Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:7]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[C:6]([O:15][CH:16]([CH3:18])[CH3:17])[C:5]([O:19][CH3:20])=[CH:4][CH:3]=1.[CH:21](N(CC)C(C)C)([CH3:23])[CH3:22].C#CC>CN(C=O)C.[Cu]I>[CH:16]([O:15][C:6]1[C:5]([O:19][CH3:20])=[CH:4][CH:3]=[C:2]([C:22]#[C:21][CH3:23])[C:7]=1[NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])([CH3:18])[CH3:17]
Reactant: COc1ccc(I)c(NC(=O)C(F)(F)F)c1OC(C)C
Reactant: CCN(C(C)C)C(C)C
Agent: [Cu]I
Agent: C#CC
Solvent: CN(C)C=O
Product: CC#Cc1ccc(OC)c(OC(C)C)c1NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A mixture of the product of Step B (0.275 g; 0.681 mmol), Cl2Pd(PPh3)2 (0.058 g; 0.083 mmol); CuI (0.025 g; 0.131 mmol), anhydrous N,N-diisopropyl ethylamine (1 ml) in anhydrous DMF (5 ml) was cooled to −40° C., degassed under reduced pressure and saturated with dry N2. To it, propyne gas (0.5 g; 12.4 mmol) was added at −40° C. The reaction flask was sealed with septum and allowed to warm up to room temperature and stirred overnight at room temperature than evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography (SiO2, hexane/ethyl acetate, 8:2) to give the title compound (0.171 g; 79% yield) as creamy solid. 1H-NMR (CDCl3) 1.21 (d, 6H, J=6.16 Hz); 2.00 (s, 3H); 3.86 (s, 3H); 4.43 (m, 1H, J=6.16 Hz); 6.79 (d, 1H, J=8.67 Hz); 7.14 (d, 1H, J=8.67 Hz); 7.72 (broad s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.Cl>N1C=CC=CC=1>[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17]([NH:4][C:3]2[C:5]([CH3:10])=[CH:6][C:7]([CH3:9])=[CH:8][C:2]=2[CH3:1])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2c(C)cc(C)cc2C)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 88.7 %

Procedure:
A 250-mL round-bottomed flask was charged with 2,4,6-trimethylaniline (mesidine, 11.88 mL, 84.62 mmol) and 50 mL of pyridine. To this mixture, a solution of p-toluenesulfonyl chloride (16.13 g, 84.62 mmol) in pyridine (50 mL) was added, and the reaction mixture was stirred at room temperature for 17 h. The reaction mixture was poured into 800 mL of acidic ice water containing 125 ml of 37% HCl. The mixture was cooled to 0° C. for 3 h, and a yellow solid precipitated. The yellow solid was collected by filtration and dissolved in 18 L of 5% NaOH. To this solution, 1850 mL of 37% HCl was added until the mixture reached a pH of 5. The resulting white precipitate was collected and washed with 800 mL of water and then dried in vacuo to give N-(p-toluenesulfonyl)-2,4,6-trimethylaniline (N-(p-toluenesulfonyl)mesidine) (21.73 g, 89%). 1H NMR (300 MHz, CDCl3): δ7.6 (d, 2H), 7.2 (d, 2H), 6.8 (s, 2H), 5.9 (s, 1H), 2.4 (s, 3H), 2.3 (s, 3H) 2.0 (s, 3H).
Reaction SMILES: N#N.O[CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10](=[O:12])[CH3:11])[CH:6]=1.CCN(CC)CC.S([Cl:24])(C)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:24][CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10](=[O:12])[CH3:11])[CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1cc(CO)on1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cc(CCl)on1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(5-hydroxymethyl-isoxazol-3-yl)-ethanone (262 mg, 1.86 mmol) in dry CH2Cl2 (2.6 mL) was treated at 0° C. with Et3N (0.34 mL, 2.41 mmol) followed by DMAP (23 mg, 0.19 mmol) and Ms-Cl (0.17 mL, 2.23 mmol). After stirring at rt for 2 h, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (2×10 mL) and the combined org. extracts were dried over NaSO4, filtered, and the solvents were removed under reduced pressure to give crude 1-(5-chloromethyl-isoxazol-3-yl)-ethanone as a pale yellow oil. In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of this crude 1-(5-chloromethyl-isoxazol-3-yl)-ethanone in DMF (3.0 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (210 mg, 1.84 mmol) in DMF (3.0 mL) pre-treated for 30 min with DIPEA (0.63 mL, 3.68 mmol) and the reaction mixture was stirred for 16 h at 50° C. Water (10 mL), followed by EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over NaSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (2:1 hept-EA) gave the title compound as a pale yellow oil: TLC:rf (2:1 hept-EA)=0.26. LC-MS-conditions 02: tR=0.90 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:5][O:6][CH2:7][C:8]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1.[F:34][C:35]1[C:40]([F:41])=[C:39]([O:42][CH3:43])[CH:38]=[CH:37][C:36]=1B(O)O>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:34][C:35]1[C:40]([F:41])=[C:39]([O:42][CH3:43])[CH:38]=[CH:37][C:36]=1[C:2]1[CH:29]=[C:28]([C:30]([F:32])([F:31])[F:33])[CH:27]=[C:4]([CH2:5][O:6][CH2:7][C:8]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:3]=1
Reactant: COc1ccc(B(O)O)c(F)c1F
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(COCC3(c4ccccc4)CCNCC3)cc(C(F)(F)F)c2)c(F)c1F
Temperature: 120 °C

