Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C@H:13]([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:10][C@H:9]1[CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:31]1([CH:34]2[CH2:38][C:37]3([CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)[C:36](=[O:44])[O:35]2)[CH2:33][CH2:32]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[CH:31]1([CH:34]2[CH2:38][C:37]3([CH2:43][CH2:42][N:41]([C:26]([C:25]4[CH:29]=[CH:30][C:22]([CH2:21][C@@H:9]5[CH2:10][CH2:11][C@H:12]([C@H:13]([OH:20])[C:14]6[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=6)[N:8]5[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:23][CH:24]=4)=[O:27])[CH2:40][CH2:39]3)[C:36](=[O:44])[O:35]2)[CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)O)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Reactant: O=C1OC(C2CC2)CC12CCNCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)N3CCC4(CC3)CC(C3CC3)OC4=O)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
To a solution of 0.16 g (0.39 mmol) of 4-({(2S,5R)-1-(tert-butoxycarbonyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)benzoic acid (i-1) in 2 ml anhydrous DMF at ambient temperature was added 0.14 g (0.58 mmol) 3-cyclopropyl-2-oxa-8-azaspiro[4.5]decan-1-one from the above, followed by 0.12 g (0.58 mmol) EDCl, 0.08 g (0.58 mmol) HOBt, and 0.34 ml (1.94 mmol) N,N-diisopropylethylamine. The solution was stirred for 2 h at ambient temperature. The solution was poured into water (20 ml) and extracted with ethyl acetate (2×20 ml). The combined organic layers were extracted with brine (20 ml). It was dried over magnesium sulfate and concentrated. The residue was purified using a Biotage Horizon® system (50-100% ethyl acetate/hexanes mixture) to give 0.135 g of the title compounds as a mixture of diastereomers in a 50:50 ratio. The two diastereomers were separated by chiral HPLC employing a Daicel CHIRALPAK® OD® column (eluent: 40% IPA in Heptane). The first eluting diastereomer was designated as Isomer 1 and is colorless solid (0.030 g, 16%). LC/MS 589.3 (M+1). The second eluting diastereomer was designated as Isomer 2 and is a colorless solid (0.025 g, 13%). LC/MS 589.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.C([Li])CCC.CN([CH:17]=[O:18])C.[Cl-].[NH4+]>C(OCC)C.O>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([CH:7]=1)[CH:17]=[O:18]
Reactant: CN(C)C=O
Reactant: Brc1cncc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: O=Cc1cncc(Br)c1
Reaction time: 0.5 h
Yield: 40 %

Procedure:
In diethyl ether (42.0 mL) was dissolved 3,5-dibromopyridine (1.00 g, 4.22 mmol). n-Butyllithium (2.76 mol/L solution in n-hexane, 1.61 mL, 4.43 mmol) was added dropwise at −78° C., and the mixture was stirred at the same temperature for 30 minutes. Further, DMF (0.98 mL, 12.7 mmol) was added and the mixture was stirred for 3 hours allowing the temperature to rise slowly to room temperature. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3) to give 5-bromonicotinaldehyde (314 mg, 40%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([C:9]#N)[CH:4]=1.[CH:11]1([Mg]Br)[CH2:13][CH2:12]1.Cl.C(=O)([O-])[OH:18].[Na+]>C1COCC1>[CH:11]1([C:9]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[N:8]=[CH:7][N:6]=2)=[O:18])[CH2:13][CH2:12]1
Reactant: O=C([O-])O
Reactant: Br[Mg]C1CC1
Reactant: COc1cc(C#N)ncn1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C(=O)C2CC2)ncn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, to a solution of 6-methoxypyrimidine-4-carbonitrile (6.00 g) in THF (120 mL) was added dropwise a 0.52 M solution of cyclopropylmagnesium bromide in THF (215 mL) at 0° C., and the mixture was stirred at 0° C. for 1 hr. 6N Hydrochloric acid (60 mL) was added to the reaction mixture at 0° C., and the mixture was stirred at room temperature for 15 min. The reaction mixture was neutralized with sodium hydrogen carbonate (35.0 g), and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product of the title compound as a brown oil. This compound was used for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=O)[NH:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.CI.[C:23](=[O:26])([O-])[O-].[Cs+].[Cs+].[C:29](#N)C.CN(C=O)C>Cl>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:14](=[O:19])[N:15]([CH3:29])[N:16]([CH3:17])[C:23]3=[O:26])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(-n2c(=O)[nH][nH]c2=O)cn1
Reactant: CC#N
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1noc(C)c1Cn1cc(-n2c(=O)n(C)n(C)c2=O)cn1
Yield: 80 %

