Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)(Cl)Cl>[C:1]([C:6](=[CH:12][NH:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][O:21][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:18][CH:19]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)C(=CNc1ccc(CO)cc1)C(=O)OCC
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCC(=O)C(=CNc1ccc(COC(=O)c2ccccc2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
A solution of ethyl 2-butyryl-3-(4-hydroxymethylphenylamino)acrylate (49.5 g, 0.17 mol) and pyridine (50 ml) in chloroform (250 ml) was stirred at 0°-5° (ice-bath). Benzoyl chloride (22 ml, 0.19 mol) in chloroform (250 ml) was added dropwise keeping the reaction temperature below 10° C. Cooling was removed and the mixture was stirred overnight at room temperature. The mixture was washed with 2 M HCl, sodium hydrogen carbonate solution and brine, dried (anhyd. MgSO4), filtered and evaporated to an oil which crystallized on standing. The product was slurried with petroleum ether, filtered off and washed with petroleum ether to give ethyl 2-butyryl-3-(4-benzoyloxymethylphenylamino)acrylate as white crystals (61.8 g, 92%), m.p. 73° C.-5° C.
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:9]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.Cl.C(OCC)(=O)C>C1COCC1>[OH:15][C:9]1([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCOC(=O)C[Zn]Br
Reactant: O=C1CCCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)CCCCC1
Yield: 95 %

Procedure:
Under nitrogen atmosphere, 30 mL of THF was added to 6.09 g (10 mmol, 1.0 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.98 g (10 mmol) of cyclohexanone in 5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. for 3 hours. 15 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 50 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 10 mL (×2) of 1N hydrochloric acid, 10 mL of an aqueous saturated sodium chloride solution, 20 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 10 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.76 g of the desired product (yield 95%).
Reaction SMILES: C(OC[C@@H](OC(C)(C)C)C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(N1CCOCC1)C=C2)(=[O:6])C(C)(C)C.[CH2:39]([O:46][C:47]1[CH:56]=[CH:55][C:54]2[C:49](=[CH:50][C:51]([CH3:72])=[C:52]([C@H:64]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])[CH2:65][OH:66])[C:53]=2[C:57]2[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=2)[N:48]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(O[C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(N1CCOCC1)C=C2)CO)(C)(C)C>>[CH2:39]([O:46][C:47]1[CH:56]=[CH:55][C:54]2[C:49](=[CH:50][C:51]([CH3:72])=[C:52]([C@H:64]([O:67][C:68]([CH3:69])([CH3:71])[CH3:70])[C:65]([OH:6])=[O:66])[C:53]=2[C:57]2[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=2)[N:48]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: Cc1cc2nc(OCc3ccccc3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Reactant: Cc1cc2nc(N3CCOCC3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: Cc1cc2nc(N3CCOCC3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Product: Cc1cc2nc(OCc3ccccc3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-(2-(Benzyloxy)-5-(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tert-butoxyacetic acid (65A) (3.3 mg) was prepared in a similar manner as compound ((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)acetic acid of Example 29 except using (S)-2-(2-(benzyloxy)-5-(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tert-butoxyethanol instead of ((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)ethanol. 