Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C(N(CC)CC)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH:23]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[NH:22][C:21]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH:38]([CH3:40])[CH3:39])=[N:20]2)=[CH:15][CH:14]=1>C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH:23]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[N:22]([C:1]([Cl:4])=[O:2])[C:21]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH:38]([CH3:40])[CH3:39])=[N:20]2)=[CH:17][CH:18]=1
Reactant: CC(C)Oc1ccccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
Phosgene (2.95 mL, 5.69 mmol, 1.93 M in toluene) was added dropwise to a cooled mixture of triethylamine (1.3 mL, 9.4 mmol) and 4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-phenyl)-4,5-dihydro-1H-imidazole (0.80 g, 1.88 mmol, example 6) in methylene chloride (15 mL) at 0° C. The reaction mixture was stirred for 30 min at 0° C. and evaporated. The residue was kept under high vacuum for 30 min. Chromatography of the residue over silica gel using 60-80% methylene chloride in hexanes gave 4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (0.71 g, 77%)
Reaction SMILES: O(Cl)Cl.[P+3].O.[NH2:6][C:7]1[CH:8]=[C:9]([C:14](=[O:21])[CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:10]=[CH:11][C:12]=1[NH2:13].[K+].[Br-].[CH:24](O)=O>>[NH:13]1[C:12]2[CH:11]=[CH:10][C:9]([C:14](=[O:21])[CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:8][C:7]=2[N:6]=[CH:24]1
Reactant: O=CO
Reactant: COC(=O)CCC(=O)c1ccc(N)c(N)c1
Agent: ClOCl
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: COC(=O)CCC(=O)c1ccc2[nH]cnc2c1
Temperature: 60 °C
Reaction time: 0.67 h

Procedure:
75 ml of phosphorus(III)oxychloride were slowly added dropwise, while cooling externally with water, to a solution of 20.0 g (0.09 mol) of methyl 4-(3,4-diaminophenyl)-4-oxobutanoate in 50 ml of formic acid and the mixture was then stirred for another 40 minutes at a reaction temperature of 60° C. It was left to cool, then the mixture was stirred into 500 g of crushed ice while cooling externally with ice and made weakly ammoniacal. It was then extracted exhaustively with ethyl acetate, the combined extracts were dried over magnesium sulphate and concentrated by evaporation in vacuo. 8.29 g (40% of theoretical) of a colourless, crystalline substance were obtained. IR (KBr): 1732.0, 1679.9 cm−1 (C═O)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39][CH:40]([C:44](O)=[O:45])[C:41](O)=[O:42])([CH3:32])[CH3:31]>C(Cl)Cl>[OH:45][C:44]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=2)[O:10][C:41](=[O:42])[C:40]=1[S:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[CH:30]([CH3:32])[CH3:31]
Reactant: CC(=O)c1cccc(O)c1
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccccc1Sc1c(O)cc(-c2cccc(O)c2)oc1=O

