Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:5]([NH2:6])=[C:4]([F:19])[CH:3]=1.[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2[CH2:26][CH2:27][CH2:28][CH2:29][C:21]1=2.N1CCCCC1.C(O)(=O)C>O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:5]([N:6]2[C:23](=[O:24])[C:22]3[CH2:26][CH2:27][CH2:28][CH2:29][C:21]=3[C:20]2=[O:25])=[C:4]([F:19])[CH:3]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: CCCCCOC(=O)COc1cc(N)c(F)cc1Cl
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCCCCOC(=O)COc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Yield: 95.1 %

Procedure:
A mixture of the compound (II) (12.0 g), 3,4,5,6-tetrahydrophthalic anhydride (7.56 g), piperidine (0.36 g), acetic acid (0.5 g) and toluene (24 g) was refluxed at 88° to 92° C. under a pressure of about 300 mmHg for 4 hours, during which water was azeotropically removed. The reaction mixture was then treated as in Example 4 to give the compound (I) (16.7 g).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([Br:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][NH:14][CH3:15]>O>[Br:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([N:14]([CH3:15])[CH3:13])[CH:11]=1
Reactant: CNC
Reactant: Brc1cc(Br)c2ccccc2n1
Solvent: O
Product: CN(C)c1cc(Br)c2ccccc2n1
Reaction time: 8 h
Yield: 40 %

Procedure:
The product from (451a) (2.0 g, 7.0 mmol) was dissolved in 10 mL of 40% dimethylamine solution in H2O. The reaction mixture was allowed to stir overnight. The solution was diluted to 40 mL with H2O and it was extracted with EtOAc for three times. The combined organic layer was dried over MgSO4. After concentration, the residue was purified on silica gel column to provide 4-bromo-2-dimethylaminoquinoline (451b) (0.69 g, 40%). MS (AP+): 251 (M+1).
Reaction SMILES: [C:1](=[O:16])([O:14][CH3:15])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([F:12])=[CH:5][C:4]=1[CH3:13]>C(O)C.C(OCC)(=O)C.[Pt](=O)=O>[F:12][C:6]1[CH:5]=[C:4]([CH3:13])[C:3]([O:2][C:1]([O:14][CH3:15])=[O:16])=[CH:8][C:7]=1[NH2:9]
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1C
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)Oc1cc(N)c(F)cc1C
Reaction time: 1.5 h
Yield: 94.1 %

Procedure:
A mixture of (4-fluoro-2-methyl-5-nitrophenyl) methyl carbonate (8 g, 35 mmol), (EP 0307777 A2), and platinum(IV)oxide (174 mg) in ethanol (100 ml) and ethyl acetate (70 ml) was stirred under hydrogen at 1.3 atmospheres pressure for 1.5 hours. The catalyst was removed by filtration through diatomaceous earth and the solvent removed by evaporation. The residue was purified by column chromatography eluting with petroleum ether/ethyl acetate (7/3) to give 2-fluoro-5-methoxycarbonyloxy-4-methylaniline (6.56 g, 94%) as an oil which crystallised. 1H NMR Spectrum (CDCl3): 2.09(s, 3H); 3.66(br s, 2H); 3.90(s, 3H); 6.54(d, 1H); 6.83(d, 1H)
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[H-].[Na+].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(=O)(O)[O-].[Na+]>O1CCCC1>[Si:10]([O:4][CH2:3][C:2]([CH3:7])([CH3:1])[CH2:5][OH:6])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(CO)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(CO)CO[Si](C)(C)C(C)(C)C
Yield: 87.7 %

Procedure:
A solution of 10 g of 2,2-dimethyl-1,3-propanediol in 100 ml of tetrahydrofuran is added in drops to a suspension of 3.85 g of sodium hydride (60%) in 30 ml of tetrahydrofuran. It is allowed to stir for 45 more minutes, and then 14.5 g of tert-butyldimethylsilyl chloride is added. Then, it is stirred for one more hour at 25° C. Then, the reaction mixture is poured into saturated sodium bicarbonate solution. It is extracted with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried on sodium sulfate, and concentrated by evaporation in a vacuum. The crude product is purified by column chromatography on silica gel. 18.4 g of product is obtained.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[CH:9])[CH2:3]1.[F:10][C:11]1[C:12](I)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.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.[Cu]I>[F:10][C:11]1[C:12]([C:9]#[C:8][CH2:7][N:4]2[CH2:5][CH2:6][C@@H:2]([OH:1])[CH2:3]2)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CCN1CC[C@@H](O)C1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CCN3CC[C@@H](O)C3)c21

