Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.O[CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][N:35]([C:39]2[CH:48]=[CH:47][CH:46]=[CH:45][C:40]=2[C:41]([O:43][CH3:44])=[O:42])[CH2:34]1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1.O>[CH3:44][O:43][C:41]([C:40]1[CH:45]=[CH:46][CH:47]=[CH:48][C:39]=1[N:35]1[CH2:36][CH2:37][CH2:38][CH:33]([CH2:32][N:24]2[C:20](=[O:30])[C:21]3=[CH:29][CH:28]=[CH:27][CH:26]=[C:22]3[C:23]2=[O:25])[CH2:34]1)=[O:42]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COC(=O)c1ccccc1N1CCCC(CO)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccccc1N1CCCC(CN2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.6 %

Procedure:
Triphenylphosphine (1.68 g, 6.20 mmol) and phthalimide (799 mg, 5.43 mmol) were added to methyl 2-[3-(hydroxymethyl)piperidin-1-yl]benzoate (1.29 g, 5.17 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature for 10 min and a 40% diethyl azodicarboxylate/toluene solution (3.52 mL, 7.76 mmol) was added. The mixture was then stirred at room temperature for 8 hours. Subsequently, water was added and the mixture was extracted with ethylacetate. The extract was washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the resulting residue by silica gel column chromatography (hexane:ethyl acetate=20:1->5:1) gave 1.85 g (95%) of the desired compound as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[Cl:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:15]2[CH:16]=[N:17][C:18]3N[CH2:20][CH2:21][CH2:22][C:23]=3[CH:24]=2)[C:11]=1[CH:12]([OH:14])[CH3:13]>>[Cl:5][C:6]1[C:11]([CH:12]([OH:14])[CH3:13])=[C:10]([C:15]2[CH:24]=[C:23]3[C:18](=[N:17][CH:16]=2)[N:1]([C:2]([NH2:4])=[O:3])[CH2:20][CH2:21][CH2:22]3)[CH:9]=[N:8][CH:7]=1
Reactant: CC(O)c1c(Cl)cncc1-c1cnc2c(c1)CCCN2
Reactant: NC(N)=O
Product: CC(O)c1c(Cl)cncc1-c1cnc2c(c1)CCCN2C(N)=O

Procedure:
6-[5-Chloro-4-(1-hydroxy-ethyl)-pyridin-3-yl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide is synthesized according to the procedure of Urea Formation Method II using 1-[3-chloro-5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-4-yl]-ethanol.
Reaction SMILES: [K+].[Br-].[F:3][C:4]([F:24])([CH:7]([F:23])[O:8][C:9]([F:22])([F:21])[C:10]([F:20])([F:19])[C:11]([F:18])([F:17])[O:12][C:13]([F:16])([F:15])[F:14])[CH2:5][OH:6].[O-]Cl.[Na+].S(=O)(=O)(O)[OH:29]>O.CC#N>[F:3][C:4]([F:24])([CH:7]([F:23])[O:8][C:9]([F:22])([F:21])[C:10]([F:19])([F:20])[C:11]([F:17])([F:18])[O:12][C:13]([F:14])([F:15])[F:16])[C:5]([OH:29])=[O:6]
Reactant: O=S(=O)(O)O
Reactant: OCC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)F
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(O)C(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)F
Temperature: 25 °C
Yield: 81 %

Procedure:
5.5 mL water, 20 mL MeCN, 0.36 g KBr, 4-MeOTEMPO (0.15 g), and 10 g of 2,2,3-trifluoro-3-(1,1,2,2,3,3-hexafluoro-3-trifluoromethoxy-propoxy)-propan-1-ol are placed in a 50 ml glass flask equipped with a dropping funnel and stirrer. 36 mL of a 15% wt. aq. NaOCl solution buffered to pH 8-9 were added via the dropping funnel in 3 portions over two days while stirring at room temperature. Concentrated sulphuric acid and water were added to make the reaction mixture acidic (pH 1 to 2). The reaction mixture was extracted three times with diethyl ether. The combined ether phases were dried over magnesium sulphate and the solvent was removed by a rotary evaporator. The residue was distilled to give 8.4 g of the acid (b.p. 58 C, 1.6 mmHg). Yield: 81%.
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[NH:7]2.[CH3:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1.CN1CCCC1=O>O>[CH3:12][C:10]1[CH:9]=[C:8]2[C:3]([CH:4]=[CH:5][C:6](=[O:13])[NH:7]2)=[C:2]([N:18]2[CH:19]=[C:15]([CH3:14])[N:16]=[CH:17]2)[N:11]=1
Reactant: Cc1cc2[nH]c(=O)ccc2c(Br)n1
Reactant: Cc1c[nH]cn1
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cn(-c2nc(C)cc3[nH]c(=O)ccc23)cn1
Temperature: 140 °C
Reaction time: 20 h
Yield: 62.5 %

