Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[C:5]2[C:10](=[C:11]([NH:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH3:18].[C:30]([OH:37])(=[O:36])[CH2:31][CH2:32][C:33]([OH:35])=[O:34]>CO>[CH3:1][O:2][C:3]1[C:4]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:27])[F:29])[CH:21]=2)=[C:5]2[C:10](=[C:11]([NH:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH:12]=1)[N:9]=[C:8]([CH:31]([C:30]([OH:37])=[O:36])[CH2:32][C:33]([OH:35])=[O:34])[CH:7]=[C:6]2[CH3:18]
Reactant: O=C(O)CCC(=O)O
Reactant: COc1cc(NCCCN)c2nccc(C)c2c1Oc1cccc(C(F)(F)F)c1
Solvent: CO
Product: COc1cc(NCCCN)c2nc(C(CC(=O)O)C(=O)O)cc(C)c2c1Oc1cccc(C(F)(F)F)c1

Procedure:
A solution of the above phthalimide 10 in 100 mL of 65% hydrazine and 100 mL of ethanol was refluxed under argon for 3 hours. After cooling to room temperature, the solution was diluted with 10% aqueous KOH solution and extracted with dichloromethane three times. The combined extract was washed with brine, dried (K2CO3), concentrated, and column chromatographed on silica gel using dichloromethane and methanol as eluants to give 1.86 g (80% yield) of 6-methoxy-8-[(3-aminopropyl)amino]-4-methyl-5-(3-trifluoromethylphenyloxy)quinoline. 1H NMR (CDCl3) δ 8.40 (d, J=4 Hz, 1 H), 7.34 (t, J=8 Hz, 1 H), 7.21 (d, J=8 Hz, 1 H), 7.06 (m, 2 H), 6.93 (d, J=8 Hz, 1 H), 6.48 (s, 1 H), 6.4 (bs, 1 H, NH), 3.83 (s, 3 H, OMe), 3.42 (t, J=8 Hz, 2 H), 2.99 (t, J=8 Hz, 2 H), 2.62 (s, 3 H, Me), 1.98 (pentet, J=8 Hz, 2 H), 1.80 (bs, 2 H, NH2). 13C NMR (CDCl3) δ 160.0, 151.1, 145.0, 143.5, 142.7, 130.2, 125.2, 118.4, 118.2, 112.2, 107.5, 92.9, 56.8, 41.6, 40.4, 33.1, 23.4. The succinic acid salt was prepared by treating 0.457 g (1.12 mmol) of the quinoline with 0.134 g (1.13 mmol) of succinic acid in 10 mL of methanol. The resulting solution was concentrated to dryness, crystallized from diethyl ether to give a quantitative yield of the succinic acid salt PQ1.
Reaction SMILES: Br[C:2]1[C:3]([Cl:10])=[C:4]([CH3:9])[C:5]([F:8])=[CH:6][CH:7]=1.[CH3:11][N:12](C=O)C>ClCCl.[C-]#N.[Zn+2].[C-]#N.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:10][C:3]1[C:4]([CH3:9])=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[C:11]#[N:12]
Reactant: Cc1c(F)ccc(Br)c1Cl
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: ClCCl
Product: Cc1c(F)ccc(C#N)c1Cl
Temperature: 120 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
3-Bromo-2-chloro-6-fluorotoluene (7.0 g, 31 mmol), zinc cyanide (3.7 g, 31 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.81 g, 1.56 mmol) was added to a flask under argon atmosphere. Dry DMF (35 mL) was added and the reaction mixture was stirred under argon at 120° C. The reaction was monitored by GC-MS and full conversion was observed after 2 hours. The mixture was diluted with dichloromethane (300 mL), washed with water (100 mL) and 4% magnesium sulfate solution (100 mL), dried over magnesium sulphate, filtered, and evaporated to give a clear oil. The product was further purified by column chromatography on silica gel using n-heptane/ethyl acetate (9:1) giving a white solid (3.79 g, 71%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:28]\[OH:29])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2Cl)ccc1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(Br)cc2)c2ccccc2Cl)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-phenyl)-3-(2-chloro-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless foam, MS (ESI+): m/z=445.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].[NH:7]1[CH:11]=[C:10]([C:12]23CCC(=O)[CH:13]2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[CH2:20]3)[N:9]=[CH:8]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:1]=[C:2]1[CH:5]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH2:13][C:12]2([C:10]2[N:9]=[CH:8][NH:7][CH:11]=2)[CH2:20][CH2:3]1
