Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[N:13]=[N:12][C:11]([NH2:14])=[N:10][CH:9]=1.[CH2:15]([O:17][CH:18]([N:20]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[N:21]1)[CH3:19])[CH3:16]>O.C1(C)C=CC=CC=1.C(O)C.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>[CH2:15]([O:17][CH:18]([N:20]1[CH:24]=[C:23]([C:8]2[N:13]=[N:12][C:11]([NH2:14])=[N:10][CH:9]=2)[CH:22]=[N:21]1)[CH3:19])[CH3:16]
Reactant: CCOC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1ncc(Br)nn1
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: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(C)n1cc(-c2cnc(N)nn2)cn1
Temperature: 110 °C
Yield: 69.4 %

Procedure:
Sodium carbonate (510 mg, 4.8 mmol) in water (1 mL) was added to a mixture of 6-bromo-1,2,4-triazin-3-amine (0.420 g, 2.40 mmol), 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.766 g, 2.88 mmol), and tetrakis(triphenylphosphine)palladium (100 mg, 0.1 mmol) in toluene (7 mL) and ethanol (5 mL). The resulting mixture was heated at 110° C. for 2 h. The mixture was cooled to RT, diluted with water, and extracted with chloroform. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was treated with CH2Cl2/Et2O and filtered to give the desired product (0.39 g, 69%). LCMS: (M+H)=235.4.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([C:39]([CH:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[O:40])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: O=C(Cl)C1CCCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(C(=O)C5CCCCC5)CC4)cn3)nc2n1C1CCCC1
Yield: 50.3 %

Procedure:
Following General Procedure G, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.230 mmol) and cyclohexane carbonyl chloride (37 mg, 0.690 mmol) gave 2-[5-(4-cyclohexanecarbonyl-piperazin-1-yl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (63 mg, 49%). MS (ESI) m/z 545.3 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.[CH3:7][O:8][C:9]([C:11]#[C:12][C:13](OC)=[O:14])=[O:10]>O1CCCC1>[CH3:7][O:8][C:9]([C:11]1[N:6]2[N:5]=[CH:4][S:3][C:2]2=[N:1][C:13](=[O:14])[CH:12]=1)=[O:10]
Reactant: Nc1nncs1
Reactant: COC(=O)C#CC(=O)OC
Solvent: C1CCOC1
Product: COC(=O)c1cc(=O)nc2scnn12
Reaction time: 72 h

Procedure:
100 ml of tetrahydrofuran are added to 10.1 g of 2-amino-1,3,4-thiadiazole, followed by the gradual introduction of 14.2 g of acetylene dicarboxylic acid dimethyl ester. The reaction mixture is left standing for 3 days, resulting in the formation of a clear, yellow colored solution. The solution thus formed is concentrated by evaporation in vacuo to dryness. Recrystallization of the residue from ethyl acetate gives 7H-1,3,4-thiadiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid methyl ester melting at 134° C. with decomposition.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:7]([CH3:14])[C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1.[C:22](=[O:29])([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[NH2:23]>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([NH:23][C:22](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:3][CH:4]=3)[O:9][C:8]([CH3:13])([CH3:12])[C:7]=2[CH3:14])=[CH:16][CH:17]=1
Reactant: CC1=C(c2ccc(F)cc2)c2ccc(Cl)cc2OC1(C)C
Reactant: CC(C)(C)OC(N)=O
Product: CC1=C(c2ccc(F)cc2)c2ccc(NC(=O)OC(C)(C)C)cc2OC1(C)C

Procedure:
The compound obtained in (3) described above (100 mg) and tert-butyl carbamate (125 mg) were treated in the same manner as Reference Example 5(4) to give the titled compound (126 mg) as a pale brown powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>>[F:8][C:5]1[CH:6]=[CH:7][C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:3][CH:4]=1
Reactant: C1CNCCN1
Reactant: Fc1ccc(Br)nc1
Product: Fc1ccc(N2CCNCC2)nc1

