Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.F[C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)[C:12]([C:14]1[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=1[CH3:22])=[O:13]>CN(C)P(=O)(N(C)C)N(C)C>[N:3]1([C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[C:12]([C:14]2[C:15]([CH3:22])=[CH:16][C:17]([CH3:21])=[CH:18][C:19]=2[CH3:20])=[O:13])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: c1c[nH]cn1
Reactant: Cc1cc(C)c(C(=O)c2cccc(F)c2)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1cc(C)c(C(=O)c2cccc(-n3ccnc3)c2)c(C)c1
Temperature: 40 °C
Yield: 80.4 %

Procedure:
To a suspension of 2.9 g of sodium hydride (60% dispersion in mineral oil) in 50 ml of hexamethylphosphoric triamide is added 5.3 g of imidazole over a 30 minute period under heating at 40° C. After the addition is complete, the mixture is stirred at room temperature for an hour. To the reaction mixture is added 16.6 g of 3-fluoro-2',4',6'-trimethylbenzophenone and the mixture is stirred at 70° C. for 24 hours. The reaction solution is poured into ice-cold water and extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried and concentrated. The residue is recrystallized from a mixture of toluene and isopropyl ether to give 16 g of 3-(1-imidazolyl)-2',4',6'-trimethylbenzophenone as white crystals, melting at 134°-136° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[N:22]1[CH:27]=[CH:26][C:25](=O)[CH2:24][CH:23]=1>COCCOC>[N:22]1[CH:27]=[CH:26][C:25]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=2)=[CH:24][CH:23]=1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: O=C1C=CN=CC1
Solvent: COCCOC
Product: N#Cc1ccc(N(CCOc2ccncc2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 1C from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-pyridone, using dry DME as reaction solvent: 1H NMR (400 MHz, CDCl3) δ 8.45 (dd, J=5.0, 1.3 Hz, 2H), 7.68 (d, J=8.8 Hz, 1H), 7.18 (d, J=2.5 Hz, 1H), 7.01 (dd, J=8.7, 2.6 Hz, 1H), 6.77 (dd, J=4.9, 1.3 Hz, 2H), 4.27 (t, J=5.2 Hz, 2H), 4.19 (q, J=8.5 Hz, 2H), 4.04 (t, J=5.3 Hz, 2H).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([CH:14]=O)[N:2]=1.CN(C)C=O.[CH3:21][N:22]([CH3:24])[NH2:23]>O>[CH3:21][N:22]([CH3:24])[N:23]=[CH:14][C:3]1[N:2]=[CH:1][C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: CN(C)N
Reactant: O=Cc1cc2c(cn1)[nH]c1ccccc12
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)N=Cc1cc2c(cn1)[nH]c1ccccc12
Reaction time: 3 h

