Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[O:27]=[C:28]1[NH:33][C:32](=[O:34])[CH2:31][N:30]([CH2:35][C:36](O)=O)[CH2:29]1>>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:2]=[CH:3][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17]2[N:18]=[C:36]([CH2:35][N:30]3[CH2:29][C:28](=[O:27])[NH:33][C:32](=[O:34])[CH2:31]3)[O:20][N:19]=2)=[O:8])=[CH:5][CH:6]=1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: O=C(O)CN1CC(=O)NC(=O)C1
Product: CON=C1C[C@@H](c2noc(CN3CC(=O)NC(=O)C3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 55 %

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and (3,5-dioxo-1-piperazinyl)acetic acid, the title compound was obtained in 55% yield (99.0% purity by HPLC).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1.[I:16]N1C(=O)CCC1=O>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][C:7]=1[I:16]
Reactant: O=C1OC(CO)CN1c1cccc(F)c1
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Product: O=C1OC(CO)CN1c1ccc(I)c(F)c1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A solution of alcohol 103 (10.74 g, 50.9 mmol) in trifluoroacetic acid (TFA, 50 mL) was treated with N-iodosuccinimide (12.03 g, 53.45 mmol, 1.05 equiv) at 25° C. and stirred for 2 h. When TLC and HPLC/MS showed the reaction was complete, the reaction mixture was concentrated in vacuo. The residue was then treated with H2O (100 mL) and 20% EtOAc/hexane (100 mL) at 25° C., and the resulting mixture was stirred at 25° C. for 30 min before being cooled to 0-5° C. for 2 h. The white solids were collected by filtration, washed with H2O (2×25 mL) and 20% EtOAc/hexane (2×25 mL), and dried in vacuo to afford the desired (SR)-3-(3-fluoro-4-iodo-phenyl)-5-hydroxymethyl-oxazolidin-2-one 104 (15.1 g, 88% yield) as an off-white powder. This product was directly used in subsequent reactions without further purification. 1H NMR (300 MHz, DMSO-d6) δ 3.58 (dd, 1H, J=4.2, 12.6 Hz), 3.67 (dd, 1H, J=3.0, 12.6 Hz), 3.67 (dd, 1H, J=6.3, 9.0 Hz), 4.07 (t, 1H, J=9.0 Hz), 4.72 (m, 1H), 5.21 (br. s, 1H, OH), 7.22 (dd, 1H, J=2.4, 8.4 Hz), 7.58 (dd, 1H, J=2.4, 11.1 Hz), 7.81 (dd, 1H, J=7.8, 8.7 Hz). C10H9FINO3, LCMS (EI) m/e 338 (M++H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[S:3]([CH2:5][C:6]([NH:8][CH:9]1[C:31](=[O:32])[N:11]2[C:12]([C:24]([O:26]C(C)(C)C)=[O:25])=[C:13]([CH:16]([S:18][C:19]3[NH:23][N:22]=[N:21][N:20]=3)[CH3:17])[CH2:14][S:15][C@H:10]12)=[O:7])=[O:4].CCOCC>FC(F)(F)C(O)=O>[F:34][C:2]([F:1])([F:33])[S:3]([CH2:5][C:6]([NH:8][CH:9]1[C:31](=[O:32])[N:11]2[C:12]([C:24]([OH:26])=[O:25])=[C:13]([CH:16]([S:18][C:19]3[NH:23][N:22]=[N:21][N:20]=3)[CH3:17])[CH2:14][S:15][C@H:10]12)=[O:7])=[O:4]
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)CS(=O)C(F)(F)F)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)CS(=O)C(F)(F)F)[C@H]2SC1
Reaction time: 0.08 h