Procedure:
The title compound was prepared by Method A using 3'-hydroxyacetophenone (2.06 g, 15.1 mmol), trimethylsilyl triflate (7.0 mL, 36.2 mmol), triethylamine (8.52 mL, 61.1 mmol), methylene chloride (30 mL), and diethyl ester of [(2-isopropylphenyl)thio] propanedioic acid (3.11 g, 10.0 mmol) m.p. 201-204° C.; 1H NMR (250 MHz, DMSO-d6) δ 1.25 (d, 6H), 3.41 (m, 1H), 6.82 (s, 1H), 6.93 (m, 2H), 7.09 (m, 2H), 7.30 (m, 4H), 9.91 (br, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:12]=[CH:11][NH:10][C:4]=2[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[H-].[Na+].[CH3:15][Si:16]([CH3:23])([CH3:22])[CH2:17][CH2:18][O:19][CH2:20]Cl>CN(C)C=O.C(OCC)(=O)C.O>[Br:1][C:2]1[C:3]2[CH:12]=[CH:11][N:10]([CH2:20][O:19][CH2:18][CH2:17][Si:16]([CH3:23])([CH3:22])[CH3:15])[C:4]=2[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)c2cc[nH]c2c1=O
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(Br)c2ccn(COCC[Si](C)(C)C)c2c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
A solution of 4-bromo-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (0.967 g, 4.26 mmol) in N,N-dimethylformamide (30.6 mL) at 0° C. was treated with sodium hydride (0.255 g, 6.38 mmol) and stirred at 0° C. for 30 min. After this time the reaction mixture was treated with [β-(trimethylsilyl)ethoxy]methyl chloride (1.13 mL, 6.39 mmol) and subsequently stirred at 20° C. for 1 h. The reaction mixture was diluted with ethyl acetate and water. Layers were separated and the organic layer was washed with water (3×), dried with magnesium sulfate, filtered, and concentrated to give a crude residue. Purification by flash column chromatography (100% hexanes to 30% EtOAc/hexanes) gave the desired product (1.03 g, 68%) as a white solid. LCMS calculated for C14H22BrN2O2Si (M+H)+: m/z=357.1, 359.1. found: 357.0, 359.0.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:15](=O)[NH:14][CH2:13][C@@H:12]([CH3:17])[N:6]3[C:7]=2[C:8]([F:11])=[CH:9][CH:10]=1.[Mg].Cl.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>CO.C(OCC)C.O>[ClH:1].[Cl:1][C:2]1[C:3]2[CH2:4][C@@H:5]3[CH2:15][NH:14][CH2:13][C@@H:12]([CH3:17])[N:6]3[C:7]=2[C:8]([F:11])=[CH:9][CH:10]=1
Reactant: C[C@@H]1CNC(=O)c2cc3c(Cl)ccc(F)c3n21
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [Al+3]
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: C[C@@H]1CNC[C@H]2Cc3c(Cl)ccc(F)c3N21
Reaction time: 3 h

Procedure:
(R)-9-Chloro-6-fluoro-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one 4.7 mmol) was dissolved in methanol and magnesium (0.69 g, 28.5 mmol) was added with stirring. Stirring was continued for 3 h at room temperature, the mixture was poured onto ice water and hydrochloric acid (1 N, 23 mL) was added. The pH was adjusted to neutral with potassium phosphate buffer (1 M, pH 6.85) and the mixture was extracted with ethyl acetate. Organic phase were pooled, washed with brine, dried with MgSO4 and the solvent was removed in vacuo to yield a mixture of (4R,10aR)- and (4R,10aS)-9-chloro-6-fluoro-4-methyl-3,4,10,10a-tetrahydro-2H-pyrazino[1,2-a]indol-1-one. Without further purification this mixture (1.2 g) was dissolved in diethylether (50 mL), lithium aluminium hydride (460 mg, 12.0 mmol) was added and the mixture was heated to reflux for 4 h. The solution was cooled and hydrolyzed by sequential addition of water (6.0 mL), sodium hydroxide solution (15%, 12.0 mL) and water (12.0 mL). Diethylether was added (300 mL), the mixture was filtered and the filtrate was evaporated after drying with MgSO4. Chromatography on silica gel (dichloromethane/methanol 97:3) separated the title compound (0.23 g; 20%) from the isomeric (4R,10aS)-9-chloro-6-fluoro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole. The title compound was characterized as its HCl salt which precipitated from diethylether, ISP-MS: m/e=241.3 (M+H+) and αD20=−18.4.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][C:14](=O)[CH:13]([C:18]([O:20]CC)=O)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:23]1([NH:29][NH2:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CC[O-].[Na+].CCO>CCO.[Cl-].[Na+].O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:16][CH2:15][C:14]3[NH:30][N:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18](=[O:20])[C:13]=3[CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CN(S(=O)(=O)c2ccc(C)cc2)CCC1=O
Reactant: NNc1ccccc1
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N2CCc3[nH]n(-c4ccccc4)c(=O)c3C2)cc1
Temperature: 25 °C
Yield: 25 %

