Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl.[NH:19]([CH2:21][C:22](OC)=[O:23])[CH3:20]>CN(C)C=O>[CH3:20][N:19]1[C:8](=[O:10])[C:3]2[N:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:22](=[O:23])[CH2:21]1
Reactant: Nc1cccnc1C(=O)O
Reactant: CNCC(=O)OC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CC(=O)Nc2cccnc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 5.18 g (37.5 mmol) of 3-aminopicolinic acid in 100 ml of dimethylformamide is treated with 6.20 g (38.2 mmol) of N,N'-carbonyldiimidazole and the mixture is stirred at room temperature for 1 hour. To the light brown solution obtained there are added 3.84 g (38 mmol) of triethylamine and 5.30 g (38 mmol) of methyl sarcosinate hydrochloride and the mixture is stirred at the boiling point for 6 hours. After removing the dimethylformamide in vacuo, the residue is crystallized from ethanol. There is obtained 3,4-dihydro-4-methyl-2H-pyrido[3,2-e][1,4]diazepine-2,5(1H)-dione of melting point 272°-274°.
Reaction SMILES: [C:1]([C:4]1[C:20]([O:21][CH2:22][C@@H:23]([NH2:28])[CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:19][C:7]2[N:8]([CH3:18])[C:9](=[O:17])[C:10]3[C:15]([C:6]=2[CH:5]=1)=[CH:14][CH:13]=[N:12][C:11]=3[CH3:16])(=[O:3])[CH3:2].[BH4-].[Na+]>C(O)C>[NH2:28][C@@H:23]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:22][O:21][C:20]1[C:4]([CH:1]([OH:3])[CH3:2])=[CH:5][C:6]2[C:15]3[C:10](=[C:11]([CH3:16])[N:12]=[CH:13][CH:14]=3)[C:9](=[O:17])[N:8]([CH3:18])[C:7]=2[CH:19]=1
Reactant: CC(=O)c1cc2c3ccnc(C)c3c(=O)n(C)c2cc1OC[C@@H](N)CC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@@H](N)CC(C)C)c(C(C)O)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.4 %

Procedure:
To a solution of (S)-9-acetyl-8-((2-amino-4-methylpentyl)oxy)-4,6 dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (100 mg, 0.257 mmol) in Ethanol (2 mL) was added NaBH4 (97 mg, 2.57 mmol) at 0° C. The reaction mixture was allowed to stir at RT for 16 h. Then, it was quenched with NH4Cl, diluted with water and extracted in ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated. The crude reaction mixture was purified by prep. HPLC which afforded 8-(((S)-2-amino-4-methylpentyl)oxy)-9-(1-hydroxyethyl)-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (0.03 g, 27% yield) as pale yellow semi-solid. LC/MS (ESI) m/e 384.1 [(M+H)+, calcd for C22H30N3O3, 384.2]; LC/MS retention time (method E): tR=0.73 min.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:25](=[O:28])(=[O:27])[NH2:26])[C:17]=1[S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=[O:31])C>OO>[CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:25](=[O:28])(=[O:27])[NH2:26])[C:17]=1[S:18]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:31])[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(NCc2ccccc2)c1Sc1ccccc1
Reactant: CC(=O)O
Agent: OO
Product: NS(=O)(=O)c1cc(C(=O)O)cc(NCc2ccccc2)c1S(=O)c1ccccc1

Procedure:
To a suspension of 3-benzylamino-4-phenylthio-5-sulphamyl-benzoic acid (0.8 g) in acetic acid (20 ml), perhydrol (1.5 ml of 30% hydrogen peroxide in water) was added while stirring. The reaction mixture was stirred for an additional 75 hours at room temperature, after which the 3-benzylamino-4-phenylsulphinyl-5-sulphamyl-benzoic acid was collected by filtration and washed with acetic acid. After recrystallization from aqueous methanol and drying, the acid had a melting point of 234°C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[CH2:6][CH2:5]2.[BH4-].[Na+]>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[CH:7]([OH:12])[CH2:6][CH2:5]2
Reactant: Cc1cc2c(cc1C)C(=O)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc2c(cc1C)C(O)CC2
Temperature: 45 °C
Yield: 106.6 %

