Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH2:30]Br)=[O:26])=[CH:23][CH:22]=1>CN(C=O)C.O>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH2:30][N:10]2[C:11]3[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=3[N:8]=[CH:9]2)=[O:26])=[CH:35][CH:36]=1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: O=C(c1ccc(Cl)cc1)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ncn2Cc2cccc(C(=O)c3ccc(Cl)cc3)c2)n(C)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 40.2 %

Procedure:
To a solution of theophylline (1.80 g) in DMF (50 ml) were added potassium carbonate (1.66 g) and 3-(4-chlorobenzoyl)benzyl bromide (3.10 g) and the mixture was stirred at room temperature for 24 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was recrystallized (acetone-hexane) to provide the title compound as white powder (1.64 g, 40%). 1H-NMR (CDCl3) δ: 3.40(3H,s), 3.60(3H,s), 5.57(2H,s), 7.42-7.79(9H,m).
Reaction SMILES: Cl.[S:2]1[CH2:6][C@@H:5]([C:7]([N:9]2[CH2:13][CH2:12][S:11][CH2:10]2)=[O:8])[NH:4][CH2:3]1.Cl.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[C:15]([N:4]1[C@H:5]([C:7]([N:9]2[CH2:13][CH2:12][S:11][CH2:10]2)=[O:8])[CH2:6][S:2][CH2:3]1)(=[O:22])[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1
Reactant: O=C([C@@H]1CSCN1)N1CCSC1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C([C@@H]1CSCN1C(=O)c1ccncc1)N1CCSC1
Yield: 74.6 %

Procedure:
To a solution of 0.48 g of 3-[(R)-(-)-thiazolidine-4-carbonyl]thiazolidine hydrochloride and 0.36 g of isonicotinoylchloride hydrochloride in 10 ml of dichloromethane was added 1.6 ml of triethylamine with stirring under cooling. The reaction mixture was stirred for 24 hours at room temperature, and then washed with water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/acetonitrile=1/1) to obtain 0.46 g of 3-[(R)-(-)-3-isonicotinoylthiazolidine-4-carbonyl]thiazolidine (yield: 42%).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[NH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15](F)[C:12]=1[C:13]#[N:14]>C1COCC1>[NH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:12]=1[C:13]#[N:14]
Reactant: N#Cc1c(N)cccc1F
Reactant: OC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1c(N)cccc1OC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
To a solution of cyclohexanol (19.1 g, 0.191 mol) in anhydrous THF (500 mL) was added NaH (7.6 g, 40% in mineral oil, 0.191 mol) in small portions at 0° C. under nitrogen. The mixture was stirred at room temperature for 1 h and a solution of 2-amino-6-fluorobenzonitrile (20.0 g, 0.15 mol) in anhydrous THF (150 mL) was added drop-wise at room temperature. The reaction mixture was heated to reflux overnight then cooled to room temperature and most of the THF removed under reduced pressure. Ice water (100 mL) was added to the concentrated reaction mixture followed by EtOAc (500 mL). The organic layer was separated and successively washed with water and brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel eluting with 25-30% EtOAc in hexanes to give 2-amino-6-(cyclohexyloxy)benzonitrile as a light yellow oil (17.9 g, 56%). 1H NMR (400 MHz, CDCl3) δ 1.32-1.43 (m, 3H), 1.51-1.55 (m, 1H), 1.62-1.69 (m, 2H), 1.79-1.95 (m, 4H), 4.31-4.36 (m, 3H), 6.23-6.27 (m, 2H), 7.18 (d, J=8.0 Hz, 1H). MS 329 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].[C:10](Cl)(Cl)=[O:11]>C(OC(=O)C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([N:7]=[C:10]=[O:11])[CH:8]=1
Reactant: O=C(Cl)Cl
Reactant: Cc1ccc(Br)cc1N
Solvent: CCOC(C)=O
Product: Cc1ccc(Br)cc1N=C=O
Yield: 90.4 %

