Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5](=[O:8])[CH2:6][CH3:7].[H][H]>CO>[CH3:1][O:2][C:3](=[O:9])[CH2:4][CH:5]([OH:8])[CH2:6][CH3:7]
Reactant: CCC(=O)CC(=O)OC
Reactant: [H][H]
Solvent: CO
Product: CCC(O)CC(=O)OC
Reaction time: 48 h

Procedure:
A solution of methyl-3-oxo-pentanoate (31) (20 g) noyori hydrogenation with RuCl2 [(S)-BINAP] (60 mg), in methanol was added. The flask was charged with hydrogen gas (5 atm) at 100° C. The resulting suspension was vigorously stirred for 48 hours. The reaction mixture was diluted with methanol and the combined organic layers were filtered through a Celite pad. The combined organic phases were evaporated in a rotary evaporator to yield the product (S) isomer of methyl-3-hydroxy-pentanoate (32). The methyl-3-hydroxy-pentanoate (secondary alcohol-32) was protected with TBDMSCl in the presence of imidazole in dichloro methane. The reaction mixture was stirred for 24 hours at room temperature. This reaction was quenched with aqueous saturated sodium bicarbonate and extracted with dichloro methane. The combined organic phases were dried over Na2SO4 and the combined organic phases were evaporated in a rotary evaporator to yield the TBS protected product (33). A stirred solution of ester was reduced with di-isobutyl aluminum hydride in dichloro methane at −78° C. for 5 hours. This reaction mixture was quenched with saturated aqueous sodium potassium tartarate. The combined organic and aqueous layers were filtered and organic layer was separated by separating funnel. The aqueous layer was extracted with dichloro methane. The combined organic phases were dried over Na2SO4 and the combined organic phases were evaporated in a rotary evaporator to yield the product primary alcohol (34) as a pale yellow liquid. The primary alcohol was protected with methane sulfonyl chloride in the presence of TEA in dichloromethane. The reaction mixture was stirred for 4 hours at 0° C. This reaction was quenched with aqueous saturated sodium bicarbonate and extracted with dichloro methane. The combined organic phases were dried over Na2SO4 and the combined organic phases were evaporated in a rotary evaporator to yield the methane sulfonyl protected product (35). The methane sulfonyl protected primary alcohol was stirred at 70° C. with NaN3 in DMF for 16 hours. A stirred solution of TBS protected secondary alcohol. This reaction was quenched with pre cooled ice water and extracted with diethyl ether. The combined organic phases were dried over Na2SO4. The combined organic phases were evaporated in a rotary evaporator to yield the azido product as a colorless liquid (36). This was deprotected with TBAF in tetrahydrofuran at room temperature. This reaction was quenched with saturated ammonium chloride solution and extracted with diethyl ether; the combined organic phases were dried over Na2SO4 and evaporated on rotary evaporator to yield the product 1-azido-3-pentanol (36A) as a colorless liquid.
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[S:33][C:32]([CH3:34])=[N:31][C:30]=2[C:35](O)=[O:36])=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[S:33][C:32]([CH3:34])=[N:31][C:30]=2[C:35]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[N:15][C:14]=2[CH3:21])=[O:12])=[O:36])=[CH:27][CH:28]=1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Product: Cc1nc(C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2ccc(F)cc2)s1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid.
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[N:5][CH:4]=1.[Cl:17][C:18]1[C:24]([OH:25])=[CH:23][C:21]([NH2:22])=[C:20]([F:26])[CH:19]=1>>[Cl:17][C:18]1[C:24]([OH:25])=[CH:23][C:21]([NH:22][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[N:5][CH:4]=2)=[C:20]([F:26])[CH:19]=1
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: COc1cc2nncc(Cl)c2cc1OC
Agent: Cl
Product: COc1cc2nncc(Nc3cc(O)c(Cl)cc3F)c2cc1OC

