Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:30][CH:31]([F:33])[F:32])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25]/[CH:26]=[CH:27]/[CH2:28]Cl)[N:9]=2)[CH:7]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:30][CH:31]([F:32])[F:33])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25]/[CH:26]=[CH:27]/[CH2:28][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[N:9]=2)[CH:7]=1
Reactant: C1COCCN1
Reactant: O=C(Nc1cn(C/C=C/CCl)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Solvent: CN(C)C=O
Product: O=C(Nc1cn(C/C=C/CN2CCOCC2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12

Procedure:
A solution of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2E)-4-chlorobut-2-en-1-yl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (160 mg, 0.324 mmol) and morpholine (0.5 mL) in DMF (4 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, silica gel; mobile phase, CH3CN/H2O=20% increasing to CH3CN/H2O=50% within 20 min; Detector, UV 254 nm. 35.4 mg product was obtained. This resulted in 35.4 mg (20%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2E)-4-(morpholin-4-yl)but-2-en-1-yl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a off-white solid. LCMS (Method 23) [M+H]+=544.0, RT=2.37 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.74 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.68-8.66 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.58 (d, 1H, J=2.8 Hz), 7.44 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 6.8 Hz), 7.06 (t, 1H, J=73.2 Hz), 5.94-5.84 (m, 1H), 5.79-5.69 (m, 1H), 4.82 (d, 2H, J=6.0 Hz), 3.56 (t, 4H, J=4.6 Hz), 2.96 (d, 2H, J=6.4 Hz), 2.40-2.30 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18]/[CH:19]=[C:20](/[C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)\[CH3:21])=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[OH-].[Na+]>>[CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18]/[CH:19]=[C:20](/[C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:35])[CH3:36])=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)\[CH3:21])=[CH:13][CH:12]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(C(C)C)cc3)cc2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(C(C)C)cc3)cc2)cc1)C(=O)O
Yield: 100.8 %

Procedure:
The title compound was prepared from (E)-(S)-ethyl 2-ethoxy-3-{4-[3-(4′-isopropyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionate (Example 103) (400 mg, 0.822 mmol) and sodium hydroxide (1M, 3.29 ml, 3.29 mmol) by a procedure analogous to that described in example 51, yielding (E)-(S)-2-ethoxy-3-{4-[3-(4′-isopropyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionic acid (380 mg, 100%) as a beige coloured solid.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)([O-:5])=[O:4].F[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.O>CN(C=O)C>[N+:3]([C:6]1[C:14]2[N:13]=[CH:12][N:11]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: N#Cc1ccc(F)cc1
Reactant: O=[N+]([O-])c1cccc2[nH]cnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(-n2cnc3c([N+](=O)[O-])cccc32)cc1
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To a stirred suspension of sodium hydride (665 mg, 16.64 mmol) in DMF (90 mL) at rt was added 4-nitro-1H-benzimidazole (2714 mg, 16.64 mmol) in several portions. After stirring for 1 h, 4-fluorobenzonitrile (1350 mg, 11.146 mmol) was added and the mixture was stirred for 15 h at 130° C. After cooling, water was added, the precipitate was filtered off, washed with water and dried to yield 4-(4-nitro-benzoimidazol-1-yl)-benzonitrile (2.47 g, 47.76%).
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=2)[C:6]([B:16]2[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]2)=[CH:5]1)([CH3:3])[CH3:2]>C(O)C.[Pd]>[CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[C:6]([B:16]2[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]2)=[CH:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1cc(B2OC(C)(C)C(C)(C)O2)c2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CCO
Product: CC(C)n1cc(B2OC(C)(C)C(C)(C)O2)c2ccc(N)cc21
Reaction time: 18 h

