Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C([O-])([O-])=O.[K+].[K+].[Cl:13][C:14]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:15]=1[CH2:16]Cl.O>CS(C)=O>[Cl:13][C:14]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:15]=1[CH2:16][N:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: O=C1NCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1NCCN1Cc1ccc(Cl)cc1Cl
Reaction time: 0.3 h
Yield: 77 %

Procedure:
A 21.5 g (0.25 mole) portion of 2-imidazolidinone in 200 ml of dimethylsulfoxide was treated with 34.5 g (0.25 mole) of K2CO3, 20 g (0.12 mole) of KI and 48.9 g (0.25 mole) of 2,4-dichlorobenzyl chloride. The reaction mixture was heated with stirring to 105° over 0.3 hours, held at 105° for 1.8 hours, and poured with rapid stirring into 1.5 l of water. The aqueous mixture was extracted with 1.3 l of chloroform. The chloroform extract was washed with 580 ml of water, dried over MgSO4 overnight and filtered. The filtrate was concentrated under reduced pressure leaving 47 g (77%) of a light yellow oil. The oil was crystallized with 125 ml of ether, filtered, air dried, and dried to a constant weight at 60° to give 19 g (31%) of a white solid, m.p. 116°-118°.
Reaction SMILES: [OH:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:29]1(O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[CH3:20][CH:19]([CH3:21])[C:18]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@@H:2]([O:1][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:12]=1)=[O:22]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](O)c3ccccc3)CC2)c1
Reactant: Oc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](Oc3ccccc3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 35.9 %

Procedure:
A mixture of N-(3-{1-[(3S)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250 mmol), phenol (4.70 mg, 0.050 mmol), triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.22 mg, 0.0300 mmol) in THF (1.0 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (4.1 mg, 36.0% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.40-7.15 (m, 10H), 6.97 (d, 1H, J=7.6 Hz), 6.88-6.82 (m, 2H), 5.26 (m, 1H), 3.18 (m, 2H), 2.75 (m, 2H), 2.53 (m, 2H), 2.40-2.10 (m, 4H), 2.10-1.80 (m, 4H), 1.25 (d, 6H, J=6.9 Hz); ESMS m/e: 457.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[Br:15]Br>ClCCl>[Br:15][C:7]1[CH:6]=[CH:5][C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: BrBr
Reactant: COc1ccccc1N1CCNCC1
Solvent: ClCCl
Product: COc1cc(Br)ccc1N1CCNCC1
Temperature: 0 °C
Yield: 99.3 %

Procedure:
Dissolve 1-(2-methoxy-phenyl)-piperazine (5.0 g, 26.0 mmol) in dichloromethane 450 mL) and cool to 0° C. Add bromine (4.16 g, 26.0 mmol) slowly dropwise. After 2 h wash the reaction mixture with 1 N sodium hydroxide (250 mL). Separate the organic portion, dry (Na2SO4), filter and concentrate in vacuo to afford 7.0 g (99%) of the title compound. MS/ES m/z (81Br) 273.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18](I)[CH3:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: O=Cc1cc(O)ccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(OCc2ccccc2)c(C=O)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 92.2 %

Procedure:
A mixture of 2-benzyloxy-5-hydroxybenzaldehyde (8.93 g), ethyl iodide (7.31 g), anhydrous potassium carbonate (5.40 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give 2-benzyloxy-5-ethoxybenzaldehyde as a colorless oil (9.25 g, 92%) from a fraction eluted with ethyl acetate-hexane (1:9, v/v).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][C:5]([F:10])=[C:6]([Cl:9])[C:7]=1[Cl:8].[OH-:12].[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[C:3](=[O:12])[NH:4][C:5]([F:10])=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: [OH-]
Reactant: Fc1nc(F)c(Cl)c(Cl)c1Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]c(F)c(Cl)c(Cl)c1Cl
Reaction time: 2 h

Procedure:
A solution of 3,4,5-trichlorodifluoropyridine (21.8 g.) in dioxan (220 ml.) was refluxed with a solution of sodium hydroxide (8 g.) in water (40 ml.). After 2 hours a further 8 g. of sodium hydroxide in water (40 ml.) was added (4 molar equivalents of sodium hydroxide in toto). After a further 2 hours, water was added to produce a homogeneous solution which was acidified to precipitate the product (17.6 g., m.p. 170°-4°). After initial purification by charcoal and silica gel column, crystallisation from benzene gave 3,4,5-trichloro-6-fluoro-2-pyridone, m.p. 172°-6°(11.8 g.), having a pale yellow colour. After vacuum sublimation at 100°-120°, the white microcrystals melted at 173°-4° (10.65 g/.).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12](=[O:21])[CH2:13][C:14]1[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=1)[CH3:10]>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:9]([O:11][C:12](=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][Br:1])[CH:15]=1)[CH3:10]
Reactant: CCOC(=O)Cc1cccc(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)Cc1cccc(CBr)c1
Yield: 33.2 %

