Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.Cl.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>CN(C)C=O>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:31][CH2:32][N:33]([C:2]3[C:3]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:4][C:5]4[C:10]([N:11]=3)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=4)[CH2:34][CH2:35]2)=[CH:26][CH:25]=1
Reactant: Clc1ccc(C2CCNCC2)cc1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(c4ccc(Cl)cc4)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), 4-(4-chlorophenyl)piperidine hydrochloride (204.2 mg, 0.88 mmol, 2.00 equiv), DIEA (170.3 mg, 1.32 mmol, 3.00 equiv), N,N-dimethylformamide (4 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The reaction was then quenched by the addition of water. The resulting solution was extracted with 6×15 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50). This resulted in 146.2 mg (71%) of methyl 3-(4-(4-chlorophenyl)piperidin-1-yl)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:14](=[O:17])([O-])[O-].[K+].[K+]>CC#N.C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:1]([N:8]2[CH2:13][CH2:14][O:17][CH2:10][CH2:9]2)=[O:2])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 195 %

Procedure:
Amine preparation: a mixture of 4-morpholinocarbonyl chloride (0.38 ml), 1-BOC-piperazine (552 mg) and potassium carbonate (439 mg) in MeCN (7 mL) was stirred at room temperature for 3 h. The reaction mixture was then diluted with DCM, washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield 4-(morpholine-4-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester (865 mg). Treatment of this compound with HCl in DCM/MeOH yielded the desired compound, which was isolated as the hydrochloride salt.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.C([O-])([O-])=O.[Na+].[Na+].Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(Cl)(Cl)Cl.O>[OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:4]1
Reactant: CCOC(=O)Cl
Reactant: OCC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCCC(CO)C1
Temperature: 10 °C
Yield: 97.9 %

Procedure:
A mixture of 3-hydroxymethyl-piperidine (0.6 mol) and Na2CO3 (130 g) in CHCl3 (600 ml) and water (600 ml) was stirred at 10° C. Ethyl chloroformate (115 g) was added dropwise (temperature was kept at 10° C.). The mixture was stirred until the temperature reached room temperature and the reaction mixture was stirred overnight. Water (500 ml) was added. The organic layer was separated, washed with water, dried, filtered and the solvent was evaporated, yielding 110 g (98%) of (±)-ethyl 3-(hydroxymethyl)-1-piperidinecarboxylate (interm. 17).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[C:4]([CH3:9])[CH:3]=1.[CH3:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[CH3:9][C:4]1[CH:3]=[C:2]([C:14]2[CH:15]=[CH:16][C:11]([CH3:10])=[CH:12][CH:13]=2)[S:6][C:5]=1[CH:7]=[O:8]
Reactant: Cc1cc(Br)sc1C=O
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2cc(C)c(C=O)s2)cc1

Procedure:
5-Bromo-3-methylthiophene-2-carbaldehyde (Spinelli, D. et al., J. Chem. Soc. Perkin Trans. 2, 1972, (12), 1866-9) was reacted with 4-methylphenylboronic acid by method J. The product with the molecular weight of 216.30 (C13H12OS) was obtained in this way; MS (ESI): 217 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH2:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:31])[CH:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([O:29][CH3:30])=[CH:24][CH:25]=3)[CH2:20]2)=[O:13])=[C:5]([N+:32]([O-])=O)[CH:4]=1.C(Cl)Cl>C(O)C>[NH2:32][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[CH:7][C:6]=1[CH2:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:31])[CH:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[CH:24][CH:25]=2)[CH2:20]1)=[O:13]
Reactant: COc1ccc2c(c1)CC(N(C)CCCNC(=O)Cc1cc(OC)c(OC)cc1[N+](=O)[O-])CC2
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc2c(c1)CC(N(C)CCCNC(=O)Cc1cc(OC)c(OC)cc1N)CC2

