Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[O:4][C:5]([CH3:18])=[CH:6][C:7](=[O:17])[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:2].S(=O)(=O)([OH:21])N.Cl([O-])=O.[Na+]>CC(C)=O.O>[C:1]([C:3]1[O:4][C:5]([CH3:18])=[CH:6][C:7](=[O:17])[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([OH:21])=[O:2]
Reactant: NS(=O)(=O)O
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(C=O)o1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(=O)c(OCc2ccccc2)c(C(=O)O)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Formyl-3-benzyloxy-6-methyl-pyran-4(1H)-one (3.67 g, 15.03 mmol, 1 eq) was dissolved in acetone (50 ml) and the solution diluted with water (50 ml). To the reaction mixture was added sulfamic acid (2.04 g, 21.04 mmol, 1.4 eq) and 80% sodium chlorite (1.78 g, 15.8 mmol, 1.05 eq) and allowed to stir for 1 hour at room temperature in an open vessel. Removal of acetone in vacuo yielded crude product as a precipitate in the remaining aqueous solution. The solid was collected, washed with absolute ethanol and dried (3.32 g, 85%). m.p. 173-175° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:14]=[C:15]([CH:39]=[CH:40][CH:41]=1)[CH2:16][CH2:17][NH:18][C:19]1[C:20](=[O:38])[N:21]([CH2:27][C:28]([O:30]CC2C=CC=CC=2)=[O:29])[C:22]([CH3:26])=[C:23](Cl)[N:24]=1)[CH2:10][O:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+].[OH-].[Na+]>[Pd].CO>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:14]=[C:15]([CH:39]=[CH:40][CH:41]=1)[CH2:16][CH2:17][NH:18][C:19]1[C:20](=[O:38])[N:21]([CH2:27][C:28]([OH:30])=[O:29])[C:22]([CH3:26])=[CH:23][N:24]=1)[CH2:10][O:11][CH3:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COCC(NC(=O)OC(C)(C)C)c1cccc(CCNc2nc(Cl)c(C)n(CC(=O)OCc3ccccc3)c2=O)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COCC(NC(=O)OC(C)(C)C)c1cccc(CCNc2ncc(C)n(CC(=O)O)c2=O)c1
Yield: 18.1 %

Procedure:
A mixture of benzyl 2-[3-[(3-{(1R/S)-1-[(tert-butoxycarbonyl)amino]-2-methoxyethyl}phenethyl)amino]-5-chloro-6-methyl-2-oxo-1(2H)-pyrazinyl]acetate (preparation 122) (248 mg, 0.42 mmol), ammonium formate (265 mg, 4.2 mmol) and 10% palladium on charcoal (100 mg) in methanol (10 ml) was heated under reflux for 25 hrs. The cooled reaction was filtered through Arbocel®, and NaOH (420 ml, 10M, 4.2 mmol) was added to the filtrate. This mixture was evaporated under reduced pressure, triturated and filtered with a dichloromethane:methanol (91:9) solution (3×), and the combined filtrates evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol (100:0 to 93:7) to give the title compound as an oil, (35 mg, 18%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH2:10][CH3:11])[CH:3]=1.Br[CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:25])([F:26])[F:27])=[CH:19][CH:18]=2)=[C:4]([CH2:10][CH3:11])[CH:3]=1
Reactant: CCc1cc(Br)cc(C)c1O
Reactant: FC(F)(F)Oc1ccc(OCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(Br)cc(C)c1OCCCOc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
To a mixture of 10 g of 4-bromo-2-ethyl-6-methylphenol, 14.0 g of 1-(3-bromopropyloxy)-4-trifluoromethoxybenzene and 100 ml of N,N-dimethylformamide was added 7 g of potassium carbonate, while stirring at room temperature. After stirring at room temperature for 12 hours, the reaction mixture was poured into ice water, and extracted twice with 200 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 18.1 g of 4-bromo-2-ethyl-6-methyl-1-[3-(4-trifluoromethoxyphenoxy)propyloxy]benzene 90% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH:13]1[CH:22]2[CH:17]([CH:18]=[CH:19][CH:20]=[CH:21]2)[C:16](=[O:23])[CH2:15][CH2:14]1.C(N(CC)CC)C.N1C2C(=CC=CC=2)C=NC=1>O1CCOCC1.CC(=O)OCC>[I:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[N:13]1[CH:22]2[CH:17]([CH:18]=[CH:19][CH:20]=[CH:21]2)[C:16](=[O:23])[CH2:15][CH2:14]1
Reactant: O=C1CCNC2C=CC=CC12
Reactant: Clc1ncnc2ccc(I)cc12
Agent: c1ccc2ncncc2c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C1CCN(c2ncnc3ccc(I)cc23)C2C=CC=CC12
Yield: 38.4 %

