Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:11]([CH2:22][CH:23]=[CH2:24])[S:12]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[NH2:21])(=[O:14])=[O:13])[CH:9]=[CH2:10].[Br:25][C:26]1[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[S:34](Cl)(=[O:36])=[O:35])=[CH:28][CH:27]=1>N1C=CC=CC=1>[CH2:22]([N:11]([CH2:8][CH:9]=[CH2:10])[S:12]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[NH:21][S:34](/[CH:33]=[CH:32]/[C:29]1[CH:30]=[CH:31][C:26]([Br:25])=[CH:27][CH:28]=1)(=[O:35])=[O:36])(=[O:14])=[O:13])[CH:23]=[CH2:24]
Reactant: C=CCN(CC=C)S(=O)(=O)c1cnccc1N
Reactant: O=S(=O)(Cl)/C=C/c1ccc(Br)cc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: C=CCN(CC=C)S(=O)(=O)c1cnccc1NS(=O)(=O)/C=C/c1ccc(Br)cc1
Reaction time: 0.08 h
Yield: 60 %

Procedure:
Triethylamine (0.440 mL, 3.16 mmol) added was to a solution of N,N-diallyl-4-aminopyridine-3-sulfonamide (0.40 g, 1.58 mmol) in pyridine (10 mL), the mixture was stirred for 5 min and (E)-2-(4-bromophenyl)ethenesulfonyl chloride (0.53 g, 1.89 mmol) was added. After stirring over night the pyridine was evaporated, diluted hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and the solvent was evaporated. Purification by column chromatography, using chloroform/methanol (97:3) as the eluent, gave the title compound in 60% yield.
Reaction SMILES: [C:1]([O:5]C(=O)N)(C)(C)C.C(OC(=O)[NH:15][C:16]1([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[C:35](=[O:36])[C:34]4[C:29](=[C:30]([NH2:40])[C:31]([N+:37]([O-])=O)=[CH:32][CH:33]=4)[O:28][C:27]=3[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:22][CH:21]=2)[CH2:19][CH2:18][CH2:17]1)(C)(C)C>CN1C(=O)CCC1.[Pd]>[NH2:15][C:16]1([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[C:35](=[O:36])[C:34]4[CH:33]=[CH:32][C:31]5[NH:37][C:1](=[O:5])[NH:40][C:30]=5[C:29]=4[O:28][C:27]=3[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:24][CH:25]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(N)c([N+](=O)[O-])ccc4c3=O)cc2)CCC1
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd]
Solvent: CN1CCCC1=O
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5[nH]c(=O)[nH]c54)c3=O)cc2)CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
1-[4-(7,8-Diamino-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester: To a solution of {1-[4-(8-amino-7-nitro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (420 mg, 0.8 mmol) in NMP (10 mL) and IMS (3 mL) was added 10% palladium on carbon (350 mg) under a nitrogen atmosphere. The nitrogen was evacuated and replaced with hydrogen (1 atm). The mixture was stirred at RT for 18 hours. The hydrogen atmosphere was evacuated and replaced with nitrogen and the mixture was filtered through a pad of Celite®, eluting with ethyl acetate. The solvent volume was reduced in vacuo and the resultant mixture was poured onto water and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and the solvents were removed in vacuo. The resulting residue was subjected to flash chromatography (SiO2, gradient 60-70% ethyl acetate in cyclohexane) and the resulting residue triturated with water, filtered and the solid collected to give the title compound as a yellow solid (280 mg, 70%). LCMS (Method H): RT=3.66 min, [M+H]+=498.
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.O[C:7]12[CH2:16]C3CC([CH2:15][CH:9]([C:10]3=[O:17])[CH2:8]1)[CH2:14]2.CI.[H-].[Na+]>O>[CH3:3][O:4][C:5]12[CH2:1][CH:2]3[CH2:14][CH:7]([CH2:8][CH:9]([C:10]3=[O:17])[CH2:15]1)[CH2:16]2
Reactant: C1CCOC1
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COC12CC3CC(C1)C(=O)C(C3)C2
Reaction time: 25 h

