Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH2:3]1[C:16]2[CH:15]=[CH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[C:6](=[O:17])[CH2:5][CH2:4]1.[CH3:18][C:19]1[N:23]([C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:22]=[N:21][C:20]=1[CH:43]=O>CO>[CH3:18][C:19]1[N:23]([C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:22]=[N:21][C:20]=1[CH:43]=[C:5]1[C:6](=[O:17])[C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[CH:15][C:16]=2[CH2:3][CH2:4]1
Reactant: Cc1c(C=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCCc2ccc3ccccc3c21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C=C2CCc3ccc4ccccc4c3C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 120 h
Yield: 63.6 %

Procedure:
A solution of potassium hydroxide (0.25 g) in methanol (5 ml) was added to a solution of 1,2-dihydro-4(3H)-phenanthrenone (0.5 g) and 5-methyl-1-(triphenylmethyl)-1H-imidazole-4-carboxaldehyde (0.9 g) in methanol (20 ml). The mixture was kept at 23° for 5 days after which time a solid had separated. This was filtered off, washed with ethanol and purified by FCC eluting firstly with hexane/dichloromethane (1:1) and then with dichloromethane to give the title compound (0.86 g), m.p. 145°-148° (decomp.).
Reaction SMILES: [C:1]1([CH:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]1[CH:16]=[N:15][CH:14]=[C:13](Cl)[N:12]=1.CCOCC>O1CCOCC1>[Cl:10][C:11]1[CH:16]=[N:15][CH:14]=[C:13]([O:9][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])[N:12]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CC(O)c1ccccc1
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(Oc1cncc(Cl)n1)c1ccccc1
Reaction time: 0.17 h

Procedure:
K-t-BuO (2.1 g, 18.7 mmol) was added to a stirred solution of 1-phenyl-1-ethanol (2.45 g, 20.1 mmol) in dioxane (30 mL) at 0° C. (ice-bath). After 10 min of stirring, 2,6-dichloropyrazine (2.49 g, 16.7 mmol) was added whereupon the reaction mixture turned orange colored. After being stirred for a further 1.5 h, ether was added and the mixture was filtered. Concentration in vacuo furnished an orange colored oil that was purified by silica gel chromatography (15×5 cm) using n-hexane ethyl acetate (9:1) as eluent. This gave 3.29 g (84%) of the title compound as a colorless oil. HRMS m/z calcd for C12H11ClN2O (M)+ 234.0560, found 234.0551.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([CH:12]=O)[CH:9]=[C:8]2[C:3]=1[CH2:4][N:5]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[C:6](=[O:22])[N:7]2[C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21].[CH:32]([N:35]1[CH2:40][CH:39]2[CH2:41][CH:36]1[CH2:37][NH:38]2)([CH3:34])[CH3:33]>>[Br:1][C:2]1[CH:11]=[C:10]([CH2:12][N:38]2[CH2:37][CH:36]3[CH2:41][CH:39]2[CH2:40][N:35]3[CH:32]([CH3:34])[CH3:33])[CH:9]=[C:8]2[C:3]=1[CH2:4][N:5]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[C:6](=[O:22])[N:7]2[C:14]1[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: CC(C)N1CC2CC1CN2
Reactant: COc1ccc(CN2Cc3c(Br)cc(C=O)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Product: COc1ccc(CN2Cc3c(Br)cc(CN4CC5CC4CN5C(C)C)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1

