Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][Mg]Cl)=[CH:4][CH:3]=1.[Br:11][C:12]1[C:13]([CH3:32])=[N:14][O:15][C:16]=1[NH:17][S:18]([C:21]1[CH:25]=[CH:24][S:23][C:22]=1[C:26](N(C)OC)=[O:27])(=[O:20])=[O:19]>C1COCC1>[Br:11][C:12]1[C:13]([CH3:32])=[N:14][O:15][C:16]=1[NH:17][S:18]([C:21]1[CH:25]=[CH:24][S:23][C:22]=1[C:26](=[O:27])[CH2:6][C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:19])=[O:20]
Reactant: CON(C)C(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Br
Reactant: Cc1ccc(C[Mg]Cl)cc1
Solvent: C1CCOC1
Product: Cc1ccc(CC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Br)cc1
Yield: 78 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenyl)acetyl]thiophene-3-sulfonamide was prepared in the same manner as described in Example 93B by reacting 4-methylbenzylmagnesium chloride with N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-methoxy(methylaminocarbonyl)]thiophene-3-sulfonamide in THF (see Example 93A) at −78° C. to room temperature, resulting in 78% yield. m.p. 146-150° C.8
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]([F:34])([F:33])[C:14]1[CH:27]=[CH:26][C:25]2[S:24][C:23]3[C:18]4=[C:19]([C:28](=[O:32])[NH:29][C:30](=[O:31])[N:17]4[C:16]=2[CH:15]=1)[CH:20]=[CH:21][CH:22]=3>CO>[F:34][C:13]([F:33])([F:12])[C:14]1[CH:27]=[CH:26][C:25]2[S:24](=[O:9])[C:23]3[C:18]4=[C:19]([C:28](=[O:32])[NH:29][C:30](=[O:31])[N:17]4[C:16]=2[CH:15]=1)[CH:20]=[CH:21][CH:22]=3
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=c1[nH]c(=O)n2c3c(cccc13)Sc1ccc(C(F)(F)F)cc1-2
Solvent: CO
Product: O=c1[nH]c(=O)n2c3c(cccc13)S(=O)c1ccc(C(F)(F)F)cc1-2

Procedure:
m-Chloroperbenzoic acid (1.9 g., 0.011 mol.) was added portion-wise to a cold (0-5°), stirred solution of 3.36 g. (0.01 mol.) of 10-trifluoromethyl-1H-pyrimido[5,4,3-kl]phenothiazine-1,3(2H)-dione in 35 ml. of absolute methanol. The reaction mixture was stirred in the cold for one hour, then an additional four hours at ambient temperature. The reaction mixture was chilled and the precipitated product was collected by filtration and washed with ice-cold methanol to give the title compound, m.p. 302-304° (methanol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].I[CH2:17][CH2:18][CH3:19].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH2:17][CH2:18][CH3:19]
Reactant: Oc1cc(F)ccc1Br
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A total of 5 g of 2-bromo-5-fluoro-phenol was dissolved in 66 ml of N,N-dimethylformamide. Under ice-cooling, 5.42 g of potassium carbonate and 3.07 ml of iodopropane were added, and the mixture was stirred at room temperature for 10 hours. Water was added to the reaction mixture, followed by extracting with diethyl ether. The resulting organic layer was washed with brine, dried over magnesium sulfate and the solvent was evaporated, to give 8.29 g of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([CH:14]2[NH:1][C:2]3[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=3[S:10](=[O:12])(=[O:11])[NH:13]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1c(Br)cc(Br)cc1S(N)(=O)=O
Product: O=S1(=O)NC(c2ccccc2)Nc2c(Br)cc(Br)cc21

