Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([Br:20])[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].[CH:22](=[O:26])[CH:23]([CH3:25])[CH3:24].O>O1CCCC1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][CH:10]=1)[NH:11][CH:12]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([Br:20])[CH:14]=1)[C:23]([CH3:25])([CH3:24])[CH:22]2[OH:26])=[O:21])[CH3:2]
Reactant: CC(C)C=O
Reactant: CCOC(=O)c1ccc(N=Cc2cc(C)cc(Br)c2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cc(C)cc(Br)c1)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 101.5 %

Procedure:
To a mixture of 4-{[1-(3-bromo-5-methyl-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (2.5 g, 7.3 mmol) and ytterbium(III) triflate hydrate (0.45 g, 0.73 mmol) in dry tetrahydrofuran (15 mL) at 25° C. was added isobutyraldehyde (0.53 g, 7.3 mmol) and water (0.13 mL, 7.3 mmol) dropwise. The reaction mixture was stirred at 25° C. for 5 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-5-methyl-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.1 g, 100%) as a light yellow oil: LC/MS m/e calcd for C21H24BrNO3 M+: 418.3, observed: 400.1.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1.OS(O)(=O)=O.[CH2:17]([N:24]1[C:36]2[CH2:35][CH2:34][CH2:33][CH:32]([C:37]([NH2:39])=[O:38])[C:31]=2[C:30]2[C:25]1=[CH:26][C:27]([O:44][CH3:45])=[CH:28][C:29]=2[O:40][CH2:41][C:42]#[N:43])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[NH2:43][CH2:42][CH2:41][O:40][C:29]1[CH:28]=[C:27]([O:44][CH3:45])[CH:26]=[C:25]2[C:30]=1[C:31]1[CH:32]([C:37]([NH2:39])=[O:38])[CH2:33][CH2:34][CH2:35][C:36]=1[N:24]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1cc(OCC#N)c2c3c(n(Cc4ccccc4)c2c1)CCCC3C(N)=O
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1cc(OCCN)c2c3c(n(Cc4ccccc4)c2c1)CCCC3C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
To 1.93 ml (1.93 mmol) 1M lithium aluminum hydride/THF in 13 ml THF at 0° C. was added H2SO4(53 μl, 0.97 mmol) dropwise over 5 min. The mixture was allowed to stir at room temperature 1 hour, then a solution of 9-benzyl-7-methoxy-5-cyanomethyloxy-1,2,3,4-tetrahydrocarbazole-4-carboxamide (0.50 g, 1.29 mmol) in 13 ml THF was added dropwise at a rate which kept the temperature below 26° C. After an additional 45 minutes, the reaction was quenched with 0.5 ml 1:1 THF/H2O, 0.75 ml 13% NaOH, and finally 80 μl H2O. The reaction was diluted with EtOAc and saturated NaHCO3, and the layers separated. The organic layer was extracted with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with 9:1:0.1 CH2Cl2/MeOH/NH4OH to give the subtitled product (0.28 g, 55%). MS (ES+) 394
Reaction SMILES: [OH-].[Na+].S(O)(O)(=O)=O.[C:8]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)(=[NH:10])[NH2:9].CO[CH:26]=[C:27]([C:32]([CH3:34])=O)[C:28]([O:30][CH3:31])=[O:29]>CO>[CH2:17]([N:14]1[CH2:15][CH2:16][N:11]([C:8]2[N:9]=[C:32]([CH3:34])[C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:10]=2)[CH2:12][CH2:13]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC=C(C(C)=O)C(=O)OC
Reactant: N=C(N)N1CCN(Cc2ccccc2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1cnc(N2CCN(Cc3ccccc3)CC2)nc1C
Yield: 87.9 %

