Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:17])([CH3:16])[C@H:3]1[OH:18].[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[OH:18][C@H:3]1[C@H:2]([NH:1][C:26]([NH:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:27])[C:7]2[CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=[CH:11][C:6]=2[O:5][C:4]1([CH3:16])[CH3:17]
Reactant: O=C=Nc1ccccc1
Reactant: CC1(C)Oc2ccc(C(F)(F)F)cc2[C@@H](N)[C@@H]1O
Solvent: CCO
Product: CC1(C)Oc2ccc(C(F)(F)F)cc2[C@@H](NC(=O)Nc2ccccc2)[C@@H]1O
Yield: 69.2 %

Procedure:
A suspension of (trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-6-trifluoromethyl-2H-1-benzopyran (0.5 g, 1.9 mmol) (prepared according to D. R. Buckle et al., J. Med. Chem., 1990, 33, p. 3028) in ethanol (5 ml) under argon was treated with phenylisocyanate (0.23 g, 1.9 mmol) and the reaction was heated at reflux temperature for 4 hours. The product precipitated out of the reaction. The reaction was then concentrated in vacuo and the residue was triturated with isopropyl ether and hexanes to give the title compound as a colorless solid (0.5 g), m.p. 174°-175° C.: 1H NMR (CDCl3) δ7.4 (s, 1H), 7.32 (d, J=9.8 Hz, 1H), 7.17 (m, 5H), 7.0 (m, 1H), 6.77 (d, J=8.2 Hz, 1H), 5.22 (br d, 1H), 4.80 (br t, 1H), 3.45 (d, J=9.4 Hz, 1H), 1.37 (s, 3H), 1.12 (s, 3H); 13C NMR (CDCl3) 157.0, 156.5, 139.1, 137.3, 129.4, 126.5, 125.0, 124.7, 122.0, 121.7, 118.0, 79.6, 76.4, 51.4, 26.3, 18.2; IR (KBr) 1118.5, 1264.8, 1332.1, 1443.4, 1500.9, 1558.3, 1598.8, 16477.8, 2981.4, 3391.3 cm-1.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[Li].C([Li])CCC.O1C=CC=C1.[Cl:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23].[Cl-].[NH4+]>CCOCC.CCCCCC>[Cl:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[OH:23]
Reactant: [Li]c1ccco1
Reactant: OCCCCCCl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: c1ccoc1
Solvent: CCOCC
Product: OC(CCCCCl)c1ccco1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of 2-furyllithium [prepared from 0.53 moles of n-butyllithium and 39.5 g of furan by the procedure of J. Org. Chem., 27, 1216 (1962)] in 350 ml of ether and with 200 ml of hexane at -78° C. is added a solution of 57.9 g of 5-chloropentanol [Chem. Abstr., 59, 7579F (1963)] in 80 ml of ether during 25 minutes. The mixture is warmed to 0° C. during 20 minutes, stirred at 0° C. for 15 minutes, and treated with 140 ml of saturated ammonium chloride. The ether phase is washed with water and brine, dried over magnesium sulfate and potassium carbonate mixture, and concentrated to give a liquid, pmr spectrum (CDCl3): δ 3.59 (triplet, CH2Cl) and 4.70 (triplet, CH2CHOH).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(Cl)Cl.C(N(CC)CC)C.[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([Cl:40])[CH:39]=1)[C:34](Cl)=[O:35]>O>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:34](=[O:35])[C:33]2[CH:32]=[C:31]([Cl:30])[CH:39]=[C:38]([Cl:40])[CH:37]=2)[N:13]=1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(NCCNc1nc(Cl)nc2c1ncn2C1CCCC1)c1cc(Cl)cc(Cl)c1
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
280 mg of the product obtained in Stage 1 of Example 7, 4 ml of methylene chloride, 0.28 ml of triethylamine and 255 mg of 3,5-dichlorobenzoyl chloride are mixed together then agitation is carried out at ambient temperature for 30 minutes. Then 2 ml of water is added, followed by extracting with methylene chloride, drying and evaporating the solvents. In this way 454 mg of expected product is obtained.
