Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9](I)[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:5]2.[C-:25]#[N:26].[Na+]>C(#N)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.[Cu]I>[Cl:1][C:2]1[CH:10]=[C:9]([C:25]#[N:26])[C:8]2[C:7](=[O:12])[N:6]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH2:5][C:4]=2[CH:3]=1
Reactant: O=C1c2c(I)cc(Cl)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Reactant: [C-]#N
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CC#N
Product: N#Cc1cc(Cl)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 80 °C
Reaction time: 18 h
Yield: 68.7 %

Procedure:
A mixture of 5-chloro-7-iodo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.339 g, 0.73 mmol), Pd(PPh3)4 (0.084 g, 0.073 mmol), sodium cyanide (0.046 g, 0.95 mmol), and CuI (0.017 g, 0.073 mmol) in acetonitrile (5 mL) was stirred at 80° C. for 18 h. Workup and silica gel column chromatography using 2:1 hexanes-ethyl acetate afforded 6-chloro-3-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-4-carbonitrile (0.184 g, 69%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.31 (s, 2H), 4.81 (s, 2H), 7.20 (d, 2H), 7.37 (d, 2H), 7.62 (s, 1H), 7.76 (s, 1H). GC-MS: m/z 366 (M)+.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5].[CH3:13]C([O-])=O.[K+]>O1CCOCC1.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]>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH:4]([OH:5])[CH3:13])[N:7]=1
Reactant: CON(C)C(=O)c1cccnn1
Reactant: CC(=O)[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(O)c1cccnn1
Temperature: 100 °C
Yield: 281.9 %

Procedure:
A suspension of compound 2 (170 mg, 0.4 mmol), compound 2A (112 mg, 0.44 mmol), PdCl2(dppf)2 (50 mg, 0.08 mmol) and KOAc (118 mg, 1.2 mmol) in anhydrous 1,4-dioxane (6 mL) was heated at 100° C. for 60 min in a CEM microwave reactor. The mixture was concentrated in vacuo and the residue was purified by preparative TLC (eluent:petroleum ether:ethyl acetate=3:1) to give compound 3 (140 mg, 70%, 67% purity) as a yellow solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[CH:13][C:8](/[CH:9]=[CH:10]/[CH2:11][OH:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[O-]O.C1(C(C)C)C=CC=CC=1.C(Cl)Cl.C([C@@](C([O-])=O)(O)[C@@](CC)(O)C([O-])=[O:34])C.[F-].[Na+].[Cl-].[Na+]>C(Cl)Cl.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[O:34]1[C@@H:9]([C:8]2[CH:13]=[CH:14][C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)[C@@H:10]1[CH2:11][OH:12]
Reactant: CC[C@](O)(C(=O)[O-])[C@](O)(CC)C(=O)[O-]
Reactant: CC(=O)Oc1ccc(/C=C/CO)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Cl-]
Solvent: CC(C)c1ccccc1
Solvent: ClCCl
Product: CC(=O)Oc1ccc([C@@H]2O[C@H]2CO)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To an ice-cooled solution of 384 Mg (2 mmol) of 4-acetoxy-trans-cinnamylalcohol (I) in 18 ml of anhydrous methylene chloride is added 1.2 ml of 3.32N-cumene hydroperoxide/methylene chloride solution under nitrogen atmosphere and the reaction mixture stirred under ice-cooling. 0.402N Solution (0.666 ml) of titanium tetraisopropoxide in methylene chloride is mixed with 0.407N solution (0.98 ml) of diethyl-L-(+)-tartrate in methylene chloride under nitrogen atmosphere, and the mixture allowed to stand for one hour and then added to the above reaction mixture in three portions every 10 minutes. After 45 minutes, the mixture is poured into a saturated aqueous solution of sodium fluoride (2.5 g) with vigorous stirring at room temperature for 15 minutes. Sodium chloride (16 g) is added and the mixture stirred for further 15 minutes. The precipitated gelatinous material is collected by filtration through a filter aid and washed with methylene chloride. The organic layer is dried over anhydrous magnesium sulfate and concentrated in vacuo. 1.24 g Oily residue is dissolved in carbon tetrachloride and filtered. The filtrate is concentrated in vacuo and a residue is dissolved in 5 ml of benzene, chromatographed on silica gel (Lobor B; made by Merck) and eluted with ethyl acetate/hexane (1:1) (each fraction 11 ml). Fractions which show a single spot in thin layer chromatography are collected and concentrated in vacuo to give 309 mg (74.3%) of the above-defined compound (II) as crystalline, mp. 59°-61° C., [α]D23 : -23.7±0.6° (c 1.017, chloroform).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=1)[OH:11]>O1CCOCC1.[Mn]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=1)=[O:11]
Reactant: Cc1cccc(C(O)c2nc3ccccc3s2)c1
Agent: [Mn]
Solvent: C1COCCO1
Product: Cc1cccc(C(=O)c2nc3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (benzothiazol-2-yl)(m-tolyl)methanol (2.41 g) in dioxane (30 mL) is added manganese dioxyde (1.2 molar equivalent). The mixture is stirred overnight at room temperature, then filtered over a clarcel pad. The filtrate is concentrated under reduced pressure. The residue is triturated in heptane and diisopropyl oxyde to give (benzothiazol-2-yl)(m-tolyl)methanone
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)=O.[CH:18]1([C:21](=O)[CH2:22][C:23]#[N:24])[CH2:20][CH2:19]1>>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:21]([CH:18]1[CH2:20][CH2:19]1)[C:22]([C:23]#[N:24])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1cccc(Cl)c1
Reactant: N#CCC(=O)C1CC1
Product: N#Cc1c(C2CC2)nc2ccc(Cl)cc2c1-c1cccc(Cl)c1

