Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[CH3:28])[C:5]2[CH:11]=[CH:10][C:9](=[O:12])[N:8]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[C:6]=2[N:7]=1.[H-].[Na+].[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1>O1CCCC1>[F:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[N:8]1[C:6]2[N:7]=[C:2]([NH:1][C:34]([CH:31]3[CH2:33][CH2:32]3)=[O:35])[N:3]=[C:4]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[CH3:28])[C:5]=2[CH:11]=[CH:10][C:9]1=[O:12]
Reactant: Cc1cc(F)ccc1-c1nc(N)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: O=C(Cl)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(NC(=O)C2CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 0.33 h

Procedure:
To a solution of the product of Example 230(a), 2-amino-8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one (100 mg, 0.26 mmol) in 3 mL of tetrahydrofuran was added NaH (19 mg, 0.78 mmol). The mixture was stirred for 20 min at 23°, a soln of cyclopropanecarbonyl chloride (27 mg, 0.26 mmol) in tetrahydrofuran (1 mL) was added. The resulting mixture was heated to solvent reflux for 16 h to give the crude material, which was purified by preparative hplc to afford 25 mg (21%). LC-MS: 451.2 (MH+, m/z), 2.14 (Rt, min).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH2:11])=[C:8]([OH:10])[CH:9]=1)([O-:3])=[O:2].CO[CH:14]1[CH2:18][CH2:17][CH:16](OC)O1>C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH:14]=[CH:18][CH:17]=[CH:16]2)=[C:8]([OH:10])[CH:9]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(-n2cccc2)c(O)c1
Yield: 44.9 %

Procedure:
In a manner similar to Example 1, Step A, the reaction of 10.0 g (0.06 mole) of 5-nitro-2-aminophenol with 9.8 g (0.07 mole) of 2,5-dimethoxytetrahydrofuran in 20 ml of glacial acetic acid produced 5.5 g of 5-nitro-2-(1H-pyrrol-1-yl)phenol.
Reaction SMILES: C([O:8][C:9]([C:11]1([C:19]([O:21]CC2C=CC=CC=2)=[O:20])[CH2:16][CH2:15][P:14]([CH3:18])(=[O:17])[CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH3:18][P:14]1(=[O:17])[CH2:13][CH2:12][C:11]([C:9]([OH:10])=[O:8])([C:19]([OH:21])=[O:20])[CH2:16][CH2:15]1
Reactant: CP1(=O)CCC(C(=O)OCc2ccccc2)(C(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CP1(=O)CCC(C(=O)O)(C(=O)O)CC1
Reaction time: 2.5 h
Yield: 96.5 %

Procedure:
To a 500 mL Parr flask was added 1-methyl-1-oxo-1λ5-phosphinane-4,4-dicarboxylic acid dibenzyl ester (23.0 g, 59.7 mmol). The solid was fully dissolved in ethanol (200 mL). To the solution was added palladium on carbon (10%, 1.15 g), and the flask was charged with hydrogen gas (48 psi). The flask was agitated with a mechanical shaker for 2.5 hours, after which time the starting material was completely consumed as determined by LC-MS. A large amount of white precipitate was present in the reaction mixture. Water (100 mL) and methanol (100 mL) was added to dissolve the precipitate, and the palladium on carbon was removed by filtration through celite, washing with water/methanol (1:1). The resulting filtrate was concentrated in vacuo to remove most of the methanol and ethanol. The remaining water was removed by lyophilization to provide 1-methyl-1-oxo-1λ5-phosphinane-4,4-dicarboxylic acid (12.68 g, 96%) as a white free-flowing powder. 1H NMR (400 MHz, D2O) δ 2.40-2.20 (m, 4H), 1.95-1.85 (m, 4H), 1.49 (d, J=13.3 Hz, 3H); ESMS m/z: found, 423 (221 (M+1)+, 441 (2M+1)+.
Reaction SMILES: [F:1][C:2]1([F:27])[CH2:7][CH2:6][CH:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22](=[O:23])[C:21]4[C:20]([C:24]#[N:25])=[CH:19][C:18]([F:26])=[CH:17][C:16]=4[CH2:15]3)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.[OH2:28].N>C(O)(=O)C.S(=O)(=O)(O)O>[F:27][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[C:22](=[O:23])[C:21]4[C:20]([C:24]([NH2:25])=[O:28])=[CH:19][C:18]([F:26])=[CH:17][C:16]=4[CH2:15]3)[CH2:12][CH2:13]2)[CH2:4][CH2:3]1
Reactant: O
Reactant: N#Cc1cc(F)cc2c1C(=O)N(C1CCN(C3CCC(F)(F)CC3)CC1)C2
Agent: N
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: NC(=O)c1cc(F)cc2c1C(=O)N(C1CCN(C3CCC(F)(F)CC3)CC1)C2
Temperature: 80 °C

