Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].Cl[CH:19]([F:21])[F:20]>CN(C)C=O>[F:20][CH:19]([F:21])[O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: FC(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OC(F)F)cc1F
Temperature: 85 °C
Reaction time: 2 h

Procedure:
N,N-Dimethylformamide (15 mL) was added to 3-fluoro-4-nitrophenol (1.01 g, 6.43 mmol) and potassium carbonate (5.33 g, 38.6 mmol) in a 50 mL stainless steel reactor. The vessel was sparged briefly with CF2HCl, chilled with dry ice, and then chlorodifluoromethane (3.34 g, 38.6 mmol) was transferred into the reactor through a polypropylene tube. The mixture was stirred at 85° C. for 2 hours. The supernatant mixture was concentrated onto silica gel. Purification via flash chromatography (0-40% ethyl acetate/hexanes) afforded the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.28 (t, J=9.16 Hz, 1H), 7.51-7.57 (m, 1H), 7.50 (t, J=72.39 Hz, 1H), 7.21-7.29 (m, 1H)
Reaction SMILES: [CH3:1][Li].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1>O1CCCC1>[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]([OH:9])[CH3:1])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1
Reactant: O=Cc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(O)c1ccc(Cl)cc1[N+](=O)[O-]
Reaction time: 0.33 h
Yield: 66 %

Procedure:
A solution of methyl lithium (46 mL, 1.4 M in Et2O), was slowly added under argon, at −78° C., to a stirred solution of 4-chloro-2-nitrobenzaldehyde (10 g, 53.9 mmol) in dry tetrahydrofuran (150 mL). After 20 min. at −78° C., the reaction mixture was quenched with water (400 mL), extracted twice with ethyl acetate (500 mL), dried (Na2SO4), and concentrated to dryness under reduced pressure. Chromatography on silica (EtOAc/CH2Cl2/EtOH, 1:6:1) yielded the title compound (7.2 g, 66%) as yellow oil: 1H NMR (400 MHz, CDCl3) δ 1.56 (d, J=6.4 Hz, 3H, ArH), 2.40 (br s, 1H, OH), 5.42 (q, J=6.4 Hz, 1H, CH), 7.63 (dd, J=8.4 Hz, J=2.0 Hz, 1H, ArH), 7.82 (d, J=8.4 Hz, 1H, ArH), 7.92 (d, J=2.0 Hz, 1H, ArH).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:16]([OH:18])=O)[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.C(Cl)(=O)C(Cl)=O.CC[N:27]([CH:31]([CH3:33])[CH3:32])C(C)C.C1(N)CC1>CN(C=O)C.C(Cl)Cl>[CH:31]1([NH:27][C:16]([C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:15]=[C:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=2)=[O:18])[CH2:33][CH2:32]1
Reactant: COCCCc1cc(C(=O)O)c2ccccc2c1
Reactant: CCN(C(C)C)C(C)C
Agent: NC1CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCCCc1cc(C(=O)NC2CC2)c2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a CH2Cl2 solution (0.1 M) of 3-[3-(methyloxy)propyl]-1-naphthalenecarboxylic acid (1 eq.) from the previous step was added at 0° C. oxalyl chloride (1.2 eq.) followed by a few drops of DMF. The resulting solution was stirred at RT for 2 h before the volatiles were removed in vacuo. The resulting residue was taken up in dichloromethane (0.1 M), cooled to 0° C. and added sequentially Hunig's base (1.2 eq.) an cyclopropylamine (1.1 eq.) dropwise. The resulting suspension was stirred at RT for 18 h. The reaction was quenched with 1 N aq. HCl and extracted with ether. The combined organic extracts were washed further with 1 N aq. NaOH, water and brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a white solid.
Reaction SMILES: [CH:1]1([C:4](=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH2:5][OH:6])[CH2:3][CH2:2]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH:1]1([C:4](=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:5]=[O:6])[CH2:2][CH2:3]1
Reactant: OCC(=C(c1ccc(F)cc1)c1ccc(F)cc1)C1CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)C1CC1
Yield: 35.2 %

