Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.Br[C:55]1[C:62]([CH3:63])=[CH:61][C:58]([C:59]#[N:60])=[CH:57][C:56]=1[CH3:64].C(N(C(C)C)CC)(C)C.N#N>O1CCOCC1>[CH3:64][C:56]1[CH:57]=[C:58]([CH:61]=[C:62]([CH3:63])[C:55]=1[S:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11])[C:59]#[N:60]
Reactant: Cc1cc(C#N)cc(C)c1Br
Reactant: O=C1CCc2c(S)cccc21
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: N#N
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C#N)cc(C)c1Sc1cccc2c1CCC2=O
Temperature: 120 °C
Yield: 87.9 %

Procedure:
4-Mercapto-indan-1-one (Step 1, 210 mg, 1.28 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (74 mg, 0.13 mmol), 4-bromo-3,5-dimethyl-benzonitrile (269 mg, 1.28 mmol) and diisopropylethylamine (0.88 mL, 5.1 mmol) are dissolved in 1,4-dioxane (2 mL). The mixture is degassed with N2, tris(dibenzylideneacetone)palladium(0) (117 mg, 0.13 mmol) added and heated under microwave irradiation at 120° C. for 2 hours. The solution is concentrated under vacuum. The crude product obtained is purified by flash chromatography (10-80% ethyl acetate in cyclohexane) to give the title compound (Yield: 330 mg). LC (METHOD 5): tR=1.36 min; Mass spectrum (ES+): m/z=294 [M+H]+.
Reaction SMILES: CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.[CH3:21][O:22][N:23]=[C:24]([N:32]1[CH:36]=[CH:35][N:34]=[CH:33]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[OH:31]>CCOCC>[CH3:21][O:22][N:23]=[C:24]([N:32]1[CH:36]=[CH:35][N:34]=[CH:33]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH2:17][C:16]1[CH:19]=[CH:20][C:13]([CH3:12])=[CH:14][CH:15]=1
Reactant: Cc1ccc(CCl)cc1
Reactant: CON=C(c1ccccc1O)n1ccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CON=C(c1ccccc1OCc1ccc(C)cc1)n1ccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
DMF (3 ml), potassium carbonate (0.22 g) and 4-methylbenzyl chloride (0.20 g) were added to 2-hydroxy-α-(1-imidazolyl)benzaldehyde O-methyloxime (0.26 g), and the mixture was stirred at room temperature overnight. After completion of the reaction, ether (100 ml) was added, and the mixture was washed with brine (80 ml) twice, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography and recrystallized from ethyl acetate/n-hexane to give α-(1-imidazolyl)-2-(4-methylbenzyloxy)benzaldehyde O-methyloxime (0.22 g) as colorless crystals. mp. 70.5°-72.0° C.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[C:4]([NH:10][C:11]2[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[N:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[C:4]([NH:10][C:11]2[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[N:3]=1
Reactant: COc1ccc(Nc2ccc(CO)c(F)n2)cn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(Nc2ccc(C=O)c(F)n2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
To [2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridin-3-yl]-methanol (55, 0.700 g, 2.81 mmol) in 20.0 mL of tetrahydrofuran, Dess-Martin periodinane (1.44 g, 3.40 mmol) is added and the reaction stirred at room temperature for 30 minutes. The reaction is poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (56, 450 mg). MS (ESI) [M+H+]+=248.0.
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[CH:4]=[CH:5][N+:6]([O-:8])=[O:7].C[Si](C)(C)[O:17][C:18]([CH:20]=[CH2:21])=[CH2:19]>C1(C)C=CC=CC=1>[N+:6]([C@@H:5]1[CH2:21][CH2:20][C:18](=[O:17])[CH2:19][C@H:4]1[C:3]1[CH:9]=[C:10]([F:14])[C:11]([F:13])=[CH:12][C:2]=1[F:1])([O-:8])=[O:7]
Reactant: C=CC(=C)O[Si](C)(C)C
Reactant: O=[N+]([O-])C=Cc1cc(F)c(F)cc1F
Solvent: Cc1ccccc1
Product: O=C1CC[C@@H]([N+](=O)[O-])[C@H](c2cc(F)c(F)cc2F)C1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
2,4,5-Trifluoro-β-nitrostyrene (7.8 g, 38.4 mmol) and 2-trimethylsiloxy-1,3-butadiene (8.18 g, 57.6 mmol) were mixed in toluene (10 ml). The reaction was heated to 120° C. overnight. The reaction mixture was cooled to room temperature, concentrated and treated with trifluoroacetic acid (10 mL) and CH2Cl2 (10 mL) at 0° C. It was stirred for 30 minutes, then saturated NaHCO3 was added to adjust pH (˜7). The mixture was extracted with ethyl acetate (3×) and the combined organic extracts were washed with water and brine, and then concentrated. A minimum amount of methylene chloride was added to the residue to induce crystallization. The crystals were collected by filtration and the mother liquid was subjected to column chromatography (eluting with 25% ethyl acetate/hexane). The recrystallized and chromatographed material was combined to yield the title compound (7.0, 70%). 1H NMR (300 MHz, CDCl3) δ ppm 2.29-2.82 (m, 6H), 3.73-3.89 (m, 1H), 5.06-5.29 (m, 1H), 6.86-7.12 (m, 2H). MS (ESI) m/z 274 (M+H)+.
Reaction SMILES: [NH3:1].[CH2:2]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([OH:22])=[C:15]([C:18](OC)=[O:19])[CH:16]=2)[NH:11][N:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl-].[Mg+2].[Cl-]>>[NH2:1][C:18]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][C:14]=1[OH:22])[NH:11][N:10]=[C:9]2[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:19]
Reactant: COC(=O)c1cc2c(Cc3ccccc3)n[nH]c2cc1O
Reactant: N
Agent: [Cl-]
Agent: [Mg+2]
Product: NC(=O)c1cc2c(Cc3ccccc3)n[nH]c2cc1O
Reaction time: 0.67 h