Procedure:
tert-Butyl 4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate (150 mg, 0.28 mmol), 2,3-difluoro-4-methoxyphenylboronic acid (139 mg, 0.84 mmol), and tetrakis(triphenylphosphine) palladium(0) (33 mg, 0.03 mmol) were combined in dry tetrahydrofuran (3 mL) in a microwave tube and sealed. After flushing with nitrogen, 1.0 mL of a 1 N potassium hydroxide aqueous solution was introduced. The mixture was heated at 120° C. for 1 h via microwave. After cooling to room temperature, the reaction mixture was concentrated and treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol and concentrated to afford 45 mg (33%). 1H-NMR (CDCl3, 500 MHz) δ 7.57 (s, 1H), 7.26-7.38 (m, 6H), 7.13-7.17 (m, 1H), 7.00-7.06 (m, 1H), 6.77-6.83 (m, 1H), 4.41 (s, 2H), 3.93 (s, 3H), 3.44 (s, 2H), 2.84-2.92 (m, 2H), 2.68-2.77 (m, 2H), 2.13-2.18 (m, 2H), 1.83-1.92 (m, 2H). Mass spec.: 492.01 (MH)+. Accurate mass spec.: m/z 492.1978 [MH]+, Δ=3.3 ppm.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([F:10])[F:9])[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:3]=1.[Br:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[Br:21][C:22]1[CH:27]=[C:26]([C:2]2[N:7]=[C:6]([CH:8]([F:10])[F:9])[CH:5]=[C:4]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)[N:3]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Reactant: OB(O)c1cccc(Br)c1
Product: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-difluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example A.5) (0.5 g, 1.62 mmol) and commercially available 3-bromo-benzene-boronic acid (0.42 g, 2.20 mmol) according to the general procedure IVb. Obtained as a white solid (0.54 g, 78%). MS (EI) 430.0 [(M)+]; mp 98.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:10]([CH2:11][C:12](=O)[C:13]2=[CH:27]O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.O.[NH2:35][NH2:36].C([O-])(O)=O.[Na+]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)(=[O:18])=[O:19])[CH:10]([CH2:11][C:12]3[NH:35][N:36]=[CH:27][C:13]=32)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC2CC(=O)C(=CO)C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC2Cc3[nH]ncc3C(C1)N2S(=O)(=O)c1ccc(Cl)cc1