Procedure:
Using Method C above, (R)-3-Hydroxy-1-prop-2-ynyl-pyrrolidine (60 mg, 0.48 mmol) (Example 92A) 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 catalylic amount of CuI in a mixture of DMF (4 mL) and Et3N (4 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 and concentrated. (R)-(Z)-1,3-Dihydro-5-fluoro-4-[3-(3-hydroxy-pyrrolidin-1-yl)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-20% MeOH in CH2Cl2 gradient and precipitation out of THF with excess of pentane. (Yield 45 mg, 76%).
Reaction SMILES: CN1CCNCC1.[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[CH2:11][CH2:10]1.[BH4-].[Na+]>CO.Cl.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[CH2:11][CH2:10]1
Reactant: CN1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl[Ni]Cl
Agent: CN1CCNCC1
Agent: Cl
Solvent: O
Solvent: CO
Product: CN1CCN(Cc2ccc(N)cc2)CC1

Procedure:
Using the procedure of Example 1, 1-methyl-piperazine Compound 46a1 was used in place of Compound 1n2 and carried forward to prepare 1-methyl-4-(4-nitro-benzyl)-piperazine Compound 46a2. Nickel chloride hexahydrate (45.7 g, 192 mmol) was added to a solution of Compound 46a2 (17.9 g, 87.4 mmol) in methanol (250 mL). Twenty portions of sodium borohydride (500 mg each, 264 mmol total) were then added to the reaction mixture over a period of about 2 hr. The mixture was then carefully diluted at 0° C. with concentrated HCl to give a transparent green solution. The mixture was subsequently washed with ethyl ether. The cooled aqueous layer was adjusted to pH 10 with NH4OH (28%) and then extracted with EtOAc. The combined organic layers were dried over MgSO4, then filtered and evaporated in vacuo to give 4-(4-methyl-piperazin-1-ylmethyl)-phenylamine Compound 46a (17.6 g) as a yellow foam. 1H NMR (DMSO-d6) δ 6.91 (d, J=8.2 Hz, 2H); 6.50 (d, J=8.2 Hz, 2H); 4.94 (br s, 2H); 3.28 (s, 2H); 2.44-2.26 (m, 8H); 2.19 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([S:7][CH2:8][C:9]2[CH2:26][S:25][C@@H:12]3[C@H:13]([NH:16][C:17]([CH2:19][N:20]4[N:24]=[N:23][N:22]=[CH:21]4)=[O:18])[C:14](=[O:15])[N:11]3[C:10]=2[C:27]([OH:29])=[O:28])=[N:4][N:3]=1.[N+:30]([O-:33])([OH:32])=[O:31]>CO.C(#N)C>[CH3:1][C:2]1[S:6][C:5]([S:7][CH2:8][C:9]2[CH2:26][S:25][C@@H:12]3[C@H:13]([NH:16][C:17]([CH2:19][N:20]4[N:24]=[N:23][N:22]=[CH:21]4)=[O:18])[C:14](=[O:15])[N:11]3[C:10]=2[C:27]([OH:29])=[O:28])=[N:4][N:3]=1.[N+:30]([O-:33])([O-:32])=[O:31]
Reactant: O=[N+]([O-])O
Agent: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)Cn4cnnn4)[C@H]3SC2)s1
Solvent: CC#N
Solvent: CO
Product: O=[N+]([O-])[O-]

