Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:13][CH3:14])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([Cl:12])[CH:8]=[CH:7][CH:6]=2.[Br:15]N1C(C)(C)C(=O)N(Br)C1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:15][CH:13]([C:3]1[C:2]([Cl:1])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:12])[N:4]=1)[CH3:14]
Reactant: CCc1nc2cccc(Cl)c2nc1Cl
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1nc2cccc(Cl)c2nc1Cl
Temperature: 25 °C
Yield: 129 %

Procedure:
3,5-Dichloro-2-ethylquinoxaline (1.10 Kg, 4.84 mol) was dissolved in CCl4 (4.4 L) at rt. 1,3-dibromo-5,5-dimethylhydantoin (762 g, 2.66 mol) and benzoyl peroxide (116 g, 0.48 mol) were then added. The resulting suspension was heated at reflux for 2 h. At this time LC-MS analysis showed that the reaction was complete. After cooling to rt white crystals formed in the reaction vessel. The white crystals were collected by filtration, washed with saturated aqueous NaHCO3 (3×5 L), and dried under high vacuum to give 2-(1-bromoethyl)-3,5-dichloroquinoxaline as a white solid (1.05 Kg). 1H NMR (DMSO-d6) δ ppm 8.04-8.12 (m, 2H), 7.78-7.90 (m, 1H), 5.76-5.84 (m, 1H), 2.09 (d, J=6.7 Hz, 3H). Mass Spectrum (ESI) m/z=304.8 [(M+1) (79Br)], 306.9 [(M+1) (81Br)].
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]1[CH:14]1[CH2:16][CH:15]1[C:17](O)=O)[CH3:2].CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:33][N:34]1[C:39]([CH3:40])=[CH:38][N:37]=[C:36]([CH3:41])[C:35]1=[NH2+:42].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]1[CH:14]1[CH2:16][CH:15]1[C:17]1[N:42]=[C:35]2[C:36]([CH3:41])=[N:37][CH:38]=[C:39]([CH3:40])[N:34]2[N:33]=1)[CH3:2]
Reactant: Cc1ncc(C)n(N)c1=[NH2+]
Reactant: CCn1cc(-c2ccccc2)nc1C1CC1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCn1cc(-c2ccccc2)nc1C1CC1c1nc2c(C)ncc(C)n2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
To a solution of 2-(1-ethyl-4-phenyl-1H-imidazol-2-yl)cyclopropanecarboxylic acid (103 mg, 0.4 mmol) in DMF (3.0 mL) was added 1-amino-3,6-dimethylpyrazin-2(1H)-iminium 2,4,6-trimethylbenzenesulfonate (135 mg, 0.400 mmol) followed by O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (128 mg, 0.400 mmol) and triethylamine (0.277 mL, 2.000 mmol) at rt. After 1 h stirring at rt, the reaction mixture was heated at 70° C. for 15 h. The crude was purified by prep HPLC using Phenomenex column and MeOH—H2O-TFA as eluent (25% to 100% over 12 min gradient; 40 mL/min flow). Collected the pure fractions and removed solvent. Prepared HCl salt by adding MeOH (3 mL) and 1.0 M HCl (3 mL) and removing solvent. Obtained 2-(2-(1-ethyl-4-phenyl-1H-imidazol-2-yl)cyclopropyl)-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine, 1.0HCl (85 mg, 0.202 mmol, 50.6% yield) as a white solid. 1H NMR (500 MHz, METHANOL-d4) δ 8.13 (d, J=0.9 Hz, 1H), 7.99 (s, 1H), 7.80-7.78 (m, 1H), 7.77-7.75 (m, 1H), 7.58-7.50 (m, 2H), 7.40-7.22 (m, 1H), 4.38 (q, J=7.3 Hz, 2H), 3.29-3.25 (m, 1H), 3.10-3.08 (m, 1H), 2.98 (s, 3H), 2.85 (s, 3H), 2.21-2.18 (m, 2H), 1.60 (t, J=7.4 Hz, 3H); MS (ESI) 359 (M+H); Rf=1.99 (Condition A).
Reaction SMILES: [CH3:1][N:2]([C@@H:9]([C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:13]=1)[CH:10]=[CH2:11])[S@:3]([C:5]([CH3:8])([CH3:7])[CH3:6])=[O:4].[OH-:31].[Na+].OO>C1COCC1>[OH:31][C:14]1[CH:13]=[C:12]([C@H:9]([N:2]([CH3:1])[S@:3]([C:5]([CH3:8])([CH3:7])[CH3:6])=[O:4])[CH:10]=[CH2:11])[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=1
Reactant: [OH-]
Reactant: C=C[C@H](c1cc(B2OC(C)(C)C(C)(C)O2)cc(C(F)(F)F)c1)N(C)[S@@](=O)C(C)(C)C
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C[C@H](c1cc(O)cc(C(F)(F)F)c1)N(C)[S@@](=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
To a solution of (S)-N,2-dimethyl-N-((R)-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)allyl)propane-2-sulfinamide (800 mg, 1.8 mmol) and NaOH (144 mg, 3.6 mmol) in THF (10 mL), was added H2O2 (122 mg, 3.6 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. After quenched with water, the resulting mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4. and then concentrated to give the title compound (500 mg, yield: 83%); m/z (ES+): 336 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:24])[CH:3]=1.[CH3:25][N:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[C:4]([CH3:24])=[CH:3][C:2]([N:28]4[CH2:29][CH2:30][N:26]([CH3:25])[C:27]4=[O:31])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3cnc(Br)cc3C)CC2)c(C)c1
Reactant: CN1CCNC1=O
Product: Cc1cnc(N2CCN(C(=O)c3cnc(N4CCN(C)C4=O)cc3C)CC2)c(C)c1
Yield: 78.2 %