Procedure:
The title compound was prepared in analogy to example 101 step B from (2-amino-5-chloro-phenyl)-(3-chloro-phenyl)-methanone (prepared as described in example 91 step A) and 3-cyclopropyl-3-oxo-propionitrile. Light yellow solid. MS (ESI): 339.3 (M+H)+.
Reaction SMILES: [CH:1]12[O:6][CH:5]1[CH2:4][CH2:3][CH2:2]2.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O1CCOCC1>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C@@H:4]2[CH2:3][CH2:2][CH2:1][C@H:5]2[OH:6])=[CH:10][CH:9]=1
Reactant: Oc1ccc(Br)cc1
Reactant: C1CC2OC2C1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Product: O[C@@H]1CCC[C@H]1Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 66 h

Procedure:
6-Oxabicyclo[3.1.0]hexane (2.04 mL, 23.5 mmol), 4-bromophenol (4.49 g, 26.0 mmol), cesium carbonate (99%, 8.93 g, 27.1 mmol) and benzyltriethylammonium chloride (99%, 1.09 g, 4.74 mmol) were suspended in dioxane (65 mL) and heated at reflux for 18 hours. Additional 6-oxabicyclo[3.1.0]hexane (0.50 mL, 5.8 mmol) was added, and heating was continued for 66 hours. Again, 6-oxabicyclo[3.1.0]hexane (0.50 mL, 5.8 mmol) was added, and the reaction mixture was heated at reflux for an additional 18 hours. The reaction was then cooled to room temperature, concentrated in vacuo and partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over calcium sulfate, filtered and concentrated under reduced pressure to afford a golden oil, which was purified via chromatography on silica gel (Gradient: 0% to 20% ethyl acetate in heptane) to provide product as an oil. Yield: 3.21 g, 12.5 mmol, 48%. GCMS m/z 256, 258 (M+). 1H NMR (400 MHz, CDCl3) δ 1.64 (d, J=3.7 Hz, 1H), 1.60-1.68 (m, 1H), 1.70-1.88 (m, 3H), 2.07 (m, 1H), 2.17 (m, 1H), 4.30 (m, 1H), 4.48 (m, 1H), 6.80 (d, J=9.0 Hz, 2H), 7.37 (d, J=9.0 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH2:4].[H-].[Na+].Cl[C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[CH:23]=[CH:24][S:25][C:16]=12>O1CCCC1>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH:4][C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[CH:23]=[CH:24][S:25][C:16]=12
Reactant: COc1cc(N)c(Cl)cc1Cl
Reactant: N#Cc1cnc2ccsc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Nc2c(C#N)cnc3ccsc23)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.7 %