Procedure:
0.75 g of 4-chloro-6-iodoquinazoline, 0.51 g of 2,3,4a,8a-tetrahydro-1H-quinolin-4-one and 0.96 ml of triethylamine in 5 ml of dioxane are heated at 80° C. in a flask until the quinazoline has reacted completely (HPLC check, about 24 hours). The cooled reaction solution is diluted with EA and washed 3 times with water. The organic phase is dried over sodium sulfate and purified by means of column chromatography (gradient heptane: EA 5-100% in 16 min.), giving 0.40 g of 1-(6-iodoquinazolin-4-yl)-2,3,4a,8a-tetrahydro-1H-quinolin-4-one as yellowish solid (yield 40%, content 91%); MS-FAB (M+H+)=402.0; Rf (polar method): 2.20 min.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:3]=1[CH3:22].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][C:3]1[C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5][N:6]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[C:2]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1cn(S(=O)(=O)c2ccc(C)cc2)c(Br)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1cn(S(=O)(=O)c2ccc(C)cc2)c(-c2ccccc2)c1C
Yield: 43.3 %

Procedure:
Ethyl 5-bromo-4-methyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrrole-3-carboxylate (1.0 g), phenylboronic acid (473 mg), sodium carbonate (823 mg) and tetrakis(triphenylphosphine)palladium (299 mg) were suspended in a mixture of 1,2-dimethoxyethane (10 mL) and distilled water (10 mL), and the mixture was refluxed under a nitrogen atmosphere for 16 hr. The reaction mixture was filtrated, water was added to the filtrate and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→1:1) to give the title compound as a pale-brown oil (yield 430 mg, 42%).
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH2:16][CH2:17][OH:18])[CH:13]=[C:12]([CH2:19]N(CC)CC)[C:11]=2[OH:25])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[N:26]1[N:27]([C:35]2[CH:40]=[C:39]([CH2:41][CH2:42][OH:43])[CH:38]=[CH:37][C:36]=2[OH:44])[N:28]=[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=12.CO.C[O-].[Na+]>C1(C)C(C)=CC=CC=1>[CH2:19]([C:12]1[CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[CH:15]=[C:10]([N:2]2[N:3]=[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]3=[N:1]2)[C:11]=1[OH:25])[C:37]1[CH:38]=[C:39]([CH2:41][CH2:42][OH:43])[CH:40]=[C:35]([N:27]2[N:28]=[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]3=[N:26]2)[C:36]=1[OH:44]
Reactant: OCCc1ccc(O)c(-n2nc3ccccc3n2)c1
Reactant: CCN(CC)Cc1cc(CCO)cc(-n2nc3ccccc3n2)c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1C
Product: OCCc1cc(Cc2cc(CCO)cc(-n3nc4ccccc4n3)c2O)c(O)c(-n2nc3ccccc3n2)c1
Temperature: 25 °C
Yield: 54 %

Procedure:
In 100 ml of xylene were dissolved 34.7 g of crude 2-(2H-benzotriazole-2-yl)-4-(2-hydroxyethyl)-6-(N,N-diethylaminomethyl)phenol synthesized in Example 9 and 25.5 g (0.1 mols) of the purified product of 2-(2H-benzotriazole-2-yl)-4-(2-hydroxyethyl)phenol synthesized in Example 6. 5 ml of methanol solution of 28% sodium methylate was added, and the mixture was refluxed in a nitrogen stream for 10 hours. After completion of the reaction, the reaction mixture was cooled to room temperature. Precipitated yellow crystals were collected by filtration and recrystallized in chloroform, giving 28.5 g of 2,2'-methylenebis[6-(2H-benzotriazole-2-yl)-4-(2-hydroxyethyl)phenol] as white crystals (yield 54%, purity 98.9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[NH:8][C:7]=2[N:13]=1.[H-].[Li+].Br[CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[I-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:22]([O:21][CH2:20][CH2:19][CH2:18][CH2:17][N:8]1[C:9](=[O:12])[CH:10]=[N:11][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:13][C:7]1=2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc2ncc(=O)[nH]c2n1
Reactant: BrCCCCOCc1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2ncc(=O)n(CCCCOCc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 73.6 %

