Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O.[NH2:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1.Cl[C:50]1[C:51]2[CH2:64][CH2:63][N:62]([C:65]3[CH:70]=[CH:69][N:68]=[CH:67][CH:66]=3)[C:52]=2[N:53]=[C:54]([N:56]2[CH2:61][CH2:60][O:59][CH2:58][CH2:57]2)[N:55]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CN(C)C=O>[N:56]1([C:54]2[N:55]=[C:50]([C:42]3[CH:41]=[C:40]([NH2:39])[CH:45]=[CH:44][CH:43]=3)[C:51]3[CH2:64][CH2:63][N:62]([C:65]4[CH:66]=[CH:67][N:68]=[CH:69][CH:70]=4)[C:52]=3[N:53]=2)[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1
Reactant: Nc1cccc(B(O)O)c1
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccncc2)c1
Temperature: 110 °C
Reaction time: 10 h
Yield: 41 %

Procedure:
Palladium acetate (9 mg, 10 mol %), S-Phos (33 mg, 20 mol %), potassium phosphate (340 mg, 4 equivalents) and 3-aminophenylboronic acid hydrate (189 mg, 3 equivalents) were weighed in a two-neck flask equipped with Dimroth condenser, and heated with a drier under reduced pressure, followed by several repetitive argon substitution. A dimethylformamide solution (4 ml) of 4-chloro-2-morpholin-4-yl-7-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine was added with a syringe, followed by stirring at 110° C. for 10 hours. The reaction mixture was added to water, followed by extraction twice with ethyl acetate, and the organic layer was washed with brine, and subsequently dried over sodium sulfate. The drying agent was filtered off, followed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane/ammonia-methanol), to obtain the desired compound (yellow powder, 62 mg, 41%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:9][O:10][C:11]([C:13]#[C:14][C:15]([O:17][CH3:18])=[O:16])=[O:12]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[N:5]([C:13]([C:11]([O:10][CH3:9])=[O:12])=[C:14]([C:15]([O:17][CH3:18])=[O:16])[C:13]=2[C:11]([O:10][CH3:9])=[O:12])[N:4]=1
Reactant: COc1cccnn1
Reactant: COC(=O)C#CC(=O)OC
Solvent: CO
Product: COC(=O)c1c(C(=O)OC)c2ccc(OC)nn2c1C(=O)OC
Temperature: 0 °C

Procedure:
Commercially available 3-methoxypyridazine (3.00 g, 27.3 mmol) was dissolved in methanol (60 mL) and cooled to 0° C. Dimethylacetylene dicarboxylate (4.00 mL, 32.8 mmol, 1.2 eq) was added dropwise while the reaction was rapidly stirred. The mixture was maintained at −20° C. for two days. A pale yellow solid formed during this time that was recovered by filtration and washed with cold methanol (2 mL) to furnish an off white solid. MS m/z 323.1 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[CH:21][C:20]([CH2:23][C:24]([NH2:26])=[O:25])=[C:19]([NH:27][CH2:28][C:29]4[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=4)[CH:18]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.N1C=CC=CC=1.[CH3:43][S:44](Cl)(=[O:46])=[O:45].O.N>C(Cl)(Cl)Cl>[F:36][C:31]1[CH:30]=[C:29]([CH:34]=[C:33]([F:35])[CH:32]=1)[CH2:28][NH:27][C:19]1[CH:18]=[C:17]([NH:16][C:13]2[CH:14]=[CH:15][C:10]([N:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][S:44]([CH3:43])(=[O:46])=[O:45])[CH2:5][CH2:6]3)=[CH:11][CH:12]=2)[N:22]=[CH:21][C:20]=1[CH2:23][C:24]([NH2:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: NCCN1CCN(c2ccc(Nc3cc(NCc4cc(F)cc(F)c4)c(CC(N)=O)cn3)cc2)CC1
Agent: N
Solvent: c1ccncc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)NCCN1CCN(c2ccc(Nc3cc(NCc4cc(F)cc(F)c4)c(CC(N)=O)cn3)cc2)CC1
Reaction time: 0.33 h
Yield: 57.6 %

