Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:14]=[O:15])=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])=[O:4].CC(=CC)C.[Cl-].[Na+].[O:23]1CCOCC1>O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]([OH:23])=[O:15])=[CH:8][C:9]=1[C:10]([F:11])([F:12])[F:13])=[O:4]
Reactant: C1COCCO1
Reactant: COC(=O)c1sc(C=O)cc1C(F)(F)F
Agent: CC=C(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1sc(C(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a solution of 5-Formyl-3-trifluoromethyl-thiophene-2-carboxylic acid methyl ester (2.05 g, 8.61 mmol) in dioxane (40 ml) was added 2-methyl-2-butene (9 ml) and a solution of Na2ClO2 (2.34 g, 25.92 mmol) and NaH2PO4 (2.82 g) in water (9 ml). The mixture was stirred at rt for 1.5 h. The solution was saturated with sodium chloride, then successively extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford the desired product (2.61 g, 100% yield).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12]C(=O)[O:10][C:8](=O)[C:7]=12.[NH:14]([CH2:16][C:17]([OH:19])=[O:18])[CH3:15].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.O>[I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:12])[C:7]=1[C:8]([N:14]([CH3:15])[CH2:16][C:17]([OH:19])=[O:18])=[O:10]
Reactant: O=c1[nH]c2cccc(I)c2c(=O)o1
Reactant: CNCC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(CC(=O)O)C(=O)c1c(N)cccc1I

Procedure:
A suspension of 8.7 g (0.03 mol) of 6-iodoisatoic acid anhydride, 2.95 g (0.033 mol) of sarcosine and 4.2 g of potassium carbonate in 50 ml of dimethylformamide is heated to 50° for 30 minutes. After cooling, the mixture is diluted with 400 ml of water, adjusted to pH 1-2 with 2 N hydrochloric acid and extracted several times with chloroform/isopropanol (4:1). After evaporation of the solvent and recrystallization of the residue from methylene chloride/hexane, there is obtained N-(6-iodoanthraniloyl)-N-methylglycine of melting point 147°-149°.
Reaction SMILES: C1([O:6][C:7](=[O:41])[C@@H:8]([NH2:40])[CH2:9][CH2:10][O:11][C:12]2[CH:21]=[C:20]3[C:15]([C:16]([O:22][C:23]4[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:37])[C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:25][CH:24]=4)=[N:17][CH:18]=[N:19]3)=[CH:14][C:13]=2[O:38][CH3:39])CCCC1.[OH-].[Li+]>C1COCC1.O>[NH2:40][C@@H:8]([CH2:9][CH2:10][O:11][C:12]1[CH:21]=[C:20]2[C:15]([C:16]([O:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:37])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:25][CH:24]=3)=[N:17][CH:18]=[N:19]2)=[CH:14][C:13]=1[O:38][CH3:39])[C:7]([OH:41])=[O:6]
Reactant: COc1cc2c(Oc3ccc(NC(=O)c4ccccc4)cc3)ncnc2cc1OCC[C@H](N)C(=O)OC1CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c(Oc3ccc(NC(=O)c4ccccc4)cc3)ncnc2cc1OCC[C@H](N)C(=O)O
Reaction time: 18 h
Yield: 36.4 %

Procedure:
To a mixture of (S)-2-amino-4-[4-(4-benzoylamino-phenoxy)-6-methoxy-quinazolin-7-yloxy]-butyric acid cyclopentyl ester (25 mg, 0.045 mmol) in THF/H2O (4 ml, 1:1) was added lithium hydroxide (5.4 mg, 0.225 mmol) and the mixture was stirred for 18 hours, acidified and concentrated under reduced pressure. The residue was purified by preparative HPLC to provide the title compound as a white solid (8 mg).