Procedure:
4-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1,2,4-triazolidine-3,5-dione (example 10-68) (100 mg, 0.36 mmol), methyl iodide (141 mg, 1 mmol), and cesium carbonate (325 mg, 1 mmol) were stirred in a 2/1 mixture of acetonitrile/DMF (5 mL) at ambient temperature for 2 hours. The mixture was diluted with aqueous 1N HCl (100 mL) and extracted with ethyl acetate (3×, 50 mL). The combined organic extracts were dried over sodium sulfate, concentrated and the crude residue taken up in MeOH and purified by reversed phase HPLC (5 to 95% acetonitrile in H2O: 25 minute gradient). The pure fractions were pooled and concentrated to afford 4-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1,2-dimethyl-1,2,4-triazolidine-3,5-dione (89 mg, 80%) as a clear semi-solid. 1H NMR (CDCl3, 400 MHz): δ2.18 (s, 3H), 2.41 (s, 3H), 3.22 (s, 6H), 5.04 (s, 2H), 7.88 (s, 1H), 8.03 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.6 μM.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([OH:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].[C:35](OC)(=[O:39])[C:36](C)=[CH2:37].C[O-].[Na+]>>[C:11]([C:7]1[CH:8]=[C:9]([CH2:37][CH2:36][C:35]([O:34][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:39])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: C=C(C)C(=O)OC
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: C[O-]
Agent: [Na+]
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
DE-A-23 64 121 discloses a further process in which, for example, 2,6-di-tert-butylphenol, n-octadecylalcohol and methyl methacrylate can be reacted directly in the presence of sodium methoxide to give n-octadecyl β-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=1[N+:23]([O-])=O.[F:26][C:27]1[CH:28]=[CH:29][C:30]([O:37][CH3:38])=[C:31]([C:33](=[N:35]O)[NH2:34])[CH:32]=1.CCN(C(C)C)C(C)C>>[F:26][C:27]1[CH:28]=[CH:29][C:30]([O:37][CH3:38])=[C:31]([C:33]2[N:34]=[C:18]([C:17]3[CH:21]=[CH:22][C:14]([N:9]4[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]4[CH3:7])=[C:15]([CH:16]=3)[NH2:23])[O:20][N:35]=2)[CH:32]=1
Reactant: COc1ccc(F)cc1C(N)=NO
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)cc1-c1noc(-c2ccc(N3CCCCC3C)c(N)c2)n1

Procedure:
Oxalyl chloride (190 mg; 1.5 mmol; 3 eq.), Intermediate 8 (132 mg; 0.5 mmol; 1 eq.), Intermediate 23 (92 mg; 0.5 mmol; 1 eq.) and DIEA (194 mg; 1.5 mmol; 3 eq.) were reacted according to general procedure 2. After purification by column chromatography c-hexane/ethyl acetate, 80/20), the residue was taken up in EtOH (20 mL) and stannous chloride dihydrate (564 mg; 2.5 mmol; 5 eq.) was added. The resulting mixture was stirred at reflux for 3 hours then concentrated in vacuo. The residue was partitioned between NaOH 0.05M and ethyl acetate. The phases were separated and the organic layer was washed with brine, dried over magnesium and concentrated in vacuo. Purification by column chromatography (c-hexane/ethyl acetate, 75/25) afforded the title compound as an off-white solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[NH2:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:16]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][C:24]1=[O:30])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1C=CC=CC=1>[CH2:16]([N:23]1[CH2:28][CH2:27][C:26]([NH:10][C:9]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:7]([O:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:8]=2)=[CH:25][C:24]1=[O:30])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccc(N)cc1OC1CCCC1
Reactant: O=C1CCN(Cc2ccccc2)C(=O)C1
Solvent: c1ccccc1
Product: COc1ccc(NC2=CC(=O)N(Cc3ccccc3)CC2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80.3 %

