Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[I-].C[S+](C)(C)=O.O=C1C[CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]C1.O>COCCOC>[O:4]1[C:2]2([CH2:5][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:3]2)[CH2:1]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reaction time: 1 h
Yield: 80.8 %

Procedure:
Potassium tert.-butoxide (31 g) was added to a stirred suspension of trimethylsulfoxonium iodide (60.8 g) in 1,2-dimethoxyethane (250 mL) at 20° C. After 1 hour, the mixture was added portionwise over 30 minutes to a stirred solution of 4-oxo-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (50 g) in 1,2-dimethoxyethane (50 mL) at 0° C. After a further 2 hours, water (500 mL) was added and the mixture was extracted with tert.-butyl methyl ether (2×500 mL). The organic extracts were washed separately with saturated sodium bicarbonate solution (250 mL). The combined organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residual oil was co-evaporated with toluene (100 mL) to give the sub-title compound (43.25g) as a solid. 1H-NMR (CDCl3, 400 MHz): δ 3.75-3.70 (m, 2H); 3.47-3.38 (m, 2H); 2.69 (s, 2H); 1.84-1.75 (m, 2H); 1.48-1.43 (m, 2H); 1.46 (s, 9H).
Reaction SMILES: Br[CH2:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:6][CH2:5]1.[F:17][C:18]([F:32])([F:31])[C:19]1[CH:20]=[C:21]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(Cl)Cl>[N:12]1[CH:13]=[CH:14][CH:15]=[N:16][C:11]=1[NH:10][C@H:7]1[CH2:8][CH2:9][C@H:4]([CH2:3][CH2:2][N:28]2[CH2:27][CH2:26][N:25]([C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:31])([F:32])[F:17])[CH:20]=3)[CH2:30][CH2:29]2)[CH2:5][CH2:6]1
Reactant: BrCC[C@H]1CC[C@H](Nc2ncccn2)CC1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: FC(F)(F)c1cccc(N2CCN(CC[C@H]3CC[C@H](Nc4ncccn4)CC3)CC2)c1

Procedure:
A mixture of trans-[4-(2-Bromoethyl)-cyclohexyl]-pyrimidin-2-yl-amine (0.26 g, 0.91 mmol), 1-(3-trifluoromethyl-phenyl)-piperazine (0.21 g, 0.91 mmol), and potassium carbonate (0.21 g, 1.5 mmol) was heated in 10 mL refluxing acetonitrile for 18 hours. The reaction was diluted with methylene chloride, filtered, and the solvents were removed under reduced pressure. The residue was partitioned between chloroform and aqueous 2N sodium carbonate solution. The organic layer was dried over sodium sulfate and evaporated. The resulting residue was recrystallized from acetonitrile to give the title compound; mp 167° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[CH3:9][O:10][C:11](=[O:22])[C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]([NH2:21])[CH:13]=1.CCN(CC)CC>C(Cl)Cl>[CH3:9][O:10][C:11](=[O:22])[C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]([NH:21][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[CH:13]=1
Reactant: COC(=O)c1cc(N)cc([N+](=O)[O-])c1
Reactant: O=C(Cl)CCCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(NC(=O)CCCCCl)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 124.6 %

Procedure:
5-Chlorovaleryl chloride (2.64 g, 17 mmol, 1.1 equiv) in CH2Cl2 (5 ml) was added over 2 min to a stirred solution of 3-amino-5-nitro-benzoic acid methyl ester (D1) (3 g, 15.3 mmol, 1 equiv) and NEt3 (2.6 ml, 18 mmol, 1.2 equiv) in CH2Cl2 (30 ml). The resulting mixture was stirred for 1 h at room temperature then washed with 2N aqueous HCl solution, dried over MgSO4 and concentrated in vacuo. The residue was triturated with CH2Cl2 to give 3-(5-Chloro-pentanoylamino)-5-nitro-benzoic acid methyl ester D3 (6 g, 112%) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:18]=2)[N:13]=1.C(#N)C>O>[C:22]1([C:16]2[N:15]=[C:14]3[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)=[N:13]3)=[CH:18][CH:17]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: Nc1ccc2ccc(-c3ccccc3)nc2n1
Solvent: CC#N
Solvent: O
Product: O=C(Nc1ccc2ccc(-c3ccccc3)nc2n1)c1cccc(Cl)c1
Temperature: 4 °C
Yield: 57.6 %