Procedure:
Using (6-bromo-4-methylpyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (195 mg) described in Preparation Example 228 and 1-methylimidazolidin-2-one (75 mg) and by the reaction and treatment in the same manner as in Example 511, 1-{5-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-4-methylpyridin-2-yl}-3-methylimidazolidin-2-one (160 mg) was obtained. The obtained 1-{5-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-4-methylpyridin-2-yl}-3-methylimidazolidin-2-one (160 mg) was dissolved in ethyl acetate, 4N hydrogen chloride/ethyl acetate (0.2 mL) was added, and the precipitate was collected by filtration to give the title compound (98 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:21][CH3:22])[C:6]2[O:10][C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:20]=1)#[N:2].[F:23][C:24]([F:40])([F:39])[C:25]1[CH:26]=[CH:27][C:28]([N:31]2[CH2:36][CH2:35][CH:34]([CH2:37][NH2:38])[CH2:33][CH2:32]2)=[N:29][CH:30]=1>>[C:1]([C:3]1[CH:4]=[C:5]([S:21][CH3:22])[C:6]2[O:10][C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([NH:38][CH2:37][CH:34]4[CH2:35][CH2:36][N:31]([C:28]5[CH:27]=[CH:26][C:25]([C:24]([F:40])([F:39])[F:23])=[CH:30][N:29]=5)[CH2:32][CH2:33]4)=[O:17])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:20]=1)#[N:2]
Reactant: CSc1cc(C#N)cc2nc(-c3ccc(C(=O)O)cc3)oc12
Reactant: NCC1CCN(c2ccc(C(F)(F)F)cn2)CC1
Product: CSc1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCN(c5ccc(C(F)(F)F)cn5)CC4)cc3)oc12

Procedure:
The title compound was prepared from 4-[5-cyano-7-(methylthio)-1,3-benzoxazol-2-yl]benzoic acid and 1-{1-[5-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}methanamine (INTERMEDIATE 5) by a procedure analogous to that described in EXAMPLE 35. Mass spectrum (ESI) 552.0 (M+1). 1H NMR (500 MHz, CDCl3) δ: 8.38 (s, 1H), 8.35 (d, J=8.3 Hz, 2H), 7.94 (d, J=8.3 Hz, 2H), 7.89 (s, 1H), 7.60 (dd, J=2.3 Hz, J=9.2 Hz, 1H), 7.45 (s, 1H), 6.65 (d, J=9.1 Hz, 1H), 6.32 (t, J=5.9 Hz, 1H), 4.46 (d, J=13.3 Hz, 2H), 3.44 (t, J=6.4 Hz, 2H), 2.94 (m, 2H), 2.70 (s, 3H), 1.99 (m, 1H), 1.90 (br d, J=11.6 Hz, 2H), 1.34 (m, 2H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][OH:12].[H-].[Na+].[Br:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20](Br)[CH:21]=1.O>CN(C)C=O>[Br:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH:21]=1
Reactant: Brc1cncc(Br)c1
Reactant: OCc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cncc(OCc2ccc3ccccc3c2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 44.6 %

