Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: IC.[Cl:3][C:4]1[N:9]=[C:8]([S:10][CH3:11])[C:7]2[NH:12][CH:13]=[N:14][C:6]=2[CH:5]=1.[C:15](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:3][C:4]1[N:9]=[C:8]([S:10][CH3:11])[C:7]2[N:12]([CH3:15])[CH:13]=[N:14][C:6]=2[CH:5]=1
Reactant: CSc1nc(Cl)cc2nc[nH]c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1nc(Cl)cc2ncn(C)c12
Reaction time: 1.5 h

Procedure:
Iodomethane (0.52 mL, 8.36 mmol) was added to a solution of 6-chloro-4-(methylthio)-3H-imidazo[4,5-c]pyridine 2.01 (1.40 g, 7.04 mmol) and potassium carbonate (1.95 g, 14.1 mmol) in 46 mL of DMF at room temperature. After 90 minutes, reaction mixture was taken up in ethyl acetate (150 mL) and washed with 50% saturated NaHCO3 (aq)(2×100 mL). After separating layers, aqueous was extracted with ethyl acetate (100 mL). All combined organic layers were washed with 50% brine (100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to yield a solid. This was purified via silica gel column chromatography (5-25% acetone in hexanes) to yield 6-chloro-3-methyl-4-(methylthio)-3H-imidazo[4,5-c]pyridine 2.02 (first eluting product).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1OC)[C:5]#[N:6].B.C1C[O:16][CH2:15]C1.CO>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][O:16][CH3:15]
Reactant: COc1ccc(C#N)cc1Br
Reactant: C1CCOC1
Agent: B
Solvent: CO
Product: CONCc1cccc(Br)c1
Temperature: 25 °C
Yield: 64 %

Procedure:
A stirring solution of 3-bromo-4-methoxy-benzonitrile (1.00 g, 4.7 mmol) in THF (30 ml) was treated drop-wise with borane-THF (14.2 ml, 1M solution in THF, 14.2 mmol). The mixture was heated at reflux, under argon for 5 h. To the cooled reaction mixture was cautiously added MeOH (20 ml). The volatiles were removed in vacuo and the residue was treated with 2N HCl (20 ml). After heating at reflux for 0.45 h and cooling to room temperature the mixture was basified by addition of solid K2CO3. The basic solution was extracted with diethyl ether (2×). The organic phase was dried (MgSO4) and the solvent removed in vacuo to afford the title compound as a colourless oil (64%).
Reaction SMILES: [OH:1][C:2]1[CH:23]=[CH:22][C:5]2[CH:6]=[C:7]([C:9](=O)[CH2:10][C:11](=O)/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:8][C:4]=2[CH:3]=1.O.[NH2:25][NH2:26]>C(O)(=O)C.C(O)C>[C:14]1(/[CH:13]=[CH:12]/[C:11]2[NH:26][N:25]=[C:9]([C:7]3[O:8][C:4]4[CH:3]=[C:2]([OH:1])[CH:23]=[CH:22][C:5]=4[CH:6]=3)[CH:10]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NN
Reactant: O=C(/C=C/c1ccccc1)CC(=O)c1cc2ccc(O)cc2o1
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Oc1ccc2cc(-c3cc(/C=C/c4ccccc4)[nH]n3)oc2c1
Temperature: 382.5 °C
Yield: 11 %

Procedure:
To a mixture of (4E)-1-(6-hydroxy-1-benzofuran-2-yl)-5-phenylpent-4-ene-1,3-dione (0.48 mmol) and hydrazine monohydrate (0.02 g, 0.48 mmol) were added ethanol (24 mL) and acetic acid (1 drop) in a sealed tube. The reaction was heated at 65-700° C. overnight. The solvent was removed under reduced pressure to afford crude product. The crude product was purified by reverse phase HPLC. The fractions from HPLC were combined, neutralized with 1.0 N aqueous sodium hydroxide solution, and diluted with ethyl acetate (200 mL). The organic layer was washed with saturated aqueous sodium chloride (50 mL), dried over magnesium sulfate, filtered, and concentrated to afford the product (11% yield): 1H NMR (400 MHz, CD3Cl): δ 7.58 (br d, 2H), 7.35 (m, 4H), 7.25 (t, 2H), 7.10 (br d, 1H), 7.05 (br s, 1H), 6.94 (br d, 1H), 6.88 (br s, 1H), 6.75 (dd, 1H); MS (EI) for C19H14N2O2: 303 (MH+).
Reaction SMILES: CC(C)([O-])C.[K+].CS(C)=O.CC[O:13][C:14]([C:16]1[C:22](=[O:23])[NH:21][C:19](=[S:20])[NH:18][CH:17]=1)=[O:15]>CO>[C:14]([C:16]1[C:22](=[O:23])[NH:21][C:19](=[S:20])[NH:18][CH:17]=1)([OH:15])=[O:13]
Reactant: CCOC(=O)c1c[nH]c(=S)[nH]c1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CO
Product: O=C(O)c1c[nH]c(=S)[nH]c1=O
Yield: 59 %