Procedure:
2.1 1.5 ml of ammonia (7 M in methanol) are added under argon to 30 mg of “A1”, and the mixture is stirred in the microwave at 100°/10 bar for 40 minutes. 0.5 ml of ammonia solution (32%) and 5.06 mg of magnesium chloride are added, and the mixture is stirred at 120°/17 bar for a further 40 minutes. The mixture is subjected to conventional work-up, and the residue is chromatographed over an RP18 silica-gel column, giving 2.7 mg of 5-aminocarbonyl-3-benzyl-6-hydroxy-1H-indazole (“A3”).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:29]=[CH:28][C:22]2[C:23](=[O:27])[CH2:24][CH2:25][O:26][C:21]=2[C:20]=1[CH2:30][CH2:31][CH3:32].[OH-].[Li+]>O1CCCC1>[O:27]=[C:23]1[C:22]2[CH:28]=[CH:29][C:19]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[CH2:5][CH2:4][C:3]([OH:33])=[O:2])=[C:20]([CH2:30][CH2:31][CH3:32])[C:21]=2[O:26][CH2:25][CH2:24]1
Reactant: CCCc1c(CCCCCCOc2ccccc2CCC(=O)OC)ccc2c1OCCC2=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1c(CCCCCCOc2ccccc2CCC(=O)O)ccc2c1OCCC2=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.2 %

