Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]([C:12]2[S:22][C:21]3[N:23]4[C:14](=[CH:15][N:16]=[C:17]4[CH:18]=[CH:19][CH:20]=3)[CH:13]=2)=[O:11])[CH2:5][CH2:4]1.C(N(CC)CC)C.I[CH2:32][CH2:33][CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(O)C.O>[C:36]1([CH2:35][CH2:34][CH2:33][CH2:32][N:3]2[CH2:4][CH2:5][CH:6]([NH:9][C:10]([C:12]3[S:22][C:21]4[N:23]5[C:14](=[CH:15][N:16]=[C:17]5[CH:18]=[CH:19][CH:20]=4)[CH:13]=3)=[O:11])[CH2:7][CH2:8]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(NC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Reactant: ICCCCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(CCCCc2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1
Temperature: 25 °C

Procedure:
To a solution of 72.5 mg (1.94 mM) of N-(piperidin-4-yl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 1.4 ml (10.0 mM) of triethylamine in ethanol (7 ml) was added 0.61 g (2.33 mM) of 1-iodo-4-phenylbutane at room temperature and the mixture was refluxed under nitrogen for 6 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over MgSO4, and concentrated. The resulting crude product was purified by column chromatography (methanol/ethyl acetate 30%) and recrystallization from ethyl acetate to provide the title compound as light-purple crystals.
Reaction SMILES: O1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]2[N:10]=[CH:11][NH:12][C:8]=2[CH:7]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:20][NH2:21]>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:20][N:21]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]2[NH:10][CH:11]=[N:12][C:8]=2[CH:7]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: c1nc2ccc(-c3nnco3)cc2[nH]1
Product: COc1ccc(Cn2cnnc2-c2ccc3[nH]cnc3c2)cc1OC

Procedure:
The compound was synthesized starting from 5-(1,3,4-oxadiazol-2-yl)benzimidazole (186 mg, 1 mmol) and 3,4-Dimethoxybenzylamine (0.5 ml) as described above; yield: 0.087 g (25.9%); MS m/z: 336.3 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 3.55 (s, 3H); 3.65 (s, 3H); 5.27 (s, 2H); 6.50 (dd, 1H, 4J=2.1 Hz, 3J=8.3 Hz); 6.64 (d, 1H, 4J=2.1 Hz); 6.81 (d, 1H, 3J=8.3 Hz), 7.62 (dd, 1H, 4J=1.2 Hz, 3J=8.7 Hz); 7.83 (d, 1H, 3J=8.7 Hz); 7.92 (br s, 1H); 8.76 (s, 1H); 8.98 (s, 1H); HPLC (METHOD [A]): rt 7.36 min (100%)
Reaction SMILES: C([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:17][C:16]([C:26]([Cl:29])([F:28])[F:27])([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=3)[O:15][N:14]=2)=[CH:9][C:8]=1[CH3:30])(C)(C)C.FC(CC(O)=O)(F)F>ClCCl>[Cl:29][C:26]([F:27])([F:28])[C:16]1([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)[O:15][N:14]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:31])=[O:5])=[C:8]([CH3:30])[CH:9]=2)[CH2:17]1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)Cl)C2)ccc1C(=O)OC(C)(C)C
Agent: O=C(O)CC(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)Cl)C2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.3 %

Procedure:
To a solution of 4-[5-(chloro-difluoro-methyl)-5-(3,5-dichloro-phenyl)-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid tert-butyl ester (1.95 g) in dichloromethane (20 ml) was added trifluoromethyl acetic acid (“TFA”) (3 ml). The reaction mixture was stirred at ambient temperature for 16 hours. The dichloromethane was removed by distillation. The residue was purified over silica gel (eluent: ethyl acetate/heptane gradient from 1:1 to 1:0) to give 4-[5-(Chloro-difluoro-methyl)-5-(3,5-dichloro-phenyl)-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid (1.37 g). 1H-NMR (CDCl3, 400 MHz): 8.10 (d, 1H), 7.65-7.45 (m, 5H), 4.15 (m, 1H), 3.75 (d, 1H), 2.70 (s, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[CH:13]=[C:14]2[S:20][CH:19]=[C:18]([C:21](=[O:35])[NH:22][C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][C:32]=3[O:33][CH3:34])[N:29]=[CH:28][CH:27]=[CH:26]4)[C:15]2=[N:16][CH:17]=1)=O)C>O1CCCC1>[CH3:34][O:33][C:32]1[CH:31]=[C:30]2[C:25]([CH:26]=[CH:27][CH:28]=[N:29]2)=[CH:24][C:23]=1[NH:22][C:21]([C:18]1[C:15]2=[N:16][CH:17]=[C:12]([CH2:10][OH:9])[CH:13]=[C:14]2[S:20][CH:19]=1)=[O:35]
Reactant: CCOC(=O)c1cnc2c(C(=O)Nc3cc4cccnc4cc3OC)csc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc2ncccc2cc1NC(=O)c1csc2cc(CO)cnc12
Reaction time: 0.17 h
Yield: 29.7 %

