Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:6][NH:7][C:8](=[O:18])[C:9]2[C:14](I)=[CH:13][CH:12]=[N:11][C:10]=2[O:16][CH3:17])[CH2:5][CH2:4][CH2:3][CH2:2]1.N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.[Cu]I>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:16][CH3:17])[C:9]=3[C:8](=[O:18])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1nccc(I)c1C(=O)NNC1CCCC1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Product: COc1nccc2c1c(=O)[nH]n2C1CCCC1
Yield: 38.8 %

Procedure:
A solution of N′-cyclopentyl-4-iodo-2-methoxynicotinohydrazide (695 mg), L-proline (44.3 mg), potassium carbonate (532 mg) and copper(I) iodide (36.6 mg) in DMSO (18 mL) was stirred under nitrogen atmosphere at room temperature for 5 hr. To the reaction mixture was added water under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was removed, to the obtained aqueous layer was added 1N hydrochloric acid (7 mL) under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (174 mg).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:20])[CH2:9][CH2:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([OH:18])=[C:13]([CH3:19])[CH:12]=2)=[CH:5][C:4]=1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[CH3:2].Cl[CH2:29][C@@H:30]([OH:33])[CH2:31][OH:32]>C(O)C.[OH-].[Na+].O>[OH:33][C@@H:30]([CH2:31][OH:32])[CH2:29][O:18][C:14]1[C:15]([CH3:17])=[CH:16][C:11]([CH2:10][CH2:9][C:8]([C:6]2[S:7][C:3]([CH2:1][CH3:2])=[C:4]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)[CH:5]=2)=[O:20])=[CH:12][C:13]=1[CH3:19]
Reactant: CCc1sc(C(=O)CCc2cc(C)c(O)c(C)c2)cc1-c1ccc(C)cc1
Reactant: OC[C@H](O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCc1sc(C(=O)CCc2cc(C)c(OC[C@@H](O)CO)c(C)c2)cc1-c1ccc(C)cc1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
A solution of 1-(5-ethyl-4-p-tolyl-thiophen-2-yl)-3-(4-hydroxy-3,5-dimethyl-phenyl)-propan-1-one (47 mg, 0.125 mmol) in ethanol (2 mL) and 3 N aq. NaOH (0.5 mL) is treated with (S)-3-chloro-propane-1,2-diol (90 μL) and the mixture is stirred at 60° C. for 20 h. Another portion of (S)-3-chloro-propane-1,2-diol (60 μL) is added and stirring is continued at 60° C. for 5 days. The reaction mixture is diluted with water and extracted with DCM. The solvent of the organic extract is evaporated and the crude product is purified on prep. TLC plates with heptane:EA 2:1 to give 3-[4-((S)-2,3-dihydroxy-propoxy)-3,5-dimethyl-phenyl]-1-(5-ethyl-4-p-tolyl-thiophen-2-yl)-propan-1-one (6 mg) as a colourless resin; LC-MS: tR=1.05 min, [M+1]+=453.25; 1H NMR (CDCl3): δ 7.56 (s, 1H), 7.30-7.21 (m, 4H), 6.88 (s, 2H), 4.11-4.05 (m, 1H), 3.87-3.80 (m, 4H), 3.18-3.11 (m, 2H), 2.98-2.85 (m, 4H), 2.39 (s, 3H), 2.25 (s, 6H), 1.29 (t, J=7.6 Hz, 3H).
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH3:3].S(Cl)([Cl:17])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:17])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CCCOCc1ccc(C(=O)O)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCOCc1ccc(C(=O)Cl)cc1