Procedure:
A solution of 16.5 grams of 5-bromo-2-methyl aniline and 100 ml. of ethylacetate was added with stirring to a solution of 20 grams of phosgene and 300 ml. of ethylacetate kept at 5° C. After the addition was completed, phosgene was bubbled through the mixture while refluxing for one-half hour. The reaction mixture was purged with nitrogen, then the solvent was removed in vacuo to obtain 17 grams of 5-bromo-2-methylphenylisocyanate. This material was dissolved in 150 ml. of chloroform and added cautiously to a solution of 18.2 grams of 3-chloropropylamine hydrochloride, 150 ml. of chloroform, and 20 ml. of triethylamine. The mixture was refluxed for one-half hour, then cooled and shaken with water. The precipitated solid was separated by filtration. Recrystallization from ethylacetate afforded N-[3-(chloropropylamino)propyl]-N'-(5-bromo-2-methylphenyl)urea, m.p. 145°-148° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=2)[C:23]([OH:25])=[O:24])[CH:13]=1.O[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C1COCC1.C(Cl)Cl>[N:32]1([CH2:31][CH2:30][O:24][C:23](=[O:25])[C:22]2[CH:26]=[CH:27][CH:28]=[C:20]([C:14]3[CH:13]=[C:12]([NH:11][CH2:10][CH2:9][C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])[N:17]=[C:16]([O:18][CH3:19])[N:15]=3)[CH:21]=2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: OCCN1CCOCC1
Reactant: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(=O)O)c2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(=O)OCCN3CCOCC3)c2)n1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 43.9 %