Procedure:
A solution of 2-naphthylmethanol (1.58 g) in dimethylformamide (20 ml) was added to a slurry of sodium hydride (55% w/w dispersion in oil, 0.48 g) in dimethylformamide (2 ml) and the mixture was stirred at ambient temperature for 20 minutes. 3,5-Dibromopyridine (2.37 g) was added and the solution was heated to 120° C. for 5 hours and then allowed to stand at ambient temperature overnight. The mixture was poured into water (160 ml) and extracted with ethyl acetate (3×50 ml). The combined extracts were washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with increasingly polar mixtures of petrol (b.p. 60°-80° C.) and ethyl acetate to give 3-bromo-5-(naphth-2-ylmethoxy)pyridine (1.4 g), m.p. 108°-109° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[CH2:13]([Mg]Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[NH4+]>C1COCC1.CCOCC>[CH2:13]([C:5]1([OH:12])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[NH:7][C:6]1=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Cl)cc2C1(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 10 g of 5-chloroisatin in 150 ml of THF is cooled to +4° C., 220 ml of a 1M solution of benzylmagnesium chloride in ether are added dropwise and the mixture is stirred for 3 hours at RT. 500 ml of a saturated solution of ammonium chloride are added and the solvents are concentrated under vacuum. The aqueous phase is extracted with AcOEt, the organic phase is washed with a saturated solution of NaCl and with water and dried over sodium sulfate and the solvent is evaporated off under vacuum to give 5.6 g of the expected product after crystallization from a THF/AcOEt mixture. M.p.=204°-205° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH2:3][CH2:2]1.[CH2:21]1[CH:23]([CH:24](O)C#N)[CH2:22]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:23]1([CH2:24][N:1]2[CH2:2][CH2:3][CH:4]([CH2:7][CH:8]3[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]3)[CH2:5][CH2:6]2)[CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC(CC2CCNCC2)CC1
Reactant: N#CC(O)C1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CC2CCN(CC3CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1-Dimethylethyl 4-(4-piperidinylmethyl)-1-piperidinecarboxylate (may be prepared as described in Description 2) (2.0 g), cyclopropyl carboxaldehyde (1.6 ml) and triethylamine (1.99 ml) were stirred in dichloromethane (70 ml) at room temperature. After 10 min sodium triacetoxyborohydride (3.1 g) was added and the reaction was stirred at room temperature overnight. The reaction mixture was washed with saturated potassium carbonate solution (2×50 ml), saturated sodium hydrogen carbonate solution (2×50 ml) and saturated brine (50 ml). The organic phase was dried (MgSO4) and evaporated to give the title compound (D9) (2.0 g).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)[O:6]CCO1.[C:17]1(/[CH:23]=[CH:24]/[C:25](O)=[O:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[O:6]=[C:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][C:13]([NH:16][C:25](=[O:26])/[CH:24]=[CH:23]/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:12]1
Reactant: O=C(O)/C=C/c1ccccc1
Reactant: CC1(CCCCn2ccc(N)n2)OCCO1
Product: CC(=O)CCCCn1ccc(NC(=O)/C=C/c2ccccc2)n1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-3-ylamine and (E)-3-phenyl-acrylic acid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:20])=[CH:4][C:5]2[O:19][CH2:18][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]3=[O:17])[C:6]=2[CH:7]=1.N1C2C(=CC=CC=2)[C:23]2([C:33]3=[CH:34][C:35]4[O:39][CH2:38]O[C:36]=4C=C3OC2)C1=O.BrCC1CCCCO1.ClC1SN=C(CCl)N=1>>[CH3:1][C:2]1[C:3]([CH3:20])=[CH:4][C:5]2[O:19][CH2:18][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:36][CH:35]4[CH2:34][CH2:33][CH2:23][CH2:38][O:39]4)[C:9]3=[O:17])[C:6]=2[CH:7]=1
Reactant: Cc1cc2c(cc1C)C1(CO2)C(=O)Nc2ccccc21
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: BrCC1CCCCO1
Agent: ClCc1nsc(Cl)n1
Product: Cc1cc2c(cc1C)C1(CO2)C(=O)N(CC2CCCCO2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 6 and making non-critical variations using 5,6-dimethylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)-tetrahydro-2H-pyran to replace 5-chloro-3-(chloromethyl)-1,2,4-thiadiazole, 5,6-dimethyl-1′-(tetrahydro-2H-pyran-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (72%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.28 (dd, J=7.6, 7.6 Hz, 1H), 7.15-6.97 (m, 1H), 6.75 (s, 1H), 6.47 (d, J=4.9 Hz, 1H), 4.89 (dd, J=8.9, 1.8 Hz, 1H), 4.65 (dd, J=8.9, 2.9 Hz, 1H), 4.03-3.60 (m, 2H), 3.44-3.32 (m, 1H), 2.19 (s, 3H), 2.05 (s, 3H), 1.92-1.80 (m, 1H), 1.73-1.27 (m, 1H); 13C NMR (75 MHz, CDCl3) δ178.0, 159.1, 143.2, 138.3, 132.6, 129.3, 128.6, 126.3, 123.9, 123.6, 123.1, 111.4, 109.7, 79.7, 75.6, 68.4, 58.0, 45.7, 29.6, 25.8, 23.0, 20.3, 19.4; MS (ES+) m/z 364.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9]C)=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH2:17][CH3:18])[N:13]=[N:12]1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH2:17][CH3:18])[N:13]=[N:12]1
Reactant: CCn1nnn(-c2cc(OC)c(Cl)cc2Cl)c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCn1nnn(-c2cc(O)c(Cl)cc2Cl)c1=O
Yield: 84.1 %