Procedure:
A mixture of 1.0 g of beta-carboline-3-carboxaldehyde, 10 ml of dimethyl-formamide and 3 ml of N,N-dimethyl hydrazine is introduced into a glass autoclave. The air is replaced by nitrogen. After stirring for 3 h, the reaction mixture is allowed to stand overnight at room temperature. After adding 25 ml of water, the reaction mixture is extracted with 100 and 50 ml of chloroform. The chloroform phase is dried using magnesium sulfate, then filtered. Then, the chloroform is evaporated. After adding 10 ml of ether, the reaction product is filtered off. 0.9 g of beta-carboline-3-carboxaldehyde-dimethylhydrazone with a m.p. of 203°-206° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([CH2:9][N:10]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:11][C:12]([O:14]CC)=[O:13])[NH:8][C:4]=2[CH:3]=1>CO.O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([CH2:9][N:10]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:11][C:12]([OH:14])=[O:13])[NH:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)CN(Cc1nc2ccc(Cl)cc2[nH]1)c1ccc(Cl)cc1
Solvent: CO
Solvent: O
Product: O=C(O)CN(Cc1nc2ccc(Cl)cc2[nH]1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
Ethyl N-[(5-chloro-2-benzimidazolyl)methyl]-N-(4-chlorophenyl)glycinate (0.15 g) was dissolved in methanol (3 ml). A solution of LiOH monohydrate (92 mg) in water (0.5 ml) was added and the cloudy mixture was stirred at rt for 2 h. Water (25 ml) was added and the aqueous layer was washed with EtOAc (20 ml) and diethyl ether (20 ml). By addition of 1M HCl a pH of 5 was adjusted. The white precipitate was extracted with EtOAc (4×50 ml). The combined organic layers were dried (sodium sulfate) and concentrated to give a yellowish solid which was further purified by trituration with acetone to provide N-[(5-chloro-2-benzimidazolyl)methyl]-N-(4-chlorophenyl)glycine (43 mg) as colourless crystals.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:12][C:13]1[CH:14]=[CH:15][C:16]([O:29][CH3:30])=[C:17]([C:19]([CH3:28])([CH3:27])[CH2:20][C:21]2([CH:24]([F:26])[F:25])[CH2:23][O:22]2)[CH:18]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CS(C)=O.C(OCC)(=O)C>[F:26][CH:24]([F:25])[C:21]([OH:22])([CH2:20][C:19]([C:17]1[CH:18]=[C:13]([F:12])[CH:14]=[CH:15][C:16]=1[O:29][CH3:30])([CH3:28])[CH3:27])[CH2:23][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2](=[O:1])[CH:3]=[CH:4]1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)F)CO1
Reactant: Oc1ccnc2ccccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cn1ccc(=O)c2ccccc21)C(F)F
Temperature: 25 °C
Reaction time: 360 h

Procedure:
To a solution of the 4-hydroxyquinoline and 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-difluoromethyloxirane in DMSO (1.0 mL) stirred under nitrogen was added NaHMDS (1.2 mL, 1.0M in THF) dropwise. The mixture was stirred at room temperature for 15 days. The mixture was diluted with ethyl acetate, washed with water, dried, filtered, and evaporated in vacuo. Trituration of the residue with diethyl ether gave the product 1-[2-difluoromethyl-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methylpentyl]-1H-quinolin-4-one as a crystalline solid that was collected by filtration and air dried (77.7 mg, 20%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:37])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([C:35]#[N:36])[CH:30]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:37]=[C:19]1[CH2:20][C:21]([C:23]2[CH:24]=[C:25]([C:29]3[CH:34]=[CH:33][N:32]=[C:31]([C:35]#[N:36])[CH:30]=3)[CH:26]=[CH:27][CH:28]=2)=[N:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[NH:18]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(C#N)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (2-{3-[3-(2-cyano-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M180) (304 mg, 0.58 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (147 mg, 62%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6](S)[C:5]=3[CH:12]=[CH:13][CH:14]=2.[N:15]1([CH2:20][CH2:21][CH2:22][NH2:23])[CH:19]=[CH:18][N:17]=[CH:16]1>C(O)C>[Cl:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([NH:23][CH2:22][CH2:21][CH2:20][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)[C:5]=3[CH:12]=[CH:13][CH:14]=2
Reactant: SC1=Nc2ccc(Cl)c3cccc1c23
Reactant: NCCCn1ccnc1
Solvent: CCO
Product: Clc1ccc2c3c(cccc13)C(NCCCn1ccnc1)=N2
Yield: 74.6 %

