Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:16])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[F:17][C:18]([C:24]([F:48])([F:47])[C:25]([F:46])([F:45])[C:26]([F:44])([F:43])[C:27]([F:42])([F:41])[C:28]([F:40])([F:39])[C:29]([F:38])([F:37])[C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])(O)[C:19]([F:22])([F:21])[F:20].C1(C)C=CC=CC=1.S(=O)(=O)(O)O>C(#N)C.O>[C:1]([O:16][C:18]([F:17])([C:24]([F:47])([F:48])[C:25]([F:45])([F:46])[C:26]([F:43])([F:44])[C:27]([F:41])([F:42])[C:28]([F:39])([F:40])[C:29]([F:38])([F:37])[C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[C:19]([F:22])([F:21])[F:20])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: OC(F)(C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCCCCCCCCCCC(=O)O
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCC(=O)OC(F)(C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 73.1 %

Procedure:
With 500 g of myristic acid were mixed 1,100 g of perfluorooctylethanol and 2,300 ml of toluene, and 20 g of concentrated sulfuric acid was slowly added with stirring. The resulting mixture was vigorously refluxed for about 2 hours and 30 minutes to carry out the reaction until water was removed azeotropically. After completion of the reaction, the reaction mixture was cooled and then treated with decoloring carbon. Acetonitrile was added with stirring and the resulting mixture was ice-cooled to 5° C. to 10° C., followed by crystallization for 1 hour. The crystals precipitated were subjected to washing filtration with acetonitrile and then dried to obtain 1,120 g (yield: 75%) of perfluorooctylethyl myristate.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH3:6])[CH3:5].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:22]([O:29][C:30]1C=C(O)C=CC=1)C1C=CC=CC=1>>[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:2][CH2:3][N:4]2[CH2:6][CH2:30][O:29][CH2:22][CH2:5]2)=[CH:19][CH:20]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN(C)CCCl
Reactant: Oc1cccc(OCc2ccccc2)c1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Product: c1ccc(COc2ccc(OCCN3CCOCC3)cc2)cc1

Procedure:
The title compound was prepared by substituting 4-(2-chloroethyl)morpholine for 2-chloro-N,N-dimethylethanamine and 4-(benzyloxy)phenol for 3-(benzyloxy)phenol in EXAMPLE 39A.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:9][CH2:10][CH2:11]Br.[CH2:13]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][C:22]=1[OH:29])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CS(C)=O>[CH2:13]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][C:22]=1[O:29][CH2:9][CH2:10][CH3:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(O)c1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCOc1cc(C=O)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 89.4 %

Procedure:
2.15 g (15.6 mmol) of potassium carbonate, 0.20 g (1.22 mmol) of potassium iodide and 1.20 ml (13.2 mmol) of n-propyl bromide were added to a solution of 2.73 g (12.0 mmol) of 4-benzyloxy-3-hydroxybenzaldehyde in 18 ml of dimethyl sulfoxide (DMSO) and were allowed to react for 24 hours at 60° C. Thereafter, the reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water and the organic phase was washed several times with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated down. Chromatography of the residue over 50 g of silica gel using toluene gave 2.90 g of 4-benzyloxy-3-propoxybenzaldehyde.
Reaction SMILES: O=C1CCC(=O)N1[C:8](=[O:20])[C:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:11])[CH3:10].[CH:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C@@H:29]([NH2:33])[C:30]([OH:32])=[O:31])=[CH:23][CH:22]=1.O.C(N(CC)CC)C>C1COCC1>[C:15]([O:14][C:13]([NH:12][C:9]([CH3:11])([CH3:10])[C:8]([NH:33][C@H:29]([CH2:28][CH2:27][C:24]1[CH:23]=[CH:22][CH:21]=[CH:26][CH:25]=1)[C:30]([OH:32])=[O:31])=[O:20])=[O:19])([CH3:18])([CH3:17])[CH3:16]
Reactant: N[C@H](CCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N1C(=O)CCC1=O
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](CCc1ccccc1)C(=O)O
Temperature: 50 °C
Reaction time: 9 h