Procedure:
To a stirred solution of [2-[1-(4,4-difluorocyclohexyl)-piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carbonitrile (1.44 g, 3.82 mmol) in acetic acid (11 mL), concentrated sulfuric acid (5.8 mL) was added dropwise during 30 min. The reaction was then warmed at 80° C. for 9 hours, cooled at room temperature and poured into cold water (20 mL). The aqueous phase was then made basic by adding concentrated aqueous ammonia and extracted with dichloromethane (3×10 mL). The combined organic phases were washed with 2N aqueous sodium hydroxide (2×12 mL) and brine, dried over sodium sulfate, and evaporated to dryness in vacuo. The title compound was obtained as a white solid (1 g, 67%) after purification through column chromatography, using dichloromethane/ethanol:95/5 as the mobile phase.
Reaction SMILES: CS(O)(=O)=O.C(OC([N:13]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][CH2:32][CH3:33])[CH:25]=1)[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)=O)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+]>ClCCl.C(O)(=O)C.CO>[Cl:22][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][NH:13][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][CH2:32][CH3:33])[CH:25]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CCCOc1cccc(CN(CCc2cccc(Cl)c2)C(=O)OC(C)(C)C)c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CCCOc1cccc(CNCCc2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Add methanesulfonic acid (70 uL) to a solution of N-t-Butoxycarbonyl-N-2-(3-chlorophenyl)ethyl-3-propoxybenzylamine in dichloromethane (4 mL) and agitate the mixture for 3 hours at room temperature. Add 10% aqueous Na2CO3 (2 mL), separate the layers, and concentrate the organic layer in a nitrogen stream to give a residue. Dissolve the residue in 4 mL of 5% acetic acid in methanol and pass through a 1 gm SCX column, eluting with 1 M ammonia in methanol to give the title compound: MS (ES+): m/e (M+1). HPLC (10–90% water/acetonitrile over 7.5 min, Tr=4.490 min).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[CH:23]=[C:22]([CH:24]=O)[N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.C(OP([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])(OCC)=O)C.[H-].[Na+]>CN(C)C=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[CH:23]=[C:22](/[CH:24]=[CH:45]/[C:46]([O:48][CH2:49][CH3:50])=[O:47])[N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1cc(COc2cc(C=O)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cc(OCc2ccc(OCc3nc(-c4ccco4)oc3C)c(OC)c2)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76 %