Procedure:
The 5-bromo-1-(2,6-dichlorophenyl)-7-[(5-isopropyl-2,5-diazabicyclo[2.2.1]hept-2-yl)methyl]-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one was prepared from 5-bromo-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carbaldehyde (EXAMPLE AAA16, STEP B) and 2-isopropyl-2,5-diazabicyclo[2.2.1]heptane (INTERMEDIATE ABA2) as described in EXAMPLE AAA1, STEP A. 1H NMR (CDCl3, 500 MHz): δ 1.15 (brs, 3H), 1.22 (brs, 3H), 1.74 (brs, 1H), 1.90 (brs, 1H), 243 (brs, 2H), 2.72 (brs, 1H), 2.88 (brs, 1H), 3.07 (brs, 1H), 3.16 (s, 2H), 3.53 (abq, 2H, J=14.2 Hz), 3.72 (brs, 1H), 3.83 (s, 3H), 4.48 (s, 2H), 4.68 (s, 2H), 6.05 (s, 1H), 6.91 (d, 2H, J=8.5 Hz), 7.17 (s, 1H), 7.36 (d, 2H, J=8.4 Hz), 7.38 (t, 1H, J=8.0 Hz), 7.52 (d, 2H, J=8.0 Hz). MS (API-ES+): 645 (M+H).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)=O.[OH:13][C:14]([CH2:17][OH:18])=[CH:15][NH2:16]>C1C=CC=CC=1>[OH:13][CH:14]([CH2:17][OH:18])[CH2:15][N:16]=[C:1]=[C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH2:4]1
Reactant: O=Cc1ccc(-c2cccs2)s1
Reactant: NC=C(O)CO
Solvent: c1ccccc1
Product: OCC(O)CN=C=C1CC=C(c2cccs2)S1
Temperature: 85 °C

Procedure:
5.74 g of 5-formyl-2,2'-bithiophene was dissolved in 60 ml of benzene, followed by dropping in excess 2,3-dihydroxy-propenylamine and refluxed at 85° C. for 5 hours with molecular sieves. Then the benzene was evaporated under reduced pressure and 9.68 g of residual solid was obtained. A yellowish product (85%) could be further recrystallized from ethanol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]([CH2:14][C:15]([O:17]C(C)(C)C)=O)=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O.[NH2:29][C:30]1[N:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][N:39]([C:42](=[O:44])[CH3:43])[CH2:38][CH2:37]2)=[CH:32][CH:31]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl>[C:42]([N:39]1[CH2:38][CH2:37][N:36]([C:33]2[CH:32]=[CH:31][C:30]([NH:29][C:15](=[O:17])[CH2:14][C:11]3[CH:12]=[N:13][C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=4)=[N:9][CH:10]=3)=[N:35][CH:34]=2)[CH2:41][CH2:40]1)(=[O:44])[CH3:43]
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: Cc1cc(-c2ncc(CC(=O)OC(C)(C)C)cn2)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3cnc(-c4ccnc(C)c4)nc3)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 2-(2-(2-methylpyridin-4-yl)pyrimidin-5-yl)acetate 183-4 (35 mg, 0.12 mmol) and TFA (0.5 mL) in DCM (3 mL) was stirred at room temperature for 2 hours. The solvents were evaporated to dryness under high vacuum. The crude product, 2-(2-(2-methylpyridin-4-yl)pyrimidin-5-yl)acetic acid 183-5, was dissolved in DMF (2 mL). 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone (35 mg, 0.16 mmol) and DIEA (107 uL, 0.61 mmol) were added to the solution before O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (70 mg, 0.18 mmol). The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(2-(2-methylpyridin-4-yl)pyrimidin-5-yl)acetamide 183. MS m/z 433.2 (M+1); 1H NMR 400 MHz (MeOD) δ 8.47(s, 2H), 8.50(d, 1H), 8.22(s, 1H), 8.14(d, 1H), 7.97(d, 1H), 7.87(d, 1H), 7.38(dd, 1H), 3.83(s, 2H), 3.68(t, 2H), 3.64(t, 2H), 3.15(t, 2H), 3.09(t, 2H), 2.58(s, 3H), 2.09(s, 3H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][NH:16][C:15](=[O:19])[CH2:14]3)=[N:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:20]N(C)C=O.[H-].[Na+].CI>O1CCCC1.O>[Br:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH3:20])[C:15](=[O:19])[CH2:14]3)=[N:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN(c2ncc(-c3cccc(Br)n3)s2)CCN1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(c2ncc(-c3cccc(Br)n3)s2)CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
4-[5-(6-bromopyridin-2-yl)thiazol-2-yl]piperazin-2-one obtained in Step 4 (200 mg, 0.59 mmol) was dissolved in tetrahydrofuran (2 ml) and N,N-dimethylformamide (2 ml) and after sodium hydride (60% oily, 26 mg, 0.65 mmol) was added, methyl iodide (39 μl, 0.62 mmol) was added and the mixture was stirred overnight at room temperature. Water was added to the reaction solution and the residue obtained by vacuum concentration was extracted with ethyl acetate and washed with a saturated brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to give the title compound (188 mg, 90%).
Reaction SMILES: CO.[O:3]=[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]1[CH:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1)[CH3:11].O.[OH-].[Li+].Cl>O>[O:3]=[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]1[CH:10]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=1)[CH3:11]
Reactant: COC(=O)c1ccc(C(C)n2ccccc2=O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(c1ccc(C(=O)O)cc1)n1ccccc1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.5 %