Procedure:
One hundred milliliters of a 1M solution of sodium hydroxide in methanol were added to a suspension (60 ml) of 26.8 g (0.1 mol) of 1-amidino-4-benzylpiperazine sulfate [which had been synthesized in accordance with the process disclosed in J. Am. Chem. Soc., 66, 263 (1944)] in methanol, followed by a dropwise addition of 15.8 g (0.1 mol) of methyl α-methoxymethyleneacetoacetate. After stirring the resultant mixture overnight at room temperature, the precipitated sodium sulfate was filtered off. After distilling off methanol, the residue was dissolved in 500 ml of ethyl acetate. The resultant solution was washed twice with 100 ml of water. The ethyl acetate layer was washed with saturated saline and then dried with anhydrous magnesium sulfate. Upon distilling off ethyl acetate, 28.7 g of the intended compound was obtained as an orange-colored oily substance (yield: 88%). When the oily substance was left over at room temperature subsequent to its distillation under a reduced pressure, it was crystallized.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][C@@H:31]([OH:33])[CH3:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:33][C@@H:31]([CH3:32])[CH2:30][NH:29][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:27])([F:26])[F:28])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: C[C@H](O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](O)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 61.4 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ((S)-2-hydroxy-propyl)-amide (70 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-yl-amino)-1H-benzoimidazole-5-carboxylic acid (100 mg), (S)-(+)-1-amino-2-propanol (20 mg), HBTU (111 mg), and DIEA (64 uL). LC/MS: m/z 466.8. 1H NMR (DMSO-d6, 400 MHz): δ 12.39 (s, 1H), 8.36 (s, 1H), 8.10 (s, 1H), 7.92 (s, 1H), 7.80 (d, 1H), 7.73 (d, 1H), 7.49 (d, 1H), 7.36 (d, 1H), 4.77 (d, 1H), 3.87-3.78 (m, 1H), 3.64 (bs, 3H), 3.27-3.20 (m, 2H), 1.09 (d, 3H).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=O)[CH2:12]Br)(=O)C.[C:15]([NH2:23])(=[S:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1>CC(C)=O>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:15]2[S:22][CH:12]=[C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[OH:4])[N:23]=2)[CH:17]=1
Reactant: CC(=O)Oc1ccccc1C(=O)CBr
Reactant: NC(=S)c1cccnc1
Solvent: CC(C)=O
Product: Oc1ccccc1-c1csc(-c2cccnc2)n1
Temperature: 20 °C
Yield: 36 %

Procedure:
o-(Bromoacetyl)phenyl acetate (2.57 g, 10 mmol) in dry acetone (30 mL) was treated with thionicotinamide (1.38 g, 10 mmol). The mixture was refluxed 16 hours, cooled to about 20° C. at which point a precipitate formed (2.46 g). The precipitate was filtered and dried in vacuo. The precipitate was dissolved in MeOH (50 mL) and treated with 10% NaOH in H2O (20 mL) for 1 hour at about 20° C. to hydrolyze the acetate ester. The pH was adjusted to neutrality with 6N HCl while chilling on ice/H2O and the volume was reduced to about 35 mL in vacuo. After cooling to about 4° C., an orange solid precipitate formed, which was removed by filtration and dried in vacuo to constant mass to yield 36-50% product (LSIMS m/s 254 (MH+)).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH2:9][CH2:8][C:7]3[S:10][C:11]([NH:13][C:14]([C:16]45[CH2:23][CH:22]6[CH2:24][CH:18]([CH2:19][CH:20]4[CH2:21]6)[CH2:17]5)=[O:15])=[N:12][C:6]=3[C:5]=12.[CH3:25][O:26][CH2:27][CH2:28]Br>>[CH3:25][O:26][CH2:27][CH2:28][N:12]1[C:6]2[C:5]3=[N:1][O:2][N:3]=[C:4]3[CH2:9][CH2:8][C:7]=2[S:10]/[C:11]/1=[N:13]\[C:14]([C:16]12[CH2:17][CH:18]3[CH2:24][CH:22]([CH2:21][CH:20]1[CH2:19]3)[CH2:23]2)=[O:15]
Reactant: O=C(Nc1nc2c(s1)CCc1nonc1-2)C12CC3CC(CC1C3)C2
Reactant: COCCBr
Product: COCCn1c2c(s/c1=N\C(=O)C13CC4CC(CC1C4)C3)CCc1nonc1-2