Procedure:
Potassium tertiary butoxide (43.7 g, 389 mmol) and dimethyl sulfoxide (400 ml) were put in a 2-L egg-plant type flask to make a solution, ethyl 2-thiouracil-5-carboxylate (5.0 g, 25.0 mmol) was slowly added dropwise to the solution, and the mixture was subjected to reaction at room temperature for 1 hour. After the completion of the reaction, methanol (500 ml) was added to the reaction mixture, and the precipitate deposited was filtered. The resultant precipitate was dissolved in water, and hydrochloric acid was added to this solution to give 5-carboxy-2-thiouracil (2.54 g) as a light yellow solid.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@H:15]([C:17]([O:19]CC2C=CC=CC=2)=[O:18])[CH3:16])[N:13]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:12]1=[O:35])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(O)C.[C].[Pd]>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@H:15]([C:17]([OH:19])=[O:18])[CH3:16])[N:13]([CH2:27][C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[C:12]1=[O:35])[CH3:10])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N(CC(=O)OC(C)(C)C)[C@@H]1[C@@H](C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N(CC(=O)OC(C)(C)C)[C@@H]1[C@@H](C)C(=O)O

Procedure:
A solution of (3S,4S)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-[(1R)-1-benzyloxycarbonylethyl]-1-(t-butyloxycarbonylmethyl)azetidin-2-one (0.45 g) in 99.5% ethanol (6 ml) was subjected to hydrogenation at room temperature in the presence of 10% palladium-carbon (90 mg) under atmospheric pressure, followed by filtration to remove the catalyst. The filtrate was evaporated to give (3S,4S)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-[(1R)-1-carboxyethyl]-1-(t-butyloxycarbonylmethyl)azetidin-2-one.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=3)[C:26]([O:28]C)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].O.[OH-].[Li+].Cl>CO.O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=3)[C:26]([OH:28])=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1

Procedure:
Methyl 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoate (3.02 g, 0.0064 mol) in MeOH (30 mL) was stirred with lithium hydroxide monohydrate (1.36 g, 0.032 mol) in H2O (15 mL) overnight at room temperature. The solution was treated with 3N HCl to adjust the pH to about 2.0 and cooled in an ice bath. Solid was collected and dried (2.4 g). The filtrate was treated with sat. aq. NaCl and extracted with EtOAc (2×). The extract was dried (Na2SO4) and concentrated to a residue. It was triturated with ether to afford the title compound as a white solid (143 mg only slightly inferior to the main product by LC-MS). Total product 2.56 g (88.7%). LC-MS m/z 452.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@@H:4]1[CH2:8][C@H:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)[CH2:6][N:5]1C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:24])[C@@H:4]1[CH2:8][C@H:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)[CH2:6][NH:5]1
Reactant: COC(=O)[C@@H]1C[C@H](Oc2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1C[C@H](Oc2ccc(Br)cc2)CN1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of trans-1-(Boc)-4-hydroxy-L-proline methyl ester (0.5 g) (2 mmol), 4-bromophenol (0.52 g) (1.5 eq.) and Ph3P (0.78 g) (1.5 eq.) in 10 mL of dry THF at 0° C. was added DEAD (0.47 mL) in a minimal volume of THF. The reaction mixture was warmed to RT overnight. The solvent was removed in vacuo and the resulting residue suspended in ether. The solids were removed by filtration and the solvent evaporated under reduced pressure to afford after SiO2 chromatography (eluent: cyclohexane/EtOAc-9/1), cis-1-(Boc)-4-(4-bromo-phenoxy)-L-proline methyl ester as a colorless oil (0.54 g). NMR (CDCl3, 200 MHz): 7.37 (2H, d), 6.70 (2H, d), 4.85 (1H, m), 4.37-4.6 (1H, m), 3.6-3.85 (5H, m), 2.35-2.50 (2H, m), 1.4-1.5(9H). To a solution cis-1-(Boc)-4-(4-bromo-phenoxy)-L-proline methyl ester (0.54 g) in 8 mL of DCM at 0° C. was added 2.5 mL of TFA. The reaction mixture was stirred at 0° C. for 1 h and warmed to RT for an additional hour. The solvents were evaporated in vacuo. The resulting residue was dissolved in water and the aqueous layer basified with aqueous NaHCO3 and extracted with EtOAc. The combined organic extracts were washed with water, dried over MgSO4, and the solvent was evaporated under reduced pressure to afford the titled compound as a colorless oil which solidified upon standing (0.39 g). NMR (CDCl3, 200 MHz): 7.35 (2H, d), 6.70 (2H, d), 4.8 (1H, m), 3.92 (1H, dd), 3.72 (3H, s), 3.35 (1H, d), 3.1 (1H, dd) 2.25-2.55 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH:8]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH:9]3[CH2:15][CH2:14][CH2:13][CH:10]32)=[C:5](OS(C(F)(F)F)(=O)=O)[CH:4]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1.C(O)C>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[C:11]3[C:6]=2[CH2:7][CH:8]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[CH:9]2[CH2:15][CH2:14][CH2:13][CH:10]23)=[CH:35][CH:34]=1
Reactant: COc1ccc(C2Cc3c(OS(=O)(=O)C(F)(F)F)cc(OC)cc3C3CCCC23)cc1
Reactant: OB(O)c1ccc(Cl)cc1
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: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(C2Cc3c(-c4ccc(Cl)cc4)cc(OC)cc3C3CCCC23)cc1
Temperature: 90 °C
Yield: 310.3 %

