Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH:9]=O)[CH2:4][CH2:3]1.Cl.[CH2:12]([O:14][C:15]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24]N)=[CH:20][CH:19]=1)=[O:16])C.C(=O)(O)[O-].[Na+]>CO.O>[C:15]([CH2:17][C:18]1[CH:23]=[C:22]2[C:21](=[CH:20][CH:19]=1)[NH:24][CH:9]=[C:8]2[CH:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)([O:14][CH3:12])=[O:16]
Reactant: CCOC(=O)Cc1ccc(NN)cc1
Reactant: CN1CCC(CC=O)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)Cc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Temperature: 25 °C
Yield: 39.3 %

Procedure:
A solution of 1-methyl-4 (formylmethyl)piperidine (2.3 g, 16 mmol) and 4-(ethoxycarbonylmethyl)phenyl hydrazine hydrochloride (3.7 g, 16 mmol) in methanol:water (20:1) (25 ml) was stirred at room temperature for 1 hour. Polyphosphoric acid (7 g) was then added and the mixture heated at reflux for 5 hours, under nitrogen. The mixture was then cooled to ambient temperature, basified with saturated sodium bicarbonate to pH9, and extracted with dichloromethane (2×20 ml). The organic phases were combined, dried (MgSO4) and evaporated to give a brown residue. This was chromatographed (eluant 50:8:1 dichloromethane:ethanol:ammonia) to give 4-[5-carbomethoxymethyl-1H-indol-3-yl]N-methylpiperidine (1.8 g, 39%) as a yellow solid. mp 105°-107° C. δ(360 MHz, CDCl3) δ1.85 (2H, m), 2.16 (4H, m), 2.36 (3H, s), 2.81 (1H, m), 3.00 (2H, m), 3.70 (3H, s), 3.73 (2H, s), 6.97 (1H, d, J=2 Hz), 7.10 (1H, dd, J=8 and Hz), 7.31 (1H, d, J=8 Hz), 7.53 (1H, s), 7.97 (1H, brs).
Reaction SMILES: [CH3:1][C:2]1([CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)[CH2:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]([O:15][CH3:16])=[O:14])[CH:8]=2)[O:3]1.CO>[Pd].C1C=CC=CC=1>[NH2:25][C:22]1[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:2]2([CH3:1])[CH2:11][C:10](=[O:12])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:13]([O:15][CH3:16])=[O:14])[CH:8]=3)[O:3]2)=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc2c(c1)C(=O)CC(C)(COc1ccc([N+](=O)[O-])cc1)O2
Agent: [Pd]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1ccc2c(c1)C(=O)CC(C)(COc1ccc(N)cc1)O2
Yield: 79.4 %

Procedure:
Following a procedure similar to that described in Preparation 4, 10 g of methyl 2-methyl-2-(4-nitrophenoxymethyl)-4-oxochroman-6-carboxylate (prepared as described in Preparation 43) were hydrogenated, using 2 g of 10% w/w palladium-on-carbon, 100 ml of methanol and 200 ml of benzene, to afford 7.3 g of the title compound as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:21](N1C=CN=C1)([N:23]1C=CN=[CH:24]1)=O.CNC>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([N:23]([CH3:24])[CH3:21])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
A suspension of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine- 3-acetic acid (5.5 g, 0.0166 mole), 1,1'-carbonyldiimidazole (2.7 g, 0.0166 mole), and anhydrous tetrahydrofuran (100 ml) was stirred at room temperature with a stream of nitrogen bubbling through it for 21/2 hours. The nitrogen flow was stopped and a solution of dimethylamine (0.5M in tetrahydrofuran) (66 ml) was added. The solution was stirred at room temperature, stoppered, for 16 hours. The reaction mixture was concentrated in vacuo and the residue triturated in water (100 ml) and filtered. The filter cake was recrystallized from ethanol to give 3.78 g (63%) of white needles, mp 224°-225° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:33]([F:36])([F:35])[F:34])[N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]([CH2:21][C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:25](=[O:32])[NH:24][N:23]=4)[CH:17]=[CH:18][C:19]=3[F:20])=[O:13])[CH2:8][C:7]=12.[CH3:37][NH2:38].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O1CCCC1>[F:20][C:19]1[CH:18]=[CH:17][C:16]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](=[O:32])[NH:24][N:23]=2)=[CH:15][C:14]=1[C:12]([N:9]1[CH2:10][CH2:11][N:6]2[C:5]([C:33]([F:36])([F:34])[F:35])=[N:4][C:3]([CH2:2][NH:38][CH3:37])=[C:7]2[CH2:8]1)=[O:13]
Reactant: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCn2c(C(F)(F)F)nc(CCl)c2C1
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CNCc1nc(C(F)(F)F)n2c1CN(C(=O)c1cc(Cc3n[nH]c(=O)c4ccccc34)ccc1F)CC2
Yield: 10.1 %