Procedure:
A solution of lithium aluminum hydride (3.5 M in toluene, 0.1 mL) was added to a suspension of 3-(7-methoxy-quinolin-6-ylcarbamoyl)-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (30 mg) in tetrahydrofuran (2 mL) and the resulting orange solution was stirred for 10 minutes. The reaction mixture was then quenched by addition of a saturated aqueous solution of ammonium chloride. The resulting mixture was filtered through a CELITE™ pad and the filter cake was washed with ethyl acetate. The filtrate was separated and the organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (DCM/MeOH, 97/3) to give 8 mg of 6-hydroxymethyl-thieno[3,2-b]pyridine-3-carboxylic acid (7-methoxy-quinolin-6-yl)-amide as an off-white solid. MS=365 [M+H]+.
Reaction SMILES: C([Li])CCC.C([Mg]Cl)CCC.Br[C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([Br:23])[CH:14]=1.CN([CH:27]=[O:28])C.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[Br:23][C:15]1[CH:14]=[C:13]([CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=1)[CH:27]=[O:28]
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1cc(Br)cc(Br)c1
Agent: CCCC[Mg]Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: O=Cc1cc(Br)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of n-butyl lithium (2.5 M in hexanes, 0.8 eq.) in toluene (0.2 M) at −15° C. was added dropwise n-butyl magnesium chloride (2.0 M in THF, 0.4 eq.). After 20 min, a solution of 1,3-dibromo-5-(trifluoromethyl)benzene (1 eq.) in toluene was added over 10 min. The reaction mixture thus obtained was stirred at −15° C. for 2 h before DMF (3 eq.) was added. The reaction was allowed to warm to 0° C. After 45 min, saturated aqueous ammonium chloride was added. The reaction mixture was extracted with ethyl acetate. The combined organic extracts were then washed with brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc) afforded the title compound.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.C(N(CC)CC)C.[CH:21]1[CH:26]=[CH:25][C:24]([CH2:27][S:28](Cl)(=[O:30])=[O:29])=[CH:23][CH:22]=1>ClCCl>[C:24]1([CH2:27][S:28]([N:1]2[CH2:5][CH2:4][CH:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]2)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:21]=[CH:22][CH:23]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a solution/suspension of 3-pyrrolidinyl-carbamic acid, 1,1-dimethylethyl ester (0.5 g) and triethylamine (0.38 ml) in dichloromethane (30 ml) at 0° C. was added benzenemethanesulfonyl chloride (0.51 g). The mixture was stirred at 0° C. for 30 minutes then stirred at room temperature for 2 days. The reaction was diluted with dichloromethane (20 ml) washed with water, saturated aq. NaHCO3(aq), dried (MgSO4) and concentrated in vacuo to give the sub-title compound (0.6 g).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].N([O-])=O.[Na+].[PH2](O)=O.[OH-].[Na+]>Cl.O>[CH3:14][C:12]1[NH:11][N:10]=[C:9]([O:8][C:5]2[CH:6]=[CH:7][CH:2]=[C:3]([C:15]([F:18])([F:16])[F:17])[CH:4]=2)[CH:13]=1
Reactant: Cc1cc(Oc2ccc(N)c(C(F)(F)F)c2)n[nH]1
Agent: Cl
Agent: O=N[O-]
Agent: O=[PH2]O
Solvent: O
Product: Cc1cc(Oc2cccc(C(F)(F)F)c2)n[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Concentrated hydrochloric acid (3 ml) and water (6 ml) were added to 3-(4-amino-3-trifluoromethylphenyloxy)-5-methylpyrazole, and the mixture was cooled to 0° C. Then, a solution of sodium nitrite (0.54 g, 7.8 mmol) in concentrated hydrochloric acid (2 ml) and water (2 ml) was dropwise added, and the mixture was stirred at an ambient temperature for 1 hour. Then, hypophosphorous acid (2.57 g, 38.9 mmol) was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 1N sodium hydroxide (50 ml) and extracted with ethyl acetate (50 ml×2). An organic layer was washed with water (50 ml×2), dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/4), to give a yellow viscous substance of 5-methyl-3-(3-trifluoromethylphenyloxy)pyrazole (1.47 g, yield: 78.0%). 1H-NMR (CDCl3, TMS, ppm): δ 2.2.3 (s, 3H), 5.63 (s, 1H), 7.27˜7.46 (m, 4H), 10.91 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:14]([CH2:15][CH:16]([OH:20])[CH2:17][CH2:18]O)[C:13]2[C:21]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:22][CH:23]=[CH:24][C:12]=2[N:11]=1.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]2=[N:11][C:12]3[CH:24]=[CH:23][CH:22]=[C:21]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[C:13]=3[N:14]2[CH2:15][CH:16]([OH:20])[CH2:17][CH2:18]1
Reactant: CCN(CC)c1cccc2nc(Nc3ccc(Cl)cc3Cl)n(CC(O)CCO)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCN(CC)c1cccc2nc3n(c12)CC(O)CCN3c1ccc(Cl)cc1Cl
Yield: 64.5 %