Reaction SMILES: C[O:2][C:3](=[O:14])[CH:4]=[C:5]1[CH2:11][CH:10]2[N:12]([CH3:13])[CH:7]([CH2:8][CH2:9]2)[CH2:6]1.[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[Li]>C1COCC1.[NH4+].[Cl-]>[NH4+:12].[OH-:2].[CH3:13][N:12]1[CH:7]2[CH2:8][CH2:9][CH:10]1[CH2:11][C:5](=[CH:4][C:3]([C:16]1[S:15][CH:19]=[CH:18][CH:17]=1)([C:16]1[S:15][CH:19]=[CH:18][CH:17]=1)[OH:14])[CH2:6]2
Reactant: [Li]c1cccs1
Reactant: COC(=O)C=C1CC2CCC(C1)N2C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1C2CCC1CC(=CC(O)(c1cccs1)c1cccs1)C2
Product: [OH-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
A solution of (8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylidene)-acetic acid methyl ester (200 mg, 1.02 mmol) in THF (3 mL) was mixed with 2-thienyllithium (2.02 mL, 1.0 M in THF, 2.02 mmol). The mixture was stirred overnight at r.t., diluted with saturated NH4Cl aqueous solution (20 mL) and extracted with EtOAc. The combined organic phases were dried over MgSO4 and concentrated. Flash chromatography (90% CH2Cl2, 8% CH3OH, 2% NH4OH) then afforded the title compound (132 mg, 39%): LCMS (ES) m/z 332 (M+H)+; 1H-NMR(MeOD) δ 1.35 (m, 1H), 1.61 (m, 1H), 1.81 (m, 1H), 1.95 (m, 1H), 2.12 (m, 3H), 2.29 (s, 3H), 2.37 (m, 1H), 2.68 (m, 1H), 3.03 (m, 1H), 3.22 (m, 1H), 3.32 (s, 1H), 6.15 (s, 1H), 6.95 (m, 4H), 7.30 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[CH3:13][Mg]Br.ClC1C(=O)C(Cl)=C(Cl)C(=O)C=1Cl.CCOC(C)=O.CCCCCC>C1COCC1>[CH3:13][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: C[Mg]Br
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1c([N+](=O)[O-])ccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
To a solution of 5-nitroindole (from Aldrich, 0.82 g, 5.1 mmol) in 20 mL of dry THF was added 5.0 mL (15 mmol) of methylmagnesium bromide for 0.5 h period and the resulting reaction mixture was stirred for 1 h at 25° C. Reaction was the quenched by adding a THF solution of tetrachloro-1,4-benzoquinone (1.2 g, 4.9 mmol). Reaction mixture was concentrated in vacuo, yielding a dark solid which was subjected to column chromatography (30% EtOAc/n-Hexane) to yield 0.72 g (4.1 mmol, 80%) of the desired product.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[F:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16]([F:23])[C:15]=1[OH:24].[C:25]([O:29][C:30](=[O:36])[NH:31][C@H:32]([CH3:35])[CH2:33]O)([CH3:28])([CH3:27])[CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:25]([O:29][C:30](=[O:36])[NH:31][C@H:32]([CH3:33])[CH2:35][O:24][C:15]1[C:16]([F:23])=[CH:17][CH:18]=[C:19]([N+:20]([O-:22])=[O:21])[C:14]=1[F:13])([CH3:28])([CH3:27])[CH3:26]
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(F)c(O)c1F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](COc1c(F)ccc([N+](=O)[O-])c1F)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
Diethylazodicarboxylate (328 μL, 2.09 mmol) in THF (1 mL) was added slowly to a solution of 2,6-difluoro-3-nitrophenol (243 mg, 1.39 mmol), ((R)-2-hydroxy-1-methyl-ethyl)carbamic acid tert-butyl ester (292 mg, 1.67 mmol) and triphenylphosphine (547 mg, 2.09 mmol) in THF (10 mL) at 0° C. The solution was stirred for 30 min at 0° C., then concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, gradient 0-30% EtOAc in cyclohexane) to afford the title compound as a pale yellow oil (333 mg, 72%). 1H NMR (CDCl3, 300 MHz): δ 7.82 (1H, ddd, J=13.0, 9.4, 5.3 Hz), 7.04 (1H, app. td, J=9.4, 2.2 Hz), 4.76 (1H, br s), 4.23-4.12 (2H, m), 4.07-3.95 (1H, m), 1.44 (9H, s), 1.34 (3H, d, J=6.8 Hz)
