Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:22])[CH:7]([CH3:21])[N:8]([C:12](=[O:20])[CH:13]([CH3:19])[CH2:14][S:15][C:16](=[O:18])[CH3:17])[CH:9]1[CH2:11][CH2:10]1)(C)(C)C>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[C:16]([S:15][CH2:14][CH:13]([CH3:19])[C:12]([N:8]([CH:9]1[CH2:10][CH2:11]1)[CH:7]([C:6]([OH:22])=[O:5])[CH3:21])=[O:20])(=[O:18])[CH3:17]
Reactant: CC(=O)SCC(C)C(=O)N(C1CC1)C(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(=O)SCC(C)C(=O)N(C1CC1)C(C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.2 %

Procedure:
Crude N-(3-acetylthio-2-methylpropanoyl)-N-cyclopropyl-(dl)-alanine tert-butyl ester (60.2 g) was dissolved in a mixture of anisole (54 ml) and trifluoroacetic acid (96 ml). The resulting solution was stirred at room temperature for one hour. Trifluoroacetic acid was removed in vacuo and the residue was distributed between ethyl acetate and saturated sodium bicarbonate. The aqueous bicarbonate phase was separated and washed twice with ethyl acetate and then acidified to pH 4-5 with concentrated hydrocloric acid. The precipitated product was extracted into chloroform and washed twice with water. The organic phase was dried over magnesium sulfate, filtered and evaporated to give the crude acid as a thick yellow oil (22.9 g). The crude product was purified by HPLC, eluting with ethyl acetate/n-hexane/acetic acid (40:60:1), to give pure product as initially a pale yellow oil (9.6 g). The product was crystallized from ether/n-hexane to give colorless crystals, m.p. 83°-85° C.
Reaction SMILES: N#N.[CH3:3][O:4][C:5](=[O:36])[CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][C:20](=[O:35])[CH2:21][CH2:22][C:23]2[CH:28]=[C:27]([O:29]C)[C:26]([O:31]C)=[C:25]([O:33]C)[CH:24]=2)[CH:10]=[CH:11][CH:12]=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:3][O:4][C:5](=[O:36])[CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][C:20](=[O:35])[CH2:21][CH2:22][C:23]2[CH:24]=[C:25]([OH:33])[C:26]([OH:31])=[C:27]([OH:29])[CH:28]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)Cc1cccc(-c2ccccc2NC(=O)CCc2cc(OC)c(OC)c(OC)c2)c1
Agent: BrB(Br)Br
Agent: N#N
Solvent: ClCCl
Product: COC(=O)Cc1cccc(-c2ccccc2NC(=O)CCc2cc(O)c(O)c(O)c2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 4.7 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Dissolve {2′-[3-(3,4,5-Trimethoxy-phenyl)-propionylamino]-biphenyl-3-yl}-acetic acid methyl ester (72) (46 mg, 0.10 mmol) in anhydrous DCM (1.0 mL), cool the solution to −78° C. and add dropwise BBr3 (85 μL, 0.90 mmol). Stir the reaction mixture for 30 min at −78° C. and after slowly warming up for additional 2 h at rt. Add dropwise ice water, separate layers and extract aqu. layer with DCM (3 times). Wash combined organic layer with brine and dry with Na2SO4. Purify the crude product by preparative RP HPLC (gradient, water/CH3CN 95:5 to 5:95) to obtain {2′-[3-(3,4,5-Trihydroxy-phenyl)-propionylamino]-biphenyl-3-yl}-acetic acid methyl ester (73) (2 mg, 5%). 1H NMR (400 MHz, CD3CN): 2.43 (t, 2H, J=7.6 Hz); 2.69 (t, 2H, J=7.6 Hz); 3.66 (s, 3H); 3.70 (s, 2H); 6.25 (s, 2H); 7.18-7.34 (m, 5 H); 7.35-7.44 (m, 2H); 7.65 (br.s, 1H); 7.89 (br.d, 1H, J=8.3 Hz).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]=[C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:9]2=[O:20])=[CH:4][CH:3]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22]1=[O:27].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.[Cu+]>[N:14]1([C:10]2[C:9](=[O:20])[N:8]([C:5]3[CH:6]=[CH:7][C:2]([N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][C:22]4=[O:27])=[CH:3][CH:4]=3)[CH2:13][CH2:12][CH:11]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: O=C1C(N2CCOCC2)=CCCN1c1ccc(I)cc1
