Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:29]([C:30]#[N:31])=[CH:28][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[C:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])=[CH:12][CH:11]=3)[NH:9][C:5]=2[CH:4]=1)#[N:2].[CH2:32]1[CH2:42]CN2C(=NCCC2)C[CH2:33]1.ICCC>CN1C(=O)CCC1>[C:1]([C:3]1[C:29]([C:30]#[N:31])=[CH:28][C:6]2[N:7]([CH2:33][CH2:32][CH3:42])[C:8]([C:10]3[CH:11]=[CH:12][C:13]([C:16]#[C:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:19]([CH3:20])[CH3:21])[CH:22]([CH3:23])[CH3:24])=[CH:14][CH:15]=3)=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(C)[Si](C#Cc1ccc(-c2nc3cc(C#N)c(C#N)cc3[nH]2)cc1)(C(C)C)C(C)C
Solvent: CCCI
Solvent: CN1CCCC1=O
Product: CCCn1c(-c2ccc(C#C[Si](C(C)C)(C(C)C)C(C)C)cc2)nc2cc(C#N)c(C#N)cc21
Temperature: 120 °C
Reaction time: 0.03 h
Yield: 60.6 %

Procedure:
A 20 mL vial was charged with 5d (763 mg, 1.79 mmol), and NMP (10 mL). The vial was capped with a septum and placed in an oil bath heated to 120° C. DBU (267 μL, 1.79 mmol) was added, and the mixture was stirred for 2 min. Then iodopropane (175 μL, 1.79 mmol) was added and the mixture was stirred for 20 min. A second dose of DBU (267 μL, 1.79 mmol), followed by iodopropane (175 μL, 1.79 mmol), was added, and 20 min later, a third identical round of DBU and iodopropane was again added. After the third round of reagents was added and the mixture was stirred for 20 min, the reaction mixture was removed from heat and added to ethyl acetate. The solution was washed three times with water, then washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was chromatographed (silica, CHCl3), yielding a colorless solid (506 mg, 61%): mp 242-243° C.; 1H NMR (d6-acetone) δ 0.89 (t, J=7.2 Hz, 3H), 1.17-1.19 (m, 21H), 1.86-1.96 (m, 2H), 4.53 (t, J=7.6 Hz, 2H), 7.75 (d, J=8.0 Hz, 2H), 7.91 (d, J=8.0 Hz, 2H), 8.36 (s, 1H), 8.50 (s, 1H); 13C NMR (d6-acetone) δ 10.5, 11.3, 18.4, 23.2, 47.1, 93.1, 106.6, 108.1, 108.3, 116.8, 116.9, 118.3, 125.8, 126.3, 129.6, 129.9, 132.5, 138.5, 145.4, 158.4; Anal. Calcd for C29H34N4Si: C, 74.63; H, 7.34; N, 12.01. Found: C, 74.75; H, 7.32; N, 12.01.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.ClCCl.Cl[Si](C)(C)C.[C:26](Cl)(=[O:30])[C:27]([CH3:29])=[O:28]>C(N(CC)CC)C>[O:30]=[C:26]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1)[C:27](=[O:28])[CH3:29]
Reactant: CC(=O)C(=O)Cl
Reactant: Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)C(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Yield: 44 %

Procedure:
Using the method for the preparation of the side chain acid in Example 3, 11.5 g (50 mmol) of 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid, 500 ml of dichloromethane, 21.0 ml (150 ml) of triethylamine, 20 ml (158 mmol) of chlorotrimethylsilane, and 8.0 g (75 mmol) of pyruvic acid chloride, [J. Org. Chem., 35, 3972 (1970)] gives 6.6 g of 6-[4(1,2-dioxopropylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid after recrystallization from N,N-dimethylacetamide; mp>280°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12]Cl)[CH:6]=[CH:5]2.C[N:15](C=O)C.CC#N.C1(=O)NC(=O)C2=CC=CC=C12.[K].NN>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][NH2:15])[CH:6]=[CH:5]2
Reactant: CN(C)C=O
Reactant: ClCc1ccc2cc(Br)ccc2n1
Agent: NN
Agent: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CC#N
Product: NCc1ccc2cc(Br)ccc2n1
Temperature: 60 °C