Procedure:
THF 5 ml solution of 5-hydroxy-2-adamantanone 100 mg and methyl iodide 0.113 ml was cooled at 0° C., and sodium hydride (60%, oil suspension) 48.2 mg was added therein, and the temperature of the reaction mixture was gradually changed to room temperature, then stirred for 25 hours. The reaction mixture was cooled again, and water was added thereto, then THF was removed by concentration in vacuo. The thus obtained residue was extracted with chloroform and dried by adding anhydrous sodium sulfate. After separation of the drying agent, the filtrate was concentrated in vacuo. Residue was purified by means of silica gel column chromatography (Wako gel, C200, n-hexane: ethyl acetate=10:1) to obtain the product.
Reaction SMILES: [CH3:1][O:2][N:3]([CH2:8][CH2:9][CH2:10][P:11](=[O:18])([O:15]CC)[O:12]CC)C(OC)=O.C(O)(=O)C.Cl.N1C=CC=CC=1>C(O)C>[CH3:1][O:2][NH:3][CH2:8][CH2:9][CH2:10][P:11](=[O:12])([OH:18])[OH:15]
Reactant: CCOP(=O)(CCCN(OC)C(=O)OC)OCC
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Solvent: c1ccncc1
Product: CONCCCP(=O)(O)O
Yield: 63.6 %

Procedure:
A mixture of diethyl 3-(N-methoxy-N-methoxycarbonylamino)propylphosphonate (4.0 g), acetic acid (20 ml) and conc. hydrochloric acid (20 ml) was refluxed for 15 hours. The resultant mixture was concentrated under reduced pressure to give a residue, which was dissolved in ethanol (15 ml). The solution was neutralized with pyridine to give crystals, which were separated by filtration, washed with a small volume of ethanol and dried to give crystalline 3-(N-methoxyamino)propylphosphonic acid (1.52 g).
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=3)[N:9]([C:17](=[O:26])[C:18]3[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=3)[C@H:8]([CH2:27][CH3:28])[C:7]2=[O:29])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([C@H]1N(C(=O)C2C=CC(O)=CC=2)C2C(=CC(F)=CC=2)N(C)C1=O)C>>[CH:1]1([N:6]2[C:15]3[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=3)[N:9]([C:17](=[O:26])[C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)[C@H:8]([CH2:27][CH3:28])[C:7]2=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC[C@@H]1C(=O)N(C2CCCC2)c2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Agent: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1ccc(O)cc1
Product: CC[C@@H]1C(=O)N(C2CCCC2)c2ccc(F)cc2N1C(=O)c1ccc(O)cc1
Yield: 40 %

