Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:7]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][NH2:29].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][NH:29][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(F)ccc2[N+](=O)[O-])CC1
Reactant: NCc1cccc(Cl)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2cc(NCc3cccc(Cl)c3)ccc2[N+](=O)[O-])CC1
Yield: 47.7 %

Procedure:
t-Butyl 4-(5-fluoro-2-nitrophenyl)piperazine-1-carboxylate (431 mg, 1.3 mmol), 3-chlorobenzylamine (187 mg, 1.3 mmol), N,N-diisopropylethylamine (342 mg, 1.3 mmol) were stirred at 80° C. in dry acetonitrile (25 mL) for 72 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 25% ethyl acetate in hexanes to afford the title compound (277 mg, 48% yield). 1H NMR (400 MHz, CD3OD): δ 7.96 (d, 1H), 7.37-7.26 (m, 4H), 6.29 (d, 1H), 6.18 (s, 1H), 4.42 (s, 2H), 3.55 (m, 4H), 2.92 (m, 4H), 1.47 (s, 9H); MS (ESI) m/z: Calculated for C22H27ClN4O4: 446.17; Observed: 469.2 (M++Na).
Reaction SMILES: C(O[C:4](=[O:23])[CH:5]([O:11][C:12]1[CH:17]=[CH:16][C:15](OC)=[CH:14][C:13]=1[N+:20]([O-])=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH2:24]([OH:26])C>>[CH2:9]([O:8][C:6]([CH:5]1[C:4](=[O:23])[NH:20][C:13]2[CH:14]=[CH:15][C:16]([O:26][CH3:24])=[CH:17][C:12]=2[O:11]1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(Oc1ccc(OC)cc1[N+](=O)[O-])C(=O)OCC
Reactant: CCO
Product: CCOC(=O)C1Oc2cc(OC)ccc2NC1=O
Reaction time: 18 h

Procedure:
A mixture of (4-methoxy-2-nitro-phenoxy)-malonic acid diethyl ester (2.3 g, 7.0 mmol) in ethanol containing 10% Pd/C was hydrogenated at 35 psi for 18 hours. The catalyst was filtered through celite and the solvents were removed under vacuum to afford a solid which was washed with ether to afford 1.25 g of a white solid. The mother liquor was concentrated and the solid again washed with ether to afford another 100 mg of product. Yield: (1.35 g, 76%): mp 138.5-139.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([Cl:10])=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=O.S(Cl)([Cl:17])=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([Cl:10])=[CH:4][C:3]=1[CH2:11][C:12]([Cl:17])=[O:14]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(Cl)cc(CC(=O)O)c1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(Cl)cc(CC(=O)Cl)c1Cl

Procedure:
By the method of Example 1, Step E, 10.92 grams (0.046 mole) of 2,5-dichloro-3-methoxyphenylacetic acid and 40 mL of thionyl chloride were reacted in approximately 200 mL of carbon tetrachloride, yielding 11.92 grams of 2,5-dichloro-3-methoxyphenylacetyl chloride as a black oil. The IR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:19]([NH:21][C@H:22]([C:30]([NH:32][C@H:33]([C:38]([OH:40])=[O:39])[C@H:34]([CH2:36][CH3:37])[CH3:35])=[O:31])[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[NH:29])[NH2:28])=[O:20])[CH2:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4]>C(O)(=O)C>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:19]([NH:21][C@H:22]([C:30]([NH:32][C@H:33]([C:38]([OH:40])=[O:39])[C@H:34]([CH2:36][CH3:37])[CH3:35])=[O:31])[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[NH:28])[NH2:29])=[O:20])[CH2:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].[CH3:11][C:12]([OH:18])=[O:13]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)CC)C(=O)O
Solvent: CC(=O)O
Product: CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@H](C(=O)O)[C@@H](C)CC

