Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][CH2:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.C(O[CH:23]=[C:24]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:25]([O:27][CH2:28][CH3:29])=[O:26])C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([NH:17][CH:23]=[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:18][CH:19]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1ccc(OC)c(CCc2ccc(N)cc2)c1
Product: CCOC(=O)C(=CNc1ccc(CCc2cc(OC)ccc2OC)cc1)C(=O)OCC

Procedure:
The mixture of 820 mg of 4-[(2,5-dimethoxyphenyl)ethyl]aniline and 690 mg of diethyl ethoxymethylene-malonate is heated to 95° for 2 hours. On cooling the product crystallises and is used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][NH:9][C:10](=S)[S:11]C)=[CH:6][CH:5]=1)([O-:3])=[O:2].O.[NH2:17][NH2:18]>C(O)C>[N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][NH:9][C:10](=[S:11])[NH:17][NH2:18])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NN
Reactant: CSC(=S)NCc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Solvent: O
Product: NNC(=S)NCc1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 187 g (772 mmole) of methyl N-(4-nitrobenzyl)dithiocarbamate and 450 ml of hydrazine hydrate in 1400 ml of absolute ethanol was stirred mechanically and heated to reflux. Precipitation began by the time the internal temperature reached about 40° C. After 2 hours at reflux, the mixture was cooled and allowed to stand at room temperature. The solid was collected on a filter, washed with ethanol, and dried to give 105 g (60%) of light yellow crystals, mp 196°-198° C. satisfactory purity by TLC in 95:5:0.5 CH2Cl2 --MeOH-concd NH4OH; mass spectrum (FAB) m/e 227 (M+1)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])=[CH:16][CH:15]=2)[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[Cl:28][C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:29])[C:22]=1[O:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([CH:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[CH:19][CH:18]=1
Reactant: Clc1cccc(Cl)c1OCc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: Clc1cccc(Cl)c1OCc1ccc(C2CNCCO2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.3 %

Procedure:
To a solution of 4-benzyl-2-[4-(2,6-dichloro-phenoxymethyl)-phenyl]-morpholine (2.25 g; 3.7 mmol) in 1,2-dichloroethane (10 mL), was added dropwise 1-chloroethyl chloroformate (0.44 mL; 4.0 mmol), at 0° C. After 15 minutes, the cooling was removed and subsequently the mixture was heated under reflux overnight. After cooling to RT the mixture was concentrated in vacuo. To the residue was added toluene and the mixture was concentrated in vacuo. This last step was repeated twice. To the final residue was added MeOH (10 mL), and this mixture was stirred overnight at RT. Once more the mixture was concentrated in vacuo. The residue was partitioned between EtOAc and 2 M Aqueous NaOH. The layers were separated, and the organic layer dried (Na2SO4), filtered, and concentrated in vacuo to afford 2-[4-(2,6-Dichloro-phenoxymethyl)-phenyl]-morpholine (0.98 g), which was used as such in the next step.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=2[C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[OH:18])[CH2:2][CH2:3][CH3:4].[CH2:24]([CH:26]1[O:28][CH2:27]1)Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([C:5]1[O:6][C:7]2[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=2[C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[O:18][CH2:24][CH:26]1[O:28][CH2:27]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1C(=O)c1ccc(Cl)cc1O
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCc1oc2ccccc2c1C(=O)c1ccc(Cl)cc1OCC1CO1

