Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[NH2:18]>>[Cl:14][C:15]1[CH:16]=[C:17]([NH:18][S:10]([C:3]2[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=2[F:1])(=[O:12])=[O:11])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1F
Reactant: COc1ccc(N)cc1Cl
Product: COc1ccc(NS(=O)(=O)c2ccc(F)c(F)c2F)cc1Cl

Procedure:
The title compound was prepared in a manner similar to that described in Example 1 by replacing 4-fluoro-3-nitrophenylsulfonyl chloride with 2,3,4-trifluorophenylsulfonyl chloride and replacing p-anisidine with 3-chloro-4-methoxyaniline. 1H-NMR (CDCl3): δ 7.56 (1H, m), 7.17 (1H, d, J=2.0 Hz), 7.02 (1H, m), 6.98 (1H, dd, J=9.0 and 2.0 Hz), 6.78 (1H, d, J=9.0 Hz), 6.72 (1H, br s), 3.83 (3H, s). MS(EI): 352 (7, M+), 351 (20), 156 (100). Anal. Calcd. for C13H9ClF3NO3S: C, 44.39; H, 2.58; N, 3.98; S. 9.11. Found: C, 44.31; H, 2.58; N, 3.96; S, 9.08.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.C(N(CC)CC)C.[C:16]1([C:22]#[CH:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:23]#[C:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][N:3]=1
Reactant: Fc1ccc(I)cn1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(C#Cc2ccccc2)cn1
Reaction time: 8 h
Yield: 129 %

Procedure:
In an 100 ml 2-necked round bottomed flask under Argon were dissolved 2-fluoro-5-iodopyridine (5.0 g, 22.4 mmol, 1.0 equiv.) in THF (30 ml). After 5 minutes at room temperature were added bis(triphenylphosphine)palladium(II)chloride (944 mg, 1.35 mmol, 0.06 equiv.), triethylamine (6.81 g, 9.32 ml, 67.3 mmol, 3.0 equiv.), phenyl acetylene (2.75 g, 2.95 ml, 26.9 mmol, 1.2 equiv.) and copper(I)iodide (128 mg, 0.67 mmol, 0.03 equiv.). The brown suspension was cooled with water (exothermic) to room temperature and stirred overnight. Then 200 ml of diethylether were added, the mixture was filtered, washed with ether and concentrated in vacuum to yield 5.7 g of a brown solid which was adsorbed on silica and was chromatographed in 2 portions over a 100 g prepacked silica column eluting with a 0-10% ethyl acetate in heptane gradient to yield 3.99 g (91%) of the title compound as a light brown solid, MS: m/e=198.1 (M+H+).
Reaction SMILES: FC1C=CC(C2CCC3C(=CC=C(O)C=3)O2)=CC=1.[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[O:35][CH:34]([C:39]2[CH:44]=[CH:43][C:42]([O:45][C:46]4[CH:51]=[CH:50][C:49]([N+:52]([O-:54])=[O:53])=[CH:48][N:47]=4)=[CH:41][CH:40]=2)[CH2:33][CH:32]3O)=[N:26][CH:27]=1)([O-:21])=[O:20]>>[N+:52]([C:49]1[CH:50]=[CH:51][C:46]([O:45][C:42]2[CH:43]=[CH:44][C:39]([CH:34]3[CH2:33][CH2:32][C:31]4[C:36](=[CH:37][CH:38]=[C:29]([O:28][C:25]5[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:27][N:26]=5)[CH:30]=4)[O:35]3)=[CH:40][CH:41]=2)=[N:47][CH:48]=1)([O-:54])=[O:53]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C3CC(O)c4cc(Oc5ccc([N+](=O)[O-])cn5)ccc4O3)cc2)nc1
Agent: Oc1ccc2c(c1)CCC(c1ccc(F)cc1)O2
Product: O=[N+]([O-])c1ccc(Oc2ccc(C3CCc4cc(Oc5ccc([N+](=O)[O-])cn5)ccc4O3)cc2)nc1

