Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH2:5][CH:6]=[CH:7][CH2:8][CH2:9][CH:10]=[CH:11][CH2:12][CH2:13][CH:2]12.[H][H]>[Pd]>[CH:2]1([OH:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C1=CCCC2OC2CCC=CCC1
Reactant: [H][H]
Agent: [Pd]
Product: OC1CCCCCCCCCCC1
Yield: 5 %

Procedure:
Also, the Drafted Report of 24th Symposium of Development in Reaction and Synthesis, Nov. 5 to 6, 1998, page 68, discloses a method of hydrogenating 1,2-epoxy-5,9-cyclododecadiene with hydrogen at ambient atmospheric pressure and room temperature in the presence of a catalyst comprising palladium carried on a carrier consisting of a carbon material. In this method, cyclododecanol was produced with a yield of 5% and no cyclododecanone was obtained.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([C:9]2[N:13]3[N:14]=[C:15]([NH:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH:16]=[CH:17][C:12]3=[N:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.CCN(C(C)C)C(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>CS(C)=O>[F:27][C:2]([F:26])([F:1])[C:3]1[CH:4]=[C:5]([C:9]2[N:13]3[N:14]=[C:15]([NH:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:23][CH2:24]4)[CH:16]=[CH:17][C:12]3=[N:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: N[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(C(F)(F)F)c4)n3n2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CS(=O)(=O)N[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(C(F)(F)F)c4)n3n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0° C. solution of trans-N1-(3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)cyclohexane-1,4-diamine (130 mg, 0.35 mmol) and DIPEA (135.7 mg, 10.5 mmol) in DMSO (1.75 mL) was added dropwise MeSO2Cl (47.6 mg, 0.42 mmol). The resulting mixture was stirred at room temperature overnight. LCMS showed most of starting material was converted. The mixture was partitioned between brine (100 mL) and EtOAc (50 mL) and separated. The aqueous layer was extracted with EtOAc (50 mL*3). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to give EX. 8-90 (30 mg, 18.9%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(O)CO.COC.O.[CH3:28][O:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([O:38][CH3:39])[C:35]=1[O:36][CH3:37].C(=O)(O)[O-].[Na+]>>[C:16]1([CH3:19])[CH:17]=[CH:18][C:13]([NH:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([C:32]3[CH:33]=[C:34]([O:38][CH3:39])[C:35]([O:36][CH3:37])=[C:30]([O:29][CH3:28])[CH:31]=3)[N:11]=2)=[CH:14][CH:15]=1
Reactant: Cc1ccc(Nc2nc(Cl)nc3ccccc23)cc1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Agent: COC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: OCCO
Product: COc1cc(-c2nc(Nc3ccc(C)cc3)c3ccccc3n2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
A mixture of (2-chloro-quinazolin-4-yl)-p-tolyl-amine, 3.76 g, 0.014 mol), ethylene-glycol-dimethyl-ether/water (1 l/120 ml), 3,4,5-trimethoxyphenylboronic acid (2.714 g, 0.014 mol) and sodium bicarbonate (3.6 g) was degassed with argon for 15 minutes. Pd(dppf)Cl2 (0.84 g) was added, and the mixture was heated to reflux overnight. After cooling to room temperature CH2Cl2 (1 l) and H2O (500 ml) were added. The organic and aqueous layers were separated, the aqueous layer was extracted with CH2Cl2 (2×500 ml), and the combined organic layers were dried over anhydrous sodium sulfate. The organic solvent was removed under reduced pressure. The crude product was purified by methanol. Filtration in a Büchner apparatus afforded p-tolyl-[2-(3,4,5-trimethoxy-phenyl)-quinazolin-4-yl]-amine, 2 (3.15 g, 0.0078 mol 56%). m.p.: >250° C.; 1H NMR (300 MHz, DMSO-d6) δ 2.33 (s, 3H), 3.74 (s, 3H), 3.91 (s, 6H), 6.81 (s, 2H), 7.24 (d, J=8.4 Hz, 2H), 7.33 (d, J=7.3 Hz, 2H), 7.58 (t, J=8.2 Hz, 1H), 7.83 (t, J=7.2 Hz, 2H), 8.54 (d, J=7.5 Hz, 1H). Anal. (C24H23N3O3) C, H, N.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[Br:21][C:22]1[CH:26]=[CH:25][NH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:21][C:22]1[CH:26]=[CH:25][N:24]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=3[N:12]=2)[N:23]=1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: Brc1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3-n3ccc(Br)n3)nc2c1
Temperature: 50 °C
Yield: 76.4 %

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.19 g of 3-bromopyrazole, 0.55 g of potassium carbonate and 2 ml of DMF was stirred while heating at 50° C. for 1.5 hours. Then, the reaction mixture was cooled to room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.31 g of 2-[3-(3-bromopyrazole-1-yl)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 59”).
