Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J1) (319 mg, 1.0 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (311 mg, 1.0 mmol) according to the general procedure M. Obtained as a pale pink foam (460 mg, 83%).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]([C:17]2[CH:18]=[C:19]3[C:25]([NH2:26])=[N:24][NH:23][C:20]3=[CH:21][N:22]=2)[CH:8]=1>N1C=CC=CC=1>[N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]([C:17]2[CH:18]=[CH:19][C:20]3[NH:23][N:24]=[C:25]([NH:26][C:4]([CH:1]4[CH2:3][CH2:2]4)=[O:5])[C:21]=3[N:22]=2)[CH:8]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1n[nH]c2cnc(-c3cnc4ccccc4c3)cc12
Solvent: c1ccncc1
Product: O=C(Nc1n[nH]c2ccc(-c3cnc4ccccc4c3)nc12)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Cyclopropane carbonyl chloride (168 mg, 1.602 mmol) was added to a stirred solution of 5-(quinolin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-ylamine (200 mg, 0.766 mmol) in anhydrous pyridine (5 mL) and the reaction was heated under reflux for 16 hours. The solvent was then removed in vacuo and the residue re-evaporated from water (10 mL) to yield a solid. This was triturated with saturated aqueous sodium bicarbonate solution and the mixture then left to stand for 0.5 hour until the pH stabilised at pH 9–10. The resulting solid was then collected by filtration, washed with water (3×25 mL) and dried in vacuo. This material was then stirred in piperidine (3 mL) at room temperature for 2 hours. The piperidine was evaporated and the residue triturated with water (5 mL) and with methanol (5 mL) to afford the title compound as a solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]([OH:16])=[O:15])[C:3]1=[O:17].[CH2:18]([CH2:25][C:26](=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([BH3-])#N.[Na+].[ClH:37]>C(O)(=O)C.CO>[ClH:37].[C:14]([CH2:13][N:4]1[C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[CH2:7][CH2:8][CH:2]([NH:1][CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:25][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:3]1=[O:17])([OH:16])=[O:15]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Reactant: NC1CCc2ccccc2N(CC(=O)O)C1=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C(CCc1ccccc1)NC1CCc2ccccc2N(CC(=O)O)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3-amino-1-carboxymethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (10.0 g) and ethyl benzylpyruvate (26.4 g) in acetic acid (75 ml) and methanol (75 ml) was stirred at room temperature under nitrogen for 1 hour. Sodium cyanoborohydride (3.4 g) in methanol (25 ml) was added dropwise over 4 hours. The reaction mixture was stirred at room temperature for 24 hours. Concentrated hydrochloric acid (4 ml) was added dropwise, and the mixture stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness. The residue was partitioned between 150 ml of water and 50 ml of ether and adjusted to pH 9 with 40% sodium hydroxide. The layers were separated and the ether layer was discarded. The aqueous layer was adjusted to pH 4.3 with concentrated hydrochloric acid and extracted with 3×75 ml of ethyl acetate. The organic portions were dried (magnesium sulfate) and concentrated to dryness. Hydrogen chloride gas was bubbled into a solution of the crude product in 310 ml of methylene chloride for 5 minutes. The solution was evaporated and the residue was stirred in 225 ml of ether. The product was collected by filtration to give a 70:30 diastereomeric mixture as determined by high pressure liquid chromatography. The product was recrystallized from ethanol/ethyl acetate (1:3) to give 1-carboxymethyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one hydrochloride melting at 246°-8° (dec.) and corresponding to the racemic isomer B.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([N:25]=[C:26]=[O:27])[CH:22]=[CH:23][CH:24]=1>>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=2)=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Reactant: COc1cccc(N=C=O)c1
Product: COc1cccc(NC(=O)Nc2ccc(OC)c(-c3c(Cl)cnn3C)c2)c1
