Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C@@:12]3([C@H:18]([C:19]4[CH:24]=[CH:23][C:22]([C:25]5[CH:26]=[N:27][CH:28]=[N:29][CH:30]=5)=[CH:21][CH:20]=4)[CH2:17][NH:16][CH2:15]3)[N:11]([CH3:31])[C:10]2=[O:32])[CH:5]=[C:6]([Cl:8])[CH:7]=1.I[CH:34]([CH3:36])[CH3:35].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C@@:12]3([C@H:18]([C:19]4[CH:20]=[CH:21][C:22]([C:25]5[CH:30]=[N:29][CH:28]=[N:27][CH:26]=5)=[CH:23][CH:24]=4)[CH2:17][N:16]([CH:34]([CH3:36])[CH3:35])[CH2:15]3)[N:11]([CH3:31])[C:10]2=[O:32])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CNC[C@H]2c1ccc(-c2cncnc2)cc1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)N1C[C@@H](c2ccc(-c3cncnc3)cc2)[C@]2(C1)C(=O)N(c1cc(Cl)cc(Cl)c1)C(=O)N2C
Temperature: 25 °C
Yield: 67.9 %

Procedure:
A mixture of Example 67 (49.7 mg, 0.11 mmol), 2-iodo propane (26 μl, 0.26 mmol) and K2CO3 (36 mg, 0.26 mmol) was heated at 80° C. for 25 h in acetonitrile (2 ml). After cooling to room temperature, the insoluble salts were removed and the filtrate concentrated to dryness. The residue was partitioned between DCM/water. The organic layer was concentrated in vacuo and chromatographed over silica gel (eluent: DCM/MeOH 95/5) to yield the above-titled compound as an amorphous white solid (38.1 mg). 1H NMR (CDCl3): 9.21 (1H, s), 8.92 (2H, s), 7.56 (2H, d, J=8.0 Hz), 7.33 (2H, d, J=8.0 Hz), 7.20 (1H, m), 6.61 (2H, d, J=1.5 Hz), 3.90 (1H, dd, J1=12 Hz , J2=6 Hz), 3.4-3.5 (2H, m), 3.2-3.4 (1H, m), 3.28 (3H, s), 3.09 (1H, d, J=11 Hz), 2.79 (1H, m), 1.23 (6H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:28]=[CH:29]/[C:30]([O:32]CC)=[O:31])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[C:11]([CH3:21])[C:10]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH-].[Na+].Cl>CCO.C1COCC1>[F:1][C:2]1[CH:3]=[C:4](/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[C:11]([CH3:21])[C:10]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3)c(C)cc3cc(OC)ccc23)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2c(Oc3ccc(/C=C/C(=O)O)cc3F)c(-c3ccccc3)c(C)cc2c1
Temperature: 25 °C
Yield: 164.2 %

Procedure:
Compound 25 (130 mg, 0.29 mmol, 1 equiv) was dissolved in EtOH (5 mL) and THF (5 mL). A solution of 1 N NaOH (2.9 mL, 2.85 mmol, 10 equiv)) was added and the solution refluxed for 1.5 h. The reaction was cooled to RT and then acidified to pH 2 with 1 N HCl. The product was extracted with EtOAc (100 mL) and the organic layer was washed with saturated aqueous NaCl (50 mL), dried over Na2SO4, filtered and concentrated to provide the title compound (26) (204 mg, 100%), as a pale yellow solid. 1HNMR (400 MHz, DMSO-d6): δ 7.74 (s, 1H), 7.58 (m, 2), 7.38 (m, 2H), 7.32-7.16 (m, 6H), 7.11 (m, 1H), 6.36 (m, 2H), 3.87 (s, 3H), 2.18 (s, 3H). LRMS m/z 429.4 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C:14]([CH:16]=[CH:17][C@@H:18]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].CO.[CH:25](OC)(OC)OC.CS(O)(=O)=O>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C:14]([O:15][CH3:25])=[CH:16][CH:17]=[C:18]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1
Reactant: COc1ccc2c3c1O[C@H]1C(=O)C=C[C@H]4[C@@H](C2)N(C)CC[C@]314
Reactant: COC(OC)OC
Agent: CS(=O)(=O)O
Solvent: CO
Solvent: Cc1ccccc1
Product: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Temperature: 25 °C

