Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:13]([NH2:38])[CH2:14][NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=2[C:27]2[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[CH:30]=[CH:29][C:28]=2[O:36][CH3:37])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCN(C(C)C)C(C)C.Cl[C:51](Cl)([O:53]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]([F:39])([F:40])[C:3]1[CH:4]=[C:5]([CH:13]2[CH2:14][N:15]([CH2:16][C:17]3[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[CH:19][C:18]=3[C:27]3[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[CH:30]=[CH:29][C:28]=3[O:36][CH3:37])[C:51](=[O:53])[NH:38]2)[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNCC(N)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1CC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)NC1=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of 1-[3,5-bis(trifluoromethyl)phenyl]-N2-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}ethane-1,2-diamine (125.2 mg, 0.217 mmol) in CH2Cl2 (30 mL) was cooled to 0° C. and DIPEA (227 μL, 1.30 mmol) was added. Next, triphosgene (32.2 mg, 0.109 mmol) was added. The reaction was stirred at 0° C. for 45 minutes and then poured into saturated NaHCO3 (20 mL). The mixture was extracted with EtOAc (100 mL) and the organic layer was washed with brine (25 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography with 40% EtOAc/hexanes to afford 4-[3,5-bis(trifluoromethyl)phenyl]-1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}imidazolidin-2-one. Rf=0.22 (40% EtOAc/hexane). LCMS=605.2 (M+1)+. 1H NMR (CDCl3, 500 MHz) (atropisomers present in 1:1 ratio; doubling of some peaks observed) δ 7.83 (s, 1H), 7.78 (s, 2H), 7.55-7.62 (m, 2H), 7.32 (d, J=7.8 Hz, 1H), 7.22 (m, 1H), 6.94 (s, 1H), 6.88 (d, J=8.3 Hz, 1H), 5.33 & 5.24 (2 singlets, 1H), 4.80-4.88 (m, 1H), 4.00-4.61 (m, 2H), 3.72 & 3.70 (2 singlets, 3H), 3.55-3.59 (m, 1H), 2.83-2.93 (m, 2H), 1.17-1.23 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12](Cl)[N:13]=1)[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6].[CH3:15][O-:16].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([O:16][CH3:15])[N:13]=1)[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6]
Reactant: C[O-]
Reactant: O=C(NC1CC1)c1cc(Cl)nc(Cl)c1
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(=O)NC2CC2)cc(Cl)n1
Temperature: 105 °C

Procedure:
To a solution of 2,6-dichloro-N-cyclopropylisonicotinamide from the previous step (1 eq.) in methanol (0.2 M) was added sodium methoxide (6 eq.). The reaction vessel was sealed and the resulting solution was heated in the microwave at 105° C. for 30 min. The volatiles were removed in vacuo and the resulting residue was partitioned between sat. aq. NH4Cl and EtOAc. The organic layer was separated and washed further with brine. Drying over Na2SO4, filtration and concentration of the filtrate in vacuo afforded the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[C:6]([C:15]2[CH:16]=[C:17]([O:23][CH3:24])[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=2)=[N:7][C:8](S(C)(=O)=O)=[N:9][CH:10]=1.[CH2:30]([S:32]([NH2:35])(=[O:34])=[O:33])[CH3:31]>>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[C:6]([C:15]2[CH:16]=[C:17]([O:23][CH3:24])[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=2)=[N:7][C:8]([NH:35][S:32]([CH2:30][CH3:31])(=[O:34])=[O:33])=[N:9][CH:10]=1
Reactant: CCS(N)(=O)=O
Reactant: COc1cc(-c2nc(S(C)(=O)=O)ncc2Oc2ccc(F)cc2F)cn(C)c1=O
Product: CCS(=O)(=O)Nc1ncc(Oc2ccc(F)cc2F)c(-c2cc(OC)c(=O)n(C)c2)n1