Procedure:
A solution of 2-cyclopropyl-3,3-bis(4-fluorophenyl)-2-propenol (0.3 g, 1.0 mmol) and pyridinium chlorochromate (0.5 g) in 20 mL of methylene chloride was stirred at 25° C for 18 hours during which time a gummy solid formed. The methylene chloride was decanted from the solid and the solution concentrated in vacuo. The residue was stirred with diethyl ether; the diethyl ether was decanted from some insoluble tar and the diethyl ether concentrated in vacuo. The residue was crystallized from petroleum ether to give 0.1 g of the title compound; m.p. =86°-88° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[CH:19]1([C:22]#[C:23][C:24]2[CH:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=2)[CH2:21][CH2:20]1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30]([C:27]3[CH:26]=[CH:25][C:24]([C:23]#[C:22][CH:19]4[CH2:21][CH2:20]4)=[CH:29][N:28]=3)=[O:31])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1ccc(C#CC2CC2)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3ccc(C#CC4CC4)cn3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 5-cyclopropylethynyl-pyridine-2-carboxylic acid (CAS1174322-62-3, WO2009091016) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=429.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH3:24])[N:19]=[CH:18]2.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:24][N:20]1[C:21]2[C:17](=[CH:16][C:15]([N:10]3[CH2:11][CH2:12][N:8]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][C:2]=4[CH3:1])[C:9]3=[O:13])=[CH:23][CH:22]=2)[CH:18]=[N:19]1
Reactant: Cn1ncc2cc(Br)ccc21
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc3c(cnn3C)c2)C1=O
Yield: 32.8 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 100 mg, 0.5649 mmol) was reacted with 5-bromo-1-methyl-1H-indazole (142 mg, 0.6794 mmol), 1,4-dioxane (15 mL), copper iodide (10 mg, 0.0526 mmol), trans-1,2-diamino cyclohexane (19 mg, 0.1666 mmol) and potassium phosphate (36 mg, 1.698 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3) afforded 57 mg of the product (32.94% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][O:12][CH2:11]2)=O)=[CH:5][CH:4]=1.O1C=CCCC1.Br.BrC1CCCOC1.C(OCC)(=O)CC(OCC)=O.O1CCCC(C(C(OCC)=O)C(OCC)=O)C1.O=S(Cl)Cl.C1(OC)C=CC=CC=1.[Al+3].[Cl-].[Cl-].[Cl-]>C1COCC1.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][O:12][CH2:11]2)=[CH:16][CH:17]=1
Reactant: COc1ccc(C(=O)CC2CCCOC2)cc1
Agent: [Pd]
Agent: Br
Agent: BrC1CCCOC1
Solvent: O=S(Cl)Cl
Solvent: CCOC(=O)CC(=O)OCC
Solvent: COc1ccccc1
Product: COc1ccc(CCC2CCCOC2)cc1

Procedure:
A solution of 23.4 g of 3-(p-methoxybenzoylmethyl)tetrahydropyran (obtainable by reaction of 2,3-dihydro-4H-pyran with HBr to give 3-bromotetrahydropyran, reaction with diethyl malonate to give diethyl tetrahydropyran-3-ylmalonate, hydrolysis, decarboxylation, reaction with SOCl2 to give tetrahydropyran-3-acetyl chloride, and reaction with anisole in the presence of AlCl3) in 500 ml of THF is hydrogenated on 5 g of 10% Pd/C at 40° and 1 bar until 0.2 mole of H2 has been taken up. The mixture is filtered, evaporated and 3-(2-p-methoxyphenylethyl)tetrahydropyran is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][N:6]([O:18][CH3:19])[C:7](=[O:17])[CH:8]=[C:9]1[C:13](=[O:14])[O:12][C:11](C)(C)[O:10]1>CO>[CH3:11][O:12][C:13](=[O:14])[C:9]([OH:10])=[CH:8][C:7](=[O:17])[N:6]([CH2:5][C:4]1[CH:20]=[CH:21][C:22]([Cl:23])=[C:2]([Cl:1])[CH:3]=1)[O:18][CH3:19]
Reactant: CON(Cc1ccc(Cl)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Solvent: CO
Product: COC(=O)C(O)=CC(=O)N(Cc1ccc(Cl)c(Cl)c1)OC
Yield: 95 %