Procedure:
To a dried 4-neck 5-liter round bottom flask equipped with a mechanical stirrer, heating mantle, pressure equalizing dropping funnel, and reflux condenser under a nitrogen atmosphere were added 100 g of codeinone, 500 mL of methanol and 73.5 mL of trimethyl orthoformate. The resulting mixture was allowed to stir at room temperature. Methanesulfonic acid (42 g) was then added to the flask at a temperature of about 25° C. over a time period of about 10 minutes. After addition of the methanesulfonic acid, 500 mL of toluene was added and the resulting mixture was allowed to reflux for about 4 to 6 h. at a temperature of about 62° C. to about 64° C. until HPLC analysis using a reverse phase C-18 silica gel column eluted with a gradient of 25:75 acetonitrile:water to 50:50 acetonitrile:water showed that at least 93% of the codeinone was consumed. The reflux condenser was replaced with a distillation apparatus, the mixture was heated at a temperature of from about 91° C. to about 93° C. and methanol was allowed to distill from the reaction mixture until substantially all the methanol was removed. At various intervals an aliquot of the reaction mixture was removed, quenched in a phosphate buffer solution having a pH value of about 8, and analyzed using HPLC. The reaction mixture was monitored hourly until HPLC analysis showed that the peak corresponding to thebaine was at least about 95 percent of the total peak area (about 3 to 4 h). Dimethylformamide (22.4 mL) was then added to the reaction mixture and the reaction mixture was allowed to cool to room temperature. The reaction mixture was then quenched with an equal volume of deionized water and allowed to stir for about 30 minutes. The aqueous and organic phases were allowed to separate. The aqueous phase was then cooled to a temperature of from about 0° to about 5° C. and allowed to stir vigorously, and 25% aqueous sodium hydroxide was added until the pH of the resulting slurry was about 12. The resulting slurry was stirred at about 0° C. for at least about 1 h and then filtered. The resulting solid was washed with deionized water until the pH of the filtrate was neutral (3×50 mL) to provide a wet cake of thebaine (150 g). The wet cake of thebaine was dried under reduced pressure (40 mm Hg) at a temperature of from about 45° to about 50° C. for about 16 h to provide dry thebaine (85 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[O:5][CH2:6][CH2:7][OH:8].[H-].[Na+].Cl[C:15]1[C:20]([N:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[N:19][CH:18]=[CH:17][N:16]=1>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[O:5][CH2:6][CH2:7][O:8][C:15]1[C:20]([N:21]2[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]2)=[N:19][CH:18]=[CH:17][N:16]=1
Reactant: OCCOc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCOc2cccc(O)c2)CC1
Temperature: 65 °C
Reaction time: 1.75 h
Yield: 94 %

Procedure:
To a stirred solution of 2-(3-hydroxyphenoxy)ethanol (7.71 g, 0.05 mol) in dry DMF to (100 mL) at ˜0° C. (ice bath) was added NaH (3.90 g, 0.163 mol) in portions under N2. When the H2-evolution had ceased, a solution of 2-chloro-3-(4-tert-butoxycarbonyl-1-piperazinyl)pyrazine (0.05 mol, 14.9 g; from Example 52, Step 1) in dry DMF (70 mL) was added in one portion. The mixture was stirred at 65° C. for 1.75 h. After cooling, the reaction was quenched by addition of H2O in DMF. The mixture was filtered and concentrated, in vacuo. The residue was dissolved in EtOAc, washed with 1 M KHSO4 and water, dried (Na2SO4+Norit), and concentrated in vacuo to give the title compound as a beige sticky oil. Yield 94%. This product was used directly in the next step without further purification.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[CH:8]=[CH:9][NH:10]3)[CH2:3][CH2:2]1.[CH3:15][N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[C:8]([C:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH:18]=2)=[CH:9][NH:10]3)[CH2:2][CH2:3]1
Reactant: c1cc(OCC2CC2)c2cc[nH]c2c1
Reactant: CN1CCC(=O)CC1
Product: CN1CC=C(c2c[nH]c3cccc(OCC4CC4)c23)CC1

