Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH2:12][NH2:13])[NH:10][N:11]=1.[C:20]([O:23][CH2:24][CH3:25])(=[O:22])C>C([O-])(O)=O.[Na+].ClC(OC)=O>[CH2:24]([O:23][C:20](=[O:22])[NH:13][CH2:12][C:9]1[NH:10][N:11]=[C:7]([C:6]2[O:5][C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:3][C:2]=2[CH3:1])[CH:8]=1)[CH3:25]
Reactant: CCOC(C)=O
Reactant: Cc1nc(-c2ccccc2)oc1-c1cc(CN)[nH]n1
Agent: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)NCc1cc(-c2oc(-c3ccccc3)nc2C)n[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
A heterogeneous mixture of the above-prepared C-[5-(4-Methyl-2-phenyl-oxazol-5-yl)-2H-pyrazol-3-yl]-methylamine (31 mg, 0.122 mmole, 1.0 eq) in ethyl acetate (0.5 ml) and 1.0N NaHCO3 (0.5 ml) was treated with excess methyl chloroformate (5 drops) and the mixture stirred at room temperature for 30 minutes. The mixture was partitioned between ethyl acetate and saturated NaHCO3. The organic phase was washed with water and brine, then dried over anhydrous sodium sulfate and evaporated in vacuo to give a yellow solid. Silica gel chromatography eluting with (4:1) hexanes-acetone provided 28 mg (74%) of the title compound as a white solid. 1H NMR (DMSO-d6): δ 2.6 (s, 3H), 3.6 (s, 3H), 4.25 (m, 2H), 6.5 (s, 1H), 7.5 (m, 3H), 7.7 (bm, 1H), 8.0 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:9]=[C:10]([CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])[CH:11]=[C:12]([CH2:14][CH2:15][NH:16][S:17]([CH2:20][C:21]([F:24])([F:23])[F:22])(=[O:19])=[O:18])[CH:13]=2)[CH:2]=1.N.C(O)(=O)C>Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:9]=[C:10]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:11]=[C:12]([CH2:14][CH2:15][NH:16][S:17]([CH2:20][C:21]([F:23])([F:24])[F:22])(=[O:18])=[O:19])[CH:13]=2)[CH:2]=1
Reactant: CCOC(=O)CCc1cc(CCNS(=O)(=O)CC(F)(F)F)cc(Cc2cccnc2)c1
Agent: Cl
Agent: N
Solvent: CC(=O)O
Product: O=C(O)CCc1cc(CCNS(=O)(=O)CC(F)(F)F)cc(Cc2cccnc2)c1
Yield: 70.6 %

Procedure:
A stirred solution of ethyl 3-{3-(3-pyridylmethyl)-5-[2-(2,2,2-trifluoroethylsulphonylamino)ethyl]phenyl}propanoate (Example 10; 400 mg) in 6N hydrochloric acid (4.0 ml) was heated at 100° C. for 4 hours. The cool solution was basified with aqueous ammonia solution (SG 0.880) and then re-acidified by the dropwise addition of glacial acetic acid. The mixture was extracted several times with ethyl acetate and the combined extracts were washed with water and dried (MgSO4). Evaporation under vacuum of the solvent gave the title compound as a gum (265 mg); Rf 0.35 (SS 7). Found: C, 53.26; H, 4.78; N, 6.31. C19H21F3N2O4S requires C, 53.01; H, 4.92; N, 6.51%.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([N+:16]([O-])=O)=[CH:11][C:10]=1[F:19])C1C=CC=CC=1>CO.C1COCC1.[Pd]>[NH2:16][C:12]1[C:13]([F:15])=[CH:14][C:9]([OH:8])=[C:10]([F:19])[CH:11]=1
Reactant: O=[N+]([O-])c1cc(F)c(OCc2ccccc2)cc1F
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cc(F)c(O)cc1F
Temperature: 32 °C
Reaction time: 10 h
Yield: 86.1 %

