Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(O)(=O)=O)=CC=1.II.[CH2:29]([O:31][C:32](=[O:35])[CH2:33]Br)[CH3:30]>O.C1(C)C=CC=CC=1>[C:32]([CH2:33][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([O:31][CH2:29][CH3:30])=[O:35]
Reactant: CCOC(=O)CBr
Reactant: O=Cc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: II
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)COc1ccc(C=O)cc1

Procedure:
4-Hydroxybenzaldehyde (250 g, 2.05 M), potassium carbonate (565 g, 4.09 M), toluene (2.5 L), p-toluene sulphonic acid (39 g, 0.21 M) and iodine (2 g, catalytic) were taken in a 5 L 4-neck round bottom flask with mechanical stirrer and a Dean-Stark condenser. Ethylbromoacetate (341 g, 2.05 M) was added and the reaction refluxed for 6-8 hours, under azeotropic removal of water, while monitoring the reaction on TLC. After the completion of the reaction, water was added and the organic layer separated while the aq. layer was extracted with toluene (2×500 ml). The combined organic layers were washed with brine and concentrated under vacuum to yield 4-((carboethoxy)methoxy)benzaldehyde as an oily material (407 g, Y=96%, P=99%).
Reaction SMILES: CS[CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][C:4]1=[O:16]>CC(O)=O.[Zn]>[F:15][C:12]([F:13])([F:14])[C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][C:4](=[O:16])[CH2:3]2
Reactant: CSC1C(=O)Nc2ccc(C(F)(F)F)cc21
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1Cc2cc(C(F)(F)F)ccc2N1
Yield: 89.7 %

Procedure:
A solution of 3-(methylthio)-5-(trifluoromethyl)oxindole (Gassman P. G., Cue B. W., Luh T-Y, J. Org. Chem. 1977;42:1344-1348) (10 g, 40 mmol) in AcOH (100 mL) was heated under reflux with Zn dust (13.3 g, 0.2 mol) for 1 hour. The mixture was cooled and filtered, and the precipitate was washed with AcOH. The combined filtrates were evaporated under reduced pressure, and the residue was diluted with 1M aqueous ammonia to give 5-trifluoromethyloxindole [VII: R1 =5-CF3, R3 =H] (7.22 g, 90%); mp (aqueous EtOH) 188.5°-191° C. (lit. [Hardtmann G. E., U.S. Pat. No. 4,160,032; Chem. Abstr, 1979;91:P107890w]; mp 188°-189° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[C:9]([OH:15])=[CH:8][CH:7]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]([CH3:35])=[C:30]([CH2:32][CH2:33]O)[N:31]=2)=[CH:23][CH:22]=1.ClC1C=CC(C=O)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[C:9]([O:15][CH2:33][CH2:32][C:30]2[N:31]=[C:27]([C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=3)[O:28][C:29]=2[CH3:35])=[CH:8][CH:7]=1
Reactant: CCOC(Cc1ccc(O)c2ccsc12)C(=O)OC
Reactant: Cc1oc(-c2ccc(Cl)cc2)nc1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=Cc1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(Cc1ccc(OCCc2nc(-c3ccc(Cl)cc3)oc2C)c2ccsc12)C(=O)OC

Procedure:
In analogy to the procedure described in example 17 a], [rac]-2-ethoxy-3-(4-hydroxy-benzo[b]thiophen-7-yl)-propionic acid methyl ester was reacted with 2-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-ethanol (prepared by conversion of the 4-chloro-benzaldehyde into 2-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-ethanol in analogy to the sequence described in examples 21 a] to 21 e]) in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-3-(4-{2-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl)-2-ethoxy-propionic acid methyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-3-(4-{2-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl)-2-ethoxy-propionic acid as light yellow solid.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].C(OC([NH:13][CH:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)=O)(C)(C)C.C(N(CC)CC)C>C(Cl)Cl>[CH3:5][O:4][C:2]([N:16]1[CH2:17][CH2:18][CH:14]([NH2:13])[CH2:15]1)=[O:3]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC(N)C1
Reaction time: 0.5 h