Reaction SMILES: C([O:9][CH2:10][CH2:11][C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[S:14]([O-:17])(=[O:16])=[O:15])(=O)C1C=CC=CC=1.[C:22]1([S+:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH-].[Na+].Cl>CO>[OH:9][CH2:10][CH2:11][C:12]([F:21])([F:20])[C:13]([F:18])([F:19])[S:14]([O-:17])(=[O:15])=[O:16].[C:35]1([S+:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(OCCC(F)(F)C(F)(F)S(=O)(=O)[O-])c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=S(=O)([O-])C(F)(F)C(F)(F)CCO
Reaction time: 70 h

Procedure:
In 8 g of methanol was dissolved 2.1 g of triphenylsulfonium 4-benzoyloxy-1,1,2,2,-tetrafluorobutanesulfonate synthesized in Synthesis Example 9. The solution was stirred under ice cooling, to which 2.5 g of a 9% sodium hydroxide aqueous solution was added dropwise at a temperature below 10° C. The solution was aged at room temperature for 70 hours, after which 22 g of 1N hydrochloric acid was added under ice cooling for quenching the reaction. The methanol was removed under vacuum. Dichloromethane was added to the organic layer, which was washed three times with water. The organic layer was concentrated and dried, obtaining the target compound. Colorless oily matter, 0.3 g.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9](Cl)[C:8]([CH:12]=[CH:13][C:14]([O:16][CH3:17])=[O:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.CCN(CC)CC>CN(C=O)C.[Pd]>[CH3:17][O:16][C:14](=[O:15])[CH:13]=[CH:12][C:8]1[C:9]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: COC(=O)C=Cc1ccc(C(C)(C)C)nc1Cl
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccc(C(C)(C)C)nc1N1CCOCC1
Temperature: 80 °C
Reaction time: 18 h
Yield: 22.5 %

Procedure:
3-(6-tert-Butyl-2-chloro-pyridin-3-yl)-acrylic acid, methyl ester (0.28 μg, 1.11 mmol) was dissolved in DMF, and morpholine (0.15 ml), NEt3 (0.31 ml) and palladium reagent (48 mg) were added stepwise and then the reaction mixture was stirred at 80° C. for 18 hours. The resulting mixture was extracted with EtOAc, and the organic phase was dried over anhydrous MgSO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex/EtOAc=8/1) to give 3-(6-tert-butyl-2-morpholin-4-yl-pyridin-3-yl)-acrylic acid methyl ester (76 mg, 0.25 mmol, 22.5%). The methyl ester was dissolved in 1,4-dioxane, treated with water and KOH, stirred and heated at reflux for 18 hrs. The reaction mixture was cooled to room temperature, diluted with water, and then washed with ether. The aqueous phase was acidified with 1N HCl, and then extracted with EtOAc, and the combined organic phase was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure to give 3-(6-tert-butyl-2-morpholin-4-yl-pyridin-3-yl)-acrylic acid (67 mg, 92%).
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7](=O)[CH2:8][C:9]1[N:13]2[CH:14]=[C:15]([CH2:18][N:19]([CH3:21])[CH3:20])[CH:16]=[CH:17][C:12]2=[N:11][CH:10]=1)C.FC(F)(F)C(O)=O.C(N1C=CN=C1)([N:32]1C=CN=C1)=O>O1CCOCC1.O>[CH3:20][N:19]([CH2:18][C:15]1[CH:16]=[CH:17][C:12]2[N:13]([C:9]([CH2:8][C:7]([NH2:32])=[O:6])=[CH:10][N:11]=2)[CH:14]=1)[CH3:21]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)Cc1cnc2ccc(CN(C)C)cn12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CN(C)Cc1ccc2ncc(CC(N)=O)n2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