1H-NMR 400 MHz (CD3OD) δ 7.82 (d, J=9.6 Hz, 1 H), 7.71 (s, 1 H), 7.80 (m, 3 H), 7.51 (m, 2 H), 7.41-7.10 (m, 4 H), 7.12 (d, J=9.6 Hz, 1 H), 5.58 (s, 2 H), 5.18 (s, 1 H), 2.66 (s, 3 H), 0.97 (s, 9 H); LCMS-ESI+ (m/z): [M+H]+ calcd for C29H29ClNO4: 490.2. Found: 490.2.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](=[O:28])(=[O:27])[N:11]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19].CCN(CC)CC.CCOCC.Cl>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl.O>[CH3:26][O:25][C:23]([C:22]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:20])([F:21])[F:19])[S:10](=[O:28])(=[O:27])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]=1[OH:2])=[O:24]
Reactant: COC(=O)CN(c1ccccc1C(F)(F)F)S(=O)(=O)c1ccccc1C(=O)OC
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1c1ccccc1C(F)(F)F
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
In a 250 mL dry RB flask, 4.50 mL of TiCl4 (40.8 mmol) was dissolved in 100 mL of CH2Cl2 and was cooled to −30° C. A solution of 2-[methoxycarbonyl-methyl-(2-trifluoromethyl-phenyl)-sulfamoyl]-benzoic acid methyl ester (8.0 g, 18.54 mmol) in 50 mL CH2Cl2 was added dropwise. The resulting solution was kept at −30° C. for 30 minutes and was then cooled to −78° C. Et3N (7.75 mL, 55.6 mmol) in 50 mL CH2Cl2 was slowly syringed in resulting a dark red solution. The reaction mixture was stirred at −78° C. for 4 hours and was then poured into a 1-L flask containing 250 mL of Et2O, 100 mL concentrated HCl, and 100 mL of H2O. The mixture was stirred at room temperature overnight. The layers were separated, and the organic layer was washed with brine and dried over MgSO4. Upon evaporation of the solvent, light yellowish crystals of 4-hydroxy-1,1-dioxo-2-(2-trifluoromethyl-phenyl)-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester were formed. The product was collected through filtration and dried in oven to provide 2.2 g, 86% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]([CH3:16])[C:11]([NH:14][CH3:15])=[N:12][N:13]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].CS(O[CH:24]([C:26]1[N:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)[O:28][N:27]=1)[CH3:25])(=O)=O>CN(C=O)C.[NH4+].[Cl-]>[Cl:37][C:33]1[CH:32]=[C:31]([C:29]2[O:28][N:27]=[C:26]([CH:24]([N:14]([CH3:15])[C:11]3[N:10]([CH3:16])[C:9]([C:4]4[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=4)=[N:13][N:12]=3)[CH3:25])[N:30]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: CC(OS(C)(=O)=O)c1noc(-c2cccc(Cl)c2)n1
Reactant: CNc1nnc(-c2cc(F)cc(F)c2)n1C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(c1noc(-c2cccc(Cl)c2)n1)N(C)c1nnc(-c2cc(F)cc(F)c2)n1C
Yield: 44.2 %

Procedure:
To a solution of 5-(3,5-difluorophenyl)-N,4-dimethyl-4H-1,2,4-triazol-3-amine (0.47 g, 2.10 mmol) in DMF (10 ml) at r.t. under nitrogen was added NaH (77 mg, 3.20 mmol).After stirring for 15 min. a solution of 1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl methanesulfonate (0.70 g, 2.30 mmol) in DMF 10 ml was added. After 3 h the mixture was diluted with sat. NH4Cl solution and then extracted with EA. The organic phase was washed with H2O and brine, dried and evaporated. Purification by silica gel chromatography using hex.:EA=1:1 afforded 400 mg of the racemic N-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-5-(3,5-difluorophenyl)-N,4-dimethyl-4H-1,2,4-triazol-3-amine, which was separated using prep. chiral HPLC on a Chiralpak AD column (hex./2-propanol 80/20 to 100% 2-propanol) to give 183 mg (21%) of the title compound which eluted last. 1H NMR: 1.68 (d, 3 H) 2.89 (s, 3 H) 3.62 (s, 3 H) 4.79 (q, 1 H) 6.80-6.90 (m, 1 H) 7.19 (d, 2 H) 7.40 (t, 1 H) 7.49 (d, 1 H) 7.94 (d, 1 H) 8.04 (s, 1 H)