Procedure:
2-Amino-3,5-dibromobenzenesulfonamide (see compound 125) was transformed by Method G (using benzaldehyde). M.p. 186–189° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.OS(O)(=O)=O.[N+:17]([O-])(O)=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:17][C:9](=[O:11])[CH2:8]2
Reactant: O=C(O)Cc1cccc(F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1Cc2cc(F)ccc2N1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
To the solution of 3-fluorophenylacetic acid (1.23 g, 8 mmol) in concentrated H2SO4 (2.0 mL, 40 mmol) at 0° C. was added HNO3 (0.374 mL, 8 mmol) slowly. The resulting reaction mixture was stirred under argon for 2 h at 0° C., and poured into ice-water. The white solid was precipitated, and the aqueous phase was extracted with ethyl acetate. The organic phase was washed with brine, dried with Na2SO4, and concentrated. The crude (5-fluoro-2-nitro-phenyl)-acetic acid was dissolved in acetic acid. To the solution was added iron power (1.79 g, 32 mmol). The reaction mixture was stirred and heated at reflux for 2 h. Then the mixture was concentrated in vacuo. The residue was extracted with ethyl acetate, and The organic layer was separated, washed by aqueous HCl (1N), brine, dried over Na2SO4, concentrated in vacuo to give the desired product (1 g, 82%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:13](=[O:14])[CH2:12][C:11](=[O:15])[CH2:10][C@H:9]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>CCOC(C)=O.CCCCCCC>[C:1]([O:5][C:6]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([O:15][S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH2:10][C@H:9]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC(=O)C[C@H]1C(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OC2=CC(=O)N(C(=O)OC(C)(C)C)[C@H](C(=O)OCc3ccccc3)C2)cc1

Procedure:
Similar to example 24c, 9.43 g of (2S)-4,6-dioxo-piperidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester [176436-10-5] are reacted with p-toluene sulfonyl chloride to afford the title compound as a yellow oil Rf=0.64 (EtOAc-heptane 1:1); Rt=5.20.
Reaction SMILES: F[C:2]12[O:13][CH2:12][O:11][CH:3]1[CH:4]=[C:5]([CH:9]=[CH:10]2)[CH2:6][CH2:7][NH2:8].Cl[C:15]1[C:16]2[C:29]([CH3:30])=[CH:28][S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:20]=1>>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:2]4[O:13][CH2:12][O:11][C:3]=4[CH:4]=3)[C:16]3[C:29]([CH3:30])=[CH:28][S:27][C:17]=3[N:18]=2)[CH:22]=1
Reactant: NCCC1=CC2OCOC2(F)C=C1
Reactant: Cc1csc2nc(-c3cccnc3)nc(Cl)c12
Product: Cc1csc2nc(-c3cccnc3)nc(NCCc3ccc4c(c3)OCO4)c12

Procedure:
With the procedure of Example 1, the reaction of 4-fluoro3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-3-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-methylenedioxyphenethylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: I[C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[C:19]([C:22]([NH:24][CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:23])=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][C:3]=1[CH3:34].[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC>[CH3:34][C:3]1[CH:4]=[C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[C:19]([C:22]([NH:24][CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:23])=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])[CH:32]=[CH:33][C:2]=1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)ccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)ccc1-c1ccccc1
Temperature: 100 °C
Yield: 117.8 %

Procedure:
A mixture of 10-(4-iodo-3-methylbenzoyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 74 (0.300 g, 0.53 mmol), phenylboronic acid (0.098 g, 0.80 mmol) and potassium carbonate (0.221 g, 1.60 mmol) in dimethoxyethane:water (8 mL:2 mL) was purged with nitrogen for 10 minutes. [1,1′-bis(Diphenylphosphino)ferrocene]dichloropalladium[II] (0.022 g, 0.0266 mmol) was then added and the reaction mixture heated to 100° C. for 4 hours. The cooled reaction mixture was then partitioned between ethyl acetate (100 mL) and 1 M sodium hydroxide (100 mL). The organic phase was separated, washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give an olive syrup (0.32 g). Purification by flash chromatography using ethyl acetate as solvent afforded the title compound (0.260 g, 95%) as a white foam, m.p. 108-112° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: c1ccc(COc2ccc(CN3CCNCC3)cc2)cc1