Procedure:
4-[[3-[1-(Chloromethyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one 9a (372 mg, 1.25 mmol) was dissolved in 5 mL of acetonitrile, followed by addition of 0.6 mL of a 2 M solution of methylamine in tetrahydrofuran and potassium carbonate (159 mg, 1.15 mmol). The reaction mixture was heated to reflux for 6 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure and was purified by thin layer chromatography with elution system A to obtain 4-[[4-fluoro-3-[1-(methylaminomethyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 9 (20 mg, yield 10.1%) as a yellow solid.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]([C:24]1[C:28](=[O:29])[CH2:27][CH2:26][C:25]=1[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=1)[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=1[S:19]([CH2:22][CH3:23])(=[O:21])=[O:20].[C:41](N1C=CN=C1)(N1C=CN=C1)=[O:42]>C(#N)C>[O:42]=[C:41]1[N:30]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:38])[F:39])[CH:32]=2)[C:25]2[CH2:26][CH2:27][C:28](=[O:29])[C:24]=2[CH:10]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=2[S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[NH:9]1
Reactant: CCS(=O)(=O)c1cc(C#N)ccc1C(N)C1=C(Nc2cccc(C(F)(F)F)c2)CCC1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (125 μL, 0.89 mmol) is added to a mixture of 4-(amino(5-oxo-2-(3-(trifluoromethyl)phenylamino)cyclopent-1-enyl)methyl)-3-(ethylsulfonyl)benzonitrile hydrochloride (intermediate 20.2, 1.78 g, 3.56 mmol) and 1,1′-carbonyldiimidazole (720 mg, 4.45 mmol) in acetonitrile (20 mL), and the mixture is stirred at room temperature for 1 h. The mixture is concentrated under reduced pressure, and the residue is treated with water (20 mL). The precipitate is filtered and dried. Yield: 1.61 g. ESI mass spectrum: [M+H]+=490; Retention time HPLC: 0.56 min (X012_801).
Reaction SMILES: CS[C:3]([S:17][CH3:18])=[C:4]([C:7](=[O:16])[C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=1[CH3:15])[C:5]#[N:6].[Cl:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([Cl:30])[C:21]=1[NH:31][NH2:32]>C(O)C>[NH2:6][C:5]1[N:31]([C:21]2[C:22]([Cl:30])=[CH:23][C:24]([C:26]([F:27])([F:28])[F:29])=[CH:25][C:20]=2[Cl:19])[N:32]=[C:3]([S:17][CH3:18])[C:4]=1[C:7](=[O:16])[C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=1[CH3:15]
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CSC(SC)=C(C#N)C(=O)c1cc(C)ccc1C
Solvent: CCO
Product: CSc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C(=O)c1cc(C)ccc1C
Yield: 88.5 %