Procedure:
A mixture of 0.65 g (1.44 mmol) of 2-[6-(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)hexyloxy]benzenepropanoic acid methyl ester, 2 mL of 3N aqueous lithium hydroxide, and 30 mL of tetrahydrofuran was stirred at room temperature for 24 hr and then concentrated in vacuo. The residue was diluted with water and extracted 3 times with ether (the ether extracts were discarded). The aqueous alkaline solution was acidified with 3N HCl and worked-up with ether in the usual manner. The oily residue was chromatographed on silica gel. Elution with 2:1 toluene-ethyl acetate containing acetic acid afforded 0.5 g (79.3%) of 2-[6-(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)hexyloxy]benzenepropanoic acid as viscous, colorless oil.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[C:11]=2[CH3:19])=[N:6]1)[CH3:4].[C:20]([C:23]1[O:24][CH:25]=[C:26]([C:28](O)=[O:29])[N:27]=1)(=[O:22])[CH3:21]>>[C:20]([C:23]1[O:24][CH:25]=[C:26]([C:28]([NH:1][CH2:2][C@@H:3]([N:5]2[CH:9]=[CH:8][C:7]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[C:11]=3[CH3:19])=[N:6]2)[CH3:4])=[O:29])[N:27]=1)(=[O:22])[CH3:21]
Reactant: Cc1c(-c2ccn([C@@H](C)CN)n2)ccc(C#N)c1Cl
Reactant: CC(=O)c1nc(C(=O)O)co1
Product: CC(=O)c1nc(C(=O)NC[C@H](C)n2ccc(-c3ccc(C#N)c(Cl)c3C)n2)co1
Yield: 33.4 %

Procedure:
(S)-2-acetyl-N-(2-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)-propyl)oxazole-4-carboxamide was prepared using the method of Example 34(d) starting from ((S)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (549 mg, 2.00 mmol) and 2-acetyloxazole-4-carboxylic acid (372 mg, 2.40 mmol). The product was purified by Flash-chromatography. Yield 33.4%. 1H-NMR (400 MHz; CDCl3): δ 1.63 (d, 3H), 2.58 (d, 3H), 2.60 (s, 3H), 3.78-3.98 (m, 2H), 4.60-4.71 (m, 1H), 6.44 (d, 1H), 7.44-7.62 (m, 4H), 8.31 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:16])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:6][CH:7]=1.C(N(CC)CC)C.[C:24]([Si:26]([CH3:29])([CH3:28])[CH3:27])#[CH:25]>O1CCCC1.[Pd](Cl)Cl.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.[Cu]I>[O:16]=[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([C:25]#[C:24][Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH:7][N:6]=1)[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)CCC(=O)Nc1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CCC(=O)Nc1ccc(C#C[Si](C)(C)C)cn1
Temperature: 65 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
To a solution of methyl 4-[(5-bromo-2-pyridyl)amino]-4-oxo-butanoate (commercially available: 0.25 g, 0.871 mmol) in tetrahydrofuran was added bis(triphenylphosphine) palladium(II) dichloride (61.7536 mg, 0.087 mmol), copper(I) iodide (16.6 mg, 0.087 mmol), triethylamine (889 mg, 1.23 mL, 8.70 mmol) and ethynyltrimethylsilane (130 mg, 0.19 mL, 1.30 mmol). The reaction mixture was stirred at 65° C. overnight. The reaction was stopped and the solution was partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate (2×). The combined organic layer was dried on magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography eluting with cyclohexane-ethyl acetate (3/1) to give methyl 4-oxo-4-[[5-(2-trimethylsilylethynyl)-2-pyridyl]amino]butanoate (26 mg, 10% yield). 1H NMR (400 MHz, CDCl3) 8.39 (s, 1H), 8.14 (m, 2H), 7.74 (d, 1H), 3.72 (s, 3H), 2.74 (m, 4H), 0.24 (s, 9H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][CH:7]=1.[C:9]1(B(O)O)[C:22]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:21]2[C:22]3[C:13]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[CH:20]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(I)c1
Reactant: OB(O)c1cccc2c1ccc1ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2cc3ccccc3c3ccccc23)c1
Yield: 84.8 %