Procedure:
0.50 g (2.41 mmole) of 3-cyclopentyloxy-4-methoxyaniline produced in Example 1(2) and 0.49 g (2.41 mmole) of 1-benzyl-2,4-dioxopiperidine were dissolved in 20 ml of benzene and the mixture was stirred at room temperature for 20 hours. After the reaction, the precipitated crystal was collected by filtration and washed with benzene, then was dried in vacuo to obtain the title compound 0.76 g (yield 80.6%) as a light pink solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([Br:10])[CH:9]=1.[CH3:12][O:13][CH2:14]Cl>C1COCC1>[Br:3][C:4]1[CH:5]=[C:6]([O:11][CH2:12][O:13][CH3:14])[CH:7]=[C:8]([Br:10])[CH:9]=1
Reactant: Oc1cc(Br)cc(Br)c1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a suspension of sodium hydride (693 mg, 17.33 mmol, 60%, oil was washed with pentane) in THF (15 mL) was added 3, 5-dibromophenol (3.0 g, 11.55 mmol) at 0° C. and the suspension was stirred for 30 minutes. Then, methoxymethyl chloride (1.4 g, 17.33 mmol) was added at 0° C. The resulting suspension was allowed to warm to room temperature and stirred for 2 days at which time TLC analysis of the mixture indicated the absence of starting material. Then, the reaction mixture was poured into an ice-water (50 mL) and the organic compound was extracted into ethyl acetate (2×100 mL). The combined extracts were washed with brine solution (250 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and the concentration of the solution under reduced pressure gave the crude residue which was purified by using an ISCO 120 g column chromatography, eluting with 5-20% ethyl acetate in hexanes to obtain 1,3-dibromo-5-methoxymethoxy-benzene (2.94 g, 86%) as a white solid: EI(+)-HRMS m/e calcd for C8H8Br2O2 (M)+ 293.8891, found 293.8893.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8]([OH:10])=[O:9].[CH3:12][Si](C=[N+]=[N-])(C)C.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27]>C1C=CC=CC=1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH:11][S:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[F:19])(=[O:28])=[O:27])[C:7]=1[C:8]([O:10][CH3:12])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1c(Cl)cccc1NS(=O)(=O)c1ccccc1F
Reaction time: 18 h
Yield: 62.9 %

Procedure:
A solution of 6-chloroanthranilic acid (1.9549 g, 11.57 mmol) in 4:1 benzene/methanol (58 mL) was treated with trimethylsilyldiazomethane (7.0 mL, 14.0 mmol, 2.0M solution in hexanes), stirred for 18 hours, quenched with acetic acid (1 mL), and concentrated. The concentrate (2.04 g, 10.99 mmol) was dissolved in pyridine (22 mL), treated with 2-fluorobenzenesulfonyl chloride (1.75 mL, 13.19 mmol), stirred for 18 hours, quenched with 1N HCl (200 mL), and treated with ethyl acetate (100 mL). The organic layer was washed with brine (100 mL), dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography (3:1 hexanes/ethyl acetate) to provide the desired product (2.50 g, 66%). MS (ESI(+)) m/e 361 (M+H)+, 366 (M+NH4)+; MS (ESI(−)) m/e 342 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 10.52 (br s, 1H), 7.72 (m, 2H), 7.43 (m, 3H), 7.37 (td, 1H), 7.22 (dd, 1H), 3.68 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.Cl.[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[CH2:20][O:21][NH2:22].C(=O)(O)[O-].[Na+]>C(O)CC>[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[CH2:20][O:21][NH:22][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: NOCc1ccccc1F
Reactant: Clc1c2c(nc3ccccc13)CCCC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCO
Product: Fc1ccccc1CONc1c2c(nc3ccccc13)CCCC2

