Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][C:20]#[N:21])[CH2:14][CH2:13]2)=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[OH:22][C@H:23]([CH3:27])[C:24](O)=[O:25].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>C(Cl)Cl>[C:20]([CH2:19][CH2:18][C@H:15]1[CH2:14][CH2:13][C@H:12]([NH:11][C:3]2[C:2]([NH:1][C:24](=[O:25])[C@H:23]([OH:22])[CH3:27])=[CH:7][N:6]=[C:5]3[CH:8]=[CH:9][S:10][C:4]=23)[CH2:17][CH2:16]1)#[N:21]
Reactant: C[C@@H](O)C(=O)O
Reactant: N#CCC[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)C(=O)Nc1cnc2ccsc2c1N[C@H]1CC[C@H](CCC#N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-{trans-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}propanenitrile (0.048 g, 0.16 mmol) and (R)-2-hydroxypropanoic acid (0.019 g, 0.21 mmol) in methylene chloride (0.96 mL) was added N,N-diisopropylethylamine (60 μL, 0.35 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (66 mg, 0.17 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was washed with water. The organic layers were concentrated and purified on silica gel (eluting with 0 to 10% MeOH in dichloromethane) to give (2R)—N-(7-{[trans-4-(2-Cyanoethyl)cyclohexyl]amino}thieno[3,2-b]pyridin-6-yl)-2-hydroxypropanamide. LCMS calculated for C19H25N4O2S (M+H)+: m/z=373.2. Found: 373.0. A solution of the amide intermediate in acetic acid (0.3 mL) was stirred at 105° C. for 5 h. The solvent in the reaction mixture was removed in vacuo, diluted with MeOH and purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (6 mg, 10%). LCMS calculated for C19H23N4OS (M+H)+: m/z=355.2. Found: 355.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][CH2:14][CH2:15][CH:16]=O)[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][CH2:14][CH2:15][CH2:16][N:30]3[CH2:29][CH2:28][N:27]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[O:20][CH3:19])[CH2:32][CH2:31]3)[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=CCCCC1CC(c2ccc(F)cc2)=NO1
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCCCC2CC(c3ccc(F)cc3)=NO2)CC1
Yield: 63.7 %

Procedure:
4-[3-(4-Fluorophenyl)-4,5-dihydroisoxazol-5-yl]butanal (22.6 mg, 0.096 mmol), 1-(2-methoxyphenyl)piperazine hydrochloride (20.0 mg, 0.087 mmol), molecular sieve (5 beads), NaBH(OAc)3 (55.6 mg, 0.262 mmol) and diisopropylethylamine (26.9 μL, 0.087 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 22.8 mg (70.4%) of the target compound was obtained.
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]1[CH2:8][CH2:7][C:6]2([CH2:12][CH2:11][N:10](CC3C=CC=CC=3)[CH2:9]2)[CH2:5]1>CO.[Pd]>[ClH:1].[ClH:1].[CH3:3][N:4]1[CH2:8][CH2:7][C:6]2([CH2:12][CH2:11][NH:10][CH2:9]2)[CH2:5]1
Reactant: CN1CCC2(CCN(Cc3ccccc3)C2)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN1CCC2(CCNC2)C1