Reaction SMILES: [F:1][C:2]([F:19])([CH3:18])[CH2:3][C@H:4]([NH:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])[C:5]([OH:7])=O.Cl.[NH2:21][CH:22]([CH2:33][CH3:34])[C@@H:23]([C:25]1[O:29][N:28]=[C:27]([CH:30]2[CH2:32][CH2:31]2)[N:26]=1)[OH:24].C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>ClCCl>[CH:30]1([C:27]2[N:26]=[C:25]([CH:23]([OH:24])[C@@H:22]([NH:21][C:5]([C@@H:4]([NH:8][C:9]([N:11]3[CH2:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[O:10])[CH2:3][C:2]([F:1])([F:19])[CH3:18])=[O:7])[CH2:33][CH3:34])[O:29][N:28]=2)[CH2:31][CH2:32]1
Reactant: CC(F)(F)C[C@H](NC(=O)N1CCCOCC1)C(=O)O
Reactant: CCC(N)[C@H](O)c1nc(C2CC2)no1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC[C@H](NC(=O)[C@H](CC(C)(F)F)NC(=O)N1CCCOCC1)C(O)c1nc(C2CC2)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
To a mixture of (S)-4,4-Difluoro-2-[(perhydro-1,4-oxazepine-4-carbonyl)-amino]-pentanoic acid (97 mg, 0.35 mmol), (S)-2-Amino-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-butan-1-ol hydrochloride (83 mg, 0.36 mmol) and diisopropylethyl amine (121 μL, 0.70 mmol) in dry dichloromethane (12 mL) is added 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (66 mg, 0.35 mmol) and 1-hydroxybenzotriazole hydrate (47 mg, 0.35 mmol). The mixture is stirred at room temperature for 16 hr then is diluted with dichloromethane (20 mL) and washed with dilute HCl (30 mL), then saturated NaHCO3 (30 mL). The organic layer is dried (Na2SO4) and concentrated in vacuum. The residue is purified over 12 g silica gel, eluting with ethyl acetate: heptane (gradient 50-100%) to afford Perhydro-1,4-oxazepine-4-carboxylic acid ((S)-1-{(S)-1-[(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-hydroxy-methyl]-propylcarbamoyl}-3,3-difluoro-butyl)-amide (120 mg, 75%) as a glassy solid. LC/MS 100% 460 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]1([OH:6])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: BrCCCCCBr
Reactant: Nc1ccc(Br)cc1C(=O)O
Product: Nc1ccc(Br)cc1C1(O)CCCCC1

Procedure:
Prepared according to the procedure of Example 1 from 2-amino-5-bromobenzoic acid and the Grignard reagent prepared from 1,5-dibromopentane A clear oil: 1H-NMR (DMSO-d6) δ 7.07 (d, 1H, J=2.3 Hz), 7.03 (dd, 1H, J=8.4, 2.4 Hz), 6.55 (d, 1H, J=8.6 Hz), 5.49 (s, 2H, H2O exchangeable), 5.00. (s, 1H, D2O exchangeable), 2.01 (d, 2H, J=1.8 Hz), 1.66-1.77 (m, 2H), 1.44-1.61 (m, 4H), 1.16-1.34 (m, 2H). MS (ESI) m/z 270/272 ([M+H]+, 98%/100%).