Procedure:
The procedure is analogous to that described in Example 1, but starting with 3-chlorobenzoic acid (1.6 g), N,N'-carbonyldiimidazole (1.6 g) and 2-amino-7-phenyl-1,8-naphthyridine (1.6 g). The product obtained by precipitation in water (2.2 g; m.p. approximately 160° C.) is dissolved in boiling acetonitrile (200 cc). After cooling for 4 hours at 4° C., the crystallized solid is separated by filtration, washed with acetonitrile (3×10 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-(7-Phenyl-1,8-naphthyridin-2-yl)-3-chlorobenzamide (1.5 g), m.p. 175° C., is obtained.
Reaction SMILES: [Cl:1][Si:2]([Cl:9])([Cl:8])[CH2:3][Si:4]([Cl:7])([Cl:6])[CH3:5].C(Cl)(Cl)(Cl)[Cl:11]>CC(N=NC(C#N)(C)C)(C#N)C>[Cl:1][Si:2]([Cl:9])([Cl:8])[CH2:3][Si:4]([Cl:7])([Cl:6])[CH2:5][Cl:11]
Reactant: C[Si](Cl)(Cl)C[Si](Cl)(Cl)Cl
Reactant: ClC(Cl)(Cl)Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: ClC[Si](Cl)(Cl)C[Si](Cl)(Cl)Cl
Reaction time: 12 h

Procedure:
120 g (0.46 mole) of 1,1,1,3,3-pentachloro-1,3-disilabutane and 1.2 g of a reaction initiator, AIBN in carbon tetrachloride as solvent were reacted in the same apparatus as Example 10. The obtained reactant was photoreacted for 12 hrs using sun lamp, while bubbling chlorine gas and refluxing carbon tetrachloride. The produced reaction mixture was distilled under vacuum to obtain 32 g of 1,1,1,3,3,4-hexachloro-1,3-disilabutane.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2([C:16]3=[CH:17][C:18]4[O:22][CH2:21][O:20][C:19]=4[CH:23]=[C:15]3[O:14][CH2:13]2)[C:5]1=[O:24].NCCCN1C2C(=CC=CC=2)C2(C3=CC4OCOC=4C=C3OC2)C1=O.[F:50][C:51]([F:63])([F:62])[O:52][C:53]1[CH:61]=[CH:60][CH:59]=[CH:58][C:54]=1[C:55](Cl)=[O:56].ClC1C=CSC=1C(Cl)=O>>[O:24]=[C:5]1[C:6]2([C:16]3=[CH:17][C:18]4[O:22][CH2:21][O:20][C:19]=4[CH:23]=[C:15]3[O:14][CH2:13]2)[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]1[CH2:3][CH2:2][NH:1][C:55](=[O:56])[C:54]1[CH:58]=[CH:59][CH:60]=[CH:61][C:53]=1[O:52][C:51]([F:50])([F:62])[F:63]
Reactant: NCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Reactant: O=C(Cl)c1ccccc1OC(F)(F)F
Agent: NCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Agent: O=C(Cl)c1sccc1Cl
Product: O=C(NCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21)c1ccccc1OC(F)(F)F