Procedure:
Beginning with 4.3 gm (22.9 mMol) 4-cyclopropylmethyloxy-1H-indole and 5.7 mL (45.9 mMol) 1-methyl-4-piperidone, 0.995 gm (33% based on recovered starting material) of the title compound were recovered as a light yellow solid.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[N:14]=[C:13]([CH2:15]I)[CH:12]=[C:11]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]2[CH3:23])[N:10]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[Cl:8][C:9]1[N:10]=[C:11]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]2[CH3:23])[CH:12]=[C:13]([CH2:15][S:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[N:14]=1
Reactant: Sc1ccncc1
Reactant: C[C@H]1COCCN1c1cc(CI)nc(Cl)n1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H]1COCCN1c1cc(CSc2ccncc2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 64.5 %

Procedure:
4-Mercaptopyridine (0.752 g, 6.77 mmol) was added to 2-chloro-4-(iodomethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine (1.596 g, 4.51 mmol) in acetonitrile (100 mL) at RT under air. DBU (0.3 mL, 2.01 mmol) was then added and the resulting solution was stirred at RT for 2 minutes. The solvent was removed and DCM was added. The reaction mixture was washed sequentially with water, the organic layer dried (MgSO4), filtered and evaporated. The crude product was chromatographed on silica, eluting with 0-2% methanol in DCM. Impure fractions were further chromatographed on silica, eluting with 0-4.5% methanol in DCM and combined with the initial pure fractions to give the desired material as a yellow gum (0.980 g).
Reaction SMILES: [CH2:1]([C@@:3]1([C:12]([O:14][CH3:15])=[O:13])[CH2:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[O:4]1)[CH3:2].[C:16](Cl)(=[O:18])[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl>[C:16]([C:9]1[CH:10]=[CH:11][C:5]2[O:4][C@:3]([CH2:1][CH3:2])([C:12]([O:14][CH3:15])=[O:13])[CH2:7][C:6]=2[CH:8]=1)(=[O:18])[CH3:17]
Reactant: CC[C@@]1(C(=O)OC)Cc2ccccc2O1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC[C@@]1(C(=O)OC)Cc2cc(C(C)=O)ccc2O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl (2S)-2-ethyl-2,3-dihydro-benzofuran-2-carboxylate(3.1 g, 15 mmol) was mixed with acetyl chloride (3.5 g, 45 mmol) and aluminum chloride (6.0 g, 45 mmol) in dichloromethane (100 mL). The reaction mixture was stirred at 25° C. for 1 hr and then poured into 1 N aqueous HCl (100 mL). The organic layer was separated and the aqueous phase was extracted with dichloromethane (50 mL). The combined extracts were washed with brine and concentrated to give essentially pure methyl (2S)-5-acetyl-2-ethyl-2,3-dihydro-benzofuran-2-carboxylate.
Reaction SMILES: [CH:1]1([NH:4][C:5]([CH2:7][CH2:8][C:9]2[C:10]([CH3:32])=[N:11][O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4([C:29]([OH:31])=[O:30])[CH2:28][CH2:27]4)=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[O:6])[CH2:3][CH2:2]1.I[CH3:34]>>[CH:1]1([N:4]([CH3:34])[C:5]([CH2:7][CH2:8][C:9]2[C:10]([CH3:32])=[N:11][O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4([C:29]([OH:31])=[O:30])[CH2:28][CH2:27]4)=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CCC(=O)NC1CC1
Reactant: CI
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CCC(=O)N(C)C1CC1