Procedure:
Synthesized according to General Procedure A: 4-benzyloxybenzyl chloride (4{18}, 3.7 g, 15.9 mmol, 1 equiv.), piperazine (8.22 g, 95.4 mmol, 6 equiv.), THF (55 mL). Purification with flash column chromatography on silica gel (4:1 EtOAc:MeOH) afforded 5{18} (3.84 g, 86%) as a white solid. 1H-NMR (500 MHz, CDCl3): δ 7.43 (d, 2H, J=7.0 Hz), 7.38 (t, 2H, J=7.5 Hz), 7.32 (t, 1H, J=7.5 Hz), 7.23 (d, 2H, J=8.5 Hz), 6.93 (d, 2H, J=8.5 Hz), 5.04 (s, 2H), 3.43 (s, 2H), 2.87 (t, 4H, J=5.0 Hz), 2.39 (br s, 4H), 1.59 (br s, 1H). 13C-NMR (125 MHz, CDCl3): δ 157.8, 137.0, 130.3, 128.4, 127.8, 127.3, 114.4, 69.9, 63.0, 54.3, 46.0.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([N+:28]([O-:30])=[O:29])=[C:7]([NH:9][C:10]2[S:11][C:12]([C:25]([NH2:27])=[O:26])=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([F:24])([F:23])[F:22])[N:14]=2)[CH:8]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>ClCCl>[CH3:45][N:46]1[CH2:51][CH2:50][N:49]([CH2:1][C:3]2[CH:4]=[CH:5][C:6]([N+:28]([O-:30])=[O:29])=[C:7]([NH:9][C:10]3[S:11][C:12]([C:25]([NH2:27])=[O:26])=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:21]([F:23])([F:22])[F:24])[N:14]=3)[CH:8]=2)[CH2:48][CH2:47]1
Reactant: CN1CCNCC1
Reactant: NC(=O)c1sc(Nc2cc(C=O)ccc2[N+](=O)[O-])nc1-c1ccccc1C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(Cc2ccc([N+](=O)[O-])c(Nc3nc(-c4ccccc4C(F)(F)F)c(C(N)=O)s3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution 0.18 g (0.41 mmole) of 2-(5-formyl-2-nitro-phenylamino)-4-(2-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide (VI.17b) and 0.18 g (0.83 mmole) of sodium triacetoxy-borohydride in 15 mL of dichloromethane was added 0.069 mL (0.62 mmole) of 1-methylpiperazine. The mixture was stirred at room temperature overnight. The mixture was then diluted with dichloromethane, washed with saturated sodium bicarbonate, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification of the residue by silica gel chromatography, eluting with dichloromethane-methanol (gradient 100:0-75:25) gave 0.16 g of 2-[5-(4-methyl-piperazin-1-ylmethyl)-2-nitro-phenylamino]-4-(2-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide (VI.17c) as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([NH:16][C@H:17]([C:22]([NH:24][CH2:25][C:26]#[N:27])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[N:13][S:14][CH:15]=2)=[CH:7][CH:6]=1)=[O:4].[CH3:28][NH:29][CH3:30].C([O-])(O)=O.[Na+]>CN(C=O)C.C1COCC1>[C:26]([CH2:25][NH:24][C:22](=[O:23])[C@H:17]([CH2:18][CH:19]([CH3:21])[CH3:20])[NH:16][C:12]1[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N:29]([CH3:30])[CH3:28])=[CH:6][CH:7]=2)=[CH:15][S:14][N:13]=1)#[N:27]
Reactant: CNC
Reactant: CC(C)C[C@H](Nc1nscc1-c1ccc(C(=O)CBr)cc1)C(=O)NCC#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)C[C@H](Nc1nscc1-c1ccc(C(=O)CN(C)C)cc1)C(=O)NCC#N