Procedure:
A mixture of 9-chloro-1,2,3,4-tetrahydroacridine (6.18 g) and O-(2-fluorobenzyl)hydroxylamine hydrochloride (5.5 g) in 125 ml of n-propanol was heated at reflux for 20 hours. The reaction mixture was then added to an iced sodium bicarbonate solution and extracted with ethyl acetate (3×). The combined organics were washed with water and dried (saturated NaCl, MgSO4).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CCN(CC)CC.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH3:33][C@H:34]1[CH2:38][CH2:37][CH2:36][NH:35]1>CC#N>[CH3:33][C@H:34]1[CH2:38][CH2:37][CH2:36][N:35]1[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: C[C@H]1CCCN1
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@H]1CCCN1c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
To a solution of 5-fluoro-2-nitrobenzotrifluoride (2.0 g, 9.56 mmol) in CH3CN (20 mL) was added Et3N (2.41 g, 23.90 mmol) followed by the addition of (S)-2-methylpyrrolidine tosylate (3.18 g, 12.43 mmol). The reaction was stirred at 80° C. overnight. The reaction was then quenched with water and the aqueous layer was extracted with DCM. The combined organics were washed with 1N HCl, dried over MgSO4, filtered and concentrated to give (S)-2-methyl-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidine (2.45 g, 94% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.11 (d, J=9.1 Hz, 1H), 6.88 (s, 1H), 6.85 (d, J=2.6 Hz, 1H), 4.17-4.13 (m, 1H), 3.59-3.54 (m, 1H), 3.33-3.28 (m, 1H), 2.14-2.00 (m, 3H), 1.80-1.71 (m, 1H), 1.14 (d, J=6.3 Hz, 3H). LC/MS: m/z 275.3 (M+H)+ at 1.98 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]2[CH:17]=[C:16]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:15]=[CH:14]2)[N:6]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=2[N+:32]([O-])=O)[N:5]=1)([CH3:3])[CH3:2].[Cl-].[NH4+]>C1COCC1.CO.O.[Fe]>[NH2:32][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:24]=1[N:6]1[C:7]2[C:12](=[C:11]([N:13]3[CH:17]=[C:16]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:15]=[CH:14]3)[CH:10]=[CH:9][CH:8]=2)[C:4]([CH:1]([CH3:3])[CH3:2])=[N:5]1)[C:28]#[N:29]
Reactant: CC(C)c1nn(-c2ccc(C#N)cc2[N+](=O)[O-])c2cccc(-n3cnc(-c4cccnc4)c3)c12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)c1nn(-c2ccc(C#N)cc2N)c2cccc(-n3cnc(-c4cccnc4)c3)c12
Temperature: 80 °C
Yield: 88.9 %

Procedure:
A solution of compound (10a) (470 mg), iron powder (584 mg) and ammonium chloride (470 mg) in THF (3.5 mL), methanol (3.5 mL) and water (3.5 mL) was stirred under heating at 80° C. for 2 hours. After completion of the reaction, the reaction solution was allowed to standing still for cooling, filtered, and the filtrate was concentrated. Water was added to the obtained residue to precipitate a solid, which was collected by filtration and dried to obtain compound (10b) (390 mg, yield 89%) as a milky white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:15][O:16][CH2:17][C:18](Cl)=O>>[CH3:15][O:16][CH2:17][C:18]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([F:12])([F:13])[F:14])[C:2]=2[N:1]=1
Reactant: COCC(=O)Cl
Reactant: Nc1c(C(=O)O)cccc1C(F)(F)F
Product: COCc1nc2c(C(F)(F)F)cccc2c(=O)o1
Temperature: 140 °C
Reaction time: 0.29 h
Yield: 60.2 %