Procedure:
A 1 L three-neck round bottom flask equipped with a condenser, mechanical stirrer, nitrogen inlet and a thermometer was charged with 5,6-dimethyl-1-indanone (21.65 g, 0.133 mol) and ethanol (450 mL). The mixture was heated with stirring to 45° C. and sodium borohydride (15.2 g, 0.40 mol) was added incrementally over 10 minutes. The reaction mixture was then heated at reflux for 18 hours, cooled, quenched in 5% HCl (1 L ice-water), and extracted with diethyl ether (500 mL). The organic phase was separated, washed with water (3×500 mL), dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure to yield 5,6-dimethyl-1-indanol (23.0 g) as an amber oil. 1HNMR (CD2Cl2, 500 MHz) δ7.12 (s, 1H); 7.01 (s, 1H); 4.81 (m, 1H); 2.95 (m, 1H); 2.72 (m, 1H); 2.28 (m, 1H); 2,26 (s, 3H); 2.23 (s, 3H).
Reaction SMILES: C(OC([NH:11][CH:12]([C:14]1[NH:18][C:17]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:16]=2[N:15]=1)[CH3:13])=O)C1C=CC=CC=1.[H][H]>CO.C(Cl)Cl.[Pd]>[Cl:23][C:21]1[CH:20]=[CH:19][C:17]2[N:18]=[C:14]([CH:12]([NH2:11])[CH3:13])[NH:15][C:16]=2[CH:22]=1
Reactant: CC(NC(=O)OCc1ccccc1)c1nc2cc(Cl)ccc2[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CC(N)c1nc2ccc(Cl)cc2[nH]1

Procedure:
5.00 g (contaminated) of rac.-N-benzyloxycarbonyl-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine is dissolved in a mixture of 100 mL of methanol and 40 mL methylene chloride, combined with 1.0 g palladium on charcoal, and hydrogenated for 1 hour at 3.4 bar hydrogen pressure. The solvents are distilled off and the crude product is purified by chromatography with silica gel (eluent: methylene chloride/ethanol=95:5+0.2% ammonia). Yield: 1.08 g (25% over 3 steps); Rf value: 0.37 (silica gel; dichloromethane/ethanol=4:1+2% ammonia); C9H10ClN3 (195.65); mass spectrum: (M+H)+=196/198 (chlorine isotope).
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:11]([CH2:12][OH:13])=[C:10]([Cl:14])[N:9]=[C:8]2[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:4][CH:3]=1.C[O-].[Na+].Br[CH2:25][C:26]1[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=1>CN(C=O)C>[C:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]([CH2:12][OH:13])=[C:10]([Cl:14])[N:9]=[C:8]2[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:19][CH:20]=1)#[N:33]
Reactant: N#Cc1ccccc1CBr
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(OCc2ccccc2C#N)cc1
Reaction time: 0.25 h
Yield: 54.7 %

Procedure:
To a solution of 1.00 g of 1-(4-hydroxybenzyl)-2-butyl-4-chloro-5-hydroxymethylimidazole in 15 mL of DMF at 25° was added 0.185 g of sodium methylate, and the resulting mixture was stirred at 25° for 0.25 hours. To this mixture was then added a solution of 0.80 g of α-bromo-o-tolunitrile in 5 mL of DMF. The reaction mixture was stirred at 25° for 16 hours. The solvent was removed in vacuo, and the residue dissolved in ethyl acetate. This solution was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Column chromatography on silica gel (elution: 10-25% ethyl acetate/benzene) provided 0.76 g of 1-[4-(2-cyanobenzyloxy)benzyl]-2-butyl-4-chloro-5-hydroxymethylimidazole; NMR (200 MHz, CDCl3): δ 7.73-7.59 (m, 3H); 7.44 (m, 1H); 6.96 (s, 4H); 5.23 (s, 2H); 5.14 (s, 2H); 4.50 (d, 2H); 2.57 (t, 2H); 1.66 (quint., 2H); 1.33 (sext., 2H); 0.87 (t, 3H).
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+].[Na+].ClC1C=CC=C(C(OO)=[O:16])C=1.[N:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:26]>C(Cl)Cl>[N+:19]1([O-:16])[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:26]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cccc(C)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccc(C)[n+]1[O-]
Reaction time: 18 h

