Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([C:9](=[N:11][OH:12])[CH3:10])[CH:6]=[CH:7][CH:8]=1.ClC1C=C(C(=NO)C)C=C(Cl)C=1.[Cl:27][C:28]1[N:29]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[CH2:41]Cl)[C:30](=[O:34])[N:31]([CH3:33])[N:32]=1>>[Cl:27][C:28]1[N:29]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[CH2:41][O:12][N:11]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:4]=2)[CH3:10])[C:30](=[O:34])[N:31]([CH3:33])[N:32]=1
Reactant: CC(=NO)c1cccc(C(F)(F)F)c1
Reactant: Cn1nc(Cl)n(-c2ccccc2CCl)c1=O
Agent: CC(=NO)c1cc(Cl)cc(Cl)c1
Product: CC(=NOCc1ccccc1-n1c(Cl)nn(C)c1=O)c1cccc(C(F)(F)F)c1

Procedure:
Preferred oximes of Formula IV for use in this process include 1-[3-(trifluoromethyl)phenyl]ethanone oxime, 1-[3,5-(bistrifluoromethyl)phenyl]ethanone oxime, and 1-[3,5-dichlorophenyl]ethanone oxime. Examples of the process of Step 2 include the reaction of 5-chloro-4-[2-(chloromethyl)phenyl]-2,4-dihydro-2-methyl-3H-1,2,4-triazol-3-one one with -1-[3,5-(bistrifluoromethyl)phenyl]ethanone oxime to form 5-chloro-2,4-dihydro-2-methyl-4-[2-[[[[1-[3(trifluoromethyl)phenyl]-ethylidene]amino]oxy]methyl]phenyl]-3H-1,2,4-triazol-3-one; the reaction of 5-chloro-4-[2-(chloromethyl)phenyl]-2,4-dihydro-2-methyl-3H-1,2,4-triazol-3-one with 1-[3,5-(bistrifluoromethyl)phenyl]ethanone oxime to form 5-chloro-2,4-dihydro-2-methyl-4-[2-[[[[1-[3(bistrifluoromethyl)phenyl]-ethylidene]amino]oxy]methyl]phenyl]-3H- 1,2,4-triazol-3-one.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.Cl.[CH3:13][O:14][C:15](=[O:30])[C@H:16]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH2:20].C(N[C@H](C(O)=O)C)(OC(C)(C)C)=O.Cl.COC(=O)[C@H](CC1C=CC=CC=1)N>CO.C(Cl)(Cl)Cl>[CH3:13][O:14][C:15](=[O:30])[C@H:16]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH:20][C:9](=[O:11])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)N
Reactant: O=C(O)Cc1ccccn1
Agent: COC(=O)[C@@H](N)Cc1ccccc1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)Cc1ccccn1

Procedure:
Following General Procedure C and using 2-pyridylacetic acid hydrochloride (Aldrich) and N-(L-alaninyl)-L-phenylalanine methyl ester hydrochloride (prepared from N-BOC-L-alanine (Sigma) and L-phenylalanine methyl ester hydrochloride (Sigma) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp=137-139° C.). The reaction was monitored by tlc (Rf=0.4 in 8% MeOH/CHCl3) and the product was purified by silica gel chromatography using 8% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane/acetonitrile.
Reaction SMILES: C([O:8][C:9]1[C:16](O)=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[OH:8][C:9]1[C:16]([O:37][CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12]
Reactant: OCCc1ccccn1
Reactant: O=Cc1cccc(O)c1OCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=Cc1cccc(OCCc2ccccn2)c1O
Reaction time: 12 h
Yield: 91.7 %

Procedure:
2-benzyloxy-3-hydroxy-benzaldehyde 16 (0.30 g, 1.3 mmol), triphenylphosphine (0.41 g, 1.6 mmol) and 2-(2-hydroxyethyl)pyridine (0.18 ml, 1.6 mmol) were stirred in THF (15 ml), followed by the addition of DEAD (0.25 ml, 1.6 mmol). After stirring for 12 h, the reaction mixture is partitioned between ethyl acetate (200 ml) and saturated aqueous sodium hydrogen carbonate (200 ml). The organic layer is separated, dried (MgSO4), filtered and concentrated to give a brown oil. The brown oil is purified by flash chromatography (50% ethyl acetate/hexanes) to afford 0.29 g (66%) of 2-hydroxy-3-(2-pyridin-2-ylethoxy)benzaldehyde 17 as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:4]=1[CH2:21]C=O.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:31]([CH2:34][CH3:35])[CH:32]=[O:33])C=CC=CC=1.[C:48]1(C)C=CC=CC=1>>[CH2:34]([C:31](=[CH:48][CH2:21][C:4]1[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:18])[CH3:19])=[C:6]2[C:10](=[C:11]([CH3:12])[C:3]=1[O:2][CH3:1])[CH2:9][O:8][C:7]2=[O:13])[CH:32]=[O:33])[CH3:35]
Reactant: CCC(C=O)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccccc1
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=O)C(=O)OC2
Product: CCC(C=O)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2
Yield: 83 %

