Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[C:5]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:4]=1.[C:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)(=[O:18])[CH3:17]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6](/[CH:7]=[CH:17]/[C:16]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)=[O:18])=[C:5]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:4]=1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1ccc(C=O)c(-c2cccs2)c1
Product: COc1ccc(/C=C/C(=O)c2ccc(C(=O)O)cc2)c(-c2cccs2)c1
Yield: 61 %

Procedure:
The title compound was prepared by condensing 4-methoxy-2-thiophen-2-yl-benzaldehyde (Ex-34A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, 61% yield, m.p. 209–211° C. 1H-NMR (300 MHz, d6-DMSO): 8.14 (m, 3H), 8.04 (d, 2H, J=9.2 Hz), 7.89 (d, 1H, J=15.5 Hz), 7.76 (d, 1H, J=15.5 Hz), 7.70 (d, 1H, J=5.0 Hz), 7.18 (dd, 1H, J=5.6 and 3.6 Hz), 7.11 (d, 1H, J=2.1 Hz), 7.05 (dd, 1H, J=8.8 and 1.8 Hz), 6.98 (d, 1H, J=1.8 Hz), 3.83 (s, 3H). MS m/z=364 ([M]+, 100%). HRMS (EI) Calcd. for C21H16O4S: 364.0769. Found: 364.0761.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:15][OH:16])[CH:14]=1)[C:8]([O:10][CH3:11])=O)([CH3:4])([CH3:3])[CH3:2].[CH3:17]I>>[C:1]([C:5]1[CH:14]=[C:13]([C:15](=[O:16])[CH3:17])[CH:12]=[C:7]([CH2:8][O:10][CH3:11])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: COC(=O)c1cc(CO)cc(C(C)(C)C)c1
Product: COCc1cc(C(C)=O)cc(C(C)(C)C)c1

Procedure:
Methyl 3-tert-butyl-5-hydroxymethylbenzoate was reacted with methyl iodide analogously to O5.043, and converted to the title compound analogously to the sequence O4:008 to O2.008. 1.54 g were obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([S:11][C:12]([F:15])([F:14])[F:13])[CH:10]=[C:5]2[N:4]=[CH:3]1.Br[C:17]1[CH:22]=[CH:21][C:20]([S:23][C:24]([F:27])([F:26])[F:25])=[CH:19][C:18]=1[S:28][CH2:29][CH3:30].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(OCC)(=O)C>[CH2:29]([S:28][C:18]1[CH:19]=[C:20]([S:23][C:24]([F:27])([F:25])[F:26])[CH:21]=[CH:22][C:17]=1[C:3]1[N:2]([CH3:1])[C:6]2=[N:7][CH:8]=[C:9]([S:11][C:12]([F:13])([F:15])[F:14])[CH:10]=[C:5]2[N:4]=1)[CH3:30]
Reactant: Cn1cnc2cc(SC(F)(F)F)cnc21
Reactant: CCSc1cc(SC(F)(F)F)ccc1Br
Agent: [Cu+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCSc1cc(SC(F)(F)F)ccc1-c1nc2cc(SC(F)(F)F)cnc2n1C
Yield: 90.3 %

Procedure:
A mixture of 0.11 g of 3-methyl-6-trifluoromethylsulfanyl-3H-imidazo[4,5-b]pyridine, 0.15 g of 1-bromo-2-ethylsulfanyl-4-trifluoromethylsulfanylbenzene, 0.01 g of palladium(II) acetate, 0.01 g of triphenylphosphine, 0.02 g of copper(II) acetate monohydrate, 0.13 g of potassium carbonate and 3 ml of toluene was stirred under heating and refluxing for 2 hours. Ethyl acetate and water were added to the cooled reaction mixture, and the mixture was filtered. The filtrate was extracted with ethyl acetate, and then dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.20 g of 2-(2-ethylsulfanyl-4-trifluoromethylsulfanylphenyl)3-methyl-6-trifluoromethylsulfanyl-3H-imidazo[4,5-b]pyridine (hereinafter, referred to as Compound 7).
Reaction SMILES: [CH2:1]([N:3]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.[C:21]1([C:27](=[O:31])[C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)C>[CH2:1]([N:3]([CH2:4][CH3:5])[CH:6]=[C:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:28](=[O:29])[C:27]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:31])[CH3:2]
Reactant: O=C(Cl)C(=O)c1ccccc1
Reactant: CCN(C=Cc1ccccc1)CC
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCN(C=C(C(=O)C(=O)c1ccccc1)c1ccccc1)CC
Reaction time: 1.25 h