Procedure:
The product from Example 71B and 2-bromoethyl methyl ether were processed according to the method of Example 1B to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.44-1.70 (m, 4H), 1.70-1.87 (m, 4H), 2.14 (d, J=11.2 Hz, 2H), 2.29 (s, 2H), 2.59 (t, J=6.8 Hz, 1H), 3.13 (t, J=7.1 Hz, 2H), 3.21-3.30 (m, 5H), 3.63-3.85 (m, 2H), 4.69 (t, J=5.8 Hz, 2H); MS (ESI+) m/z 401 (M+H)+; Anal. Calculated for C20H24N4O3S: C, 59.98; H, 6.04; N, 13.99. Found: C, 59.90; H, 6.09; N, 13.95.
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:31])=[C:9]([CH3:30])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](OCC)=[O:24])=[CH:17][CH:16]=3)[C:11]=2[C:28]=1[CH3:29])=[O:5]>C(OCC)(=O)C.CCCCCC>[OH:24][CH2:23][CH2:22][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([CH:12]2[C:11]3[C:28]([CH3:29])=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:1])([CH3:33])[CH3:32])[C:8]([CH3:31])=[C:9]([CH3:30])[C:10]=3[O:14][CH2:13]2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)CCc1ccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(CCCO)cc1)CO2
Yield: 77 %

Procedure:
Using ethyl 3-(4-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)phenyl)propanoate obtained in Example 181, the title compound was synthesized in the same manner as in Example 193. Yield: 77%. Melting point: 119-120° C. (ethyl acetate-hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:34])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=O)[NH:12][CH:11]3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])[C:5]2=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:44]2)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:34])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[S:44])[NH:12][CH:11]3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])[C:5]2=[CH:4][CH:3]=1
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2ccccc2C(F)(F)F)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: O=C1Nc2cc(Cl)ccc2C12C(c1cccc(Cl)c1)CC(=S)NC2c1ccccc1C(F)(F)F
Yield: 36.4 %

Procedure:
In a manner similar to the method described in example 30, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(trifluoromethyl)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.4 g, 0.79 mmol) prepared in example 32b was reacted with 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (0.4 g, 0.99 mmol) in toluene to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-6′-thioxo-2′-[2-(trifluoromethyl)-phenyl]spiro[3H-indole-3,3′-piperidine]-2(1H)-one (Yield 0.15 g, 36%).
Reaction SMILES: S.N1C=CC=CC=1.Br[C:9]1[CH:10]=[CH:11][C:12]([N+:16]([O-:18])=[O:17])=[C:13](O)[CH:14]=1.FC(F)(F)C(N)=[O:22]>>[N+:16]([C:12]1[CH:11]=[CH:10][C:9]([OH:22])=[CH:14][CH:13]=1)([O-:18])=[O:17]
Reactant: NC(=O)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(Br)cc1O
Agent: S
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(O)cc1

Procedure:
Subunit containing the base of FIG. 30C. 3-Bromophenol was nitrated to produce 5-bromo-2-nitrophenol. This was reduced with hydrogen sulfide/pyridine to the aminophenol, and the amino group masked as the trifluoroacetamide. A second nitration produced the 4-nitrophenol species which was treated with ammonia to cleave the trifluoroacetamide. This was reacted with cyanogen bromide to produce the aminobenzoxazole which is protected as the trifluoroacetamide. The nitro group was reduced with pyridine hydrogen sulfide and the amine treated with ethyl chloroformate to generate the carbamate. Nitration, nitro reduction, and heating provided the fused imidazolone. Ammonolysis of the trifluoroacetamide gave the aminobenxoxazole which was protected as the beta(trimethylsilyl)ethylcarbamate. This was coupled with the pyranoid glycal as in Example 4Aii to produce the subunit with the glucose moiety. Following complete desilylation, the amino group was protected as the trifluoro- or trichloroacetamide as per Example 1. The glucosyl subunit may be converted into the morpholine containing subunit by the method of Example 2C except that two equivalents of sodium periodate is employed in the oxidation step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:27]=[CH2:28])=[C:4]([CH:8]=[C:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[CH:25][CH:24]=[N:23]3)=[CH:18][CH:17]=2)[C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=O.Cl.[NH2:30][C@@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]1[OH:37].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.O.C(N(CC)CC)C>[Cl:1][C:2]1[C:3]([CH:27]=[CH2:28])=[C:4]([CH:8]=[C:9]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([N:22]3[CH:26]=[CH:25][CH:24]=[N:23]3)=[CH:20][CH:21]=2)[C:10]=1[C:11]([F:14])([F:12])[F:13])[C:5]([NH:30][C@@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]1[OH:37])=[O:7]
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: C=Cc1c(C(=O)O)cc(Cc2ccc(-n3cccn3)cc2)c(C(F)(F)F)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C=Cc1c(C(=O)N[C@@H]2CCCC[C@H]2O)cc(Cc2ccc(-n3cccn3)cc2)c(C(F)(F)F)c1Cl
Reaction time: 16 h
Yield: 113 %