Procedure:
To a solution of 1.54 g (0.004 mol) of 7-amino-3-(1-methyl-1,2,3,4-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, t-butyl ester and 0.825 g (0.004 mol) of dicyclohexylcarbodiimide in 50 ml of benzene was added 0.704 g (0.004 mol) of trifluoromethylsulfinylacetic acid. The reaction mixture was stirred at 25° for 2 hr., then it was filtered and adsorbed onto 4 g of silica gel. Chromatography on 100 g of silica gel with 50:50 benzene-ethyl acetate gave 1.55 g (69 percent) of 7-trifluoromethylsulfinylacetamido-3-(1-methyl-1,2,3,4-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, t-butyl ester as a white foam. The ester was dissolved in 9 ml of trifluoroacetic acid and stirred at 25° for 5 minutes, then added dropwise to 200 ml of ether. The precipitate was collected, dissolved in 5 percent sodium bicarbonate and the solution was diluted to 150 ml. After extraction with ethyl acetate the aqueous phase was acidified to pH 1.5 and extracted thrice more with ethyl acetate. The combined extracts were dried (MgSO4) and concentrated to 35 ml, to which residue (the free acid) was added a solution of 1.5 of 30 percent sodium 2-ethylhexanoate in isopropanol followed by 200 ml of ether. The precipitated salt was collected, reprecipitated from methanol-ether and dried in vacuo to give 0.680 g of product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1.Br[C:22]1[CH:23]=[C:24]([C:27]([OH:29])=[O:28])[S:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>O1CCOCC1.O>[N+:9]([C:8]1[C:3]([O:2][CH3:1])=[C:4]([C:22]2[CH:23]=[C:24]([C:27]([OH:29])=[O:28])[S:25][CH:26]=2)[CH:5]=[CH:6][CH:7]=1)([O-:11])=[O:10]
Reactant: O=C(O)c1cc(Br)cs1
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)cccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(-c2csc(C(=O)O)c2)cccc1[N+](=O)[O-]
Yield: 133.4 %