Procedure:
Seven grams of N,N-diethylstyrylamine was dissolved in 100 ml. of diethyl ether and the solution was cooled to 0°C. Four grams of anhydrous triethylamine was added. A 7 g. portion of phenylglyoxyloyl chloride was dissolved in 50 ml. of diethyl ether and the solution was added dropwise, with stirring, to the first solution over about 75 minutes. As soon as the addition was complete, the reaction mixture was filtered, and the precipitated amine hydrochloride was washed with an additional 50 ml. of diethyl ether. The filtrate contained the intermediate enamine, 1-diethylamino-2,4-diphenyl-1-buten-3,4-dione, in dissolved form, and was used in the next step of the synthesis without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](O)=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:7]=1.[NH2:37]C1C=CC(C(=O)C)=CC=1.[OH-].[K+]>C(O)C>[NH2:37][C:3]1[CH:2]=[CH:7][C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)c1ccc(N)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)cc1
Yield: 10 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(4-amino-phenyl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (14 mg, 10% yield). MS: 463.23 (M+H+); HPLC Procedure A, retention time=8.62 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([I:9])=[CH:4][N:3]=1.C=O.[C:12](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCOC(C)=O>CC(O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH3:12])[C:5]([I:9])=[CH:4][N:3]=1
Reactant: Nc1cc(Cl)ncc1I
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CNc1cc(Cl)ncc1I
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 78.1 %

Procedure:
2-Chloro-5-iodopyridin-4-amine (2.0 g, 7.86 mmol) and paraformaldehyde (0.472 g, 15.7 mmol) were dissolved in AcOH (56.1 mL) and stirred for 2.5 hours at 40° C. Sodium triacetoxyborohydride (3.66 g, 17.3 mmol) was added and the mixture was stirred at 40° C. for 1.5 hours. Further sodium triacetoxyborohydride (3.66 g, 17.3 mmol) was added and the mixture was stirred for a further 19 hours. The reaction mixture was reduced in volume by half by evaporation in vacuo. Water was added to the mixture, followed by basification with NaHCO3. The mixture was extracted with EtOAc (3×70 mL) and the combined organic layers were dried over MgSO4. Silica was added and the solution was concentrated. Gradient chromatography, eluting with 5-10% EtOAc in c-Hex for 4 column volume and then 10% EtOAc in c-Hex for a further 11 column volume, gave 2-chloro-5-iodo-N-methylpyridin-4-amine (1.65 g, 6.14 mmol, 78% yield) as a white crystalline powder.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[C:16]([C:20]4[CH:25]=[C:24]([NH:26][CH:27]5[CH2:29][CH2:28]5)[N:23]=[C:22]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=5)[CH:21]=4)[CH:17]=[N:18][CH:19]=3)=[CH:10][CH:9]=2)[CH2:3]1.C(OC(=O)N[C@H]1CCNC1)(C)(C)C>>[NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:15]=[C:16]([C:20]4[CH:25]=[C:24]([NH:26][CH:27]5[CH2:28][CH2:29]5)[N:23]=[C:22]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=5)[CH:21]=4)[CH:17]=[N:18][CH:19]=3)=[CH:12][CH:13]=2)[CH2:3]1
Reactant: N[C@@H]1CCN(Cc2ccc(-c3cncc(-c4cc(NC5CC5)nc(-c5ccccn5)c4)c3)cc2)C1
Agent: CC(C)(C)OC(=O)N[C@H]1CCNC1
Product: N[C@H]1CCN(Cc2ccc(-c3cncc(-c4cc(NC5CC5)nc(-c5ccccn5)c4)c3)cc2)C1