Procedure:
The title compound here is prepared from 1-[2-(4,5-dimethoxy-2-nitro-phenyl)-1-oxo-ethylamino]-3-[N-methyl-N-(7-methoxy-1,2,3,4-tetrahydro-naphth-2-yl)-amino]-propane (8.2 g, 0.0174 mol) analogously to Example S(c). Yield: 7.4 g. Rf value: 0.2 (alumina, eluant: 98 parts by volume of methylene chloride+2 parts by volume of ethanol).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[C:20]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])=[O:11])[S:7][CH:8]=1.C1(=O)[O:32][C:30](=[O:31])[CH2:29][CH2:28]1>C(Cl)Cl>[CH:22]1([C:20]([C:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:10](=[O:11])[NH:9][C:6]2[S:7][CH:8]=[C:4]([CH2:3][CH2:2][NH:1][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:5]=2)=[O:21])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: O=C1CCC(=O)O1
Reactant: Cc1ccc(NC(=O)Nc2nc(CCN)cs2)c(C(=O)C2CCCC2)c1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)Nc2nc(CCNCCC(=O)O)cs2)c(C(=O)C2CCCC2)c1
Yield: 56.2 %

Procedure:
1-[4-(amino-ethyl)-thiazol-2-yl]-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (0.03 g, 0.08 mmol) and succinic anhydride (0.02 g, 0.16 mmol) in 10 mL DCM were refluxed for 2 h. Reaction was concentrated and purified on silica gel using 5% MeOH/EtOAc to yield the pure product (20 mg, 53%).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.CS(O[CH2:23][C:24]([F:27])([F:26])[CH3:25])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:26][C:24]([F:27])([CH3:25])[CH2:23][O:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[CH:4][CH:3]=1
Reactant: CC(F)(F)COS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(F)(F)COc1ccc(CCNC(=O)OC(C)(C)C)cc1
Temperature: 115 °C
Reaction time: 3 h
Yield: 13.9 %

Procedure:
A mixture of tert-butyl 4-hydroxyphenethylcarbamate (700 g, 2.94 mmol), 2,2-difluoropropyl methanesulfonate (668 mg, 3.84 mmol) and cesium carbonate (1.92 g, 5.88 mmol) in DMF (5 mL) was stirred at 115° C. in a microwave reactor for 3 h. After cooling to room temperature, water was added and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under vacuum to give the crude product, which was purified by preparative thin layer chromatography (22% ethyl acetate in petroleum ether) to afford the title compound (130 mg, 0.41 mmol, 14% yield). MS (ESI) m/z 316.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F:8][CH:9]([F:13])[C:10](O)=[O:11].CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C1C=CN=CC=1)C>[F:8][CH:9]([F:13])[C:10]([N:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]1)=[O:11]
Reactant: Nc1ccccn1
Reactant: O=C(O)C(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(N=c1cccc[nH]1)C(F)F
Temperature: 25 °C
Reaction time: 61 h
Yield: 13.9 %

Procedure:
400 mg (4.26 mmol) of 2-aminopyridine was dissolved in 10 ml of anhydrous dichloromethane, 322 μl (490 mg, 5.11 mmol) of difluoroacetic acid, 982 mg (5.10 mmol) of EDC-HCl and 622 mg (5.11 mmol) of DMAP were added thereto, and the resulting mixture was stirred at room temperature for 61 hours. After the reaction was completed, the reaction solution was diluted with dichloromethane, washed once with water and twice with a 1% HCl aqueous solution, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 102 mg (yield 14%) of 2,2-difluoro-N-(pyridin-2(1H)-ylidene)acetamide.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([CH:22]=O)([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:24])[N:3]1[CH2:25][CH2:26][CH3:27].Cl.[NH2:29][OH:30].CC([O-])=O.[Na+]>CO.O>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:15][CH2:16][C:17]([CH:22]=[N:29][OH:30])([CH2:18][CH2:19]3)[CH2:20][CH2:21]4)[NH:6][C:5]=2[C:4](=[O:24])[N:3]1[CH2:25][CH2:26][CH3:27]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(C=O)(CC3)CC4)nc2n(CCC)c1=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(C34CCC(C=NO)(CC3)CC4)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a stirred solution of 4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbaldehyde (1.6 g, 4.3 mmol) in MeOH (30 ml) was added hydroxylamine hydrochloride (1.2 eq, 5.16 mmol, 356 mg) and a solution of NaOAc (trihydrate, 1.5 eq, 6.45 mmol, 890 mg) in water (10 ml). The resulting mixture was stirred at rt overnight might. The mixture was concentrated in vacuo and the solid residue was suspended in water (15 ml), collected, washed with water and dried to afford a white powder (1.4 g, 84%).
Reaction SMILES: C(O[CH:4]1[NH:9][C:7](=[O:8])[CH2:6][CH2:5]1)C.S(=O)(=O)(O)O.[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)(=O)C>[OH:21][C:15]1[CH:20]=[CH:19][C:18]([CH:4]2[NH:9][C:7](=[O:8])[CH2:6][CH2:5]2)=[CH:17][CH:16]=1
Reactant: Oc1ccccc1
Reactant: CCOC1CCC(=O)N1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C1CCC(c2ccc(O)cc2)N1
Temperature: 25 °C
Reaction time: 48 h
Yield: 18.9 %