Procedure:
Under an atmosphere of argon, 3-bromoiodobenzene (7.0 g, 25 mmole), phenanthreneboronic acid (5.0 g, 23 mmole) and tetrakis-(triphenylphosphine)palladium(0) (0.5 g, 0.43 mmole, 1.7% Pd) were dissolved into toluene (100 ml). To the obtained solution, an aqueous solution of sodium carbonate (7.3 g, 69 mmole, 3 eq/35 ml) was added and the resultant solution was heated under refluxing for 10 hours and left standing for one night. The formed organic layer was separated, washed with a saturated aqueous solution of sodium chloride (50 ml) and dried with anhydrous magnesium sulfate. Then, the solvent was removed by distillation and a yellow oil was obtained. The obtained oil was purified by the column chromatography (silica gel/hexane, hexane+3% dichloromethane and hexane+5% dichloromethane, successively) and white needle crystals (6.5 g, 85%) were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:23]=[CH:22][CH:21]=[C:20]4[C:16]=3[CH2:17][CH2:18][CH:19]4[NH:24][CH2:25][CH2:26][OH:27])[N:11]=2)=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=O.[K+].[K+].Br[CH2:35][CH:36]([CH3:38])[CH3:37]>CC(N(C)C)=O>[OH:27][CH2:26][CH2:25][NH:24][CH:19]1[C:20]2[C:16](=[C:15]([C:12]3[N:11]=[C:10]([C:7]4[CH:8]=[CH:9][C:2]([O:1][CH2:35][CH:36]([CH3:38])[CH3:37])=[C:3]([CH:6]=4)[C:4]#[N:5])[O:14][N:13]=3)[CH:23]=[CH:22][CH:21]=2)[CH2:17][CH2:18]1
Reactant: CC(C)CBr
Reactant: N#Cc1cc(-c2nc(-c3cccc4c3CCC4NCCO)no2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)COc1ccc(-c2nc(-c3cccc4c3CCC4NCCO)no2)cc1C#N
Temperature: 75 °C
Reaction time: 6 h
Yield: 36.8 %

Procedure:
Prepared using General Procedure 11. To a solution of 2-hydroxy-5-(3-(1-(2-hydroxyethylamino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)benzonitrile 102 (15.0 mg, 0.041 mmol) in DMA (2 mL) was added K2CO3 (16.9 mg, 0.12 mmol) and 1-bromo-2-methylpropane (11.3 mg, 0.08 mmol). The mixture was stirred 6 h at 75° C. The solvent was evaporated and the mixture was partitioned between EA and brine. The organic layer was dried over MgSO4, filtered, and the solvent evaporated. The final compound was purified by preparative HPLC to give 6.31 mg (37%) of 5-(3-(1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isobutoxybenzonitrile 103 as a white solid. LCMS-ESI (m/z) calculated for C24H16N4O3: 418.5. found 419.2 [M+H]+, tR=2.61 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([CH2:13][C@@H:14]([CH3:15])[N:8]3[CH:7]=[C:6]([C:16]([OH:18])=[O:17])[C:5]2=[O:19])[C:11]=1F.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([CH2:13][C@@H:14]([CH3:15])[N:8]3[CH:7]=[C:6]([C:16]([OH:18])=[O:17])[C:5]2=[O:19])[C:11]=1[N:24]1[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]1
Reactant: CN1CCNCC1
Reactant: C[C@@H]1Cc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Product: C[C@@H]1Cc2c(N3CCN(C)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23

Procedure:
(-)-8,9-difluoro-2-(R)-methyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid (Compound (b)) and N-methylpiperazine were used, and treated in a manner analogous to Example 7, to give the title compound.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=1.[O:11]1CCO[CH:12]1[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH3:23])[CH:17]=1>>[CH:12]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:2]2[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=2)=[C:18]([CH3:23])[CH:17]=1)=[O:11]
Reactant: NC(=O)c1ccc(F)cn1
Reactant: Cc1cc(C2OCCO2)ccc1O
Product: Cc1cc(C=O)ccc1Oc1ccc(C(N)=O)nc1
Yield: 35.5 %

Procedure:
Using a method similar to Example 388 Part D, using 5-fluoropyridine-2-carboxamide (Example 388 Part C) (0.400 g, 2.85 mmol) and 4-[1,3]dioxolan-2-yl-2-methylphenol (Example 388, Part C2) (0.514 g, 2.85 mmol) gives the title compound (0.259 g): TLC [silica gel 60 F254, 30% ethyl acetate in dichloromethane] Rf=0.20; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 19 min], tR=12.1 min, 73.1% purity.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:13]([C:24]([O:26][CH3:27])=[O:25])[C:12]2=[O:28])=[CH:2]1.C(O)[CH2:30][OH:31]>CN(C)C(=O)C.[Zn]>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[C:13]([C:24]([O:26][CH2:27][CH2:30][OH:31])=[O:25])[C:12]2=[O:28])=[CH:2]1
Reactant: OCCO
Reactant: COC(=O)C1=C(Nc2ccc(F)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Agent: [Zn]
Solvent: CC(=O)N(C)C
Product: O=C(OCCO)C1=C(Nc2ccc(F)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 9.8 %