Procedure:
A mixture of 1.0 g of 6-chloro-benz(cd)indole-2-thiol, 540 mg of 3-(1H-imidazol-l-yl) propanamine, 1.26 g of mercuric acetate and 100 ml of ethanol was reacted as described in Example 1, giving 1.0 g of the desired compound, mp 177° C.-178° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=O)[O:7][C:8](=O)[C:9]3[C:10]=2[C:11]=1[CH:12]=[CH:13][CH:14]=3.[BH4-].[Na+].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][O:7][CH2:8][C:9]3[C:10]=2[C:11]=1[CH:12]=[CH:13][CH:14]=3
Reactant: O=C1OC(=O)c2ccc(Br)c3cccc1c23
Agent: CC[SiH](CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccc2c3c(cccc13)COC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 6-bromo-1H,3H-naphtho[1,8-cd]pyran-1,3-dione (1.5 g, 5.4 mmol) in ethanol (10 mL) was added sodium borohydride (0.41 g, 10.8 mmol) and the mixture stirred at room temperature for 1 h. The reaction was quenched with 3M hydrochloric acid and extracted into dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in dichloromethane and trifluoroacetic acid (1.05 mL, 13.53 mmol) and triethylsilane (4.3 mL, 27 mmol) added. After stirring for 5 min at room temperature, the solvent was removed in vacuo and the residue purified by column chromatography on silica gel, eluting with dichloromethane, to yield 6-bromo-1H,3H-naphtho[1,8-cd]pyran as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:5]=2[N:6]=1.[CH3:12][C:13]1[S:17][C:16]([C:18](Cl)=[O:19])=[CH:15][CH:14]=1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[F:11][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:18]([C:16]3[S:17][C:13]([CH3:12])=[CH:14][CH:15]=3)=[O:19])[S:3][C:4]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Nc1nc2c(F)cccc2s1
Reactant: Cc1ccc(C(=O)Cl)s1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)Nc2nc3c(F)cccc3s2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Amino-4-flourobenzothiazol (84 mg, 0.50 mmol) is dissolved in pyridine (3 ml) and treated with 4-dimethylaminopyridine (1 mg) and 5-methyl-thiophene-2-carbonyl chloride (161 mg, 1.0 mmol). After stirring for 1 h at ambient temperature, the reaction mixture was evaporated to dryness. Flash chromatography on silica (eluent diethyl ether/cyclohexane 1:1 containing 0.5% of 25% aqueous ammonia) and final recrystallization from ethyl acetate affords the product as off-white solid.(34 mg, 69%). MS: m/e=292 (M+).
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[C:8]([Cl:12])[N:9]=[C:10](Cl)[C:5]=2[S:4][CH:3]=1.CO.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[Br:1][C:2]1[C:6]2[N:7]=[C:8]([Cl:12])[N:9]=[C:10]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:5]=2[S:4][CH:3]=1
Reactant: Clc1nc(Cl)c2scc(Br)c2n1
Reactant: C1COCCN1
Solvent: CO
Product: Clc1nc(N2CCOCC2)c2scc(Br)c2n1
Reaction time: 1.5 h
Yield: 35.9 %

Procedure:
7-Bromo-2,4-dichlorothieno[3,2-d]pyrimidine (2.9 g, 10.0 mmol) was dissolved in methanol (100 mL, 2000 mmol) and added morpholine (2 mL, 22 mmol) and let the reaction mixture stir for 1.5 h. Complete reaction confirmed by LCMS. Concentrated in vacuo and diluted with water. Extracted with DCM and concentrated in vacuo again. The product was purified by silica gel chromatography (0 to 100% ethyl acetate/heptanes) on the CombiFlash® Rf system and concentrated in vacuo to give 4-(7-bromo-2-chlorothieno[3,2-d]pyrimidin-4-yl)morpholine (1.2 g, 35% yield). 1H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 4.01 (m, 4H), 3.85 (m, 4H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1.C([Li])CCC.[S].Cl[CH:15]([OH:17])[CH3:16]>>[CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH2:16][CH2:15][OH:17]
Reactant: CC(O)Cl
Reactant: COc1ccsc1
Agent: [Li]CCCC
Agent: [S]
Product: COc1ccsc1CCO

Procedure:
The compound is produced analogously to Example 1 from 11.4 g. (100 mmol) of 3-methoxythiophene, 45.5 ml. (about 100 mmol) of about 22% butyllithium solution (in hexane), 3.2 g. (100 mmol) of sulfur, and 8.05 g. (100 mmol) of chloroethanol. Bulb tube distillation at 0.04 torr (bath temperature: 118°-129°) yields the alcohol as a slightly yellow oil.
Reaction SMILES: C.[NH2:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:6]=2[N:7]=1>Cl>[Br:12][C:10]1[CH:9]=[CH:8][C:6]([NH:7][C:3]([NH2:2])=[S:4])=[CH:5][CH:11]=1
Reactant: Nc1nc2ccc(Br)cc2s1
Agent: Cl
Product: NC(=S)Nc1ccc(Br)cc1