Procedure:
This compound is prepared analogously to {5″-[4-((R)-3-Amino-pyrrolidin-1-ylmethyl)-phenyl]-[2,2′;4′,3″]terpyridin-6′-yl}-cyclopropyl-amine (Example 2.76) by replacing (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester with (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester. [M+H]+ 463.
Reaction SMILES: N[C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[Br-].[K+].O.O[S:14](O)(=O)=O>>[SH:14][CH:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[C:7]([OH:9])=[O:8]
Reactant: CC(C)C[C@@H](N)C(=O)O
Reactant: O=S(=O)(O)O
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: CC(C)CC(S)C(=O)O

Procedure:
A solution of D-Leucine (5 g) and potassium bromide (114 g) in 400 ml of 2.5 N H2SO4 was cooled to -5° C. in an ice salt bath. A cold solution of NANO2 (30 g/70 ml water, 0°-50° C.) was added dropwise with stirring. The reaction was allowed to proceed for ~14 hours at room temperature. The reaction was then extracted with 75 ml portions of ether three times. The ether extract was dried over anhydrous sodium sulfate. The solution was filtered and the ether was evaporated. The resulting clear oil, 2-bromo-4-methylpentanoic acid (Martin and Greco, (1968) J. Org. Chem. 33, 1275-1276) (18 g) was committed to a 250 ml solution of 33% sodium trithiocarbonate with stirring at 0° C. The reaction was stirred for 48 hrs and then acidified at 0° C. with judicious addition of 10N H2SO4. The acidified solution was then extracted with 75 ml portions of ether three times. The ether extracts were dried over anhydrous sodium sulfate, and subsequently the ether was removed in vacuo. The resulting yellowish oil (17 g) was vacuum distilled. The final yield was 15.3 g of (S)-2-mercapto-4-methylpentanoic acid; b.p. 92-93 (0.75 mmHg); [α]D 25=-23.2 (cl,MeOH).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=O)C.C1(C)C=CC=CC=1>CCN(CC)CC.CCOC(C)=O.CCCCCC>[CH:17]([C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc(-c2ccccn2)cc1
Reactant: CC(=O)OC=Cc1ccccc1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C(=Cc1ccccc1-c1ccccn1)c1ccccc1
Temperature: 25 °C
Reaction time: 32 h
Yield: 69 %

Procedure:
A Teflon-coated magnetic stirring rod was placed in a 10 mL two-necked flask which was then equipped with a reflux condenser. The reflux condenser was connected to a pressure reduced/nitrogen line, and the whole apparatus was dried with heating under reduced pressure. Thereafter N2 gas was charged in the reaction apparatus and the whole reaction apparatus was purged with nitrogen. The reaction vessel was left to cool to room temperature, then, Ru(cod)(cot) complex (0.05 mmol, 15.8 mg), 2-phenylpyridine (1 mmol, 155.2 mg), styryl acetate (3 mmol, 486.6 mg) and toluene (1.5 mL) were added. The mixture was heated by an oil bath and reacted under reflux condition for 32 hours. 32 hours after, the reaction solution was left to cool to room temperature, then, triethylamine (0.3 mL) was added. Isolation of the product was carried out by silica gel column chromatography (i.d.=30 mm; length=170-250 mm; hexane:EtOAc:Et3N=9:1:0.1; 25 mL each). A subject substance 2-(2-styrylphenyl)-pyridine was obtained with a yield of 69%.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:11]([F:14])([F:13])[F:12])[C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1.N([O-])=O.[Na+].[BrH:19].[OH-].[Na+]>S(=O)(=O)(O)O.O>[Br:19][C:2]1[CH:3]=[C:4]([C:11]([F:14])([F:13])[F:12])[C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1
Reactant: CC(=O)c1ncc(N)cc1C(F)(F)F
Reactant: Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(=O)c1ncc(Br)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1-(5-amino-3-trifluoromethyl-pyridin-2-yl)-ethanone (408 mg, 2.0 mmol) in 75% sulfuric-acid (6 mL) at 0° C. add sodium nitrite (152 mg, 2.2 mmol) in water (1 mL). Stir the mixture for 30 minutes and add CuBr (343 mg, 2.4 mmol) and 48% HBr (2 mL). Heat the mixture at 60° C. for 30 minutes, cool to 0° C. and basify by dropwise addition of 10M sodium hydroxide. Extract the mixture with ethyl acetate (3×20 mL) and wash the combined organics with brine (50 mL). The organic extract is dried over MgSO4 and the solvent removed under reduced pressure to yield the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:19]([O:21][CH3:22])=[O:20])[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:10]=2)=[CH:7][CH:8]=1.[C:23]([O-:26])(=[S:25])[CH3:24].[K+]>CC(C)=O>[C:23]([S:25][CH2:2][C:3]1[CH:4]=[C:5]([C:19]([O:21][CH3:22])=[O:20])[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:10]=2)=[CH:7][CH:8]=1)(=[O:26])[CH3:24]
Reactant: CC([O-])=S
Reactant: COC(=O)c1cccc(-c2ccc(CBr)cc2C(=O)OC)c1
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(-c2ccc(CSC(C)=O)cc2C(=O)OC)c1
Temperature: 25 °C
Yield: 76.7 %