Procedure:
A mixture of 2-n-butyl-3-(4'-chloro-2'-hydroxybenzoyl)benzofuran, 30 ml. of epichlorohydrin and 15 g. of potassium carbonate in 200 ml. of ethanol was refluxed for 18 hours. The reaction mixture was concentrated, water was added to the residue and the aqueous solution was extracted with methylene chloride. The extracts were washed with water, dried (MgSO4) and concentrated in vacuo to give 2-n-butyl-3-[4'-chloro-2'-(2,3-epoxy)propoxybenzoyl]benzofuran which was purified by dry column chromatography on alumina with chloroform as eluant.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1)[NH:8][C:7]2=O)([O-:3])=[O:2].CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:32]>>[Cl:32][C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=[C:9]([C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(-c2cnccn2)nc2ccc([N+](=O)[O-])cc12
Solvent: CN(C)c1ccccc1
Product: O=[N+]([O-])c1ccc2nc(-c3cnccn3)nc(Cl)c2c1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a mixture of 6-nitro-2-(pyrazin-2-yl)quinazolin-4(3H)-one (1.00 g, 3.7 mmol) in POCl3 (10 mL) was added N,N-dimethylbenzenamine (0.1 mL). The resulting mixture was stirred at 120° C. for 2 h. After the reaction was completed, POCl3 was removed in vacuo, and the residue was co-evaporated with toluene twice to give a dark crude product, which was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:13]O)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:10])([F:11])[F:12])[CH2:13][N:19]1[C:15](=[O:25])[C:16]2[C:17](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:18]1=[O:20]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1ccc(OC(F)(F)F)c(F)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(OC(F)(F)F)c(F)c1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
To a solution of the compound (2.95 g) obtained in Step 1 in THF (30 ml) were added phthalimide (3.10 g) and triphenylphosphine (5.52 g) with stirring at room temperature, and the mixture was stirred under ice-cooling. With stirring under ice-cooling, diisopropyl azodicarboxylate (4.15 ml) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=2:8-3:7) to give the title compound (4.30 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH2:12][N:13]1[C:19](=[O:20])[C@@H:18]([NH:21][C:22](=[O:28])OC(C)(C)C)[C@H:17]([CH3:29])[N:16]([C:30](=[O:36])[CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:15]3[CH:37]=[CH:38][CH:39]=[CH:40][C:14]1=3)=[C:7]([O:41][CH3:42])[CH:6]=[CH:5]2.[C:43]([N:50]([CH3:56])[C@H:51](C(O)=O)[CH3:52])([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>Cl.O1CCOCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH2:12][N:13]1[C:19](=[O:20])[C@@H:18]([NH:21][C:22](=[O:28])[C@@H:51]([N:50]([CH3:56])[C:43](=[O:44])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[CH3:52])[C@H:17]([CH3:29])[N:16]([C:30](=[O:36])[CH2:31][S:32]([CH3:35])(=[O:33])=[O:34])[C:15]3[CH:37]=[CH:38][CH:39]=[CH:40][C:14]1=3)=[C:7]([O:41][CH3:42])[CH:6]=[CH:5]2
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)N(C(=O)CS(C)(=O)=O)c2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(=O)CS(C)(=O)=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.3 %

Procedure:
A rt solution of tert-butyl(3S,4S)-1-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (75 mg, 114 μmol) in 4 M HCl in 1,4-dioxane (568 μl) was stirred for 1.5 h then concentrated. This material was taken up in DMF (380 μl) and Boc-N-methyl-L-alanine (25.5 mg, 125 μmol), N,N-diisopropylethylamine (78.9 μl, 456 μmol), and HBTU (47.6 mg, 125 μmol) were added. The reaction was stirred at rt for 20 min, then diluted with EtOAc, washed with sat. aq. NaHCO3 and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(S)-1-((3S,4S)-1-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (81 mg, 95%) as a white solid. MS m/z 767/769 (M+Na)+
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([O:7][CH2:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:25][OH:26].C(N(CC)CC)C>C(O)C>[OH:26][N:25]=[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH2:14]2)=[CH:22][CH:23]=1)[NH2:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(C#N)cc2)CC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(C(N)=NO)cc2)CC1
Temperature: 25 °C
Yield: 78.7 %