Procedure:
2-(2-Methoxy-3-nitro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 4d (0.81 g, 2.9 mmol), 4-bromo-thiophene-2-carboxylic acid (0.3 g, 1.45 mmol), tetrakis (triphenylphosphine)palladium (80 mg, 0.073 mmol) and sodium carbonate (0.31 g, 2.9 mmol) were dissolved in a solvent mixture of 20 mL of 1,4-dioxane and 10 mL of water. The reaction was heated to reflux for 0.5 hours. The mixture was adjusted to pH 3 with 1 N hydrochloric acid and extracted with ethyl acetate (20 mL×3). The combined organic extracts were concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound 4-(3-nitro-2-methoxy-phenyl)-thiophene-2-carboxylic acid 19a (0.54 g) as a brown oil, which was directly used in the next step.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([I:38])C(=O)C1.C(O)(C(F)(F)F)=O>CC#N>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[C:13]([I:38])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:24][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:26]2)[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1CN(Cc2ccc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)C1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CN(Cc2ccc3c(I)c(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methyl 1-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylate (410 mg, 1 mmol) and NIS (247 mg, 1.1 mmol, 2.0 eq.) were dissolved in CH3CN (5 mL). Then CF3COOH (35 mg, 0.3 mmol, 0.3 eq.) was added to the mixture dropwise at 0° C. The mixture was warmed to r.t. and stirred for another 1.5 h. Then the mixture was extracted with EtOAc and the organic layer was concentrated and purified by silica gel chromatography using PE/EA (1/1) as eluent to give product the title compound as a slight red solid (300 mg, 56%). ESI-MS (M+H+): 536.2. 1H NMR (400 MHz, CDCl3) δ: 8.19 (d, 1H), 7.93 (s, 1H), 7.81 (d, 1H), 7.62 (d, 1H), 7.22 (d, 1H), 4.34-4.28 (m, 4H), 3.91-3.67 (m, 1H), 3.80-3.78 (m, 3H), 3.75 (s, 3H), 2.24-2.21 (m, 2H), 1.90-1.88 (m, 2H), 1.62-1.58 (m, 2H), 1.15-1.12 (m, 3H), 0.89 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:30]([F:33])([F:32])[F:31])[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[C:19]([C:26]([F:29])([F:28])[F:27])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:67]1[C:72](=[O:73])[CH2:71][NH:70][CH2:69][C:68]1=[O:74]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:30]([F:32])([F:31])[F:33])[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([N:70]4[CH2:71][C:72](=[O:73])[NH:67][C:68](=[O:74])[CH2:69]4)=[O:22])=[C:19]([C:26]([F:28])([F:29])[F:27])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=C1CNCC(=O)N1
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(C(F)(F)F)c4)(C(F)(F)F)C3)cc2C(F)(F)F)CC(=O)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 25-mL round-bottom flask, was placed 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)benzoic acid (70 mg, 0.14 mmol, 1.00 equiv), N,N-dimethylformamide (3 mL), HATU (105 mg, 0.28 mmol, 2.00 equiv), DIEA (36 mg, 0.28 mmol, 1.96 equiv), piperazine-2,6-dione (32 mg, 0.28 mmol, 1.99 equiv). The resulting solution was stirred for 1 h at 25° C. The reaction was then quenched by the addition of 10 ml of water. The resulting solution was extracted with 2×10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×20 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a TLC plate with ethyl acetate/petroleum ether (1/1). This resulted in 70 mg (76%) of 4-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)phenyl)carbonyl]piperazine-2,6-dione as colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][CH2:16][C:17]([OH:19])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:22](CC)CC)C.ClC(OCC)=O.[OH-].[NH4+]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][CH2:16][C:17](=[O:19])[NH2:22])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OCC(=O)O)CC1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OCC(N)=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of trans (4-tert-butoxycarbonylamino-cyclohexyloxy)-acetic acid (600 mg, 2.20 mmol) and triethylamine (400 μL, 2.90 mmol) in THF (22 mL) at 0° C. was treated dropwise with ethyl chloroformate (250 μL, 2.60 mmol). After 30 minutes ammonium hydroxide (2.20 mL, 170 mmol) was added dropwise. The golden solution was stirred at ambient temperature for 30 minutes and then concentrated under vacuum. The residue was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2×). The combined organic extracts were washed with 1M HCl, a saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated under vacuum to afford 550 mg (92%) of trans (4-carbamoylmethoxy-cyclohexyl)-carbamic acid tert-butyl ester as a white solid. LCMS (Method Q, ESI): RT=2.82 min, m+H=295.0; 1H NMR (400 MHz, CDCl3) δ: 6.52 (s, 1H), 5.55 (s, 1H), 4.38 (s, 1H), 3.96 (s, 2H), 3.44 (s, 1H), 3.30 (m, 1H), 2.03 (d, 4H), 1.44 (s, 9H), 1.38 (m, 2H), 1.16 (m, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:17])([CH3:16])[C:5]([NH:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1)=[O:6].[CH3:18]I>CN(C=O)C>[CH3:18][N:7]([C:5](=[O:6])[C:4]([CH3:17])([CH3:16])[CH3:3])[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1
Reactant: CI
Reactant: CC(C)(C)C(=O)Nc1ccc(C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)C(C)(C)C)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
Add sodium hydride (0.21 g, 8.6 mmol, 95%) to a solution of 4-(2,2-dimethyl-propionylamino)-benzonitrile (1.589 g, 7.857 mmol) in anhydrous DMF (16 mL) at 0° C. under nitrogen. Add methyl iodide (0.54 mL, 8.6 mmol) after bubbling ceased (˜20 min) Stir the mixture to room temperature overnight. Partition the reaction mixture between DCM (250 mL) and water (100 mL). Wash the organic phase with water (2×100 mL). Dry over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (1:0 to 1:1 gradient over 71 min; 50 mL/min) to obtain the desired intermediate as a white solid (1.201 g, 71%).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][C:7]([CH:10]=[O:11])=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[CH2:12](O)[CH2:13][OH:14].CCCP(=O)=O>CCOC(C)=O.C([O-])(O)=O.[Na+]>[O:11]1[CH2:12][CH2:13][O:14][CH:10]1[C:7]1[N:6]=[C:5]2[NH:1][CH:2]=[CH:3][C:4]2=[CH:9][CH:8]=1
Reactant: OCCO
Reactant: O=Cc1ccc2cc[nH]c2n1
Agent: CCCP(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: c1cc2ccc(C3OCCO3)nc2[nH]1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of 1H-pyrrolo[2,3-b]pyridine-6-carbaldehyde (840 mg, 5.60 mmol), ethylene glycol (3.13 ml, 56.0 mmol) and propylphosphonic anhydride (50% in EtOAc, 3.34 ml, 5.60 mmol) in EtOAc (15 ml) was stirred at 80° C. After 18 h, the reaction mixture was cooled to room temperature, diluted with sat. aq. NaHCO3 and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4 and evaporated. The crude material was applied to a 120 g RediSep® silica column and purified by normal phase chromatography, eluting with EtOAc. Product-containing fractions were combined and evaporated. The residue was triturated with Et2O to give the title compound as an white solid. (UPLC-MS 6) tR 0.66; ESI-MS 191.1 [M+H]+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:11]=[CH:12][C:13]([O:27][CH3:28])=[C:14]([C:16]([CH3:26])([CH3:25])[CH2:17][C:18]2([C:21]([F:24])([F:23])[F:22])[CH2:20][O:19]2)[CH:15]=1>C(O)C>[F:24][C:21]([F:22])([F:23])[C:18]([CH2:20][NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([OH:19])[CH2:17][C:16]([C:14]1[CH:15]=[C:10]([F:9])[CH:11]=[CH:12][C:13]=1[O:27][CH3:28])([CH3:26])[CH3:25]
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Reactant: NCc1ccccc1
Solvent: CCO
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNCc1ccccc1)C(F)(F)F
Temperature: 80 °C
Yield: 95.3 %

