Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:19][CH2:20][CH2:21][C:22](Cl)=[O:23]>>[Cl:19][CH2:20][CH2:21][C:22]([N:16]1[CH2:15][CH2:14][N:13]([C:10]2[CH:11]=[CH:12][C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:8][CH:9]=2)[CH2:18][CH2:17]1)=[O:23]
Reactant: c1cc(N2CCNCC2)ccc1C1CCCCC1
Reactant: O=C(Cl)CCCl
Product: O=C(CCCl)N1CCN(c2ccc(C3CCCCC3)cc2)CC1

Procedure:
A target compound (2.2 g, 6.569 mmol) was yielded as white solid in the same manner as Reference Example 13 by reacting 1-(4-cyclohexylphenyl)piperazine (2.01 g, 8.224 mmol) with 3-chloropropionyl chloride (0.79 mL, 8.224 mmol) and purifying by separation through column chromatography (EtOAc:hexane:CH2Cl2, 1:1:5).
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:7]=1[CH2:8][N:9]1[C:21]2[CH:20]=[N:19][C:18]([C:22]([OH:24])=[O:23])=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2.S(Cl)(Cl)=O.[CH:34](O)([CH3:36])[CH3:35].C(N(CC)CC)C>C(Cl)Cl>[Cl:5][C:6]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:7]=1[CH2:8][N:9]1[C:21]2[CH:20]=[N:19][C:18]([C:22]([O:24][CH:34]([CH3:36])[CH3:35])=[O:23])=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: O=C(O)c1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Reactant: CC(C)O
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)OC(=O)c1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Temperature: 25 °C
Yield: 70 %

Procedure:
A mixture of 9-(2,5-dichlorobenzyl)-9H-β-carboline-3-carboxylic acid acetate salt (1.30 g, 3.02 mmol) and thionyl chloride (2.2 mL, 30 mmol) was stirred and refluxed for 2 hours. The reaction mixture was concentrated in vacuo and the resulting dark oil was used without further purification. The oil was dissolved in 15 mL of DMF (theor. 0.2M). A portion (2.5 mL, 0.5 mmol) of this solution was added to a large excess of isopropanol and triethylamine and the resulting mixture stirred at 60° C. overnight. After cooling to room temperature, the mixture was shaken with methylene chloride, and the mixture was washed with water and brine. The organic phase was dried with anhydrous sodium sulfate and the solvent removed in vacuo. Purification by flash chromatography on silica gel afforded the product as an oil (144 mg, 70%). 1H NMR (300 MHz, DMSO-d6) δ8.80 (s, 1H), 8.75 (s, 1H), 8.13-8.16 (m, 1H), 7.50-7.56 (m, 1H), 7.20-7.33 (m, 3H), 7.08 (dd,J=2.6, 8.7, 1H), 6.48 (d,J=2.3, 1H), 5.48 (s, 2H), 5.37 (septet, J=6.4, 1 H), 1.43 (d, J=6.4, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:11]1([CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:18][NH2:19])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH:17]([N:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:6]
Reactant: NCC(c1ccccn1)N1CCOCC1
Reactant: Cc1ccccc1C(=O)O
Product: Cc1ccccc1C(=O)NCC(c1ccccn1)N1CCOCC1

Procedure:
From 2-methylbenzoic acid and (2-morpholin-4-yl-2-pyridin-2-ylethyl)amine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][NH:7][NH2:8])=[CH:4][C:3]=1[O:11][CH3:12].C([O:15][C:16](=O)[CH:17]=[C:18]([NH2:22])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:22][C:18]1[NH:8][N:7]([CH2:6][C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([O:11][CH3:12])[CH:4]=2)[C:16](=[O:15])[CH:17]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: COc1cc(CNN)ccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: COc1cc(Cn2[nH]c(N)cc2=O)ccc1Cl
Reaction time: 8 h