Reactant: O=C1CCCCN1
Agent: [Cu+]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: O=C1CCCCN1c1ccc(N2CCC=C(N3CCOCC3)C2=O)cc1
Temperature: 7.5 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
Part B. Soluble copper(I)-catalyzed Ullmann coupling reaction. A suspension of 1-(4-iodo-phenyl)-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (10, 2.2 g, 5.73 mmol), piperidin-2-one (42, 851 mg, 8.59 mmol, 1.5 equiv), and Cs2CO3 (3.73 g, 11.46 mmol, 2.0 equiv) in toluene (15 mL) was treated with Cu(PPh3)3Br (1.065 g, 1.146 mmol, 20% equiv) at room temperature under N2, and the resulting reaction mixture was degassed three times under a steady stream of nitrogen. The reaction mixture was warmed up to reflux for 6 h. When HPLC showed the Ullmann coupling reaction was complete, the reaction mixture was cooled down to 5-10° C. before being quenched with 14% of ammonium hydroxide aqueous solution (20 mL) and EtOAc (30 mL) at 5-10° C. The mixture was stirred for an additional 4 h at 25° C. The two layers were then separated, and the aqueous layer, was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with saturated NaCl aqueous solution (10 mL), dried over MgSO4, and concentrated in vacuo. The residue was directly purified by flash column chromatography (SiO2, 15-40% EtOAc/hexane gradient elution) to afford the desired 3-morpholin-4-yl-1-[4-(2-oxo-piperidin-1-yl)-phenyl]-5,6-dihydro-1H-pyridin-2-one (63, 1.568 g, 2.036 g theoretical, 77%) as a pale-yellow oil, which solidified upon standing at room temperature in vacuo. For 63, CIMS m/z 356 (M++H, C2OH25N3O3).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](I)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH:11]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=[CH2:12]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:11][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C=Cc1ccncc1
Reactant: O=[N+]([O-])c1cccc(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: O=[N+]([O-])c1cccc(C=Cc2ccncc2)c1
Temperature: 100 °C
Yield: 66.3 %

Procedure:
A mixture of 3.0 g (20 mmol) of 3-nitroiodobenzene, 3.5 mL (25 mmol) of TEA, 0.045 g (0.20 mmol) of palladium(II) acetate and 2.77 g (25.0 mmol) of 4-vinylpyridine was suspended in 4 mL of dry acetonitrile in a pyrex sealed tube and heated to 100° C. for 48 h. The mixture was cooled to rt and was quenched with 200 mL of 10% hydrochloric acid. The resulting yellow solid was isolated by filtration and partitioned between 250 mL of EtOAc and 250 mL of 1 N aqueous sodium hydroxide. The organic phase was dried over MgSO4 and concentrated to give 3.0 g (66%) of 4-[2-(3-nitrophenyl)ethenyl]-pyridine as a yellow solid: 1H NMR (DMSO-d6): δ 3.0-4.6 (br s, 1H), 7.71-7.78 (m, 2H), 8.07 (d, J=15.8 Hz, 1H), 8.13-8.16 (m, 3H), 8.24 (d, J=8.0 Hz, 1H), 8.56 (s, 1H), 8,84 (d, J=5.7 Hz, 2H); ESI−MS m/z 227 (M+1)+. A portion (1.3 g, 7.1 mmol) of this solid was dissolved in 100 mL of EtOAc, and 0.5 g of 10% palladium on charcoal was added. The mixture was hydrogenated on a Parr apparatus at 40 psi for 1.5 h. Another 0.5 g batch of 10% palladium on charcoal was added and the mixture was subjected to further hydrogenation for 1 h. The palladium catalyst was removed by filtration through a pad of celite, and the filtrate was concentrated to give 1.13 g (100%) of 3-(4-pyridinyl)ethylaniline: 1H NMR (DMSO-d6): δ 2.69 (m, 2H), 2.80 (m, 2H), 4.9 (bs, 2H), 6.33 (d, J=7.7 Hz, 2H), 6.38 (s, 1H), 6.86 (t, J=7.7 Hz, 1H), 7.20 (d, J=5.8 Hz, 2H), 8.41 (d, J=5.8 Hz, 2H). Conversion of 3-[2-(4-pyridinyl)ethyl]-aniline to 4-(2-pyridin-4-yl-ethyl)-1H-indole-2,3-dione was accomplished according to Procedure A in 24% overall yield: 1H NMR (DMSO-d6): δ 2.80 (m, 2H), 3.10 (m, 2H), 6.70 (d, J=8.0 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H), 7.24 (m, 2H), 7.40 (t, J=8.0 Hz, 1H), 8.42 (bs, 2H), 11.00 (s, 1H). Conversion of 4-(2-pyridin-4-ylethyl)-1H-indole-2,3-dione to the title compound was accomplished according to Procedure G in 40% overall yield: 1H NMR (DMSO-d6): δ 2.98 (t, J=7.9 Hz, 2H), 3.30 (m, 2H, underneath water peak), 6.78 (d, J=7.7 Hz, 1H), 6.88 (d, J=7.6 Hz, 1H), 7.17 (t, J=7.6 Hz, 1H), 7.25 (s, 2H), 7.29 (d, J=6.0 Hz, 2H), 7.37 (d, J=8.8 Hz, 2H), 7.66 (d, J=8.8 Hz, 2H), 8.47 (d, J=6.0 Hz, 2H), 11.13 (s, 1H), 12.98 (s, 1H); APCI−MS m/z 420 (M−1)−. Anal. Calcd for C21H19N5O3S.0.15 HCl: C, 55.93, H, 4.43; N, 15.53; S, 7.11. Found C, 56.05, H, 4.36; N, 15.38; S, 7.18.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15](O)=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.P(Br)(Br)([Br:24])=O>CN(C=O)C.CCOC(C)=O.O>[Br:24][C:15]1[CH:16]=[CH:17][N:12]([C:9]2[CH:10]=[CH:11][C:6]3[N:7]([C:20]([CH3:21])=[C:4]([CH:1]4[CH2:3][CH2:2]4)[N:5]=3)[CH:8]=2)[C:13](=[O:19])[CH:14]=1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Reactant: O=P(Br)(Br)Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(Br)cc3=O)cn12
Temperature: 110 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (3.0 g) in DMF (25 ml) was added phosphorus oxybromide (2.17 ml) at room temperature, and the mixture was stirred at 110° C. for 1 h. The mixture was diluted with EtOAc and water, quenched with saturated NaHCO3 solution, and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (hexane/EtOAc) to give the title compound (0.70 g) as a pale yellow solid.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:9]Br>[Fe](Cl)Cl.O>[Br:9][C:4]1[CH:5]=[CH:6][C:1]([S:7][CH3:8])=[CH:2][CH:3]=1
Reactant: BrBr
Reactant: CSc1ccccc1
Agent: Cl[Fe]Cl
Solvent: O
Product: CSc1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
A one-liter four-necked flask equipped with a stirrer, thermometer, dropping funnel and Liebig condenser was charged with 124.2 g (1.00 mole) of thioanisole and 0.32 g (0.002 mole) of iron(II) chloride, and 160 g (1.0 mole) of bromine was added dropwise with stirring at 50° C. over 4 hours. Thereafter, the reaction was further allowed to proceed for 1 hour. After completion of the reaction, 50 g of water was added, and the organic layer was separated, whereby 202.9 g of crude 4-bromothioanisole was obtained. The purity of the thus-obtained crude 4-bromothioanisole was 90.3% as determined by gas chromatography.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][CH2:10][CH:11]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:15][CH2:16][CH3:17])=[O:14]>C(Cl)Cl>[C:1]1([C:7]#[C:8][CH2:9][CH2:10]/[CH:11]=[CH:18]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CCCC#Cc1ccccc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)/C=C/CCC#Cc1ccccc1
Yield: 83.2 %

Procedure:
5-Phenylpent-4-ynal (3 g) in dry CH2Cl2 (30 ml) was added to a solution of carbethoxymethylenetriphenyl phosphorane (10 g) in dry dichloromethane (20 ml), and the mixture was heated at reflux under a nitrogen atmosphere for 5 hours. The solvent was removed under reduced pressure, and the product was purified by chromatography on silica (150 g), eluting with 2:1 hexane:ether to yield ethyl 7-phenylhept-2E-en-6-ynoate (3.6 g).
