Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][C:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([CH3:15])[CH3:14])/[C:8]([OH:10])=O)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].CS(Cl)(=O)=O.Cl.[NH2:35][C@@H:36]1[C:57](=[O:58])[N:38]2[C:39]([C:45]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=3)=[O:46])=[C:40]([CH2:43][Cl:44])[CH2:41][S:42][C@H:37]12>CN(C)C(=O)C.O.C(OCC)(=O)C.C(N(CC)CC)C>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][C:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([CH3:15])[CH3:14])/[C:8]([NH:35][C@@H:36]2[C:57](=[O:58])[N:38]3[C:39]([C:45]([O:47][CH2:48][C:49]4[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=4)=[O:46])=[C:40]([CH2:43][Cl:44])[CH2:41][S:42][C@H:37]23)=[O:10])[N:3]=1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](N)C(=O)N23)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)O)c1nsc(N)n1
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c4nsc(N)n4)C(=O)N23)cc1
Temperature: 10 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
To a solution of (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetic acid (319 g) in N,N-dimethylacetamide (1.5 L) were added potassium carbonate (113 g) and methanesulfonyl chloride (126 ml) under ice-cooling. The mixture was stirred at 10° C. for 2 hours. The reaction mixture was added to a mixture of ethyl acetate and water. The organic layer was washed with water and brine to give an activated acid solution. On the other hand, a suspension of 4-methoxybenzyl 7β-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochloride (300 g) in a mixture of water (1 L) and ethyl acetate (1 L) was adjusted to pH 6 with triethylamine under ice-cooling. To the resulting mixture was dropwise added the above obtained activated acid solution at 10° C. under stirring. Stirring was continued at 5–10° C. for 1.5 hours keeping pH of the reaction mixture at 6 with triethylamine. The organic layer was separated, washed with water and brine, and evaporated in vacuo. The concentrate was poured into diisopropyl ether (15 L), and the resulting precipitate was collected by filtration and dried to give 4-methoxybenzyl 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-chloromethyl-3-cephem-4-carboxylate (495.7 g).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:9](=O)[CH2:8][CH2:7][S:6]1)=[O:4].[Cl:11][C:12]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:14][C:13]1[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:12]=1[Cl:11])=[O:4]
Reactant: Cc1cccc(N)c1Cl
Reactant: COC(=O)C1SCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1sccc1Nc1cccc(C)c1Cl
Reaction time: 1 h

Procedure:
15.9 g (0.1 mole) of 3-oxotetrahydro-2-thiophencarboxylic acid methyl ester, 14.2 g of 2-chloro-3-methylaniline and 200 mg of p-toluenesulfonic acid are heated in 500 ml of toluene for six hours using a water separator. 24.6 g (0.1 mole) of chloranil are then added, and the mixture is boiled for a further one hour. It is cooled and filtered; the filtrate is washed with 100 ml each of 2 N sodium hydroxide solution, sodium dithionite solution and water and concentrated; the residue is purified by column chromatography (silica gel, toluene/ethyl acetate 4/1). 3-(2-Chloro-3-methylanilino)-2-thiophencarboxylic acid methyl ester is obtained as an oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25](O)=[O:26])[C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[N:20][NH:21]3)=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[N:20][NH:21]3)=[CH:17][CH:16]=2)[CH2:24][C:25]([N:30]([CH2:31][CH3:32])[CH2:28][CH3:29])=[O:26])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3cn[nH]c3c2)cc1
Reactant: CCNCC
Product: CCN(CC)C(=O)CN(c1ccc2cn[nH]c2c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(1H-indazol-6-yl)-amino]-acetic acid with diethylamine
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.S(Cl)([Cl:14])=O>>[CH3:1][N:2]=[C:3]([Cl:14])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: CNC(=O)c1ccc(Cl)cc1
Product: CN=C(Cl)c1ccc(Cl)cc1
Yield: 83.3 %