Procedure:
Following the procedure as described in EXAMPLE 17, and making non-critical variations using 1′-(2-aminoethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 1′-(3-aminopropyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 2-(trifluoromethoxy)benzoyl chloride to replace 3-chlorothiophene-2-carbonyl chloride, the title compound was obtained (91%) as a colorless solid: mp 183-184° C.; 1H NMR (300 MHz, CDCl3) δ 7.86-7.83 (m, 1H), 7.50-7.45 (m, 1H), 7.37-7.27 (m, 3H), 7.16-7.11 (m, 2H), 7.07-7.02 (m, 1H), 6.84 (t, 1H), 6.47 (s, 1H), 6.10 (s, 1H), 5.82 (dd, 2H), 4.87 (d, 1H), 4.64 (d, 1H), 4.10-3.94 (m, 2H), 3.90-3.68 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 178.2, 165.0, 155.9, 148.8, 145.9, 142.3, 141.9, 132.4, 132.1, 131.3, 129.2, 127.6, 127.3, 124.0, 123.6, 121.2, 121.1, 119.2, 108.7, 103.0, 101.4, 93.6, 80.4, 58.2, 39.5, 38.2; MS (ES+) m/z 513.4 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=1)[NH2:25]>>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=1)[NH:25][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: COc1ccc(C)c(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: COc1ccc(C)c(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 5-methoxy-2-methylaniline (26 mg, 0.193 mmol) similar to Example 13 and isolated as a tan solid (8 mg, 12%). 1H NMR (CDCl3): 9.72 (d, J=0.6 Hz, 1H), 8.74–8.68 (m, 2H), 7.70 (s, 1H), 7.44–7.40 (m, 1H), 7.27 (s, 1H), 7.25 (s, 1H), 6.99 (s, 1H), 6.85 (dd, J=2.7, 8.7 Hz, 1H), 6.64 (s, 1H), 3.83 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[C:12](B(O)O)[CH:11]=[CH:10][N:9]=1.FC(F)(F)S(O[C:23]1[CH:36]=[C:35]2[C:26]([O:27][C:28]3[CH:29]=[CH:30][C:31]([C:52]4[C:53]([F:58])=[N:54][CH:55]=[CH:56][CH:57]=4)=[CH:32][C:33]=3[C:34]32[C:40]2=[N:41][CH:42]=[CH:43][N:39]2[C:38]([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[N:37]3)=[C:25]([F:59])[CH:24]=1)(=O)=O>O1CCOCC1.O>[F:59][C:25]1[C:26]2[O:27][C:28]3[C:33](=[CH:32][C:31]([C:52]4[C:53]([F:58])=[N:54][CH:55]=[CH:56][CH:57]=4)=[CH:30][CH:29]=3)[C:34]3([C:40]4=[N:41][CH:42]=[CH:43][N:39]4[C:38]([NH:44][C:45](=[O:46])[O:47][C:48]([CH3:50])([CH3:49])[CH3:51])=[N:37]3)[C:35]=2[CH:36]=[C:23]([C:12]2[CH:11]=[CH:10][N:9]=[C:8]([F:7])[CH:13]=2)[CH:24]=1
Reactant: CC(C)(C)OC(=O)NC1=NC2(c3cc(-c4cccnc4F)ccc3Oc3c(F)cc(OS(=O)(=O)C(F)(F)F)cc32)c2nccn21
Reactant: OB(O)c1ccnc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1=NC2(c3cc(-c4cccnc4F)ccc3Oc3c(F)cc(-c4ccnc(F)c4)cc32)c2nccn21
Temperature: 100 °C
Yield: 54.5 %

Procedure:
PdCl2dppf (25.1 mg, 0.031 mmol), potassium carbonate (1232 μL, 1.232 mmol), 2-fluoropyridin-4-ylboronic acid (87 mg, 0.616 mmol), and 5-(tert-butoxycarbonylamino)-5′-fluoro-2′-(2-fluoropyridin-3-yl)spiro[imidazo[1,5-a]imidazole-7,9′-xanthene]-7′-yl trifluoromethanesulfonate (200 mg, 0.308 mmol) were combined in dioxane/water 4:1 (3079 μL) and heated at 100° C. for 2 hours. The solution was concentrated. The product was purified via silica gel column chromatography using 0-60% EtOAc in hexane to afford tert-butyl 4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-(2-fluoropyridin-4-yl)spiro[imidazo[1,5-a]imidazole-7,9′-xanthene]-5-ylcarbamate (100 mg, 0.168 mmol, 54.4% yield). This material was treated with TFA (0.323 ml, 4.19 mmol) in DCM (2 ml) and stirred at RT for 1 hr. The solution was concentrated, and the racemic residue was separated by SFC using an IC (10×0.46 cm) column, eluting with 20% IPA (DEA)/CO2, 100 bar, 4 mL/min, 220 nm to afford (S)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-(2-fluoropyridin-4-yl)spiro[imidazo[1,5-a]imidazole-7,9′-xanthen]-5-amine (Example 8A) and (R)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-(2-fluoropyridin-4-yl)spiro[imidazo[1,5-a]imidazole-7,9′-xanthen]-5-amine (Example 8B). Mass Spec is in Table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[F:11][C:12]1[CH:19]=[CH:18][C:15]([NH:16][CH3:17])=[CH:14][CH:13]=1.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:16]([C:15]2[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=2)[CH3:17])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: CNc1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CN(C(=O)c1ccc(Cl)nc1)c1ccc(F)cc1
Reaction time: 1.5 h

