Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][NH:13]1)=[S:11].C(N(CC)CC)C.C.[C:26](Cl)(Cl)=[O:27]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]1[N:12]2[N:13]([CH2:14][O:15][CH2:16][CH2:17]2)[C:26](=[O:27])[S:11]1
Reactant: O=C(Cl)Cl
Reactant: S=C(Nc1ccc(Cl)cc1Cl)N1CCOCN1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1sc(=Nc2ccc(Cl)cc2Cl)n2n1COCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.8 g (6.2 mmol) N-(2,4-dichlorophenyl)tetrahydro-4H-1,3,4-oxadiazine-4-carbothioamide was dissolved in 30 mL toluene and 1 mL triethylamine in the presence of a small quantity of activated charcoal at 0°-5° C. 3.49 g (6.81 mmol) phosgene as 20% solution in 30 mL toluene was added dropwise over 1.5 h. The reaction mixture was then left to warm up to room temperature and stirred overnight. The activated charcoal was removed by filtration and the solvent evaporated in vacuo. The desired product was isolated after chromatography on silica gel.
Reaction SMILES: Br[CH2:2][C:3]1[NH:4][CH:5]=[CH:6][N:7]=1.[OH:8][N:9]1C(=O)C2=CC=CC=C2C1=O.[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=O)[C:27]([OH:29])=[O:28])[N:25]=1>>[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:9]/[O:8][CH2:2][C:3]2[NH:4][CH:5]=[CH:6][N:7]=2)/[C:27]([OH:29])=[O:28])[N:25]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: BrCc1ncc[nH]1
Reactant: Nc1nc(C(=O)C(=O)O)cs1
Product: Nc1nc(/C(=N/OCc2ncc[nH]2)C(=O)O)cs1

Procedure:
N.m.r. in solvent A: 4.15 (m, 1H), 4.38 (m, 1H), 4.48 (m, 1H , 4.92 (m, 1H , 6.94 (s, 1H), 7.4 (s, 15H). 9. N.m.r. in solvent C: 3.4 (m, 2H), 4.2 - 4.6 (m, 4H), 4.7 (m, 1H), 5.0 (m, 1H), 5.1 (d, 1H), 5.9 (d, 1H), 6.9 (s, 1H), 7.4 (s, 15H). 10. The starting material was prepared by reaction of 2-bromomethylimidazole with N-hydroxy-phthalimide, deprotection to give 0-(imidazol-2-yl)methylhydroxylamine and condensation with 2-(2-aminothiazol-4-yl)glyoxylic acid to give 2-(2-aminothiazol-4-yl)-2-[(Z)-(imidazol-2-yl)-methoxyimino]acetic acid.
Reaction SMILES: [C:1]([Cl:4])(=[O:3])[CH3:2].[Cl:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=[C:8]2[CH2:16][CH2:17][CH2:18][NH:19][CH2:20][C:7]=12.C(N(CC)CC)C>C(Cl)(Cl)Cl>[ClH:4].[C:1]([N:19]1[CH2:18][CH2:17][CH2:16][C:8]2=[N:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]([Cl:5])=[C:7]2[CH2:20]1)(=[O:3])[CH3:2]
Reactant: Clc1c2c(nc3ccccc13)CCCNC2
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCCc2nc3ccccc3c(Cl)c2C1
Product: Cl
Reaction time: 100 h