Procedure:
A solution of tert-butyl 4-[(4-cyanophenoxy)methyl]piperidine-1-carboxylate (Step 1, 1.47 g, 4.22 mmol, purity 91%), hydroxylamine hydrochloride (646 mg, 9.30 mmol) and triethylamine (1.30 mL, 9.30 mmol) in ethanol (24 mL) was stirred and heated at reflux for 1 h. After being cooled to rt, the reaction mixture was evaporated to dryness. The resulting material was treated with ethyl acetate, and the solid was filtered off. The ethyl acetate solution was washed with water and saturated sodium chloride solution, dried with anhydrous magnesium sulfate and filtered. After evaporation of the solvent, the crude product was stirred in tert-butyl methyl ether. The solid was filtered off and dried in vacuo to give the title compound (1.16 g, 78%): 1H NMR (400 MHz, CDCl3) δ 7.53 (d, 2H), 6.89 (d, 2H), 4.82 (s, 2H), 4.22-4.08 (broad m, 2H), 3.81 (d, 2H), 2.81-2.66 (m, 2H), 2.02-1.90 (m, 1H), 1.85-1.78 (d, 2H), 1.46 (s, 9H), 1.35-1.18 (m, 2H); ES-MS m/z 350, HPLC RT (Method D) 1.56 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:5])[O:4][CH2:3]1.[CH:6]1([N:9]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:8][CH2:7]1>CO.O>[CH:6]1([N:9]([CH:23]2[CH2:28][CH2:27][N:26]([CH2:3][C:2]([OH:4])([CH3:5])[CH3:1])[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:8][CH2:7]1
Reactant: CC1(C)CO1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Solvent: O
Solvent: CO
Product: CC(C)(O)CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
1,1-Dimethyloxirane (88 μL) is added to N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide (100 mg) in methanol (5 mL). The mixture is stirred for 4 h at room temperature and at 50° C. over night. Since the conversion is still incomplete, another portion of 1,1-dimethyloxirane (88 μL) is added and the mixture is stirred for 8 h at 50° C. The reaction mixture is diluted with water (10 mL) and stirred for 1 h at room temperature. The precipitate is filtered off and washed with water and t-butyl methylether to give the title compound. LC (method 2): tR=1.00 min; Mass spectrum (ESI+): m/z=384 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[H-].[Na+].ClC(OCC)=O.[C:19]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1COCC1.C(O)(=O)C>[CH2:24]([O:23][C:21](=[O:22])[CH:20]([C:4]([C:3]1[C:2]([CH3:1])=[N:10][CH:9]=[CH:8][CH:7]=1)=[O:6])[C:19]([O:27][CH2:28][CH3:29])=[O:26])[CH3:25]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ncccc1C(=O)O
Agent: CCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1cccnc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To a slurry of 2-methyl-nicotinic acid (10.2 g, 74.45 mmol) in THF (30 mL) chilled to −10° C. was added sodium hydride (60% in mineral oil; 3.89 g, 89.3 mmol) portionwise and the reaction mixture stirred till no further gas evolution was noticed. Ethyl chloroformate (6.0 mL, 74.45 mmol) was added slowly at the same temperature and stirring continued for another 1 h, whereby a thick white slurry developed. Simultaneously, in a separate vessel, diethyl malonate (11.9 mL, 74.45 mmol) was added dropwise to a slurry of sodium hydride (60% in mineral oil; 3.24 g, 74.45 mmol)) in THF (20 mL) at −10° C., stirred for 30 min and slowly added to the slurry of the mixed anhydride. The reaction mixture was allowed to warm to r.t. and stirred overnight. The pH was adjusted to ˜pH 6 with acetic acid and evaporated to dryness. The residue was partitioned between water and ethyl acetate, the organics separated, then washed with water, brine, dried over sodium sulfate, filtered and concentrated to yield 2-(2-methyl-pyridine-3-carbonyl)-malonic acid diethyl ester (18.16 g, 87%) as an oil.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH:8]2[CH2:10][CH2:9]2)[N:5]([CH3:7])[CH:6]=1.Cl.BrC1N=C(C2CC2)N(C)C=1.C1(C2N(C)C=CN=2)CC1.C([O-])([O-])=O.[K+].[K+].C1C(=O)N([I:44])C(=O)C1>C(OC(C)C)(=O)C>[I:1][C:2]1[N:3]=[C:4]([CH:8]2[CH2:10][CH2:9]2)[N:5]([CH3:7])[C:6]=1[I:44]
Reactant: O=C1CCC(=O)N1I
Reactant: Cn1cc(I)nc1C1CC1
Agent: Cl
Agent: Cn1cc(Br)nc1C1CC1
Agent: Cn1ccnc1C1CC1
Solvent: CC(=O)OC(C)C
Product: Cn1c(C2CC2)nc(I)c1I
Temperature: 75 °C
Reaction time: 3 h