Procedure:
Add methyl chloroformate (460 μL, 560 mg, 6.0 mmol, 3.0 equiv) to a solution of 3-(tert-butoxycarbonylamino)pyrrolidine (TCI; 373 mg, 2.00 mmol, 1 equiv) and triethylamine (1.1 mL, 800 mg, 7.9 mmol, 3.9 equiv) in anhydr CH2Cl2 (4 mL). Vigorous gas evolution, a slight exotherm, and precipitation can occur. After stirring 30 min, rotary evaporate the reaction mixture (60° C.). Dissolve the resultant material in MeOH to quench any residual chloroformate and rotary evaporate the solution (60° C.). Add trifluoroacetic acid (5 mL) to this material causing gas evolution. Rotary evaporate the reaction solution (40° C.; azeotroping 2× with MeOH). Resultanting in a yellow oil then dissolve in MeOH (30 mL) and add hydroxide resin (Bio-Rad AG® 1-X8, 20-50 mesh; 9.3 g) to free-base the amine. Filter the mixture and evaporate the filtrate by rotary (40° C.; azeotroped 2× with CH2Cl2) to yield 914 mg (300%) of crude product as a light-brown oil. Mass spec indicates desired product is present. Absorb this oil to an SCX column (20 g) activated with 10% AcOH/MeOH. Push MeOH through the column to elute any non-amine material. Elute the product with 2.0 M NH3 in MeOH to yield 269 mg (93.2%) of 3-amino-pyrrolidine-1-carboxylic acid methyl ester as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([O-])=O)=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[CH:7]=1.[Na+].ClC[C:16]([O:18][CH3:19])=[O:17]>C1(C)C=CC=CC=1.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH2:10][C:16]([O:18][CH3:19])=[O:17])=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C([O-])c1nc(Cl)c(Cl)cc1Cl
Reactant: COC(=O)CCl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)Cc1nc(Cl)c(Cl)cc1Cl
Temperature: 105 °C
Yield: 90 %

Procedure:
Essentially equimolar amounts of sodium 3,5,6-trichloropyridinate and methyl α-chloroacetate in toluene were blended together in the presence of from 2 to 5 mole percent of benzyltriethylammonium chloride and the mixture refluxed at 105°C for 3 hours. The product, methyl α-(3,5,6-trichloropyridyl)acetate, was thus obtained in approximately 90 percent yield.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[CH2:10]([O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)[CH2:11][CH3:12]>>[F:9][C:4]1[CH:3]=[C:2]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([O:13][CH2:10][CH2:11][CH3:12])[CH:19]=2)[CH:8]=[CH:7][C:5]=1[NH2:6]
Reactant: CCCOc1cccc(B(O)O)c1
Reactant: Nc1ccc(Br)cc1F
Product: CCCOc1cccc(-c2ccc(N)c(F)c2)c1
Yield: 71.3 %

Procedure:
The title compound (280 mg) was prepared from 4-bromo-2-fluoroaniline (390 mg, 1.6 mmol) and 3-propoxyphenylboronic acid (369 mg, 2 mmol) as a colourless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7](=[CH:10][N:11]([CH3:13])C)[CH:8]=[O:9])=[CH:4][CH:3]=1.NC[C:18]([O:20][CH2:21][CH3:22])=[O:19].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7](=[CH:10][NH:11][CH2:13][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:8]=[O:9])=[CH:14][CH:15]=1
Reactant: CCOC(=O)CN
Reactant: CN(C)C=C(C=O)Oc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CNC=C(C=O)Oc1ccc(Cl)cc1

