Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH3:18][N:19]([CH3:30])[CH2:20][CH2:21][O:22][C:23]1[N:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:29][C:26]1[CH:27]=[N:28][C:23]([O:22][CH2:21][CH2:20][N:19]([CH3:30])[CH3:18])=[CH:24][CH:25]=1
Reactant: CN(C)CCOc1ccc(N)cn1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CN(C)CCOc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cn1
Yield: 74.7 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1 mmol) was reacted with 6-(2-(dimethylamino)ethoxy)pyridin-3-amine (340 mg, 1.8 mmol) to afford the desired product (340 mg, 75%) as a yellow solid: ESI MS m/z 455 [C22H23BrN4O2+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10](Cl)=[O:11])[CH:6]=[CH:7][CH:8]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1ccccc1
Reactant: COc1cccc(CC(=O)Cl)c1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cccc(CC(=O)Nc2ccccc2)c1
Reaction time: 3 h
Yield: 88.5 %

Procedure:
To a solution of 3-methoxyphenylacetyl chloride (2.3 g, 12.5 mmol) in ethyl acetate (30 mL) was added a solution of aniline (1.16 g, 12.5 mmol) in ethyl acetate (30 mL). After 3 hours, the reaction was poured into water (50 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated to provide the title compound (2.67 g, 89% yield): EI-MS (m/z) 241.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=S)[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:36][NH2:37].O>C1COCC1>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=[N:36][NH2:37])[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=S)CO4)cc2)CCC1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=NN)CO4)cc2)CCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl(1-(4-(7-phenyl-2-thioxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (20 mg, 0.04 mmol) in THF (2 mL) was added hydrazine.H2O (10 μL, 0.20 mmol) under nitrogen. The resulting mixture was stirred at room temperature for 1.5 h. After cooled down to room temperature, the mixture was concentrated to dryness under reduced pressure to give the title compound which was used directly in the next step without any purification.
Reaction SMILES: [OH:1][CH:2]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)[C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[C:14](=[O:15])[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][CH:18]=3)=[C:12]([CH2:31][CH2:32][CH3:33])[N:11]3[N:34]=[CH:35][N:36]=[C:10]23)[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl>CS(C)=O>[CH3:44][O:43][C:40]1[CH:39]=[CH:38][C:37]([C:2]([C@H:3]2[CH2:4][CH2:5][C@H:6]([N:9]3[C:14](=[O:15])[C:13]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([C:23]5[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=5)=[CH:19][CH:18]=4)=[C:12]([CH2:31][CH2:32][CH3:33])[N:11]4[N:34]=[CH:35][N:36]=[C:10]34)[CH2:7][CH2:8]2)=[O:1])=[CH:42][CH:41]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](C(O)c3ccc(OC)cc3)CC2)c2ncnn12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](C(=O)c3ccc(OC)cc3)CC2)c2ncnn12
Reaction time: 2 h

Procedure:
To a mixture of 4′-[(4-{trans-4-[hydroxy(4-methoxyphenyl)methyl]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (2.2 g), triethylamine (2.6 mL) and dimethyl sulfoxide (10 mL) was added a solution (10 mL) of sulfur trioxide-pyridine complex (1.8 g) in dimethyl sulfoxide at room temperature, and the mixture was stirred for 2 hr. The reaction mixture was poured into 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.7 g, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[S:30]1[CH:34]=[CH:33][N:32]=[C:31]1[CH2:35]O>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:35][C:31]5[S:30][CH:34]=[CH:33][N:32]=5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: OCc1nccs1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1Cc1nccs1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(1,3-thiazol-2-ylmethyl)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and thiazol-2-yl-methanol following General Procedure J.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].[CH:34]([O:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH2:35].C(N(CC)CC)C>C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].CN(C=O)C>[CH2:37]([O:36][C:34]([C:2]1[CH:3]=[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][CH:25]=2)=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:16])[F:18])[CH:10]=2)[C:7]=1[CH3:8])=[CH2:35])[CH2:38][CH2:39][CH3:40]
Reactant: Cc1c(I)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: C=COCCCC
Agent: [Pd]
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=C(OCCCC)c1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C
Temperature: 100 °C
Yield: 28.5 %