Procedure:
To a solution of 4-[2-[(2,4-dichlorophenyl)amino]-7-(diethylamino)-1H-benzimidazol-1-yl]butane-1,3-diol (Reference Example 84; 175 mg, 0.400 mmol) in pyridine (4 mL) was added methanesulfonyl chloride (0.0929 mL, 1.20 mmol) at 0° C. After the resultant mixture was stirred at 0° C. for 3 hr, the mixture was diluted with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting mesylate was diluted with N,N-dimethylformamide (4 mL) and to the solution was added potassium carbonate (110 mg, 0.797 mmol) at room temperature. After the resultant mixture was stirred at 80° C. for 1 hr, the mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 40% ethyl acetate/n-hexane mixture to give the title compound as a solid (108 mg, 0.258 mmol, 65%). Analytically pure material was obtained by recrystallization from ethyl acetate/n-hexane.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([NH2:20])=[C:9]([C:18]#[N:19])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)=[O:5])[CH3:2].[CH3:21][S:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([NH2:20])=[C:9]([C:18]#[N:19])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[S:22][CH3:21])=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: CSc1ccccc1B(O)O
Reactant: CCOC(=O)c1sc(N)c(C#N)c1-c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1sc(N)c(C#N)c1-c1ccc(-c2ccccc2SC)cc1
Reaction time: 3 h

Procedure:
Combine 5-amino-4-cyano-3-(4-iodo-phenyl)-thiophene-2-carboxylic acid ethyl ester (0.829 mmol) in dioxane and add 2-(methylthio)phenylboronic acid, tetrakis(triphenylphosphine)palladium (0), and 1.4 ml of 2M sodium carbonate solution and heat to reflux. After 3 hours, purification by radial chromatography (6000 micron Si plate) eluting with 10-20% ethylacetate/methylene chloride provides the title compound: 1H NMR (400 MHz, CDCl3) δ 7.49-7.19 (m, 8H), 5.26 (s, 2H), 4.17 (q, 2H, J=7.2 Hz), 2.38 (s, 3H), 1.18 (t, 3H, J=7.0 Hz), MS found (M+1) 395.1.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2.[C:12]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[C:19]2Cl)#[N:13].Cl>O1CCOCC1>[C:12]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[C:21]([C:10]1[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:11])[CH:8]=3)[NH:3][C:2]=1[CH3:1])[CH:20]=[CH:19]2)#[N:13]
Reactant: N#Cc1cccc2c(Cl)ccnc12
Reactant: Cc1ccc2[nH]c(C)cc2c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc2[nH]c(C)c(-c3ccc4cccc(C#N)c4n3)c2c1

Procedure:
The sub-title compound was prepared by the method of Example 40 step a, using 2,5-dimethyl indole and 8-cyano-4-chloroquinoline and 1 molar equivalent of 4M HCl in dioxane.
Reaction SMILES: O.NN.[C:4]([O:8][CH:9]([O:27][C:28]1[CH:29]=[C:30]([N+:72]([O-])=O)[CH:31]=[C:32]([O:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])[C:33]=1[O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])(=[O:7])[CH:5]=[CH2:6]>C(O)C>[C:4]([O:8][CH:9]([O:27][C:28]1[CH:29]=[C:30]([CH:31]=[C:32]([O:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])[C:33]=1[O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[NH2:72])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])(=[O:7])[CH:5]=[CH2:6]
Reactant: C=CC(=O)OC(CCCCCCCCCCCCCCCCC)Oc1cc([N+](=O)[O-])cc(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Agent: NN
Solvent: CCO
Solvent: O
Product: C=CC(=O)OC(CCCCCCCCCCCCCCCCC)Oc1cc(N)cc(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Yield: 71.4 %