Procedure:
In the manner of Example 11, Step A, the reaction of 1.56 g (0.0054 mole) of 1-(2,4-dichloro-5-methoxyphenyl)-1,4-dihydro-4-ethyl-5H-tetrazol-5-one (compound 7) and 4.06 g (0.016 mole) of boron tribromide in 20 mL of methylene chloride produced 1.25 g of 1-(2,4-dichloro-5-hydroxyphenyl)-1,4-dihydro-4-ethyl-5H-tetrazol-5-one, mp 149°-150° C.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:17](=[O:20])[CH2:18][CH2:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15][CH3:16])[CH:10]=3.[CH:21]1[N:26]=[CH:25][N:24]=[CH:23][C:22]=1[CH:27]=O.[OH-].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:17](=[O:20])[C:18]([CH2:27][C:22]5[CH:23]=[N:24][CH:25]=[N:26][CH:21]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15][CH3:16])[CH:10]=3
Reactant: O=Cc1cncnc1
Reactant: COc1cc2c3c(c1)c1ccc(Br)cc1n3CCC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc2c(=O)c(Cc3cncnc3)cn3c4cc(Br)ccc4c(c1)c23
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.6 %

Procedure:
9-bromo-5,6-dihydro-2-methoxy-4H-pyrido[3,2,1-jk]carbazole-4-one (300 mg) obtained in Example 101, step 6 was suspended in ethanol (17 ml), and pyrimidine-5-carboxyaldehyde (157 mg) prepared by the procedure described in Syn. Commun. 24, 253 (1994) and sodium hydroxide (291 mg) dissolved in water (1.7 ml) were added to the suspension at room temperature. The mixture was stirred at room temperature for 12 hours, and approximately half of the solvent was evaporated under reduced pressure. The crystals precipitated were recovered by filtration, and the residue was purified by alumina flash column chromatography (eluent: methylene chloride containing 4% methanol) to obtain the title compound (300 mg, 79%).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[CH3:8][O:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:30][C:31]([F:41])([F:40])[C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1.O>C1COCC1>[CH3:8][O:9][CH:10]=[CH:36][C:35]1[CH:38]=[CH:39][C:32]([C:31]([F:41])([F:40])[F:30])=[CH:33][CH:34]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC=Cc1ccc(C(F)(F)F)cc1
Reaction time: 1 h
Yield: 60.4 %

