Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1(O)[CH:13]2[CH2:14][O:15][CH2:16][CH:12]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:13]2[CH2:14][O:15][CH2:16][CH:12]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1
Reactant: CC1(O)CCCCCCCCCC2COCC21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=CCCCCCCCCC2COCC12
Reaction time: 8 h
Yield: 82.1 %

Procedure:
Crude 4-methyl-dodecahydro-2-oxa-cyclopentacyclododecen-4-ol (133 g) from Step 3 was dissolved in toluene (1 L). p-Toluenesulfonic acid (pTSA) (4 g) was added and the reaction was heated to reflux with a water trap. After 8 hours, there was no more water separated. The reaction was cooled and washed with sodium carbonate solution. Further distillation afforded 13-methyl-3a,4,5,6,7,8,9,10,11,13a-decahydro-1H,3H-2-oxa-cyclopentacyclododecene (101 g, ˜82% yield).
Reaction SMILES: [C-:1]#[N:2].[K+].Cl.[NH2:5][C:6]1[N:11]=[C:10]([OH:12])[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[CH:16][CH:15]=2)=[C:8]([CH3:22])[N:7]=1>CN(C=O)C.CS(C)=O>[NH2:5][C:6]1[N:11]=[C:10]([OH:12])[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:1]#[N:2])=[CH:16][CH:15]=2)=[C:8]([CH3:22])[N:7]=1
Reactant: Cc1nc(N)nc(O)c1Cc1ccc(CCl)cc1
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(N)nc(O)c1Cc1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Potassium cyanide (2 g) was added to a solution of the product from step (ii) in DMF (20 ml) and DMSO (10 ml) and the mixture stirred at rt for 18 h. The mixture was flushed with nitrogen for 20 min, then diluted with brine (80 ml), stirred for 10 min and the precipitate filtered, washed with water then ether and dried to afford the subtitle compound, 2.46 g.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]2[CH2:8][C@H:4]([C@@H:5]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[N:6]2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[C:26]([O:30][CH2:31][CH3:32])(=[O:29])[C:27]#[CH:28]>ClCCl>[CH2:31]([O:30][C:26](=[O:29])/[CH:27]=[CH:28]/[O:1][C@H:2]1[C@H:7]2[CH2:8][C@H:4]([C@@H:5]([C:16]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:17])[N:6]2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1)[CH3:32]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2O)[C@H]1C(=O)OCc1ccccc1
Reactant: C#CC(=O)OCC
Solvent: ClCCl
Product: CCOC(=O)/C=C/O[C@@H]1C[C@@H]2C[C@H]1N(C(=O)OC(C)(C)C)[C@@H]2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a solution of 3-benzyl 2-tert-butyl (1R,3S,4S,6R)-6-hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate obtained in Example 30-1 (593 mg) in dichloromethane (10 mL), were added ethyl propiolate (670 mg) and 4-methylmorphorine (190 mg). The mixture was stirred at room temperature for 3 hrs. The resulting mixture was evaporated in vacuo and the residue was chromatographed on silica gel eluting with hexane and ethyl acetate (4:1) to give the target compound (760 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)=[CH2:2].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1>Cl.CCOCC>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)=[O:11])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C1=COCCC1
Reactant: C=Cc1ccc(CC(=O)O)cc1
Agent: Cl
Solvent: CCOCC
Product: C=Cc1ccc(CC(=O)OC2CCCCO2)cc1
Temperature: 45 °C
Yield: 70.8 %