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCC2(c3c[nH]cn3)Cc3ccccc3C12
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=C1CCC2(c3c[nH]cn3)Cc3ccccc3C12
Yield: 44 %

Procedure:
A mixture of potassium tert-butoxide (0.38 g) and methyltriphenyl-phosphonium bromide (1.2 g) in dry toluene (20 ml) was heated at reflux for 0.5 hour. To the mixture was then added 0.55 g of 8a-(1H-imidazol-4-yl)-1,3a,8,8a-tetrahydro-2H-cyclo-penta[a]inden-3-one and the resulting mixture was heated at reflux for 4 hours. After the removal of toluene, the residue was suspended in water and extracted with methylene chloride. The combined organic layers were dried over sodium sulfate and the solvent removed under reduced pressure. The crude product was purified by flash chromatography using methylene chloride/methanol (95:5) as eluent. Recrystallization from ethyl acetate afforded 240 mg of the product, m.p. 167-174° C.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)[C@H:3]([OH:5])[CH3:4].C(N(CC)CC)C.[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:22]=1[C:23](Cl)=O.C(N(S(F)(F)F)CC)C>ClCCl.O.C1COCC1>[Br:12][C:9]1[CH:8]=[CH:7][C:6]([C@H:2]2[C@@H:3]([CH3:4])[O:5][C:23]([C:22]3[C:21]([F:20])=[CH:29][CH:28]=[CH:27][C:26]=3[F:30])=[N:1]2)=[CH:11][CH:10]=1
Reactant: C[C@@H](O)C(N)c1ccc(Br)cc1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@H]1OC(c2c(F)cccc2F)=N[C@H]1c1ccc(Br)cc1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
A 50 mL round bottom flask equipped with a stir bar, thermocouple, and a reflux condenser was charged with (2R)-1-amino-1-(4-bromophenyl)propan-2-ol (480 mg, 2.09 mmol), triethylamine (222 mg, 0.3 mL, 2.19 mmol) and THF (10 mL). The reaction mixture was cooled to 10° C. 2,6-Difluorobenzoyl chloride (387 mg, 2.1 mmol) was added to the THF solution keeping the temperature <30° C. The reaction mixture was stirred at 25-30° C. for 2 hours. Dichloromethane (40 mL) and water (60 mL)were added and the phases were separated. The aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic extracts were washed with aq. 0.5 N HCl (50 mL) and brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude amide, which was placed in a 50 mL round bottom flask equipped with a stir bar, thermocouple, and a reflux condenser. The residue was dissolved in dichloromethane (25 mL), and the reaction mixture was cooled to −78° C. (Diethylamino)sulfur trifluoride (337 mg, 0.28 mL, 2.09 mmol) was added to the dichloromethane solution keeping the temperature −70° C. The reaction mixture was allowed to warm to 25° C. while stirring over 16 h. The reaction mixture was poured into 50 g ice containing conc. ammonium hydroxide (5 mL). The phases were separated and the aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude product as a mixture of diastereomers. Column chromatography gave two products (270 mg of (4S,5S) as an oil and 171 mg of (4S,5R) as an oil, 60% overall yield for the combined isomers over the two steps).