Procedure:
Thereafter, loaded were 3 ml of hydrazine monohydrate and 10 ml of ethanol in the presence of graphite, 3.9 g of 3-(1′-acryloyloxyoctadecyloxy)-4,5-dioctadecyloxy nitrobenzene was reduced via heat-refluxing for 24 hours. Via recrystallized from mix solution of chloroform-methanol to obtain 2.7 g of 3-(1′-acryloyloxyoctadecyloxy)-4,5-dioctadecyloxy aniline (yield: 71%).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][N:17]([CH3:40])[CH2:18][CH2:19][CH:20]1[CH:26]=[CH:25][N:24]([C:27](=[O:35])[C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)[C:23]2[CH:36]=[CH:37][CH:38]=[CH:39][C:22]=2[S:21]1.C(N(CC)CC)C.O>C(Cl)Cl>[CH3:40][N:17]([CH3:16])[CH2:18][CH2:19][CH:20]1[CH:26]=[CH:25][N:24]([C:27](=[O:35])[C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:9](=[O:10])[C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:30][CH:29]=2)[C:23]2[CH:36]=[CH:37][CH:38]=[CH:39][C:22]=2[S:21]1
Reactant: CN(C)CCC1C=CN(C(=O)c2ccc(N)cc2)c2ccccc2S1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)CCC1C=CN(C(=O)c2ccc(NC(=O)c3ccccc3-c3ccccc3)cc2)c2ccccc2S1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Phenylbenzoyl chloride (0.36 g, 1.67 mM)(prepared from 2-biphenylcarboxylic acid as described in Example 3) was slowly added to a solution of Compound 12 as prepared in Example 7 (0.5 g, 1.4 mM) and triethylamine (0.38 ml, 3.3 mM)in methylene chloride (30 ml). The mixture was stirred at room temperature for 16 hours and water (80 ml) was added. The layers were separated. The methylene chloride layer was dried (MgSO4), filtered and evaporated in vacuo to give a crude product. Purification by flash column chromatography (EM silica gel 60; 30% EtOAc in CH2Cl2) yielded the desired product as a white solid. m/z (MH+) 536.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][C@H:7]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[O:16])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:5].[C:27]([O:31][C:32]([NH:34][CH:35]([C:46]([NH:48][C@@H:49]([C:51](OC)=[O:52])[CH3:50])=[O:47])[CH2:36][C:37]1[C:42]([CH3:43])=[CH:41][C:40]([OH:44])=[CH:39][C:38]=1[CH3:45])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([NH:34][C@H:35]([C:46]([NH:48][C@@H:49]([C:51]([NH:2][CH2:3][C:4]([NH:6][C@H:7]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[O:16])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:5])=[O:52])[CH3:50])=[O:47])[CH2:36][C:37]1[C:42]([CH3:43])=[CH:41][C:40]([OH:44])=[CH:39][C:38]=1[CH3:45])=[O:33])([CH3:28])([CH3:29])[CH3:30]
Reactant: COC(=O)CCCCCNC(=O)[C@H](CC1CCCCC1)NC(=O)CN
Reactant: COC(=O)[C@@H](C)NC(=O)C(Cc1c(C)cc(O)cc1C)NC(=O)OC(C)(C)C
Agent: Cl
Product: COC(=O)CCCCCNC(=O)[C@H](CC1CCCCC1)NC(=O)CNC(=O)[C@@H](C)NC(=O)[C@H](Cc1c(C)cc(O)cc1C)NC(=O)OC(C)(C)C