Procedure:
4.3 gm (55 millimols) of acetyl chloride were added dropwise to a mixture of 11.8 gm (50 millimols) of 11-chloro-2,3,4,5-tetrahydro-1H-azepino[4,3-b]quinoline, 5.5 gm. (55 millimols) of triethylamine and 300 ml of chloroform. After 100 hours of standing, the mixture was washed with water, and the chloroform phase was evaporated. The raw crystalline base was purified on a silicagel column with benzene/acetone (2:1) as the eluant. The hydrochloride was precipitated from isopropanol with isopropanolic hydrochloric acid.
Reaction SMILES: [OH-:1].[Na+].BrBr.[CH3:5][C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH2:7][C:8](=[O:10])C>>[CH3:11][C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:5])[CH2:7][C:8]([OH:10])=[O:1]
Reactant: CC(=O)CC(C)(C)c1ccccc1
Reactant: [OH-]
Agent: BrBr
Agent: [Na+]
Product: CC(C)(CC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of NaOH (47.2 g, 1.18 mole) in ice/H2O (270 g) maintained at 4°-5° C. was added Br2 (68.7 g, 0.43 mole) followed by 4-methyl-4-phenyl-2-pentanone (23.7 g, 0.135 mole). The reaction was stirred for 18 hours at room temperature. The crude reaction mixture was extracted with CCl4 (discarded), acidified to pH 1-2 with concentrated HCl solution and extracted with ethyl acetate. The combined organics were washed with saturated NaCl solution, dried over Na2SO4 and evaporated in vacuo to obtain 22.5 g of the title B compound as an off-white solid. This was used in the next step without further purification. MS: (M+NH4)+ @ 196.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:7]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19].[CH3:28][C:29]1[N:30]=[CH:31][NH:32][CH:33]=1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH:8]2[N:7]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)(=[O:20])=[O:19])[CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:32]3[CH:33]=[C:29]([CH3:28])[N:30]=[CH:31]3)[CH2:10][CH2:9]2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCCCl)CCC2c2ccc(F)cc2)cc1
Reactant: Cc1c[nH]cn1
Product: Cc1ccc(S(=O)(=O)N2C(CCCCn3cnc(C)c3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=456.5 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(4-chloro-butyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 4-methyl-1H-imidazole.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([NH:18][C:19]2[N:24]=[C:23]([C:25]3[C:26]([C:44]4[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=4)=[N:27][N:28]4[CH:33]=[C:32]([C:34]([O:41][CH2:42][CH3:43])([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[CH:31]=[CH:30][C:29]=34)[CH:22]=[CH:21][N:20]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1.C(Cl)(Cl)(Cl)[Cl:52]>O1CCCC1>[Cl:52][C:33]1[N:28]2[N:27]=[C:26]([C:44]3[CH:45]=[CH:46][C:47]([F:50])=[CH:48][CH:49]=3)[C:25]([C:23]3[CH:22]=[CH:21][N:20]=[C:19]([NH:18][CH:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)[N:24]=3)=[C:29]2[CH:30]=[CH:31][C:32]=1[C:34]([O:41][CH2:42][CH3:43])([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCOC(OCC)(OCC)c1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(OCC)(OCC)c1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
To a cold (0° C.) solution of diisopropylamine (4.1 mL, 29 mmol) in tetrahydrofuran (25 mL) was added butyllithium (17 mL, 1.6 M in hexanes, 28 mmol) dropwise. The resultant solution was stirred at 0° C. for 10 minutes then cooled to −78° C. The reaction mixture was transferred via syringe to a cold (−78° C.) solution of N-cyclopentyl-4-[2-(4-fluorophenyl)-6-(triethoxymethyl)pyrazolo[1,5-α]pyridin-3-yl]-2-pyrimidinamine (4.86 g, 9.35 mmol) in tetrahydrofuran (25 mL). The reaction mixture was stirred at −78° C. for 30 minutes. Carbon tetrachloride (3.6 mL 37 mmol) was added and the resulting mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was poured onto ice. After the ice had melted, the aqueous mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate. Filtration and concentration followed by flash chromatography (4:1 hexanes:ethyl acetate) provided 4-[7-chloro -2-(4-fluorophenyl)-6-(triethoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (2.37 g, 46%) as a yellow solid. Rf 0.36 (4:1 hexanes:ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 8.36 (d, 1H), 8.08 (d, 1H), 7.85 (d, 1H), 7.67 (m, 2H), 7.15 (t, 2H), 6.33 (d, 1H), 5.15 (d, 1H), 4.36 (m, 1H), 3.46 (q, 6H), 2.10 (m, 2H), 1.81–1.53 (m, 6H), 1.26 (t, 9H); MS m/z 554 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:11]OS(C2C=CC(C)=CC=2)(=O)=O)[C:9]#[N:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[SH:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([NH2:10])=[C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[S:30][N:11]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CS
Reactant: Cc1ccc(S(=O)(=O)ON=C(C#N)c2ccc(F)cc2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1snc(-c2ccc(F)cc2)c1N
Temperature: 5 °C
Reaction time: 16 h
Yield: 41.3 %