Yield: 27 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 3-Methoxyphenyl isocyanate in a similar manner as described in Example 1.53, providing 7.5 mg (27%) of Compound 30 (Note: Compound 30 did not precipitate out. Therefore, the CH2Cl2 was removed under reduced pressure, the residue was dissolved in 5 mL DMSO, and purified by preparative HPLC): LCMS m/z (%)=389 (M+H37Cl, 39), 387 (M+H35Cl, 100). 1H NMR (400 MHz, acetone-d6) δ: 7.99 (s, 1H), 7.49 (dd, J1=8 Hz, J2=2 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 7.28 (s, 1H), 7.12 (t, J=2 Hz, 1H), 6.95 (d, J=2 Hz, 1H), 6.93 (d, J=4 Hz, 1H), 6.81 (dd, J1=8 Hz, J2=4 Hz, 1H), 6.37 (dd, J1=8 Hz, J2=4 Hz, 1H), 3.63 (s, 3H), 3.57 (s, 3H), 3.47 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)[N:9]=2)=[CH:6][N:5]=[C:4]([S:23][CH3:24])[N:3]=1.[CH:25]([Mg]Br)([CH3:27])[CH3:26]>C1COCC1.CN1C(=O)CCC1>[CH:25]([C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)[N:9]=2)=[CH:6][N:5]=[C:4]([S:23][CH3:24])[N:3]=1)([CH3:27])[CH3:26]
Reactant: CC(C)[Mg]Br
Reactant: CSc1ncc(-c2ccnc(Nc3ccc(C#N)cc3)n2)c(Cl)n1
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CSc1ncc(-c2ccnc(Nc3ccc(C#N)cc3)n2)c(C(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
4-(4′-Chloro-2′-(methylthio)-4,5′-bipyrimidin-2-ylamino)benzonitrile (35) (125 mg, 0.352 mmol) and ferric acetylacetonate (12.44 mg, 0.035 mmol) were dissolved in THF (1791 μl) and NMP (134 μl), then isopropylmagnesium bromide (528 μl, 0.528 mmol) was added dropwise. According to LC/MS, approximately 40% conversion was observed. Additional isopropylmagnesium bromide (528 μl, 0.528 mmol) was added, and the reaction was stirred at rt for an additional 1 hour. The reaction was quenched with 1N HCl, then was extract with EtOAc. The organic extracts were combined, washed with brine, dried over sodium sulfate, then concentrated in vacuo. The crude product was dry-loaded onto silica gel, then was purified by Biotage™ silica gel chromatgraphy [25 g SNAP column, 30% EtOAc/heptane to 100% EtOAc] to obtain the desired product (51.1 mg, 40%). MS (ES+): m/z=363.3 [M+1] (100). HPLC: tR=1.70 minutes over 3 minutes.
Reaction SMILES: [CH2:1]([NH:7][CH:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C=O.[BH3-][C:30]#N.[Na+]>>[CH2:1]([N:7]([CH3:30])[CH:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCNC1CCc2cc(Oc3ccc(C(N)=O)cn3)ccc21
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Product: CCCCCCN(C)C1CCc2cc(Oc3ccc(C(N)=O)cn3)ccc21
Yield: 73.6 %

Procedure:
Using a method similar to Example 13, using 6-(1-hexylamino-indan-5-yloxy)-nicotinamide (example 12, 490 mg, 1.38 mmol), paraformaldehyde (443 mg), and NaBH3CN (261 mg, 4.16 mmol) gives the title compound (373 mg) as a light yellow solid. Mass spectrum (ion spray): m/z=368 (M+1); 1HNMR (CDCl3): 8.59 (s, 1H), 8.16 (d, 1H), 7.38 (d, 1H), 6.98-6.93 (m, 3H), 5.89 (br. s, 2H), 4.42 (t, 1H), 2.97-2.78 (m, 2H), 2.40 (m, 2H), 2.22 (s, 3H), 2.08 (m, 2H), 1.51 (m, 2H), 1.36-1.22 (m, 6H), 0.88 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[O:16][CH3:17].Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[C:22]([Cl:38])=[CH:21][N:20]=1>>[Cl:38][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[N:24][C:19]([NH:1][C:2]2[CH:15]=[CH:14][C:5]3[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[C:3]=2[O:16][CH3:17])=[N:20][CH:21]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCCc2c1ccc(N)c2OC
Product: CCN1C(=O)CCCc2c1ccc(Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)c2OC

Procedure:
Following a procedure analogous to Example 113, 7-Amino-1-ethyl-6-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (40 mgs) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide (59 mgs) were converted to the title compound (18 mgs as a white solid). 1H-NMR (CDCl3): δ 9.48 (s, 1H), 8.58 (d, J=8.3 Hz, 1H), 8.24 (d, J=8.8 Hz, 1H), 8.19 (s, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.63 (t, J=7.6 Hz, 1H), 7.50 (s, 1H), 7.31-7.28 (m, 1H), 6.94 (d, J=8.9 Hz, 1H), 4.40-4.10 (broad absorption, 2H), 3.83 (s, 3H), 3.70-2.90 (broad absorption, 2H), 2.78 (s, 6H), 2.31-2.00 (broad absorptions, 4H), 1.16 (t, J=7.0 Hz, 3H). LC/MS: (M+H)+ found=545.16; MP 183° C.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][O:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.N1CCCC1.[C:27]1([CH2:33][CH2:34][CH:35]=O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)C>[C:27]1([CH2:33][CH2:34][CH:35]=[C:18]2[O:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]3[N:4]4[CH:3]=[CH:2][N:1]=[C:5]4[CH:6]=[CH:7][CH:8]=3)[C:19]2=[O:20])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1COC(=O)N1CCCCSc1cccc2nccn12