Procedure:
N2-{4-[4-(bromoacetyl)phenyl]isothiazol-3-yl}-N1-(cyanomethyl)leucinamide (29 mg, 0.064 mmol) was dissolved in DMF (0.6 mL) and dimethylamine (0.13 mL of a 2 M solution in THF, 0.26 mmol) was added. The reaction mixture was stirred until disappearance of the starting material was observed by TLC (˜1 h). Aqueous sat. NaHCO3 was added, the product was extracted with EtOAc (3×), dried over MgSO4, concentrated in vacuo and purified by flash chromatography with dichloromethane, methanol and ammonium hydroxide to yield N1-(cyanomethyl)-N2-{4-[4-(N,N-dimethylglycyl)phenyl]isothiazol-3-yl} leucinamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[C:18]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:17]2=[N:16][C:15]=3[NH2:26])=[C:5]([CH3:27])[CH:4]=1.C(O)C.[H][H]>[Pd].C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[C:18]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:17]2=[N:16][C:15]=3[NH2:26])=[C:5]([CH3:27])[CH:4]=1
Reactant: [H][H]
Reactant: COc1ccc(C#Cc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round bottom flask was added 2-((4-methoxy-2-methylphenyl)ethynyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine (from the previous step) (1 eq.) with a stirring bar. Ethanol and methylene chloride (1:2, 0.2 M) were added, followed by palladium in carbon (activated powder, wet, 10% on carbon, 0.1 eq.). The content were vacuumed followed by hydrogen flush for three times. The reaction mixture was stirred vigorously under hydrogen balloon at room temperature overnight. Afterwards the reaction mixture was filtered through a celite pad, and the celite pad was washed subsequently with methylene chloride and EtOAc until the filtrate had no UV absorption. Combined organic washes were concentrated. Flash chromatography (silica gel, 0-50% EtOAc in CH2Cl2) afforded the product 2-(4-Methoxy-2-methylphenethyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine.hylphenethyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine. 1H NMR (CDCl3): δ 8.53 (d, 1H), 8.29 (d, 1H), 8.01 (d, 1H), 7.44 (s, 1H), 7.12 (dd, 1H), 6.93 (d, 1H), 6.67 (d, 1H), 6.60 (dd, 1H), 5.93 (bs, 2H), 3.70 (s, 3H), 3.05-3.00 (dd, 2H), 2.93-2.88 (dd, 2H), 2.44 (s, 3H), 2.19 (s, 3H). LRMS [M+H]=358.2
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])([C:20]#[N:21])[CH:10]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:9]1)=[O:7])(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[Br:19][C:15]1[CH:14]=[C:13]([CH:12]2[C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:10]([CH2:30][C:31]([CH3:33])([CH3:34])[CH3:32])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Br)c2)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Br)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 83 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2S,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 67a (1.3 g, 2.4 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2S,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.2 g, 83%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[CH:16][CH:17]=[N:18][C:11]=3[N:10]=[C:9]2[C@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:20])=[CH:4][CH:3]=1.[C-:29]#[N:30].[Na+]>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.[Cu]I>[C:29]([C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[CH:16][CH:17]=[N:18][C:11]=3[N:10]=[C:9]2[C@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH3:20])=[CH:4][CH:3]=1)#[N:30]
Reactant: [C-]#N
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1nc2ncccc2c(=O)n1-c1ccc(I)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Product: C[C@@H](NC(=O)OC(C)(C)C)c1nc2ncccc2c(=O)n1-c1ccc(C#N)cc1
Temperature: 70 °C

Procedure:
A3 (2.02 g, 4.10 mmol), (Ph3P)4Pd (439 mg, 0.38 mmol), CuI (157 mg, 0.82 mmol) and NaCN (406 mg, 8.29 mmol) were combined in a 25 mL pear shaped flask equipped with a reflux condenser. The mixture was evacuated under high vacuum and backfilled with dry N2 three times. Acetonitrile (6 mL) was then added and the resulting suspension heated to 70° C. for 30 min. at which point TLC and HPLC analysis indicated near complete consumption of A3. The mixture was diluted with EtOAc (100 mL) and filtered through a pad of celite. The filtrate was washed with saturated NaHCO3 (100 mL). The aqueous wash was extracted with additional EtOAc (2×50 mL). The combined extracts were dried over Na2SO4 and concentrated. Purification of the residue by silica gel chromatography (50×400 mm column; 80% EtOAc/hexanes to 100% EtOAc) gave 1 (1.42 g, 89%; purity 96% AUC; 92% e.e. by chiral HPLC analysis). Rf=0.35 (80% EtOAc/hexanes).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]([CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)([CH2:16][C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:13](O)=[O:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH2:32][OH:33]>>[OH:33][NH:32][C:13](=[O:14])[C:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:10])=[O:11])([CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[CH2:16][C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: NO
Reactant: CCCCCC#CCC(Cc1cccnc1)(C(=O)O)S(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Product: CCCCCC#CCC(Cc1cccnc1)(C(=O)NO)S(=O)(=O)c1ccc(OC)cc1
Yield: 67 %