Procedure:
A suspension of 7.94 g (28.6 mmol) of the product of step C and 7.01 g (28.6 mmol) of 2,6-dichloro-4-trifluoromethylphenylhydrazine in 100 mL of ethanol was heated at reflux for 2 hours, solution occurring as the reaction mixture was warmed. Then the ethanol was mostly removed on the rotary evaporator and the residues were partitioned between dilute aqueous hydrogen chloride solution and ethyl acetate. The organic phase was washed once with water and with brine, then dried with magnesium sulfate and treated with decolorizing carbon. The filtered solution was evaporated and the residues crystallized from 10:1 hexane/ethyl acetate to give 12.00 g (88%) of the title product in two crops, m.p. 130-132° C.
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[C:3]([N:5]=[C:6]=O)=[O:4].[O:10]=[C:11]1[C:16]2[CH:17]=[C:18]3[C:23](=[C:24]([CH2:25][CH2:26][CH3:27])[C:15]=2[O:14][C:13]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:12]1)[NH:22][C:21]([C:28]([O:30][CH3:31])=[O:29])=[CH:20]C3=O>ClCCl>[CH3:31][O:30][C:28]([C:21]1[CH:20]=[C:6]([NH:5][C:3](=[O:4])[C:2]([Cl:9])([Cl:8])[Cl:1])[C:18]2[C:23](=[C:24]([CH2:25][CH2:26][CH3:27])[C:15]3[O:14][C:13]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:12][C:11](=[O:10])[C:16]=3[CH:17]=2)[N:22]=1)=[O:29]
Reactant: CCCc1c2[nH]c(C(=O)OC)cc(=O)c2cc2c(=O)cc(C(=O)OCC)oc12
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCc1c2nc(C(=O)OC)cc(NC(=O)C(Cl)(Cl)Cl)c2cc2c(=O)cc(C(=O)OCC)oc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Trichloroacetyl isocyanate (1.18 ml, 10 mmol) was added to a solution of ethyl 6,9-dihydro-4,6-dioxo-8-methoxycarbonyl-10-propyl-4H-pyrano [3,2-g]quinoline-2-carboxylate (3.85 g, 10 mmol) in dichloromethane (20 ml) at room temperature. The solution was then agitated gently for 24 hours at room temperature and then the solvent removed by distillation in vacuo. Trituration of the resulting solid with ether gave the sub-title compound as yellow cubes, 4.25 g (80%), mp 167°-169° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[C@H:24]([CH3:25])[CH2:23][CH2:22][C@H:21]3[CH3:26])=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH:27]([NH2:30])([CH3:29])[CH3:28]>>[CH3:26][C@@H:21]1[CH2:22][CH2:23][C@@H:24]([CH3:25])[N:20]1[C:18]([C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:30][CH:27]([CH3:29])[CH3:28])=[CH:7][CH:8]=2)=[CH:13][CH:14]=1)=[O:19]
Reactant: C[C@@H]1CC[C@@H](C)N1C(=O)c1ccc(-c2ccc(OCCCCl)cc2)cc1
Reactant: CC(C)N
Product: CC(C)NCCCOc1ccc(-c2ccc(C(=O)N3[C@H](C)CC[C@H]3C)cc2)cc1

Procedure:
The product from Example 4A and isopropylamine were processed as described in Example 10F to provide the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N+:7]([C:10]1[CH:20]=[CH:19][C:13]([CH2:14][P:15](=[O:18])([OH:17])[OH:16])=[CH:12][CH:11]=1)([O-:9])=[O:8].N1C=C[CH:24]=[CH:23][CH:22]=1>O1CCCC1>[N+:7]([C:10]1[CH:20]=[CH:19][C:13]([CH2:14][P:15]2(=[O:16])[O:17][CH2:24][CH2:23][CH2:22][O:18]2)=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc(CP(=O)(O)O)cc1
Reactant: c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CP2(=O)OCCCO2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 26.4 %