Procedure:
N-Methyl 4-chlorobenzamide (42.6 g, 251 mmole) and thionyl chloride (153.3 g, 1.28 mole) were reacted as in Example I to yield 39.3 g (83.4%) of the title compound, b.p. 125° C. (15 mm Hg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:35][C:36]1[CH:37]=[C:38]([NH2:43])[CH:39]=[CH:40][C:41]=1[CH3:42].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O.O>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:43][C:38]2[CH:39]=[CH:40][C:41]([CH3:42])=[C:36]([CH3:35])[CH:37]=2)=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: Cc1ccc(N)cc1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(NC(=O)c2ccc(N)c([N+](=O)[O-])c2)cc1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-amino-3-nitrobenzoic acid (1.82 g) in DMF (20 mL) was added HOBT (1.49 g) and EDCI (2.1 g). After stirring at room temperature for 10 min, 3,4-dimethylphenylamine (1.2 g) and DIPEA (5.3 mL) were added. The solution was stirred at room temperature for 18 h then the mixture was partioned between water and EtOAc The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, brine, dried, filtered and concentrated. The residue was purified by recrystallization from EtOAc and gave 4-amino-N-(3,4-dimethylphenyl)-3-nitrobenzamide as a yellow solid. MS (ESI)m/z 286 (M+H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].C[O-].[Na+].[Na].[CH:15](Br)([CH3:17])[CH3:16]>CO>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH:15]([CH3:17])[CH3:16])([CH3:3])[CH3:2]
Reactant: CC(C)Br
Reactant: CC(C)c1ccccc1O
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CC(C)Oc1ccccc1C(C)C

Procedure:
A solution of 2-isopropylphenol (75 g, 0.54 mol) in 60 ml methanol was added, under nitrogen, to a solution of sodium methoxide, prepared by reacting 13.1 g (0.57 mol) sodium with 150 ml dry methanol. To this stirred solution was added isopropyl bromide (82.2 g, 0.66 mol) dropwise over several hours, after which the reaction mixture was heated at reflux overnight. The cooled mixture was filtered to remove solids and methanol was removed on a rotary evaporator. The residue, containing both liquid and solid, was treated with about equal volumes of diethyl ether and water, with the aqueous phase then separated and discarded. The ether phase was washed with Claisen solution, water being added to facilitate separation of phases, and the organic phase retained. The combined aqueous phases was extracted with ether, the extract being added to the prior retained organic phase, and the combined material was dried over anhydrous magnesium sulfate. Ether was removed by evaporation and the residue was distilled to afford isopropyl (2-isopropylphenyl) ether.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[CH:3]=1.[H-].[K+].C([Li])(C)(C)C.[CH2:20]([N:27]1[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH2:20]([N:27]1[CH2:32][CH2:31][C:30]([OH:33])([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=3)[CH:3]=2)[CH2:29][CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: [H-]
Agent: [K+]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Oc1ccc2cc(C3(O)CCN(Cc4ccccc4)CC3)ccc2c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 15.2 %

Procedure:
A solution of 10.0 gm (44.8 mMol) 2-bromo-6-hydroxynaphthalene in tetrahydrofuran was added dropwise to a suspension of 9.42 gm (47.1 mMol) potassium hydride (20% suspension) in 180 mL tetrahydrofuran at 0° C. After stirring at this temperature for 2 hours the reaction mixture was cooled further to -78° C. and to it was added dropwise 58 mL (98.6 mMol) tert-butyllithium (1.7M in tetrahydrofuran). The mixture was stirred for 20 minutes at this temperature and then a solution of 8.73 mL (47.1 mMol) 1-benzyl-4-piperidone in 30 mL tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm gradually to room temperature and was stirred at this temperature for 18 hours. The reaction mixture was then partitioned between ethyl acetate and dilute ammonium hydroxide. The phases were separated and the aqueous phase was extracted well with ethyl acetate. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with 5% methanol in dichloromethane. Fractions containing product were combined and concentrated under reduced pressure to provide 2.27 gm (15%) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].[Br:12]Br>CC(O)=O>[NH2:11][C:10]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[N:6][C:7]([Br:12])=[CH:8][N:9]=1
Reactant: COC(=O)c1nccnc1N
Reactant: BrBr
Solvent: CC(=O)O
Product: COC(=O)c1nc(Br)cnc1N
Temperature: 50 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
3-Aminopyrazine-2-carboxylic acid methyl ester (200 g, 1.3 mol, 3B Scientific Corporation) was dissolved in AcOH (1 L). The solution was warmed to 50° C. and Br2 (312 g, 1.9 mol) added dropwise. When the addition was completed, the mixture was stirred at 50° C. for additional 3 hours. The reaction mixture was poured slowly to ice-water (4 L). The precipitate was filtered, washed with water and dried under a reduced pressure to afford the subtitle compound (iii) as a red brown solid (300 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH3:17])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1.CS(C)=O.[C-:22]#[N:23].[Na+]>O>[CH3:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:8]2[CH:7]=[CH:6][C:5]([CH3:17])=[CH:4][C:3]=2[CH2:2][C:22]#[N:23])=[CH:11][CH:12]=1
Reactant: Cc1ccc(Oc2ccc(C)cc2CCl)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(Oc2ccc(C)cc2CC#N)cc1
Temperature: 36 °C
Reaction time: 4 h

