Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCCCCC.C1COCC1>[CH2:10]([O:9][C:3](=[O:8])[CH2:4][C:5]([CH2:7][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:6])[CH3:11]
Reactant: CCOC(=O)CC(C)=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)CC(=O)CCc1ccccc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
NaH (13.8 g, 0.6 mole) was washed twice with hexane (2×50 ml) and suspended in 250 ml of freshly distilled THF. Next ethyl acetoacetate (75 ml, excess) was added dropwise carefully while the receiving flask was cooled at -10° C. After the addition was complete, it was stirred at -10° C. for 2 hours and at room temperature for 30 min. Benzylbromide (51.0 g, 0.3 mole) in THF was added dropwise at room temperature to the above solution. The reaction mixture was stirred overnight at room temperature. The reaction was terminated the next day by pouring into ice cold water, brought to neutral pH, and extracted with ether/ethylacetate. The combined ether/ethylacetate extracts were rinsed over brine and dried over Na2SO4. Removal of the solvent followed by careful vacuum distillation gave ethyl-benzylacetoacetate, bp 276° C. IR: (neat), cm-1 : 2900-3050, 1690-1760 (broad), 1655. NMR (CDCl3):δ:1.25 (t1 3H, CH2CH3); 2.25 (s, 3H, COCH3); 3.20 (d, 2H, benzylic CH2); 3.8 (t, 1H, COCHCO); 4.20 (q, 2H, OCH2CH3); 7.15-7.35 (m, 5H, Ar-H).
Reaction SMILES: Br[C:2]1[C:3]([N:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)=[C:4]([C@H:10]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[CH2:29]([O:36][C:37]1[N:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:29]([O:36][C:37]1[N:42]=[CH:41][C:40]([C:2]2[C:7]([CH3:8])=[N:6][C:5]([CH3:9])=[C:4]([C@H:10]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:3]=2[N:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)=[CH:39][CH:38]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(Br)c1N1CCC(C)(C)CC1
Reactant: OB(O)c1ccc(OCc2ccccc2)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCc3ccccc3)nc2)c1N1CCC(C)(C)CC1
Reaction time: 2 h
Yield: 24 %

Procedure:
A mixture of (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (0.0553 g, 0.121 mmol), (6-(benzyloxy)pyridin-3-yl)boronic acid (0.042 g, 0.182 mmol) and 2M Na2CO3 (0.152 ml, 0.304 mmol) in DMF (2 mL) was degassed for 10 min. Then, Pd(Ph3P)4 (0.014 g, 0.012 mmol) added, degassed for 5 min and placed in a pre-heated oil bath at 110° C. After 2 h, cooled and purified by prep-HPLC to afford (S)-ethyl 2-(6′-(benzyloxy)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-[3,3′-bipyridin]-5-yl)-2-(tert-butoxy)acetate (0.016 g, 0.029 mmol, 23.54% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 8.08-8.10 (m, 0.5H), 8.00 (d, J=1.9 Hz, 0.5H), 7.51-7.54 (m, 2.5H), 7.39-7.44 (m, 2.5H), 7.34-7.38 (m, 1H), 6.92-6.96 (m, 1H), 6.05 (s, 1H), 5.41-5.55 (m, 2H), 4.23-4.30 (m, 1H), 4.15-4.22 (m, 1H), 3.26 (d, J=12.3 Hz, 0.5H), 3.19 (d, J=11.5 Hz, 0.5H), 2.87-2.96 (m, 0.5H), 2.75-2.83 (m, 0.5H), 2.63 (s, 1.5H), 2.62 (s, 1.5H), 2.38 (d, J=11.2 Hz, 0.5H), 2.26-2.31 (m, 0.5H), 2.25 (s, 1.5H), 2.23 (s, 1.5H), 2.05-2.18 (m, 1H), 1.50-1.57 (m, 1H), 1.35-1.44 (m, 1H), 1.27 (dt, J=2.2, 7.1 Hz, 3H), 1.22 (s, 4.5H), 1.21 (s, 4.5H), 1.06-1.16 (m, 2H), 0.92 (s, 3H), 0.67 (br. s., 3H). LCMS (M+H)=560.4.
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:6][N:5](C(OC(C)(C)C)=O)[C@@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.FC(F)(F)C(O)=O>ClCCl>[F:18][C:2]1([F:1])[CH2:6][NH:5][C@@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1
Reactant: COC(=O)[C@H]1CC(F)(F)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H]1CC(F)(F)CN1
Temperature: 25 °C
Reaction time: 5 h
Yield: 74.2 %