Procedure:
2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-4-ynoic acid hydroxyamide was prepared according to the procedure outlined in Example 1. Starting from 2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-4-ynoic acid (0.71 g, 1.62 mmol) and hydroxylamine hydrochloride (1.39 g, 20 mmol), 0.48 g of the product was isolated. Yield 67%; off-white solid; mp 65° C.; MS: 445.0 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ0.84 (t, J=6.8 Hz, 3H), 1.10-1.40 (m, 6H), 1.85-2.00 (m, 2H), 2.79 (d, J=17.9 Hz, 1H), 2.90 (d, J=17.9 Hz, 1H), 3.50 (d, J=13.7 Hz, 1H), 3.74 (d, J=13.7 Hz, 1H), 3.89 (s, 3H), 7.19 (d, J=9.0 Hz, 2H), 7.76 (d, J=9.0 Hz, 2H), 7.85-7.89 (m, 1H), 8.37-8.40 (m, 1H), 8.70-8.80 (m, 2H), 11.0 (brs, 1H); IR (KBr, cm−1): 3157m, 3095m, 2954s, 2932s, 2858m, 1671m, 1593s; Anal. Calc'd for C23H28N2O5S.HCl.0.9H2O: C, 55.56; H, 6.24; N, 5.63. Found: C, 55.84; H, 6.19; N, 5.59.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:55]1[CH:64]=[CH:63][C:62]([OH:65])=[C:61]2[C:56]=1[CH:57]=[CH:58][C:59](=[O:66])[NH:60]2)[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]NC(C1C=C(S(C2C=C3C(=C(C)C=2)N=CC(C(N)=O)=C3NC2C=CC=C(OC)C=2)(=O)=O)C=CC=1)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:67][O:68][C:69]1[CH:70]=[C:71]([NH:75][C:76]2[C:85]3[C:80](=[C:81]([CH3:111])[CH:82]=[C:83]([S:86]([C:89]4[CH:94]=[CH:93][CH:92]=[C:91]([C:95](=[O:110])[NH:96][C:97]5C=CC(C#CCCC=O)=[CH:99][C:98]=5[CH3:109])[CH:90]=4)(=[O:88])=[O:87])[CH:84]=3)[N:79]=[CH:78]C=2C(N)=O)[CH:72]=[CH:73][CH:74]=1>>[Si:1]([O:8][C@H:9]([C:55]1[CH:64]=[CH:63][C:62]([OH:65])=[C:61]2[C:56]=1[CH:57]=[CH:58][C:59](=[O:66])[NH:60]2)[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:17]1[CH:18]=[CH:19][C:97]([NH:96][C:95]([C:91]2[CH:90]=[C:89]([S:86]([C:83]3[CH:84]=[C:85]4[C:80](=[C:81]([CH3:111])[CH:82]=3)[N:79]=[CH:78][C:58]([C:59]([NH2:60])=[O:66])=[C:76]4[NH:75][C:71]3[CH:72]=[CH:73][CH:74]=[C:69]([O:68][CH3:67])[CH:70]=3)(=[O:87])=[O:88])[CH:94]=[CH:93][CH:92]=2)=[O:110])=[C:98]([CH3:109])[CH:99]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c5ccc(O)c6[nH]c(=O)ccc56)c4)cc23)c1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(C#CCCC=O)cc5C)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(C#CCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c6ccc(O)c7[nH]c(=O)ccc67)cc5C)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described in Intermediate 148, using Intermediate 117 in place of Intermediate 112. ES/MS calcd. for C52H56N6O9SSi 978.4. Found m/z=979 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[O:15]=[C:16]1[N:20]([C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=2)[CH2:19][CH2:18][O:17]1>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([N:20]3[CH2:19][CH2:18][O:17][C:16]3=[O:15])=[CH:29][CH:28]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: O=C(O)c1ccc(N2CCOC2=O)cc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(N2CCOC2=O)cc1