Procedure:
N-(3,4-Dichlorobenzyl)-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamide was treated with methanol as described in the preparation of Compound 44-D and gave the title ester as white crystals (95% yield); mp 111° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.72 (3H, s, OCH3), 3.90 (3H, s, OCH3), 4.77 (2H, s, NCH2), 6.46 (1H, s, CH), 7.17 (1H, dd, J=2.0 Hz, J=8.0 Hz, aromatic), 7.42 (1H, d, J=8.0 Hz, aromatic), 7.43 (1H, d, J=2.0 Hz, aromatic). Anal. calcd for C13H13Cl2NO5: C, 46.73; H, 3.92; N, 4.19. Found: C, 46.95; H, 3.82; N, 3.97.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[S:35][CH:36]=[CH:37][N:38]=3)[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]2[N:23]=[C:22]([S:33]([C:34]3[S:35][CH:36]=[CH:37][N:38]=3)=[O:9])[NH:21][C:20]=2[C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(-c2nc(Sc3nccs3)[nH]c2-c2ccc(OC)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3nccs3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is added dropwise to a solution of 3.95 g of 4,5-bis(4-methoxyphenyl)-2-(2-thiazolylthio)imidazole in 100 ml of dichloromethane. The solution is stirred for 3 hours at room temperature, washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is chromatographed on 150 g of silica gel with acetone/hexane 2:3, thus obtaining 3.28 g of 4,5-bis(4-methoxyphenyl)-2-(2-thiazolylsulfinyl)imidazole as an amorphous foam.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:11]([N:14]1[C:23](=[O:24])[C:22]2[NH:21][C:20]([C:25]3[N:29]([CH3:30])[N:28]=[C:27]([O:31][CH2:32][C:33](O)=[O:34])[CH:26]=3)=[N:19][C:18]=2[N:17]([CH2:36][CH2:37][CH3:38])[C:15]1=[O:16])[CH2:12][CH3:13]>>[CH3:38][CH2:37][CH2:36][N:17]1[C:15](=[O:16])[N:14]([CH2:11][CH2:12][CH3:13])[C:23](=[O:24])[C:22]2[C:18]1=[N:19]/[C:20](/[N:21]=2)=[C:25]1/[CH:26]=[C:27]([O:31][CH2:32][C:33]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[O:34])[NH:28][N:29]/1[CH3:30]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CCCn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)nn3C)nc2n(CCC)c1=O
Product: CCCn1c(=O)c2c(n(CCC)c1=O)=N/C(=C1/C=C(OCC(=O)Nc3ccc(C(=O)O)cc3)NN1C)N=2

Procedure:
Using 4-(amino)benzoic acid and 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid (Example 36), according to the method described in Example 36.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7]O.C(O[CH:12]=[C:13]([C:30]([C:32]1([CH3:35])[CH2:34][CH2:33]1)=[O:31])[C:14]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][C:17]=1[C:26]([F:29])([F:28])[F:27])=[O:15])C>>[CH3:25][S:22]([C:19]1[CH:20]=[CH:21][C:16]([C:14]([C:13]2[CH:12]=[N:7][O:31][C:30]=2[C:32]2([CH3:35])[CH2:34][CH2:33]2)=[O:15])=[C:17]([C:26]([F:29])([F:28])[F:27])[CH:18]=1)(=[O:24])=[O:23]
Reactant: NO
Reactant: CCOC=C(C(=O)c1ccc(S(C)(=O)=O)cc1C(F)(F)F)C(=O)C1(C)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: CC1(c2oncc2C(=O)c2ccc(S(C)(=O)=O)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.3 %