Procedure:
In N,N-dimethylformamide (15 ml) was dissolved 6-Methoxypyrido[2,3-b]pyrazin-3(4H)-one (600 mg, 3.39 mmol). The solution was cooled in an ice bath, lithium hydride (purity 90%, 35.9 mg, 4.06 mmol) was then added thereto and the mixture was stirred at room temperature for 40 minutes. The reaction solution was cooled again in an ice bath, benzyl 4-bromobutyl ether (0.774 ml, 4.06 mmol) and sodium iodide (609 g, 4.06 mmol) were added and then the mixture was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, washed sequentially with saturated sodium chloride solution (2×), water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to yield 847 mg (74%) of the title compound in the form of a light yellow syrup.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:24])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][OH:23])[CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:27][C@H:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[C:34]1[N:38]2[CH:39]=[C:40]([O:43][C@H:44]3[C:53]4[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=4)[C@@H:47]([NH2:54])[CH2:46][CH2:45]3)[CH:41]=[CH:42][C:37]2=[N:36][N:35]=1.CCN(C(C)C)C(C)C.CO>O1CCOCC1.C(Cl)Cl>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:54][C@@H:47]2[C:48]3[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=3)[C@H:44]([O:43][C:40]3[CH:41]=[CH:42][C:37]4[N:38]([C:34]([N:29]5[CH2:30][CH2:31][CH2:32][CH2:33][C@@H:28]5[CH3:27])=[N:35][N:36]=4)[CH:39]=3)[CH2:45][CH2:46]2)=[O:24])[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][OH:23])[CH:17]=2)[N:9]=1)([CH3:14])([CH3:15])[CH3:13]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(CO)c2)n1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CO
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(CO)c4)c4ccccc43)cn12
Yield: 72.4 %

Procedure:
A brown solution of Intermediate 29c (177 mg, 0.420 mmol), Intermediate 81d (151 mg, 0.400 mmol) and DIPEA (0.087 mL, 0.50 mmol) in dry dioxane (5 mL) was stirred at 100° C. for 3 h. The cooled solution was concentrated in vacuo, suspended in water (10 mL) and extracted with DCM (2×10 mL). The combined organics were passed through a hydrophobic frit and concentrated under vacuum to leave a dark brown gum. FCC, using 3-8% MeOH in DCM, gave the title compound as an orange solid (188 mg, 72%). LCMS (Method 4): Rt 3.63 min, m/z 649 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[S:20][C:19]2[C:18]([NH:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[NH:27][CH:26]=[CH:25]4)=[N:17][CH:16]=[N:15][C:14]=2[CH:13]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[S:20][C:19]3[C:18]([NH:21][C:22]4[CH:23]=[C:24]5[C:28](=[CH:29][CH:30]=4)[NH:27][CH:26]=[CH:25]5)=[N:17][CH:16]=[N:15][C:14]=3[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Brc1cc2ncnc(Nc3ccc4[nH]ccc4c3)c2s1
Reactant: OB(O)c1ccc(F)cc1
Product: Fc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from p-fluorobenzeneboronic acid and (6-bromo-thieno[3,2-d]pyrimidin-4-yl)-(1H-indol-5-yl)-amine by a procedure analogous to example 2. 1H NMR (400 MHz, DMSO) d 11.4 (s, 1H), 8.82 (s, 1H), 7.79 (m, 4H), 7.41 (m, 5H), 7.21 (d, 1H). 6.50 (s, 1H), M.P. 193-205° C.; LC-MS: 361 (MH+); HPLC RT: 4.88 minutes.
Reaction SMILES: CC(C)(C)C([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[C:7]([C:17]2[C:18](=[O:33])[NH:19][C:20](=[O:32])[C:21]=2[C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH3:31])[CH:23]=2)=[CH:6]1)=O.O(C)[Na]>CO>[CH3:31][N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([C:21]2[C:20](=[O:32])[NH:19][C:18](=[O:33])[C:17]=2[C:7]2[C:8]3[C:13](=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=3)[NH:5][CH:6]=2)=[CH:23]1
Reactant: Cn1cc(C2=C(c3cn(C(=O)C(C)(C)C)c4cc([N+](=O)[O-])ccc34)C(=O)NC2=O)c2ccccc21
Agent: CO[Na]
Solvent: CO
Product: Cn1cc(C2=C(c3c[nH]c4cc([N+](=O)[O-])ccc34)C(=O)NC2=O)c2ccccc21
Yield: 28.2 %