Procedure:
60 mg of 6-({4-[4-(2-aminoethyl)piperazin-1-yl]phenyl}amino)-4-[(3,5-difluorobenzyl)amino]pyridine-3-carboxyamide (the compound of Example 248) was suspended in 6 mL of chloroform, to which, under ice cooling, 20 mg of pyridine and 17 mg of methanesulfonyl chloride were added, and stirred at the same temperature for 20 minutes. To the reaction mixture, ammonia water was added, extracted with chloroform, the extract was washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform:methanol=5:1), recrystallized from chloroform-methanol-ether to obtain 40 mg (57%) of the title compound as a slight yellow crystalline powder.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:17])[NH:11][NH:12][C:13]=2[CH:14]([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[CH3:18][C:19]([O:21][CH2:22][C@H:23]1[O:28][C@H:27](Br)[C@H:26]([O:30][C:31]([CH3:33])=[O:32])[C@@H:25]([O:34][C:35]([CH3:37])=[O:36])[C@H:24]1[O:38][C:39]([CH3:41])=[O:40])=[O:20].CC(OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O)=O>>[C:31]([O:30][C@@H:26]1[C@@H:25]([O:34][C:35](=[O:36])[CH3:37])[C@@H:24]([O:38][C:39](=[O:40])[CH3:41])[C@@H:23]([CH2:22][O:21][C:19](=[O:20])[CH3:18])[O:28][C@H:27]1[O:17][C:10]1[C:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)=[C:13]([CH:14]([CH3:15])[CH3:16])[NH:12][N:11]=1)(=[O:32])[CH3:33]
Reactant: CC(C)c1[nH][nH]c(=O)c1Cc1ccc(I)cc1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(I)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 12 using 1,2-dihydro-4-[(4-iodophenyl)methyl]-5-isopropyl-3H-pyrazol-3-one and acetobromo-α-D-galactose instead of 4-{[4-(2-benzyloxycarbonyl-2-methylpropoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and acetobromo-α-D-glucose, respectively.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([O:13][CH2:14][C@H:15]([CH3:16])[N:8]3[CH:7]=[C:6]([C:17](O)=[O:18])[C:5]2=[O:20])[C:11]=1[F:12].[Cl:21][C:22]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25]>>[Cl:21][C:22]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:23]=1[CH2:24][NH:25][C:17]([C:6]1[C:5](=[O:20])[C:4]2[C:9]3=[C:10]([O:13][CH2:14][C@H:15]([CH3:16])[N:8]3[CH:7]=1)[C:11]([F:12])=[C:2]([F:1])[CH:3]=2)=[O:18]
Reactant: C[C@H]1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: NCc1ccc(Cl)cc1Cl
Product: C[C@H]1COc2c(F)c(F)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4Cl)cn1c23

Procedure:
The compound is prepared in analogy to the instructions of Example 37A, from (3S)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid (for preparation: see Journal of Medicinal Chemistry 1987, 30(12), 2283-2286) and 2,4-dichlorobenzylamine.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][CH:22](OC)[N:21]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+]>>[Si:1]([O:18][CH2:19][C@@H:20]1[CH2:25][CH2:24][CH:23]=[CH:22][N:21]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC1CCC[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)N1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(C)OC(=O)N1C=CCC[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 150 °C
Yield: 85.7 %