Procedure:
59 g of 4-chloro-3-methoxybenzylhydrazine were added dropwise, under nitrogen, to a solution of 50.5 g of β-aminoβ-ethoxyacrylic acid ethyl ester and 1.5 g of p-toluenesulphonic acid in 250 ml of ethanol. After standing overnight, the compound identified above, which had separated out as a precipitate, was filtered off and recrystallised from ethanol. Melting point: 148°, 30 g. (38%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([C:9]2[C:10](=[O:20])[N:11]([CH3:19])[C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:14]=2)=[C:4]([F:21])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:29]([CH3:32])[C:30]#[CH:31].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH:30]([C:29]#[CH:32])[CH3:31])=[CH:6][C:5]([C:9]2[C:10](=[O:20])[N:11]([CH3:19])[C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:14]=2)=[C:4]([F:21])[CH:3]=1
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: C#CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CC(C)Oc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 70 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
First, 100 mg of 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-61) was dissolved in 0.60 ml of N,N-dimethylformamide, to which 64 mg of potassium carbonate and 45 mg of 3-bromo-1-butyne were added, and the mixture was stirred at 70° C. for 1 hour. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 96 mg (yield, 83%) of 3-{4-chloro-2-fluoro-5-(3-butyn-2-yloxy)phenyl}-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-157).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([OH:24])[CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[F:32][C:33]([O:37][C:38]([F:41])([F:40])[F:39])=[C:34]([F:36])[F:35].C(OCC)(=O)C>CN(C)C=O>[C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:19])([F:20])[F:21])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][C:34]([F:36])([F:35])[CH:33]([F:32])[O:37][C:38]([F:41])([F:40])[F:39])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(O)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Reactant: FC(F)=C(F)OC(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(OC(F)(F)C(F)OC(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F

Procedure:
3.0 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-hydroxypyrazole was dissolved in 40 mL of dimethylformamide, 25 g of triethylamine was added, and stirring was carried out at 50° C. for 3 hours while trifluoromethyl trifluorovinyl ether was blown. To this solution, ethyl acetate was added, the solution was washed with a saturated aqueous solution of citric acid, the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:4) to obtain 1.71 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([F:36])[C:18]=1[C:19]1[N:23]([CH2:24][C@H:25]2[O:30][CH2:29][CH2:28][NH:27][CH2:26]2)[C:22]2[CH:31]=[CH:32][C:33]([CH3:35])=[CH:34][C:21]=2[N:20]=1)[C:12]([NH:14][CH3:15])=[O:13].Cl[C:38]([O:40][CH3:41])=[O:39].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:36][C:17]1[CH:16]=[C:11]([C:12](=[O:13])[NH:14][CH3:15])[CH:10]=[C:9]([F:8])[C:18]=1[C:19]1[N:23]([CH2:24][C@H:25]2[O:30][CH2:29][CH2:28][N:27]([C:38]([O:40][CH3:41])=[O:39])[CH2:26]2)[C:22]2[CH:31]=[CH:32][C:33]([CH3:35])=[CH:34][C:21]=2[N:20]=1
Reactant: COC(=O)Cl
Reactant: CNC(=O)c1cc(F)c(-c2nc3cc(C)ccc3n2C[C@@H]2CNCCO2)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cc(F)c(-c2nc3cc(C)ccc3n2C[C@@H]2CN(C(=O)OC)CCO2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.6 %