Procedure:
A solution of 2-methyl-7-(phenylmethyl)-2,7-diazaspiro[4.4]nonane dihydrochloride in 150 ml of methanol with 1.0 g 20% palladium on carbon catalyst was hydrogenated at 50 psi for two days. After filtration, the filtrate was concentrated to a thick syrup which crystallized on addition of acetonitrile to give 11.50 g of 2-methyl-2,7-diazaspiro[4.4]nonane dihydrochloride, softened at 164° C. and melted at 168°-170° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[N:10]1[N:11]([CH2:15][C:16]2[CH:25]=[CH:24][C:19]([O:20][CH2:21][CH2:22]Br)=[CH:18][CH:17]=2)[N:12]=[CH:13][CH:14]=1>CN(C)C=O>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[O:3][CH2:22][CH2:21][O:20][C:19]1[CH:24]=[CH:25][C:16]([CH2:15][N:11]2[N:12]=[CH:13][CH:14]=[N:10]2)=[CH:17][CH:18]=1
Reactant: Oc1ccccn1
Reactant: BrCCOc1ccc(Cn2nccn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(OCCOc2ccc(Cn3nccn3)cc2)nc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 5 ml of anhydrous N,N-dimethylformamide and 51 mg of sodium hydride (60% oil dispersion) is added dropwise an anhydrous N,N-dimethylformamide (3 ml) solution of 121 mg of 2-hydroxypyridine under stirring over 10 minutes. After stirring at room temperature for 1 hour, the mixture is cooled to 5° to 10° C., to which an anhydrous N,N-dimethylformamide (2 ml) solution of 300 mg of 2-[4-(2-2H-1,2,3-triazolyl)methylphenoxy]ethyl bromide is added dropwise over 30 minutes. The mixture is then stirred at room temperature overnight. The reaction mixture is poured into 50 ml of ice water, which is extracted with twice with 30 ml of toluene. The organic layers are combined, washed with water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography, which affords 4-(2-2H-1,2,3-triazolyl)methylphenyl 2-(2-pyridyloxy)ethyl ether.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[F:10][C:11](I)([F:13])[F:12]>CN(C)C=O.O.[Cu]>[F:10][C:11]([F:13])([F:12])[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: FC(F)(F)I
Agent: [Cu]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)cc(C(F)(F)F)c1
Reaction time: 6 h

Procedure:
A solution of 5-iodo-m-xylene (2.3 g) in dimethylformamide (DMF)(30 ml) and copper bronze (0.65 g) in a stainless steel tube is cooled and treated with trifluoromethyliodide (15 g). The tube is sealed and heated at 130°-140° C.in a rocking autoclave for 6 hours. After cooling and venting, the reaction mixture is diluted with water and extracted with n-hexane (2×200 ml). The combined hexane extracts are washed with aqueous NaHCO3 and water. After drying over MgSO4, the solvent is removed under reduced pressure. The residue is subjected to chromatography over silica gel to yield purified 5-(trifluoromethyl)-m-xylene.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:9][CH:10]2[C:19]3[N:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:20]([Si:24]([CH3:32])([CH3:31])[O:25][CH2:26][CH2:27][CH2:28][CH:29]=O)([CH3:23])([CH3:22])[CH3:21].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:20]([Si:24]([CH3:31])([CH3:32])[O:25][CH2:26][CH2:27][CH2:28][CH2:29][N:9]([C:3]1[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=1)[CH:10]1[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:13][CH2:12][CH2:11]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)OCCCC=O
Reactant: Cc1cnc(NC2CCCc3cccnc32)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(N(CCCCO[Si](C)(C)C(C)(C)C)C2CCCc3cccnc32)c(C)c1

Procedure:
Using General Procedure B, reaction of (3,5-dimethyl-pyridin-2-yl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine, 4-(tert-butyl-dimethyl-silanyloxy)-butyraldehyde and NaBH(OAc)3 in CH2Cl2 gave [4-(tert-butyl-dimethyl-silanyloxy)-butyl]-(3,5-dimethyl-pyridin-2-yl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[NH:3][CH:2]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:46]([CH:48]([NH2:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH3:47]>CN(C=O)C>[C:49]1([CH:48]([NH:55][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[O:12])[CH2:46][CH3:47])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: CCC(N)c1ccccc1
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(NC(=O)c1ccc2[nH]cnc2c1)c1ccccc1
Reaction time: 0.08 h