Procedure:
A mixture of ((2S)-tert-butyl 2-((tert-butyldiphenylsilyloxy)methyl)-6-methoxypiperidine-1-carboxylate (9 g, 18.6 mmol) and ammonium chloride (150 mg, 2.8 mmol) was heated at 150° C. under reduced pressure (50 mbar) for 2 h, cooled to RT, and purified by silica gel chromatography (eluting with 0-10% EtOAc in petroleum ether) to provide the title intermediate (7.2 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:14]([CH2:15][O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:13]=[C:12]([CH2:24][CH2:25][CH2:26][CH2:27][OH:28])[C:4]=2[N:5]=[C:6]([CH2:8][CH2:9][CH2:10][CH3:11])[N:7]=1.C[N+]1([O-])CCOCC1.C(#N)C>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[NH2:1][C:2]1[C:3]2[N:14]([CH2:15][O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:13]=[C:12]([CH2:24][CH2:25][CH2:26][CH:27]=[O:28])[C:4]=2[N:5]=[C:6]([CH2:8][CH2:9][CH2:10][CH3:11])[N:7]=1
Reactant: CCCCc1nc(N)c2c(n1)c(CCCCO)cn2COCc1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: CCCCc1nc(N)c2c(n1)c(CCCC=O)cn2COCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.5 %

Procedure:
A mixture of 4-(4-amino-5-((benzyloxy)methyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)butan-1-ol (884 mg, 2.311 mmol), N-methylmorpholine N-Oxide (420 mg, 3.59 mmol), powdered 4 Å molecular sieves and tetrapropylammonium perruthenate (58 mg, 0.165 mmol) was placed under nitrogen and a mixture of anhydrous dichloromethane (27 mL) and anhydrous acetonitrile (3 mL) added. The reaction mixture was stirred at ambient temperature for 2 hours, Additional N-methylmorpholine N-Oxide (390 mg, 3.33 mmol) and tetrapropylammonium perruthenate (38 mg, 0.108 mmol) in anhydrous DCM (5 mL) was added and the reaction mixture stirred at ambient temperature for a further 2 hours. Additional N-methylmorpholine N-Oxide (130 mg, 1.11 mmol) and tetrapropylammonium perruthenate (100 mg, 0.284 mmol) were added and the reaction mixture stirred at ambient temperature for a further 30 mins, The reaction mixture was filtered through Celite and the cake washed with DCM three times. The reaction solvent was removed in vacuo and the residue dissolved in DCM and passed through Celite a second time. The cake was washed with DCM three times and the solvent removed in vacuo to give a black gum. The sample was dissolved in dichloromethane and purified by chromatography on on silica (100 g) using a gradient of 0-25% methanol-dichloromethane over 40 mins. The appropriate fractions were combined and evaporated in vacuo to give an orange gum with a black tinge. The sample was dissolved in dichloromethane and purified by chromatography on on silica (100 g) using a gradient of 0-25% methanol-dichloromethane over 80 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a pale yellow gum (268 mg).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][NH:3]1.BrBr.C([O-])(O)=O.[Na+]>C(O)C>[O:1]=[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][NH:3]1
Reactant: CCOC(=O)C(C)C1=NNC(=O)CC1
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C)c1ccc(=O)[nH]n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 34.1 %

Procedure:
To a solution of ethyl (3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-propionate (50.0 mmol, 9.90 g) in ethanol (50 mL) was added bromine (75.0 mmol, 11.99 g). The mixture was stirred at rt for 14 h and the mixture was poored into NaHCO3 (sat. aqueous) (500 mL). The resulting mixture was extracted exhaustively with diethylether (5×500 mL). The combined organic fractions were dried over MgSO4 and evaporated in vacuo. The crude product was recrystallized from toluene to give the title compound (3.35 g, 34.1%) as colorless needles of high purity (HPLC at 260 nm). UV λmax 228 nm and 285 nm. 1H NMR (CDCl3): δ 11.62 (s br, 1H, NH), 7.18 (d, J=9.7 Hz, 1H, arom.), 7.88 (d, J=9.7 Hz, 1H, arom.), 4.11 (q, J=7.1 Hz, 2H, CH2), 2.90 (t, J=7.0 Hz, 2H, CH2), 2.64 (t, J=7.0 Hz, 2H, CH2), 1.25 (t, J=7.1 Hz, 3H, CH3). 13C NMR (CDCl3): δ 172.20, 161.50, 146.73, 134.06, 129.74, 60.45, 31.47, 25.89, 13.97. FAB+ MS: 197.10 (M+H+, calc. for C9H12N2O3+H+ 197.0926).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[CH:13]([C:15]1[NH:16][CH:17]=[CH:18][N:19]=1)=O.[BH4-].[Na+]>[OH-].[Na+].C(O)C>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([NH:12][CH2:13][C:15]2[NH:16][CH:17]=[CH:18][N:19]=2)([CH3:10])[CH3:11])=[CH:7][CH:8]=1
Reactant: O=Cc1ncc[nH]1
Reactant: CC(C)(N)c1ccc(Cl)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(NCc1ncc[nH]1)c1ccc(Cl)cc1
Reaction time: 48 h