Procedure:
The compound is prepared by adding to a Cefazolin solution (1.5 g, 3.3 mmoles) in methanol (50 ml) a 65% nitric acid solution (0.250 ml) in acetonitrile (5 ml) and following then the procedure reported in Example 5. Cefazolin nitrate as amorphous solid is obtained. Yield 60%.
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]1[S:9][C:8]2[CH2:10][CH2:11][N:12]([CH:14]([C:22]([CH:24]3[CH2:26][CH2:25]3)=[O:23])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[F:21])[CH2:13][C:7]=2[CH:6]=1)=[O:3].[N+:27]([O-:30])([OH:29])=[O:28].CCCCCCC>CC(C)=O>[CH3:1][C:2]([O:4][C:5]1[S:9][C:8]2[CH2:10][CH2:11][N:12]([CH:14]([C:22]([CH:24]3[CH2:26][CH2:25]3)=[O:23])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[F:21])[CH2:13][C:7]=2[CH:6]=1)=[O:3].[N+:27]([O-:30])([O-:29])=[O:28]
Reactant: O=[N+]([O-])O
Agent: CC(=O)Oc1cc2c(s1)CCN(C(C(=O)C1CC1)c1ccccc1F)C2
Solvent: CC(C)=O
Solvent: CCCCCCC
Product: O=[N+]([O-])[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 251 mg of prasugrel base form I in 3.75 ml acetone at room temperature (20-25° C.), a solution of 50.6 μl (1.1 eq) 65% aqueous nitric acid in 1.25 ml acetone was added in portions and the resulting mixture was stirred at room temperature for about 15 minutes. After addition of 5 ml heptane at 0-5° C. (ice bath), the clear reaction mixture turned to an emulsion (clear oil drops on the bottom of the flask). A white precipitate was obtained after storage for 17 hours at about −25° C. The mixture containing the precipitate was stirred for 1 hour at 0-5° C. (ice bath), filtered off, washed with 1 ml cold acetone/heptane (1:1) and dried at 40° C./10 mbar for about 2.5 hours. White crystals (269 mg) of prasugrel nitrate were obtained.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].[CH3:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=1[C:15]1[NH:24][C:22](=[O:23])[C:18]2[NH:19][N:20]=[N:21][C:17]=2[N:16]=1>C(#N)C.C(OCC)C>[CH3:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=1[C:15]1[NH:24][C:22](=[O:23])[C:18]2[NH:19][N:20]=[N:21][C:17]=2[N:16]=1.[N+:1]([O-:4])([O-:3])=[O:2]
Reactant: O=[N+]([O-])O
Agent: CCCOc1ccccc1-c1nc2nn[nH]c2c(=O)[nH]1
Solvent: CC#N
Solvent: CCOCC
Product: O=[N+]([O-])[O-]
Reaction time: 0.5 h

Procedure:
0,5 ml of a solution nitric acid 65%/ acetonitrile (2,7 ml/7,3 ml) was added at 0° C. to a solution of Zaprinast (0,5 g, 1,84 mmoles) in acetonitrile (10 ml) and the obtained mixture was stirred in the dark and under a nitrogen atmosphere for 30 minutes. The solution was then diluted with diethyl ether and the formed precipitate filtered, washed with diethyl ether and dried under vacuum.( 0,4 g).
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[F-].[Ca+2:21].[Ca+2].[Ca+2].[Ca+2].[Ca+2]>O>[N+:1]([O-:4])([O-:3])=[O:2].[Ca+2:21].[N+:1]([O-:4])([O-:3])=[O:2]
Reactant: O=[N+]([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [Ca+2]
Agent: [F-]
Solvent: O
Product: O=[N+]([O-])[O-]

Procedure:
In Austrian Patent No. 176,219, Joham, Sept. 25, 1953 there is described the reaction of nitric acid with phosphate rock to produce a liquid reaction mixture which is subsequently evaporated and dried at 200° C. to provide a solid material which was dispersed in water and filtered to produce a concentrated calcium nitrate solution and a solid product containing 34.3 percent P2O5, of which 88 percent was citrate soluble. A variation of the procedure involved the addition of lime to the initially produced acidulate to bring the pH to 1.4 and to precipitate CaF2, which was then filtered along with the gangue. Subsequent treatment of the filtrate, as described above, resulted in a solid product containing 44.8 percent P2O5, of which 89 percent was citrate soluble. It should be noted, however, that this procedure probably also results in partial reversion of phosphate to fluorapatite as indicated by the phase equilibria of Farr, et al., supra. Furthermore, neither variation of the procedure provides for a completely citrate soluble phosphate product, or for the recovery of the excess nitric acid liberated during the evaporation process.
Reaction SMILES: [Cl-].[Zn+2:2].[Cl-].[Zn].[N+:5]([O-:8])([OH:7])=[O:6]>>[N+:5]([O-:8])([O-:7])=[O:6].[Zn+2:2].[N+:5]([O-:8])([O-:7])=[O:6]
Reactant: O=[N+]([O-])O
Agent: [Cl-]
Agent: [Zn+2]
Agent: [Zn]
Product: O=[N+]([O-])[O-]