Procedure:
To solution of (R)-1-tert-butyl 2-methyl 4,4-difluoropyrrolidine-1,2-dicarboxylate (4.33 g, 16.32 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (12.58 mL, 163 mmol) and the resulting mixture was stirred at rt for 5 h, then concentrated and sat. aqueous sodium bicarbonate (50 mL) was added followed by stirring for 20 min before extracting with diethyl ether (40 mL×3). The combined extracts were washed with brine and dried over sodium sulfate, filtered, and concentrated at rt (note: product is volatile) to afford 2.0 g (74%) of the title compound as a light tan oil that was used directly in the next transformation without any further purification. 1H NMR (400 MHz, MeOD) δ ppm 4.03 (1 H, dd, J=8.80, 6.82 Hz), 3.77 (3 H, s), 3.22-3.32 (1 H, m), 3.07-3.23 (1 H, m), 2.51-2.69 (1 H, m), 2.30-2.50 (1 H, m).
Reaction SMILES: [NH:1]([C:5]1[C:6]([CH3:20])=[C:7]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:2]([CH3:4])=[O:3].CC1C([N+:28]([O-])=O)=CC(C)=CC=1O>>[C:2]([N:1]1[C:5]2[C:6](=[C:7]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=[C:9]([CH3:11])[CH:10]=2)[CH:20]=[N:28]1)(=[O:3])[CH3:4]
Reactant: CC(=O)Nc1cc(C)cc(OCc2ccccc2)c1C
Reactant: Cc1cc(O)c(C)c([N+](=O)[O-])c1
Product: CC(=O)n1ncc2c(OCc3ccccc3)cc(C)cc21

Procedure:
The (3-acetamino-2,5-dimethyl-phenyl)-benzyl ether used as starting material in Example 2 is prepared from 2,5-dimethyl-3-nitrophenol by the following reactions:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21](Cl)=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1)[NH2:28].C1(C)C=CC=CC=1>CCOCC>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]([NH:28][C:27]3[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=[C:25]([O:24][CH3:23])[CH:26]=3)=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: O=S(=O)(Nc1nc2ccccc2nc1Cl)c1ccc(Cl)nc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(Cl)nc2)cc(OC)c1
Temperature: 125 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
6-Chloro-N-(3-chloroquinoxalin-2-yl)pyridine-3-sulfonamide (775 mg, 2.2 mmol), 3,5-dimethoxyaniline (355 mg, 2.3 mmol) and toluene (12 mL) were combined and heated to 125° C. with stirring overnight. The reaction was allowed to cool to room temperature and diluted with Et2O with vigorous stirring. The resulting solids were filtered, washed with Et2O and dried to give 6-chloro-N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)pyridine-3-sulfonamide (920 mg, 89%). 1H NMR (400 MHz, DMSO-d6) δ 12.20 (br s, 1H), 9.12 (d, 1H), 9.01 (br s, 1H), 8.53 (dd, 1H), 7.91 (br d, 1H), 7.77 (d, 1H), 7.60 (dd, 1H), 7.40 (m, 4H), 6.26 (m, 1H), 3.78 (s, 6H). MS (EI) m/z for C21H18ClN5O4S: 472.0 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:25]([O:27]C)=[O:26])[CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:11].[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:25]([OH:27])=[O:26])[CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])=[O:11]
Reactant: COC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)C=Cc1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)C=Cc1ccccc1F)C(=O)O
Reaction time: 21 h
Yield: 81.1 %

Procedure:
To methanol (260 mL) of the compound obtained in Example 57 (6.9 g) was added dropwise 1 mol/L of an aqueous sodium hydroxide solution (26 mL) at room temperature, and the mixture was allowed to stir for 21 hours. To the residue obtained by distilling off the solvent under a reduced pressure was added water, and the mixture was made acidic with 10% citric acid. The solution was extracted with ethyl acetate and thereafter the organic layer was washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under a reduced pressure, to give the captioned compound (5.4 g, 81%) as an oily product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]1[C:9](=[O:10])[C:8]2[CH:11]=[C:12]([S:17](Cl)(=O)=O)[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[O:6]1.COC(=O)CN1C(=O)C2C=C(SCC3SC(C4C=CC(C(F)(F)F)=CC=4)=NC=3C)C(OC)=CC=2O1>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]1[C:9](=[O:10])[C:8]2[CH:11]=[C:12]([SH:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[O:6]1
Reactant: COC(=O)Cn1oc2cc(OC)c(S(=O)(=O)Cl)cc2c1=O
Agent: COC(=O)Cn1oc2cc(OC)c(SCc3sc(-c4ccc(C(F)(F)F)cc4)nc3C)cc2c1=O
Product: COC(=O)Cn1oc2cc(OC)c(S)cc2c1=O

