Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[CH:2][CH:3]([OH:6])[CH:4]=[CH2:5].[F:7][CH2:8][CH:9]([NH2:12])[CH2:10][F:11].[N-]=C=O>ClCCCl.CO>[F:7][CH2:8][CH:9]([N:12]1[CH2:5][CH2:4][C:3](=[O:6])[CH2:2][CH2:1]1)[CH2:10][F:11]
Reactant: C=CC(O)C=C
Reactant: NC(CF)CF
Agent: [N-]=C=O
Solvent: ClCCCl
Solvent: CO
Product: O=C1CCN(C(CF)CF)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 37.9 %

Procedure:
1,4-Pentadien-3-ol (200 mg, 2.38 mmol) and IBX (999 mg, 3.57 mmol) were dissolved in DCE (15 mL) and heated at 70° C. for 3 h. The reaction mixture was filtered, diluted with MeOH (10 mL) and 2-fluoro-1-fluoromethyl-ethylamine (226 mg, 2.38 mmol) was added. The reaction mixture was stirred at 70° C. for 3 h. Isocyanate resin was added and the reaction mixture stirred at room temperature for 6 h, filtered and concentrated in vacuo to give the crude title compound (160 mg, 38%) as an orange gum. LCMS (ES+): 178.1 [MH]+.
Reaction SMILES: [C:1](=[O:4])([OH:3])[OH:2].[CH2:5]([OH:11])[CH2:6][CH2:7][CH:8]([OH:10])[CH3:9].[CH2:12](O)[CH3:13]>>[C:1](=[O:3])([O:2][CH2:12][CH3:13])[O:4][CH2:5][CH3:6].[C:1](=[O:2])([OH:4])[OH:3].[CH2:5]([OH:11])[CH2:6][CH2:7][CH:8]([OH:10])[CH3:9]
Reactant: CCO
Agent: CC(O)CCCO
Agent: O=C(O)O
Product: CCOC(=O)OCC

Procedure:
Adding 1,4-pentanediol carbonate and ethanol in a tubular ester exchange reactor; then adding the prepared metal-rare earth oxide composite catalyst, uniformly mixing and performing an ester exchange reaction, then distilling the reaction product to obtain diethyl carbonate, wherein the mole ratio of 1,4-pentanediol carbonate to ethanol is 1:10, and the weight ratio of the metal-rare earth oxide composite catalyst to the total weight of 1,4-pentanediol carbonate and ethanol is 1:100; the ester exchange reaction is performed at a temperature of 180° C. and under an absolute pressure of 2 MPa for 10 minutes; in the ester exchange reaction, the conversion rate of 1,4-pentanediol carbonate is 100%, and yield of diethyl carbonate is 95%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:16][CH2:17][C:18]2([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[C:12]([O:14]C)=[O:13])[C:8]2[C:4](=[CH:5][N:6]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[N:7]=2)[CH:3]=1.O.[OH-].[Li+]>O1CCCC1.CO.O>[C:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][C:18]([CH2:17][O:16][CH:11]([C:9]2[C:8]3[C:4](=[CH:5][N:6]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:43])([CH3:44])[CH3:45])[N:7]=3)[CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:12]([OH:14])=[O:13])([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:19][CH2:20]1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: COC(=O)C(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(COC(C(=O)O)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-methoxy-2-oxoethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (150 mg, 0.226 mmol) in tetrahydrofuran (1 mL) and methanol (1 mL) at 0° C. was added a solution of lithium hydroxide monohydrate (28.5 mg, 0.679 mmol) in water (0.5 mL). After 1 h, the reaction was concentrated to remove most of the solvent. The resulting residue was dissolved in a minimum of water, and acidified with 1N hydrochloric acid to give a white solid which was collected by filtration. 1H-NMR (CDCl3, 500 MHz) δ 8.83 (bs, 1H), 8.05 (s, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.28 (dd, J=8.9, 5.5 Hz, 2H), 7.10 (s, 1H), 6.98 (dd, J=8.9, 8.6 Hz, 2H), 5.65 (s, 2H), 5.23 (s, 1H), 3.62-3.82 (m, 3H), 3.58 (t, J=8.2 Hz, 2H), 3.37 (d, J=8.9 Hz, 1H), 3.02 (m, 2H), 2.17 (m, 1H), 2.08 (m, 1H), 1.92 (m, 1H), 1.84 (m, 1H), 1.41 (s, 9H), 0.91 (m, 2H), −0.05 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 170.7, 161.5 (d, J=246 Hz), 155.1, 145.3, 138.1, 128.9 (d, J=7.7 Hz), 128.2, 126.5, 126.4, 123.3, 122.7, 119.9, 115.3 (d, J=20.2 Hz), 82.0, 79.7, 78.7, 77.7, 68.0, 41.3, 39.8, 32.1, 31.9, 28.5, 17.9, −1.4.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:42][CH3:43])=[C:10]([CH2:19][NH:20][C:21](=[O:41])[CH2:22][C:23]([NH:25][CH2:26][C:27]3[CH:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([CH:39]=O)[CH:34]=4)[CH:30]=[CH:31][CH:32]=3)=[O:24])[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].[CH:44]12[CH2:50][CH:47]([NH:48][CH2:49]1)[CH2:46][N:45]2C(OC(C)(C)C)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O.C(O)(C(F)(F)F)=O>CS(C)=O.ClCCl>[CH:44]12[CH2:50][CH:47]([NH:48][CH2:49]1)[CH2:46][N:45]2[CH2:39][C:35]1[CH:34]=[C:33]([C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([CH2:26][NH:25][C:23](=[O:24])[CH2:22][C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:42][CH3:43])=[O:41])[CH:28]=2)[CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1cccc(-c2cccc(C=O)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1cccc(-c2cccc(CN3CC4CC3CN4)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.5 %