Procedure:
With stirring, 500 mg (2.84 mmol) of 2-bromo-5-fluoropyridine and 1.22 g (14.2 mmol) of piperazine are heated at 150° C. for 24 h. After cooling, excess piperazine is distilled off in vacuo (Kugelrohr, 1.5 mbar, 120° C.). The residue is purified by flash chromatography (dichloromethane/ethanol/conc. ammonia solution, 30:1:0.1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:18])([CH2:12][CH2:13][C@@H:14]([CH3:17])[CH2:15][CH3:16])[C:4](=[O:19])[C:3]=1[C:20]1[NH:25][C:24]2[CH:26]=[CH:27][C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][C:23]=2[S:22](=[O:36])(=[O:35])[N:21]=1.[OH-].[Na+:38]>O>[CH3:18][C:5]1([CH2:12][CH2:13][C@@H:14]([CH3:17])[CH2:15][CH3:16])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([O-:1])=[C:3]([C:20]2[NH:25][C:24]3[CH:26]=[CH:27][C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][C:23]=3[S:22](=[O:36])(=[O:35])[N:21]=2)[C:4]1=[O:19].[Na+:38]
Reactant: CC[C@H](C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC[C@H](C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C([O-])c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A suspension of the product of Example 43H in water (3 mL) was treated with 0.997N sodium hydroxide solution (0.204 mL) and stirred at 25° C. for 1 hour. The solution was lyophilized to give 112 mg (84%) of a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 0.49 (m, 1H) 0.66 (m, 6H) 0.92 (m, 2H) 1.11 (m, 2H) 1.38 (s, 3H) 1.72 (m, 1H) 2.14 (m, 1H) 2.96 (s, 3H) 7.33 (m, 3H) 7.45 (m, 3H) 8.05 (d, J=7.72 Hz, 1H) 9.88 (s, 1H) 15.50 (s, 1H); MS (ESI−) m/z 530 (M−H)−.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:11][C:12]([CH3:43])([CH2:41]C)[CH2:13][C:14]1[N:15]=[C:16]([C:25](=[O:40])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][N:34]=3)=[CH:29][CH:28]=2)[N:17]([S:19]([N:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH:18]=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:54])(=O)=O)=CC=1>O1CCCC1>[CH3:11][C:12]([CH3:43])([CH3:41])[CH2:13][C:14]1[N:15]=[C:16]([C:25](=[O:40])[CH:26]([F:54])[C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][N:34]=3)=[CH:29][CH:28]=2)[N:17]([S:19]([N:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH:18]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(=O)Cc2ccc(-c3ccc(F)cn3)cc2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(=O)C(F)c1ccc(-c2ccc(F)cn2)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Lithium hexamethyldisilazide (1 M in tetrahydrofuran) (92 mL, 0.09 mmol) was added to a −78° C. solution of 4-(2,2-dimethylbutyl)-2-{[4-(5-fluoropyridin-2-yl)phenyl]acetyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide (35 mg, 0.08 mmol) in tetrahydrofuran (2 mL). After stirring at −78° C. for 10 min, a solution of N-fluorobenzenesulfonimide (36 mg, 0.11 mmol) in tetrahydrofuran (1 mL) was added. The reaction was allowed to warm to ambient temperature, quenched with water and extracted with methylene chloride and ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-50% ethyl acetate/hexane afforded 4-(2,2-dimethylpropyl)-2-{fluoro[4-(5-fluoropyridin-2-yl)phenyl]acetyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]#[N:16])=[CH:9][C:8]=1[CH2:17][CH:18]([CH3:20])[CH3:19])(=O)=O.[CH2:23]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.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>[CH2:23]([C:30]1[CH:31]=[C:32]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]#[N:16])=[CH:9][C:8]=2[CH2:17][CH:18]([CH3:20])[CH3:19])[CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(B(O)O)cc1Cc1ccccc1
Reactant: CC(C)Cc1cc(CCC#N)ccc1OS(=O)(=O)C(F)(F)F
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: CCO
Solvent: COCCOC
Product: COc1ccc(-c2ccc(CCC#N)cc2CC(C)C)cc1Cc1ccccc1
Temperature: 80 °C
Yield: 52.1 %