Procedure:
Sodium acetate (1.0 g) was added to a stirring mixture of hydroxylamine hydrochloride (0.85 g) and 2-ethoxymethylene-1-(4-methylsulphonyl-2-trifluoromethylphenyl)-3-(1-methylcyclopropyl)-propane-1,3-dione (4.2 g) in industrial methylated spirit (200ml). The mixture was stirred at room temperature for 3 hours. The mixture was evaporated to dryness and then suspended in ethyl acetate (100 ml). The resultant suspension was washed with water (100 ml), dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 4-(4-methylsulphonyl-2-trifluoromethylbenzoyl)-5-(1-methylcyclopropyl)isoxazole (compound 99, 3.5 g) as a white solid, m.p. 141°-142° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:8]=[CH:9][C:10]([N+:14]([O-])=O)=[C:11]([CH3:13])[CH:12]=2)[CH:6]=1.[H][H]>[Pd].CO>[NH2:14][C:10]1[CH:9]=[CH:8][C:7]([N:5]2[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]2)=[CH:12][C:11]=1[CH3:13]
Reactant: Cc1cn(-c2ccc([N+](=O)[O-])c(C)c2)cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cn(-c2ccc(N)c(C)c2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
A mixture of 5-(4-methylimidazol-1-yl)-2-nitrotoluene (198 mg), 10% Pd/C (58 mg) and methanol (3.0 ml) was hydrogenated with hydrogen of 1 atmosphere. The mixture was stirred at room temperature for 2 hours and filtered. The filtrate was distilled under reduce pressure to give 149 mg (87.6%) of the title compound.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][NH2:18])[CH3:14]>>[CH2:13]([N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][NH:18][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:14]
Reactant: CCN(CC)CCN
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)NCCN(CC)CC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and N,N-diethylethane-1,2-diamine as starting materials to give the aimed compound.
Reaction SMILES: [C:1]([NH:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH2:10][C:9]1=[O:18])=[O:7])(=[O:4])[CH2:2][CH3:3].C(NC(N1C2[C:31](=[CH:32]C(Cl)=CC=2)[CH2:30][C:29]1=O)=O)(=O)C(C)(C)C.C(NC(N1C2C(=CC(F)=CC=2)CC1=O)=O)(=O)CCC.C(NC(N1C2C(=CC(F)=CC=2)CC1=O)=O)(=O)C1C=CC=CC=1.C(NC(N1C2C(=CC(F)=CC=2)CC1=O)=O)(=O)C.C(NC(N1C2C(=CC(Br)=CC=2)CC1=O)=O)(=O)C1C=CC=CC=1.C(NC(N1C2C(=CC(Br)=CC=2)CC1=O)=O)(=O)CC>>[C:1]([NH:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH2:10][C:9]1=[O:18])=[O:7])(=[O:4])[C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:3]=1
Reactant: CC(C)(C)C(=O)NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Reactant: CCC(=O)NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Agent: CC(=O)NC(=O)N1C(=O)Cc2cc(F)ccc21
Agent: CCC(=O)NC(=O)N1C(=O)Cc2cc(Br)ccc21
Agent: CCCC(=O)NC(=O)N1C(=O)Cc2cc(F)ccc21
Product: O=C(NC(=O)N1C(=O)Cc2cc(Cl)ccc21)c1ccccc1