Procedure:
10.7 g of Z-Ile-Asp(OtBu)-Arg-Ile-OH are catalytically hydrogenated in 150 ml of 90% acetic acid in analogy to Example 1b.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].N1C=CC=CC=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][N:27]2[S:32]([C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH:21]=1.C(OCC)(=O)C>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:39][C:38]1[CH:37]=[CH:36][C:35]([S:32]([N:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH:26]2[C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)(=[O:34])=[O:33])=[CH:41][CH:40]=1)=[O:5]
Reactant: Nc1ccc(S(=O)(=O)N2CCCCC2c2cccnc2)cc1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(S(=O)(=O)N2CCCCC2c2cccnc2)cc1)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 220 mg portion of 2-chloro-5-nitrobenzoyl chloride was added to a pyridine solution (10 ml) of 318 mg of 4-{[2-(pyridin-3-yl)piperidin-1-yl]sulfonyl}aniline and stirred overnight at room temperature. After stirring at 50° C. for 4 hours, 220 mg of 2-chloro-5-nitrobenzoyl chloride was further added thereto and stirred at 50° C. for 2 hours. Ethyl acetate and water were added thereto to carry out layer separation operation, and the organic layer was washed with saturated sodium chloride aqueous solution. After drying with anhydrous sodium sulfate, this was concentrated under a reduced pressure and the thus obtained residue was purified by a silica gel column chromatography using chloroform:methanol (98:2) as the elution solvent, thereby obtaining 426 mg of 2-chloro-5-nitro-N-(4-{[2-(pyridin-3-yl)piperidin-1-yl]sulfonyl}phenyl)benzamide as colorless crystals.
Reaction SMILES: [ClH:1].C(O[C:5](=[NH:8])[CH2:6][F:7])C.[C:9]([NH:12][CH:13]([CH2:17][C:18]#[C:19][CH2:20][NH2:21])[C:14]([OH:16])=[O:15])(=[O:11])[CH3:10].C1CCN2C(=NCCC2)CC1>C(O)C>[ClH:1].[C:9]([NH:12][CH:13]([CH2:17][C:18]#[C:19][CH2:20][NH:21][C:5](=[NH:8])[CH2:6][F:7])[C:14]([OH:16])=[O:15])(=[O:11])[CH3:10]
Reactant: CCOC(=N)CF
Reactant: CC(=O)NC(CC#CCN)C(=O)O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CC(=O)NC(CC#CCNC(=N)CF)C(=O)O
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Ex-8h) 2.86 g of ethylfluoroacetimidate hydrochloride, 1 equivalent of 2-acetylamino-6-amino-4-hexynoic acid and 6.84 g of DBU are taken up in 200 mL absolute ethanol and stirred for 16 h at 20° C. under argon. Solvent is removed under vacuum and 100 mL water is added. This reaction mixture is filtered through acidic ion exchange column and the product is eluted with 10% pyridine/water. (±)-2-Acetylamino-6-(1-imino-2-fluoroethylamino)-hex-4-ynoic acid hydrochloride is obtained by removing the solvent under vacuum.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:28])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])=[CH:14][C:13]=2[Cl:27])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].[CH2:29]([OH:33])[CH2:30][C:31]#[CH:32]>>[Cl:27][C:13]1[CH:14]=[C:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[CH3:26])[CH:16]=[CH:17][C:12]=1[C:10]([C:8]1[CH:9]=[C:4]([N:1]2[CH:32]=[C:31]([CH2:30][CH2:29][OH:33])[N:3]=[N:2]2)[CH:5]=[CH:6][C:7]=1[CH3:28])=[O:11]
Reactant: Cc1cc(F)ccc1Nc1ccc(C(=O)c2cc(N=[N+]=[N-])ccc2C)c(Cl)c1
Reactant: C#CCCO
Product: Cc1cc(F)ccc1Nc1ccc(C(=O)c2cc(-n3cc(CCO)nn3)ccc2C)c(Cl)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 116, using compound 439 (0.29 mmol) and but-3-yn-1-ol (0.40 mmol). The crude product was purified by continuous gradient flash chromatography using MeOH/DCM 0:100 to 5:95 as the eluent to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH2:11]([OH:15])[CH2:12][C:13]#[CH:14]>C(N(CC)CC)C.CN(C)C=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:15][CH2:11][CH2:12][C:13]#[C:14][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: C#CCCO
Reactant: O=C(O)c1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)c1cccc(C#CCCO)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 105.7 %

