Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:22])([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:10][C:11](OCC)=[O:12])=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(OCC)C>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)([OH:22])[CH2:10][CH2:11][OH:12])=[CH:7][CH:8]=1
Reactant: CCOC(=O)CC(O)(c1ccc(Br)cc1)c1cccnc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: CCOCC
Product: OCCC(O)(c1ccc(Br)cc1)c1cccnc1
Temperature: 0 °C
Yield: 39 %

Procedure:
The base (9.5 g, 0.027 moles) from ethyl 3-(4-bromophenyl)-3-hydroxy-3-(3-pyridyl)propanoate hydrochloride (step 1) was prepared and dissolved in ethyl ether (50 ml). This solution was added dropwise to an ice-cold mixture of lithium aluminum hydride (1.0 g, 0.027 moles) and ethyl ether (150 ml). The reaction mixture was refluxed for 5 hours, cooled and a saturated sodium sulphate solution was added until a white precipitate was formed. This was filtered off and the filtrate evaporated. The residue was crystallized from chloroform. 1-(4-bromophenyl)-1-(3-pyridyl)-1,3-propanediol was obtained. Yield: 39%. M.p. 130°-132° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[C:10]2[O:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1OCC2=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1COc2c(CBr)cccc21
Temperature: 25 °C
Yield: 44.8 %

Procedure:
A solution of 7-methylbenzofuran-3(2H)-one (0.759 g, 5.12 mol) in carbon tetrachloride (50 mL) was added with N-bromosuccinimide (1.00 g, 5.63 mmol) and benzoyl peroxide (0.0830 g, 0.256 mmol), and the mixture was refluxed for 4 hours by heating. The reaction mixture was cooled to room temperature, and then filtered, and the resulting filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 7-bromomethylbenzofuran-3(2H)-one (0.573 g, 49%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5](=[O:12])[N:6]([CH3:11])[C:7](=[O:10])[NH:8][N:9]=1.[F:13][C:14]([F:20])([F:19])[CH2:15][CH2:16][CH2:17]I>CN(C=O)C.O>[Br:3][C:4]1[C:5](=[O:12])[N:6]([CH3:11])[C:7](=[O:10])[N:8]([CH2:17][CH2:16][CH2:15][C:14]([F:20])([F:19])[F:13])[N:9]=1
Reactant: Cn1c(=O)[nH]nc(Br)c1=O
Reactant: FC(F)(F)CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c(Br)nn(CCCC(F)(F)F)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
0.85 g (21.3 mmol) of NaH (60% in paraffin) is placed in 10 ml of DMF under nitrogen. A solution of 4 g (19.4 mmol) of intermediate 2a in 40 ml of DMF is added dropwise. The reaction medium is stirred for 1 h at ambient temperature and then 5 g (21.3 mmol) of 1,1,1-trifluoro-4-iodo-butane are added; stirring is then continued for 3 h at ambient temperature. After dry concentration, the residue obtained is taken up in H2O and extracted with ethyl acetate. After drying on MgSO4, the organic phases are evaporated and the oil obtained is purified by flash chromatography on silica (petroleum ether:AcOEt 80:20). 5.3 g of crystals corresponding to compound 4a are isolated (yield=87%). TLC silica gel 60 F 254 Merck, petroleum ether:AcOEt 70:30, Rf=0.58.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10](I)[C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4].[F:18][C:19](I)([F:21])[F:20].N1C=CC=CC=1>C(OCC)C.C(OCC)(=O)C.[Cu]>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([C:19]([F:21])([F:20])[F:18])[C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2c(I)c(OC)ccc12
Reactant: FC(F)(F)I
Agent: [Cu]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1cccc2c(C(F)(F)F)c(OC)ccc12
Temperature: 120 °C
Yield: 75.1 %