Procedure:
4-Iodo-2-cyclopropyl-1-methyl-1H-imidazole, 5k′. To a solution of 2-cyclopropyl-1-methyl-1H-imidazole (4a) (5.5 g, 45.0 mmol) in isopropyl acetate (110 mL) was added K2CO3 (1.25 g, 9.0 mmol) followed by NIS (40.3 g, 179.1 mmol) in portions over 2 h. The solution was stirred at 75° C. for 3 h, allowed to cool to room temperature and quenched with a 10% aqueous solution of K2CO3. The organic layer was washed with 10% K2CO3. The combined organic layers were concentrated affording crude 4,5-diiodo-2-cyclopropyl-1-methyl-1H-imidazole (10.5 g) as a dark solid. A solution of the resulting solid in THF (100 mL) was cooled to −20° C. and treated with 2 M i-PrMgCl in THF (17.5 mL, 35.0 mmol) dropwise. The reaction mixture was quenched with water and filtered. The organic layer was washed with brine and water, and concentrated afford 5k′ (8.64 g, 77% yield) as a dark orange oil. 1H-NMR (400 MHz, CDCl3) δ 6.85 (s, 1H), 3.66 (s, 3H), 1.74 (dt, J=8.4, 5.2 Hz, 1H), 1.03-0.91 (m, 4H); 13C-NMR (100 MHz, CDCl3) δ 151.9, 125.8, 79.1, 32.5, 6.9, 6.8.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[N:9]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:10]=[CH:11][C:3]=12.C([N-]C(C)C)(C)C.[Li+].O1CCCC1.CCCCCCC.C(C1C=CC=CC=1)C.[I:49]I>O1CCCC1>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[N:9]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:10]([I:49])=[CH:11][C:3]=12
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Cl)c(F)cnc21
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: O=S(=O)(c1ccccc1)n1c(I)cc2c(Cl)c(F)cnc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of Example 231A (3.560 g, 11.46 mmol) in tetrahydrofuran (75 mL) at 78° C. was added dropwise 2M lithium diisopropylamide in tetrahydrofuran/heptane/ethylbenzene (11.46 mL, 22.91 mmol). The mixture was stirred at −78° C. for 30 minutes and iodine (5.82 g, 22.91 mmol) in tetrahydrofuran (25 mL) was added. After stirring at −78° C. for 3 hours, the reaction was quenched with aqueous sodium thiosulfate and extracted with ethyl acetate (twice). The combined organic layers were dried over magnesium sulfate, filtered, concentrated until most solvent was removed. The suspension was diluted with ethyl acetate and warmed with a heat gun. Heptanes were added to the suspension and the mixture was stirred for 1 hour. The solid was filtered, washed with heptanes/ethyl acetate (1:1), and vacuum oven-dried to give the title compound. The filtrate was concentrated and triturated with heptanes/ethyl acetate (1:1) to give additional title compound. MS (ESI+) m/z 436.9 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:11][C:12]([F:26])([F:25])[C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[CH2:16]Br>>[F:11][C:12]([F:25])([F:26])[C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:20]=1)[CH2:16][O:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1
Reactant: N#Cc1ccc(O)cc1F
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Product: N#Cc1ccc(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1F
Yield: 99 %

Procedure:
As described for example 1a, 2-fluoro-4-hydroxy-benzonitrile (1.5 g, 10.5 mmol) [using 3,5-bis(trifluoromethyl)benzylbromide instead of 3-fluorobenzylbromide] was converted to the title compound (3.8 g, 99%) which was obtained as a white solid. MS: m/e=363.0 (M+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][CH2:14][CH:15]([OH:18])[CH2:16][OH:17]>O1CCOCC1.O>[Cl:8][C:6]1[CH:5]=[C:4]([NH:13][CH2:14][CH:15]([OH:18])[CH2:16][OH:17])[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([NH:13][CH2:14][CH:15]([OH:18])[CH2:16][OH:17])[CH:7]=1
Reactant: O=[N+]([O-])c1c(Cl)cc(Cl)cc1Cl
Reactant: NCC(O)CO
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1c(NCC(O)CO)cc(Cl)cc1NCC(O)CO

Procedure:
A mixture of 0.1 mole (22.6 g) of 2,4,6-trichloro nitrobenzene and 54.7 g of 3-amino-1,2-propanediol in 20 ml of dioxan was refluxed for 4 hours followed by evaporation of the dioxan under reduced pressure. The oil obtained was diluted in about 300 ml of water. The desired product was obtained using HPLC in two stages. About 200 ml of the aqueous solution of the product containing 3-amino-1,2-propanediol were injected onto a C18RD chromatographic column (Instrument: Waters Prep 500). The desired product was eluted using 35% methanol-65% water solution. After evaporation of the fractions containing the desired product, a dry extract was obtained which was recrystallized from 96° alcohol. The product melted at 146° C.
Reaction SMILES: Cl.[C:2]([N:9]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10]1)([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3]>CS(C)=O.C(N(CC)CC)C>[C:5]([O:4][C:2]([N:9]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10]1)=[O:3])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(=O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.6 %