Procedure:
Using a similar procedure, 1-(N-propionylcarbamoyl)-5-chlorooxindole, 1-(N-pivaloylcarbamoyl)-5-chlorooxindole, 1-(N-butyrylcarbamoyl)-5-fluorooxindole, 1-(N-benzoyl-carbamoyl)-5-fluorooxindole, 1-(N-acetylcarbamoyl)-5-fluorooxindole, 1-(N-benzoylcarbamoyl)-5-bromooxindole, 1-(N-i-butyrylcarbamoyl)-5-bromooxindole and 1-(N-propionylcarbamoyl)-5-bromooxindole are prepared.
Reaction SMILES: C(C1CO[C:10](=O)[N:9]1[C:14](=[O:41])[CH2:15][CH:16]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:23]([O:35][CH:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[CH:22]=1)C[N+]([O-])=O)C1C=CC=CC=1>CCOC(C)=O.[Ni]>[CH2:28]([O:27][C:24]1[CH:25]=[CH:26][C:21]([CH:16]2[CH2:10][NH:9][C:14](=[O:41])[CH2:15]2)=[CH:22][C:23]=1[O:35][CH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(CC(C[N+](=O)[O-])c1ccc(OCc2ccccc2)c(OC2CCCC2)c1)N1C(=O)OCC1Cc1ccccc1
Agent: [Ni]
Solvent: CCOC(C)=O
Product: O=C1CC(c2ccc(OCc3ccccc3)c(OC3CCCC3)c2)CN1
Temperature: 50 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
Nitro-compound 16 (4 g) was partially dissolved in 75 mL EtOAc/75 mL EtOH/75 mL dioxane, and a suspension of Raney Ni was added. The mixture was flushed with H2 three times. The mixture was stirred under H2 at 50° C. overnight, then filtered through celite. Concentration and chromatography of the residue on silica gel gave 2.2 g of the desired product. Yield: 88%.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)[CH:3]=1.B(Br)(Br)Br.O>C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1
Reactant: COc1ccc(/C=C/c2cccc(I)c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(/C=C/c2cccc(I)c2)cc1
Temperature: 25 °C
Yield: 91.9 %

Procedure:
To a solution of 8 (350 mg, 1.00 mmol) in CH2Cl2 (200 mL) was added BBr3 (10 mL, 1M in hexane) dropwise at −78° C. in a dry ice-acetone bath. The mixture was allowed to warm up to room temperature. Water was added while the reaction mixture was cooled at 0° C. in an ice bath. The mixture was extracted with CH2Cl2. The organic phase was dried and filtered. The filtrate was purified by flash chromatography (EtOAc: Hex, 1:9) to give 9 (296 mg, 92%). 1H NMR (200 MHz, CDCl3): δ 4.81 (s, 1H), 6.83 (d, J=16.17 Hz, 1H), 6.84 (m, 2H), 7.03 (d, J=16.32 Hz, 1H), 7.06 (t, J=7.8 Hz, 1H), 7.36–7.57 (m, 4H), 7.84 (s, 1H); 13C NMR (50 MHz, CDCl3): δ 94.75, 115.67, 124.96, 125.49, 128.09, 129.48, 129.87, 130.25, 135.01, 135.96, 139.90, 155.53; HRMS: m/z Calcd for C14H11IO: 321.9855; Found: 321.9840.
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH:13]([C:14]3[C:19]([O:20][CH3:21])=[CH:18][C:17]([F:22])=[CH:16][C:15]=3[O:23][CH3:24])[CH2:12][CH:11]=[CH:10][C:9]2=[O:25])[CH:2]=1>CCOC(C)=O>[C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH:13]([C:14]3[C:19]([O:20][CH3:21])=[CH:18][C:17]([F:22])=[CH:16][C:15]=3[O:23][CH3:24])[CH2:12][CH2:11][CH2:10][C:9]2=[O:25])[CH:2]=1
Reactant: COc1cc(F)cc(OC)c1C1CC=CC(=O)N1Cc1cccc(-c2ccccc2)c1
Solvent: CCOC(C)=O
Product: COc1cc(F)cc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-([1,1′-biphenyl]-3-ylmethyl)-6-(4-fluoro-2,6-dimethoxyphenyl)-5,6-dihydropyridin-2(1H)-one (130 mg; 0.31 mmol; 1.0 equiv.), 10% Pd(C) (13 mg; 10% in mass) in anh. AcOEt (2 ml) was stirred at rt, under hydrogen atmosphere (1 atm), for 1 h. Filtration over a pad of celite, concentration to dryness under reduced pressure, and subsequent purification by preparative HPLC afforded 1-([1,1′-biphenyl]-3-ylmethyl)-6-(4-fluoro-2,6-dimethoxyphenyl)piperidin-2-one as a yellow solid. LC-MS (conditions A): tR=0.94 min.; [M+H]+: 419.92 g/mol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:30][C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:24]4[O:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C1[C@H]2CNCCN2C(=O)O1>>[O:23]1[C:24]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[O:30][C@@H:21]([C:18]2[CH:19]=[CH:20][C:15]([CH2:14][N:11]3[CH2:10][CH2:9][N:8]4[C:6](=[O:7])[O:5][CH2:1][C@H:13]4[CH2:12]3)=[CH:16][CH:17]=2)[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Agent: O=C1OC[C@H]2CNCCN12
Product: O=C1OC[C@H]2CN(Cc3ccc([C@H]4COc5cccnc5O4)cc3)CCN12