Procedure:
To 4a (440 mg, 1.7 mmol) in 1:1 DMF/MeCN (3 mL) at room temperature was added potassium phthalimide (350 mg, 1.9 mmol), and the reaction was heated to 60° C. overnight. The mixture was poured into water and filtered, and the solid was suspended in EtOH (10 mL). Hydrazine (82 mg, 2.5 mmol) was added, and the mixture was heated to 70° C. for 30 minutes. The reaction was then concentrated, and the crude material, 4b, was used directly in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:12]([CH3:13])=[CH:11][N:10]=[C:9](O)[C:8]1=[O:15])=[O:5])[CH3:2].P(Br)(Br)([Br:18])=O.[OH-].[NH4+]>C(Cl)(Cl)Cl.ClCCl>[Br:18][C:9]1[C:8](=[O:15])[N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:12]([CH3:13])=[CH:11][N:10]=1
Reactant: O=P(Br)(Br)Br
Reactant: CCOC(=O)Cn1c(C)cnc(O)c1=O
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cn1c(C)cnc(Br)c1=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
A slurry of 1-(ethoxycarbonylmethyl)-3-hydroxy-6-methylpyrazinone (4.24 g, 20 mmol), as prepared in the preceding step, and phosphorous oxybromide (6.3 g, 22 mmol) in chloroform (15 mL) was stirred at 50° C. under nitrogen for 2 hours, then allowed to cool to room temperature overnight. The reaction mixture was diluted with dichloromethane and ice-water, basified with ammonium hydroxide, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over Na2SO4, treated with activated carbon, filtered and concentrated. The solid was collected, washed with 15% ethyl acetate in hexane, and dried under high vacuum to give the title compound as an orange colored solid (5.1 g, 93%). 1H NMR (400 MHz, CDCl3) δ 7.06 (s, 1H), 4.77 (s, 2H), 4.26 (q, 2 H, J=7.1 Hz), 2.24 (s, 3H), 1.31 (t, 3H, J=7.1 Hz).
Reaction SMILES: [CH2:1]1[CH2:7][CH:6]([C:8]([NH2:10])=[O:9])[C:4](=O)[CH2:3][CH2:2]1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC=CC=1>O>[CH2:11]([NH:18][C:4]1[CH2:3][CH2:2][CH2:1][CH2:7][C:6]=1[C:8]([NH2:10])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC(=O)C1CCCCC1=O
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: NC(=O)C1=C(NCc2ccccc2)CCCC1

Procedure:
A mixture of cyclohexanone-2-carboxamide (U.S. Pat. No. 4,169,952 to du Pont de Nemours, (1979)) (10.0 g), benzylamine (8.4 g), toluene (35 mL) and molecular sieves (Union Carbide 3A, 2 g) was refluxed for 2 h in a Dean-Stark water separator. The reaction mixture was filtered, and the filtrate was evaporated. The residue was crystallized from light petroleum to give the title compound (16 g). Mp 73-74° C.
Reaction SMILES: [Na].CS(C)=O.[Cl:6][C:7]1[CH:8]=[C:9]([N:13]2[CH:17]=[N:16][C:15]([OH:18])=[N:14]2)[CH:10]=[CH:11][CH:12]=1.Br[CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CO>[Cl:6][C:7]1[CH:8]=[C:9]([N:13]2[CH:17]=[N:16][C:15]([O:18][CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:26])=[N:14]2)[CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ncn(-c2cccc(Cl)c2)n1
Agent: [Na]
Solvent: CO
Solvent: CS(C)=O
Product: CCOC(=O)C(C)Oc1ncn(-c2cccc(Cl)c2)n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 29.4 %