Procedure:
5-Iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (Example 1 (d), 101.5 mg, 0.17 mmol), bis[1,2-bis(diphenylphosphino)ethane]-palladium (0) (16.5 mg, 18.3 μmol), n-butyl vinyl ether (60 μl, 0.46 mmol), triethylamine (0.5 ml, 3.6 mmol) and DMF (6 ml) were placed in a Schlenk vessel equipped with a magnetic stirring bar. The vessel was purged with argon, sealed, and heated at 100° C. overnight. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound as a white solid (27.3 mg, 28%).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Cl:6][C:7]1[CH:12]=[C:11]([N:13]2[C:18](=[O:19])[NH:17][C:16](=[O:20])[CH:15]=[N:14]2)[CH:10]=[CH:9][C:8]=1[CH:21]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:22]#[N:23]>O>[Cl:6][C:7]1[CH:12]=[C:11]([N:13]2[C:18](=[O:19])[NH:17][C:16](=[O:20])[CH:15]=[N:14]2)[CH:10]=[CH:9][C:8]=1[CH:21]([C:24]1[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=1)[C:22]([NH2:23])=[O:2]
Reactant: N#CC(c1ccc(Cl)cc1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Reactant: O=S(=O)(O)O
Solvent: O
Product: NC(=O)C(c1ccc(Cl)cc1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
To 30 parts of a sulfuric acid solution in water (90:10 by volume) were added portionwise during a period of 5 minutes 2 parts of 2-chloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetonitrile at room temperature. Upon completion, stirring was continued for 2 hours at 80° C. The reaction mixture was poured into ice water. The product was filtered off, washed with water and purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated in vacuo. The residue was stirred in 2,2'-oxybispropane. The product was filtered off and dried, yielding 1.1 parts (54%) of 2-chloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-benzeneacetamide; mp. 160.7° C. (intermediate 26).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:14]=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:12]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:11][C:7]=2[C:8](=[O:10])[CH:9]=1)(O)=[O:2].S(Cl)([Cl:29])=O.CN(C)C=O>C(Cl)Cl>[CH3:19][S:16]([NH:15][C:13]1[C:12]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:11][C:7]2[C:8](=[O:10])[CH:9]=[C:4]([C:1]([Cl:29])=[O:2])[O:5][C:6]=2[CH:14]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Nc1cc2oc(C(=O)O)cc(=O)c2cc1Oc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cc2oc(C(=O)Cl)cc(=O)c2cc1Oc1ccccc1
Yield: 98.5 %

Procedure:
3.0 g of 2-carboxy-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was suspended in 30 ml of methylene chloride. Thereto were added 3.8 g of thionyl chloride and 0.1 ml of N,N-dimethylformamide. The mixture was refluxed for 1.5 hours. After the completion of the reaction, the solvent was removed by distillation under reduced pressure to obtain 3.1 g (yield: 98.4%) of 7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one-2-carboxylic acid chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[NH:7][C:8]1[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=1[C:10]([NH:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[O:11])([O-:3])=[O:2].[H-].[Na+].ClC(Cl)(Cl)[C:29](Cl)=[O:30]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([N:7]2[C:8]3[C:9](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:10](=[O:11])[N:12]([CH2:13][C:14]([F:15])([F:16])[F:17])[C:29]2=[O:30])[CH:22]=[CH:23][CH:24]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: O=C(NCC(F)(F)F)c1ccccc1Nc1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1c2ccccc2n(-c2cccc([N+](=O)[O-])c2)c(=O)n1CC(F)(F)F
Reaction time: 1 h
Yield: 87.4 %

Procedure:
To a solution of 3.4 g of 2-(m-nitroanilino)-N-(2,2,2-trifluoroethyl) benzamide and 25 ml of dry tetrahydrofuran was added 0.5 g of approximately 55 % sodium hydride, and stirring was continued for one hour at room temperature. To this was added dropwise under cooling 5.5 g of trichloroacetyl chloride and the mixture was allowed to stand for one hour at room temperature, and then refluxed for 5 hours. After the reaction was complete, the solvent was distilled off from the resulting mixture under reduced pressure. To the residue was added water to precipitate a crude product. This product was recrystallized from ethanol to give 3.2 g of 1-(m-nitrophenyl)-3-(2,2,2-trifluoroethyl) quinazoline-2,4(1H, 3H)-dione as pale yellow prisms, melting at 182°-184° C.
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:6]=2[CH2:5][CH2:4]1)[CH3:2].Cl[C:16]1[N:21]=[C:20]([NH:22][CH2:23][CH:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH3:25])[C:19]([Cl:31])=[CH:18][N:17]=1.Cl.O1CCOCC1>CC(O)C>[Cl:31][C:19]1[C:20]([NH:22][CH2:23][CH:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH3:25])=[N:21][C:16]([NH:14][C:11]2[CH:12]=[CH:13][C:6]3[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:9][CH2:8][C:7]=3[CH:10]=2)=[N:17][CH:18]=1
Reactant: CC(CNc1nc(Cl)ncc1Cl)NS(C)(=O)=O
Reactant: CCN1CCc2ccc(N)cc2CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(NCC(C)NS(C)(=O)=O)n3)cc2CC1
Temperature: 140 °C
Yield: 21.8 %