Procedure:
Compound 22E was prepared according to the method of example 1C utilizing compound 22D. Compound 22E was prepared in 10% yield. MS: 268 (M−1)+. Preparation of 6-Methoxy-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-3-oxo-3H-benzo[d]isoxazol-2-yl-acetic acid methyl ester (Compound 22F)
Reaction SMILES: C([N:8]1[C@H:12]([C:13]#[CH:14])[CH2:11][C@@H:10]([OH:15])[CH2:9]1)(OC(C)(C)C)=O.[F:16][C:17]1[C:18](I)=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])/[C:20]/2=[CH:27]\[C:28]1[NH:29][CH:30]=[CH:31][C:32]=1[O:33][CH3:34].O>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.FC(F)(F)C(O)=O.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:16][C:17]1[C:18]([C:14]#[C:13][C@@H:12]2[CH2:11][C@@H:10]([OH:15])[CH2:9][NH:8]2)=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])/[C:20]/2=[CH:27]\[C:28]1[NH:29][CH:30]=[CH:31][C:32]=1[O:33][CH3:34]
Reactant: C#C[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#C[C@@H]3C[C@@H](O)CN3)c21
Reaction time: 2 h

Procedure:
Using Method C above, (3R,5S)-N-Boc-3-Hydroxy-5-ethynyl-pyrrolidine (98 mg, 0.47 mmol) (Example 99C above) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (60 mg, 0.16 mmol) (Starting Material 6) using (Ph3P)4Pd (18 mg, 0.02 mmol) and a catalytic amount of Cul in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 6 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4, concentrated and the residue was chromatographed on a silica gel column with a 0-100% EtOAc in hexanes gradient. The intermediate that resulted from this operation was directly dissolved in 5 mL of a 50% trifluoroacetic acid in CH2Cl2 solution that contained 0.2 mL of H2O at 0° C. and stirred for 2 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with ammonium hydroxide. The organic layer was dried over Na2SO4 and concentrated. (Z)-1,3-Dihydro-5-fluoro-4-[(2S,4R)-(4-hydroxy-pyrrolidin-2-yl)-ethynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with 0-20% MeOH in CH2Cl2 gradient and precipitation out of THF with excess of pentane. (Yield 12 mg, 31%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1)[CH3:3]>[C].[Pd].C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CN(C)Cc1ccc(N)cc1

Procedure:
In a 30 l autoclave was placed a suspension in which 10 g. of a palladium-carbon catalyst was suspended in 50 ml of ethanol, and 890 g. of N,N-dimethyl-p-nitrobenzylamine and 10 l of ethanol were charged thereinto. Then, hydrogenation was carried out at 35° C. under 30 atm., and when the consumption of hydrogen was ceased, the reaction mixture was taken out of the autoclave. After the palladium-carbon was removed by filtration and the ethanol was removed by distillation to concentrate the filtrate, the resulting residue was distilled under reduced pressure to give a light-yellow liquid which was the desired product boiling at 105° to 108° C./2 mmHg. Yield: 675 g. (90%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:2].[Cl:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:46]3[CH:47]=[CH:48][C:43]([Cl:42])=[CH:44][CH:45]=3)[CH:25]=[C:26]([S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[CH:27]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(S(=O)(=O)CC)c2)c1CCC(=O)OCC
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccc(Cl)cc3)cc(S(=O)(=O)CC)c2)c1CCC(=O)OCC
Yield: 75.7 %

Procedure:
A similar procedure as described in Example 41, step 1 was used, starting from 4-[3-[6-(3-bromo-5-ethanesulfonyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (161 mg, 0.25 mmol), 4-chloro-phenylboronic acid (81 mg, 0.50 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (27 mg, 0.038 mmol), and cesium carbonate (162 mg, 0.5 mmol) to afford 4-[3-[6-(5-ethanesulfonyl-4′-chloro-biphenyl-3-yloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (130 mg, 77%) as a colorless viscous oil: ES(+)-HRMS m/e calcd for C37H47ClO8S (M+Na)+ 709.2572, found 709.2572.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:22])[CH:9]=[C:10]([C:11]3[CH:19]=[C:18]4[C:14]([CH2:15][CH:16]([CH3:21])[N:17]4[CH3:20])=[CH:13][CH:12]=3)[C:3]=12.[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[N:25]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:20][N:17]1[C:18]2[C:14](=[CH:13][CH:12]=[C:11]([C:10]3[C:3]4[C:4](=[N:5][CH:6]=[CH:7][C:2]=4[NH:32][S:29]([C:26]4[CH:27]=[CH:28][N:24]([CH3:23])[N:25]=4)(=[O:31])=[O:30])[N:8]([CH3:22])[CH:9]=3)[CH:19]=2)[CH2:15][CH:16]1[CH3:21]
Reactant: CC1Cc2ccc(-c3cn(C)c4nccc(Br)c34)cc2N1C
Reactant: Cn1ccc(S(N)(=O)=O)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC1Cc2ccc(-c3cn(C)c4nccc(NS(=O)(=O)c5ccn(C)n5)c34)cc2N1C
Temperature: 120 °C
Yield: 30.9 %