Procedure:
4-Dimethylaminopyridine (4.4 mg, 0.036 mmol) is added to a stirred solution of 3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-benzoic acid (100 mg, 0.24 mmol), N-(2-hydroxyethyl) morpholine (29.07 μL, 0.24 mmol) and 1,3-dicyclohexylcarbodiimide (0.31 mL, 1 M solution in DCM) in dry THF/DCM (6 mL, 1:1) and the reaction mixture is stirred for 5.5 hours at room temperature under nitrogen atmosphere. The mixture is filtered over a pad of Celite and the filtrate concentrated under reduced pressure. The residue is dissolved EtOAc (30 mL), washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue is purified by chromatography (SiO2 packed column) eluting with ethyl acetate/heptane to afford 3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-benzoic acid 2-morpholin-4-yl-ethyl ester (56 mg, Example 75). LCMS: RT=2.07 minutes, MS: 534 (M+H); 1H NMR, (300 MHz, CDCl3): □8.62 (1H, s), 8.3 (1H, d, J=3.5 Hz), 8.1 (1H, d, J=3.5 Hz), 7.55 (1H, t, J=3.5 Hz), 7.42 (1H, s), 7.2 (2H, s), 6.48 (1H, s), 5.04 (1H, b), 4.5 (2H, t, J=2 Hz), 4.05 (3H, s), 3.72 (6H, t, J=2 Hz), 3.1 (2H, t, J=2 Hz), 2.8 (2H, t, 2 Hz), 2.6 (4H, t, 2 Hz).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([O:26][C:27]([NH:29][CH2:30][C@H:31]([O:107][Si](C(C)(C)C)(C)C)[CH2:32][C@H:33]([NH:99][C:100]([O:102][C:103]([CH3:106])([CH3:105])[CH3:104])=[O:101])[C:34]([NH:36][C@@H:37]([CH2:48][C:49]1[CH:50]=[C:51]([C:63]2[CH:68]=[CH:67][C:66]([O:69][CH2:70][C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=3)=[C:65]([CH2:77][C@H:78]([NH:88][C:89]([O:91][CH2:92][C:93]3[CH:98]=[CH:97][CH:96]=[CH:95][CH:94]=3)=[O:90])[C:79]([O:81]CC[Si](C)(C)C)=[O:80])[CH:64]=2)[CH:52]=[CH:53][C:54]=1[O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])=[O:35])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OCC)(=O)C.Cl>C1COCC1.CN(C=O)C>[CH2:92]([O:91][C:89]([NH:88][C@@H:78]([CH2:77][C:65]1[CH:64]=[C:63]([C:51]2[CH:52]=[CH:53][C:54]([O:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:49]([CH2:48][C@@H:37]([C:38]([O:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[O:39])[NH:36][C:34](=[O:35])[C@@H:33]([NH:99][C:100]([O:102][C:103]([CH3:104])([CH3:106])[CH3:105])=[O:101])[CH2:32][C@@H:31]([OH:107])[CH2:30][NH:29][C:27]([O:26][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:28])[CH:50]=2)[CH:68]=[CH:67][C:66]=1[O:69][CH2:70][C:71]1[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=1)[C:79]([OH:81])=[O:80])=[O:90])[C:93]1[CH:98]=[CH:97][CH:96]=[CH:95][CH:94]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](CNC(=O)OCc1ccccc1)O[Si](C)(C)C(C)(C)C)C(=O)N[C@@H](Cc1cc(-c2ccc(OCc3ccccc3)c(C[C@H](NC(=O)OCc3ccccc3)C(=O)OCC[Si](C)(C)C)c2)ccc1OCc1ccccc1)C(=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](C[C@@H](O)CNC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1cc(-c2ccc(OCc3ccccc3)c(C[C@H](NC(=O)OCc3ccccc3)C(=O)O)c2)ccc1OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
1.8 ml of 1N tetrabutylammonium fluoride in THF are added dropwise to a solution of 800 mg (0.6 mmol) of benzyl 2(S)-[5-benzyloxycarbonylamino-2(S)-tert-butoxycarbonylamino-4(R)-(tert-butyldimethylsilyloxy)pentanoylamino]-3-{4,4′-bisbenzyloxy-3′-[2(S)-benzyloxycarbonylamino-2-(2-trimethylsilylethoxycarbonyl)ethyl]biphenyl-3-yl}propionate (Example 16A) in 26 ml of absolute DMF at RT. After 25 min at RT, the mixture is cooled to 0° C. and a large amount of ice-water is added. Ethyl acetate and a little 1N hydrochloric acid solution are immediately added; the organic phase is dried with magnesium sulfate, concentrated and dried under high vacuum for 1 h. The crude product is reacted without further purification.
Reaction SMILES: CON(C)[C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[CH:6]=1.[CH3:23][Mg]Br.Cl>C1COCC1.CC(OC)(C)C>[F:20][C:17]([F:18])([F:19])[CH2:16][O:15][C:7]1[CH:6]=[C:5]([C:4](=[O:21])[CH3:23])[CH:10]=[CH:9][C:8]=1[C:11]([F:12])([F:13])[F:14]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc(C(F)(F)F)c(OCC(F)(F)F)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CC(=O)c1ccc(C(F)(F)F)c(OCC(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of N-methoxy-N-methyl-3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-benzamide from step 7 (10.467 g, 32 mmol) in THF (100 mL) at −5° C. was added methylmagnesium bromide (3 M in Et2O, 21.1 mL, 64 mmol). The mixture was stirred at 0° C. for 15 min, then warmed up to 23° C., stirring was continued for further 1.5 h at 23° C. Cooled to 0° C., 1 N HCl (150 mL) was added dropwise, stirring was continued at 23° C. for 15 min, the mixture was diluted with TBME, the phases were separated, the organic layer was washed with water and brine, dried over MgSO4. Removal of the solvent in vacuum left a yellow solid (9.021 g, 100%), which was used without further purification. MS (EI) 286.1 [M].
Reaction SMILES: COC1C=CC([CH2:7][N:8](C)[C:9]2[N:10]=[CH:11][CH:12]3[CH:17]([CH:18]=2)[N:16]([CH2:19][CH3:20])[C:15](=[O:21])[C:14]([C:22]2[C:23]([F:41])=[CH:24][C:25]([F:40])=[C:26]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([F:39])[CH:33]=4)=[O:30])[CH:27]=2)=[CH:13]3)=CC=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:39][C:34]1[CH:33]=[C:32]([NH:31][C:29]([NH:28][C:26]2[CH:27]=[C:22]([C:14]3[C:15](=[O:21])[N:16]([CH2:19][CH3:20])[CH:17]4[CH:12]([CH:13]=3)[CH:11]=[N:10][C:9]([NH:8][CH3:7])=[CH:18]4)[C:23]([F:41])=[CH:24][C:25]=2[F:40])=[O:30])[CH:37]=[C:36]([F:38])[CH:35]=1
Reactant: CCN1C(=O)C(c2cc(NC(=O)Nc3cc(F)cc(F)c3)c(F)cc2F)=CC2C=NC(N(C)Cc3ccc(OC)cc3)=CC21
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCN1C(=O)C(c2cc(NC(=O)Nc3cc(F)cc(F)c3)c(F)cc2F)=CC2C=NC(NC)=CC21
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
A solution of 1-(5-(7-((4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2,4a,8a-tetrahydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-(3,5-difluorophenyl)urea (0.112 g, 0.185 mmol) and anisole (0.202 mL, 1.849 mmol) in DCM (2 mL) was treated with TFA (2 mL, 26.0 mmol) and stirred at RT overnight. The mixture was concentrated to dryness, treated with EtOAc and satd. NaHCO3, stirred for 1 h and the resulting solid collected via filtration and dried to afford 1-(3,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2,4a,8a-tetrahydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea (57 mg, 64% yield). The material was dissolved in MeCN (2 mL), treated with 0.1N HCl (1.17 mL, 0.117 mmol), diluted with water (3 mL), frozen, lyophilized, triturated with Et2O and the resulting solid was collected via filtration and dried to yield 1-(3,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2,4a,8a-tetrahydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea hydrochloride (57 mg, 96% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.95 (s, 1H), 8.80 (s, 1H), 8.51 (s, 1H), 8.07 (t, 1H), 7.92 (s, 1H), 7.70 (br s, 1H), 7.40 (t, 1H), 7.15 (d, 2H), 6.82-6.77 (m, 1H), 6.43 (s, 1H), 4.15 (q, 2H), 2.91 (s, 3H), 1.21 (t, 3H); MS (ESI) m/z: 486.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=3)[C:5]([CH3:17])([CH3:16])[C:4]=2[CH:3]=1.[CH3:18][C:19]1([CH3:53])[C:43]2[C:23]([CH:24]=[C:25]3[CH:42]=[C:41]4[C:28]([C:29]5[C:34]([C:35]6[C:40]4=[CH:39][CH:38]=[CH:37][CH:36]=6)=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:27][C:26]3=2)=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20]1.C([O-])([O-])=O.[Na+].[Na+].CCO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:12]([C:11]3[CH:10]=[CH:9][C:8]([C:21]4[CH:22]=[C:23]5[C:43]([C:19]([CH3:53])([CH3:18])[CH:20]=4)=[C:26]4[C:25]([CH:42]=[C:41]6[C:28](=[CH:27]4)[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=4[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:40]6=4)=[CH:24]5)=[CH:7][C:6]=3[C:5]2([CH3:16])[CH3:17])=[CH:13][CH:14]=1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Reactant: CC1(C)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CO
Product: CC1(C)C=C(c2ccc3c(c2)C(C)(C)c2cc(Br)ccc2-3)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Temperature: 90 °C
Yield: 42.9 %