Procedure:
To a mixed solution of methanol (10 mL) and water (2 mL), methyl 4-(1-(2-oxopyridin-1(2H)-yl)ethyl)benzoate (145 mg, 0.56 mmol) and lithium hydroxide hydrate (40 mg, 0.95 mmol) were added. The reaction mixture was stirred at room temperature for 12 hours. Then the mixture was acidified by hydrogen chloride aqueous solution (1N) to pH=6 and extracted with dichloromethane (20 mL×3). The organic phase was concentrated to give 4-(1-(2-oxopyridin-1(2H)-yl)ethyl)benzoic acid (111 mg, 81%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11](=[O:18])[CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15]>>[CH3:9][O:10][C:11](=[O:18])[CH2:12]/[C:13](/[C:14]([O:16][CH3:17])=[O:15])=[CH:1]/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)CCC(=O)OC
Product: COC(=O)C/C(=C/c1ccccc1)C(=O)OC
Yield: 4.9 %

Procedure:
Benzaldehyde (21.2 g) and succinic acid dimethyl ester (40.9 g) are treated in the same manner as in Reference Example 1, and the resulting product is purified by silica gel column chromatography to give (Z)-3-methoxycarbonyl-4-phenyl-3-butenoic acid methyl ester (2.3 g) as colorless syrup.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:12]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([OH:30])([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])[CH:16]=2)=[CH:7][CH:6]=1.[Li+].[OH-].OS([O-])(=O)=O.[K+]>C1COCC1>[C:31]1([CH:12]([O:11][C:8]2[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:37])=[O:2])=[CH:10][CH:9]=2)[CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([OH:30])([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])[CH:16]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COC(=O)Cc1ccc(OC(COc2cccc(C(O)(C(F)(F)F)C(F)(F)F)c2)c2ccccc2)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(OC(COc2cccc(C(O)(C(F)(F)F)C(F)(F)F)c2)c2ccccc2)cc1
Yield: 70.5 %