Procedure:
Prepared according to the procedure described in Example 34, Step 4, using 1-{4′-[4-(2-Cyclopropylcarbamoyl-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid and iodomethane.
Reaction SMILES: [OH:1][C@@H:2]([CH3:21])[CH2:3][C@@H:4]([CH3:20])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].Cl>N1C=CC=CC=1>[C:22]([O:1][C@@H:2]([CH3:21])[CH2:3][C@@H:4]([CH3:20])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)(=[O:24])[CH3:23]
Reactant: C[C@H](O)C[C@@H](C)Oc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)O[C@@H](C)C[C@@H](C)Oc1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
2.81 g of the (R,S)-4-[4'-(3"-hydroxy-1"-methylbutoxy)phenyl]benzonitrile prepared in the above Example 1 was mixed with 5.10 g of acetic anhydride and 0.3 g of pyridine. The mixture was stirred at 100° C. for one hour. After cooling, the reaction mixture was carefully poured into 50 ml of 2N hydrochloric acid and extracted with diethyl ether. After washing with water, drying and desolvating, the obtained residue was purified by silica gel column chromatography with the use of a mixture of n-hexane and ethyl acetate (3:1) as a developing solvent. Thus 2.65 g of (R,S)-4-[4'-(3"-acetoxy-1"methylbutoxy)phenyl]benzonitrile was obtained.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH2:5][N:4]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(N(CC)CC)C>[CH3:29][S:30]([NH:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH2:5][N:4]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17])(=[O:32])=[O:31]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CN)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CNS(C)(=O)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1

Procedure:
To a solution of (2S,4R)-2-aminomethyl-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2 g) were successively added triethylamine (0.82 ml) and methanesulfonyl chloride (0.42 ml) under ice-cooling with stirring, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo to give (2S,4R)-2-methanesulfonylaminomethyl-4-t-butyldimethylsilyloxy-1-(4nitrobenzyloxycarbonyl)pyrrolidine (2.15 g).
Reaction SMILES: [C:1]([N:5]([N:9]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][CH:11]([NH:28]C(=O)C(N)CC2C=CC=CC=2)[C:10]1=[O:40])[C:6](=[O:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C>[C:1]([N:5]([N:9]1[CH:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:14][CH:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][CH:11]([NH2:28])[C:10]1=[O:40])[C:6](=[O:8])[CH3:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)N(N1C(=O)C(NC(=O)C(N)Cc2ccccc2)CC(c2ccccc2)CC1c1ccccc1)C(C)(C)C
Solvent: CCOC(C)=O
Product: CC(=O)N(N1C(=O)C(N)CC(c2ccccc2)CC1c1ccccc1)C(C)(C)C
Yield: 92 %

Procedure:
Prepared as above from 1-(N-t-butylacetamido)-3-(2-amino-3-phenylpropionamido)-5,7-diphenylhexahydroazepin-2-one (less polar isomer) as an oil in 92% yield, αD =+3.21° (c=0.8, ethyl acetate). The 1H-NMR spectrum matches that of the racemate.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[Cl:6][C:7]([C:13]([C:18]#N)=[CH:14][N:15](C)C)=[N:8][CH:9]=[N+:10]([CH3:12])[CH3:11].C1(C=CC=C(O)C=1O)[OH:21]>O.C(O)C>[Cl:6][C:7]([N:8]=[CH:9][N:10]([CH3:12])[CH3:11])=[C:13]([CH:18]=[O:21])[C:14]#[N:15]
Reactant: Oc1cccc(O)c1O
Reactant: CN(C)C=C(C#N)C(Cl)=NC=[N+](C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCO
Solvent: O
Product: CN(C)C=NC(Cl)=C(C#N)C=O
Temperature: 0 °C
Yield: 8968.5 %