Procedure:
(3R)-1-Cyclopentyl-3-ethyl-6-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one was treated according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-4(4-hydroxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 1) to yield (3R)-1-cyclopentyl-3-ethyl-6-fluoro-4-(4-hydroxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (40%). [α]D25=−309° (c=0.0095 G/ML, CHCl3); MS (ESI) m/z 383 ([M+H]+); MS (ESI) m/z 381 ([M−H]−); HRMS: calcd for C22H23FN2O3, 382.1693; found (ESI_FT), 383.17555.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[C:7](OC(=O)C)(=[O:9])[CH3:8]>N1C=CC=CC=1>[C:7]([N:4]1[CH:5]=[CH:6][C:2]([OH:1])=[N:3]1)(=[O:9])[CH3:8]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1cc[nH]n1
Solvent: c1ccncc1
Product: CC(=O)n1ccc(O)n1
Temperature: 95 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
A solution of 3-hydroxy-1H-pyrazole (8.2 g, 97.5 mmol) in pyridine (40 mL) was heated to 95° C. A mixture consisting of acetic anhydride (9.4 mL, 102 mmol) and pyridine (20 mL) was added over 15 min; then stirring at 95° C. was continued for 60 min. All volatiles were then removed under reduced pressure and to the residue was added 200 mL of diethyl ether. The slurry was stirred overnight at room temperature, then the solid was filtered off and rinsed with diethyl ether. The product was obtained as an off-white solid (10.3 g, 81.7 mmol, 84% yield).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Br:5][C:6]1[CH:7]=[C:8]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:9]([O:18][CH3:19])=[C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:11]=1.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[Br:5][C:6]1[CH:7]=[C:8]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:9]([O:18][CH3:19])=[C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:1](=[O:3])[CH3:2])[CH2:16][CH2:17]2)[CH:11]=1
Reactant: CC(=O)Cl
Reactant: COc1c(N2CCNCC2)cc(Br)cc1C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1c(N2CCN(C(C)=O)CC2)cc(Br)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
Acetyl chloride (0.10 ml) was mixed with a solution of 1-[5-bromo-3-(tert-butyl)-2-methoxyphenyl]piperazine (370 mg) and triethylamine (0.32 mL) in methylene chloride (8 ml), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and, after filtering off the insoluble portion, was concentrated. The residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (338 mg) as colorless crystals (81%).
Reaction SMILES: [Br-].[CH3:2][O:3][CH2:4][CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH:32]([C:34]1[N:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]2=[N:36][C:35]=1[C:43]([O:45][CH2:46][CH3:47])=[O:44])=O.O>C1COCC1>[CH3:2][O:3][CH2:4][CH2:5]/[CH:6]=[CH:32]/[C:34]1[N:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]2=[N:36][C:35]=1[C:43]([O:45][CH2:46][CH3:47])=[O:44]
Reactant: CCOC(=O)c1nc2ccccn2c1C=O
Reactant: COCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1nc2ccccn2c1/C=C/CCOC
Reaction time: 0.5 h
Yield: 12 %

Procedure:
To a suspension of (3-methoxypropyl) (triphenyl)phosphonium bromide (3.56 g) in THF (50 ml) was added potassium tert-butoxide (0.38 g) at −78° C., and the mixture was stirred at the same temperature for 30 min. Ethyl 3-formylimidazo[1,2-a]pyridine-2-carboxylate (1.7 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 12 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (256 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12](=O)[CH2:13][C:14](=O)[C:15]([F:18])([F:17])[F:16])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:21][C:22]1[C:26]([C:27]2[CH:32]=[C:31]([CH3:33])[N:30]=[C:29]([CH3:34])[CH:28]=2)=[CH:25][NH:24][N:23]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[N:23]3[N:24]=[CH:25][C:26]([C:27]4[CH:32]=[C:31]([CH3:33])[N:30]=[C:29]([CH3:34])[CH:28]=4)=[C:22]3[N:21]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)c(F)c1
Reactant: Cc1cc(-c2c[nH]nc2N)cc(C)n1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)c(F)c4)nc23)cc(C)n1
Yield: 20.2 %

Procedure:
Reaction of 1-(3-fluoro-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (151 mg, 0.5 mmol), prepared from commercially available 3-fluoro-4-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2,6-dimethyl-pyridine, CAS No. 130138-46-4, see part synthesis of amino-pyrazole derivatives] (94 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (46 mg, 20%). MS (ISP) 455.0 [(M+H)+]; mp 245° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][O:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([C:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:25]=[CH:24]4)[N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][O:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([CH:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:25]=[CH:24]4)[N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C=C(c1ccccc1)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC(c1ccccc1)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Yield: 95.7 %