Procedure:
6-Chloronicotinoyl chloride (353 mg, 2.0 mmol) was dissolved in anhydrous DMF (2 mL) and slowly added to a stirring solution of 4-fluoro-N-methylaniline (242 μL, 2.0 mmol) and DBU (300 μL, 2.0 mmol) in anhydrous DMF (2 mL). After 90 minutes, the DMF was removed in vacu and the reaction was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water and brine, dried over sodium sulfate, filtered, and dried in vacu. The crude solid was purified by silica plug (1:1 ethyl acetate/hexanes) to yield 6-Chloro-N-(4-fluoro-phenyl)-N-methyl-nicotinamide as an off-white, glassy solid (411 mg, 77%).
Reaction SMILES: [N+:1]([C:4]1[CH:34]=[CH:33][C:7]([CH2:8][O:9][C:10]([C:12]2[N:17]3[C:18](=[O:31])[CH:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@H:16]3[S:15][CH2:14][C:13]=2[OH:32])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+](=[CH2:37])=[N-]>>[O:23]([CH2:22][C:21]([NH:20][CH:19]1[C:18](=[O:31])[N:17]2[C:12]([C:10]([O:9][CH2:8][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:34][CH:33]=3)=[O:11])=[C:13]([O:32][CH3:37])[CH2:14][S:15][C@H:16]12)=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Reactant: C=[N+]=[N-]
Product: COC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1

Procedure:
More recently in my copending application Ser. No. 310,191 filed on Nov. 28, 1972 now U.S. Pat. No. 3,917,587 issued Nov. 4, 1974 the oxidation of 3-exomethylenecepham esters with ozone is described. The predominant product of the ozonolysis described therein is the 3-hydroxy-3-cephem ester which is reacted with a diazoalkene to provide the corresponding ester of a 3-alkoxy-3-cephem. Removal of the ester group provides the alkoxylated antibiotic compound. For example, 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester, obtained by the ozonolysis of the corresponding 3-exomethylene compound, is reacted with diazomethane to form p-nitrobenzyl 7-phenoxyacetamido-3-methoxy-3-cephem4-carboxylate. The p-nitrobenzyl ester group is removed by catalytic hydrogenolysis in the presence of 5% palladium on carbon catalyst to provide the free carboxylic acid antibiotic compound. In the same application Ser. No. 310,191, the formation of 3-exomethylenecepham-4-carboxylic ester sulfoxides and 3-hydroxy-3-cephem-4-carboxylic acid ester sulfoxides are disclosed as side products of the ozonolysis reaction of 3-exomethylenecepham esters.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:21])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[C:29](O)(=[O:31])[CH3:30]>C1COCC1.C(Cl)Cl>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:6]3[N:5]=[C:4]([NH:19][C@H:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH3:21])[C:3]([CH2:2][NH:1][C:29](=[O:31])[CH3:30])=[CH:8][C:7]=3[F:9])[CH:15]=2)[CH2:18][CH2:17]1
Reactant: CC(=O)O
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CN)c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)NCc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1N[C@@H](C)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 50 %

Procedure:
A round bottom flask was charged with (S)-3-(aminomethyl)-N6-(5-cyclopropyl-1H-pyrazol -3-yl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine (Example 3; 0.08 g, 0.2 mmol) and acetic acid loaded TFP resin (1.4 mmol/g loading, 0.2 mmol) in mixture of THF-DCM (1:1, 3 ml) at 0° C. The resulting solution was shaken vigorously at 0° C. for 45 min and filtered. The resulting resin was washed with a THF-DCM solution (1:1, 3×5 ml for 30 min. each). The resulting organic layers were combined and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give the title compound (0.045 g, 50%). 1H NMR (400 MHz, CD3OD) δ 7.34-7.33 (m, 2H), 7.11 (d, J=10.7 Hz, 1H), 7.01-6.97 (m, 2H), 5.14-5.04 (m, 1H), 4.30-4.17 (m, 2H), 1.99 (s, 3H), 1.88-1.81 (m, 1H), 1.50 (d, J=6.8 Hz, 3H), 0.94-0.92 (m, 2H), 0.67-0.63 (m, 2H). MS: Calcd.: 426. Found: [M+H]+ 427.
Reaction SMILES: O.[NH2:2]N.C[N:5](C)[CH:6]=[CH:7][C:8]([C:10]1[CH:33]=[CH:32][CH:31]=[CH:30][C:11]=1[O:12][CH2:13][CH:14]([OH:29])[CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)=O.Cl>C(O)C>[NH:5]1[CH:6]=[CH:7][C:8]([C:10]2[CH:33]=[CH:32][CH:31]=[CH:30][C:11]=2[O:12][CH2:13][CH:14]([OH:29])[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)[CH2:18][CH2:17]2)=[N:2]1
Reactant: CN(C)C=CC(=O)c1ccccc1OCC(O)CN1CCN(c2ccc(Cl)cc2)CC1
Reactant: NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: OC(COc1ccccc1-c1cc[nH]n1)CN1CCN(c2ccc(Cl)cc2)CC1
Yield: 88 %