Procedure:
190 Parts of sulfuryl chloride were added homogeneously within 4 hours at a temperature of 45°-50° C. with stirring to 231 parts of 4-bromophenylthiourea suspended in 1,200 parts of o-dichlorobenzene. After the gas development had ceased, the batch was cooled to about 20° C., the curde 2-amino-6-bromobenzothiazolium chloride precipitated was suction-filtered and washed with o-dichlorobenzene. The filter cake moist with the solvent was suspended in 1,000 parts of water, the adhering o-dichlorobenzene was distilled off by blowing in steam, and the solution of 2-amino-6-bromobenzothiazolium chloride obtained was filtered off from the greasy undissolved matter after having added 10 parts of active charcoal at 95° C. The clear filtrate was adjusted to pH 8 with 25% sodium hydroxide solution, which caused the free 2-amino-6-bromobenzothiazole to precipitate as yellowish, slightly tacky matter. After cooling, the solids having become vitreous were isolated and dried in vacuo at 40°-50° C. 167 Parts of 2-amino-6-bromobenzothiazole having a purity degree of 88% were obtained (=147.1 parts of 100% compound, 64.2% of th.). By repeated redissolution in dilute hydrochloric acid with addition of active charcoal, 2-amino-6-bromobenzothiazole having a purity degree of >95% was obtained. However, this purification was very expensive and caused great losses, so that at best 82 parts of the intended compound were obtained (35.8% of th., relative to 4-bromophenylthiourea used).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]1([S:18]([CH2:20][N:21]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[S:22]2(=[O:24])=[O:23])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([S:18]([CH2:20][N:21]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[S:22]2(=[O:24])=[O:23])(=[O:9])=[O:19])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CS(=O)c1ccccc1
Product: O=C1c2ccccc2S(=O)(=O)N1CS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of m-chloroperbenzoic acid (2.2 g, 12.8 mmol) and 2-(phenylsulfinylmethyl) saccharin (3.75 g, 11.6 mmol) in MDC (50 ml) was stirred at room temperature for 2 hours. An additional spatula of peracid was added, and stirring was continued for an additional 1 hour. m-Chlorobenzoic acid was removed by filtration and the solid was washed with a small amount of MDC. The filtrate was washed with sodium bicarbonate solution, dried (Na2SO4) and freed of solvent under vacuum. The resultant solid was recrystallized from 50:50 ethanol:acetonitrile to afford 2-(phenylsulfonylmethyl)saccharin as a white solid, mp 169°-171° C. 1H nmr (90 MHz, DMSO-d6, CDCl3):5.15 (2H, s). FDMS: m/e 196 (M+ -PMT).
Reaction SMILES: C([Br:4])(=O)C.C[O:6][C:7]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)O[CH:12]2[CH:9]([CH2:10][CH2:11]2)[O:8]1>>[Br:4][C@@H:12]1[CH2:11][CH2:10][C@H:9]1[O:8][C:7](=[O:6])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC1(c2ccccc2)OC2CCC2O1
Reactant: CC(=O)Br
Product: O=C(O[C@@H]1CC[C@H]1Br)c1ccccc1
Yield: 101.1 %

Procedure:
16.9 g (0.189 mol) of acetyl bromide are added dropwise to 26.0 g (0.126 mol) of 3-methoxy-3-phenyl-2,4-dioxa-bicyclo[3,2,0]heptane (stereoisomer mixture), at 20° to 30° C. After the reaction has subsided, the mixture is heated to the reflux for 4 hours. Distillation in vacuo gives 32.5 g (99%) of trans-1-bromo-2-benzoyloxy-cyclobutane as a colourless oil of boiling point0.2 94°-97°, which solidifies in the receiver.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[OH:10].C(N(CC)CC)C.Cl[S:19]([C:22]1[N:26]=[CH:25][NH:24][N:23]=1)(=[O:21])=[O:20]>O1CCCC1>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[O:10][S:19]([C:22]1[N:26]=[CH:25][NH:24][N:23]=1)(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)c1nc[nH]n1
Reactant: Cc1c(Cl)ccc(O)c1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(Cl)ccc(OS(=O)(=O)c2nc[nH]n2)c1Cl