Procedure:
A mixture of (S)-3,5-difluoro-N-methyl-4-(5-methyl-1-(morpholin-2-ylmethyl)-1H-benzo[d]imidazol-2-yl)benzamide trifluoroacetic acid salt (150 mg, 0.37 mmol), methyl chloroformate (0.058 mL, 0.75 mmol), and N,N-diisopropylethylamine (0.072 mL, 0.41 mmol) in DCM (10.00 mL) was stirred at room temperature for 30 min. The mixture was then concentrated under reduced pressure, and the residue was purified on preparative HPLC MS using the short high pH shallow gradient method (mobile phase: 30-50% B; A: H2O with 10 mM NH4CO3 and 0.375% NH4OH v/v; B: CH3CN; 10 min run; XBridge Prep C18 OBD, Waters reverse phase column; column size: 30×50 mm; particle size: 5 μm). This produced to afford (R)-methyl 2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-5-methyl-1H-benzo[d]imidazol-1-yl)methyl)morpholine-4-carboxylate (41.7 mg, 24% yield) as a solid. The solid was analyzed on analytical HPLC MS using the high pH gradient method (mobile phase: 5-95% B; A: H2O with 10 mM NH4CO3 and 0.375% NH4OH v/v; B: CH3CN; 2.25 min run; X-Bridge C18; column size: 2.1×30 mm; and particle size: 5 μm). MS m/z 459.3 [M+H]+ (ESI), Rt 1.58 min. 1H NMR (400 MHz, methanol-d4) δ ppm 2.50 (s, 3H) 2.54 (dd, J=4.49, 3.71 Hz, 1H) 2.69-2.84 (m, 1H) 2.96 (s, 3H) 3.25 (td, J=11.91, 2.73 Hz, 1H), 3.55-3.64 (m, 2H), 3.66 (s, 3H), 3.74 (d, J=12.89 Hz, 1H), 3.96 (d, J=12.89 Hz, 1H), 4.16 (dd, J=15.23, 7.42 Hz, 1H), 4.37 (dd, J=15.23, 3.12 Hz, 1H), 7.26 (dd, J=8.59, 1.17 Hz, 1H), 7.53 (s, 1H), 7.58 (d, J=8.59 Hz, 1H), 7.64 (d, J=8.59 Hz, 2H). HRMS m/z calcd for C23H25F2N4O4 459.1838 [M+H]+. found 459.1849.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14]([C:16]1[S:17][C:18]([C:22]2[CH2:26][C:25]([C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=3)([C:27]([F:30])([F:29])[F:28])[O:24][N:23]=2)=[CH:19][C:20]=1[CH3:21])=O)C>C(OCC)C>[Cl:38][C:33]1[CH:32]=[C:31]([C:25]2([C:27]([F:28])([F:30])[F:29])[O:24][N:23]=[C:22]([C:18]3[S:17][C:16]([CH2:14][OH:13])=[C:20]([CH3:21])[CH:19]=3)[CH2:26]2)[CH:36]=[C:35]([Cl:37])[CH:34]=1
Reactant: CCOC(=O)c1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1CO
Reaction time: 0.25 h
Yield: 79.5 %

Procedure:
Diisobutylaluminium hydride (DIBAL-H, 28.4 ml, 1M in Toluene) is added to a solution of 5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylic acid ethyl ester (6.42 g) in diethyl ether (120 ml) under nitrogen at −5° C. After 15 min at −5° C., the cold bad is removed. After 3 hours at room temperature, the reaction mixture is diluted with ethyl acetate and is quenched with a saturated solution of NaHCO3. The organic phase is separated and the aqueous phase is extracted once with ethyl acetate. The combined organic phases are extracted with a saturated solution of NaHCO3 and with a saturated aqueous solution of NaCl, dried over Na2SO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield {5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophen-2-yl}-methanol (4.63 g) as a light yellow foam. MS (HPLC/MS): 410 (MH+). Retention time: 1.90 min.
Reaction SMILES: [N:1](OCC(C)C)=[O:2].[CH2:8]([N:13]([C@:20]1([OH:35])[C@H:26]([OH:27])[C@@H:25]([CH2:28][OH:29])[O:24][C@:22]([CH2:30][CH:31]([CH3:33])[CH3:32])([OH:23])[C@@H:21]1[OH:34])[C:14](=[O:19])[NH:15][CH2:16][CH2:17][Cl:18])[CH2:9][CH:10]([CH3:12])[CH3:11].O1CCCC1.Cl>C(O)C>[CH2:8]([N:13]([C@:20]1([OH:35])[C@H:26]([OH:27])[C@@H:25]([CH2:28][OH:29])[O:24][C@:22]([CH2:30][CH:31]([CH3:33])[CH3:32])([OH:23])[C@@H:21]1[OH:34])[C:14](=[O:19])[N:15]([CH2:16][CH2:17][Cl:18])[N:1]=[O:2])[CH2:9][CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)CON=O
Reactant: CC(C)CCN(C(=O)NCCCl)[C@]1(O)[C@H](O)[C@@H](CO)O[C@@](O)(CC(C)C)[C@@H]1O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)CCN(C(=O)N(CCCl)N=O)[C@]1(O)[C@H](O)[C@@H](CO)O[C@@](O)(CC(C)C)[C@@H]1O
Yield: 67.3 %