Procedure:
Under a nitrogen atmosphere, a stirred suspension of 2-(4-fluorophenyl)-2-(4-methylphenylsulfonyloxy)iminoacetonitrile (64.0 g, 0.2 mole) and triethylamine (61.8 g, 0.61 mole) in 1 l of absolute ethanol was cooled to 5° C. Ethyl 2-mercaptoacetate (26.8 g, 0.22 mole) was added dropwise over a four hour period. The reaction mixture was then stirred for 16 hours and warmed to room temperature. The reaction mixture was concentrated and poured into 2 l of ice water. The resultant precipitate was collected by filtration. The solid filter cake was washed with water and dried. The solid was dissolved in 1.5 l of boiling heptane, and the solution was slurried with silica gel. The hot mixture was filtered; on cooling the filtrate, the solid recrystallized and was collected by filtration, washed with heptane, and dried to give ethyl 3-(4-fluorophenyl)-4-amino-5-isothiazolecarboxylate (22.0 g, mp 137°-139° C.).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:10]=1[C:11]#[N:12])=[O:5])C.[H-].[Na+].Br[CH2:21][C:22]1[CH:26]=[C:25]([C:27]2[S:28][C:29]([Cl:32])=[CH:30][CH:31]=2)[O:24][N:23]=1.[OH-].[Na+]>CN(C=O)C>[Cl:32][C:29]1[S:28][C:27]([C:25]2[O:24][N:23]=[C:22]([CH2:21][N:7]3[C:6]([C:4]([OH:3])=[O:5])=[C:10]([C:11]#[N:12])[C:9]([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)=[N:8]3)[CH:26]=2)=[CH:31][CH:30]=1
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Reactant: CCOC(=O)c1[nH]nc(-c2cccs2)c1C#N
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1c(-c2cccs2)nn(Cc2cc(-c3ccc(Cl)s3)on2)c1C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
287 mg (1.2 mmol) of 4-Cyano-5-thiophen-2-yl-2H-pyrazole-3-carboxylic acid ethyl ester was dissolved in 2 ml of DMF and 51.1 mg (1.3 mmol) of sodium hydride (60% in mineral oil) were added at RT. After stirring for 20 min at room temperature the solution was cooled to −70° C. and 355 mg (1.3 mmol) of 3-bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole were added. The reaction was stirred at room temperature for 3 h. The reaction solution was treated with 1 ml of 2N aqueous NaOH for 16 h at room temperature. The product was purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). After lyophilization the product was obtained as a white solid.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[CH3:7][S:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:30][C@H:29]([CH2:31][NH:32][C:33](=[O:35])[CH3:34])[O:28][C:27]4=[O:36])=[CH:22][CH:21]=3)=[O:19])=[CH:16][N:17]=2)[CH:14]=1.[OH2:37]>CCO>[CH3:7][S:8]([C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH2:30][C@H:29]([CH2:31][NH:32][C:33](=[O:35])[CH3:34])[O:28][C:27]4=[O:36])=[CH:24][CH:25]=3)=[O:19])=[CH:16][N:17]=2)[CH:14]=1)(=[O:1])=[O:37]
Reactant: CSc1ccc2ncc(C(=O)c3ccc(N4C[C@H](CNC(C)=O)OC4=O)cc3)n2c1
Reactant: O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CCO
Product: CC(=O)NC[C@H]1CN(c2ccc(C(=O)c3cnc4ccc(S(C)(=O)=O)cn34)cc2)C(=O)O1

Procedure:
A solution of Oxone (0.356 g. 0.579 mM) in water (2.5 ml) was added to a stirred suspension of the title product from Example 37 (0.117 g. 0.276 mM) in EtOH (10 ml) and the mixture heated at gentle reflux for 2.75 hours. The mixture was allowed to cool. The solid which precipitated was filtered, washed with water and ether to give the title compound (0.1 09 g). MS: 457 (MH+); NMR(250 MHz) 1.83 (3H, s); 3.38 (3H, s); 3.45 (2H, t); 3.85 (1H, m); 4.23 (1H, t); 4.79 (1H, m); 7.78 (2H, d); 8.0 (2H, d); 8.08 (2H, m); 8.24 (1H, t); 8.48 (1H, s); 10.01 (1H, s).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:28])([CH3:27])[CH2:19][NH:20][S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1.C(N(CC)CC)C.O>C1COCC1>[F:28][C:18]([C:15]1[CH:16]=[CH:17][C:12]([C:8]2[CH:7]=[C:6]([NH:5][C:1](=[O:3])[CH3:2])[CH:11]=[CH:10][CH:9]=2)=[CH:13][CH:14]=1)([CH3:27])[CH2:19][NH:20][S:21]([CH:24]([CH3:25])[CH3:26])(=[O:23])=[O:22]
Reactant: CC(=O)Cl
Reactant: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2cccc(N)c2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(-c2ccc(C(C)(F)CNS(=O)(=O)C(C)C)cc2)c1
Temperature: 25 °C
Yield: 54 %