Procedure:
The title compound of Example 150 was treated with EtSO2NH2 instead of MeSO2NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.35 (d, J=2.0 Hz, 1H), 8.18 (s, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.25-7.22 (m, 1H), 7.12-7.07 (m, 1H), 7.04-7.01 (m, 1H), 3.93 (s, 3H), 3.70 (s, 3H), 3.38 (s, 3H). LCMS: 423.9 (M+1)+
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH:11]1[C:17]2=[CH:18][NH:19][C:20]3[CH:21]=[CH:22][CH:23]=[C:15]([C:16]=32)[C:14](=[O:24])[NH:13][CH2:12]1)C)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:1][NH:8][CH2:10][CH:11]1[C:17]2=[CH:18][NH:19][C:20]3[CH:21]=[CH:22][CH:23]=[C:15]([C:16]=32)[C:14](=[O:24])[NH:13][CH2:12]1
Reactant: [H][H]
Reactant: CN(Cc1ccccc1)CC1CNC(=O)c2cccc3[nH]cc1c23
Agent: [Pd]
Solvent: CO
Product: CNCC1CNC(=O)c2cccc3[nH]cc1c23
Yield: 52.7 %

Procedure:
2.38 g of 3-(N-benzyl-N-methylaminomethyl)-3,4,5,6-tetrahydro-6-oxo-1H-azepino[5,4,3-cd]indole (see Example 3 for preparation) were dissolved in 150 ml of methanol. A spatula tip of a palladium/carbon catalyst (10%) was added to the solution under a stream of nitrogen. The mixture was subsequently hydrogenated in an autoclave under a hydrogen pressure of 3.5 bar at a temperature of 50° C. while stirring. After 3 hours the hydrogen was discharged, the reaction mixture was flushed with nitrogen and the catalyst was filtered out. The remaining solution was evaporated and the oily crude product remaining as residue was purified by low pressure chromatography on silica gel using methanol/25% strength aqueous ammonia solution 96:4 as eluent. 0.9 g of 3-methylaminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino[5,4,3-cd]indole was obtained as a foam-like product.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]([OH:16])[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:17]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[CH2:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]([OH:16])[C:11]=1[I:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1cc(COCc2ccccc2)ncn1
Solvent: ClC(Cl)Cl
Product: Oc1ncnc(COCc2ccccc2)c1I
Yield: 91.9 %

Procedure:
A solution of 6-benzyloxymethyl-4-hydroxy-pyrimidine (4.55 g, 20.87 mmol) and N-iodosuccinimide (5.165 g, 23 mmol) in chloroform (250 ml) was kept at reflux under argon for 2 h. The solution was washed with water, 0.5 N sodium thiosulfate, and brine. After drying (MgSO4), filtration and concentration gave a white solid (6.56 g, 91%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]Br.[S:8]([O-:11])([O-:10])=[O:9].[Na+:12].[Na+].C(O)C.BrCCS([O-])(=O)=O.[Na+]>O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:8]([O-:11])(=[O:10])=[O:9].[Na+:12]
Reactant: O=S([O-])[O-]
Reactant: BrCCCCCBr
Agent: O=S(=O)([O-])CCBr
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=S(=O)([O-])CCCCCBr

Procedure:
1,5-Dibromopentane (16.4 g, 71 mmol), sodium sulfite (3 g, 24 mmol), ethanol (25 mL) and water (20 mL) were reacted and worked up analogously to sodium 2-bromoethane sulfonate. Yield: 7.4 g (41%) colorless solid. IR (ATR): {tilde over (ν)}=3485 (m), 3411 (w), 2978 (w), 2930 (m), 2908 (w), 2895 (w), 2867 (w), 2851 (w), 1636 (w), 1616 (w), 1487 (w), 1466 (m), 1410 (w), 1390 (w), 1329 (w), 1314 (w), 1293 (w), 1262 (w), 1224 (m), 1207 (s), 1180 (s), 1044 (s), 988 (w), 938 (w), 823 (w), 804 (w), 792 (w), 729 (w), 618 cm−1 (w). HRMS (ESI) (C5H11BrNaO3S+): calculated 252.9504. found 252.9820, Δ=31.6 mmu.
Reaction SMILES: O[CH:2](C)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=1.S(=O)(=O)(O)O.F[C:25](F)(F)[C:26]([OH:28])=[O:27]>O>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C:7]1[CH:8]=[CH:9][C:4]([CH:3]([CH3:2])[CH2:25][C:26]([OH:28])=[O:27])=[CH:5][CH:6]=1
Reactant: CC(O)Cc1ccc(-c2ccc(F)cc2F)cc1
Reactant: O=C(O)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1
Reaction time: 0.33 h