Procedure:
A mixture of 7 g (43 mmol) of 4-vinylphenylacetic acid, 12.0 g (142 mmol) of 3,4-dihydro-2H-pyran and 2 drops of 32% hydrochloric acid is warmed at 45° C. for 90 minutes in a 50 ml three-necked round-bottom flask fitted with magnetic stirrer and nitrogen blanketing system. 100 ml of ether are then added. The organic phase is then washed twice with 50 ml of 1 N sodium hydroxide solution in each case and twice with 50 ml of water in each case, dried over magnesium sulfate and evaporated, giving a colourless oil, which is recrystallized from three times the amount of n-hexane, giving 7.5 g (70% of theory) of tetrahydro-2H-pyran-2-yl 4-vinylphenylacetate having a melting point of 34° C. 1H-NMR (CDCl3, 300 MHz): δ [ppm] 7.4-7.1/m/4H 6.68/dd/1H 5.98/dd/1H 5.73/dd/1H 5.22/dd/1H -3.7/m/2H 3.64/s/2H 1.9-1.5/m/6H
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[CH:5]=1.O.O.[OH-].[Li+].Cl>CO>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[CH2:14][CH2:13][O:12][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][CH3:11])[C:3]([OH:23])=[O:2]
Reactant: COC(=O)c1ccc(OC)c(OCCc2ccc(Cl)cc2Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)O)cc1OCCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
17 g of 3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-benzoic acid methyl ester were dissolved in 200 ml of MeOH:water/3:1. 4.1 g of lithium hydroxide monohydrate was added to the solution, and the reaction was stirred at RT for 16 h then at 90° C. for 2 h. The solution was cooled to RT, then acidified with half-concentrated hydrochloric acid. The solvents were removed under reduced pressure and the residue was washed twice with warm water to remove salts. The so obtained acid was used for the subsequent reaction without further purification.
Reaction SMILES: [CH2:1]([C:4]1([CH3:32])[C:10](=[O:11])[N:9]([CH2:12][C:13]([N:15]([CH:24]([CH3:26])[CH3:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[O:14])[C:8]2[CH:27]=[CH:28][CH:29]=[CH:30][C:7]=2[NH:6][C:5]1=[O:31])[CH:2]=[CH2:3].Br[C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1.C([O-])(=O)C.[K+]>CN(C=O)C.CCOC(C)=O.[Cu]>[CH2:1]([C:4]1([CH3:32])[C:10](=[O:11])[N:9]([CH2:12][C:13]([N:15]([CH:24]([CH3:26])[CH3:25])[C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[O:14])[C:8]2[CH:27]=[CH:28][CH:29]=[CH:30][C:7]=2[N:6]([C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[C:5]1=[O:31])[CH:2]=[CH2:3]
Reactant: Brc1cccnc1
Reactant: C=CCC1(C)C(=O)Nc2ccccc2N(CC(=O)N(c2ccc(OC)cc2)C(C)C)C1=O
Agent: [Cu]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCC1(C)C(=O)N(CC(=O)N(c2ccc(OC)cc2)C(C)C)c2ccccc2N(c2cccnc2)C1=O
Temperature: 125 °C
Yield: 53 %