Procedure:
31.4 g of N-(3-chloro-4-cyano-5-dimethylamino-2-aza-2,4-pentadienylidene)-N,N-dimethyl ammonium perchlorate and 0.1 g of pyrogallol are stirred in a mixture of 140 ml of water and 200 ml of ethanol for one hour at 25° to 30° C. Precipitaion of reaction products is completed by addition of 500 g of ice. Vacuum filtration is then carried out. This is followed by washing with cold water. Drying is effected at 20°C over P2O5. 13.2 g (71.2%) of 3-chloro-5-dimethylamino-2-formyl-4-aza-2,4-pentadienenitrile, with a melting point of 145° to 147°C (with decomposition), are thus obtained in the form of pale needles.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24](I)=[CH:23][C:22]=2[F:28])=[N:16]1.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[CH:37])[C:31]=1[F:38].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:37]#[C:36][C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([Cl:29])[C:31]=3[F:38])=[CH:23][C:22]=2[F:28])=[N:16]1
Reactant: O=C(NCc1ccc(Cl)c(-n2nc(-c3ccc(I)cc3F)[nH]c2=O)c1)C1CC1
Reactant: C#Cc1cccc(Cl)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: O=C(NCc1ccc(Cl)c(-n2nc(-c3ccc(C#Cc4cccc(Cl)c4F)cc3F)[nH]c2=O)c1)C1CC1
Yield: 57.3 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 using N-(4-chloro-3-(3-(2-fluoro-4-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide (Intermediate-48, 0.050 g, 0.097 mmol), 1-chloro-3-ethynyl-2-fluorobenzene (Intermediate-24, 0.022 g, 0.14 mmol), TBAF (0.061 g, 0.19 mmol), bis(triphenylphosphine)palladium(II) chloride (catalytic) and DMSO (1.0 mL) at 80° C. to afford 0.030 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 0.69 (m, 4H), 1.60 (m, 1H), 4.33 (d, J=5.7 Hz, 2H), 7.30-7.41 (m, 3H), 7.48-7.74 (m, 5H), 7.87-7.93 (m, 1H), 8.69 (m, 1H), 12.40-12.58 (br s, 1H); MS (m/z): 539.36 (M+).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:17][CH2:16][C@@H:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]2)(=O)=O)=CC=1.[CH3:26][CH:27]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]1>C(Cl)Cl>[CH3:26][CH:27]1[CH2:32][CH2:31][CH2:30][N:29]([CH2:12][C@H:13]2[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:20])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:14]2)[CH2:28]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)C2)cc1
Reactant: CC1CCCNC1
Solvent: ClCCl
Product: CC1CCCN(C[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)C2)C1
Temperature: 0 °C
Yield: 72.3 %

Procedure:
To a stirred solution of ((1S,3R)-3-(tert-butoxycarbonylamino)cyclopentyl)methyl 4-methylbenzenesulfonate (Intermediate 18-step 2, about 0.5 g) in DCM (50 ml) potassium carbonate (about 0.3 g) was added at room temperature and cooled to about 0° C. After ten minutes, 3-methylpiperidine (0.21 g) was added and stirred the reaction at room temperature for about 6 hours and completion of the reaction was monitored by TLC. The reaction mixture was neutralized and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure to furnish the title compound (0.29 g) as a pale yellow solid. 1H NMR (300 MHz, CDCl3: 1.08-1.09 (m, 3H); 1.24-1.29 (m, 1H); 1.39-1.40 (s, 9H); 2.29-2.60 (m, 6H); 2.79-2.80 (m, 8H); 3.70-3.73 (m, 4H); ES Mass: 297 (100%), [M+1].
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[OH:11]O>>[CH3:1][N+:2]([O-:11])([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCN(C)C
Reactant: OO
Product: CCCCCCC[N+](C)(C)[O-]

Procedure:
To 28.6 g of dimethylheptyl amine was added slowly 100 ml 30% H2O2 as in Example 4 to give the dimethylheptyl amine oxide. NMR showed the resulting semisolid material to contain 29% water and 71% of the amine oxide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH2:8].Cl[CH2:10][C:11]([CH3:16])([CH3:15])[C:12](Cl)=[O:13].Cl.C(N(CC)CC)C>ClCCl.C(N(CC)CC)C>[CH3:10][C:11]1([CH3:16])[CH2:15][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[NH:8][C:12]1=[O:13]
Reactant: CC(C)(CCl)C(=O)Cl
Reactant: NNc1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CN(c2ccccn2)NC1=O
Reaction time: 0.25 h
Yield: 71.2 %