Procedure:
15 ml of hydrazine hydrate are added to 8.0 g (0.017 mole) of 1-[2-(3-Dimethylamino-1-oxo-propenyl)-phenoxy]-3-[4-(4-chlorophenyl)-piperazin-1-yl]-propan-2-ol.HCl (Example 4b) in 100 ml of ethanol, and the mixture is refluxed for 3 days. The solvent is distilled off and the residue is recrystallized from ethanol. 6.2 g (88%) of a product of melting point 120°-121° C. are isolated.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([NH2:6])=[O:5].[N:13]1[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=1.S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[F:12][C:7]1[CH:8]=[C:9]([F:11])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:19]([C:16]1[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=1)=[N:1]2
Reactant: O=Cc1ccncc1
Reactant: NC(=O)c1c(N)cc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=c1[nH]c(-c2ccncc2)nc2cc(F)cc(F)c12
Temperature: 115 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2-amino-4,6-difluoro-benzamide (0.50 g, 2.9 mmol) and pyridine-4-carbaldehyde (0.35 g, 3.2 mmol) in N,N-dimethylacetamide (10 mL) were added sodium hydrogen sulfite (0.63 g, 3.5 mmol) and p-toluenesulfonic acid (0.06 g, 0.3 mmol); the reaction mixture was stirred at 115° C. for 16 hours. The solvent was evaporated in vacuo, water was added, and the precipitated solid was filtered off to obtain 5,7-difluoro-2-pyridin-4-yl-3H-quinazolin-4-one as a yellow solid, which was used in the next step without further purification. Yield: 0.4 g (53%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[O:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20](O)=[O:21].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([C:20]([C@@H:16]2[CH2:17][CH2:18][CH2:19][O:15]2)=[O:21])[CH2:3]1
Reactant: O=C(O)[C@@H]1CCCO1
Reactant: CC1(C)CNc2cc([N+](=O)[O-])ccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CN(C(=O)[C@@H]2CCCO2)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3,3-dimethyl-6-nitroindoline (385 mg, 2 mmol), (S)-tetrahydrofuran-2-carboxylic acid (250 mg, 2.2 mmol), HOBt (266 mg, 2 mmol), EDAC (700 mg, 3.5 mmol), and DIEA (2 mL) in DCM (50 ml) was stirred at RT for overnight. The reaction mixture was washed in turn with aqueous NaHCO3 (sat., 50 mL), aqueous HCl (0.5N, 50 mL), H2O (50 mL), and brine (50 mL). The DCM layer was concentrated in vacuum to give the desired compound. MS: (ES+) 291(M+H). Calc'd. for C15H18N2O4—290.31.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:30])/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=CC=1)([O-])=O.[CH3:31][C:32]([CH3:43])([NH2:42])[CH2:33][CH2:34][CH2:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1>O1CCCC1>[F:29][C:25]1[CH:24]=[C:23]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:42][C:32]([CH3:43])([CH3:31])[CH2:33][CH2:34][CH2:35][C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)=[O:30])[CH:28]=[CH:27][CH:26]=1
Reactant: O=C(/C=C/C=C(c1cccc(F)c1)c1cccc(F)c1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(N)CCCc1cccnc1
Solvent: C1CCOC1
Product: CC(C)(CCCc1cccnc1)NC(=O)/C=C/C=C(c1cccc(F)c1)c1cccc(F)c1

