Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH3:3][N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[C:9]1[CH:10]=[C:11]([C:15]#[C:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=2)[CH:12]=[N:13][CH:14]=1.CC(O)=O>CO>[CH3:3][N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[C:9]1[CH:10]=[C:11]([C:15]#[C:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=2)[CH:12]=[N:13][CH:14]=1
Reactant: COC(=O)c1ccc(C#Cc2cncc(C3CCCN3C)c2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCCC1c1cncc(C#Cc2ccc(C(=O)O)cc2)c1
Temperature: 25 °C

Procedure:
KOH (168 mg, 3 mmol) was added to YH19 (0.32 g, 1 mmol) in MeOH (5 mL). The stirred mixture was refluxed for 2 h and then cooled to room temperature. HOAc was added to pH8 and the volatiles were evaporated. The residue was chromatographed [SiO2, CHCl3/MeOH (5:1)] to give 0.19 g (62%) of YH20; 1H NMR (270 MHz, CDCl3) δ 11.00 (br s, OH), 8.75 (br s, 1H), 8.44 (m, 2H), 8.10 (d, J=8 Hz, 2H), 7.42 (d, J=8.5 Hz, 2H), 3.94-3.84 (m, 1H), 3.63-3.52 (m, 1H), 2.69-2.58 (m, 1H), 2.42 (s, 3H), 2.42-1.98 (m, 4H); 13C NMR (270 MHz, CDCl3) δ 169.5, 151.6, 148.9, 139.0, 133.8, 132.9, 131.5, 129.6, 125.3, 120.8, 93.0, 87.4, 69.0, 55.5, 38.8, 33.2, 21.7;
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]1[CH2:17][CH2:18][CH2:19][CH:20]([CH2:21][C:22]([O:24]CC)=[O:23])[C:12]1=[CH:11]2.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1.O>[F:32][C:30]([F:31])([F:33])[C:28]1[CH:27]=[C:5]([CH:4]=[C:3]([C:2]([F:35])([F:34])[F:1])[CH:29]=1)[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]1[CH2:17][CH2:18][CH2:19][CH:20]([CH2:21][C:22]([OH:24])=[O:23])[C:12]1=[CH:11]2
Reactant: CCOC(=O)CC1CCCn2c1cc1cc(OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)ccc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CC1CCCn2c1cc1cc(OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of ethyl 2-(2-(3,5-bis(trifluoromethyl)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (145 mg, 0.29 mmol) in dioxane (1.5 mL) was added 1 M LiOH aqueous solution (1.16 mL, 1.161 mmol). The reaction was stirred at room temperature for 8 h, diluted with water, and acidified to pH 4 with 0.5 M aqueous citric acid. The solid precipitate was collected to give the title compound (125 mg). LCMS m/z=471.8 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.55-1.65 (m, 1H), 2.00-2.10 (m, 1H), 2.17-2.26 (m, 2H), 2.65 (dd, J=16.1, 8.5 Hz, 1H), 3.00 (dd, J=16.1, 5.4 Hz, 1H), 3.45-3.54 (m, 1H), 3.85-3.94 (m, 1H), 4.14-4.22 (m, 1H), 5.19 (s, 2H), 6.23 (s, 1H), 6.91 (dd, J=8.8, 2.4 Hz, 1H), 7.09 (d, J=2.4 Hz, 1H), 7.19 (d, J=8.7 Hz, 1H), 7.83 (s, 1H), 7.94 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].CC[O-].[Na+].[Na].[Cl:17][C:18]1[CH:19]=[C:20]([CH2:24][CH2:25][CH2:26]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:21]=[CH:22][CH:23]=1>O.C(O)C>[CH2:1]([O:3][C:4](=[O:11])[CH:5]([CH2:26][CH2:25][CH2:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[CH:19]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ccc(S(=O)(=O)OCCCc2cccc(Cl)c2)cc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(CCCc1cccc(Cl)c1)C(=O)OCC
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 41.7 %