Procedure:
Isobutyl nitrite (3.5 ml) was dropped into a solution of 3-isopentyl-3-(isobutyl α-D-glucopyranose-3-yl)-1-(2-chloroethyl)urea (3.48 g, 8.47 mmol) in a mixture of ethanol (50 ml), tetrahydrofuran (150 ml), and 2N hydrochloric acid (30 ml) with well stirring at 0° to 5° C. Thereafter, 2.51 g of 3-isopentyl-3-(isobutyl α-D-glucopyranose-3-yl)-1-(2-chloroethyl)-1-nitrosourea was obtained by the same operations of Example 63(2); yield 67.3%, m.p. 69°-71° C., [α]D20 +45.8° (C 1.0, methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:12]([C:13]3[CH:22]=[CH:21][C:16]([C:17](OC)=[O:18])=[CH:15][CH:14]=3)[CH:11]([CH2:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:10]2=[O:32])=[CH:5][CH:4]=1.O.[NH2:34][NH2:35].NN.CCOC(C)=O>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:12]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([NH:34][NH2:35])=[O:18])=[CH:15][CH:14]=3)[CH:11]([CH2:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:10]2=[O:32])=[CH:5][CH:4]=1
Reactant: NN
Reactant: COC(=O)c1ccc(C2C(CCCc3ccccc3)C(=O)N2c2ccc(OC)cc2)cc1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COc1ccc(N2C(=O)C(CCCc3ccccc3)C2c2ccc(C(=O)NN)cc2)cc1
Yield: 50.6 %

Procedure:
Reflux a mixture of the product of Step 1 (7.5 g, 17.5 mmol, 12/1 trans/cis mixture) and hydrazine hydrate (4.7 mL, 87.3 mmol) in CH3OH (40 mL) overnight, monitoring the reaction by TLC (30% EtOAc/hexanes) and adding additional hydrazine and refluxing further as necessary. Evaporate most of the solvent in vacuo and partition the resultant residue between water and EtOAc. Wash with water and brine, dry over Na2SO4 and concentrate onto silica gel to obtain a free-flowing powder. Load the powder onto a chromatography column packed with silica and EtOAc. Elute with EtOAc to obtain 3.8 g (50%) of the title compound as a 6/1 trans/cis mixture. 1H NMR (400 MHz, CDCl3, trans isomer) 7.74(2H, d, J=8.2 Hz), 7.39(2H, d, J=8.2 Hz), 7.28(2H, m), 7.16(5H, m), 6.76(2H, d, J=9.1 Hz), 4.63(1H, d, J=2.1 Hz), 3.73(3H, s), 3.06(1H, m), 2.65(2H, m), 1.98(1H, m), 1.85(3H, m). Diagnostic C-4 proton for cis diastereomer 5.16(J=5.6 Hz). MS(EI): 429(M+,74), 249(100), 149(35). HRMS calculated for C26H27N3O3 : 429.2052; found 429.2052.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[C:10]([OH:17])[CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH2:3][CH2:2]1.Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C([O-])([O-])=O.[K+].[K+]>CC#N>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[C:10]([O:17][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)CBr
Reactant: Oc1cccc2ccc(N3CCOCC3)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1cccc2ccc(N3CCOCC3)nc12
Temperature: 80 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
To a stirred mixture of 2-morpholinoquinolin-8-ol (200 mg, 0.87 mmol) in MeCN (5 mL) was added ethyl bromoacetate (216 mg, 1.31 mmol) and K2CO3 (360 mg, 2.61 mmol). The mixture was stirred at 80° C. for 4 hours. After filtration, the filtrate was concentrated to give crude product which was used directly for the next step (250 mg, Yield 90%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.O>[CH2:18]([O:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([F:1])[CH:7]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1F
Yield: 96.5 %