Procedure:
A mixture of 5-iodo-6-methoxy-1-naphthalenecarboxylic acid methyl ester (10.26 g, 30 mmoles, described in Example 1f), trifluoromethyl iodide (12 g, 61.2 mmoles), freshly prepared copper powder (5.7 g, prepared according to the procedure of R. Q. Brewster and T. Groening, "Organic Syntheses", Coll. Vol. II, John Wiley and Sons, New York, N.Y., U.S.A., 1948, p. 445) and pyridine (45 ml) was charged into a stainless steel autoclave. The vessel was shaken and heated at 120° C. for 20 hr and cooled to room temperature. The mixture was diluted with diethyl ether-ethyl acetate (1:1). The insoluble material was removed by filtration. The filtrate was washed with 1 N aqueous HCl, water and dried (MgSO4). The solvent was removed under reduced pressure. The residue was crystallized from ethanol to give 6.4 g of 5-(trifluoromethyl)-6-methoxy-1-naphthalenecarboxylic acid methyl ester; mp 79°-80° C., NMR (CDCl3) δ3.95 (s, 6H), 8.00 (m, 5H). A mixture of the latter ester (6.3 g, 22 mmoles), 1 N aqueous NaOH solution (34.12 ml) and methanol (100 ml) was stirred at 20°-22° C. for 4 hr. The mixture was adjusted to pH 7 with 1 N aqueous HCl, methanol was removed from the mixture by distillation and the concentrated mixture was made acidic (pH 2) with 1 N aqueous HCl. The resulting precipitate was collected and dried to yield 6 g of the title compound; mp 218°-219° C.; NMR (DMSO-d6) δ4.0 (s, 3H),8.3 (m, 5H), 10.6 (broad, 1H).
Reaction SMILES: CN(C)CCCN=C=NCC.[CH3:12][O:13][CH2:14][CH2:15][NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][C:18]=1[N+:29]([O-])=O.[N:32]([C:35]1[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=1)=[C:33]=S>O1CCCC1.C(OCC)(=O)C>[CH3:12][O:13][CH2:14][CH2:15][N:16]1[C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][C:18]=2[N:29]=[C:33]1[NH:32][C:35]1[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=1
Reactant: COCCNc1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Reactant: COC(=O)c1ccc(N=C=S)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCn1c(Nc2ccc(C(=O)OC)cc2)nc2cc(-c3ccccc3)ccc21
Yield: 55.6 %

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide (EDC, 200 mg, 1.44 mg) is added to a solution of N-(2-methoxyethyl)-3-nitrobiphenyl-4-amine (119 mg, 0.48 mmol) and methyl 4-isothiocyanatobenzoate (83 mg, 0.43 mmol) in tetrahydrofuran. The reaction may reflux for an appropriate time period, such as 2 hours and cooled. The mixture may be diluted with ethyl acetate, filtered and concentrated. The residue may be purified by any appropriate method including Biotage column chromatography to give methyl 4-(1-(2-methoxyethyl)-5-phenyl-1H-benzo[d]imidazol-2-ylamino)benzoate (96 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C:14](=[O:15])[CH:13]=[C:12]([OH:16])[CH:11]2[CH2:17][CH:18]2[CH2:20][CH2:19]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(O)(=O)C.[BH4-].[Na+].O>C(#N)C>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C:14](=[O:15])[CH2:13][C@H:12]([OH:16])[C@@H:11]2[CH2:17][CH:18]2[CH2:20][CH2:19]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(N2C(=O)C=C(O)C2CC2CC2)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(N2C(=O)C[C@H](O)[C@@H]2CC2CC2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a mixture of 2-chloro-4-[2-(cyclopropylmethyl)-3-hydroxy-5-oxo-2,5-dihydro-1H-pyrrol-1-yl]benzonitrile (400 mg) and acetic acid (0.87 mL) in acetonitrile (10 mL) was added sodium borohydride (131 mg) at 0° C. in small portions. The mixture was warmed to room temperature and stirred for 1 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluent: hexane:ethyl acetate=4:1-3 ethyl acetate), and recrystallized from tetrahydrofuran-hexane to give the title compound as colorless crystals (yield: 310 mg, 77%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]([CH3:32])[C:6]([C:8]1[N:9]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:10]([C:21]([F:24])([F:23])[F:22])=[C:11]([CH3:20])[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=[O:7].CCN(CC)CC.[C:40](Cl)(=[O:42])[CH3:41]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:40]([NH:2][CH2:3][CH2:4][N:5]([CH3:32])[C:6]([C:8]1[N:9]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:10]([C:21]([F:23])([F:24])[F:22])=[C:11]([CH3:20])[C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)=[O:7])(=[O:42])[CH3:41]
Reactant: CC(=O)Cl
Reactant: Cc1c(-c2ccc(Cl)cc2)c(C(=O)N(C)CCN)n(Cc2ccccc2)c1C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCN(C)C(=O)c1c(-c2ccc(Cl)cc2)c(C)c(C(F)(F)F)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of N-(2-aminoethyl)-1-benzyl-3-(4-chlorophenyl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide hydrochloride (150 mg, 0.308 mmol) in DCM (2 mL) were added dropwise Et3N (0.094 mL, 0.679 mmol) and acetyl chloride (0.024 mL, 0.339 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with DCM and saturated aqueous NaHCO3. The layers were separated using a phase separator and the solvents were evaporated. The product was purified by flash column chromatography (silica, gradient heptane/EtOAc, 1:2→0:1) to afford 106 mg (70%) of SC-37.
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:4]=2[C:5](I)=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:25]B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>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>[OH:1][C:2]1[C:3]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:4]=2[C:5]([CH3:25])=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1nc(I)c2c(-c3ccc(OC)cc3)noc2c1O
Reactant: CB(O)O
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: [Cs+]
Product: CCOC(=O)c1nc(C)c2c(-c3ccc(OC)cc3)noc2c1O
Yield: 16.7 %