Procedure:
To a solution of 4-bromomethyl-[1,1′-biphenyl]-2,3′-dicarboxylic acid, dimethyl ester (1.59 g, 4.4 mmol) in acetone (75 mL) was added potassium thioacetate (0.60 g, 5.3 mmol), and the mixture was refluxed for 1 h. The mixture was allowed to cool to rt, filtered, and concentrated. The residual product was purified by column chromatography (hexanes/EtOAc, 9/1) to afford 4-acetylthiomethyl-[1,1′-biphenyl]-2,3′-dicarboxylic acid, dimethyl ester (1.21 g, 76%): 1H NMR (DMSO-d6) δ 2.39 (s, 3H), 3.60 (s, 3H), 3.88 (s, 3H), 4.23 (s, 2H), 7.42–7.44 (d, J=8.0 Hz, 1H), 7.57–7.60 (m, 3H), 7.74 (s, 1H), 7.83 (s, 1H), 7.96–7.99 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:2]1([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: Nc1ccccc1
Product: c1ccc(Nc2ccccc2)cc1
Reaction time: 4 h
Yield: 98.1 %

Procedure:
According to general procedure B, chlorobenzene (57 mg, 0.50 mmol) reacted with aniline (48 mg, 0.50 mmol) using 1 mol % of Pd(dba)2, 2 mol % of Ph5FcP(t-Bu)2, and sodium tert-butoxide (59 mg, 0.60 mmol) in toluene at 70° C. to give the title compound (73 mg, 86%) as a white solid. The coupling reaction of bromobenzene (158 mg, 1.00 mmol) with aniline (93 mg, 1.00mmol) occurred at room temperature over 4 h using 1 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 to give the title compound (166 mg, 98%): 1H-NMR (400 MHz, CDCl3): δ 7.34 (t, 4H, J=7.8 Hz and 7.5 Hz), 7.14 (d, 4H, J=8.7 Hz), 7.00 (t, 2H, J=7.2 and 7.5 Hz), 5.74 (bs, 1H). 13C{1H}-NMR (100 MHz, CDCl3): δ 143.09, 129.32, 120.97, 117.78. GC/MS(EI): m/z 169 (M+).
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH2:12][CH2:11]3)=[N:6][NH:5][C:4](=[O:17])[CH2:3]1.C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(Cl)(Cl)Cl>[CH3:1][CH:2]1[C:7]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([C:25](=[O:27])[CH3:26])[CH2:12][CH2:11]3)=[N:6][NH:5][C:4](=[O:17])[CH2:3]1
Reactant: CC1CC(=O)NN=C1c1ccc2c(c1)CCN2
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCc2cc(C3=NNC(=O)CC3C)ccc21
Temperature: 25 °C

Procedure:
To a solution of 5-(5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)indoline in 100 ml of chloroform was added 5 ml of triethylamine with stirring. To the mixture was added dropwise 3 ml of acetic anhydride. After maintaining at room temperature for one hour, the reaction mixture was concentrated under reduced pressure. The residual crystals were filtered off, washed with water and recrystallized from ethanol to give 4.3 g of 5-(5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-acetylindoline as white crystals, melting at 258°-261° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1)[CH3:2].S(=O)(=O)(O)[OH:11].C(OC(=O)C)(=O)C.C([O-])([O-])=O.[Na+].[Na+].[Cr](O)(O)(=O)=O>O.C(O)(=O)C>[CH3:9][C:6]1[N:7]=[CH:8][C:3]([C:1](=[O:11])[CH3:2])=[CH:4][CH:5]=1
Reactant: O=S(=O)(O)O
Reactant: CCc1ccc(C)nc1
Agent: O=[Cr](=O)(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1ccc(C)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.6 %

