Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[N:11]1[C:15]2[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=2[N:13]=[C:12]1[Br:22])(=O)C.N>CO>[Br:22][C:12]1[N:11]([C@@H:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C@H:5]2[OH:4])[C:15]2[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=2[N:13]=1
Reactant: CC(=O)O[C@@H]1CCCC[C@H]1n1c(Br)nc2cc(Cl)c(Cl)cc21
Agent: N
Solvent: CO
Product: O[C@@H]1CCCC[C@H]1n1c(Br)nc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
(±)-Trans-2-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)cyclohexyl acetate (part c of this example, 500 mg, 1.23 mmol) was dissolved in methanol half-saturated with ammonia (at 0° C.) and the solution stirred at room temperature for 18 hours. Volatiles were evaporated and the residual solid recrystallized from methanol-water to give title compound as white crystals (350 mg, 78%), m.p. 186-188° C.; 1H-NMR (DMSO-d6, 200 MHz) δ: 8.23, 7.93 (both s, each 1, 2 aromatic CH), 4.99 (d, J=4.7 Hz, 1, OH), 4.34.1 (m, 2, OCH and NCH), 2.4-1.3 (m, 8, 4CH2).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].[CH3:12][C:13]([O:16][C:17]([NH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:18])([CH3:15])[CH3:14].C(N(CC)C(C)C)(C)C>CO>[C:13]([O:16][C:17](=[O:18])[NH:19][CH:20]1[CH2:25][CH2:24][N:23]([C:8]2[CH:9]=[C:2]([F:1])[C:3]([C:4]#[N:5])=[C:6]([F:11])[CH:7]=2)[CH2:22][CH2:21]1)([CH3:15])([CH3:12])[CH3:14]
Reactant: N#Cc1c(F)cc(F)cc1F
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(c2cc(F)c(C#N)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 57 %

Procedure:
To a solution of 1.0 g (6.4 mmol) of 2,4,6-trifluorobenzonitrile in MeOH (25 mL) was added 1.3 g (6.5 mmol) of 4-N-boc-amino-piperidine along with 1.2 mL (6.7 mmol) of N,N-diisopropylethylamine. The mixture was stirred at room temperature for 3 days then concentrated under reduced pressure to provide a white solid. The solid was washed with large amounts of H2O and dried under vacuum. The solid was recrystallized from hexane/EtOAc to provide 1.23 g (56%) of [1-(4-cyano-3,5-difluoro-phenyl)-piperidin-4-yl]-carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: Cl[C:2]1[C:6]([C:7]#[N:8])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=2[F:16])[S:4][N:3]=1.[Al](C)(C)[CH3:18]>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.O1CCOCC1>[F:16][C:10]1[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=1[C:5]1[S:4][N:3]=[C:2]([CH3:18])[C:6]=1[C:7]#[N:8]
Reactant: Cc1ccc(-c2snc(Cl)c2C#N)c(F)c1
Reactant: C[Al](C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1ccc(-c2snc(C)c2C#N)c(F)c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-chloro-5-(2-fluoro-4-methylphenyl)-1,2-thiazole-4-carbonitrile (500 mg, 1.98 mmol, 1.00 equiv), 1,4-dioxane (20 mL), Al(CH3)3 (6 mL), Pd(PPh3)4 (343 mg, 0.30 mmol, 0.15 equiv). The resulting solution was stirred for 3 h at 110° C. The reaction was then quenched by the addition of 2 mL of water. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 200 mg (44%) of 5-(2-fluoro-4-methylphenyl)-3-methyl-1,2-thiazole-4-carbonitrile as a yellow solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][OH:4].S(=O)(=O)(O)O.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)O)=[CH:13][CH:12]=1.O>C1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][O:4][CH:17]([C:14]1[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=1)[C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1
Reactant: OCCCl
Reactant: OC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: O
Product: Fc1ccc(C(OCCCl)c2ccc(F)cc2)cc1