Procedure:
Using the procedure of Example 1, Step F, the N-deprotection reaction of 1.3 g (2.76 mmol) of 3-[1-(2,2-dimethyl-propionyl)-6-nitro-1H-indol-3-yl]-4-(1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione (20) from Step D above with 4.3 ml (6.88 mmol) of a 1.6 molar solution of NaOCH3 in 65 ml of methanol yielded 300.6 mg (28.1%) of 3-(1-methyl-1H-indol-3-yl)-4-(6-nitro-1H-indol-3-yl)-pyrrole-2,5-dione (III) as a red solid after crystallization from ethyl acetate and hexane. mp>260° C. MS: (M+), m/z 386.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[C:3]1=[O:10].[C:11]([O-])(C)(C)C.[K+].CI>C(O)(C)(C)C>[CH3:1][C:2]1([CH3:11])[CH2:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[C:3]1=[O:10]
Reactant: CC1Cc2sccc2C1=O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CI
Product: CC1(C)Cc2sccc2C1=O
Reaction time: 1.5 h
Yield: 83.2 %

Procedure:
A solution of 28.6 g of 5,6-dihydro-5-methyl-4H-cyclopenta[b]thiophen-4-one in 210 ml of tert.-butanol is added dropwise at from +25° to +30° C. to a solution of 23.1 g of potassium tert.-butanolate in 250 ml of tert.-butanol. The dark reddish-brown solution is stirred for 1.5 hours, and then 12.9 ml of methyl iodide are added. After stirring for 1 hour, the reddish-brown suspension is filtered and the filtrate is concentrated by evaporation. After distillation of the residue there are obtained 26.0 g of 5,6-dihydro-5,5-dimethyl-4H-cyclopenta[b]thiophen-4-one in the form of a colourless oil having a boiling point of 43° C. at 0.03 mbar.
Reaction SMILES: Cl.[C:2]([NH:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)(=[O:4])[CH3:3].Cl.Cl[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])O.[Na+]>CC(C)CCO>[C:2]([NH:5][CH:6]1[CH2:11][CH2:10][N:9]([C:18]2[CH:17]=[CH:16][N:15]=[CH:14][CH:19]=2)[CH2:8][CH2:7]1)(=[O:4])[CH3:3]
Reactant: CC(=O)NC1CCNCC1
Reactant: Clc1ccccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)CCO
Product: CC(=O)NC1CCN(c2ccncc2)CC1

Procedure:
A mixture of the product from step (ii) (1.79 g), -chloropyridine hydrochloride (1.50 g), sodium hydrogen carbonate (2.86 g) in 3-methyl 1-butanol (25 ml) was heated at reflux temperature for 16 hours. The cooled mixture was filtered and the filtrate concentrated in vacuo. Purification of the residue by flash chromatography on silica, eluting with methanol/dichloromethane (1:2 v/v) gave 4-acetylamino-1-(4-pyridyl)piperidine as a foam, 0.69 g: NMR(d6DMSO) δ8.10(2H,d), 7.80(1H,bd), 6.80(2H,dd), 3.82(3H,m), 2.93(2H,dt), 1.78(3H,s), 1.77(2H,m), 1.33(2H,dq); m/e 220 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:27])[C@H:10]([N:18](C(OC(C)(C)C)=O)[CH3:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:27])[C@H:10]([NH:18][CH3:19])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](Cc1ccccc1)C(=O)NCCCOC(C)=O
Reaction time: 0.17 h
Yield: 94.9 %