Procedure:
A solution of 2-fluoro-4-hydroxynitrobenzene (5.08 g, 32.36 mmol), cesium carbonate (11.71 g, 36.24 mmol), benzyl bromide (4.31 mL, 36.24 mmol), and tetrabutylammonium iodide (50 mg) in N,N-dimethylformamide (50 mL) was stirred at 25° C. for 24 hours, diluted with water (200 mL) and extracted with ethyl acetate (3×). The combined organic layers were washed with water (3×) and saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (7.72 g, 97%). 1H NMR (300 MHz, CDCl3): δ 8.10 (m, 1 H), 7.40 (m, 5 H), 6.82 (m, 2 H), 5.15 (s, 2 H).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([CH3:15])([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)[CH3:5].Cl.[C:18]([NH2:23])(=[NH:22])[CH:19]([CH3:21])[CH3:20].CN(C)C(N(C)C)=N>CN(C=O)C.O>[CH:19]([C:18]1[NH:22][CH:2]=[C:3]([C:4]([CH3:15])([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=2)[CH3:5])[N:23]=1)([CH3:21])[CH3:20]
Reactant: CC(C)C(=N)N
Reactant: CC(C)(C(=O)CBr)c1cccc([N+](=O)[O-])c1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1nc(C(C)(C)c2cccc([N+](=O)[O-])c2)c[nH]1
Yield: 29.7 %

Procedure:
A solution of 1-bromo-3-methyl-3-(3-nitro-phenyl)-butan-2-one (2.28 g, 8.0 mmol), isobutyramidine hydrochloride (3.58 g, 23.7 mmol) and 1,1,3,3-tetramethylguanidine (2.4 mL, 19.1 mmol) in DMF (10 mL) was heated at reflux for 24 h. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated to afford 2-isopropyl-4-[1-methyl-1-(3-nitro-phenyl)-ethyl]-1H-imidazole (0.65 g, 30%) as a cream-coloured solid.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][N:10]=[C:9]([C:12](OCC)=[O:13])[CH:8]=2)[O:6][CH2:5][CH2:4][O:3]1.CCO.C1COCC1>O>[CH3:1][C:2]1([C:7]2[O:11][N:10]=[C:9]([CH2:12][OH:13])[CH:8]=2)[O:6][CH2:5][CH2:4][O:3]1
Reactant: CCOC(=O)c1cc(C2(C)OCCO2)on1
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC1(c2cc(CO)no2)OCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
To a solution of the dioxolane 318 (3.14 g, 13.8 mmol) in a 1:2 mixture of EtOH-THF (45 mL) NaBH4 (0.68 g, 18.0 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, treated with water and the organic solvents were evaporated. The aqueous phase was extracted with EtOAc and combined organic layers were successively washed with H2O and brine, dried over MgSO4 and concentrated under reduced pressure to afford the title compound as oil (2.39 g, 93% yield) which was used for next step without further purification. 1H NMR (DMSO-d6) δ (ppm): 6.43 (s, 1H), 5.47 (t, J=5.9 Hz, 1H), 4.47 (d, J=5.9 Hz, 2H), 4.06-4.02 (m, 2H), 3.94-3.90 (m, 2H), 1.66 (s, 3H). MS (m/z): 185.18 (calc) 186.1 (MH+) (found).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH:14]=[CH:13][C:10](C#N)=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2].C[Mg]Br.C([O:20][CH2:21][CH3:22])C>C1(C)C=CC=CC=1>[CH2:1]([N:3]([CH2:6][C:7]1[CH:14]=[CH:13][C:10]([C:21](=[O:20])[CH3:22])=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)Cc1ccc(C#N)cc1
Reactant: CCOCC
Agent: C[Mg]Br
Solvent: Cc1ccccc1
Product: CCN(CC)Cc1ccc(C(C)=O)cc1
Temperature: 0 °C