Procedure:
To a mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-5-carbaldehyde (1.0 g), ethyl diethylphosphonoacetate (0.52 g) and N,N-dimethylformamide (30 mL) was added sodium hydride (60% in oil, 0.10 g) under ice-cooling, and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-5-yl}-2-propenoate as colorless crystals (0.87 g, yield 74%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 127-128° C.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:42])[CH:4]=[C:5]([C:8]([N:10]([CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])[NH:11][S:12]([NH:15][C:16]([N:18]2[CH2:21][C@H:20]([NH:22]C(OCC3C=CC=CC=3)=O)[C:19]2=[O:33])=[O:17])(=[O:14])=[O:13])=[O:9])[NH:6][CH:7]=1.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].C1(SC)C=CC=CC=1>>[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[NH2:22][C@H:20]1[CH2:21][N:18]([C:16]([NH:15][S:12]([NH:11][N:10]([CH2:34][C:35]([OH:37])=[O:36])[C:8]([C:5]2[NH:6][CH:7]=[C:2]([OH:1])[C:3](=[O:42])[CH:4]=2)=[O:9])(=[O:13])=[O:14])=[O:17])[C:19]1=[O:33]
Reactant: CC(C)(C)OC(=O)CN(NS(=O)(=O)NC(=O)N1C[C@H](NC(=O)OCc2ccccc2)C1=O)C(=O)c1cc(=O)c(O)c[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: N[C@H]1CN(C(=O)NS(=O)(=O)NN(CC(=O)O)C(=O)c2cc(=O)c(O)c[nH]2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 0° C., 2.39 g (3.9 mmol) of (3S)-[1-[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]-2-[[[[2-oxo-3-[[(phenylmethoxy)carbonyl]amino]-1-azetidinyl]carbonyl]amino]sulfonyl]hydrazino]acetic acid, 1,1-dimethylethyl ester was added to a mixture of 7.0 ml of trifluoroacetic acid and 1.66 ml of thioanisole. After stirring overnight at room temperature, the solution was evaporated in vacuo. The residue was successively washed (stirred) with ethyl acetate, ethyl acetate/petroleum ether (1:1), petroleum ether and dichloromethane and then dried in vacuo. This crude salt was used in the next step without any further purification. Yield: 2.15 g.
Reaction SMILES: [CH:1]1[N:5]([CH2:6][O:7][CH2:8][CH2:9][OH:10])[C:4]2[N:11]=[C:12]([NH2:16])[N:13]=[C:14]([OH:15])[C:3]=2[N:2]=1.[C@@H:17]1([N:26]2[CH:34]=[N:33][C:32]3[C:27]2=[N:28][CH:29]=[N:30][C:31]=3[NH2:35])[O:23][C@H:22]([CH2:24][OH:25])[C@@H:20]([OH:21])[C@@H:18]1[OH:19].C([O-])(O)=O.[Na+].C[C@@H](NC)[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3OC[C@@](O)(C)[C@H]([NH:66]C)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](N)CC1>>[CH:1]1[N:5]([C@@H:6]2[O:7][C@H:8]([CH2:9][OH:10])[C@@H:18]([OH:19])[C@H:17]2[OH:23])[N:66]=[C:3]([C:14]([NH2:13])=[O:15])[N:2]=1.[CH:1]1[N:5]([CH2:6][O:7][CH2:8][CH2:9][OH:10])[C:4]2[N:11]=[C:12]([NH2:16])[N:13]=[C:14]([OH:15])[C:3]=2[N:2]=1.[C@@H:17]1([N:26]2[CH:34]=[N:33][C:32]3[C:27]2=[N:28][CH:29]=[N:30][C:31]=3[NH2:35])[O:23][C@H:22]([CH2:24][OH:25])[C@@H:20]([OH:21])[C@@H:18]1[OH:19]
Reactant: CN[C@@H]1[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H]([C@@H](C)NC)CC[C@H]3N)[C@@H](N)C[C@H]2N)OC[C@]1(C)O
Agent: Nc1nc(O)c2ncn(COCCO)c2n1
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: O=C([O-])O
Product: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1

Procedure:
Ribavirin was obtained from ICN Pharmaceuticals, Costa Mesa, Calif. Acyclovir and 9β-D-arabinofuranosyladenine (ara-A) were purchased from Sigma Chemical Co., St. Louis, Mo. Ribavirin, acyclovir and ara-A were prepared and diluted in MEM without serum, plus 0.18% NaHCO3, 50 μg gentamicin/ml. Oligonucleotides were diluted in the same solution.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22]C1CCCCO1)(=[O:3])[CH3:2].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CCO.CCOC(C)=O>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCCCCCCCCCCCCCCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)OCCCCCCCCCCCCCCCCCO
Temperature: 55 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
THP ether 39 (1.207 g, 3.03 mmol) was dissolved in 95% EtOH (12 ml) and PPTS (76 mg, 0.3 mmol) was added. The mixture was stirred at 55° C. for 4 h, cooled to room temperature and diluted with EtOAc. This mixture was washed with H2O three times, the organic phase was dried over Na2SO4 and evaporated. The residue was chromatographed on silica gel to give 864 mg (91%) of 17-acetoxy-heptadecanol.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][CH:10]=[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=3)[C:14](=[O:22])[NH:13][C:12]2=[O:23])[CH:5]=[CH:4][C:3]=1C1C=CC=CC=1.[I:30]C1C=C2C(=CC=1)C(=O)NC(=O)C2=COC.NCC1C=C(O)C=CC=1I>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([I:30])=[C:6]([CH:7]=1)[CH2:8][NH:9][CH:10]=[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=2)[C:14](=[O:22])[NH:13][C:12]1=[O:23]
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Reactant: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccccc2)c(O)c1
Agent: NCc1cc(O)ccc1I
Product: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1cc(O)ccc1I
Yield: 73 %