Procedure:
3-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (86.7 mg, 0.456 mmol, 1.0 eq) and N-[2-(2,5-dichloro-pyrimidin-4-ylamino)-1-methyl-ethyl]-methanesulfonamide (150 mg, 0.502 mmol, 1.1 eq) were dissolved in IPA (3 mL). 4.0 M HCl in dioxane (126 μL, 0.502 mmol, 1.1 eq) was added and the reaction was heated at 140° C. in a microwave for 90 minutes. The reaction was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 (20 mL) and washed with sat. NaHCO3 (20 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by amine capped silica gel chromatography using a gradient of 0-100% EtOAc/hex as the eluting solvent to obtain N-{2-[5-chloro-2-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-1-methyl-ethyl}-methanesulfonamide as a white foam (45 mg, 22%). LCMS (m/e) 453 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.95 (s, 1H), 7.32 (d, 1H, J=8.6 Hz), 7.06 (d, 1H, J=8.2 Hz), 6.93 (s, 1H), 5.72-5.62 (m, 1H), 5.41-5.31 (m, 1H), 3.81-3.65 (m, 2H), 3.55-3.43 (m, 1H), 2.99-2.86 (m, 4H), 2.90 (s, 3H), 2.74-2.60 (m, 4H), 2.60 (q, 2H, J=6.9 Hz), 1.32 (d, 3H, J=6.6 Hz), 1.12 (t, 3H, J=6.9 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:20]([OH:22])=O)=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])[N:5]2[C:10]=1[CH:9]=[CH:8][N:7]=[CH:6]2.[CH3:23][C:24]1([CH3:32])[O:28][C@@H:27]([CH2:29][O:30][NH2:31])[CH2:26][O:25]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:23][C:24]1([CH3:32])[O:28][C@@H:27]([CH2:29][O:30][NH:31][C:20]([C:3]2[C:2]([Cl:1])=[C:10]3[CH:9]=[CH:8][N:7]=[CH:6][N:5]3[C:4]=2[NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[O:22])[CH2:26][O:25]1
Reactant: CC1(C)OC[C@H](CON)O1
Reactant: O=C(O)c1c(Cl)c2ccncn2c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OC[C@H](CONC(=O)c2c(Cl)c3ccncn3c2Nc2ccc(I)cc2F)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.9 %

Procedure:
5-Chloro-7-(2-fluoro-4-iodo-phenylamino)-pyrrolo[1,2-c]pyrimidine-6-carboxylic acid (145 mg, 0.34 mmol), O—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (50 mg, 0.34 mmol), HOBt (50 mg, 0.37 mmol), EDCI hydrochloride (71 mg, 0.37 mmol) and DIPEA (63 μL, 0.37 mmol) were dissolved in DMF (3 mL). The reaction was stirred at room temperature for 3 hours then concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 25-100% ethylacetate in cyclohexane) to yield the title compound as a brown solid (57 mg, 25%). LCMS (Method B): RT=3.63 min, M+H+=561.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].Cl[CH2:10][C:11]([CH3:13])=[CH2:12].[OH-].[Na+].COS([O:21][CH3:22])(=O)=O>O>[CH3:10][C:11]1([CH3:13])[CH2:12][C:8]2[CH:7]=[CH:6][CH:5]=[C:3]([OH:4])[C:1]=2[O:2]1.[CH3:12][C:11]1([CH3:13])[CH2:10][C:8]2[CH:7]=[CH:6][CH:5]=[C:3]([O:21][CH3:22])[C:1]=2[O:2]1
Reactant: C=C(C)CCl
Reactant: COS(=O)(=O)OC
Reactant: Oc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)Cc2cccc(O)c2O1
Product: COc1cccc2c1OC(C)(C)C2