Procedure:
A mixture of 2,4-dichloro-5-methoxyaniline (336 mg, 1.75 mmol) and 60% sodium hydride (70 mg, 1.75 mmol) in 10 mL of tetrahydrofuran is heated at reflux for 30 minutes. The solution is cooled and 7-chlorothieno[3,2-b]pyridine-6-carbonitrile (200 mg, 1.02 mmol) is added. The reaction mixture is heated at reflux for 3.5 hours then allowed to stir at room temperature overnight. The resultant black solution is partitioned between ethyl acetate and water. The organic layer is washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 1:1 ethyl acetate:hexane. The fractions containing product are combined and concentrated. Diethyl ether is added and the insoluble material collected by filtration to provide 131 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile as a tan solid, mp 216–220° C.; 1 H NMR (DMSO-d6) δ 3.85 (s, 3H), 7.40 (3, 1H), 7.46 (d, J=5 Hz, 1H), 7.76 (s, 1H), 8.11 (d, J=5 Hz, 1H), 8.61 (s, 1H), 9.71 (s, 1H); MS 350.2 (M+H)+.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:18]=[CH:19][C:20]([O:24][CH3:25])=[C:21]([NH2:23])[CH:22]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[CH:12]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6](=[CH:16][C:17]3[CH:18]=[CH:19][C:20]([O:24][CH3:25])=[C:21]([NH:23][S:27]([CH3:26])(=[O:29])=[O:28])[CH:22]=3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C=C2c3ccccc3CCc3ccccc32)cc1N
Product: COc1ccc(C=C2c3ccccc3CCc3ccccc32)cc1NS(C)(=O)=O
Yield: 77 %

Procedure:
Following procedures essentially as described in Example 90-, 5-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-2-methoxy-phenylamine and methanesulfonyl chloride gives the title compound in 77% yield as a tan foam, mp 192.1° C. 1H NMR (CDCl3) δ 2.74 (s, 3H), 2.80-4.61 (br m, 4H), 4.81 (s, 3H), 6.67-7.50 (m, 13H); MS (ES) 423 (M+NH4), 404 (M−H). HPLC shows 100% purity.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]3[CH2:15][CH2:16][CH:17]([NH2:18])[CH:11]3[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](O)=[O:26].OC1C2N=NNC=2C=CC=1.CN(C)CCCN=C=NCC>ClCCl>[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([NH:18][C@H:17]1[C@@H:11]2[CH2:10][N:9]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:19])[F:20])[N:8]=3)[CH2:14][CH2:13][N:12]2[CH2:15][CH2:16]1)=[O:26]
Reactant: NC1CCN2CCN(c3cccc(C(F)(F)F)n3)CC12
Reactant: O=C(O)c1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: O=C(N[C@@H]1CCN2CCN(c3cccc(C(F)(F)F)n3)C[C@@H]12)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 96B (100 mg, 0.349 mmol), 3-fluorobenzoic acid (58.7 mg, 0.419 mmol) and hydroxybenzotriazole (58.8 mg, 0.384 mmol) in dichloromethane (1.5 mL), was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.067 mL, 0.384 mmol). The mixture was stirred at room temperature overnight. The mixture was then purified via HPLC (Gilson®, XBridge™ 30×100 mm column, eluted with pH=10 aqueous ammonium bicarbonate-ammonium hydroxide/methanol, UV=250 nm) to give the title compound as the first eluting diastereomer. 1H NMR (500 MHz, methanol-d4) δ ppm 1.74-1.81 (m, 1 H), 2.19-2.25 (m, 1 H), 2.34 (td, 1H, J=11, 3 Hz), 2.38-2.44 (m, 1 H), 2.49 (m, 1H), 2.83 (dd, 1H, J=12, 10 Hz), 2.98-3.06 (m, 1 H), 3.08-3.18 (m, 2 H), 4.31-4.40 (m, 2 H), 4.51-4.57 (m, 1 H), 6.96 (d, 1H, J=7 Hz), 6.99 (d, 1H, J=8 Hz), 7.29 (td, 1H, J=8, 1 Hz), 7.49 (td, 1H, J=8, 6 Hz), 7.59 (dt, 1H, J=9, 2 Hz), 7.63-7.70 (m, 2 H); MS (DCI) m/z 409 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][NH:9][C:10]1[CH:11]=[C:12]([C:16]2[N:21]=[CH:20][C:19]([CH:22]=[C:23]([O:29][CH2:30][CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][CH:17]=2)[CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>O1CCCC1.[Pd]>[C:1]([O:5][C:6]([CH2:8][NH:9][C:10]1[CH:11]=[C:12]([C:16]2[N:21]=[CH:20][C:19]([CH2:22][CH:23]([O:29][CH2:30][CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][CH:17]=2)[CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=Cc1ccc(-c2cccc(NCC(=O)OC(C)(C)C)c2)nc1)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(-c2cccc(NCC(=O)OC(C)(C)C)c2)nc1)OCC
Yield: 51.3 %