Procedure:
A 2.2 g portion of sodium was dissolved in 75 ml of methanol and the solution was added to 100 ml of dimethylsulfoxide. To that was added 19.2 g of 1-(3-chlorophenyl)-3-hydroxy-1,2,4-1H-triazole, and the mixture was stirred on the steam bath for 4 hours. To it was then added 17.7 g of ethyl 2-bromopropionate, and heating was continued for 2 hours more. The mixture was then cooled and poured over ice-water, and the solid was collected, dried and recrystallized from ethanol and then from toluene to obtain 8.5 g of the desired product, m.p. 70°-72°.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[C:47]1([CH2:53][CH2:54][C:55](Cl)=[O:56])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(N(CC)CC)C>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH:46][C:55](=[O:56])[CH2:54][CH2:53][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH:43]=[CH:44][CH:45]=2)=[N:8]1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCc1ccccc1)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol) in 2.5 mL of tetrahydrofuran was added 3-phenyl propanoyl chloride (0.084 g, 0.498 mmol), followed by triethyl amine (0.173 mL, 1.24 mmol). The reaction was stirred at room temperature for 2 hours. The reaction mixture was then partitioned between ethyl acetate and water. (Yield not calculated) ES-MS (m/z) 735 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]([CH2:21][CH3:22])[CH:4]([C:6]1[N:10]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[N:9]=[CH:8][CH:7]=1)O)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:68]=[N+:69]=[N-:70])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[N:68]([CH:4]([C:6]1[N:10]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[N:9]=[CH:8][CH:7]=1)[CH:3]([CH2:21][CH3:22])[CH2:1][CH3:2])=[N+:69]=[N-:70]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCC(CC)C(O)c1ccnn1S(=O)(=O)c1ccc(C)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(CC)C(N=[N+]=[N-])c1ccnn1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.2 %

Procedure:
To 2-ethyl-1-{1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-5-yl}butan-1-ol (0.250 g, 0.778 mmol) in THF (10 mL) at 0° C. was added triphenylphosphine (0.307 g, 1.17 mmol), diethyl azodicarboxylate (0.18 mL, 1.2 mmol), and diphenylphosphoryl azide (0.25 mL, 1.2 mmol). The reaction mixture was warmed to room temperature and stirred for 20 h. The solvent was removed in vacuo and the resulting residue was purified by column chromatography (EtOAc/hexanes, 15:85) to give 0.260 g (97%) of 5-(1-azido-2-ethylbutyl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrazole with an aromatic impurity as judged by 1H NMR. This compound was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11](I)[C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH3:16][C:17]1([CH3:24])[C:21]([CH3:23])([CH3:22])[O:20][BH:19][O:18]1>O1CCOCC1.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]([B:19]2[O:20][C:21]([CH3:23])([CH3:22])[C:17]([CH3:24])([CH3:16])[O:18]2)[C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)(C)OC(=O)c1c(F)cccc1I
Reactant: CC1(C)OBOC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1c(F)cccc1B1OC(C)(C)C(C)(C)O1
Temperature: 165 °C
Reaction time: 0.17 h
Yield: 31 %

Procedure:
To a degassed mixture of tert-butyl 2-fluoro-6-iodobenzoate (161 mg, 0.5 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.1 mL, 0.6 mmol) and TEA (0.25 mL, 1.5 mmol) in 2 mL dioxane, was added Pd(PPh3)2Cl2 (7 mg, 0.01 mmol). The mixture was stirred at 165° C. for 10 min in a microwave oven. The mixture was diluted with EtOAc, washed with sat. NH4C1, H2O and brine, dried over (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (0-10% EtOAc/hexanes gradient) to afford 50 mg (45%) of Intermediate 436.2.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([S:12](Cl)(=[O:14])=[O:13])[CH2:9][CH2:10][CH3:11].I.[CH:17]12[CH2:28][CH2:27][CH:20]([CH2:21][CH:22]1[C:23]([O:25][CH3:26])=[O:24])[CH2:19][NH:18]2>C(Cl)(Cl)Cl>[CH2:8]([S:12]([N:18]1[CH2:19][C@H:20]2[CH2:27][CH2:28][C@@H:17]1[C@H:22]([C:23]([O:25][CH3:26])=[O:24])[CH2:21]2)(=[O:14])=[O:13])[CH2:9][CH2:10][CH3:11]
Reactant: COC(=O)C1CC2CCC1NC2
Reactant: CCCCS(=O)(=O)Cl
Agent: I
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCS(=O)(=O)N1C[C@H]2CC[C@@H]1[C@H](C(=O)OC)C2
Temperature: 25 °C
Reaction time: 13 h