Procedure:
A mixture of 20 parts of 2-chloroethanol, 3 parts of sulfuric acid and 16 parts of benzene was heated on a water-bath. Then there were added dropwise 35 parts of 4-fluoro-α-(4-fluorophenyl)benzenemethanol dissolved in 32 parts of benzene. After the addition was complete, the whole was stirred and refluxed for 4 hours. After cooling the reaction mixture was poured into water. The benzene layer was separated, dried over calcium chloride and evaporated. The residue was distilled in vacuo, yielding 35 parts of 1,1'-[(2-chloroethoxy)methylene]bis[4-fluorobenzene]; bp. 164°-166° C. at 1.5 mm. pressure; nD20 : 1.5462; d2020 : 1.2290 (intermediate 1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[S:13]1[CH2:17][C:16](=[O:18])[NH:15][C:14]1=[O:19]>>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[C:17]3[S:13][C:14](=[O:19])[NH:15][C:16]3=[O:18])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc2ncccc2c1
Reactant: O=C1CSC(=O)N1
Product: O=C1NC(=O)C(=Cc2ccc3ncccc3c2)S1

Procedure:
Following the general method as outlined in Example 1, starting from quinoline-6-carbaldehyde (intermediate 5) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:13]1([C:19]2[N:20]=[CH:21][NH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[C:13]1([C:19]2[N:20]=[CH:21][N:22]([C:2]3[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:9][CH:10]=[CH:11][N:12]=3)[CH:23]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: CCOC(=O)c1cccnc1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccnc1-n1cnc(-c2ccccc2)c1
Temperature: 160 °C
Yield: 28.9 %

Procedure:
A mixture of 5.0 g of ethyl 2-chloronicotinate (26.94 mmol), 3.4 g of 4-phenylimidazole (23.58 mmol), 7.6 g of K2CO3 and 80 mg of 18-crown-6 in 18 ml of N,N-dimethylformamide was heated in a microwave at 160° C. for about 1 hour. This was followed by concentrating, taking up the residue in dichloromethane, washing with water and sat. NaCl solution, drying over MgSO4, filtering and evaporating. Chromatography on silica gel (eluent: CH2Cl2/methanol 2%-5%) resulted in 2 g of a dark oil, which was immediately reacted further; ESI-MS [M+H]+=294.15.
Reaction SMILES: [C:1]([N:11](C)[C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:20]([C:24]1[CH:25]=[C:26]([CH2:31][CH:32]([NH2:38])[C:33]2[O:34][CH:35]=[N:36][N:37]=2)[CH:27]=[CH:28][C:29]=1[OH:30])([CH3:23])([CH3:22])[CH3:21].O>C1COCC1>[C:20]([C:24]1[CH:25]=[C:26]([CH2:31][CH:32]([NH:38][C:16](=[O:18])[CH:12]([NH:11][C:1]([O:3][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2])[CH:13]([CH3:14])[CH3:15])[C:33]2[O:34][CH:35]=[N:36][N:37]=2)[CH:27]=[CH:28][C:29]=1[OH:30])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Reactant: CC(C)(C)c1cc(CC(N)c2nnco2)ccc1O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)c1nnco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To a solution of Z-N-Me-Val-OH (914 mg, 3.45 mmol), 2-(3-t-butyl-4-hydroxyphenyl)-1-(1,3,4-oxadiazol-2-yl)ethylamine (0.75 g, 2.87 mmol) and CMPI (881 mg, 3.45 mmol) in THF (30 ml), TEA (0.96 ml) was added under cooling with ice and stirred at room temperature for 2 hours. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:1), giving 2-benzyloxycarbonylamino-3-methylbutyric acid 2-(3-t-butyl-4-hydroxyphenyl)-1-(1,3,4-oxadiazol-2-yl)ethylamide (1.28 g, 88%).
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18]CC3C=CC=CC=3)[CH:13]=2)[C:7]([CH:26]=[CH:27][CH2:28][CH2:29][CH3:30])=[C:6]([CH:31]([CH3:33])[CH3:32])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[C:7]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[C:6]([CH:31]([CH3:32])[CH3:33])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1cccc(OCc2ccccc2)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1cccc(O)c1