Procedure:
2-Pyridylhydrazine (10.9 g) in dichloromethane (120 ml) and dry triethylamine (28 ml) were chilled in an ice bath. -chloropivaloyl chloride (15.5 g) in dichloromethane (20 ml) was added dropwise with stirring for 15 minutes and the mixture was refluxed for 3 hours. When cool the triethylamine hydrochloride was filtered off and the filtrate evaporated to dryness and rinsed four times with the minimum quantity of ether to give the title compound (13.6 g) after recrystallisation from cyclohexane mp 141°-144°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:7]=1.[C:19]([O-])(=O)[CH3:20].[Na+]>C(OC(=O)C)(=O)C>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:18][C:19]([CH3:20])=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)[C:8]2=[O:17]
Reactant: O=C(Cc1cccc(F)c1)c1cc(F)ccc1O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cc1oc2ccc(F)cc2c(=O)c1-c1cccc(F)c1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
Intermediate 73 (24 g, 0.096 moles) was taken in a RB flask and to this acetic anhydride (230 ml) and sodium acetate (55.2 g, 0.673 moles) were added and the mixture was refluxed for 12 h. After cooling to RT, the reaction mixture was quenched by the addition of ice cold water. The solid formed was filtered and washed with water. The product was dried under vacuum to afford the title compound as brown solid (26 g, quant. yield). 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 7.87 (dd, J=8.2, 3.0 Hz, 1H), 7.48-7.36 (m, 3H), 7.10-6.99 (m, 3H), 2.33 (s, 3H).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[CH:9][N:8]=1.CN([CH:26]=[O:27])C.[BH4-].[Na+]>C1COCC1.CO>[Si:16]([O:15][CH2:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:26][OH:27])=[N:8][CH:9]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(Br)nc1
Reactant: CN(C)C=O
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(CO)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
BuLi (14.6 ml of a 1.6 M solution in hexanes, 23 mmol) was added to a stirred solution of 2-bromo-5-[2-(tert-butyldimethylsilyloxy)ethyl]pyridine (4.92 g, 15.6 mmol) in THF (100 ml) at −78° C. The resulting pale yellow solution was stirred for 1 h and then DMF (3.6 ml, 46.6 mmol) was added in one portion. The reaction mixture was warmed to room temperature and stirred for 90 min. MeOH (70 ml) was added, followed by NaBH4 (589 mg, 15.6 mmol) and stirring was continued for a further 1 h. The reaction was quenched by cautious addition of NH4Cl (sat. 100 ml) and the organics extracted with EtOAc (3×100 ml). The combined extracts were then washed with H2O (70 ml) and brine (70 ml), dried (MgSO4) and concentrated under reduced pressure. The material was used crude without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]1[N:12]2[N:13]=[C:14]([CH3:22])[CH:15]=[C:16]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:11]2=[N:10][C:9]=1[CH3:23].C(Cl)Cl.C1C(=O)N([Br:34])C(=O)C1>CCOCC>[Br:34][C:5]1[S:4][C:3]([C:8]2[N:12]3[N:13]=[C:14]([CH3:22])[CH:15]=[C:16]([CH:17]([CH2:18][CH3:19])[CH2:20][CH3:21])[C:11]3=[N:10][C:9]=2[CH3:23])=[C:2]([CH3:1])[C:6]=1[CH3:7]
Reactant: CCC(CC)c1cc(C)nn2c(-c3scc(C)c3C)c(C)nc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOCC
Solvent: ClCCl
Product: CCC(CC)c1cc(C)nn2c(-c3sc(Br)c(C)c3C)c(C)nc12
Reaction time: 1 h
Yield: 80.8 %

Procedure:
To a solution of 3-(3,4-dimethyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.41 g, 1.25 mmol) and CH2Cl2 (30 mL) is added NBS (0.23 g, 1.32 mmol). The solution is stirred for 1 hour, diluted with Et2O (100 mL), washed with water (3×100 mL), brine (100 mL), dried (MgSO4) filtered and concentrated to furnish the title compound (0.41 g, 1.01 mmol, 80%). 1H NMR (CDCl3) δ 0.86 (t, J=7.4 Hz, 6H), 1.72-1.94 (m, 4H), 2.02 (s, 3H), 2.18 (s, 3H), 2.43 (s, 3H), 2.49 (s, 3H), 3.27-3.36 (m, 1H), 6.67 (s, 1H). LC/MS (m/z): calcd. for C19H24BrN3S (M+H)+: 407.4; found: 407.3.