Procedure:
Ethyl 7-hydroxy-4-iodo-3-(4-methoxyphenyl)isoxazolo[4,5-c]pyridine-6-carboxylate (280 mg, 0.64 mmol), methylboronic acid (155 mg, 127 mmol), Pd(PPh3)4 (147 mg, 0.13 mmol) and cesium carbonate (622 mg, 1.91 mmol) were added to a flask and the flask evacuated. After refilling with nitrogen, 6.5 mL of 1,2-dimethoxyethane was added and the resulting suspension was refluxed for 16 h. The reaction mixture diluted with EtOAc (40 mL) and the solid was filtered. The solid was added to a mixture of 10% hydrochloric acid and extracted several times with EtOAc. The combined organic layer was dried over MgSO4 and concentrated, and the residue was purified flash chromatography (0-40% EtOAc/hexanes) to afford 35 mg of the title compound. MS: (+) m/z 329.41 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([N:9]1[CH:13]=[C:12](B2OC(C)(C)C(C)(C)O2)[CH:11]=[N:10]1)[CH3:8].Cl[C:24]1[CH:33]=[C:32]2[C:27]([CH:28]=[CH:29][CH:30]=[N:31]2)=[C:26]([NH:34][CH2:35][C@:36]2([F:49])[CH2:41][CH2:40][CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]2)[N:25]=1.O>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:7]([N:9]1[CH:13]=[C:12]([C:24]2[CH:33]=[C:32]3[C:27]([CH:28]=[CH:29][CH:30]=[N:31]3)=[C:26]([NH:34][CH2:35][C@:36]3([F:49])[CH2:41][CH2:40][CH2:39][N:38]([C:42]([O:44][C:45]([CH3:47])([CH3:46])[CH3:48])=[O:43])[CH2:37]3)[N:25]=2)[CH:11]=[N:10]1)[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@](F)(CNc2nc(Cl)cc3ncccc23)C1
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCn1cc(-c2cc3ncccc3c(NC[C@]3(F)CCCN(C(=O)OC(C)(C)C)C3)n2)cn1
Temperature: 150 °C

