Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH2:13])[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1.[NH2:29][C:30]1[N:35]=[CH:34][C:33]([C:36](O)=[O:37])=[CH:32][N:31]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:29][C:30]1[N:35]=[CH:34][C:33]([C:36]([NH:13][C:10]2[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]3[CH:6]=[CH:5][C:4]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=4)=[C:3]([O:2][CH3:1])[C:12]=3[N:11]=2)=[O:37])=[CH:32][N:31]=1
Reactant: Nc1ncc(C(=O)O)cn1
Reactant: COc1c(OCc2ccc(S(C)(=O)=O)cc2)ccc2c1N=C(N)N1CCN=C21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(OCc2ccc(S(C)(=O)=O)cc2)ccc2c1N=C(NC(=O)c1cnc(N)nc1)N1CCN=C21
Reaction time: 8 h
Yield: 12.1 %

Procedure:
7-Methoxy-8-{[4-(methylsulfonyl)benzyl]oxy}-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (Step 1, 76 mg, 0.19 mmol) was dissolved in DMF (5 mL), and 2-aminopyrimidine-5-carboxylic acid (40 mg, 0.29 mmol) was added. PyBOP (152 mg, 0.29 mmol) and diisopropylethylamine (0.15 mL, 0.85 mmol) were subsequently added. The mixture was stirred at it overnight, during which a tan solid precipitated. The DMF was removed under reduced pressure and the residue purified via silica gel chromatography (0-3% MeOH/CH2Cl2+0.1% Et3N). The solvent was evaporated under reduced pressure, the residue triturated in water (5 mL), collected by vacuum filtration, then washed with acetone. High vacuum drying gave the title compound (12 mg, 12%): HPLC MS RT=2.06 min, MH+=522.1; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 3.22 (3H, s), 4.00 (3H, s), 4.19-4.25 (2H, m), 4.48-4.55 (2H, m), 5.53 (2H, s), 7.53 (1H, d), 7.77 (2H, d), 7.97-8.03 (3H, m), 9.06 (2H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[S:10][C:6]=2[CH:5]=1)([O-])=O.CN(C)C=O>[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:21]=[CH:20][C:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[S:10][C:6]=2[CH:5]=1
Reactant: O=C(Nc1nc2ccc([N+](=O)[O-])cc2s1)c1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccc2nc(NC(=O)c3ccccc3)sc2c1
Yield: 92.9 %

Procedure:
A mixture of N-(6-nitrobenzothiazol-2-yl)benzamide (3.77 g, 12.6 mmol), palladium on charcoal (2 g, 10% Pd, 1.88 mmol Pd), dimethyl formamide (80 mL) and ethyl acetate (20 mL) was hydrogenated (1 bar) for 2 h at 60° C. The palladium was removed by filtration through a pad of celite. After concentration to 20 mL, water was added and the resulting precipitate was separated by filtration to obtain N-(6-aminobenzothiazol-2-yl)-benzamide (3.15 g, 11.7 mmol, 93%) as a grey solid. LC/ESI-MS: m/z=270 [M+H]+; m/z=268 [M−H]−; Rt=2.27 min.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]3[NH:15][C:14](=[O:16])[CH:13]=[CH:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1>[Pd].CO>[O:1]1[C:5]2([CH2:6][CH2:7][CH:8]([CH:11]3[NH:15][C:14](=[O:16])[CH2:13][CH2:12]3)[CH2:9][CH2:10]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C1C=CC(C2CCC3(CC2)OCCO3)N1
Agent: [Pd]
Solvent: CO
Product: O=C1CCC(C2CCC3(CC2)OCCO3)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrrol-2(5H)-one (330 mg, 1.48 mmol), prepared in the previous step, and Palladium on Carbon (299 mg, 0.14 mmol, 5%, “Degussa, wet”) was carefully added methanol (30 mL). The reaction flask was evacuated, backfilled with hydrogen via balloon and stirred at room temperature overnight. The catalyst was removed by filtration and the filtrate concentrated in vacuo to afford the product.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:33]=[CH:32][C:16]2[S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3([C:30](=[O:31])[C:15]=2[CH:14]=1)[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3.C(=O)(O)[O-].[Na+].[I-].[K+]>CN(C)C=O.O>[Cl:12][C:13]1[CH:33]=[CH:32][C:16]2[S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3([C:30](=[O:31])[C:15]=2[CH:14]=1)[CH2:25][CH2:26][N:27]([CH2:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:28][CH2:29]3