Procedure:
Into a 100 mL single-neck flask, 49 mg of acetyl chloride was added dropwise to 200 mg of {2-[4-(3-aminophenyl)phenyl]-2-fluoropropyl}[(methylethyl)sulfonyl]amine (prepared in example 5) and 63 mg of triethylamine in THF (25 mL) while stirring under a nitrogen atmosphere at room temperature. The reaction was allowed to stir at this temperature for 2 h. The mixture was then poured into H2O and the desired product was extracted into ethyl acetate. The organic layer was backwashed once with H2O, dried over K2CO3, and concentrated under reduced vacuum to yield 193 mg as a foam. This material was purified via silica gel chromatography employing the Chromatotron, using a 4000 micron rotor and eluting with a solvent of hexane/ethyl acetate 1:1 to yield the title compound (121 mg, 54%) as a white foam. Ion spray M.S. 391.2 (M*−1).
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH:13]=[O:14])[CH2:5][C:4](=O)[CH2:3]1.[Cl:17][C:18]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O.[NH2:27]/[C:28](/[CH3:35])=[CH:29]\[C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(O)C>[Cl:17][C:18]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]1[C:3]2[S:2](=[O:16])(=[O:1])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[N:6]([CH:13]=[O:14])[CH2:5][C:4]=2[NH:27][C:28]([CH3:35])=[C:29]1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: O=CN1CC(=O)CS(=O)(=O)c2ccccc21
Reactant: CCOC(=O)/C=C(/C)N
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC2=C(C1c1cccc(Cl)c1Cl)S(=O)(=O)c1ccccc1N(C=O)C2
Yield: 86.4 %

Procedure:
A solution of 1,1-dioxo-5-N-formyl-2,3,4,5-tetrahydro-[1,5]-benzothiazepin-3-one (0.410 g, 1.71 mmole) from Example 16, 2,3-dichlorobenzaldehyde (0.297 g, 1.71 mmole) and ethyl 3-aminocrotonate (0.219 g, 1.71 mmole) in 7 mL of ethanol was heated to reflux for 18 hours. The solvent was removed under reduced pressure and the residue was chromatographed (silica gel, 1:1 hexane:ethyl acetate) to obtain the product as an oil (0.75 g, 86% yield). The product was recrystallized from chloroform-ether.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28]OS(C)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:28][CH2:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OCCc1ccccn1
Reactant: Cc1cccnc1[C@@H]1CCC[C@H](c2ncccc2C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccnc1[C@H]1CCC[C@@H](c2ncccc2C)N1CCc1ccccn1
Temperature: 85 °C
Yield: 43.4 %