Procedure:
A mixture comprising of tert-Butyl 1-(2,5-dioxopyrrolidin-1-yl)-2-methyl-1-oxopropan-2-ylcarbamate (1 g, 3.52 mmol) (prepared according to the procedure described in EP1486498A1 page 20) and H-D-Homophe-OH (0.630 g, 3.52 mmol) in THF (16 ml)/water (4 ml) was treated with triethylamine (1.471 ml, 10.55 mmol). The reaction mixture was stirred at 50° C. for 9 hours. THF was removed in vacuo. The aqueous solution was further diluted with water and the pH adjusted to pH 2-3 using 1M HCl. The resulting aqueous phase was extracted with EtOAc. The organic portion was dried (MgSO4) and concentrated in vacuo to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[C:30]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(=[O:32])[CH3:31].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:36]2[CH2:37][CH2:38][N:33]([C:30](=[O:32])[CH3:31])[CH2:34][CH2:35]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: CC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: O
Product: CC(=O)N1CCN(Cc2ccc3c(c2)cc(-c2ccc(Cl)c4c2C(=O)NC4)n3C(=O)OC(C)(C)C)CC1
Yield: 122.5 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (41.5 mg, 0.101 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with 1-acetylpiperazin (54 mg, 0.42 mmol), acetic acid (0.116 mL, 2.03 mmol) and sodium triacetoxyborohydride (51 mg, 0.25 mmol). The reaction mixture was added with water and sodium carbonate to adjust the pH to 9. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-(4-acetylpiperazin-1-ylmethyl)indol-2-yl]isoindolinone (64.7 mg).
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[Cl:11][C:12]1[N:17]2[N:18]=[C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[C:16]2[CH:15]=[CH:14][CH:13]=1.O>ClCCl>[Cl:11][C:12]1[N:17]2[N:18]=[C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH:3]=[O:4])=[C:16]2[CH:15]=[CH:14][CH:13]=1
Reactant: Clc1cccc2cc(-c3ccco3)nn12
Reactant: CN(C)C=O
Solvent: ClCCl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c(-c2ccco2)nn2c(Cl)cccc12
Reaction time: 2.5 h
Yield: 79 %

Procedure:
A dry flask charged with dry N,N-dimethylformamide (100 mL) was treated with phosphorous oxychloride (6.0 mL 64.5 mmol). The resultant solution was stirred at room temperature for 1 hour. 7-Chloro-2-(2-furyl)pyrazolo[1,5-a]pyridine (9.4 g, 43 mmol, example 21) was added to the previous solution and stirred for 2.5 hours. Water and dichloromethane were added to quench the reaction. The aqueous phase and organic phase were separated. The aqueous phase was extracted with dichloromethane. The organics were combined and washed with water, dried over magnesium sulfate, filtered and concentrated. Crystallization from a small amount of methanol gave 7-chloro-2-(2-furyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (8.4 g, 79%) as pale yellow crystalline compound. 1H NMR (CDCl3): δ 10.57 (s, 1H), 8.41 (d, 1H), 7.71 (d, 1H), 7.51 (t, 1H), 7.27 (d, 1H), 7.22 (d, 1H), 6.66 (m, 1H). MS m/247 (M+1).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([C:10]1[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=1)=[O:9].[F:17][CH:18]([F:30])[O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:30][CH:18]([F:17])[O:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([N:6]2[CH2:5][CH2:4][N:3]([C:8]([C:10]3[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=3)=[O:9])[C@@H:2]([CH3:1])[CH2:7]2)(=[O:28])=[O:27])=[CH:24][CH:25]=1
Reactant: Cc1ccc(C(=O)N2CCNC[C@@H]2C)cn1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)F)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc(OC(F)F)cc3)C[C@@H]2C)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 37.1 %

Procedure:
To a solution of (2S)-2-methyl-1-[(6-methyl-3-pyridinyl)carbonyl]piperazine (Description 13) (100 mg, 0.456 mmol) in DMF (10 ml) was added 4-[(difluoromethyl)oxy]benzenesulfonyl chloride (133 mg, 0.547 mmol). Finally DIPEA (0.239 ml, 1.368 mmol) was added and the reaction mixture was stirred at room temperature for 20 h. Solvent was removed by evaporation, the residue was dissolved in ethyl acetate and the solution washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4, filtered and evaporated to dryness and the residue was purified by MDAP to yield the title compound (72 mg) as a white powder.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([OH:20])=[C:15]([CH3:21])[CH:14]=1)=[C:7]2[CH3:22].Br.[CH2:24]([N:26]([CH2:30][CH3:31])[CH2:27][CH2:28]Br)[CH3:25].O>CN(C)C=O>[CH2:24]([N:26]([CH2:30][CH3:31])[CH2:27][CH2:28][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([OH:20])=[C:15]([CH3:21])[CH:14]=1)=[C:7]2[CH3:22])[CH3:25]
Reactant: Cc1cc(-c2[nH]c3ccc(O)cc3c2C)cc(C)c1O
Reactant: CCN(CC)CCBr
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc2[nH]c(-c3cc(C)c(O)c(C)c3)c(C)c2c1
Reaction time: 0.5 h