Procedure:
Under a nitrogen atmosphere, a solution of the compound (0.038 g, 0.10 mmol) of Example 51, ethylene glycol (0.50 mL, 9.0 mmol) and zinc cluster catalyst (Zn4(OCOCF3)6O) (0.0019 g, 0.0020 mmol) in N,N-dimethylacetamide (0.5 mL) was stirred with the microwave synthesizer (Biotage Initiator™) at 150° C. for 1 h. Cooled to ambient temperature, the precipitate was removed by filtration. The filtrate was purified by preparative HPLC to afford the titled compound as solid (0.0040 g, y. 10%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[Al+3].[Cl-].[Cl-].[Cl-].[C:14](Cl)(=[O:16])[CH3:15]>C(Cl)Cl>[NH:1]1[C:9]2=[N:8][CH:7]=[CH:6][CH:5]=[C:4]2[C:3]([C:14](=[O:16])[CH3:15])=[CH:2]1
Reactant: CC(=O)Cl
Reactant: c1cnc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.6 %

Procedure:
(Ref.: J. Org. Chem. 2002, 67, 6226-6227) 7-Azaindole (5 g, 42.3 mmol) is added to a stirred suspension of AlCl3 (22.6 g, 169 mmol) in DCM (300 mL). After stirring at rt for 1 h, acetyl chloride (13.3 g, 169 mmol) is added drop wise and the resulting mixture is stirred for 18 h. The mixture is cooled to 00 C., quenched with MeOH (150 mL) and stirred for 1 h. Silica gel is added to the mixture, the solvents are removed under vacuum, and the residue is purified by silica gel chromatography eluting with 10% MeOH in DCM to afford 1-(1H-pyrrolo[2,3-b]pyridin-3-yl)-ethanone (1.6 g). 1H NMR (300 MHz, CH3OD): δ 8.93(d, 1H), 8.45(s, 2H), 7.50(t, 1H), 3.30(s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1.[I-].[K+].[CH3:27][CH:28]=[CH:29][CH2:30][NH2:31]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH:31][CH2:30][CH2:29][CH:28]=[CH2:27])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1
Reactant: Fc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Reactant: CC=CCN
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCCNCc1nnc2n1-c1ccc(F)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 32, 8-fluoro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, potassium iodide, and methylallylamine in tetrahydrofuran are reacted to give 8-fluoro-1-[(allylmethylamino)methyl]-6-(0-chlorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [NH2:1][C:2]1[C:12]([C:13]#[N:14])=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[C:4]([O:15][CH3:16])[CH:3]=1.[OH-].[Na+]>O>[NH2:1][C:2]1[C:12]([C:13]#[N:14])=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:15][CH3:16])[CH:3]=1
Reactant: CCOC(=O)c1cc(C#N)c(N)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(N)c(C#N)cc1C(=O)O
Temperature: 50 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
A suspension of 10.69 parts of ethyl 4-amino-5-cyano-2-methoxybenzoate in 12 parts of a sodium hydroxide solution 50% and 500 parts of water was stirred and heated to 50° C. and stirring was continued for 1 hour at 50°-55° C. The reaction mixture was cooled and filtered. The filtrate was acidified with concentrated hydrochloric acid to pH 1-2. The precipitated product was filtered off, washed thoroughly with water and dried overnight at 80° C., yielding 8.6 parts (93.2%) of 4-amino-5-cyano-2-methoxybenzoic acid; mp. 236.7° C. (intermediate 111).
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH:12]=O)=[CH:8][C:7]([CH2:14][CH2:15][CH3:16])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:21]=[CH:22][C:23]=1[Cl:24].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH2:12][N:28]2[CH2:27][CH2:26][N:25]([C:20]3[CH:21]=[CH:22][C:23]([Cl:24])=[C:18]([Cl:17])[CH:19]=3)[CH2:30][CH2:29]2)=[CH:8][C:7]([CH2:14][CH2:15][CH3:16])=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: CCCc1cc(CCC=O)n(C(C)(C)C)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccc(Cl)c(Cl)c3)CC2)n(C(C)(C)C)n1

