Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]1[CH2:24][O:23][CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:21][CH2:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Br:31]N1C(=O)CCC1=O.C(=O)([O-])[O-].[Ba+2]>ClCCl>[C:22]([O:21][CH2:20][CH:19]([CH2:24][Br:31])[CH2:18][O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:23])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCCCCCCCCCCCCOCC1COC(c2ccccc2)OC1
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCOCC(CBr)COC(=O)c1ccccc1
Temperature: 0 °C
Yield: 79.2 %

Procedure:
A mixture of 14.703 g (35.2 mM) of 5-n-hexadecyloxymethyl-2-phenyl-1,3-dioxane n2, 6.90 g (38.4 mM) of N-bromosuccinimide and 700 mg of barium carbonate in 200 ml of dichloromethane is heated under refluxing for 1 hour. After cooling, the mixture is poured into an ice cooled saturated aqueous sodium bicarbonate and the product is isolated by dichloromethane extraction. The dichloromethane layer is washed with 10% aqueous sodium thiosulfate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated. Purification of the residue by column silica gel chromatography using n-hexane-ethyl acetate (9:1) mixture as an eluent affords 13.843 g (79.3% yield) of the titled compound n3.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=[O:5])C.[CH3:28][C:29]1([CH3:44])[CH2:34][N:33]([CH3:35])[CH2:32][CH2:31][N:30]1[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[CH3:28][C:29]1([CH3:44])[CH2:34][N:33]([CH3:35])[CH2:32][CH2:31][N:30]1[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([NH:43][C:4]([C:6]2[C:7]3[N:8]=[CH:9][CH:10]=[N:11][C:12]=3[C:13]([C:16]3[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=3[F:22])=[CH:14][CH:15]=2)=[O:5])=[N:41][CH:42]=1
Reactant: CN1CCN(Cc2ccc(N)nc2)C(C)(C)C1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4(C)C)cn3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 6 h

Procedure:
The title compound was prepared in analogy to the procedures described in Example 115 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1), 5-(2,2,4-trimethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Step 110.1), 1.5 equiv of trimethyl aluminum, stirring the reaction mixture for 6 h at 80° C. and pouring it onto a saturated aqueous solution of NaHCO3 and DCM. Title compound: ESI-MS: 563.1 [M+H]+; tR=3.55 min (System 1); TLC: Rf=0.08 (DCM/MeOH, 95:5).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:53][O:54][C:55]1[CH:56]=[C:57]([C:63]2[CH:68]=[CH:67][CH:66]=[C:65]([NH2:69])[CH:64]=2)[CH:58]=[CH:59][C:60]=1[O:61][CH3:62]>CN(C=O)C>[CH3:53][O:54][C:55]1[CH:56]=[C:57]([C:63]2[CH:68]=[CH:67][CH:66]=[C:65]([NH:69][C:24]([C:19]3[C:20](=[O:23])[O:21][C:22]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][C:13]=4[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:64]=2)[CH:58]=[CH:59][C:60]=1[O:61][CH3:62]
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Reactant: COc1ccc(-c2cccc(N)c2)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc(NC(=O)c3cc4cccc(OC(F)(F)F)c4oc3=O)c2)cc1OC
Temperature: 25 °C
Yield: 66.6 %