Procedure:
Sodium sulphate (6 g) and a solution of m-chloroperbenzoic acid (40 g) in DCM (140 ml) was added to a solution of 2,6-lutidine (5 ml) in dry DCM (60 ml). The mixture was stirred at 23° and under a nitrogen atmosphere for 18 h; then it was quenched with a saturated aqueous sodium bicarbonate solution (200 ml). Then a solution of potassium carbonate was added and the aqueous phase was saturated with NaCl and then it was extract with DCM (3×100 ml). The organic extract was dried and concentrated in vacuo to a yellow oil which was purified by flash chromatography (eluting in gradient from EA to EA-MeOH 9:1) to give the title compound as a yellow oil (4.7 g).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Br:19][C:20]1[CH:21]=[C:22]([C:26](=[O:28])[CH3:27])[CH:23]=[N:24][CH:25]=1.C[Si](C)(C)[C:31]([F:34])([F:33])[F:32]>C1COCC1.O>[Br:19][C:20]1[CH:21]=[C:22]([C:26]([OH:28])([CH3:27])[C:31]([F:34])([F:33])[F:32])[CH:23]=[N:24][CH:25]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(=O)c1cncc(Br)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)(c1cncc(Br)c1)C(F)(F)F
Reaction time: 0.5 h

Procedure:
Tetrabutylammonium fluoride (1.0 M in THF, 33 μl, 0.033 mmol) was added to a solution of 1-(5-bromopyridin-3-yl)ethanone (65 mg, 0.33 mmol) and trimethyl(trifluoromethyl)silane (92 mg, 0.65 mmol) in THF (1.1 mL) at ambient temperature. After 30 minutes, the reaction mixture was diluted with water and extracted with DCM, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-30% ethyl acetate/hexanes, linear gradient) to afford 2-(5-bromopyridin-3-yl)-1,1,1-trifluoropropan-2-ol. MS ESI calc'd. for C8H8BrF3NO [M+H]+ 270 and 272. found 270 and 272. 1H NMR (500 MHz, CDCl3) δ 8.72 (s, 1H), 8.69 (d, J=2.5 Hz, 1H), 8.10-8.08 (m, 1H), 2.58 (s, 1H), 1.82 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[Cl:20][C:21]1[CH:37]=[CH:36][CH:35]=[CH:34][C:22]=1[CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O>>[Cl:20][C:21]1[CH:37]=[CH:36][CH:35]=[CH:34][C:22]=1[CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: OB(O)c1ccccc1OCc1ccccc1Cl
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccccc3OCc3ccccc3Cl)n2)c1

Procedure:
Example 27 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and {2-[(2-chlorobenzyl)oxy]phenyl}boronic acid (Aldrich Chemical Company Inc.). The batch was purified by preparative HPLC.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[CH2:14][CH2:15][NH2:16])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[NH:24]1[CH:28]=[C:27]([CH2:29][C:30](Cl)=[O:31])[N:26]=[CH:25]1>C(Cl)(Cl)Cl.O>[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[CH2:14][CH2:15][NH:16][C:30](=[O:31])[CH2:29][C:27]2[N:26]=[CH:25][NH:24][CH:28]=2)=[CH:6][CH:5]=1
Reactant: O=C(Cl)Cc1c[nH]cn1
Reactant: COc1ccc2cccc(CCN)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc2cccc(CCNC(=O)Cc3c[nH]cn3)c2c1
Temperature: 25 °C

Procedure:
0.01 mol of 2-(7-methoxynaphth-1-yl)ethylamine hydrochloride is dissolved in 60 ml of a chloroform/water mixture, and 0.025 mol of potassium carbonate is added under magnetic agitation. The mixture is cooled, and 0.012 mol of 4-imidazoleacetyl chloride hydrochloride is added dropwise. The agitation is maintained for 30 minutes at room temperature and the chloroform phase is evaporated to dryness. The residue is then recrystallized.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C[S:10]([CH3:12])=O.O>[Cl-].[Na+].O>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][S:10][C:12]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[NH2:1])[CH:3]=1
Reactant: CS(C)=O
Reactant: Nc1cccc(S)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Nc1cccc(SSc2cccc(N)c2)c1
Yield: 97.6 %

