Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([C:10]([OH:12])=[O:11])[C:7]([N+:13]([O-:15])=[O:14])=[CH:6][CH:5]=1)[CH3:2].[C:16](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([C:10]([O:12][CH3:16])=[O:11])[C:7]([N+:13]([O-:15])=[O:14])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc([N+](=O)[O-])c(C(=O)O)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOc1ccc([N+](=O)[O-])c(C(=O)OC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
A mixture of the compound prepared in Example 424 (1.8 g) in N,N-dimethylformamide (25 mL) was treated with potassium carbonate (1.76 g), followed by iodomethane (2.65 mL). The mixture was stirred at room temperature overnight. The solvent was concentrated in vacuo and the residue diluted with water, crude precipitated solids were collected by filtration, 2.14 g. These solids were taken in dichloromethane and purified by column chromatography on silica gel (5-25% ethyl acetate in hexanes) to provide the title compound (1.16 g) having the following physical data.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:16])[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[C:17]1([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:16][C:3]1([CH2:2][N:28]2[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:26][CH2:27]2)[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1
Reactant: c1ccc(CCN2CCNCC2)cc1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CBr)O2
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCN(CCc3ccccc3)CC1)O2
Yield: 50 %

Procedure:
Using 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine and 1-(2-phenylethyl)piperazine, the procedure of Example 1 was otherwise repeated to provide the title compound.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH2:21]([NH:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:21]([N:28]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CC(C)(C)NCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)N(Cc1ccccc1)C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with N-benzyl-2-methylpropan-2-amine (CAN 3378-72-1) in the presence of TBTU and DIEA to obtain the title compound as colorless solid; MS (EI): m/e=430.5 [MH+].
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[CH:4][C:5]2[C:6](=[O:14])[CH:7]3[CH2:13][CH2:12][CH2:11][CH:8]3[C:9]=2[CH:10]=1.S([O-])([O-])(=O)=O.O[NH3+:24].O[NH3+].C([O-])(=O)C.[Na+]>C1COCC1.C(O)C.O>[CH3:1][C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[CH:4][C:5]2[NH:24][C:6](=[O:14])[CH:7]3[CH2:13][CH2:12][CH2:11][CH:8]3[C:9]=2[CH:10]=1.[N+:15]([C:3]1[CH:2]=[CH:10][C:9]2[CH:8]3[CH2:11][CH2:12][CH2:13][CH:7]3[C:6](=[O:14])[NH:24][C:5]=2[CH:4]=1)([O-:17])=[O:16]
Reactant: [NH3+]O
Reactant: Cc1cc2c(cc1[N+](=O)[O-])C(=O)C1CCCC21
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc2c(cc1[N+](=O)[O-])NC(=O)C1CCCC21
Product: O=C1Nc2cc([N+](=O)[O-])ccc2C2CCCC12
Temperature: 60 °C
Reaction time: 6 h