Procedure:
At 0° C., 12.9 g of γ-ethoxy-γ-butyrolactam, 10 ml of conc. sulphuric acid and 90 ml of glacial acetic acid were initially charged and admixed, a little at a time, with a total of 18.8 g of phenol. After thawing, the mixture was stirred at room temperature for 2 days. For work-up, the mixture was poured onto ice and extracted three times with ethyl acetate, and the combined extracts were washed once each with water and saturated sodium chloride solution, dried and concentrated. After some time, γ-2-hydroxyphenyl-γ-butyrolactam (XI-2b) of melting point 220° C. (6.4 g, 36% of theory) crystallized from the aqueous phase. The residue obtained after concentration was stirred with a 1:1 mixture of cyclohexane/ethyl acetate and gave, after filtration with suction, 4.65 g of γ-4-hydroxyphenyl-γ-butyrolactam (XI-2a) of melting point 183° C. The filtrate was concentrated. A further 3.35 g (total: 45% of theory) of γ-4-hydroxyphenyl-γ-butyrolactam were obtained by recrystallization from dichloromethane/hexane.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH:13]1[CH2:18][N:17]2[N:19]=[C:20]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:27][CH:26]=3)[C:21]([C:22]([NH2:24])=[O:23])=[C:16]2[NH:15][CH2:14]1.O.NN>CO>[NH2:3][CH2:12][CH:13]1[CH2:18][N:17]2[N:19]=[C:20]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:27][CH:26]=3)[C:21]([C:22]([NH2:24])=[O:23])=[C:16]2[NH:15][CH2:14]1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC(CN1C(=O)c3ccccc3C1=O)C2
Agent: NN
Solvent: O
Solvent: CO
Product: NCC1CNc2c(C(N)=O)c(-c3ccc(Oc4ccccc4)cc3)nn2C1
Temperature: 70 °C
Reaction time: 4 h
Yield: 43.3 %

Procedure:
To a solution of 6-((1,3-dioxoisoindolin-2-yl)methyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (200 mg, 0.40 mmol) in CH3OH (5 mL) was added hydrazine hydrate (1 mL, 80% of aqueous solution). The mixture was stirred at 70° C. under N2 for 4 hr, concentrated and purified by chromatography column on 5 g of silica gel eluting with DCM/CH3OH to afford 63 mg (43%) of 6-(aminomethyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide as colorless oil. MS (ESI) m/e [M+1]+ 363.9.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])C.[F:35][C:36]1[CH:37]=[C:38]([OH:42])[CH:39]=[CH:40][CH:41]=1>>[Cl:20][C:18]1[CH:19]=[C:14]([CH:15]=[C:16]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][C:23]=2[O:42][C:38]2[CH:39]=[CH:40][CH:41]=[C:36]([F:35])[CH:37]=2)[CH:17]=1)[O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([OH:3])=[O:34])=[C:8]([CH3:33])[CH:9]=1
Reactant: CCOC(=O)CCc1ccc(Oc2cc(Cl)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Reactant: Oc1cccc(F)c1
Product: Cc1cc(Oc2cc(Cl)cc(Oc3ccc(C(F)(F)F)cc3Oc3cccc(F)c3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepare by reacting the compound of 3-{4-[3-(2-Bromo-4-trifluoromethyl-phenoxy)-5-chloro-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester with 3-fluorophenol as in Example 45 to afford 0.025 g (23%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C29H21O5F4Cl 560, found 578 and 580 (M+NH4, 100%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[N:14]1([C:2]2[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=2)[C:7]([NH2:9])=[O:8])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: NC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 24 h
Yield: 19.9 %