Procedure:
490 mg (1.46 mmol) Trifluoro-methanesulfonic acid 4-(2-Cyanoethyl)-2-isobutyl-phenyl ester (6), 505 mg (2.09 mmol, 1.4 eqv) crude 3-Benzyl-4-methoxy-benzene-1-boronic acid (22) and 169.4 mg (0.15 mmol, 0.1 eqv) Pd(Ph3P)4 were dissolved in 20 ml DME/EtOH (9+1). 1.46 ml (2.92 mmol, 2 eqv) of a 2 M aq. Na2CO3-solution was added to this yellow solution and the resulting mixture was heated at 80° C. for 17 h. After concentrating the mixture in vacuo the residue was taken up in water and extracted with CH2Cl2. The comb. org. fractions were dried over MgSO4 and evaporated. Column chromatography (Hexanes/EtOAc (3+1)) yielded 290.8 mg (0.76 mmol, 52%) 24 as a clear oil: Rf (Hexanes/EtOAc (3+1)) 0.34; 1H NMR (400 MHz, CDCl3) δ 0.63 (d, 6H, J=6.70 Hz), 1.55 (m, 1H), 2.35 (d, 2H, J=7.33 Hz), 2.57 (t, 2H, J=7.45 Hz), 2.88 (t, 2H, J=7.45 Hz), 3.79 (s, 3H), 3.92 (s, 2H), 6.82 (d, 1H, J=8.34 Hz), 6.92 (d, 1H, J=2.15 Hz), 6.96-7.20 (m, 9H); LRMS (EI) m/z 383 (13), 335 (15), 293 (23), 214 (17), 187 (21), 161 (20), 160 (100), 145 (35), 144 (35), 105 (50), 91 (58), 77 (11); HRMS (EI) Calcd. for C27H29NO: 383.224914. Found: 383.225267.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][C:21]([NH:27][C:28](=O)[CH2:29][O:30][CH2:31][CH3:32])=[C:20]2[NH:34][CH2:35][CH2:36][CH3:37])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[CH2:9]([O:16][C:17]1[CH:26]=[CH:25][C:24]2[N:23]=[CH:22][C:21]3[N:27]=[C:28]([CH2:29][O:30][CH2:31][CH3:32])[N:34]([CH2:35][CH2:36][CH3:37])[C:20]=3[C:19]=2[CH:18]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCCNc1c(NC(=O)COCC)cnc2ccc(OCc3ccccc3)cc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCn1c(COCC)nc2cnc3ccc(OCc4ccccc4)cc3c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.8 %

Procedure:
Triethylamine (22.16 mL, 159.0 mmol) was added to a solution of N-(6-benzyloxy-4-propylaminoquinolin-3-yl)-2-ethoxyacetamide hydrochloride (16.1 g) in ethanol (265 mL), and the reaction mixture was heated at reflux and stirred for 3 hours. The reaction mixture was allowed to cool to ambient temperature. The ethanol was removed under reduced pressure and the residue dissolved in chloroform. The resulting solution was washed sequentially with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting oil was dissolved in acetonitrile and concentrated under reduced pressure to yield 14.32 g of 8-benzyloxy-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinoline as a brown, crystalline solid.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[CH3:20][O:21][CH2:22][C:23]([CH3:27])([OH:26])[C:24]#[CH:25]>>[F:19][C:3]1[C:2]([C:25]#[C:24][C:23]([OH:26])([CH3:27])[CH2:22][O:21][CH3:20])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: C#CC(C)(O)COC
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Product: COCC(C)(O)C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2
Yield: 19 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 1-methoxy-2-methylbut-3-yn-2-ol to give the titled compound as a grey solid (59 mg, 19%).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=3)[S:10][C:11]=2[C:12]([NH2:14])=[O:13])=[CH:4][CH:3]=1.CO[CH:26](OC)[N:27]([CH3:29])[CH3:28]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=3)[S:10][C:11]=2[C:12]([N:14]=[CH:26][N:27]([CH3:29])[CH3:28])=[O:13])=[CH:22][CH:23]=1
Reactant: COC(OC)N(C)C
Reactant: NC(=O)c1sc(-c2ccnc(Cl)c2)nc1Cc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: CN(C)C=NC(=O)c1sc(-c2ccnc(Cl)c2)nc1Cc1ccc(Cl)cc1