Procedure:
2.33 g of 2.4-dichloro-3-methylphenol was dissolved in 15 ml of tetrahydrofuran, and 1.84 ml of triethylamine was added while stirring the solution. Then, 2.0 g of 3-chlorosulfonyl-1,2,4-triazole was gradually added while cooling with ice and stirring the solution. Then, the solution was stirred at room temperature for 14 hours. Tetrahydrofuran was removed by distillation at reduced pressure, 2N hydrochloric acid was added, and extracted with ethyl acetate. The organic layer was washed with brine, and dried with magnesium sulfate. Then, the solvent was removed by distillation, so that coarse crystals were obtained. The coarse crystals were recrystallized from n-hexane/ethyl acetate, so that 2.25 g of the titled compound was obtained.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:26]([NH:28][CH2:29][C@H:30]([OH:45])[CH2:31][N:32]5[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]5)=[O:27])=[C:21]5[C:25]=4[O:24][CH2:23][CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:46])[C:8](=[O:47])[C@H:7]2[CH2:48][CH3:49])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(=O)(O)[O-].[Na+].Br[C:57]1([CH3:60])[CH2:59][CH2:58]1>ClCCl.C(N(CC)CC)C>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:26]([NH:28][CH2:29][C@H:30]([OH:45])[CH2:31][N:32]5[CH2:37][CH2:36][N:35]([CH2:60][CH:57]6[CH2:59][CH2:58]6)[CH2:34][CH2:33]5)=[O:27])=[C:21]5[C:25]=4[O:24][CH2:23][CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:46])[C:8](=[O:47])[C@H:7]2[CH2:48][CH3:49])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(Br)CC1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)NC[C@H](O)CN4CCN(C(=O)OC(C)(C)C)CC4)c4c3OCC4)nc2N1C1CCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)NC[C@H](O)CN4CCN(CC5CC5)CC4)c4c3OCC4)nc2N1C1CCCC1
Reaction time: 0.5 h

Procedure:
Tert-butyl 4-[(2S)-3-[[7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carbonyl]amino]-2-hydroxy-propyl]piperazine-1-carboxylate 7d (300 mg, 0.44 mmol) was dissolved in 40 mL of dichloromethane. The reaction solution was filled with gas of hydrogen chloride and stirred for 0.5 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was dissolved in 41 mL of acetonitrile followed by the addition of 183 mL of triethylamine, sodium bicarbonate (148 mg, 1.76 mmol) and bromo-methyl-cyclopropane (130 mg, 0.97 mmol). The resulting solution was stirred for 12 hours and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 7-[[(7R)-8-cyclopentyl-7-ethyl-1-methyl-6-oxo-7H-pteridin-2-yl]amino]-N-[(2S)-3-[4-(cyclopropylmethyl)piperazin-1-yl]-2-hydroxy-propyl]-2,3-dihydrobenzofuran-4-carboxamide 7 (200 mg, yield: 72.0%) as a white solid.
Reaction SMILES: [OH:1][C:2]1([CH2:11][NH:12][C:13]([C:15]2[C:16]3[CH:17]=[CH:18][C:19](Cl)=[N:20][C:21]=3[CH:22]=[CH:23][C:24]=2[Cl:25])=[O:14])[CH2:7][CH2:6][CH2:5][CH:4]([CH:8]2[CH2:10][CH2:9]2)[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:36][N:37]([CH3:43])[C@@H:38]1[CH2:42][CH2:41][NH:40][CH2:39]1>>[OH:1][C:2]1([CH2:11][NH:12][C:13]([C:15]2[C:16]3[CH:17]=[CH:18][C:19]([N:40]4[CH2:41][CH2:42][C@@H:38]([N:37]([CH3:43])[CH3:36])[CH2:39]4)=[N:20][C:21]=3[CH:22]=[CH:23][C:24]=2[Cl:25])=[O:14])[CH2:7][CH2:6][CH2:5][CH:4]([CH:8]2[CH2:10][CH2:9]2)[CH2:3]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: O=C(NCC1(O)CCCC(C2CC2)C1)c1c(Cl)ccc2nc(Cl)ccc12
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)[C@@H]1CCN(c2ccc3c(C(=O)NCC4(O)CCCC(C5CC5)C4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (1-hydroxy-3-cyclopropyl-cyclohexylmethyl)-amide, DIPEA and (R)-3-dimethylamino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.26 (s, 1H), 3.87 (t, 1H), 3.75 (m, 2H), 3.56 (m, 1H), 3.49 (m, 1H), 3.36 (m, 2H), 3.24 (m, 2H), 2.84 (m, 1H), 2.22 (s, 6H), 1.85 (m, 1H), 1.67 (m, 2H), 1.44-1.38 (m, 4H), 1.27 (m, 2H), 0.30 (m, 2H), 0.23 (m, 2H). m/z: 458 [M+H]
Reaction SMILES: [N+](C1C=C(S([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=3)(=[O:25])=[O:24])=[CH:18][CH:17]=2)(=O)=O)C=CC=1)([O-])=O.O[C:36]1[CH:43]=[CH:42][C:39]([CH:40]=[O:41])=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:32]([C:28]1[CH:27]=[C:26]([S:23]([O:22][C:19]2[CH:18]=[CH:17][C:16]([CH2:15][CH2:14][O:13][C:36]3[CH:43]=[CH:42][C:39]([CH:40]=[O:41])=[CH:38][CH:37]=3)=[CH:21][CH:20]=2)(=[O:25])=[O:24])[CH:31]=[CH:30][CH:29]=1)([O-:34])=[O:33]
Reactant: O=Cc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OCCc2ccc(OS(=O)(=O)c3cccc([N+](=O)[O-])c3)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1ccc(OCCc2ccc(OS(=O)(=O)c3cccc([N+](=O)[O-])c3)cc2)cc1
Temperature: 25 °C
Yield: 85.9 %