Procedure:
A mixture of 4.9 g (14 mmol) of 2,7-dibromo-9,9-dimethyl-9H-fluorene, 7.53 g (16 mmol) of 2-(10,10-dimethyl-10H-indeno[1,2-b]triphenylen-12-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 0.16 g (0.14 mmol) of Tetrakis(triphenylphosphine)palladium, 11 ml of 2M Na2CO3, 30 ml of EtOH and 65 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 12 h. After finishing the reaction, the mixture was allowed to cool to room temperature. Than 500 ml MeOH was added, while stirring and the precipitated product was filtered off with suction. To give 3.7 g (yield 43%) of yellow product which was recrystallized from toluene.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:19])[C:16]([OH:18])=O)=[CH:11][C:10]=1[CH2:20][CH2:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[NH2:31][C@H:32]1[CH2:41][CH2:40][C:39]2[C:34](=[CH:35][C:36]([OH:42])=[CH:37][CH:38]=2)[CH2:33]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:19])[C:16]([NH:31][C@H:32]2[CH2:41][CH2:40][C:39]3[C:34](=[CH:35][C:36]([OH:42])=[CH:37][CH:38]=3)[CH2:33]2)=[O:18])=[CH:11][C:10]=1[CH2:20][CH2:21][O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(O)c1ccc(OCc2ccccc2)c(CCOCc2ccccc2)c1
Reactant: N[C@H]1CCc2ccc(O)cc2C1
Agent: Br
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CCc2ccc(O)cc2C1)C(O)c1ccc(OCc2ccccc2)c(CCOCc2ccccc2)c1
Temperature: 25 °C