Procedure:
To a suspension of 1-(benzyloxy)-2,5-difluoro-4-nitrobenzene (1.06 g, 4 mmol) in CH3OH (25 mL) and THF (5 mL) was added Pd/C (50% Pd content, 185 mg). The reaction was stirred at 32° C. under H2 atmosphere for 10 hours. The mixture was filtered through a CELITE® pad and the filtrate was concentrated in vacuo. The residue was washed with DCM (15 mL) to give the title compound as a dark brown solid (500 mg, 86%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[C:24]1([C:30]2[C:31]([C:36](O)=[O:37])=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:36]([C:31]3[C:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:35][CH:34]=[CH:33][N:32]=3)=[O:37])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CCO1
Reactant: O=C(O)c1ncccc1-c1ccccc1
Product: C[C@@]1(c2cc(NC(=O)c3ncccc3-c3ccccc3)ccc2F)CCOC(N)=N1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F1 (R3=Me) and 3-phenyl-pyridine-2-carboxylic acid followed by deprotection using procedure H yielded the title compound.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:15]1([C:23](=[O:24])[NH:22][C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:20]1)[CH2:14]2)C1C=CC=CC=1>CO.[Pd]>[NH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:15]1([C:23](=[O:24])[NH:22][C:21]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[N:20]1)[CH2:14]2
Reactant: O=C(Nc1ccc2c(c1)CC1(C2)N=C(c2ccccc2)NC1=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)CC1(C2)N=C(c2ccccc2)NC1=O

Procedure:
To a solution of (±)-benzyl (5-oxo-2-phenyl-1,1′,3′,5-tetrahydrospiro[imidazole-4,2′-inden]-5′-yl)carbamate from Step A (568 mg, 1.94 mmol) in degassed MeOH (2 mL) was added 10% palladium on carbon (5 mg). The suspension was placed under a hydrogen balloon for 3 h, then filtered through a pad of Celite, concentrated, and dried under high vacuum to give the title compound. MS: m/z=278 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:4][CH2:3]1.Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([NH2:25])[CH:20]=1>O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:19]3[CH:20]=[C:21]([NH2:25])[N:22]=[CH:23][N:24]=3)=[CH:13][CH:12]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(CCOc2ccc(N)cc2)CC1
Reactant: Nc1cc(Cl)ncn1
Solvent: O
Product: CN1CCN(CCOc2ccc(Nc3cc(N)ncn3)cc2)CC1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
The title compound is prepared as described in Example 152A but using 4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenylamine (300 mg, 1.28 mmol, 1 eq.), 6-chloro-pyrimidin-4-ylamine, water (0.5 ml), and stirring the reaction mixture for 2 h at 150° C. The crude product is purified by trituration in diethyl ether to afford the title compound as a white solid. ESI-MS: 329.1 [MH]+; tR=0.98 min (purity: 100%, gradient J).
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[C:5](F)[CH:4]=1.C1CC(C(N)=O)[C:15](=[O:16])CC1>>[N:9]1[C:6]2[C:5](=[CH:4][CH:3]=[CH:8][CH:7]=2)[C:15](=[O:16])[N:10]=1
Reactant: NNc1ccc(Cl)cc1F
Reactant: NC(=O)C1CCCCC1=O
Agent: Cl
Product: O=C1N=Nc2ccccc21

Procedure:
The pH of the 4-chloro-2-fluorophenylhydrazine hydrochloride slurry was adjusted to 3.8-4.0 and the temperature was raised to 90°-95°. To this mixture was added an aqueous solution (preheated to 90°-95°) of 1118 parts of cyclohexanone-2-carboxamide prepared as previously described. The resulting mixture was heated for 1-2 hr at 90°-95° during which time the product precipitated from solution. The product was isolated by filtration, washed by digestion with toluene and air-dried to give 1771 parts of an indazolone, an off-white solid mp 179-182 which was 2-(4-chloro-2-fluorophenyl)-1,2,4,5,6,7-hexahydro-3H-indazol-3-one.
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]1)=[O:14])C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][CH2:9][CH2:10][O:11][CH2:12][C:13]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]1)=[O:14]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)COCCOCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)COCCO)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (S)-3-[2-[2-(benzyloxy)ethoxy]acetyl]amino-1-(tert-butoxycarbonyl)pyrrolidine (25 g) prepared in Step B in ethanol (150 ml) was added with 10% palladium/carbon (2.5 g, Merck), and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. The atmosphere in the reaction vessel was replaced with nitrogen gas, then the insoluble solids were removed by filtration through Celite, and the solvent was evaporated under reduced pressure to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].[C:51](=O)([O-])[O-].[K+].[K+].IC>>[OH:24][C@H:22]1[C@:21]2([O:25][CH3:26])[C@@:8]([OH:45])([C:9](=[O:44])[C:10]3[C:19]([C:20]2=[O:27])=[C:18]([OH:28])[C:17]2[C:16](=[O:29])[CH:15]=[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)[C:13](=[O:43])[C:12]=2[CH:11]=3)[C:7]2[C:2]([O:1][CH3:51])=[C:3]([C:47]([O:49][CH3:50])=[O:48])[C:4]([CH3:46])=[CH:5][C:6]=2[CH2:23]1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Agent: [K+]
Solvent: CI
Product: COC(=O)c1c(C)cc2c(c1OC)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Yield: 48.2 %