Procedure:
4-(Propoxymethyl)benzoic acid (1.4 g, 7.2 mmol) was mixed with thionyl chloride (1.3 g, 10.9 mmol), pyridine (0.1 ml) and toluene (3 ml), followed by reacting them at 80° C. for 2 hours, and distilling off superfluous thionyl chloride and toluene under reduced pressure, to obtain raw 4-(propoxymethyl) benzoyl chloride.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[C:10]1([S:20](Cl)(=[O:22])=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.Cl>O.[OH-].[Na+].O1CCCC1>[C:4]([CH2:3][C@H:2]([NH:1][S:20]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)(=[O:22])=[O:21])[C:7]([OH:9])=[O:8])(=[O:6])[NH2:5]
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: NC(=O)C[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)C[C@H](NS(=O)(=O)c1cccc2ccccc12)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
132.12 g (1 mol) of (S)-asparagine were dissolved in a mixture of 800 ml of water and 500 ml of 2 N sodium hydroxide. Then 500 ml of tetrahydrofuran were added. The mixture was cooled to 0° C., and while keeping the pH at 12.0-12.5 with 2 N sodium hydroxide a solution of 226.7 g (1 mol) of naphthalene-1-sulfonyl chloride in 500 ml of tetrahydrofuran was added within 1 h. The mixture was stirred for 1 h at 0° C. while maintaining the pH at 12.5. Then the mixture was allowed to warm to room temperature, stirred for further 2 h and left at room temperature overnight. The pH was adjusted to about 7 with concentrated hydrochloric acid and the tetrahydrofuran was removed in vakuum in a rotary evaporator. The remaining aqueous solution was cooled to 0° C. and with stirring acidified to pH 0.8 by addition of concentrated hydrochloric acid. After stirring for 30 min at 0° C. the precipitated product was filtered off, washed with water and dried in vacuo at 40° C. Yield: 240 g (75%).
Reaction SMILES: [CH3:1][C@H:2]1[N:7](CC2C=CC=CC=2)[C@@H:6]([CH3:15])[CH2:5][N:4]([C:16]2[CH:17]=[C:18]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]4[O:35][C:36]([CH3:39])=[CH:37][CH:38]=4)=[C:30]([F:40])[CH:29]=3)(=[O:27])=[O:26])[C:19]([O:22]C)=[N:20][CH:21]=2)[CH2:3]1.Cl>O1CCOCC1.O>[CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:15])[CH2:5][N:4]([C:16]2[CH:17]=[C:18]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]4[O:35][C:36]([CH3:39])=[CH:37][CH:38]=4)=[C:30]([F:40])[CH:29]=3)(=[O:27])=[O:26])[C:19](=[O:22])[NH:20][CH:21]=2)[CH2:3]1
Reactant: COc1ncc(N2C[C@@H](C)N(Cc3ccccc3)[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2ccc(C)o2)c(F)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccc(S(=O)(=O)Nc3cc(N4C[C@@H](C)N[C@@H](C)C4)c[nH]c3=O)cc2F)o1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A solution of N-[5-[cis-3,5-dimethyl-4-(phenylmethyl)-1-piperazinyl]-2-(methyloxy)-3-pyridinyl]-3-fluoro-4-(5-methyl-2-furanyl)benzenesulfonamide (D31) 60 mg, 0.1 mmol) in dioxan (2 ml) was treated with 4.0M hydrogen chloride in dioxan (1 ml) and water (0.5 ml). The mixture was heated at 70° C. for 4 hours. The solvent was evaporated and the residue dissolved in ethanol (5 ml) and 2M hydrochloric acid (2 ml). 10% Palladium on carbon (10 mg) was added and the mixture stirred in a hydrogen atmosphere for 4 hours. The mixture was filtered through ‘celite’ and the solvent was evaporated. Purification by MDAP gave the title compound (E15). MS (ES+) m/e 461 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:4][CH:3]=1.Cl[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:17][N:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH:22]1([O:21][C:18]2[CH:19]=[CH:20][C:15]([O:1][C:2]3[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:6][CH:7]=3)=[N:16][CH:17]=2)[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CC(=O)NCCc1ccc(O)cc1
Reactant: Clc1ccc(OC2CCCC2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)NCCc1ccc(Oc2ccc(OC3CCCC3)cn2)cc1