Procedure:
Combine trifluoro-methanesulfonic acid 8-methoxy-4-(4-methoxy-phenyl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-6-yl ester (0.046 g, 0.1 mmol), 4-chlorophenyboronic acid (0.019 g, 0.12 mmol), tetrakis(triphenylphosphine)palladium(0) (0.006 g, 5 mole %), sodium carbonate (0.12 ml 2N), and toluene/ethanol (4-1). Purge in vacuo briefly, and heat at 90° C. for 12 hours. Remove solvent, take in ethyl acetate and wash with water. Dry over anhydrous sodium sulfate and chromatograph the residue on silica gel with 5% ethyl acetate in hexanes to yield the titled compound (0.13 g, 31%). 1H NMR (CDCl3): 7.34 (d, J=8.8 Hz, 2H), 7.26 (d, J=8.8 Hz, 2 H), 7.1 (d, J=8.87 Hz, 2H), 6.8 (d, J=8.8 Hz, 2H), 6.78 (s, 1H), 6.62 (s, 1H), 3.82 (s, 3H), 3.77 (s, 3H), 3.45 (m, 1H), 2.98 (m, 1H), 2.85(m, 1H), 2.57 (m, 1H), 2.3 (m, 1H), 2.21 (m, 1H), 1.65-1.2 (m, 5H).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7])([O-])=O.[B][B][B][B][B][B][B][B][B][B]>CO.[Pd]>[NH2:1][C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7]
Reactant: O=C(Nc1ccccc1)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: Nc1ccccc1C(=O)Nc1ccccc1
Temperature: 60 °C

Procedure:
To a solution of 2-nitro-N-phenylbenzamide (5 g; 20.7 mmol; 1 equiv.) in MeOH (65 mL) was added palladium on charcoal (550 mg) and decaborane (757 mg; 6.2 mmol; 0.3 equiv.) at room temperature. The mixture was heated at 60° C. for 6 hours, filtered over celite, washed with AcOEt and evaporated to give 2-amino-N-phenylbenzamide as brown solid (4.2 g; 96%) which was used without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C[O:16][C:17]([CH:19]1[CH2:21][CH:20]1[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([F:29])[CH:23]=1)=[O:18]>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:28][C:25]3[CH:26]=[CH:27][C:22]([CH:20]4[CH2:21][CH:19]4[C:17]([OH:18])=[O:16])=[CH:23][C:24]=3[F:29])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: ClCc1cccnc1SC1CCCC1
Reactant: COC(=O)C1CC1c1ccc(O)c(F)c1
Product: O=C(O)C1CC1c1ccc(OCc2cccnc2SC2CCCC2)c(F)c1
Yield: 71 %