Procedure:
40 mg (0.08 mmol) of rac (4-{1-phenyl-2-[3-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenoxy]-ethoxy}-phenyl)-acetic acid methyl ester (example 9) in 1 mL of THF were treated with 0.76 mL of 1M LiOH at room temperature for 2 h. 1M KHSO4 solution was added, the phases were separated, and the inorganic one was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4) and evaporated. The crude product was purified by column chromatography to give 29 mg (74%) of rac (4-{1-phenyl-2-[3-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenoxy]-ethoxy}-phenyl)-acetic acid as a colorless oil, MS: 513 (M−H)−.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.Cl.[CH3:14][O:15][C:16](=[O:27])[C@H:17]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[NH2:18].[Cl:28][C:29]1[N:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](O)=[O:32].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[CH3:14][O:15][C:16](=[O:27])[C@H:17]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=1)[NH:18][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][CH:36]=[N:37][C:29]=1[Cl:28]
Reactant: O=C(O)c1cccnc1Cl
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
EDC.HCl (2.11 g, 11 mmol) was added to a mixture of L-tyrosine methyl ester hydrochloride (2.32 g, 10 mmol), 2-chloronicotinic acid (1.58 g, 10 mmol), HOBT (1.49 g, 11 mmol) and NMM (2.31 ml, 21 mmol) in DMF (50 ml). The mixture was stirred overnight at room temperature. The solvent was removed in vacuo. the residue dissolved in EtOAc (300 ml) and washed with dilute HCl (100 ml), saturated aqueous NaHCO3 (100 ml), water (3×100 ml) and brine (50 ml), dried (Na2SO4) and solvent removed in vacuo to give the title compound as a yellow gum (3.27 g, 98%). δH (DMSO-d6, 300 MHz) 9.21 (1H, s, OH), 9.03 (1H, d, J 7.9 Hz, CONH), 8.45 (1H, dd, J 4.8, 1.9 Hz, pyrH), 7.67 (1H, dd, J 7.4, 1.9 Hz, pyrH), 7.47 (1H, dd, J 7.5, 4.8 Hz, pyrH), 7.05 (2H, d, J 8.5 Hz, ArH), 6.67 (2H, d, J 8.5 Hz, ArH), 4.58 (1H, ddd, J 9.6, 7.9, 5.4 Hz, CHα), 3.65 (3H, s, CO2Me), 3.01 (1H, dd, J 13.9, 5.4 Hz, CHAHBAr) and 2.85 (1H, dd, J 13.9, 9.6 Hz, CHAHBAr), m/z (ESI, 60V) 335 (MH+).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH3:10][C:11]1[CH:16]=[C:15]([N:17]2[CH:21]=[CH:20][NH:19][CH2:18]2)[CH:14]=[CH:13][N:12]=1.C([O-])(O)=O.[Na+]>>[N+:6]([CH:18]1[N:17]([C:15]2[CH:14]=[CH:13][N:12]=[C:11]([CH3:10])[CH:16]=2)[CH:21]=[CH:20][NH:19]1)([O-:9])=[O:7]
Reactant: Cc1cc(N2C=CNC2)ccn1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1cc(N2C=CNC2[N+](=O)[O-])ccn1
Temperature: 110 °C
Reaction time: 10 h
Yield: 66 %

Procedure:
To a stirred solution of sulfuric acid (14 ml, 95-97%) and HNO3 (10 ml, fum.) was added at 0° C. 3-(2-methyl-4-pyridinyl)-1H-imidazole (4.0 g, 25.1 mmol). The reaction mixture was stirred at room temperature for 50 min, at 100° C. for 2.5 h and at 110° C. for 10 h and poured into ice-water (70 ml). Solid NaHCO3 was added to the stirred mixture until the pH reached 5. The solution was extracted with THF (4×200 ml), the combined organic layers were dried (MgSO4) and evaporated to give 2-nitro-3-(2-methyl-4-pyridinyl)-1H-imidazole (3.4 g, 66%) as a light yellow solid; MS (ISP) 205.2 [(M+H)+].
Reaction SMILES: [C:1]1([CH:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:8]2[C:16]3[CH:15]=[C:14]4[O:17][CH2:18][CH2:19][O:20][C:13]4=[CH:12][C:11]=3[C:10](O)([C:21]3[C:22]([OH:30])=[CH:23][C:24]4[O:28][CH2:27][CH2:26][C:25]=4[CH:29]=3)[C:9]2=[O:32])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[C:33]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[C:16]3[CH:15]=[C:14]4[O:17][CH2:18][CH2:19][O:20][C:13]4=[CH:12][C:11]=3[CH:10]([C:21]3[C:22]([OH:30])=[CH:23][C:24]4[O:28][CH2:27][CH2:26][C:25]=4[CH:29]=3)[C:9]2=[O:32])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2cc3c(cc2C1(O)c1cc2c(cc1O)OCC2)OCCO3
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1C(c2cc3c(cc2O)OCC3)c2cc3c(cc2N1C(c1ccccc1)c1ccccc1)OCCO3
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of 6-(diphenylmethyl)-8-hydroxy-8-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one (0.78 g, 1.5 mmol), triethylsilane (1.2 mL) and trifluoroacetic acid (1.2 mL) in dichloromethane (10 mL) was stirred at 0° C. for 1 h and then at ambient temperature for 1 h. The mixture was concentrated in vacuo to afford crude 6-(diphenylmethyl)-8-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one (100%): MS (ES+) m/z 492.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][NH:12][C:11](=[O:23])[C:10]=2[C:24]#[N:25])=[CH:5][CH:4]=1.[CH:26](Cl)([CH3:28])[CH3:27]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][N:12]([CH:26]([CH3:28])[CH3:27])[C:11](=[O:23])[C:10]=2[C:24]#[N:25])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2n[nH]c(=O)c(C#N)c2-c2ccc(OC)cc2)cc1
Reactant: CC(C)Cl
Product: COc1ccc(-c2nn(C(C)C)c(=O)c(C#N)c2-c2ccc(OC)cc2)cc1
Yield: 72.6 %