Procedure:
N-[2-(4-Hydroxyphenyl)ethyl]acetamide (668.3 mg, 3.73 mmol), 2-chloro-5-cyclopentyloxypyridine (737 mg, 3.73 mmol) and cesium carbonate (1.458 g, 4.475 mmol) were treated at 230° C. in 24 ml of DMF in a microwave reactor for 2 h. The reaction mixture was concentrated, and the residue was taken up in ethyl acetate and water. The organic phase was separated off, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 8 mg (1%), M+H+: 341.13.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:18]([OH:20])=[O:19])[C:8]2=[O:25].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(CC)C(C)C)(C)C.[N-]=C=O>CC(N(C)C)=O.C(Cl)Cl>[CH3:24][C:23]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=1[N:9]1[C:8](=[O:25])[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([O:4][CH2:3][CH2:2][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:6]=2)[N:11]=[CH:10]1
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(OCCCl)cc2c1=O
Reactant: C1CCNC1
Agent: [N-]=C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(OCCN3CCCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 3-[6-(2-chloroethoxy)-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoic acid (0.50 g), pyrrolidine (0.46 ml), N,N-diisopropylethylamine (0.98 ml) and KI (0.47 g) in DMA (2 ml) was heated to 120° C. for 30 minutes in a microwave (Personal Chemistry Emrys Optimizer with 300 W magnetron). The reaction mixture was diluted with methylene chloride (20 ml), CombiZorb isocyanate resin (loading 1.03 mmol/g from Agilent) (6 g) added and stirred at room temperature for 16 hours. The resin was removed by filtration and the filtrate washed with water (50 ml). The aqueous phase was purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to give 4-methyl-3-[4-oxo-6-(2-pyrrolidin-1-ylethoxy)quinazolin-3(4H)-yl]benzoic acid (0.195 g); NMR Spectrum: (DMSOd6) 1.70 (m, 4H), 2.13 (s, 3H), 2.64 (m, 4H), 2.92 (m, 2H), 4.24 (m, 2H), 7.53 (m, 3H), 7.69 (d, 1H), 7.89 (s, 1H), 7.96 (d, 1H), 8.15 (s, 1H); Mass Spectrum: M+H+ 394.
Reaction SMILES: [CH2:1]([C:3]1([C:16]([OH:18])=O)[CH2:15][CH:6]2[CH2:7][N:8]([C:10](=[O:14])[N:11]([CH3:13])[CH3:12])[CH2:9][CH:5]2[CH2:4]1)[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[N-:32]=[N+:33]=[N-:34].[Na+]>CC(C)=O.O>[CH2:1]([C:3]1([C:16]([N:32]=[N+:33]=[N-:34])=[O:18])[CH2:15][CH:6]2[CH2:7][N:8]([C:10](=[O:14])[N:11]([CH3:13])[CH3:12])[CH2:9][CH:5]2[CH2:4]1)[CH3:2]
Reactant: CCC1(C(=O)O)CC2CN(C(=O)N(C)C)CC2C1
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: CCC1(C(=O)N=[N+]=[N-])CC2CN(C(=O)N(C)C)CC2C1
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 81.4 %

Procedure:
5-Ethyl-2-dimethylcarbamoyl-hexahydro-cyclopenta[c]pyrrole-5-carboxylic acid 19c (0.56 g, 2.2 mmol) was dissolved in 60 mL of acetone upon cooling by an ice-water bath. When cooled to −5° C., triethylamine (0.245 mg, 2.43 mmol) and a solution of 2 mL of ethyl chloroformate (263 mg, 2.43 mmol) in acetone were added dropwise. After the reaction mixture was stirred for 15 minutes, a solution of sodium azide (0.286 g, 4.4 mmol) in 2 mL of water was added. The reaction mixture was stirred at −5° C.˜0° C. for another 30 minutes. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was diluted with 10 mL of water, extracted with ethyl acetate (10 mL×5). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound 5-ethyl-2-dimethylcarbamoyl-hexahydro-cyclopenta[c]pyrrole-5-carbonyl azide 19d (0.5 g) as a light yellow oil which was directly used in the next step.
Reaction SMILES: C([O:9][CH:10]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][C:12]#[CH:13])(=O)C1C=CC=CC=1.[OH-].[K+].OC(CCCC)CC#C.C(OCC)(=O)C>CO.O>[OH:9][C@@H:10]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][C:12]#[CH:13]
Reactant: C#CCC(CCCC)OC(=O)c1ccccc1
Agent: C#CCC(O)CCCC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: C#CC[C@@H](O)CCCC
Reaction time: 24 h