Procedure:
A mixture of 1 g of methyl 4-iodobenzoate, 399 mg of 2-oxozolidone, 1.1 g of potassium carbonate, 34 mg of N,N′-dimethylethylenediamine and 73 mg of copper iodide in 10 mL of toluene was heated to 150° C. in a sealed microwave reactor for 2 h. The reaction mixture was diluted with ethyl acetate, washed with H2O, dried (MgSO4) and evaporated. Purified by silica gel chromatography (20-70% ethyl acetate/hexane) to afford methyl 4-(2-oxooxazolidin-3-yl)benzoate. 530 mg of methyl 4-(2-oxooxazolidin-3-yl)benzoate was hydrolyzed via Procedure M to give 4-(2-oxooxazolidin-3-yl)benzoic acid. 70 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-oxooxazolidin-3-yl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-oxooxazolidin-3-yl)benzamide. MS (Q1) 394.2 (M)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:15][CH3:16])=[C:4]([CH:8]=[C:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.C1CCN2C(=NCCC2)CC1.[C:28]([O:32][CH2:33][CH3:34])(=[O:31])[CH:29]=[CH2:30]>C(#N)C>[Br:1][C:2]1[C:3]([CH2:15][CH3:16])=[C:4]([CH:8]=[C:9]2[CH2:10][CH2:11][N:12]([CH2:30][CH2:29][C:28]([O:32][CH2:33][CH3:34])=[O:31])[CH2:13][CH2:14]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)OCC
Reactant: CCc1c(Br)cccc1C=C1CCNCC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CCN1CCC(=Cc2cccc(Br)c2CC)CC1
Temperature: 60 °C
Yield: 99.4 %

Procedure:
To a solution of 4-[(3-bromo-2-ethylphenyl)methylidene]piperidine (D137) (1 g, 3.57 mmol) in Acetonitrile (10 mL) was added DBU (0.807 mL, 5.35 mmol) and ethyl 2-propenoate (0.429 g, 4.28 mmol). The reaction solution was heated to 60° C. for overnight. The solvent was removed in vacuo and the residue was diluted with ethyl acetate, washed with water, dried and concentrated to afford ethyl 3-{4-[(3-bromo-2-ethylphenyl)methylidene]-1-piperidinyl}propanoate (D138) (1.35 g), which was used directly without further purification. MS (ES): C19H26BrNO2 requires 379.1. found 380.1 (M+H+).
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([CH:15]=[O:16])=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].[CH3:17][N:18]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]2[CH:30]=[CH:29]C(N)=[CH:27][CH:26]=2)[CH2:20][CH2:19]1>>[CH3:17][N:18]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]2[CH:30]=[CH:29][C:14]([N:12]3[C:3](=[O:4])[C:5]4[S:6][C:7]([CH:15]=[O:16])=[CH:8][C:9]=4[N:10]=[CH:11]3)=[CH:27][CH:26]=2)[CH2:20][CH2:19]1
Reactant: CN1CCCN(c2ccc(N)cc2)CC1
Reactant: COC(=O)c1sc(C=O)cc1N=CN(C)C
Product: CN1CCCN(c2ccc(-n3cnc4cc(C=O)sc4c3=O)cc2)CC1

Procedure:
3-(Dimethylaminomethyleneamino)-5-formylthiophene-2-carboxylic acid methyl ester was reacted with 4-(4-methylperhydro-1,4-diazepin-1-yl)phenylamine by method A1. The product with the molecular weight of 368.46 (C19H20N4O2S) was obtained in this way; MS (ESI): 369 (M+H+).