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(3-benzyloxyphenyl)-5-(pent-1-enyl)pyridine (Example 152) by the procedure described in Example 126. 1H NMR (300 MHz, CDCl3): δ 0.78 (t, J=7.0 Hz, 3 H), 1.28 (m, 18 H), 2.28 (m, 2 H), 3.22 (m, 1 H), 3.39 (m, 1 H), 4.34 (m, 2 H), 5.52 (s, 1 H), 6.63 (m, 1 H), 6.71 (d, J=8.0 Hz, 1 H), 6.81 (m, 1 H), 7.26 (m, 1 H). FAB-MS: calculated for C23H33NO2 356; found 357 (M+H, 100%). Elemental analysis: calculated for C23H33NO2: C 77.70; H 9.36; N 3.94, found: C 76.51; H 9.49; N 3.85. Rf 0.21 (10% ethyl acetate/n-hexane). mp 121-122° C.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[Cl:26][CH:27]1[CH2:30][CH:29]([C:31](O)=[O:32])[CH2:28]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:31]([CH:29]5[CH2:30][CH:27]([Cl:26])[CH2:28]5)=[O:32])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)C1CC(Cl)C1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)C1CC(Cl)C1

Procedure:
The title compound, white solid (15 mg, 51.4%), MS (ISP) m/z=447.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) ((25 mg, 0.062 mmol) and 3-chlorocyclobutanecarboxylic acid
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[OH:14].[CH2:15]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([O-])=O)=[CH:25][CH:24]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>O>[CH2:15]([C:23]1[CH:31]=[CH:30][C:26]([C:27]2[O:14][C:3]3[CH:4]=[CH:5][C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:7][C:2]=3[N:1]=2)=[CH:25][CH:24]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCc1ccc(C(=O)[O-])cc1
Reactant: CCCCCCc1ccc(O)c(N)c1
Solvent: O
Product: CCCCCCCCc1ccc(-c2nc3cc(CCCCCC)ccc3o2)cc1
Temperature: 250 °C
Reaction time: 3.5 h
Yield: 28 %

Procedure:
In a 50 ml-round-bottomed flask, 19 g of polyphosphoric acid, 0.30 g (1.55 mM) of 2-amino-4-hexylphenol and 0.37 g (1.58 mM) of 4-octylbenzoate acid were placed, followed by stirring for 3.5 hours at about 250° C. After the reaction, the reaction mixture was poured into water to precipitate a crystal. The crystal was recovered by filtration and was washed with 10% K2CO3. The crystal was dissolved in ethyl acetate and washed with water, followed by drying with anhydrous sodium sulfate and distilling-off of the solvent. The resultant residue was purified by silica gel column chromatography (eluent: toluene/hexane=1/2) to obtain 0.17 g of 2-(4-octylphenyl)-5-hexylbenzoxazole (yield: 28.0%). ##STR72##
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][C:10]1([CH3:14])[CH2:13][O:12][CH2:11]1.[OH:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:14][C:10]1([CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[CH2:13][O:12][CH2:11]1
Reactant: CC1(COCCCCCCBr)COC1
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(COCCCCCCOc2ccc(C(=O)O)cc2)COC1
Temperature: 90 °C
Reaction time: 4 h
Yield: 69.9 %

Procedure:
A solution comprising 20 g of 3-[(6-bromohexyloxy)methyl]-3-methyloxetane, 11.6 g of 4-hydroxybenzoic acid, 13 g of potassium carbonate and 150 ml of dimethylformamide was stirred at 90° C. for 4 hours. Water was added to the reaction liquid to terminate the reaction, and the liquid was extracted with ethyl acetate. The organic layer was washed with water, and the solvent was distilled off. A 5% sodium hydroxide aqueous solution was added to the resulting residue, and the solution was refluxed for 8 hours. Then, the solution was acidified with hydrochloric acid and extracted with ether, followed by drying on anhydrous magnesium sulfate. The solvent was distilled off to obtain 17 g of 4-[6-(3-methyloxetane-3-ylmethoxy)hexyloxy]benzoic acid. Melting point: 61° C.
Reaction SMILES: [IH:1].O.[CH2:3]1[O:11][CH:4]1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)C>[I:1][CH:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:11]
Reactant: c1ccc(C2CO2)cc1
Reactant: I
Solvent: O
Solvent: CCO
Product: OCC(I)c1ccccc1
Temperature: 0 °C