Reactant: O=CCCc1ccccc1
Solvent: C1CCNC1
Solvent: CCO
Product: O=C1OC(=CCCc2ccccc2)C(=O)N1CCCCSc1cccc2nccn12
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
1.53 g (5 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]oxazolidine-2,4-dione and 20 ml of ethanol were placed in a reaction flask, followed by stirring at 60° C. for 20 minutes, to dissolve the starting materials. After this mixture was kept standing to 50° C., an ethanol solution of 0.05 ml (0.5 mmol) of pyrrolidine was added. Next, an ethanol solution of 0.66 ml (5 mmol) of 3-phenylpropionaldehyde was added, followed by refluxing for 19 hours. Six hours later, 0.66 ml (5 mmol) of 3-phenylpropionaldehyde and 0.05 ml (0.5 mmol) of pyrrolidine were added. After the reaction mixture was cooled, the solvent was distilled off, followed by extraction with dichloromethane and water. After the organic layer was dried with sodium sulfate, the solvent was distilled off. The residue was eluted by column chromatography (eluent, hexane/ethyl acetate=1/1) to yield 26 mg (1.2%, yellow oily substance) of the desired product.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:14]2[CH2:15][O:16][C@H:12]([O:13]2)[C@H:11]([O:17][CH3:18])[C@@H:10]1[OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20](I)[CH3:21]>>[CH2:1]([O:8][C@@H:9]1[C@H:14]2[CH2:15][O:16][C@H:12]([O:13]2)[C@H:11]([O:17][CH3:18])[C@@H:10]1[O:19][CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@H]1[C@@H]2OC[C@@H](O2)[C@@H](OCc2ccccc2)[C@H]1O
Reactant: CCI
Product: CCO[C@H]1[C@@H](OC)[C@@H]2OC[C@@H](O2)[C@H]1OCc1ccccc1

Procedure:
The title compound was prepared from 1,6-anhydro-4-O-benzyl-2-O-methyl-β-D-allopyranose (0.135 g) (see Example 29) in the same way as described for the 3-O-methyl analogue (see Example 30) but employing ethyl iodide (0.624 g) instead of methyl iodide. It was obtained as a colourless oil (0.089 g); 1H-nmr data: 7.2-7.5 (m, Ph), 5.6 (d, H-1), 4.8 (m, PhCH2O), 4.55 (m, H-5), 1.25 (t, CH2CH3), and 3.4-3.7 (m, remaining protons).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH2:12]([C@@H:19]1[CH2:23][O:22][C:21](=[O:24])[NH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>C1(C)C=CC=CC=1>[CH2:12]([C@@H:19]1[CH2:23][O:22][C:21](=[O:24])[N:20]1[C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(Cc1ccc(Br)cc1)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
2-(4-Bromophenyl)acetic acid (7.85 g, 36.5 mmol) and (R)-4-benzyloxazolidin-2-one (3.23 g, 18.3 mmol) were combined in toluene (30 mL) and triethylamine (10.2 mL, 73.0 mmol). The solution was then heated to 80° C., and a solution of pivaloyl chloride (4.49 mL, 36.5 mmol) in toluene (7.5 mL) was added slowly. The reaction was heated to 110° C. and stirred overnight. The reaction was then cooled, and the toluene solution was washed with 2N HCl, water, 5% Na2CO3, brine and then dried over Na3SO4. After removal of the solvent, the residue was purified by column chromatography to give (R)-4-benzyl-3-(2-(4-bromophenyl)acetyl)oxazolidin-2-one (5.65 g, 83%) as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:13](O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C>C1COCC1>[CH2:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: CCCCCCCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc([N+](=O)[O-])c(C=O)c1
Reaction time: 24 h
Yield: 57 %

Procedure:
5-Hydroxy-2-nitrobenzaldehyde (3.60 g, 0.0215 mol), 1-heptanol (2.50 g, 0.0215 mol) and triphenylphosphine polymer bound (3 mmol/g loading; 9 g, 0.028 mol) were placed in a flask followed by tetrahydrofuran (300 mL, 4 mol). A solution of azodicarboxylic acid di-tert-butyl ester (5.94 g, 0.0258 mol) in THF (15 mL) was then added dropwise at 23° C. The reaction mixture was then allowed to stir for 1 day. Filtered through a celite pad, and the crude mixture was then purified via chromatography (SiO2, 120 g, 0-100% ethyl acetate/hexanes) to give a pure product (3.25 g, 57%). 1H NMR (CHLOROFORM-d) δ: 10.50 (s, 1H), 8.16 (d, J=9.0 Hz, 1H), 7.32 (d, J=3.0 Hz, 1H), 7.14 (dd, J=9.0, 2.8 Hz, 1H), 4.11 (t, J=6.5 Hz, 2H), 1.76-1.92 (m, 2H), 1.42-1.53 (m, 2H), 1.21-1.42 (m, 6H), 0.82-0.99 (m, 3H). MS (M+1): 266.20.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:12][C:13]1[CH:28]=[CH:27][C:16]([O:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=2)=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.Cl.[CH2:67]([O:74][NH2:75])[C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:10])[CH:11]([NH:29][C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:19]=[CH:20][C:21]([C:22](=[O:24])[NH:75][O:74][CH2:67][C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)=[CH:25][CH:26]=2)=[CH:27][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NOCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccc(C(=O)O)cc2)cc1)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccc(C(=O)NOCc3ccccc3)cc2)cc1)C(=O)OCc1ccccc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 54.9 %

Procedure:
The acid compound 4 (0.6 g, 1.22 mmol) was dissolved in dry DMF (15 mL) and cooled to 0-5° C. 1-Hydroxybenzotriazole (0.18 g, 1.34 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.23 g, 1.22 mmol), and triethylamine (0.6 mL, 3.66 mmol) were added to the above mixture followed by stirring for 15 min. O-Benzylhydroxylamine hydrochloride (0.22 g, 1.34 mmol) was added and the mixture was allowed to come to room temperature and stirred for 18 h. The solvent was evaporated under reduced pressure and the residual oil was taken up in EtOAc (50 mL). The organic layer was extracted with 2.0 M HCl (1×10 mL), saturated NaHCO3 (1×10 mL), water (1×25 mL) and brine (1×25 mL). The resulting EtOAc layer was dried and concentrated to yield the crude product. Flash chromatography using hexanes-ethyl acetate (1:1) yielded the desired benzyl hydroxamate 7 (0.4 g, 56%). 1H NMR (DMSO-d6): 11.73 (s, 1H), 7.75 (d, J=8.4 Hz, 2H), 7.29-7.47 (m, 13H), 6.99 (d, J=8.8 Hz, 2H), 6.99 (5.12 (s, 2H), 4.92 (s, 2H), 4.23-4.28 (m, 1H), 3.03 (dd, J=13.6 and 5.2 Hz, 1H), 2.90 (dd, J=13.6 and 10.0 Hz, 1H), 1.33 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH3:9][C:10]([CH3:15])=[CH:11][C:12](Cl)=[O:13]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:12](=[O:13])[CH:11]=[C:10]([CH3:15])[CH3:9])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: CC(C)=CC(=O)Cl
Solvent: C1CCOC1
Product: CC(C)=CC(=O)Nc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a suspension of Nail (4.15 g, 173 mmol, 60% in oil) in 50 ml of THF was cannulated a solution of 20.322 g (118 mmol) of 3-bromo-aniline in 50 ml of THF. The resulting mixture was stirred at 0° C. for 45 min and warmed to room temperature over a period of 15 min. To this solution was added through cannulation 13.123 g (173 mmol) of 3,3-dimethylacryloyl chloride. The mixture was stirred at room temperature for 24 h and thereafter slowly poured into ice water. The resulting mixture was extracted with methylene chloride (twice), dried over MgSO4 and concentrated to yield a solid. The solid was purified by recrystallization in hexane/EtOAc (2:1) to give the title compound as a light brown solid. PNMR (CDCl3) d 7.83 (1H, b), 7.30 (4H, m), 5.68 (1H, s), 2.22 (3H, s), 1.90 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C@@H:22]([NH:32][C:33](=[O:49])[CH2:34][N:35]3[C:39]4[C:40]([F:45])([F:44])[C@@H:41]5[CH2:43][C@@H:42]5[C:38]=4[C:37]([CH:46]([F:48])[F:47])=[N:36]3)[CH2:23][C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=3)=[N:13][C:14]([N:17]([CH2:19][CH2:20][OH:21])[CH3:18])=[CH:15][CH:16]=2)=[C:7]2[C:3]=1[C:4]([NH:51][S:52]([CH3:55])(=[O:54])=[O:53])=[N:5][N:6]2[CH3:50].[F:56]C1(F)C2N(CC(O)=O)N=C(C(F)(F)F)C=2[C@H]2C[C@@H]12>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C@@H:22]([NH:32][C:33](=[O:49])[CH2:34][N:35]3[C:39]4[C:40]([F:44])([F:45])[C@@H:41]5[CH2:43][C@@H:42]5[C:38]=4[C:37]([C:46]([F:56])([F:47])[F:48])=[N:36]3)[CH2:23][C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=3)=[N:13][C:14]([N:17]([CH2:19][CH2:20][OH:21])[CH3:18])=[CH:15][CH:16]=2)=[C:7]2[C:3]=1[C:4]([NH:51][S:52]([CH3:55])(=[O:53])=[O:54])=[N:5][N:6]2[CH3:50]