Procedure:
A solution of [6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-acetaldehyde (1.5 g, 4.46 mmol) in toluene (14 mL) was heated at 100° C. with 2-(triphenyl-phosphanylidene)-butyraldehyde (1.68 g, 5.35 mmol) overnight. A second portion of 2-(triphenyl-phosphanylidene)-butyraldehyde (495 mg, 1.49 mmol) was added and the reaction mixture was heated for an additional day. After concentration, the residue was purified by silica gel chromatography to provide 1.3 g (83%) of the desired product as oil. 1H NMR (300 MHz, CDCl3) δ 0.01 (s, 9H), 1.03 (t, 3H), 1.10-1.21 (m, 2H), 2.15 (s, 3H), 2.15-2.44 (m, 2H), 3.67-3.76 (m, 2H), 3.74 (s, 3H), 4.31-4.36 (m, 2H), 5.10 (s, 2H), 6.34-6.38 (m, 1H), 9.28 (s, 1H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([S:14](O)(=[O:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[C:4]([F:18])[CH:3]=1.CN(C=O)C.C1(C)C=CC=CC=1.S(Cl)([Cl:33])=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([S:14]([Cl:33])(=[O:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[C:4]([F:18])[CH:3]=1
Reactant: O=S(=O)(O)c1ccccc1-c1ccc(Br)cc1F
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccccc1-c1ccc(Br)cc1F

Procedure:
4′-Bromo-2′-fluorobiphenyl sulfonic acid (5 g) was refluxed in thionyl chloride (30 mL) with a catalytic quantity of DMF (0.5 mL) for 4 hours. Toluene was added and the solvents evaporated under vacuum. The residue collected was recrystallised from petrol/ethyl acetate to give white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].Br[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[O:14]([CH2:13][CH2:12][O:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCCOc1ccccc1
Reactant: COC(=O)c1sccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1sccc1OCCOc1ccccc1
Temperature: 80 °C
Reaction time: 4.5 h
Yield: 93 %

Procedure:
To a solution of methyl 3-hydroxythiophene-2-carboxylate (0.992 g, 6.27 mmol) in N,N-dimethylformamide (12 ml) were added β-bromophenetole (1.268 g, 6.31 mmol) and potassium carbonate (1.059 g, 7.66 mmol), and the mixture was stirred at 80° C. for 4.5 hr. Ethyl acetate was added to the reaction mixture, the mixture was washed with water, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give methyl 3-(2-phenoxyethoxy)thiophene-2-carboxylate (1.624 g, 5.83 mmol, yield 93%). This was dissolved in methanol (12 ml), 1N-aqueous sodium hydroxide solution (12 ml) was added at room temperature, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was concentrated under reduced pressure and neutralized with 1N-aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give a carboxylic acid compound 3-(2-phenoxyethoxy)thiophene-2-carboxylic acid (1.491 g, 5.64 mmol, yield 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:10](OCC)OCC)=[CH:4][C:3]=1[F:17]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([F:17])=[CH:4][C:5]2[O:8][CH:9]=[CH:10][C:6]=2[CH:7]=1.[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH:9]=[CH:10][C:4]=2[C:3]=1[F:17]
Reactant: CCOC(COc1ccc(Cl)c(F)c1)OCC
Solvent: Cc1ccccc1
Product: Fc1c(Cl)ccc2occc12
Product: Fc1cc2occc2cc1Cl
Temperature: 200 °C
Reaction time: 0.17 h
Yield: 22.6 %

