Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][NH:8][C@@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](O)=[O:11]>C1COCC1>[CH3:7][NH:8][C@@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][OH:11]
Reactant: CN[C@H](C(=O)O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN[C@H](CO)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a suspension of LiAlH4 (0.689 g, 18.16 mmol) in THF (20.18 mL) was added (S)-2-(methylamino)-2-phenylacetic acid (1 g, 6.05 mmol) in THF (20 mL) slowly over 10 min at 0° C. The reaction mixture was stirred at room temperature for overnight. After quenched with water (0.7 mL), NaOH (2.1 mL), water (0.7 mL). The reaction mixture was filtered off. The filtrate was extracted with EtOAc 3 times. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered off, and concentrated in vacuo. The crude product was purified by flash chromatography (10% methanol in DCM) yielding (S)-2-(methylamino)-2-phenylethanol as a colorless oil in 55% yield. LCMS (m/z): 152.1 (MH+), 0.31 min; 1H NMR (400 MHz, CDCl3) δ7.40-7.33 (m, 2H), 7.32-7.27 (m, 3H), 3.77-3.69 (m, 1H), 3.69-3.63 (m, 1H), 3.58 (d, J=9.8 Hz, 1H), 2.36 (s, 3H).
Reaction SMILES: C(OC([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](CCOS(C)(=O)=O)[CH:18]=2)[NH:13][C:12]=1C)=O)C1C=CC=CC=1.C([N:31](C1CCNC1)C)(=O)C>O1CCOCC1>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[C:12]1[NH2:31]
Reactant: Cc1[nH]c2ccc(CCOS(C)(=O)=O)cc2c1C(=O)OCc1ccccc1
Reactant: CC(=O)N(C)C1CCNC1
Solvent: C1COCCO1
Product: Nc1cc2ccccc2[nH]1
Yield: 196.5 %

Procedure:
5-(2-Methanesulfonyloxy-ethyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (0.300 g, 0.770 mmol, 1 eq, Example 56, Step D) was suspended in Dioxane (20 mL) under Ar. 3-(N-Acetyl-N-methylamino)-pyrrolidine (0.330 g, 2.320 mmol, 3 eq) was added. The reaction mixture was stirred and heated to reflux for 18 hours. Then the reaction was quenched with saturated sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic phases were washed with brine and dried over Na2SO4. After removing the solvent, the residue was loaded on silica gel and chromatographed, eluting with ethyl acetate/methanol/triethyl amine (100/10/1). 0.200 g (60%) of the indole-amine was obtained as a white solid. This was converted to the .HCl salt. LC/MS (ESI+) 434 (M+1); Anal. Calcd for C26H31N3O3.1HCl.1.25H2O: C, 63.40; H, 7.06; N, 8.53; Found: C, 63.51; H, 6.95; N, 8.30.
Reaction SMILES: [CH:1]1([C:4]2[C:9]([CH:10]3[CH2:12][CH2:11]3)=[CH:8][C:7]([CH2:13][OH:14])=[C:6]([O:15][CH:16]([CH3:18])[CH3:17])[CH:5]=2)[CH2:3][CH2:2]1>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[CH:1]1([C:4]2[C:9]([CH:10]3[CH2:12][CH2:11]3)=[CH:8][C:7]([CH:13]=[O:14])=[C:6]([O:15][CH:16]([CH3:18])[CH3:17])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC(C)Oc1cc(C2CC2)c(C2CC2)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CC(C)Oc1cc(C2CC2)c(C2CC2)cc1C=O
Reaction time: 1 h
Yield: 94.3 %

Procedure:
Manganese dioxide (14.7 g) was added at room temperature to a toluene (80 mL) solution of (4,5-dicyclopropyl-2-isopropoxyphenyl)methanol (5.22 g), and the mixture was stirred at 80 C for 1 hour in a nitrogen atmosphere. The reaction mixture was filtered through celite, and then, the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (4.88 g).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([OH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl[C:13]([CH3:21])([CH2:15][CH2:16][C:17](Cl)([CH3:19])[CH3:18])[CH3:14]>>[CH3:14][C:13]1([CH3:21])[CH2:15][CH2:16][C:17]([CH3:19])([CH3:18])[C:9]2[CH:10]=[C:5]([OH:11])[CH:6]=[CH:7][C:8]1=2
Reactant: Oc1ccccc1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC1(C)CCC(C)(C)c2cc(O)ccc21
Temperature: 0 °C
Reaction time: 48 h
Yield: 32.1 %