Procedure:
Following General Procedure: Method A using (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (25 mg, 0.035 mmol), potassium carbonate (15 mg, 0.11 mmol) and iodomethane (7 μL, 0.11 mmol), the product was purified by preparative TLC (silica gel, 95:5 dichloromethane/methanol) to afford (6R,6aS,14aR)-methyl 6,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-1,6a-dimethoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (12 mg, 48%) as a brown solid: 1H NMR (500 MHz, CDCl3) δ 14.15 (s, 1H), 8.11 (s, 1H), 6.84 (d, J=9.0 Hz, 1H), 6.81 (s, 1H), 5.88 (s, 1H), 5.04 (br s, 1H), 4.96 (dd, J=10.3, 6.6 Hz, 1H), 4.69 (d, J=8.9 Hz, 1H), 4.54 (d, J=10.6 Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.74-3.71 (m, 1H), 3.69 (dd, J=3.1, 1.2 Hz, 1H), 3.60 (s, 3H), 3.59 (s, 3H), 3.61-3.56 (m, 1H), 3.40 (s, 3H), 3.39-3.33 (m, 2H), 3.12 (t, J=9.2 Hz, 1H), 2.47 (d, J=4.6 Hz, 1H), 2.18 (s, 3H), 1.36 (d, J=6.2 Hz, 3H); MS (ESI+) m/z 712 (M+H); HPLC 95.9% (AUC), tR 12.66 min.
Reaction SMILES: [CH3:1][C:2](=[C:5]([CH3:8])[CH2:6][CH3:7])[CH2:3][CH3:4].[CH3:9][SiH:10]([CH3:12])[Cl:11].[Al+3].[Cl-].[Cl-].[Cl-]>>[CH2:3]([C:2]([Si:10]([CH3:12])([CH3:9])[Cl:11])([CH3:1])[CH:5]([CH2:6][CH3:7])[CH3:8])[CH3:4]
Reactant: CCC(C)=C(C)CC
Reactant: C[SiH](C)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCC(C)C(C)(CC)[Si](C)(C)Cl

Procedure:
According to Example 2, 200 mg of 3,4-dimethylhex-3-ene, 0.2 ml (1.8 mmol) of dimethylchlorosilane and 50 mg (0.37 mmol) of AlCl3 are reacted and the product is worked up. This gives 180 mg (50% of theory) of colourless liquid of boiling point= 95° -97° C./0.26 mbar.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[C:14]([Br:15])[C:9]2=[N:8][C:7]=1[S:17][CH3:18])=[O:5])C.[OH-].[Na+].Cl>C(O)C>[Br:15][C:14]1[C:9]2[N:10]([C:6]([C:4]([OH:5])=[O:3])=[C:7]([S:17][CH3:18])[N:8]=2)[CH:11]=[C:12]([CH3:16])[CH:13]=1
Reactant: CCOC(=O)c1c(SC)nc2c(Br)cc(C)cn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1nc2c(Br)cc(C)cn2c1C(=O)O
Yield: 90.4 %

Procedure:
8-Bromo-6-methyl-2-(methylsulfanyl)imidazo[1,2-a]pyridin-3-carboxylic acid ethyl ester (1.33 g) was dissolved in ethanol (50 mL), then a 5N aqueous sodium hydroxide solution (3 mL) was added thereto, and the mixture was stirred under reflux for 1 hour. Ice was added to the reaction mixture, then 2N hydrochloric acid (8 mL) was further added thereto, and as a result, the precipitates were obtained. The resulting precipitates were collected by filtration, washed with water, and dried under reduced pressure to give 8-bromo-6-methyl-2-(methylsulfanyl)imidazo[1,2-a]pyridine-3-carboxylic acid (1.1 g) as a white powder.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:11])[CH3:2].[N:12]#[C:13]Br>C1(C)C=CC=CC=1>[CH2:1]([N:3]([C:13]#[N:12])[C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:11])[CH3:2]
Reactant: N#CBr
Reactant: CCNc1c(C)cccc1C
Solvent: Cc1ccccc1
Product: CCN(C#N)c1c(C)cccc1C