Procedure:
10% Palladium on activated carbon (0.06 g) was added to 7-{2-[1-(2-ethoxycarbonyl-1-phenyl-vinyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (0.50 g, 0.88 mmol) in methanol (10 mL) under argon. The solution was exposed to a hydrogen atmosphere (50 psi) using a Parr shaker for 24 h. The reaction was filtered through celite and washed with methanol. The filtrate was concentrated in vacuo to yield the title compound (0.48 g, 98%). 1H NMR (CDCl3) δ 7.15–7.36 (m, 9H), 6.96 (d, 1H, J=7.6 Hz), 6.83 (dd, 1H, J=2.3, 6.6 Hz), 6.46 (d, 1H, J=3.0 Hz), 6.06 (d, 1H, J=7.6 Hz), 4.39 (m, 2H), 4.06 (q, 2H, J=7.1 Hz), 3.78 (m, 2H), 3.31–3.20 (m, 4H), 2.75 (m, 2H), 1.94 (m, 2H), 1.54 (s, 9H), 1.11 (t, 3H, J=7.1 Hz).
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][C:4]1[CH:8]=[C:7]([NH:9][C:10]2[N:20]=[CH:19][CH:18]=[CH:17][C:11]=2[C:12]([O:14]CC)=[O:13])[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[N:5]=1.O.[OH-].[Li+].Cl>C(O)C.C1COCC1.O>[CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][C:4]1[CH:8]=[C:7]([NH:9][C:10]2[N:20]=[CH:19][CH:18]=[CH:17][C:11]=2[C:12]([OH:14])=[O:13])[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[N:5]=1
Reactant: CCOC(=O)c1cccnc1Nc1cc(CC(C)(C)C)nn1-c1ccccc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccccc1-n1nc(CC(C)(C)C)cc1Nc1ncccc1C(=O)O
Temperature: 40 °C
Yield: 96.8 %

Procedure:
To a solution of ethyl 2-{[3-(2,2-dimethylpropyl)-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}nicotinate (266 mg, 0.68 mmol) (step 1) in a mixture of ethanol (1 mL) and THF (1 mL) was added lithium hydroxide monohydrate (284 mg, 6.8 mmol) in water (2 mL), and the mixture was then heated to 40° C. for 1 h. The reaction mixture was cooled to rt, the pH of the solution was adjusted to 5 by addition of 0.5 N hydrochloric acid solution, and was concentrated to dryness. The crude product was redissolved in methanol and subjected to HPLC purification using a gradient elution from 30% to 90% acetonitrile in water to afford 240 mg (97%) of the desired product. 1H NMR (300 MHz, CD2Cl2) δ 10.39 (s, 1H), 8.43 (dd, 1H), 8.14 (dd, 1H), 7.25-7.42 (m, 4H), 6.81-6.86 (m, 2H), 2.57 (s, 2H), 2.05 (s, 3H), 1.00 (s, 9H); ES-MS m/z 365.3 (MH+); HPLC RT (min) 3.67.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:20])[C@H:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[NH2:14].C(N(CC)CC)C>C(Cl)Cl.O>[CH3:10][O:11][C:12](=[O:20])[CH:13]([NH:14][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C[C@H](N)C(=O)OC
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CC(NC(=O)c1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
A mixture of benzoyl chloride (3.20 mL, 27.7 mmol), L-aspartic acid dimethyl ester (5.0 g, 25.2 mmol) and triethyl amine (5.3 mL, 38 mmol) in CH2Cl2 (50 mL) was stirred at ambient temperature for 2 h and diluted with water. The organic layer was dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (hexanes/EtOAc 1/1) to afford a white solid (5.3 g, 79%). MS (ESI) m/z 266 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[CH2:12]([O:14][C:15](=[O:22])[CH:16]([CH2:20][OH:21])[CH2:17][CH2:18]Br)[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:12]([O:14][C:15](=[O:22])[CH:16]([CH2:20][OH:21])[CH2:17][CH2:18][N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH2:1])=[N:3][C:4]=2[Cl:11])[CH3:13]
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: CCOC(=O)C(CO)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CO)CCn1cnc2c(Cl)nc(N)nc21
Temperature: 25 °C
Reaction time: 92 h
Yield: 15.9 %