Reaction SMILES: CC(C)(OC([NH:7][C@@H:8]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH:9]([OH:28])[CH2:10][NH:11][C:12](=[O:27])[CH:13]([C:17]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:14][CH2:15][CH3:16])=O)C.[ClH:34].C1(CC(C(N)=O)(CCC)C(N)=O)C=CC=CC=1>Cl.C(OCC)(=O)C>[ClH:34].[NH2:7][C@@H:8]([CH2:29][CH:30]([CH3:31])[CH3:32])[CH:9]([OH:28])[CH2:10][NH:11][C:12](=[O:27])[CH:13]([C:17]([NH:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])[CH2:14][CH2:15][CH3:16]
Reactant: CCCC(C(=O)NCc1ccccc1)C(=O)NCC(O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: CCCC(Cc1ccccc1)(C(N)=O)C(N)=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCC(C(=O)NCc1ccccc1)C(=O)NCC(O)[C@@H](N)CC(C)C

Procedure:
A solution of N-[(3S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-5-methylhexyl]-2-[[(phenylmethyl)amino]carbonyl]-pentanamide (0.7 g., 1.46 mmole) in saturated hydrochloric acid/ethyl acetate (25 ml.) is stirred at 0° for 2 hours. The reaction mixture is concentrated to a solid residue. Trituration with ether gives 0.60 g. of N-[(3S)-3-amino-2-hydroxy-5-methylhexyl]-2-[[(phenylmethyl)amino[carbonyl]-pentanamide, monohydrochloride as an oily white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]3[O:23][CH2:22][CH2:21][CH2:20][N:19]([CH2:24][C:25](O)=[O:26])[C:18]=3[CH:28]=1)=[O:12])=[CH:5]2.B.C1COCC1>C1COCC1>[OH:26][CH2:25][CH2:24][N:19]1[C:18]2[CH:28]=[C:14]([NH:13][C:11]([C:6]3[NH:7][C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=4)=[O:12])[CH:15]=[CH:16][C:17]=2[O:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(O)CN1CCCOc2ccc(NC(=O)c3cc4cc(Cl)ccc4[nH]3)cc21
Agent: B
Solvent: C1CCOC1
Product: O=C(Nc1ccc2c(c1)N(CCO)CCCO2)c1cc2cc(Cl)ccc2[nH]1
Yield: 35 %

Procedure:
{2-[(5-Chloro-1H-indole-2-carbonyl)-amino]-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl}-acetic acid (80 mg) was dissolved in THF (3 mL) and treated with 1.0 M BH3/THF at room temperature. The reaction was concentrated in vacuo, diluted with EtOAc and washed with 1N HCl. The crude product was purified by preparative TLC (EtOAc) to yield 27 mg of the product as a crystalline solid. LCMS: AP+ 386/388.