Procedure:
In a 1 l three-necked flask, 10 g of N-Boc-3-hydroxypyrrolidine are dissolved in 350 ml of dimethyl sulphoxide in the presence of 52.3 ml of triethylamine. 28 g of pyridine-sulphur trioxide complex dissolved in 350 ml of dimethyl sulphoxide are added dropwise to the above solution. The reaction mixture is stirred for 4 hours at ambient temperature. The reaction medium is acidified to pH 4.5-5 with a 1M solution of hydrochloric acid and the reaction mixture is then extracted with ethyl acetate. The organic phases are combined and then dried over anhydrous sodium sulphate. The residue is filtered through silica gel (1/1 heptane/ethyl acetate). 5.7 g of 3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester are obtained. Yield: 58%.
Reaction SMILES: CS([C:5]1[N:6]=[N:7][CH:8]=[C:9]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:10]=1)(=O)=O.[NH3:17]>C1COCC1>[N:12]1[CH:13]=[CH:14][CH:15]=[N:16][C:11]=1[C:9]1[N:10]=[C:5]([NH2:17])[N:6]=[N:7][CH:8]=1
Reactant: N
Reactant: CS(=O)(=O)c1nncc(-c2ncccn2)n1
Solvent: C1CCOC1
Product: Nc1nncc(-c2ncccn2)n1
Yield: 23 %

Procedure:
5-(Pyrimidin-2-yl)-1,2,4-triazin-3-amine (1.0 g, 23%) was prepared from 3-(methylsulfonyl)-5-(pyrimidin-2-yl)-1,2,4-triazine (5.0 g, crude) and 0.5 M ammonia in THF (20 mL) according to the general procedure of Preparation 2.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:41]=[CH:40][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)\[CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[CH:19][CH:18]=1.CO.Cl>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)\[CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:40][CH:41]=1
Reactant: CCOC(=O)CCCC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCCCC(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (3 ml) was added to a solution of ethyl E-6-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanoate (530 mg) in tetrahydrofuran (6 ml)-methanol (3 ml) and stirred at room temperature for 1 hour. 1N hydrochloric acid (3.3 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-6-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanoic acid (451 mg, yield 90%) as colorless crystals. m.p. 112-113° C.
Reaction SMILES: Cl.[C:2]1([CH2:8][C:9]([NH2:11])=[NH:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:12][C:13]([SH:16])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[CH2:8]([C:9]1[N:11]=[C:13]([Cl:12])[S:16][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(N)Cc1ccccc1
Reactant: SC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Clc1nc(Cc2ccccc2)ns1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 2-phenyl-acetamidine hydrochloride (1.078 g, 6 mmol) in dichloromethane (10 ml) was added perchloromethyl mercaptan (0.61 ml, 5 mmol) via syringe. The mixture was cooled in an ice-methanol bath to −10° C. and a solution of sodium hydroxide (1.2 g, 30 mmol) in water (3 ml) was added dropwise keeping the temperature below −8° C. After complete addition the mixture was stirred 10 min at 0° C. The reaction mixture was diluted with water and the aqueous phase was extracted three times with dichloromethane. The combined organic phases were dried over Na2SO4, filtered and the solvents were evaporated. The residue was purified by chromatography on silica gel using heptane/ethyl acetate as eluent. The title compound was obtained as an orange liquid (0.779 g, 62%). MS ISP (m/e): 211.0 (100) [(M+H)+].
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH2:18][CH:19]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:20]([O:22][CH3:23])=[O:21])=[CH:12]2)C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH2:18][CH:19]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:20]([O:22][CH3:23])=[O:21])=[CH:12]2
Reactant: COC(=O)C(Cc1ccccc1)Cc1cc2cc(OCc3ccccc3)ccc2[nH]1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C(Cc1ccccc1)Cc1cc2cc(O)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
A mixture of methyl 3-(5-benzyloxyindolyl)-2-benzylpropanoate (0.16, 0.39 mmol), as prepared in the preceding step, 10% palladium(0) on carbon (0.02 g) in ethanol (10 mL) was stirred at ambient temperature under hydrogen (balloon) overnight (16 h). The catalyst was removed by filtration through Celite. The filtrate was concentrated to give the title compound as a light brown oil (0.12 g, 100%) which was used directly in next reaction.