Procedure:
Compound 285 is synthesized from Intermediate C and (R)-hexahydro-oxazolo[3,4-a]pyrazin-3-one according to General Method M. (LC/MS method 16: ES+ m/z 368.4 [M+H]+, Rt=2.52 min).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[N:13]=[C:14]3[N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16][N:15]3[C:11]=2[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[N:4]=1>O1CCOCC1.CO>[N:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[C:11]1[N:15]3[CH2:16][CH2:17][NH:18][C:14]3=[N:13][C:12]=1[C:3]([NH2:2])=[N:4]2
Reactant: CC(C)(C)OC(=O)N1CCn2c1nc1c(N)nc3cccnc3c12
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1nc2cccnc2c2c1nc1n2CCN1
Reaction time: 3 h
Yield: 114.1 %

Procedure:
Hydrogen chloride (3.37 mL of a 4 N solution in 1,4-dioxane) was added to a mixture of tert-butyl 6-amino-9,10-dihydro-8H-imidazo[1′,2′:1,2]imidazo[4,5-c][1,5]naphthyridine-8-carboxylate (0.22 g, 0.67 mmol) in methanol (5 mL), and the resulting solution was stirred for three hours. Analysis by HPLC indicated the presence of starting material, and additional hydrogen chloride solution (3 mL) was added. The reaction was stirred at room temperature overnight and concentrated under reduced pressure. The resulting orange solid was triturated with hot acetonitrile and methanol, isolated by filtration, and washed with diethyl ether to provide 173 mg of 9,10-dihydro-8H-imidazo[1′,2′:1,2]imidazo[4,5-c][1,5]naphthyridin-6-amine as a pale orange solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[N:18]=[C:19]([NH:22][C:23](=[O:26])[CH:24]=[CH2:25])[S:20][CH:21]=3)[CH2:12][CH2:11]2)=[CH:2]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[N:18]=[C:19]([NH:22][C:23](=[O:26])[CH2:24][CH2:25][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[S:20][CH:21]=3)[CH2:12][CH2:11]2)=[CH:2]1
Reactant: C1COCCN1
Reactant: C=CC(=O)Nc1nc(CN2CCC(c3c[nH]c4ccccc34)CC2)cs1
Product: O=C(CCN1CCOCC1)Nc1nc(CN2CCC(c3c[nH]c4ccccc34)CC2)cs1
Temperature: 105 °C