Procedure:
Method P Add a solution of 1-isopropyl-6-nitro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole, (4, R1=i-Pr) (14.48 g, 43.88 mmol) in ethanol to a suspension of 5% palladium on carbon (1.44 g) and ethanol in a Parr reaction bottle. Place the contents of the reaction bottle under a hydrogen atmosphere (60 psi) and shake on a Parr shaker at room temperature for 18 hr. After 18 hr, filter the contents of the reaction vessel through a pad of Celite, and concentrate the resulting filtrate in vacuo. The resulting crude, light-pink, crystalline material (11.84 g, 90%) can be used without further purification. 1H NMR (DSMO-d6) δ 7.39 (s, 1H), 7.39 (d, 1H, J=8.3 Hz), 6.54 (d, 1H, J=1.8 Hz), 6.41 (dd, 1H, J=8.3 Hz, 1.8 Hz), 4.73 (br s, 2H), 4.37 (septet, 1H, J=6.8 Hz), 1.37 (d, 6H, J=6.8 Hz), 1.23 (br s, 12H); MS (API ES+) m/e 301 (M+1).
Reaction SMILES: [CH3:1][C:2]12[C:14]3[C:6](=[CH:7][C:8]([NH2:15])=[CH:9][C:10]=3[CH2:11][CH2:12][CH2:13]1)[CH2:5][CH2:4][CH2:3]2.C1C=CC=CC=1.Cl[S:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)(=[O:25])=[O:24].Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:1][C:2]12[C:14]3[C:6](=[CH:7][C:8]([NH:15][S:23]([C:26]4[CH:27]=[CH:28][C:29]([C:30]([OH:32])=[O:31])=[CH:33][CH:34]=4)(=[O:25])=[O:24])=[CH:9][C:10]=3[CH2:11][CH2:12][CH2:13]1)[CH2:5][CH2:4][CH2:3]2
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC12CCCc3cc(N)cc(c31)CCC2
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC12CCCc3cc(NS(=O)(=O)c4ccc(C(=O)O)cc4)cc(c31)CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
6a-Methyl-5,6,6a,7,8,9-hexahydro-4H-2-phenalenylamine (0.100 g) was dissolved in pyridine (5 ml) and anhydrous benzene (2 ml), the solution was added with 4-chlorosulfonylbenzoic acid (0.115 g) and 4-dimethylaminopyridine (one pellet), and the mixture was stirred overnight at room temperature. The reaction mixture was added with 2 N aqueous hydrochloric acid and thereby made acidic, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was recrystallized from ethyl acetate-n-hexane to obtain the title compound (0.110 g, yield: 57%) as colorless needles (melting point: 215-217° C.).
Reaction SMILES: CS(O[C@H:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=4)[CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:7]1)(=O)=O.[CH3:28][C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:28][C@@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[C@@H:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]3[CH:19]=[C:18]([C:20]4[CH:21]=[CH:22][C:23]([C:26]#[N:27])=[CH:24][CH:25]=4)[CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:7]1
Reactant: C[C@@H]1CCCN1
Reactant: CS(=O)(=O)O[C@H]1CCN(c2nc3ccc(-c4ccc(C#N)cc4)cc3s2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H]1CCCN1[C@@H]1CCN(c2nc3ccc(-c4ccc(C#N)cc4)cc3s2)C1
Temperature: 25 °C

Procedure:
A stirred solution of (S)-1-(6-(4-cyanophenyl)benzo[d]thiazol-2-yl)pyrrolidin-3-yl methanesulfonate (Reference Example 13c, 32 mg, 0.080 mmol), (R)-2-methylpyrrolidine (27.3 mg, 0.320 mmol), and N,N-diisopropylethylamine (0.17 mL, 0.961 mmol) in acetonitrile (2 mL) was heated to 150° C. under microwave irradiation for 20 minutes. The reaction mixture was cooled to room temperature then purified by silica gel chromatography (98:2:0 to 98:2:1 dichloromethane/methanol/aqueous NH4OH). Fractions containing product were dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give to give 4-(2-((2R,3′R)-2-methyl-1,3′-bipyrrolidin-1′-yl)benzo[d]thiazol-6-yl)benzonitrile.
Reaction SMILES: [NH:1]([C:3]1[CH2:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]=1)[NH2:2].[CH3:20][N:21]([CH3:29])[CH2:22][CH2:23][C:24](=O)[C:25]([OH:27])=[O:26]>>[C:25]([C:24](=[N:2][NH:1][C:3]1[CH2:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]=1)[CH2:23][CH2:22][N:21]([CH3:29])[CH3:20])([OH:27])=[O:26]
Reactant: CN(C)CCC(=O)C(=O)O
Reactant: NNC1=Nc2ccccc2C(c2ccccc2)=NC1
Product: CN(C)CCC(=NNC1=Nc2ccccc2C(c2ccccc2)=NC1)C(=O)O

