Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]=1.O>CCCCCC.O1CCCC1>[C:4]1([CH2:3][O:10][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: Cc1ccnc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: Cc1ccnc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.9 %

Procedure:
Sodium hydride (60% paraffin dispersion, 5.0 g, 120 mmol) was washed with hexane (5 mL) twice and suspended in tetrahydrofuran (200 mL). To this suspension was added dropwise a solution of benzyl alcohol (14 g, 120 mmol) in tetrahydrofuran (50 mL) at 0° C. and then, the mixture was allowed to warm up to room temperature with stirring for 15 minutes. To this solution was added a solution of 2-bromo-4-methylpyridine (19.5 mL, 110 mmol) in tetrahydrofuran (50 mL) and heated to reflux for 14 hours. To the reaction mixture was added water (200 mL) and extracted with ethyl acetate. The extract was dried and the solvent was distilled off. The crude product was distilled under reduced pressure to obtain 13 g of the title compound (67 mmol, yield 67%).
Reaction SMILES: [CH:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:31][C:32]1[N:36]([CH2:37][C:38]([N:40]2[CH2:45][CH2:44][CH:43]([C:46]3[S:47][CH:48]=[C:49]([C:51](O)=[O:52])[N:50]=3)[CH2:42][CH2:41]2)=[O:39])[N:35]=[C:34]([C:54]([F:57])([F:56])[F:55])[CH:33]=1>O1CCCC1>[CH3:31][C:32]1[N:36]([CH2:37][C:38]([N:40]2[CH2:41][CH2:42][CH:43]([C:46]3[S:47][CH:48]=[C:49]([C:51]([O:11][CH:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH2:4][CH2:3][CH2:2]4)=[O:52])[N:50]=3)[CH2:44][CH2:45]2)=[O:39])[N:35]=[C:34]([C:54]([F:57])([F:55])[F:56])[CH:33]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Reactant: OC1CCCc2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)OC3CCCc4ccccc43)cs2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
At room temperature, 1,2,3,4-tetrahydronaphthalen-1-ol (155 mg) and triphenylphosphine (758 mg) are added to a solution of 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-4, 380 mg) in tetrahydrofuran (2.5 ml). The mixture is stirred at 0 C under argon for 5 minutes, and diethyldiazene 1,2-dicarboxylate (383 mg) is then added dropwise. The reaction mixture is slowly warmed to room temperature. After 2 hours, the solvent is removed under reduced pressure and the residue is purified chromatographically. This gives 1,2,3,4-tetrahydronaphthalen-1-yl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (196 mg, 39%).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][N:5]=[C:4]2[CH:13]=[CH:14][S:15][C:3]=12>[OH-].[Na+]>[O:1]=[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][NH:5][C:4]2[CH:13]=[CH:14][S:15][C:3]1=2
Reactant: CCOC(=O)c1cnc2ccsc2c1O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1c[nH]c2ccsc2c1=O
Temperature: 25 °C
Yield: 68.3 %