Procedure:
4-Bromo-3-(1,2-dimethylindolin-6-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (541 mg, 1.519 mmol), 1-methyl-1H-pyrazole-3-sulfonamide (D94) (367 mg, 2.278 mmol), Pd2(dba)3 (139 mg, 0.152 mmol), xantphos (176 mg, 0.304 mmol) and cesium carbonate (1484 mg, 4.56 mmol) charged into a microwave vial and suspended in 1,4-dioxane (8.0 mL). The reaction mixture was degassed under nitrogen for 10 mins before subjected to microwave heating at 120° C. for 30 mins. The reaction mixture was then partitioned between ethyl acetate/water (ca. 30 mL each). Aqueous layer was separated and re-extracted with ethyl acetate (ca. 25 mL twice). The combined organic layers were dried over MgSO4 and solvent removed in vacuo. The residue was purified using chromatography on silica, eluting with a gradient of 0-100% ethyl acetate in cyclohexane and followed by another purification on silica, eluting with a gradient of 0-40% ethyl acetate in DCM to afford title compound (205 mg). LCMS (A): m/z (M+H)+ 437, C22H24N6O2S requires 436 (acidic).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([CH3:23])[N:16]=1.[C:24](=[O:26])=[O:25]>O1CCCC1.O>[CH3:22][O:21][C:19]1[CH:20]=[C:15]([O:14][CH3:13])[N:16]=[C:17]([CH2:23][C:24]([OH:26])=[O:25])[N:18]=1
Reactant: COc1cc(OC)nc(C)n1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC)nc(CC(=O)O)n1
Reaction time: 0.33 h

Procedure:
n-Butyllithium (200 ml of 2N in pentane) was added dropwise over 30 minutes to a stirred solution of di-isopropylamine (40.4 g) in tetrahydrofuran (200 ml) at -70° C. under nitrogen. The mixture was stirred for 20 minutes and then 4,6-dimethoxy-2-methylpyrimidine (61.6 g) in tetrahydrofuran (200 ml) was added dropwise over 20 minutes. The mixture was stirred at -70° C. for 30 minutes before being poured onto a large excess of solid carbon dioxide. The mixture was allowed to warm to room temperature before water (800 ml) was added. The clear solution was concentrated to half volume under vacuum and was then washed with ether. The aqueous phase was acidified with concentrated hydrochloric acid and the resulting solid was filtered, washed with water and dried to give 58.3 g of (4,6-dimethoxypyrimidin-2-yl)acetic acid.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:21]([O:22]C(=O)C)[C@H:20]([O:26][C@H:27]2[O:44][C@H:43]([CH2:45][O:46]C(=O)C)[C@@H:38]([O:39]C(=O)C)[C@H:33]([O:34]C(=O)C)[C@H:28]2[O:29]C(=O)C)[C@@H:19]([CH2:50][O:51]C(=O)C)[O:18][C@H:6]1[S:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)(=O)C>CO>[C@H:27]1([O:26][C@@H:20]2[C@@H:19]([CH2:50][OH:51])[O:18][C@@H:6]([S:7][C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=3)[C@H:5]([OH:4])[C@H:21]2[OH:22])[O:44][C@H:43]([CH2:45][OH:46])[C@@H:38]([OH:39])[C@H:33]([OH:34])[C@H:28]1[OH:29]
Reactant: CC(=O)OC[C@H]1O[C@@H](Sc2cccc(C(F)(F)F)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1O[C@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: CO
Product: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](Sc3cccc(C(F)(F)F)c3)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 8 h