Procedure:
In the manner given in Example 13, 2-hydrazino-5-phenyl-3H-1,4-benzodiazepine can be stirred with 4-(dimethylamino)-2-oxobutyric acid at room temperature to give 2-[[1-carboxy-3-(dimethylamino)propylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-:7].[F:8][C:9]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[C:15]2[C:10]=1[C:11](=[O:27])[CH:12]=[C:13]([C:23]([F:26])([F:25])[F:24])[NH:14]2.S([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.CN(C=O)C>[F:8][C:9]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[C:15]2[C:10]=1[C:11](=[O:27])[C:12]([I:7])=[C:13]([C:23]([F:25])([F:26])[F:24])[NH:14]2
Reactant: [I-]
Reactant: CCCOc1ccc(F)c2c(=O)cc(C(F)(F)F)[nH]c12
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOc1ccc(F)c2c(=O)c(I)c(C(F)(F)F)[nH]c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54.7 %

Procedure:
Potassium carbonate (3.73 g, 27 mmol) and iodide (6.85 g, 27 mmol) were added to a DMF solution (20 ml) of 5-fluoro-8-propoxy-2-trifluoromethyl-1H-quinolin-4-one (6.0 g, 20.7 mmol) in that order, and the resulting mixture was stirred at room temperature for 1.5 hours. A saturated sodium sulfite aqueous solution (20 ml) and ethyl acetate were added to the reaction mixture, and the precipitated solid was collected by filtration. The filtrate was washed with water, and then dried over anhydrous sodium sulfate. The dried filtrate was concentrated under reduced pressure. The residue and the substance collected by the advance filtration were combined, and dissolved in ethanol, and then concentrated. The residue was recrystallized from an ethyl acetate-n-hexane mixed solvent to thereby obtain 4.7 g of powdery white 5-fluoro-3-iodo-8-propoxy-2-trifluoromethyl-1H-quinolin-4-one (yield: 55%).
Reaction SMILES: [NH2:1][C@@:2]1([C:19]2[CH:24]=[C:23]([Br:25])[CH:22]=[CH:21][C:20]=2[F:26])[CH2:7][O:6][C@@H:5]([CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4][C@H:3]1[CH2:17]O.C([N:35]=[C:36]=[S:37])(=O)C1C=CC=CC=1.Cl>ClCCl.CO>[CH2:10]([O:9][CH2:8][C@@H:5]1[O:6][CH2:7][C@@:2]2([C:19]3[CH:24]=[C:23]([Br:25])[CH:22]=[CH:21][C:20]=3[F:26])[C@H:3]([CH2:17][S:37][C:36]([NH2:35])=[N:1]2)[CH2:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: N[C@@]1(c2cc(Br)ccc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: NC1=N[C@@]2(c3cc(Br)ccc3F)CO[C@@H](COCc3ccccc3)C[C@H]2CS1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
[(2R,4R,5S)-5-Amino-2-benzyloxymethyl-5-(5-bromo-2-fluorophenyl)tetrahydropyran-4-yl]methanol (2.22 g) was dissolved in dichloromethane (30 ml), and benzoyl isothiocyanate (776 μl) was added. The mixture was stirred at room temperature for five hours, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain an intermediate. The resulting intermediate was dissolved in methanol (50 ml), and concentrated hydrochloric acid (2 ml) was added. The mixture was heated under reflux for six hours and then cooled to room temperature. The solvent was evaporated under reduced pressure. Methanol (30 ml) and DBU (2 ml) were added to the residue, followed by heating under reflux for three hours. The reaction solution was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (2.30 g).
Reaction SMILES: Cl[C:2]1([Cl:8])[CH2:7][O:6][CH2:5][CH2:4][O:3]1.[N+:9]([C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1)([O-:11])=[O:10]>>[Cl:8][CH2:2][CH2:7][O:6][CH2:5][C:4]([NH:16][C:15]1[CH:17]=[CH:18][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=1)=[O:3]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: ClC1(Cl)COCCO1
Product: O=C(COCCCl)Nc1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
1.53 g of a mixture of 2-chlorodioxene and 2,2-dichlorodioxane (molar ratio 1:1) are added to 1.00 g (7.24 mmol) of 4-nitroaniline, and the mixture is heated to 80° C. with stirring. A solid brown mass forms within one hour and becomes liquid again and crystallises within the following 12 hours. The crude product is recrystallised from ethanol with addition of water, giving 1.80 g of 2-(2-chloroethoxy)-N-(4-nitrophenyl)acetamide (“A1”) as yellowish crystals, m.p. 101-102° C. 1H-NMR (d6-DMSO): δ=3.82 (m; 4H), 4.23 (s; 2H), 7.91 (d, J=9 Hz, 2H), 8.23 (d, J=9 Hz, 2H), 10.34 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([O:41]CC=C)[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:31][C@H:30]([CH2:32][O:33]CC4C=CC=CC=4)[C@@H:21]([O:22]CC4C=CC=CC=4)[C@@H:12]3[O:13]CC3C=CC=CC=3)[C:6]=2[N:7]=1.COC(O)C.[H][H]>[Pd].C(O)(=O)C>[NH2:1][C:2]1[NH:3][C:4](=[O:41])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:31][C@H:30]([CH2:32][OH:33])[C@@H:21]([OH:22])[C@@H:12]3[OH:13])[C:6]=2[N:7]=1
Reactant: C=CCOc1nc(N)nc2c1ccn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: COC(C)O
Solvent: CC(=O)O
Product: Nc1nc2c(ccn2[C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)[nH]1