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:19]#[N:20])(O[Si](C)(C)C)[CH2:6]1)=[O:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([CH2:19][NH2:20])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CC(C#N)(O[Si](C)(C)C)c2ccccc21
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)C1CC(CN)c2ccccc21
Reaction time: 0.25 h
Yield: 88.9 %

Procedure:
To a solution of 5.79 g of 3-cyano-3-trimethylsilanyloxy-indan-1-carboxylic acid methyl ester (20.0 mmol, 1.0 equivalent) in 25 mL of methanol was added 5.71 g of p-toluenesulfonic acid monohydrate (30.0 mmol, 1.5 equivalent). The solution was stirred for 15 minutes and then 4.21 g of 20% palladium hydroxide on carbon, 50% wet by weight, (3.00 mmol, 0.15 equivalent) was added. The reaction mixture was subjected to hydrogenolysis at 50 psi of hydrogen over 24 hours. After this time, the reaction mixture was filtered through Celite and typically used-filtrate in the next step (Example 60D). The isolation of the title compound was conducted as follows: the filtrate was concentrated in vacuo; the residue was partitioned between 30 mL of methylene chloride and 20 mL of a saturated aqueous solution of sodium carbonate; the aqueous layer was extracted with 15 mL of methylene chloride; the combined aqueous layers were washed with 40 mL of a saturated aqueous solution of sodium chloride; the organic solution was dried over anhydrous sodium sulfate and concentrated to afford the title compound as an oil (3.65 g, 89%) with approximately a 10:1 ratio of diastereomers; (major diastereomer) 1H NMR (400 MHz, CDCl3): δ 7.43 (dd, J=6.9, 1.6 Hz, 1H), 7.29–7.25 (m, 3H), 4.09 (t, J=8.1 Hz, 1H), 3.80 (s, 3H), 3.31–3.24 (m, 1H), 3.14 (dd, J=12.8, 4.7 Hz, 1H), 2.98 (dd, J=12.8, 7.3 Hz,1H), 2.62–2.52 (m, 1H), 2.31–2.42 (m, 1H), 1.3 (bs, 2H).
Reaction SMILES: [CH2:1]([Zn]CC)C.FC(F)(F)C(O)=O.ICI.[CH2:16]=[C:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:18]1.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]1[C:17]2([CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:24])[CH2:18]2)[CH2:16]1
Reactant: C=C1CCCN(C(=O)OCc2ccccc2)C1
Reactant: CC[Zn]CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ICI
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCCC2(CC2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
To a stirred solution of Diethyl zinc (1.38 g, 11.2 ml, 1 M solution in hexane 11.24 mmol) in dichloromethane (10 ml) was added trifluoroacetic acid (1.28 g, 0.84 ml, 11.24 mmol) drop wise manner at 0° C. Diiodomethane (3.01 g, 0.90 ml, 11.24 mmol) in dichloromethane (5 ml) was added and reaction mixture was stirred at 0° C. for 30 min. A solution of benzyl 3-methylenepiperidine-1-carboxylate (prepared according to the procedure given in European Journal of Medicinal Chemistry 1991, 26, 625-631), (1.3 g, 5.62 mmol) in dichloromethane (10 ml) was added and reaction mixture stirred at 0° C. for 30 min and then at 25° C. for 18 hr. The progress of reaction was monitored by TLC. Reaction mixture was diluted with dichloromethane (25 ml) and poured in to a saturated solution of sodium bicarbonate (50 ml). Solid precipitated out was filtered, organic layer was separated and dried over sodium sulphate and concentrated under reduced pressure to obtain a crude product, which was purified by flash column chromatography using 6% ethyl acetate in hexanes to obtain the title compound (0.95 g, 68.9%). MS: m/z 246 (M+1).