Procedure:
To a solution of 3-chloro-2-ethenyl-5-[4-(1H-pyrazol-1-yl)benzyl]-4-(trifluoromethyl)benzoic acid (0.05 g), trans-2-aminocyclohexanol hydrochloride (0.03 g), 1-hydroxybenzotriazole (0.03 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.04 g) in dichloromethane (5.00 mL) was added triethylamine (0.04 g), and the mixture was stirred for 16 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated aqueous sodium bicarbonate solution, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.07 g).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([F:12])[CH:3]=1.Cl[CH2:14][CH2:15][CH2:16][S:17](Cl)(=[O:19])=[O:18]>>[O:18]=[S:17]1(=[O:19])[CH2:16][CH2:15][CH2:14][N:1]1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: COC(=O)c1ccc(N)cc1F
Reactant: O=S(=O)(Cl)CCCCl
Product: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1F

Procedure:
Using methyl 4-amino-2-fluorobenzoate (1.02 g) and 3-chloropropane-1-sulfonyl chloride (0.97 mL) and by the reaction and treatment in the same manner as in Preparation Example 16, the title compound (1.09 g) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([CH:9]3[CH2:12][C:11](=[CH2:13])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.B.C1C[O:20]CC1.OO.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([CH:9]3[CH2:10][CH:11]([CH2:13][OH:20])[CH2:12]3)[S:8][C:4]=2[CH:3]=1
Reactant: C1CCOC1
Reactant: C=C1CC(c2nc3ccc(Br)cc3s2)C1
Agent: B
Agent: OO
Agent: [Na+]
Product: OCC1CC(c2nc3ccc(Br)cc3s2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 42.1 %