Procedure:
A mixture of 8.0 g of 2-amino-4-allyloxy-7-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine, 1.5 g of 20% palladium on charcoal, 6.7 ml of acetic acid, and 150 ml of methoxy ethanol is hydrogenated at 50° C. and approximately 3 atmospheres until the uptake of hydrogen ceases. The mixture is filtered, evaporated in vacuo, dissolved in water, and treated with 60 ml of wet IR-45 ion exchange resin. The filtrate is concentrated to dryness in vacuo and the residue is recrystallized from water to provide pure 2-amino-7-β-D-arabinofuranosyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one.
Reaction SMILES: [CH:1]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15]([O:8][CH:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CCCCCC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCCCCC2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Into a one liter, four-necked, round bottom flask equipped with stirrer, condenser, and thermometer, 200.0 parts of pyridine and 28.5 parts of cycloheptanol were mixed under a nitrogen blanket and chilled to 0° C. with an ice water bath. To this solution 53.5 parts of p-toluenesulfonyl chloride were added in portions over thirty minutes. The solution was stirred for one hour at 0° C. and then allowed stand for twenty-four hours at 15° C. The mixture was poured into one liter of ice water and subsequently extracted with 700 parts of methylene chloride. The organic layer was washed successively with cold 6 N sulfuric acid (until the water layer was acidic to pH paper), dilute sodium bicarbonate (three times with 500 part-portions), and water (twice with 500 part-portions). It was then dried over sodium sulfate, filtered, and the solvent removed in vacuo to yield cycloheptyl para-toluenesulfonate.
Reaction SMILES: [Li+].[OH-].[C:3]([O:7][C:8]([N:10]([CH3:50])[C@@H:11]([CH3:49])[C:12]([NH:14][C@H:15]1[C@H:21]([CH3:22])[O:20][C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[N:17]([CH2:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([C:37]3[CH:45]=[CH:44][C:40]([C:41]([O-:43])=[O:42])=[CH:39][C:38]=3[C:46]#[N:47])[N:29]=2)[C:16]1=[O:48])=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[C:3]([O:7][C:8]([N:10]([CH3:50])[C@@H:11]([CH3:49])[C:12]([NH:14][C@H:15]1[C@H:21]([CH3:22])[O:20][C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[N:17]([CH2:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([C:37]3[CH:45]=[CH:44][C:40]([C:41]([OH:43])=[O:42])=[CH:39][C:38]=3[C:46]#[N:47])[N:29]=2)[C:16]1=[O:48])=[O:13])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: C[C@@H]1Oc2ccccc2N(Cc2nn(-c3ccc(C(=O)[O-])cc3C#N)c3ccccc23)C(=O)[C@H]1NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1Oc2ccccc2N(Cc2nn(-c3ccc(C(=O)O)cc3C#N)c3ccccc23)C(=O)[C@H]1NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C
Yield: 97.7 %