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][N:9]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH2:10][CH2:11][C:12]([F:26])([F:25])[CH2:13][N:14]2C(=O)C3=CC=CC=C3C2=O)C(=O)C2=CC=CC=C12.O.NN.C(O)C.[OH-].[Na+]>O.Cl.CC(C)=O>[NH2:5][CH2:6][CH2:7][CH2:8][N:9]([S:27]([C:30]1[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=1)(=[O:29])=[O:28])[CH2:10][CH2:11][C:12]([F:25])([F:26])[CH2:13][NH2:14]
Reactant: Cc1ccc(S(=O)(=O)N(CCCN2C(=O)c3ccccc3C2=O)CCC(F)(F)CN2C(=O)c3ccccc3C2=O)cc1
Agent: Cl
Agent: NN
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N(CCCN)CCC(F)(F)CN)cc1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
The compound 1,8-diphthalimido-4-p-toluenesulfonyl-7,7-difluoro-4-aza-octane (58.95 g, 99.07 moles) and 1M hydrazine hydrate in ethanol (235 mL, 235 mmoles) are stirred and heated at 90° C. overnight. Conc. HCl (150 mL) is added, and heating (90° C.) and stirring are continued for 45 min. After cooling to room temperature, phthalhydrazide is removed by filtration, and the solvent is evaporated. The residue is dissolved in water, the solution is filtered and evaporated to yield a residue which solidifies upon stripping with acetone. This material is dissolved in water (300 mL), aqueous NaOH (25 g NaOH/150 mL water) is added, and the mixture is extracted with dichloromethane (3×400 mL). Washing with water (200 mL), drying (Na2SO4) and evaporation of the solvent yields a yellow oil, 35.0 g, which is dissolved in 6N HCl (300 mL), evaporated, and stripped with ethanol (twice), CCl4 (twice) and acetone (twice) to yield 1,8-diamino-4 -p-toluenesulfonyl-7,7-difluoro-4-aza-octane as a white solid. This compound is recrystallized by dissolving in the minimum amount of methanol and the addition of acetone/ether: 31.3 g (78%).
Reaction SMILES: [CH:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27](Cl)=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl.[C:42]1(C)[C:43]([C:48]([N:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)=O)=[CH:44][CH:45]=[CH:46][CH:47]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27]([N:53]5[CH2:52][CH2:51][N:50]([C:48]6[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=6[CH3:42])[CH2:55][CH2:54]5)=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Reactant: Cc1ccccc1C(=O)N1CCNCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1N1CCN(C(=O)c2ccc3n2Cc2ccccc2N(C(=O)c2ccc(C4CCCCC4)cc2)C3)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude 10-(4-cyclohexyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carbonyl chloride prepared in the manner of Example 23 (0.5 g) was added to a stirred mixture of N,N-diisopropylethyl amine (0.47 g), 4-(2-toluoyl)piperazine hydrochloride (0.51 g) and 4-(dimethylamino)pyridine (0.05 g) in dichloromethane (25 mL). After stirring overnight at room temperature the reaction mixture was washed with water and saturated aqueous sodium bicarbonat, and dried over anhydrous sodium sulfate. The solution was filtered through a short column of Magnesol®. Refluxing the eluate with the gradual addition of hexane resulted in crystallization of the desired title compound (0.46 g) as colorless crystals, m.p. 141–143° C.