Procedure:
The mixture that consists of 6-nitro-2,3,3a,8a-tetrahydro-1H-cyclopentta]inden-8-one and 5-methyl-6-nitro-2,3,3a,8a-tetrahydro-1H-cyclopent[a]inden-8-one (3.76 g) is dissolved with hydroxylammonium sulfate (5.58 g, 34 mmol) and sodium acetate (9.25 g, 68 mmol) in THF-ethanol-water 1:1:1 (180 ml). The batch is stirred for 6 hours at 60° C., left for three days at room temperature, concentrated by evaporation, diluted with ether, washed with saturated NaCl, dried (Na2SO4) and concentrated by evaporation in a vacuum. The residue is purified on silica gel with the eluant ether-hexane. Yield: 3.76 g; the oxime mixture is dissolved at 120° C. in polyphosphoric acid. The batch is stirred for four hours at 120° C., it is poured onto ice water after cooling and extracted with ethyl acetate. The combined extracts are dried (Na2SO4) and concentrated by evaporation in a vacuum. The residue is prepurified on silica gel with ethyl acetate-hexane, and the mixture is then separated using preparative HPLC (LC.50 Novapak column, eluant: methanol-aqueous ammonium acetate solution):
Reaction SMILES: P(N)([O-])[O-].[CH3:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[CH2:12])=[CH:9][CH:8]=1.[C:15]1(=[O:21])[CH2:20][CH2:19][CH2:18][CH:17]=[CH:16]1.C[Si](Cl)(C)C>CCOCC.C(Cl)Cl.[Cu].C1C=CC=CC=1>[CH3:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][CH2:12][C@H:17]2[CH2:18][CH2:19][CH2:20][C:15](=[O:21])[CH2:16]2)=[CH:9][CH:8]=1
Reactant: O=C1C=CCCC1
Reactant: C=Cc1ccc(OC)cc1
Agent: [Cu]
Agent: C[Si](C)(C)Cl
Agent: NP([O-])[O-]
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(CC[C@H]2CCCC(=O)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
(C6H6) (10.1 mg, 0.02 mmol, 0.05 eq.) and the phosphoramidite ligand (21.6 mg, 0.040 mmol, 0.10 eq.) were dissolved in Et2O (2.0 mL) under an argon atmosphere and allowed to stir for 1 h at room temperature. In another flask, Cp2ZrHCl (206.0 mg, 0.80 mmol, 2.0 eq.) was added to a stirred, room temperature, solution of 4-methoxystyrene (0.13 mL, 1.0 mmol, 2.5 eq.) in CH2Cl2 (0.40 mL) under an argon atmosphere. After stirring for 15 min, the resulting clear red/orange solution was transferred via syringe over about 1 min to the stirred solution containing the copper and ligand under an argon atmosphere. The resulting black mixture was allowed to stir for an additional 10 minutes before cyclohexenone (39 μL, 0.40 mmol, 1.0 eq) and then TMSCl (0.26 mL, 2.0 mmol, 5.0 eq.) were added dropwise via syringe. Stirring continued at room temperature for 4 h before the reaction was quenched by the addition of Et2O (ca 3 mL) and then NH4Cl (1M aq., ca 1.5 mL). The mixture was partitioned between the aqueous and Et2O layers and the aqueous phase extracted with Et2O (3×10 mL). The combined organic phase was washed with NaHCO3 (aq. sat., ca 10 mL), dried (Na2SO4), filtered and concentrated in vacuo. Flash column chromatography of the yellow residue (1:9 EtOAc/petrol; SiO2) gave (R)-3-(4-methoxyphenethyl)cyclohexanone (45 mg, 0.19 mmol, 48%) as a colourless oil. HPLC analysis indicated an enantiomeric excess of 90% [Chiralpak® IA; flow: 1 mL/min; hexane/i-PrOH: 90:10; λ=210 nm; minor enantiomer (S)-3-(4-methoxyphenethyl)-cyclohexanone, tR=11.4 minutes; major enantiomer (R)-3-(4-methoxyphenethyl)-cyclohexanone, tR=12.2 minutes]. 1H NMR (500 MHz, CDCl3) δH/ppm 1.33-1.44 (m, 1H) 1.55-1.71 (m, 3H) 1.81 (apparent tspt, J=11.03, 3.50 Hz, 1H) 1.92-1.99 (m, 1H) 2.02-2.10 (m, 2H) 2.27 (dddd, J=13.70, 12.50, 6.50, 1.40 Hz, 1H) 2.33-2.40 (m, 1H) 2.48 (ddt, J=13.75, 4.14, 1.93, 1.93 Hz, 1H) 2.58 (t, J=8.04 Hz, 2H) 3.79 (s, 3H) 6.83 (d, J=8.83 Hz, 2H) 7.09 (d, J=8.80 Hz, 2H); 13C NMR (126 MHz, CDCl3) δC/ppm 25.2, 31.2, 32.0, 38.4, 38.6, 41.5, 48.0, 55.2, 113.8 (2C), 129.1 (2C), 134.0, 157.8, 211.8; HRMS (ESI) m/z calcd for C16H20NaO2 [M+Na]+: 255.1356 found: 255.1349; [α]24589=−20.1 (c 1.03, CHCl3); IR (vmax/cm−1): 1710, 2933.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]1[C@H:13]([C:14]2[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=2[F:22])[CH2:12][CH2:11][C:10]([O:23][Si](C(C)C)(C(C)C)C(C)C)=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(C)C>O1CCCC1.CCCCCCC>[O:23]=[C:10]1[CH2:9][C@H:8]([NH:7][C:6](=[O:34])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C@@H:13]([C:14]2[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=2[F:22])[CH2:12][CH2:11]1
Reactant: CC(C)[Si](OC1=C[C@@H](NC(=O)OC(C)(C)C)[C@H](c2cc(F)c(F)cc2F)CC1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCCCC
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC(=O)CC[C@@H]1c1cc(F)c(F)cc1F
Reaction time: 1 h