Procedure:
To a 2-5 mL microwave vial under nitrogen was added caesium carbonate (990 mg, 3.04 mmol) and 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (292 mg, 1.317 mmol) (Boron Molecular). 1,1-Dimethylethyl (3R)-3-{[(7-chloro-1,6-naphthyridin-5-yl)amino]methyl}-3-fluoro-1-piperidinecarboxylate (400 mg, 1.013 mmol) was dissolved in 1,4-dioxane (4 ml) and water (0.8 ml) and added in one aliquot. Nitrogen was bubbled through the resultant suspension for ˜2 min. Tetrakis(triphenylphosphine)palladium (0) (117 mg, 0.101 mmol) was then added in one portion and nitrogen bubbled through the yellow suspension for a further ˜1 min. The microwave vial was sealed and heated at 150° C. in a microwave reactor for 1 h. LCMS showed the reaction had gone to completion. The reaction was partitioned between water (20 ml) and ethyl acetate (20 ml). The aqueous layer was further extracted with ethyl acetate (2×20 ml) and the combined organics washed with brine (10 ml). The organics were dried (Na2SO4) and concentrated in vacuo.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([O:13][C:14](=[O:25])[C:15](=[CH:21]OCC)[C:16](OCC)=[O:17])[CH3:12]>CN(C=O)C>[OH:17][C:16]1[N:6]2[C:2](=[N:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=32)[N:1]=[CH:21][C:15]=1[C:14]([O:13][CH2:11][CH3:12])=[O:25]
Reactant: Nc1nc2ccccc2[nH]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2nc3ccccc3n2c1O
Temperature: 25 °C

Procedure:
266 g. of 2-aminobenzimidazole (2 mol.) and 432 g. of ethoxymethylene malonic acid diethyl ester are heated with stirring in 3 liters of DMF at 80° for 3 hours. The solution is cooled to room temperature and then filtered off and the crystalline 4-hydroxypyrimido[1,2-a]-benzimidazole-3-carboxylic acid, ethyl ester is recrystallized from acetic acid, yield 490 g. (95%); m.p. 309°-310°.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[CH2:5][C:6]([CH:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH:10]=[CH:11]2)=[O:7]>CCOCC>[CH3:1][N:2]([CH2:5][C:6]([CH:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH:10]=[CH:11]2)=[O:7])[CH3:3]
Reactant: CNC
Reactant: O=C(CCl)C1CC2C=CC1C2
Solvent: CCOCC
Product: CN(C)CC(=O)C1CC2C=CC1C2
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of 3.5 g (5.2 ml; 0.078 mole) of dimethylamine in 40 ml of ether at -15° was added 6.5 g (0.038 mole) of 5-chloroacetyl-2-norbornene. The reaction mixture was stirred for 7 hr. at 0° (ice bath) and then allowed to warm to room temperature overnight. The solid dimethylamine hydrochloride was removed by filtration and the ether was removed at reduced pressure to give 6.1 g (89%) of crude product. Distillation gave product bp 83°-90°/0.8 mm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B(O)O)[CH:5]=[C:4]([F:11])[N:3]=1.FC1C=C(NN)C=C(F)N=1.[Br:22]Br>>[Br:22][C:6]1[CH:7]=[C:2]([F:1])[N:3]=[C:4]([F:11])[CH:5]=1
Reactant: BrBr
Reactant: OB(O)c1cc(F)nc(F)c1
Agent: NNc1cc(F)nc(F)c1
Product: Fc1cc(Br)cc(F)n1