Procedure:
In a three-necked flask, under a N2 atmosphere, 0.300 g (0.92 mmol) of ethyl 1-[(4-methyl phenyl)sulfonyl]-4-oxopiperidine-3-carboxylate and 0.099 g (0.92 mmol) of phenyl hydrazine were stirred in 3 mL of EtOH for 1 h at 50° C. HPLC and UPLC-MS analysis revealed the formation of the hydrazone intermediate. After having cooled to room temperature, a solution of EtONa/EtOH—prepared by dissolution of 42 mg (1.84 mmol) of Na in 2 mL of EtOH—was added to the reaction mixture and it was stirred for 1 additional hour at room temperature (reaction monitored by HPLC and UPLC-MS). The reaction mixture was diluted with brine (10 mL) and extracted with ethylacetate (50 mL×3). The combined organic phases were dried over Na2SO4 and evaporated. The crude (400 mg) was purified by silica flash chromatography using ethylacetate/petroleum ether (80/20, gradient to 100% ethylacetate) yielding 84 mg of a white solid as the desired 5-[(4-methylphenyl)sulfonyl]-2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo[4,3-c]pyridin-3-one (25% yield). 1HNMR (500 MHz, DMSO-d6): 3.95 (s, 3H); 2.64 (t, J=5.5 Hz, 2H); 3.17 (d, J=5 Hz, 2H); 3.30 (m, 2H, hidden by H2O); 7.20 (t, J=7.25 Hz, 1H); 7.40-7.45 (m, 4H); 7.65-7.7 (m, 4H); 11.36 (bs, NH); 370.
Reaction SMILES: CC(C)([O-])C.[K+].[Br-].[C:8]([CH2:13][CH2:14][CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:10][CH2:11][CH3:12])=[O:9].[C:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=O)[CH3:36].[Cl-].[Na+]>O.O1CCCC1>[CH3:36][C:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[CH:15][CH2:14][CH2:13][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CC(=O)c1ccccc1
Reactant: CCOC(=O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CCC=C(C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
A mixture of potassium tert-butoxide (10.27 g, 91.6 mmol), 3-carboethoxypropyltriphenylphosphonium bromide (41.87 g, 91.6 mmol) and tetrahydrofuran (300 ml) was stirred at room temperature. Acetophenone (10.0 g, 83.2 mmol) was added dropwise to the mixture, and the resulting mixture was stirred at room temperature for another 1 hour and then allowed to stand overnight. Water (100 ml) was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 1 hour, poured into an aqueous sodium chloride solution, and then extracted twice with ethyl acetate. The extract solution was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/98) to obtain 17.3 g of ethyl 5-methyl-5-phenyl-4-pentenoate.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:3]1[CH2:4][NH:5][CH2:6]2.Br[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH:13]=1.CC(C)([O-])C.[K+].[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34]>C(OCC)C.C(O)C.O.O1CCOCC1>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34].[CH3:23][O:22][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([N:5]1[CH2:4][CH:3]3[N:2]([CH3:1])[CH:7]([CH2:8][CH2:9][CH2:10]3)[CH2:6]1)[CH:21]=[CH:20]2
Reactant: CN1C2CCCC1CNC2
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: CC(C)(C)[O-]
Agent: O=C(O)/C=C/C(=O)O
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: COc1ccc2cc(N3CC4CCCC(C3)N4C)ccc2c1
Temperature: 25 °C