Procedure:
N-ethyl-2,6-dimethylaniline (5.9 g, 39.6 mmol) was added to a stirred solution of cyanogen bromide (2.1 g, 19.8 mmol) in toluene (50 mL). The reaction mixture was allowed to react overnight at room temperature during which a solid formed. A small temperature rise to 30° C. was observed. The suspension was filtered and the residue was washed with toluene (3×25 mL). The combined filtrates were evaporated to dryness by rotatory evaporation and the resulting residue was purified by Kugelrohr distillation (0.2 mbar, 110-125° C.) yielding a brown oil. Yield: 3.09 g (90%). The residue (N-ethyl-2,6-dimethylaniline hydrobromide) of the filtration step was used in the following synthetic step.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.CCN(CC)CC.[CH3:20][O:21][C:22]1[CH:38]=[CH:37][C:25]([CH2:26][NH:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[CH:24][CH:23]=1>C(Cl)Cl.O>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:27]([CH2:26][C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:38][CH:37]=2)[CH2:28][C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)S(=O)(=O)c2ccc(CBr)cc2)cc1
Reaction time: 12 h

Procedure:
A solution of 4-(bromomethyl)benzenesulfonyl chloride (5.6 mmol) in 5 mL of CH2Cl2 at 25° C. is treated with Et3N (8.4 mmol) followed by bis-(4-methoxy-benzyl)-amine (5.8 mmol). The reaction is stirred for 12 hours, diluted with H2O, extracted with CH2Cl2, dried (MgSO4), filtered and concentrated. The resultant crude material is purified by silica flash chromatography (20% EtOAc/hexanes) to yield 4-bromomethyl-N,N-bis-(4-methoxy-benzyl)-benzenesulfonamide: 1H NMR (400 MHz, CDCl3): δ 7.72 (apparent t, J=8.4 Hz, 2H), 7.44 (dd, J1=1.6 Hz, J2=8.4 Hz, 2H), 6.91-6.86 (m, 4H), 6.69 (d, J=8.8 Hz, 4H), 4.5 (s, 2H), 4.19 (s, 4H), 3.71 (s, 3H); LC/MS: (ES+) 490.1 (M+1)+.
Reaction SMILES: Cl.[CH2:2]([C:5]1([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH2:14][CH2:13][C:8]2(OCC[O:9]2)[CH2:7][CH2:6]1)[CH:3]=[CH2:4].C(=O)([O-])O.[Na+].ClCCl>CC(C)=O.O>[CH2:2]([C:5]1([NH:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[CH2:14][CH2:13][C:8](=[O:9])[CH2:7][CH2:6]1)[CH:3]=[CH2:4]
Reactant: C=CCC1(NCc2ccc(OC)cc2)CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: ClCCl
Product: C=CCC1(NCc2ccc(OC)cc2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Concentrated hydrochloric acid (0.5 ml) was added to a solution of (8-allyl-1,4-dioxaspiro[4.5]dec-8-yl)-(4-methoxybenzyl)amine (C-9) (1.0 g, 3.15 mmol) in acetone (10 ml) and water (0.5 liter), and the mixture was stirred for 16 h at room temperature. Then saturated sodium hydrogen carbonate solution (40 ml) was added to the solution, and extraction with dichloromethane (3×40 ml) was carried out. The combined organic phases were dried with sodium sulfate and concentrated in vacuo.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]2[O:14][CH2:15][C:16]3([CH2:18][CH2:17]3)[N:7]3[C:8]=2[C:3]=1[C:4](=[O:21])[C:5]([C:19]#[N:20])=[CH:6]3.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][CH2:30][NH2:31])[CH:23]=1.C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:31][CH2:30][CH2:29][CH2:28][C:24]2[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=2)[C:9]2[O:14][CH2:15][C:16]3([CH2:18][CH2:17]3)[N:7]3[C:8]=2[C:3]=1[C:4](=[O:21])[C:5]([C:19]#[N:20])=[CH:6]3
Reactant: NCCCc1cccnc1
Reactant: N#Cc1cn2c3c(c(F)c(F)c(N)c3c1=O)OCC21CC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1cn2c3c(c(NCCCc4cccnc4)c(F)c(N)c3c1=O)OCC21CC1
Yield: 25.1 %