Procedure:
To a solution of 9-(4-chloro-benzenesulfonyl)-6-hydroxymethylene-7-oxo-3,9-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (4.91 g, 11.1 mmol) in ethanol (20 mL) was added glacial acetic acid (0.5 mL) followed by hydrazine monohydrate (5.39 mL, 111.1 mmol). The reaction mixture was stirred at room temperature for 1 h after which saturated NaHCO3 (10 mL) was added. The resulting solution was extracted with EtOAc (3×20 mL), the organic extracts were combined, dried (Na2SO4), filtered, concentrated and purified by silica gel column chromatography (eluant hexane/EtOAc, 9/1 to 2/8) and preparative HPLC to give 12-(4-chloro-benzenesulfonyl)-4,5,10,12-tetraaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene-10-carboxylic acid tert-butyl ester as a white solid. Retention time (min)=1.794, method [1], MS (ESI) 439.1 (M+H); 1H NMR (300 MHz, CDCl3) δ 7.60 (d, J=8.2 Hz, 2H), 7.40 (s, 1H), 7.32 (d, J=8.2 Hz, 2H), 5.39 (s, 1H), 4.31 (s, 1H), 4.15-4.00 (m, 1H), 3.90 (d, J=12.1 Hz, 1H), 3.39-3.10 (m, 2H), 2.75-2.60 (m, 2H), 1.20-1.07 (m, 9H).
Reaction SMILES: [C:1]([C:4]#[C:5][CH2:6][CH2:7][CH2:8][C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[C:20](=[O:21])[C:19]([CH3:22])=[C:18]([CH3:23])[C:17](=[O:24])[C:16]=1[CH3:25])([OH:3])=[O:2].[N+](=C)=[N-].S(S([O-])=O)([O-])=O.[Na+].[Na+].[C:37]([Si:41](Cl)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:40])([CH3:39])[CH3:38].N1C=CN=[CH:56]1>CCOCC.O>[Si:41]([O:24][C:17]1[C:16]([CH3:25])=[C:15]([CH2:14][CH2:13][CH2:12][CH2:11][C:10]#[C:9][CH2:8][CH2:7][CH2:6][C:5]#[C:4][C:1]([O:3][CH3:56])=[O:2])[C:20]([OH:21])=[C:19]([CH3:22])[C:18]=1[CH3:23])([C:37]([CH3:40])([CH3:39])[CH3:38])([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC1=C(C)C(=O)C(CCCCC#CCCCC#CC(=O)O)=C(C)C1=O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: c1c[nH]cn1
Agent: C=[N+]=[N-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: COC(=O)C#CCCCC#CCCCCc1c(C)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(C)c(C)c1O
Reaction time: 1 h

Procedure:
6-(11-Carboxyundeca-5,10-diyn-1-yl)-2,3,5-trimethyl-1,4-benzoquinone (340 mg, 1 mmol) was dissolved in ether (10 ml). A solution of diazomethane in ether was added under ice-cooling for methyl-esterification. Nitrogen gas was introduced to remove excess diazomethane. Then water (5 ml) containing sodium hydrosulfite (400 mg, 2.3 mmol) was added, and the mixture was stirred for 1 hour. The ether layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dichloromethane (5 ml), and tert-butylchlorodiphenylsilane (550 mg, 2 mmol) was added. Then imidazole (136 mg, 2 mmol) was added under a stream of nitrogen, and the mixture was stirred at 43° C. for 16 hours. The reaction mixture was washed with water (5 ml), and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain crude 4-tert-butyldiphenylsilyloxy-6-(11-methoxycarbonylundeca-5,10-diyn-1-yl)-2,3,5-trimethylphenol. This crude product was dissolved in dichloromethane (10 ml), and methyl 1-O-trichloroacetimidoyl-2,3,4-tri-O-acetyl-α-D-glucopyranosiduronate (1 g, 2.1 mmol) was added. Boron trifluoride diethyl ether (0.2 ml) was added under reduced pressure, and the mixture was stirred at the same temperature for 30 minutes. Then water (10 ml) containing sodium bicarbonate (1 g) was added, and the mixture was stirred for 5 minutes. The dichloromethane layer was separated and concentrated under reduced pressure. To the residue were added tetrahydrofuran (15 ml), methanol (10 ml) and 1N sodium hydroxide solution (20 ml), and the mixture was allowed to react at room temperature for 40 hours and concentrated under reduced pressure. The residue was extracted with ether and the aqueous layer was subjected to Sephadex (trade mark) LH-20 column chromatography and eluted with water. The desired fraction was lyophilized to obtain the desired compound (290 mg) as white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na+].[CH2:19](I)[CH3:20].O>CN(C)C=O>[CH2:19]([O:10][C:9](=[O:11])[CH2:8][C:6]1[CH:5]=[CH:4][C:3]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:2]([NH2:1])[CH:7]=1)[CH3:20]
Reactant: CCI
Reactant: Nc1cc(CC(=O)[O-])ccc1-c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(-c2ccccc2)c(N)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium 2-amino-4-biphenylacetate is dissolved in dimethylformamide and the solution treated with ethyliodide. The solution is stirred at room temperature for about 3 hours, the solution added to water and the mixture extracted several times with benzene. The combined benzene extracts are washed with dilute base and water, dried over sodium sulfate, concentrated and crystallized to give ethyl-2-amino-4-biphenylacetate.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:20][CH3:21])[C:7]([CH2:9][CH2:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=O)=[N:8][C:4]=2[CH:3]=1.CN(C([N:31]([CH3:33])C)N(C)C)C.C(O)(=O)C.[NH2:38]N>CCO>[Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:20][CH3:21])[C:7]([CH2:9][C:10]3[C:11]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=4)=[N:38][NH:31][CH:33]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CCn1c(CCC(=O)c2cccc(F)c2)nc2cc(Br)ccc21
Reactant: CN(C)C(N(C)C)N(C)C
Reactant: NN
Solvent: CCO
Solvent: CC(=O)O
Product: CCn1c(Cc2c[nH]nc2-c2cccc(F)c2)nc2cc(Br)ccc21
Temperature: 60 °C