Procedure:
DIEA (0.0144 mL, 0.072 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.018 g, 0.065 mmol) and HATU (0.027 g, 0.072 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3′,4′-Dimethoxy-biphenyl-3-ylamine (0.015 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.021 g of product in 65% yield: LCMS (ESI) m/z 486 (MH+).
Reaction SMILES: C([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34]C=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)C.[N:40]1([C:44](=O)[CH2:45]Cl)[CH2:43][CH2:42][CH2:41]1>>[N:40]1([CH2:44][CH2:45][O:10][C:8]2[CH:7]=[CH:6][C:36]([CH2:37][CH2:32][CH2:31][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=3[CH:14]3[CH2:23][CH2:22][C:21]4[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=4[CH2:15]3)=[CH:35][CH:34]=2)[CH2:43][CH2:42][CH2:41]1
Reactant: O=C(CCl)N1CCC1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1cc(NCCCc2ccc(OCCN3CCC3)cc2)c(C2CCc3cc(O)ccc3C2)cc1OC
Yield: 9.7 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 1-azetidin-1-yl-2-chloroethanone (9.4 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (0.9 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[F:8][C:9]([F:39])([F:38])[C:10]1[CH:11]=[C:12]([C:16]2[CH:37]=[CH:36][C:19]3[NH:20][C:21]([NH:23][C:24]([C:26]4[N:27]=[C:28]5[CH:33]=[CH:32][C:31](Cl)=[N:30][N:29]5[CH:35]=4)=[O:25])=[N:22][C:18]=3[CH:17]=2)[CH:13]=[CH:14][CH:15]=1.O>CN(C=O)C>[F:8][C:9]([F:39])([F:38])[C:10]1[CH:11]=[C:12]([C:16]2[CH:37]=[CH:36][C:19]3[NH:20][C:21]([NH:23][C:24]([C:26]4[N:27]=[C:28]5[CH:33]=[CH:32][C:31]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[N:30][N:29]5[CH:35]=4)=[O:25])=[N:22][C:18]=3[CH:17]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Nc1nc2cc(-c3cccc(C(F)(F)F)c3)ccc2[nH]1)c1cn2nc(Cl)ccc2n1
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc2nc(C(=O)Nc3nc4cc(-c5cccc(C(F)(F)F)c5)ccc4[nH]3)cn2n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-methoxy-ethanol (0.013 mL) in dry DMF (0.25 mL), sodium hydride (8 mg, 60% dispersion in mineral oil) was added, and the mixture was stirred at room temperature for 20 minutes under nitrogen. 6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide (30 mg) was added to the reaction mixture, and the mixture was warmed to 70° C. The reaction was monitored by LCMS for 1 hour until substantially complete. After cooling the reaction mixture, 10 mL of water was added and the reaction mixture was stirred for 10 minutes. The reaction was then filtered through a fine fritted funnel and the crude product was washed with water. After air drying, the product was purified by column chromatography (pre-packed silica column) using a gradient of 0 to 6% 2M ammonia-methanol in DCM. 20 mg of 6-(2-methoxy-ethoxy)-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide was obtained. LCMS (m/z): 497.8. 1H NMR (400 MHz, DMSO-d6) δ 8.83 (1H, s) 8.14 (1H, d) 7.93-8.03 (2H, m) 7.83 (1H, s) 7.67-7.74 (2H, m) 7.57-7.63 (1H, m) 7.51 (1H, dd) 7.10 (1H, d) 4.42-4.49 (2H, m) 3.70-3.76 (2H, m) 3.32-3.34 (3H, m).
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:14]=2)[C:9]1=[O:21])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:14]=2)[C:9]1=[O:21]
Reactant: O=[O+][O-]
Reactant: CC=CCC1Cc2ccc(C(C)(C)C)cc2C1=O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)c1ccc2c(c1)C(=O)C(CC=O)C2
Reaction time: 0.58 h
Yield: 92 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 35 minutes while stirring through a solution, cooled to -70°, of 7.35 g of (RS)-2-(2-buten-1-yl)-6-tert-butyl-1-indanone in 150 ml of anhydrous dichloromethane and 30 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 3.36 ml of dimethyl sulfide, the mixture was stirred at room temperature for 17 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 100 ml of dichoromethane and, after the addition of 15 ml of water and 15 ml of trifluoroacetic acid, stirred at room temperature for 3 hours. The mixture was subsequently poured into 100 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 150 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 6.44 g (92%) of (RS)-2-(2-oxoethyl)-6-tert-butyl-1-indanone were obtained as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[C:7]([C@H:20]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:6]([CH3:31])=[CH:5]2.O=[C:33]([C:39]1C2C(C3C=CC=CC=3C=1OS(C(F)(F)F)(=O)=O)=CC=CC=2)[C:34](OCC)=O>>[C:27]([O:26][C@@H:20]([C:7]1[C:6]2[C:5]([C:4]3[CH:3]=[CH:2][CH:11]=[CH:10][C:9]=3[C:8]=1[O:12][S:13]([C:16]([F:17])([F:18])[F:19])(=[O:14])=[O:15])=[CH:39][CH:33]=[CH:34][CH:31]=2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH3:29])([CH3:28])[CH3:30]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(Br)ccc2c1OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)C(=O)c1c(OS(=O)(=O)C(F)(F)F)c2ccccc2c2ccccc12
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(OS(=O)(=O)C(F)(F)F)c2ccccc2c2ccccc12