Procedure:
The product of Example 1B (600.0 mg, 2.14 mmole) was dissolved in 4 ml of THF and cooled to 0° C. BH3.THF (1 M in THF, 5.35 ml, 5.35 mmole) was added to it and the mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was cooled to 0° C., 30% H2O2 (2.5 ml) and 3M NaOH were successively added dropwise. The mixture was slowly warmed to room temperature and stirred for 5 hours. The mixture was quenched with brine, and extracted three times with dichloromethane. The combined organics were washed with sodium bisulfite and brine, dried over sodium sulfate, filtered and concentrated to the crude product, which was purified by chromatography (5% methanol in dichloromethane) to provide the title compound (268.9 mg, 42.1%). 1H NMR (300 MHz, CDCl3) 7.98 (d, J=2.0 Hz, 1H) 7.83 (d, J=8.8 Hz, 1H) 7.56 (dd, J=8.7, 1.9 Hz, 1H) 3.79 (m, 2H) 3.66 (m, 1H) 2.55-2.70 (m, 3H) 2.42 (m, 1H) 2.26 (m, 1H). MS: (M+H)+=298/300.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[H-].[Na+].Cl[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.O>CN(C)C=O>[CH2:1]([S:3][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[CH3:2]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Ethanethiol (6.11 ml, 0.082 mol) was added slowly to a suspension of sodium hydride (3.3 g, 60% dispersion) in dry dimethylformamide (225 ml) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 15 min before the addition of 1-chloro-4-nitrobenzene (10 g, 0.063 mol) dissolved in dry dimethylformamide (25 ml). After addition, the resultant mixture was allowed to warm to 60° C. and was stirred for 24 hr. The mixture was then concentrated in vacuo to yield a yellow oil. Ice and water were added and a yellow solid was precipitated and filtered off. The solid was then dissolved in methanol (100 ml) and insoluble by-products were isolated by filtration. The filtrate was then concentrated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and washed with water (2×50 ml). The organic layer was then dried (MgSO4) and concentrated in vacuo to afford 1-(ethylthio)-4-nitrobenzene as a yellow solid. δ(1H NMR, DMSO, ppm): 1.15 (3H, t), 3.05 (2H, q) 7.45 (2H, d), 8.10 (2H, d)
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[N:7]([CH:9]([C:11](=[O:38])[NH:12][CH:13]([C:18]([N:20]1[CH2:24][CH2:23][CH:22]2[NH:25][CH2:26][CH:27]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=3)[CH:21]12)=[O:19])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:40](O)(=[O:44])[C:41]([CH3:43])=[O:42].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:39])[N:7]([CH:9]([C:11](=[O:38])[NH:12][CH:13]([C:18]([N:20]1[CH2:24][CH2:23][CH:22]2[N:25]([C:40](=[O:44])[C:41](=[O:42])[CH3:43])[CH2:26][CH:27]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=3)[CH:21]12)=[O:19])[C:14]([CH3:16])([CH3:17])[CH3:15])[CH3:10])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)C(=O)O
Reactant: CC(C(=O)NC(C(=O)N1CCC2NCC(COc3ccc(F)c(F)c3)C21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(=O)C(=O)N1CC(COc2ccc(F)c(F)c2)C2C1CCN2C(=O)C(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.6 %

Procedure:
A solution of amine 84 (480 mg, 0.87 mmol) in DCM (8 mL) was cooled to 0° C. and treated with pyruvic acid (0.06 mL, 0.91 mmol), EDC (200 mg, 1.04 mmol), HOBt (141 mg, 1.04 mmol), and DIPEA (0.47 mL, 2.69 mmol). The reaction mixture was allowed to warm to ambient temperature. After 16 h, the reaction mixture was diluted with DCM, washed successively with 1M HCl, saturated aqueous NaHCO3, and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 87 (529 mg, 97%) as a white foam that was used with out further purification. 1H NMR (CDCl3, 300 MHz): δ7.10-7.01 (m, 1H), 6.88 (br s, 1H), 6.71-6.64 (m, 1H), 6.56-6.53 (m, 1H), 4.72-4.68 (m, 1H), 4.62-4.53 (m, 2H), 4.44 (d, J=6.3 Hz, 1H), 4.15-3.97 (m, 2H), 3.89-3.81 (m, 1H), 3.72-3.61 (m, 1H), 3.53-3.36 (m, 1H), 2.88-2.79 (m, 4H), 2.49-2.00 (m, 5H), 1.49 (s, 9H), 1.32 (d, J=6.9 Hz, 3H), 0.98 (s, 9H) ppm.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:6]2[CH:7]=[C:8]([CH2:20][OH:21])[CH:9]=[C:10](B3OC(C)(C)C(C)(C)O3)[C:5]=2[O:4][CH2:3]1.Br[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][C:33]([F:36])([F:35])[F:34])[CH:27]=[O:28]>>[OH:21][CH2:20][C:8]1[CH:9]=[C:10]([C:30]2[CH:29]=[C:26]([CH:25]=[CH:24][C:31]=2[O:32][C:33]([F:34])([F:35])[F:36])[CH:27]=[O:28])[C:5]2[O:4][CH2:3][C:2]([CH3:1])([CH3:22])[C:6]=2[CH:7]=1
Reactant: CC1(C)COc2c(B3OC(C)(C)C(C)(C)O3)cc(CO)cc21
Reactant: O=Cc1ccc(OC(F)(F)F)c(Br)c1
Product: CC1(C)COc2c(-c3cc(C=O)ccc3OC(F)(F)F)cc(CO)cc21
Yield: 59 %