Procedure:
A solution of 1.15 g (5.0 mmoles) of (S)-4-benzoyl-oxy-1-octyne (Example 141) and 1.40 g (25 mmoles) of potassium hydroxide in 50 ml of 10:1 methanol-water is allowed to stand at room temperature for 24 hours. The bulk of the methanol is evaporated at room temperature, and the mixture is extracted with ether. The extract is washed with brine, dried over magnesium sulfate, and evaporated to give a colorless oil, identical to 4-hydroxy-1-octyne [α]D25 = +17+ 1.0° (C=0.77, ethyl acetate). This compound has the (S)-configuration.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=[CH:16][C:17]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:18])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[CH3:32][NH:33][C:34](=[O:37])[CH2:35]Cl>C1(C)C=CC=CC=1.C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=[CH:16][C:17]([N:19]2[CH2:20][CH2:21][N:22]([CH2:35][C:34]([NH:33][CH3:32])=[O:37])[CH2:23][CH2:24]2)=[O:18])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C=CC=CC(=O)N2CCNCC2)cc(OC)c1OC
Reactant: CNC(=O)CCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CNC(=O)CN1CCN(C(=O)C=CC=Cc2cc(OC)c(OC)c(OC)c2)CC1
Yield: 71.7 %

Procedure:
To a solution of 302 mg of 1-[5-(3,4,5-trimethoxyphenyl)-2,4-pentadienoyl]-piperazine in dry toluene (12 ml) were added in an atmosphere of argon 1.3 ml of triethylamine and subsequently a solution of 254 mg of N-methylchloroacetamide in dry toluene-chloroform (1:1, 2 ml). The mixture was refluxed for 8 hours. To the reaction mixture was added water, and extraction was made with methylene chloride. The organic layer was concentrated under reduced pressure, and the residue thus obtained was chromatographed on silica gel column. There was obtained 263 mg of 1-[5-(3,4,5-trimethoxyphenyl)-2,4-pentadienoyl]-4-(methylaminocarbonylmethyl)-piperazine. Spectrophotometric data of the product support the structure of the formula (V) shown below. ##STR5##
Reaction SMILES: [CH2:1]([NH:8][CH:9]([C:19]1[C:27]2[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=2)[NH:21][C:20]=1[C:29]([O:31]CC)=[O:30])[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCO.[OH-].[K+].Cl>O>[CH2:1]([NH:8][CH:9]([C:19]1[C:27]2[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=2)[NH:21][C:20]=1[C:29]([OH:31])=[O:30])[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1[nH]c2cc(Cl)ccc2c1C(NCc1ccccc1)C(=O)NC1CCCCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1[nH]c2cc(Cl)ccc2c1C(NCc1ccccc1)C(=O)NC1CCCCC1
Yield: 79.8 %

Procedure:
The mixture of 10 (28 mg), EtOH (0.5 mL), water (0.5 mL), KOH (10 mg) was reflux for 5 h. After cooling, the reaction mixture was acidified with 1M HCl (pH˜6). Then the mixture was extracted with DCM (10 mL×3). The combined organic layer was dried over sodium sulfate. After evaporation of the solvent, 21 mg of yellow solids (74%) was obtained. HPLC/MS: tR=12.10 min; m/z=440.4 [M+H]+ HRMS: C24H27N3O3Cl, 440.1741 (calcd.), 440.1721 (found). 1H NMR (600 MHz, DMSO, a mixture of rotamers): 0.85-1.63 (m, 16H), 3.57 (m, 2H), 4.17 (ABd, 1H, J=16.2 Hz), 4.22 (ABd, 1H, J=15.6 Hz), 4.67 (ABd, 1H, J=16.8 Hz), 4.88 (ABd, 1H, J=15.6 Hz), 6.10 (s, 1H), 6.51 (m, 1H), 6.60 (s, 1H), 6.78 (m, 2H), 6.91-7.28 (m, 7H), 7.66-7.91 (m, 4H), 8.27 (s, 1H), 8.34 (s, 1H), 11.56 (s, 1H), 11.88 (s, 1H), 13.15 (br.s, 1H), 13.53 (br.s, 1H). 13C NMR (150 MHz, DMSO, a mixture of rotamers): 25.0, 25.1, 25.5, 32.5, 32.6, 47.0, 48.5, 56.2, 112.4, 121.3, 122.4, 125.2, 125.8, 126.7, 126.8, 127.1, 127.7, 127.9, 129.0, 129.3, 136.4, 138.0, 164.2, 168.8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13]([OH:22])C(C3C=CC=CC=3)O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].C([O-])(=O)C.[Pb+4].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13]=[O:22])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OC(c1ccccc1)C(O)c1nnn(-c2cccc(Cl)c2)n1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=Cc1nnn(-c2cccc(Cl)c2)n1
Yield: 67.7 %