Procedure:
Using General Procedure A: A suspension of 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-cis-[2,2′;6′,2″]terpyridine (252 mg, 0.94 mmol), methanesulfonic acid 2-pyridin-2-yl-ethyl ester (approx. 4.9 mmol) and K2CO3 (1.30 g, 9.42 mmol) in DMF (5 mL) was heated at 85° C. for 2.5 d. Purification of the crude material by column chromatography on silica gel (CH2Cl2—CH3OH—NH4OH, 96:4:0 then 94:4:2) followed by radial chromatography on silica gel (1 mm plate, CH2Cl2—CH3OH—NH4OH, 25:1:1) provided 152 mg (43%) of COMPOUND 97 as a pale yellow oil. 1H NMR (CDCl3) δ 1.60-1.72 (m, 3H), 1.96-2.23 (m, 5H), 2.51 (s, 6H), 2.61-2.66 (m, 2H), 4.15 (d, 2H, J=12 Hz), 6.33-6.38 (m, 1H), 6.85 (dd, 1H, J=7.2, 5.1 Hz), 7.07 (dd, 2H, J=7.5, 4.8 Hz), 7.27 (dt, 1H, J=7.5, 1.5 Hz), 7.40 (d, 2H, J=7.5 Hz), 8.19 (d, 1H, J=4.8 hz), 8.42-8.47 (m, 2H); 13C NMR (CDCl3) δ 19.18, 25.52, 30.76, 34.77, 49.87, 63.61, 120.80, 122.22, 122.76, 131.72, 136.15, 138.83, 147.10, 149.18, 160.47, 161.42; ES-MS m/z 373 (M+H). Anal. Calcd. for C24H28N4.1.6 H2O: C, 71.83; H, 7.84; N, 13.96. Found: C, 71.84; H, 7.53; N, 13.65.
Reaction SMILES: BrC1C=C(N[N:9]=[C:10]([C:13]#[N:14])[C:11]#[N:12])C=CC=1.[Br:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].C(#N)CC#N.O.[NH2:29][NH2:30]>>[Br:15][C:16]1[CH:17]=[C:18]([NH:19][N:9]=[C:10]2[C:11]([NH2:12])=[N:30][N:29]=[C:13]2[NH2:14])[CH:20]=[CH:21][CH:22]=1
Reactant: NN
Reactant: N#CC(C#N)=NNc1cccc(Br)c1
Reactant: Nc1cccc(Br)c1
Solvent: O
Solvent: N#CCC#N
Product: NC1=NN=C(N)C1=NNc1cccc(Br)c1

Procedure:
4-[(3-bromophenyl)hydrazono]-4H-pyrazole-3,5-diamine was prepared using 125 mg (0.5 mmol) of 2-[(3-bromophenyl)hydrazono]malononitrile, which was derived from 3-bromoaniline (172 mg, 1.0 mmol) and malononitrile (1.5 mmol), and hydrazine hydrate. The hydrazine hydrate was added to the solution at a temperature of 75° C. despite the fact that the starting material had not fully dissolved. The solution cleared briefly and then a precipitate formed. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 93 mg (66%) of the compound as an orange solid; 1H NMR (ppm, DMSO-d6): 6.2 (br s, 4H), 7.21-7.32 (m, 2H), 7.50-7.62 (m, 1H), 7.90 (s, 1H), 10.71 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:16]=O)[CH:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:18]([S:20]([NH2:23])(=[O:22])=[O:21])[CH3:19].[C:24]([Mg]Br)([CH3:26])=[CH2:25]>C1(C)C=CC=CC=1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([CH:16]([NH:23][S:20]([CH2:18][CH3:19])(=[O:22])=[O:21])[CH:24]([CH3:26])[CH3:25])[CH:13]=[N:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C=C(C)[Mg]Br
Reactant: N#Cc1ccc(-c2cncc(C=O)c2)cc1Cl
Reactant: CCS(N)(=O)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Product: CCS(=O)(=O)NC(c1cncc(-c2ccc(C#N)c(Cl)c2)c1)C(C)C
Temperature: -40 °C
Reaction time: 4 h
Yield: 23.8 %

Procedure:
(General Grignard addition reaction procedure): a mixture of 2-Chloro-4-(5-formyl-pyridin-3-yl)-benzonitrile (0.243 g, 1 mmol), titanium(IV) isopropoxide (0.586 mL, 2.000 mmol), ethanesulfonamide (0.109 g, 1.000 mmol) in Toluene (20 mL) was heated to reflux for 4 hr. After concentration, the residue was dissolved in THF (15 mL) and cooled to −40° C. A solution of isopropenylmagnesium bromide (1.500 mL, 3.000 mmol) was added dropwise and the resulting mixture was slowly warmed up to −20° C. and stirred at this temperature for 4 hr. After quenched by NH4Cl solution, filtration, extraction with CH2Cl2, the solution was dried over Na2SO4, and concentrated, the residue was purified by flash column (MeOH—CH2Cl2, v/v, 1%-3%) and yielded a yellow solid (90 mg). Enantiomers were separated by 40% EtOH 60% heptane on a Chiralpak IA column. First peak 14 min (enantiomer 1), second peak 20 min (enantiomer 2). ESI-MS m/z: 378.1 [M+H]+, 1H NMR (400 MHz, CDCl3): δ 0.93 (d, J=6.7 Hz, 3H), 1.06 (d, J=6.7 Hz, 3H), 1.21 (t, J=8.0 Hz, 3H), 2.04-2.11 (m, 1H), 2.76-2.91 (m, 2H), 4.36 (t, J=7.4 Hz, 1H), 4.90 (d, J=7.6 Hz, 1H), 7.58 (d, J=8.2 Hz, 1H), 7.72 (s, 1H), 7.77 (s, 1H), 7.78 (d, J=8.2 Hz, 1H), 8.61 (s, 1H), 8.77 (s, 1H).
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH2:21][CH2:22][OH:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Br:24][CH2:25][CH2:26][CH2:27]Br>[Cl-].C([N+](C)(C)C)CCCCCCCCCCCCCCC>[Br:24][CH2:25][CH2:26][CH2:27][O:23][CH2:22][CH2:21][CH2:20][O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOCCCO
Reactant: BrCCCBr
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Cl-]
Product: CCCCCCCCCCCCCCCCCCOCCCOCCCBr
Yield: 7.7 %