Procedure:
A mixture of 5-chloro-2-nitrobenzamide (2.0 g, 10.0 mmol), morpholine (2.6 mL, 30 mmol), and K2CO3 (4.1 g, 30 mmol) in DMF (20 ml) was stirred at 110° C. for 24 h. The reaction mixture was poured into water (100 mL) and the resulting precipitate was collected by filtration and recrystallized from ethanol to yield the product as a yellow solid (0.5 g, 20%).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH:26]([CH3:32])[CH2:27][CH2:28][C:29]([OH:31])=[O:30]>C[O-].[Na+].CO>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][CH:26]([CH3:32])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: CC(N)CCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(CCC(=O)O)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 25 °C
Yield: 66.3 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (50 mg, 0.16 mmole) and 4-amino-pentanoic acid (prepared from hydrolysis of 5-methyl-2-pyrrolidinone in 6 N HCl at reflux for 2 days, followed by lyophilization, 274 mg, 2.4 mmole) in 0.5 M sodium methoxide in methanol (4.6 ml) was refluxed for twenty hours before it was cooled to room temperature, concentrated and dissolved in water, extracted with dichloromethane. The remaining aqueous layer was acidified with 1N hydrochloric chloride, extracted with a mixture of dichloromethane and methanol. The organic layer was dried over anhydrous sodium sulfate, concentrated and purified by flash column chromatography on silica gel with a gradient of dichloromethane and methanol to give the title compound as a white solid (43 mg). LC-MS ESI−: 404 (M−1)−.
Reaction SMILES: Br[C:2]1[C:3]([CH3:15])=[C:4]([O:13][CH3:14])[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]=2[C:11]=1[CH3:12].[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1>>[CH3:14][O:13][C:4]1[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]=2[C:11]([CH3:12])=[C:2]([N:26]2[CH2:27][CH2:28][N:23]([C:20]3[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][CH:19]=3)[CH2:24][CH2:25]2)[C:3]=1[CH3:15]
Reactant: COc1c(C)c(Br)c(C)c2c1OC(C)C2
Reactant: Cc1ccc(N2CCNCC2)cc1
Product: COc1c(C)c(N2CCN(c3ccc(C)cc3)CC2)c(C)c2c1OC(C)C2
Yield: 41.7 %

Procedure:
By using 5-bromo-7-methoxy-2,4,6-trimethyl-2,3-dihydro-1-benzofuran (542 mg, 2.0 mmol) synthesized in Reference example 83 and 1-(4-methylphenyl)piperazine (704 mg, 4.0 mmol), the reaction was carried out in the same manner as Example 21 to synthesize the title compound 306 mg (yield 42%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[CH:34][C:35]([C:38]([NH2:40])=[O:39])=[N:36][CH:37]=2)O1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:33]=[CH:34][C:35]([C:38]([NH2:40])=[O:39])=[N:36][CH:37]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC1(C)OB(c2ccc(C(N)=O)nc2)OC1(C)C
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(C(N)=O)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.105 mmol) and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid amide (Stage 14.1.1, 106 mg, 0.427 mmol) to give the title compound as a lightly yellow solid. (HPLC: tR 2.28 min (Method A); M+H=414 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.01 (s, 1H), 8.73-8.67 (m, 1H), 8.22-8.04 (m, 5H), 8.03-7.98 (m, 1H), 7.71-7.61 (m, 2H), 3.92 (s, 3H), 3.59 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: [Li]CCCC.CN(C)CCN(C)C.[O:14]1[CH2:18][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]1=2.[C:23](=[O:25])=[O:24]>CCCCCC.O>[O:14]1[CH2:18][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:22]([C:23]([OH:25])=[O:24])[C:15]1=2
Reactant: c1ccc2c(c1)CCO2
Reactant: O=C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Product: O=C(O)c1cccc2c1OCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.7 %