Procedure:
A solution of 4-(4-chlorobenzyl)-2-(2-chloropyridin-4-yl)thiazole-5-carboxamide (128 mg, 0.351 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (0.467 mL, 3.51 mmol) in toluene (3.75 mL) was heated at 100° C. for 1 hour. The reaction was cooled and concentrated in vacuo to give the intermediate, 4-(4-chlorobenzyl)-2-(2-chloropyridin-4-yl)-N-((dimethylamino)methylene)thiazole-5-carboxamide, as a solid. LC/MS (FA) ES+ 419, 421. The intermediate was dissolved in acetic acid (3.60 mL). Hydrazine hydrate (0.0855 mL, 1.76 mmol) was added and the resulting solution was heated at 90° C. for 2 hours. The mixture was cooled and concentrated in vacuo, and the residue was azeotroped with toluene. The residue was slurried in DCM (30 mL) and saturated sodium bicarbonate (20 mL). Some undissolved solids were filtered to give one batch of desired product. The layers of the filtrate were separated and the aqueous layer was extracted with DCM (2×20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give another batch of desired product. The two product batches were combined and purified by silica gel chromatography (methanol/DCM=0/100→20/80) to give 85 mg of the title compound as a beige solid (62% yield). LC/MS (FA) ES+ 388, 390. 1H NMR (300 MHz, d6-DMSO) δ: 14.48 (bs, 1H), 8.76 (s, 1H), 8.54-8.51 (m, 1H), 7.96-7.95 (m, 1H), 7.92-7.89 (m, 1H), 7.38-7.30 (m, 4H), 4.65 (s, 2H).
Reaction SMILES: S1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[CH:16]=[C:15]([NH:17][CH:18]([CH3:20])[CH3:19])[C:14]([C:21]4[O:22][C:23]([NH:26][CH2:27][CH2:28][CH2:29][O:30][Si](C(C)(C)C)(C)C)=[N:24][N:25]=4)=[CH:13][N:12]=3)[CH:8]=[CH:9][C:4]=2N=C1.CCC[CH2:41][N+:42](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:30][CH2:29][CH2:28][CH2:27][NH:26][C:23]1[O:22][C:21]([C:14]2[C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[CH:16][C:11]([NH:10][C:7]3[CH:6]=[CH:5][C:4]([C:41]#[N:42])=[CH:9][CH:8]=3)=[N:12][CH:13]=2)=[N:25][N:24]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1-c1nnc(NCCCO[Si](C)(C)C(C)(C)C)o1
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)Nc1cc(Nc2ccc(C#N)cc2)ncc1-c1nnc(NCCCO)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N2-(benzo[d]thiazol-6-yl)-5-(5-((3-((tert-butyldimethylsilyl)oxy)propyl)amino)-1,3,4-oxadiazol-2-yl)-N4-isopropylpyridine-2,4-diamine (52a) (150 mg, 0.2 mmol) in THF (10 mL) was cooled to 0° C. Added TBAF (1M in THF) (2 equiv.) to the reaction mixture. Reaction mixture was warmed to room temperature and stirred for 1 h. Reaction mixture was quenched by using 10% NaHCO3 solution. The aqueous layer was extracted with EtOAc (twice). The organic layers were collected together, dried over Na2SO4, filtered and concentrated. The crude material was purified by column chromatography through silica gel and MeOH: DCM as eluent. The material obtained was further purified by prep HPLC to provide the desired compound, 4-((5-(5-((3-hydroxypropyl)amino)-1,3,4-oxadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)amino)benzonitrile. 1H NMR: 400 MHz, CD3OD: δ 1.35 (d, J=6.40 Hz, 6H), 1.89-1.96 (m, 2H), 3.46 (t, J=6.80 Hz, 2H), 3.71 (t, J=6.00 Hz, 2H), 3.79-3.83 (m, 1H), 6.21 (s, 1H), 7.58-7.65 (m, 3H), 7.73-7.76 (m, 2H), 8.37 (s, 1H). LC/MS: XBridge Phe 8, 4.6×30 mm, 3.5 μm; Solvent A=2% ACN: 98% H2O: 10 mM NH4COOH; Solvent B=98% ACN: 2% H2O: 10 mM NH4COOH; gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 1.486 min; LCMS (ES-API), m/z 394.0 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 5.812 min; Purity: 99.4%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1.[C:31]([C:35]1[CH:36]=[C:37]([CH:40]=[C:41]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:42]=1)[CH2:38]Br)([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:38][C:37]2[CH:36]=[C:35]([C:31]([CH3:33])([CH3:32])[CH3:34])[CH:42]=[C:41]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:40]=2)[CH:6]=1
Reactant: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)c1
Reactant: COC(=O)Cc1cccc(OCCCNCC(c2ccccc2)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(OCCCN(Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2)CC(c2ccccc2)c2ccccc2)c1
Temperature: 45 °C
Reaction time: 18 h
Yield: 92.4 %