Procedure:
A solution of 0.2 g (0.5 mmol) of ethyl 3-{6-[3-(tert-butoxycarbonylmethylamino)phenyl]pyrid-3-yl}-2-ethoxyacrylate in 10 ml of tetrahydrofuran is degassed and 0.02 g (10% by mass) of 10% Pd/C is added. After reaction for 5 hours under an atmospheric pressure of hydrogen, the reaction medium is stirred under 3 atm of hydrogen for 24 hours. After filtration through Celite and evaporation of the filtrate, 0.11 g (55%) of ethyl 3-{6-[3-(tert-butoxycarbonylmethylamino)phenyl]pyrid-3-yl}-2-ethoxypropanoate is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:13][C:12](=[O:14])[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1.[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:28]Br>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[CH:10][C:11]([C:15]#[N:16])=[C:12]([O:14][CH2:28][C:27]2[CH:30]=[CH:31][C:32]([F:33])=[C:25]([F:24])[CH:26]=2)[N:13]=1
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)[nH]c1=O
Reactant: Fc1ccc(CBr)cc1F
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nc1OCc1ccc(F)c(F)c1
Temperature: 75 °C

Procedure:
To the product of Step C (0.500 g, 1.465 mmol) was added Ag2CO3 (0.606 g, 2.198 mmol), DMF (8 mL), and 3,4-difluorobenzyl bromide (0.28 mL, 2.198 mmol). The reaction was heated to 75° C. for 75 min before cooling and filtering through Celite®545 diatomaceous earth. The solution was concentrated and the residue was purified by flash chromatography (silica gel) eluting with a gradient of 15 to 46% ethyl acetate/hexane affording the product. MS (electrospray) m/e 467.0 MH+ (Rt=4.7 min LC/MS).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=2)[CH:3]=1.C([Mg]Cl)(C)C.[Li]C(C)(C)C.[O:36]1[CH2:41][CH2:40][C:39](=[O:42])[CH2:38][CH2:37]1>C1COCC1>[CH3:24][C:21]1([CH3:25])[CH2:22][CH2:23][C:18]([C:4]2[CH:3]=[C:2]([C:39]3([OH:42])[CH2:40][CH2:41][O:36][CH2:37][CH2:38]3)[CH:7]=[CH:6][C:5]=2[NH:8][C:9]([C:11]2[NH:15][C:14]([C:16]#[N:17])=[CH:13][N:12]=2)=[O:10])=[CH:19][CH2:20]1
Reactant: CC1(C)CC=C(c2cc(Br)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Reactant: O=C1CCOCC1
Agent: CC(C)[Mg]Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC1(C)CC=C(c2cc(C3(O)CCOCC3)ccc2NC(=O)c2ncc(C#N)[nH]2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 79.3 %