Reaction SMILES: [C:1]([C:3]1[CH:17]=[C:16](I)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2].[C:19]([NH:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)(=[O:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+].C(NC1C=C(C2C3N(C4C=CC=CC=4)C=NC=3C=C(C#N)C=2)C=CC=1)(=O)C>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.C(O)C.C1(C)C=CC=CC=1>[C:19]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:16]2[C:6]3[N:7]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:8]=[N:9][C:5]=3[CH:4]=[C:3]([C:1]#[N:2])[CH:17]=2)=[CH:25][CH:24]=1)(=[O:21])[CH3:20]
Reactant: N#Cc1cc(I)c2c(c1)ncn2-c1ccccc1
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)Nc1cccc(-c2cc(C#N)cc3ncn(-c4ccccc4)c23)c1
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc(-c2cc(C#N)cc3ncn(-c4ccccc4)c23)cc1
Yield: 37.5 %

Procedure:
This was prepared from 5-cyano-7-iodo-1-phenylbenzimidazole (173 mg, 0.5 mmol), toluene (3.0 ml), tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol), 4-acetamidophenylboronic acid (90 mg, 0.5 mmol), ethanol (3.0 ml) and potassium carbonate (138 mg, 1.0 mmol) in a similar manner to 7-(3-acetamidophenyl)-5-cyano-1-phenylbenzimidazole. Purification by a similar procedure afforded the title compound (66 mg, 37%) m/z, 353.0 (M+H)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=1)(=O)=O.[S:22]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23]1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.[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>[S:22]1[CH:26]=[CH:25][C:24]([C:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:11][CH:12]=2)=[CH:23]1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: OB(O)c1ccsc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2ccsc2)CC1
Yield: 71.6 %

Procedure:
To a solution of tert-butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate (610 mg) in 1,2-dimethoxyethane (15 ml) was added 3-thienylboronic acid (353 mg), tetrakis(triphenylphosphine) palladium (106 mg) and aq. 2M cesium carbonate solution (2.7 ml) and the mixture was refluxed 2 hours under nitrogen atmosphere. After removal of solvent in vacuo, the residue was extracted by EtOAc. The extract was washed with brine, dried over MgSO4 and concentrated in vacuo. The resultant residue was purified by silica gel column (n-hexane:EtOAc=80:20) to give tert-butyl 4-(3-thienyl)-3,6-dihydropyridine-1(2H)-carboxylate (350 mg) as a colorless oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[C@:10]([NH2:21])([CH3:20])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[NH2:21][C@@:10]([CH3:20])([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH2:9][OH:8]
Reactant: COC(=O)[C@@](C)(N)CCc1ccccc1Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: C[C@@](N)(CO)CCc1ccccc1Cl
Reaction time: 2 h

Procedure:
To a suspension of lithium aluminum hydride (0.072 g, 1.9 mmol) in tetrahydrofuran (10 ml) was added a solution of (S)-2-amino-4-(2-chloro-phenyl)-2-methyl-butyric acid methyl ester (0.23 g, 0.95 mmol) in tetrahydrofuran (3 ml) and the mixture was stirred for 2 hours. Sodium sulphate solution (2M, 0.3 ml) was added and the mixture was filtered through Celite. The solvent was evaporated and the residue was purified by chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: ethyl acetate/MeOH=95:5) to yield a colourless oil, (0.190 g, 93%);
Reaction SMILES: [C:1]([O:5][P:6]([O:13][CH2:14][C:15]([NH:18]C(=O)OCC1C=CC=CC=1)([CH3:17])[CH3:16])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.[H][H]>[OH-].[OH-].[Pd+2].CO>[P:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:13][CH2:14][C:15]([NH2:18])([CH3:17])[CH3:16])=[O:7]
Reactant: [H][H]
Reactant: CC(C)(COP(=O)(OC(C)(C)C)OC(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(N)COP(=O)(OC(C)(C)C)OC(C)(C)C
Yield: 94.8 %

Procedure:
The product of Example 438B (0.40 g, 0.96 mmol) and 20% palladium hydroxide on carbon (0.21 g) in a ethyl acetate (10 mL) and methanol (1 mL) was stirred under a an atmosphere of hydrogen for 0.5 hours. The reaction was filtered through a bed of celite and concentrate to give the title product (0.256 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][CH2:20][CH3:21])=[C:6]([C:8]2[N:16]=[C:15]3[C:11](=[N:12][N:13]=[N:14]3)[C:10](=[O:17])[N:9]=2)[CH:7]=1.Cl.[NH2:23]C1C=CC(OCCC)=C(C2N=C3C(=NN=N3)C(=O)N=2)C=1.N([O-])=O.[Na+].S(=O)(=O)(O)N.N(O)=O.[C:56]([CH2:59][C:60](=[O:62])[CH3:61])(=[O:58])[CH3:57].C([O-])(=O)C.[Na+]>Cl.O.C(O)C>[O:58]=[C:56]([CH:59]([N:23]=[N:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][CH2:20][CH3:21])=[C:6]([C:8]2[N:16]=[C:15]3[C:11](=[N:12][N:13]=[N:14]3)[C:10](=[O:17])[N:9]=2)[CH:7]=1)[C:60](=[O:62])[CH3:61])[CH3:57]
Reactant: CC(=O)CC(C)=O
Reactant: CCCOc1ccc(N)cc1C1=NC(=O)C2=NN=NC2=N1
Agent: CC(=O)[O-]
Agent: Cl
Agent: NS(=O)(=O)O
Solvent: O
Solvent: CCO
Product: CCCOc1ccc(N=NC(C(C)=O)C(C)=O)cc1C1=NC(=O)C2=NN=NC2=N1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-(5-Amino-2-propoxyphenyl)-8-azapurin-6-one (1.5 g) was dissolved in a hot mixture of concentrated hydrochloric acid (4 ml) and water (20 ml). The solution was then cooled to 0° C. to give a suspension of 2-(5-amino-2-propoxyphenyl)-8-azapurin-6-one hydrochloride. The stirred suspension was treated with a solution of sodium nitrite (0.5 g) in water (2 ml) during 10 minutes. After stirring for one hour at 0° C., a sufficient quantity of sulphamic acid was added to decompose the excess of nitrous acid. The resulting ice-cold solution was then added, dropwise, to a stirred mixture of acetylacetone (2 ml), ethanol (20 ml), water (10 ml) and sodium acetate (5 g) at 0° C. during 30 minutes. After a further 30 minutes, the thick yellow mixture was filtered, and the precipitate was washed with water and sucked dry. Recrystallisation from a mixture of dimethylformamide and methanol gave 2-[5-(2,4dioxopent-3-ylazo)-2-propoxyphenyl]-8-azapurin-6-one (1.4 g), m.p. 288°-290° C. (with decomposition).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].CC1C=C[C:9]([O:12]C)=CC=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]>Cl>[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:9]=[O:12])=[CH:17][C:16]=1[CH3:21]
Reactant: Cc1ccccc1F
Reactant: COc1ccc(C)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C=O)ccc1F
Temperature: 30 °C
Yield: 131.4 %

Procedure:
229.30 g of aluminum chloride (mol. Wt. 133.34; 1,719.7 mmol), 110.0 g (4-Methylanisole (mol. Wt. 122.17; 900.4 mmol), and about 500 g of 2-fluorotoluene (mol. Wt. 110.13; 4,540.1 mmol) were charged to a 2 liter Parr®-brand 4522 stainless steel reaction vessel. To this mixture was added 5 drops of concentrated HCl. The vessel was sealed, heated to 30° C., and purged three times with carbon monoxide with the pressure of the vessel increased to 100 psi for each purging. After the third purge, the vessel was vented and a final introduction of CO was made at a pressure of about 550 psi, the pressure at which the reaction was maintained for the total reaction time of about 66 hours (the reaction temperature was maintained at 30° C. for the duration as well). Once the reaction was complete, the resultant mixture (exhibiting a greenish-brown color) was poured into about 500 mL of ice water (which turned the solution a yellow color), to which was added 500 mL of cyclohexane. The top, organic layer was removed and washed three times with water using a separatory funnel and dried over magnesium sulfate. The residual organic phase was then distilled under vacuum to remove excess cyclohexane, 2-fluorotoluene, and left about 98.01 g of 4-fluoro-3-methylbenzaldehyde product (mol. Wt. 138.14; 709.5 mmol; yield of approximately 86.7%). The 4-fluoro-3-methylbenzaldehyde product may then be easily separated from any residual 4-methylanisole by conversion into its corresponding bisulfite adduct, filtration, and decomposition of the bisulfite adduct under acidic or basic conditions.