Procedure:
The crude product of the title compound from Example 13.1 (50.0 mg, 0.158 mmol) was weighed into a vial and toluene (3 mL) was added. Potassium carbonate (47.0 mg, 0.340 mmol) and lead (IV) acetate (70.0 mg, 0.158 mmol) were added with stirring. The reaction was allowed to stir for 2.5 hours. The reaction was filtered and ethyl acetate was added to the filtrate and an aqueous workup was done. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (40% EtOAc/hexanes) to yield the pure product as a white solid (22.3 mg, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[CH:13]=[CH:12][NH:11][N:10]=2)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(C)=O>[CH2:20]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[C:9]1[CH:13]=[CH:12][NH:11][N:10]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Cl)cc1-c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Clc1ccc(OCc2ccccc2)c(-c2cc[nH]n2)c1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a stirred solution of 4-chloro-2-(1H-pyrazol-3-yl)-phenol (1 g, CAS 18704-67-1) at r.t. in acetone (20 ml) under an argon atmosphere were added K2CO3 (746 mg) and benzylbromid (0.61 ml). The reaction mixture was stirred at r.t. for 21 h. The solids were filtered off and washed with acetone. The filtrate was concentrated to leave a light orange oil. The crude product was purified by chromatography (silica gel, cyclohexane/ethyl acetate 2:1) to give 3-(2-benzyloxy-5-chloro-phenyl)-1H-pyrazole as off-white solid. MS 284.8 ([M+H]+)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C:9](=[O:11])[NH:8][C:5]2=[N:6][CH:7]=1.CC1C2C(=NC=C([C:22]3[CH:23]=[C:24]([NH:28][C:29](=[O:34])[C:30]#[C:31]CC)[CH:25]=[CH:26][CH:27]=3)C=2)NC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Li+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:11]=[C:9]1[NH:8][C:5]2=[N:6][CH:7]=[C:2]([C:26]3[CH:25]=[C:24]([NH:28][C:29](=[O:34])[CH:30]=[CH2:31])[CH:23]=[CH:22][CH:27]=3)[CH:3]=[C:4]2[CH2:10]1
Reactant: CCC#CC(=O)Nc1cccc(-c2cnc3[nH]cc(C)c3c2)c1
Reactant: O=C1Cc2cc(Br)cnc2N1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: C=CC(=O)Nc1cccc(-c2cnc3c(c2)CC(=O)N3)c1
Temperature: 90 °C