Procedure:
1.6 g of 60% sodium hydride was suspended in 50 ml of dimethylformamide, and under ice cooling, 5-hydroxy-2-(4-hydroxy-3,5-dimethylphenyl)-3-methylindole was added. After stirring for 30 minutes, 2.8 g of 2-diethylaminoethylbromide hydrobromide was added. The mixture was stirred for 2 hours. The reaction mixture was poured into cold water, and extracted with ethyl acetate. The extract was purified by silica gel column chromatography, and then subjected to thin-layer chromatography to give 5-(2-diethylaminoethoxy)-2-(4-hydroxy-3,5-dimethylphenyl)-3-methylindole.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1Cl.[CH2:10]([NH2:14])[CH2:11][CH2:12][CH3:13].C(=O)([O-])O.[K+].[CH2:20]([NH:24][C:25]1[N:30]=[C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH3:35])[N:28]=[C:27](Cl)[N:26]=1)[CH2:21][CH2:22][CH3:23]>C(#N)C.O.C1(C)C=CC=CC=1>[CH2:10]([NH:14][C:27]1[N:28]=[C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH3:35])[N:30]=[C:25]([NH:24][CH2:20][CH2:21][CH2:22][CH3:23])[N:26]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCN
Reactant: CCCCNc1nc(Cl)nc(NCCCC)n1
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: O
Product: CCCCNc1nc(NCCCC)nc(NCCCC)n1
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 18.5 g (0.1 mol) of cyanuric chloride in 150 mL of acetonitrile cooled to 0° C. was dropwise added a solution of 14.6 g (0.2 mol) of butylamine in 20 mL of water over 1 hour with stirring by keeping the reaction temperature not to exceed 5° C. Further, while continuing the stirring, a solution of 20.0 g (0.2 mol) of potassium hydrogen carbonate in 100 mL of water was dropwise added at the same temperature. Thereafter, the reaction temperature was gradually elevated and the stirring was continued at 45° C. for 8 hours. After confirming the completion of conversion to 2,4-bis(butylamino)-6-chloro-1,3,5-triazine by high performance liquid chromatography, the reaction mixture was cooled and the product was separated by filtration. The filtration cake was washed well with a large amount of water and this 2,4-bis(butylamino)-6-chloro-1,3,5-triazine was suspended in 100 mL of water. To the suspension was added 29.2 g (0.4 mol) of butylamine and allowed to react by heating under reflux for 6 hours. After cooling, 200 mL of toluene was added and the mixture was stirred vigorously, followed by separation of the aqueous layer. Further, the toluene layer was washed three times with 150 mL of water. Subsequently, toluene in the organic layer was distilled off by heating under reduced pressure to obtain 28.2 g (yield 96%) of the titled compound. Propery: oily product
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][N:11]=[C:10]([C:13]([F:16])([F:15])[F:14])[N:9]=2)[CH:5]=[CH:4][C:3]=1[OH:17].Br[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[C@H:28]([C@H:32]([CH3:37])[C:33]([O:35][CH3:36])=[O:34])[CH2:27][CH2:26]2.C([O-])([O-])=O.[Cs+].[Cs+]>O.CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][N:11]=[C:10]([C:13]([F:16])([F:15])[F:14])[N:9]=2)[CH:5]=[CH:4][C:3]=1[O:17][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[C@H:28]([C@H:32]([CH3:37])[C:33]([O:35][CH3:36])=[O:34])[CH2:27][CH2:26]2
Reactant: COC(=O)[C@@H](C)[C@@H]1CCc2cc(OCCCBr)ccc21
Reactant: Cc1cc(-c2nc(C(F)(F)F)ns2)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](C)[C@@H]1CCc2cc(OCCCOc3ccc(-c4nc(C(F)(F)F)ns4)cc3C)ccc21
Temperature: 40 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
2-Methyl-4-[3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl]phenol (57.7 mg, 0.22 mmol), methyl (2S)-2-[(1S)-5-(3-bromopropoxy)-2,3-dihydro-1H-inden-1-yl]propanoate (Example 234) (72.0 mg, 0.21 mmol), Cs2CO3 (82.5 mg, 0.25 mmol), and water (3 drops) were combined in DMF (4 mL) and stirred at 40° C. for 16 h. The reaction mixture was concentrated under reduced pressure, water was added and the aqueous phase was extracted with EtOAc (2×). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc/hexane (v/v)=1:20) gave 70 mg (64%) of the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 1.07 (d, 3H), 1.90 (m, 1H), 2.17 (m, 1H), 2.29 (s, 3H), 2.34 (m, 2H), 2.77-2.91 (m, 3H), 3.50 (m, 1H), 3.71 (s, 3H), 4.17 (t, 2H), 4.25 (t, 2H), 6.70 (d, 1H), 6.78 (s, 1H), 6.92 (d, 1H), 6.99 (d, 1H), 7.79 (m, 2H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH3:20])[C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([S:27][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]([CH3:20])[C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cc(OCCCCCl)cc2c1NC(=O)OC2(C)C
Reactant: Sc1ccccc1
Product: Cc1cc(OCCCCSc2ccccc2)cc2c1NC(=O)OC2(C)C