Procedure:
A solution of 3-((2R)-2-(N-tert-butoxycarbonyl-N-methylamino)-3-phenyl-propionylamino)propyl acetate (862 mg, 2.28 mmol) in dichloromethane (3 mL) was cooled to 0° C. Trifluoroacetic acid (3 mL) was added. The solution was stirred for 10 min. The solvents were removed in vacuo without warming. The residue was dissolved in dichloromethane (50 mL) and the solvent was removed in vacuo. The procedure was repeated twice. The crude product was purified by flash chromatography on silica (70 g) with dichloromethane/methanol/25% ammonia in water (100:10:1) to give 602 mg of 3-((2R)-2-(methylamino)-3-phenylpropionylamino)propyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:8][C:7](=[O:9])[C:6]1[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=1)[OH:11])[CH3:18]
Reactant: CCO
Reactant: O=C(O)c1cc(Br)ccc1O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(Br)ccc1O
Temperature: 25 °C

Procedure:
To 5-bromosalicylic acid (25 g, 115 mmol) in ethyl alcohol (300 mL) was added sulfuric acid (98%, 2 mL). The mixture was refluxed in a Dean-Stark apparatus for 2 days. The reaction mixture was cooled to room temperature. Most of the ethyl alcohol was removed by distillation. The residue was diluted with ethyl acetate, washed with water, aq. Na2CO3 and brine. The organic layer was dried (Na2SO4) and the solvent was removed to afford the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:18]([OH:20])=O)[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:17]=1.Cl.[CH3:22][NH:23][O:24][CH3:25].CCN=C=NCCCN(C)C.Cl.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:25][O:24][N:23]([CH3:22])[C:18]([C:4]1[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:17]=[C:2]([OH:1])[CH:3]=1)=[O:20]
Reactant: CNOC
Reactant: O=C(O)c1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of acid 24 (0.35 g, 1.3 mmol), DMAP (0.5 g, 4.1 mmol), N,O Dimethylhydroxyl amine HCl (0.5 g, 5.1 mmol) in DMF (15 ml) was added EDCl (0.5 g, 2.6 mmol) and the reaction was stirred at rt for 1 hr. The reaction was then poured into 2N HCl and extracted with EtOAc, The EtOAc was dried, concentrated, and the resulting solid was triturated with CH2Cl2 and collected by filtration to give 119 as a white solid (0.22 g, 55%): Mp=125-127° C.; 1NMR (DMSO-d6) δ 9.88 (br s, 1 H), 9.44 (s, 1 H), 7.65(d, 2 H, 8.6 Hz), 7.08 (br s, 1 H), 6.97 (d, 1 H, J=2.3 Hz), 6.88 (d, 2 H, J=8.6 Hz), 6.71 (d, 1 H, J=2.6 Hz), 3.59 (s, 3 H), 3.30 (s, 3 H): MS 312 [M−H]−
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[H-].[Na+].[CH2:12]([O:19][C:20]([N:22]1[CH2:26][CH:25]2[CH2:27][CH:28]([CH2:30][O:31][C:32]3[CH:41]=[C:40]4[C:35]([C:36](Cl)=[N:37][CH:38]=[N:39]4)=[CH:34][C:33]=3[O:43][CH3:44])[CH2:29][CH:24]2[CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C.CCOC(C)=O>[CH2:12]([O:19][C:20]([N:22]1[CH2:23][CH:24]2[CH2:29][CH:28]([CH2:30][O:31][C:32]3[CH:41]=[C:40]4[C:35]([C:36]([O:8][C:5]5[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][C:4]=5[F:9])=[N:37][CH:38]=[N:39]4)=[CH:34][C:33]=3[O:43][CH3:44])[CH2:27][CH:25]2[CH2:26]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccc(O)c(F)c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CC2CN(C(=O)OCc3ccccc3)CC2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2c(Oc3ccc(N)cc3F)ncnc2cc1OCC1CC2CN(C(=O)OCc3ccccc3)CC2C1
Temperature: 25 °C
Yield: 149.6 %