Procedure:
Into a 500-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-bromobenzoic acid (10 g, 49.75 mmol, 1.00 equiv) in triethylamine/N,N-dimethylformamide (100/20 mL), but-3-yn-1-ol (6.98 g, 99.57 mmol, 2.00 equiv), copper(I) iodide (1.90 g, 9.97 mmol, 0.20 equiv), Pd(PPh3)2Cl2 (6.98 g, 9.94 mmol, 0.20 equiv). The resulting solution was stirred overnight at 80° C. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 100 mL of water. The pH value of the solution was adjusted to 11-12 with sodium hydroxide (1 mol/L). The resulting solution was extracted with 3×300 mL of dichloromethane and the aqueous layers combined. The solution was adjusted to pH 1-2 with hydrochloric acid (1 mol/L). The resulting solution was extracted with 5×300 mL of dichloromethane and the organic layers combined, dried over sodium sulfate, and concentrated under vacuum. This resulted in 10 g crude product as brown oil.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:33])[C:16]([N:18]2[CH2:23][CH2:22][C:21](=[CH2:24])[CH2:20][C@@H:19]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[CH3:32])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:36][C:37]([O:40][C:41]([NH:43][C@H:44]([CH2:49]C=C)[C:45]([O:47][CH3:48])=[O:46])=[O:42])([CH3:39])[CH3:38]>CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:33])[C:16]([N:18]2[CH2:23][CH2:22]/[C:21](=[CH:24]\[CH2:49][C@@H:44]([NH:43][C:41]([O:40][C:37]([CH3:36])([CH3:39])[CH3:38])=[O:42])[C:45]([O:47][CH3:48])=[O:46])/[CH2:20][C@@H:19]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[CH3:32])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: C=C1CCN(C(=O)N(C)[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccc(F)cc2C)C1
Reactant: C=CC[C@@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Product: COC(=O)[C@@H](C/C=C1\CCN(C(=O)N(C)[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccc(F)cc2C)C1)NC(=O)OC(C)(C)C
Temperature: 47 °C

Procedure:
A solution of (2R)-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-4-methylidene-1-piperidinecarboxamide (intermediate 53 3 g, 5.97 mmol) and methyl (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-pentenoate (4.11 g, 17.91 mmol) in dry, degassed dichloromethane (DCM) (24 ml), was added to a flame dried round bottomed flask containing (1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium, Hoveyda-Grubbs catalyst 2nd generation, (0.187 g, 0.299 mmol) under a nitrogen atmosphere. The green mixture was stirred and heated at reflux for 30 h (T bath=47° C.).
Reaction SMILES: [F:1][C:2]([F:21])([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1)[C:3]1[N:12]=[C:11](O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([C:2]([F:21])([F:1])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)[N:12]=1
Reactant: Oc1nc(C(F)(F)c2ccc(F)cn2)nc2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1ccc(C(F)(F)c2nc(Cl)c3ccccc3n2)nc1
Temperature: 95 °C
Yield: 82 %

Procedure:
To 2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazolin-4-ol from Example 2 Step D (1.82 g, 6.25 mmol) was added phosphorousoxychloride (20 mL) and the mixture was heated at 95° C. for 3 h. The mixture was concentrated under reduced pressure and then toluene (20 mL) was added and evaporated. The residue was dissolved in EtOAc and washed with saturated NaHCO3 (1×) and brine (1×), dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography eluting with 10-80% EtOAc/hexanes to afford 4-chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazoline (1.59 g, 82%). 1H NMR (300 MHz, DMSO-d6) δ 8.61 (d, J=2.6 Hz, 1H), 8.38 (d, J=8.3 Hz, 1H), 8.17-8.29 (m, 2H), 8.06-8.15 (m, 1H), 7.96-8.06 (m, 2H); LC-MS (ESI) m/z 310 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH2:19])=[N-]>C1COCC1>[OH:13][C@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@H:9]([C:14]([O:16][CH3:19])=[O:15])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: C=[N+]=[N-]
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Yield: 96.1 %

Procedure:
To a solution of compound 235 (5.2 g, 22.49 mmol) in THF (50 mL) was added diazomethane (38.5 mL, 27.0 mmol, 0.7M) dropwise until yellow color persists. The mixture was concentrated to afford title compound 236 (5.3 g, 96%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ (ppm): 4.50-4.47 (m, 1H), 4.44 (t, J=7.7 Hz, 1H), 3.76-3.43 (m, 2H), 3.73 (s, 3H), 2.33-2.22 (m, 1H), 2.11-2.03 (m, 1H), 1.91 (m, 1H), 1.45-1.41 (m, 9H). LRMS (ESI): (calc.) 245.13. (found) 146.0 (M-Boc+H)+.
Reaction SMILES: C([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:16][C:15]3[C:17]([F:23])=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:14]=3[CH:13]=2)=[CH:8][CH:7]=1)(C)(C)C.C(OC1C=CC(C2SC3C=C(OC)C=CC=3C=2)=CC=1)(C)(C)C.OS(C(F)(F)F)(=O)=O>FC(F)(F)CO>[F:23][C:17]1[C:15]2[S:16][C:12]([C:9]3[CH:10]=[CH:11][C:6]([OH:5])=[CH:7][CH:8]=3)=[CH:13][C:14]=2[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COc1ccc2cc(-c3ccc(OC(C)(C)C)cc3)sc2c1F
Agent: COc1ccc2cc(-c3ccc(OC(C)(C)C)cc3)sc2c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: OCC(F)(F)F
Product: COc1ccc2cc(-c3ccc(O)cc3)sc2c1F
Reaction time: 1 h