Procedure:
A mixture containing 9.56 g of 5-bromo-7-methyl-1,6-naphthyridin-2(1H)-one, 8.2 g of 4-methyl-1H-imidazole and 22 ml of N-methylpyrrolidin-one was heated with stirring in an oil bath at 140° C. for 20 hours. The reaction mixture containing some separated solid was diluted with about 150 ml of water and the solid was collected, triturated with water, washed with ethanol and dried to give 6.0 g of 7-methyl-5-(4-methyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, m.p. 307°-308° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([Cl:11])=[CH:5][C:3]=1[NH2:4].[O-:12][C:13]#[N:14].[K+].[OH-].[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([Cl:11])=[CH:5][C:3]=1[NH:4][C:13]([NH2:14])=[O:12]
Reactant: N#C[O-]
Reactant: COc1cc(Br)c(N)cc1Cl
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(Br)c(NC(N)=O)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
To a solution of 2.0 g (8.5 mmol) 2-bromo-5-chloro-4-methoxy aniline in 20 ml acetic acid and 20 ml water was added in small portions 1.37 g (17 mmol) potassium cyanate. The mixture was stirred at r.t. for 2 hours, neutralized with 2N NaOH and the product was extracted into ethyl acetate. Removal of the solvent and crystallization with ether gave 0.69 g (29%) of the desired urea.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])/[CH:4]=[CH:5]/[C:6]1[S:7][C:8](Br)=[CH:9][CH:10]=1.[CH3:13][S:14][C:15]1[N:20]=[C:19]([Sn](CCCC)(CCCC)CCCC)[CH:18]=[CH:17][N:16]=1>>[CH3:1][O:2][C:3](=[O:12])/[CH:4]=[CH:5]/[C:6]1[S:7][C:8]([C:17]2[CH:18]=[CH:19][N:20]=[C:15]([S:14][CH3:13])[N:16]=2)=[CH:9][CH:10]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(SC)n1
Reactant: COC(=O)/C=C/c1ccc(Br)s1
Product: COC(=O)/C=C/c1ccc(-c2ccnc(SC)n2)s1
Yield: 45 %

Procedure:
(E)-3-[5-(2-Methylsulfanyl-pyrimidin-4-yl)-thiophen-2-yl]-acrylic acid methyl ester was prepared analogous to Step A of Method D, using (E)-3-(5-bromo-thiophen-2-yl)-acrylic acid methyl ester and 2-methylsulfanyl-4-tributylstannanyl-pyrimidine. Yield: 45%.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:5]([C:15]([O:17][CH3:18])=[O:16])[CH2:4]1.[F:19][C:20]([F:28])(S(F)(=O)=O)C(O)=O>C(#N)C>[F:19][CH:20]([F:28])[O:1][CH2:2][C@@H:3]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])[C@H:5]([C:15]([O:17][CH3:18])=[O:16])[CH2:4]1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: COC(=O)[C@@H]1C[C@H](CO)CN1C(=O)OC(C)(C)C
Solvent: CC#N
Product: COC(=O)[C@@H]1C[C@H](COC(F)F)CN1C(=O)OC(C)(C)C
Temperature: 45 °C
Yield: 60.7 %