Procedure:
To a round-bottomed flask (500 mL) containing trans tert-butyl(6-(2,4,5-trifluorophenyl)-3-[(triisopropylsilyl)oxy]cyclohex-2-en-1-yl)carbamate (10.7 g) dissolved in tetrahydrofuran (100 mL), tetrabutylammonium fluoride (1M in tetrahydrofuran, 26 mL) was added and the mixture was stirred for 1 h. The solution was concentrated to a dark brown oil and purified by chromatography (silica gel, gradient 20%-40% ethyl acetate in hexane) to yield the product as a mixture of enantiomers. HPLC using a chiral AD column (12% isopropanol in heptane) gave the title compound as the slower eluting isomer. LC/MS 227.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12](C=O)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc(N2CCN(C=O)CC2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cccc(N2CCNCC2)n1
Temperature: 0 °C
Yield: 83 %

Procedure:
A mixture of the formamide intermediate, prepared above, (3.55 g) in 6 N HCl (30 mL) was heated at reflux for 1/2 h. The reaction was cooled to 0° C., made basic with 10N NaOH, and extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with sat. NaCl solution, dried with anhydrous K2CO3, filtered, and concentrat.ed under reduced pressure to afford 1-(6-methoxy-2-pyridinyl)piperazine (2.72 g; 83%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:12])[CH:8]=[C:7]([CH3:20])[C:3]=1[C:4]([OH:6])=[O:5].[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:33][CH2:34][CH3:35])[C:31]=1[F:32])[CH:27]=O)[CH3:22].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:33][CH2:34][CH3:35])[C:31]=1[F:32])[CH2:27][N:17]1[CH2:16][CH2:15][CH:14]([NH:13][C:11](=[O:12])[C:9]2[CH:10]=[C:2]([CH3:1])[C:3]([C:4]([OH:6])=[O:5])=[C:7]([CH3:20])[CH:8]=2)[CH2:19][CH2:18]1)[CH3:22]
Reactant: Cc1cc(C(=O)NC2CCNCC2)cc(C)c1C(=O)O
Reactant: CCOc1cc(C=O)cc(OCC)c1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CCO
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(C)c(C(=O)O)c(C)c3)CC2)cc(OCC)c1F

Procedure:
In analogy to the procedure described in example 50k), 2,6-dimethyl-N-piperidin-4-yl-terephthalamic acid (example 126b) was reacted with 3,5-diethoxy-4-fluoro-benzaldehyde (example 50 g), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless solid. MS: 472.9 (MH+).
Reaction SMILES: [H-].[Na+].[N:3]1([C:10]2[C:19]3[C:14](=[CH:15][C:16]([CH2:20][OH:21])=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:22])[CH:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:24][CH2:25][O:26][CH3:27]>CN(C)C=O>[N:3]1([C:10]2[C:19]3[C:14](=[CH:15][C:16]([CH2:20][O:21][CH2:24][CH2:25][O:26][CH3:27])=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:22])[CH:11]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: COCCBr
Reactant: Cc1cc(N2CCCCCC2)c2ccc(CO)cc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCc1ccc2c(N3CCCCCC3)cc(C)nc2c1
Reaction time: 22 h
Yield: 32 %