Procedure:
A mixture of 3-(5-Bromo-1-ethyl-1H-benzoimidazol-2-yl)-1-(3-fluoro-phenyl)-propan-1-one (0.1 g, 0.27 mmol) and tris(dimethylamino)methane (0.077 g, 0.54 mmol) is heated at 60° C. in a sealed tube for 6 hours. The volatile material is removed in vacuo. EtOH (5 mL) and hydrazine acetate (1.1 mmol) are added to the residue. The mixture is heated at 120° C. for 2 hours. The solvent is removed. NaHCO3 (aq.) (10 mL) and DCM (30 mL) are added to the residue. The organic layer is separated and the aqueous layer is extracted with DCM (2×15 mL). The combined organic layers are dried and the solvent removed. The crude is purified by PTLC (ethyl acetate/Hexanes 1:1) to give 5-bromo-1-ethyl-2-[3-(3-fluoro-phenyl)-1H-pyrazol-4-ylmethyl]-1H-benzoimidazole as a solid. LRMS: calcd 399.3. found [M+1] 401.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25](=[O:34])[C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])=[O:23])=[CH:17][N:16]=2)[C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:35](Cl)(=[O:39])[C:36](Cl)=[O:37]>ClCCCl>[F:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[C:25]([N:24]1[C:36](=[O:37])[C:35](=[O:39])[N:21]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[C:10]([F:12])([F:11])[F:13])=[N:16][CH:17]=2)[C:22]1=[O:23])=[O:34]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(NC(=O)c1c(F)cccc1F)Nc1ccc(OC(c2ccc(Cl)c(Cl)c2)C(F)(F)F)nc1
Solvent: ClCCCl
Product: O=C1C(=O)N(c2ccc(OC(c3ccc(Cl)c(Cl)c3)C(F)(F)F)nc2)C(=O)N1C(=O)c1c(F)cccc1F
Yield: 73.1 %

Procedure:
To a stirred solution of N-[[[2-[1-(3,4-dichlorophenyl)-2,2,2-trifluoroethoxy]pyridin-5-yl]amino]carbonyl]2,6-difluorobenzamide (1.0 g, 0.002 mole) in 1,2-dichloroethane (10 ml) was added oxalyl chloride (0.24 g, 0.0020 mole). This mixture was heated at reflux for five days. Additional oxalyl chloride (0.24 g) was added, and refluxing was continued for one more day. The solvent was removed from the reaction mixture by distillation under reduced pressure, leaving an oil. This oil was purified by column chromatography on silica gel, elution with toluene: ethyl acetate (9:1), yielding 0.84 g of 1-[(2,6-difluorophenyl)carbonyl]-3-[2-[1-(3,4-dichlorphenyl)2,2,2-trifluoroethoxy]pyridin-5-yl]imidazolidinetrione as a solid (mp 160° C.). The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:14]([O-])=O)=[C:4]([NH:8][C:9](=O)[CH2:10][O:11][CH3:12])[CH:5]=[CH:6][CH:7]=1.O.O.[Sn](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[C:3]2[NH:14][C:9]([CH2:10][O:11][CH3:12])=[N:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: COCC(=O)Nc1cccc(Cl)c1[N+](=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COCc1nc2cccc(Cl)c2[nH]1
Temperature: 100 °C
Reaction time: 4 h
Yield: 98.1 %