Procedure:
The ethyl 7-hydroxythieno[3,2-b]pyridine-6-carboxylate 3 (1.0 g, 4.5 mmol) was heated to reflux in 15% NaOH for 30 min. After the reaction was completed it was allowed to cool to room temperature and the solid was removed by filtration, washed with water and ether to give the desired compound as an off-white powder (0.6 g, 70% yield). LC/MS (10-99% CH3CN/0.05% TFA gradient over 5 min): m/z 196.0, m/z 210.0, retention time 0.94 minutes. 1H NMR (DMSO-d6) δ: 15.50 (bs, 1.0H), 14.0 (s, 1.0H), 8.80 (s, 1.0H), 8.30 (d, 1.0H, J=5.4 Hz), 7.48 (d, 1.0H, J=5.4 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[CH2:21][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[Cl:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:41](=[O:42])[C:40]3[CH:44]=[CH:45][C:37]([Cl:36])=[CH:38][CH:39]=3)=[CH:16][C:15]=2[CH2:21][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(N)cc2CN(CC)C(=O)OCc2ccccc2)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(NC(=O)c3ccc(Cl)cc3)cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
{4′-Amino-2′-[(benzyloxycarbonyl-ethyl-amino)-methyl]-6-methoxy-biphenyl-3-yl}-acetic acid ethyl ester (0.08 g, 0.2 mmol), 4-chlorobenzoyl chloride (0.04 mL, 0.3 mmol), and triethylamine were reacted in CH2Cl2 to give the title compound.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5](O)=[CH:4][C:3]=1[N+:9]([O-])=O.NC1C=CC(OC2C=CN=C(C(NC)=O)C=2)=CC=1[N+:30]([O-:32])=[O:31].C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>COCCOC.O.O.C(OCC)(=O)C>[N+:30]([NH:9][C:3]1[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=1)([O-:32])=[O:31]
Reactant: CNC(=O)c1cc(Oc2ccc(N)c([N+](=O)[O-])c2)ccn1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: O=[N+]([O-])Nc1ccccc1
Temperature: 100 °C

Procedure:
A solution of 5 (1 eq), 6 (1 eq), and sodium carbonate (1.2 eq) in DME/H2O (3:1) was degassed by bubbling argon through the solution for 10 minutes. Pd(II)(dppf)Cl2. MeCl2 (0.1 eq) was added to the reaction solution and the reaction was sealed. The reaction was heated at 100° C. overnight. The reaction was cooled to RT and ethyl acetate and water were added. The organic layer was separated from the aqueous layer. The aqueous layer was washed once more with ethyl acetate. The organic layers were combined, dried (Na2SO4), and concentrated under vacuum to yield the desired product 7. MS: MH+=469
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[C:18]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:20][CH2:21][CH3:22])=[O:19].O>O1CCOCC1>[CH2:21]([O:20][C:18](=[O:19])/[CH:23]=[CH:14]/[C:13]1[CH:16]=[CH:17][C:10]([CH:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:7][CH2:8][CH3:9])=[CH:11][CH:12]=1)[CH3:22]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCC(c1ccc(C=O)cc1)n1ccnc1
Solvent: C1COCCO1
Solvent: O
Product: CCCC(c1ccc(/C=C/C(=O)OCC)cc1)n1ccnc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 50.3 %

Procedure:
0.228 g of 4-[1-(1-imidazolyl)-butyl]-benzaldehyde (example 6) is dissolved in 5 ml of dioxane and mixed with 0.35 g of carbethoxymethylene triphenyl phosphorane and stirred for 48 hours at room temperature. The reaction mixture is poured into 100 ml of water and extracted with ethyl acetate. The organic phases are combined and evaporated to dryness, the residue is distilled on a bulb tube. 0.15 g of the title compound with a boiling point of 200°-220° C./0.03 mbar is obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH3:17])[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[S:7]1)=[O:5])C.[OH-].[Na+]>O1CCOCC1>[CH3:17][C:6]1([C:4]([OH:5])=[O:3])[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[S:7]1
Reactant: CCOC(=O)C1(C)Sc2ccccc2NC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC1(C(=O)O)Sc2ccccc2NC1=O
Yield: 104.8 %