Lithium hydroxide monohydrate (55 mg, 1.31 mmol, 1.5 equiv) is added to a solution of (6-dimethylaminomethyl-imidazo[1,2-a]pyridin-3-yl)-acetic acid ethyl ester (240 mg, 0.87 mmol) in dioxane (10 ml) and water (10 ml). After 1 hour at room temperature, the reaction mixture is concentrated in vacuo. The residue is taken up in N,N-dimethylformamide (10 ml) and treated with trifluoroacetic acid (0.34 ml, 4.5 mmol, 4.5 equiv). Carbonyldiimidazole (167 mg, 0.98 mmol, 1.0 equiv) is added, and the mixture is stirred at room temperature for 1 hour. After removal of the solvent, concentrated aqueous ammonia (10 ml) is added to the activated acid. The mixture is stirred at room temperature for 30 minutes. Volatiles are removed in vacuo, and purification of the residue via flash chromatography (CH2Cl2/MeOH 7:3) affords the title compound (186 mg, 76%). 1H NMR (400 MHz, d4-MeOH): δ=8.31 (s, 1H), 7.55 (d, J=9.0 Hz, 1H), 7.49 (s, 1H), 7.35 (dd, J=9.0/1.5 Hz, 1H), 3.95 (s, 2H), 3.71 (s, 2H), 2.42 (s, 6H). MS (ES+): 233 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([O:9][C:10]([C@H:12]1[CH2:17][CH2:16][C@H:15]([N:18]2[C:22]([C:23]([F:26])([F:25])[F:24])=[C:21]([C:27](O)=[O:28])[CH:20]=[N:19]2)[CH2:14][C@H:13]1[CH3:30])=[O:11])[CH3:8].[Cl:31][C:32]1[C:33]([O:47][CH3:48])=[N:34][CH:35]=[C:36]([Cl:46])[C:37]=1[CH2:38][CH2:39][NH:40][CH2:41][C:42]([CH3:45])([CH3:44])[CH3:43].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[Cl:31][C:32]1[C:33]([O:47][CH3:48])=[N:34][CH:35]=[C:36]([Cl:46])[C:37]=1[CH2:38][CH2:39][N:40]([CH2:41][C:42]([CH3:45])([CH3:43])[CH3:44])[C:27]([C:21]1[CH:20]=[N:19][N:18]([C@H:15]2[CH2:16][CH2:17][C@H:12]([C:10]([O:9][CH2:7][CH3:8])=[O:11])[C@H:13]([CH3:30])[CH2:14]2)[C:22]=1[C:23]([F:24])([F:26])[F:25])=[O:28]
Reactant: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)O)c2C(F)(F)F)C[C@H]1C
Reactant: COc1ncc(Cl)c(CCNCC(C)(C)C)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(CCc3c(Cl)cnc(OC)c3Cl)CC(C)(C)C)c2C(F)(F)F)C[C@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
Oxalyl chloride (2.0M in DCM, 0.52 mL, 1.03 mmol) was added to a solution of 1-((1S,3R,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (239 mg, 0.687 mmol) in DCM (2.0 mL) followed by 1 drop of DMF while cooling in an ice bath. The solution was removed from the ice bath and allowed to stir at room temperature for 1 h. The reaction mixture was concentrated to dryness under reduced pressure (rotary evaporator) and the crude residue was treated with DCM (2.0 mL) and cooled to 0° C. The stirring solution was then treated with N-(2-(3,5-dichloro-2-methoxypyridin-4-yl)ethyl)-2,2-dimethylpropan-1-amine (200 mg, 0.687 mmol) in DCM (2 mL) followed by the addition of DIPEA (0.36 mL, 2.06 mmol) and allowed to warm to room temperature and stirred overnight (16 h). The reaction mixture was concentrated to dryness under reduced pressure (rotary evaporator) and the crude residue was purified on an ISCO Combiflash™ RF (25 g Grace Reveleris column, using a gradient of 0-50% EtOAc in heptane) affording (1S,2R,4S)-ethyl 4-(4-((2-(3,5-dichloro-2-methoxypyridin-4-yl)ethyl)(neopentyl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylcyclohexanecarboxylate (350 mg, 0.56 mmol, 82% yield) as a white crystalline solid. MS (ESI) 621.2, 623.2 [M+H]+.