Procedure:
4 ml. of formic acid are added over 20 minutes to a solution of 2.3 g. of 4-(2-propneyl)-2',4'-difluorobiphenyl, obtained by eliminating water from 4-(2-hydroxypropyl)-2',4'-difluorobiphenyl with polyphosphoric acid, in a mixture of 12 ml. of sulfuric acid and 8 ml. of trifluoroacetic acid. After 20 minutes more, the mixture is poured into water to give 3-(2',4'-difluoro-4-biphenylyl)butyric acid, m.p. 109°-110°.
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[CH3:10][O:11][C:12](=[O:22])/[C:13](/I)=[CH:14]\[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:42][C:43]1[CH:48]=[C:47](I)[CH:46]=[CH:45][C:44]=1[N:50]1[C:54]([CH3:55])=[N:53][N:52]=[N:51]1.[Cl-].[NH4+]>O1CCCC1.[Zn].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]>[CH3:10][O:11][C:12](=[O:22])/[C:13](/[C:47]1[CH:46]=[CH:45][C:44]([N:50]2[C:54]([CH3:55])=[N:53][N:52]=[N:51]2)=[C:43]([Cl:42])[CH:48]=1)=[CH:14]/[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)/C(I)=C\C1CCCCC1
Reactant: Cc1nnnn1-c1ccc(I)cc1Cl
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COC(=O)/C(=C/C1CCCCC1)c1ccc(-n2nnnc2C)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.6 %

Procedure:
A mixture of zinc dust (320 mg, 5 mmol, Aldrich, −325 mesh) and dry tetrahydrofuran (1 mL) under argon was treated with 1,2-dibromoethane (94 mg, 0.5 mmol). The zinc suspension was then heated with a heat gun to ebullition, allowed to cool, and heated again. This process was repeated three times to make sure the zinc dust was activated. The activated zinc dust suspension was then treated with trimethylsilyl chloride (55 mg, 0.5 mmol), and the suspension was stirred for 15 min at 25° C. The reaction mixture was then treated dropwise with a solution of (E)-3-cyclohexyl-2-iodo-acrylic acid methyl ester (588 mg, 2 mmol) in dry tetrahydrofuran (2 mL). After the addition, the reaction mixture was stirred for 1 h at 40-45° C. and then stirred overnight at 25° C. The reaction mixture was then diluted with dry tetrahydrofuran (2 mL), and the stirring was stopped to allow the excess zinc dust to settle down (˜2 h). In a separate reaction flask, bis(dibenzylideneacetone)-palladium(0) (27 mg, 0.05 mmol) and triphenylphosphine (57 mg, 0.2 mmol) in dry tetrahydrofuran (4 mL) was stirred at 25° C. under argon for 10 min and then treated with 1-(2-chloro-4-iodo-phenyl)-5-methyl-1H-tetrazole (320.5 mg, 1 mmol) and the freshly prepared zinc compound in tetrahydrofuran. The resulting brick red solution was heated at 50° C. for 15 h. The reaction mixture was cooled to 25° C. and then poured into a saturated aqueous ammonium chloride solution (30 mL), and the organic compound was extracted into ethyl acetate (3×20 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 4/1/1 hexanes/ethyl acetate/methylene chloride) afforded (E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-acrylic acid methyl ester (233 mg, 64%) as an amorphous white solid: EI-HRMS m/e calcd for C18H21ClN4O2 (M+) 360.1353, found 360.1354.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([NH:11][S:12]([C:15]2[C:16]3[N:17]=[CH:18][CH:19]=[N:20][C:21]=3[CH:22]=[CH:23][CH:24]=2)(=[O:14])=[O:13])[CH:3]=1.Cl.[CH3:26][O:27][C:28](=[O:41])[CH:29]([NH2:40])[C:30]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([Cl:39])[CH:33]=1)=[O:31]>>[CH3:26][O:27][C:28](=[O:41])[CH:29]([NH:40][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=1[NH:11][S:12]([C:15]1[C:16]2[N:17]=[CH:18][CH:19]=[N:20][C:21]=2[CH:22]=[CH:23][CH:24]=1)(=[O:14])=[O:13])[C:30]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([Cl:39])[CH:33]=1)=[O:31]
Reactant: COC(=O)C(N)C(=O)c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Agent: Cl
Product: COC(=O)C(NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12)C(=O)c1ccc(Cl)c(Cl)c1