Procedure:
Following the same procedure for the preparation of 4-{[(2-Hydroxy-biphenyl-4-ylmethyl)-amino]-methylene}-6-iodo-4H-isoquinoline-1,3-dione, the title compound is prepared from 6-iodo-4-methoxymethylene-4H-isoquinoline-1,3-dione (100 mg, 0.30 mmol) and 3-Aminomethyl-4-iodo-phenol (80 mg, 0.32 mmol) in 73% yield: MS (ESI): 545.0 (M−1)−1.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][C:5]1[C:6]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[N:7][C:8](F)=[N:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>CS(C)=O>[Cl:4][C:5]1[C:6]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[N:7][C:8]([C:1]#[N:2])=[N:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: Fc1nc(Nc2ccc(Cl)cc2)c(Cl)c(N2CCOCC2)n1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1nc(Nc2ccc(Cl)cc2)c(Cl)c(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium cyanide (0.057 g) was added to a solution of the product from step (ii) (0.2 g) in dimethylsulphoxide (5 ml) and the mixture stirred at room temperature. After 18 h, the mixture was partitioned between ethyl acetate and water, the organics separated, washed with water, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 5% ethyl acetate in toluene. Yield 0.09 g
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[C:6]([O:9][N+:10]12[CH2:17][CH2:16][N:13]([CH2:14][CH2:15]1)[CH2:12][CH2:11]2)(=[O:8])[CH3:7].B(F)(F)[F:19].FF>C(#N)C>[F:1][B-:2]([F:5])([F:4])[F:3].[F:1][B-:2]([F:5])([F:4])[F:3].[C:6]([O:9][N+:10]12[CH2:17][CH2:16][N+:13]([F:19])([CH2:12][CH2:11]1)[CH2:14][CH2:15]2)(=[O:8])[CH3:7]
Reactant: CC(=O)O[N+]12CCN(CC1)CC2
Reactant: FB(F)F
Agent: FF
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: CC(=O)O[N+]12CC[N+](F)(CC1)CC2

Procedure:
A solution of 1-acetoxy-4-aza-1-azoniabicyclo[2.2.2]octane tetrafluoroborate (25.8 g, 10 mmole) and boron trifluoride gas (6.7 g, 10 mmole) in acetonitrile (125 mL) was cooled to 8° C. and treated with a mixture of fluorine in nitrogen (10% V/V, 12 mmole). The reaction was evaporated, the remaining solid washed with dimethoxyethane and dried to afford 1-acetoxy-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]#[CH:17])[C:5]=1[C:6]([O:8][CH3:9])=[O:7]>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][C:4]1[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:10]2[C:11]([CH:17]=[CH:16][CH2:15][O:14]2)=[CH:12][CH:13]=1
Reactant: C#CCOc1cccc(COC)c1C(=O)OC
Solvent: Cc1ccccc1
Product: COCc1ccc2c(c1C(=O)OC)OCC=C2
Yield: 62.5 %