Procedure:
[step 1] 3-Chloro-2-nitroaniline (2.0 g, 11.6 mmol) was dissolved in dichloromethane (58 mL), triethylamine (2.6 mL, 18.5 mmol) and methoxyacetyl chloride (1.4 mL, 15.1 mmol) were added at 0° C., and the mixture was stirred under reflux for 18 hr. To the mixture was added 4 mol/L hydrochloric acid (90 mL), and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 50/50) to give N-(3-chloro-2-nitrophenyl)-2-methoxyacetamide (1.7 g, 62%). [step 2] N-(3-Chloro-2-nitrophenyl)-2-methoxyacetamide (900 mg, 3.68 mmol) obtained in step 1 was dissolved in ethanol (7.4 mL), tin chloride dihydrate (4.0 g, 17.7 mmol) was added and the mixture was stirred at 100° C. for 4 hr. The mixture was adjusted to pH 10 with 4 mol/L aqueous sodium hydroxide solution and filtered. The filtrate was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (710 mg, 98%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.C([O-])(O)=O.[Na+]>C(OCC)(=O)C.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: C1=COCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(COC2CCCCO2)cc1
Temperature: 25 °C
Yield: 96.3 %

Procedure:
To a solution of 4-nitrobenzylalcohol (50 g, 0.326 mol) in ethyl acetate (EtOAc) (200 ml) were added 3,4-dihydropyran (35.7 ml, 0.392 mol) and CSA (camphor sulfonic acid) (379 mg, 1.63 mmol) under stirring at room temperature, and the mixture was stirred at room temperature for 1 hour. After the reaction completed, the reaction mixture was neutralized with saturated NaHCO3 solution and separated ethyl acetate layer was dried with MgSO4 and concentrated under reduced pressure. The residue was purified with silica gel column chromatography to give 4-(2-tetrahydro-pyranyloxymethyl)nitrobenzene (74.5 g, 96%) as syrup.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:42]=[CH:41][CH:40]=[CH:39][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH:18]2[O:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:13][CH:12]=1.C(=O)(O)[O-].[Na+].Cl[C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:42]=[CH:41][CH:40]=[CH:39][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:49]([O:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[O:50])[CH2:19][CH:18]2[O:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:15][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)CCc1ccccc1OCCOC1CNCCC1c1ccc(OCCCOCc2ccccc2OC)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccccc1OCCOC1CN(C(=O)OCc2ccccc2)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 0.15 g of methyl 3-{2-[2-(4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidin-3-yloxy)ethoxy]phenyl}propionate (Example 52) in 3 ml of ethyl acetate is admixed with 3 ml of saturated aqueous sodium bicarbonate solution. The mixture is cooled to 0° C. and admixed with 0.046 ml of benzyl chloroformate. After 1 hour, another 1 ml of saturated aqueous sodium bicarbonate solution and 0.020 ml of benzyl chloroformate are added. The aqueous phase is removed and extracted with ethyl acetate (2×). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.32 (2:5 EtOAc-heptane); Rt=6.07.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28](B(O)O)[CH:29]=2)[CH:24]=[N:23]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:14]([N:12]([CH3:13])[C:11]1[C:2]([C:28]2[CH:29]=[C:30]3[C:25]([CH:24]=[N:23][N:22]3[CH3:21])=[CH:26][CH:27]=2)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:5]=2)([CH3:16])[CH3:15]
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: Cn1ncc2ccc(B(O)O)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc4cnn(C)c4c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 29.5 %

Procedure:
To a solution of methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (Scheme I, 180.0 mg, 0.61 mmol) in dioxane (1 mL) was added 1-methyl-1H-indazol-6-ylboronic acid (276.0 mg, 1.57 mmol), K3PO4 (391.2 mg, 1.85 mmol), and Pd(PPh3)4 (35.0 mg, 0.03 mmol) under nitrogen atmosphere. After stirring 20 min at 90° C., the reaction mixture was dissolved in dichloromethane (30 mL), washed with water (3×20 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 0.05%-0.2% ethyl acetate in petroleum ether to afford methyl 3-(isopropyl(methyl)amino)-2-(1-methyl-1H-indazol-6-yl)quinoxaline-6-carboxylate as a light yellow solid (70 mg, 29%).