Procedure:
Ethyl-2-methyl-3,4-dihydro-3-oxo-2H-1,4-benzothiazine-2-carboxylate (0.251 g, 1 mmole) and 1N NaOH (2.2 ml, 2.2 mmoles) were stirred in dioxan (5 ml) for 48 hours at room temperature. The solvent was evaporated, water (5 ml) was added to the residue and it was acidified with 20% HCl to pH=2. The crystals which separated were filtered off by suction and recrystallized from absolute ethanol. Thus there were obtained 0.234 g (98.0%) of the title product in the form of white crystals, m.p. 164-°165° C.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C:13]2[C:14]([CH2:22][CH3:23])=[N:15][N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=23)[CH2:6][CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.C([Li])CCC.FC1C([I:36])=C(F)C(F)=C(F)C=1F.O.O1CCCC1>O1CCCC1.CCCCCCC.O>[CH:1]1([CH2:4][N:5]([C:13]2[C:14]([CH2:22][CH3:23])=[N:15][N:16]3[C:21]([I:36])=[CH:20][CH:19]=[CH:18][C:17]=23)[CH2:6][CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1
Reactant: CCc1nn2ccccc2c1N(CC1CCOCC1)CC1CC1
Reactant: Fc1c(F)c(F)c(I)c(F)c1F
Agent: [Li]CCCC
Solvent: CCCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCc1nn2c(I)cccc2c1N(CC1CCOCC1)CC1CC1
Reaction time: 1 h
Yield: 87.2 %

Procedure:
A solution of N-cyclopropylmethyl-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(tetrahydro-2H-4-pyranylmethyl)amine (180 g, 574 mmol) in tetrahydrofuran (1620 mL) was cooled in a dry ice-ethanol bath. Into the reaction mixture was dropped n-butyllithium (1.6M hexane solution; 538 mL, 854 mmol) at an inner temperature of −73° C. to −64.5° C. At the same temperature, the reaction mixture was stirred for 1 hour, and into the reaction mixture was dropped pentafluoroiodobenzene (115 mL, 861 mmol). The reaction mixture was further stirred for 1 hour and 20 minutes at the same temperature, and to the reaction mixture was added water/tetrahydrofuran (1/1, v/v, 360 mL). Into the reaction mixture was added water (3600 mL) and heptane (3600 mL). An aqueous layer was removed, and an organic layer was washed with water (3600 mL). Then, to the organic layer was added 5N hydrochloric acid (1800 mL) and the aqueous layer was separated. Then, the aqueous layer was cooled in an ice water bath, and a 5N sodium hydroxide aqueous solution (1620 mL) was added, then, toluene (3600 mL) was added, and an organic layer was separated. The remaining aqueous layer was further extracted with toluene (3600 mL), and both the organic layers were combined. The solution was concentrated under reduced pressure, to obtain 220 g of a title compound as deep green oil (yield: 87.3%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:12]=2)[CH:9]=O)=[CH:4][CH:3]=1.[CH:25]([C:27]([CH3:29])=[O:28])=[CH2:26].[OH-].[K+].Cl>C1COCC1.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]4[CH2:21][CH2:22][CH2:23][CH2:24]4)[CH:12]=3)[CH2:26][CH2:25][C:27](=[O:28])[CH:29]=[CH:9]2)=[CH:6][CH:7]=1
Reactant: C=CC(C)=O
Reactant: COc1ccc(C(C=O)c2ccc(Br)cc2)cc1OC1CCCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C2(c3ccc(Br)cc3)C=CC(=O)CC2)cc1OC1CCCC1
Temperature: -10 °C