Reaction SMILES: [CH3:1][C:2]1[N:19]([S:20]([C:23]2[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=[C:8]([NH:10][NH:11]C(OC(C)(C)C)=O)[N:9]=[C:4]2[CH:3]=1.Cl>O1CCOCC1>[NH:10]([C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([CH3:1])[N:19]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:21])=[O:22])[C:5]2=[N:6][CH:7]=1)[NH2:11]
Reactant: Cc1ccc(S(=O)(=O)n2c(C)cc3nc(NNC(=O)OC(C)(C)C)cnc32)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2c(C)cc3nc(NN)cnc32)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 73.8 %

Procedure:
tert-Butyl 2-(6-methyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazine carboxylate (0.16 g, 0.38 mmol) was stirred in 1,4-dioxane (1.9 mL) in a sealed vial to give a brown solution. HCl (4 M in 1,4-dioxane, 0.958 mL, 3.83 mmol) was added and the reaction stirred at ambient temperature for about 20 h. The solvents were removed under reduced pressure. The residue was partitioned between saturated aqueous NaHCO3 (10 mL) and EtOAc (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×10 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concd in vacuo to provide 2-hydrazinyl-6-methyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (0.089 g, 73%): LC/MS (Table 1, Method a) Rt=1.92 min; MS m/z: 318 (M+H)+.
Reaction SMILES: Cl.[CH3:2][N:3]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4]1.C[O:10][C:11]([C:13]1[CH:23]=[C:22]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27]([F:33])[CH:26]=2)[C:16]2[CH2:17][C:18]([CH3:21])([CH3:20])[O:19][C:15]=2[CH:14]=1)=O>>[CH3:2][N:3]1[N:7]=[C:6]([NH:8][C:11]([C:13]2[CH:23]=[C:22]([O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27]([F:33])[CH:26]=3)[C:16]3[CH2:17][C:18]([CH3:21])([CH3:20])[O:19][C:15]=3[CH:14]=2)=[O:10])[CH:5]=[N:4]1
Reactant: Cn1ncc(N)n1
Reactant: COC(=O)c1cc(Oc2ccc(C#N)c(F)c2)c2c(c1)OC(C)(C)C2
Agent: Cl
Product: Cn1ncc(NC(=O)c2cc(Oc3ccc(C#N)c(F)c3)c3c(c2)OC(C)(C)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Example 1, from 2-methyl-2H-1,2,3-triazol-4-amine hydrochloride (662 mg, 4.92 mmol) and 4-(4-cyano-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (183a) (168 mg, 0.49 mmol) to give a white solid (154 mg, 77% yield). 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1 H) 8.06 (s, 1 H) 7.57 (dd, J=8.59, 7.33 Hz, 1 H) 7.06-7.15 (m, 2 H) 6.67-6.88 (m, 2 H) 4.10 (s, 3 H) 2.88 (s, 2 H) 1.49 (s, 6 H); LCMS for C21H18FN5O3 m/z 408.00 and 409.00 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=O.[CH3:13][C:14]1[CH:15]=[C:16]([CH:31]=[CH:32][C:33]=1[NH2:34])[CH2:17][N:18]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][C:20]([C:27]([F:30])([F:29])[F:28])=[N:19]1>C(O)(=O)C>[F:30][C:27]([F:28])([F:29])[C:20]1[CH:21]=[C:22]([C:23]([F:26])([F:24])[F:25])[N:18]([CH2:17][C:16]2[CH:31]=[CH:32][C:33]([N:34]3[C:8](=[O:9])[C:3]4[C:4](=[CH:10][CH:11]=[CH:12][C:2]=4[F:1])[C:5]3=[O:7])=[C:14]([CH3:13])[CH:15]=2)[N:19]=1
Reactant: Cc1cc(Cn2nc(C(F)(F)F)cc2C(F)(F)F)ccc1N
Reactant: O=C1OC(=O)c2c(F)cccc21
Solvent: CC(=O)O
Product: Cc1cc(Cn2nc(C(F)(F)F)cc2C(F)(F)F)ccc1N1C(=O)c2cccc(F)c2C1=O
Yield: 76.4 %