Procedure:
Using 5,6-bis(4-methoxyphenyl)-4-cyano-2H-pyridazin-3-one and isopropyl chloride as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 72.6%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH:22]([CH3:24])[CH3:23])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=O)#[N:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH:22]([CH3:24])[CH3:23])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=[S:34])#[N:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1cccc(NC(=O)c2ccc(OCC(C)C)c(C#N)c2)c1
Solvent: Cc1ccccc1
Product: COc1cccc(NC(=S)c2ccc(OCC(C)C)c(C#N)c2)c1
Reaction time: 8 h
Yield: 132.2 %

Procedure:
A solution of 3-cyano-4-isobutyloxy-N-(3-methoxyphenyl)benzamide (972 mg, 3.0 mmol) and Lawesson's reagent (808 mg, 2.0 mmol) in toluene (5 mL) was heated under reflux for 3.5 hours. After addition of toluene (approx. 20 mL), the heated solution was allowed overnight to lapse at room temperature. The precipitated crystalline product was collected by filtration, to give 900 mg (yield 88%) of the desired compound in the form of a yellow crystalline product.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[F:10][C:11]([F:22])([F:21])[O:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=[O:16]>>[N+:6]([C:18]1[CH:19]=[CH:20][C:13]([O:12][C:11]([F:10])([F:21])[F:22])=[C:14]([CH:17]=1)[CH:15]=[O:16])([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1ccccc1OC(F)(F)F
Agent: O=S(=O)(O)O
Product: O=Cc1cc([N+](=O)[O-])ccc1OC(F)(F)F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a mixture of concentrated sulfuric acid (81 mL) and concentrated nitric acid (15.5 mL), cooled to 0° C., was added 2-trifluoromethoxybenzaldehyde (25 g, 0.13 mol) portionwise while maintaining the temperature of the reaction below 0° C. After 1.5 hours, the reaction mixture was poured cautiously over 1000 mL of ice in a large beaker and left to stand for 0.5 hours. The resulting suspension was filtered, washed well with H2O and air dried to give crude 5-nitro-2-trifluoromethoxybenzaldehyde, m.p. 32°-34° C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH2:8])[CH3:3].[CH3:10][CH:11]1[CH2:15][CH2:14][CH2:13][C:12]1=O.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH:8][CH:12]1[CH2:13][CH2:14][CH2:15][CH:11]1[CH3:10])[CH3:3]
Reactant: CC1CCCC1=O
Reactant: CCOC(=O)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)CCNC1CCCC1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of 9.2 g (0.060 mole) of 3-amino-propanoic acid ethyl ester HCl salt and 5.9 g (0.060 mole) of (rac)-2-methyl-cyclopentanone in 300 mL of dichloromethane was added 10.8 g (0.132 mole) of sodium acetate and 19.1 g (0.090 sodium triacetoxyborohydride (19.1 g, 90 mmol). The mixture was stirred at ambient temperature overnight and then quenched by the addition of 100 mL of 10% sodium bicarbonate solution. The aqueous layer was extracted twice with 200 mL of dichloromethane, and the combined dichloromethane layers dried over anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and distilled at 0.0015 mm Hg (bp 70 degrees), to give 9.8 g of (rac)-3-(2-methyl-cyclopentylamino)-propanoic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][O:10][N:11]1C(=O)C2C(=CC=CC=2)C1=O)([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl>[NH2:11][O:10][CH2:9][CH2:8][NH:7][C:6](=[O:22])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCON1C(=O)c2ccccc2C1=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCON
Reaction time: 2 h
Yield: 98.2 %