Procedure:
2-(4-Chlorophenoxy)-3-dimethylaminoacrylaldehyde (11.3 g., 50 mmoles) was dissolved in 200 ml. of ethanol, mixed with a solution of ethyl glycinate (14 g., 100 mmoles) in 90 ml. of 1N sodium hydroxide and refluxed for 15 hours. Ethanol was evaporated in vacuo, the aqueous residue diluted with 150 ml. of water and product extracted into 200 ml. of ethyl acetate. The ethyl acetate was back-washed with water and concentrated to an oil. Trituration of the oil with 100 ml. of ether gave crystalline 2-(4-chlorophenoxy)-3-carbethoxymethylaminoacrylaldehyde in two crops (7.3 g., Rf 0.55 on silica gel thin layer chromatography with ethyl acetate-1/hexane-1/5% acetic acid as eluant).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:19])=[CH:4][CH:3]=1.I[C:21]1C=C[C:24]([N:27]2[C:35]3[C:30](=CC(OC)=CC=3)[CH:29]=[C:28]2C)=[CH:23][CH:22]=1.COC1C=C2C(=CC=1)NC(C)=C2.BrC1C=CC(I)=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>C1(C)C=CC=CC=1.[Cu]I>[CH3:18][O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([C:21]#[C:22][CH2:23][CH2:24][N:27]3[CH2:35][CH2:30][CH2:29][CH2:28]3)=[CH:3][CH:4]=1)[C:9]([CH3:19])=[CH:10]2
Reactant: COc1ccc2c(c1)cc(C)n2-c1ccc(Br)cc1
Reactant: COc1ccc2c(c1)cc(C)n2-c1ccc(I)cc1
Agent: [Cu]I
Agent: Brc1ccc(I)cc1
Agent: CNCCNC
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)cc(C)n2-c1ccc(C#CCCN2CCCC2)cc1
Temperature: 80 °C

Procedure:
1-(4-Bromophenyl)-5-methoxy-2-methyl-1H-indole and 1-(4-Iodophenyl)-5-methoxy-2-methyl-1H-indole. 5-Methoxy-2-methylindole (500 mg, 3.1 mmol) and 1-bromo-4-iodobenzene (877 mg, 3.1 mmol) were dissolved in toluene (6 mL). To the resulting solution were added copper(I) iodide (12 mg, 0.062 mmol), potassium phosphate tribasic (1.32 g, 6.2 mmol), and N,N′-dimethylethylenediamine (6.6 μL, 0.062 mmol). The mixture was heated at 80° C. overnight, allowed to cool to room temperature and filtered through a pad of silica. The resulting solution was concentrated to give a mixture of both the bromo and the iodo halophenyl indoles, which were used without further purification (assumed quantitative).
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:54][S:55]([C:58]1[CH:63]=[CH:62][C:61](Br)=[CH:60][CH:59]=1)(=[O:57])=[O:56].[C:65]([C:68]1[CH:69]=[CH:70][C:71]([CH3:74])=[N:72][CH:73]=1)(=[O:67])[CH3:66]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:74][C:71]1[N:72]=[CH:73][C:68]([C:65](=[O:67])[CH2:66][C:61]2[CH:62]=[CH:63][C:58]([S:55]([CH3:54])(=[O:57])=[O:56])=[CH:59][CH:60]=2)=[CH:69][CH:70]=1
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Reactant: CC(=O)c1ccc(C)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Product: Cc1ccc(C(=O)Cc2ccc(S(C)(=O)=O)cc2)cn1
Temperature: 87.5 °C
Yield: 90.1 %

Procedure:
To a four-neck round-bottom 250 ml flask equipped with mechanical stirring and condenser were added at 20-25° C. and under nitrogen atmosphere Xantphos, palladium acetate, tripotassium phosphate trihydrate, PVP, 4-bromophenyl methyl sulfone, 5-acetyl-2-methyl pyridine, water (50.00 ml). A vacuum/nitrogen cycle was repeated for at least three times at 20-25° C. The resulting reaction mixture was heated up to 85-90° C. and stirred for at least 24 h. The reaction mixture was transferred in an other recipient then cooled down to 40-50° C. and diluted with water (400 ml). The resulting mixture was stirred at 40-45° C. for 15 min and cooled down to −5-0° C. The resulting reaction mixture was stirred at −5-0° C. for at least 2 h, then it was filtered and the cake was washed with water (3×100 ml) and dried at 65-70° C. under reduced pressure to afford a crude product of formula (I) as a yellow solid (48.3 g). yield: 90.1%, Purity: 75.7% by HPLC A %.
Reaction SMILES: [CH2:1]([C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([CH2:13][OH:14])[C:6]=2[N:5]=1)[CH2:2][CH3:3].Br[CH2:16][C:17]1[CH:36]=[CH:35][C:20]2/[C:21](=[C:31](/[CH3:34])\[C:32]#[N:33])/[C:22]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=3[O:24][CH2:25][C:19]=2[CH:18]=1>>[F:30][C:27]1[CH:28]=[CH:29][C:22]2=[C:23]([CH:26]=1)[O:24][CH2:25][C:19]1[CH:18]=[C:17]([CH2:16][N:8]3[C:7]4[CH:9]=[CH:10][CH:11]=[C:12]([CH2:13][OH:14])[C:6]=4[N:5]=[C:4]3[CH2:1][CH2:2][CH3:3])[CH:36]=[CH:35][C:20]=1/[C:21]/2=[C:31](/[CH3:34])\[C:32]#[N:33]
Reactant: CCCc1nc2c(CO)cccc2[nH]1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Product: CCCc1nc2c(CO)cccc2n1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 90.7 %