Procedure:
To 13a (3.44 g, 13.09 mmol) in toluene (13.09 ml) at room temperature was added amberlyst 15 (700 mg, 13.09 mmol). The mixture was stirred at 200° C. for 10 min in microwave. The mixture was cooled to room temperature and then the solvent was concentrated. The residue was purified via Biotage (heptane; SNAP25 column) giving 13b (505 mg, 23%) as a colorless oil. 1H NMR of major isomer in mixture (400 MHz, MeOD) δ ppm 6.84 (dd, J=2.27, 0.95 Hz, 1H) 7.46 (dd, J=9.16, 0.95 Hz, 1H) 7.71 (d, J=7.39 Hz, 1H) 7.81 (d, J=2.27 Hz, 1H).
Reaction SMILES: NC1[N:3]=[C:4]([CH2:48][CH2:49][CH2:50][CH3:51])[N:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)C=1C(OC)=O.[H-].[Na+].[C:54]([O:57][CH2:58]C)(=[O:56])[CH3:55].[CH3:60][N:61]([CH:63]=O)[CH3:62]>CI.C(O)(=O)C>[CH2:48]([C:4]1[N:5]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)([C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[N:27]=[N:26][N:25]=3)=[CH:16][CH:17]=2)[C:55]([C:54]([O:57][CH3:58])=[O:56])=[C:63]([N:61]([CH3:62])[CH3:60])[N:3]=1)[CH2:49][CH2:50][CH3:51]
Reactant: CN(C)C=O
Reactant: CCOC(C)=O
Reactant: CCCCc1nc(N)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CC(=O)O
Product: CCCCc1nc(N(C)C)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 103 mg (0.15 mmol) 2-butyl-4-amino-5-carbomethoxy-1-(2'-(N-triphenylmethyltetra-zol-5-yl)-biphen-4-yl)methylimidazole (Example 1, Step I) in 1 mL dry DMF at room temperature was added 7 mg sodium hydride/oil dispersion (60% dispersion; 0.18 mmol, 1.1 eq). After 15 minutes at room temperature, two drops of methyl iodide were added and the mixture capped tightly and stirred at room temperature for 16 hours. Two drops of glacial acetic acid were added and the mixture diluted into 20 mL ethyl acetate and washed with pH 7.0 phosphate buffer (2×) and brine (1×). The organic layer was removed, dried over magnesium sulfate, filtered and stripped; the residue was purified by medium pressure liquid chromatography on silica, eluting with ethyl acetate/hexane (2:1) to afford 65 mg of a 2:1 mixture of mono- and di-methylated products in addition to 23 mg of recovered starting material.
Reaction SMILES: [OH:1][CH:2]1[C:7]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][C:11]([O:16][CH3:17])=[CH:10][C:9]=2[O:18][CH3:19])=[CH:6][CH2:5][N:4]([CH3:20])[CH2:3]1.C(N(CC)CC)C.Cl[C:29]([O:31][CH3:32])=[O:30].O>O1CCCC1>[CH3:32][O:31][C:29]([O:1][CH:2]1[C:7]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][C:11]([O:16][CH3:17])=[CH:10][C:9]=2[O:18][CH3:19])=[CH:6][CH2:5][N:4]([CH3:20])[CH2:3]1)=[O:30]
Reactant: COC(=O)Cl
Reactant: COc1cc(OC)c(C2=CCN(C)CC2O)c(OC)c1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)OC1CN(C)CC=C1c1c(OC)cc(OC)cc1OC
Temperature: 5 °C
Reaction time: 3 h

Procedure:
8.37 g (30 mmol) of 3(R,S)-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine (VII) were dissolved in 83.7 ml of tetrahydrofuran and treated with 12.4 ml (90 mmol) of triethylamine. The mixture was cooled to 5° C., 2.55 ml (33 mmol) of methyl chloroformate were added dropwise in the course of 15 min and the mixture was stirred at 5-10° C. for a further 3 h. Since TLC checking still showed starting material, a further 1.0 ml (12.9 mmol) of methyl chloroformate were added and the mixture was stirred again for 1 h. 50 ml of water were then added and the mixture was extracted twice with 50 ml of ethyl acetate each time. The combined organic phases were washed with 30 ml of saturated sodium chloride solution, then dried over sodium sulfate and evaporated in vacuo on a rotary evaporator.
Reaction SMILES: [C:1]1([CH2:17]O)[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.P(Br)(Br)[Br:20].N#N.C(=O)(O)[O-].[Na+]>ClCCl>[C:1]1([CH2:17][Br:20])[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc2ccc3cccc4ccc1c2c34
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: BrCc1ccc2ccc3cccc4ccc1c2c34
Reaction time: 12 h