Procedure:
A mixture of 1-(4-chlorophenyl)-1-methylethylamine hydrochloride (2.7 g) was dissolved in 2M sodium hydroxide solution (50 ml) and the amine free base was extracted into diethyl ether to give an oil. This oil was dissolved in absolute ethanol (15 ml) and 2-formylimidazole (1.5 g) in absolute ethanol (20 ml) was added dropwise. The mixture was boiled under reflux for 4 hours and then left to stand at ambient temperature for 48 hours. Sodium borohydride (0.67 g) was added in portions to the solution and the mixture was boiled under reflux with stirring for 7 hours. The ethanol was removed under reduced pressure and water (40 ml) added to the residue. The mixture was filtered to give 1-(4-chlorophenyl)-N-(imidazol-2-ylmethyl)-1-methylethylamine, m.p. 164-165° C.
Reaction SMILES: [K].[Cl:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[OH:11].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>>[Cl:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[O:11][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][Br:12]
Reactant: COc1ccc(O)c(Cl)c1
Reactant: BrCCCCCBr
Agent: [K]
Product: COc1ccc(OCCCCCBr)c(Cl)c1

Procedure:
The intermediate 5-(2-chloro-4-methoxyphenoxy)pentyl bromide was prepared from the potassium salt of 2-chloro-4-methoxyphenol and 1,5-dibromopentane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](/[C:10](/[C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:31][CH:30]=2)=[CH:11]/[C@@H:12]2[N:16](CC3C=CC(OC)=CC=3OC)[C:15](=[O:28])[CH2:14][CH2:13]2)=[N:6][C:7]=1[O:8][CH3:9].C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5](/[C:10](/[C:29]2[CH:30]=[CH:31][C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:33][CH:34]=2)=[CH:11]/[C@@H:12]2[NH:16][C:15](=[O:28])[CH2:14][CH2:13]2)=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(N)c(OC)n2)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)ccc1N
Yield: 43.5 %

Procedure:
A solution of (5R)-5-[(E)-2-(5-amino-6-methoxypyridin-2-yl)-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (198 mg) in trifluoroacetic acid (4 mL) and anisole (2 mL) was stirred at 80° C. for six hours. Saturated aqueous sodium bicarbonate was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:4) to give (5R)-5-[(E)-2-(5-amino-6-methoxypyridin-2-yl)-2-(4-tert-butylphenyl)ethenyl]pyrrolidin-2-one as a light brown solid (61 mg, 44%).
Reaction SMILES: C(N(CC)CC)C.Cl.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:20][CH2:19][NH:18][CH2:17]2)=[CH:12][CH:11]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C1COCC1.O>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:20][CH2:19][N:18]([S:22]([CH3:21])(=[O:24])=[O:23])[CH2:17]2)=[CH:14][CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: Brc1ccc(C2CCNC2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 108.1 %