Procedure:
To a suspension of 4-cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (0.550 g, 1.38 mmol) (prepared in the previous step) in 20 mL THF at −40° C. was added i-PrMgCl (1.40 mL, 2.80 mmol, 2 M in THF) and the solution was then warmed to 0° C. and stirred for 10 min. The solution was then cooled to −78° C. and t-BuLi (2.15 mL, 3.65 mmol, 1.7 M in pentane) was added dropwise over 5 min and then tetrahydro-pyran-4-one (0.650 mL, 7.05 mmol) was added immediately thereafter. After 5 min at −78° C. the reaction was quenched with satd NH4Cl (20 mL) and extracted with EtOAc (3×20 mL) and dried over Na2SO4. The title compound was purified by flash chromatography (Si gel) eluting with 50% EtOAc/DCM to give 0.460 g (79%) of a white solid. 1H-NMR (400 MHz, DMSO-d6): δ 14.28 (s, 1H), 9.77 (s, 1H), 8.21 (s, 1H), 7.98 (d, J=8.5 Hz, 1H), 7.38 (dd, J=8.5, 2.2 Hz, 1H), 7.34 (d, J=2.2 Hz, 1H), 5.67 (m, 1H), 5.03 (s, 1H), 3.83-3.66 (m, 4H), 2.31-2.22 (m, 2H), 2.04-1.92 (m, 4H), 1.58-1.46 (m, 4H), 1.01 (s, 6H). Mass spectrum (ESI, m/z): calcd. for C24H28N4O3, 421.2 (M+H). found 421.1.
Reaction SMILES: COC(=O)[CH:4]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[Cl:22])[C:5]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH3:13])[CH:8]=1)=[O:6].[Cl-].[Na+].O>CS(C)=O>[Cl:22][C:15]1[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=1[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH3:13])[CH:8]=1)=[O:6]
Reactant: COC(=O)C(C(=O)c1ccnc(C)c1)c1ccc(OC)cc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CC(=O)c2ccnc(C)c2)c(Cl)c1
Temperature: 140 °C
Reaction time: 8 h
Yield: 65.6 %

Procedure:
A mixture of 2-(2-chloro-4-methoxy-phenyl)-3-(2-methyl-pyridin-4-yl)-3-oxo-propionic acid methyl ester (13.95 g), sodium chloride (2.71 g), water (1.14 mL) and DMSO (400 mL) was heated to 140° C. for 3 hours. Stirring was continued overnight at r.t. The reaction mixture was poured into ice/water and extracted two times with ethyl acetate. The organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a yellow solid (7.56 g, 62%). MS (m/e)=276.2 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:15])[CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)O[CH:8]=1.CC(O)=O.[NH2:20][C:21]1[CH:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:25][CH:26]=1>O>[C:23]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:25][CH:26]=[C:21]([N:20]2[CH:8]=[C:3]([O:2][CH3:1])[C:4](=[O:15])[CH:5]=[C:6]2[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:22]=1
Reactant: Nc1cccc(-c2ccccc2)c1
Reactant: COc1coc(-c2ccccc2)cc1=O
Solvent: CC(=O)O
Solvent: O
Product: COc1cn(-c2cccc(-c3ccccc3)c2)c(-c2ccccc2)cc1=O
Temperature: 130 °C
Yield: 44 %

Procedure:
To a solution of 5-methoxy-2-phenyl-4H-pyran-4-one (35 mg, 0.17 mmol) in a 1:1 mixture of AcOH:water (0.6 mL) was added 3-aminobiphenyl (59 mg, 0.35 mmol). The reaction vessel was sealed and heated at 130° C. for 3 h before being cooled to room temperature and purified by reversed phase HPLC (2 cm×5 cm C18, acetonitrile-water gradient, 0.05% TFA added) to provide (44%) 1-(biphenyl-3-yl)-5-methoxy-2-phenylpyridin-4(1H)-one. LC/MS (M+H)+ 354.
Reaction SMILES: [C:1]([CH:4]1[NH:9][CH2:8][C:7]2[S:10][C:11]([CH2:13][CH2:14]Br)=[CH:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:17][C:18]1[CH:32]=[CH:31][C:21]2[C:22]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:23][O:24][C:20]=2[CH:19]=1.C([O-])(=O)C([O-])=O>>[C:1]([CH:4]1[NH:9][CH2:8][C:7]2[S:10][C:11]([CH2:13][CH2:14][N:28]3[CH2:27][CH2:26][CH:25]([C:22]4[C:21]5[CH:31]=[CH:32][C:18]([F:17])=[CH:19][C:20]=5[O:24][N:23]=4)[CH2:30][CH2:29]3)=[CH:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)C1Cc2cc(CCBr)sc2CN1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C([O-])C(=O)[O-]
Product: CC(=O)C1Cc2cc(CCN3CCC(c4noc5cc(F)ccc45)CC3)sc2CN1
Yield: 68.9 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 0.7 g of 5-acetyl-2-(2-bromoethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine and 0.61 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 0.7 g of 5-acetyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno[ 2,3-c]pyridine as an oil, m.p. 170°-172° C. as oxalate thereof.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[Br-].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Zn+]>C1COCC1.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>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=1
Reactant: [Zn+]c1ccccn1
Reactant: COc1cc([N+](=O)[O-])ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])ccc1-c1ccccn1