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:6]([OH:7])[CH2:5][N:4]([C:8]2[CH:27]=[CH:26][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([Cl:25])([F:24])[F:23])=[CH:17][CH:16]=3)=[O:13])=[CH:10][C:9]=2Br)[CH2:3]1.[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>C(Cl)Cl.CCCCCC>[NH2:1][C@@H:2]1[C@@H:6]([OH:7])[CH2:5][N:4]([C:8]2[CH:27]=[CH:26][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([Cl:25])([F:24])[F:23])=[CH:17][CH:16]=3)=[O:13])=[CH:10][C:9]=2[C:33]2[CH:34]=[N:29][CH:30]=[N:31][CH:32]=2)[CH2:3]1
Reactant: N[C@H]1CN(c2ccc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2Br)C[C@@H]1O
Reactant: OB(O)c1cncnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Solvent: CCCCCC
Product: N[C@H]1CN(c2ccc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2cncnc2)C[C@@H]1O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
4-((3S,4S)-3-amino-4-hydroxypyrrolidin-1-yl)-3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)benzamide (Stage 245.1, 60 mg, 0.121 mmol), 5-pyrimidineboronic acid (22.46 mg, 0.181 mmol) and Na2CO3 aq. (0.181 mL, 0.362 mmol) were added to a vial containing DME (1.5 mL) under argon atmosphere. PdCl2(dppf)-(CH2Cl2) (5.92 mg, 7.25 μmol) was added. The RM was stirred at 80° C. for 2 h, then filtered through Hyflo® and the solvent was evaporated off under reduced pressure to give the crude product which was purified by preparative HPLC (Condition 14). Fractions containing the product were combined, treated with sat. aq. Na2CO3 and the MeCN was removed. The aq. residue was extracted with DCM and the combined extracts were dried over Na2SO4, filtered and the filtrate was evaporated off under reduced pressure to give a residue that was suspended in DCM/n-hexane. The obtained solid was filtered off and washed with n-hexane then purified by SFC. The residue diluted with sat. aq. Na2CO3 (20 mL) and DCM (20 mL). Aq. phase was extracted with DCM (2×10 mL) and with EtOAc (3×10 mL). The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to afford the title product as a beige solid. HPLC (Condition 10) tR=5.77 min, UPLC-MS (Condition 3) tR=0.79 min, m/z=476.1/478.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.65-2.73 (m, 2H) 3.09-3.15 (m, 1H) 3.21-3.30 (m, 2H) 3.71-3.79 (m, 1H) 5.00 (d, J=3.50 Hz, 1H) 6.95 (d, J=8.99 Hz, 1H) 7.34 (d, J=8.20 Hz, 2H) 7.83-7.90 (m, 3H) 7.94 (dd, J=8.60, 2.30 Hz, 1H) 8.86 (d, J=0.78 Hz, 2H) 9.17 (d, J=1.17 Hz, 1H) 10.10 (s, 1H).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(OC=O)(=O)C.Br.[NH2:15][C:16]1[N:17]=[C:18]([Br:21])[S:19][CH:20]=1.C([O-])(=O)C.[Na+]>N1C=CC=CC=1.C(O)=O>[Br:21][C:18]1[S:19][CH:20]=[C:16]([NH:15][CH:5]=[O:7])[N:17]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1csc(Br)n1
Agent: Br
Agent: CC(=O)OC=O
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: O=CO
Product: O=CNc1csc(Br)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
Acetic anhydride (100 ml) was cooled to 0° C. and treated with 98% formic acid (50 ml.). The resulting mixture was heated at 50° C. for 15 minutes then cooled to 0° C. To this solution of formic-acetic anhydride was added 4-amino-2-bromothiazole hydrobromide (26 g, 0.1 m) followed dropwise by pyridine (25 ml.). The reaction mixture was allowed to stand for 1 hour at room temperature then poured onto 20% aqueous sodium acetate solution (500 ml). The resulting crystals were removed by filtration, washed once with water (100 ml) then recrystallised from ethanol to give the 2-bromo-4-formamidothiazole (12 g, 58%). m.p. 167° C. d. (Found: C, 23.55; H, 1.6; N, 13.45. C4H3N2BrOS requires C, 23.2; H, 1.45; N, 13.5%).