Procedure:
Sodium hydride (55–65% dispersion in mineral oil, 10 mg, 0.25 mmol) was added to a solution of (4-azepan-1-yl-2-methyl-quinolin-7-yl)-methanol (example 3, 50 mg, 0.19 mmol) and 1-bromo-2-methoxy-ethane (15 mg, 0.19 mmol) in N,N-dimethylformamide (2 mL). After 22 h at 50° C., another portion of sodium hydride (10 mg) and 1-bromo-2-methoxyethane (15 mg) was added, and stirring was continued for 16 h. Then the reaction mixture was partitioned between 1 M aq. sodium carbonate solution and ethyl acetate. The organic layer was separated washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, dichloromethane/methanol 9:1) yielded the title compound (20 mg, 33%). Yellow oil, ISP-MS: m/e=329.4 ([M+H]+).
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH3:24])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]1([CH:31]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:32]2[CH2:35][C:34](=O)[CH2:33]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[C:25]1([CH:31]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:32]2[CH2:35][C:34](=[CH:20][C:21]([O:23][CH3:24])=[O:22])[CH2:33]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C=C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
Methyl (triphenylphosphoranylidene)acetate (2.77 g, 8.29 mmol) was added to a mixture of 1-(diphenylmethyl)azetidin-3-one (1.64 g, 6.91 mmol) in THF (24 mL) and the resultant mixture was left to stir overnight. The mixture was concentrated under vacuum, then the residue was dissolved in hot 1:4 EtOAc/heptane (40 mL) and allowed to cool to room temperature. The resultant solid was filtered off and the filtrate was concentrated under vacuum. The crude residue was purified by FCC, eluting with 20% EtOAc in heptane, to afford the title compound (917 mg, 44%) as a pale yellow solid. Method B HPLC-MS: MH+ m/z 294, RT 1.43 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:14](O)=[O:15])=[CH:13][C:8]=3[O:7][C:6]=2[CH:17]=1.B>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12]([CH2:14][OH:15])=[CH:13][C:8]=3[O:7][C:6]=2[CH:17]=1
Reactant: O=C(O)c1ccc2c(c1)oc1cc(Br)ccc12
Agent: B
Solvent: C1CCOC1
Product: OCc1ccc2c(c1)oc1cc(Br)ccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.7 %

Procedure:
A cloudy solution of 3-bromo-dibenzofuran-7-carboxylic acid (3.2 g, 10.9 mmol) in 80 ml THF was cooled to 0° C. and a solution of borane in THF (1.0M, 13.0 ml, 13.0 mmol) was added dropwise. The cooling bath was removed and the reaction was stirred at room temperature for 20 hours and was then quenched by the cautious addition of methanol (10 ml). The solution was evaporated to dryness in vacuo and the residue was dissolved in methanol--CH2Cl2 (1:1) and again evaporated. After one repetition of this dissolution-evaporation process, 2.74 g (90%) of the title compound was obtained as a brown solid and used in the next reaction without purification.
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[CH2:3][CH:4]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][N:23]=1)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Li+].[OH-].Cl>O.O1CCCC1>[CH3:1][CH:2]([CH3:32])[CH2:3][CH:4]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][N:23]=1)[NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(C(CC(C)C)Nc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC(Nc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
Methyl 6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-ylamino)butyl)nicotinate (190 mg, 0.429 mmol) was dissolved in water (3 mL) and tetrahydrofuran (3 mL). 1N LiOH (54.0 mg, 1.29 mmol) was added. The reaction was stirred at room temperature for 2 hours. The reaction was neutralized with 1N HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated to give 6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-ylamino)butyl)nicotinic acid (180 mg, 98%) as a yellow solid. 1H NMR (400 MHz, CD3OD, δ): 9.08 (s, 1H), 8.25 (d, 1H), 7.59-7.63 (m, 5H), 7.38 (d, 2H), 6.63 (d, 2H), 4.65 (m, 1H), 1.85 (m, 2H), 1.65 (m, 1H), 1.00 (m, 6H).
Reaction SMILES: [BH4-].[CH2:2]([C:9]1[N:10]([CH3:15])[C:11]([SH:14])=[N:12][N:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:16][O:17][C:18](=[O:43])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31](I)=[CH:30][C:29]=2[O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:22][CH:21]=1>O1CCCC1.C(O)C>[CH3:16][O:17][C:18](=[O:43])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([S:14][C:11]3[N:10]([CH3:15])[C:9]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[N:13][N:12]=3)=[CH:30][C:29]=2[O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:24][CH:25]=1
Reactant: CCCCCCCc1nnc(S)n1C
Reactant: CCCCCCCOc1cc(I)ccc1COc1ccc(CC(=O)OC)cc1
Agent: [BH4-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCCOc1cc(Sc2nnc(CCCCCCC)n2C)ccc1COc1ccc(CC(=O)OC)cc1
Reaction time: 8 h