Procedure:
5-Ethyl-2-methyl-pyridine (40 g, 0.33 mol) was placed in a three-necked flask immersed in an ice bath and equipped with an efficient mechanical stirrer, a thermometer and a dropping funnel. Sulfuric acid (14.9 ml, 0.26 mol) was added with vigorous stirring. Then acetic acid (47.5 ml), acetic anhydride (46.3 ml) and finally CrO3 (44 g, 0.44 mol) were added in small portions, at a rate to maintain the temperature of the reaction mixture between 20-30° C. Stirring was continued for 24 hours. Then 200 ml of water and Na2CO3 were added slowly, until the brown color of chromic acid was gone, and the product was extracted with ethyl acetate (3×200 ml). Combined organic layers were washed with water and brine and dried over magnesium sulfate and solvent was removed. The residue was distilled under reduced pressure (110° C., 19 mbar) to give 12.85 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:15](/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])[CH:14]3[N:9]([CH2:10][CH2:11][C:12]4[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=43)[C:8](=[O:26])[C:7]=2[CH:27]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:15](/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])=[C:14]3[N:9]([CH2:10][CH2:11][C:12]4[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=43)[C:8](=[O:26])[C:7]=2[CH:27]=1
Reactant: COC(=O)/C=C/C1c2ccc(OC)cc2C(=O)N2CCc3ccccc3C12
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1c2n(c(=O)c3cc(OC)ccc13)CCc1ccccc1-2

Procedure:
5.5 g (15.13 mmol) of methyl (E)-3-(10-methoxy-8-oxo-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizin-13-yl)prop-2-enoate are dissolved in 150 ml of toluene in a 500 ml round-bottomed flask, 5.15 g (22.7 mmol) of 2,3-dichloro-5,6-dicyanocyclohexa-2,5-diene-1,4-diene are added and the mixture is heated at reflux for 2 h 30.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]2[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:40])[C:32]3[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=3[F:39])=[N:26]2)=[C:20]([C:41]([F:44])([F:43])[F:42])[CH:19]=1>C1COCC1>[F:38][C:37]1[CH:36]=[CH:35][CH:34]=[C:33]([F:39])[C:32]=1[C:31]([NH:30][C:27]1[CH:28]=[CH:29][N:25]([CH2:24][C:21]2[CH:22]=[CH:23][C:18]([CH2:17][N:2]3[N:3]=[CH:4][CH:5]=[N:1]3)=[CH:19][C:20]=2[C:41]([F:42])([F:43])[F:44])[N:26]=1)=[O:40]
Reactant: O=C(Nc1ccn(Cc2ccc(CBr)cc2C(F)(F)F)n1)c1c(F)cccc1F
Reactant: c1c[nH]nn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1ccn(Cc2ccc(Cn3nccn3)cc2C(F)(F)F)n1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 1H-1,2,3-triazole (34 mg, 0.492 mmol, Alfa Aesar) in THF (2 ml) at ambient temperature under nitrogen was added 1.0 M lithium bis(trimethylsilyl)amide in THF (0.5 ml, 0.500 mmol). The resulting yellow cloudy mixture was stirred at ambient temperature for 10 min. To a solution of N-(1-{[4-(bromomethyl)-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)-2,6-difluorobenzamide (for a preparation see Intermediate 22)(49 mg, 0.103 mmol) in THF (2 ml) at ambient temperature was added a solution of the 1H-1,2,3-triazole anion (0.5 ml, 0.167 mmol). After 1.5 h, a further amount of 1H-1,2,3-triazole anion (0.5 ml, 0.167 mmol) was added to the mixture and stirred overnight. The solvent was removed in vacuo and the residue was dissolved in 1:1 MeOH:DMSO (1 ml) and purified by MDAP on Sunfire C18 column using Acetonitrile-Water with a Formic acid modifier (Method B). The solvent was evaporated in vacuo to give the title compound as a colourless gum (1.8 mg); LCMS: (System 4) MH+=463.1, tRET=2.85 min.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:26][C@H:27]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45])[CH:33]=1)[CH:28]([CH3:30])[CH3:29])[C@@H:9]([OH:25])[CH2:10][C@H:11]([C:15](=[O:24])[NH:16][CH2:17][C:18]([C:21](=[O:23])[NH2:22])([CH3:20])[CH3:19])[CH:12]([CH3:14])[CH3:13])(C)(C)C.C(=O)(O)[O-].[Na+]>Cl.O1CCOCC1>[NH2:7][C@@H:8]([CH2:26][C@H:27]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45])[CH:33]=1)[CH:28]([CH3:29])[CH3:30])[C@@H:9]([OH:25])[CH2:10][C@@H:11]([CH:12]([CH3:13])[CH3:14])[C:15]([NH:16][CH2:17][C:18]([C:21](=[O:23])[NH2:22])([CH3:20])[CH3:19])=[O:24]
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@H](C(=O)NCC(C)(C)C(N)=O)C(C)C)C(C)C)ccc1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COCCCOc1cc(C[C@@H](C[C@H](N)[C@@H](O)C[C@H](C(=O)NCC(C)(C)C(N)=O)C(C)C)C(C)C)ccc1OC