Procedure:
The mixture of 2-(4-tert-butoxyphenyl)-7-fluoro-6-methoxybenzo[b]thiophene and 2-(4-tert-butoxyphenyl)-6-methoxybenzo[b]thiophene (Part B; 3.12 g) in 45 mL of 2,2,2-trifluorethanol at −5° C. was treated with triflic acid (45 μL, 0.51 mmol). After 1 h, the reaction mixture was partitioned between 1 N NaOH and CH2Cl2 (50 mL each). The layers were separated, and the aqueous layer was extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2; gradient of 5% to 20% THF in hexanes) to give 859 mg of the title compound as a white powder.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH:15][C:16](=[O:33])[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=2)[CH:21]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=4)[CH:21]=3)[CH2:17][C:16](=[O:33])[NH:15][C:9]=2[CH:10]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)ccc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4ccc(Cl)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (4-chloro-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M67) (0.40 g, 0.83 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (239 mg, 79%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([N:13]1[C@H:17]([CH3:18])[C@H:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:15][C:14]1=[O:25])=[O:12].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O([CH2:44][CH3:45])S(C(F)(F)F)(=O)=O>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C@H:10]([CH2:44][CH3:45])[C:11]([N:13]1[C@H:17]([CH3:18])[C@H:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:15][C:14]1=[O:25])=[O:12]
Reactant: CCOS(=O)(=O)C(F)(F)F
Reactant: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)CCc1ccc(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@@H](Cc1ccc(F)cc1F)C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
A flask was charged with 54 g (156 mmol) of (4R,5S)-3-[3-(2,4-difluoro-phenyl)-propionyl]-4-methyl-5-phenyl-oxazolidin-2-one and 300 mL of dry THF, and the solution was cooled to −78° C. To this solution was added 172 mL (172 mmol) of 1 M NaHMDS in THF, and the mixture was stirred cold for 1 hour. Then 30.6 g (172 mmol) of ethyl triflate was added dropwise to the enolate solution, and the reaction mixture was warmed to −40° C. to −30° C. and stirred for 1.5 hours. The reaction mixture was quenched by the addition of aqueous brine. The THF was removed under reduced pressure and the residue was partitioned between EtOAc and water. The organics were collected, and EtOAc was removed under reduced pressure. The resulting crude oil was purified by column chromatography (3:1 hexanes/EtOAc eluent) to get 29.5 g of an impure oil that was used without further purification.
Reaction SMILES: [NH2:1][OH:2].[C:3]1([N:9]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:10][CH2:11][C:12](OCC)=[O:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>C(OCC)C>[OH:2][NH:1][C:12](=[O:13])[CH2:11][CH2:10][N:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18]
Reactant: NO
Reactant: CCOC(=O)CCN(c1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)N(CCC(=O)NO)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.1 %

Procedure:
Freshly prepared hydroxylamine reagent (20 mL; 20 mmol) was added to ethyl 3-[(phenyl)-(4-methoxy-benzenesulfonyl)-amino]-propionate (3.30 g; 9.1 mmol) and the resulting mixture stirred for 18 h at room temperature. The mixture was poured into 1 N HCl (100 mL) and extracted with CH2Cl2 (2×100 mL). The combined extracts were washed with saturated aqueous NaCl (1×100 mL), dried over MgSO4, and evaporated under reduced pressure to give a crude gum. Trituration with diethyl ether afforded 2.14 g (68%) of the title compound as an off-white solid. 300 MHz 1H-NMR (DMSO-d6): δ 2.12 (t, 2H), 3.74 (t, 2H), 3.86 (s, 3H), 7.03 (d, 2H), 7.08 (d, 2H), 7.32 (m, 3H), 7.47 (d, 2H), 8.74 (s, 1H), 10.35 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1I.[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15].[Li+].[Cl-].CCOC(C)=O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH2:15][CH:14]=[CH2:13]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: O=C1OCc2c1ccc(Br)c2I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CCc1c(Br)ccc2c1COC2=O
Temperature: 95 °C