Procedure:
Prepared by the similar method to make (S)-ethyl 2-(6-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-tert-butoxyacetate in Example 20, using ethyl 2-oxo-2-(10-(trifluoromethylsulfonyloxy)phenanthren-9-yl)acetate instead of ethyl 2-(6-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate. 1H-NMR: 400 MHz, (CDCl3) δ: 8.74-8.69 (m, 2H), 8.41 (d, J=4.4 Hz, 1H), 8.19 (d, J=4.2 Hz, 1H), 7.79-7.61 (m, 4H), 6.00 (s, 1H), 4.189-4.14 (m, 1H), 4.05-4.00 (m, 1H), 1.25 (s, 9H), 1.03 (t, J=7 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].CI.[C:14](=O)([O-])O.[K+]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: Cc1cccc(Br)c1C(=O)O
Reactant: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1c(C)cccc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-bromo-6-methylbenzoic acid (5.02 g) and methyl iodide (2.9 mL) in N,N′-dimethylformamide (30 mL) was added powdered potassium hydrogen carbonate (4.67 g). The mixture was stirred at ambient temperature for 16 hours and concentrated. The concentrate was partitioned between ethyl acetate and water. The extract was washed with brine and concentrated, and the concentrate was purified by flash chromatography on silica gel with 60% ethyl acetate in hexanes.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:35])[F:34])=[O:26])[CH2:21][CH2:20]2)=[N:17][CH:18]=1>ClCCl.C(N(C(C)C)CC)(C)C>[C:4]1([CH2:3][CH2:2][C:1]([NH:12][C:13]2[CH:18]=[N:17][C:16]([N:19]3[CH2:20][CH2:21][N:22]([C:25](=[O:26])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]([F:36])([F:35])[F:34])[CH2:23][CH2:24]3)=[CH:15][CH:14]=2)=[O:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nc1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCc1ccccc1)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 7.6 %

Procedure:
Hydrocinnamoyl chloride (0.037 mL, 0.25 mmol) in dichloromethane was added to a solution of [4-(5-aminopyridin-2-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone (0.070 g, 0.20 mmol) in dichloromethane (2 mL) and diisopropylethylamine (0.087 mL) at 0° C. The mixture was stirred at 25° C. for 16 h and then diluted with dichloromethane. The organic phase was washed with water and saturated NaCl solution, dried over anhydrous MgSO4. After removal of dichloromethane, the title compound was obtained in 7.6% yield (7.3 mg) after column purification. 1H NMR (300 MHz, CDCl3) δ 7.99, 7.80, 7.71, 7.56, 7.27, 6.91, 6.61, 3.91, 3.57, 3.43, 3.27, 3.04, 2.64. MS (ES+) m/z 483.0 (M+1).
Reaction SMILES: [N+]([C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[N+:7]([O-])=[CH:6][CH:5]=1)([O-])=O.P(Cl)(Cl)[Cl:16].[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:16][C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[N:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1cc[n+]([O-])c2c1CCCC2
Reactant: ClP(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Clc1ccnc2c1CCCC2
Temperature: 25 °C