Procedure:
[step 2] Using (2-propyl-1H-benzo[d]imidazol-4-yl)methanol (47 mg, 0.25 mmol) obtained in step 1 and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (92 mg, 0.26 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (106 mg, 92%) was obtained.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[C:16]2[C:11](=[C:12](C(C)C)[CH:13]=[CH:14][CH:15]=2)[C:10]([C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[C:9](C(C)C)[C:8]=1[Si](C)(C)C)=[O:6])([CH3:3])[CH3:2].[Br:33]N1C(=O)CCC1=O>C(#N)C>[CH:1]([O:4][C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:9][C:8]=1[Br:33])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1c([Si](C)(C)C)c(C(C)C)c(C(=O)OC(C)C)c2c(C(C)C)cccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(C)OC(=O)c1cc(Br)c(C(=O)OC(C)C)c2ccccc12
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
Under a nitrogen stream, a mixture of diisopropyl 2-trimethylsilanyl-naphthalene-1,4-dicarboxylic acid diisopropyl ester (0.25 g, 0.671 mmol), N-bromosuccinimide (179 mg, 1.006 mmol) and acetonitrile (12.5 mL) was stirred for 30 minutes at 150° C. under microwave irradiation. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel flash column chromatography (developing solution=ethyl acetate:n-hexane (1:9)), to thereby obtain the titled compound (209 mg, 82%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:14][C:15]([S@:18]([NH2:20])=[O:19])([CH3:17])[CH3:16]>S([O-])([O-])(=O)=O.[Cu+2].ClCCCl>[F:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1/[CH:4]=[N:20]/[S@@:18]([C:15]([CH3:17])([CH3:16])[CH3:14])=[O:19]
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCCl
Product: CC(C)(C)[S@@](=O)/N=C/c1ccc(C(F)(F)F)cc1F
Temperature: 55 °C
Yield: 95 %

Procedure:
To a oven dried round bottom flask with stir bar was added 2-fluoro-4-(trifluoromethyl)benzaldehyde (5 g, 26.0 mmol), (R)-2-methylpropane-2-sulfinamide (3.47 g, 28.6 mmol) and DCE (52 mL). To this mixture was then added copper (II) sulfate (6.23 g, 39.0 mmol). The reaction mixture was heated in a preheated oil bath at 55° C. for 18 hours. The reaction mixture was filtered through a pad celite, washing the solids with DCE. The filtrate was concentrated to afford a viscous green oil of (R,E)-N-(2-fluoro-4-(trifluoromethyl)benzylidene)-2-methyl propane-2-sulfinamide (7.3 g, 24.7 mmol, 95% yield). Material was taken onto next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 1.29 (s, 9H) 7.44 (d, J=10.08 Hz, 1H) 7.51 (d, J=8.27 Hz, 1H) 8.13 (t, J=7.46 Hz, 1H) 8.92 (s, 1H). LCMS m/z 296.0 (M+H)+, Rt 1.02 min.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][C:5]([CH2:21][O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:6][C:7](=[O:20])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>CC(C)=O.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[O:4][C:5]([CH2:21][O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:6][C:7](=[O:20])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:1]
Reactant: CCOC(=O)CCCCCOc1c(CO)oc(COC(=O)C(C)(C)C)cc1=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: CCOC(=O)CCCCCOc1c(C=O)oc(COC(=O)C(C)(C)C)cc1=O
Reaction time: 3 h
Yield: 69.9 %