Reaction SMILES: FC1C=C(C=CC=1F)C[N:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([I:17])[CH:13]=2)[N:8]([CH3:18])[C:7]1=[O:19].C(N(C(C)C)CC)(C)C.C1(CC#C)C=CC=CC=1.O>CN(C=O)C.[Cu]I>[I:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:18])[C:7](=[O:19])[NH:6][C:15]2=[O:16]
Reactant: Cn1c(=O)n(Cc2ccc(F)c(F)c2)c(=O)c2cc(I)ccc21
Agent: [Cu]I
Agent: C#CCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c(=O)c2cc(I)ccc21
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To 0.45 g (1.1 mmol) 3-(3,4-Difluoro-benzyl)-6-iodo-1-methyl-1H-quinazoline-2,4-dione and 0.56 g (4.4 mmol) di-isopropyl ethylamine in 15 ml DMF is added bis-triphenylphosphine palladium di-chloride (catalytic) followed by CuI (catalytic). 0.18 g (1.3 mmol) 3-phenyl-propyne is added and the mixture is heated to 70° C. for 6 hours. The mixture is allowed to cool to room temperature and stirred overnight. Water is added and the mixture stirred 30 minutes. Filtered and triturated solid in hot EtOAc and filtered. Purified by flash chromatography (EtOAc/hexane eluent).
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:13]1[C:18]([CH3:19])=CC(C)=C(C)C=1O)[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][CH:5]=1.[C:23]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:54]1([CH3:60])[CH:59]=CC=[CH:56][CH:55]=1>C1COCC1>[CH:10]([C:7]1[CH:8]=[CH:9][C:4]([CH:3]2[C:13]3[C:18]([CH3:19])=[CH:56][C:55]([CH3:23])=[C:54]([CH3:60])[C:59]=3[O:1][CH2:2]2)=[CH:5][CH:6]=1)([CH3:11])[CH3:12]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ccccc1
Reactant: Cc1cc(C)c(C(CO)c2ccc(C(C)C)cc2)c(O)c1C
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: Cc1cc(C)c2c(c1C)OCC2c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of 2-(2-hydroxy-1-(4-isopropylphenyl)ethyl)-3,5,6-trimethylphenol obtained in Reference Example 8 (7.85 g, 26.3 mmol) and triphenylphosphine (7.58 g, 28.9 mmol) in THF (60 mL) was added diethylazodicarboxylate (a 40% toluene solution 12.6 g, 28.9 mmol) with ice-cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 5.70 g (yield 84%) of the title compound. Melting point: 48-49° C. (methanol).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][C@@:21]2([CH3:23])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:20]2[C@H:19]([NH:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C:31]([O:33][CH3:34])=[O:32])[CH2:7][C@@H:6]1[OH:35])(=[O:3])[CH3:2].CC1C=CC(S(O)(=O)=O)=CC=1.[C:47](OC(=O)C)(=[O:49])[CH3:48]>C(Cl)(Cl)Cl.C(O)C.C(OCC)(=O)C>[CH:25]1([NH:24][C@@H:19]2[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C@@H:15]3[C:31]([O:33][CH3:34])=[O:32])[C@H:11]3[C@H:20]2[C@:21]2([CH3:23])[C@@H:8]([CH2:9][CH2:10]3)[CH2:7][C@H:6]([O:35][C:47](=[O:49])[CH3:48])[C@@H:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:22]2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OC(C)=O)C[C@]4(C)[C@H]3[C@H](NC3CCCCC3)C[C@]12C
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC(C)=O)[C@@H](OC(C)=O)C[C@]4(C)[C@H]3[C@H](NC3CCCCC3)C[C@]12C
Reaction time: 0.33 h

Procedure:
Methyl 2β-acetoxy-11α-cyclohexylamino-3α-hydroxy-5α-androstane-17β-carboxylate (1.156 g) in chloroform (12.5 ml) containing dry PTSA (1.0 g) was stirred for 20 min. then treated with acetic anhydride (2.9 ml) and the mixture left for 18 h. The mixture was diluted with ethanol and evaporated to give an oil. This was dissolved in ethyl acetate, and washed with dilute ammonia solution (1×) water (1×), dried and evaporated under reduced pressure to give a foam. This was purified by preparative t.l.c. in chloroform/methanol (9:1) to give the title compound (790 mg), [α]D +36.8°, νmax 1724 cm-1.