Procedure:
2-iodo-2-phenylethanol was synthesized as described in Golumbic, C. and Cottle, D. L. J. Am. Chem. Soc. 61, 996 (1939). An aqueous HI solution (81.7 grams, 54.7%) and 556 ml of water were added to a 1 L reaction flask equipped with an addition funnel, which was cooled to zero degrees C. Styrene oxide (40 grams) and 50 grams of ethanol were added to the addition funnel. The styrene oxide solution was added dropwise to the flask over a 40-minute period during which a white precipitate was formed. Filtration over a fritted glass funnel followed by drying under vacuum for four hours yielded 69.8 grams of a white solid having a melting point of 62-66° C. The solid was dissolved in 560 ml of ethanol and poured into rapidly stirred water (2.5 L containing 100 ml of 5% NaHSO3). The white precipitate was collected on a fritted glass funnel and dried in a vacuum oven at room temperature for four hours in the presence of P2O5 as a desiccant. The white solid (24 grams) had a melting point of 75.5-76° C. NMR analysis was consistent with the reports in the above-cited literature.
Reaction SMILES: [O-:1]C#N.[Na+].[NH2:5][C:6]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]>C(O)(=O)C.O>[Br:16][C:14]1[CH:13]=[CH:12][C:7]2[C:8](=[O:9])[O:10][C:11](=[O:1])[NH:5][C:6]=2[CH:15]=1
Reactant: N#C[O-]
Reactant: COC(=O)c1ccc(Br)cc1N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c2cc(Br)ccc2c(=O)o1
Temperature: 25 °C
Yield: 72.5 %

Procedure:
87.0 g (1.33 mol) of sodium cyanate were added to 269.0 g (1.17 mol) of methyl 2-amino-4-bromobenzoate in 1.2 l of acetic acid with stirring at room temperature, and the mixture was subsequently stirred for a further 22 h. The reaction mixture was diluted with 1.5 l of water, and the residue was filtered off with suction. 0.42 l of sodium hydroxide solution (32%) was added to the solid, the mixture was diluted with 3.5 l of water and heated on a steam bath for 4 h. After cooling, the solid residue was filtered off with suction. Conventional work-up gave 205.2 g of 7-bromo-1H-benzo[d]-1,3-oxazine-2,4-dione; HPLC/MS (M+H)+=243 as solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].[Cl:6][CH2:7][C:8](Cl)=[O:9]>O.ClCCl.[OH-].[Na+]>[Cl:6][CH2:7][C:8]([NH:1][C@@H:2]([CH3:5])[CH2:3][OH:4])=[O:9]
Reactant: C[C@H](N)CO
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: C[C@@H](CO)NC(=O)CCl
Yield: 82.2 %

Procedure:
To a stirred solution of (S)-2-aminopropan-1-ol (10 g, 0.13 mol) in water at 0° C. was added simultaneously a solution of chloroacetyl chloride (18 g, 0.16 mol) in dichloromethane (50 mL) and 1.6M aqueous sodium hydroxide (100 mL) dropwise over 1 h. The dichloromethane was removed under reduced pressure then the aqueous layer was extracted with ethyl acetate. The separated organic layer was dried (Na2SO4) and concentrated to afford (S)-2-chloro-N-(1-hydroxypropan-2-yl)acetamide (16.2 g, 83%) as a colourless oil which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9]([C:11]2[C:12]([NH:17][CH2:18][CH3:19])=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[C:6]([C:20]([F:23])([F:22])[F:21])[CH:5]=[C:4]([CH3:24])[N:3]=1.[H-].[Na+]>N1C=CC=CC=1>[CH2:18]([N:17]1[C:12]2[N:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:9](=[O:10])[NH:8][C:7]2[C:6]([C:20]([F:23])([F:22])[F:21])=[CH:5][C:4]([CH3:24])=[N:3][C:2]1=2)[CH3:19]
Reactant: CCNc1ncccc1C(=O)Nc1c(C(F)(F)F)cc(C)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCN1c2ncccc2C(=O)Nc2c(C(F)(F)F)cc(C)nc21
Temperature: 150 °C
Yield: 20 %