Procedure:
27.5 g (0.2 mol) of anhydrous aluminum chloride were added by spatula to 250.0 g (2.65 mol) of phenol plus 414.5 g (2.27 mol) of 2,5-dichloro-2,5-dimethylhexane in 500 ml of petroleum ether at room temperature while stirring. After 48 hours, the reaction mixture was poured into ice-water and extracted with ether, and the organic phase was washed to neutrality with water, dried over sodium sulfate and evaporated under reduced pressure. Two recrystallizations of the residue from methanol yielded 148.7 g of the title compound of melting point 219°-220° C.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[Br:9]N1C(=O)CCC1=O.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[Br:9]/[CH:6]=[C:5]1\[CH2:4][CH2:3][CH2:2][C:1](=[O:8])[O:7]\1
Reactant: C#CCCCC(=O)O
Reactant: O=C1CCC(=O)N1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: ClCCl
Product: O=C1CCC/C(=C\Br)O1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 58 %

Procedure:
This compound was prepared according to the procedure set forth in Kraft et al, J. Am. Chem. Soc., 103, 5459-5466 (1981). A mixture of the 5-hexynoic acid of Part A (1.1 g, 9.8 mmol), KHCO3 (1.5 g, 15 mmol), N-bromosuccinimide (2.6 g, 15 mmol) and 0.4M aqueous tetrabutylammonium hydroxide (2 mL, 0.8 mmol) in CH2Cl2 (90 mL) was stirred at room temperature for 3.5 h. The mixture was washed with 5% Na2S2O3 and saturated NaCl. The organic phase was dried (MgSO4) and the solvent was removed in vacuo to give a residue weighing 1.8 g. The residue was purified by flash chromatography (silica gel, Aldrich catalog #22,719-6, 230-400 mesh). The column was eluted with CH2Cl2 and fractions having a spot with Rf =0.32 (CH2Cl2, Bakerflex IBF-2 silica TLC plates) were combined. The solvent was removed in vacuo to give 1.0 g (58% yield) of product as a colorless oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[CH2:11][N:12]1[C@H:21]2[C@@H:16]([CH2:17][CH2:18][CH2:19][CH2:20]2)[NH:15][C:14](=O)[CH2:13]1)C.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1>[N:12]1([CH2:11][CH2:10][OH:9])[C@H:21]2[C@@H:16]([CH2:17][CH2:18][CH2:19][CH2:20]2)[NH:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)CN1CC(=O)N[C@@H]2CCCC[C@H]21
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1COCCO1
Solvent: O
Product: OCCN1CCN[C@@H]2CCCC[C@H]21
Temperature: 25 °C
Yield: 96.5 %

Procedure:
Lithium aluminum hydride (1.00 g, 26.4 mmol) was suspended in anhydrous dioxane (40 ml). To the suspension, an anhydrous dioxane (10 ml) solution of (trans-3-oxodecahydroquinoxalin-1-yl)acetic acid ethyl ester (2.35 g, 9.78 mmol) was added dropwise with stirring at room temperature, and the mixture was then stirred under reflux for 10 minutes. The reaction mixture was cooled on ice, and sodium sulfate decahydrate was added thereto in small portions until no gas was generated. This mixture was filtered through celite and washed with methylene chloride, and the filtrate was then concentrated under reduced pressure to obtain 2-(trans-decahydroquinoxalin-1-yl)ethanol (1.74 g, yield: 97%) in a brown oil form.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[C:4]([F:13])[C:3]=1[CH3:14].[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1>O1CCCC1.C(OCC)(=O)C.CS(O)(=O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20][O:15]3)[CH:11]=[N:10][N:9]=2)=[C:4]([F:13])[C:3]=1[CH3:14]
Reactant: Cc1c(Br)ccc(-c2nc[nH]n2)c1F
Reactant: C1=COCCC1
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(Br)ccc(-c2nncn2C2CCCCO2)c1F
Temperature: 85 °C
Reaction time: 20 h
Yield: 94.8 %