Procedure:
A mixture of 9-methyl-3,9-diaza-bicyclo[3.3.1]nonane (2.0 g, 14.3 mmol), 2-bromo-6-methoxynaphthalene (5.07 g, 21.4 mmol), palladacycle (100 mg, 0.11 mmol), potassium tert-butoxide (3.2 g, 28.5 mmol) and dioxane (30 ml) was stirred at reflux for 40 h. The mixture was cooled to room temperature. Water (50 ml) was added and the mixture was extracted with ethylacetate (3×30 ml). The crude product was purified by silica gel column chromatography using a solvent mixture of dichloromethane, methanol and aqueous ammonia (18:1:1%). The fumarate salt was precipitated from 1.1 eq of fumaric acid and a mixture of ethanol and diethylether (2:5). Yield 1.4 g (33%). Mp 190.0-198.3° C. LC-ESI-HRMS of [M+H]+ shows 297.1955 Da. Calc. 297.196688 Da, dev. −4 ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6](OC)=[O:7].O.[NH2:14][NH2:15]>CO>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:14][NH2:15])=[O:7])=[C:4]([OH:12])[CH:3]=1
Reactant: NN
Reactant: COC(=O)c1ccc(F)cc1O
Solvent: CO
Solvent: O
Product: NNC(=O)c1ccc(F)cc1O
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 4-fluorosalicylate (500 mg, 2.94 mmol, commercially available from e.g. Apollo, Alfa Aesar or ABCR) in methanol (15 ml) stirred under argon at room temp was added neat hydrazine monohydrate (0.722 ml, 14.69 mmol). The reaction mixture was stirred at 80° C. for 18 hr. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate (˜50 ml) and water (˜25 ml). The aqueous phase was extracted with ethyl acetate (2×25 ml) and the combined organic extracts washed with brine (25 ml), dried over sodium sulphate, evaporated in vacuo and dried (vacuum oven, 40° C., 24 hr) to afford the crude product as an off-white solid in 385 mg.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:9])=[C:4](I)[CH:5]=[CH:6][CH:7]=1.C([Mg]Cl)(C)C.O1CCCC1.C(OC([N:27]1[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1)=O)(C)(C)C.[Cl-].[NH4+].[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[C:3]([F:9])=[C:4]([C:30]2([OH:33])[CH2:31][CH2:32][NH:27][CH2:28][CH2:29]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1c(Cl)cccc1I
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2cccc(Cl)c2F)CCNCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 43.4 %

Procedure:
3-Chloro-2-fluoroiodobenzene (Tokyo Chemical Industry CO., LTD., 3.1 g) was dissolved in tetrahydrofuran (20 ml) and the mixture was cooled to 0° C. An isopropylmagnesium chloride-tetrahydrofuran solution (2M, 18 ml) was added, and the mixture was stirred for 3 hr. Then, 1-(tert-butoxycarbonyl)-4-piperidone (2 g) was added and the mixture was stirred for 3 hr. After completion of the reaction, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted three times with ethyl acetate. The organic layer was dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate (5:1-2:1)). Then, the residue was dissolved in 1,4-dioxane (30 ml) and 10% aqueous sulfuric acid (5 ml) was added thereto. The mixture was stirred with heating at 70° C. for 2 hr. After completion of the reaction, the reaction system was basified (pH=9) with a 1N aqueous sodium hydroxide solution and extracted three times with chloroform. The organic layer was dried and the solvent was evaporated under reduced pressure to give 4-(3-chloro-2-fluorophenyl)piperidin-4-ol (1.0 g, yield 44%).
Reaction SMILES: Br[C:2]1[C:3]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([NH:15][CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[O:14])=[CH:9][CH:8]=2)[S:5][CH:6]=1.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C([O-])([O-])=O.[K+].[K+].ClCCl>O1CCOCC1.O.CCOC(C)=O.CCCCCC>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[C:3]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([NH:15][CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[O:14])=[CH:9][CH:8]=2)[S:5][CH:6]=1
Reactant: CCC(CC)NC(=O)c1ccc(-c2scc(Br)c2CC(=O)OC)cc1
Reactant: OB(O)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCCCCC
Product: CCC(CC)NC(=O)c1ccc(-c2scc(-c3ccccc3Cl)c2CC(=O)OC)cc1
Yield: 74.1 %