Procedure:
A solution of the crude product of Step 1 (36.5 g, 188 mmol) in chloroform (500 ml) was treated over 30 min with phosphorus trichloride (80 g, 580 mmol) at 0°, heated under reflux for 1 h, cooled to room temperature, and poured onto ice (2 Kg). The mixture was basified with sodium hydroxide and the layers separated. The aqueous phase was extracted with chloroform (500 ml).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[N:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)=[CH:39][CH:38]=1>ClCCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([N:48]3[CH2:49][CH2:50][N:45]([CH2:44][CH2:43][C:40]4[CH:39]=[CH:38][N:37]=[CH:42][CH:41]=4)[CH2:46][CH2:47]3)=[O:22])[CH:17]=2)(=[O:11])=[O:12])=[C:5]([CH3:24])[CH:4]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: c1cc(CCN2CCNCC2)ccn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N3CCN(CCc4ccncc4)CC3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AA using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (63 mg, 0.18 mmol), CDI (58 mg, 0.36 mmol) and 1-[2-(pyridin-4-yl)ethyl]piperazine (57 mg, 0.30 mmol) in DCE (4.5 mL). The crude product was purified using Ambersep and PL-MIA resins, then using prep method A.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[C:4]([F:10])[CH:3]=1.C([Li])CCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.[OH-].[K+]>C1COCC1>[F:10][C:4]1[CH:3]=[C:2]([B:16]([OH:21])[OH:17])[CH:7]=[CH:6][C:5]=1[S:8][CH3:9]
Reactant: CSc1ccc(Br)cc1F
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [K+]
Agent: [Li]CCCC
Agent: [OH-]
Solvent: C1CCOC1
Product: CSc1ccc(B(O)O)cc1F
Temperature: -40 °C
Reaction time: 1.5 h
Yield: 5.2 %

Procedure:
A solution of 4-bromo-2-fluorothioanisole (0.5 g, 22.6 mmol) in dry THF (20 mL) was chilled to −78° C. under a nitrogen atmosphere. The reaction mixture was treated with 1.6 M n-butyllithium in hexanes (1.7 mL, 27.1 mmol), and the mixture was warmed to −40° C. where it was maintained for 0.5 hours. The reaction mixture was then chilled to −78° C. and three equivalents of triisopropyl borate (1.56 mL, 67.8 mmol) were added. The reaction mixture was allowed to warm to room temperature and stirred for 1.5 hours. At this point, 10% aqueous KOH (200 mL, 360 mmol) was added and the mixture was stirred overnight at room temperature. The reaction mixture was then poured into an ice/concentrated HCl mixture with stirring to yield a white precipitate. This solid was dried in a vacuum oven (65° C., 29 in Hg) overnight to provide the title compound (yield: 0.22 g; 52.4%). 1H NMR (300 MHz, DMSO-d6) δ 2.48 (s, 3H), 7.31 (t, J=9 Hz, 1H), 7.49 (dd, J=12 Hz, 1.5 Hz, 1H) 7.54 (dd, J=9 Hz, 1.5 Hz, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:22][CH3:23])=[C:18]([OH:21])[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[C:24]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35]O)[CH2:29][CH2:28]1)(=[O:26])[CH3:25]>>[C:24]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][O:21][C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][C:17]=2[O:22][CH3:23])[N:14]=[CH:13][N:12]=[C:11]3[O:10][C:6]2[CH:5]=[C:4]3[C:9](=[N:8][CH:7]=2)[NH:1][CH:2]=[CH:3]3)[CH2:29][CH2:28]1)(=[O:26])[CH3:25]
Reactant: CC(=O)N1CCN(CCCO)CC1
Reactant: COc1cc2ncnc(Oc3cnc4[nH]ccc4c3)c2cc1O
Product: COc1cc2ncnc(Oc3cnc4[nH]ccc4c3)c2cc1OCCCN1CCN(C(C)=O)CC1
Yield: 53.4 %