Procedure:
Benzylamine (38.6 mL, 0.353 mol) was added in one portion to a stirred solution of racemic 2-{2-[5-fluoro-2-(methyloxy)phenyl]-2-methylpropyl}-2-(trifluoromethyl)oxirane (which may be prepared according to WO 04/063163, 50 g, 0.171 mol) in ethanol (500 mL) at 20° C. and the resulting mixture heated at 80° C. overnight. The solvent was removed under reduced pressure and the resulting oil was purified by silica gel column chromatography eluting with 4% ethyl acetate in cyclohexane to give the title compound as a white solid (65.1 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]3[CH:12]=[C:11]([C:13]([OH:15])=O)[O:10][C:8]3=[CH:9][C:4]=2[NH:3][C:2]1=[O:16].C(N(CC)CC)C.[CH2:24]([CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH2:24]([CH:31]1[CH2:36][CH2:35][N:34]([C:13]([C:11]2[O:10][C:8]3[C:7](=[CH:6][C:5]4[O:1][C:2](=[O:16])[NH:3][C:4]=4[CH:9]=3)[CH:12]=2)=[O:15])[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(O)c1cc2cc3oc(=O)[nH]c3cc2o1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1cc2cc3oc(=O)[nH]c3cc2o1)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.5 %

Procedure:
A mixture of 0.42 g (1.9 mmol) of 3H-furo[2,3-f]benzoxazole-2-one-6-carboxylic acid, 0.3 ml (2.1 mmol) of triethylamine, 0.35 ml (2.0 mmol) of 4-benzylpiperidine, 0.76 g (2.0 mmol) of HBTU (Advanced Chem. Tech.) and 10 ml of dimethylformamide is stirred at room temperature for 6 h. The reaction mixture is concentrated and the residue is purified by column chromatography using Kieselgel 60 as adsorbent (Merck) and toluene:aceton=2:1 as eluent, then the product is crystallized with diethylether to yield 0.39 g (54%) of the title compound. Mp.: 205-210° C. (diethyl ether).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].[S-:10][C:11]#[N:12].[NH4+].N>CO>[Cl:1][C:2]1[CH:7]=[C:6]([S:10][C:11]#[N:12])[CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9]
Reactant: Oc1c(Cl)cccc1Cl
Reactant: N#C[S-]
Agent: N
Agent: [NH4+]
Solvent: CO
Product: N#CSc1cc(Cl)c(O)c(Cl)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 14.8 %

Procedure:
2,6-Dichlorophenol (100 g, 0.613 mole) and ammonium thiocyanate (102.73 g, 1.350 mole) were mixed in methanol and the solution cooled to 0° C. Chlorine gas was bubbled throught the reaction, maintaining the temperature below 10° C. The solution turned a pale yellow color. The reaction was stirred for a total of 3 hours until acidic, at which time ammonia gs was bubbled through and the solution stirred for an additional three hours at 0° to 10° C. The reaction was poured into iced distilled water, and filtered, yielding approximately 20 g of a yellow solid which was dried overnight in vacuo. The filtrate was extracted with ethyl acetate, the extracts dried over magnesium sulfate and solvent removed in vacuo to yield approximately 100 g of crude product. Following purification by silica chromatography, the material was taken up in 1 liter of toluene, charcoal added, filtered and recrystallized from hexane to yield 55.03 g of product as a yellow solid, m.p. about 94.5°-97° C. The structure was confirmed by NMR.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[C:14]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[N+:19]([O-])=O.[H][H]>[OH-].[Na+].[Ni]>[NH2:19][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([S:15](=[O:18])(=[O:17])[NH2:16])[C:6]=1[NH:5][CH2:4][CH2:3][O:2][CH3:1])[C:10]([OH:12])=[O:11]
Reactant: [H][H]
Reactant: COCCNc1c([N+](=O)[O-])cc(C(=O)O)cc1S(N)(=O)=O
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Product: COCCNc1c(N)cc(C(=O)O)cc1S(N)(=O)=O