Procedure:
A mixture of 7.1 g of 2-amino-3-trifluoromethylbenzoic acid [prepared by the process of J. Med. Chem., Vol. 16 (2) (1973), p. 101-106] and 10 g of methoxy acetic acid chloride was progressively heated and at 35° to 40° C., a very important disengagement of gas occurred for 15 to 20 minutes and at 120° C. a brown solution was formed and gas disengagement slackened but continued. The temperature was maintained at 140° C. for one hour during which gas formation practically ceased. The mixture was cooled to room temperature and excess acid chloride was distilled under reduced pressure. The residue was taken up in 70 ml of water and the mixture was vacuum filtered. The product was washed with water and was dissolved in methylene chloride. The organic phase was dried and filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and eluted with methylene chloride to obtain 5.4 g of 2-methoxymethyl-8-trifluoromethyl-4-H-3,1-benzoxazine-4-one melting at 104° to 106° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:17])=[C:7]([S:13](Cl)(=[O:15])=[O:14])[CH:8]=2)[N:3]=1.[F-:18].[K+]>C(Cl)Cl.[Br-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[Cl:1][C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:17])=[C:7]([S:13]([F:18])(=[O:15])=[O:14])[CH:8]=2)[N:3]=1
Reactant: O=S(=O)(Cl)c1cc2nc(Cl)c(Cl)nc2cc1Cl
Reactant: [F-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(F)c1cc2nc(Cl)c(Cl)nc2cc1Cl
Temperature: 25 °C
Reaction time: 17.5 h
Yield: 80.1 %

Procedure:
To a solution of 46 g of 2,3,7-trichloro-6-quinoxalinesulfonyl chloride in 200 ml of methylene chloride were added 0.42 g of benzyltriethylammonium bromide and a solution of 20.2 g of potassium fluoride in 20.9 ml of water. The resulting mixture was stirred for 17.5 hours at ambient temperature, filtered, dried over magnesium sulfate, treated with activated carbon and filtered again. Solvent was removed under vacuum, leaving a yellowish solid which was recrystallized from hexane to provide 35 g of 2,3,7-trichloro-6-quinoxalinesulfonyl fluoride as a light-yellow solid, having a melting point of 111°-113°.
Reaction SMILES: [F:1][C:2]1([F:33])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:18]=[C:19]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:20]5[C:25]([CH:26]=4)=[CH:24][CH:23]=[CH:22][CH:21]=5)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.BrC1C2C(=CC=CC=2)C=C(NC(C2(C3C=CC4OC(F)(F)OC=4C=3)CC2)=O)N=1.[CH3:62][N:63]1[CH2:68][CH2:67][N:66]([C:69](C2C=CC(B(O)O)=CC=2)=[O:70])[CH2:65][CH2:64]1>>[F:33][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:18]=[C:19]([C:27]5[CH:28]=[CH:29][C:30]([C:69]([N:66]6[CH2:67][CH2:68][N:63]([CH3:62])[CH2:64][CH2:65]6)=[O:70])=[CH:31][CH:32]=5)[C:20]5[C:25]([CH:26]=4)=[CH:24][CH:23]=[CH:22][CH:21]=5)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: CN1CCN(C(=O)c2ccc(B(O)O)cc2)CC1
Reactant: O=C(Nc1cc2ccccc2c(-c2ccccc2)n1)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Agent: O=C(Nc1cc2ccccc2c(Br)n1)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Product: CN1CCN(C(=O)c2ccc(-c3nc(NC(=O)C4(c5ccc6c(c5)OC(F)(F)O6)CC4)cc4ccccc34)cc2)CC1