Procedure:
2-{2-[4-(5-Nitropyridin-2-yloxy)-phenyl]-chroman-6-yloxy}-5-nitropyridine was prepared as described for 2-(4-fluorophenyl)chroman-6-ol in Example 2(c) but starting from 6-(5-nitropyridin-2-yloxy)-2-[4-(5-nitropyridin-2-yloxy)phenyl]-chroman-4-ol. 1H NMR (400 MHz, d6-DMSO) δ: 9.05 (d, 2H, J 2.9 Hz), 8.65-8.58 (m, 2H), 7.58-7.55 (m, 2H), 7.30-7.26 (m, 3H), 7.20 (d, 1H, J 9.1 Hz), 7.03-6.91 (m, 3H) 5.20 (dd, 1H, J 2.0, 10.1 Hz), 3.06-2.97 (m, 1H), 2.81-2.75 (m, 1H), 2.26-2.21 (m, 1H), 2.11-2.02 (m, 1H).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([C:26](O)=[O:27])[N:16]([CH3:25])[C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1>>[C:1]([NH:5][C:26]([C:15]1[N:16]([CH3:25])[C:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:13]([C:10]2[CH:9]=[CH:8][C:7]([Cl:6])=[CH:12][CH:11]=2)[N:14]=1)=[O:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(C(=O)O)nc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Reactant: CC(C)(C)N
Product: Cn1c(C(=O)NC(C)(C)C)nc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1

Procedure:
Using essentially the same procedure as Example 20, Step B, but using t-butylamine (0.020 mL, 0.12 mmol), 4,5-di-(4-chlorophenyl)-1-methylimidazole-2-carboxylic acid (20 mg, 0.060 mmol) from Example 20, Step A was converted to the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH2:19][C@H:18](OS(C)(=O)=O)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([C@@H:20]2[CH2:19][CH2:18][CH2:17][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:21]2)[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](OS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2cc(Br)cn2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromopyrazole (4.68 g, 31.83 mmol) in DMF (300 mL) at 0° C. was added sodium hydride (60% on mineral oil, 1.27 g, 31.83 mmol). The solution was allowed to stir at 0° C. for one hour, at which point a solution of (S)-3-Methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (Compound 1007, which was prepared from (S)-tert-butyl 3-hydroxypiperidine-1-carboxylate, 9.78 g, 31.83 mmol) in DMF (50 mL) was added dropwise. The reaction mixture was allowed to stir at room temperature for 1 hour before refluxing overnight. Disappearance of both starting materials was tracked by TLC (1:1 Hexanes/Ethyl Acetate). The reaction was cooled to room temperature and quenched by addition of aqueous NaCl (300 mL), extracted with ethyl acetate (3×200 mL), washed with 1% aqueous LiCl (200 mL×3), dried and concentrated in vacuo. The resulting crude bromide (Compound 1008) was purified by silica gel chromatography (0-25% Ethyl Acetate in Hexanes) to give (R)-tert-butyl 3-(4-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylate as a colourless waxy solid (4.54 g, 43% yield); 1H NMR (300.0 MHz, CDCl3): δ 7.42 (s, 1H), 7.40 (s, 1H), 4.13-4.05 (m, 2H), 3.82 (d, J=13.2 Hz, 1H), 3.20 (dd, J=10.3, 14.0 Hz, 1H), 2.94-2.85 (m, 1H), 2.08-1.97 (m, 2H), 1.74-1.45 (m, 2H) and 1.39 (s, 9H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[N:22]3[C:17]([CH:18]=[CH:19][C:20]([O:23]CC4C=CC=CC=4)=[CH:21]3)=[C:16]([O:31][CH3:32])[C:15]=2[CH3:33])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([O-])=O.[NH4+].C(OC(C)C)(C)C>CN(C)C=O.[Pd]>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[N:22]3[C:17]([CH:18]=[CH:19][C:20]([OH:23])=[CH:21]3)=[C:16]([O:31][CH3:32])[C:15]=2[CH3:33])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C(=O)c2c(C)c(OC)c3ccc(OCc4ccccc4)cn23)ccc1N
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(=O)c2c(C)c(OC)c3ccc(O)cn23)ccc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.4 %