Procedure:
To a stirring solution of 2.5 g (5.74 mmol) of 2-(3-Allyl-3-methyl-2,4-dioxo-2,3,4,5-tetrahydro benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxyphenyl) acetamide, prepared as in Part A, in 25 mL of DMF is added 1.81 g (11.5 mmol, 2 equiv.) of 3-bromopyridine, 1.12 g (11.5 mmol, 2 equiv.) of potassium acetate, and 364 mg (11.5 mmol) of copper powder. The suspension is heated to 125° C. for 4 h and then cooled to RT. It is diluted with 350 mL EtOAc and filtered through a bed of celite. The filtrate is washed with H2O (2×300 mL), conc. NH4OH (2×150 mL) and then dried (MgSO4), and the solvents removed in vacuo. Purification by silica gel flash column chromatography using hexane/EtOAc 1/1 as eluent afforded 1.56 g of 2-(3-Allyl-3-methyl-2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydro benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-[4-methoxyphenyl]acetamide as an oil: 1H NMR (CDCl3, 300 MHz) δ8.51 (m, 2H), 7.68 (d, 1H, J=9), 7.39-6.93 (m, 8H), 6.71 (d, 1H, J=8), 5.78-5.64 (m, 1H), 5.08-5.00 (m, 2H), 4.72 (d, 1H, J=16), 4.39 (d, 1H, J=17), 4.08 (m, 1H), 3.85 (s, 3H), 3.81-3.79 (m, 1H), 2.11 (d, 1H, J=8), 1.77 (s, 1H), 1.60 (s, 2H), 1.21-1.07 (m, 6H).
Reaction SMILES: [S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([C:23]45[CH2:30][CH2:29][C:26]([NH2:31])([CH2:27][CH2:28]4)[CH2:25][CH2:24]5)=[N:21][N:22]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CCN(C(C)C)C(C)C.[N:41]1([S:46](Cl)(=[O:48])=[O:47])[CH2:45][CH2:44][CH2:43][CH2:42]1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([C:23]45[CH2:30][CH2:29][C:26]([NH:31][S:46]([N:41]6[CH2:45][CH2:44][CH2:43][CH2:42]6)(=[O:48])=[O:47])([CH2:27][CH2:28]4)[CH2:25][CH2:24]5)=[N:21][N:22]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C45CCC(N)(CC4)CC5)n23)cc1
Reactant: O=S(=O)(Cl)N1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C45CCC(NS(=O)(=O)N6CCCC6)(CC4)CC5)n23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A round bottom flask was charged with 4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-amine (0.12 g, 0.28 mmol), DIEA (0.48 mL, 2.8 mmol) in DMA (2.75 mL). Pyrrolidine-1-sulfonyl chloride (0.07 g, 0.41 mmol, Matrix) was added dropwise and reaction mixture was stirred at ambient temperature for about 1 h. K2CO3 (0.190 g, 1.37 mmol) was added and the reaction mixture was stirred at ambient temperature for about 16 h. The solvent was removed under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with a gradient of 0-10% MeOH in DCM to give N-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)pyrrolidine-1-sulfonamide, which was dissolved in NaOH (1 N aqueous, 1.10 mL, 1.10 mmol) and 1,4-dioxane (1 mL) and heated at about 50° C. for about 1 h. The crude material was purified by preparative reverse phase HPLC (Table 2, Method 1) to give N-(4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)pyrrolidine-1-sulfonamide (0.042 g, 37%) as a white solid: LC/MS (Table 1, Method a) Rt=1.81 min; MS m/z 416 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[N:33]1([CH:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH2:38][CH2:37][CH2:36][CH:35]([OH:39])[CH2:34]1>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:43]5[CH2:42][CH2:41][CH:40]([N:33]6[CH2:38][CH2:37][CH2:36][CH:35]([OH:39])[CH2:34]6)[CH2:45][CH2:44]5)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:30])[F:31])[CH:3]=1
Reactant: OC1CCCN(C2CCNCC2)C1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCC(N3CCCC(O)C3)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-hydroxy-[1,4′]bipiperidinyl-1′-yl)-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and [1,4′]Bipiperidinyl-3-ol following General Procedure B.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:25]([CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1)=O.CCCCCC>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:25][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1cccc(CCCC=O)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1cccc(CCCC=C(Br)Br)c1
Reaction time: 0.17 h
Yield: 94.8 %

Procedure:
To a solution of carbon tetrabromide (16.7 g) in methylene chloride (35 ml) was added triphenylphosphine (26.0 g) in methylene chloride (35 ml) at 0° C., and the mixture was stirred for 10 min. To the mixture was added a solution of 1-(3-formylpropyl)-3-methoxybenzene (3.00 g) in methylene chloride (20 ml) at 0° C. The mixture was stirred for 30 min at 0° C. To the mixture was added gradually n-hexane and to remove triphenylphosphineoxide. The mixture was filtered was washed with water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=24:1) to give the title compound (5.33 g) having the following physical data.
Reaction SMILES: [H-].[Na+].[Br:3][CH:4]1[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH2:8][CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:6][C:5]1=[O:24].C([CH:29](I)[C:30]([NH2:32])=[O:31])(C)(C)C>>[C:9]([NH:32][C:30](=[O:31])[CH2:29][N:6]1[CH:7]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH2:10][CH:4]([Br:3])[C:5]1=[O:24])([CH3:11])([CH3:10])[CH3:8]
Reactant: Cc1ccccc1C1CC(Br)C(=O)NC(c2ccccc2)C1
Reactant: CC(C)(C)C(I)C(N)=O
Agent: [H-]
Agent: [Na+]
Product: Cc1ccccc1C1CC(Br)C(=O)N(CC(=O)NC(C)(C)C)C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 60 h
Yield: 184.9 %