Procedure:
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (0.032 g, 0.14 mmol) obtained in Step C of Preparation Example 8 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (less polar) (0.030 g, 0.14 mmol) obtained in Step C of Preparation Example 64 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.033 g, 71%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[C:5]([F:27])=[CH:4][N:3]=1.[CH3:28][O-:29].[K+]>CN1C(=O)CCC1>[F:27][C:5]1[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[N:7][C:2]([O:29][CH3:28])=[N:3][CH:4]=1
Reactant: C[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCN(c3nc(Cl)ncc3F)CC2)CC1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ncc(F)c(N2CCC(C3CCN(C(=O)OC(C)(C)C)CC3)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The tert-butyl 1′-(2-chloro-5-fluoropyrimidin-4-yl)-4,4′-bipiperidine-1-carboxylate (40 mg, 0.10 mmol) was added to NMP (1 mL), and then potassium methoxide (8.1 mg, 0.11 mmol) was added to the mixture. The reaction was stirred for 30 min at r.t. and was quenched with ammonium chloride solution (5 mL), extracted with ethylacetate (10 mL). The organic phase was washed with brine (10 mL, ×1), dried over magnesium sulfate, filtered and concentrated by rotavapor. The crude mixture was purified by preparative TLC with 30% acetone:hexane to yield the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]([CH3:22])[C:19]([OH:21])=[O:20])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].O1CCCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]([CH3:22])[C:19]([OH:21])=[O:20])=[CH:23][CH:24]=1
Reactant: CC(C(=O)O)c1ccccc1OCCOc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C(=O)O)c1ccccc1OCCOc1ccc(N)cc1

Procedure:
8.4 g (0.025 M) of 2-[2-(4-nitrophenoxy)ethoxy]phenylpropanoic acid and 0.9 g of wet 10% palladium-on-charcoal are added to 60 ml of tetrahydrofuran in a 500 ml reactor. The reaction medium is then stirred vigorously for 3 hours under ambient pressure of hydrogen: exothermicity is observed and the temperature of the reaction medium rises to 40° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:17]=C)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:20].[Na+]>C1COCC1.O.C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:17]=[O:20])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1ccc2c(c1)CN(C(=O)OC(C)(C)C)C2
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2ccc(C=O)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a stirred solution of 3.79 mmol 5-vinyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester in 25 ml THF and 5 ml water were added 11.4 mmol sodium metaperiodate and 0.08 mmol osmium tetroxide solution (2.5% in tBuOH) and the mixture was stirred at RT for 2 h before being taken up in ethyl acetate and washed sequentially with water and brine. The organic phase was then dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a white solid (62% yield). MS (m/e): 192.1 ([M+H−Me2C═CH2]+, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1.[O:11]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12]1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[O:11]1[CH:15]=[CH:14][C:13]([C:2]2[CH:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=2)=[CH:12]1
Reactant: CC(=O)c1ccc(Br)cn1
Reactant: OB(O)c1ccoc1
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: CCO
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(-c2ccoc2)cn1
Temperature: 100 °C
Yield: 74.8 %

Procedure:
To a solution of 1-(5-bromopyridin-2-yl)ethanone (0.5 g, 2.5 mmol) in toluene (10 mL) and ethanol (5 mL) was added furan-3-ylboronic acid (0.335 g, 3.0 mmol) and a 2 M solution of aq. Na2CO3. The reaction mixture was degassed with argon, Pd(PPh3)4 (0.144 g, 0.125 mmol) was added, the reaction mixture was degassed with argon for 10 min, and the reaction was heated to 100° C. for 4 h. The reaction mixture was evaporated under vacuum to remove the ethanol, diluted with water (30 mL), extracted with ethyl acetate (100 mL), dried over sodium sulphate, filtered and evaporated under reduced pressure to obtain crude product. The crude product was purified by Biotage Isolera® One column (using 10% ethyl acetate and hexane) to give 1-(5-(furan-3-yl)pyridin-2-yl)ethanone (0.35 g, 74% yield); 1H NMR (400 MHz, DMSO-d6): δ 9.00 (s, 1H), 8.44 (s, 1H), 8.20-8.17 (m, 1H); 7.95 (d, 1H), 7.83 (s, 1H), 7.13 (s, 1H), 2.57 (s, 3H): LC-MS m/z calcd for [M+H]+ 187.06. found 188.0.
Reaction SMILES: [CH2:1]([CH:8]([NH:22][C:23]([C:25]1[CH:34]=[N:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1)=[O:24])[CH:9]([OH:21])[CH2:10][CH:11]([C:18](=[NH:20])[NH2:19])[CH2:12][CH2:13][C:14]([F:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:35]#[C:36]Br>C(Cl)Cl>[C:36]([N:20]=[C:18]([NH2:19])[CH:11]([CH2:12][CH2:13][C:14]([F:17])([CH3:16])[CH3:15])[CH2:10][CH:9]([OH:21])[CH:8]([NH:22][C:23]([C:25]1[CH:34]=[N:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1)=[O:24])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)#[N:35]
Reactant: CC(C)(F)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(=N)N
Reactant: N#CBr
Solvent: ClCCl
Product: CC(C)(F)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(N)=NC#N
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 1.0 equivalents of quinoxaline-2-carboxylic acid (1-benzyl-4-carbamimidoyl-7-fluoro-2-hydroxy-7-methyl-octyl)-amide in methylene chloride is added 1.0 equivalents of cyanogen bromide. The reaction is stirred at ambient temperature for approximately 15 hours. After standard aqueous work-up and extraction, followed by concentration and silica gel chromatography the title compound is obtained.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH:26]=[C:25]([OH:27])[C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:23]1>CN(C=O)C.CCOC(C)=O>[CH2:7]([O:27][C:25]1[C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:23][N:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[F:15])[CH:26]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)c1nn(-c2ccccc2F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(-c2ccccc2F)cc1OCc1ccccc1
Reaction time: 8 h