Procedure:
The starting material 2,3-dihydro-2,2-dimethyl-7-benzofuranol is prepared from catechol and 3-chloro-2-methylpropene as described by Neth. No. 6,500,340. The material (16.4 g) is added to 125 ml of water and contacted with 8 ml of 50% NaOH. After stirring one-half hour, 16.4 g of dimethylsulfate is added and the resulting suspension is stirred and heated at 60° for 2 hours. The resulting mixture is extracted with methylene chloride. The organic phase is dried over sodium sulfate and the solvent is evaporated under reduced pressure. The residual oil is distilled to afford 2,3-dihydro-2,2-dimethyl-7-methoxybenzofuran.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([CH2:10][N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH2:12][C:13](OC)=[O:14])=[CH:8][C:7]([Br:26])=[CH:6][N:5]=1.O>CS(C)=O>[Br:26][C:7]1[CH:6]=[N:5][C:4]2[NH:3][C:13](=[O:14])[CH2:12][N:11]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH2:10][C:9]=2[CH:8]=1
Reactant: COC(=O)CN(Cc1ccc(OC)cc1)Cc1cc(Br)cnc1N
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CN2CC(=O)Nc3ncc(Br)cc3C2)cc1
Reaction time: 8 h
Yield: 62.3 %

Procedure:
Sodium hydride (60% in oil, 140 mg, 3.40 mmol) was added to a solution of methyl 2-(((2-amino-5-bromopyridin-3-yl)methyl)(4-methoxybenzyl)amino)acetate (1.05 g, 2.66 mmol) in DMSO (17 mL) at room temperature. The reaction mixture was stirred overnight then diluted by addition of water (45 mL). After 2 hours stirring at room temperature, the reaction mixture was filtered. The resulting solid was dried under high vacuum to give the title compound as a yellow solid (600 mg, 63%) 1H NMR (DMSO-d6, 400 MHz): δ (ppm): 10.37 (s, 1H), 8.37 (s, 1H), 7.88 (s, 1H), 7.19 (d, J=8.4 Hz, 2H), 6.89 (d, J=8.4 Hz, 2H), 3.81 (s, 2H), 3.75 (s, 3H), 3.62 (s, 2H), 3.39 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:35]=[CH:34][CH:33]=[CH:32][C:7]=1[CH2:8][N:9]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][O:37]C1(C2C=CC=CC=2)CCCCN1.C(OC1C=CC=CC=1CN(CC1C=CC=CN=1)CCCCl)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>>[C:1]([O:5][C:6]1[CH:35]=[CH:34][CH:33]=[CH:32][C:7]=1[CH2:8][N:9]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[CH2:10][CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=2[O:37][CH3:36])[CH2:17][CH2:18]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Oc1ccccc1CN(CCCN1CCC(c2ccccc2)CC1)Cc1ccccn1
Reactant: COC1(c2ccccc2)CCCCN1
Agent: CC(C)(C)Oc1ccccc1CN(CCCCl)Cc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1C1CCN(CCCN(Cc2ccccn2)Cc2ccccc2OC(C)(C)C)CC1
Yield: 59 %