Procedure:
The second step in the synthetic procedure used in synthesizing the 2,6-difluoropyridin-4-ylboronic acid involves bromination of 2,6-difluoro-4-hydrazinopyridine by elemental bromine to produce 4-bromo-2,6-difluoropyridine. This reaction can be depicted as follows:
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[CH3:11][CH:12]([C@H:14]1[CH2:18][O:17][C:16](=[O:19])[N:15]1[C:20](=[O:23])[CH2:21][CH3:22])[CH3:13].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:13][CH:12]([C@H:14]1[CH2:18][O:17][C:16](=[O:19])[N:15]1[C:20](=[O:23])[C@H:21]([CH3:22])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:11]
Reactant: CCC(=O)N1C(=O)OC[C@@H]1C(C)C
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)[C@H]1COC(=O)N1C(=O)[C@H](C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
A solution of lithium hexamethyl-disilazane (LiHMDS, 1.0M in THF, 120 mL, 120 mmol) was added to dry THF (300 mL). The resultant solution was cooled to 0°. Meanwhile, a solution of (4S)-(1-methylethyl)-3-(1-oxopropyl)-2-oxazolidinone (20.9 g, 113 mmol) in dry THF (200 mL) was cooled to 0°, and then cannulated into the LiHMDS solution. After 30 min at 0°, benzyl bromide (13.4 mL, 113 mmol) was added. The resultant mixture was stirred at 0° for 2 h and then allowed to warm to room temperature. The mixture was treated with 10% aqueous citric acid and then extracted with EtOAc (2 X). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated to provide a yellow oil mixed with a solid. This material was purified by flash chromatography [SiO2, eluent: EtOAc-hexane (1:10 to 1:3)] to provide 4(S)-(1-methylethyl)-3-(2(R)-methyl-1-oxo-3-phenylpropyl)-2-oxazolidinone as a clear pale yellow liquid (26.8 g, 86% yield). 1H NMR (CDCl3) δ 7.29-7.24 (m, 4H), 7.22-7.16 (m, 1H), 4.45-4.41 (m, 1H), 4.26-4.13 (m, 3H), 3.13 (dd, J=13, 7.5 Hz, 1H), 2.64 (dd, J=13, 7.5 Hz, 1H), 2.22-2.12 (m, 1H), 1.16 (d, J=6.5 Hz, 3H), 0.84 (d, J=7 Hz, 3H), 0.61 (d, J=7 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH2:12][CH3:13])[C:9]=1[OH:10])[CH:5]=[O:6].[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23]Br)[CH:18]=1>>[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:10][C:9]2[C:8]([O:11][CH2:12][CH3:13])=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[Br:1])[CH:18]=1
Reactant: CCOc1cc(C=O)cc(Br)c1O
Reactant: COC(=O)c1cccc(CBr)c1
Product: CCOc1cc(C=O)cc(Br)c1OCc1cccc(C(=O)OC)c1

Procedure:
Alkylation of 3-bromo-5-ethoxy-4-hydroxy benzaldehyde (2 g) with 3-bromomethyl-benzoic acid methyl ester (2.06 g) was performed according to the method described in example 1a. The residue was chromatographed on silica gel in heptane/ethyl acetate=7/3 (v/v) as eluent. Yield: 2.42 g. MS-ESI: [M+H]+=393/395
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][N:10]([CH:12]3[CH2:16][NH:15][CH:14]([C:17]([N:19]4[CH2:24][CH2:23][N:22]([C:25]5[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=5[C:27]#[N:28])[CH2:21][CH2:20]4)=[O:18])[CH2:13]3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:33](=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:33]([N:15]1[CH2:16][CH:12]([N:10]2[N:9]=[N:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:11]2)[CH2:13][CH:14]1[C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[C:27]#[N:28])[CH2:21][CH2:20]1)=[O:18])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=Cc1ccccc1
Reactant: N#Cc1ccccc1N1CCN(C(=O)C2CC(n3nnc(-c4ccccc4)n3)CN2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: N#Cc1ccccc1N1CCN(C(=O)C2CC(n3nnc(-c4ccccc4)n3)CN2Cc2ccccc2)CC1
Reaction time: 0.33 h

Procedure:
2-(4-{4-[5-(Phenyl)-tetrazol-2-yl]-pyrrolidine-2-carbonyl}-piperazin-1-yl)-benzonitrile (2), benzaldehyde and acetic acid (cat) is dissolved in DCM and the solution is stirred for 20 min. Then NaBH(OAc)3 is added. The resulting mixture is warmed to r.t and stirred overnight. The solution is then washed with sat NaHCO3, brine, dried and concentrated to afford 2-(4-{1-Benzyl-4-[5-(phenyl)-tetrazol-2-yl]-pyrrolidine-2-carbonyl}-piperazin-1-yl)-benzonitrile (I).
Reaction SMILES: [CH3:1][C:2]([NH:19]C(=O)OCC1C=CC=CC=1)([CH2:4][CH2:5][S:6]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])(=[O:8])=[O:7])[CH3:3]>CO>[CH3:3][C:2]([NH2:19])([CH2:4][CH2:5][S:6]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])(=[O:8])=[O:7])[CH3:1]
Reactant: COCCOCCOCCS(=O)(=O)CCC(C)(C)NC(=O)OCc1ccccc1
Solvent: CO
Product: COCCOCCOCCS(=O)(=O)CCC(C)(C)N
Reaction time: 1.5 h