Procedure:
To a solution of 2.3 g of 2-hydroxymethyl-3-(5-carboethoxypentyloxy)-6-(trimethylacetoxymethyl)-4-pyrone in 75 ml of acetone was added 4 g of activated manganese dioxide. The resulting suspension was stirred for 3 hr, at which time the mixture was filtered and the filtrate evaporated to an oil. The oil was chromatographed on silica gel to give the oily aldehyde, 2-formyl-3-(5-carboethoxypentyloxy)-6-(trimethylacetoxymethyl)-4-pyrone weighing 1.6 g (70%). NMR (CDCl3): δ1.28 (3H, t, J = 7 Hz), 1.30 (9H, s), 2.31 (2H, t, J = 5.5 Hz), 4.17 (2H, q, J = 7 Hz), 4.48 (2H, t, J = 7Hz).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][C:25]([CH3:27])=O>>[CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][N:14]([CH:25]([CH3:27])[CH3:24])[CH2:13][CH2:12][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cn2nc(-c3ccccc3)c3c2CCNCC3)cc1
Reactant: CC(C)=O
Product: CC(C)N1CCc2c(-c3ccccc3)nn(Cc3ccccc3)c2CC1

Procedure:
The title compound (0.03 g) was prepared from 1-benzyl-3-phenyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 44, 0.07 g) and 22 μL of acetone as in Example 35. MS (ESI): exact mass calculated for C23H27N3, 345.22; found, m/z 346.3 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.57-7.52 (m, 2H), 7.50-7.27 (m, 6H), 7.22-7.20 (m, 2H), 5.47 (s, 2H), 3.77-3.61 (m, 3H), 3.29-3.28 (m, 3H), 3.24-3.08 (m, 3H), 1.40 (d, J=6.0 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])C(O)=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:35])C=CC=CC=1.O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[O:35])=[CH:4][CH:3]=1
Reactant: O=C(O)C(=Cc1ccc(Br)cc1)c1ccc(Cl)cc1Cl
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(Cc1ccc(Br)cc1)c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 60.3 %

Procedure:
Part B; 3-(4-Bromophenyl)-2-(2,4-dichlorophenyl)acrylic acid (26.55 gram, 71 mmol) is dissolved in anhydrous toluene (130 mL) and the resulting solution is cooled to 0° C. Triethylamine (7.40 gram, 73 mmol) and diphenylphosphoryl azide (19.8 gram, 72 mmol) are successively added and the resulting mixture Is stirred at 0° C. for 20 minutes and 150 minutes at room temperature. The reaction mixture is poured into water and extracted three times with diethyl ether. The collected organic layers are dried over MgSO4 and the diethyl ether Is removed in vacuo. The resulting toluene layer is slowly added to refluxing toluene (150 mL). t-Butanol is added after 90 minutes and heating at reflux temperature is continued for 1 hour, followed by slow addition of concentrated hydrochloric acid (5 mL). After stirring the resulting solution overnight at 90° C. it is allowed to attain room temperature, washed twice with water, dried over MgSO4, filtered and evaporated in vacuo to give a yellow oil. This oil is crystallised from n-hexane to give 2-(4-bromophenyl)-1-(2,4-dichlorophenyl)ethanone (14.72 gram, 60% yield). Melting point: 69-70° C.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:13]3[S:14][CH:15]=[CH:16][N:17]=3)[CH:10]=2)[NH:5][C:4](=[O:25])[CH:3]=1.[F:26][C:27]1[CH:28]=[C:29](/[CH:33]=[CH:34]/B(O)O)[CH:30]=[CH:31][CH:32]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([CH:12]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[NH:5][C:4](=[O:25])[CH:3]=[C:2]3/[CH:34]=[CH:33]/[C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([F:26])[CH:28]=2)=[CH:19][CH:20]=1
Reactant: OB(O)/C=C/c1cccc(F)c1
Reactant: O=c1cc(Br)c2cc(C(c3ccc(Cl)cc3)c3nccs3)ccc2[nH]1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: O=c1cc(/C=C/c2cccc(F)c2)c2cc(C(c3ccc(Cl)cc3)c3nccs3)ccc2[nH]1
Reaction time: 72 h