Reaction SMILES: [CH3:1][CH:2]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)[CH3:3].[Li]CCCC.CCCCCC.[C:21](Cl)(=[O:24])[CH2:22][CH3:23]>C1COCC1>[O:24]=[C:21]([N:5]1[C@@H:4]([CH:2]([CH3:3])[CH3:1])[CH2:8][O:7][C:6]1=[O:9])[CH2:22][CH3:23]
Reactant: CCC(=O)Cl
Reactant: CC(C)[C@H]1COC(=O)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(=O)N1C(=O)OC[C@@H]1C(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 79.8 %

Procedure:
To a cooled solution (-78° C.) of 1.5910 g (12.316 mmole of (+)-(4S)-3-(1-oxopropyl)-4-(1-methylethyl)-2-oxoazolidinone (A) in 20 ml of THF under N2 atmosphere is added 5.80 ml of 2.32M n-BuLi in hexane (13.55 mmole, 1.1 equiv.) to form the conjugate base. The milky slurry is stirred for 1 hour before 1.11 ml (1.1852 g, 12.81 mmoles, 1.04 equiv., mwt 92.53, bp 77°-9° C., d 1.065) of propionyl chloride is added in one portion. The slurry dissolves instantly to a clear orange solution. After stirring an additional 15 min. at -78° C., the reaction is quenched with 20 ml sat. NH4Cl, and the THF is removed in vacuo at RT (room temp). The resultant concentrate is taken up in ether and extracted successively with aq. NaHCO3, water, brine and dried over anh. Na2SO4. Evaporation of the solvent followed by flash chromatography affords 1.82 g (80%) of purified product B as a viscous yellow oil. Proton NMR (200 MHz) in CDCl3 shows: ##STR58## 4.41 (d of t, 1H, J=7.6 Hz, J=3.6 Hz, C3 -H); 4.22 (m, 2H, 2J=5.4 Hz, C4 -H); 2.92 (q of d, 2H, J=7.7 Hz, J=4.0 Hz, C9 -H); 2.35 (m, 1H, J=7.0 Hz, J=3.9 Hz, C2 -H); 1.14 (t, 3H, J=7.7 Hz, C10 -H); 0.89, 0.85 (d, 6H, J=7.0 Hz, C1 -H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=3)=[CH:9][S:8][C:7]=2[CH:24]=1.O=P(Cl)(Cl)Cl.CN([CH:33]=[O:34])C>C(Cl)(Cl)Cl>[CH:33]([C:9]1[S:8][C:7]2[CH:24]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=1)=[O:34]
Reactant: CN(C)C=O
Reactant: COC(=O)/C=C/c1ccc(Oc2csc3cc(OC)ccc23)cc1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)/C=C/c1ccc(Oc2c(C=O)sc3cc(OC)ccc23)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 95.5 %

Procedure:
To a solution of (E)-methyl 3-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (30 mg, 0.088 mmol) in CHCl3 (1.5 mL) at 0° C. was added POCl3 (0.5 mL, 5.36 mmol) followed by DMF (0.5 mL, 6.46 mmol). The resulting mixture was stirred at 0° C. for 5 min and then allowed to warm to room temperature for 2 h after which time the reaction was again cooled to 0° C. and quenched by dropwise addition of water. The mixture was then partitioned between 1N aqueous NaOH and CH2Cl2. The layers were separated and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford (E)-methyl 3-(4-((2-formyl-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (31 mg, 0.084 mmol, 95% yield) which was used without further purification. LC/MS (m/z, MH+): 369.0.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C@H:7]([NH:9]C(=O)OC(C)(C)C)[CH3:8])=[N:4][CH:3]=1.[ClH:17].CO>>[ClH:17].[CH3:1][C:2]1[S:6][C:5]([C@H:7]([NH2:9])[CH3:8])=[N:4][CH:3]=1
Reactant: Cc1cnc([C@@H](C)NC(=O)OC(C)(C)C)s1
Agent: Cl
Solvent: CO
Product: Cc1cnc([C@@H](C)N)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