Procedure:
The zinc chloride solution is then subjected to a cationic extractant (Di-2-ethylhexyl phosphoric acid) D2EHPA (50%) and 50% kerosene to produce a loaded solvent containing about 5 gpl zinc. An O/A ratio of about one is employed to produce a raffinate containing less than 0.05 gpl zinc. The loaded organic is contacted with a 200 gpl HNO3 strip solution with O/A ratio of 1/4 to produce a zinc nitrate solution containing 30 gpl zinc and about 150 gpl HNO.
Reaction SMILES: CC(OC(C)=O)=O.[C:8]([O:14][C:15]([C:17](F)(F)F)=[O:16])([C:10]([F:13])([F:12])[F:11])=[O:9]>>[F:11][C:10]([F:13])([F:12])[C:8]([O:14][C:15](=[O:16])[CH3:17])=[O:9]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC(=O)C(F)(F)F

Procedure:
Acetyl trifluoroacetate was prepared by the method of Bourne in which equimolar amounts of Ac2O and TFAA are combined and heated to reflux for an hour, then fractionally distilled and the material boiling between 90-100° C. collected and characterized by IR and NMR: 1H NMR (CDCl3): δ 2.39 ppm; 13C NMR (CDCl3): δ 162.7,158.7 (q, JCF=44.7 Hz), 113.9 (q, JCF=286.3 Hz), 22.0 ppm; IR (CH2Cl2) VC═O=1854,1782; vC—O—C=1075 cm−1.
Reaction SMILES: [NH3:1].[C:2]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])#[N:3]>C1COCC1>[C:2]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH2:1])=[O:8])#[N:3]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: N
Solvent: C1CCOC1
Product: N#Cc1cccc(C(N)=O)c1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A mixture of 28% aqueous ammonia (20 ml) and THF (30 ml) was cooled to 5° C. and 3-cyanobenzoyl chloride (1.45 g) was slowly added. The mixture was stirred for one hr. and the reaction mixture was extracted with ethyl acetate. The organic layer was dried and concentrated. The residue was recrystallized from ethyl acetate to give the title compound (802 mg) as colorless needle crystals.
Reaction SMILES: [CH:1]1([C:6]2[CH:31]=[CH:30][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[NH:17][C:16]5[CH:21]([CH2:24][C:25]([O:27]CC)=[O:26])[CH2:22][CH2:23][C:15]=5[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:32]([F:35])([F:34])[F:33])[CH2:5][CH2:4][CH2:3][CH2:2]1.CO.O[Li].O.Cl>O.O1CCCC1>[CH:1]1([C:6]2[CH:31]=[CH:30][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[NH:17][C:16]5[CH:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:22][CH2:23][C:15]=5[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:32]([F:35])([F:33])[F:34])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)cc21
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC1CCc2c1[nH]c1ccc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a solution of ethyl 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (38.7 mg, 0.080 mmol) in a mixed solvent of methanol (1.5 mL), tetrahydrofuran (0.5 mL), and water (0.5 mL) was added LiOH hydrate (11.7 mg, 0.279 mmol). The mixture was stirred at room temperature overnight before the mixture was acidified to pH 4 with 1 N aqueous HCl solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and dried under vacuum. The foam was triturated with water to give a solid. The solid was filtered to give the title compound as a light pink solid (25.7 mg). LCMS m/z=458.4[M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.56-1.70 (m, 4H), 1.80-1.87 (m, 2H), 1.95-2.11 (m, 3H), 2.34 (dd, J=16.04, 8.97 Hz, 1H), 2.59-2.74 (m, 4H), 3.21-3.25 (m, 1H), 3.41-3.49 (m, 1H), 5.11 (s, 2H), 6.70 (dd, J=8.72, 2.40 Hz, 1H), 6.92 (d, J=2.27 Hz, 1H), 7.19 (d, J=8.72 Hz, 1H), 7.61 (d, J=8.00 Hz, 1H), 7.68 (d, J=8.00 Hz, 1H), 7.70 (s, 1H), 10.45 (s, 1H), 12.18 (bs, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH:10](O)[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:35][O:36][C:37]1[CH:42]=[C:41]([O:43][CH3:44])[N:40]=[C:39]([SH:45])[N:38]=1.[Na].CN(C=O)C>ClCCl>[CH2:1]([O:8][C:9]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:16])[CH:10]([S:45][C:39]1[N:38]=[C:37]([O:36][CH3:35])[CH:42]=[C:41]([O:43][CH3:44])[N:40]=1)[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(O)C(C)(OCc1ccccc1)c1ccccc1
Reactant: COc1cc(OC)nc(S)n1
Agent: CS(=O)(=O)Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(Sc1nc(OC)cc(OC)n1)C(C)(OCc1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 28.2 %