Procedure:
Oxalyl chloride (22.09 g) was added dropwise to a mixture of 4-nitrobenzylphosphonic acid (17.99 g), pyridine (13.76 g) and tetrahydrofuran (500 ml) at -78° C. After the mixture was stirred at -78° C. for 30 minutes and then at room temperature for 1.5 hours, the insoluble solid was filtered off. The filtrate was concentrated under reduced pressure, and the residual oily substance was dissolved in tetrahydrofuran (500 ml). To this solution, a solution of 1,3-propanediol (2.58 g) in acetonitrile (30 ml) was added dropwise at -78° C. over a 15-minute period. Then, pyridine (5.62 g) was added dropwise at -78° C. over a 5-minute period, and the mixture was stirred at room temperature for 15 hours. After the insoluble solid was filtered off, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-chloroform-methanol (10:10:1, v/v) to yield 2-(4-nitrobenzyl)-1,3,2-dioxaphosphorinane-2-oxide (5.62 g, 26%), which was then recrystallized from ethanol-hexane to yield colorless needles having a melting point of 144° to 145° C.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](=[O:10])[CH2:8]I)=[CH:5][CH:4]=1)#[N:2].[I:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>C(O)C>[I:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][CH2:8][C:7]([C:6]2[CH:11]=[CH:12][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[O:10])=[CH:16][CH:15]=1
Reactant: Nc1ccc(I)cc1
Reactant: N#Cc1ccc(C(=O)CI)cc1
Solvent: CCO
Product: N#Cc1ccc(C(=O)CNc2ccc(I)cc2)cc1
Reaction time: 16 h

Procedure:
p-Cyanophenacyl iodide (18.0 g, 0.08 mole) was combined with p-iodoaniline (35.2 g, 0.16 mole) in 32.1 g of absolute ethanol and stirred 16 hours. Precipitated title product was recovered by filtration and repulped in 400 ml ether: 42.4 g; m.p. 160°-165°; ms 362, 232, 219.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[C:9]([O:27][CH3:28])=[CH:8][C:5]=1[C:6]#[N:7])([O-:3])=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[N+:1]([C:4]1[CH:11]=[C:10]([O:12][CH2:13][CH:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)[C:9]([O:27][CH3:28])=[CH:8][C:5]=1[C:6]#[N:7])([O-:3])=[O:2]
Reactant: COc1cc(C#N)c([N+](=O)[O-])cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C#N)c([N+](=O)[O-])cc1OCC1CCNCC1
Yield: 88.1 %

Procedure:
2-nitro-4-((1-tert-butyloxycarbonylpiperidin-4-yl)methoxy)-5-methoxybenzonitrile (1.17 g, 3 mmol) in CH2Cl2 (12 ml) was treated with TFA (2.4 ml) for 1 hour at room temperature. The solvent was evaporated, the residue was taken up in a mixture of CH2Cl2 and concentrated sodium bicarbonate, extracted with CH2Cl2. The organic phase was dried over MgSO4, concentrated to give title compound as a solid (770 mg, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[NH:19][C:18]2=[O:28])=[CH:12][C:3]=1[C:4]([O:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5].C(=O)(O)[O-].[K+].S(OCC)(O[CH2:38][CH3:39])(=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[N:19]([CH2:38][CH3:39])[C:18]2=[O:28])=[CH:12][C:3]=1[C:4]([O:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11]1)=[O:5]
Reactant: O=C(OC1CCCC1)c1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Product: CCn1c(C(F)(F)F)cc(=O)n(-c2cc(C(=O)OC3CCCC3)c(Cl)cc2F)c1=O