Procedure:
A solution of 0.5 g of N-(2-chloro-6-methyl-4-trifluoromethyl-3-pyridinyl)-2-ethylamino-3-pyridinecarboxamide in 3 ml of pyridine was added to 0.2 g of a 50% dispersion of sodium hydride in oil. The mixture was heated to 150° C. and then cooled and concentrated in vacuo. Water was added to the residue and the product was extracted with ethyl acetate, dried (magnesium sulfate), filtered, and concentrated. The product was purified by column chromatography over silica gel (methylene chloride, then methylene chloride/methanol). After concentrating in vacuo, the residue was crystallized from hexane to give 0.09 g of the title compound, m.p. 150°-151° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][OH:12])=[CH:9][N:10]=2)[N:7]=1>C(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: OCc1cnc2ccc(Cl)nn12
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1cnc2ccc(Cl)nn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
To a solution of (6-chloro-imidazo[1,2-b]pyridazin-3-yl)-methanol (1.3 g, 7.1 mmol) in DCM (50 mL) was added active MnO2 (3 g, 34.5 mmol). The mixture was stirred at rt overnight and filtered. The filtrate was concentrated under vacuum and the residue was washed with EtOAc to affrode 6-chloro-imidazo[1,2-b]pyridazine-3-carbaldehyde (0.7 g) in 54% yield. 1H-NMR (400 MHz, CDCl3) δ ppm 10.36 (s, 1H), 8.42 (s, 1H), 8.08 (d, 1H), 7.38 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])=[O:12]>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=[O:12])[CH:7]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: COc1ccccc1C(=O)CBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccccc1C(=O)Cn1cc(Cl)cnc1=O
Yield: 30 %

Procedure:
A solution of 5-chloropyrimidin-2-one (541 mg) and 2-bromo-2'-methoxyacetophenone (954 mg) in triethylamine (1 ml) and ethanol (25 ml) was stirred at ambient temperature for 31/2 hours. After evaporation of solvents, the residue was dissolved in ethyl acetate (150 ml) and this solution was washed with water (50 ml) and brine (25 ml), dried (MgSO4) and evaporated to give a foam. This was purified by preparative thin-layer chromatography on silica, developed in chloroform, then chloroform-ethanol (25:1) before crystallisation from ethyl acetate to give the title pyrimidinone (347 mg,); m.p. 123°-125°; λmax 248.5 nm ε 12200), 317.5 nm (ε 6700), λinf 229.5 nm (ε 12440), 349 nm (ε 2640).
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[CH3:11][N:12]1[CH2:17][NH:16][C:15](=[S:18])[NH:14][CH2:13]1>CC(C)=O>[OH:3][C:2]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:16]2[CH2:17][N:12]([CH3:11])[CH2:13][N:14]=[C:15]2[S:18][CH2:1]1
Reactant: CN1CNC(=S)NC1
Reactant: O=C(CBr)c1ccccc1
Solvent: CC(C)=O
Product: CN1CN=C2SCC(O)(c3ccccc3)N2C1