Procedure:
Benzyl 2-methyl-4-(2-(2-(2-methoxyethoxy)ethoxy)ethylsulfonyl)butan-2-ylcarbamate (790 mg, 1.83 mmol) was dissolved in methanol (15 ml) and was purged with nitrogen. Palladium on carbon (10%, 40 mg) was added, and the suspension was put under a blanket of hydrogen (1.3 atmospheres). The suspension was stirred for 1.5 hours, filtered through a 0.45 um PTFE filter, and the solution concentrated in vacuo. The material was used without further purification. 1H NMR (400 MHz, CDCl3) δ 1.19 (s, 6H), 1.91 (m, 2H), 2.14 (s, 2H), 3.2-3.3 (m, 4H), 3.38 (s, 3H), 3.5-3.7 (m, 8H), 3.92 (m, 2H); LRMS (ESI/APCI) m/z 298 [M+H]+.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].C[CH2:21][N:22](C(C)C)[CH:23](C)C.CS(Cl)(=O)=O.CNC.C1COCC1>C(Cl)Cl>[CH3:21][N:22]([CH2:2][C:3]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[CH3:23]
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1ccc(-c2ccccc2C)c(CO)c1
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccccc2C)c(CN(C)C)c1
Reaction time: 0.42 h
Yield: 86.6 %

Procedure:
To a solution of methyl 2-(hydroxymethyl)-2′-methylbiphenyl-4-carboxylate (2.12 g, 8.27 mmol) in DCM (65 mL) was added DIEA (7.03 mL, 41.4 mmol) and methanesulfonyl chloride (768 μL, 9.93 mmol) at 0° C. and stirred for 25 min. After this time, a 2M solution of dimethylamine in THF (12.4 mL, 24.8 mmol) was added and the resulting mixture was stirred at RT for 16 hours. The reaction mixture was partitioned between DCM and a 5N aqueous solution of NaOH. The organic layer was dried (MgSO4) and concentrated under vacuum. A purification by chromatography (silica, DCM/MeOH) gave the title compound as a light yellow solid (2.03 g, 86%). 1H NMR (DMSO-d6) δ 8.27 (d, J=1.4 Hz, 1H), 7.95 (dd, J=7.8, 1.9 Hz, 1H), 7.32-7.18 (m, 4H), 7.06 (d, J=7.3 Hz, 1H), 3.94 (s, 3H), 3.24-3.10 (m, 2H), 2.11 (s, 6H), 2.01 (s, 3H). HPLC (Method A) Rt 2.90 min (Purity 100.0%). LC/MS (Method B): 284.1 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].[CH:17](I)([CH3:19])[CH3:18].[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH:10][CH:17]([CH3:19])[CH3:18])=[O:4]
Reactant: CC(C)I
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-c2ccccc2)cc1NC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
A DMF (15 mL) solution of 3-Amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (500 mg, 21.5 mmol) was cooled to 0° C. and then isopropyl iodide (2.57 mL) and NaH (60%, 775 mg, 32.3 mmol) were added under an atmosphere of N2. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 h. The mixture was partitioned between ether and water, the ether layer was separated, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate and hexane (5:95) as eluent to obtain 3-isopropylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester (189 mg, 32%) as a solid. 1H NMR (CDCl3, 400 MHz): 7.62 (d, 2H), 7.40 (m, 3H), 6.91 (s, 1H), 3.84 (s, 3H), 1.35 (d, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]([CH3:27])[C:6]1[CH:18]=[CH:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:19]CC4C=CC=CC=4)[CH:14]=3)[NH:9][C:8]=2[CH:7]=1)[CH3:2]>[Pd].C(O)C>[CH2:1]([O:3][C:4](=[O:28])[CH:5]([CH3:27])[C:6]1[CH:18]=[CH:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=3)[NH:9][C:8]=2[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)C(C)c1ccc2c(c1)[nH]c1ccc(OCc3ccccc3)cc12
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)c1ccc2c(c1)[nH]c1ccc(O)cc12
Yield: 90.5 %

Procedure:
A mixture consisting of 6-benzyloxy-α-methyl carbazole-2-acetic acid ethyl ester (7.3 g, 0.0195 mol) and ethanol (130 mL) is subjected to hydrogenation over 10% Pd/c (0.9 g) for 18 hours at 35 psi. The reaction mixture is filtered and concentrated to give 5.0 g product as a foam.