Procedure:
Methyl [4-bromo-2-(4-{[(1-ethylpropyl)amino]carbonyl}phenyl)thien-3-yl]acetate (0.200 g, 0.5 mmol) was dissolved in dioxane (3 mL) and 2-chlorophenylboronic acid (0.156 g, 1.0 mmol). K2CO3 (0.207 g, 1.5 mmol) was dissolved in H2O (0.2 mL) and added to the dioxane. The solution was degassed by bubbling argon through the mixture for five minutes. {1,1′-Bis(diphenylphosphino)-ferrocene}dichloropalladium(II) complex with dichloromethane (1:1) (0.012 g, 0.015 mmol) was added and the mixture heated under argon to 70° C. for 3 hours (followed by TLC 15:1 hexane:EtOAc). The solvents were removed and the mixture partitioned between EtOAc and H2O. The EtOAc layer was dried (MgSO4) and absorbed onto silica gel. The product was purified by flash chromatography (20:1 hexane:EtOAc) to yield methyl [4-(2-chlorophenyl)-2-(4-{[(1-ethylpropyl)amino]carbonyl}phenyl)thien-3-yl]acetate (0.169 g) as a white solid. mp 57-59° C.; 1H NMR (500 MHz, DMSO-d6) δ: 0.87 (t, 6H, J=7.3 Hz), 1.50 (m, 2H), 1.55 (m, 2H), 3.35 (s, 3H), 3.53 (s, 2H), 3.75 (m, 1H), 7.31 (d, 1H, J=7.2 Hz), 7.43 (m, 3H), 7.59 (m, 3H), 7.96 (d, 2H, J=8.4 Hz), 8.12 (d, 1H, J=8.7 Hz). MS (ES) m/z456.1 ([M+H]+). MS (ES) m/z488.1 ([M+CH3OH+H]+). MS (ES) m/z 911.2 ([2M+H]+). Anal. Calcd for C25H26ClNO3S: C, 65.85; H, 5.75; N, 3.07. Found: C, 65.92; H, 5.96; N, 3.27.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([C:23]3[O:24][CH:25]=[CH:26][C:27]=3[CH3:28])=[O:22])[CH:15]=2)=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][N:3]=1.[OH-].[Na+].C(O)(=O)C.CCOC(C)=O>C1COCC1>[NH2:1][C:2]1[C:11]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([C:23]3[O:24][CH:25]=[CH:26][C:27]=3[CH3:28])=[O:22])[CH:15]=2)=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: COC(=O)c1cnc(N)c(C#Cc2cccc(NC(=O)c3occc3C)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cc(C(=O)O)cnc2N)c1
Temperature: 50 °C
Yield: 93.2 %

Procedure:
Methyl 6-amino-5-((3-(3-methylfuran-2-carboxamido)phenyl)ethynyl)nicotinate (0.550 g, 1.47 mmol) was dissolved in THF (15 mL) and then treated with 1.0 M NaOH (7.33 mL, 7.33 mmol). The reaction mixture was heated to 50° C. Once the reaction was done by TLC, the reaction was cooled to room temperature and then acidified with acetic acid. The reaction mixture was taken up in of EtOAc (˜15 mL) then extracted with H2O (2×15 mL). The water layer then was re-washed with EtOAc (˜15 mL) and the combined organic layers were dried over anhydrous Na2SO4(s). The mixture was then filtered and concentrated in vacuo to give the title compound (0.495 g, 1.37 mmol).
Reaction SMILES: Br[C:2]1[C:3]([F:28])=[C:4]([N:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]3[N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]=[CH:19][CH:18]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.[F:30][C:31]1([F:36])[CH2:35][CH2:34][NH:33][CH2:32]1.CC([O-])(C)C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C([O-])(O)=O.[Na+].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:30][C:31]1([F:36])[CH2:35][CH2:34][N:33]([C:2]2[C:3]([F:28])=[C:4]([N:8]3[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]4[N:21]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:20]=[CH:19][CH:18]=4)=[N:9]3)[CH:5]=[CH:6][CH:7]=2)[CH2:32]1
Reactant: COc1cn(-c2cccc(Br)c2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reactant: FC1(F)CCNC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1cn(-c2cccc(N3CCC(F)(F)C3)c2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 90 °C
Yield: 50.9 %