Procedure:
2-Amino-6-chloropurine (3.37 g, 19.9 mmol), 4-bromo-2-hydroxymethylbutyric acid ethyl ester (4.49 g, 19.9 mmol) and anhydrous potassium carbonate (2.75 g, 19.9 mmol) were mixed with 50 ml of dimethylformamide and the mixture was stirred at room temperature during 92 hours. The mixture was then filtered and the filtrate evaporated. The residue was extracted with 3×50 ml chloroform and the combined extracts were evaporated. Flash chromatography (silica gel, chloroform-methanol 10:1) and two recrystallizations from water afforded 0.995 g of the 4-(2-amino-6-chloropurin-9-yl)-2-hydroxymethylbutyric acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([CH2:21][CH3:22])[CH2:8][CH:9]([OH:20])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:23])[N:7]([CH2:8][CH:9]([OH:20])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1)[CH2:21][CH3:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(CC(O)Cc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCN(CC(O)Cc1ccc(N)cc1)C(=O)OC(C)(C)C

Procedure:
The [3-(4-amino-phenyl)-2-hydroxy-propyl]-ethyl-carbamic acid tert-butyl ester was prepared by the following procedure: To a stirred solution of 1-allyl-4-nitrobenzene (2.85 g, 17.47 mmol; prepared by the procedure of EP 1013636 A1, 1999) in dichloromethane (100 mL) at room temperature was added 3-chlorperoxybenzoic acid (6.03 g, 57–86%, Aldrich) and the mixture stirred overnight. The solution was washed with excess aqueous sodium thiosulfate, then with aqueous sodium bicarbonate solution and the organic solution was dried (magnesium sulfate), evaporated, and chromatographed on silica gel giving 1.94 g (62%) of 2–4-nitorbenzyloxirane as a yellow oil. This oil (0.92 g 5.13 mmol) in methanol was stirred overnight at room temperature with aqueous ethylamine (2 mL, 70% in water, Aldrich). The methanol was removed by evaporation and the residue was dissolved in 1N aqueous hydrochloric acid. The aqueous solution was washed with ether and the aqueous layer was made basic with 4N aqueous sodium hydroxide. Tetrahydrofuran was added to dissolve the solids and di-tert-butyl dicarbonate (1.35 g, 6.16 mmol, Aldrich) was added and the mixture stirred at room temperature for 2 hours. The reaction was extracted with dichloromethane, dried (magnesium sulfate), evaporated and chromatographed on silica gel to give ethyl-[2-hydroxy-3-(4-nitro-phenyl)-propyl]carbamic acid tert-butyl ester as a yellow oil, 1.23 g, 74%. MS(ES) (M+H)+=325. This nitro compound (1.06 g, 3.26 mmol) in ethanol (40 mL) and 10% Palladium on Carbon was hydrogenated at 35 psi for 1.5 hours. The mixture was filtered and evaporated to give [3-(4-amino-phenyl)-2-hydroxy-propyl]-ethyl-carbamic acid tert-butyl ester as a yellow gum, 0.94 g (98%) MS(ES) (M+H)+=295.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][O:7][CH2:8][C:9]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11][CH2:10]1.[OH2:31].OO.[OH-].[Na+]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]([F:29])([F:30])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][O:7][CH2:8][C:9]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:15][CH2:14][CH2:13][CH:12]([OH:31])[CH2:11][CH2:10]1
Reactant: FC(F)(F)c1cc(COCC2(c3ccccc3)CCC=CCC2)cc(C(F)(F)F)c1
Reactant: O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC1CCCC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (Z)-5-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-5-phenylcyclohept-1-ene (56 mg) from step E in THF (0.55 mL) at 0° C. was added borane-tetrahydrofuran complex (1.5 M solution, 0.17 mL) drop wise, and the resulting solution was warmed to room temperature and stirred at room temperature for 12 h. The reaction mixture was cooled to 0° C., and water (10.50 mL) was added slowly followed by 30% hydrogen peroxide (0.19 mL) and 1 N sodium hydroxide (0.30 mL). The resulting solution was stirred at room temperature for 5 min, and ethyl acetate (2.0 mL) was added. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated in vacuo. The residue was purified by preparative TLC eluting with 40% ethyl acetate/60% hexanes to give the title compound as an oily material (27 mg). 1H NMR (400 MHz, CDCl3) δ 1.3-2.4 (m), 3.40 (s), 3.44 (s), 4.43 (s), 7.32 (m), 7.56 (s), and 7.73 (s). HRMS m/z calcd for C23H23F6O2 (M−H)− 445.1602, found 445.1607.
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[C:4]([S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)(=[O:9])=[O:8])[C:5]#[N:6].[Cl:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([Cl:33])[C:24]=1[NH:34][NH2:35].O>C(O)C>[NH2:6][C:5]1[N:34]([C:24]2[C:23]([Cl:22])=[CH:28][C:27]([C:29]([F:30])([F:32])[F:31])=[CH:26][C:25]=2[Cl:33])[N:35]=[C:3]([S:2][CH3:1])[C:4]=1[S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[CH:11]=1)(=[O:9])=[O:8]
Reactant: CSC(SC)=C(C#N)S(=O)(=O)c1cccc(C(F)(F)F)c1
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: O
Solvent: CCO
Product: CSc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
A suspension of 0.50 g (1.42 mmol) of 3,3-bis-methylthio-2-(3-trifluoromethylphenylsulfonyl)acrylonitrile and 0.35 g (1.42 mmol) of 2,6-dichloro-4-trifluoromethylphenylhydrazine in 10 mL of ethanol was heated at reflux for 2.5 hours, solution occurring as the reaction mixture was warmed. The mixture was stirred overnight at room temperature and was then poured into cold water. The product was extracted into ethyl acetate and the extracts were dried with magnesium sulfate and evaporated. The residues were crystallized from ether, and the product was filtered off and air dried to give 314 mg (40%) of the desired product, m.p. 201°-203° C. Anal. Calcd. for C18H11O2N3S2Cl2F6 : C, 39.28; H, 2.02; N, 7.64. Found: C, 39.35; H, 2.19; N, 7.48.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]([NH:18][CH2:19][CH2:20][OH:21])=[O:17])=O)C1C=CC=CC=1>CO.[C].[Pd]>[OH:21][CH2:20][CH2:19][NH:18][C:16]([C@@H:12]1[CH2:13][CH2:14][CH2:15][NH:11]1)=[O:17]
Reactant: O=C(NCCO)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(NCCO)[C@@H]1CCCN1
Yield: 99.9 %