Procedure:
K2CO3 (2.00 g) and benzylchloride (1.2 mL) were added to a solution of ethyl 1-(2-fluorophenyl)-4-hydroxypyrazole-3-carboxylate (2.47 g) in anhydrous DMF (20 mL) at room temperature, and the mixture was stirred overnight. The mixture was diluted with EtOAc and washed with H2O, sat. NaHCO3 and brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (EtOAc/hexane 1/19, 1/9, 1/4 and 1/2) to yield 3.09 g of the title compound.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH2:32]([NH2:42])[C:33]1[CH:41]=[CH:40][C:39]2[O:38][CH2:37][O:36][C:35]=2[CH:34]=1>>[O:38]1[C:39]2[CH:40]=[CH:41][C:33]([CH2:32][NH:42][C:3]([C:5]3[N:14]4[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][O:21][C:22]5[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=5)[C:11]5[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=5[CH2:13]4)=[CH:7][CH:6]=3)=[O:4])=[CH:34][C:35]=2[O:36][CH2:37]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: O=C(COc1ccc(Cl)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Product: O=C(NCc1ccc2c(c1)OCO2)c1ccc2n1Cc1ccccc1N(C(=O)COc1ccc(Cl)cc1)C2

Procedure:
The title compound was synthesized from 2,2,2-trichloro-1-{10-[(4-chlorophenoxy) acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 67 (0.3 mmol) and piperonylamine (2.2 eq.) in the manner of Example 68, m.p. 168-169° C. MS [(+)ESI, m/z]: 530 [M+H]+ Anal. Calcd for C29H24CIN3O5: C, 65.72; H, 4.56; N, 7.93. Found: C, 65.79; H, 4.59; N, 7.89.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N:22]=[C:21]2[C:29]([F:32])([F:31])[F:30])=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[OH-].[Na+]>CCO.O>[CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N:22]=[C:21]2[C:29]([F:30])([F:31])[F:32])=[CH:15][CH:16]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OCCn2c(C(F)(F)F)nc3ccccc32)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(Cc1ccc(OCCn2c(C(F)(F)F)nc3ccccc32)cc1)C(=O)O
Yield: 79.1 %

Procedure:
To a stirred solution of ethyl 2-ethoxy-3-(4-{2-[2-(trifluoromethyl)-1H-benzimidazol-1-yl]ethoxy}phenyl)propanoate (238.5 mg, 0.5 mmol) in EtOH (5 ml) was added NaOH (2 ml, 2M aq. Solution, 2 mmol) in water (2 ml) at 0° C. at once. The reaction mixture was stirred at RT until all the ester disappeared (TLC). EtOH was removed in vacuo and the residue was dissolved in water. The solution was acidified to pH4 using 3N HCl and the precipitated acid was extracted with EtOAc to give the product as white solid (167 mg, 77.3%).
Reaction SMILES: P(Br)(Br)[Br:2].[Br:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([F:13])=[CH:8][C:7]=1[CH2:14]O>ClCCl.C(OCC)C>[Br:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([F:13])=[CH:8][C:7]=1[CH2:14][Br:2]
Reactant: OCc1cc(F)c(Cl)cc1Br
Reactant: BrP(Br)Br
Solvent: ClCCl
Solvent: CCOCC
Product: Fc1cc(CBr)c(Br)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.55 mmol of phosphorous tribromid is added dropwise to a solution of 1 mmol of (2-Bromo-4-chloro-5-fluoro-phenyl)-methanol in 40 ml of dichloromethane. The trouble reaction solution is stirred at room temperature for 2 hours, diluted with 100 ml of diethylether and decanted. The supernatant is washed with 10 ml of 2N sodium bicarbonate solution, 20 ml of water and 20 ml of brine, dried over sodium sulfate, filtered and concentrated under reduced pressure at 28° C. to afford the title compound which is identified based on the Rf value.