 24 hours. The reaction mixture is evaporated and the residue is crystallized from ethanol. The product is filtered off and recrystallized from a mixture of N,N-dimethylformamide and water, yielding 3 parts (45.5%) of 5-chloro-1-{1-[3-(2,3-dihydro-2-thioxo-1H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 266.6° C.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[CH3:31])[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O>CN(C=O)C>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([CH:11]([C:12]2[C:20]3[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:9][C:1]#[N:2])=[C:25]([CH3:31])[CH:26]=1
Reactant: [C-]#N
Reactant: CSCc1cccc2c(C(CCOS(C)(=O)=O)c3ccc(Cl)cc3C)c[nH]c12
Agent: [K+]
Solvent: CN(C)C=O
Product: CSCc1cccc2c(C(CCC#N)c3ccc(Cl)cc3C)c[nH]c12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
419 mg (6.44 mmol) of potassium cyanide were added to 1.41 g (3.22 mmol) of the compound from Example 61A in 20 ml of DMF. The mixture was stirred at 80° C. for 2 h and then concentrated, and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 987 mg (83% of theory) of the title compound.
Reaction SMILES: [O-]CC.[Na+].S.Cl[CH2:7][C:8]1[NH:9][C:10]([CH3:33])=[C:11]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].O[S:35](O)(=O)=O>COCCOC.O>[SH:35][CH2:7][C:8]1[NH:9][C:10]([CH3:33])=[C:11]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)C1=C(C)NC(CCl)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Agent: CC[O-]
Agent: S
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C1=C(C)NC(CS)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Temperature: -15 °C
Reaction time: 1 h

Procedure:
A stirred ethanolic solution (200 ml) of an alkaline alkoxide, for example sodium ethoxide (20 g), is saturated, at +10° C., with dry hydrogen sulfide, cooled to -15° C., and added with a solution of 2-chloromethyl-3,5-dicarboethoxy-4-(m-nitrophenyl) -6-methyl-1,4-dihydropyridine (25 g) in DME (70 ml). After one hour, the reaction mixture is warmed to 0° C., acidified with H2SO4 (10% water solution; 100 ml) and diluted with water (1400 ml). The precipitate is filtered off, dried in vacuum, and recrystallized from Et2O to give 23 g of 2-mercaptomethyl-3,5-dicarboethoxy-4-(m-nitrophenyl) -6-methyl-1,4-dihydropyridine, m.p. 145°-147° C.
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([N:9]2[C:13](=[O:14])[C:12]([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)=[CH:11][NH:10]2)[CH:4]=1.Cl.[F:21][C:22]1([F:27])[CH2:26][CH2:25][NH:24][CH2:23]1.C(N(C(C)C)C(C)C)C>O1CCCC1>[F:21][C:22]1([F:27])[CH2:26][CH2:25][N:24]([C:3]2[N:8]=[CH:7][N:6]=[C:5]([N:9]3[C:13](=[O:14])[C:12]([N:15]4[CH:19]=[CH:18][N:17]=[CH:16]4)=[CH:11][NH:10]3)[CH:4]=2)[CH2:23]1
Reactant: FC1(F)CCNC1
Reactant: O=c1c(-n2ccnc2)c[nH]n1-c1cc(Cl)ncn1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=c1c(-n2ccnc2)c[nH]n1-c1cc(N2CCC(F)(F)C2)ncn1

Procedure:
100 mg (0.3 mmol) of the compound from Example 13A, 58 mg (0.4 mmol) of 3,3-difluoropyrrolidine hydrochloride and 175 ml (130 mg, 1.0 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine are initially charged in 2 ml of tetrahydrofuran and reacted in a single mode microwave (Emrys Optimizer) at 120° C. for 1 h. After concentration under reduced pressure, the residue is taken up in acetonitrile/water and purified by preparative HPLC (RP 18 column; mobile phase: acetonitrile/water gradient). Yield: 111 mg (99% of theory)
Reaction SMILES: [H-].[Na+].[Br-].[C:4]([CH2:7][CH2:8][CH2:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:6])=[O:5].[C:30]1([CH2:36][CH2:37][CH:38]=O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CS(C)=O>[C:30]1([CH2:36][CH2:37]/[CH:38]=[CH:10]\[CH2:9][CH2:8][CH2:7][C:4]([OH:6])=[O:5])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=CCCc1ccccc1
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(O)CCC/C=C\CCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A stirred suspension of sodium hydride (12.0 g, 50% dispersion in oil) in dry dimethyl sulphoxide (100 ml) was heated to 70° to 75° C. under nitrogen for 40 minutes. The dark solution was cooled, a solution of 4-carboxybutyltriphenylphosphonium bromide (53 g) in dry dimethyl sulphoxide (100 ml) was added over 20 minutes at 20° to 25° C., and the solution was stirred for a further 10 minutes. 3-Phenyl-propionaldehyde (12.5 ml) was added with cooling to maintain a temperature of 30° to 35° C. and the mixture was stirred for a further 4 hours at room temperature, then poured on to ice-water (600 ml) and washed with chloroform. The aqueous phase was acidified and extracted with chloroform. The extract was washed with water, dried, and evaporated. The residual oil was distilled under vacuum to give the above product, b.p. 134° to 139° C./0.07 mm. 13C NMR spectroscopy showed the presence of about 5% (E)-isomer.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])=[C:5]([C:14]([NH:16][O:17]C2CCCCO2)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:3]1[C:4]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])=[C:5]([C:14]([NH:16][OH:17])=[O:15])[S:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)#[N:2]
Reactant: N#Cc1c(N2CCOCC2)sc(C(=O)NOC2CCCCO2)c1-c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c(N2CCOCC2)sc(C(=O)NO)c1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
4-Cyano-3-(2,4-dichlorophenyl)-5-morpholin-4-yl-N-(tetrahydro-2H-pyran-2-yloxy)thiophene-2-carboxamide (0.050 g, 0.10 mmol) was dissolved in DCM (3 mL) and TFA (0.24 mL, 3.11 mmol) was added. The solution was stirred at room temperature overnight. Solvent was evaporated and the residue was purified by column chromatography (silica gel, elution with DCM to 10% MeOH in DCM over 20 minutes) to give the title compound 24 (0.030 g, 67%). LCMS: (FA) ES+ 398.