Procedure:
Triethylamine (192 mg, 1.9 mmol) was added to a suspension of 3-(4-bromophenyl)pyrrolidine hydrochloride (200 mg, 0.76 mmol) in anhydrous THF (5 mL). The reaction mixture was stirred at room temperature for 5 minutes and treated with methanesulfonyl chloride (100 mg, 0.84 mmol). After the reaction mixture was stirred at room temperature for 20 hours, the mixture was diluted with water and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give 3-(4-bromophenyl)-1-(methylsulfonyl)pyrrolidine (0.25 g, quantitative yield) as a solid which was used for next step directly. MS (ES+) 303.9, 305.9 (79Br M+H, 81Br M+H)+
Reaction SMILES: [F-].[CH2:2]([N+](CCCC)(CCCC)CCCC)[CH2:3]CC.[CH2:19]([CH:26]1[N:31]([CH3:32])[C:30](=[O:33])[CH:29]([CH:34](C#C[Si](C)(C)C)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:28]([CH3:47])[C:27]1=[O:48])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[NH4+].[Cl-]>C1COCC1>[CH2:19]([CH:26]1[N:31]([CH3:32])[C:30](=[O:33])[CH:29]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:2]#[CH:3])[N:28]([CH3:47])[C:27]1=[O:48])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CN1C(=O)C(C(C#C[Si](C)(C)C)c2ccccc2)N(C)C(=O)C1Cc1ccccc1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#Cc1ccccc1CC1C(=O)N(C)C(Cc2ccccc2)C(=O)N1C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
At 0° C., tetrabutylammonium fluoride (1 mM in THF, 0.5 ml, 0.5 mmol) was added dropwise to 3-benzyl-1,4-dimethyl-6-(2-trimethylsilanylethynylbenzyl)piperazine-2,5-dione (140 mg, 0.22 mmol) in THF (abs., 5 ml). The mixture was stirred at this temperature for 1 h. After addition of NH4Cl solution (saturated, aq.), the mixture was extracted with ethyl acetate and the organic phases were dried and concentrated. Purification by column chromatography gave 50 mg (65%) of the target compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[O:7])=[CH:4][CH:3]=1.CC(C)=O.Cl.[CH2:24]([NH:26][CH2:27][CH2:28][NH:29][S:30]([C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)(=[O:32])=[O:31])[CH3:25]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([N:26]([CH2:27][CH2:28][NH:29][S:30]([C:33]2[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=2)(=[O:32])=[O:31])[CH2:24][CH3:25])=[O:12])=[O:7])=[CH:17][CH:18]=1
Reactant: CCNCCNS(=O)(=O)c1ccc(C)cc1
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CCN(CCNS(=O)(=O)c1ccc(C)cc1)C(=O)c1ccccc1C(=O)c1ccc(Cl)cc1

Procedure:
A solution of 13 grams of ψ-acid chloride of 0-(p-chlorobenzoyl)benzoic acid in 30 ml. of acetone was added dropwise to a stirred solution of 14 grams of N-[2-(ethylamino)ethyl]-p-toluenesulfonamide hydrochloride in 100 ml. of pyridine. The solution was refluxed for 1.75 hours then the solvent was removed in vacuo. The residue dissolved in ethyl acetate and extracted successively with water, and saturated sodium carbonate solution. After drying over magnesium sulfate, the ethyl acetate was removed in vacuo. The solid was slurried with ethyl acetate and separated. On recrystallization from ethyl acetate there was obtained 2-(p-chlorobenzoyl)-N-[2-(p-toluenesulfonamido)ethyl]-N-ethylbenzamide, m.p. 145°-147°C.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:11])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9].[OH:12][C:13]1[CH:22]=[C:21]2[C:16]([CH2:17][CH2:18][CH2:19][O:20]2)=[CH:15][CH:14]=1>>[CH3:11][C:4]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])=[CH:3][CH2:2][O:12][C:13]1[CH:22]=[C:21]2[C:16]([CH2:17][CH2:18][CH2:19][O:20]2)=[CH:15][CH:14]=1
Reactant: CC(C)=CCCC(C)=CCBr
Reactant: Oc1ccc2c(c1)OCCC2
Product: CC(C)=CCCC(C)=CCOc1ccc2c(c1)OCCC2

Procedure:
Following the procedure of Example 1, 1-bromo-3,7-dimethyl-2,6-octadiene and 7-hydroxy-chromane are reacted to form 7-(3,7-dimethyl-2,6-octadienyloxy)-chromane; nD20 = 1.5359.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([NH:17][C:18]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:19]=2[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=2)=[O:21])=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O>[NH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([NH:17][C:18]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:19]=2[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=2)=[O:21])=[O:16])[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCC(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Product: NC1CCC(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Reaction time: 0.08 h
Yield: 79.9 %