tert-butyl [(1R)-1-(5-methyl-1,3-thiazol-2-yl)ethyl]carbamate (2.8 g, 11.5 mmol) was dissolved into HCl-MeOH (40 ml), and the resulting mixture was stirred at r.t. for 2 h. After concentration to remove most of solvent, to the residue was added fresh ethanol, and the residue was concentrated again. The crude product was recrystallized from ethanol and ether to give 1.8 g (87.8%) of (1R)-1-(5-methyl-1,3-thiazol-2-yl)ethanamine hydrochloride as solid hydrochloric salt. 1H-NMR DMSO δ 8.76 (br, 3H), 7.52 (s, 1H), 4.69 (m, 1H), 1.56 (d, J=6.8 Hz, 3H). ES-MS [M+1]+: 143.25.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([SH:22])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[H-].[Na+].Br[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1>CN(C)C=O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[N:12]=[C:11]([S:22][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[NH:10][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(-c2nc(S)[nH]c2-c2ccc(OC)cc2)cc1
Reactant: Brc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(Sc3ccccn3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
3.12 g of 4,5-bis(4-methoxyphenyl)-2-mercaptoimidazole is dissolved in 50 ml of absolute dimethylformamide and combined with 0.3 g of sodium hydride (80% strength in white oil). The mixture is stirred for 30 minutes, and then 1.74 g of 2-bromopyridine in 25 ml of dimethylformamide is added dropwise thereto. The reaction mixture is stirred at room temperature under argon for 30 hours. Then the solution is poured into 300 ml of ice water, the product is extracted with ethyl acetate, the organic solution is dried over sodium sulfate and concentrated to dryness under vacuum. The residue is recrystallized from methylene chloride/ether, thus obtaining 2.94 g of 4,5-bis(4-methoxyphenyl)-2-(2-pyridylthio)imidazole, mp 94°.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[N:13]=[C:14]([C:18]3[CH:33]=[CH:32][C:21]([C:22]([NH:24][CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:23])=[CH:20][CH:19]=3)[O:15][C:16]=2[CH3:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>CS(C)=O>[CH3:17][C:16]1[O:15][C:14]([C:18]2[CH:33]=[CH:32][C:21]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[O:23])=[CH:20][CH:19]=2)=[N:13][C:12]=1[CH2:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:38]2[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]2)=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CN1CCNCC1
Reactant: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccc(F)cc1
Solvent: CS(C)=O
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccc(N2CCN(C)CC2)cc1
Temperature: 130 °C
Reaction time: 16 h
Yield: 31 %

Procedure:
A mixture of fluoride 48 (112 mg, 0.24 mmol) and 1-methylpiperazine (1 mL) in DMSO (1 mL) was stirred in a sealed tube at 130° C. for 16 h. The solvent was evaporated and the residue was suspended in ice/water (50 mL) for 1 h. The mixture was partitioned between CHCl3 (200 mL) and water (50 mL) and the solvent evaporated. The mixture was dissolved in EtOAc (5 mL) and the precipitated filtered to give benzamide 49 (41 mg, 31%) as a white powder: mp (EtOAc) 210-215° C.; 1H NMR δ 9.23 (s, 1H, CONH), 8.56 (br s, 1H, H-2′), 8.46 (dd, J=4.8, 1.6 Hz, 1H, H-6′), 8.00 (d, J=8.6 Hz, 2H, H-2, H-6), 7.91 (d, J=8.6 Hz, 2H, H-3, H-5), 7.73 (dt, J=8.0, 2.0 Hz, 1H, H-4′), 7.50 (d, J=9.1 Hz, 2H, H-3″, H-5″), 7.36 (ddd, J=7.9, 4.7, 0.6 Hz, 1H, H-5′), 7.02 (d, J=9.1 Hz, 2H, H-2″, H-6″), 4.49-4.53 (m, 4H, CH2SO2, CH2N), 3.30 (br t, J=4.9 Hz, 4H, 2×CH2N), 2.40 (br t, J=4.9 Hz, 4H, 2×CH2N), 2.20 (s, 3H, CH3), 2.12 (s, 3H, CH3); 13C NMR δ 165.5, 157.8, 154.0, 149.6, 148.8, 148.1, 135.3, 135.1, 134.9, 129.7 (2), 128.8, 128.0 (2), 126.4, 125.4 (2), 123.4 (2), 113.3 (2), 54.1 (2), 53.2, 46.4 (2), 45.6, 40.4, 9.6; MS m/z 546.8 (MH+, 100%).