Procedure:
The mixture of 0.95 g (2.14 mmol) of methyl 2-amino-5-[(6-benzyloxy-1-methoxy-2-methylindolizin-3-yl)carbonyl]benzoate, 0.21 g (3.21 mmol) of ammonium formate and 0.19 g of palladium-on-charcoal at 10% in 12 ml of N,N-dimethylformamide is stirred for 4 hours at ambient temperature. It is then filtered and concentrated to dryness. The solid obtained is taken up with diisopropyl ether and then filtered, to give 0.64 g (85%) of a yellow powder.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:21])([F:20])[C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1.Cl[C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[CH2:31][CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>>[CH3:33][N:32]1[C:25]2[N:26]([C:27](=[O:29])[N:28]=[C:23]([O:19][CH2:18][C:15]3[CH:16]=[CH:17][C:12]([O:11][C:9]4[CH:8]=[CH:7][N:6]=[C:5]([C:4]([F:3])([F:20])[F:21])[CH:10]=4)=[CH:13][CH:14]=3)[CH:24]=2)[CH2:30][CH2:31]1
Reactant: OCc1ccc(Oc2ccnc(C(F)(F)F)c2)cc1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Product: CN1CCn2c1cc(OCc1ccc(Oc3ccnc(C(F)(F)F)c3)cc1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using sodium hydride (4.85 mg, 0.121 mmol), (4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol (35 mg, 0.130 mmol) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (24.13 mg, 0.130 mmol).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:11][C:12](=[O:26])[C@H:13]([CH2:22][CH2:23][S:24][CH3:25])[NH:14][C:15]([O:17]C(C)(C)C)=O)[CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:42]([O:49][C:50]([N:52]1[CH2:59][CH2:58][CH2:57][C@H:53]1C(O)=O)=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>Cl.O1CCOCC1.O1CCCC1.CN(C)C=O>[CH2:42]([O:49][C:50]([N:52]1[CH2:59][CH2:58][CH2:57][C@H:53]1[C:15]([NH:14][C@H:13]([C:12]([NH:11][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:7]=1[C:8]([OH:10])=[O:9])=[O:26])[CH2:22][CH2:23][S:24][CH3:25])=[O:17])=[O:51])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccc(C)c1C(=O)O
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CN1CCOCC1
Product: CSCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)Nc1cccc(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.2 %

Procedure:
6-methyl-2-[(N-tert-butoxycarbonyl-L-methionyl)amino]benzoic acid (346 mg) was dissolved in 4N-hydrochloric acid/dioxane (2.5 ml) stirred at room temperature for two hours. An N,N-dimethylformamide solution (2.5 ml) containing the residue obtained by concentrating and drying the above reaction solution and N-methylmorpholine (0.21 ml) was added to a tetrahydrofuran mixture, and the resultant solution was stirred at -15° C. for 0.5 hour. This tetrahydrofuran mixture was prepared by adding N-methylmorpholine (0.15 ml) and isobutyl chloroformate (0.17 ml) to a tetrahydrofuran solution (3.0 ml) of N-benzyloxycarbonyl-L-proline (328 mg) at -15° C. followed by stirring for 0.5 hour. The resultant reaction mixture was further stirred at room temperature for two hours and treated by the same procedures as in item (c) of Example 1 to obtain 2-(N-benzyloxycarbonyl-L-prolyl-L-methionyl)amino-6-methylbenzoic acid (173 mg).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Br[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:15]([CH2:14][CH2:13][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccccc1O
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1OCCOc1ccccc1
Temperature: 80 °C
Reaction time: 10 h

Procedure:
To a solution of methyl salicylate (100.0 g, 657 mmol) in N,N-dimethylformamide (100 ml) were added β-bromophenetole (138.8 g, 690 mmol) and potassium carbonate (136.3 g, 986 mmol), and the mixture was stirred at 80° C. for 10 hr. After cooling the reaction mixture, water (1000 ml) was added, and the precipitated insoluble material was filtered to give methyl 2-(2-phenoxyethoxy)benzoate. This was suspended in methanol (250 ml), aqueous solution (200 ml) of sodium hydroxide (32 g, 800 mmol) was added at room temperature, and the mixture was stirred at 70° C. for 2 hr. After cooling, the mixture was neutralized with 6N-aqueous hydrochloric acid solution, and the precipitated insoluble material was filtered to give a carboxylic acid compound 2-(2-phenoxyethoxy)benzoic acid (160.8 g, 623 mmol, yield 95%). The obtained carboxylic acid compound (160.8 g, 623 mmol) was suspended in toluene (320 ml), thionyl chloride (81.5 g, 685 mmol) was added, and the mixture was stirred at 40° C. for 4 hr. N,N-Dimethylhydrazine (82.2 g, 1.37 mol) was added under ice-cooling, and the mixture was further stirred at room temperature for 0.5 hr. The reaction mixture was added dropwise to water (1000 ml), and the precipitated insoluble material was filtered to give an acylhydrazine compound N′,N′-dimethyl-2-(2-phenoxyethoxy)benzohydrazide 131.6 g (yield 70%) as a white powder.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].BrC1C2[O:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[N:12][C:11]=2[CH:10]=[C:9]([O:24][CH3:25])[CH:8]=1.ICC>C1COCC1>[CH2:3]([C:2]1[C:1]2[O:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)=[N:12][C:11]=2[CH:10]=[C:9]([O:24][CH3:25])[CH:8]=1)[CH3:4]
Reactant: COc1ccc(-c2nc3cc(OC)cc(Br)c3o2)cc1
Reactant: [Li]CCCC
Solvent: CCI
Solvent: C1CCOC1
Product: CCc1cc(OC)cc2nc(-c3ccc(OC)cc3)oc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
n-Butyllithium (2.5 N, 0.43 mL, 1.08 mmol) was added dropwise into a cold (−78° C.) mixture of 7-bromo-5-methoxy-2-(4-methoxyphenyl)-1,3-benzoxazole (300 mg, 0.90 mmol) and THF (2 mL). The mixture was allowed to stir for 0.5 h. Iodoethane (0.14 mL, 1.8 mmol) was added dropwise into the mixture. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched with aqueous ammonium chloride, poured into water, and extracted with EtOAc. The organic extracts were washed with brine and dried over MgSO4. Evaporation and flash chromatography (20% EtOAc/petroleum ether) gave (231 mg, 91% yield) of the product as a light brown solid: m.p. 85° C.; MS m/e 284 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22][Cl:23].O>CN(C=O)C>[Cl:23][CH2:22][CH2:21][CH2:20][NH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5]
Reactant: CN(C)C(=O)c1ccccc1N
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccccc1NCCCCl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-amino-N,N-dimethylbenzamide (1.15 g, 6,97 mmol), prepared as in Example 22, potassium carbonate (1.44 g, 10.46 mmol) and 1-bromo-3-chloro-propane (0.7 mL, 7 mmol) in 10 mL of DMF was stirred at room temperature for 16 hours and then at 70° C. for an additional 4 hours. The mixture was poured into water and extracted with ethyl acetate (3×20 mL). The combined extract was washed with brine, dried (MgSO4) and concentrated to give 2-(3-chloropropyl)amino-N,N-dimethylbenzamide as a crude mixture.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)[CH3:2].S(Cl)([Cl:22])=O>>[CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([Cl:22])=[O:16])=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC[C@H]1CC[C@H](CCc2ccc(C(=O)O)cc2)CC1
Product: CC[C@H]1CC[C@H](CCc2ccc(C(=O)Cl)cc2)CC1
Yield: 100 %