Reaction SMILES: C(O[N:19]1[C:24](=O)[CH2:23][CH2:22][C:20]1=O)(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.Cl.N[C@@H:28](CC=CC)[C:29]([OH:31])=[O:30].C([O-])(O)=O.[Na+].Cl>CC(C)=O.O>[CH2:24]([NH:19][CH2:28][C:29]([OH:31])=[O:30])[CH:23]=[CH:22][CH3:20]
Reactant: CC=CC[C@H](N)C(=O)O
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC=CCNCC(=O)O
Yield: 211.3 %

Procedure:
2-N-Fluorenylmethoxycarbonylaminohex-4-enoic acid 100 was prepared according to the procedure described by Paquet.230 Fmoc-OSu (2.36 g, 7.00 mmol) was added to a stirred suspension of L-crotylglycine HCl 101 (1.16 g, 7.03 mmol) and NaHCO3 (2.95 g, 35.0 mmol) in a mixture of acetone:water (1:1, 30 mL). The resultant suspension was stirred at room temperature for 15 h. The reaction mixture was then acidified with concentrated HCl (pH 2) and the acetone was removed under reduced pressure. The resultant suspension was extracted into DCM (3×25 mL) and the combined organic extract was washed with dilute HCl solution (1 M, 2×25 mL), water (2×25 mL), dried (MgSO4) and evaporated under reduced pressure to afford the titled Fmoc-amino acid 100 as colourless solid (1.91 g, 78%), m.p. 119-121° C. νmax (KBr): 3390bm, 3033m, 2961s, 2357w, 1730s, 1651w, 1505w, 1450w, 1395w, 850w cm−1. 1H n.m.r. (300 MHz, CDCl3): δ 1.67 (d, J=6.2 Hz, 3H, H6), 2.37-2.69 (m, 2H, H3), 4.23 (t, J=6.8 Hz, 1H, H9′), 4.42-4.48 (m, 3H, CH2O, H2), 5.30-5.37 (m, 2H, H5, NH), 5.61 (m, 1H, H4), 7.31 (td, J=7.2, 1.3 Hz, 2H, H2′, 7′), 7.34 (td, J=7.4, 1.5 Hz, 2H, H3′, 6′), 7.60 (d, J=7.3 Hz, 2H, H1′, 8′), 7.74 (d, J=7.0 Hz, 2H, H4′, 5′), one exchangeable proton (OH) not observed. 13C n.m.r. (75 MHz, CDCl3): δ 16.7 (C6), 34.1 (C3), 46.2 (C9′), 52.3 (C2), 66.2 (CH2O), 118.9 (C5), 123.0 (C2′, 7′), 124.6 (C3′, 6′), 125.2 (C1′, 8′), 127.5 (C4′, 5′), 129.7 (C4), 140.3 (C8′a, 9′a), 142.7 (C4′a, 4′b), 154.9 (OCONH), 175.0 (C1). Mass Spectrum (ESI+, MeOH): m/z 352.1 (M+H)+, C21H22NO4 requires 352.2. Spectroscopic data were in agreement with those reported in the literature.146
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)[CH:9]=[C:8]([CH3:20])[N:7]=1)=[O:5])C.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=1>>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=3)[CH:9]=[C:8]([CH3:20])[N:7]=2)=[O:5])=[N:23][CH:24]=1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(F)c2)cc(C)n1
Reactant: Cc1ccc(N)nc1
Product: Cc1ccc(NC(=O)c2cc(-c3cc(F)cc(F)c3)cc(C)n2)nc1

Procedure:
The title compound, was prepared from 4-(3,5-Difluorophenyl)-6-methyl-pyridine-2-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using 2-Amino-5-methylpyridine instead of 3-chloroaniline to yield the final compound as a white crystalline, MS (ISP): m/e=340.2 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]1(=[O:12])[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH2:6]1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:1]([O:11][C:7]1[CH2:8][CH2:9][CH2:10][C:5](=[O:12])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: O=C1CCCC(=O)C1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)OC1=CC(=O)CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
According to Scheme 4 Step 1: Acetyl chloride (19.6 mmol, 1.39 mL) was added to a solution of cyclohexane-1,3-dione (17.8 mmol, 2.00 g) and pyridine (17.8 mmol, 1.28 mL) in CHCl3 (60 mL) and the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with the addition of water and the organic phase was washed with a solution of HCl (0.1 M, 30 mL), a saturated solution of NaHCO3 (30 mL) and water (30 mL). The organic phase was dried over Na2SO4 and concentrated to yield 3-oxocyclohex-1-enyl acetate (13.2 mmol, 2.04 g, 74%) as a yellow oil.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][N:12]=1.N1C=CC=CC=1>O>[N+:20]([C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[C:11]2[NH:10][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([O-:22])=[O:21]