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1C(F)(F)[C@@H]1C[C@H]21
Reactant: CN(CCO)c1ccc(-c2ccc(Cl)c3c(NS(C)(=O)=O)nn(C)c23)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)[C@@H]2C[C@H]32)n1
Product: CN(CCO)c1ccc(-c2ccc(Cl)c3c(NS(C)(=O)=O)nn(C)c23)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2C(F)(F)[C@@H]2C[C@H]32)n1

Procedure:
The title compound (58) was prepared according to the method presented for the synthesis of compound 57G of Example 57 utilizing 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (30J). 1H NMR (400 MHz, Methanol-d4) δ 7.43-6.05 (m, 7H), 5.18-5.09 (m, 1H), 4.85-4.75 (m 2H), 4.04-3.69 (m, 3H), 3.42 (s, 2H), 3.27-3.20 (m, 6H), 3.20-3.11 (m, 2H), 3.05 (s, 1H), 2.95 (s, 1H), 2.61-2.43 (m, 2H), 1.51-1.35 (m, 1H), 1.11 (m, 1H). MS (m/z) 829.20 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH2:21][C:22]#[CH:23])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH2:3][C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][N:2]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH2:21][C:22]#[CH:23])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: C#CCNc1ccc(S(=O)(=O)N(C)CC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C#CCNc1ccc(S(=O)(=O)N(C)CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 866.7 %

Procedure:
To a solution of 0.160 g (0.047 mmol) of 2-(methyl{[4-(prop-2-ynylamino)phenyl]sulfonyl}amino)acetic acid, tert-butyl ester in 1 mL of dichloromethane was added 1 mL of trifluoroacetic acid and the reaction was stirred at room temperature for 19 h. Concentration of the mixture in vacuo provides 0.115 g (86%) of 2-(methyl{[4-(prop-2-ynylamino)phenyl]sulfonyl}amino)acetic acid as a brown glass. Electrospray Mass Spec 281.1 (M−H)−
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:14])=[CH:4][C:5]2[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:13]=1.[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:15]([O:1][C:2]1[C:3]([OH:14])=[CH:4][C:5]2[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:13]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: O=C1CCCCc2cc(O)c(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1CCCCc2cc(OCc3ccccc3)c(O)cc21
Temperature: 50 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
A mixture of 2,3-dihydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (10 g), benzyl chloride (8 g), anhydrous potassium carbonate (9 g) and acetone (200 ml) is stirred at 50° C. for two hours. The reaction mixture is cooled and filtered off. The filtrate is concentrated under reduced pressure. The concentrate is dissolved in ethyl acetate. The organic layer is washed with water, dried and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent, hexane:ethyl acetate:methylene chloride=3:1:1) to afford 2-benzyloxy-3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (8.8 g). This product is recrystallized from ethyl acetate-hexane to give colorless needles, m.p. 127°-128° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:26]([O:11][CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](COC(=O)C(C)(C)C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A cooled solution of (R)-2-(tert-butoxycarbonylamino)-3-phenyl-1-propanol (92) (1 g, 4 mmol) in CH2Cl2 (20 ml) at 0° C. was treated with triethylamine (1.12 m, 8 mmol), pivaloyl chloride (0.74 ml, 6 mmol) followed by 4-(dimethylamino)pyridine (50 mg 0.4 mmol) and stirred overnight at room temperature. The mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel with EtOAc/hexanes (1:4) as an eluant to give compound 94.