Procedure:
2-[[4-(tert-Butoxycarbonylamino)cyclohexylcarbonyl]amino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide (2.90 g, 5.71 mmol) was dissolved in TFA (10 mL). After 5 minutes, the reaction was concentrated in vacuo. The residue was diluted with methylene chloride and methanol. The organics were washed with saturated aqueous sodium carbonate (2×50 mL) and water (50 mL). The organic layer was dried over sodium sulfate, filtered and concetrated to give the title product (1.86 g, 4.56 mmol, 80%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([N+:17]([O-:19])=O)[C:13]=1[CH2:14][CH:15]=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:20]N(C=O)C>[Pd]>[CH3:20][O:19][N:17]1[C:12]2[C:13](=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:11]=2)[CH:14]=[CH:15]1
Reactant: CCOC(=O)c1cc(OC)c(CC=O)c([N+](=O)[O-])c1
Reactant: CN(C)C=O
Agent: [Pd]
Product: CCOC(=O)c1cc(OC)c2ccn(OC)c2c1
Reaction time: 2 h

Procedure:
250 mg of ethyl 3-(methoxy)-5-nitro-4-(2-oxoethyl)benzoate was dissolved in 5 ml of DMF and the solution was stirred over 50 mg of 10% Pd/C (50% wet) under hydrogen atmosphere for 6 hrs. Then the mixture was purged with N2 and 126 uL of MeI and 276 mg of K2CO3 was added thereto. After stirred for 2 hrs, the mixture was diluted with Et2O, filtered through Celite. The filtrate was concentrated and purified on SiO2 column chromatography to give 184 mg of the intended compound as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(O)(O)=O.[Br:14]Br.C(=O)([O-])[O-].[K+].[K+]>CO.O>[Br:14][C:7]1[CH:8]=[CH:9][C:2]([CH3:1])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: Cc1ccccc1C#N
Reactant: BrBr
Agent: O=C(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ccc(Br)cc1C#N
Temperature: 50 °C
Yield: 82.8 %

Procedure:
117 g (998 mmol) of 2-methylbenzonitrile was dropped to 1000 g of a Na-X type zeolite dried powder (Zeolam type F-9 manufactured by Toyo Corp.; 100 mesh or less) while stirring under air cooling. The resulted mixed was allowed to cool, and after cooled to 50° C. or lower, to this was added 213 g (1.33 mol) of bromine, and the mixture was stirred at 80 to 85° C. for 1.5 hours, then, cooled to 15° C. or lower. This was added into mixture of 100 g of potassium carbonate, 500 ml of water and 2 L of methanol at 10° C. or lower. The mixture was stirred for 0.5 hours, then, filtrated. The filtrated residue, zeolite powder was washed with 90% methanol water (2.2L×2), the filtrate and washed solution were combined, and concentrated until the total liquid quality reached 750 ml. The resulted while crystal was filtrated, and the crystal was washed with water to obtain 162 g (826 mmol) of 5-bromo-2-methylbenzonitrile.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([O:10]C)=[O:9].O.[OH-].[Li+].Cl>O1CCCC1.O>[CH3:1][C:2]1[C:3]2[N:4]([N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1ccn2nc(-c3ccccc3)nc2c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)O)ccn2nc(-c3ccccc3)nc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 118.3 %

Procedure:
A mixture of methyl 8-methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (634 mg, 2.37 mmol) and lithium hydroxide monohydrate (398 mg, 9.49 mmol) in tetrahydrofurane (15 ml) and water (5 ml) is stirred for 3 days at 25° C. The mixture is diluted with water, acidified to pH=0 with hydrochloric acid 37% and extracted with ethyl acetate; the organic layer is washed with water and brine, dried with magnesium sulfate and the solvent is evaporated affording 8-methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid (710 mg, 118%) as a white solid. mp.: >250° C. MS: m/z=254.1 (M+H+).