Procedure:
2-[4-Benzyloxy-3-(2-benzyloxyethyl)phenyl]-2-hydroxyacetic acid (1.73 g), 1.18 g of (S)-2-amino-7-hydroxytetralin hydrobromide and 1.95 g of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate were dissolved in 11 ml of N,N-dimethylformamide, 1.23 ml of triethylamine was added to the solution with stirring at room temperature and the mixture was subjected to 3 hours of reaction. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The extract was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was partially purified by silica gel medium pressure liquid column chromatography (eluent: hexane/ethyl acetate=1/1) to give 2-[4-benzyloxy-3-(2-benzyloxyethyl)phenyl]-2-hydroxy-N-((2S)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2yl)acetamide (diastereomer mixture). The mixture was separated by silica gel medium pressure liquid column chromatography (eluent: diethyl ether) to give 1.08 g of amorphous (-)-(2R)-2-[4-benzyloxy-3-(2-benzyloxyethyl)phenyl]-2-hydroxy-N-((2S)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide (low polarity isomer) and 0.94 g of amorphous (-)-(2S)-2-[4benzyloxy-3-(2-benzyloxyethyl)phenyl]-2-hydroxy-N-((2S)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide (high polarity isomer).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=1.Cl[C:12]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[C:17]([Cl:24])[C:13]=1[C:14]([OH:16])=[O:15].CN(C)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:24][C:17]1[C:13]([C:14]([OH:16])=[O:15])=[C:12]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:2][CH3:1])=[CH:5][CH:6]=2)[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=1
Reactant: CCOc1ccc(N)cc1
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Solvent: CN(C)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOc1ccc(Nc2c([N+](=O)[O-])ccc(Cl)c2C(=O)O)cc1

Procedure:
A mixture of 28.0 g of p-phenetidine, 23.6 g of 2,6-dichloro-3-nitrobenzoic acid, and 80 ml of N,N-dimethylaniline was heated five hours on a steam bath. The resulting mixture was diluted with chloroform and extracted with 1N sodium hydroxide. Acidification of the aqueous extract yielded 6-chloro-2-[(4-ethoxyphenyl)amino]-3-nitrobenzoic acid as reddish brown crystals.
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]2[O:12][CH2:13][O:14][C:10]=2[CH:9]=1)=[O:5].[NH2:24][CH:25]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:26][OH:27]>>[OH:27][CH2:26][CH:25]([NH:24][C:2]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]2[O:12][CH2:13][O:14][C:10]=2[CH:9]=1)=[O:5])[CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: O=C(NCc1ccc2c(c1)OCO2)c1cc([N+](=O)[O-])ccc1F
Reactant: CCCCC(N)CO
Product: CCCCC(CO)Nc1ccc([N+](=O)[O-])cc1C(=O)NCc1ccc2c(c1)OCO2
Yield: 77.8 %

Procedure:
2-[1-(1-Hydroxymethyl)pentylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (203 mg) was prepared from 2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (200 mg) and 2-amino-1-hexanol (221 mg) in a similar manner to that of Example 1(1) as yellow crystals. mp 112-115° C.
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[N:6][C:5]([Br:9])=[CH:4][N:3]=1.Cl[C:11]1C(F)=CC=C(F)[C:12]=1CN.[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:23]=1[CH2:24][NH2:25]>>[Br:9][C:5]1[N:6]=[C:7]2[N:25]([CH2:24][C:23]3[C:22]([Cl:21])=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:30])[CH2:11][CH2:12][NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NCc1c(Cl)cccc1Cl
Reactant: Nc1ncc(Br)nc1Br
Reactant: NCc1c(F)ccc(F)c1Cl
Product: Clc1cccc(Cl)c1CN1CCNc2ncc(Br)nc21