Procedure:
To a 1000 mL 3-necked round-bottomed flank equipped with addition funnel and nitrogen inlet was added 3.9 grams (97.6 mmol) sodium hydride, which was then washed with hexane, and 400 mL dry tetrahydrofuran. To the stirring suspension was added a solution of 31.8 grams (88.8 mmol) 3-Bromo-5-(2-methylphenyl)-7-phenyl-2,3,4,5,6,7-hexahydroazepin-2-one and 23.5 grams (97.6 mmol) t-butyl iodoacetamide. The reaction was stirred at room temperature for 60 hours, quenched with ammonium chloride solution, then poured into water, extracted twice into ethyl acetate, washed with brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using 2/1-hexane/ethyl acetate an eluent to afford 38.7 grams (92%) of a foam, a mixture of diastereomers.
Reaction SMILES: [F:1][C:2]1([F:15])[CH2:7][C@H:6]2[CH2:8][C@H:4]([C:5]2([CH3:10])[CH3:9])[C@@H:3]1[CH2:11][C:12](Cl)=[O:13].[NH2:16][N:17]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:34].N1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[O:34])[N:17]([NH:16][C:12](=[O:13])[CH2:11][C@@H:3]3[C:2]([F:15])([F:1])[CH2:7][C@H:6]4[CH2:8][C@@H:4]3[C:5]4([CH3:10])[CH3:9])[N:26]=2)=[CH:28][CH:29]=1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Reactant: CC1(C)[C@@H]2C[C@H]1[C@H](CC(=O)Cl)C(F)(F)C2
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC1(C)[C@@H]2C[C@H]1[C@H](CC(=O)Nn1nc(-c3ccc(Cl)cc3)c3ccccc3c1=O)C(F)(F)C2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of the above crude 2-((1S,2S,5R)-3,3-difluoro-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)acetyl chloride (50 mg, 0.211 mmol) and the product from Example 86A (57.4 mg, 0.211 mmol) in 10 mL of CHCl3 was added pyridine (0.051 mL, 0.634 mmol). The reaction is stirred at rt for 12 hours and then reluxed for 16 hours, and quenched with 1M NaHCO3 (10 mL). The aq layer was extracted with EtOAc (2×20 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-40% of EtOAc in hexanes). 1H NMR (300 MHz, DMSO-d6) δ ppm 11.51 (s, 1H), 8.39-8.43 (m, 1H), 7.94-8.00 (m, 2H), 7.70-7.76 (m, 1H), 7.58-7.70 (m, 4H), 2.92-3.09 (m, 1H), 2.81 (dd, J=15.3, 6.4 Hz, 1H), 2.36-2.45 (m, 3H), 2.11-2.16 (m, 1H), 1.93-2.04 (m, 1H), 1.27 (s, 3H), 1.08-1.20 (m, 2H), 1.01 (s, 3H); MS (ESI+) M/Z 472 (M+H)+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)(=[O:8])[CH3:7].[C:30]([O-])(=[O:32])C.[Na+]>CN(C=O)C>[C:6]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][C:21]([CH:30]=[O:32])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)OCc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CC(=O)OCc1ccc(N(c2ccccc2)c2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60 %