Procedure:
A solution of 8-amino-9,10-difluoro-7-oxo-2,7-dihydrospiro[[1,4]oxazino-[2,3,4-ij]quinoline-3,1′-cyclopropane]-6-carbonitrile (150 mg, 0.52 mmol), 3-(pyridine-3-yl)propan-1-amine (176 mg, 1.3 mmol), and triethylamine (108 μL, 1.3 mmol) in DMSO (3 mL) was stirred at 120° C. for 15 hr. The reaction mixture was cooled and concentrated. The crude product was taken up in acetonitrile and purified by preparative HPLC to yield the title compound as a yellow solid (52.9 mg). MS (EP) m/z: 406.2 (M++1). (Calcd for C22H20FN5O2, 405.42). 1H NMR (400 MHz, D2O) δ 1.20 (2H, t), 1.50 (2H, t), 2.00 (2H, m,), 2.94 (2H, m,), 3.51 (2H, m), 4.14 (2H, s), 7.86 (1H, m), 8.03 (1H, m), 8.41 (1H, m), 8.52 (1H, m), 8.58 (1H, s)
Reaction SMILES: C([O:5][C:6](=[O:13])[C@H:7]([CH2:9][CH2:10][CH2:11][CH3:12])[NH2:8])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl.C1C=CC=CC=1>[NH2:8][C@H:7]([C:6]([OH:13])=[O:5])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCC[C@H](N)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccccc1
Solvent: ClCCl
Product: CCCC[C@H](N)C(=O)O

Procedure:
32 mg of L-N-[(2R or S)-3-(1-methyltetrazol-5-yl)sulfonyl-2-(1-naphthylmethyl)propionyl]norleucine tert-butyl ester was dissolved in 0.7 ml of dichloromethane. Then, 0.5 ml of TFA was added thereto, and the mixture was reacted at room temperature for one hour. Then, the reaction solution was concentrated under reduced pressure. The syrup thereby obtained was sequentially dissolved in benzene and benzene/n-hexane and then subjected to azeotropic concentration under reduced pressure to obtain a slightly yellow powder. L-N-[(2R or S)-3-(1-methyltetrazol-5-yl)sulfonyl-2-(1-naphthylmethyl)propionyl]norleucine thus obtained was throughly dried under reduced pressure and then dissolved in 0.5 ml of dry DMF. Then, 21 μl of triethylamine and 17 μl of DPPA were sequentially added thereto at -20° C., and the mixture was stirred. Five minutes later, a solution mixture comprising 22 mg of (2RS,4S,5S)-5-amino-2-ethyl-4-hydroxy-7-methyloctanoic acid isobutylamide hydrochloride, 22 μl of triethylamine and 8.5 ml of dry DMF, was added to the reaction solution, and the mixture was stirred at -20° C. for one hour and at 5° C. overnight. The reaction solution thereby obtained was diluted with 20 ml of ethyl acetate and washed sequentially with 10 ml of a 2% sodium hydrogencarbonate aqueous solution and with 10 ml of a saturated sodium chloride aqueous solution. The ethyl acetate layer was separated and dried over anhydrous sodium sulfate. Then, the inorganic salt was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue thereby obtained was purified by silica gel column chromatography (chloroform/methanol=10/1). The eluted fractions containing the desired product were collected and concentrated. The residue was reprecipitated in an ethyl ether/pentane solution to obtain 33 mg of (2S,4S,5 S)-5-{L-N-[(2R or S)-3-(1-methyltetrazol-5-yl)sulfonyl-2-(1-naphthylmethyl)propionyl]norleucil}amino-2-ethyl-4-hydroxy-7-methyloctanoic acid isobutylamide as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.ClC1C=C(C2ON=C(C3C=C4C(=CC=3)NC=C4)N=2)C=CC=1OC>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6]2
Reactant: COc1ccc2[nH]ccc2c1
Agent: COc1ccc(-c2nc(-c3ccc4[nH]ccc4c3)no2)cc1Cl
Product: COc1ccc2c(c1)CCN2
Yield: 84 %