Procedure:
A solution of 4-chloro-6,7-dimethoxycinnoline hydrochloride (261 mg, 1 mmol), (prepared as described for the starting material in Example 1), and 4-chloro-2-fluoro-5-hydroxyaniline (193 mg, 1.2 mmol), (prepared as described in EP 061741), was treated in a manner similar to that described in Example 21 in order to produce 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6,7-dimethoxycinnoline as an hydrochloride salt (315 mg, 82%).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[C:23]([O:27][C:28]([NH:30][C@@H:31]([C:33]([NH:35][CH2:36][C:37](=O)[CH3:38])=O)[CH3:32])=[O:29])([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[CH3:38][C:37]1[S:10][C:33]([C@H:31]([NH:30][C:28](=[O:29])[O:27][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:32])=[N:35][CH:36]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)CNC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: Cc1cnc([C@@H](C)NC(=O)OC(C)(C)C)s1
Yield: 33.5 %

Procedure:
Lawesson's Reagent (14 g, 35 mmol) was added to a solution of N2-(tert-butoxycarbonyl)-N-(2-oxopropyl)-D-alaninamide (8.5 g, 34.5 mmol) in THF (300 ml), and the resulting mixture was refluxed for 6 h. After concentration, the residue was purified by column, and 2.8 g of tert-butyl [(1R)-1-(5-methyl-1,3-thiazol-2-yl)ethyl]carbamate was obtained as solid (35%). 1H-NMR CDCl3 δ 7.31 (s, 1H), 5.24 (br, 1H), 5.00 (m, 1H), 2.42 (s, 3H), 1.55 (d, J=6.8 Hz, 3H), 1.44 (s, 9H) ES-MS [M+1]+: 243.14.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[CH3:9][C@@H:10]1[N:15]([CH3:16])[CH2:14][CH2:13][N:12]([CH2:17][CH2:18][OH:19])[CH2:11]1.[OH-].[K+]>CS(C)=O.O>[CH3:9][C@@H:10]1[N:15]([CH3:16])[CH2:14][CH2:13][N:12]([CH2:17][CH2:18][O:19][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH2:11]1
Reactant: C[C@H]1CN(CCO)CCN1C
Reactant: Nc1cc(Cl)ccn1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: C[C@H]1CN(CCOc2ccnc(N)c2)CCN1C
Temperature: 95 °C
Yield: 49.7 %

Procedure:
4-Chloropyridin-2-amine (0.500 g, 3.89 mmol), (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol (1.23 g, 7.78 mmol), and crushed potassium hydroxide (0.546 g, 9.72 mmol) were combined in 8 mL of DMSO in a pressure tube and heated to 95° C. for 16 hours. The mixture was then diluted with water (100 mL), extracted 2 times with EtOAc, extracts washed with brine, dried and concentrated under reduced pressure. Column chromatography (5% MeOH/DCM) afforded 0.484 g (50%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH:14][CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:22]([Cl:37])=[CH:21][N:20]=1>>[Cl:37][C:22]1[C:23]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[N:24][C:19]([NH:1][C:2]2[CH:17]=[CH:16][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH:14][CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:20][CH:21]=1
Reactant: CNC(=O)CN1CCc2ccc(N)cc2CC1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)CN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)cc2CC1

Procedure:
2-{7-[5-Chloro-4-((1R,2R)-2-methanesulfonylamino-cyclohexylamino)-pyrimidin-2-ylamino]-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl}-N-methyl-acetamide was prepared from 2-(7-amino-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N-methyl-acetamide and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to Example 308c. Product isolated as a pale yellow foam (85 mg, 44%). LCMS (m/e) 536 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.94 (s, 1H), 7.40-7.23 (m, 3H), 7.06 (d, 1H, J=8.0 Hz), 6.86 (s, 1H), 5.47-5.35 (m, 2H), 3.93-3.81 (m, 1H), 3.31-3.19 (m, 1H), 3.15 (s, 2H), 2.96-2.86 (m, 4H), 2.90 (d, 3H, J=5.0 Hz), 2.81 (s, 3H), 2.78-2.66 (m, 4H), 2.29-2.16 (m, 2H), 1.90-1.79 (m, 2H), 1.46-1.30 (m, 4H).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:20][CH2:21][O:22][CH:23]([F:25])[F:24])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=O)(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[NH2:8][C@@H:9]([CH2:20][CH2:21][O:22][CH:23]([F:24])[F:25])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOC(F)F)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](CCOC(F)F)C(=O)OCc1ccccc1