Procedure:
4-Amino-2-fluoro-phenol (1.53 g, 12.0 mmol) was dissolved in dry DMF (30 ml) to which was added 60% NaH (774 mg, 19.3 mmol). After the mixture was stirred at room temperature for several minutes, a suspension of 5-(4-chloro-6-methoxy-quinazolin-7-yloxymethyl)-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid benzyl ester (4.70 g, 6.7 mmol) in dry DMF (40 ml) was added. The reaction mixture was stirred at room temperature for 1-2 hrs, then diluted with EtOAc and washed with sat'd NaHCO3 (3×), H2O (1×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo to give crude 5-[4-(4-amino-2-fluoro-phenoxy)-6-methoxy-quinazolin-7-yloxymethyl]-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid benzyl ester (5.6 g, ˜100%) which was used in the next reaction without further purification. 1H-NMR (400 MHz, DMSO): 8.50 (s, 1H), 7.48 (s, 1H), 7.34 (m, 5H), 7.28 (m, 1H), 7.02 (t, 1H), 6.48 (dd, 1H), 6.40 (dd, 1H), 5.40 (br s, 2H), 5.05 (s, 2H), 4.16 (d, 2H), 3.92 (s, 3H), 3.48 (m, 2H), 3.30 (m, 2H), 2.65 (m, 2H), 2.52 (m, 1H), 2.10 (m, 2H), 1.30 (m, 2H). LC/MS Calcd for [M+H]+ 559.2, found 559.4.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:35]([O:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][N:39]=1)[CH3:36]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[N:29]=[C:30]([C:41]5[CH:40]=[N:39][C:38]([O:37][CH2:35][CH3:36])=[CH:43][CH:42]=5)[CH:31]=[CH:32][CH:33]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Reactant: CCOc1ccc(B(O)O)cn1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5ccc(OCC)nc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2-ethoxy-5-pyridineboronic acid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]Cl)=[CH:18][CH:17]=1>CC(C)=O>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:1]2[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH2:2]2)=[CH:18][CH:17]=1
Reactant: ClCc1ccc(Br)cc1
Reactant: O=S1(=O)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=S1(=O)CCN(Cc2ccc(Br)cc2)CC1

Procedure:
To a well stirred suspension of thiomorpholine 1,1-dioxide (0.36 g, 2.7 mmol) and potassium carbonate (0.37 g, 2.7 mmol) in acetone (5 mL) was added 1-bromo-4-chloromethyl-benzene (0.50 g, 2.4 mmol). The mixture was stirred for 48 hours at room temperature. The mixture was filtered and the volatiles were evaporated. The residue was suspended in ether (100 mL), filtered and evaporated to a solid. The material was purified via chromatography utilizing an ISCO automated purification apparatus (24 g silica gel column 10%→100% ethyl acetate in hexane). 4-(4-Bromo-benzyl)-thiomorpholine 1,1-dioxide was isolated as a white solid (0.72 g, 97%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.47 (d, J=7.6 Hz, 2H), 7.19 (d, J=7.7 Hz, 2H), 3.60 (s, 2H), 3.08-2.94 (m, 8H). MS=304, 306 (MH)+. 114b) N-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}-8-[4-(methylsulfonyl)phenyl][1,2,4]triazolo[1,5-a]pyridin-2-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 4-(4-bromo-benzyl)-thiomorpholine 1,1-dioxide (90.0 mg, 0.296 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a pale yellow foam (0.039 g, 29%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.50 (d, J=6.7 Hz, 1H), 8.23 (d, J=7.4 Hz, 2H), 8.09 (d, J=8.0 Hz, 2H), 7.67 (d, J=6.9 Hz, 1H), 7.56 (d, J=7.2 Hz, 2H), 7.29 (d, J=7.8 Hz, 2H), 7.04 (t, J=7.2 Hz, 1H), 6.94 (s, 1H), 3.62 (s, 2H), 3.10 (s, 3H), 3.08-3.03 (m, 4H), 3.02-2.97 (m, 4H). MS=512 (MH)+.