Procedure:
When 5-methoxy-1H-indole was substituted for 5-(3-chloro-4-methoxyphenyl)-3-(1H-indol-5-yl)-1,2,4-oxadiazole in Example 7, Step F, the identical process afforded the title compound in 84% yield., as a creamy syrup. 1H-NMR (CDCl3) 2.99 (tr, 2H, J=8.35 Hz); 3.28 (broad s, 1H); 3.52 (tr, 2H, J=8.35 Hz); 3.73 (s, 3H); 6.57 (m, 2H); 6.75 (s, 1H).
Reaction SMILES: CS(Cl)(=O)=O.[Br:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH:14](O)[CH3:15].CCN(CC)CC.[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)=[CH:27][CH:26]=1>C(Cl)Cl>[Br:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH:14]([NH:37][C:34]1[CH:33]=[CH:32][C:31]([C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=2)=[CH:36][CH:35]=1)[CH3:15]
Reactant: Nc1ccc(-c2ccc(F)cc2)cc1
Reactant: CC(O)c1ccc(Cl)cc1Br
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Nc1ccc(-c2ccc(F)cc2)cc1)c1ccc(Cl)cc1Br
Temperature: 25 °C

Procedure:
Neat methanesulfonyl chloride (0.18 mL, 2.4 mmol) was added to a 0° C., DCM solution (20 mL) of 1-(2-bromo-4-chlorophenyl)ethanol (558 mg, 2.4 mmol) and Et3N (0.36 mL, 2.6 mmol) and the resulting mixture was allowed to warm to room temperature gradually. After 30 min Et3N (0.36 mL, 2.6 mmol) and 4′-fluoro-[1,1′-biphenyl]-4-amine (444 g, 2.4 mmol) were added sequentially and stirred at room temperature. After 16 h the resulting mixture was concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: C[O:2][CH:3]1[CH:7]([CH:8]=O)[CH2:6][CH:5](OC)O1.[C:12]1([S:18]([NH2:21])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:12]1([S:18]([N:21]2[CH:5]=[CH:6][C:7]([CH:3]=[O:2])=[CH:8]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC1CC(C=O)C(OC)O1
Reactant: NS(=O)(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1ccn(S(=O)(=O)c2ccccc2)c1
Yield: 88.2 %

Procedure:
A solution of 5.91 g (0.037 mol) of 2,5-dimethoxytetrahydrofuran-3-carbaldehyde, 5.80 g (0.037 mol) of phenylsulfonamide and a spatula tip of 4-toluenesulfonic acid in 50 ml of toluene was refluxed with a water trap until water no longer separated out. The reaction mixture was washed three times with water. The organic phase was dried over magnesium sulfate with addition of activated carbon and silica gel and concentrated in vacuo. 7.68 g of a brown resin were obtained.
Reaction SMILES: [C:1]1([CH:7]([CH:9]([C:15]([O-:17])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CC(C)=O.O>[CH2:13]([O:12][C:10]([CH:9]([CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:8])[C:15]([OH:17])=[O:16])=[O:11])[CH3:14]
Reactant: CCOC(=O)C(C(=O)[O-])C(C)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C(C(=O)O)C(C)c1ccccc1
Yield: 65 %

Procedure:
The ethyl (1-phenylethyl)malonate is stirred overnight with sodium hydroxide (1.3 eq) in an acetone/water (3:1 by volume) mixture. After concentrating to dryness, the residue is taken up with water (40 mL) and the mixture is then extracted three times with ethyl acetate (25 mL). The organic phase is washed, dried, filtered and concentrated to dryness to yield 3.5 g of 2-ethoxycarbonyl-3-phenylbutanoic acid in a 65% yield in the form of an oil, having the following characteristics: Rf =0.50 [methylene chloride/methanol (9:1 by volume)].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[CH2:9][CH2:10][CH:11]=[CH2:12])=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:13])[CH2:9][CH2:10][CH:11]=[CH2:12])=[CH:6][CH:7]=1
Reactant: C=CCCC(O)c1ccc(F)cc1
Agent: O=[Cr](=O)([O-])Cl
Solvent: ClCCl
Product: C=CCCC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.4 %

Procedure:
To a stirred solution of 1-(4-fluoro-phenyl)-pent-4-en-1-ol (4.9 g) in dichloromethane (5 ml) was added pyridimium chlorochromate (7.033 g). The reaction mixture was stirred for 16 hours at room temperature. Silica gel was added and the solvent was evaporated. Column chromatography (SiO2; heptane/EtOAc 4:1) gave 1-(4-fluoro-phenyl)-pent-4-en-1-one (4.67 g, 96%) as a light yellow liquid.MS (EI): 178.0 ([M+H]+)), 123.0 (F—C6H4CO+)