Procedure:
A solution of 12.1 g of 4-[diethylaminomethyl]benzonitrile in 40 ml of toluene was added to a solution of methylmagnesium bromide (43 ml of a 3 M solution in diethyl ether) in 40 ml of toluene, and the mixture was heated to reflux. Completion of the reaction was followed by pouring into ice-water, extracting with methyl tert-butyl ether, adjusting the aqueous phase to pH 11-12 by adding NaOH, and renewed extracting with methyl tert-butyl ether. The organic phase was dried and the solvent was evaporated. 12.1 g of the title compound were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]([F:27])([F:26])[O:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21]>>[F:15][C:16]([F:26])([F:27])[O:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][NH:21][C:8]1[CH:7]=[CH:6][C:5]2[C:4]([NH2:1])=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: NCc1ccccc1OC(F)(F)F
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: Nc1cccc2nc(NCc3ccccc3OC(F)(F)F)ccc12

Procedure:
The title compound, MS: m/e=334.3 (M+H+), was prepared in accordance with the general method of example 1 from 5-nitro-2-chloroquinoline and 2-(trifluoromethoxy)benzylamine.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1[Sn](CCCC)(CCCC)CCCC)[CH3:2].I[C:30]1[CH:31]=[C:32]([OH:36])[CH:33]=[CH:34][CH:35]=1.C1COCC1.CCOCC>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=1)[CH3:2]
Reactant: Oc1cccc(I)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(C#N)c2ccc(OC)cc2n1CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCn1c(-c2cccc(O)c2)c(C#N)c2ccc(OC)cc21
Temperature: 65 °C
Yield: 71.8 %

Procedure:
1-Ethyl-6-methoxy-2-tributylstannanyl-1H-indole-3-carbonitrile (1.0 g, 2.05 mmol), prepared in step A, is combined with 3-iodophenol (474 mg, 2.15 mmol), Pd(PPh3)2Cl2 (67 mg, 0.102 mmol), CuI (75 mg, 0.39 mmol) and THF (4.0 mL). This mixture is heated at 65° C. overnight. The reaction mixture is diluted in EtOAc, and is filtered through celite. The filtrate is concentrated and the residue is purified by silica gel chromatography (4:1, CH2Cl2/EtOAc) to yield crude product. Ether trituration yields 1-ethyl-2-(3-hydroxy-phenyl)-6-methoxy-1H-indole-3-carbonitrile (430 mg, 72%) as a yellow-white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:11]#[N:12])=[CH:6][CH:5]=2.[Sn](Cl)(Cl)(Cl)Cl.[C:18](Cl)(=[O:20])[CH3:19].[OH-].[Na+]>ClCCl>[C:18]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]#[N:12])[CH:8]=2)[NH:3][C:2]=1[CH3:1])(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: Cc1cc2cc(C#N)ccc2[nH]1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)c1c(C)[nH]c2ccc(C#N)cc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A 500 mg portion of 2-methyl-1H-indole-5-carbonitrile was dissolved in 5 ml of dichloromethane, and 27.0 ml of 1 M tin tetrachloride (a dichloromethane solution) was added dropwise thereto at 0° C., followed by stirring at 0° C. for 10 minutes. Then, 0.27 ml of acetyl chloride was added thereto at 0° C., followed by overnight stirring at room temperature. A 25 ml portion of a 2 M sodium hydroxide aqueous solution was added thereto at 0° C. to adjust the pH to 12, followed by stirring at 0° C. for 1 hour and extraction with a 20% methanol-chloroform mixed solvent. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure to obtain 607 mg of 3-acetyl-2-methyl-1H-indole-5-carbonitrile as a beige solid.