Procedure:
7-bromo-1-(2,6-dichlorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazine was prepared from 2-amino-3,5-dibromopyrazine as described in Example 1 by replacing 2-chloro-3,6-difluorobenzylamine in step 1 with 2,6-dichlorobenzylamine.
Reaction SMILES: [CH2:1]([C@@:8]12[O:33][C:11]3=[C:12]([OH:32])[CH:13]=[CH:14][C:15]4[CH2:16][C@H:17]5[N:28]([CH3:31])[CH2:29][CH2:30][C@:9]1([C@@:18]5([O:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:19][CH2:20][C:21]2=[O:22])[C:10]=43)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][I:35]>O>[I-:35].[CH2:1]([C@@:8]12[O:33][C:11]3=[C:12]([OH:32])[CH:13]=[CH:14][C:15]4[CH2:16][C@H:17]5[N+:28]([CH3:34])([CH3:31])[CH2:29][CH2:30][C@:9]1([C@@:18]5([O:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:19][CH2:20][C:21]2=[O:22])[C:10]=43)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: CCCCO[C@@]12CCC(=O)[C@]3(Cc4ccccc4)Oc4c(O)ccc5c4[C@@]31CCN(C)[C@@H]2C5
Solvent: O
Product: CCCCO[C@@]12CCC(=O)[C@]3(Cc4ccccc4)Oc4c(O)ccc5c4[C@@]31CC[N+](C)(C)[C@@H]2C5
Product: [I-]

Procedure:
A solution of 5β-benzyl-14β-butoxy-4,5α-epoxy-3-hydroxy-17-methylmorphinan-6-one (0.32 g, 0.72 mmol) and methyl iodide (0.51 g, 3.58 mmol) in 10 ml of water-free acetonitrile was stirred under N2 at 40° C. (bath temperature) for 2 days and then evaporated down. The evaporation residue (0.41 g of brown oil) was purified using column chromatography (silica gel; CH2Cl2/MeOH 250:6). Yield: 0.22 g (54%) slightly beige crystals of the compound 45. Fp. 188-195° C.; MS (CI): 462 (M+); IR (KBr): 1729 (C═O) cm−1; 1H-NMR (DMSO-d6, δ in ppm): 9.49 (s, OH), 7.28-7.20 (m, 5 arom. H), 6.69 (d, 1 arom. H, J=8.2 Hz), 6.62 (d, 1 arom. H, J=8.2 Hz), 3.61 (s, CH3N+, axial), 3.23 (s, CH3N+, equatorial), 1.01 (t, 3H, C14-O(CH2)3CH3, J=7.0 Hz).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=[O:12])[C:7]([OH:9])=O.[C:20](OC(=O)CC)(=O)[CH2:21]C.O>N1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=[O:12])[C:7](=[O:9])[CH2:20][CH3:21]
Reactant: Cc1ccc(C(=O)NC(CCCCCl)C(=O)O)cc1
Reactant: CCC(=O)OC(=O)CC
Solvent: O
Solvent: c1ccncc1
Product: CCC(=O)C(CCCCCl)NC(=O)c1ccc(C)cc1
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
6-Chloro-2-(p-toluoylamino)hexanoic acid (10.0 g) was dissolved in 15 ml of dry pyridine, and 15 ml of propionic anhydride was added and stirred for 2.5 hours at 90° C. To the mixture was added 15 ml of water slowly so that the maximum temperature did not exceed 85° C., and stirred for 20 minutes at 80° C. The reaction solution was cooled, poured into ice-cold water and extracted with diethyl ether. The extract was washed with 10% hydrochloric acid, an aqueous solution of saturated sodium hydrogen carbonate and brine sequentially, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=8:1–4:1) to provide 6.0 g of the objective compound as colorless crystals. M.p. 85–86° C.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:12][NH:13][OH:14].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:14][N:13]([CH3:12])[C:8](=[O:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CNO
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(O)C(=O)Cc1ccccc1

Procedure:
At 0° C. phenyl-acetyl chloride (11.2 mL) is added drop wise to a solution of N-methyl-hydroxylamine hydrochloride (7.07 g) and triethylamine (59 mL) in DCM (300 mL). After stirring for 90 min a sat. aqueous NaHCO3 solution is added, the layers are separated and the aqueous layer is extracted twice with DCM (2×200 mL). The solvents are removed in vacuo and the residue is purified by flash chromatography (EA/heptane 1/1) to give the desired N-hydroxy-acetamide as a colorless liquid.