Procedure:
To N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-3-biphenylyl)methyl]propanediamide (50 mg, 0.086 mmol) was added 1,1-dimethylethyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (34 mg, 0.172 mmol) followed by NaB(OAc)3H (36.4 mg, 0.172 mmol) and AcOH (4.91 μL, 0.086 mmol) in dimethyl sulfoxide (DMSO) (0.5 mL). The mixture was stirred overnight at room temperature. The reaction was quenched with saturated NaHCO3 and extracted with EtOAc (3×1 ml). Combined organic layers were washed with saturated NaCl, dried (Na2SO4) and concentrated. The crude products were redissolved in MeOH/DMSO (1/1) and purified using a Gilson HPLC (acidic condition). Product fractions were combined and the solvent evaporated using a GeneVac EZ-2 evaporator. To the resulting residue was added TFA (0.198 mL, 2.57 mmol) in dichloromethane (0.2 mL) and the mixture was placed in a Glas-Col evaporator overnight and then the residue was redissolved in MeOH/DMSO and purified using a Gilson HPLC (acidic condition) Product fractions were combined and the solvent evaporated using a GeneVac EZ-2 evaporator, basified by amine cartridge to afford the title compound 6.6 mg (11%). LC-MS m/z 665 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH:32]([C:34]2[CH:39]=[C:38]([CH2:40][CH3:41])[CH:37]=[C:36]([O:42][Si](C(C)(C)C)(C)C)[C:35]=2[F:50])[OH:33])[N:11]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH:32]([OH:33])[C:34]2[C:35]([F:50])=[C:36]([OH:42])[CH:37]=[C:38]([CH2:40][CH3:41])[CH:39]=2)[N:11]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=1
Reactant: CCc1cc(O[Si](C)(C)C(C)(C)C)c(F)c(C(O)c2nc(-c3ccccc3Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1cc(O)c(F)c(C(O)c2nc(-c3ccccc3Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of intermediate 217.2 (500 mg, 0.669 mmol) in 5 mL THF at rt, was added TBAF (1M in THF, 0.669 mL, 0.669 mmol). The mixture was stirred at rt for 30 min. The mixture was diluted with EtOAc, washed with H2O (2×) and brine, dried (Na2SO4) and concentrated. The crude product was triturated with hexanes (10 mL) to afford 3-((4-(2-bromophenyl)-1-trityl-1H-imidazol-2-yl)(hydroxy)methyl)-5-ethyl-2-fluorophenol. To a solution of this product in 5 mL DMF at rt, were added K2CO3 (111 mg, 0.803 mmol) and iodoethane (161 μL, 2.01 mmol). The mixture was stirred at rt for 15 h, then diluted with EtOAc. The organic phase was washed with H2O (2×), sat. Na2SO3 and brine, dried (Na2SO4), filtered through a 1″ pad of silica gel and concentrated to afford 433 mg of Intermediate 217.3 as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8](=[CH:14][NH:15][C:16]([CH3:27])([CH3:26])[CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[C:4](Cl)[CH:3]=1>CS(C)=O.O>[Br:1][C:2]1[CH:29]=[C:28]2[C:5]([C:6](=[O:7])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][N:15]2[C:16]([CH3:27])([CH3:26])[CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=CNC(C)(C)CO[Si](C)(C)C(C)(C)C)C(=O)c1ccc(Br)cc1Cl
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cn(C(C)(C)CO[Si](C)(C)C(C)(C)C)c2cc(Br)ccc2c1=O
Reaction time: 0.25 h
Yield: 61.3 %