Procedure:
A mixture of methyl 2-methoxymethyl-6-propargyloxybenzoate (Intermediate 10, 1.4 g) and [Bis-(trifluoromethanesulfonyl)imidate](triphenyl phosphine) gold 2:1 complex with toluene (0.188 g) in toluene (40 mL) was stirred and heated under an atmosphere of nitrogen overnight. After cooling, the mixture was filtered through Celite and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica, eluting with a mixture of TBME and cyclohexane with a gradient of 0-30% to give methyl 7-methoxymethyl-2H-chromene-8-carboxylate (0.875 g) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[N:25]=[N:26][N:27]([CH2:29][CH2:30][C:31]([OH:34])([CH3:33])[CH3:32])[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:35]C(=O)C)[CH:10]=1.[CH:39]1([S:42](Cl)(=[O:44])=[O:43])[CH2:41][CH2:40]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[N:25]=[N:26][N:27]([CH2:29][CH2:30][C:31]([OH:34])([CH3:32])[CH3:33])[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:35][S:42]([CH:39]2[CH2:41][CH2:40]2)(=[O:44])=[O:43])[CH:10]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn(CCC(C)(C)O)nn4)ccc32)c1
Product: CC(C)(O)CCn1cc(-c2ccc3c(c2)ncn3-c2cc(NS(=O)(=O)C3CC3)cc(-c3ccc(F)cc3F)c2)nn1

Procedure:
The compound was prepared from the compound of Example 44 using the procedures of Example 45 and cyclopropane sulfonyl chloride. 1H NMR (400 MHz, CD3OD): δ 9.09 (s, 1H), 8.47 (s, 1H), 8.30 (s, 1H), 8.0 (d, 1H), 7.83 (d, 1H), 7.69-7.60 (m, 4H), 7.17-7.10 (m, 2H), 4.62-4.58 (m, 2H), 2.78-2.69 (m, 1H), 2.17-2.13 (m, 2H), 1.29-1.15 (m, 8H), 1.10-1.02 (m, 2H); LC-MS (ESI): Calculated mass: 578.63; Observed mass: 579.2 [M+H]+ (rt: 1.449 min).
Reaction SMILES: [CH2:1]([C@H:8]([CH2:19][C:20](=[O:27])[CH2:21][S:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:36])C=1>C(Cl)Cl>[CH2:1]([C@H:8]([CH2:19][C:20](=[O:27])[CH2:21][S:22]([C:23]([CH3:24])([CH3:26])[CH3:25])=[O:36])[C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)SCC(=O)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)S(=O)CC(=O)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Yield: 99.9 %

Procedure:
The resultant compound from Example 37 (44.4 mg, 0.115 mmol) in CH2Cl2 (2 ml) at -10° C. was treated with meta-chloroperbenzoic acid (25.0 mg, 0.116 mmol, 80% pure). After 2 h at -10°-0° C. the solvent was evaporated and the residue was dissolved in ethyl acetate which was washed with 1:1 10% Na2SO4 solution/ saturated NaHCO3 solution, saturated NaHCO3 solution and brine, and then dried over Na2SO4 and evaporated to afford 46.0 mg (99%) of a colorless oil. 1H NMR (CDCl3) δ7.05-7.40 (m,10H), 5.08 (m,2H), 3.36-3.53 (m,2H), 3.30 (m,1H), 2.95-3.18 (m,2H), 2.80 (2dd,total 1H), 2.69 (2dd,total 1H), 1.24 (s,9H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([B:14]3[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]3)=[CH:10][CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2C=CC(N)=[CH:32][CH:31]=2)[CH2:26][CH2:25]1>>[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:3]=[CH:2][C:1]([NH:4][C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([B:14]4[O:18][C:17]([CH3:19])([CH3:20])[C:16]([CH3:21])([CH3:22])[O:15]4)=[CH:10][CH:9]=3)=[O:6])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Product: CN1CCN(c2ccc(NC(=O)Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1

Procedure:
A procedure analogous to that used for the preparation of 1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea was used, using 4-(4-methylpiperazin-1-yl)aniline as the amine component.
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].CC(C)([O-])C.[Na+].[C:12]([O:16][C:17](=[O:41])[N:18]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[C:34](F)[CH:33]=2)=[CH:27][CH:26]=1)[CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])([CH3:15])([CH3:14])[CH3:13].CCOCC>CN(C=O)C>[C:12]([O:16][C:17](=[O:41])[N:18]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[C:34]([O:5][N:4]=[C:2]([CH3:3])[CH3:1])[CH:33]=2)=[CH:27][CH:26]=1)[CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])([CH3:14])([CH3:15])[CH3:13]
Reactant: CC(C)CCN(Cc1ccc(Oc2ccc(C#N)c(F)c2)cc1)C(=O)OC(C)(C)C
Reactant: CC(C)=NO
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)=NOc1cc(Oc2ccc(CN(CCC(C)C)C(=O)OC(C)(C)C)cc2)ccc1C#N
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 27 %