Procedure:
91.3 g of malonic acid diethyl ester are added dropwise, at 50° C., to a sodium ethylate solution freshly prepared from 13.11 g of sodium and 650 ml of ethanol. The mixture is kept at that temperature for 2.5 hours, and 185 g of p-toluenesulfonic acid [3-(3-chlorophenyl)propyl] ester are then added dropwise. When the addition is complete, the obtained mixture is stirred at 50° C. for 6 hours; 800 ml of water are then added, and the mixture is extracted 3 times with a total of 1 liter of diethyl ether. The combined organic phases are dried over sodium sulfate; the solvent is evaporated off, and the residue is distilled. 74.2 g of 3-(3-chlorophenyl)propylmalonic acid diethyl ester (b.p. 145° to 152° C. under 0.01 mm Hg) are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:12])[C:9]=1[O:10][CH3:11])[CH2:5]Cl.[CH2:13]([NH:16][C:17]1[C:18]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:19][CH:20]=[CH:21][CH:22]=1)[CH2:14][CH3:15]>>[CH3:11][O:10][C:9]1[C:2]([CH3:1])=[CH:3][C:4]([CH2:5][N:26]2[CH2:27][CH2:28][N:23]([C:18]3[C:17]([NH:16][CH2:13][CH2:14][CH3:15])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:24][CH2:25]2)=[CH:7][C:8]=1[CH3:12]
Reactant: COc1c(C)cc(CCl)cc1C
Reactant: CCCNc1cccnc1N1CCNCC1
Product: CCCNc1cccnc1N1CCN(Cc2cc(C)c(OC)c(C)c2)CC1

Procedure:
Following the general procedure of EXAMPLE 1 and making non-critical variations but starting with 3,5-dimethyl-4-methoxybenzyl chloride (I, PREPARATION 4, 0.41 g) and 1-[3-(propylamino)-2-pyridinyl]piperazine (II, PREPARATION 7, 0.42 g), the title compound is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][C:10](=[O:13])[CH:9]([C:14]([O:16][CH3:17])=[O:15])[S:8][C:7]=2[CH:18]=1.[C:19]1([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33]Cl)[CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(C(C)=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][C:10](=[O:13])[C:9]([CH2:33][CH2:32][CH2:31][N:28]3[CH2:29][CH2:30][N:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)([C:14]([O:16][CH3:17])=[O:15])[S:8][C:7]=2[CH:18]=1
Reactant: COC(=O)C1Sc2cc(OC)ccc2OCC1=O
Reactant: ClCCCN1CCN(c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)C1(CCCN2CCN(c3ccccc3)CC2)Sc2cc(OC)ccc2OCC1=O

Procedure:
A mixture of methyl 7-methoxy-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate (10 g), 3-(4-phenylpiperazin-1yl)propyl chloride (9.8 g), anhydrous potassium carbonate (6.2 g), potassium iodide (3.0 g) and methyl ethyl ketone (150 ml) was refluxed under heating for 25 hours. After cooling, inorganic matter was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and dried. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=3:1) to give methyl 7-methoxy-3-oxo-4-[3-(4-phenylpiperazine-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate. Recrystallization from methanol yielded white crystals, melting point 110°-112° C., yield 2.1 g.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([F:8])[N:5]=[C:4](Cl)[N:3]=1.[F:10]C1N=C(Cl)N=C(Cl)N=1>>[N:3]1[C:4]([F:10])=[N:5][C:6]([F:8])=[N:7][C:2]=1[F:1]
Reactant: Fc1nc(Cl)nc(Cl)n1
Reactant: Fc1nc(F)nc(Cl)n1
Product: Fc1nc(F)nc(F)n1

Procedure:
If 2,4-difluoro-6-chloro-s-triazine or 2-fluoro-4,6-dichloro-s-triazine is used in place of cyanuric chloride as the starting material, very good yields of pure cyanuric fluoride are possible even with molar ratios of hydrogen fluoride/cyanuric halide which are lower than those mentioned above. For example, when 2,4-difluoro-6-chloro-s-triazine is used the reaction is advantageously carried out with a molar ratio of hydrogen fluoride/2,4-difluoro-6-chloro-s-triazine of 1:1 to 4:1, preferably about 2:1; if 2-fluoro-4,6-dichloro-s-triazine is used as the starting material, advantageous results are obtained with a molar ratio of hydrogen fluoride/2-fluoro-4,6-dichloro-s-triazine of 2:1 to 5:1 and preferably the reaction is carried out using a molar ratio of hydrogen fluoride/2-fluoro-4,6-dichloro-s-triazine of 3:1. When 2,4-difluoro-6-chloro-s-triazine or 2-fluoro-4,6-dichloro-s-triazine is used as the starting material, the reaction is also carried out at temperatures betwen 150° C. and 300° C.; preferably the reaction is carried out at between 180° C. and 220° C., as when cyanuric chloride is used as the starting material. Pure cyanuric fluoride is likewise obtaining in high yield when a mixture of 2,4-difluoro-6-chloro-s-triazine and 2-fluoro-4,6-dichloro-s-triazine or a mixture of cyanuric chloride, 2,4-difluoro-6-chloro-s-triazine and 2-fluoro-4,6-dichloro-s-triazine is employed, in place of cyanuric chloride, 2,4-difluoro-6-chloro-s-triazine or 2-fluoro-4,6-dichloro-s-triazine, as the starting material. In this case the most advantageous molar ratio of hydrogen fluoride/cyanuric halide mixture depends on the mixing ratio of the two or the three cyanuric halide components in the starting mixture. The most advantageous temperature range for the reaction when a mixture of cyanuric halides is used is the same as that when pure cyanuric chloride is employed as the starting material.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>C(O)C.O>[C:10]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8](=[N:17][OH:18])[NH2:9])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N#CC(c1ccccc1)c1ccccc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=NO)C(c1ccccc1)c1ccccc1
Yield: 30.5 %