Procedure:
To a solution of 2-(4-bromophenyl)-2-(3-cyclopentyloxy-4-methoxyphenyl) acetaldehyde (2.60 g, 6.7 mmol) in THF (10 ml) was added methyl vinyl ketone (670 ul, 8.4 mmol). The solution was stirred at −10° C. and 10% ethanolic potassium hydroxide (480 ul) was added slowly. After 0.5 h the reaction mixture was warmed to room temperature and stirred for additional 1 h. Water and ethyl acetate were added and the mixture was neutralized with 3N hydrochloric acid. The layers were separated and the aqueous layer washed twice with ethyl acetate. The combined organic extract was washed with water then brine, dried (sodium sulfate) and evaporated. Purification by flash chromatography (silica gel, 12% ethyl acetate/82% hexane) provided the title compound as a pale white waxy solid (1.39 g, 47%). MS (m/e): 441 [(M+1)+], 443 [(M+3)+].
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]2[CH2:11][CH2:10]2)=[CH:6][C:5]([F:12])=[CH:4][N:3]=1.[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[NH:22][C@H:23]1[CH2:26][C@H:25]([NH2:27])[CH2:24]1.CC(C)([O-])C.[Na+]>[Pd+2]>[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[NH:22][C@H:23]1[CH2:24][C@H:25]([NH:27][C:2]2[C:7]([NH:8][CH:9]3[CH2:11][CH2:10]3)=[CH:6][C:5]([F:12])=[CH:4][N:3]=2)[CH2:26]1
Reactant: Fc1cnc(Cl)c(NC2CC2)c1
Reactant: N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Agent: [Pd+2]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: Fc1cnc(N[C@H]2C[C@H](Nc3nc4ccccc4s3)C2)c(NC2CC2)c1
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
2-Chloro-N-cyclopropyl-5-fluoropyridin-3-amine (intermediate 39, 0.230 g, 1.232 mmol), trans-N1-(benzo[d]thiazol-2-yl)cyclobutane-1,3-diamine (intermediate 11, 0.270 g, 1.232 mmol), chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2′-4′-6′-triisopropyl-1,1′-biphenyl) 2-(2-aminoethyl)phenyl)palladium(II) (0.049 g, 0.062 mmol), and sodium t-butoxide (0.296 g, 3.08 mmol) were sealed in a microwave vial under argon. Dry, sparged dioxane (1 mL) was added and the reaction heated at 80° C. After 45 minutes the vial was opened and the crude and dry loaded on silica gel. Purification using silica chromatography (hexane to ethyl acetate gradient) gave N2-(trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)-N3-cyclopropyl-5-fluoropyridine-2,3-diamine (0.304 g, 0.824 mmol, 66.8% yield).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=O)[CH2:11][C:10]([C:17](=O)[N:18]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14](O)=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].S(=O)(=O)(O)O.Cl>O1CCCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:17][N:18]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([CH2:14][OH:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(C(=O)O)(C(=O)N(Cc2ccccc2)Cc2ccccc2)CN1Cc1ccccc1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [BH4-]
Solvent: C1CCOC1
Product: OCC1(CN(Cc2ccccc2)Cc2ccccc2)CCN(Cc2ccccc2)C1
Yield: 80.2 %

Procedure:
1-Benzyl-3-(N,N-dibenzylcarbamoyl)-5-oxopyrrolidine-3-carboxylic acid (124 g) was dissolved in tetrahydrofuran (1.1 l) and sodium borohydride (79.7 g) was added over 15 minutes under ice-cooling. A solution of sulfuric acid (56 ml) in tetrahydrofuran (560 ml) was added over 1 hour under ice-cooling, and the mixture was refluxed for 3 hours. 3N Hydrochloric acid (500 ml) was added under ice-cooling and the mixture was refluxed for 2.5 hours. After concentration, water (1 l) was added and the resulting mixture was made alkaline with an aqueous solution of sodium hydroxide. The resulting mixture was extracted with ethyl acetate and washed with saturated brine. After drying, the organic layer was concentrated and purified by silica gel column chromatography to give 90 g of the object compound as white crystals, melting point 65°-67° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:27][N:26]([S:28]([NH2:31])(=[O:30])=[O:29])[CH2:25]3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:34][OH:35].C(=O)([O-])O.[Na+]>>[OH:35]/[N:34]=[C:8](/[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)\[CH2:9][C@H:10]([C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:25][N:26]([S:28]([NH2:31])(=[O:29])=[O:30])[CH2:27]2)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(C3CN(S(N)(=O)=O)C3)cc2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(C3CN(S(N)(=O)=O)C3)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 1, step 2, from (R)-3-(4-(3-(2-methylpyridin-4-yl)-3-oxo-1-o-tolylpropyl)phenyl)azetidine-1-sulfonamide and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white foam, MS (ESI+): m/z=465.3 ([M+H]+).
Reaction SMILES: [CH:1]([O:4][C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].C([Li])CCC.CN(C)[CH:17]=[O:18].Cl>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH:1]([O:4][C:5]1[S:6][C:7]([CH:17]=[O:18])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cccs1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(C=O)s1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 36 %