Reactant: O=C1c2cc(Cl)ccc2Sc2ccccc2C12CCNCC2
Reactant: BrCCCOc1ccccc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2cc(Cl)ccc2Sc2ccccc2C12CCN(CCCOc1ccccc1)CC2
Reaction time: 16 h

Procedure:
A solution of 1.6 g of 3-phenoxypropyl bromide in 10 ml of diemthylformamide is added, portionwise over a 20 minute span to a mixture, at 80° C., of 2.1 g of 2-chloro-10,11-dihydro-11-oxospiro[dibenz(b,f)thiepin-10,4'-piperidine], free base of Example 5, 2.1 g of sodium bicarbonate and 1.7 g of potassium iodide, in 15 ml of dimethylformamide. After total addition, the reaction mixture is stirred at 80°-85° C. for 16 hours. Thereafter, the mixture is cooled in an ice bath before being diluted with 75 ml of water. The diluted mixture is extracted with 40 ml of ether and both phases (organic and aqueous) are passed through filter paper. The filtered aqueous phase is extracted thrice with 40 ml portions of ether and the combined ether extracts are successively washed twice with 40 ml portions of ether and the combined ether extracts are successively washed twice with 40 ml portions of water, once with 20 ml of a saturated sodium chloride solution and dried. The residue is purified by passing through an alumina column, ether eluant, to provide 2-chloro-10,11-dihydro-11-oxo-1'-(3-phenoxypropyl)spiro[dibenz(b,f)thiepin-10,4'-piperidine].
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.ClCl.[N:13]([CH2:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21])=[N+:14]=[N-:15]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[N:13]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([CH:5]1[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:9])=[O:21])=[N+:14]=[N-:15]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: [N-]=[N+]=NCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: ClCl
Solvent: ClCCl
Product: CC1(C)OC(=O)C(C(=O)CCCCN=[N+]=[N-])C(=O)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To the solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (4.45 g, 30.9 mmol) and 4-dimethylaminopyridine (7.55 g, 61.8 mmol) in 100 ml of CH2 Cl2 was added the solution of crude 5-azidovaleric chloride in 10 ml of CH2Cl2 at 0° C. The mixture was stirred at 0° C. for 1 hr and at room temperature for 1 hr. The solution was washed with 1N aqueous HCl (100 ml), brine (250 ml) and dried over Na2SO4. After evaporation of solvent, 5-(5-azidopentanoyl)-2,2-dimethyl-1,3-dioxane-4,6-dione was obtained as a light pink oil (8.17 g, 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11](=[O:19])[C:10]=2[NH:20][C:21]([NH:23][C:24]2[C:29]([CH:30]([CH3:32])[CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=2[CH:33]([CH3:35])[CH3:34])=[O:22])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:45][CH:46]1[CH2:48][CH2:47]1>CN(C=O)C.O>[CH:46]1([CH2:45][N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][N:14]=3)[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[C:10]([NH:20][C:21]([NH:23][C:24]3[C:29]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:27]=[CH:26][C:25]=3[CH:33]([CH3:35])[CH3:34])=[O:22])[C:11]2=[O:19])[CH2:48][CH2:47]1
Reactant: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)[nH]c3ncccc23)c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)n(CC3CC3)c3ncccc23)c1
Reaction time: 10 h
Yield: 78.8 %

Procedure:
To a solution of N-[4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (400 mg, 0.85 mmol) in DMF (10 ml) were added potassium carbonate (141 mg, 1.02 mmol), potassium iodide (28 mg, 0.17 mmol), and (bromomethyl)cyclopropane (138 mg, 1.02 mmol), and the mixture was stirred at 40°-50° C. for 10 hours. After allowed to stand for cooling, the mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The resultant was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (1% methanol in chloroform), and crystallized from ether to give the title compound (354 mg, 0.67 mmol) as a colorless crystal.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH:4]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14]Br)=[CH:8][CH:7]=1.[CH:32]1[C:44]2[NH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36]=2[CH:35]=[CH:34][CH:33]=1.[OH-].[Na+]>C1C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[NH:16][CH:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][CH2:14][C:41]2[C:42]3[NH:43][C:44]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:37]=3[CH:38]=[CH:39][CH:40]=2)=[CH:10][CH:11]=1)[C:3]([OH:2])=[O:31])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: COC(=O)C(Cc1ccc(OCCBr)cc1)Nc1ccccc1C(=O)c1cccnc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(c1cccnc1)c1ccccc1NC(Cc1ccc(OCCc2cccc3c2[nH]c2ccccc23)cc1)C(=O)O
Yield: 18.4 %

Procedure:
To a solution of 2-((2-nicotinoylphenyl)amino)-3-[4-(2-bromoethoxy)-phenyl]-propionic acid methyl ester (0.24 g, 0.49 mmol) and carbazole (0.082 g, 0.49 mmol) in benzene (10 ml) is added tetrabutyl ammonium bromide (0.08 g) and 50% NaOH aqueous solution (0.084 g, 1.08 mmol), then the mixture is heated to reflux for 10 h. After cooled, benzene (30 ml) is added, and the mixture is washed with water (3×30 ml). Then the solvent is evaporated under a vacuum. The crude product is purified by silica gel chromatography using CHCl3/MeOH (4:1) as eluent to give the title compound (0.05 g, 18%). HRMS calcd for C35H29N3O4: 555.6331. Found: 555.6329. MA calcd for C35H29N3O4: C, 75.66%; H, 5.26%; N, 7.56%. Found: C, 75.42%; H, 5.27%; N, 7.53%.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[C:4]([S:12][C:13]2[NH:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[C:16]=3[N:22]=2)=[CH:5][C:6]2[O:10][CH2:9][O:8][C:7]=2[CH:11]=1.[C:24]([O:27][C@@H:28]([CH3:50])[C:29]([N:31]1[CH2:36][CH2:35][CH:34]([CH2:37][CH2:38]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:33][CH2:32]1)=[O:30])(=[O:26])[CH3:25]>>[C:24]([O:27][C@@H:28]([CH3:50])[C:29]([N:31]1[CH2:36][CH2:35][CH:34]([CH2:37][CH2:38][N:14]2[C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[C:16]=3[N:22]=[C:13]2[S:12][C:4]2[C:3]([N:2]([CH3:23])[CH3:1])=[CH:11][C:7]3[O:8][CH2:9][O:10][C:6]=3[CH:5]=2)[CH2:33][CH2:32]1)=[O:30])(=[O:26])[CH3:25]
Reactant: CC(=O)O[C@@H](C)C(=O)N1CCC(CCOS(=O)(=O)c2ccc(C)cc2)CC1
Reactant: CN(C)c1cc2c(cc1Sc1nc3c(N)nccc3[nH]1)OCO2
Product: CC(=O)O[C@@H](C)C(=O)N1CCC(CCn2c(Sc3cc4c(cc3N(C)C)OCO4)nc3c(N)nccc32)CC1

Procedure:
The title compound was prepared by a similar procedure described for step 7 of example 1 using 2-{[6-(dimethylamino)-1,3-benzodioxol-5-yl]sulfanyl}-1H-imidazo[4,5-c]pyridin-4-amine (150 mg, 0.45 mmol) and (2S)-1-[4-(2-{[(4-methylphenyl)sulfonyl]oxy}ethyl)piperidin-1-yl]-1-oxopropan-2-yl acetate (542 mg, 1.36 mmol). TOF LC-MS [M+H]+ 555.238.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1Cl.CC[Mg+].[Br-].[C:13]1([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.ClC1C=CC=CC=1CC1C=CC=CC=1>CCOCC.C1COCC1>[CH2:14]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:13][C:19]=1[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccccc1Cl
Reactant: c1ccc(CCc2ccccc2)cc1
Agent: CC[Mg+]
Agent: Clc1ccccc1Cc1ccccc1