Procedure:
979 mg (2.45 mmol, 3 eq) of resin-supported borohydride and 11 mg (0.02 mmol, 0.03 eq) of bis(bipyridine)dibromonickel (II) are added to a solution of 244 mg (1.22 mmol, 1.5 eq) of 5-heptyl-4-methyl-4H-[1,2,4]-triazole-3-thiol in 4 ml of tetrahydrofuran/ethanol 5/5. To the suspension obtained there is added a solution of 405 mg (0.82 mmol, 1 eq) of [4-(2-heptyloxy-4-iodobenzyloxy)phenyl]acetic acid methyl ester in 4 ml of tetrahydrofuran/ethanol 5/5. The reaction mixture is stirred overnight under reflux. After returning to room temperature, the reaction medium is filtered and then concentrated. The residue is chromatographed on silica gel (heptane/ethyl acetate: gradient from 70/30 to 50/50). After concentration, 427 mg (92%) of the expected compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][S:9][CH2:10][CH2:11][NH2:12])=[N:4][CH:5]=[CH:6][CH:7]=1.CS[C:15](=[N:20][CH3:21])[S:16]([O-:19])(=[O:18])=[O:17]>C(#N)C>[Cl:1][C:2]1[C:3]([CH2:8][S:9][CH2:10][CH2:11][NH:12][C:15]([S:16]([OH:19])(=[O:17])=[O:18])=[N:20][CH2:21][CH2:10][S:9][CH2:8][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCSCc1ncccc1Cl
Reactant: CN=C(SC)S(=O)(=O)[O-]
Solvent: CC#N
Product: O=S(=O)(O)C(=NCCSCc1ncccc1Cl)NCCSCc1ncccc1Cl
Reaction time: 1 h

Procedure:
A solution of 2-(3-chloropyrid-2 ylmethylthio)ethylamine (4.06 g) in dry acetonitrile (200 ml) was added dropwise, with stirring, to a solution of 1-methylthio-1-methyliminomethanesulphonate (1.69 g) in dry acetonitrile (150 ml) at 50°. The mixture was stired at 60° for 1 hour and then allowed to cool. The mixture was evaporated to dryness, dissolved in methanol and absorbed onto silica gel. Chromatography on a column of silica gel produced a viscous oil which was collected by eluting the column with a chloroform/methanol mixture and evaporating off the solvent. The viscous oil analysed by microanalysis and nuclear magnetic resonance spectroscopy to the title compound.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16]2.[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[CH2:30]([CH:16]1[C:15]2[C:19](=[CH:20][CH:21]=[C:13]([O:12][CH3:11])[CH:14]=2)[C:18](=[O:22])[N:17]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COc1ccc2c(c1)CN(C(=O)OC(C)(C)C)C2=O
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(Cc1ccccc1)N(C(=O)OC(C)(C)C)C2=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
Lithium bis(trimethysilyl)amide (4.8 mL, 4.8 mmol, 1 M in THF) was added to a solution of the tert-butyl 5-methoxy-1-oxoisoindoline-2-carboxylate (0.975 g) in THF (7 mL) at −78° C. After stirring the solution at −78° C. for 1 hr, benzyl bromide (0.88 mL, 7.41 mmol) was added, this was stirred at −78° C. for 1.5 hours. LC/MS showed complete conversion. Quenched the reaction mixture with saturated NaCl solution, then extracted with ethyl acetate, the combined organic layer was washed 1× with saturated NaCl solution. The organic phase was dried on Na2SO4 and the solvent was evaporated. The residue was purified by flash-chromatography on silica gel with 25-40% ethyl acetate in hexane, 0.92 g (2.59 mmol, 70%) of the product was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:18]2[CH2:22][C@H:21]([CH2:23][OH:24])[O:20][C:19]2=[O:25])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][F:16])[C:10](=[O:17])[CH2:9]1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:18]2[CH2:22][C@H:21]([CH2:23][O:24][S:34]([CH3:33])(=[O:36])=[O:35])[O:20][C:19]2=[O:25])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][F:16])[C:10](=[O:17])[CH2:9]1
Reactant: O=C1CN(c2ccc(N3C[C@H](CO)OC3=O)cc2F)CCN1CCF
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CS(=O)(=O)OC[C@H]1CN(c2ccc(N3CCN(CCF)C(=O)C3)c(F)c2)C(=O)O1
Reaction time: 2 h