Procedure:
Potassium tert butoxide (13.46 g, 0.120 mol) was added to methoxymethyl triphenyl phosphonium chloride (38.30 g, 0.112 mol) in 150 ml dry THF at −30° C. under argon atmosphere and stirred for 1 h. 4-trifluoromethylbenzaldehyde (15.0 g, 0.086 mol) in 60 ml THF was added dropwise at the same temperature and stirring continued for 3 h at room temperature. The reaction mixture was treated with 100 ml water, 150 ml petroleum ether and filtered through celite. Organic layer was separated and the aq. layer was extracted with petroleum ether (2×100 ml). Combined organic layer was washed with brine and dried over sodium sulfate. Solvent evaporation under reduced pressure followed by purification over silica gel using petroleum ether as eluent afforded (10.5 g) of the sub-title compound as a colorless liquid. This was directly taken for next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]2[NH:6][C:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=3)=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>CN(C)C=O>[CH2:29]([O:28][C:26]([N:8]1[C:4]2[CH:3]=[C:2]([Cl:1])[C:21]([Cl:22])=[CH:20][C:5]=2[N:6]=[C:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=1)=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc3cc(Cl)c(Cl)cc3n2C(=O)OCc2ccccc2)cc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 43.8 %

Procedure:
Dimethylformamide (25 mL) was added to 5,6-dichloro-2-(4-methoxy-3-nitro-phenyl)-1H-benzoimidazole (1.01 g, 3 mmol) from Step A. As the mixture stirred, sodium hydride (0.168 g, 4.2 mmol) was gradually added. After 3 hours, benzyl chloroformate (0.857 mL, 6 mmol) was added dropwise to the mixture. The reaction mixture was stirred overnight and then was partitioned between water (1,000 mL) and ethyl acetate (500 mL). The solvent was removed on the rotary evaporator and the residue triturated with 4:1 hexane:ethyl acetate to give the product (0.62 g), mp 212-214° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[NH:5][N:4]=1.C(N(CC)CC)C.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>CS(C)=O>[C:6]1(=[O:13])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([CH:2]=[O:1])=[N:4][NH:5]1
Reactant: O=c1[nH]nc(CO)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=Cc1n[nH]c(=O)c2ccccc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under N2 atmosphere, 50 g (284 mmol) 4-hydroxymethylphthalazin-1(2H)-one is dissolved in 900 ml DMSO and 119 ml (851 mmol) triethylamine. A solution of 90.3 g (567 mmol) sulfur trioxide pyridine complex in 733 ml DMSO is added and the mixture stirred for about 2 h. After the reaction is completed (TLC control), the mixture is poured onto a mixture of 2 l 5% Na2CO3 solution with 2 kg ice and 5 l EtOAc and then stirred. The aqueous phase of the resulting suspension is separated off and twice extracted with 2 l EtOAc. The first organic phase comprises crystalline product, this is filtered off and washed with water and EtOAc. The organic phase is separated off from the filtrate and, together with the second and third organic phase, washed with water and brine, dried (Na2SO4) and evaporated. The evaporation residue is combined with the above crystalline product, stirred in EtOAc, and hexane added before being filtered. This yields the title compound; m.p. 262-265° C.; 1H-NMR (DMSO-d6) 9.82 (s, HCO), 8.88 (d, 1H), 8.27 (d, 1H), 7.95 (m, 2H); FAB-MS (M+H)+=175, (M+H+MeOH)+=207.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH3:11].[Cu][C:13]#[N:14]>CCOC(C)=O>[CH3:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:13]#[N:14])[CH:3]=2)[NH:7][CH:6]=1
Reactant: N#C[Cu]
Reactant: Cc1c[nH]c2ccc(Br)cc12
Solvent: CCOC(C)=O
Product: Cc1c[nH]c2ccc(C#N)cc12
Temperature: 200 °C
Reaction time: 5 h
Yield: 81.1 %