Procedure:
Methanesulfonic acid (0.090 mL, 1.390 mmol) was added to a stirred solution of 3-(4-bromo-2-fluoro-3-methylphenyl)-1H-1,2,4-triazole (7.0 g, 27.3 mmol) and 3,4-dihydro-2H-pyran (12.68 mL, 139 mmol) in tetrahydrofuran (33 mL). The resulting mixture stirred at 85° C. under a reflux condenser under nitrogen for 20 h. The mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified using flash chromatography (20-30-50% ethyl acetate in hexane). Product containing fractions were combined and solvent removed under reduced pressure to afford the desired product (8.8 g, 95% yield) as a yellow solid. MS (ESI) m/z 340.0 [M]+
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[OH:13])#[N:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:33]([O:37][C:38]([N:40]1[CH2:45][C:44](=[O:46])[N:43]([C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([Cl:53])[CH:48]=2)[CH2:42][C@@H:41]1[CH2:54][CH2:55]O)=[O:39])([CH3:36])([CH3:35])[CH3:34].CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CCCCCC.CCOC(C)=O>[C:33]([O:37][C:38]([N:40]1[CH2:45][C:44](=[O:46])[N:43]([C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([Cl:53])[CH:48]=2)[CH2:42][C@@H:41]1[CH2:54][CH2:55][O:13][C:4]1[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=[CH:12][C:3]=1[C:1]#[N:2])=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: COC(=O)c1ccc(C#N)c(O)c1
Reactant: CC(C)(C)OC(=O)N1CC(=O)N(c2cccc(Cl)c2)C[C@@H]1CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C#N)c(OCC[C@H]2CN(c3cccc(Cl)c3)C(=O)CN2C(=O)OC(C)(C)C)c1
Reaction time: 16 h

Procedure:
To a solution of 250 mg of methyl 4-cyano-3-hydroxybenzoate (1.42 mmol), as described in Example 4, Step C, and PPh3 (465 mg, 1.77 mmol) in THF (10 mL) was added dropwise a solution of the alcohol from Step E above (503 mg, 1.42 mmol) and DEAD (0.28 mL, 1.77 mmol) in THF (5 mL). After stirring for 16 hr, the solution was concentrated in vacuo and the residue taken up in EtOAc. This was then washed with 10% citric acid solution, saturated NaHCO3 solution, brine and dried over MgSO4. Filtration and removal of the solvent afforded an oil. Column chromatography (silica gel; hexane:EtOAc 4:1) afforded the title compound as a clear oil.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]([NH:9][NH2:10])=[O:8].[CH3:11][O:12][C:13](OC)(OC)[CH2:14][CH2:15][CH3:16]>C(O)C>[CH3:11][O:12][C:13](=[N:10][NH:9][C:7]([C:3]1[N:4]=[CH:5][NH:6][C:2]=1[CH3:1])=[O:8])[CH2:14][CH2:15][CH3:16]
Reactant: CCCC(OC)(OC)OC
Reactant: Cc1[nH]cnc1C(=O)NN
Solvent: CCO
Product: CCCC(=NNC(=O)c1nc[nH]c1C)OC