Procedure:
The same procedure as described for compound 20 was applied to 2-methoxy-2-phenylpiperidin (0.33 g, 1.73 mmol), compound 19 (0.4 g, 1.15 mmol), KI (0.57 g, 3.45 mmol) and K2CO3 (0.79 g, 5.75 mmol). Purification was carried out on a silica gel TLC plate that was developed in with a 5% methanolic NH3 (7 M NH3 in methanol/95% CH2Cl2. The product was isolated as pale yellow oil (59%). 1H NMR (CDCl3) δ 8.486 (m, 1H, Ar), 7.591 (m, 3H, Ar), 7.22 (dd, 1H, Ar), 7.135 (m, 3H, Ar), 7.017 (dd, 2H, Ar), 6.901 (dd, 1H, Ar), 6.819 (d, 1H, Ar), 3.781 (s, 3H, —OCH3), 3.764, (s, 2H, —CH2—), 3.691 (s, 2H, —CH2—), 3.002 (d, 2H, —CH2—), 2.939 (m, 1H, —CH—), 2.521 (t, 2H, —CH2—), 2.373 (t, 2H, —CH2—), 2.053 (m, 3H, —CH—CH2—), 1.769 (m, 6H), 1.354 (s, 9H, —C(CH3)3). Mass Spec.=502.34 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH2:22][C@@H:23]3[N:29]([CH:30]=2)[C:28](=[O:31])[C:27]2[CH:32]=[C:33]([O:74][CH3:75])[C:34]([O:36][CH2:37][CH2:38][CH2:39][O:40][C:41]4[C:71]([O:72][CH3:73])=[CH:70][C:44]5[C:45](=[O:69])[N:46]6[CH:61]=[C:60](S(C(F)(F)F)(=O)=O)[CH2:59][C@H:47]6[C:48](=[O:58])[N:49]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[C:43]=5[CH:42]=4)=[CH:35][C:26]=2[N:25]([CH2:76][O:77][CH2:78][CH2:79][Si:80]([CH3:83])([CH3:82])[CH3:81])[C:24]3=[O:84])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:60]2[CH2:59][C@@H:47]3[N:46]([CH:61]=2)[C:45](=[O:69])[C:44]2[CH:70]=[C:71]([O:72][CH3:73])[C:41]([O:40][CH2:39][CH2:38][CH2:37][O:36][C:34]4[C:33]([O:74][CH3:75])=[CH:32][C:27]5[C:28](=[O:31])[N:29]6[CH:30]=[C:21]([C:18]7[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:20][CH:19]=7)[CH2:22][C@H:23]6[C:24](=[O:84])[N:25]([CH2:76][O:77][CH2:78][CH2:79][Si:80]([CH3:81])([CH3:83])[CH3:82])[C:26]=5[CH:35]=4)=[CH:42][C:43]=2[N:49]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:55])([CH3:56])[CH3:57])[C:48]3=[O:58])=[CH:6][CH:5]=1
Reactant: COc1ccc(C2=CN3C(=O)c4cc(OC)c(OCCCOc5cc6c(cc5OC)C(=O)N5C=C(S(=O)(=O)C(F)(F)F)C[C@H]5C(=O)N6COCC[Si](C)(C)C)cc4N(COCC[Si](C)(C)C)C(=O)[C@@H]3C2)cc1
Reactant: NCc1ccc(B(O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(C2=CN3C(=O)c4cc(OC)c(OCCCOc5cc6c(cc5OC)C(=O)N5C=C(c7ccc(CN)cc7)C[C@H]5C(=O)N6COCC[Si](C)(C)C)cc4N(COCC[Si](C)(C)C)C(=O)[C@@H]3C2)cc1
Temperature: 30 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
Solid 4-aminomethylbenzeneboronic acid hydrochloride (0.111 g, 0.59 mmol) was added to a solution of 17 (0.394 g, 0.37 mmol), sodium carbonate (175 mg, 1.654 mmol) and palladium tetrakis triphenylphosphine (28.0 mg, 0.024 mmol) in toluene (10 mL), ethanol (5 mL) and water (5 mL). The reaction mixture was allowed to stir overnight at 30° C. The following day the reaction mixture was heated for a further 3 hours at 70° C. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulphate. Excess solvent was removed by rotary evaporation under reduced pressure and the resulting residue was subjected to flash column chromatography (silica gel; gradient elution EtOAc/hexane 2/98→15/85). Removal of excess eluent from selected fractions afforded the desired product (0.230 mg, 0.22 mmol, 61%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:42]=[CH:41][C:31]([C:32]([NH:34][CH2:35][CH2:36][C:37]([O:39]C)=[O:38])=[O:33])=[CH:30][CH:29]=4)=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[Li+].[OH-].O.Cl>C1COCC1.CO>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:42]=[CH:41][C:31]([C:32]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:29]=4)=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: COC(=O)CCNC(=O)c1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)CCNC(=O)c1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Compound 7a (0.20 g, 0.36 mmol) was suspended in THF/MeOH (4:1 v/v, 5 mL), and treated with 1 N LiOH solution (2.0 mL). The resulting mixture was stirred at rt for 3 h, and treated with water. The pH of the mixture was adjusted to ca. pH 5 using 1 N HCl solution. The resulting mixture was extracted with DCM (2×200 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue obtained was washed with MeOH, and dried under high vacuum to give the title compound 44 as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.14 (d, J=8.6 Hz, 1H), 8.06 (d, J=8.6 Hz, 1H), 7.97-8.03 (m, 3H), 7.94 (d, J=15.6 Hz, 1H), 7.76-7.86 (m, 3H), 7.64-7.76 (m, 3H), 7.46-7.55 (m, 1H), 6.15 (d, J=5.6 Hz, 1H), 4.08 (d, J=3.4 Hz, 4H), 4.01 (d, J=3.4 Hz, 4H), 3.74 (t, J=5.9 Hz, 2H), 2.70 (t, J=5.9 Hz, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C31H28N6O4: 549.2 (M+H). Found 549.2.