Procedure:
The title compound is prepared by the method of Example 1 from the title product of Example 121 and the fast diastereomer (D) of Example 114.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][CH3:25])=[N:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C(OC(C)C)(C)C>CN(C)C=O.O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:15][C:16]2[CH:21]=[N:20][C:19]([O:22][CH2:23][CH2:24][CH3:25])=[CH:18][CH:17]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCOc1ccc(CCl)cn1
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)OC(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccc(CSc2cnn(C(C)(C)C)c(=O)c2Cl)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
To a solution of 2.2 g of 2-t-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone and 1.9 g of 5-chloromethyl-2-propyloxypyridine in 20 ml of N,N-dimethylformamide was added under stirring 1.5 g of potassium carbonate at room temperature. After additional stirring for 8 hours at room temperature, the mixture was poured into 50 ml of water and then extracted twice with 50 ml of benzene. The organic layer was washed with water, dried over anhydrous sodium sulfate and then freed of solvent by distillation under reduced pressure to obtain 3.7 g of a crude product. The crude product was added with isopropyl ether and recrystallized therefrom to give 3.0 g of 2-t-butyl-4-chloro-5{-(6-propyloxy-3-pyridyl)-methylthio}-3(2H)-pyridazinone, m.p. 92.0°~93.5° C.
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1)=[C:2]=[S:3].[Cl:15][C:16]1[CH:17]=[C:18]([NH2:30])[C:19]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:21]=1>O1CCCC1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:18]([NH:30][C:2]([NH:1][CH:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]2)=[S:3])[CH:17]=1
Reactant: Nc1cc(Cl)ccc1NCc1ccccc1
Reactant: CCOC(=O)N1CCC(N=C=S)CC1
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(NC(=S)Nc2cc(Cl)ccc2NCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 10.6 parts of ethyl 4-isothiocyanato-1-piperidinecarboxylate, 11.6 parts of 4-chloro-N1 -(phenylmethyl)-1,2-benzenediamine and 90 parts of tetrahydrofuran is stirred overnight at room temperature. The reaction mixture is evaporated, yielding 21 parts (100%) of ethyl 4-[{[{5-chloro-2-[(phenylmethyl)amino]phenyl}amino]thioxomethyl}amino]-1-piperidinecarboxylate; mp. 162° C.
Reaction SMILES: I[CH:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([C@:14]2([O:23][C@H:22]([CH2:24][OH:25])[C@@H:20]([OH:21])[C@H:18]([OH:19])[C@H:16]2[OH:17])[OH:15])=[CH:10][C:9]=1[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.[Cl-].[Na+].O>[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([C@:14]2([O:23][C@H:22]([CH2:24][OH:25])[C@@H:20]([OH:21])[C@H:18]([OH:19])[C@H:16]2[OH:17])[OH:15])=[CH:10][C:9]=1[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH:2]2[CH2:6][CH2:5][CH2:4][CH2:3]2)=[CH:31][CH:32]=1
Reactant: IC1CCCC1
Reactant: Cc1ccc([C@@]2(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc([C@@]2(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc(OC2CCCC2)cc1

Procedure:
0.17 mL iodocyclopentane are added to a mixture of 0.38 g 1-methyl-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene and 0.53 g cesium carbonate in 4 mL dimethylformamide. The mixture is stirred at 65° C. for 4 h, before another 0.35 g cesium carbonate and 0.1 mL iodocyclopentane are added. After stirring the mixture for an additional 14 h at 45° C. brine is added and the resulting mixture is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate, the solvent is removed and the residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0->8:1).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:20]([C:21]3[CH:22]=[CH:23][C:24]4[N:25]([C:27]([C:30]5[S:31][CH:32]=[CH:33][CH:34]=5)=[CH:28][N:29]=4)[CH:26]=3)=[CH:19][N:18]([C:35]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:17]=2)=[CH:12][CH:11]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O>[Br:1][C:32]1[S:31][C:30]([C:27]2[N:25]3[CH:26]=[C:21]([C:20]4[C:16]([C:13]5[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=5)=[N:17][N:18]([C:35]([C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:48]5[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=5)[CH:19]=4)[CH:22]=[CH:23][C:24]3=[N:29][CH:28]=2)=[CH:34][CH:33]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Fc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4cccs4)n3c2)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccc(Br)s4)n3c2)cc1
Reaction time: 1 h
Yield: 108.2 %

Procedure:
160 mg N-bromosuccinimide was added to 5 mL solution of 500 mg 6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]-3-(2-thienyl)imidazo[1,2-a]pyridine obtained in Example 3 in N,N-dimethylformamide, and the mixture was stirred for 1 hour. An aqueous sodium thiosulfate solution was added thereto and stirred for 30 minutes, and the reaction solution was extracted with ethyl acetate and dried over magnesium sulfate. The residue was purified by NH silica gel column chromatography (hexane/dichloromethane/ethyl acetate) to give 612 mg of the title compound as pale yellow crystals.