Procedure:
11 g (25 mmol) of methyl 3-benzyloxy-3-phenyl-2-hydroxybutyrate (comp. 1.1) are dissolved in 50 ml of dichloromethane, 3 g (30 mmol) of triethylamine are added and, while stirring, 3.2 g (28 mmol) of methanesulfonyl chloride are added dropwise. The mixture is stirred at room temperature for 2 hours, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is taken up in DMF and added dropwise to a suspension of 12.9 g (75 mmol) of 4,6-dimethoxypyrimidine-2-thiol and 8.4 g (100 nmol) of sodium DMF at 0° C. After stirring at room temperature for 2 hours and at 60° C. for a further 2 hours, the mixture is poured into 1 1 of ice-water, and the precipitate is filtered off with suction. Drying results in 3.2 g of a white powder.
Reaction SMILES: CO[C:3](=[O:21])[CH2:4][C:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:9][CH:10]=1.[NH2:22][C:23]1[C:28]([Br:29])=[CH:27][CH:26]=[CH:25][N:24]=1>ClCCCl>[Br:29][C:28]1[C:23]([NH:22][C:3](=[O:21])[CH2:4][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:12])[CH2:9][CH:10]=2)=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: Nc1ncccc1Br
Reactant: COC(=O)CC1=CCN(C(=O)OCc2ccccc2)CC1
Solvent: ClCCCl
Product: O=C(CC1=CCN(C(=O)OCc2ccccc2)CC1)Nc1ncccc1Br
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 189 %

Procedure:
Timethylaluminum (2.0 M, 2.05 mL, 4.10 mol) was added slowly to a 0° C. solution of benzyl 4-(2-methoxy-2-oxoethyl)-3,6-dihydropyridine-1(2H)-carboxylate (0.79 g, 2.73 mol) and 2-amino-3-bromopyridine (0.520 g, 3.00 mmol) in 1,2-dichloroethane (15 mL). After 30 min, the reaction was heated to 55° C. for 48 h. The reaction was quenched by the careful addition of saturated aqueous sodium bicarbonate and the mixture extracted with dichlormethane (4×). The combined organic layers were washed with 1N sodium potassium tartrate, brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel chromatography, eluting with a gradient of 50 to 100% ethyl acetate:hexanes to give the title compound (2.44 g). MS: m/z=430.0 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.C(N1C=CN=C1)([N:15]1C=CN=C1)=O>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH2:15])=[O:12]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Solvent: C1CCOC1
Product: NC(=O)c1cc2ccccc2[nH]1
Reaction time: 1 h