Procedure:
A mixture of 10 g of 5-methyl-1H-imidazole-4-carboxylic acid hydrazide, 80 ml of trimethylorthobutyrate and 395 ml of absolute ethanol was treated and described in Example 1, giving 16.5 g of 5-methyl-4-imidazolecarboxylic acid, 2-(1-methoxybutylidene)hydrazide.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([Cl:49])[C:44]=1[S:50](Cl)(=[O:52])=[O:51]>C(#N)C>[Cl:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([Cl:49])[C:44]=1[S:50]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:52])=[O:51]
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3c(Cl)cccc3Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 36.9 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0313 g, 0.0678 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 2,6-dichlorobenzenesulfonylchloride (0.0479 g, 0.195 mmol) to obtain 4-(2,6-dichlorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0168 g, yield 37%).
Reaction SMILES: [Li+].[OH-].[C:3]1([CH2:9][O:10][C:11]2[CH:20]=[CH:19][C:18]([C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])=[CH:17][C:12]=2[C:13]([O:15]C)=[O:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>O.O1CCCC1>[C:3]1([CH2:9][O:10][C:11]2[CH:20]=[CH:19][C:18]([C:21]([N:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)=[O:22])=[CH:17][C:12]=2[C:13]([OH:15])=[O:14])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1cc(C(=O)N2CCCC2)ccc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(C(=O)N2CCCC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of LiOH (495 mg, 11.79 mmol) in water (8 ml) was added to a stirred solution of methyl 2-[(phenylmethyl)oxy]-5-(1-pyrrolidinylcarbonyl)benzoate (may be prepared as described in Description 54; 400 mg, 1.18 mmol) in tetrahydrofuran (2 ml) at room temperature. The mixture was stirred at room temperature for 3 h. The mixture was acidified by HCl (6 mol/l). The precipitate was collected and dried to yield the title compound as a white solid. 300 mg.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6](OCC)=[O:7])#[N:2]>N.CO.[Ni]>[C:11]1([CH:5]2[CH2:4][CH2:3][CH2:1][NH:2][C:6]2=[O:7])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(CCC#N)c1ccccc1
Agent: [Ni]
Agent: N
Solvent: CO
Product: O=C1NCCCC1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of the product from Example 91A (2.42 g, 11.14 mmol) in 7 M ammonia/methanol (40 mL) was added to solvent washed Raney®-nickel (24.20 g, 412 mmol) in a 250 mL stainless steel pressure bottle and stirred for 16 hours under hydrogen at 30 pounds per square inch at room temperature. The mixture was filtered through a nylon membrane and concentrated to supply the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.39-7.17 (m, 5H), 6.00 (s, 1H), 3.65 (dd, J=6.2, 8.3, 1H), 3.54-3.32 (m, 2H), 2.33-2.10 (m, 1H), 2.06-1.70 (m, 3H); MS (ESI+) m/z 176.1 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])#[N:2].[H-].[Na+].[CH3:18]I>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH3:18])[C:10](=[O:15])[C:11]([F:13])([F:12])[F:14])#[N:2]
Reactant: CI
Reactant: N#Cc1ccccc1NC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)C(F)(F)F)c1ccccc1C#N
Reaction time: 4 h
Yield: 93.9 %

Procedure:
N-(2-Cyanophenyl)-2,2,2-trifluoroacetamide (3 g, 0.014 mol) was added to sodium hydride (60% in oil, 0.62 g, 0.026 mol) in THF (40 ml) under nitrogen and stirred for 4 h. Methyl iodide (8.7 ml, 0.14 mol) was added and stirring continued overnight. The mixture was poured onto brine and extracted with ethyl acetate, dried over sodium sulphate and evaporated to give the product (3 g), MS (+EI) 228 (M+). 1H NMR (CDCl3) 7.8 (1H, d), 7.7 (1H, dd), 7.4 (1H, dd), 7.4 (1H, d), 3.43 (3H, s).
Reaction SMILES: I(Cl)(=O)=O.I(Cl)(=O)=O.I(Cl)(=O)=O.I([Cl:16])(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1.[CH3:28][O:29][C:30]([C:32]1[C:37]([Cl:38])=[C:36]([Cl:39])[C:35]([Cl:40])=[C:34]([C:41]2[O:42][CH:43]=[CH:44][CH:45]=2)[N:33]=1)=[O:31]>C(O)(=O)C.C(OCC)C>[Cl:38][C:37]1[C:32]([C:30]([O:29][CH3:28])=[O:31])=[N:33][C:34]([C:41]2[O:42][C:43]([Cl:16])=[CH:44][CH:45]=2)=[C:35]([Cl:40])[C:36]=1[Cl:39]
Reactant: O=I(=O)Cl
Reactant: COC(=O)c1nc(-c2ccco2)c(Cl)c(Cl)c1Cl
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)c1nc(-c2ccc(Cl)o2)c(Cl)c(Cl)c1Cl
Reaction time: 1 h
Yield: 51.5 %