Procedure:
(S)-benzyl 2-(tert-butoxycarbonylamino)-4-(difluoromethoxy)butanoate (161 mg, 0.448 mmol) was stirred in 30% TFA in dichloromethane (5 mL) for 1 h. The resulting mixture was concentrated down on rotovap and redissolved and concentrated down with toluene three times, and finally the residue was dried on high vacuum pump. The desired product was used as-is in the next step.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C1(S([CH:21]2[C:29]3C(=CC=CC=3)C(=O)[O:22]2)(=O)=O)C=CC=CC=1.C1(=O)C2C(CC3C(C=2)=CC2C(=CC=CC=2)C3)CCC1>CN(C)C=O>[C:21]([CH:7]1[CH2:8][CH2:9][CH:10]2[CH:5]([CH2:4][CH:3]=[CH:2][C:1]2=[O:11])[CH2:6]1)(=[O:22])[CH3:29]
Reactant: O=C1OC(S(=O)(=O)c2ccccc2)c2ccccc21
Reactant: O=C1CCCC2CCCC=C12
Agent: O=C1CCCC2CC3Cc4ccccc4C=C3C=C12
Solvent: CN(C)C=O
Product: CC(=O)C1CCC2C(=O)C=CCC2C1

Procedure:
reacting the hexahydronaphthalenone product with phenylsulfonyl isobenzofuranone to create a hexahydronaphthacenone product having the formula ##STR21## and heating the hexahydronaphthacenone product in dimethylforamide under an oxygen atmosphere to produce the compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=1.[OH:18][C:19]1[C:24]([CH2:25][CH2:26][CH3:27])=[C:23](O)[CH:22]=[CH:21][C:20]=1[C:29](=[O:31])[CH3:30].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C(OCC)C.C1(C)C=CC=CC=1.ClCCl>[C:29]([C:20]1[CH:21]=[CH:22][C:23]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=2)[O:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=2)=[C:24]([CH2:25][CH2:26][CH3:27])[C:19]=1[OH:18])(=[O:31])[CH3:30]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: N#Cc1ccc(Oc2cccc(CO)c2)nc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCc1c(OCc2cccc(Oc3ccc(C#N)cn3)c2)ccc(C(C)=O)c1O
Temperature: -20 °C
Reaction time: 0.08 h
Yield: 33.1 %

Procedure:
Mix 6-(3-hydroxymethyl-phenoxy)-nicotinonitrile (1.63 g, 7.18 mmol) and 1-(2,4-dihydroxy-3-propyl-phenyl)-ethanone (1.33 g, 6.84 mmol) in 2:1 toluene/dichloromethane (24 mL). Cool to −20° C. and add tributylphosphine (2.6 mL, 10.26 mmol) dropwise. After stirring for 5 minutes, add 1,1′-(azodicarbonyl)dipiperidine in three batches. Allow the reaction mixture to warm to ambient temperature overnight. Concentrate under reduced pressure to give a yellow solid. Dilute with diethyl ether (50 mL) and cool to 0° C. Filter the white precipitate and concentrate the filtrate under reduced pressure to give a residue. Purification by flash chromatography, using 5% ethyl acetate/hexanes to 30% ethyl acetate/hexanes as a gradient eluent yields the title compound (0.91 g, 33%): MS (m/z): 401.2 (M−1). 1H NMR (CDCl3) 12.78 (s, 1H), 8.50 (s, 1H), 7.97 (dd, J=2.2 Hz, 8.8 Hz, 1H), 7.62 (d, J=8.8 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.25 (s, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.09 (d, J=8.8 Hz, 1H), 6.51 (d, J=8.8 Hz, 1H), 5.22 (s, 2H), 2.72 (t, J=7.6 Hz, 2H), 2.60 (s, 3H), 1.62-1.53 (m, 2H), 0.94 (t, J=7.6 Hz, 3H).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]([O:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:12])[CH2:3][CH2:2]1.O.O[Li].O>C1COCC1>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]([O:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:12])[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(OC(=O)C2CCOc3ccccc32)cc1OC
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC(=O)C2CCOc3ccccc32)ccc1C(=O)O
Temperature: 45 °C