Procedure:
A mixture of N-bromo-succinimide (10.68 g, 60.0 mmol), m-tolyl-acetic acid ethyl ester (10.0 g, 56.1 mmol; available from Aldrich Chemical Company, Inc., Milwaukee, Wis.) and benzoyl peroxide (40 mg, 0.17 mmol) in carbon tetrachloride (250 mL) was heated at reflux under nitrogen for 36 h. The reaction mixture was filtered, evaporated, and purified by chromatography on silica gel, eluting with 0-100% dichloromethane in hexane to give (3-bromomethyl-phenyl)-acetic acid ethyl ester (4.79 g, 33%). MS m/z 257. 1HNMR (DMSO-d6): δ 7.2-7.35 (m, 4H), 4.50 (s, 2H), 4.18 (q, 2H), 3.62 (s, 2H), 1.28 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[C:13]3[C:20]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[CH:19][S:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:4][CH:3]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>C(Cl)Cl>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]2[C:13]3[C:12]([NH:11][CH2:10][CH2:9][CH2:8][C:5]4[CH:6]=[CH:7][C:2]([NH:1][C:28](=[O:30])[CH3:29])=[CH:3][CH:4]=4)=[N:17][CH:16]=[N:15][C:14]=3[S:18][CH:19]=2)=[CH:26][CH:25]=1
Reactant: Nc1ccc(CCCNc2ncnc3scc(-c4ccc(F)cc4)c23)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)Nc1ccc(CCCNc2ncnc3scc(-c4ccc(F)cc4)c23)cc1
Temperature: 60 °C
Yield: 90 %

Procedure:
A mixture of N-[3-(4-aminophenyl)propyl]-5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-amine (0.014 g, 0.037 mmol) and acetic anhydride (0.01 mL) in methylene chloride (2.0 mL) was heated to 60° C. for 6 h. The reaction was allowed to cool to room temperature and concentrated in vacuo. The residue was then dissolved in ethyl acetate (30 mL) and the organic layer was washed with sodium bicarbonate (2×25 mL). Concentration, followed by followed by silica gel column chromatography purification (using 3% methanol in 1:1 ethyl acetate/hexane and ammonia (0.03%) as eluent) afforded N-[4-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]amino}propyl)phenyl]acetamide in 90% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].C(N(CC)CC)C.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CN(C1C=CC=CN=1)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([S:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:18][CH:19]=2)(=[O:13])=[O:12])[CH2:10][CH2:9][N:8]([C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCNCC2)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(C(=O)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.9 %

Procedure:
To a solution of 4-(4-but-2-ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid methyl ester, (400 mg, 1.03 mmol) in chloroform (10 ml) was added triethylamine (416 mg, 4.12 mmol), benzoyl chloride(144 μl, 1.24 mmol) followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred for 15 hours at room temperature, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 375 mg (80%) of the product as a solid. MS-ES: m/z 456.1 (M+H)+.
Reaction SMILES: C([C:4]1[C:5]([C:24]([O-:26])=[O:25])=[C:6](C(C)C)[C:7]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]([CH:12]=1)[C:9]([O-:11])=[O:10])(C)C.CO.[OH-].[K+]>O>[CH2:14]([S:13][C:7]1[CH:6]=[C:5]([C:24]([OH:26])=[O:25])[CH:4]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)c1cc(C(=O)[O-])c(SCc2ccccc2)c(C(C)C)c1C(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(C(=O)O)c(SCc2ccccc2)c1
Yield: 87 %

Procedure:
The diisopropyl-(benzylthio)-terephthalate obtained in Preparation 2 is refluxed with 500 ml. of methanol, 25 g. of potassium hydroxide and 50 ml. of water for 2 hours. The reaction mixture is then concentrated to a small volume, cooled, diluted with water and filtered through diatomaceous earth (Celite). The thus-obtained filtrate is acidified with 4N hydrochloric acid and the precipitate with forms is collected by filtraton and dried in an oven at 90°-100° C. to yield 45 g. (yield 87%) of (benzylthio)-terephthalic acid having a melting point of 299°-300° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][CH2:10][CH:9]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=O)[CH2:15][CH2:14]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:22]([NH2:26])[CH:23]([CH3:25])[CH3:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:24][CH:23]([CH3:25])[CH2:22][NH:26][C:19]([CH:16]1[CH2:15][CH2:14][N:13]([CH:9]2[CH2:10][CH2:11][CH2:12][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8]2)[CH2:18][CH2:17]1)=[O:21]
Reactant: CCOC(=O)N1CCCC(N2CCC(C(=O)O)CC2)CC1
Reactant: CC(C)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCCC(N2CCC(C(=O)NCC(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.4 %