Procedure:
13bm) 4.3 g of ethyl 2-(4-bromo-2-chloro-benzoyl)-3-[2-(tert.-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethylamino]-acrylate (Example 13bl)) were dissolved in 40 ml of dimethyl sulphoxide under argon, treated with 1.1 g of potassium tert.-butylate and stirred for 15 min. Then, the mixture was stirred at 50° for 1.5 hrs. After cooling the mixture was diluted with 200 ml of water and the product was then extracted with two 200 ml portions of ethyl acetate, purified by silica gel chromatography in hexane/ethyl acetate 1:1 and crystallized from 30 ml of hexane/ethyl acetate 1:1. 2.45 g (62%) of ethyl 7-bromo-1-[2-(tert.-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-4-oxo-1,4-dihydro-quinoline-3-carboxylate were obtained as white crystals. M.p. 133° C.
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=CC=1[O-])([O-])=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]2[O:21][CH2:22][CH2:23][C:17]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[C:30]([O:34][CH2:35][CH3:36])(=[O:33])[C:31]#[CH:32]>CN(C)C=O.O>[C:31]1([C:30]([O:34][CH2:35][CH3:36])=[O:33])[CH:32]=[N:14][N:15]2[CH:20]=[CH:19][C:18]3[O:21][CH2:22][CH2:23][C:17]=3[C:16]=12
Reactant: C#CC(=O)OCC
Reactant: N[n+]1ccc2c(c1)CCO2
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc([O-])c([N+](=O)[O-])c1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn2ccc3c(c12)CCO3
Temperature: 25 °C
Reaction time: 20 h
Yield: 16.9 %

Procedure:
To a mixture of 5-amino-2,3-dihydrofuro[3,2-c]pyridin-5-ium 2,4-dinitrobenzenolate (8.00 g, 25.0 mmol) and potassium carbonate (4.84 g, 35.0 mmol) in dimethylformamide (100 mL) was added ethyl propiolate (2.80 mL, 27.6 mmol) under ice-cooling, and the mixture was stirred at room temperature for 20 hr. The reaction solution was diluted with water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→40/60) to give the title compound (980 mg, yield 17%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:46](=[O:50])[CH:47]([CH3:49])[CH3:48].O>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][CH:10]=1)[NH:11][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:47]([CH3:49])([CH3:48])[CH:46]2[OH:50])=[O:19])[CH3:2]
Reactant: CCOC(=O)c1ccc(N=Cc2ccccc2)cc1
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1ccccc1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.4 %