Procedure:
A solution of 5-bromo-1H-pyrrolo[2,3-b]pyridin-2(3H)-one 149 (100 mg, 0.4673 mmol) and (3-acrylamidophenyl)boronic acid 64 (98.55 mg, 0.514 mmol) in toluene/ethanol/water was added sodium carbonate (198 mg, 1.8692 mmol). Lithium chloride (59.3 mg, 1.40 mmol) was added to the reaction. The reaction was degassed and purged nitrogen for 10 min. Pd(dppf)Cl2 (19.03 mg, 0.0233 mmol) was added to the reaction. The reaction was degassed and purged with nitrogen for another 10 min. The reaction was heated to 90° C. under sealed condition for overnight. The reaction mixture was allowed to cool to room temperature, diluted with chloroform. The organic layer was filtered through celite plug and concentrated to get the crude. The crude was purified through flash chromatography by using 100-200 mesh silica gel. The compound was eluted in ethyl acetate in hexane as half white solid N-(3-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide 150. MS-ES+338.9, 1H NMR (400 MHz, DMSO): 11.09 (s, 1H), 10.24 (s, 1H), 8.30 (s, 1H), 7.97 (s, 1H), 7.61 (d, 1H), 7.35 (m, 2H), 6.44 (m, 1H), 6.25 (d, 1H), 5.76 (d, 1H), 3.63 (s, 2H).
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[F:33][C:34]1[CH:66]=[CH:65][C:37]([C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:55]=[C:54]4[C:50]([CH2:51][N:52]([C@@H:57]([CH:62]([CH3:64])[CH3:63])[C:58]([O:60]C)=[O:59])[C:53]4=[O:56])=[CH:49][CH:48]=3)=[CH:43][CH:42]=2)=[O:39])=[CH:36][C:35]=1[CH3:67]>>[F:33][C:34]1[CH:66]=[CH:65][C:37]([C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:55]=[C:54]4[C:50]([CH2:51][N:52]([C@@H:57]([CH:62]([CH3:64])[CH3:63])[C:58]([OH:60])=[O:59])[C:53]4=[O:56])=[CH:49][CH:48]=3)=[CH:43][CH:42]=2)=[O:39])=[CH:36][C:35]=1[CH3:67]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(F)c(C)c4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: Cc1cc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)cc2)ccc1F
Yield: 85 %

Procedure:
The compound of example 162 was prepared analogous to compound of example 98 by hydrolysis of compound of example 161.
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@@H:10]([N:11]2[CH2:15][CH2:14][C@H:13]([NH:16]C(OCC3C=CC=CC=3)=O)[C:12]2=[O:27])[CH2:9][CH2:8][C@@H:7]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:6]1)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([NH:4][C@H:5]1[C@@H:10]([N:11]2[CH2:15][CH2:14][C@H:13]([NH2:16])[C:12]2=[O:27])[CH2:9][CH2:8][C@@H:7]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: CC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of tert-butyl (1R,3R,4S)-3-acetamido-4-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)cyclohexylcarbamate (1.7 g, 3.48 mmol; see Example 1, Step 6) in methanol (10 mL) was added 10% Pd/C (0.6 g of 50% wet catalyst). The flask was evacuated and back-filled with hydrogen with a hydrogen balloon. The mixture was stirred at room temperature under 1 atm of hydrogen for 14 h and the catalyst was removed by filtration. The filtrate was concentrated in vacuo to provide tert-butyl (1R,3R,4S)-3-acetamido-4-((S)-3-amino-2-oxopyrrolidin-1-yl)cyclohexylcarbamate, which was taken on to the next step without further purification. LC/MS found [M+H]+=355.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:23][C:22]([SH:24])=[N:21][N:20]=4)[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)=[CH:6][CH:5]=1)=[O:3].[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br>>[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][S:24][C:22]1[O:23][C:19]([C:16]2[CH:17]=[CH:18][C:13]3[O:12][CH:11]=[C:10]([C:7]4[CH:6]=[CH:5][C:4]([S:2]([CH3:1])=[O:3])=[CH:9][CH:8]=4)[C:14]=3[CH:15]=2)=[N:20][N:21]=1
Reactant: Fc1cccc(CBr)c1
Reactant: CS(=O)c1ccc(-c2coc3ccc(-c4nnc(S)o4)cc23)cc1
Product: CS(=O)c1ccc(-c2coc3ccc(-c4nnc(SCc5cccc(F)c5)o4)cc23)cc1
Yield: 87 %

Procedure:
In the same manner as in Example 7 and using 5-[3-[4-(methylsulfinyl)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole-2-thiol instead of 5-(1H-indazol-5-yl)-1,3,4-oxadiazole-2-thiol and 3-fluorobenzyl bromide instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 87%) was obtained as colorless crystals.