Procedure:
Product 13 is dissolved in a mixture of 4.0M hydrochloric acid in dioxane. The solution is stirred for 24 hours at room temperature and neutralized with solid sodium bicarbonate. The suspension is filtered and the solvent removed in vacuum to give the product as a foam (for characterization see e.g. EP 0 678 503, Example 137).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:44][CH2:45][CH:46]4[CH2:48][CH2:47]4)=[C:24]([NH:27][C:28](=[O:43])[CH:29]=[CH:30][CH2:31][N:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH:33]4[C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[F:15].C(N(CC)CC)C>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:44][CH2:45][CH:46]4[CH2:47][CH2:48]4)=[C:24]([NH:27][C:28](=[O:43])[CH:29]=[CH:30][CH2:31][N:32]4[CH2:37][CH2:36][N:35]([C:1]([CH3:2])=[O:3])[CH2:34][CH:33]4[C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: CCOC(=O)C1CNCCN1CC=CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CN(C(C)=O)CCN1CC=CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.12 ml of acetic acid anhydride are added dropwise to a mixture of 500 mg of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-({4-[2-(ethoxycarbonyl)-piperazin-1-yl]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline and 0.18 ml of triethylamine in 5 ml of methylene chloride at 0° C. The reaction mixture is stirred for one hour at 0° C. followed by one hour at room temperature, washed with water, concentrated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The crude product is purified by column chromatography on silica gel with ethyl acetate/methanol (98:2 to 95:5). Yield: 291 mg (54% of theory), Melting point: 152-156° C. Mass spectrum (ESI+): m/z=625, 627 [M+H]+
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:27]4[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc3oc(-c4ccc(OC)c([N+](=O)[O-])c4)nc3c2)cc1

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 4-methoxyphenylboronic acid (129 mg, 0.85 mmol) the subtitle compound was obtained (193 mg, 60%). 1H NMR (DMSO) δ 8.63(d, 1H), 8.45(dd, 1H), 7.99(d, 1H), 7.83(d, 1H), 7.67(d, 3H), 7.62(d, 1H), 7.05(d, 2H), 4.05(s, 3H), 3.81(s, 3H).
Reaction SMILES: O=[C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].Cl.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26]N)=[CH:22][CH:21]=1>>[CH3:19][C:20]1[CH:21]=[C:22]2[C:23](=[CH:24][CH:25]=1)[NH:26][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:3]2[CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CCCCC(=O)c1ccccc1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Product: CCOC(=O)CCCc1c(-c2ccccc2)[nH]c2ccc(C)cc12
Yield: 58 %

Procedure:
The expected ester is obtained in the form of a brown solid with a yield of 58% by following a procedure analogous to Preparation X and starting from ethyl ε-oxobenzenehexanoate and 4-methylphenylhydrazine hydrochloride.