Procedure:
A 100 mL round-bottom flask was charged with (2S,4S)-1-tert-butyl 2-methyl 4-(hydroxymethyl)pyrrolidine-1,2-dicarboxylate (3.33 g, 12.84 mmol), Cul (0.489 g, 2.56 mmol), and anhydrous acetonitrile (57.1 mL). The reaction was heated to 45° C. (ext. oil bath). 2,2-difluoro-2-(fluorosulfonyl)acetic acid (2.655 mL, 25.68 mmol) was added at 45° C. over 30 minutes via syringe pump. The reaction was heated for 30 minutes. Upon completion as monitored by TLC, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was diluted in EtOAc and washed with sodium bicarbonate (aq). The bicarbonate layer was back extracted with ethyl acetate twice. Combined organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated. The resulting residue was further purified via silica gel chromatography (10 to 40% EtOAc/Hexanes) to afford (2S,4S)-1-tert-butyl 2-methyl 4-((difluoromethoxy)methyl)pyrrolidine-1,2-dicarboxylate (2.41 g, 61%). MS (ESI) m/z 210.21 [M+H−Boc]+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[C:19]([C:22]1[C:31]([CH3:32])=[CH:30][C:29]2[C:28]([CH3:34])([CH3:33])[CH2:27][CH2:26][C:25]([CH3:36])([CH3:35])[C:24]=2[CH:23]=1)(=[O:21])[CH3:20].[CH:37](/[C:39](/[CH3:46])=[CH:40]/[C:41]([O:43][CH2:44][CH3:45])=[O:42])=[O:38].[NH4+].[Cl-]>C1COCC1>[OH:38][CH:37]([CH2:20][C:19](=[O:21])[C:22]1[C:31]([CH3:32])=[CH:30][C:29]2[C:28]([CH3:34])([CH3:33])[CH2:27][CH2:26][C:25]([CH3:36])([CH3:35])[C:24]=2[CH:23]=1)/[C:39](/[CH3:46])=[CH:40]/[C:41]([O:43][CH2:44][CH3:45])=[O:42]
Reactant: CC(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Reactant: CCOC(=O)/C=C(\C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)C(O)CC(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Reaction time: 0.42 h
Yield: 79.2 %

Procedure:
To a solution of diisopropylamine (0.5 mL, 3.52 mmol) in 7 mL of THF at -78° C. under argon was added a 1.6M solution of n-butyllithium in hexane (2.2 mL, 3.52 mmol). The mixture was stirred for 25 min, and a solution of ketone 39 (0.78 g, 3.2 mmol) in 4 mL of THF was added slowly. The mixture was stirred for 20 min, and a solution of ethyl (E)-3-formyl-2-butenoate 40 (0.45 g, 3.2 mmol) (ethyl (E)-3-formyl-2-butenoate 40 is readily available from Fluka) in 3 mL of THF was added slowly. The mixture was stirred for 35 min at -78° C., poured into saturated aqueous NH4Cl, and extracted with 40% ethyl acetate/hexane. The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated to afford a light-yellow solid. Flash chromatography yielded the desired alcohol 41 as a white crystalline solid (0.98 g, 80%): m.p. 126°-128° C.; Rf 0.13 (10% ethyl acetate/hexane). The structure of the product was also confirmed using IR, 1H NMR and mass spectroscopy.
Reaction SMILES: I[CH3:2].[SH:3][C:4]1[NH:5][C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:8]=1.C[O-].[Na+]>CO>[CH3:2][S:3][C:4]1[NH:8][C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:5]=1
Reactant: CCOC(=O)c1nc(S)[nH]c1C(=O)OCC
Reactant: CI
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1nc(SC)[nH]c1C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.3 %