Procedure:
A mixture of diphenylacetonitrile (7.0 g), hydroxylamine hydrochloride (3.03 g), and sodium acetate (6.67 g) in 150 ml of 5:1 ethanol-water was refluxed for 4 h. The mixture was concentrated under reduced pressure. The residue was triturated with water, filtrated, and dried to give the title compound (2.5 g) having the following physical data.
Reaction SMILES: [F:1][C:2]([F:12])([CH2:10][CH3:11])[C:3]([F:9])([F:8])[C:4]([OH:7])([F:6])[F:5].[C:13](Cl)(=[O:17])[C:14]([Cl:16])=[O:15]>>[C:14]([Cl:16])(=[O:15])[C:13]([O:7][C:4]([F:6])([F:5])[C:3]([F:8])([F:9])[C:2]([F:12])([F:1])[CH2:10][CH3:11])=[O:17]
Reactant: CCC(F)(F)C(F)(F)C(O)(F)F
Reactant: O=C(Cl)C(=O)Cl
Product: CCC(F)(F)C(F)(F)C(F)(F)OC(=O)C(=O)Cl
Yield: 52.8 %

Procedure:
In this example the product was prepared in two synthetic steps. In the first step hexafluoroamyl alcohol was reacted with 100% molar excess of oxalyl chloride. Upon completion of the reaction the excess oxalyl chloride was stripped from the product at reduced pressure to produce hexafluoroamyl chlorooxalate having an assay of 91.3% and in a corrected yield of 52.8%. In the second step hexafluoroamyl chlorooxalate was reacted with 2,5-dimethyl-2,5-dihydroperoxyhexane, in the presence of pyridine, to yield the product as described below:
Reaction SMILES: CCCCCC.Br[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][CH:9]=1.[Br:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=[O:22].[Cl-].[NH4+]>O1CCCC1>[Br:17][C:18]1[CH:19]=[C:20]([CH:21]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)[OH:22])[CH:23]=[CH:24][CH:25]=1
Reactant: CCOc1ccc(Br)cc1
Reactant: O=Cc1cccc(Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOc1ccc(C(O)c2cccc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
A 2.6 M n-butylithium hexane solution (5.8 mL) was added to a mixture of 4-bromophenetole (2.87 g, 0.0143 mol) and tetrahydrofuran (30 mL) at −78° C. After the mixture was stirred for 0.5 hours, a tetrahydrofuran (15 mL) solution of 3-bromobenzaldehyde (2.65 g, 0.0143 mol) was added, and further stirred for 15 minutes to warm the reaction mixture to room temperature. After the reaction mixture was added with a saturated ammonium chloride aqueous solution and extracted with ethyl acetate, the organic layer was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=7:1 to 5:1) to obtain colorless oily (3-bromophenyl)(4-ethoxyphenyl)methanol (3.94 g, 90%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][NH:7][CH2:8][CH:9]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>C(#N)C>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][N:7]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:8][CH:9]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)CCNCC(C(=O)OCC)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CCN(Cc1ccccc1)CC(C(=O)OCC)c1ccc(Cl)c(Cl)c1
Temperature: 75 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a solution of the compound (27.8 g) obtained in step 2 and sodium carbonate (16.3 g) in acetonitrile (132 mL) was added benzyl bromide (14.4 g) at room temperature, and the mixture was stirred at 75° C. for 2 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5→20% ethyl acetate/hexane) to give N-benzyl-N-[2-(3,4-dichlorophenyl)-3-ethoxy-3-oxopropyl]-β-alanine ethyl ester (34.6 g, 99%) as a colorless oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][N:6]=1)=O.[BH4-].[Na+]>CO>[Br:11][C:10]1[C:5]([CH2:3][OH:2])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ncccc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ncccc1Br
Temperature: 0 °C
Reaction time: 3 h
Yield: 1808.3 %