Procedure:
A solution of 2-bromo-5-nitroanisole (5.8 g, 25 mmol) in THF (50 mL) was treated with 2-pyridyl-zinc bromide (50 mL of a 0.5M solution in THF, 25 mmol) and Pd(PPh3)4 (1.44 g, 1.25 mmol). The reaction mixture was degassed by bubbling argon through the solution for min and was subsequently heated to reflux for 12 h while under an atmosphere of argon. The cooled reaction mixture was concentrated and purified by flash column chromatography on silica gel eluting with EtOAc:hexanes (1:19 to 2:3) to afford the desired 2-(2-methoxy-4-nitrophenyl)pyridine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:14]([NH2:17])=[N:15][OH:16])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][C:21]([C:23]#[C:24][C:25]([O:27][CH3:28])=[O:26])=[O:22]>C(Cl)(Cl)Cl>[CH3:19][O:20][C:21](=[O:22])[C:23]([O:16][N:15]=[C:14]([NH2:17])[C:8]1([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:18])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)=[CH:24][C:25]([O:27][CH3:28])=[O:26]
Reactant: CC(C)(C)OC(=O)NC1(C(N)=NO)CCOCC1
Reactant: COC(=O)C#CC(=O)OC
Solvent: ClC(Cl)Cl
Product: COC(=O)C=C(ON=C(N)C1(NC(=O)OC(C)(C)C)CCOCC1)C(=O)OC

Procedure:
A solution of tert-butyl-4-[amino(hydroxyimino)methyl]tetrahydro-2H-pyran-4-yl-carbamate (C-27) and dimethylacetylendicarboxylate (1.2 eq.) in chloroform was refluxed for 1 hour under nitrogen and the solution was concentrated. Residue was purified by flash chromatography on silica gel (eluent:petroleum ether:ethyl acetate=7:3) to give the desired product (C-28) as a mixture of isomers in ratio 7:3.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH:5]1[C:10](=O)[N:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:8]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:6]1=[O:7].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[C:37]([O:45]C(=O)C1C=CC=NC=1)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[N:40][CH:39]=1.C(=O)(O)[O-].[Na+].[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>CC(C)=O.ClCCl>[C:12]1([N:9]2[C:10]([C:39]3[C:38]([C:37]([OH:45])=[O:44])=[CH:43][CH:42]=[CH:41][N:40]=3)=[C:5]([CH2:4][CH2:3][CH2:2][CH3:1])[C:6](=[O:7])[N:8]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCCCC1C(=O)N(c2ccccc2)N(c2ccccc2)C1=O
Reactant: O=C(OC(=O)c1cccnc1)c1cccnc1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC(C)=O
Product: CCCCc1c(-c2ncccc2C(=O)O)n(-c2ccccc2)n(-c2ccccc2)c1=O
Reaction time: 1 h
Yield: 77.1 %

Procedure:
Phenylbutazone (1,2-diphenyl-3,5-pyrazolidinedione; 11.00 g, 0.035 mole) was treated with 11.55 g (0.055 mole) of trifluoroacetic anhydride. The resulting solid suspension was shaken or mechanically stirred until a homogeneous solution was obtained, then it was stirred with a magnetic stirrer at room temperature in a tightly closed flask for one hour. The solution was concentrated in vacuo for one hour and the oily residue obtained was dissolved in 50 ml of acetone and allowed to react with 12.5 g (0.055 mole) of nicotinic anhydride. The initial suspension became homogeneous after 0.25 hours with concomitant formation of a yellow color. After an additional one hour at room temperature, the yellow solution was concentrated in vacuo and the residue was dissolved in 200 ml of dichloromethane. The dichloromethane solution was extracted first with an aqueous sodium bicarbonate solution (12.2 g, 0.145 mole in 150 ml), then with an aqueous sodium hydroxide solution (28 g, 0.07 mole in 56 ml) and subsequently dried over sodium sulfate. The dichloromethane solution was concentrated in vacuo and the residue was crystallized from dichloromethane petroleum ether bp 30-60° C to give 11.16 g (mp 139-141° C, 77.5% yield) of the title compound.