Procedure:
Iodomethane (15.62 g; 0.11 mol) was added to a solution of 24.4 g (0.10 mol) of the above-produced diethyl 2-mercapto-4,5-imidazole-dicarboxylate (24.4 g; 0.10 mol) and sodium methoxide (6.0; 0.11 mol) in absolute methanol (500 mL) at room temperature. Additional iodomethane (5 g) was added after 1 hour and the yellow solution was allowed to stir at room temperature for 3 hours. The methanol was then removed in vacuo, the residue was treated with cold water and the light yellow solid was filtered and dried to give diethyl 2-(methylthio)imidazole-4,5-dicarboxylate (22.3 g; 86%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH:21]([CH2:29][CH2:30][CH3:31])[CH2:22][CH:23]=[CH:24][CH2:25][C:26]([OH:28])=[O:27])[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][S:9]2)=[CH:4][CH:3]=1.[C:32](OCC)(=O)C>O.[Pt](=O)=O>[CH3:32][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH:21]([CH2:29][CH2:30][CH3:31])[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][S:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: CCCC(CC=CCC(=O)O)C1c2ccc(O)cc2SCC1(C)c1ccc(OC)cc1
Agent: O=[Pt]=O
Solvent: O
Product: CCCC(CCCCC(=O)O)C1c2ccc(OC)cc2SCC1(C)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
To a solution of 6-[7-hydroxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-yl]-3-nonenoic acid (254 mg, 0.56 mmol) in ethyl acetate (5 ml) was added platinum(IV) oxide hydrate (130 mg, 0.56 mmol) and the mixture was stirred for 16 h at room temperature under hydrogen atmosphere. The catalyst was filtered off and washed with methanol. The filtrate was concentrated and the residue was subjected to flash chromatography on silica gel (ethyl acetate) to give the title compound (222 mg, yield: 87%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C@:17]23[CH2:51][CH2:50][C@@H:49]([C:52]([CH3:54])=[CH2:53])[C@@H:18]2[C@@H:19]2[C@@:32]([CH3:35])([CH2:33][CH2:34]3)[C@@:31]3([CH3:36])[C@@H:22]([C@:23]4([CH3:48])[C@@H:28]([CH2:29][CH2:30]3)[C:27]([CH3:38])([CH3:37])[C:26]([C:39]3[CH:47]=[CH:46][C:42]([C:43]([OH:45])=[O:44])=[CH:41][CH:40]=3)=[CH:25][CH2:24]4)[CH2:21][CH2:20]2)[CH2:10][CH2:9]1)=O)(C)(C)C.CN1CCNCC1>>[CH3:35][C@:32]12[C@@:31]3([CH3:36])[C@@H:22]([C@:23]4([CH3:48])[C@@H:28]([CH2:29][CH2:30]3)[C:27]([CH3:37])([CH3:38])[C:26]([C:39]3[CH:40]=[CH:41][C:42]([C:43]([OH:45])=[O:44])=[CH:46][CH:47]=3)=[CH:25][CH2:24]4)[CH2:21][CH2:20][C@@H:19]1[C@H:18]1[C@H:49]([C:52]([CH3:54])=[CH2:53])[CH2:50][CH2:51][C@:17]1([NH:16][CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][N:8]([CH3:6])[CH2:13][CH2:12]1)[CH2:34][CH2:33]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(=O)OC(C)(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CN1CCNCC1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described in above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using 1-methylpiperazine as the alkylating reagent in Step 3. The product was isolated as a white solid (3 mg, 19%). LCMS: m/e 656.62 (M+H)+, 2.19 min (method 11). 1H NMR (500 MHz, Acetic) δ 8.04 (d, J=8.0 Hz, 2H), 7.30 (d, J=8.0 Hz, 2H), 5.38 (d, J=5.7 Hz, 1H), 4.84 (s, 1H), 4.74 (s, 1H), 3.73 (br. s., 1H), 3.62-2.85 (m, 12H), 2.94 (s, 3H), 2.34-1.15 (m, 22H), 1.77 (s, 3H), 1.29 (s, 3H), 1.15 (s, 3H), 1.11 (s, 3H), 1.03 (s, 3H), 1.01 (s, 3H).
Reaction SMILES: O[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[Br-:19].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(O)C>[Br:19][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: O=c1cc(-c2cccnc2)c2ccc(O)cc2o1
Reactant: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: O=c1cc(-c2cccnc2)c2ccc(Br)cc2o1
Yield: 29.9 %

Procedure:
Commercially available 7-hydroxy-4-(3-pyridyl)coumarin (1.48 g, 6.19 mmol) and triphenylphosphine dibromide (5.22 g, 12.4 mmol) were heated in a sand bath at 320-350° for 1.5 h. The cooled solid was taken up with ethanol (200 ml) and silica gel (100 g) and evaporated to dryness. Column chromatography (toluene/acetone; 80:20) gave 0.56 g of the title compound.
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:47][CH2:48][CH2:49][NH:50][C:51]1[N:56]=[C:55]([C:57]2[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=2)[N:54]=[C:53]([NH:64][CH2:65][CH2:66][NH:67][C:68](=[O:70])[CH3:69])[CH:52]=1>CN1C(=O)CCC1>[C:68]([NH:67][CH2:66][CH2:65][NH:64][C:53]1[N:54]=[C:55]([C:57]2[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=2)[N:56]=[C:51]([NH:50][CH2:49][CH2:48][NH:47][C:1]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[O:13])[CH:52]=1)(=[O:70])[CH3:69]
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: CC(=O)NCCNc1cc(NCCN)nc(-c2ccc(Cl)cc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCNc1cc(NCCNC(=O)c2ccc3ccccc3n2)nc(-c2ccc(Cl)cc2)n1
Reaction time: 48 h