Procedure:
LiOH (1 N, 448 μl, 448 μmol, Eq: 1.3) was added to a solution of 4-(3-(((2S,3S)-3-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-2-methyl-4-oxo-3,4-dihydrobenzo[b][1,4]oxazepin-5(2H)-yl)methyl)-1H-indazol-1-yl)-3-cyanobenzoate (230 mg, 345 μmol, Eq: 1.00) in THF (7 mL) at 0° C. and H2O (3 mL) was added. After 7 h the mixture was acidified with citric acid to pH 4-5 and was extracted with EtOAc. The combined extracts were washed with H2O, dried over Na2SO4 and concentrated to give 4-(3-(((2S,3S)-3-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-2-methyl-4-oxo-3,4-dihydrobenzo[b][1,4]oxazepin-5(2H)-yl)methyl)-1H-indazol-1-yl)-3-cyanobenzoic acid (220 mg, 97.7%) which was used without purification.
Reaction SMILES: [C:1]([O-:16])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].P(OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.[C@@H:48]1([N:86]2[C:95]3[N:94]=[CH:93][N:92]=[C:90]([NH2:91])[C:89]=3[N:88]=[CH:87]2)[O:85][C@H:57]([CH2:58][O:59][P:60]([O:63][P:64]([O:67][CH2:68][C:69]([C@H:72]([C:74]([NH:76][CH2:77][CH2:78][C:79]([NH:81][CH2:82][CH2:83][SH:84])=[O:80])=[O:75])[OH:73])([CH3:71])[CH3:70])([OH:66])=[O:65])([OH:62])=[O:61])[C@@H:51]([O:52][P:53]([OH:56])([OH:55])=[O:54])[C@H:49]1[OH:50]>>[C:1]([S:84][CH2:83][CH2:82][NH:81][C:79](=[O:80])[CH2:78][CH2:77][NH:76][C:74](=[O:75])[C@H:72]([OH:73])[C:69]([CH3:70])([CH3:71])[CH2:68][O:67][P:64]([OH:66])(=[O:65])[O:63][P:60]([OH:62])(=[O:61])[O:59][CH2:58][C@H:57]1[O:85][C@@H:48]([N:86]2[C:95]3[N:94]=[CH:93][N:92]=[C:90]([NH2:91])[C:89]=3[N:88]=[CH:87]2)[C@H:49]([OH:50])[C@@H:51]1[O:52][P:53]([OH:56])([OH:55])=[O:54])(=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CC(C)(COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O)[C@@H](O)C(=O)NCCC(=O)NCCS
Reactant: CCCCCCCCCCCCCC(=O)[O-]
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Product: CCCCCCCCCCCCCC(=O)SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O

Procedure:
The compounds are then tested on the supernatant in competition with the peptide substrate Gly-Asn-(Ala)4 -(Arg)2 ("G8R") according to the conditions which follow, as described by TOWLER et al. (PNAS, (1987), 84, 2708-2711). Myristoylcoenzyme A is synthesized enzymatically immediately before use by incubation of myristate with ATP, Coenzyme A (lithium salt) and Pseudomonas Acyl-Coa synthetase (20 min at 30° C.). The peptide substrate and the biological source as obtained above are then added. The mixture is incubated for 10 min at 37° C.; the reaction is then stopped with 110 μl of methanol and 10 μl of trichloroacetic acid. The medium is left at 4° C. for 10 min and then centrifuged at 10,000 g for 5 min. An aliquot (30 μl) of the final supernatant is injected into an HPLC system equipped with a μBondapak column (Waters) and developed with a linear gradient as described by Towler et al. (PNAS, (1987), 84, 2708-11). Detection of the acylated peptide is performed using a radioactive line detector (Berthold) by means of the addition of 5 ml/min of scintillation fluid (Zinsser). The acylated peptide is eluted at 85% acetonitrile-TFA/15% H20-TFA.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[N:10]([CH2:15][CH2:16][CH3:17])[C:11](=[O:14])[CH2:12][CH3:13].C(O)(=O)C.[Br:22]Br>ClCCl>[Br:22][C:7]1[CH:8]=[C:9]2[C:4]([CH2:3][CH:2]([N:10]([CH2:15][CH2:16][CH3:17])[C:11](=[O:14])[CH2:12][CH3:13])[CH2:1]2)=[CH:5][CH:6]=1
Reactant: CCCN(C(=O)CC)C1Cc2ccccc2C1
Reactant: BrBr
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCN(C(=O)CC)C1Cc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.6 %