Procedure:
DMF (2.63 g, 0.036 mol) was added to a three-neck flask (50 mL) equipped with a condenser, CaCl2 drying tube, and a glass stopper and cooled in an ice bath. Phosphorus oxychloride (1.8 g, 0.012 mol) was then added dropwise, and the resulting mixture stirred for 5 minutes and then allowed to warm slowly to room temperature. A solution of 4-(N,N-diphenylamino)benzyl acetate (1.88 g, 0.0059 mol) in DMF (20 mL) was then added dropwise. After addition was complete, the mixture was heated to 70° C. and stirred overnight. The mixture was then poured over ice (20 g) and the product obtained by filtration after slowly neutralizing the solution in an ice bath with saturated sodium acetate solution to pH 6. After washing with deionized water and drying, the product was recrystallized by dissolving in a small quantity of chloroform and pouring into excess hexane to yield the desired product (1.21 g, 60%). m.p. 86-89° C.; 1H NMR δ: 2.12(s, 2H, CH3), 5.09 (s, CH2), 7.0-7.37 (m, 12H, phenyl), 7.65-7.70 (d, 2H, phenyl), 9.81 (s, 1H, CHO). Analysis: Calculated for C22H19NO3: C, 76.52%; H, 5.51%; N, 4.06%. Found: C, 76.27%; H, 5.72%; N, 4.01%.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:10](I)=[C:9]([C:12]2[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:14][C:13]=2[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:8][N:7]=1)=[O:5])[CH3:2].[C:35]([O-:38])(O)=O.[Na+].CN(C=O)C>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>[CH2:1]([NH:3][C:4]([C:6]1[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH:35]=[O:38])=[CH:14][CH:13]=2)=[C:9]([C:12]2[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:14][C:13]=2[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1I
Reactant: O=C([O-])O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(C=O)cc1
Temperature: 80 °C
Yield: 163.6 %

Procedure:
5-(2,4-Bis-benzyloxy-5-chloro-phenyl)-4-iodo-isoxazole-3-carboxylic acid ethylamide (prepared as for Example 31) (2 g, 3.4 mmol), 4-formylboronic acid (0.612 g, 4.08 mmol), NaHCO3 (10.2 ml, 1M aq. solution, 10.2 mmol), PdCl2(PPh3)2 (119 mg, 0.17 mmol) and DMF (50 ml) were combined. The mixture was then degassed by bubbling N2 through it for 5 minutes before being heated at 80° C. for 1 hour. The mixture was then evaporated in vacuo and partitioned between EtOAc (3×50 ml) and water (50 ml). The combined, dried (Na2SO4) organics were evaporated in vacuo to give a crude oil. This was dissolved in EtOAc and passed through a plug of SiO2, washing through with EtOAc. The filtrate was evaporated in vacuo and the resulting oil triturated with Et2O to afford 5-(2,4-Bis-benzyloxy-5-chloro-phenyl)-4-(4-formyl-phenyl)-isoxazole-3-carboxylic acid ethylamide (1.577 g, 82%) as a pale coloured solid, LC/MS: RT=2.908 min. 567.3 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[O:20][C:19](=[O:21])[NH:18][N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[Br:28][CH2:29][CH2:30][CH2:31]Br>CN(C)C=O>[Br:28][CH2:29][CH2:30][CH2:31][N:18]1[N:17]=[C:16]([C:7]2[CH:8]=[C:9]([C:12]([CH3:14])([CH3:15])[CH3:13])[C:10]([OH:11])=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=2)[O:20][C:19]1=[O:21]
Reactant: BrCCCBr
Reactant: CC(C)(C)c1cc(-c2n[nH]c(=O)o2)cc(C(C)(C)C)c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(-c2nn(CCCBr)c(=O)o2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.5 %

Procedure:
To a solution of 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3,4-oxadiazol-2(3H)-one (0.50 g) in dimethylformamide (8 ml) were added sodium carbonate (0.36 g) and 1,3-dibromo-propane (1.74 g), followed by stirring at room temperature for 5 hours. After completion of the reaction, the reaction mixture was poured into ice-water, and the product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform) and then recrystallized from chloroform/n-hexane to afford 0.45 g (63%) of the title compound as colorless crystals. mp 130-131° C. NMR (CDCl3) (200 MHz) δ: 1.46 (18H, s), 2.1-2.6 (2H, m), 3.46 (2H, t, J=6.6 Hz), 3.93 (2H, t,J=6.6 Hz), 5.60 (1H, s), 7.63 (2H, s)
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2[N:17]([CH3:21])[N:18]=[C:19]([CH3:20])[C:6]1=2)=[O:4].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:21][N:17]1[C:7]2[C:8](=[O:16])[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]([C:3](=[O:4])[CH2:2][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[C:6]=2[C:19]([CH3:20])=[N:18]1
Reactant: Cc1nn(C)c2c1N(C(=O)CCl)c1ccccc1NC2=O
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nn(C)c2c1N(C(=O)CN1CCCC1)c1ccccc1NC2=O
Yield: 92 %