Procedure:
3-Fluorophthalic anhydride (4.98 g) and 1-(3-methyl-4-aminobenzyl)-3,5-bis(trifluoromethyl)-1H-pyrazole (9.70 g) were refluxed in acetic acid (43 ml) for 3 hours. After finishing the reaction, the acetic acid was distilled off under the reduced pressure and the obtained crude crystals were washed with t-butyl methyl ether to obtain the aimed 2-{4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl-methyl]-2-methylphenyl}-4-fluoroisoindol-1,3-dione (10.80 g). mp. 158-159° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[Cl:21][C:22]1[CH:31]=[CH:30][C:25]([O:26][CH2:27][CH2:28]O)=[CH:24][CH:23]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:28][CH2:27][O:26][C:25]2[CH:30]=[CH:31][C:22]([Cl:21])=[CH:23][CH:24]=2)=[CH:7][CH:6]=1
Reactant: OCCOc1ccc(Cl)cc1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccc(Cl)cc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 60.6 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with the mesylate of 2-(4-chlorophenoxy)ethanol (1.25 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material from dichloromethane extraction was purified by HPLC (dichloromethane-hexane; 4:1 ) and crystallized from dichloromethane-hexane to provide 0.815 g of 4-[[2-(4-chlorophenoxy) ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester, mp 103°-105° C.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=3[CH:25]=O)[CH:8]=2)[N:3]=1.[C:32]([NH2:36])([CH3:35])([CH3:34])[CH3:33].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O1CCCC1.O>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=3[CH2:25][NH:36][C:32]([CH3:35])([CH3:34])[CH3:33])[CH:8]=2)[N:3]=1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)ccc3C=O)ccc2n1
Reactant: CC(C)(C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)NCc1ccc(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
150 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]-4-fluorobenzaldehyde are dissolved in 2 ml of 1,2-dichloroethane and 2 ml of tetrahydrofuran. 53 μl of tert-butylamine and 40 μl of glacial acetic acid are added, and the mixture is stirred at 60° C. for 6 h. After cooling to 25° C., 161 mg of sodium triacetoxyborohydride are added and stirred at 25° C. for a further 12 h. The mixture is poured into water, extracted three times with dichloromethane, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH:19]1[CH2:21][O:20]1>CC#N>[O:20]1[CH2:21][CH:19]1[CH2:18][N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1
Reactant: c1ccc2c(c1)CCNC2
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc2c(c1)CCN(CC1CO1)C2
Temperature: 22 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
To a solution of 1,2,3,4-tetrahydroisoquinoline (15 g, 0.11 mol) in MeCN (100 mL) was added K2CO3 (30.7 g, 0.23 mol) at 0° C. 2-(bromomethyl)oxirane (17 g, 0.12 mol) was added to the reaction after 1 h. The solution was stirred at 22° C. for 16 h at which time the solids were filtered and washed with MeCN. The solution was concentrated and the residue was used in the next step without further purification (17 g, Yield 78%). LCMS (m/z): 190.1 (M+1).