Procedure:
Triethylamine (0.51 mL, 3.7 mmol) and 1-butanesulfonyl chloride (0.233 mL, 1.84 mmol) were added to a chloroform (5 mL) solution of methyl 2-azabicyclo[2.2.2]octane-6-carboxylate hydroiodide (298 mg, 0.989 mmol) synthesized according to the method described in literature (Chem. Pharm. Bull. 53(1) 81-85 (2005)), and the mixture was stirred at room temperature for 13 hours. The reaction mixture was washed once with distilled water, and once with a saturated sodium hydrogen carbonate aqueous solution. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was then purified using silica gel column chromatography to obtain the target (157 mg, 55%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[CH3:24][C:25]1([CH3:33])[CH2:30][C:29](=[O:31])[CH2:28][C:27](=[O:32])[CH2:26]1.CC(C)(O)C#N>ClCCl>[CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([CH:28]2[C:29](=[O:31])[CH2:30][C:25]([CH3:33])([CH3:24])[CH2:26][C:27]2=[O:32])=[O:10])=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)(=[O:4])=[O:3]
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)c([N+](=O)[O-])c1
Agent: CC(C)(O)C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CC(=O)C(C(=O)c2ccc(S(C)(=O)=O)cc2[N+](=O)[O-])C(=O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.8 %

Procedure:
A solution of 4-methylsulphonyl-2-nitrobenzoyl chloride (9.62 g) in dry dichloromethane (50 ml) was added to a stirred solution of triethylamine (5.6 ml) and 5,5-dimethylcyclohexane-1,3-dione (5 g) in dry dichloromethane (70 ml) during 30 minutes and the reaction mixture stirred at ambient temperature for 4 hours. Triethylamine (15.3 ml) and acetone cyanohydrin (0.5 ml) were added successively and the reaction mixture stirred at ambient temperature for 18 hours. The reaction mixture was washed successively with 2N hydrochloric acid (2×50 ml) and water (2×50 ml), dried over magnesium sulphate and evaporated under reduced pressure to give a yellow glass which was recrystallised from methanol (20 ml) to give 2-(4-methylsulphonyl-2-nitrobenzoyl)-5,5-dimethylcyclohexane-1,3-dione (6.4 g), m.p. 156.5°-158° C., as a yellow crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)[CH:5]=[N:6][CH:7]=1.O.NN>CCO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH2:9])[CH:5]=[N:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cncc(Br)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1cncc(Br)c1
Yield: 115.8 %

Procedure:
A solution of 2-((5-bromopyridin-3-yl)methyl)isoindoline-1,3-dione (LIII) (1.9 g, 6.0 mmol, 1 eq) and hydrazine hydrate (2.0 g, 40 mmol, 6 eq) in EtOH (20 mL) was heated at 70° C. for 3 h. The mixture was filtered through a Celite® pad and the filtrate was concentrated in vacuo, the crude product was dissolved in 1N HCl solution (15 mL) and concentrated to dryness, then it was washed with acetone (10 mL×3), the precipitate was collected by filtration, dried in vacuo to give (5-bromopyridin-3-yl)methanamine (LIV) (1.3 g, 6.95 mmol, 97.7% yield) as a white solid. 1H NMR (D2O, 500 MHz) δ ppm 4.34 (s, 2H), 8.56 (s, 1H), 8.75 (d, J=1.2 Hz, 1H), 8.91 (d, J=1.6 Hz, 1H). ESIMS found for C6H7BrN2 m/z 187 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH:18]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1.C([O:23][B:24](OC(C)C)[O:25]C(C)C)(C)C.[Li]CCCC>C1(C)C=CC=CC=1.C1COCC1>[Cl:19][C:5]1[CH:4]=[CH:3][C:2]([B:24]([OH:25])[OH:23])=[CH:18][C:6]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: FC(F)(F)c1ccc(Oc2cc(Br)ccc2Cl)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OB(O)c1ccc(Cl)c(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: -40 °C
Reaction time: 1 h
Yield: 120.8 %