Procedure:
To a solution of {3-[3-(2,2-diphenyl-ethylamino)-propoxy]-phenyl}-acetic acid methyl ester (3) (0.40 g, 0.001 mol) in DMF (10 mL), was added 3,5-di-tert-butyl-benzyl bromide (0.30 g, 0.0011 mol) and powdered potassium carbonate (0.96 g, 0.007 mol), the reaction mixture was heated and stirred at 45° C. for 18 hours. After cooling, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, concentrated to an oil, which was purified by flash chromatography (9:1 Hexanes/EtOAc) to give the desired product as oil 0.56 g in 92% yield. 1H NMR (CDCl3) δ 7.19 (m, 10H), 7.12 (t, 2H), 7.01 (d, 2H), 6.82 (d, 1H), 6.63 (s, 1H), 6.59 (d, 1H), 4.17 (t, 1H), 3.67 (s, 3H), 3.62 (s, 2H), 3.57 (t, 2H), 3.55 (s, 2H), 3.10 (d, 2H), 2.58 (t, 2H), 1.77 (t, 2H), 1.26 (s, 18H). 13C NMR (CDCl3) δ 173.3, 160.6, 151.8, 145.1, 140.1, 136.5, 130.8, 129.8, 129.7, 129.6, 129.5, 127.6, 124.5, 122.6, 122.1, 117.0, 114.6, 67.3, 61.3, 53.4, 52.3, 51.2, 51.1, 42.7, 36.1, 32.9, 28.2.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[S:4][CH:5]=[C:6]([C:8](=[O:11])[CH2:9]Br)[N:7]=1.O[CH2:15][CH2:16][NH:17][CH:18]([CH3:32])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=1.C([SiH](CC)CC)C.N>>[C:28]([CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH:18]([N:17]2[CH2:16][CH2:15][O:11][CH:8]([C:6]3[N:7]=[C:3]([C:2]([F:13])([F:12])[F:1])[S:4][CH:5]=3)[CH2:9]2)[CH3:32])=[CH:21][CH:22]=1)([O:30][CH3:31])=[O:29]
Reactant: COC(=O)COc1ccc(CC(C)NCCO)cc1
Reactant: O=C(CBr)c1csc(C(F)(F)F)n1
Agent: CC[SiH](CC)CC
Agent: N
Product: COC(=O)COc1ccc(CC(C)N2CCOC(c3csc(C(F)(F)F)n3)C2)cc1
Reaction time: 6 h

Procedure:
Prepared analogously to Example 3 by reaction of 11.6 g (0.043 mol) of 2-trifluoromethyl-4-bromoacetyl-thiazole with 23 g (0.086 mol) of N-(2-hydroxyethyl)-2-(4-carbomethoxymethoxyphenyl)-1-methylethylamine. To complete the reaction the mixture is heated to boiling for 6 hours. It is then concentrated in vacuo, and the resulting residue is dissolved in 85 ml of trifluoroacetic acid and, at room temperature, 7 g (0.06 mol) of triethylsilane are added. After 90 hours the solution is poured onto ice, and concentrated ammonia is added, and the mixture is extracted several times with methylene chloride. The organic phase is dried over sodium sulphate and concentrated, and the residue is purified on a silica gel column using toluene/ethyl acetate=8/2 as eluant.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C:9]2[S:19][C:12]3=[N:13][C:14]([OH:18])=[CH:15][C:16](=[O:17])[N:11]3[N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:20]([O-])([OH:22])=[O:21]>C(O)(=O)C>[CH:1]1([CH2:7][CH2:8][C:9]2[S:19][C:12]3=[N:13][C:14]([OH:18])=[C:15]([N+:20]([O-:22])=[O:21])[C:16](=[O:17])[N:11]3[N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=c1cc(O)nc2sc(CCC3CCCCC3)nn12
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=c1c([N+](=O)[O-])c(O)nc2sc(CCC3CCCCC3)nn12
Reaction time: 2.5 h