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: c1ccc(Cc2ccccc2Cc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
This Example illustrates the use of EtMgBr/[NitriphosCl]PF6 as an activator/catalyst to improve yield. To 2.00 g (13.61 mmoles) of o-dichlorobenzene, 0.050 g (0.065 mmoles) of [NitriphosCl]PF6 in 5 mL of ether at 0° C. was added 0.5 mL (1.5 mmoles) of 2.9M EtMgBr in ether. After stirring for 0.5 hrs, 30 mL of ether and 7.0 mL (14 mmoles) of 2M benzylMgCl in THF were added. The mixture was refluxed for 3 days and worked up as usual. After removing the solvent, the residue was distilled at 0.1 mm to initially remove 0.550 g (3.7 mmoles, 27%) of o-dichlorobenzene and then 1.482 g (bp: 68° to 83° C.) of a clear liquid was collected. 1H NMR spectrum in CDCl3 indicated a 10:1 ratio of 1-chloro-2-benzylbenzene to bibenzyl (representing 6.7 mmoles (67 % based on reacted o-dichlorobenzene) of 1-chloro-2-benzylbenzene and 0.67 mmoles of bibenzyl). The material that remained in the pot was chromatographed on silica gel eluted with 10% EtOAc/hexane to give 0.602 g (2.57 mmoles, 19%) of 1,2-dibenzylbenzene (mp: 61° to 67° C.).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[NH2:21][NH2:22]>C(O)C>[NH:21]([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:8]=[CH:7][N:6]=1)[NH2:22]
Reactant: CS(=O)(=O)c1nccc(-c2cccc(C(F)(F)F)c2)n1
Reactant: NN
Solvent: CCO
Product: NNc1nccc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
A solution of 6.0 g. of 2-methylsulfonyl-4-(m-trifluoromethylphenyl)pyrimidine in 75 ml. of absolute ethanol is treated with 1.9 g. of 95% hydrazine and is refluxed for 8 hours. Isolation as in the previous example gives the desired compound, m.p. 103°-106° C.; resolidifies and melts at 120°-122° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)[CH:5]=[CH:4][CH:3]=1.[CH3:14][N:15]1[CH:19]=[C:18]([NH2:20])[CH:17]=[N:16]1.CN(C1C=CC=CN=1)C.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[Br:1][C:2]1[N:7]=[C:6]([C:8]([CH3:13])([CH3:12])[C:9]([NH:20][C:18]2[CH:17]=[N:16][N:15]([CH3:14])[CH:19]=2)=[O:11])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C(=O)O)c1cccc(Br)n1
Reactant: Cn1cc(N)cn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Product: Cn1cc(NC(=O)C(C)(C)c2cccc(Br)n2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-(6-bromopyridin-2-yl)-2-methylpropanoic acid (120 mg, 0.49 mmol) in dimethylformamide (3 mL) was charged with 1-methyl-1H-pyrazol-4-amine (48 mg, 0.49 mmol). Dimethylaminopyridine (60 mg, 0.49 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (94 mg, 0.49 mmol) were added and the reaction was stirred overnight at room temperature. The reaction was purified by reverse phase HPLC (10-100% acetonitrile/water+0.05% TFA modifier) to afford the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)(=[O:27])=[O:26])[CH:20]=[CH:21][C:22]=2[F:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][Zn]C>>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:36])[N:7]=2)=[C:9]([C:17]2[C:18]([F:35])=[C:19]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)(=[O:27])=[O:26])[CH:20]=[CH:21][C:22]=2[F:23])[N:10]=1)([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1nc(-c2c(F)ccc(NS(=O)(=O)c3cccc(F)c3)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: C[Zn]C
Product: Cc1nccc(-c2sc(C(C)(C)C)nc2-c2c(F)ccc(NS(=O)(=O)c3cccc(F)c3)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 25 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-3-fluorobenzenesulfonamide (100 mg, 0.186 mmol) and dimethylzinc (0.186 mL, 0.371 mmol), the title compound was obtained as an off white solid (90 mg, 94% yield). MS (ESI): 519.1 [M+H]+.