Procedure:
A solution of 5.0 grams (0.025 moles) of phenacylbromide in 40 milliliters of acetone was mixed with a solution of 3.27 grams (0.025 moles) of 3,4,5,6-tetrahydro-5-methyl-s-triazin 2(1H)thione in 450 milliliters of acetone. 6-Hydroxy-3-methyl-6-phenyl-3,4,6,7-tetrahydro-2H-thiazolo[3,2-a]-s-triazine hydrobromide crystallized out as a colourless solid, m.p. 149°-150° C. (decomposition). The yield was 7.35 grams (89%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([N+:16]([O-])=O)=[CH:11][C:10]=1[F:19])C1C=CC=CC=1>CO.C1COCC1.[Pd]>[NH2:16][C:12]1[C:13]([F:15])=[CH:14][C:9]([OH:8])=[C:10]([F:19])[CH:11]=1
Reactant: O=[N+]([O-])c1cc(F)c(OCc2ccccc2)cc1F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc(F)c(O)cc1F
Temperature: 32 °C
Reaction time: 10 h
Yield: 86.1 %

Procedure:
To a suspension of 1-(benzyloxy)-2,5-difluoro-4-nitrobenzene (1.06 g, 4 mmol) in CH3OH (25 mL) and THF (5 mL) was added Pd/C (50% Pd content, 185 mg). The reaction was stirred at 32° C. under H2 atmosphere for 10 hours. The mixture was filtered through a CELITE® pad and the filtrate was concentrated in vacuo. The residue was washed with DCM (15 mL) to give the title compound as a dark brown solid (500 mg, 86%).
Reaction SMILES: [CH2:1]([N:8]([C@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])[C@@H:9]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.O1CCCC1.CO.Cl>C1COCC1>[CH2:1]([N:8]([C@H:18]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:19])[C@@H:9]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC[C@@H](CC(=O)O)N(Cc1ccccc1)[C@@H](C)c1ccccc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCCC[C@@H](CCO)N(Cc1ccccc1)[C@@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
The product from step (iii) (12 g) was dissolved in THF (120 mL) and borane-tetrahydrofuran complex (1M in THF, 132.3 ml1) added dropwise. The reaction mixture was stirred at rt overnight then MeOH was added followed by 2M HCl (20 mL). The mixture was evaporated and the residue taken up in MeOH and purified via SCX resin and the residue was further purified via column chromatography eluting with 10-20% EtOAc in isohexane to give the subtitle compound 6 g.
Reaction SMILES: [CH:1]1([N:7]2[C:11]([OH:12])=[CH:10][C:9]([CH3:13])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(OC)(O[CH3:18])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].C>O.C(Cl)Cl>[CH:1]1([N:7]2[C:11](=[O:12])[CH:10]=[C:9]([CH3:13])[N:8]2[CH3:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COS(=O)(=O)OC
Reactant: Cc1cc(O)n(C2CCCCC2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(=O)n(C2CCCCC2)n1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 17.9 %

Procedure:
A mixture of 2-cyclohexyl-3-hydroxy-5-methylpyrazole (16.5 g) and dimethyl sulfate (10.9 g) was heated with stirring at 150°-160° for 6 hours and then allowed to cool to room temperature. A solution of sodium carbonate (6.5 g) in water (100 ml) was added, and the reaction mixture was heated at reflux temperature for 2 hours, cooled, and extracted with chloroform. The layer was dried and concentrated to give a dark oil, which was dissolved in methylene chloride, treated with charcoal and diatomaceous earth, filtered and concentrated. The concentrate was fractionally distilled, and the portion distilling at 118°/0.020 mm Hg was further purified by column chromatography on silica gel. Elution with chloroform-ethyl acetate (7:3), chloroform-ethyl acetate gradients, ethyl acetate, and ethanol afforded product from the ethyl acetate-rich chloroform-ethyl acetate gradient fractions and the ethyl acetate and ethanol fractions as determined by thin-layer chromatography and nuclear magnetic resonance spectroscopy. Product-rich fractions which were shown by gas chromatography to be highly pure were combined and concentrated to give 2-cyclohexyl-1,5-dimethyl-1,2-dihydro-3H-pyrazol-3-one (3.0 g) as an oil. The assigned structure was confirmed by infrared and nuclear magnetic resonance spectral analysis.