Procedure:
To a solution of 2-(5-bromo-2-chlorophenoxy)-5-(trifluoromethyl)pyridine (2.6 g, 7.3 mmol) and triisopropylborate (2.0 mL, 8.76 mmol) in toluene (15 mL) and THF (7 mL) under a N2 atmosphere was added n-BuLi (6.8 mL, 10.95 mmol) while maintaining the reaction at −70° C. The reaction was stirred for 1 h at −40° C. Gradually the temperature was increased to −20° C. and then 0° C. The reaction was quenched with 2N HCl and allowed to warm to RT. The reaction mixture was concentrated and extracted with EtOAc. The organic extract was dried over Na2SO4 and concentrated under reduced pressure to give the title compound (2.8 g). 1H NMR (500 MHz, DMSO-d6): δ 8.56 (s, 1H), 8.29 (m, 3H), 7.94 (s, 1H), 7.81 (d, J=7.9 Hz, 1H), 7.36 (d, J=8.05 Hz, 2H); m/z (316.4, M− H−).
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.[O:25]1[CH2:34][CH:26]1[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[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]([CH2:34][CH:26]([OH:25])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=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: c1ccc(CC2CO2)cc1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1n(CC(O)Cc2ccccc2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 85 °C
Yield: 70.4 %

Procedure:
To a stirred solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (500 mg, 1.4 mmol), prepared as described in Example 1, in 7 mL of DMF was added 2,3-epoxypropylbenzene (0.18 mL, 1.4 mmol) and 0.39 g of K2CO3. The resulting red solution was heated to 85° C. for 27 h and, upon cooling to room temp, the mixture was diluted with 200 mL of ethyl acetate and 200 mL of 1N HCL. The layers were extracted, and the organic layer was washed with 200 mL of saturated aqueous NaCl. The organic layer was dried over MgSO4, filtered and evaporated to a yellow oil. The material was purified by silica gel column chromatography using a gradient of 0-100% ethyl acetate/hexanes to give 484 mg of racemic 7,8-bis(4-chlorophenyl)-2-(2-hydroxy-3-phenylpropyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one as a yellow solid containing 15% starting material 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one. Separation of enantiomers was performed on 200 mg of material using Chiracel OD 5 cm×50 cm 20 micron column, flow rate 50 mL/min isocratic 65% heptane/17.5% ethanol/17.5% methanol, monochrome detection at 220 nm. Fraction A was collected at 49 min post injection to give 47 mg of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one enantiomer A as a yellow solid; Fraction B was collected at 55 min post injection to give 45 mg of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one enantiomer B as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]1[CH:12]=[C:11]([CH3:13])[CH2:10][CH2:9][C:3]21[CH:7]([OH:8])[O:6][CH2:5][CH2:4]2.[CH3:14]O>>[CH3:14][O:8][CH:7]1[C:3]2([CH2:9][CH2:10][C:11]([CH3:13])=[CH:12][CH:2]2[CH3:1])[CH2:4][CH2:5][O:6]1
Reactant: CO
Reactant: CC1=CC(C)C2(CCOC2O)CC1
Product: COC1OCCC12CCC(C)=CC2C