Procedure:
Employing 3-(octadecyloxy)propanol (5 g), 1,3-dibromopropane (9.2 g) and cetyltrimethylammonium chloride (0.97 g), a reaction and aftertreatment are conducted in the same manner as those in Reference Example 4 to obtain the above-titled compound (0.53 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.[C:17]1([CH2:23][CH2:24]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.[I-].[Na+]>CN(C)C=O.O>[CH2:24]([N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[CH2:5][CH2:6]1)[CH2:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCCc1ccccc1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccccc2n1C1CCN(CCc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 1-piperidin-4-yl-1,3-dihydro-benzimidazol-2-one (0.5 g, 2.3 mmol), 2-phenyl-ethylbromid (0.34 ml, 2.5 mmol), triethylamine (0.35 ml, 2.5 mmol) and sodium iodide (0.01 g, 0.67 mmol) in dry N,N-dimethyl foramide (5 ml) was stirred at 100° C. for 3 hours. The reaction mixture was cooled to room temperature, and then poured into water (20 ml). The product precipitated upon stirring on a ice/water bath and was isolated by filtration. Yield 0.45 g (1.4 mmol, 61%). M.p. 181-185° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][C:8]#[N:9])[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl-].[CH3:11][O:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[CH:15]=[N+:16]([CH3:18])[CH3:17]>>[CH3:18][N:16]([CH:15]([C:14]1[CH:19]=[CH:20][CH:21]=[CH:22][C:13]=1[O:12][CH3:11])[C:2]1[N:1]([CH2:6][CH2:7][C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1)[CH3:17]
Reactant: N#CCCn1cccc1
Reactant: COc1ccccc1C=[N+](C)C
Agent: [Cl-]
Product: COc1ccccc1C(c1cccn1CCC#N)N(C)C

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 3-pyrrol-1-yl-propionitrile and (2-methoxy-benzylidene)-dimethyl-ammonium chloride, which had been prepared in accordance with example 7.
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CO.CN(C=O)C>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(-c2ccccc2)ccn1
Reactant: NO
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(CCCCCCN(c1ccccn1)c1cc(-c2ccccc2)ccn1)NO
Reaction time: 24 h
Yield: 23 %

Procedure:
HONH2 (50% aqueous, 4 mL) was added to II (120 mg, 0.3 mmol) in MeOH (4 mL) and DMF (2 mL) at rt. The reaction mixture was stirred for 24 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (3×5 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:2 to 100:8) to furnish III as a yellow oil (28 mg, 23%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH:14]3[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]3)[N:8]=2)=[CH:4][CH:3]=1.[CH3:24][C:25]([NH2:29])([CH3:28])[C:26]#[CH:27]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:29][C:25]([CH3:28])([CH3:24])[C:26]#[C:27][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH:14]3[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(Nc2nccc(-c3ccc(Br)s3)n2)CC(C)(C)N1
Reactant: C#CC(C)(C)N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(N)C#Cc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)s1

Procedure:
{4-[5-Bromothiophen-2-yl]-pyrimidin-2-yl}-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine (100 mg, 0.253 mmol), PdCl2(PPh3)2 (18 mg, 0.025 mmol), 1,1-dimethyl-prop-2-ynylamine (0.03 ml, 0.253 mmol) and CuI (15 mg) were dissolved in triethylamine (25 ml) and refluxed for 1 hour. The reaction mixture was filtered, evaporated to dryness and taken up in DCM, filtered and evaporated again and the residue crystallized from ether to give the title compound as red-yellow crystals. Yield: 50 mg (50%).