Procedure:
4-Chloro-2-(quinoxaline-5-sulfonylamino)-benzoic acid was coupled to (±)-2-amino-3-(3,4-dichloro-phenyl)-3-oxo-propionic acid methyl ester hydrochloride as in EXAMPLE 1, Part C. HPLC: RT=10.65 min. MS (ESI+): mass calcd. for C25H17Cl3N4O6S, 605.99; m/z found, 607/609 [M+H]+. 1H NMR (500 MHz, CDCl3): 11.23 (s, 1H), 8.88 (d, J=1.8, 1H), 8.85 (d, J=1.8, 1H), 8.58 (dd, J=7.4, 1.4, 1H), 8.32 (dd, J=8.5, 1.4, 1H), 8.24 (d, 2.1, 1H), 8.03 (dd, J=8.4, 2.1, 1H), 7.89-7.86 (m, 1H), 7.79 (d, J=2.0, 1H), 7.69 (d, J=8.4, 1H), 7.45 (d, J=8.5, 1H), 7.30 (d, J=6.9, 1H), 6.97 (dd, J=8.4, 2.0, 1H), 6.19 (d, J=6.9, 1H), 3.78 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]([CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]#[C:18][CH2:19]OS(C)(=O)=O)[CH2:13][CH2:12]2)[CH3:9])=[N:6][CH:7]=1.[Na+].[I-].[CH3:27][NH:28][CH3:29]>CO>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]([CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]#[C:18][CH2:19][N:28]([CH3:29])[CH3:27])[CH2:13][CH2:12]2)[CH3:9])=[N:6][CH:7]=1
Reactant: CNC
Reactant: CN(C[C@H]1CC[C@H](C#CCOS(C)(=O)=O)CC1)c1ncc(Br)cn1
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CN(C)CC#C[C@H]1CC[C@H](CN(C)c2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 323 mg (corresponding to 0.49 mmol) of trans-Methanesulfonic acid 3-(4-{[(5-bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-cyclohexyl)-prop-2-ynyl ester in 5 ml of methanol was cooled (0° C.), treated with a catalytic amount of NaI, 0.88 ml (4.94 mmol) of Dimethylamine (33% in EtOH 5.6M) and stirred for 16 h at RT. The solvent was evaporated and the residue extracted with aqueous saturated NaHCO3/Et2O (3×). The organic phase was dried with Na2SO4, filtered and evaporated. Purification by flash column chromatography on silica gel (CH2Cl2/MeOH 40:1) gave 137 mg (76%) of pure trans-(5-Bromo-pyrimidin-2-yl)-[4-(3-dimethylamino-prop-1-ynyl)-cyclohexylmethyl]-methyl-amine, mp: 71–72° C.; MS: 365 (MH+, 1Br).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:19](=[O:32])[NH:20][C:21](=[O:31])[C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=[CH:13][CH:12]=1)=O)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl.C(OCC)(=O)C>[NH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]2[C:19](=[O:32])[NH:20][C:21](=[O:31])[C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=[CH:15][CH:16]=1
Reactant: COc1ccccc1C1=C(Nc2ccc(CCNC(=O)OC(C)(C)C)cc2)C(=O)NC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COc1ccccc1C1=C(Nc2ccc(CCN)cc2)C(=O)NC1=O