Procedure:
The title compound was prepared from 6,8-dimethyl-2-oxaspiro[4.5]dec-7-en-1-ol and methanol according to Example 1, producing 2 isomers in a ratio of 7:3.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:14][C:9]2=[CH:10][N:11]=[CH:12][CH:13]=[C:8]2[C:7]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][C:17]=1[F:23])=[O:5])[CH3:2].[I-:24].[Na+].CN[C@@H]1CCCC[C@H]1NC>O1CCOCC1.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[S:14][C:9]2=[CH:10][N:11]=[CH:12][CH:13]=[C:8]2[C:7]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:24])=[CH:18][C:17]=1[F:23])=[O:5])[CH3:2]
Reactant: [I-]
Reactant: CCOC(=O)c1sc2cnccc2c1Nc1ccc(Br)cc1F
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1sc2cnccc2c1Nc1ccc(I)cc1F
Temperature: 105 °C
Reaction time: 24 h
Yield: 85.2 %

Procedure:
A mixture of 3-(4-bromo-2-fluoro-phenylamino)-thieno[2,3-c]pyridine-2-carboxylic acid ethyl ester (288 mg, 0.73 mmol), copper (1) iodide (7 mg, 0.036 mmol), sodium iodide (219 mg, 1.46 mmol) and trans-N,N′-dimethyl-1,2-cyclohexane diamine (10.4 mg, 0.073 mmol) in 1,4-dioxane (1.0 ml) was heated at 105° C. for 24 hours under an argon atmosphere. Copper (I) iodide (7 mg, 0.036 mmol) and trans-N,N′-dimethyl-1,2-cyclohexane diamine (10.4 mg, 0.073 mmol) were added and heating continued for a further 24 hours. The reaction was cooled to room temperature and the mixture was partitioned between DCM (30 ml), concentrated aqueous ammonia (2 ml) and water (13 ml). The organic layer was isolated, dried over sodium sulphate, filtered and evaporated then the residue was purified by flash chromatography (Si-SPE, DCM) to afford the title compound as a yellow solid (275 mg, 85%). LCMS (method B): RT=4.23 min, M+H+=443.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[C-:13]#[N:14].[Na+]>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.C1C=CC=CC=1.O>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[CH:12][C:3]([CH2:2][C:13]#[N:14])=[CH:4][CH:5]=1
Reactant: [C-]#N
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)c1ccc(CC#N)cc1
Yield: 60.1 %

Procedure:
A mixture of methyl 4-(bromomethyl)benzoate (10.09 g, 44.05 mmol), sodium cyanide (6.42 g, 131 mmol) and cetyltrimethylammonium bromide (1.59 g, 4.36 mmol) in benzene/water (2:1, 187.5 mL) was heated at reflux for 5 h then extracted with CH2Cl2 3×50 mL). The organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure. Purification of the crude material by chromatography on silica gel (35% EtOAc/hexanes) gave 4-cyanomethyl-benzoic acid methyl ester as a colourless solid (4.64 g, 60%). 1H NMR (CDCl3) δ 3.82 (s, 2H), 3.93 (s, 3H), 7.42 (d, 2H, J=9 Hz), 8.06 (d, 2H, J=9 Hz).
Reaction SMILES: [OH:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:8]1([Mg]Cl)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl-].[NH4+]>ClCCl.O=[Mn]=O>[C:8]1([CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][N:2]2[OH:1])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ON1CCCCC1
Reactant: Cl[Mg]c1ccccc1
Agent: O=[Mn]=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: ON1CCCCC1c1ccccc1
Reaction time: 1 h
Yield: 37.6 %

Procedure:
Activated MnO2 (1.29 g, 14.8 mmol) was added to a solution of N-hydroxypiperidine (0.50 g, 4.95 mmol) in dichloromethane (25 mL) at 0° C. and the mixture was stirred for 1 h. The reaction mixture was filtered through a pad of Celite™ and Na2SO4. The filtrate was added dropwise to a solution of phenylmagnesium chloride (2.0 M in tetrahydrofuran, 4.95 mL, 9.90 mmol) at −10° C. The reaction mixture was stirred at 0° C. for 0.5 h and then saturated aqueous ammonium chloride solution (25 mL) and dichloromethane (25 mL) were added. The aqueous phase was separated and extracted with dichloromethane (2×30 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The crude product was subjected to flash chromatography on SiO2 eluting with 30% diethyl ether in hexanes to give the title compound (0.330 g, 38%) as a white crystalline solid.