Procedure:
To a solution of tert-butyl(2-((1,3-dioxoisoindolin-2-yl)oxy)ethyl)carbamate (1.83 g, 6.00 mmol) described in Reference Example 7 in methylene chloride (11 mL) was gradually added 9.8M methylamine methanol solution (1.83 mL), followed by stirring for 2 hours. The reaction solution was filtered and the filtrate was distilled off under reduced pressure, followed by extracting with 0.5M hydrochloric acid (24 mL). To the resulting aqueous layer were added methylene chloride and 1M sodium hydroxide (18 mL), thereby the target was extracted with ethylene chloride. The resulting organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. 1.038 g of the title compound was afforded as the crude product (yield 98%).
Reaction SMILES: [OH-:1].[Na+].O.[Cl:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:14]2[C:15](=[O:31])[N:16]([CH3:30])[N:17]=[CH:18][C:19]=2N2C3C(=CC=CC=3)C(Cl)=N2)[N:6]=1>CO>[Cl:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH:14]2[C:19](=[O:1])[CH:18]=[N:17][N:16]([CH3:30])[C:15]2=[O:31])[N:6]=1
Reactant: Cn1ncc(-n2nc(Cl)c3ccccc32)c(-n2nc(Cl)c3ccccc32)c1=O
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1N=CC(=O)C(n2nc(Cl)c3ccccc32)C1=O
Temperature: 80 °C

Procedure:
A 1:1 w/w 32% NaOH:water mixture (8 g total) is added to 4,5-bis(3-chloroindazol-1-yl)-2-methyl-pyridazin-3-one (768 mg, 1.87 mmol) in methanol (30 mL) and then the mixture heated at 80° C. for 20 minutes. The mixture is allowed to cool to room temperature then concentrated in vacuo. Dichloromethane (50 mL) and water (50 mL) are added to the residue and the organic layer removed. The aqueous layer is acidified to pH 1 with conc. HCl. then extracted with dichloromethane (40 mL×2). The combined organic extracts are passed through a phase separator cartridge and concentrated in vacuo to give the title compound as a white solid (490 mg). 1H nmr (DMSO-d6) δ (ppm) 7.93 (1 H, s) 7.71-7.79 (1 H, m) 7.45-7.54 (1 H, m) 7.26-7.38 (2 H, m) 3.66 (3 H, s). Some other dione products prepared analogously were triturated with ethyl acetate or ether.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH2:10][O:11][CH3:12])=[CH:4][C:3]=1[CH3:13].CN(C)[CH:16]=[O:17].O.Cl>O1CCCC1.C([Li])CCC.CCCCCC>[CH3:12][O:11][CH2:10][O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH:16]=[O:17])=[C:3]([CH3:13])[CH:4]=1
Reactant: COCOCc1ccc(Br)c(C)c1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCOCc1ccc(C=O)c(C)c1
Temperature: -65 °C
Reaction time: 0.5 h

Procedure:
4.00 g of 1-bromo-4-[(methoxymethoxy)methyl]-2-methylbenzene was dissolved in 40 mL of tetrahydrofuran, to which 11.5 mL of a solution of n-butyllithium in n-hexane (1.56 M) was added dropwise at −65 to −60° C., and then this mixture was stirred for 30 minutes at −65° C. Then, 20 mL of N,N-dimethylformamide was added dropwise thereto at −65 to −40° C., and a temperature of this reaction mixture was raised to room temperature over one hour and was stirred for another one hour at room temperature. Water was added to the reaction mixture and adjusted to pH 5 with 6M hydrochloric acid, followed by addition thereto of ethyl acetate, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=5:1] to yield 1.54 g of 4-[(methoxymethoxy)methyl]-2-methylbenzaldehyde as colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[SH:12][C:13]1[N:14]([CH3:18])[CH:15]=[CH:16][N:17]=1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([S:12][C:13]2[N:14]([CH3:18])[CH:15]=[CH:16][N:17]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Cn1ccnc1S
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Product: Cn1ccnc1Sc1ccc(Cl)cc1[N+](=O)[O-]
Yield: 37.1 %

Procedure:
Starting with 1.92g (10 moles) 2,5-dichloronitrobenzene and 1.14 g (10 mmoles) of 2-mercapto-1-methylimidazole and following the procedure described in Example 1 there was obtained 1.0 g (37%) of the product as yellow prisms, mp 143°-145° C.