Reaction SMILES: CC[OH:3].[Br:4][C:5]1[CH:6]=[C:7]([N+:13]([O-])=O)[C:8]([C:11]#[N:12])=[N:9][CH:10]=1.C(OCC)(=O)C>[Ni].CCCCCC>[NH2:13][C:7]1[C:8]([C:11]([NH2:12])=[O:3])=[N:9][CH:10]=[C:5]([Br:4])[CH:6]=1
Reactant: CCO
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: NC(=O)c1ncc(Br)cc1N
Temperature: 25 °C
Reaction time: 14 h
Yield: 23 %

Procedure:
To a 100 mL round bottom flask, Raney Nickel (2.5 g) and EtOH (150 mL) were added. To the same flask was added 5-bromo-3-nitropyridine-2-carbonitrile (5 g, 0.0219 mol). The reaction mass was stirred under hydrogen for 14 h at ambient temperature. The catalyst was removed by filtration. The clear filtrate was evaporated to provide the crude product. The crude was subjected to column chromatography (60-120 silica gel, 30% ethyl acetate in hexane) to provide the title compound as a light yellow solid [1.1 g, 23%]. 1H NMR (300 MHz, DMSO-d6): δ 7.89 (brs, 1H), 7.79 (d, J=1.8 Hz, 1H), 7.40 (brs, 1H), 7.38 (d, J=1.8 Hz, 1H), 7.04 (brs, 2H): LC-MS (ESI): Calculated mass: 215.0; Observed mass: 216.8 [M+H]+ (RT: 0.38 min).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C@@H:3]([N:7]1[C:16](=[O:17])[C:15]2=[CH:18][NH:19][C:13]3[C:14]2=[C:9]([CH:10]=[CH:11][N:12]=3)[CH2:8]1)[C:4](O)=[O:5].C1C=[C:26]2[N:28]=N[N:30](O)[C:25]2=CC=1.O.CCN=C=NCCCN(C)C.Cl.NCC#N.CN1CCOCC1>CN(C=O)C>[C:26]([CH2:25][NH:30][C:4](=[O:5])[C@H:3]([N:7]1[C:16](=[O:17])[C:15]2=[CH:18][NH:19][C:13]3[C:14]2=[C:9]([CH:10]=[CH:11][N:12]=3)[CH2:8]1)[C:2]([CH3:20])([CH3:21])[CH3:1])#[N:28]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)[C@H](C(=O)O)N1Cc2ccnc3[nH]cc(c23)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N#CCN
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: CC(C)(C)[C@H](C(=O)NCC#N)N1Cc2ccnc3[nH]cc(c23)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
(R)-3,3-Dimethyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoic acid (40.0 mg, 0.139 mmol), HOBt hydrate (25.6 mg, 0.167 mmol), and EDC hydrochloride (40.0 mg, 0.209 mmol) were combined in DMF (2 mL). 2-Aminoacetonitrile (11.71 mg, 0.209 mmol) and 4-methylmorpholine (0.062 mL, 0.557 mmol) were added, and the reaction mixture was stirred at room temperature for 2 h. The product was purified by preparative HPLC (10-45% AcCN/H2O with 0.035% TFA), concentrated in vacuo, and lyophilized to afford the title compound as a pale yellow solid (36 mg, 59%). 1H NMR (500 MHz, DMSO-d6) δ 1.09 (s, 9H), 4.01-4.12 (m, 2H), 5.13-5.22 (m, 2H), 5.33 (br s, 1H), 7.10 (d, J=4.5 Hz, 1H), 7.87 (s, 1H), 8.26 (d, J=4.5 Hz, 1H), 8.86 (br s, 1H), 12.25 (br s, 1H). [M+H] calc'd for C17H19N5O2, 326; found, 326.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N+:13]([O-])=O)=[N:11][CH:12]=2)=[CH:4][C:3]=1[N+:18]([O-])=O.Cl.C(O)C>O>[NH2:18][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:2]=1[Cl:1])[O:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(Cl)c([N+](=O)[O-])c2)cn1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(Oc2ccc(Cl)c(N)c2)cn1
Temperature: 85 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
A mixture of 5-(4-chloro-3-nitrophenoxy)-2-nitropyridine (3.80 g, 12.9 mmol), reduced iron (4.84 g, 86.7 mmol), 6N hydrochloric acid (2 mL), ethanol (20 mL) and water (4 mL) was stirred at 85° C. for 2 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (2.02 g, 66%) as a gray solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[CH3:9].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[Ba+2].[OH-].COCCOC>O>[Cl:1][C:2]1[CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1ccc(I)cc1Cl
Reactant: OB(O)c1ccccc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2ccccc2)cc1Cl

Procedure:
A mixture of 2-chloro-4-iodotoluene(2.94 g, 11.63 mmol), phenyl boronic acid (1.56 g, 12.79 mmol), barium hydroxide (5.50 g, 17.44 mmol), DME (3 mL) and water (15 mL) was purged with dry argon. Tetrakis(triphenyl-phosphine)palladium(O) (672 mg, 0.58 mmol) was added, and the resultant solution was stirred at 80° C. for 4 hours. The solvents were evaporated in vacuo, and the residue partitioned between EtOAc and water and acidified with 1M aq. HCl. The aqueous extract was separated, and extracted with EtOAc. The organic extracts were combined, washed with NaHCO3 and 5% aq. Na2S2O3, dried, (Na2SO4) filtered and the solvent evaporated in vacuo. The residue was purified by chromatography (Silica gel, 10% EtOAc in hexanes) to afford the title compound. 1H NMR (CDCl3 400 MHz) δ 7.62-7.54 (3H, m), 7.48-7.25(5H, m) and 2.43(3H, s) ppm.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C:13]([CH3:16])([CH3:15])[N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:11]1[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:31](Cl)(=O)C.C[Mg]Br.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1COCC1.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][C@H:10]1[O:14][C:13]([CH3:16])([CH3:15])[N:12]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C@H:11]1[CH2:24][C:25]1[CH:26]=[CH:27][N:28]=[C:29]([CH3:31])[CH:30]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccncc2)[C@@H](CO[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: CC(=O)Cl
Agent: C[Mg]Br
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C[C@H]2[C@@H](CO[Si](C)(C)C(C)(C)C)OC(C)(C)N2C(=O)OC(C)(C)C)ccn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(4S,5S)-Tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl-4-(pyridin-4-ylmethyl)oxazolidine-3-carboxylate (0.150 g, 0.344 mmol) was dissolved in THF (3.5 mL) and cooled to 0° C. Acetyl chloride (0.0256 ml, 0.361 mmol) was added and the reaction was stirred 30 minutes before METHYLMAGNESIUM BROMIDE (0.294 ml, 0.412 mmol) was added. The reaction was stirred 1 hr. at 0° C. and then warmed to RT and quenched with saturated ammonium chloride and diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with a 9:1 aqueous solution of saturated ammonium chloride/ammonium hydroxide, water, brine, and dried over sodium sulfate. The crude product was dissolved in isopropylacetate (4 mL) and heated to 50° C. before DDQ (0.117 g, 0.515 mmol) was added. After 30 minutes the reaction was cooled and diluted with ethyl acetate and washed twice with saturated sodium bicarbonate, once with water, brine, and dried over sodium sulfate. The mixture was passed through a plug of silica gel with 2:1 Hexanes/EtOAc and concentrated to afford the title compound, MS m/z: 451.3(100%, M+1)).
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:18])[C:6]([C:16]#[N:17])=[N:7][NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])[CH2:2][CH3:3].[Cl-].[Al+3].[Cl-].[Cl-].O.[OH-].[Na+]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[NH2:17][C:16]1[C:14]2[C:9](=[C:10]([F:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[N:7][C:6]=1[C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[O:18]
Reactant: CCCNC(=O)C(C#N)=NNc1ccccc1F
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CCCNC(=O)c1nnc2c(F)cccc2c1N
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 3.6 %

Procedure:
To a suspension of N-propyl-2-cyano-2-[(2-fluorophenyl)hydrazono]acetamide (11.1 g, 44.71 mmol) in toluene (275 mL) was added aluminum chloride (20.90 g, 156.74 mmol). The mixture was stirred at 90° C. for 2.5 hours. The reaction mixture was cooled to 0° C., and then diluted with chloroform (1 L). A small amount of water was added to quench the reaction at 0° C. Aqueous sodium hydroxide (750 mL, 20% w/v solution) was poured into the mixture slowly at 0° C., and the mixture stirred at ambient temperature for one hour. A precipitate was formed gradually. The mixture was diluted with chloroform (2 L) until all of the precipitate was dissolved, washed twice with water, dried through magnesium sulfate, and concentrated to a volume of approximately 200 mL to leave a suspension of the product. The title compound as a light beige solid (11.06 g) was collected by filtration and washed with methylene chloride (50 mL×2), methanol (50 mL) and hexane (100 mL×2). The mother liquor was concentrated, and purified by flash chromatography using a gradient of ethyl acetate in hexane to give an additional 400 mg of the title compound as a beige solid. 1H NMR (300 MHz, CDCl3) δ 8.55 (br, 1H), 7.55-7.70 (m, 2H), 3.49 (m, 2H), 1.71 (m, 2H), 1.03 (t, J=7.4 Hz, 3H) MS APCI, m/z=249 (M+H) HPLC 1.30 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([C:20]#[N:21])[N:3]=1.[CH3:22][O-:23].[Na+]>CN(C=O)C>[CH3:22][O:23][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([C:20]#[N:21])[N:3]=1