Procedure:
3-Bromo-pyridine-2-carboxylic acid methyl ester (12.8 g, 59 2 mmol) is dissolved in methanol (150 mL) and cooled to 0° C. To the mixture is added NaBH4 (11.2 g, 296 mmol) in 1.0 g portions. The mixture is warmed to room temperature and stirred for 3 h. The methanol is removed under reduced pressure, ethyl acetate is added and the solution is washed with saturated, aqueous ammonium chloride and brine. The organic portion is dried over MgSO4, filtered, and concentrated under reduced pressure to yield 6.8 g (62%) of the title compound as a white solid. GCMS m/e 187, 189 [M]−.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12](O)=[O:13])=[CH:11][C:6]=2[N:5]=[C:4]1[NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([O:25][C:26]([F:29])([F:28])[F:27])[CH:22]=[CH:21][C:19]=2[N:20]=1)[CH3:2].[NH2:30][CH2:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]1)=[O:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:40][N:37]1[CH2:38][CH2:39][N:34]([C:32](=[O:33])[CH2:31][NH:30][C:12]([C:10]2[CH:9]=[CH:8][C:7]3[N:3]([CH2:1][CH3:2])[C:4]([NH:15][C:16]4[S:17][C:18]5[CH:24]=[C:23]([O:25][C:26]([F:28])([F:27])[F:29])[CH:22]=[CH:21][C:19]=5[N:20]=4)=[N:5][C:6]=3[CH:11]=2)=[O:13])[CH2:35][CH2:36]1
Reactant: CN1CCN(C(=O)CN)CC1
Reactant: CCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)N3CCN(C)CC3)ccc21
Yield: 37.6 %

Procedure:
1-Ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]amide (50.0 mg) was prepared by following General Procedure F starting from 1-ethyl-2-(6-trifluoromethoxybenzo-thiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100.0 mg), 2-amino-1-(4-methyl-piperazin-1-yl)-ethanone (40.0 mg), HBTU (190.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 563; and 1H NMR (DMSO-d6, 400 MHz): δ 8.51-8.48 (1H, m), 8.12 (1H, br. s), 7.93 (1H, br. s), 7.74-7.71 (2H, m), 7.55 (1H, m), 7.37 (1H, m), 4.26 (2H, bs. s), 4.16-4.15 (2H, m), 3.51-3.50 (4H, m), 2.40-2.33 (4H, m), 2.24 (3H, s), 1.35-1.31 (3H, t), —NH proton signal was not observed.
Reaction SMILES: C(O)C.C[O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][CH:16]1[C:25]2[C:20]3=[C:21]([N:26]=[C:27]([CH2:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:19]3[CH2:18][CH2:17]1)[CH:22]=[CH:23][CH:24]=2)=[O:7].[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][CH:16]1[C:25]2[C:20]3=[C:21]([N:26]=[C:27]([CH2:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:19]3[CH2:18][CH2:17]1)[CH:22]=[CH:23][CH:24]=2)([OH:7])=[O:5]
Reactant: COC(=O)c1ccccc1COC1CCn2c(CCc3ccccc3)nc3cccc1c32
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccccc1COC1CCn2c(CCc3ccccc3)nc3cccc1c32
Yield: 61.7 %

Procedure:
Ethanol (4 mL) was added to 0.62 g of the 5,6-dihydro-6-(2-methoxycarbonylphenyl)methoxy-2-(2-phenylethyl)-4H-imidazo[4,5,1-ij]quinoline obtained in Example 19; to the solution, another solution having potassium hydroxide (0.19 g) dissolved in water (0.4 mL) was added and the mixture was heated under reflux for 1 hr. After standing to cool, the reaction solution was poured into water and its pH was adjusted to 4-5 using 10% aqueous citric acid; after extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate) to yield the titled compound as pale yellow crystals (0.37 g).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][C:5](=[O:7])[O:4][C:3]1=O.[CH2:9]([N:11](CC)CC)C.Cl.CN.C1N=CN(C(N2C=NC=C2)=O)C=1>ClCCl>[CH3:9][N:11]1[C:5](=[O:7])[CH2:6][C@H:2]([CH3:1])[C:3]1=[O:4]
Reactant: C[C@H]1CC(=O)OC1=O
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: C[C@H]1CC(=O)N(C)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
600 mg (5.26 mmol) of (3S)-3-methyldihydro-2,5-furandione (preparation: S. G. Davies, D. J. Dixon, J. Chem. Soc., Perkin Trans. 1, 1998, 17, 2635-2643) are introduced to a vessel together with 559 mg (0.77 ml, 5.52 mmol) of triethylamine in 5 ml of dichloromethane at 0° C. and 373 mg (5.52 mmol) of methylamine hydrochloride are added. The reaction mixture is stirred at room temperature overnight and then 938 mg (5.78 mmol) of N,N-carbonyldiimidazole are added in portions. The mixture is stirred at room temperature for 1.5 h and at reflux temperature for 30 minutes. After it has cooled to room temperature the reaction mixture is washed with 5% strength hydrochloric acid and water, the organic phase is dried over magnesium sulfate, filtered and concentrated and the product is dried under a high vacuum. This gives 605 mg of the product (88% of theory).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:10][CH2:9][CH2:8][C:7]=1[NH:11][CH3:12])=[O:5])[CH3:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[NH:11][CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(NC)CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C1CCCC1NC
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.1 %