Procedure:
To a stirred solution of methyl 4-(4-chromanoyloxy)-2-methoxybenzoate (260 mg, 0.82 mmol) in THF:H2O (4 mL:0.8 mL) was added LiOH.H2O (172 mg, 4.1 mmol). The reaction was heated to 45° C. over 12 h and then cooled to ambient temperature. The solvent was removed under reduced pressure. The crude solid was passed through a small plug of silca gel packed in 90:10 CH2Cl2 :MeOH(NH3) and eluted with same. The solvent was removed under reduced pressure to afford 4-(4-chromanoyloxy)-2-methoxybenzoic acid as a foam.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:46])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[O:36][N:35]=[C:34]([CH3:37])[C:33]=2[CH2:38][O:39]C2CCCCO2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:19])([F:18])[F:20])=[CH:10][C:9]2[NH:21][C:22](=[O:46])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[O:36][N:35]=[C:34]([CH3:37])[C:33]=4[CH2:38][OH:39])[CH:27]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1noc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)c1COC1CCCCO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc(-c2cccc(C3=Nc4cc(N(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)c1CO

Procedure:
The title compound was prepared from (RS)-[5-dimethylamino-2-(3-{3-[3-methyl-4-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-5-yl]-phenyl}-3-oxo-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example M60) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (64 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[OH:10].[Cl:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[C:14]([N:16]=[C:17]=[O:18])=[O:15]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:17]([NH:16][C:14](=[O:15])[C:13]2[CH:19]=[CH:20][CH:21]=[CH:22][C:12]=2[Cl:11])=[O:18])[CH:5]=[C:4]([Cl:9])[C:3]=1[OH:10]
Reactant: O=C=NC(=O)c1ccccc1Cl
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1ccccc1Cl)Nc1cc(Cl)c(O)c(Cl)c1
Temperature: 100 °C
Yield: 95.3 %

Procedure:
Into a reaction flask containing 6.23 grams (35.0 mmol) of 2,6-dichloro-4-aminophenol in 100 milliliters of toluene (heated to a temperature of 100° C. to dissolve the solid) was added with continuous stirring a solution of 7.63 grams (42.0 mmol) of 2-chlorobenzoyl isocyanate dissolved in 25 milliliters of toluene. The resulting exothermic reaction raised the temperature to boiling with the formation of a solid precipitate. Additional amounts of toluene were added to the reaction flask to facilitate stirring until the addition of 2-chlorobenzoyl isocyanate was complete. After cooling to ambient temperature, the solid precipitate was filtered and the residue was washed successively with toluene and hexane and air dried to afford 11.99 grams of 1-(3,5-dichloro-4-hydroxyphenyl)-3-(2-chlorobenzoyl)urea as a light brown solid having a melting point of 220° C.-222° C. Elemental analysis of the light brown solid indicated the following:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:26]([C@@H:39]1[CH2:43][CH2:42][CH2:41][NH:40]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[CH:26]([C@@H:39]1[CH2:43][CH2:42][CH2:41][N:40]1[C:4]([C:3]1[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])=[CH:10][C:2]=1[Cl:1])=[O:6])([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: c1ccc(C(c2ccccc2)[C@@H]2CCCN2)cc1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCC[C@H]2C(c2ccccc2)c2ccccc2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, (2S)-2-benzhydrylpyrrolidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 5.18 minutes; C34H30Cl2N4O2 (597.54); mass spectrum: (M−H)−=597/599/601 (chlorine isotope).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2.[CH:19]1([CH2:22][N:23]([CH3:29])[CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])[CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:28][CH2:27][CH2:26][CH2:25][CH2:24][N:23]([CH2:22][CH:19]1[CH2:21][CH2:20]1)[CH3:29])=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2
Reactant: CN(CCCCN)CC1CC1
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Product: COc1ccc2nc3cc(Cl)ccc3c(NCCCCN(C)CC3CC3)c2c1