Procedure:
1-(1-(ethoxycarbonyl)azepan-4-yl)piperidine-4-carboxylic acid (0.26 g assumed 0.89 mmol) was dissolved in DMF (4 mL) and isobutylamine (0.81 g, 1.1 mL, 11.0 mmol), HATU (0.51 g, 1.34 mmol) and DIPEA (0.46 g, 0.62 mL, 3.56 mmol) were added. The reaction mixture was stirred at rt overnight and the solvents were removed in vacuo. The residue was partitioned between DCM and sat. NaHCO3 sol., the organic layer was washed with sat. NaCl sol. and dried (MgSO4). The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 Å, 25 mL per min, gradient 0% to 3% MeOH in DCM]) to give ethyl 4-(4-((2-methylpropyl)carbamoyl)piperidin-1-yl)azepane-1-carboxylate (17 mg, 2%) as a pale yellow gum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH2:26]([NH2:32])[C:27]1[O:31][CH:30]=[CH:29][CH:28]=1>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:32][CH2:26][C:27]1[O:31][CH:30]=[CH:29][CH:28]=1)=[O:20]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: NCc1ccco1
Solvent: CC#N
Product: O=C(NCc1ccco1)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), furfurylamine (0.320 g, 3.29 mmol), and acetonitrile (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred for 2 hours at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-furfuryl-3,4,5,6-tetrahydrophthalamide as light brown crystals (0.860 g, 68.0% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12]CC3C(Cl)=CC=C([N+]([O-])=O)C=3Cl)[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:25])[CH:3]=1.[CH3:26][N:27](C)[CH:28]=O>>[OH:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([CH3:25])[CH:3]=[C:2]2[N:27]([CH3:28])[CH3:26]
Reactant: Cc1cc(Cl)c2cccc(OCc3c(Cl)ccc([N+](=O)[O-])c3Cl)c2n1
Reactant: CN(C)C=O
Product: Cc1cc(N(C)C)c2cccc(O)c2n1

Procedure:
A mixture of 4-chloro-8-(2,6-dichloro-3-nitrobenzyloxy)-2-methylquinoline (200 mg) and N,N-dimethylformamide (3 ml) was heated under reflux for 18 hours. The reaction mixture was partitioned into ethyl acetate and saturated aqueous solution of sodium bicarbonate. The organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (dichloromethane-methanol) to give 8-hydroxy-2-methyl-4-dimethylaminoquinoline (26 mg) as a brownish powder.
Reaction SMILES: Cl.[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.Cl[C:26]1[S:27][C:28]([C:31]([F:34])([F:33])[F:32])=[N:29][N:30]=1>CN1CCCC1=O>[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][N:22]([C:26]3[S:27][C:28]([C:31]([F:34])([F:33])[F:32])=[N:29][N:30]=3)[CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:8]=[CH:9][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:11][CH:12]=2)[CH2:4][CH2:3]1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reactant: FC(F)(F)c1nnc(Cl)s1
Agent: Cl
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2nnc(C(F)(F)F)s2)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide hydrochloride and 2-chloro-5-trifluoromethyl-[1,3,4]thiadiazole following a procedure analogous to that described in Example 19 using N-methylpyrrolidinone as solvent. LC (method 17): tR=1.42 min; Mass spectrum (ESI+): m/z=464 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][NH:6][C:7](=[O:10])[CH2:8][NH2:9])[CH3:2].C1(=O)N([O:17][C:18](=O)[C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)([CH3:21])[CH3:20])C(=O)CC1>>[CH2:1]([O:3][C:4](=[O:11])[CH2:5][NH:6][C:7](=[O:10])[CH2:8][NH:9][C:18](=[O:17])[C:19]([O:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)([CH3:21])[CH3:20])[CH3:2]
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)ON1C(=O)CCC1=O
Reactant: CCOC(=O)CNC(=O)CN
Product: CCOC(=O)CNC(=O)CNC(=O)C(C)(C)Oc1ccc(Cl)cc1