Procedure:
To a solution of acetone oxime (1.1 equiv) in DMF was added sodium tert-butoxide (1.1 equiv). The mixture was stirred at room temperature for 45 min followed by the addition of a solution of compound from Step 3 (1 equiv). The reaction was stirred at room temperature for 3 hours. It was poured on NH4Cl sat and ether. Washed with water and dry over magnesium sulphate, filtered and concentrate. It was purified by silica gel chromatography using hexane:ethyl acetate (15%) to afford the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11]([CH3:22])=[N:10][N:9]=2)=[CH:4][CH:3]=1.C(O[C:27](=[O:29])[CH3:28])(=O)C>>[C:17]([N:1]([C:27](=[O:29])[CH3:28])[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11](=[CH2:22])[N:10]([C:16](=[O:21])[CH3:15])[N:9]=2)=[CH:4][CH:3]=1)(=[O:19])[CH3:18]
Reactant: CC1=NN=C(c2ccc(N)cc2)c2cc3c(cc2C1)OCO3
Reactant: CC(=O)OC(C)=O
Product: C=C1Cc2cc3c(cc2C(c2ccc(N(C(C)=O)C(C)=O)cc2)=NN1C(C)=O)OCO3
Yield: 34.4 %

Procedure:
2.93 g (0.01 mol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine were refluxed with 20 ml of acetic anhydride for 6 hours. The solution was evaporated at reduced pressure, the residue was taken up in 2×20 ml of anhydrous ethanol, the solution was repeatedly evaporated and the resulting residue of 4.55 g was submitted to column chromatography (adsorbent: Kieselgel 60, eluant: ethyl acetate--benzene 4:1). The raw product was triturated with 20 ml of hot isopropanol to yield 1.44 g (34.4%) of the aimed product, m.p. 240°-245 ° C. (slight decomp.).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Br[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=1
Reactant: Cc1ccc(Br)nc1
Reactant: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(NC[C@@H]2[C@H](C)CCCN2C(=O)c2cc(C)ccc2-c2ccccn2)nc1

Procedure:
The title compound was synthesized following the same general protocol as described in Example A44, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyridin-2-yl)phenyl)methanone and 2-bromo-5-methylpyridine. ESI-MS (m/z): 415 [M+1]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[S:30][C:29]([NH:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=2)=[N:28][C:27]=1[C:42]([NH2:44])=[O:43]>C1COCC1.N1C=CC=CC=1>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:25][C:26]2[S:30][C:29]([NH:31][C:32]3[CH:41]=[CH:40][C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=3)=[N:28][C:27]=2[C:42]([NH2:44])=[O:43])=[O:11])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1
Reactant: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C(=O)Nc2sc(Nc3ccc4ccccc4c3)nc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.8 %

Procedure:
To a mixture of 4-acetamidobenzoic acid (0.204 g, 1.14 mmol) and a catalytic amount of DMF in dry THF (15 mL) was added dropwise oxalyl chloride (0.2 mL, 2.30 mmol) at 0° C., and the mixture was stirred for 2 hrs at rt. The solvent was evaporated, and the residual oxalyl chloride was removed with azeotropic distillation using toluene under nitrogen atmosphere 4 times. The resulting acid chloride was then dissolved in pyridine (6 mL) and cooled to 0° C. To this solution, a solution of 5-amino-2-(naphthalene-2-ylamino)thiazole-4-carboxamide (0.27 g, 0.95 mmol) in pyridine (6 mL) was added at 0° C., and the mixture was stirred for 12 hrs at rt. The solvent was evaporated, and the residue was suspended into 1M HCl, and the resulting solids were collected and dried. The crude solids were purified by silica gel column chromatography eluted with 3% MeOH in DCM to give 16 mg (3.7% yield) of the titled compound.