Procedure:
To a mixture of 4-(benzylidene-amino)-benzoic acid ethyl ester (5.1 g, 20.0 mmol) and ytterbium(III) triflate hydrate (1.3 g, 2.0 mmol) in dry tetrahydrofuran (20.0 mL) at 25° C. was added isobutyraldehyde (18.2 mL, 200 mmol) and water (0.36 mL, 20.0 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 4-hydroxy-3,3-dimethyl-2-phenyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (6.6 g, quant.) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C20H23NO3 (M+H)+: 326.40, observed: 308.0.
Reaction SMILES: Br[C:2]1[C:3]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:4][C:5]([NH2:11])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[F:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1[Sn](CCCC)(CCCC)CCCC>C1(P([Pd-](Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I.CN(C)C=O>[F:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1[C:2]1[C:3]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:4][C:5]([NH2:11])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: Nc1nc(-c2cccnc2)c(Br)cc1[N+](=O)[O-]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1F
Agent: Cl[Pd-]([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: Nc1nc(-c2cccnc2)c(-c2ccncc2F)cc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 50.2 %

Procedure:
An oven dried resealable Schlenk tube was charged with 3-bromo-5-nitro-2,3′-bipyridin-6-amine (4.51 g, 15.3 mmol), 3-fluoro-4-(tributylstannyl)pyridine (11.8 g, 30.6 mmol) and dimethylformamide (150 mL). The Schienk tube was subjected to three cycles of evacuation-backfilling with argon, and bis(triphenylphosphino)-palladium (II) chloride (1.1 g, 1.53 mmol) and copper (I) iodide (291 mg, 1.53 mmol) were added. After three new cycles of evacuation-backfilling with argon, the Schlenk tube was capped and placed in a 160° C. oil bath. After 3 h, the solvent was evaporated and the crude residue was treated with 2N hydrogen chloride (130 mL) aqueous solution for 45 minutes. The aqueous solution was washed with ethyl acetate and then neutralised with 6N sodium hydroxide aqueous solution. The solution was extracted with ethyl acetate, dried (MgSO4) and evaporated. The residue was purified by silica gel flash chromatography (95:5 dichloromethane/methanol) to give the title compound (2.39 g, 51%) as a solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:18]=[CH:17][C:16]2[C:7](=[C:8]3[C:13](=[CH:14][C:15]=2[NH2:19])[CH:12]=[CH:11][CH:10]=[N:9]3)[N:6]=1)=[O:4].[NH3:20]>CN(C)C=O>[NH2:20][CH2:2][C:3]([C:5]1[CH:18]=[CH:17][C:16]2[C:7](=[C:8]3[C:13](=[CH:14][C:15]=2[NH2:19])[CH:12]=[CH:11][CH:10]=[N:9]3)[N:6]=1)=[O:4]
Reactant: N
Reactant: Nc1cc2cccnc2c2nc(C(=O)CBr)ccc12
Solvent: CN(C)C=O
Product: NCC(=O)c1ccc2c(N)cc3cccnc3c2n1
Reaction time: 1 h

Procedure:
Bromoacetyl-5-amino-1,10-phenanthroline (4) (Preparation 3; 1.00 g; 3.15 mmol) was dissolved in 50 ml dimethylformamide. Into this solution, was added 0.2 ml concentrated ammonia. The reaction mixture was stirred 1 hr. in the dark. The volume of the reaction mixture then was reduced to 2 ml by evaporation, and the product then was precipitated by addition of 2 ml of ice-cold deionized water. The resulting precipitate was collected by vacuum filtration, was washed with 20 ml ice-cold deionized water, and was washed with 50 ml acetonitrile. Yield: 0.45 g, 32%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2([CH3:20])[CH3:19].[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([NH:18][S:28]([C:25]3[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=3)(=[O:30])=[O:29])[CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2([CH3:20])[CH3:19]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(Cl)cc21
Solvent: c1ccncc1
Product: CC1(C)CC(c2cccc(NS(=O)(=O)c3ccc(F)cc3)c2)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
3-(6-Chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (150 mg, 0.53 mmol) and 4-fluoro-benzenesulfonyl chloride (98 mg, 0.63 mmol) were dissolved in pyridine (5 ml). The mixture was stirred at room temperature overnight. The solvent was removed and the residue was purified on column chromatography using petroleum ether/ethyl acetate=5:1 as eluent to afford N-[3-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-4-fluoro-benzenesulfonamide (135 mg, yield: 46%) as yellow solid. MS (ESI+APCI) M+1=445.1.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C@@H:10]([OH:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[N+:50]([O:53][CH2:54][CH2:55][CH2:56][CH2:57]O)([O-:52])=[O:51]>C(Cl)Cl>[N+:50]([O:53][CH2:54][CH2:55][CH2:56][CH2:57][O:12][C:11](=[O:13])[C@H:10]([OH:14])[CH2:9][C@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:6][CH:5]=1)([O-:52])=[O:51]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@H](O)C(=O)O
Reactant: O=[N+]([O-])OCCCCO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@H](O)C(=O)OCCCCO[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 45.9 %