Reaction SMILES: F[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[NH2:12][C:13]1[CH:14]=[C:15]2[C:28](=[CH:29][CH:30]=1)[CH2:27][C:17]1([C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[NH:19][C:18]1=[O:26])[CH2:16]2>CC(O)C>[O:26]=[C:18]1[NH:19][C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:25]2[C:17]21[CH2:16][C:15]1[C:28](=[CH:29][CH:30]=[C:13]([NH:12][C:6]3[CH:5]=[CH:4][N:3]=[CH:2][C:7]=3[C:8]([OH:10])=[O:9])[CH:14]=1)[CH2:27]2
Reactant: O=C(O)c1cccnc1F
Reactant: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Agent: Cl
Solvent: CC(C)O
Product: O=C(O)c1cnccc1Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C

Procedure:
0.13 g (0.92 mmol) of 2-fluoropyridine-3-carboxylic acid and 20 μL (0.08 mmol) of a 4M aqueous HCl solution were added to 0.20 g (0.78 mmol) 5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one in 5.0 mL of 2-propanol. The reaction mixture was refluxed for 2 h, then cooled to RT and the resulting solid was filtered off and dried.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[C:24](=[O:25])[C:23]3[S:22][C:21]4[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=4[C:15]=3[CH:14]=[N:13]2)=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[CH:32]=[C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][C@@H:44]([CH3:46])[N:43]([CH:47]4[CH2:50][O:49][CH2:48]4)[CH2:42][C@@H:41]3[CH3:51])=[CH:36][N:35]=2)[C:30](=[O:52])[N:29]([CH3:53])[CH:28]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[CH3:51][C@H:41]1[CH2:42][N:43]([CH:47]2[CH2:50][O:49][CH2:48]2)[C@H:44]([CH3:46])[CH2:45][N:40]1[C:37]1[CH:38]=[CH:39][C:34]([NH:33][C:31]2[C:30](=[O:52])[N:29]([CH3:53])[CH:28]=[C:27]([C:7]3[C:6]([CH2:5][OH:4])=[C:11]([N:12]4[C:24](=[O:25])[C:23]5[S:22][C:21]6[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=6[C:15]=5[CH:14]=[N:13]4)[CH:10]=[C:9]([F:26])[CH:8]=3)[CH:32]=2)=[N:35][CH:36]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4C[C@@H](C)N(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)c2)cc(F)cc1-n1ncc2c3c(sc2c1=O)CCCC3
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: C[C@@H]1CN(c2ccc(Nc3cc(-c4cc(F)cc(-n5ncc6c7c(sc6c5=O)CCCC7)c4CO)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Temperature: 30 °C
Reaction time: 1 h
Yield: 38.2 %

Procedure:
A mixture of 118a (100 mg, 0.135 mmol) and lithium hydroxide (33 mg, 1.35 mmol) in i-propanol/THF (1:1, 4 mL) and water (1 mL) was stirred at 30° C. for 1 h. The mixture was evaporated under reduced pressure. The resulting residue was extracted with ethyl acetate (2×10 mL). The combined organic layer was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 118 (36 mg, 38%) as a white solid. MS: [M+H]+ 698.3. 1H NMR (500 MHz, CDCl3) δ 8.64 (d, J=2.0 Hz, 1H), 8.27 (s, 1H), 8.05 (d, J=2.0 Hz, 1H), 7.88 (s, 1H), 7.48 (d, J=2, 5 Hz, 1H), 7.37 (d, J=5.5 Hz, 1H), 7.30 (dd, J=2.5, 9.0 Hz, 1H), 7.11 (dd, J=2.5, 8.5 Hz, 1H), 6.82 (d, J=9.0 Hz, 1H), 4.79-4.73 (m, 2H), 4.67-4.61 (m, 2H), 4.31 (s, 2H), 3.77 (t, J=7.0 Hz, 1H), 3.72 (s, 3H), 3.21-3.19 (m, 1H), 2.99-2.98 (m, 2H), 2.94-2.91 (m, 1H), 2.88-2.86 (m, 2H), 2.78-2.71 (m, 2H), 2.51-2.49 (m, 1H), 1.99-1.96 (m, 6H), 0.92-0.90 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[O:13][C:14]3[CH:24]=[C:23]4[C:18]([CH:19]=[CH:20][CH:21]=[CH:22]4)=[CH:17][C:15]=3[N:16]=2)[C:5]([NH:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:7]=1.