Procedure:
To a mixture of 5-benzimidazole-carboxylic acid in DMF was added DIPEA (1.3 equiv) and HATU (1.2 equiv). The mixture was stirred for 5 min, and then α-ethylbenzylamine (1.1 equiv) was added. The reaction mixture was stirred at rt. for 1 h. After the reaction was completed, the solvent was removed in vacuo to obtain the crude which was purified by flash chromatography to obtain the title compound. LC-MS 280 (M+H).
Reaction SMILES: [Cl:1]OC(C)(C)C.[CH:7]([C:10]1([CH3:26])[C:14](=[O:15])[NH:13][C:12]([C:16]2[N:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([O:20][CH3:21])=[O:19])=[N:11]1)([CH3:9])[CH3:8].CO>C(Cl)Cl>[Cl:1][N:13]1[C:14](=[O:15])[C:10]([CH:7]([CH3:9])[CH3:8])([CH3:26])[N:11]=[C:12]1[C:16]1[N:25]=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1cccnc1C1=NC(C)(C(C)C)C(=O)N1
Reactant: CC(C)(C)OCl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cccnc1C1=NC(C)(C(C)C)C(=O)N1Cl
Reaction time: 24 h
Yield: 63.7 %

Procedure:
Tert-butyl hypochlorite (5.92 g, 0.0545 mol) is added to a solution of methyl 2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinate (10.0 g, 0.0363 mol) and methanol. The reaction mixture is covered with foil and stirring is continued for 1 day. The reaction mixture is concentrated in vacuo to give a liquid. The liquid is dissolved into methylene chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo to yield a yellow syrup. The yellow syrup is chromatographed using silica gel and 5% ethyl acetate in hexanes as eluent to give the title compound as a colorless syrup (7.16 g, 64%), identified by IR and NMR spectral analyses.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH2:19]([C:26]1[O:27][C:28]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:29]([C:31](O)=[O:32])[N:30]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:31]([C:29]3[N:30]=[C:26]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[O:27][C:28]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1nc(Cc2ccccc2)oc1-c1ccccc1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3nc(Cc4ccccc4)oc3-c3ccccc3)n2)o1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-benzyl-5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([CH3:21])([CH3:20])[CH2:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.[Na].O>C(O)CC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:9])([C:11]([CH3:21])([CH3:20])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:10][N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)=[CH:4][CH:3]=1
Reactant: c1c[nH]cn1
Reactant: CC(C)(Cc1ccc(Cl)cc1)C1(c2ccc(Cl)cc2)CO1
Agent: [Na]
Solvent: CCCO
Solvent: O
Product: CC(C)(Cc1ccc(Cl)cc1)C(O)(Cn1ccnc1)c1ccc(Cl)cc1
Yield: 30.2 %

Procedure:
30 g (0.935 mol) of 2-(4-chlorophenyl)-2-(4-chlorophenyl-tert.-butyl)-oxirane in 40 ml of n-propanol are added dropwise to a solution of 7.7 g (0.108 mol) of sodium imidazole in 60 ml of n-propanol at the reflux temperature. The reaction mixture is subsequently stirred under reflux for 48 hours and cooled, water is added and the mixture is extracted with methylene chloride. The organic phase is dried over sodium sulphate and concentrated in vacuo. The oily residue is stirred into diisopropyl ether. The resulting crystalline precipitate is filtered off with suction and dried. 12.7 g (35% of theory) of 2,4-bis-(4-chlorophenyl)-3,3-dimethyl-1-(imidazol-1-yl)-2-butanol of melting point 174° C. are obtained.
Reaction SMILES: [CH3:1][NH2:2].CO[C:5](=[O:24])[C@H:6]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:7][C:8]([NH:10][C:11]1[S:12][C:13](=[S:16])[NH:14][N:15]=1)=[O:9]>C(O)C>[S:16]=[C:13]1[S:12][C:11]([NH:10][C:8]([NH:7][C@@H:6]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:5]([NH:2][CH3:1])=[O:24])=[O:9])=[N:15][NH:14]1
Reactant: CN
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)Nc1n[nH]c(=S)s1
Solvent: CCO
Product: CNC(=O)[C@H](Cc1ccccc1)NC(=O)Nc1n[nH]c(=S)s1