Procedure:
2-Methylamino-cyclopent-1-enecarboxylic acid ethyl ester (1.28 g, 7.57 mmol) was dissolved in glacial acetic acid (20 mL) and sodium triacetoxyborohydride (4.81 g, 22.71 mmol) was added at 0° C. The solution was allowed to warm to 25° C. and stirred for 3 h. The acetic acid was removed in vacuo and the residue was dissolved in dichloromethane. The solution was washed with saturated aqueous sodium bicarbonate solution followed by saturated aqueous brine solution. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the desired product, 2-methylamino-cyclopentanecarboxylic acid ethyl ester (285 mg, 1.67 mmol, 22.1%), as a yellowish oil. LC-MS (ESI) calcd for C9H17NO2 171.13, found 172.1 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:14]([C:15](=O)[NH:16][CH2:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)=O)[CH2:13][C:10]2([CH2:12][CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+:32]>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH:14]([C:15]2[NH:32][C:18]([C:20]3[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=3)=[CH:17][N:16]=2)[CH2:13][C:10]2([CH2:12][CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CC2(CC2)CC1C(=O)NCC(=O)c1ccc(Br)cc1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(Br)cc2)[nH]1
Temperature: 140 °C
Yield: 61.4 %

Procedure:
15 mL Xylenes was added to 6-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester (424 mg, 0.97 mmol) and ammonium acetate (20 eq., 1.5 g). The mixture was heated in microwave at 140° C. for 60 minutes. The mixture was diluted with EtOAc and washed with sat. NaHCO3 aqueous solution. The organic layer was concentrated down and purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexane) to give 6-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester (249 mg, yield 61%). LCMS-ESI−: calc'd for C20H24BrN3O2: 418.33. Found: 418. (M+H+).
Reaction SMILES: P(Br)(Br)[Br:2].O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]#[N:15])=[CH:9][CH:8]=1.O>CC(OC)(C)C>[Br:2][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]#[N:15])=[CH:9][CH:8]=1
Reactant: BrP(Br)Br
Reactant: N#CCc1ccc(CO)cc1
Solvent: O
Solvent: COC(C)(C)C
Product: N#CCc1ccc(CBr)cc1

Procedure:
0.86 mL (9 mmol) of phosphorus tribromide are added dropwise to a solution of 2.6 g (17.66 mmol) of (4-hydroxymethyl-phenyl)-acetonitrile in 25 mL MTBE at 0° C. After the reaction has ended the reaction mixture is combined with water at RT, the organic phase is separated off and these are extracted successively with sodium hydrogen carbonate solution and water. The organic phase is dried over magnesium sulphate and the solvent is distilled off using the rotary evaporator.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]#[C:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)CCC.C(C1C=C(C(C)C)C=C(C(C)C)C=1S(O[C:41]1[CH:46]=[CH:45][N:44](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:43](=[O:66])[N:42]=1)(=O)=O)(C)C>CN(C=O)C.[Cu]I.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>[C:8]1([C:7]#[C:6][C:41]2[CH:46]=[CH:45][NH:44][C:43](=[O:66])[N:42]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCCC[Sn](C#Cc1ccccc1)(CCCC)CCCC
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Oc2ccn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c(=O)n2)c(C(C)C)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=c1nc(C#Cc2ccccc2)cc[nH]1
Temperature: 55 °C

Procedure:
Tributyl(phenylethynyl)stannane (315 mg, 0.8 mmol) was added to a stirred solution of 2-oxo-1-trityl-1,2-dihydropyrimidin-4-yl 2,4,6-triisopropylbenzenesulfonate Part A (200 mg, 0.3 mmol), copper (I) iodide (18.4 mg, 0.1 mmol) and palladium tetrakis (55.8 mg, 0.05 mmol) in 5 mL DMF under nitrogen. The reaction mixture was heated at 55° C. for 16 h, concentrated and subjected to flash chromatography (silica gel/methylene chloride to 15% MeOH-methylene chloride gradient to afford 4-(phenylethynyl)pyrimidin-2(1H)-one 4B (66 mg) as a brownish solid.