Procedure:
A solution of 3-aminobenzenethiol (0.85 mL, 8.0 mmol) in dimethyl sulfoxide (0.57 mL, 8.0 mmol) was heated at 85° C. for 4 h. The reaction mixture was poured into a solution of brine (25 mL) and water (25 mL) and extracted with ethyl acetate (100 mL). The organic layer was separated and washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to a crude oil. This material was purified by flash column chromatography to give the desired product (0.97 g, 98%) as a yellow oil. LCMS for C12H13N2S2 (M+H)+: m/z=249.0.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4](Cl)[N:3]=1.[O:25]1[CH2:30][CH2:29][C@@H:28]([NH2:31])[C@@H:27]([NH2:32])[CH2:26]1.CCN(C(C)C)C(C)C>C(#N)C>[NH2:32][C@@H:27]1[C@H:28]([NH:31][C:4]2[N:3]=[C:2]([Cl:1])[C:7]3[C:8](=[O:22])[N:9]([CH2:11][C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=4[O:20][CH3:21])[CH2:10][C:6]=3[C:5]=2[F:23])[CH2:29][CH2:30][O:25][CH2:26]1
Reactant: COc1ccc(CN2Cc3c(F)c(Cl)nc(Cl)c3C2=O)c(OC)c1
Reactant: N[C@@H]1CCOC[C@@H]1N
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCOC[C@@H]4N)nc(Cl)c3C2=O)c(OC)c1
Temperature: 85 °C
Reaction time: 72 h
Yield: 9.6 %

Procedure:
A mixture of 4,6-dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (2.5 g, 6.74 mmol), (3R,4R)-tetrahydro-2H-pyran-3,4-diamine (0.711 g, 6.12 mmol), and DIPEA (5.35 mL, 30.6 mmol) in ACN (30 mL) was stirred at 85° C. for 3 d in a sealed tube. Additional (3R,4R)-tetrahydro-2H-pyran-3,4-diamine (0.356 g, 3.06 mmol) and DIPEA (2.14 mL, 12.2 mmol) were added and the mixture was heated at 100° C. overnight. The mixture was concentrated and purified via preparative HPLC. The fractions corresponding to the desired regioisomer were collected to give the title compound (265 mg, 9.60%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.64-1.65 (m, 1H), 1.80-1.82 (s, 1H), 3.40 (td, J=11.47, 2.44 Hz, 1H), 3.53 (dd, J=11.23, 1.95 Hz, 1H), 3.67 (dd, J=11.47, 2.20 Hz, 1H), 3.71-3.73 (m, 1H), 3.75 (s, 3H), 3.77-3.79 (m, 1H), 3.81 (s, 3H), 4.09-4.11 (m, 1H), 4.33 (s, 2H), 4.50 (s, 2H), 6.48 (dd, J=8.30, 2.44 Hz, 1H), 6.58 (d, J=2.44, 1H), 6.90 (br s, 1H), 7.06 (d, J=8.30 Hz, 1H). [M+H] calc'd for C21H24ClFN4O4, 451. found, 451.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:34]=[CH:33][NH:32][CH:31]=3)[C@H:14]2[CH3:35])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[K+].I[CH:41]([CH3:43])[CH3:42].O>CS(C)=O>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:34]=[CH:33][N:32]([CH:41]([CH3:43])[CH3:42])[CH:31]=3)[C@H:14]2[CH3:35])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1cc[nH]c1
Reactant: CC(C)I
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)n1ccc(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Reaction time: 0.25 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(1H-pyrrol-3-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one (6.8 mg, 0.0127 mmol) (Example 120) in DMSO (300 μL) was added powdered KOH (3.6 mg, 0.0643 mmol). After stirring for 15 minutes, 2-iodopropane (3.2 μL, 0.032 mmol) was added. After 1.5 hours of stirring at room temperature, water (5 mL) was added, and the mixture was extracted, first with CH2Cl2 (2×15 mL) and then with EtOAc (2×15 mL). The combined organics were dried over Na2SO4, filtered, and concentrated. Purification of the residue by PTLC (25% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(1-isopropyl-1H-pyrrol-3-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.33 (25% EtOAc/hexanes). LCMS=579.2 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.85 (s, 1H), 7.71 (s, 2H), 7.61 (s, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 6.83 (t, J=2.1 Hz, 1H), 6.79 (t, J=2.5 Hz, 1H), 6.24 (t, J=2.3 Hz, 1H), 5.49 (d, J=8.0 Hz, 1H), 5.04 (d, J=15.5 Hz, 1H), 4.48 (d, J=15.6 Hz, 1H), 4.27 (m, 1H), 3.76 (m, 1H), 1.48 (d, J=6.6 Hz, 6H), 0.49 (d, J=6.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[I:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]2[CH:48]=[CH:47][C:46]([CH2:49][NH2:50])=[CH:45]2)=[CH:40][CH:39]=1.O>CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:50][CH2:49][C:46]2[CH:47]=[CH:48][N:44]([C:41]3[CH:42]=[CH:43][C:38]([I:37])=[CH:39][CH:40]=3)[CH:45]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: NCc1ccn(-c2ccc(I)cc2)c1
Reactant: O=C(O)c1ccc(Cl)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccn(-c2ccc(I)cc2)c1)c1ccc(Cl)s1
Reaction time: 0.17 h
Yield: 86 %