Procedure:
In 125 ml of acetic acid was suspended 9.77 g of 2-(2-cyclohexylethyl)-7-hydroxy-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one, and 3.5 ml of fuming nitric acid was added thereto dropwise while stirring under ice-cooling. The stirring was continued at room temperature for an additional 2.5 hours, and the precipitate formed was collected by filtration and washed successively with water, isopropanol, and diethyl ether to obtain 10.3 g of 2-(2-cyclohexylethyl)-7-hydroxy-6-nitro-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one as a pale yellow crystal.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[C:12]([OH:19])[C:11]=1[CH2:20][CH2:21][CH3:22].[S:24]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33]OS(=O)(=O)C)(=[O:27])(=[O:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[C:12]([O:19][CH2:33][CH2:32][O:31][CH2:30][CH2:29][O:28][S:24]([CH3:25])(=[O:27])=[O:26])[C:11]=1[CH2:20][CH2:21][CH3:22]
Reactant: CS(=O)(=O)OCCOCCOS(C)(=O)=O
Reactant: CCCc1c(OCCCCCC(=O)OC)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCCCCCC(=O)OC)ccc(C(C)=O)c1OCCOCCOS(C)(=O)=O
Yield: 81.9 %

Procedure:
A mixture of 4.0 g (0.012 mole) of 6-(4-acetyl-3-hydroxy-2-propylphenoxy)hexanoic acid methyl ester, 16.3 g (0.062 mole) of diethyleneglycol dimesylate and 3.4 g (0.024 mole) of anhydrous potassium carbonate in 90 ml of anhydrous acetone and 4 ml of anhydrous dimethylformamide was stirred at reflux for 22 hours. The solvents were removed in vacuo and the residue was treated with 100 ml of 50% ethyl acetate-hexane. Some of the residual starting dimesylate was insoluble and was removed by filtration. The filtrate was concentrated in vacuo and the residual oil was purified by HPLC to give 4.8 g (80% yield) of 6-[4-acetyl-3-[2-[2-[(methylsulfonyl)oxy]ethoxy]ethoxy]-2-propylphenoxy]hexanoic acid methyl ester as an oil.
Reaction SMILES: [SH2:1].[Cl:2][C:3]1[C:8]2[C:9](=[O:21])[N:10]3[CH2:20][CH2:19][C@H:11]3[C:12]3[N:13]([CH:14]=[N:15][C:16]=3[C:17]#[N:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1>N1C=CC=CC=1.C(N(CC)CC)C>[Cl:2][C:3]1[C:8]2[C:9](=[O:21])[N:10]3[CH2:20][CH2:19][C@H:11]3[C:12]3[N:13]([CH:14]=[N:15][C:16]=3[C:17](=[S:1])[NH2:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: N#Cc1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: NC(=S)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Reaction time: 48 h
Yield: 35 %

Procedure:
A stream of hydrogen sulphide was conducted for 1 hr. through a solution of 11.3 g (0.0396 mol) of (S)-8-chloro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carbonitrile in 230 ml of pyridine and 2.3 ml of triethylamine. The green solution was left to stand for 48 hrs., then de-gassed with a stream of nitrogen and subsequently completely freed from the solvents. The residue was partitioned between dichloromethane and water and extracted. The pale yellow product was recrystallized in tetrahydrofuran and subsequently in methanol. There were obtained 4.44 g (35%) of (S)-8-chloro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-thiocarboxamide as pale yellow crystals; m.p. 250-253° and [α]D20 =-330.6° (DMF, c=1%).