Procedure:
A mixture of 4-[4-(3-indolyl)piperidinomethyl]-2-acryloylaminothiazole (360 mg) and morpholine (870 mg) was heated at 105° C. After the reaction finished, excess morpholine was distilled off, and the residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (20:1 V/V) to give 4-[4-(3-indolyl)piperidinomethyl]2-(3-morpholinopropionylamino)thiazole, which was treated with an ethanol solution of hydrogen chloride to give dihydrochloride thereof.
Reaction SMILES: Br[C:2]1[C:3]2[NH:7][C:6]([C:8](C3C(C)=CC(C)=CC=3C)=[C:9]3[N:35]=[C:12]([C:13](Br)=[C:14]4[NH:33][C:17](=[C:18](C5C(C)=CC(C)=CC=5C)[C:19]5[CH:20]=[CH:21][C:22]=1[N:23]=5)[CH:16]=[CH:15]4)[CH:11]=[CH:10]3)=[CH:5][CH:4]=2.C([C@@H]1COC(=O)N1)C1C=CC=CC=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+]>C1COCC1.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].C(OCC)(=O)C>[C:3]12[CH:2]=[C:22]3[N:23]=[C:19]([CH:20]=[CH:21]3)[CH:18]=[C:17]3[NH:33][C:14]([CH:15]=[CH:16]3)=[CH:13][C:12]3=[N:35][C:9]([CH:10]=[CH:11]3)=[CH:8][C:6]([NH:7]1)=[CH:5][CH:4]=2
Reactant: Cc1cc(C)c(-c2c3nc(c(Br)c4ccc([nH]4)c(-c4c(C)cc(C)cc4C)c4nc(c(Br)c5ccc2[nH]5)C=C4)C=C3)c(C)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3

Procedure:
The general procedure was used to couple 5,15-dibromo-10,20-di(2′,4′,6′-trimethylphenyl)porphyrin (0.035 g, 0.05 mmol) with (R)-(+)4-benzyl-2-oxazolidinone (0.0708 g, 0.4 mmol), using Pd2(dba)3 (0.0046 g, 0.005 mmol) and Xantphos (0.0116 g, 0.02 mmol) in the presence of Cs2CO3 (0.0652 g, 0.2 mmol). The reaction was conducted in THF (5 mL) at 80° C. for 20 h. The title compound was isolated by flash column chromatography (silica gel, ethyl acetate:hexanes (v/v)=1:2) as purple mixture of two atropic isomers (0.032 g, 72%, α,α and αβ, =50%/50%). 1H NMR (300 MHz, CDCl3): δ 9.45 (d, J=4.8 Hz, 2H), 9.41 (d, J=4.8 Hz, 2H), 9.22 (m, 4H), 8.88 (d, J=4.8 Hz, 2H), 8.82 (m, 6H), 7.35 (m, 8H), 7.10 (m, 8H), 6.95 (m, 4H), 6.86 (m, 8H), 5.36 (m, 2H), 5.20 (m, 2H), 5.03 (m, 4H), 4.86 (m, 4H), 3.28 (m, 4H), 3.07 (dd, J=13.2, 3.6 Hz, 2H), 2.75 (dd, J=13.2, 3.3 Hz, 2H), 2.67 (s, 12H), 2.04 (s, 6H), 1.89 (s, 6H), 1.86 (s, 6H), 1.73 (s, 6H), −2.67 (s, 2H), −2.76 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 159.5, 139.5, 139.3, 139.1, 138.2, 137.3, 137.2, 135.0, 128.8, 128.6, 128.5, 128.1, 127.9, 127.7, 127.1, 126.9, 119.9, 111.1, 110.8, 68.8, 66.3, 40.4, 21.9, 21.7, 21.6, 21.5. UV-vis (CHCl3, λmax, nm): 416, 512, 544, 590, 646. HRMS-MALDI ([M+H]+): calcd for C58H53N6O4, 897.4123, found 897.4109 with an isotope distribution pattern that is the same as calculated one.