Procedure:
Likewise, by following the procedure of Example 1 but replacing proline methyl ester hydrochloride with glycylglycine ethyl ester and replacing the "activated ester" N-{N-[2-(p-chlorophenoxy)-2-methylpropionyl]glycine} succinimido ester with an equivalent amount of the "activated ester", 2-(p-chlorophenoxy)-2-methyl-propionic acid succinimido ester, obtained in an analogous manner as the aforementioned "activated ester", N-{N-[2-(p-chlorophenoxy)-2-methylpropionyl]glycyl}glycine ethyl ester again is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9]([C:11](=[O:20])[CH2:12][O:13][C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH2:8][C:7](=[O:21])[N:6]1[CH2:22][C:23]1[CH:28]=C[C:26](C#N)=[C:25](N)[CH:24]=1)=[O:4].[N:32]1[CH:37]=[N:36][CH:35]=[N:34][CH:33]=1.CC(O)=O>CCO>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9]([C:11](=[O:20])[CH2:12][O:13][C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH2:8][C:7](=[O:21])[N:6]1[CH2:22][C:23]1[CH:28]=[C:33]2[C:26]([C:37]([NH2:32])=[N:36][CH:35]=[N:34]2)=[CH:25][CH:24]=1)=[O:4]
Reactant: COC(=O)C1CN(C(=O)COc2ccc(Cl)s2)CC(=O)N1Cc1ccc(C#N)c(N)c1
Reactant: c1ncncn1
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)C1CN(C(=O)COc2ccc(Cl)s2)CC(=O)N1Cc1ccc2c(N)ncnc2c1
Yield: 40.8 %

Procedure:
A solution containing (±)-1-(3-amino-4-cyano-benzyl)-4-[(5-chloro-thiophen-2-yloxy)-acetyl]-6-oxo-piperazine-2-carboxylic acid methyl ester (110 mg, 0.25 mmol), 1,3,5-triazine (207 mg, 2.55 mmol), and glacial HOAc (157 mg, 2.55 mmol) in absolute EtOH (5 mL) is maintained at reflux for 16 hours. The reaction mixture is concentrated to dryness and then purified by reverse-phase HPLC [Buffer A: water w/0.1% TFA; Buffer B: CH3CN w/0.1% TFA; Gradient: 0% B to 60% B over 30 min] to provide 50 mg (32%) of the title compound as a white solid. 1H NMR (300 MHz, d6-DMSO) δ3.34-3.89 (m, 2H), 3.60 (s, 3H), 4.14-4.54 (m, 3H), 4.64 (br d, J=14.4 Hz, 1H), 4.78-5.11 (m, 3H), 6.19 (d, J=4.1 Hz, 1H), 6.73 (d, J=4.1 Hz, 1H), 7.64 (s, 1H), 7.65 (d, J=9.0 Hz, 1H), 8.34 (d, J=9.0 Hz, 1H), 8.79 (s, 1H), 9.71 (br s, 2H) ppm; MS (ion spray): m/z 490 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18]([C:20]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[CH2:22][CH2:21]2)=O)=[CH:11][C:10]=1[O:31][CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(#N)C.P(Cl)(Cl)(Cl)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]2[C:12]([CH2:15][CH2:16][N:17]=[C:18]2[C:20]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[CH2:22][CH2:21]2)=[CH:11][C:10]=1[O:31][CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(CCNC(=O)C2(c3ccccc3OC)CC2)ccc1OCc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1cc2c(cc1OCc1ccccc1)C(C1(c3ccccc3OC)CC1)=NCC2
Reaction time: 0.17 h

Procedure:
A mixture of N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-1-(2-methoxyphenyl)cyclopropane carboxamide (30.3 g) in acetonitrile (450 ml) and phosphoryl chloride (50 ml) was heated under reflux for 80 minutes. The solvent was evaporated in vacuo below 50° C. and the residue washed with ethyl acetate and then stirred with ethyl acetate (300 ml) and ice-cold 5% aqueous ammonia solution (200 ml) for 10 minutes. The organic layer was dried over potassium carbonate and the solvent removed by evaporation to give 7-benzyloxy-6-methoxy-1-[1-(2-methoxyphenyl)cyclopropyl]-3,4-dihydroisoquinoline.
Reaction SMILES: [F:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:18]([O:20]CC)=[O:19])=[CH:8][N:9]2[C@@H:14]2[CH2:16][C@@H:15]2[F:17])=[CH:4][CH:3]=1.Cl>C(O)(=O)C>[F:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:18]([OH:20])=[O:19])=[CH:8][N:9]2[C@@H:14]2[CH2:16][C@@H:15]2[F:17])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(OC)c(F)ccc2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: COc1c(F)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 0 °C