Procedure:
A saturated solution of methylamine in ethanol (50 mL) and N-[[(4,5-dihydro-5-thioxo-1,3,4-thiadiazol-2-yl)amino]carbonyl]-L-phenylalanine methyl ester (EXAMPLE 1; 0.770 g, 2.28 mmol) is stirred at room temperature for 6 days. The solution is concentrated, diluted with water, and acidified with 1N HCl. The resultant solids are filtered and dried to give 576 mg of the amide. Recrystallization from hot EtOAc/CH2 Cl2 /MeOH gives 390 mg (51%) of the desired product as a white solid (mp 234°-236° C.).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH:16]2[CH2:21][CH2:20][N:19](C(OCC3C=CC=CC=3)=O)[CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6](=[O:7])[CH2:8][O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)[CH2:12][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)COC1CCN(C2CCN(C(=O)OCc3ccccc3)CC2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)COC1CCN(C2CCNCC2)CC1
Reaction time: 2 h

Procedure:
A suspension of 3.08 g (7.12 mmol) benzyl 4-tert-butoxycarbonylmethoxy-[1,4′]bipiperidinyl-1′-carboxylate and 300 mg 10% Pd/C in 60 mL MeOH was hydrogenated for 2 h at 50° C. and 3447 hPa hydrogen pressure. The catalyst was removed by suction filtering and the filtrate was evaporated to dryness. The product was reacted further without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C([CH:24]([CH2:31][CH2:32]Cl)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])(=O)C.C(=O)([O-])[O-].[Na+].[Na+].[CH3:40][C:41](=[O:44])CC>>[C:41]([CH:25]([CH2:24][CH2:31][CH2:32][N:12]1[CH2:11][CH2:10][C:9](=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:14][CH2:13]1)[C:26]([O:28][CH2:29][CH3:30])=[O:27])(=[O:44])[CH3:40]
Reactant: Fc1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Reactant: CCOC(=O)CC(CCCl)C(C)=O
Reactant: CCC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)C(CCCN1CCC(=C(c2ccccc2)c2ccc(F)cc2)CC1)C(C)=O

Procedure:
0.019 mol of 4-[(4-fluorophenyl)phenylmethylene]piperidine, 0.019 mol of ethyl 3-acetyl-5-chloropentanoate, blocked in cyclic form (Chem. Ber. (1967), 100, p. 1675-1679), and 2.03 g of sodium carbonate in 80 ml of 2-butanone are brought to reflux. After evaporation of the solvent, the residue is taken up in water and extracted with dichloromethane. Deprotection is then performed according to the method described in Chem. Ber. (1967), 100, p. 1675-1679.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:44])[CH2:10][C@@H:11]([N:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[CH:26]1)[C:12]([NH:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][OH:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:52]C(=O)C(N)[C@@H](C(OCCCC)=O)C(N[C@@H](CC1C=CC=CC=1)CO)=O)C1C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(=O)C[C@@H](N)C(N[C@@H](CC1C=CC=CC=1)CO)=O)C1C=CC=CC=1>ClCCCl>[CH2:1]([O:8][C:9](=[O:44])[CH2:10][CH:11]([N:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[CH:32][C:33]([C:36]3[CH:37]=[CH:38][C:39]([C:42](=[O:52])[NH2:43])=[CH:40][CH:41]=3)=[CH:34][CH:35]=2)=[CH:26]1)[C:12]([NH:14][CH:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][OH:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(-c2ccc(-c3ccn([C@H](CC(=O)OCc4ccccc4)C(=O)N[C@H](CO)Cc4ccccc4)c3)cc2)cc1
Reactant: CCCCOC(=O)[C@@H](C(=O)N[C@H](CO)Cc1ccccc1)C(N)C(=O)OCc1ccccc1
Agent: N[C@H](CC(=O)OCc1ccccc1)C(=O)N[C@H](CO)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: NC(=O)c1ccc(-c2ccc(-c3ccn(C(CC(=O)OCc4ccccc4)C(=O)NC(CO)Cc4ccccc4)c3)cc2)cc1
Yield: 31 %