Procedure:
To a solution of 2-isopropoxythiophene (250 mg, 1.76 mmol) in 9 mL of 9:1 tetrahydrofuran/hexamethylphosphoramide under argon at −78° C. was added n-butyllithium (0.77 mL, 2.5 M in hexanes) dropwise. After stirring at −78° C. for 20 minutes, dimethylformamide (0.68 mL, 8.80 mmol) was added in a single portion and the reaction mixture allowed to warm to room temperature while stirring, before being poured into 30 mL of 1 N hydrochloric acid. Organics were extracted with 1:1 ether/hexanes (2×35 mL), washed with 1 N hydrochloric acid (2×20 mL), water (20 mL) and brine, dried over magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel (7% ethyl acetate in hexanes) to give 5-isopropoxy-2-thiophenecarbaldehyde (108 mg, 36%). Used without further characterization.
Reaction SMILES: [CH2:1]([O:9][CH:10]([CH3:13])[CH2:11][OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.Cl>N1C=CC=CC=1>[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([O:12][CH2:11][CH:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:13])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: CCCCCCCCOC(C)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCOC(C)COS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 99.1 %

Procedure:
53 g of dry pyridine and 22.2 g of 2-octyloxypropanol were added into a four-necked flask and cooled with NaCl-ice. 35.4 g of p-toluenesulfonic acid chloride was added little by little, and after the reaction was carried out for 4 hours, the mixture was left standing at room temperature for 18 hours. The reaction product was added into 500 g of ice-cooled 6% HCl aq. and the mixture was extracted with 500 ml of benzene and dried over anhydrous Na2SO4, followed by evaporation of benzene, to give 40 g of (2'-octyloxypropyl) p-toluenesulfonate as an oily product.
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:3]=1[C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:9]=2[CH:10]=1)=[O:5].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[F:21][C:18]1[CH:19]=[CH:20][C:2]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[C:3]([CH:17]=1)[C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:9]=2[CH:10]=1)=[O:5]
Reactant: COc1ccc2oc(C(=O)c3cc(F)ccc3F)cc2c1
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Product: COc1ccc2oc(C(=O)c3cc(F)ccc3N3CCOCC3)cc2c1

Procedure:
A mixture of 2-(2,5-difluorobenzoyl)-5-methoxybenzofuran (100 mg, 0.28 mmol) and morpholine (100 mg, 1.12 mmol) in toluene (10 ml) is heated at reflux for 24 hours. Evaporation and chromatography on silicagel gives the title compound, m.p. 85-88° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]([OH:16])=O)[CH:8]=[CH:9][C:10]=1[CH3:11])(=[O:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[N-:30]=[N+:31]=[N-:32].[Na+]>CC(C)=O.O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]([N:30]=[N+:31]=[N-:32])=[O:16])[CH:8]=[CH:9][C:10]=1[CH3:11])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(C=CC(=O)O)ccc1C
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)Nc1cc(C=CC(=O)N=[N+]=[N-])ccc1C
Temperature: 25 °C
Yield: 95.5 %

Procedure:
To a slurry of 3-(3-acetamido-4-methylphenyl)propenoic acid (20.11 g, 91.7 mmol) in acetone (450 mL) at 0° C. is added triethylamine (12.8 mL, 91.8 mmol) followed by dropwise addition of ethyl chloroformate (11.8 mL, 123 mmol) over a 10 minutes period. The resulting yellow slurry is stirred using a mechanical stirrer for 1.5 hours, then a solution of sodium azide (8.94 g, 138 mmol) in water (25 mL) is added slowly so as to maintain the temperature below 5° C. The thick mixture is stirred at 0° C. for 1 hours, then the ice bath is removed and the reaction mixture allowed to warm to room temperature. The suspension is poured over water (800 mL) then filtered. The remaining solid is washed generously with water and dried under vacuum over P2O5 overnight to give the product as a pale yellow solid (21.40 g, 87.6 mmol).
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([OH:5])=[O:4].N#N>C(O)C.[Pd]>[CH3:1][C:2]([CH3:12])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([OH:5])=[O:4]
Reactant: CCCCC=CC(C)(C)C(=O)O
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: CCCCCCC(C)(C)C(=O)O
Reaction time: 6 h