Procedure:
4-[2-(trans-4-Ethylcyclohexyl)ethyl]-benzoic acid (10.5 gram, 40.38 m moles) prepared as in Example 2 was refluxed with thionyl chloride (60 ml) for 1 hour. The excess thionyl chloride was then distilled off to give 4-[2-(trans-4-ethylcyclohexyl)ethyl]benzoyl chloride (11.2 gram 100% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>ClCCl>[CH2:21]([O:20][C:18](=[O:19])[O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Cl:1])[CH3:22]
Reactant: CCOC(=O)Cl
Reactant: Oc1ccc(F)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Oc1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
To a solution of 2-chloro-4-fluoro-phenol (0.8 mL, 7.64 mmol) and triethylamine (1.3 mL, 9.16 mmol) in dichloromethane (10 mL) at 0° C. was added ethyl chloroformate (0.9 mL, 9.16 mmol) dropwise. The ice bath was removed and the solution was allowed to warm to room temperature and stirred for an additional 16 hours. Afterwards dichloromethane (20 mL) was added to the mixture, the organic solution was washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide the title product as an oil (1.65 g, 100%).
Reaction SMILES: ClCCl.[NH2:4][C:5]1[C:10]([C:11](OCC)=[O:12])=[N:9][C:8]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:7]([CH2:24][CH:25]([CH3:27])[CH3:26])[N+:6]=1[O-:28].[H-].C([Al+]CC(C)C)C(C)C.Cl>CCCCCC.O>[NH2:4][C:5]1[C:10]([CH2:11][OH:12])=[N:9][C:8]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:7]([CH2:24][CH:25]([CH3:26])[CH3:27])[N+:6]=1[O-:28]
Reactant: CCOC(=O)c1nc(OCc2ccccc2)c(CC(C)C)[n+]([O-])c1N
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)Cc1c(OCc2ccccc2)nc(CO)c(N)[n+]1[O-]
Temperature: -35 °C
Reaction time: 0.67 h
Yield: 65.4 %