Procedure:
Add to the 2-indole carboxylic acid (12.4 mmol) in anhydrous THF (30 ml), carbonyldiimidazole (1.5 equiv, 18.6 mmol) and stir for 1 h. Add the desired amine [for example, methylamine, ethylamine, dimethylamine, pyrrolidine, piperidine, piperazine, or morpholine, (3.0 equiv, 37.2 mmol)] in one portion and stir the reaction at rt. After 16 hours, quench the reaction with H2O, collect the resulting precipitate by filtration and dry under vacuum to afford the desired 2-indole carboxamide.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([NH:9][C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].[O:12]1[C@@H:14]([CH2:15][CH3:16])[CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[OH:12][C@@H:14]([CH2:15][CH3:16])[CH2:13][N:9]1[C:7](=[O:8])[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[C:10]1=[O:11]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC[C@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@H](O)CN1C(=O)c2ccccc2C1=O
Temperature: 60 °C

Procedure:
To 1,2-Benzenedicarboximide (4.29 g) in DMF (10 ml), (S)-(−)-1,2-epoxybutane (2.1 g) was added followed by K2CO3 (4.03 g) and heated at 60° C. for 48 h. The reaction was diluted with water, extracted with EtOAc, dried and solvent removed to give the subtitle compound as a white solid, 1.8 g.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[C:10]([CH3:19])=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12](OC)=[O:13].OS(O)(=O)=O>C1COCC1>[CH3:7][O:8][C:9]1[C:10]([CH3:19])=[C:11]([CH2:12][OH:13])[CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1cccc(OC)c1C
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1cccc(CO)c1C
Yield: 95.8 %

Procedure:
A suspension of 4.5 g (0.118 mol) of lithium aluminum hydride in 100 mL of THF was treated dropwise with a solution of 14.22 g (78.9 mmol) of methyl 3-methoxy-2-methylbenzoate in 120 mL of THF. The mixture was heated at reflux for 2.5 hours, then cautiously decomposed with 1N H2SO4. The mixture was extracted with EtOAc, and the EtOAc washed with dilute HCl, H2O, saturated NaHCO3, and saturated NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure left 11.5 g (95.8% yield) of the product as a tan solid, mp 63-64° C. The structure was confirmed by NMR and mass spectroscopy. MS m/z 153 (M+H+).
Reaction SMILES: [OH:1][CH2:2]/[C:3](/[CH2:12][CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:4]/[CH2:5][CH2:6]/[C:7](/[CH3:11])=[CH:8]/[CH2:9][OH:10].[S:23](=[O:27])(=[O:26])([OH:25])[OH:24].[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1C=CC=CC=1>[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[S:23]([O:25][S:23]([OH:26])(=[O:25])=[O:24])([OH:24])(=[O:27])=[O:26].[OH:1][CH2:2]/[C:3](/[CH2:12][CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:4]/[CH2:5][CH2:6]/[C:7](/[CH3:11])=[CH:8]/[CH2:9][OH:10]
Reactant: O=S(=O)(O)O
Agent: CC(C)=CCC/C(C)=C/CC/C(=C\CC/C(C)=C/CO)CO
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=S(=O)(O)OS(=O)(=O)O

Procedure:
Following the same manner as in Example 26, the reaction was conducted with 3.0 g of (E,Z,E) and (E,E,E)-7-hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraen-1-ol and 5.0 g of anhydrous sulfuric acid-pyridine reagent in anhydrous benzene and after-treatment was conducted to afford 4.4 g of the end product.
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)([CH3:19])[CH3:18].N1C=CC=CC=1C.[Cl-].[NH4+]>CS(C)=O.[Cu](I)I>[CH3:18][CH:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:2]2[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:22][CH:21]=1)[CH3:19]
Reactant: Nc1ncccc1Br
Reactant: CC(C)c1ccc(O)cc1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: Cc1ccccn1
Product: CC(C)c1ccc(Oc2cccnc2N)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 11.4 %

Procedure:
A mixture of 3-bromopyridin-2-amine (1200 mg), tripotassium phosphate (2945 mg), 4-isopropylphenol (1134 mg), copper iodide (I) (132 mg) and picoline acid (171 mg) in DMSO (40 mL) was stirred under a nitrogen atmosphere at 80° C. overnight. The reaction mixture was added to saturated aqueous ammonium chloride solution, filtered through celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (180.4 mg) as a pale-brown solid.