Procedure:
To a solution of 5-chloro-thiophene-2-carboxylic acid (60 mg, 0.37 mmol) and TEA (0.102 mL, 0.73 mmol) in DMF (4 mL) was added BOP (196 mg, 0.44 mmol). After 10 min of stirring, the solution was added to a sample of (1-(4-iodophenyl)-1H-pyrrol-3-yl)methanamine (91 mg, 0.31 mmol) in a flask. The mixture was stirred at room temperature overnight. H2O was added to induce precipitation. The resulting precipitate was collected and dried on vacuum to give 5-chloro-N-((1-(4-iodophenyl)-1H-pyrrol-3-yl)methyl)thiophene-2-carboxamide (118 mg).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[C:11]1[C:16]([O:17][CH2:18][CH3:19])=[CH:15][C:14]([C:20]2[C:25]([CH2:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:28][CH3:29])=[N:13][C:12]=1[CH3:30])C>C1COCC1.CCOCC>[CH2:28]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([CH2:26][CH3:27])[C:20]=1[C:14]1[N:13]=[C:12]([CH3:30])[C:11]([CH2:10][OH:9])=[C:16]([O:17][CH2:18][CH3:19])[CH:15]=1)[CH3:29]
Reactant: CCOC(=O)c1c(OCC)cc(-c2c(CC)cccc2CC)nc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOc1cc(-c2c(CC)cccc2CC)nc(C)c1CO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of LiAlH4 (1 M in THF, 20 mL) is added dropwise to a solution of 6-(2,6-diethyl-phenyl)-4-ethoxy-2-methyl-nicotinic acid ethyl ester (2.3 g, 6.7 mmol) in THF (20 mL). The reaction mixture is stirred at room temperature for 4 hours, diluted with ether (10 mL), and quenched with Na2SO4.10H2O (10 g). The resulting mixture is stirred for one hour, filtered through Celite, and concentrated in vacuo to give [6-(2,6-diethyl-phenyl)-4-ethoxy-2-methyl-pyridin-3-yl]-methanol.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:40]=[CH:39][C:18]([CH2:19][C:20]23[C:28](=[O:29])[N:27]([C:30]4[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[CH:31]=4)[C:26](=[O:38])[N:25]2[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:17][CH:16]=1)=[O:6]>CO.O>[C:5]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:16]=[CH:17][C:18]([CH2:19][C:20]23[C:28](=[O:29])[N:27]([C:30]4[CH:31]=[C:32]([Cl:37])[CH:33]=[C:34]([Cl:36])[CH:35]=4)[C:26](=[O:38])[N:25]2[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:39][CH:40]=1)([OH:6])=[O:4]
Reactant: COC(=O)CCc1ccccc1-c1ccc(CC23CCCCN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCc1ccccc1-c1ccc(CC23CCCCN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Reaction time: 18 h
Yield: 101.7 %