Procedure:
14 Milliliters of dry dichloromethane was added to 670 mg of 2-amino-5-benzyloxy-3-ethoxycarbonyl-6-isobutylpyrazine 1-oxide. The mixture was cooled to -35° C. Thereto was dropwise added in about 5 minutes 4.7 ml of a solution of 1 mol of diisobutylaluminum hydride dissolved in n-hexane. After completion of the dropwise addition, a reaction was effected for 40 minutes at -30° C., then the temperature of the reaction mixture was returned to room temperature by adding 1 ml of water to the reaction mixture. Further, 30 ml of 2% hydrochloric acid was added thereto and the reaction mixture was extracted with dichloromethane, and the extract was dried over magnesium sulfate. The solvent was removed by evaporation. The residue was purified by a silica gel column chromatography (eluting solvent: 70% by volume of methanol-dichloromethane), followed by recrystallization from benzene to obtain 385 mg of 2-amino-5-benzyloxy-3-hydroxymethyl-6-isobutylpyrazine 1-oxide (Compound B-11) as pale yellow fine needle-like crystals having a melting point of 129.0°-131.3° C.
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].C1CCC(N=C=NC2CCCCC2)CC1.C([O:43][C:44](=[O:50])/[CH:45]=[CH:46]/[C:47](O)=[O:48])(C)(C)C>C(#N)C.CN(C1C=CN=CC=1)C>[CH3:23][O:22][C:10]1[CH:9]=[CH:8][C:7]2[CH2:20][C@H:19]3[N:2]([CH3:1])[CH2:3][CH2:4][C@:5]45[C:6]=2[C:11]=1[O:12][C@H:13]4[C:14]([O:15][C:47](=[O:48])/[CH:46]=[CH:45]/[C:44]([OH:50])=[O:43])=[CH:16][CH2:17][C@@:18]35[OH:21]
Reactant: CC(C)(C)OC(=O)/C=C/C(=O)O
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: COc1ccc2c3c1O[C@H]1C(OC(=O)/C=C/C(=O)O)=CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Reaction time: 16 h

Procedure:
Oxycodone free base, 1-1, (13 mg, 0.04 mmol) in 0.5 mL acetonitrile was stirred with TEA (0.034 mL 0.24 mmol) for 30 min at rt. DMAP (15 mg, 0.12 mmol) and DCC (25 mg, 0.12 mmol) were then added to the solution followed by a solution comprised of 4-2 (41 mg, 0.24 mmol) in 1 mL of acetonitrile. The resulting mixture was stirred for 16 h and concentrated under reduced pressure. The resulting residue was stirred with 4 mL of acetone for 30 min, the precipitated DCU removed by filtration, and the acetone removed under reduced pressure. The residue was treated with 0.8 mL of TFA (5 min at rt) to remove the tert-butyl group. The TFA was then removed under reduced pressure and the resulting residue purified by HPLC on a C-18 column eluted with 20% acetonitrile in 0.07% aqueous TFA to yield fraction containing essentially pure 4-3.
Reaction SMILES: [F:1][C:2]([F:17])=[CH:3][CH2:4][CH2:5][S:6][C:7]1[O:8][C:9]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:10]=2[N:11]=1.IC.[C:20](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:17][C:2]([F:1])=[CH:3][CH2:4][CH2:5][S:6][C:7]1[O:8][C:9]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:20])[C:10]=2[N:11]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc2oc(SCCC=C(F)F)nc12
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cccc2oc(SCCC=C(F)F)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-(4,4-difluorobut-3-enylthio)-4-hydroxy benzoxazole (Compound No. 82, Example 4B(iii), 504mg) in acetone (10 cm3) was added iodomethane (278 mg) and potassium carbonate (270 mg). The reaction mixture was stirred at the ambient temperature for 51/2 hours, then allowed to stand at the ambient temperature for 18 hours. Gc analysis indicated complete consumption of starting material. The reaction mixture was poured into ethyl acetate and and water, the layers separated and the aqueous phase extracted twice with ethyl acetate. The combined organic layers were washed with water, brine, dried (MgSO4) and evaporated under reduced pressure to a yellow oil. Purification by silica-gel chromatography using 5% ethyl acetate in hexane as the eluent gave 2-(4,4-difluorobut-3-enylthio)-4-methoxy-benzoxazole as a colourless oil (290 mg). 1H NMR (CDCl3) δ7.19(1H,t); 7.08(1H,d); 6.78(1H,d); 4.30(1H,ddt); 3.39(1H,t); 2.55(q).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[N:23]([CH2:28][CH3:29])[N:24]=[C:25]([CH3:27])[CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:30](OCC)=[O:31].[O-]CC.[Na+].Cl>C(O)C>[OH:31][CH:30]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[N:23]([CH2:28][CH3:29])[N:24]=[C:25]([CH3:27])[CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: CCOC=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Temperature: 78 °C
Yield: 73.2 %

Procedure:
2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (1.00 g, 2.57 mmol) and ethyl formate (0.619 mL, 7.72 mmol) were dissolved in anhydrous ethanol (5.20 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (4.80 mL, 12.80 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a pale orange precipitate. The suspension was filtered yielding an orange solid as the pure 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.786 g, 1.88 mmol, 73%).