Procedure:
After dissolving ethyl 7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylate (34.0 g, 105 mmol) in acetic acid (400 ml) and then adding concentrated hydrochloric acid (400 ml) thereto, it was heated under reflux for 3 hours. After cooling, the reaction solution was poured into ice water (1500 ml), and the precipitated crystals were filtered out. After washing the filtered-out crystals with an excess amount of water, it was washed with cold ethanol and diethyl ether in that order, and after drying under a reduced pressure, the crude crystals obtained were purified by recrystallization from a mixed solvent of acetonitrile-ethanol and then dried under a reduced pressure. 27.1 g (87.4%) of the title compound was there by obtained in the form of a white powder.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([Br:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[N:30]1([CH2:35][CH2:36][CH2:37][CH2:38][NH2:39])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[Br:24][C:20]1[CH:19]=[C:18]([F:25])[C:17]([CH2:16][O:15][C:12]2[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:39][CH2:38][CH2:37][CH2:36][CH2:35][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:29])[S:14][N:13]=2)=[C:22]([F:23])[CH:21]=1
Reactant: NCCCCN1CCCC1
Reactant: NC(=O)c1c(OCc2c(F)cc(Br)cc2F)nsc1NC(=O)Oc1ccccc1
Product: NC(=O)c1c(OCc2c(F)cc(Br)cc2F)nsc1NC(=O)NCCCCN1CCCC1

Procedure:
The title compound was prepared from [3-(4-bromo-2,6-difluoro-benzyloxy)-4-carbamoyl-isothiazol-5-yl]-carbamic acid phenyl ester and 4-pyrrolidin-1-yl-butylamine by the procedure analogous to Example 1. MS (APCl, m/z): 532 and 534 [M+H]+.
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([O:15]CC)=[O:14])=[CH:4]2.[OH-].[Na+].Cl>C(O)C.O>[N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([OH:15])=[O:14])=[CH:4]2
Reactant: CCOC(=O)C1=Cc2cnc3cccc(n23)S1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1=Cc2cnc3cccc(n23)S1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 193.69 g of the above ethyl 5-thia-1,8b-diazaacenaphthylene-4-carboxylate in 1 l of ethanol was added a solution of 62.9 g (1.57 mol) of sodium hydroxide in 500 ml of water, and the mixture was stirred at room temperature for 0.5 hour. To this reaction mixture was added about 130 ml of concentrated hydrochloric acid with stirring to bring the pH into the range of 4-5 and the resulting precipitate was recovered by filtration and rinsed with ethanol, acetone, and diethyl ether in that order to provide the title compound.
Reaction SMILES: Cl.[Br:2][C:3]1[C:4]([O:21][CH3:22])=[CH:5][C:6]2[C@@H:15]3[C@H:10]([CH2:11][CH2:12][N:13]([CH3:16])[CH2:14]3)[CH2:9][C:8](=[O:17])[C:7]=2[C:18]=1[O:19]C.B(Br)(Br)Br>C(Cl)Cl>[Br:2][C:3]1[C:4]([O:21][CH3:22])=[CH:5][C:6]2[C@@H:15]3[C@H:10]([CH2:11][CH2:12][N:13]([CH3:16])[CH2:14]3)[CH2:9][C:8](=[O:17])[C:7]=2[C:18]=1[OH:19]
Reactant: COc1cc2c(c(OC)c1Br)C(=O)C[C@H]1CCN(C)C[C@H]21
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: COc1cc2c(c(O)c1Br)C(=O)C[C@H]1CCN(C)C[C@H]21
Reaction time: 1 h
Yield: 8.4 %

Procedure:
A solution of 0.421 g (1:11 mmol) of trans-8-bromo-7,9-dimethoxy-2-methyl-1,3,4,4a,5,10b-hexahydro-2H-benzo[h] isoquinolin-6-one hydrochloride in 40 ml of methylene chloride was treated at −70° with 1.23 ml of a 1M BBr3 solution in methylene chloride. After 15 minutes the cooling bath was removed. After the solution had reached room temperature it was stirred for one hour, subsequently poured on to 80 ml of ice/sat. sodium hydrogen carbonate solution and extracted three times with 60 ml of methylene chloride. The organic phase was dried (Na2SO4), filtered and evaporated. Chromatography (silica gel, methylene chloride/methanol 9:1) yielded 0.315 g (83%) of trans-8-bromo-7-hydroxy-9-methoxy-2-methyl-1,3,4,4a,5,10b-hexahydro-2H-benzo[h]isoquinolin-6-one, which was converted with HCl in methanol into the hydrochloride with m.p. 257-259°.