Procedure:
A 3.5 g portion of 3-trifluoromethylphenyl 2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl)-1-thio-β-D-glucopyranoside was reacted as described in Example 8. Rather than refrigerating overnight, this mixture was allowed to stand at room temperature for 20 hours, giving 2.5 g of the desired intermediate as a white solid, [α]D26 =+25°±2° (0.496%, methanol).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:5]=1[C:6](O)=[O:7])[CH3:2].S(Cl)([Cl:30])=O.CN(C)C=O>CCCCCC>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:5]=1[C:6]([Cl:30])=[O:7])[CH3:2]
Reactant: CCCCCCCCCCCCCCCc1cccc(OCC)c1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCc1cccc(OCC)c1C(=O)Cl

Procedure:
To a stirred solution of 2-Ethoxy-6-pentadecylbenzoic Acid (6.5 g, 16 mmol) in hexane (60 mL) were added thionyl chloride (2.5 g, 21 mmol) and N,N-dimethylformamide (0.5 mL). The reaction mixture was heated to reflux for 1 h. After the reaction was complete, the solvent was evaporated under reduced pressure to yield the desired 2-Ethoxy-6-pentadecylbenzoyl Chloride, which was redissolved in dichloromethane (50 mL) and used for the condensation with anilides.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:23][C:24]([F:27])([F:26])[F:25])[CH2:10][CH2:11][O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)=[CH:5][C:4]=1[C:28]([F:31])([F:30])[F:29])#[N:2].O[Li].O.O>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:23][C:24]([F:25])([F:26])[F:27])[CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=2)=[CH:5][C:4]=1[C:28]([F:29])([F:30])[F:31])#[N:2]
Reactant: COC(=O)c1ccc(OCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(N(CCOc2ccc(C(=O)O)cc2)CC(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 19 h
Yield: 97.8 %

Procedure:
To a solution of methyl 4-({2-[[4-cyano-3-(trifluoromethyl)phenyl](2,2,2-trifluoroethyl)amino]ethyl}oxy)benzoate (0.0863 g, 0.193 mmol, Example 32) in THF (3 mL) at rt was added LiOH.H2O (0.041 g, 0.97 mmol) and water (0.30 mL). The mixture was stirred 19 h at rt, then 8 h at reflux, cooled and partitioned between 1 N NaOH/Et2O. Layers were separated, and the aqueous layer extracted with Et2O (×1). The aqueous layer was then acidified to approximately pH 1 by addition of 2N HCl and extracted with EtOAc (×3). Combined EtOAc extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo yielding 0.0816 g of the title compound as a colorless film which crystallized when triturated with CDCl3: 1H NMR (400 MHz, CD3OD) δ 7.97-7.90 (m, 2H), 7.75 (d, J=8.9 Hz, 1H), 7.38 (d, J=2.3 Hz, 1H), 7.28 (dd, J=8.9, 2.5 Hz, 1H), 6.97-6.92 (m, 2H), 4.45 (q, J=8.8 Hz, 2H), 4.31 (t, J=5.2 Hz, 2H), 4.08 (t, J=5.2 Hz, 2H); MS (ESI) m/z 431 (M−1).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6](Cl)[N:5]=1.[CH2:14]([OH:16])[CH3:15]>>[NH2:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([O:16][CH2:14][CH3:15])[N:5]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Product: CCOc1ccc([N+](=O)[O-])c(N)n1
Reaction time: 0.17 h

Procedure:
2.4 g of 60% sodium hydride was slowly added to 100 ml of ethanol and stirred as it was at room temperature for 10 minutes. 10 g of 2-amino-6-chloro-3-nitropyridine was added thereto and reacted at room temperature for 30 minutes. After concentration, water was added thereto, and it was extracted with ethyl acetate. It was washed with water and brine sucsessively, and dried over anhydrous sodium sulfate. After concentration, 9.7 g of the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9](=[O:12])[CH2:8][CH2:7]2.[Cl-].[Cl-].[Cl-].[Al+3].O>CO>[OH:10][C:11]1[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]2[C:6]=1[CH2:7][CH2:8][C:9]2=[O:12]
Reactant: Cc1cccc2c1OC(=O)CC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: Cc1ccc2c(c1O)CCC2=O
Temperature: 177.5 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
The mixture of 8-Methyl dihydrocoumarin (20 gm, 0.123 mole) and Aluminum trichloride (49.3 gm, 0.370 mole) was stirred for 2 hours at 175-180° C. To the reaction mixture, water (250 ml) was added slowly and stirred for an hour. Further it was filtered and obtained solid was stirred in Methanol (60 ml). Finally the suspension was filtered and obtained solid was dried under vacuum to give 13.5 gm of desired product as a solid.