Procedure:
Firstly, 500 mg of (1-pyrenyl)methanol as the starting material was dissolved in 20 mL of dehydrated dichloromethane, and then 1 mL of PBr3 was slowly dropped into the solution that was kept in an ice bath of 0° C. in an N2-atmosphere. After 12 hours of stirring with a magnetic stirrer, the mixture was neutralized with 50 ml of 0.3M sodium bicarbonate solution (4 g/150 mL) three times using a separating funnel, and then CH2Cl2 was used to extract the organic phase in the mixture. After the moisture in the organic phase was removed by anhydrous MgSO4, the solvent in the organic phase was removed under a reduced pressure to obtain 547 mg of (1-pyrenyl)bromomethane in a high purity. The completion of the bromination was confirmed by the 1H-NMR spectrum of the product in FIG. 3A and the mass spectrum (molecular weight=295.17) of the same.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[S:24][CH:25]=[CH:26][C:27]=1[CH2:28]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.CCOC(C)=O>[Cl:22][C:23]1[S:24][CH:25]=[CH:26][C:27]=1[CH2:28][O:20][C:17]1[CH:18]=[CH:19][N:14]([C:11]2[CH:12]=[CH:13][C:6]3[N:5]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[N:8]([CH3:9])[C:7]=3[CH:10]=2)[C:15](=[O:21])[CH:16]=1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: OCc1ccsc1Cl
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccsc4Cl)cc3=O)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
To a mixture of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg), (2-chloro-3-thienyl)methanol (106 mg) and tributylphosphine (0.264 ml) in THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (269 mg), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was diluted with EtOAc, washed with water and brine successively, dried over MgSO4, and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc), followed by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH) to give the title compound (42.4 mg) as an off-white solid.
Reaction SMILES: [CH2:1]([N:5]1[CH2:22][CH:21]([CH2:23][F:24])[O:20][C:7]2([CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[CH2:6]1)[C:2]#[C:3][CH3:4].[ClH:25].O1CCOCC1>ClCCl.C(=O)(O)[O-].[Na+]>[ClH:25].[CH2:1]([N:5]1[CH2:22][CH:21]([CH2:23][F:24])[O:20][C:7]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6]1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCN1CC(CF)OC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC#CCN1CC(CF)OC2(CCNCC2)C1
Reaction time: 2 h
Yield: 98 %

Procedure:
Tert-butyl 8-but-2-ynyl-10-(fluoromethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (23.0 mg, 0.0676 mmol) was dissolved in dichloromethane (2 mL) and treated with HCl in dioxane (1.69 mL of 4 M, 6.76 mmol). The reaction mixture was stirred for 2 h, then diluted with dichloromethane (10 mL) and 1:1 saturated sodium bicarbonate/1 M NaOH (10 mL). The organic layer was separated, dried over Na2SO4, and concentrated to yield 8-but-2-ynyl-10-(fluoromethyl)-11-oxa-3,8-diazaspiro[5.5]undecane hydrochloride (16.0 mg, 0.0666 mmol, 98%). ESI-MS m/z calc. 240.2. found 241.5 (M+1)+; Retention time: 0.22 minutes (3 min run).
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]3[C:21]([O:22][CH:23]([CH3:25])[CH3:24])=[N:20][CH:19]=[CH:18][N:17]3[C:26]=2[C:27]2[CH:32]=[CH:31][N:30]=[C:29](SC)[N:28]=2)=[CH:10][CH:9]=1.[C:35]([O-])([O-])=O.[Na+].[Na+]>O.C(Cl)Cl.CO>[F:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:15]=[C:16]3[C:21]([O:22][CH:23]([CH3:25])[CH3:24])=[N:20][CH:19]=[CH:18][N:17]3[C:26]=2[C:27]2[CH:32]=[CH:31][N:30]=[C:29]([S:3]([CH3:35])(=[O:5])=[O:2])[N:28]=2)=[CH:12][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: O=S([O-])OO
Reactant: CSc1nccc(-c2c(-c3ccc(F)cc3)nc3c(OC(C)C)nccn23)n1
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(C)Oc1nccn2c(-c3ccnc(S(C)(=O)=O)n3)c(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
A solution of Oxone® (3.17 g, 5.15 mmol) in water (9 mL) was added to a solution of 2-(4-fluoro-phenyl)-8-isopropoxy-3-(2-methylsulfanylpyrimidin-4-yl)-imidazo[1,2-a]pyrazine (1.02 g, 2.57 mmol) in 41 mL of DCM/MeOH (1:1). The resulting reaction mixture was stirred overnight at ambient temperature, neutralized with a saturated aqueous solution of Na2CO3, and extracted with DCM. The organic phase was dried over MgSO4, filtered, and concentrated. The crude material was sequentially triturated with MeOH and ACN to give 0.387 g (35%) of the title compound: LC/MS (Table 1, Method g) Rt=2.69 min; MS m/z: 428.2 (M+H)+.
Reaction SMILES: [CH:1]1([O:6][C:7]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[CH:14]=[C:13]3[CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][C:22]=2[O:31][CH3:32])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+]>CO.O1CCCC1.O>[CH:1]1([O:6][C:7]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[CH:14]=[C:13]3[CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=2[O:31][CH3:32])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(NC(=O)OC4CCCC4)cc23)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)O)ccc1Cc1cn(C)c2ccc(NC(=O)OC3CCCC3)cc12
Reaction time: 20 h
Yield: 87.6 %