[CH:25]1[C:30]([C:31]([OH:33])=[O:32])=[CH:29][C:28]2[C:34]([O:36][C:37](=O)[C:27]=2[CH:26]=1)=[O:35]>>[O:13]1[C:14]2[CH:24]=[C:23]3[C:18](=[CH:17][C:15]=2[N:16]=[C:12]1[C:4]1[CH:3]=[C:2]([N:1]2[C:34](=[O:35])[C:28]4[C:27](=[CH:26][CH:25]=[C:30]([C:31]([OH:33])=[O:32])[CH:29]=4)[C:37]2=[O:36])[CH:7]=[CH:6][C:5]=1[NH:8][CH2:9][CH2:10][CH3:11])[CH:19]=[CH:20][CH:21]=[CH:22]3
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: CCCNc1ccc(N)cc1-c1nc2cc3ccccc3cc2o1
Product: CCCNc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc3ccccc3cc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-propylaminophenyl)naphth[2,3-d]oxazole (100 mg, 0.32 mmol) and 1,2,4-benzenetricarboxylic anhydride (67 mg, 0.35 mmol) the title compound was obtained (97 mg, 62%). 1H NMR (DMSO) δ 8.61(t, 1H), 8.42(dd, 1H), 8.32(m, 2H), 8.19(m, 2H), 8.11–8.05(m, 3H), 7.51(m, 3H), 7.05(d, 1H), 3.39(q, 2H), 1.79(m, 2H), 1.10(t, 3H). MS 490.0 m/z (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[CH3:32][N:33]([CH3:38])[C:34](=[O:37])[CH:35]=[CH2:36]>>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([CH:36]=[CH:35][C:34](=[O:37])[N:33]([CH3:38])[CH3:32])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1cc(Br)cc(C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: C=CC(=O)N(C)C
Product: COC(=O)c1cc(C=CC(=O)N(C)C)cc(C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 80 %

Procedure:
In the same manner as described in Example 203, 550.4 mg (1.0 mmol) of the product of Example 89 and 297.4 mg (3.0 mmol) of N,N-dimethylacrylamide provided 419 mg (80%) of the desired product as a white solid. Electrospray Mass Spec 524(M+H).
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:6]=[C:7]([C:11]2[O:15][N:14]=[C:13]([OH:16])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1.[CH2:17]([CH:19]1[O:21][CH2:20]1)Br>CN(C)C=O>[Cl:4][C:5]1[CH:6]=[C:7]([C:11]2[O:15][N:14]=[C:13]([O:16][CH2:17][CH:19]3[O:21][CH2:20]3)[CH:12]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: Oc1cc(-c2cccc(Cl)c2)on1
Reactant: BrCC1CO1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cccc(-c2cc(OCC3CO3)no2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
29.6 g (0.153 moles) of sodium methoxide (as a 28% w/v methanolic solution) were added to a solution of 30.0 g (0.153 moles) of 5-(m-chlorophenyl)-3-hydroxyisoxazole in 300 ml of dimethylformamide, and the mixture was stirred at room temperature for 30 minutes. At the end of this time, 41.9 g (0.306 moles) of epibromohydrin were added dropwise, and the mixture was stirred for a further 3 days. The reaction mixture was then concentrated by evaporation under reduced pressure, and the residue was diluted with ethyl acetate. The resulting mixture was washed with 800 ml of a 10% w/v aqueous solution of sodium chloride. The organic layer was then dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, eluted with a 2:1 by volume mixture of benzene and ethyl acetate, to give a solid residue, which was recrystallized from diisopropyl ether, to give 23.6 g (yield 73.5%) of the title compound as colorless needles, melting at 86°-87° C.