Procedure:
Using an analogous procedure to that described for the preparation of Example 2, 4-(7-azaindol-5-yloxy)-6-hydroxy-7-methoxyquinazoline (0.133 g, 0.432 mmol), (prepared as described for the starting material in Example 2), was reacted with 3-(4-acetylpiperazin-1-yl)propan-1-ol (0.097, 0.51 mmol), (prepared as described for the starting material in Example 1 or Example 7), to give 6-(3-(4-acetylpiperazin-1-yl)propoxy)-4-(7-azaindol-5-yloxy)-7-methoxyquinazoline (0.11 g, 53%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH2:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(OCC)C>[O:4]=[C:1]([N:16]1[CH2:17][CH2:18][N:13]([CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:14][CH2:15]1)[CH:2]=[CH2:3]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: C=CC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCN(Cc2ccccc2)CC1
Reaction time: 8 h
Yield: 13 %

Procedure:
A solution of acryloyl chloride (4.52 g, 0.05 mole) in 25 ml of ethyl ether was added to a cold solution of 1-benzylpiperazine (8.8 g, 0.05 mole) and triethylamine (30 ml, 0.20 mole) in 500 ml of ethyl ether. A white precipitate formed. The reaction mixture was stirred overnight, filtered and the precipitate washed well with ethyl ether. The solvent and triethylamine were removed and the product chromatographed on silica, eluting with ethyl acetate/hexane [30:70 (v/v)] to yield 1.5 g of the title compound. The structure was confirmed by NMR.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[C:24]#[N:25])[CH2:18][CH2:17]2)=[O:15])[CH2:3]1.[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([Cl:40])[CH:39]=1)[C:34](Cl)=[O:35]>>[CH2:7]([N:5]1[C@H:4]([C:14]([N:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[C:24]#[N:25])[CH2:20][CH2:21]2)=[O:15])[CH2:3][C@H:2]([NH:1][C:34](=[O:35])[C:33]2[CH:32]=[C:31]([Cl:30])[CH:39]=[C:38]([Cl:40])[CH:37]=2)[CH2:6]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#Cc1ccccc1N1CCN(C(=O)C2CC(N)CN2Cc2ccccc2)CC1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Product: N#Cc1ccccc1N1CCN(C(=O)[C@@H]2C[C@H](NC(=O)c3cc(Cl)cc(Cl)c3)CN2Cc2ccccc2)CC1
Yield: 11.5 %