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4,8-trimethyl-4H-3,1-benzoxazin-2-one and thiophenol.
Reaction SMILES: C(O)=O.[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@:13]([C:18]#[C:19][CH2:20][OH:21])([OH:17])[C@@H:12]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:10])([CH3:7])([CH3:6])[CH3:5].C1(C)C=CC=CC=1P.C(N(CCCC)CCCC)CCC.I[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[O:56][CH3:57]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@:13](/[CH:18]=[C:19](/[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[O:56][CH3:57])\[CH2:20][OH:21])([OH:17])[C@@H:12]1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@](O)(C#CCO)[C@@H]1c1ccccc1
Reactant: COc1ccccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P
Solvent: O=CO
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Product: COc1ccccc1/C(=C/[C@]1(O)CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1)CO
Temperature: 70 °C
Yield: 35 %

Procedure:
Formic acid (138 ml, 3.77 mmol) was added to a stirred, degassed solution of (2S,3R)-1-tert-butoxycarbonyl-3-(3-hydroxypropyn-1-yl)-2-phenylpiperidin-3-ol (Description 7, 473 mg, 1.43 mmol), palladium (II) acetate (33 mg, 0.14 mmol), trio-o-tolylphosphine (85 mg, 0.28 mmol), tributylamine (1.12 ml, 4.87 mmol) and 2-iodoanisole (446 ml, 3.44 mmol) in N,N-dimethylformamide (3 ml) at room temperature and the resulting mixture was heated at 70° C. for 5 h. The mixture was cooled, filtered, diluted with ethyl acetate (50 ml), washed with water (100 ml), hydrochloric acid (2M, 50 ml) and saturated aqueous sodium chloride (50 ml), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel, eluting with hexane/ethyl acetate (60:40) to give the title compound as a yellow glass (220 mg, 35%). 1H NMR (360 MHz, CDCl3) δ7.41 (2H, d, J 7.6 Hz), 7.22-7.34 (4H, m), 7.12 (1H, dd, J 1.7, 7.4 Hz), 6.94 (1H, t, J 7.5 Hz), 6.89 (1H, d, J 8.2 Hz), 5.84 (1H, s), 5.00 (1H, s), 4.40 (1H, d, J 12.7 Hz), 4.15 (1H, dd, J 6.0, 13.1 Hz), 4.05 (1H, d, J 12.5 Hz), 3.86 (3H, s), 3.44 (1H, dt, J 5.6, 12.3 Hz), 2.04-2.18 (1H, m), 1.80-1.96 (3H, m), 1.28 (9H, s), and 1.64-1.84 (3H, m). m/z (ES+) 440 (M+1).
Reaction SMILES: [CH2:1]([Li])CCC.C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:26][O:27][C:28]1[CH:35]=[C:34]([O:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH3:42])[CH:33]=[CH:32][C:29]=1[CH:30]=O.O>O1CCCC1>[CH3:26][O:27][C:28]1[CH:35]=[C:34]([O:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH3:42])[CH:33]=[CH:32][C:29]=1[CH:30]=[CH2:1]
Reactant: [Li]CCCC
Reactant: COCCOCOc1ccc(C=O)c(OC)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1ccc(OCOCCOC)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
12.5 ml (31.2 mmol) of n-butyllithium is added dropwise to a solution at −40° C. of 11.1 g (31.2 mmol) of methyl-triphenyl-phosphonium diluted in 100 ml of tetrahydrofuran. The reaction mixture is stirred at 0° C. for 30 minutes and then cooled to −25° C. and a solution of 5 g (20.8 mmol) of 2-methoxy-4-(2-methoxy-ethoxymethoxy)-benzaldehyde diluted in 50 ml of tetrahydrofuran is added dropwise. The reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is treated by adding water and then extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered, and evaporated. The raw product is purified by silica column chromatography, eluted with a heptane/ethyl acetate mixture 75/25 to give 4.4 g (90%) of 2-methoxy-4-(2-methoxy-ethoxymethoxy)-1-vinyl-benzene in the form of a colorless oil.
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:13]([NH:15][NH2:16])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[H][H]>CO.[C].[Pd]>[NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:13]([NH:15][NH:16][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NN
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NNCc1ccccc1