Procedure:
A mixture of 5-bromo-4-iodo-2-benzofuran-1(3H]-one (2.42 g, 7.13 mmol), allyltributyltin (2.36 g, 7.13 mmol), LiCl (1.50 g, 35.7 mmol) and Pd (PPh3)4 (200 g, 0.173 mmol) in toluene (50 mL) was heated at 90-100° C. under N2 overnight; LC indicated that reaction had gone to completion, to the solution was poured EtOAc (100 mL) and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated to dryness, absorbed into silica gel and was then separated over silica gel column to give 5-bromo-4-prop-2-en-1-yl-2-benzofuran-1(3H)-one. 1H-NMR (400 MHz, CDCl3) δ ppm 7.795 (d, J=8 Hz, 1H), 7.680 (d, J=8 Hz, 8.5 Hz, 1H), 5.938-5.925 (m, 1H), 5.302 (s, 2H), 5.192-5.172 (m, 1H), 5.075-5.041 (m, 1H), 3.611-3.599 (m, 2H)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C:14](O)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.O1CCCC1.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1CO
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a solution of (R)-Piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (5 g, 21.8 mmol) in anhydrous THF (32 mL) at 0-5° C. was added borane-tetrahydrofuran complex (1M solution in THF) (3.6 g, 41.84 mmol) over a period of 15 min. The mixture was stirred at 0-5° C. for 2 h and then at rt for 2 h. The mixture was added over a period of 10 min to cold water (75 mL) and extracted with EtOAc (300 mL). The aqueous layer was re-extracted with EtOAc (2×150 mL). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated to obtain the title product as a colorless oil (4.65 g., 99%).
Reaction SMILES: [CH2:1]([S:9][C:10]1[CH:11]=[C:12]([C:15]([OH:17])=O)[NH:13][CH:14]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:18][C:19]1[CH:30]=[CH:29][C:22]([O:23][CH2:24][C:25]([CH3:28])([OH:27])[CH3:26])=[C:21]([O:31][CH3:32])[CH:20]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>ClC(Cl)C.CCOC(C)=O>[OH:27][C:25]([CH3:28])([CH3:26])[CH2:24][O:23][C:22]1[CH:29]=[CH:30][C:19]([NH:18][C:15]([C:12]2[NH:13][CH:14]=[C:10]([S:9][CH2:1][CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:11]=2)=[O:17])=[CH:20][C:21]=1[O:31][CH3:32]
Reactant: COc1cc(N)ccc1OCC(C)(C)O
Reactant: O=C(O)c1cc(SCCc2ccccc2)c[nH]1
Agent: On1nnc2ccccc21
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COc1cc(NC(=O)c2cc(SCCc3ccccc3)c[nH]2)ccc1OCC(C)(C)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.9 %

Procedure:
To a solution of 4-(phenethylthio)-1H-pyrrole-2-carboxylic acid (25.0 mg, 0.101 mmol) and 1-(4-amino-2-methoxyphenoxy)-2-methylpropan-2-ol (21.4 mg, 0.101 mmol) in dichloroethane (0.880 mL) was added EDC (38.8 mg, 0.202 mmol) and HOBT (30.9 mg, 0.202 mmol) and the reaction was allowed to stir at rt for 16 h. The reaction mixture was diluted with EtOAc (15 mL), washed with sat. NaHCO3 (3×20 mL), water, brine, dried over anhydrous Na2SO4, concentrated and purified by preparative HPLC: Phenomenex Luna AXIA 5μ C18 21.2×100 mm, 15 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 5 min hold; 20 mL/min, UV detection at 220 nm, 10.739 min retention time to afford 21.3 mg of the title compound as brown solid: 1H NMR (500 MHz, CDCl3) δ 1.34 (s, 6H), 2.85-2.97 (m, 4H), 3.81 (s, 2H), 3.85 (s, 3H), 6.67 (br. s., 1H), 6.88 (d, J=8.8 Hz, 1H), 6.95 (dd, J=8.8, 2.2 Hz, 1H), 7.02 (s, 1H), 7.15-7.23 (m, 3H), 7.24-7.32 (m, 2H), 7.37 (s, 1H), 7.55 (d, J=3.8 Hz, 1H), 9.83 (br. s., 1H);); HPLC a) column: Phenomenex Luna 5μ 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% H3PO4 to 90% MeOH/10% H2O/0.1% H3PO4; 1 min hold, 4 mL/min UV detection at 220 nm, 3.650 min retention time, (>98%); HPLC b) column: Phenomenex Luna C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold; 4 mL/min, UV detection at 220 nm, 3.660 min retention time; MS (ES) 441 [M+H]+.