Reactant: Nc1n[nH]c2ccc([N+](=O)[O-])cc12
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1n[nH]c2ccc([N+](=O)[O-])cc12)c1ccccc1
Reaction time: 18 h

Procedure:
N-(5-Nitro-1H-indazol-3-yl)benzamide can be obtained in the following way: 0.39 ml of benzoyl chloride is added dropwise to a solution, cooled to 0° C., of 0.6 g of 3-amino-5-nitro-1H-indazole and of 5 ml of pyridine. The medium is brought back to a temperature in the region of 20° C. and maintained with stirring for 18 hours. After addition of 20 ml of distilled water, the medium is extracted with 20 ml and 10 ml of ethyl acetate. The organic phases are pooled, dried over magnesium sulfate, filtered and concentrated by evaporation under reduced pressure. The residue thus obtained is purified by chromatography on a silica column with a dichloromethane/methanol (99/1 by volume) mixture as eluent. 0.9 g of N-(5-nitro-1H-indazol-3-yl)benzamide is thus obtained in the form of an orange solid melting at 231° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].CC1(C)COC2=CC3OCC4(C=3C=C12)C1C(=CC=CC=1)NC4=O.Br[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([O:53][C:54]([F:57])([F:56])[F:55])[CH:48]=1.BrCC1OC(C(F)(F)F)=CC=1>>[F:55][C:54]([F:56])([F:57])[O:53][C:49]1[CH:48]=[C:47]([CH:52]=[CH:51][CH:50]=1)[CH2:46][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Agent: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2cccc(OC(F)(F)F)c2)c2ccccc2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure described in EXAMPLE 10.21, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1H)-one to replace 5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 1-(bromomethyl)-3-(trifluoromethoxy)benzene to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (65%) as a white solid: mp 88-91° C.; MS (ES+) m/z 456.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1>C1(C)C=CC=CC=1.CCOCC>[Br:1][C:2]1[C:3]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1cc(OC)ncc1Br
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)CCc1cc(OC)ncc1Br
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To solution of ethyl (2E)-3-(5-bromo-2-methoxypyridin-4-yl)acrylate (1 eq.) from step 2 in Toluene (0.23M) at 110° C. was added benzenesulfonyl hydrazide (3 eq.). The reaction mixture was stirred at 110° C. for 3 h, cooled to room temperature and diluted with Et2O. The organic phase was washed with saturated NaOH (1N), brine, dried over MgSO4, filtered and concentrated. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (0 to 50% in 30 min) afforded the desired compound.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.CCOCC.[Cl:17][CH:18]([Cl:22])[C:19](Cl)=[O:20]>O>[C:1]([O:5][C:19](=[O:20])[CH:18]([Cl:22])[Cl:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)O
Reactant: O=C(Cl)C(Cl)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)C(Cl)Cl
Reaction time: 3 h
Yield: 76.4 %

Procedure:
74 g of t-butylalcohol, 79 g of pyridine and 250 ml of anhydrous ether were heated to boiling and 146 g of dichloroacetyl chloride were added dropwise to the reaction mixture at such a rate that the mixture continued to boil without further supply of heat. When all the dichloroacetyl chloride has been added, boiling was continued for 3 hours. Water was then added to the reaction mixture and the ethereal phase was separated off. The resulting reaction solution was processed in the usual manner to yield 140 g of α, α-dichloroacetic acid-t-butyl ester.