Procedure:
Following the general procedure of Example 1 and making non-critical variations but using 6,9-dichloro-2-methoxyacridine and N1-(cyclopropylmethyl)-N1-methylbutane-1,4-diamine (Step 1), the title compound was obtained; MS (Found M+1=398). 1H NMR (CDCl3, 300 Hz): 8.05-7.94 (m, 3H), 7.40-7.36 (m, 1H), 7.26-7.23 (m, 2H), 3.93 (s, 3H), 3.75-3.71 (t, 2H, J=6 Hz), 2.48-2.43 (t, 2H, J=6 Hz), 2.29-2.22 (m, 5H), 1.85-1.78 (m, 2H), 1.76-1.65 (m, 2H), 0.87-0.85 (m, 1H), 0.50-0.45 (d, 2H, J=2.4 Hz), 0.09-0.05 (d, 2H, J=4.8 Hz).
Reaction SMILES: [C:1]12[C:18](=[O:19])[O:17][C:15](=O)[C:13]3=[C:14]1[C:5](=[CH:6][C:7]1[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:4]=[CH:3][CH:2]=2.[NH2:20][CH2:21][CH2:22][NH:23][CH2:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:29][NH2:30]>C1(C)C=CC=CC=1>[O:17]=[C:15]1[C:13]2[C:14]3[C:5](=[CH:4][CH:3]=[CH:2][C:1]=3[C:18](=[O:19])[N:30]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21][N:20]1[C:18](=[O:19])[C:1]3[CH:2]=[CH:3][CH:4]=[C:5]4[C:14]=3[C:13](=[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]3=[CH:6]4)[C:15]1=[O:17])[CH:6]=[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]1=2
Reactant: O=C1OC(=O)c2c3ccccc3cc3cccc1c23
Reactant: NCCNCCCNCCN
Solvent: Cc1ccccc1
Product: O=C1c2cccc3cc4ccccc4c(c23)C(=O)N1CCNCCCNCCN1C(=O)c2cccc3cc4ccccc4c(c23)C1=O
Yield: 49.9 %

Procedure:
A mixture of 1.6 g (6 mmol) of anthracene-1,9-dicarboxylic anhydride in 40 ml of toluene was treated with 0.5 g (3 mmol) of N,N'-bis(2-aminoethyl)-1,3-propanediamine dissolved in 10 ml of toluene. The mixture was refluxed for 4 h and then filtered. The solution was allowed to cool and the solid formed was filtered, washed, dried and recrystallized from toluene. 0.93 g (50%) of N,N'-bis[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]isoquinolin-2-yl)ethyl]-1,3-propanediamine were obtained. M.p. 191° C. (toluene). 1 H-NMR (CDCl3) δ=1.84 (q, 2H, J=6 Hz, --CH2 --); 2.74 (broad, s, 2H, NH); 2.89 (t, 4H, J=6 Hz, CH2); 3.02 (t, 4H, J=6 Hz, CH2); 4.31 (t,4H, J=6 Hz, CH2); 7.54 (m, 4H, H-5 and H-9); 7.73 (m, 2H,H-10); 7.89 (d, 2H, J=8 Hz, H-8); 8.22 (d, 1H, J=8 Hz, H-4); 8.51 (s,2H, H-7); 8.57 (d, 2H, J=8 Hz, H-6); 9.78 (d,2H, J=8 Hz, H-11) p.p.m.. Anal. Calculated for C39H32N4O4 : C 75.46; H 5.19; N 9.02. Found: C 75.14; H 5.37; N 8.78. Acetate m.p. 155° C. Methanesulfonate m.p. 243° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([CH3:8])=[N:6][CH:7]=1.N1C=CC=CC=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:16](=[O:18])[CH3:17])[C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: Cc1ncc(Br)cc1N
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1cc(Br)cnc1C
Temperature: 80 °C
Reaction time: 16 h
Yield: 79.6 %