Procedure:
A vessel was charged with 5-bromo-3-methyl-1H-indole (1.06 g, 5.05 mmol), copper (I) cyanide (542.83 mg, 6.0608 mmol), and degassed NMP (10 mL), sealed and heated to 200° C. with stirring for 5 h, then at 110° C. for 16 h. The cooled reaction was diluted with EtOAc and the organic layer was washed sequentially with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with an EtOAc/heptane gradient (0 to 100% EtOAc) to afford 640 mg (81.1%) of 3-methyl-1H-indole-5-carbonitrile (192): 1H NMR (400 MHz, CDCl3): δ 8.22 (br s, 1H), 7.91 (s, 1H), 7.42-7.35 (m, 2H), 7.07 (s, 1H), 2.32 (s, 3H).
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:17]1[CH2:21][CH2:20][C:19]2[CH:22]=[C:23]([CH:26]=O)[CH:24]=[CH:25][C:18]1=2.CS(O)(=O)=O>CCOCC>[CH:1]1([N:6]2[C:10]3=[N:11][C:26]([C:23]4[CH:24]=[CH:25][C:18]5[O:17][CH2:21][CH2:20][C:19]=5[CH:22]=4)=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: O=Cc1ccc2c(c1)CCO2
Agent: CS(=O)(=O)O
Solvent: CCOCC
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccc4c(c3)CCO4)nc(=O)c1-2
Reaction time: 48 h
Yield: 52.3 %

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2.0 g, 9.0 mmol), 2,3-dihydrobenzo[b]furan-5-carboxaldehyde (1.73 g, 11.7 mmol), methanesulfonic acid (0.25 ml) and xylenes (50 ml) was refluxed for 20 hours and then allowed to stand for about 2 days. The reaction mixture was diluted with ether and the product was collected by filtration and dried to afford 1.65 g (52%) of 1-cyclopentyl-3-ethyl-6-(2,3-dihydrobenzo[b]furan-5-yl)pyrazolo[3,4-d]pyrimidin-4-one 1/10 hydrate, m.p. 253°-254° C.
Reaction SMILES: CC1C(N2CCN(C(C3C=CC(I)=CC=3)=O)CC2)=NC=C(C)C=1.C(C1CN(CC2C=CC(OC)=CC=2)C(=O)N1)C.[CH3:41][C:42]1[C:43]([N:49]2[CH2:54][CH2:53][N:52]([C:55]([C:57]3[CH:62]=[CH:61][C:60]([N:63]4[CH:67]([CH2:68][CH3:69])[CH2:66][N:65](CC5C=CC(OC)=CC=5)[C:64]4=[O:79])=[CH:59][CH:58]=3)=[O:56])[CH2:51][CH2:50]2)=[N:44][CH:45]=[C:46]([CH3:48])[CH:47]=1>>[CH3:41][C:42]1[C:43]([N:49]2[CH2:50][CH2:51][N:52]([C:55]([C:57]3[CH:58]=[CH:59][C:60]([N:63]4[CH:67]([CH2:68][CH3:69])[CH2:66][NH:65][C:64]4=[O:79])=[CH:61][CH:62]=3)=[O:56])[CH2:53][CH2:54]2)=[N:44][CH:45]=[C:46]([CH3:48])[CH:47]=1
Reactant: CCC1CN(Cc2ccc(OC)cc2)C(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)cc1
Agent: CCC1CN(Cc2ccc(OC)cc2)C(=O)N1
Agent: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: CCC1CNC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)cc1

Procedure:
Using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (253 mg) described in Preparation Example 113 and 4-ethyl-1-(4-methoxybenzyl)imidazolidin-2-one (140 mg) described in Preparation Example 208 and by the reaction and treatment in the same manner as in Example 506, the title compound (162 mg) was obtained via 3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-4-ethyl-1-(4-methoxybenzyl)imidazolidin-2-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][CH2:10][OH:11])=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CS(C)=O>[CH3:1][O:2][C:3]1[C:8]([CH2:9][CH:10]=[O:11])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ncccc1CC=O
Reaction time: 0.5 h
Yield: 16.9 %

Procedure:
A solution of 2.7 g of pyridine-sulfur trioxide complex dissolved in DMSO was added dropwise at 20° C. or less to a solution of 1.2 g of 2-(2-methoxy-3-pyridyl)ethanol and 4.8 ml of triethylamine dissolved in DMSO. After stirring for 0.5 hour, a cooled sodium bicarbonate was added thereto, and the mixture was extracted with ethyl acetate. After drying over sodium sulfate, the solvent was evaporated. The residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1), to give 200 mg of a yellow oil.