Procedure:
To a solution of n-BuLi (1.7 M, 123 ml, 0.21 mol) in 400 ml of hexane at room temperature was added 24.3 g (0.21 mol) of N,N,N',N'-tetramethylethylenediamine (TMEDA), followed by a hexane (40 ml) solution of 2,3-dihydrobenzo[b]furan (14) (12.56 g, 0.11 mol). The mixture was stirred under argon at room temperature for 4 hours, and then poured into dry ice (pre-washing with anhydrous ether). After stirring at ambient temperature overnight, the mixture was diluted with water (300 ml), and the layers separated. The aqueous layer was acidified with conc. HCl to pH 1, cooled and the precipitate collected on a filter. This was recrystallized from CH2Cl2 to give 15a (9.43 g, 54.7%) as a white solid, mp 167°-169.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.CO[CH:11]1[CH2:15][CH2:14][CH:13](OC)O1>C(O)(=O)C>[Cl:1][C:2]1[C:7]([N:8]2[CH:11]=[CH:15][CH:14]=[CH:13]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COC1CCC(OC)O1
Reactant: Nc1cccnc1Cl
Solvent: CC(=O)O
Product: Clc1ncccc1-n1cccc1
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of acetic acid (25 ml), 2-chloro-3-aminopyridine (5.1 g, 0.04 m) and 2,5-dimethoxytetrahydrofuran (0.05 m) was heated to reflux. After two hours, the mixture was concentrated to dryness, treated with ice and neutralized with saturate Na2CO3 solution. The aqueous layer was extracted with CHCl3 (3×100 ml). The organic extract was dried over Na2SO4, filtered and concentrated to dryness. The residue was distilled to yield 5.3 g (75% yield) of 2-chloro-3-(1-pyrrolyl) pyridine; b.p=95°-100° at 0.5 mm.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:14]OS(C)(=O)=O)[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C-:22]#[N:23].[Na+]>CS(C)=O.O>[F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:14][C:22]#[N:23])[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: [C-]#N
Reactant: CS(=O)(=O)OCC1(c2ccc(C(F)(F)F)cc2)CCCC1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCC1(c2ccc(C(F)(F)F)cc2)CCCC1
Temperature: 140 °C
Reaction time: 6 h
Yield: 60 %

Procedure:
To a stirred solution of methanesulfonic acid 1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl ester (240) (7 g, 21.73 mmol) in dimethyl sulfoxide (200 mL) were added KI (0.361 g, 2.17 mmol) and NaCN (1.6 g, 32.6 mmol). The reaction mixture was then stirred at 140° C. for 6 h. After completion of the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate (2×300 mL) and the organic layer was washed with water and brine. It was then dried over Na2SO4 and concentrated. The crude product was purified by 100-200 silica column chromatography using 5% ethyl acetate in hexane as the eluent to give [1-(4-trifluoromethyl-phenyl)-cyclopentyl]-acetonitrile (241) (3.3 g, 60%) as a colorless thick liquid.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.C(O)(=O)C.[C:9]([O:13][C:14]([N:16]1[CH:20]=[CH:19][C:18]([NH2:21])=[N:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:9]([O:13][C:14]([N:16]1[CH:20]=[CH:19][C:18]([NH:21][CH:2]([CH3:4])[CH3:1])=[N:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)=O
Reactant: CC(C)(C)OC(=O)n1ccc(N)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)Nc1ccn(C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of acetone (0.1 mL, 1.4 mmol), acetic acid (0.078 mL, 1.43 mmol) and 3-amino-pyrazole-1-carboxylic acid tert-butyl ester (200 mg, 1.1 mmol) in DCM (5 mL) was stirred at RT for 1 hour. Sodium triacetoxyborohydride (467 mg, 2.2 mmol) was added and the mixture stirred overnight. The mixture was extracted with ethyl acetate, washed with water, dried and concentrated. The residue was purified by flash column to give 3-Isopropylamino-pyrazole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:20]=[CH:19][C:8]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1.O>C(O)C>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([CH:9]([C:8]2[CH:19]=[CH:20][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[OH:10])=[CH:16][CH:15]=1
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 99.2 %

Procedure:
1.03 g of sodium borohydride was added to 4.84 g of 4,4'-dimethoxybenzophenone in 80 ml of ethanol, followed by stirring for 7 hours at room temperature. Next, after adding water and stirring for 30 minutes, the solution was concentrated to roughly 20 ml. Moreover, ethyl acetate and water were added and after extracting with ethyl acetate (50 ml×3), the product was washed with saturated brine and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 4.84 g of the target compound. Yield: 99%