Procedure:
The intermediate 3-(5-hydroxymethyl-3,3-dimethyl-2,3-dihydro-benzofuran-7-yl)-4-trifluoromethoxy-benzaldehyde was prepared in a similar manner to example 1a using [3,3-dimethyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-benzofuran-5-yl]-methanol and 3-bromo-4-trifluoromethoxy benzaldehyde. 59% yield. 1H-NMR (300 MHz, CDCl3): 1.39 (s, 6H), 1.71 (m, 1H), 4.26 (s, 2H), 4.68 (s, 2H), 7.14 (d, J=2.3 Hz, 1H), 7.21 (d, J=1.5 Hz, 1H), 7.49 (dd, J1=8.5 Hz, J2=1.5 Hz, 1H), 7.91 (dd, J1=8.5 Hz, J2=2.1 Hz, 1H), 8.01 (d, J=2.3 Hz, 1H), 10.03 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[C:4](Cl)=[O:5].[CH2:15]([NH2:18])[C:16]#[CH:17]>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[C:4]([NH:18][CH2:15][C:16]#[CH:17])=[O:5]
Reactant: C[Si](C)(C)c1cccc(Br)c1C(=O)Cl
Reactant: C#CCN
Product: C#CCNC(=O)c1c(Br)cccc1[Si](C)(C)C
Yield: 81 %

Procedure:
The compound of Example d was reacted with propargylamine (3 eq) according to General Method El and the crude product was recrystallized from hexanes to afford 0.55 g of the title compound as off-white needles in 81% yield. m.p. 120-121° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:5][NH:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]([C:15](NC[C@@H]2C[C@H](S)CN2C(OCC=C)=O)=[O:16])=[N:13][CH:14]=1)=[O:8].[CH3:35][O:36]C(C1C=CC(C(Cl)=O)=CN=1)=O.ClC1C=C(C=CC=1Cl)CN.C(OC(C1SC(C(=O)NCC2C=CC(Cl)=C(Cl)C=2)=CC=1)=O)C>>[CH3:35][O:36][C:15]([C:12]1[CH:11]=[CH:10][C:9]([C:7](=[O:8])[NH:6][CH2:5][C:4]2[CH:31]=[CH:32][C:33]([Cl:34])=[C:2]([Cl:1])[CH:3]=2)=[CH:14][N:13]=1)=[O:16]
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1CNC(=O)c1ccc(C(=O)NCc2ccc(Cl)c(Cl)c2)cn1
Reactant: COC(=O)c1ccc(C(=O)Cl)cn1
Agent: CCOC(=O)c1ccc(C(=O)NCc2ccc(Cl)c(Cl)c2)s1
Agent: NCc1ccc(Cl)c(Cl)c1
Product: COC(=O)c1ccc(C(=O)NCc2ccc(Cl)c(Cl)c2)cn1
Yield: 61 %

Procedure:
Starting material (13(e)) was prepared as follows. 5-chlorocarbonyl-pyridine-2-carboxylic acid methyl ester was reacted with 3,4-dichlorobenzylamine analogously with preparation of compound (12(a)) in Example 12 to obtain 5(3,4-dichlorobenzylcarbamoyl)-pyridine-2-carboxylic acid methyl-ester (13(a)) as a cream solid (61%).
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23]C)=[O:22])=[CH:17][N:16]=2)(=[O:14])=[O:13])=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].[OH-].[Na+].O>C1COCC1>[C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][N:16]=2)(=[O:14])=[O:13])=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCS(=O)(=O)c2ccc(C(=O)OC)cn2)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(OCCCS(=O)(=O)c2ccc(C(=O)O)cn2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of Example 3, (570 mg, 1.31 mmoles) was dissolved in THF (6 ml) to which was added 1N NaOH (3 ml) and H2O (3 ml). The reaction mixture was stirred at room temperature under N2 overnight. The THF was removed in vacuo. The aqueous phase was washed with CHCl3. Then the aqueous phase was acidified with concentrated HCl until slightly acid (pH about 5-6). The resulting beige solid was filtered, taken up in CHCl3 (about 500 ml), and the organic solvent was dried and concentrated. The residue was triturated with ether and filtered to afford the title compound, m.p. 177°-179°.