Procedure:
(2R,4R)-5-Biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxypentanoic acid (30 mg, 78 μmol), HOBt (63 mg, 470 μmol), and EDCI (83 μL, 470 μmol) were dissolved into DCM. After stirring for 10 minutes, 4-nitrooxybutan-1-ol (84.1 mg, 623 μmol) was added. The resulting mixture was stirred at room temperature and the reaction monitored for completion (˜30 minutes). The mixture was stirred for an additional 2 hours and then left open to dry. The product was then purified (Interchim reverse phase chromatography column; 35-95% MeCN in water with 0.05% TFA) to yield the title compound (18 mg).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH:10]=[CH2:11])[CH:5]=[C:4]([CH:12]([OH:14])[CH3:13])[N:3]=1.C1CC=CCC=1>C(O)C.[Pd]>[CH3:9][O:8][C:7]1[CH:2]=[N:3][C:4]([CH:12]([OH:14])[CH3:13])=[CH:5][C:6]=1[CH2:10][CH3:11]
Reactant: C=Cc1cc(C(C)O)nc(Cl)c1OC
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CCO
Product: CCc1cc(C(C)O)ncc1OC
Yield: 62.2 %

Procedure:
A solution of 2-chloro-3-methoxy-4-vinyl-6-(1-hydroxyethyl)-pyridine (485 mg, 2.27 mmol) in 10 mL of ethanol is treated with 485 mg of 20% palladium on carbon and 1,4-cyclohexadiene (2.0 mL, 21 mmol) and the reaction is refluxed for 4 h. The catalyst is removed by filtration through celite and the filter pad washed well with methanol. The filtrate is concentrated in vacuo and the residue is partitioned between 25 mL of saturated sodium bicarbonate and 4×25 mL of ethyl acetate. The combined organics are dried over potassium carbonate and concentrated in vacuo. The crude material is chromatographed over 20 g of silica gel (230-400 mesh), eluting with 100 mL of 50% ethyl acetate/hexanes followed by 80% ethyl acetate/hexanes to afford 256 mg (63%) of 3-methoxy-4-ethyl-6-(1-hydroxyethyl)-pyridine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[C:9]1(=O)[O:14][C:12](=[O:13])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12](=[O:13])[C:11]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]3[C:9]2=[O:14])[CH:3]=1
Reactant: Cc1ccnc(N)c1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1ccnc(N2C(=O)c3ccccc3C2=O)c1
Reaction time: 12 h
Yield: 42.5 %

Procedure:
To a stirring solution of 4-methyl-2-aminopyridine (50 g, 460 mmol) in acetic acid (1 L) was added phthalic anhydride (68 g, 460 mmol) and the reaction was heated to reflux. After 12 h, acetic anhydride (43 mL, 460 mmol) was added and the solution continued to stir at reflux for an additional 48 h. The solvent was then removed in vacuo and the solid residue was suspended in toluene and concentrated in vacuo twice. The solid was then suspended in ethyl acetate with vigorous stirring and filtered. After repeating this ethyl acetate washing procedure the solid was dried overnight in vacuo to give 46.6 g (42%) of a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18]C(C)(C)C)=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:27].Cl>>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([OH:18])=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:27]
Reactant: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c-2ccc(F)c1Cl
Agent: Cl
Product: O=C(O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c-2ccc(F)c1Cl