Procedure:
An aqueous solution of NaOH (2 mL; 0.5 N) was added to a solution of 6-[4-[2-(2-methoxycarbonylethyl)phenyl]benzyl]-8-(3,5-dichlorophenyl)-1,8-diazabicyclo[4.3.0]nonane-7,9-dione (0.11 g) in MeOH (7 mL) and the mixture was stirred for 18 hours. The reaction mixture was acidified, diluted with water and extracted with EtOAc. The extract was washed with water, brine, dried (MgSO4), filtered, and concentrated to give the titled compound (0.109 g). MS (m/z) 559 (M++Na).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH3:25][CH:26]1[CH2:35][CH2:34][CH2:33][C:32]2[C:31]([OH:36])=[CH:30][CH:29]=[CH:28][C:27]1=2>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:36][C:31]3[C:32]4[CH2:33][CH2:34][CH2:35][CH:26]([CH3:25])[C:27]=4[CH:28]=[CH:29][CH:30]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: CC1CCCc2c(O)cccc21
Product: CC1CCCc2c(Oc3nc(C(=O)NC(C)c4cc(F)c(NS(C)(=O)=O)c(F)c4)co3)cccc21
Yield: 85.2 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 5-methyl-5,6,7,8-tetrahydro-naphthalen-1-ol (43 mg, 0.26 mmol) to give the title compound (56 mg, 92%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [Cl:1][C:2]1[S:9][C:8]2[CH:7]=[C:6]([C:10]([NH:12][C@@H:13]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C@H:14]3[NH:22][CH3:23])=[O:11])[NH:5][C:4]=2[C:3]=1[Cl:24].C(N(CC)CC)C.[Cl:32][CH2:33][C:34](Cl)=[O:35]>C(Cl)Cl>[Cl:1][C:2]1[S:9][C:8]2[CH:7]=[C:6]([C:10]([NH:12][C@@H:13]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C@H:14]3[N:22]([C:34](=[O:35])[CH2:33][Cl:32])[CH3:23])=[O:11])[NH:5][C:4]=2[C:3]=1[Cl:24]
Reactant: CN[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)CCl)[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
2,3-Dichloro-N-[(1R,2R)-1-(methylamino)-2,3-dihydro-1H-inden-2-yl]-4H-thieno[3,2-b]pyrrole-5-carboxamide (Method 11; 300 mg, 0.79 mmol) and triethylamine (167 μL, 1.2 mmol) was dissolved in DCM (5 mL), chloroacetyl chloride (73 μL, 0.9 mmol) added and the reaction stirred at ambient temperature for 2 hours. The volatiles were removed by evaporation under reduced pressure and EtOAc (15 mL) added. The mixture was washed with water (10 mL), brine (10 ml), dried (MgSO4) and the volatiles were removed by evaporation under reduced pressure to give the title compound (310 mg, 86%) as a pale brown foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:13])[C:6]2[O:10][CH2:9][C:8](=[O:11])[C:7]=2[CH:12]=1.[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:5]1[C:6]2[O:10][CH2:9][C:8](=[O:11])[C:7]=2[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(C)c2c(c1)C(=O)CO2
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(CBr)c2c(c1)C(=O)CO2
Yield: 11.1 %

Procedure:
The synthesis was performed with reference to the known literature (Bioconjugate Chemistry, Vol. 18, p. 275, 2007). A solution of 5-methoxy-7-methylbenzofuran-3(2H)-one (0.25 g, 1.4 mmol) in carbon tetrachloride (15 mL) was successively added with N-bromosuccinimide (0.27 g, 1.5 mmol), and benzoyl peroxide (0.025 g, 0.070 mmol), and the mixture was refluxed for 2 hours by heating. The solid in the reaction mixture was removed by filtration, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (eluted with hexane/ethyl acetate (75:25)) to obtain 7-(bromomethyl)-5-methoxybenzofuran-3(2H)-one (0.040 g, 11%).
Reaction SMILES: [CH2:1]1[N:9]2[C:4](=[N:5][S:6](=[O:16])(=[O:15])[C:7]3[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:8]=32)[CH2:3][CH2:2]1.[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)=[O:20]>>[O:16]=[S:6]1(=[O:15])[C:7]2[CH:13]=[C:12]([O:14][C:25]3[CH:26]=[C:21]([CH:22]=[CH:23][CH:24]=3)[C:19]([O:18][CH3:17])=[O:20])[CH:11]=[CH:10][C:8]=2[N:9]2[CH2:1][CH2:2][CH2:3][C:4]2=[N:5]1
Reactant: O=S1(=O)N=C2CCCN2c2ccc(O)cc21
Reactant: COC(=O)c1cccc(B(O)O)c1
Product: COC(=O)c1cccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)c1

Procedure:
The procedure is as in Step B of Example 1, using the compound obtained in Step A of Example 1 and [3-(methoxycarbonyl)phenyl]boronic acid as starting materials.