Reactant: COc1ccc2c(Cl)nc(C#N)c(-c3ccccc3)c2c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(OC)nc(C#N)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-chloro-6-methoxy-4-phenylisoquinoline-3-carbonitrile (50 mg) in 1 mL of DMF was added NaOMe (3 equivalents). The reaction was stirred at room temp overnight, then concentrated and purified by flash chromatography (30% EtOAc/hexanes). Trituration (ether/hexanes) of the concentrated material gave the titled compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:23])=[C:11]([CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][C@H:16]3[CH2:20][O:21][CH3:22])[N:12]=2)=[CH:4][CH:3]=1.[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])=[O:26]>>[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]([CH3:23])=[C:11]([CH2:13][CH2:14][N:15]4[CH2:19][CH2:18][CH2:17][C@H:16]4[CH2:20][O:21][CH3:22])[N:12]=3)=[CH:4][CH:3]=2)=[CH:30][CH:29]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: COC[C@@H]1CCCN1CCc1nc(-c2ccc(Br)cc2)oc1C
Product: COC[C@@H]1CCCN1CCc1nc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)oc1C

Procedure:
Starting with 2-(4-Bromo-phenyl)-4-[2-(S)-(+)-(2-methoxymethyl-pyrrolidin-1-yl)-ethyl]-5-methyl-oxazole (See Example 27) and 4-methylsulfonylphenylboronic acid, follow a procedure significantly analogous to Example 22 to give the titled compound. MS (m/e): 455.2 (M+1)
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[C:11]1(B2OC(C)(C)C(C)(C)O2)[CH2:15][CH2:14][CH2:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.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]>[C:11]1([C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH2:15][CH2:14][CH2:13][CH:12]=1
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Reactant: O=C(O)c1cccc(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cccc(C2=CCCC2)n1
Temperature: 100 °C
Yield: 26.4 %

Procedure:
A mixture of 6-bromo-pyridine-2-carboxylic acid (CAN 21190-87-4, 0.375 g, 1.86 mmol), 2-cyclopentenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAN 287944-10-9, 0.3 g, 1.6 mmol), Pd(dppf)Cl2 (CAN 95464-05-4, 0.06 g, 0.08 mmol) and K2CO3 (0.642 g, 4.7 mmol) in DMF (10 mL) and water (1 mL) was heated to 100° C. overnight. After filtration, the filtrate was concentrated and the residue was purified by column chromatography (silica gel, 15 g, eluting with 10% ethyl acetate in petroleum ether) to give the title compound (0.08 g, 23%) as white solid; MS (EI): m/e=190.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cu][C:22]#[N:23]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([C:22]#[N:23])=[CH:16][CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: N#C[Cu]
Reactant: Clc1ccc(C2(c3ccc(I)cc3)CCNCC2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(C2(c3ccc(Cl)cc3)CCNCC2)cc1
Temperature: 140 °C
Yield: 16 %

Procedure:
A mixture of 4-(4-chloro-phenyl)-4-(4-iodo-phenyl)-piperidine and copper (I) cyanide in DMF was heated at 140° C. under nitrogen for 6 hours then allowed to cool. The mixture was diluted with ethyl acetate, washed with a mixture of conc. ammonia and brine (×5), dried (MgSO4), filtered and concentrated to give a residue which was partially purified by column chromatography (SiO2), eluting with a gradient of 2M ammonia in methanol (5% to 10%) and dichloromethane to afford the title compound (46 mg, <16%). This was taken on to the next reaction without further purification. LCMS (PS-A2) Rt 2.39 min [M+H]+ 297.