Procedure:
A solution of quinaldic acid (60 μl of a 0.3M solution in NMP), HATU (60 μl of a 0.3M solution in NMP) and diisopropylethylamine (60 μl of a 0.3M solution in NMP) was shaken at ambient temperature in a well of a 96 position microtitre plate for 5 min. N-(2-{[6-[(2-aminoethyl)amino]-2-(4-chlorophenyl)pyrimidin-4-yl]amino}ethyl) acetamide (30 μl of a 0.3M solution in NMP) was then added and the mixture shaken for a further 48 hrs. Purification via ion exchange silica (SCX) yields the title compound. LCMS (Method A) RT=2.58 min; m/z (ES+) 504 (MH)+
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([CH3:22])([CH3:21])[C:11]([C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)=[O:12])[CH2:6][CH2:5]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br.C([O-])(=[S:49])C.[K+]>C(Cl)Cl.CC(N(C)C)=O.C(O)C>[SH:49][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([CH3:22])([CH3:21])[C:11]([C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)=[O:12])[CH2:6][CH2:5]1
Reactant: CSc1ccc(C(=O)C(C)(C)N2CCC(CCO)CC2)cc1
Reactant: CC([O-])=S
Agent: BrC(Br)(Br)Br
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Solvent: CCO
Product: CSc1ccc(C(=O)C(C)(C)N2CCC(CCS)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
9.81 g (30.5 mmol) of 2-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-2-methyl-1-[4-(methylthio)-phenyl]-propan-1-one and 8.0 g of triphenylphosphine are dissolved in 100 ml of methylene chloride. 10.1 g of carbon tetrabromide is dissolved in 50 ml of methylene chloride and is added dropwise to the above solution at 5 ° C. After stirring for 1 h, the resulting solution is concentrated to give a slurry, this material is purified by column chromatography on silica gel with ethyl acetate-hexane (10:90) as an eluent, and an oily product is obtained. The resulting material is used for the next reaction. 13.0 g of the above oily product are dissolved in 100 ml of dried dimethylacetamide and 4.56 g of potassium thioacetate are added. After stirring for 2.5 h at 50° C., the reaction mixture is poured into ice-water and extracted with ethyl acetate. The combined organic layers are washed with saturated sodium chloride solution and dried over MgSO4. The solvent is removed by evaporator and the crude oil is further purified by column chromatography on silica gel with ethyl acetate-hexane (10:90) as an eluent, and an oily product is obtained. The product is dissolved in 40 ml of ethanol and the solution is bubbled by nitrogen for 10 min. to remove oxygen. To the solution are added 10 ml of 2N sodium hydroxide solution and stirred at 0° C. for 1 h. After the reaction mixture is neutralized by adding 2N hydrochloric acid solution, the resulting solution is poured into 10 ml of water and extracted with ethyl acetate. The organic layer is washed with water and saturated sodium chloride solution, and dried over MgSO4. After ethyl acetate is distilled off, the residue is purified by means of column chromatography on silica gel with ethyl acetate-hexane (5-95) as an eluent, and an oily product is obtained. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm] 1.16 (m, 2H), 1.28 (s, 6H), 1.31 (t, 1H), 1.42 (m, 1H), 1.56 (q, 2H), 1.63 (d, 2H), 2.24 (t, 2H), 2.52 (s, 3H), 2.53 (m, 2H), 2.79 (d, 2H), 7.21 (d, 2H), 8.53 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N:44]1[CH:49]=[CH:48][CH:47]=[N:46][C:45]=1[N:50]1[CH2:55][CH2:54][CH:53]([CH2:56]O)[CH2:52][CH2:51]1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH2:56][CH:53]4[CH2:52][CH2:51][N:50]([C:45]5[N:44]=[CH:49][CH:48]=[CH:47][N:46]=5)[CH2:55][CH2:54]4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Reactant: OCC1CCN(c2ncccn2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1n(CC2CCN(c3ncccn3)CC2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Yield: 41.6 %