Procedure:
(5R)-3-(3-Fluoro-4-[4-(2-fluoroethyl)-3-oxopiperazin-1-yl]phenyl)-5-hydroxymethyloxazolidin-2-one (0.8 g) is dissolved in pyridine (15 ml) and the mixture cooled to 0°. Triethylamine (0.38 ml) and methanesulfonyl chloride (0.19 ml) are added to the mixture, and stirring continued at 20–25° for 2 hours. The solvent is removed and the residue dissolved in dichloromethane, washed with water, saline, dried over magnesium sulfate and concentrated. The resulting residue is triturated with ether to give (5R)-3-(3-fluoro-4-[4-(2-fluoroethyl)-3-oxopiperazin-1-yl]phenyl)-5-(methanesulfonyloxymethyl)oxazolidin-2-one (0.76 g) which is used without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.[Cl:15][C:16]([Cl:27])([Cl:26])[C:17]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:18]=1[CH2:19]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][N:2]([CH2:19][C:18]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:17]=1[C:16]([Cl:26])([Cl:15])[Cl:27])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:8]=1
Reactant: Clc1ccc(C(Cl)(Cl)Cl)c(CBr)c1
Reactant: CCOC(=O)Cc1ccc(NC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)Cc1ccc(N(C)Cc2cc(Cl)ccc2C(Cl)(Cl)Cl)cc1
Yield: 49.8 %

Procedure:
N-methyl-4-ethoxycarbonylmethylaniline (5.8 g) and 2-trichloromethyl-5-chlorobenzylbromide (9.7 g) were dissolved in acetone (50 g), and anhydrous potassium carbonate (4.2 g) was added to the solution. The mixture was heated for 3 days with stirring. Then, the inorganic material was removed by filtration, and the solvent was distilled off. The residue was purified by liquid chromatography using a silica gel column to obtain N-methyl-N-(2-trichloromethyl-5-chlorobenzyl)-4-ethoxycarbonylmethylaniline (6.5 g).
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH:7]([N:13]2[C:17]3[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:16]=3[N:15]=[CH:14]2)[CH2:8][C:9]([O:11]C)=[O:10])=[CH:3][CH:2]=1>Cl>[C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:2]=[CH:3][C:4]([CH:7]([N:13]2[C:17]3[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:16]=3[N:15]=[CH:14]2)[CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:6]=1
Reactant: COC(=O)CC(c1ccc(-c2ccccc2)cc1)n1cnc2cc([N+](=O)[O-])ccc21
Agent: Cl
Product: O=C(O)CC(c1ccc(-c2ccccc2)cc1)n1cnc2cc([N+](=O)[O-])ccc21

Procedure:
A solution of methyl 3-(1,1′-biphenyl)-4-yl-3-(5-nitro-1H-benzimidazol-1-yl)propanoate (21 mg, 52 μmol) in hydrochloric acid (10 mL of a 5N solution) was stirred at room temperature for 48 hours. The solution was evaporated in vacuo to afford the title compound, [LCMS (Method A, Mobile Phase I) RT=5.63 min, MH+ 388].