Reaction SMILES: [C:1]1([NH:7][N:8]=[CH:9][C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH2:23][CH3:24])[C:15]4[C:20]([C:21]=3[CH:22]=2)=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].C(=O)([O-])[O-].[K+].[K+].[CH3:33][C:34]([CH3:36])=[O:35]>C(C1OC1)Cl.CCOCC.CCCCCC>[O:35]1[CH2:36][CH:34]1[CH2:33][N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[N:8]=[CH:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH2:23][CH3:24])[C:15]3[C:20]([C:21]=2[CH:22]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3
Reactant: CCn1c2ccccc2c2cc(C=NNc3ccccc3)ccc21
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: ClCC1CO1
Product: CCn1c2ccccc2c2cc(C=NN(CC3CO3)c3ccccc3)ccc21
Temperature: 25 °C
Yield: 81.2 %

Procedure:
A mixture of 9-ethyl-3-carbazolecarboxaldehyde phenylhydrazone (3.1 g, 0.01 mol), 85% powdered potassium hydroxide (2.0g, 0.03 mol) and anhydrous potassium carbonate (˜5 g) in 25 ml of epichlorohydrin was stirred vigorously at 55–60° C. for 1.5–2 h. The course of the reaction was monitored using thin layer chromatography on silica gel 60 F254 plates (commercially obtained from Merck) using a 1:4 volume per volume mixture of acetone and hexane as the eluant. After termination of the reaction, the mixture was cooled to room temperature, diluted with ether and washed with water until the wash water was neutral in pH. The organic layer was dried over anhydrous magnesium sulfate, treated with activated charcoal, and filtered. Ether was removed, and the residue was dissolved in the mixture of toluene and 2-propanol in 1:1 ratio by volume. The crystals formed upon standing were filtered off, and washed with 2-propanol to give 3.0 g (81.2%) of 9-ethyl-3-carbazolecarboxaldehyde N-2,3-epoxypropyl-N-phenylhydrazone. The solid product had a melting point (m.p.) of 136–137° C. after being recrystallized from a mixture of toluene and 2-propanol in 1:1 ratio by volume. A 1H-NMR spectrum of 9-ethyl-3-carbazolecarboxaldehyde N-2,3-epoxypropyl-N-phenylhydrazone was obtained in CDCl3 with a 250 MHz NMR. The peaks were found at (ppm) δ=8.35 (s, 1H, 4-HHt); δ=8.14 (d, J=7.8 Hz, 1H, 1-HHt); δ=7.93 (d, J=7.6 Hz, 1H, 2-HHt); δ=7.90 (s, 1H, CH═N); δ=7.54–7.20 (m, 8H, Ph, Ht); δ=6.96 (t, J=7.2 Hz, 1H, 4-HPh); δ=4.37 (m, 3H, CH2CH3, one of the NCH2 protons); δ=4.04 (dd, J1=4.3 Hz, J2=16.4 Hz, 1H, next of the NCH2 protons); δ=3.32 (m, 1H, CH); δ=2.88 (dd, 1H, part of the ABX system, cis-HA of CH2O, JAX=2.6 Hz, JAB=4.9 Hz); δ=2.69 (dd, 1H, part of the ABX system, trans-HB of CH2O, JBX=4.0 Hz); δ=1.44 (t, J=7.2 Hz, 3H, CH3). An elemental analysis found the following weight percents of the elements: C, 78.32; H, 6.41; N, 11.55, which compares with the following calculated elemental weight percent for a compound with the formula C24H23N3O: C, 78.02; H, 6.28; N, 11.37.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][C@H:10]([CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH3:11])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[C:18]([O:23][CH2:24][CH3:25])(=[O:22])[C:19]#[C:20][CH3:21].[Cl-].[Li+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:8][C:5]1[N:6]=[CH:7][C:2]2[C:19]([C:18]([O:23][CH2:24][CH3:25])=[O:22])=[C:20]([CH3:21])[N:9]([C@H:10]([CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH3:11])[C:3]=2[N:4]=1
Reactant: CC#CC(=O)OCC
Reactant: C[C@H](Nc1nc(Cl)ncc1Br)C1CCOCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)n([C@@H](C)C2CCOCC2)c2nc(Cl)ncc12
Temperature: 120 °C
Reaction time: 3 h
Yield: 16.3 %

Procedure:
To a solution of (S)-5-bromo-2-chloro-N-(1-(tetrahydro-2H-pyran-4-yl)ethyl)Pyrimidin-4-amine (1.5 g, 4.7 mmol) in DMF (20 mL) was added ethyl but-2-ynoate (1.05 g, 9.4 mmol), lithium chloride (296 mg, 7.05 mmol), palladium(II) acetate (105 mg, 0.47 mmol) and potassium carbonate (1.95 g, 14.1 mmol) at 25° C. under N2. The reaction was stirred at 120° C. for 3 hrs. The mixture was filtered and the crude product was purified by column chromatography on silica gel eluted with petroleum ether: ethyl acetate=30:1 to give (S)-ethyl 2-chloro-6-methyl-7-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (270 mg, 16.4%) as a yellow oil.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.[C:15]([Si:19]([CH3:34])([CH3:33])[O:20][CH2:21][CH2:22]OC1C=CC(I)=CC=1C=O)(C)(C)C.C[Si](Cl)(C)C.[CH2:40]([N:42](CC)CC)C.C(Cl)(=O)C>C(OCC)C.O1CCCC1>[CH3:15][Si:19]([CH3:34])([CH3:33])[O:20][C:21](=[CH2:22])[N:42]=[CH2:40]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(I)cc1C=O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(=O)Cl
Product: C=NC(=C)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 1,1,1,3,3,3-hexamethyldisilazane (4.36 mL, 21 mmol) (Aldrich) under nitrogen at room temperature was added n-butyllithium (2.5 M, 8.4 mL, 21 mmol) (Aldrich). The reaction mixture was stirred at room temperature for 10 minutes. Then dry tetrahydrofuran (60 mL) was added, followed by the addition of 2-[2-(tert-butyl -dimethyl-silanyloxy)-ethoxy]-5-iodo-benzaldehyde (8.53 g, 21 mmol). After the mixture was stirred at room temperature for 0.5 h, trimethylsilyl chloride (2.66 mL, 21 mmol) (Aldrich) was added dropwise. Then the temperature of the mixture was lowered to 0° C. on a cooling ice bath. To this mixture was added triethylamine (3.8 mL, 27.2 mmol) in one portion, followed by the dropwise addition of a solution of acetyl chloride (1.94 mL, 27.2 mmol) in diethyl ether (100 mL). The cooling bath was removed, and the mixture was stirred at room temperature for 1 h. The mixture was quickly filtered on celite under nitrogen, and filtrate was concentrated under reduced pressure to give crude 1-[2-(tert -butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow oil and used for the next step without further purification.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH:15]2OCC[O:16]2)[CH:11]=[CH:12][C:13]=1[F:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O.O>S(=O)(=O)(O)O.C(OCC)C>[CH2:1]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:13]=1[F:14])[CH:15]=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2OCCO2)cc1Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Solvent: CCOCC
Product: O=Cc1ccc(F)c(Cc2ccccc2)c1
Reaction time: 16 h

Procedure:
A mixture of 2-(3-benzyl-4-fluorophenyl)-1,3-dioxolane (0.7 h) acetone (10 cm3), water (1 cm3) and concentrated sulphuric acid (5 drops) was stirred for 16 hours. The reaction mixture was poured into diethyl ether and the organic layer washed with sodium bicarbonate solution, water and brine, then dried over anhydrous magnesium sulphate. Evaporation of the solvents under reduced pressure gave 3-benzyl-4-fluorobenzaldehyde (0.59 g), which was used without further purification.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH3:30][C:31]1[CH:35]=[C:34]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=2)[S:33][C:32]=1[C:46](=O)[CH3:47]>C1(C)C=CC=CC=1.C1COCC1>[CH3:2][O:3][CH:4]=[C:46]([C:32]1[S:33][C:34]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=2)=[CH:35][C:31]=1[CH3:30])[CH3:47]
Reactant: CC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)cc1C
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC=C(C)c1sc(-c2ccc(C(F)(F)F)cc2)cc1C
Reaction time: 0.5 h

Procedure:
To a solution of (methoxymethyl)triphenyl phosphonium chloride (3.96 g, 10.76 mmole) in toluene/THF (2:1, 60 mL), is added potassium t-butoxide (1.21 g, 10.76 mmole) in one portion and stirred for 30 minutes. To the resulting ylide, is injected into a solution of 1-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-ethanone (1.53 g, 5.38 mmole). The reaction is stirred for 2 hours, and then concentrated on rota vapor. The residue is purified on a silica gel column, eluting with 0-10% ethyl acetate in hexane and concentrated to provide 2-(2-Methoxy-1-methyl-vinyl)-3-methyl-5-(4-trifluoromethyl-phenyl)-thiophene as brown oil. The generated vinyl ether is treated with concentrated HCl(aq) (2 mL) in THF (60 mL) at 60° C. for 2 hours. The solvents are removed on rota vapor, and the residue is purified on a silica gel column, eluting with 0-20% ethyl acetate in hexane and concentrated to provide the titled compound as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH2:12][NH:11][N:10]=1.N#N.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH2:12][N:11]([C:31](=[O:33])[CH3:32])[N:10]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(c1)CNN=C2Cc1c(Cl)cncc1Cl
Agent: N#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CN(C(C)=O)N=C2Cc1c(Cl)cncc1Cl
Reaction time: 0.17 h
Yield: 86.4 %

Procedure:
As an alternative to the previous synthesis, the title compound was prepared starting from a solution of 4-(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-1,2-dihydro-phthalazine (2 g, 6.2 mmoles), prepared as described in example 22, in dry THF (60 ml) under stirring and dry N2 at 0° C. The mixture was added with triethylamine (1.57 g, 15.5 mmoles), then with acetyl chloride (0.44 ml, 6.2 mmoles). After 10 minutes the mixture was brought to room temperature and kept at such temperature for 2.5 hours, then poured into water/ice and extracted more times with CH2Cl2. The organic phases were washed with 5% NaOH and water, anhydrified and brought to dryness to give a solid which, by crystallisation from acetonitrile (70 ml), gave 1.95 g of the title compound having the same physo-chemical characteristics set forth at point A.
Reaction SMILES: O[CH2:2][C:3]1[CH:14]=[N:13][C:6]2[N:7]([CH3:12])[CH2:8][C:9](=[O:11])[NH:10][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.Cl.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH2:41][CH2:42][NH:43][CH2:44][CH:45]=2)=[CH:36][CH:35]=1>C(#N)CC.O>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH2:45][CH2:44][N:43]([CH2:2][C:3]3[CH:14]=[N:13][C:6]4[N:7]([CH3:12])[CH2:8][C:9](=[O:11])[NH:10][C:5]=4[CH:4]=3)[CH2:42][CH:41]=2)=[CH:36][CH:35]=1
Reactant: CN1CC(=O)Nc2cc(CO)cnc21
Reactant: Clc1ccc(C2=CCNCC2)cc1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN1CC(=O)Nc2cc(CN3CC=C(c4ccc(Cl)cc4)CC3)cnc21
Temperature: 90 °C
Reaction time: 2 h
Yield: 18.6 %

Procedure:
7-(hydroxymethyl)-4-methyl-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one (85.0 mg, 0.44 mmol) was suspended in propionitrile (1 mL) and (cyanomethyl)trimethylphosphonium iodide (123.0 mg, 0.51 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (180 ul, 1.03 mmol). To the stirred mixture was then added 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (103.5 mg, 0.45 mmol). The reaction was heated to 90° C. with stirring for 2 h. The reaction was then cooled to room temperature and diluted with water (3 mL) and filtered. The solids were collected and refluxed in ethanol (5 mL) for 1 h. The suspension was cooled back to room temperature and filtered. The precipitate was filtered off and dried in vacuum to afford the title compound (30.2 mg, 19%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.51 (s, 1H), 7.64 (s, 1H), 7.41-7.47 (m, 2H), 7.34-7.40 (m, 2H), 6.97 (d, J=1.8 Hz, 1H), 6.18 (s, 1H), 3.93 (s, 2H), 3.41 (s, 2H), 3.01 (br. s., 2H), 2.91 (s, 3H), 2.60 (br. s., 2H), 2.39-2.47 (m, J=7.3 Hz, 2H). [M+H] calc'd for C20H21ClN4O, 369. found, 369.