Procedure:
In 600 ml of MeOH were dissolved 60.00 g of Boc-Trp-NHNH2 and 21.00 g of benzaldehyde, and the mixture was stirred in the presence of 3.80 g of 10% palladium carbon for 18 hours in a hydrogen stream. Subsequent procedures were carried out in the same manner as in Reference example 21 to obtain the title compound.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH2:12][CH3:13])[C:9]2[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO>[Cl:18][C:15]1[CH:16]=[CH:17][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH2:12][CH3:13])[C:9]=2[CH:14]=1
Reactant: CCC1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC1CNCCc2ccc(Cl)cc21
Reaction time: 3.5 h
Yield: 80.6 %

Procedure:
A solution of N-trifluoroacetyl-8-chloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine (63 mg, 0.207 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH (2 mL), and stirred for 3.5 hours at 60 C. The product mixture was concentrated, extracted 3 times with CH2Cl2 (5 mL), dried with Na2SO4 and concentrated to give 35 mg of a clear oil. 1H NMR (400 MHz, DMSO-d6) d 7.2 (m, 3 H), 3.3-3.0 (m, 7 H), 1.9-1.6 (m, 2 H), 0.91 (t, J=7 Hz, 3 H). MS calculated for C12H16ClN+H: 210, observed: 210.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Cl:23])C(=O)C1>C(#N)C>[Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][C:3]=1[Cl:23]
Reactant: Brc1cccc(NCC2CCOCC2)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Clc1ccc(NCC2CCOCC2)nc1Br
Temperature: 80 °C
Yield: 53.1 %

Procedure:
To a solution of 6-bromo-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (20 g, 74 mmol) in acetonitrile (240 mL) was added NCS (9.85 g, 74 mmol). The mixture was heated to 80° C. for 3 hr. The reaction mixture was allowed to cool to ambient temperature and concentrated in vacuo. The resulting residue was diluted with brine (200 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2, EtOAc/heptane= 0/100 to 50/50] providing 6-bromo-5-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (12 g) and a mixture of 6-bromo-3,5-dichloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine/6-bromo-3-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (5 g, ratio ˜2:3).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[C:18]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:16][CH:17]=2)=[CH:7][CH:6]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc(OCCCOc2ccccc2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(c1ccccc1)c1ccc(OCCCOc2ccc(C(=O)c3ccccc3)cc2)cc1

Procedure:
1,3-Diphenoxypropane (22.8 g), benzoyl chloride (31 g) and anhydrous aluminum chloride (33 g) are reacted in 1,2-dichloroethane (300 ml) for 18 hours at 70° to yield 33.4 g (77% of theory) of colorless crystals mp 146°-8°.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[C:9]1([CH3:19])[CH:14]=[CH:13][CH:12]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:10]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:15]([C:11]1[CH:10]=[C:9]([CH3:19])[CH:14]=[CH:13][CH:12]=1)(=[O:17])=[O:16]
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: Cc1noc(N)c1Br
Product: Cc1cccc(S(=O)(=O)Nc2onc(C)c2Br)c1
Yield: 63 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-3-toluenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 3-toluenesulfonyl chloride according to the procedures described in Example 30. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 138-140° C., yield 63%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][SH:6].S(Cl)[Cl:12].SC1C=CC=C[N+]=1[O-]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][S:6][Cl:12])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: ClSCl
Reactant: SCc1ccc(Cl)c(Cl)c1
Agent: [O-][n+]1ccccc1S
Product: ClSCc1ccc(Cl)c(Cl)c1

Procedure:
3,4-Dichlorophenylmethanesulfenyl chloride is prepared from the corresponding 3,4-dichlorobenzyl mercaptan in accordance with the procedure of Example I for the preparation of the sulfenyl chloride, except that this reaction is conducted under cooling conditions. The sulfenyl chloride is reacted with the mercaptopyridine-1-oxide as described in Example I, giving an 84% yield of 3,4-dichlorobenzyl 1-oxo-2-pyridyl disulfide having a melting point of 133.0°-134.0° C. and