Procedure:
A solution of 108 g. of 3-chloromethyl-4-(4-methyl-phenoxy)-toluene in 70 ml. of dimethylsulfoxide is added dropwise at 20°-25° C. to a suspension of 23 g. of sodium cyanide in 35 ml. of dimethylsulfoxide. The mixture is subsequently stirred for 4 hours at 36° C., then diluted with 1 liter of water and extracted three times with benzene. The benzene extracts are washed three times with water, then dried over sodium sulfate and evaporated in vacuo, and there is obtained crude 2-(4-methyl-phenoxy)-5-methyl-phenylacetonitrile as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[C:5]([NH2:18])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:26][C:27]([F:38])([F:37])[C:28]([F:36])([F:35])[C:29]([F:34])([F:33])[C:30](O)=O>O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]2[NH:18][C:30]([C:29]([F:33])([F:34])[C:28]([F:35])([F:36])[C:27]([F:38])([F:37])[F:26])=[N:19][C:4]=2[CH:3]=1
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Nc1cc(Cl)c(-c2ccc(C(F)(F)F)cc2)cc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: FC(F)(F)c1ccc(-c2cc3[nH]c(C(F)(F)C(F)(F)C(F)(F)F)nc3cc2Cl)cc1
Yield: 48 %

Procedure:
The solution of 4-chloro-5-[4-(trifluoromethyl)phenyl]benzene-1,2-diamine (250 mg, 0.87 mmol) in heptafluorobutanoic acid (1.5 ml) was stirred overnight at 80° C. The result mixture was diluted with water (50 ml) and adjusted to pH 7 with saturated aqueous sodium carbonate. The resulting solution was extracted with ethyl acetate (3×50 ml), combined and dried over anhydrous magnesium sulfate and concentrated under vacuum to give a residue, which was precipitated from dichloromethane (5 ml) to produce 5-chloro-2-(heptafluoropropyl)-6-[4-(trifluoromethyl)phenyl]-1H-1,3-benzodiazole as a white solid (194.8 mg, 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH:29]([F:31])[F:30])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C@H:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[C:17]([OH:19])=O)[C:10](=[O:27])[CH:9]=2)[CH:7]=1.[NH2:32][C:33]1[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:35][CH:34]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH:29]([F:30])[F:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C@H:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[C:17]([NH:32][C:33]3[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])=[CH:35][CH:34]=3)=[O:19])[C:10](=[O:27])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(C[C@H]2CCCCO2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1OC(F)F
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: COc1cn(C(C[C@H]2CCCCO2)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1OC(F)F

Procedure:
82 mg (purity 85%, 0.15 mmol) of 2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-3-[(2R)-tetrahydro-2H-pyran-2-yl]propanoic acid (mixture of enantiomerically pure diastereomers 1 and 2) and 32 mg (0.17 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 67 mg (70% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:12][CH3:13])[CH:7]=[C:6]([C:14]([O:16][CH2:17][CH2:18][CH2:19][OH:20])=[O:15])[C:5]2=[O:21].[P:22](O)([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].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>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:12][CH3:13])[CH:7]=[C:6]([C:14]([O:16][CH2:17][CH2:18][CH2:19][O:20][P:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:23])=[O:15])[C:5]2=[O:21]
Reactant: CCn1cc(C(=O)OCCCO)c(=O)c2cc(Br)cnc21
Reactant: O=P(O)(OCc1ccccc1)OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCn1cc(C(=O)OCCCOP(=O)(OCc2ccccc2)OCc2ccccc2)c(=O)c2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.4 %