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:15][CH:16]1[CH:21]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]1>>[Cl:29][C:24]1[CH:23]=[C:22]([CH:21]2[CH2:20][CH2:19][NH:18][CH2:17][CH:16]2[NH:15][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH:27]=[CH:26][C:25]=1[F:28]
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)c(Cl)c2)C(N)C1
Product: NC(=O)c1ccnc2c(NC3CNCCC3c3ccc(F)c(Cl)c3)ncnc12

Procedure:
Compound 23 was prepared following general synthesis scheme 9 wherein 4-hydroxy-pyrido[3,2-d]pyrimidine-8-carboxylic acid amide was reacted with tert-butyl 3-amino-4-(3-chloro-4-fluoro-phenyl)piperidine-1-carboxylate to give the title compound. LC-MS [401 (M+H)].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([C:13]([O:15][CH3:16])=[O:14])[CH3:12])=[CH:7][C:6]=1[S:17]([NH2:20])(=[O:19])=[O:18])=[O:4].S(Cl)(Cl)=O.N1C=CC=CC=1.[C:31](Cl)(Cl)=[O:32]>ClCCCl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([C:13]([O:15][CH3:16])=[O:14])[CH3:12])=[CH:7][C:6]=1[S:17]([N:20]=[C:31]=[O:32])(=[O:19])=[O:18])=[O:4]
Reactant: O=C(Cl)Cl
Reactant: COC(=O)c1ccc(N(C)C(=O)OC)cc1S(N)(=O)=O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: COC(=O)c1ccc(N(C)C(=O)OC)cc1S(=O)(=O)N=C=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5.0 g of 2-methoxycarbonyl-5-(N-methoxycarbonyl-N-methylamino)benzenesulfonamide are suspended in 17 ml of 1,2-dichloroethane. 4 ml of thionyl chloride are added and the reaction mixture is heated at boiling for 5 h. The reaction mixture is cooled to room temperature, 0.3 ml of pyridine is added, phosgene is passed into the reaction mixture, and the solution is heated at reflux for 4 h. The reaction mixture is concentrated to give 6.3 g of an oil which is employed directly in the subsequent reaction (Examples m, n, o).
Reaction SMILES: C(NCC)C.C(O)(C)(C)C.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1.Br[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH2:19][CH2:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])=[CH:14][CH:13]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: O=C(CBr)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Solvent: CCNCC
Product: O=C(CCC(=O)c1ccc(F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.8 %

Procedure:
Diethylamine (55 mmol, 5.69 mL) and t-Butanol (55 mmol, 5.26 mL) are added to a stirred solution of Zinc Chloride (74 mmol, 10 g) in anhydrous toluene (100 mL). After two hours of stirring at room temperature, Zinc Chloride is completely dissolved. 1-(4-Fluorophenyl)-ethanone (40 mmol, 4.90 mL) is added, followed by the addition of bromoacetophenone (37 mmol, 7.4 g). The reaction is allowed to stir at room temperature for 3 days. A 5% aqueous solution of sulfuric acid (75 mL) is added and the organic phase is separated from the aqueous phase. The aqueous phase is extracted with Ethyl Acetate (50 mL) and the two organic phases are combined. The organic phase is dried with Sodium Sulfate, filtered and concentrated to give 1-(4-fluoro-phenyl)-4-phenyl-butane-1,4-dione (5.2 g) confirmed by LCMS, as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]=2[CH:5]=[C:4]([CH3:20])[CH:3]=1.[H-].[Na+].Br[CH2:24][C:25]([O:27][CH3:28])=[O:26]>CN(C=O)C>[C:16]([O:15][C:13](=[O:14])[CH2:12][N:7]1[C:6]2[CH:5]=[C:4]([CH3:20])[CH:3]=[C:2]([CH3:1])[C:10]=2[N:9]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:8]1=[O:11])([CH3:17])([CH3:19])[CH3:18]
Reactant: Cc1cc(C)c2[nH]c(=O)n(CC(=O)OC(C)(C)C)c2c1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(=O)n(CC(=O)OC(C)(C)C)c2cc(C)cc(C)c21