Procedure:
Benyltrimethylammonium tetrachloroiodate (292 mg, 0.70 mmol) was added to a solution of methyl-3,4,5-trichloro-6-(2-furyl)pyridine-2-carboxylate (101 mg, 0.33 mmol) in acetic acid (5 mL). After one hour, the suspension was diluted with diethyl ether and the organic mixture was washed with 0.1 N sodium thiosulphate, 0.1 N sodium bicarbonate and dried (MgSO4). The residue was purified by column chromatography (diethyl ether:hexane, 5:95) to give methyl 3,4,5-trichloro-6-(5-chloro-2-furyl)pyridine-2-carboxylate (58 mg, 0.17 mmol): 1H NMR (CDCl3): δ 7.41 (d, J=3.6 Hz, 1H), 6.40 (d, J=3.6 Hz, 1H), 4.05 (s, 3H).
Reaction SMILES: [OH-].[Na+].[CH2:3]1[C:11]2[C:6](=[CH:7][C:8]([CH:12]=O)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[CH3:14][C:15]([CH3:17])=[O:16]>O>[CH2:3]1[C:11]2[C:6](=[CH:7][C:8]([CH:12]=[CH:14][C:15](=[O:16])[CH3:17])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1
Reactant: CC(C)=O
Reactant: O=Cc1ccc2c(c1)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1ccc2c(c1)CCC2
Yield: 81 %

Procedure:
An aqueous solution of 10% sodium hydroxide (50-70 ml) was added dropwise over a period of 5 minutes to a suspension of indane-5-carboxaldehyde (18.50 g; 127 mmole) in acetone (50 ml) and water (50 ml). The mixture was stirred at a temperature of 65° C. for a period of 11/2 hours and then extracted with dichloromethane (200 ml). The organic extract was washed several times with water, dried over anhydrous sodium sulphate, and the solvent was removed under reduced pressure using a rotary evaporator to give 1-(5-indanyl)but-1-en-3-one (19.25 g; 81%) as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[C:27]([F:34])[CH:26]=4)=[O:23])[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:36]1C=C(S(Cl)(=O)=O)C=C[C:41]=1Cl>>[CH2:36]([O:30][C:29](=[O:31])[C:28]1[CH:32]=[CH:33][C:25]([NH:24][C:22]([C:19]2[CH:20]=[C:21]3[C:16]([CH2:15][CH2:14][CH2:13][N:12]3[S:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)(=[O:11])=[O:10])=[CH:17][CH:18]=2)=[O:23])=[CH:26][C:27]=1[F:34])[CH3:41]
Reactant: O=C(Nc1ccc(C(=O)O)c(F)c1)c1ccc2c(c1)N(S(=O)(=O)c1ccc(Cl)c(Cl)c1)CCC2
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2ccc(Cl)c(Cl)c2)CCC3)cc1F

Procedure:
4-{[1-(3,4-Dichloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-2-fluoro-benzoic acid, m/z (ES+): 523.22 (M+H+.), was prepared in analogy to example 48, steps 1 to 5. Step 4 was performed using 3,4-dichloro-benzenesulfonyl chloride, yielding 4-{[1-(3,4-dichloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, which was hydrolyzed in step 5.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]([CH3:22])=[C:14]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:23][CH3:24])[CH:6]=1)(=O)C.Cl.C(=O)(O)[O-].[Na+]>>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]([CH3:22])=[C:14]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:23][CH3:24])[CH:6]=1
Reactant: COc1cc(NC(C)=O)ccc1-c1nc(-c2cccnc2)c(C)[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc(N)ccc1-c1nc(-c2cccnc2)c(C)[nH]1
Yield: 50.2 %