Procedure:
4-Bromo-6-((4-chlorophenyl)(thiazol-2-yl)methyl)quinolin-2(1H)-one (80 mg, 0.185 mol, 1 equip), trans-2-(3-fluorophenyl)vinylboronic acid (61.5 mg, 0.371 mmol, 2 equip), SPhos (15.5 mg, 0.037 mmol, 0.2 equip), tripotassium phosphate (78.7 mg, 0.371 mmol, 2 equip), and palladium acetate (4.2 mg, 0.019 mmol, 0.1 equip) were added to 1,4-dioxane (5 mL) and the resulting mixture stirred for 72 h. The reaction mixture was diluted with water and ethyl acetate and the layers were separated. The organic phase was washed with saturated sodium bicarbonate, then water, dried over Na2SO4, filtered and concentrated. The residue was purified by RP-HPLC and the fractions were lyophilized. The lyophilized product was washed with hot hexanes to remove residual SPhos, filtered, and dried under vacuum to yield (E)-6-((4-chlorophenyl)(thiazol-2-yl)methyl)-4-(3-fluorostyryl)quinolin-2(1H)-one as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:10]([O:12]C)=[O:11]>[OH-].[Na+].CO>[Cl:1][C:2]1[CH:3]=[N:4][NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:10]([OH:12])=[O:11]
Reactant: COC(=O)c1ccc(C)c(-c2[nH]ncc2Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(C(=O)O)cc1-c1[nH]ncc1Cl
Temperature: 50 °C
Yield: 119.6 %

Procedure:
Methyl 3-(4-chloro-1H-pyrazol-5-yl)-4-methylbenzoate (compound 51.2, 133 mg, 0.53 mmol) was dissolved in a mixture of aqueous NaOH (2 M, 3 mL) and methanol (10 mL). The solution was heated at 50° C. for 16 hrs then the volatiles were removed under reduced pressure. Aqueous HCl (2 M) was added to adjust the pH to 4-5 then concentrated to yield 150 mg of a white solid which was used in the next step without further purification. m/z (ES−) 235 (M−H)−.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][O:18][C:19](=[O:46])[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([N:30]3[CH2:39][C:38]4[CH:37]=[N:36][N:35]([CH3:40])[C:34]=4[NH:33][C:32]4[CH:41]=[CH:42][CH:43]=[CH:44][C:31]3=4)=[O:29])=[CH:24][C:23]=2[CH3:45])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[NH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][O:18][C:19](=[O:46])[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([N:30]3[CH2:39][C:38]4[CH:37]=[N:36][N:35]([CH3:40])[C:34]=4[NH:33][C:32]4[CH:41]=[CH:42][CH:43]=[CH:44][C:31]3=4)=[O:29])=[CH:24][C:23]=2[CH3:45])[CH2:13][CH2:12]1
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)OCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)OCC1CCNCC1
Yield: 98 %

Procedure:
4-{3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionyloxymethyl}-piperidine-1-carboxylic acid benzyl ester from Example E77.1 (44 mg, 0.07 mmol) was dissolved in methanol (5 ml) and hydrogenated over 10% Pd/C catalyst (5 mg) for 2 h. The mixture was filtered through Celite® filter agent and the filtrate concentrated in vacuo to give a white powder identified as the title compound (34 mg, 98%).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[NH2:13][C:14]1[C:23]2[N:24]=[C:25]([CH2:33]Cl)[N:26]([CH2:27][C:28]3([OH:32])[CH2:31][CH2:30][CH2:29]3)[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1>CN(C=O)C>[NH2:13][C:14]1[C:23]2[N:24]=[C:25]([CH2:33][N:5]3[C:1](=[O:11])[C:2]4[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4]3=[O:6])[N:26]([CH2:27][C:28]3([OH:32])[CH2:31][CH2:30][CH2:29]3)[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: Nc1nc2ccccc2c2c1nc(CCl)n2CC1(O)CCC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: Nc1nc2ccccc2c2c1nc(CN1C(=O)c3ccccc3C1=O)n2CC1(O)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
Under a nitrogen atmosphere, potassium phthalimide (1.21 g, 6.52 mmol) was added to a solution of 1-{[4-amino-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclobutanol (1.88 g, 5.93 mmol) in DMF (30 mL), and the reaction mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was partitioned between chloroform (200 mL) and water (25 mL)/saturated aqueous sodium bicarbonate (2×40 mL). The organic layer was washed with brine (2×40 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 2.42 g of 2-({4-amino-1-[(1-hydroxycyclobutyl)methyl]-1H-imidazo[4,5-c]quinolin-2-yl}methyl)-1H-isoindole-1,3(2H)-dione.