Procedure:
The title compound was prepared using 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (50 mg, 0.14 mmol), prepared as described in Example 1, Ph3P (110 mg, 0.42 mmol) and (1-(pyrimidin-2-yl)piperdin-4-yl-)methanol (28 mg, 0.14 mmol) in THF (1.0 mL) and by following the procedure described in Example 2. The title compound, 7,8-bis(4-chlorophenyl)-2-((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (31 mg, 42%) was obtained as yellow powder. MS M+H=532; 1H NMR (CDCl3) δ 8.28 (2H, d, J=5.0 Hz), 8.16 (1H, s), 7.28-7.36 (6H, m), 7.11 (2H, d, J=10.0 Hz), 6.44 (1H, t, J=5.0 Hz), 4.75 (2H, d, J=15.0 Hz), 3.96 (2H, d, J=10.0 Hz), 2.85 (2H, m), 2.20-2.30 (1H, m), 1.74 (2H, d, J=10.0 Hz), 1.30-1.40 (2H, m).
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:21]=[C:20]4[N:22]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:23]([O:25][C@@H:26]5[CH2:30][O:29][C@@H:28]6[C@H:31]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:32][O:33][C@H:27]56)=[N:24][C:19]4=[CH:18][C:17]=3[Cl:50])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[Si:35]([O:34][C@H:31]1[C@H:28]2[O:29][CH2:30][C@@H:26]([O:25][C:23]3[N:22]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:20]4=[N:21][C:16]([C:13]5[CH:14]=[CH:15][C:10]([C@H:7]6[CH2:8][CH2:9][C@H:4]([NH2:1])[CH2:5][CH2:6]6)=[CH:11][CH:12]=5)=[C:17]([Cl:50])[CH:18]=[C:19]4[N:24]=3)[C@H:27]2[O:33][CH2:32]1)([C:38]([CH3:40])([CH3:41])[CH3:39])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@H](N=[N+]=[N-])CC4)cc3)nc2n1COCC[Si](C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@H](N)CC4)cc3)nc2n1COCC[Si](C)(C)C
Temperature: 40 °C
Reaction time: 24 h

Procedure:
5-(4-((trans)-4-Azidocyclohexyl)phenyl)-2-((3R,3aR,6R,6aS)-6-(tert-butyldimethyl-silyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine (130 mg) is dissolved in tetrahydrofurane (1 mL), treated with triphenylphosphine (57 mg) and stirred for 24 hours at 40° C. Then water (220 μL) is added and the mixture is stirred for 12 hours at 80° C. The mixture is partitioned between ethylacetate and saturated aqueous NH4Cl solution. The organic phase is dried (MgSO4) and concentrated. The residue is purified by HPLC on reversed phase to give the product, which is partitioned between 1 M aqueous NaOH solution and ethylacetate. The organic phase is washed with brine and dried (MgSO4). The residue is concentrated to give the title compound. LC (method 1): tR=1.24 min; Mass spectrum (ESI+): m/z=715 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[N+:5]([O-])=[C:4]([CH3:10])[CH:3]=1.[F:11][C:12]([F:23])([F:22])[C:13]([O:15]C(=O)C(F)(F)F)=[O:14]>C(Cl)Cl>[F:11][C:12]([F:23])([F:22])[C:13]([O:15][CH2:8][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[C:4]([CH3:10])[N:5]=1)=[O:14]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc(Br)cc(C)[n+]1[O-]
Solvent: ClCCl
Product: Cc1cc(Br)cc(COC(=O)C(F)(F)F)n1
Reaction time: 20 h

Procedure:
To a stirring solution of 2.14 g 4-bromo-2,6-dimethylpyridine 1-oxide in 10 mL of CH2Cl2 was added 7.4 mL of trifluoroacetic anhydride. After 20 h, the solution was concentrated, and the crude product was purified by flash silica gel chromatography (5% MeOH/CHCl3) to give 1.93 g of (4-bromo-6-methylpyridin-2-yl)methyl 2,2,2-trifluoroacetate with some impurity.