Procedure:
A solution of 2-(4-acetamido-2-methoxyphenyl)-5-methyl-4-(3-pyridyl)imidazole (0.55 g) in 1N-hydrochloric acid (25 ml) was refluxed for 5.5 hours, and cooled. After neutralized with aqueous sodium bicarbonate, the mixture was extracted with chloroform. The extract was dried over sodium sulfate, evaporated, and the residue was triturated with a mixture of methanol and diisopropyl ether to give 2-(4-amino-2-methoxyphenyl)-5-methyl-4-(3-pyridyl)imidazole (0.24 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].[CH:13]([O:15][CH3:16])=O.[H-].[Na+].BrC1C=CC=CC=1C(=CO)C(OC)=O.C(=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[C:8](=[CH:13]\[O:15][CH3:16])/[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)Cc1ccccc1Br
Reactant: COC=O
Agent: COC(=O)C(=CO)c1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: CO/C=C(/C(=O)OC)c1ccccc1Br
Reaction time: 3 h
Yield: 84 %

Procedure:
A mixture of methyl ortho-bromophenylacetate (5.23 g) and methyl formate (27.46 g) in DMF(6 ml) was added dropwise to a stirred suspension of sodium hydride (1.10 g) in DMF (45 ml) at 0° to 5° C. (frothing). When thin-layer chromatography showed that reaction was complete, the mixture was poured into water, acidified and extracted with ether. The extracts were dried and concentrated to give crude methyl 2-(2-bromophenyl)-3-hydroxypropenoate (5.95 g) as a yellow liquid which was used directly in the next step. The crude methyl 2-(2-bromophenyl)-3-hydroxypropenoate (5.95 g) was stirred with anhydrous potassium carbonate (6.38 g) and dimethyl sulphate (2.75 g) in DMF (40 ml). After 3 hours at room temperature, the reaction mixture was poured into water and extracted with ether (2×75 ml). The combined ether layers were washed with water and brine (×1) and dried. Filtration and evaporation gave a yellow oil which crystallised on standing to give (E)-methyl 2-(2-bromophenyl)-3-methoxypropenoate (5.20 g, 88% yield from methyl ortho-bromophenylacetate) as a crystalline solid, m.p. 68°-69° C., IR maxima 1712, 1638 cm-1 ; 1H n.m.r delta 3.73 (3H, s); 3.86 (3H, s); 7.56 (1H, s) p.p.m.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]3[C:12]([CH3:15])=[N:13][N:14]=[C:7]3[CH2:6][CH2:5][C:4]=2[C:3]=1[C:16]#[N:17].[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[N:23][CH:24]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[F:18][C:19]1[CH:20]=[C:21]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]4[C:12]([CH3:15])=[N:13][N:14]=[C:7]4[CH2:6][CH2:5][C:4]=3[C:3]=2[C:16]#[N:17])[CH:22]=[N:23][CH:24]=1
Reactant: Cc1nnc2n1-c1ccc(Br)c(C#N)c1CC2
Reactant: OB(O)c1cncc(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nnc2n1-c1ccc(-c3cncc(F)c3)c(C#N)c1CC2
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 7-bromo-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline-6-carbonitrile (145-4; 0.20 g, 0.0006 mol) and (5-fluoropyridin-3-yl)boronic acid (0.97 g, 0.0006 mol) in the mixture of 1,4-dioxan (10 mL) and water (10 mL) was added sodium carbonate (0.190 g, 0.0018). Reaction mass was purged with argon for 20 min. Then catalyst Pd(dppf)2Cl2 (0.048 g, 0.00006 mol) was added and allowed to stir at 80° C. for 12 h. The reaction mixture was filtered through celite bed and filter bed was thoroughly washed with ethyl acetate. The collected organic part was concentrated under vacuum to afford the crude compound, which was purified by silica gel column chromatography to obtain title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.739-8.732 (d, J=2.8 Hz, 1H), 8.685 (s, 1H), 8.095-8.066 (d, J=11.6 Hz, 2H), 7.782-7.742 (d, J 8 Hz, 1H), 3.282-3.240 (t, J=8.8 Hz, 2H), 3.143-3.109 (t, J=7.6 Hz, 2H), 2.702 (s, 3H). MS (M+1): 306.1