Procedure:
2,2-Dimethyl octanoic acid is prepared by dissolving 2,2-dimethyl-3-octenoic acid (0.20 g, 1.1 mmol) in absolute ethanol blanketed with N2 and 10% palladium on carbon which is then hydrogenated for 6 hours. The catalyst is removed by filtration and the filtrate concentrated under vacuum to give 2,2-dimethyl octanoic acid.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:3]=1[CH2:4][N:5]1[C:10]([CH3:11])=[C:9]([CH:12]=[O:13])[C:8](=[O:14])[C:7](Br)=[C:6]1[CH3:16].[CH3:22][O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>C1C=CC=CC=1.C(O)C.COCCOC.[OH-].[Ba+2].[OH-].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:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:3]=1[CH2:4][N:5]1[C:10]([CH3:11])=[C:9]([CH:12]=[O:13])[C:8](=[O:14])[C:7]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([O:23][CH3:22])[CH:29]=2)=[C:6]1[CH3:16]
Reactant: COc1cccc(B(O)O)c1
Reactant: Cc1c(Br)c(=O)c(C=O)c(C)n1Cc1c(F)cccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: CCO
Solvent: COCCOC
Solvent: c1ccccc1
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3F)c(C)c(C=O)c2=O)c1
Reaction time: 8 h
Yield: 42.1 %

Procedure:
1-(2,6-Difluorobenzyl)-2,6-dimethyl-3-bromo-5-formyl-pyrid-4-one (1.36 g, 3.8 mmol) stirred with 3-methoxyphenyl boronic acid (696 mg, 4.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (439 mg, 380 μmol) in benzene/ethanol/DME (76 ml, 10/1/11) and barium hydroxide (30 mL, sat., aq.) under N2 at 90° C., protected from light over 8 hours. The organic layer was then concentrated and purified using flash silica chromatography (ethyl acetate/hexane-1/9), giving the product as a cream-colored solid (622 mg, 1.6 mmol, 42% yield). 1H NMR (CDCl3, 300 MHz) δ 10.55 (s, 1H), 7.41-7.31 (m, 2H), 7.00-6.74 (m, 5H), 5.35 (s, 2H), 3.81 (s, 3H), 2.79 (s, 3H), 2.25 (s, 3H); MS: 384 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C:14]2[CH:26]=[CH:25][C:17]([C:18]([O:20]C(C)(C)C)=[O:19])=[C:16]([NH:27][C:28]([C:30]3[CH:35]=[C:34]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:33]=[CH:32][N:31]=3)=[O:29])[CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([C:14]2[CH:26]=[CH:25][C:17]([C:18]([OH:20])=[O:19])=[C:16]([NH:27][C:28]([C:30]3[CH:35]=[C:34]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:33]=[CH:32][N:31]=3)=[O:29])[CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2ccccc2)ccn1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cc(-c2ccccc2)ccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.2 %

Procedure:
Trifluoroacetic acid (5 mL) was added to the obtained tert-butyl 4-phenyl-2-(4-phenylpyridine-2-carboxamido)benzoate (64 mg), followed by stirring at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and ethyl acetate and water were added to the obtained residue. After adjusting the pH to 6.5 with a saturated aqueous solution of sodium bicarbonate, the organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride sequentially, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 50 mg of 4-phenyl-2-(4-phenylpyridine-2-carboxamido)benzoic acid as a white solid.