Procedure:
A mixture of 4.7 g (12 mmol) of t-butyl (S)-8-chloro-7-fluoro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate and 24 ml of 1N hydrochloric acid is heated to boiling under reflux for 1.5 hours. The mixture is then cooled to about 5°, the product is filtered off under suction, rinsed with water and dried at 85° in vacuo. There is obtained (S)-8-chloro-7-fluoro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylic acid of decomposition point 261°-263°.
Reaction SMILES: [C:1]1([OH:9])[C:2]([CH3:8])=[CH:3][CH:4]=[C:5]([CH3:7])[CH:6]=1.S(Cl)([Cl:13])(=O)=O.S(=O)(O)[O-].[Na+]>ClCCl.C1(SC2C=CC=CC=2)C=CC=CC=1>[Cl:13][C:4]1[CH:3]=[C:2]([CH3:8])[C:1]([OH:9])=[CH:6][C:5]=1[CH3:7]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1ccc(C)c(O)c1
Agent: O=S([O-])O
Agent: [Na+]
Agent: c1ccc(Sc2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(Cl)c(C)cc1O
Temperature: 10 °C
Yield: 97.8 %

Procedure:
To a solution of 100 g (0.82 mol) of 2,5-xylenol and 0.9 g of diphenyl sulfide in 700 mL of dichloromethane was added a solution of 106 g (0.79 mol) of sulfuryl chloride in 100 mL of dichloromethane, maintaining the temperature at 5-15° C. The mixture was stirred for an additional hour and then poured onto 400 g of ice-water containing 5 g of sodium bisulfite. The layers were separated, and the organic phase was washed with water, dried (MgSO4), and concentrated to dryness. The crude solids were slurried with a minimum amount of hexanes, filtered, and suction-dried to give 121 g (94%) of product, homogeneous by Thin Layer Chromatography (TLC), GC, and 1H-NMR analysis. 1H-NMR (CDCl3) δ 2.18 (s, 3H), 2.27 (s, 3H), 4.61 (s, 1H), 6.63 (s, 1H), 7.07 (s, 1H). Lit (Blackstock, Aust. J. Chem. 1973, 26, 775): mp 74-75° C.
Reaction SMILES: [Li]CCCC.[O:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[N:19]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[CH:20]=[C:21]([C:23]([N:25]2[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]2)=[O:24])[N:22]=1.[NH4+].[Cl-]>C1COCC1.O>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[N:19]([C:32]2[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=2)[CH:20]=[C:21]([C:23]([N:25]2[CH2:26][CH2:27][C:28]([C:7]3[O:6][CH:10]=[CH:9][CH:8]=3)([OH:31])[CH2:29][CH2:30]2)=[O:24])[N:22]=1
Reactant: c1ccoc1
Reactant: O=C1CCN(C(=O)c2cn(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)n2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1)N1CCC(O)(c2ccco2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 43.3 %

Procedure:
BuLi (0.875 mL, 1.40 mmol, 1 M solution in THF) was added slowly to a solution of furan (0.106 mL, 1.45 mmol) in THF (2 mL) at −78° C., and the mixture was stirred at −78° C. for 1 h. A solution of 1-{[2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazol-4-yl]carbonyl}-4-piperidinone (0.3 g, 0.68 mmol) in THF (1 mL) was added slowly. The mixture was stirred at −78° C. for 2 h and saturated NH4Cl (3 mL) and water added. The mixture was extracted with ethyl acetate (3×20 mL) and dried over MgSO4. The product (0.142 g, 61%) was isolated by column (ethyl acetate). MS (Electrospray) 482 (M)+; 1H NMR (300 MHz, CD2Cl2) δ .7.85 (s, 1H), 7.51-7.31 (m, 7H), 7.10-6.98 (m, 4H), 7.17-7.10 (m, 2H), 6.39 (s, 1H), 6.29 (s, 1H), 4.68 (br, 1H), 4.28 (br, 1H), 3.94 (br, 1H), 3.57 (br, 1H), 2.26-1.91 (m, 4H).