Procedure:
As described in Example 4(a) for the preparation of N-(1(S)-benzyl-2-hydroxyethyl)-3(R)-[3-(4′-cyano-biphenyl-4-yl)-1H-pyrrol-1-yl]succinamic acid benzyl ester, N-(1(S)-benzyl-2-hydroxyethyl)-3(R)-butoxycarbonyl-amino-succinamic acid benzyl ester (0.320 mmol) was deprotected. A solution of the resultant crude N-(1(S)-benzyl-2-hydroxyethyl)-3(R)-amino-succinamic acid benzyl ester trifluoroacetate salt and crude 3-(4′-carboxamidobiphenyl-4-yl)-2,5-dimethoxytetrahydrofuran (110 mg, 0.330 mmol) in 1,2-dichloroethane condensed in 18 hours to give a brown solid, which was purified via flash column chromatography with 5% MeOH/CH2Cl2as eluant to provide 60 mg(31%) of N-(1-benzyl-2-hydroxyethyl)-3-[3-(4′-carbamoylbiphenyl-4-yl)-1H-pyrrol-1-yl]succinamic acid benzyl ester as a pale yellow solid, mp 1924° C. 1H NMR (DMSO-d6): δ 8.18 (d, 1H, J=8.5 Hz), 8.00 (s, 1H), 7.94 (d, 2H, J=8.1 Hz), 7.76 (d, 2H, J=8.5 Hz), 7.68 (d, 2H, J=8.5 Hz), 7.58 (d, 2H, J=8.5 Hz), 7.36-7.14 (bm, 7H), 6.84 (t, 1H, J=2.2 Hz), 6.47 (s, 1H), 5.10-4.95 (m, 3H), 4.81 (t, 1H, J=5.1 Hz), 3.88-3.75 (m, 1H), 3.00 (d, 2H, J=7.4 Hz), 2.80 (dd, 1H, J=5.5, 13.2 Hz), 2.67-2.60 (m, 1H). IR (KBr): 3330, 2962, 1729, 1655, 1606, 1560, 1498, 1261, 1092 cm−1. FABMS: 602 (M+H+). Anal. Calculated for C37H35N3O5.0.4CH2Cl2: C, 70.67; H, 5.68; N, 6.61. Found: C, 70.78; H, 5.86; N, 6.98.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@@H:12]([CH2:14][N:15]3C(=O)C4C(=CC=CC=4)C3=O)[O:11][C:10]2=[O:26])[CH:5]=[CH:6][C:7]=1[I:8].O.NN>C(O)C>[NH2:15][CH2:14][C@@H:12]1[O:11][C:10](=[O:26])[N:9]([C:4]2[CH:5]=[CH:6][C:7]([I:8])=[C:2]([F:1])[CH:3]=2)[CH2:13]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Agent: NN
Solvent: O
Solvent: CCO
Product: NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
A solution of (5R)-2-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-isoindole-1,3-dione (1021, 23.3 g, 50.0 mmol) in ethanol (EtOH, 150 mL) was treated with hydrazine monohydrate (12.52 g, 12.1 mL, 250 mmol, 5.0 equiv) at 25° C., and the resulting reaction mixture was warmed up to reflux for 2 h. White precipitates were formed while the reaction mixture was refluxed. When TLC and HPLC showed that the reaction was complete, the reaction mixture was cooled down to room temperature before being quenched with H2O (100 mL). The white precipitates were totally dissolved when water was introduced into the reaction mixture and a homogeneous solution was generated. The aqueous solution was then extracted with CH2Cl2 (3×200 mL), and the combined organic extracts were washed with H2O (2×100 mL) and saturated NaCl aqueous solution (100 mL), dried over MgSO4, and concentrated in vacuo. The residue was further dried in vacuo to afford the crude (5S)-5-aminomethyl-3-(3-fluoro-4-iodo-phenyl)-oxazolidin-2-one (1022, 16.0 g, 16.8 g theoretical, 95.2%) as white powders, which were found to be essentially pure and was directly used in the subsequent reactions without further purifications. For 1022: C10H10FIN2O2, LCMS (EI) m/e 337 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C:15]3[NH:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:17])[N:8]([CH2:18][O:19][CH3:20])[C:7]=2[CH:6]=[C:5]([CH2:21][NH:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:4]=1.[C:29](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[CH3:1][O:2][C:3]1[C:16]2[C:15]3[NH:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:17])[N:8]([CH2:18][O:19][CH3:20])[C:7]=2[CH:6]=[C:5]([CH2:21][N:22]([CH3:29])[N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[CH:4]=1
Reactant: COCn1c(=O)c2c(c3c(OC)cc(CNN4CCOCC4)cc31)NCCC2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COCn1c(=O)c2c(c3c(OC)cc(CN(C)N4CCOCC4)cc31)NCCC2
Temperature: 0 °C
Reaction time: 18 h
Yield: 7.5 %