Procedure:
A mixture of 1-(3-bromo-2-fluorophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (221 mg, 0.5 mmol), 3,3-difluoropyrrolidine hydrochloride (86.1 mg, 0.6 mmol), NaOt-Bu (125 mg, 1.3 mmol), Xantphos (46.3 mg, 0.08 mmol) and Pd2(dba)3 (18.3 mg, 0.02 mmol) in 1,4-dioxane (2.5 mL) was heated to 90° C. for 24 h under N2. The mixture was diluted with saturated NaHCO3 aqueous solution, extracted with AcOEt, dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on basic silica gel (hexane/AcOEt=50/50 to 0/100) to yield the title compound (119 mg, 51% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 2.42-2.50 (2H, m), 3.56 (2H, t, J=7.4 Hz), 3.71-3.88 (5H, m), 6.43-6.54 (1H, m), 6.84-7.13 (3H, m), 7.27-7.49 (5H, m), 7.78 (1H, d, J=1.9 Hz), 8.47 (1H, d, J=2.3 Hz). Anal. Calcd for C24H20F3N5O2.0.2H2O: C, 61.20; H, 4.37; N, 14.87. Found: C, 61.36; H, 4.45; N, 14.56.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C@@H:13]2[O:15][C@H:14]2[CH2:16][CH2:17][CH2:18][C@H:19]([NH:31]C(=O)OCC2C=CC=CC=2)[C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=2[Br:30])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[F:12][C:9]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([C@H:13]([C@@H:14]2[CH2:16][CH2:17][CH2:18][C@@H:19]([C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][C:21]=3[Br:30])[NH:31]2)[OH:15])[CH:4]=[C:3]([C:2]([F:42])([F:1])[F:43])[CH:8]=1
Reactant: O=C(N[C@@H](CCC[C@@H]1O[C@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(C(F)(F)F)ccc1Br)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O[C@H](c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CCC[C@@H](c2cc(C(F)(F)F)ccc2Br)N1
Temperature: 125 °C
Yield: 69.6 %

Procedure:
To benzyl {(1S)-4-{(2S,3S)-3-[3,5-bis(trifluoromethyl)phenyl]oxiran-2-yl}-1-[2-bromo-5-(trifluoromethyl)phenyl]butyl}carbamate (500 mg, 0.731 mmol) in DMF (2 mL) was added DBU (111 mg, 0.731 mmol). The system was heated to 125° C. for 6 hours. The solvent was removed in vacuo. The reaction was diluted with ethyl acetate and water. The organic was dried over sodium sulfate, filtered and concentrated. The resultant oil was purified by column chromatography to yield (R)-[3,5-bis(trifluoromethyl)phenyl]{(2S,6S)-6-[2-bromo-5-(trifluoromethyl)phenyl]piperidin-2-yl}methanol (280 mg, 0.509 mmol). 1H NMR (500 MHz, CDCl3) δ7.9 (s, 2H), 7.81 (d, J=5.4 Hz, 2H), 7.64 (d, J=8.3 Hz, 1H), 7.35 (d, J=8.3 Hz, 1H), 5.14 (d, J=8.2 Hz, 1H), 4.51 (m, 1H), 3.16 (m, 1H), 2.06 (m, 1H), 1.95 (m, 1H), 1.80 (m, 2H), 1.62 (m, 1H), 1.29 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11](O)[CH2:12][CH2:13][OH:14].CO.C1C(=O)N(Br)C(=O)C1>ClCCl>[CH3:10][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[O:14][CH2:13][CH2:12][CH2:11][O:9]1
Reactant: OCCCO
Reactant: CC(=O)c1ccc(C)cc1
Agent: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(C2(C)OCCCO2)cc1
Temperature: 25 °C
Reaction time: 70 h
Yield: 25 %

Procedure:
To a stirred mixture of 4-methylacetophenone (1.3 mL, 10 mmol), triethylformate (2.0 mL, 12 mmol), 1,3-propanediol (2.2 mL, 30 mmol) and dry methanol (1.2 mL) in dry dichloromethane (50 mL) was added NBS (53 mg, 0.30 mmol). The mixture was protected from light and stirred at room temperature under an inert atmosphere of nitrogen for 70 h. After the mixture was washed with saturated sodium bicarbonate solution (20 mL), the aqueous phase was extracted with dichloromethane (3×30 mL). The combined organic solution was washed with water (2×20 mL), brine (1×20 mL), then dried (Na2SO4) and concentrated under reduced pressure. Flash column chromatography of the residue, eluting with 37% aqueous ammonia:ether:hexane (0.02:1:6) afforded 2-methyl-2-(4-methylphenyl)-1,3-dioxane (22) as a colourless oil (480 mg, 24%). 1H nmr (200 MHz, CDCl3) 1.50 (s, 3H, CH3), 1.96-2.25 (m, 2H, OCH2CH2CH2O), 2.37 (s, 3H, ArCH3), 3.70-4.00 (m, 4H, OCH2CH2CH2O), 7.23 (d, J=8.3 Hz, 2H, 2×ArH), 7.33 (d, J=8.3 Hz, 2H, 2×ArH).