Procedure:
3-Hydroxypropyl 6-bromo-1-ethyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Intermediate 24, 100 mg, 0.28 mmol), dibenzyl hydrogen phosphate (124 mg, 0.44 mmol) and triphenylphosphine (367 mg, 1.4 mmol) was dissolved in tetrahydrofuran (15 mL). Diisopropyl azodicarboxylate [DIAD] (281 mg, 1.40 mmol) was added and the mixture was stirred for 4 h at room temperature. The reaction mixture was concentrated under reduced pressure and water (100 mL) was added. The aqueous mixture was extracted with ethyl acetate (2×100 mL) and the combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give a crude compound. The crude compound was purified by flash column chromatography over silica gel (0-50% ethyl acetate/petroleum ether) to afford 80 mg (47%) of 3-{[bis(benzyloxy)phosphoryl]oxy}propyl 6-bromo-1-ethyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[C:16]([C:18]1[CH:19]=[C:20]([C:24]2[CH:47]=[CH:46][C:27]([C:28]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]3[CH2:44][CH2:43][C:42]4[C:37](=[CH:38][C:39](O)=[CH:40][CH:41]=4)[CH2:36]3)=[O:29])=[CH:26][CH:25]=2)[CH:21]=[CH:22][CH:23]=1)#[N:17]>N1C=CC=CC=1.S([O-])([O-])(=O)=O.[Cu+2]>[C:16]([C:18]1[CH:19]=[C:20]([C:24]2[CH:47]=[CH:46][C:27]([C:28]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]3[CH2:44][CH2:43][C:42]4[C:37](=[CH:38][C:39]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:40][CH:41]=4)[CH2:36]3)=[O:29])=[CH:26][CH:25]=2)[CH:21]=[CH:22][CH:23]=1)#[N:17]
Reactant: N#Cc1cccc(-c2ccc(C(=O)NCCCCN3CCc4ccc(O)cc4C3)cc2)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: c1ccncc1
Product: N#Cc1cccc(-c2ccc(C(=O)NCCCCN3CCc4ccc(OS(=O)(=O)C(F)(F)F)cc4C3)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.1 %

Procedure:
Trifluoromethanesulfonic anhydride (0.21 ml, 1.25 mmol) was added dropwise with stirring to an ice cooled solution of 2-(4-(4-(3-cyanophenyl)benzoylamino)butyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline (0.41 g, 0.96 mmol) in anhydrous pyridine (5 ml). After stirring at room temperature for 18 h. the mixture was poured into 10% aqueous copper (II) sulphate (100 ml). The mixture was extracted with ethyl acetate (2×50 ml) and the combined extracts washed with 10% aqueous copper (II) sulfate (2×50 ml). water (50 ml), dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica gel using 10-100% ethyl acetate-hexane gradient elution to afford the title compound (0.263 g, 49%).
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:2][C:3]([O:5]N1C(=O)CCC1=O)=O.[NH2:20][C@@H:21]([C:26]([NH:28][C@H:29]([C:34]([NH2:36])=[O:35])[CH2:30][CH2:31][S:32][CH3:33])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24]>>[NH:1]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:2][C:3]([NH:20][C@@H:21]([C:26]([NH:28][C@H:29]([C:34]([NH2:36])=[O:35])[CH2:30][CH2:31][S:32][CH3:33])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:5]
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Reactant: CSCC[C@H](NC(=O)[C@H](N)CC(C)C)C(N)=O
Product: CSCC[C@H](NC(=O)[C@@H](CC(C)C)NC(=O)CNC(=O)OC(C)(C)C)C(N)=O
Yield: 95 %

Procedure:
Condensation of BocDLeuOH (2.49 g.) and HMetNH2 (1.85 g.) by the mixed anhydride method using isobutyl chloroformate gave BocDLeu-MetNH2 in 47% yield. De-t-butoxycarbonylation of BocDLeu-MetNH2 (1.70 g.) using hydrogen chloride in acetic acid gave HDLeu-MetNH2 in 78% yield. Condensation of BocGlyOSu (1.8 g.) and HDLeu-MetNH2 (1.0 g.) by the activated ester method gave BocGly-DLeu-MetNH2 in 95% yield. De-t-butoxycarbonylation of BocGly-DLeu-MetNH2 (1.35 g.) using hydrogen chloride in acetic acid gave HGly-DLeu-MetNH2 in 55% yield.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]#[N:13])=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.[OH-].[K+].[CH3:16][N:17]([CH3:21])[C:18](Cl)=[S:19].C(OCC)(=O)C>CC(C)=O.O>[C:12]([C:3]1[C:2]([O:1][C:18](=[S:19])[N:17]([CH3:21])[CH3:16])=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=1)#[N:13]
Reactant: N#Cc1cc2c(cc1O)CCCC2
Reactant: CN(C)C(=S)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: CN(C)C(=S)Oc1cc2c(cc1C#N)CCCC2
Reaction time: 0.75 h
Yield: 64.3 %