Procedure:
4-(2-Methoxyethylamino)-3-nitro-5-sulphamyl-benzoic acid (3.2 g) was dissolved in 1N sodium hydroxide (10 ml) and hydrogenated after addition of moist Raney-Nickel (1 g). When the hydrogen uptake had become negligible, the catalyst was removed by filtration, and the resulting 3-amino-4-(2-methoxyethylamino)-5-sulphamyl-benzoic acid was precipitated from the filtrate by addition of 4N hydrochloric acid until pH 3. After recrystallization from water, the melting point was 209°-211° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([OH:16])[C:10]3[N:11]([N:13]=[CH:14][CH:15]=3)[CH:12]=2)[CH:4]=[N:3]1.[Br:17]N1C(=O)CCC1=O>C(#N)C.ClCCl>[Br:17][C:15]1[CH:14]=[N:13][N:11]2[CH:12]=[C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[CH:8]=[C:9]([OH:16])[C:10]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1cc(-c2cc(O)c3ccnn3c2)cn1
Solvent: ClCCl
Solvent: CC#N
Product: Cn1cc(-c2cc(O)c3c(Br)cnn3c2)cn1
Reaction time: 0.5 h

Procedure:
6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ol (75.0 mg, 0.350 mmol) was suspended in acetonitrile (4 ml). N-bromosuccinimide (68.5 mg, 0.385 mmol) was added and the mixture was allowed to stir. After 30 minutes, additional N-bromosuccinimide (6.9 mg, 0.039 mmol) was added and the mixture was allowed to stir for 1 h. The reaction mixture was diluted in dichloromethane, washed with water and 1 N aqueous sodium hydroxide. The pH of the combined aqueous layers was adjusted to pH 7 with 6 N HCl, then the aqueous layers were extracted with ethyl acetate (2×) and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol/dichloromethane gradient) to afford 3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ol.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11]1[C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[CH:14]=[CH:13][C:12]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(OCC)C>[C:1]1([S:7][CH2:8][CH2:9][O:10][C:13]2[CH:12]=[CH:11][C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccc2c(c1)CCCC2
Reactant: OCCSc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: c1ccc(SCCOc2ccc3c(c2)CCCC3)cc1

Procedure:
5.1 g (0.033 mol) of 2-phenylthioethanol, 3.7 g (0.025 mol) of 5,6,7,8-tetrahydro-β-naphthol and 7.9 g (0.03 mol) of triphenylphosphine were dissolved in 60 g of diethyl ether and a solution of 5.2 g (0.03 mol) of diethyl azodicarboxylate in diethyl ether was added dropwise to the solution at room temperature.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[O:38]1[C:43]2[CH:44]=[CH:45][C:46]([CH2:48][NH2:49])=[CH:47][C:42]=2[O:41][CH2:40][CH2:39]1>>[O:38]1[C:43]2[CH:44]=[CH:45][C:46]([CH2:48][NH:49][C:3]([C:5]3[N:14]4[C:8]([CH2:9][N:10]([C:19]([C:21]5[CH:26]=[CH:25][C:24]([C:27]6[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=6[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=5)=[O:20])[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:47][C:42]=2[O:41][CH2:40][CH2:39]1
Reactant: NCc1ccc2c(c1)OCCO2
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCc4ccc5c(c4)OCCO5)n3Cc3ccccc32)ccc1-c1ccccc1C

Procedure:
The title compound was prepared in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and C-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-methylamine. Purification was performed using HPLC with a normal phase column and eluting with a two phase solvent system (A=hexane, B=dichloromethane/methanol, 4:1), m.p. 153-155° C. MS [(+)ESI, m/z]: 600 [M+H]+
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:18][C:19]1[CH:20]=[C:21]([NH2:28])[C:22](=[CH:26][CH:27]=1)[C:23](O)=[O:24].C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]2[C:23](=[O:24])[O:17][C:14]3([NH:28][C:21]=2[CH:20]=1)[CH2:15][CH2:16][N:11]([C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=1)[CH2:12][CH2:13]3
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: CS(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CS(=O)(=O)c1ccc(N2CCC3(CC2)Nc2cc(Cl)ccc2C(=O)O3)cc1
Yield: 94 %

Procedure:
A mixture of 5.82 g (0.023 mol) of the compound of (B), 4 g (0.023 mol) of 4-chloroanthranilic acid, 75 ml of toluene, and 0.1 of p-toluenesulfonic acid is stirred at reflux with the azeotropic removal of water for 5 hours. After cooling, the resulting precipitate is collected, and washed with cold toluene to give 8.8 g (94%) of title compound: m.p. 193°-194° C.; IR (KBr) 3350, 1695, and 1600 cm-1 ; NMR (DMSO-d6) δ 7.84-7.70 (m, 2H), 7.76 (d, 2H), 7.16 (d, 2H), 6.90-6.84 (m, 1H), 3.78-3.66 (m, 2H), 3.48-3.36 (m, 2H), 3.12 (s, 3H), 2.18-2.08 (m, 2H) and 1.96-1.82 (m, 2H); MS m/e 487 (M+1).