Procedure:
2.0 g of 4-chloroacetyl-1,3-dimethyl-1,4,9,10-tetrahydropyrazolo[4,3-b][1,5]benzodiazepin-10-one, 0.55 g of pyrrolidine, 0.85 g of ground sodium carbonate and 15 ml of absolute ethanol are heated at the boil for 2 hours; the hot solution is then filtered and concentrated in vacuo. The thus-obtained residue is dissolved in ethylene chloride, and the resulting organic solution is washed at pH 7 with water and concentrated to yield 2.05 g of 1,3-dimethyl-4-(pyrrolidinoacetyl)-1,4,9,10-tetrahydropyrazolo[4,3-b][1,5]benzodiazepin-10-one, mp 114° to 116° C. (from toluene).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH3:31])[CH2:26][CH2:25]2)[CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][N:9]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:16](O)=[O:17])[C:8]2=[O:23])#[N:2].[NH2:32][C:33]1[CH:37]=[CH:36][O:35][N:34]=1>>[C:1]([C:3]1[CH:4]=[C:5]([N:24]2[CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH2:29]2)[CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][N:9]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:16]([NH:32][C:33]1[CH:37]=[CH:36][O:35][N:34]=1)=[O:17])[C:8]2=[O:23])#[N:2]
Reactant: CCN1CCN(c2cc(C#N)c3ncn(-c4cc(C(=O)O)ccc4C)c(=O)c3c2)CC1
Reactant: Nc1ccon1
Product: CCN1CCN(c2cc(C#N)c3ncn(-c4cc(C(=O)Nc5ccon5)ccc4C)c(=O)c3c2)CC1

Procedure:
Using an analogous procedure to that described paragraph (A) in the portion of Example 4, 3-[8-cyano-6-(4-ethylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoic acid was reacted with 3-aminoisoxazole to give 3-[8-cyano-6-(4-ethylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]-N-isoxazol-3-yl-4-methylbenzamide; NMR Spectrum: (DMSOd6) 1.03 (t, 3H), 2.19 (s, 3H), 2.38 (q, 2H), 2.53 (m, 4H), 3.35 (m, 4H), 7.04 (s, 1H), 7.60 (d, 1H), 7.69 (s, 1H), 8.10 (m, 3H), 8.29 (s, 1H), 8.84 (s, 1H), 11.47 (s, 1H); Mass Spectrum: M+H+ 484.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][CH:21]=[CH:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[Br:26]Br>CN(C=O)C>[Br:26][C:20]1[C:19]2[C:23](=[CH:24][CH:25]=[C:17]([C:14]3[N:13]=[C:12]([C:4]4[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[C:2]([Cl:1])[CH:3]=4)[O:16][N:15]=3)[CH:18]=2)[NH:22][CH:21]=1
Reactant: BrBr
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]ccc4c3)no2)cc1Cl
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]cc(Br)c4c3)no2)cc1Cl
Reaction time: 0.25 h
Yield: 29.1 %

Procedure:
To 5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indole (D5) (450 mg, 1.27 mmol) dissolved in DMF (12 ml) was added bromine (213 mg, 1.35 mmol) dropwise. Stirred for 15 minutes, evaporated off the DMF, added diethyl ether (70 ml) and washed with water (2×70 ml). Dried over MgSO4 and evaporated off the solvent. The residue was crystallised from diethyl ether/hexane to give 160 mg of the title compound as a white solid. δH (400 MHz, d6-DMSO) 1.37 (6H, d), 4.88 (1H, sept), 7.44 (1H, d), 7.59 (1H, dd), 7.72 (1H, d), 7.91 (1H, dd), 8.13-8.32 (3H, m). MS (ES) C19H1579BrClN3O2 requires 431; found 432 (MH+).