Reaction SMILES: [Cl-].[NH2:2][C:3]1[CH:8]=[C:7]([NH:9][CH3:10])[C:6]([C:11]#[N:12])=[C:5]([Cl:13])[N+:4]=1[CH3:14].[C:15](#[N:19])[CH2:16][C:17]#[N:18].C(N(CC)CC)C>O>[Cl-:13].[NH2:2][C:3]1[CH:8]=[C:7]([NH:9][CH3:10])[C:6]([C:11]#[N:12])=[C:5]([CH:16]([C:15]#[N:19])[C:17]#[N:18])[N+:4]=1[CH3:14]
Reactant: N#CCC#N
Reactant: CNc1cc(N)[n+](C)c(Cl)c1C#N
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: O
Product: CNc1cc(N)[n+](C)c(C(C#N)C#N)c1C#N
Yield: 75 %

Procedure:
2.3 gms (.01 mole) of 2-amino-6-chloro-5-cyano-1-methyl-4-methylamino pyridinium chloride (compound 1 - Table 1) was dissolved in water and 0.66 gms (.01 mole) of malononitrile and 2.0 gms (.02 mole) of triethylamine added. After a few minutes 1.7 gms (75% yield of 2-amino-5-cyano-1-methyl-4-methylamino-6-dicyanomethyl pyridinium chloride (compound 83 - Table 6) (MPt>240°C) crystallised out.
Reaction SMILES: [CH2:1]1[C:4]2([CH:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][NH:6][CH2:5]2)[CH2:3][CH2:2]1.[C:17]([C:19]1([C:22](O)=[O:23])[CH2:21][CH2:20]1)#[N:18].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[C:17]([C:19]1([C:22]([N:6]2[CH2:7][CH:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[C:4]3([CH2:1][CH2:2][CH2:3]3)[CH2:5]2)=[O:23])[CH2:21][CH2:20]1)#[N:18]
Reactant: N#CC1(C(=O)O)CC1
Reactant: CC(C)(C)OC(=O)NC1CNCC12CCC2
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)NC1CN(C(=O)C2(C#N)CC2)CC12CCC2
Reaction time: 16 h
Yield: 76.4 %

Procedure:
A solution of (+/−)-tert-butyl 6-azaspiro[3.4]octan-8-ylcarbamate (from Step 1 of Example 318, 0.177 g, 0.783 mmol), 1-cyanocyclopropanecarboxylic acid (0.104 g, 0.939 mmol), EDC (0.300 g, 1.565 mmol), HOBT (0.144 g, 0.939 mmol), and Hunig's Base (0.547 mL, 3.13 mmol) in DMA (7.67 mL) was stirred @ r. t. under N2 for 16 hrs. +/−MS analysis after 16 hrs indicated that the reaction had proceeded essentially to completion and no starting material was detected. The volatiles were removed under high vacuum. EtOAc, THF, and 10% aq LiCl solution were added. The layers were separated, the organic layer was washed with 10% aq LiCl solution, 1N HCl (3×), sat. aq NaHCO3 solution (3×), brine, dried over Na2SO4, and concentrated under vacuum to yield 0.223 g of the crude product as an orange viscous semi-solid. Flash chromatography on silica gel (Teledyne-Isco RediSep Rf 4 g column), eluting with 100 mL of 75:25 hexane:EtOAc yielded 0.191 g of the title compound as a pale yellow solid. +/−MS: m/e 320.3 (M+H). 318.5 (M−H), 220.2 (M+H-Boc), 264.2 (M+H-isobutylene). This material was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([C:8](O)([CH3:10])[CH3:9])[CH:7]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.Cl>CCOCC>[F:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:12][CH3:13])([CH3:10])[CH3:9])[CH:16]=1
Reactant: Oc1ccc(F)cc1
Reactant: COc1ccc(F)cc1C(C)(C)O
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(F)cc1C(C)(C)c1cc(F)ccc1O
Reaction time: 8 h
Yield: 43 %

Procedure:
2-(5-fluoro-2-methoxyphenyl)propan-2-ol (6 g) was added in small portions to a melt of 4-fluorophenol (12 g) and concentrated hydrochloric acid (10 days) at 90° C. The mixture was stirred at this temperature overnight and was then cooled and dissolved in ether. The excess of p-fluorophenol was removed by extraction with 5% aqueous sodium hydroxide solution. The alkali insoluble material crystallised from hexane to give 2-(5-fluoro-2-hydroxyphenyl)-2-(5-fluoro-2-methoxyphenyl) propane (3.9 g) as colourless prisms; m.p. 90° C.