Procedure:
199 mg (93%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propanal (100 mg, 0.450 mmol), 1-(3,4-dichlorophenyl)piperazine (104 mg, 0.450 mmol), DIPEA (0.118 mL, 0.675 mmol) and NaBH(OAc)3 (286 mg, 1.350 mmol).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25]([OH:27])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:29]=[C:30]([NH2:36])[CH2:31][S:32]([CH3:35])(=[O:34])=[O:33]>>[CH3:35][S:32]([CH2:31][C:30]1[N:36]=[C:25]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:27][N:29]=1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)CC(N)=NO
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: CS(=O)(=O)Cc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
250 mg (about 0.65 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid and 108 mg (0.71 mmol) of N′-hydroxy-2-(methylsulphonyl)ethanimidamide were reacted according to the General Method 1. Yield: 5 mg (2% of theory)
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:12])([CH3:11])[CH2:9][OH:10])[C:5]([F:13])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:12])([CH3:11])[CH2:9][O:10][S:22]([CH3:21])(=[O:24])=[O:23])[C:5]([F:13])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)(CO)c1nc(Br)ccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(O)(COS(C)(=O)=O)c1nc(Br)ccc1F
Reaction time: 0.5 h

Procedure:
To a solution of 2-(6-bromo-3-fluoro-pyridin-2-yl)-propane-1,2-diol (18.29 g, 73.1 mmol) in dichloromethane (350 ml) was added triethylamine (20.39 ml, 146 mmol). Methanesulfonyl chloride (6.27 ml, 80 mmol) was added dropwise at 0° C. over 10 minutes. Stirring was continued at 0° C. for 30 minutes. The reaction mixture was washed with sat. sodium bicarbonate solution, water and brine. The organic layer was dried over sodium sulfate, filtered and evaporated. 31.46 g (crude, used without further purification in the next step). LCMS RtH5=0.81 min. (ES+ 328, 330); 1H-NMR (360 MHz, CDCl3): 7.52 (dd, 1H), 7.41 (dd, 1H), 5.13 (s, 1H, OH), 4.61 (d, 1H), 4.45 (d, 1H), 3.05 (s, 3H, CH3SO2), 1.61 (s, 3H, CH3).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl)([O-:3])=[O:2].[SH:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][S:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1CCl
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CSCc1ccccc1[N+](=O)[O-]

Procedure:
A mixture of o-nitrobenzylchloride (17.2 g), methyl mercaptoacetate (8.9 ml), and potassium carbonate (27.6 g) was refluxed with stirring in acetone (200 ml) for 6 hours. The reaction mixture was filtered and evaporated to leave the title compound as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C=O)C>[CH2:1]([O:8][C:9]1[N:14]=[CH:13][N:12]([CH2:15][C:16](=[O:17])[C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:20][CH:19]=2)[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: O=C(Cn1cnc(OCc2ccccc2)cc1=O)c1ccc(CBr)cc1
Solvent: CN(C)C=O
Product: O=C(Cn1cnc(OCc2ccccc2)cc1=O)c1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 52 mg (0.13 mmol) 6-benzyloxy-3-[2-(4-bromomethyl-phenyl)-2-oxo-ethyl]-3H-pyrimidin-4-one (preparation 20b) in 2.00 mL of DMF is added 42 μL (0.50 mmol) pyrrolidine. The reaction mixture is stirred 30 min at RT and is directly purified by HPLC (Waters Xbridge; water (0.1% formic acid)/acetonitrile (0.1% formic acid) 95:5 to 0:100).