Procedure:
N-Indan-2-yl-N-propyl-propionamide (Preparation 13, 1 g, 4.32 mmol) was dissolved in dichloromethane (100 mL). Glacial acetic acid was added to adjust the pH to 4. This was followed by the addition of bromine (0.4 ml, 7.78 mmol). The solution was stirred at room temperature for 8 h. Additional bromine (0.2 ml, 3.89 mmol) was added and the solution was refluxed for 18 h. Since the reaction was not complete another portion of bromine (0.2 ml, 3.89 mmol) was added and the reaction mixture was refluxed for another 4 h. The organic layer was extracted with aqueous Na2CO3 (10%) and the layers were separated. The organic layer was dried (MgSO4). The solvent was evaporated and the remaining crude product was chromatographed (SiO2) with n-hexane:ethyl acetate (4:1) as eluant. The pure fractions were pooled yielding 0.45 g (34%) of N-(6-Bromo-indan-2-yl)-N-propyl-propionamide. 1H NMR (300 MHz, CDCl3) δ 0.85 (t, 3H), 1.15 (t, 3H), 1.50-1.65 (m, 2H), 2.30-2.50 (m, 2H), 2.90-3.25 (m, 6H), 4.70-5.10 (m, 1H), 7.00-7.10 (t, 1H), 7.25-7.40 (m, 2); MS m/e 309 (1, M+), 116 (100), 115 (92), 194 (57), 196 (55).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]([NH:13][C:14]1[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH2:24])[CH:20]=3)[N:15]=1)[CH2:10][CH2:9][CH2:8]2.[CH3:25][O:26][CH2:27][C:28](O)=[O:29]>>[CH3:25][O:26][CH2:27][C:28]([NH:24][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([NH:13][CH:11]1[C:12]3[C:7](=[CH:6][CH:5]=[CH:4][C:3]=3[O:2][CH3:1])[CH2:8][CH2:9][CH2:10]1)[CH:23]=[CH:22]2)=[O:29]
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CCC2
Reactant: COCC(=O)O
Product: COCC(=O)Nc1ccc2nc(NC3CCCc4cccc(OC)c43)ccc2c1

Procedure:
The title compound was prepared in accordance with the general method 14 described in example 119 from rac-N2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-quinoline-2,6-diamine and methoxyacetic acid; MS: m/e=392.3 (M+H+).
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16]([N:19]=[C:20]=[O:21])(=[O:18])=[O:17])=[CH:8][CH:9]=1)([O:3][CH3:4])=[O:2].[NH2:22][C:23]1[N:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[N:24]=1.C1N2CCN(CC2)C1>C(#N)C>[C:1]([C:5]1[O:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16]([NH:19][C:20]([NH:22][C:23]2[N:24]=[C:25]([O:31][CH3:32])[CH:26]=[C:27]([O:29][CH3:30])[N:28]=2)=[O:21])(=[O:17])=[O:18])=[CH:8][CH:9]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccc(-c2ccccc2S(=O)(=O)N=C=O)o1
Reactant: COc1cc(OC)nc(N)n1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: COC(=O)c1ccc(-c2ccccc2S(=O)(=O)NC(=O)Nc2nc(OC)cc(OC)n2)o1
Reaction time: 8 h
Yield: 93.2 %

Procedure:
Under a nitrogen atmosphere, a mixture of 2.5 g of the product of Example 3, 0.9 g of 2-amino-4,6-dimethoxypyrimidine, and a few crystals of DABCO in 15 ml of dry acetonitrile was heated at 50°-55° for 1 hour, then stirred at 25° overnight. The solid was filtered off, washed with acetonitrile and 1-chlorobutane, and dried at 60° in vacuo to give 2.5 g of the title compound, mp=215°-217° (d).