Procedure:
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-phenylisoquinolin-3-yl)cyclopropanecarboxamide was made by the procedure shown above starting from N-(1-bromoisoquinolin-3-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide and 4-(4-methylpiperazine-1-carbonyl)phenylboronic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1>>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:25][CH3:26])[N:16]=[CH:15][N:14]=[C:13]2[NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1ccc2ccccc2n1
Product: COc1cc2ncnc(Nc3ccc4ccccc4n3)c2cc1OC
Yield: 56 %

Procedure:
Using an analogous procedure to that described in Example 9, 2-aminoquinoline was reacted with 4-chloro-6,7-dimethoxyquinazoline to give 6,7-dimethoxy-4-(2-quinolylamino)quinazoline in 56% yield, m.p. 215°-216° C.;
Reaction SMILES: [N:1]1(O)[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[N:15]1(O)[C:27]2[C:26]3[N:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[CH:19][C:18]=2[N:17]=[CH:16]1>>[NH:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[NH:15]1[C:27]2[C:26]3[N:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[CH:19][C:18]=2[N:17]=[CH:16]1
Reactant: On1cnc2cnc3ccccc3c21
Reactant: On1cnc2cnc3cccnc3c21
Product: c1ccc2c(c1)ncc1nc[nH]c12
Product: c1cnc2c(c1)ncc1nc[nH]c12

Procedure:
In step (4) of Reaction Scheme I, a 1H-imidazo[4,5-c]quinolin-1-ol or 1H-imidazo[4,5-c][1,5]naphthyridin-1-ol of Formula XXIII is cyclized by an intramolecular displacement of the halogen under basic conditions to provide 1H-imidazo[4,5-c]quinoline or 1H-imidazo[4,5-c][1,5]naphthyridine of Formula XXIV. The reaction can be carried out by adding a base such as potassium tert-butoxide or sodium hydride to a solution of a compound of Formula XXXIII in a suitable solvent such as tetrahydrofuran or N,N-dimethylformamide. The reaction can be carried out at ambient temperature. Alternatively, a solution of a compound of Formula XXXIII in a suitable solvent such as dichloromethane can be treated with an aqueous solution of a base such as potassium carbonate or sodium carbonate. The reaction can be carried out at ambient temperature.
Reaction SMILES: [CH3:1][S:2][C:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[NH:4].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:25]([C:26](O)=[O:27])=[C:24]([CH3:29])[O:23][N:22]=2)=[CH:17][CH:16]=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[C:25]([C:26]([N:5]([C:3]([S:2][CH3:1])=[NH:4])[C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])=[O:27])=[C:24]([CH3:29])[O:23][N:22]=2)=[CH:19][CH:20]=1
Reactant: COc1ccc(-c2noc(C)c2C(=O)O)cc1
Reactant: CSC(=N)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(-c2noc(C)c2C(=O)N(C(=N)SC)C(=O)OC(C)(C)C)cc1
Reaction time: 3 h
Yield: 59.2 %

Procedure:
A mixture of tert-butyl methylthiocarbonoimidoylcarbamate (Preparation AU, 0.98 g, 5.16 mmol), 3-(4-methoxyphenyl)-5-methyl-4-isoxazolecarboxylic acid (Preparation Y, 1.17 g, 5 mmol), EDCI (1.2 g, 6.26 mmol) and DIPEA (1 g, 7.75 mmol) in DCM (30 mL) was stirred for 3 hours. The solvent was concentrated by rotovap and residue was purified by column with EtOAc/DCM (5/95) as the eluant. The product was obtained as a white solid (1.2 g, 60%). 1H NMR (CD3OD): δ 1.52 (s, 9H), 1.89 (s, 3H), 2.76 (s, 3H), 3.86(s, 3H), 7.00,7.02 (d, 2H), 7.47,7.49 (d, 2H). MH+=406.19