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (4,6-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)acetate from Step B (100 mg, 0.36 mmol) in DMF (3 mL) was added sodium hydride (17 mg of a 60% dispersion in mineral oil, 0.43 mmol) followed by methyl bromoacetate (0.041 mL, 0.43 mmol) and the reaction mixture was stirred for 2 h. The reaction was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. Lyophilization of the product-containing fractions afforded the title compound. MS: m/z=349 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]2[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=2)[CH:19]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=3)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Product: COc1cc(-c2cc(CNCC3CCN(C(=O)OC(C)(C)C)CC3)ccn2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-aminomethylpiperidine (200 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (183 mg) were condensed in the same manner as described in Example 2 to give the title compound as yellow syrup.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:5]2[CH2:6][CH2:7][N:8]([CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[C:9](=[O:12])[C:10]=2[CH:11]=1.N1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(=O)([O-])O.[Na+]>ClCCl.O>[CH3:30][S:31]([NH:1][C:2]1[CH:3]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:5]2[CH2:6][CH2:7][N:8]([CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[C:9](=[O:12])[C:10]=2[CH:11]=1)(=[O:33])=[O:32]
Reactant: CCCC(CCC)N1CCc2c(C(=O)OC)cc(N)cc2C1=O
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCCC(CCC)N1CCc2c(C(=O)OC)cc(NS(C)(=O)=O)cc2C1=O
Reaction time: 20 h

Procedure:
0.5 g of methyl 7-amino-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate is dissolved under an inert atmosphere in 5 cm3 of dichloromethane at a temperature close to 20° C. 0.142 cm3 of pyridine is poured into the reaction mixture which is then cooled to a temperature close to 5° C. 0.122 cm3 of methanesulfonyl chloride is introduced over 30 min. The stirring is continued for 20 h while gradually allowing it to climb back up to a temperature close to 20° C. 20 cm3 of a saturated aqueous solution of sodium hydrogen carbonate and 5 cm3 of water are added to the reaction mixture. Stirring is continued for 1 h at a temperature close to 20° C. The aqueous phase is extracted with 10 cm3 of dichloromethane. After decanting, the organic phase is dried over magnesium sulfate, filtered then concentrated using a rotary evaporator under reduced pressure (5 kPa). The crude product obtained is purified by trituration in 10 cm3 of hot diisopropyl ether. After filtering at a temperature close to 20° C., washing with 2 lots of 5 cm3 of diisopropyl ether and drying under vacuum, 0.6 g of methyl 7-[(methylsulfonyl)amino]-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate is obtained in the form of pink crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[C:4]([CH3:12])[CH:3]=1.[Br-:13].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[Br:13][CH:9]([CH3:10])[C:8]([C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][C:4]=1[CH3:12])=[O:11]
Reactant: [Br-]
Reactant: CCC(=O)c1cnc(Cl)cc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: Cc1cc(Cl)ncc1C(=O)C(C)Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1-(6-chloro-4-methyl-pyridin-3-yl)-propan-1-one (0.25 g, 1.36 mmol) in DCM (6 ml) is added tetrabutylammonium tribromide (0.656 g, 1.36 mmol). The resulting orange solution is stirred at RT for 2 h (after 1 h a precipitate is observed). The reaction mixture is diluted with DCM and then quenched with water. The organic phase is separated and washed with water, dried over Na2SO4, filtered and evaporated. The crude product is purified on silica gel, using Heptane/EtOAc 99:1 to 80/20 gradient elution over 20 min to afford the title compound as a yellow oil; MS: m/z 261.9 [M+H]+.