Reaction SMILES: [CH2:1]([C:3]1([CH2:31][CH3:32])[C@H:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14]Br)=[CH:10][CH:9]=2)[N:5]([C:16]([NH:18][C@H:19]([CH2:27][CH2:28][CH3:29])[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[O:17])[C:4]1=[O:30])[CH3:2].C1([P:39]([O:43]CC)[O:40][CH2:41][CH3:42])C=CC=CC=1.C(OCC)(=O)C.[CH3:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57]>>[CH2:1]([C:3]1([CH2:31][CH3:32])[C@H:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([C:54]3[CH:53]=[CH:52][CH:57]=[CH:56][CH:55]=3)[PH:39]([O:40][CH2:41][CH3:42])=[O:43])=[CH:10][CH:9]=2)[N:5]([C:16]([NH:18][C@H:19]([CH2:27][CH2:28][CH3:29])[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[O:17])[C:4]1=[O:30])[CH3:2]
Reactant: CCC[C@@H](NC(=O)N1C(=O)C(CC)(CC)[C@@H]1Oc1ccc(CBr)cc1)c1ccc(C)cc1
Reactant: CCCCCC
Reactant: CCOP(OCC)c1ccccc1
Solvent: CCOC(C)=O
Product: CCC[C@@H](NC(=O)N1C(=O)C(CC)(CC)[C@@H]1Oc1ccc(C(c2ccccc2)[PH](=O)OCC)cc1)c1ccc(C)cc1
Temperature: 80 °C

Procedure:
A mixture of (4S)-3,3-diethyl-1-[(R)-α-n-propyl-(4-methyl)-benzylaminocarbonyl]-4-[4-(bromomethyl)phenoxy]-azetidin-2-one (203 mg, 0.40 mmol) and diethyl phenylphosphonite (155 μL, 0.81 mmol) was heated for 1 hour at 80° C. The desired product was obtained pure after flash chromatography on silica gel using initially 33% ethyl acetate in hexane and subsequently 50% ethyl acetate in hexane as the mobile phase; yield 223 mg (93%); FAB MS m/z 591 (M+1).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:19]([O-:21])=[O:20])[CH:8]=2)[N:3]=1.O.[NH2:23][NH2:24]>>[N+:19]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:23][NH2:24])[CH:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])([O-:21])=[O:20]
Reactant: NN
Reactant: O=[N+]([O-])c1ccc2nc(Cl)cc(-c3ccccc3Cl)c2c1
Solvent: O
Product: NNc1cc(-c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2n1

Procedure:
In the manner given in Example 1, 2-chloro-6-nitro-4-(o-chlorophenyl)quinoline is reacted at reflux with hydrazine hydrate to give 6-nitro-4-(o-chlorophenyl)-2-hydrazinoquinoline
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29]2[C:38]3[C:33](=[C:34]([C:40]#[N:41])[CH:35]=[C:36]([CH3:39])[CH:37]=3)[CH:32]=[CH:31][CH:30]=2)[C@@H:9]([C:13]2[CH:28]=[CH:27][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.C1COCC1.CO.[Li+].[OH-].Cl>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:29]2[C:38]3[C:33](=[C:34]([C:40]#[N:41])[CH:35]=[C:36]([CH3:39])[CH:37]=3)[CH:32]=[CH:31][CH:30]=2)[C@@H:9]([C:13]2[CH:28]=[CH:27][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:6][CH:7]=1
Reactant: CCC[C@H](c1ccc(C(=O)NCCC(=O)OCC)cc1)C(c1ccc(Cl)cc1)c1cccc2c(C#N)cc(C)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)O)cc1)C(c1ccc(Cl)cc1)c1cccc2c(C#N)cc(C)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl N-(4-{(1S)-1-[(4-chlorophenyl)(5-cyano-7-methyl-1-naphthyl)methyl]butyl}benzoyl)-β-alaninate (18 mg, 0.032 mmol) in 2:1 THF/MeOH (3 mL) at room temperature was added LiOH (2.0 N in water, 0.265 mL, 0.530 mmol). The mixture was stirred at room temperature for one hour. The mixture was acidified with 2.0 N HCl (aq) and diluted with EtOAc. The organic layer was washed twice with water, dried over sodium sulfate, filtered, then concentrated to afford the title product as a white solid. LC1 1.59 min. [M+H]+ 538.