Procedure:
As in Example 134, a solution of (E)-5,5-bis(3-fluorophenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (1.63 g) and alpha,alpha-dimethyl-3-pyridinebutanamine (0.9 mL) in tetrahydrofuran (20 mL) was stirred for 29 hours at reflux and was then worked up in the usual manner. The crude amide was crystallized from ethyl acetate-hexane to furnish 1.6 g of (E)-5,5-bis(3-fluorophenyl)-N-[1,1-dimethyl-4-(3-pyridinyl)butyl]-2,4-pentadienamide mp 135°-136° C. Anal. Calculated for C28H28F2N2O : C, 75.32: H, 6.32; F, 8.51; N, 6.27 Found: C, 75.30; H, 6.49; F, 8.21; N, 6.30.
Reaction SMILES: [O:1]=[C:2]([OH:14])[C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([C:11]([OH:13])=[O:12])[OH:10])[OH:8])[OH:6])[OH:4].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18](S(O)(=O)=O)=[CH:17][CH:16]=1>C[Re](=O)(=O)=O.C(O)CCCCCC>[O:1]=[C:2]([O:14][CH2:25][CH2:15][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])[C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([C:11]([O:13][CH2:25][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C(O)[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C[Re](=O)(=O)=O
Solvent: CCCCCCCO
Product: CCCCCCCOC(=O)[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)C(=O)OCCCCCCC
Temperature: 150 °C
Reaction time: 12 h

Procedure:
In one specific embodiment of the present disclosure, 20 ml of 1-heptanol, 1 mmol of galactaric acid, 0.05 mmol of methyltrioxorhenium catalyst, and 0.05 mmol of para-toluenesulfonic acid were poured into a 50 cc reactor. The temperature in the reactor was then raised to 150° C. and the reaction was performed for 12 hours, maintaining the reactor temperature at 150° C. to obtain diheptyl galactarate.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.Br[CH2:9][CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[CH:12]=1>>[OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=3)[CH:12]=2)[CH2:4]1
Reactant: COc1ccc2cc(CCBr)ccc2c1
Reactant: OCC1CCNC1
Product: COc1ccc2cc(CCN3CCC(CO)C3)ccc2c1
Temperature: 120 °C

Procedure:
A mixture of 3.6 g (29.4 mmol) of 3-hydroxymethyl-pyrrolidine and 4.7 g (14.7 mmol) of 2-(2-bromoethyl)-6-methoxy-naphthalene is heated to 120° C. for 2 hours. The reaction mixture is purified over 200 g of silica gel (0.063-0.2 mm) with methylene chloride and then with increasing amounts of ethanol (up to 5%).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13][C:14]3([CH2:20][C:21]([NH:23][OH:24])=[O:22])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[OH:27]OS([O-])=O.[K+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([S:13]([C:14]3([CH2:20][C:21]([NH:23][OH:24])=[O:22])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:27])=[CH:11][CH:12]=2)=[CH:25][CH:26]=1
Reactant: O=C(CC1(Sc2ccc(Oc3ccc(F)cc3)cc2)CCOCC1)NO
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(CC1(S(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCOCC1)NO
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
2-{4-[4-(4-Fluorophenoxy)phenylthio]-tetrahydropyran-4-yl}-N-hydroxyacetamide (500 mg) was dissolved in methanol (25 ml). OXONE (400 mg) in water (5 ml) was added. After stirring for 30 minutes, the mixture was partitioned between methylene chloride and water. Preparative TLC on silica gel and elution with 10% methanol/methylene chloride gave 2-{4-[4-(4-fluorophenoxy)phenylsulfinyl]-tetrahydropyran-4-yl}-N-hydroxyacetamide (402 mg, m.p. 120° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([CH2:21][CH3:22])[CH:15]=1>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>[NH2:18][C:17]1[CH:19]=[CH:20][C:14]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:15][C:16]=1[CH2:21][CH3:22]
Reactant: CCc1cc(Br)ccc1N
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCc1cc(-c2cccc([N+](=O)[O-])c2)ccc1N
Yield: 26.6 %

Procedure:
This compound was prepared by General Method 14 (EXAMPLE 191) from 3-nitrobenzeneboronic acid (0.47 g, 2.8 mmol), 4-bromo-2-ethylaniline (432 mg, 2.16 mmol), and (PPh3)4Pd (75 mg, 0.065 mmol) to afford 139 mg (20%) of 4-amino-3-ethyl-3′-nitrobiphenyl. Data for 4-amino-3-ethyl-3′-nitrobiphenyl: 1H NMR (400 MHz, acetone-d6) 8.38 (t, J=2.1, 1H), 8.08 (m, 1H), 8.00 (m, 1H), 7.66 (t, J=8.0, 1H), 7.45 (d, J=2.3, 1H), 7.39 (dd, J=8.3, 2.3, 1H), 6.83 (d, J=8.3, 1H), 4.68 (br s, 2H).