Procedure:
To a solution of 5-bromo-2-methylpyridin-3-amine (3.2 g, 17 mmol) in dichloromethane (100 mL) was added pyridine (2.03 g, 25.7 mmol) and acetic anhydride (2.63 g, 25.7 mmol). The mixture was stirred at 80° C. for 16 h. The mixture was poured into water (80 mL) and extracted with dichloromethane (3×150 mL). The organic layer was concentrated in vacuo, and the resultant residue was purified by flash column chromatography (15→30% ethyl acetate in petroleum ether) to afford N-(5-bromo-2-methylpyridin-3-yl)acetamide (3.1 g, 80% yield). 1H NMR (400 MHz, Chloroform-d) δ 8.48 (s, 1 H), 8.32 (s, 1 H), 7.09 (br s. 1 H), 2.45 (s, 3 H), 2.23 (s, 3 H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:29])[CH2:16][CH:17]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:18][C:19]([OH:21])=[O:20])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:30]([O-])([OH:32])=[O:31].O>C(O)(=O)C>[N+:30]([C:12]1[CH:13]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=[CH:10][C:11]=1[NH:14][C:15](=[O:29])[CH2:16][CH:17]([C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1)[CH2:18][C:19]([OH:21])=[O:20])([O-:32])=[O:31]
Reactant: O=C(O)CC(CC(=O)Nc1ccc(Oc2ccccc2)cc1)c1ccc(Cl)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CC(CC(=O)Nc1ccc(Oc2ccccc2)cc1[N+](=O)[O-])c1ccc(Cl)cc1
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
N-(4-Phenoxyphenyl)-3-(4-chlorophenyl)glutaramic acid (1.41 g) was dissolved in acetic acid (3 ml) with heating. The solution was allowed to cool to 30° C. With vigorous stirring fuming nitric acid (0.7 ml) was rapidly added in portions. The resulting hot, orange coloured solution was stirred at rt for 0.5 h. With ice cooling water (15 ml) was added slowly. From the gummy, yellow precipitate the aqueous layer is removed by decantation. Crystallisation is induced by heating with methanol (4 ml). After cooling to rt the precipitate is isolated by filtration, washed with methanol, and dried in vacuo to yield bright yellow crystals (1.21 g) of N-(2-nitro-4-phenoxyphenyl)-3-(4-chlorophenyl)glutaramic acid.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)=[O:10].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[Cl:8][C:7]1[C:2]([C:14]2[CH:15]=[CH:16][C:11]([CH:9]=[O:10])=[CH:12][CH:13]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Clc1cccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=Cc1ccc(-c2ncccc2Cl)cc1
Yield: 81 %

Procedure:
{circle around (1)} 100 g (0.676 mol) of 2,3-dichloropyridine, 101.4 g (0.676 mol) of (4-formylphenyl)boronic acid and 86 g (0.811 mol) of sodium carbonate were dissolved in 500 mL of 1,2-dimethoxyethane and 500 mL of distilled water, and 78 g (0.0676 mol) of Pd(PPh3)4 was added. The mixture was heated to reflux for 18 hours so that it was allowed to react. After completion of the reaction, the reaction solution was concentrated under reduced pressure to remove 1,2-dimethoxyethane, and then extracted with ethyl acetate. The extract was treated with magnesium sulfate, filtered and concentrated under reduced pressure, yielding 4-(3-chloropyridin-2-yl)benzaldehyde as represented below in a 81% yield.