Procedure:
As described for Example 89e, 2-[4-(4-amino-1-benzyl-pyrrolidine-2-carbonyl)-piperazin-1-yl]-benzonitrile (50.0 mg, 0.128 mmol) was converted, using 3,5-dichloro-benzoyl chloride instead of 2-chloro-benzoyl chloride, to the title compound (8.3 mg, 11.5%) as light yellow oil. MS m/e=562.2 [M+H]+.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:10]1[C@@:14]2([CH3:29])[CH2:15][CH2:16][C@@H:17]3[C@@:22]4([CH3:28])[CH2:23][CH2:24][C@H:25]([OH:27])[CH2:26][C:21]4=[CH:20][CH:19]=[C:18]3[C@@H:13]2[CH2:12][CH2:11]1)/[CH:3]=[CH:4]/[C@@H:5]([CH:7]([CH3:9])[CH3:8])[CH3:6].[CH3:30][O:31][CH2:32]OC.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[CH3:30][O:31][CH2:32][O:27][CH:25]1[CH2:24][CH2:23][C@@:22]2([CH3:28])[C:21](=[CH:20][CH:19]=[C:18]3[C@@H:17]2[CH2:16][CH2:15][C@@:14]2([CH3:29])[C@H:13]3[CH2:12][CH2:11][C@@H:10]2[C@H:2]([CH3:1])[CH:3]=[CH:4][C@H:5]([CH3:6])[CH:7]([CH3:8])[CH3:9])[CH2:26]1
Reactant: CC(C)[C@@H](C)/C=C/[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: COCOC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COCOC1CC[C@@]2(C)C(=CC=C3[C@@H]4CC[C@H]([C@H](C)C=C[C@H](C)C(C)C)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
Ergosterol (35.7 g, 90.0 mmol) was dissolved in dimethoxymethane (350 mL, 6.3 mol), and diphosphorous pentoxide (17.9 g, 126 mmol) was added thereto, followed by stirring at room temperature for 1 hour. Diatomaceous earth was added to the reaction mixture, followed by stirring for 30 minutes and filtration, and the filtrate was concentrated. Ethyl acetate was added to the resulting residue for trituration to obtain the title compound (35.1 g, 89%).
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:42]=[CH:41][C:6]([CH2:7][N:8]2[C:13](=[O:14])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[C:10]3=[N:29][N:30](COCC[Si](C)(C)C)[C:31](=[O:32])[N:9]23)=[CH:5][CH:4]=1>Cl.O1CCOCC1>[F:44][C:2]([F:1])([F:43])[C:3]1[CH:42]=[CH:41][C:6]([CH2:7][N:8]2[C:13](=[O:14])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[C:10]3=[N:29][NH:30][C:31](=[O:32])[N:9]23)=[CH:5][CH:4]=1
Reactant: C[Si](C)(C)CCOCn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c(=O)n(Cc3ccc(C(F)(F)F)cc3)n2c1=O
Agent: Cl
Solvent: C1COCCO1
Product: O=c1c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c2n[nH]c(=O)n2n1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
The solution of 5-(4-(trifluoromethyl)benzyl)-7,8-bis(4-chlorophenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazine-3,6(2H,5H)-dione (118 mg, 0.18 mmol) in 4M HCl in dioxane (4 ml) in a sealed tube was heated at 90° C. for 6 hours. After this time, the reaction mixture was cooled to RT, and subsequently concentrated under reduced pressure. The resulting crude product was purified by reverse phase HPLC to give the title compound, the final product, 5-(4-(trifluoromethyl)benzyl)-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine-3,6(2H,5H)-dione, as colorless foam (60 mg, 66%). MS M+H=531; 1H (CDCl3) d 11.46(1H), 7.70(2H), 7.55(2H), 7.27(4H), 7.14(2H), 7.06(2H), 5.96(2H).
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[C:11]([Cl:16])[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[NH:19]1[CH2:29][CH2:28][CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:21][CH2:20]1.C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C.O1CCOCC1>[CH2:26]([O:25][C:23]([CH:22]1[CH2:28][CH2:29][N:19]([C:2]2[CH:18]=[CH:17][C:5]([C:6](=[O:7])[NH:8][C:9]3[CH:14]=[CH:13][C:12]([I:15])=[C:11]([Cl:16])[CH:10]=3)=[CH:4][N:3]=2)[CH2:20][CH2:21]1)=[O:24])[CH3:27]
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(Nc1ccc(I)c(Cl)c1)c1ccc(Cl)nc1
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(I)c(Cl)c3)cn2)CC1
Temperature: 95 °C

Procedure:
A solution of 6-Chloro-N-(3-chloro-4-iodo-phenyl)-nicotinamide (100 mg, 0.26 mmol), ethyl isonipecotate (60 mg, 0.38 mmol), diisopropyl ethyl amine (0.14 mL, 0.77 mmol) and a catalytic amount of DMAP in dioxane, in a sealed tube was heated at 85° C. for 19 h. Followed addition of another portion of ethyl isonipecotate (60 mg, 0.38 mmol) and the mixture was heated at 95° C. for 24 h. The mixture was then cooled, the solvent was evaporated and the residue was purified with a silica gel column and 20-40% EtOAc in hexanes to afford the product. HRMS m/z calcd for C20H21N3O3ClI [M+H]+: 514.0389. Found: 514.0387.