Procedure:
A solution of 3-[4-[2-(t-butoxycarbonylamino)ethyl]phenylamino]-4-(2-methoxyphenyl)-1H-pyrrole-2,5-dione (0.060 g. 0.13 mmol) and trifluoroacetic acid (4 drops) in dry DCM (5 mL) was stirred for 18 hours at room temperature. The suspension was diluted with ethyl acetate (10 mL), poured onto sodium bicarbonate (20 mL) and extracted with ethyl acetate (3×10 mL). The combined organic solutions were washed with brine, dried with magnesium sulfate, evaporated and the residue triturated with a mixture of hexane-dichloromethane (95:5 v/v) to afford the tide compound as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:52]([CH:55]2[CH2:57][CH2:56]2)(=[O:54])=[O:53])=[C:6]([CH2:8][N:9]([CH3:51])[C:10]([CH:12]([NH:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][C:34]=2[F:35])[C:31]([N:36]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[N:30][CH:29]=[CH:28]3)[C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]([CH3:22])[CH2:20][OH:21])=[C:15]([CH3:23])[CH:14]=2)=[O:11])[CH:7]=1.[C:58](Cl)(Cl)=[O:59]>C(#N)C.ClCCl>[C:39]([O:38][C:37]([N:36]([C:31]1[C:32]2[C:27](=[CH:26][C:25]([NH:24][C@H:12]3[C:10](=[O:11])[N:9]([CH3:51])[CH2:8][C:6]4[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=4[S:52]([CH:55]4[CH2:56][CH2:57]4)(=[O:54])=[O:53])[NH:1][C:58](=[O:59])[O:21][CH2:20][C@H:19]([CH3:22])[C:16]4[CH:17]=[CH:18][C:13]3=[CH:14][C:15]=4[CH3:23])=[C:34]([F:35])[CH:33]=2)[CH:28]=[CH:29][N:30]=1)[C:44](=[O:45])[O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:43])([CH3:41])([CH3:40])[CH3:42]
Reactant: Cc1cc(C(Nc2cc3ccnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c3cc2F)C(=O)N(C)Cc2cc(N)ccc2S(=O)(=O)C2CC2)ccc1[C@@H](C)CO
Reactant: O=C(Cl)Cl
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cc2ccc1[C@@H](C)COC(=O)Nc1ccc(S(=O)(=O)C3CC3)c(c1)CN(C)C(=O)[C@@H]2Nc1cc2ccnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2cc1F
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 36.4 %

Procedure:
To a solution of 26A (80 mg, 0.099 mmol) in acetonitrile (6 mL) and dichloromethane (3 mL) at 0° C., was added phosgene solution (20% in toluene, 0.063 mL, 0.119 mmol) dropwise. The mixture was stirred at 0° C. for 40 min, then at rt for 30 min. Extra phosgene was removed by bubbling Ar though the reaction mixture (30 min). The mixture was added dropwise via syringe pump into a solution of TEA (0.111 mL, 0.794 mmol) in dichloromethane (40 ml) at rt over 3.0 h. The solution was stirred at rt overnight, quenched with 0.5 N HCl, extracted with CH2Cl2. The organic layer was washed with water and dried over sodium sulfate, then concentrated. The crude residue was purified by flash chromatography (30-100% EtOAc/hexanes) to give a mixture of diastereoisomers (70 mg, 0.084 mmol, 85% yield). The diastereomers were separated by a prep chiral HPLC (R,R-Whelk-O column 21.1×250 mm) to give 26B (30 mg, 0.036 mmol, 42.9% yield). MS (ESI) m/z: [M+1]+. 19F NMR (376 MHz, CDCl3) d ppm −128.71 (s, 1F).
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:5]2[CH2:20][CH2:19][CH2:18][CH2:17][C:6]=2[S:7][C:8]=1[NH:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:3]>O>[O:3]=[C:2]1[NH:1][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:9][C:8]2[S:7][C:6]3[CH2:17][CH2:18][CH2:19][CH2:20][C:5]=3[C:4]1=2
Reactant: CCOC(=O)C(=O)Nc1sc2c(c1C(N)=O)CCCC2
Solvent: O
Product: CCOC(=O)c1nc2sc3c(c2c(=O)[nH]1)CCCC3
Reaction time: 0.17 h
Yield: 48 %