Procedure:
4.5 g of cyclopentyl 2-chloro-5-[3.6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorobenzoate, 2.1 g of potassium bicarbonate and 1.5 ml of diethyl sulphate are heated at reflux temperature in 50 ml of acetone for 4 hours. Subsequently. the solvent is distilled off and the residue is partitioned in 150 ml of diethyl ether and 150 ml of water. The aqueous phase is extracted with a further 150 ml of diethyl ether and the combined organic phases are washed twice with 150 ml of water each time, dried over anhydrous magnesium sulphate and concentrated. The residue is purified by chromatography on a silica gel column using ethyl acetate/n-hexane (1:4) as the eluent. In this manner there are obtained cyclopentyl 2-chloro-5-[3-ethyl-3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorobenzoate as a colourless oil, 1H-NMR (CDCl 3, 400 MHz : 1 36 (t3H), 1.56-2.04 (m,8H), 4.02 (q,2H), 5.36-5.45 (m,1H), 6.35 (s,1H), 7.36 (d,1H), 7.82 (d,1H); mass spectrum (m/e): M+ 448 (1), as well as cyclopentyl 2-chloro- 5-[2-ethoxy-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-4-fluorobenzoate, m.p. 90°-91° C.
Reaction SMILES: [N+](C1C=CC=CC=1)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.[Cl:27][C:28]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31]>O>[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:30]([C:29]3[CH:33]=[CH:34][C:35]([Cl:37])=[CH:36][C:28]=3[Cl:27])=[O:31])=[CH:25][CH:26]=2)=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Cc1ccc(-c2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1ccc(-c2ccc(C(=O)c3ccc(Cl)cc3Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
35 mL of nitrobenzene were cooled in an ice bath and then treated in succession with 5.2 g of aluminium chloride and 5.0 g of 4-methylbiphenyl. The mixture was brought to room temperature and then treated slowly with 7.7 g of 2,4-dichlorobenzoyl chloride. The mixture was stirred at room temperature overnight, poured into water and extracted with methylene chloride. The extracts were washed with 2N hydrochloric acid and water, dried over magnesium sulphate and evaporated. The residue was chromatographed on silica gel with toluene/ethyl acetate 9:1. There were obtained 6.7 g (63%) of 2,4-dichlorophenyl 4'-methyl-4-biphenylyl ketone as a colorless solid with a m.p. of 184°-185° C.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:16][N:17]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[CH:7][CH:6]=2.C(O)(=[O:25])C>>[CH2:21]([O:20][C:18]([C:15]1[N:4]2[C:5]3[C:10]([NH:11][C:2](=[O:25])[C:3]2=[N:17][N:16]=1)=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[CH:7][CH:6]=3)=[O:19])[CH3:22]
Reactant: CCOC(=O)c1nnc2c(Cl)nc3cc([N+](=O)[O-])ccc3n12
Reactant: CC(=O)O
Product: CCOC(=O)c1nnc2c(=O)[nH]c3cc([N+](=O)[O-])ccc3n12
Temperature: 25 °C
Yield: 90 %

Procedure:
A mixture of 1.5 g (~4.7 mmol) of 4-chloro-1-ethoxycarbonyl-7-nitro[1,2,4]triazolo[4,3-a]quinoxaline and 25 ml of glacial acetic acid was refluxed for 60 min. After cooling to 25° C. the precipitate was filtered off to give 1.5 g of a crude product. Purification by column chromatography (silica gel; eluent: ethyl acetate) gave 1.2 g (~90%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=2)=[N:17][C:18]([CH3:22])=[C:19]([CH3:21])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][CH2:39][OH:40]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:37][CH2:38][CH2:39][OH:40])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=2)=[N:17][C:18]([CH3:22])=[C:19]([CH3:21])[CH:20]=1
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccc(C)n3)ccnc2cc1O
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccc(C)n3)ccnc2cc1OCCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
6-Methoxy-4-(5,6,6′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinolin-7-ol (compound 443) (50 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate (54 mg) and 3-bromo-1-propanol (0.03 ml) were added to the solution, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (36 mg, yield 62%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:23])[CH2:10][CH2:9][C:8]2[C:11]([CH3:22])=[C:12]([O:17][CH2:18][CH2:19][CH2:20][OH:21])[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]=2[O:6]1)=[O:4].[CH3:24][S:25](Cl)(=[O:27])=[O:26].S(=O)(=O)(O)O>C(Cl)Cl.C(N(CC)CC)C>[CH3:1][O:2][C:3]([C:5]1([CH3:23])[CH2:10][CH2:9][C:8]2[C:11]([CH3:22])=[C:12]([O:17][CH2:18][CH2:19][CH2:20][O:21][S:25]([CH3:24])(=[O:27])=[O:26])[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]=2[O:6]1)=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C1(C)CCc2c(C)c(OCCCO)c(C)c(C)c2O1
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1(C)CCc2c(C)c(OCCCOS(C)(=O)=O)c(C)c(C)c2O1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 0.3 g of racemic-3,4-dihydro-2,5,7,8-tetramethyl-6-(3-hydroxypropoxy)-2H-1-benzopyran-2-carboxylic acid methyl ester in 5 ml of anhydrous methylene chloride and 0.33 ml of triethylamine was added 0.17 ml of methanesulfonyl chloride. The mixture was stirred at room temperature for 45 minutes then treated with 1N sulfuric acid and worked-up with methylene chloride in the usual manner. There was obtained 0.461 g of racemic-3,4-dihydro-2,5,7,8-tetramethyl-6-(3-methanesulfonyloxypropoxy)-2H-1-benzopyran-2-carboxylic acid methyl ester as an oil which was used without further purification.
Reaction SMILES: [C:1]([CH2:8][N:9]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][N:16]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+:31]([C:34]1[CH:42]=[CH:41][C:37]([CH2:38][CH2:39]Br)=[CH:36][CH:35]=1)([O-:33])=[O:32].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[C:24]([CH2:23][N:16]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][N:9]([CH2:8][C:1]([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2])[CH2:22][CH2:21][CH2:20][N:19]([CH2:39][CH2:38][C:37]2[CH:36]=[CH:35][C:34]([N+:31]([O-:33])=[O:32])=[CH:42][CH:41]=2)[CH2:18][CH2:17]1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: CC(C)(C)OC(=O)CN1CCCNCCN(CC(=O)OC(C)(C)C)CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CN1CCCN(CCc2ccc([N+](=O)[O-])cc2)CCN(CC(=O)OC(C)(C)C)CCCNCC1
Yield: 68.4 %