Procedure:
To a solution of 3-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile prepared in method II-2 (3.00 g, 17.3 mmol) in acetone (60 mL) was added dropwise a solution of potassium hydroxide (1.07 g, 19.1 mmol, 1.1 eq) in water (40 mL) at 0° C. After stirring for 45 min, a solution of dimethylthiocarbamoyl chloride (2.35 g, 19.1 mmol, 1.1 eq) in acetone (40 mL) was added at 0° C. over 30 min. The reaction mixture was then stirred at room temperature for 16 h, and poured into ethyl acetate and water. The organic layer was washed with saturated aqueous ammonium chloride, water, and brine. The combined aqueous wash was re-extracted with ethyl acetate, and the organic washes were dried over magnesium sulfate and evaporated at reduced pressure. The crude oil was crystallized from ether/hexane to give dimethyl-thiocarbamic acid O-(3-cyano-5,6,7,8-tetrahydro-naphthalen-2-yl) ester (2.90 g, 64.3%) as a beige solid. 1H-NMR (Acetone-d6) δ 7.46 (s, 1H), 6.98 (s, 1H), 3.43 (d, J=4.2 Hz, 6H), 2.80 (m, 4H), 1.81 (m, 4H); MS ES (MH+=261). Rf=0.70 (30% ethyl acetate-hexane).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:14]=[N:15][C:16]([F:19])=[CH:17][CH:18]=2)([NH2:12])[C@@H:9]([NH2:11])[CH3:10])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24](=[O:27])[NH:23][C:22]=1[C:28](O)=O>>[F:20][C:21]1[CH:26]=[CH:25][C:24](=[O:27])[NH:23][C:22]=1[C:28]1[NH:11][C@@H:9]([CH3:10])[C@:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)([C:13]2[CH:14]=[N:15][C:16]([F:19])=[CH:17][CH:18]=2)[N:12]=1
Reactant: C[C@H](N)C(N)(c1ccc(F)cc1)c1ccc(F)nc1
Reactant: O=C(O)c1[nH]c(=O)ccc1F
Product: C[C@@H]1NC(c2[nH]c(=O)ccc2F)=N[C@@]1(c1ccc(F)cc1)c1ccc(F)nc1

Procedure:
According to the method of Example 1, optically active (2S)-1-(4-fluorophenyl)-1-(6-fluoro-3-pyridyl)-1,2-propanediamine described in Reference Example 5–1 of WO 01/62738 was reacted with 3-fluoro-6-oxo-1,6-dihydro-2-pyridinecarboxylic acid to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10]C)=[C:4]([O:12]C)[CH:3]=1.B(Br)(Br)Br>>[Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([OH:10])=[C:4]([OH:12])[CH:3]=1
Reactant: COc1cc(Cl)c(C=O)cc1OC
Agent: BrB(Br)Br
Product: O=Cc1cc(O)c(O)cc1Cl

Procedure:
6-Chloroveratraldehyde is treated with boron tribromide as described in Example 4 to give 6-chloroprotocatechualdehyde as a white solid, m.p. 217°-218°C. which is dibenzylated to give 6-chloro-3,4-dibenzyloxybenzaldehyde, m.p. 100°-102°C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([O:11]COC)=[C:6]([O:15][CH3:16])[CH:5]=1.Cl>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([OH:11])=[C:6]([O:15][CH3:16])[CH:5]=1
Reactant: COCOc1c(C)cc(C(=O)OC)cc1OC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c(O)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
To a solution of 3-methoxy-4-methoxymethoxy-5-methylbenzoic acid methyl ester (650 mg) in THF (5 mL) was added 6N-hydrochloric acid (5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1, v/v) to give the title compound (365 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[C:7]([CH3:9])[NH:6][N:5]=1.Br[CH2:11][CH2:12][F:13]>CN(C=O)C.O>[F:13][CH2:12][CH2:11][N:5]1[C:4]([CH3:3])=[CH:8][C:7]([CH3:9])=[N:6]1
Reactant: Cc1cc(C)[nH]n1
Reactant: FCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)n(CCF)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
To a suspension of sodium hydride (1.37 mol, (60% in oil) in DMF (350 mL) was added 3,5-dimethyl-1H-pyrazole (120 g, 1.25 mol). After this, the reaction mixture was stirred for 1 h at room temperature and treated with 1-bromo-2-fluoroethane (175 g, 1.37 mol) in DMF (200 mL). The reaction mixture was left to stir overnight, diluted with water (2 L), and the product was extracted with ethyl acetate (3×300 mL). The combined organic extracts were washed with water (1 L), dried with sodium sulfate, and evaporated. The liquid residue (120 g) was chromatographed on a “Biotage” apparatus with silica gel using ethyl acetate/hexane (1:5) as the eluent (Rf=0.3) to give 88 g (49.7%) of the title product.