Procedure:
A stirred solution of methyl 4-[5-(cyclopentyloxycarbonyl)amino-1-methylindol-3-ylmethyl]-3-methoxybenzoate (0.25 g. ) in methanol (5 ml.) and tetrahydrofuran (4 ml.), under an atmosphere of nitrogen, was treated with a solution of lithium hydroxide monohydrate (0.12 g.) in water (2 ml.). The mixture was stirred for 20 hours and then concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified with 1M hydrochloric acid (20 ml.). The white precipitate which formed was separated by filtration, washed with a little water, and recrystallized from a mixture of toluene and hexane to give the title compound (0.212 g., 88%) as an off-white powder; m.p. 157°-158° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([OH:19])=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2ccc(O)cc2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCOc1ccc2c(c1)C[C@@H](NC(=O)OC(C)(C)C)CC2

Procedure:
(S)-2-(tert-Butoxycarbonylamino)-7-hydroxytetralin (400 mg) was dissolved in N,N-dimethylformamide (8 ml), and cesium carbonate (3.16 g) and ethyl 4-bromobutyrate (650 μl) were added to the solution at room temperature with stirring. After reaction for 1.5 hours, water was poured into the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. Purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: hexane/ethyl acetate=1/1) gave ethyl (S)-4-[2-(tert-butoxycarbonyl-amino)-1,2,3,4-tetrahydronaphthalen-7-yloxy]butyrate (488 mg) having a melting point of 96-98° C.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:4]=1[CH2:10][C:11]([OH:13])=O.Cl.[C:16]1([C:22]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:30]3[CH:26]([CH2:27][NH:28][CH2:29]3)[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[CH3:14][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:4]=1[CH2:10][C:11]([N:28]1[CH2:27][CH:26]2[CH:30]([C:22]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH2:24][C:25]2=[O:31])[CH2:29]1)=[O:13]
Reactant: CN(C)c1cccc(F)c1CC(=O)O
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1cccc(F)c1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 1.5 h
Yield: 76.7 %

Procedure:
N,N'-Carbonyldiimidazole (1.62 g) is added to a solution of (2-dimethylamino-6-fluorophenyl)acetic acid (1.97 g) in dry dichloromethane (50 cc), cooled to +5° C. The mixture is stirred for 90 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (3.27 g) and triethylamine (2.8 cc) in dichloromethane (50 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with water (2×100 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 4 cm, height 25 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and collecting 50 cc fractions. Fractions 6 to 19 are combined and concentrated to dryness under reduced pressure. The residue is triturated in ethyl ether. The crystals are drained and dried. (3aRS,7aRS)-2-[(2-dimethylamino-6-fluorophenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolone (3.6 g) is obtained in the form of white crystals melting at 210° C.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH2:12][C:13]#[CH:14])=[CH:4][C:3]=2[O:2]1.[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16].O1CC[CH2:23]OO1>O1CCOCC1>[CH2:15]([N:17]([CH2:18][CH3:19])[CH2:23][C:14]#[C:13][CH2:12][CH2:11][CH2:10][C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1)[CH3:16]
Reactant: C1COOOC1
Reactant: C#CCCCc1ccc2c(c1)OCO2
Reactant: CCNCC
Solvent: C1COCCO1
Product: CCN(CC)CC#CCCCc1ccc2c(c1)OCO2

Procedure:
Add 5-(3,4-methylenedioxyphenyl)pent-1-yne (24.5 g) in dioxan (15 cc) to a mixture of diethylamine (16 g), trioxan (7.2 g) and cuprous chloride (0.3 g) in dioxan (20 cc) and heat the mixture at 100° for 15 hours under an atmosphere of nitrogen. Filter the cooled solution, remove the solvent and distil the residue at 0.1 mm Hg to obtain 1-diethylamino-6-(3,4-methylenedioxyphenyl)-hex-2-yne after a forerun of more volatile material.