Procedure:
A solution of compound (5) (1.37 g, 3.19 mmol), 4-nitrophenethyl bromide (1.47 g, 6.38 mmol), anhydrous K2CO3 (1.32 g, 9.57 mmol) and KI (1.59 g, 9.57 mmol) dissolved in dry toluene (150 ml) was stirred under reflux for 24 hours. The solvent was evaporated from the reaction mixture under reduced pressure, and CH2Cl2 (250 ml) was added thereto. The resultant brown slurry was filtered through a celite pad, and washed with CH2Cl2 (2×30 ml). The solvent was evaporated from the combined filtrate under reduced pressure. The residue thus obtained was purified via alumina (basic) column chromatography using EtOAc/methanol (10:2) as an eluent to provide compound (8) as a yellow oil (1.26 g, 68% yield). 1H NMR (500 MHz, CDCl3): δ 8.07-8.06 (dd, 2H), 7.35-7.33 (dd, 2H), 3.23-3.20 (dd, 4H), 2.97 (brs, 4H), 2.87-2.82 (m, 4H), 2.71-2.51 (m, 12H), 1.88 (brs, 2H), 1.61 (brs, 2H), 1.39-1.37 (dd, 18H); 13C NMR (125 MHz, CDCl3): δ 170.7, 170.5, 148.6, 146.3, 129.5, 123.5, 81.3, 81.1, 55.7, 55.3, 55.0, 52.5, 52.0, 50.2, 49.5, 48.4, 46.1, 32.0, 28.1, 24.4, 24.3, 23.2; HRMS (FAB) calculated for C30H52N5O6: 578.3918 [(M+H)+], measured value: 578.3915 [(M+H)+].
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2].Br[CH2:19][C:20]1[CH:21]=[C:22]([S:26]([CH3:34])(=[N:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:27])[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH2:32]([O:31][C:29]([N:28]=[S:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([CH2:19][O:17][C:11]2[CH:10]=[C:9]3[C:14]([C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[N:6][CH:7]=[N:8]3)=[CH:13][C:12]=2[O:15][CH3:16])[CH:21]=1)([CH3:34])=[O:27])=[O:30])[CH3:33]
Reactant: COc1cc2c(NC(C)C)ncnc2cc1O
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc3ncnc(NC(C)C)c3cc2OC)c1

Procedure:
4-(Isopropylamino)-6-methoxyquinazolin-7-ol (65 mg, 0.21 mmol) and (RS)-S-[3-(bromomethyl)phenyl]-N-(ethoxycarbonyl)-S-methylsulphoximide (102 mg, 0.27 mmol) are suspended in 14 ml of acetone. After addition of caesium carbonate (2427 mg, 0.74 mmol), the reaction mixture is stirred at reflux for 3 hours. After cooling, the batch is concentrated, the residue is taken up in ethyl acetate, and the organic phase is washed with water and dried over sodium sulphate. After removal of the solvent, the residue (144 mg, 97% of theory) is employed in the next reaction without further purification.