Procedure:
The product of Procedure 1, 8.89 (0.030 mole) is melted in a round bottom flask equipped with a magnetic stirring bar and immersed in an oil bath at 261° C. The molten material is heated with stirring until the evolution of water as is evidenced by bubbling of the reaction mixture is no longer evident. About 5-15 min. is sufficient. The molten mass is then dissolved in dimethylformamide and the warm solution is poured into a volume of methanol larger than the reaction mixture. The precipitate is collected, and recrystallized from a mixture of dimethylformamide and methanol to yield 4.92 g. (48%) of the desired product as fine yellow needles, m.p. 207.0°-209.0° C.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])=[O:5].[CH2:15](OCC)C>>[OH:8][C@:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([CH3:15])[CH2:6][C:4]([O:3][CH2:2][CH3:1])=[O:5]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CCOCC
Product: CCOC(=O)C[C@@](C)(O)c1ccccc1
Reaction time: 24 h

Procedure:
Ethyl benzoyl acetate (192 mg, 1 mmol) was added to diethylether (10 mL) and the solution applied to a sheet of filter paper. The solvent was left to evaporate. Yeast (10 g/mmol) was mixed with water (10 ml) and the resultant paste spread onto the filter paper and left for 24 h. The product was extracted from the yeast using ethyl acetate (2×30 mL). Evaporation under reduced pressure produced an essentially pure ethyl (R)-3-hydroxy-3-phenylbutanoate as an oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][NH:13][C:14]([C:16]1[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][C:17]=1[CH2:25][CH2:26][CH2:27][CH3:28])=[O:15])[CH:6]=[CH:5]2.Br[CH2:38][C:39]#[N:40].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[C:39]([CH2:38][O:1][C:2]1[C:3]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][NH:13][C:14]([C:16]1[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][C:17]=1[CH2:25][CH2:26][CH2:27][CH3:28])=[O:15])[CH:6]=[CH:5]2)#[N:40]
Reactant: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(-c3ccc(OC)cc3)c(O)ccc2c1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(-c3ccc(OC)cc3)c(OCC#N)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
A mixture of 2-butyl-benzofuran-3-carboxylic acid [6-hydroxy-5-(4-methoxy-phenyl)-naphthalen-2-ylmethyl]-amide (301 mg, 0.63 mmol), prepared in the previous step, bromoacetonitrile (52 μL, 0.75 mmol) and potassium carbonate (434 mg, 3.14 mmol) in 20 mL of DMF was stirred under nitrogen at room temperature for 21 h (overnight). The reaction was diluted with ethyl acetate, extracted multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 2-butyl-benzofuran-3-carboxylic acid [6-cyanomethoxy-5-(4-methoxy-phenyl)-naphthalen-2-ylmethyl]-amide (325 mg, 99%) as a brown solid, mp 139-142° C.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][C@H:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[C@H:23]([CH2:34][OH:35])[CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[ClH:36]>C(Cl)(Cl)Cl.CCOCC>[ClH:36].[ClH:36].[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][C@H:21]4[CH2:26][CH2:25][NH:24][C@H:23]([CH2:34][OH:35])[CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)C[C@H]1CO
Agent: Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: OC[C@@H]1C[C@@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)CCN1
Temperature: 25 °C
Reaction time: 7 h
Yield: 60.7 %