Procedure:
The compound (40 mg, 0.10 mmol) prepared in step 3 of Example 96 and potassium carbonate (22 mg, 0.15 mmol) were dissolved in acetonitrile (5 ml), added with iodo methane (0.008 ml, 0.12 mmol). The resulting mixture was heated to reflux temperature and stirred for 18 hours. The reaction mixture was poured into ice water and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was then purified by flash column chromatography (dichloromethane:methanol=15:1) to obtain the title compound (3 mg, yield: 8%, yellow solid).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[C:29]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][N:30]=1>C1COCC1.O.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>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Fc1cccnc1Br
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2ncccc2F)c(Cl)cc1Cl
Temperature: 25 °C

Procedure:
To a solution of methyl 2,4-dichloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.95 mol) in THF (4 L), was added portionwise a solution of potassium carbonate (807 g, 5.85 mol) in water (1.6 L), followed by 2-bromo-3-fluoropyridine (361 g, 2.05 mol) and the mixture degassed with argon. To this mixture was added tetrakis(triphenylphosphine)palladium (56.4 g, 48.8 mmol) and the mixture heated at reflux for 5 h. The mixture was cooled to room temperature and the organic layer separated and washed with brine (1 L). This organic solution containing the title compound was used directly in the next reaction (Preparation 27A).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[N:6]([C:7](=[O:17])[CH2:8][NH:9]C(=O)OC(C)(C)C)[C@@H:5]([CH2:18][CH:19]=[CH2:20])[CH2:4][O:3]1.C(Cl)Cl.[F:25][C:26]([F:36])([F:35])[S:27]([O:30][Si](C)(C)C)(=[O:29])=[O:28]>>[F:25][C:26]([F:36])([F:35])[S:27]([OH:30])(=[O:29])=[O:28].[CH3:1][C:2]1([CH3:21])[N:6]([C:7](=[O:17])[CH2:8][NH2:9])[C@@H:5]([CH2:18][CH:19]=[CH2:20])[CH2:4][O:3]1
Reactant: C=CC[C@H]1COC(C)(C)N1C(=O)CNC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: C=CC[C@H]1COC(C)(C)N1C(=O)CN
Product: O=S(=O)(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,1-dimethylethyl {2-[(4S)-2,2-dimethyl-4-(2-propen-1-yl)-1,3-oxazolidin-3-yl]-2-oxoethyl}carbamate D22 (28.67 g) in DCM (300 ml) 2,6-dimethylpyridine (27.9 ml, 240 mmol) was added followed by trimethylsilyl trifluoromethanesulfonate (34.7 ml, 192 mmol) the mixture was stirred at room temperature for 30 min. The reaction was quenched with 2 ml of water and the solvent was removed under reduced pressure, the residue was charged on a Biotage 75 L column eluting with [DCM/MeOH 100:0 then 98:2 then 96:4 then 85:15]. Evaporation of the solvent gave: the title compound D23 (21 g). UPLC (Acid FINAL_QC): rt=0.36 minutes, peak observed: 199 (M+1−CHF3O3S)C10H18N2O2.CHF3O3S requires 348. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.40 (s, 3 H), 1.50 (s, 3 H), 2.17-2.43 1.40 (m, 2 H), 3.68-3.98 (m, 4 H), 3.99-4.09 (m, 1 H), 4.83-5.40 (m, 2 H), 5.58-5.97 (m, 1H), 7.63-8.36 (br.s., 2 H)