Procedure:
A mixture of 32.5 g (64 mmole) 4-([3-nitrophenylsulfonyl]oxy)phenethyl 3-nitrobenzenesulfonate, 8 g (65 mmole) p-hydroxybenzaldehyde and 20 g (145 mmole) potassium carbonate in 300 ml acetonitrile was refluxed for 10 minutes, then stirred at room temperature over night and thereafter refluxed for 30 minutes. The salts were filtered off and the solvent evaporated in vacuo. Dichloromethane and water were added, the phases were separated, the organic phase was dried and the solvent was evaporated in vacuo. Purification by chromatography on silica gel using dichloromethane as eluent and crystallization in diisopropyl ether gave 23.5 g (yield 86%) of 4-[2-(4-formylphenoxy)ethyl]phenyl 3-nitrobenzenesulfonate.
Reaction SMILES: [CH3:1][C:2]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:6][C:5]2[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:27](O)=[O:28]>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:27]([N:19]1[CH2:20][CH2:21][N:16]([CH2:15][C:2]2([CH3:1])[CH2:6][C:5]3[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=3[O:3]2)[CH2:17][CH2:18]1)=[O:28]
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCNCC1)O2
Product: COc1ccc(C(=O)N2CCN(CC3(C)Cc4c(C)c(N)c(C)c(C)c4O3)CC2)cc1OC
Yield: 74 %

Procedure:
Using 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1-piperazinyl)methyl]-5-benzofuranamine and 3,4-dimethoxybenzoic acid, the procedure of Example 10, presented hereinafter, was otherwise followed to provide the title compound. Yield 74%.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[NH:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:20]=[O:21])[C:14]=2[CH:13]=[CH:12]1>>[CH2:2]([N:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:20]=[O:21])[C:14]=2[CH:13]=[CH:12]1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: O=C(CBr)c1ccccc1
Product: O=Cc1cccc2c1ccn2CC(=O)c1ccccc1
Yield: 13.6 %

Procedure:
The same procedures used in Example 7 were repeated except for using 5.49 g of bromoacetophenone and 2.00 g of indole-4-carbaldehyde as a starting material to give 494 mg of 1-phenacylindole-4-carbaldehyde as yellow crystals. The yield thereof was found to be 14%.