Procedure:
The product from Step A (0.017 g, 0.036 mmol) was dissolved in CHCl3 (1.0 mL). HCl (0.27 mL, 1.1 mmol, 4.0M in dioxane) was added. The reaction stirred at ambient temperature for 7 hours. The reaction was diluted with Et2O (10 mL) and the mixture filtered. The solid was washed with Et2O and dried in vacuo to afford 0.0098 g (55%) of the desired product as an off-white solid. MS ESI (+) m/z 376.1 (M+1) detected.
Reaction SMILES: F[B-](F)(F)F.[CH2:6]([N+:8]1[S:9][C:10]([Cl:15])=[C:11]([Cl:14])[C:12]=1Cl)[CH3:7].C([O-])(=[O:18])C.[Na+]>>[Cl:14][C:11]1[C:12](=[O:18])[N:8]([CH2:6][CH3:7])[S:9][C:10]=1[Cl:15]
Reactant: CC(=O)[O-]
Reactant: CC[n+]1sc(Cl)c(Cl)c1Cl
Agent: F[B-](F)(F)F
Agent: [Na+]
Product: CCn1sc(Cl)c(Cl)c1=O
Yield: 45 %

Procedure:
2-Ethyl-3,4,5-trichloroisothiazolium tetrafluoroborate (14.5 g), 0.048 mole) was added in portions to 150 ml of a saturated sodium acetate solution. The aqueous phase was extracted with 3×50 ml of CH2Cl2. The combined extracts were dried (MgSO4), filtered and concentrated. The oil was distilled to yield 4.2 g (45%) 4,5-dichloro-2-ethyl-4-isothiazolin-3-one, bp 89-92 (0.1 mm).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:14]1[C:19]([CH2:20][CH2:21][CH3:22])=[CH:18][C:17]([NH:23][C:24]([C:26]2[C:27]([CH3:33])=[N:28][N:29]([CH3:32])[C:30]=2[CH3:31])=[O:25])=[C:16]([CH3:34])[CH:15]=1)([C:10]([F:13])([F:12])[F:11])[C:6]([F:9])([F:8])[F:7].[C:35](OC(=O)C)(=[O:37])[CH3:36].Cl>O1CCCC1>[C:35]([N:23]([C:17]1[CH:18]=[C:19]([CH2:20][CH2:21][CH3:22])[C:14]([C:5]([O:4][CH3:3])([C:6]([F:9])([F:8])[F:7])[C:10]([F:13])([F:11])[F:12])=[CH:15][C:16]=1[CH3:34])[C:24]([C:26]1[C:27]([CH3:33])=[N:28][N:29]([CH3:32])[C:30]=1[CH3:31])=[O:25])(=[O:37])[CH3:36]
Reactant: CCCc1cc(NC(=O)c2c(C)nn(C)c2C)c(C)cc1C(OC)(C(F)(F)F)C(F)(F)F
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1cc(N(C(C)=O)C(=O)c2c(C)nn(C)c2C)c(C)cc1C(OC)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
Sodium hydride (32 mg, 60%, 0.8 mmol) was suspended in tetrahydrofuran (10 ml), and a solution of N-{4-[1-methoxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]-2-methyl-5-n-propylphenyl}-1,3,5-trimethylpyrazole-4-carboxamide (250 mg, 0.53 mmol) in tetrahydrofuran (5 ml) was added dropwise. After stirring at room temperature for 30 min, a solution of acetic anhydride (80 mg, 0.78 mmol) in tetrahydrofuran (2 ml) was added, and the mixture was stirred for one day. The reaction mixture was poured into diluted hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:3) to give the desired compound (139 mg).