Procedure:
In 70 ml of methanol was dissolved 5.92 g of compound (79) and the compound was catalytically reduced by an ordinary method using 10% palladium-carbon as a catalyst. After the reaction, the catalyst and the solvent were removed to provide 3.2 g of syrupy (S)-N-2-hydroxyethyl-2-pyrrolidinecarboxamide (53). The product was solidified when it was refrigerated.
Reaction SMILES: [H-].[Li+].[F:3][C:4]1[CH:13]=[C:12]2[C:7]([N:8]=[CH:9][C:10](=[O:14])[NH:11]2)=[CH:6][CH:5]=1.Br[CH2:16][CH2:17][CH:18]1[O:22][CH2:21][CH2:20][O:19]1.O>CN(C)C=O>[O:19]1[CH2:20][CH2:21][O:22][CH:18]1[CH2:17][CH2:16][N:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([F:3])[CH:13]=2)[N:8]=[CH:9][C:10]1=[O:14]
Reactant: BrCCC1OCCO1
Reactant: O=c1cnc2ccc(F)cc2[nH]1
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cnc2ccc(F)cc2n1CCC1OCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.1 %

Procedure:
Lithium hydride (88 mg, 011 mmol) was added to a solution of 7-fluoroquinoxalin-2(1H)one (1.3 g, 7.8 mmol) in N,N-dimethylformamide (40 ml) under cooling on ice and the mixture was stirred at room temperature for 30 minutes. The mixture was cooled on ice and 2-(2-bromoethyl)-1,3-dioxolane (1.33 ml, 11 mmol) was added thereto. The obtained mixture was stirred at room temperature for 24 hours, water was then gradually added thereto and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (dichloromethane/methanol) to yield 0.6 g (29%) of the title compound.