Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5](OC)[C:4]=1/[CH:11]=[N:12]/[CH:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH3:2].[CH2:20]([Li])[CH:21]([CH3:23])[CH3:22]>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:4]=1/[CH:11]=[N:12]/[CH:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH3:2]
Reactant: [Li]CC(C)C
Reactant: CCc1cccc(OC)c1/C=N/C(C(C)C)C(C)C
Product: CCc1cccc(CC(C)C)c1/C=N/C(C(C)C)C(C)C

Procedure:
(E)-[1-(2-Ethyl-6-isobutyl-phenyl)-methylidene]-(1-isopropyl-2-methyl-propyl)-amine was prepared from (E)-[1-(2-ethyl-6-methoxy-phenyl)-methylidene]-(1-isopropyl-2-methyl-propyl)-amine (Example 3 a) and isobutyl lithium in analogy to procedure Example 5 a): colourless liquid; NMR (CDCl3, ppm): 0.88 t, 18H (2×(CH3)2C), 1.20 t, 3H(CH3—CH2), 1.88 septett, 1H(CH(CH3)2), 2.08 m, 2H(NCH(CH(CH3)2)2), 2.48 t, 1H(NCH), 2.68 d, 2H (aryl -CH2CH), 2.88 q, 2H(CH3-CH2), 7.00 d, 1H and 7.08 d, 1H and 7.19 t, 1H (aryl-H), 8.49 1H (═CHN).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][CH:9]([C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1)[N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)(C)(C)C.N1C=CC=CC=1>C(#N)C>[OH:6][CH2:7][CH2:8][CH:9]([C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1)[N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: CC(C)(C)[Si](C)(C)OCCC(c1ccc(C#N)cc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CC#N
Product: N#Cc1ccc(C(CCO)n2ccnc2)cc1
Reaction time: 1 h

Procedure:
The 4-[3-(tert-butyl-dimethyl-silanyloxy)-1-imidazol-1-yl-propyl]-benzonitrile (2.0 gm, mmol) was suspended in acetonitrile (20 mL) in a teflon flask and HF/pyridine (4 mL) was added and the reaction was stirred for 1 hour. The reaction was quenched with cold aqueous sodium hydroxide and the resulting solution was concentrated in vacuo. The residue was dissolved in methylene chloride and chromatographed on silica gel eluting with 1:1 ethyl acetate:hexanes. The desired fractions were concentrated in vacuo to give the desired product as an oil.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:20]C)[CH:16]=2)[C:11]=1[O:22][C:23]1[CH:37]=[CH:36][C:26]([O:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:25][CH:24]=1.B(Br)(Br)Br>ClCCl>[ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C:10]1[C:11]([O:22][C:23]2[CH:37]=[CH:36][C:26]([O:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:25][CH:24]=2)=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13]2
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3cc(F)ccc3F)ccc2c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: Oc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3cc(F)ccc3F)ccc2c1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
Dissolve 1-(2-{4-[2-(2,5-difluoro-phenyl)-6-methoxy-naphthalen-1-yloxy]-phenoxy}-ethyl)-piperidine hydrochloride (133 mg, 0.25 mmol) in dichloromethane (5 ml), cool in an ice bath and add boron tribromide (1M in dichloromethane, 0.76 mL, 0.76 mmol). Let slowly warm to ambient temperature over 18 hours, quench with saturated aqueous solution of sodium bicarbonate, dry organic layer with magnesium sulfate, filter and chromatograph on silica gel with dichloromethane/methanol mixtures. Combine fractions containing product, add 1M hydrogen chloride in ether (1 mL) and remove solvent under vacuum to give 108 mg (83%) of the title compound: mass spectrum (ion spray) m/z=476 (M−Cl).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH2:29][CH2:30][CH3:31])[N:14]([CH2:15][CH2:16][C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH:18]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:32]>CO>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:19]2[CH:18]=[C:17]([CH2:16][CH2:15][N:14]3[C:10]4[C:9]5[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=5[N:3]=[C:2]([NH2:32])[C:11]=4[N:12]=[C:13]3[CH2:29][CH2:30][CH3:31])[O:21][N:20]=2)=[CH:23][CH:24]=1
Reactant: CCCc1nc2c(Cl)nc3ccccc3c2n1CCc1cc(-c2ccc(F)cc2)no1
Reactant: N
Solvent: CO
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCc1cc(-c2ccc(F)cc2)no1
Temperature: 150 °C

Procedure:
A mixture of 4-chloro-1-{2-[3-(4-fluorophenyl)isoxazol-5-yl]ethyl}-2-propyl-1H-imidazo[4,5-c]quinoline (1.22 g, 2.81 mmol) and 7 N ammonia in methanol (100 mL) was sealed in a pressure vessel and heated at 150° C. for 12 hours and allowed to cool to room temperature. The volatiles were removed under reduced pressure, and the crude product was purified by column chromatography on silica gel (eluting with 10% to 15% CMA in chloroform). The product was then triturated sequentially with toluene and hexane/diethyl ether to provide 0.312 g of 1-{2-[3-(4-fluorophenyl)isoxazol-5-yl]ethyl}-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, mp 208.0-209.0° C.
Reaction SMILES: [CH2:1]([NH:5][C:6]([CH:8]=[C:9]1[C:17]2[CH:16]=[C:15]([C:18]([OH:20])=[O:19])[S:14][C:13]=2[CH2:12][CH2:11][CH2:10]1)=[O:7])[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)O.CO.[CH3:28]COC(C)=O>O>[CH2:1]([NH:5][C:6]([CH:8]=[C:9]1[C:17]2[CH:16]=[C:15]([C:18]([O:20][CH3:28])=[O:19])[S:14][C:13]=2[CH2:12][CH2:11][CH2:10]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)C=C1CCCc2sc(C(=O)O)cc21
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: CCCCNC(=O)C=C1CCCc2sc(C(=O)OC)cc21

Procedure:
A mixture of 4-(N-butylcarbamoyl)methylidene-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylic acid (0.57 g), conc. sulfuric acid (H2SO4) (3 ml), and methanol (MeOH) (15 ml) was stirred at reflux for 1.5 hours. The reaction mixture was poured into a mixture of AcOEt and water. The organic layer was washed with saturated aqueous solution of NaHCO3, water and brine, and dried over MgSO4, and evaporated in vacuo. After evaporation, the resulting oil was purified by chromatography on silica gel (AcOEt-n-hexane as an eluent). The fractions including the object compound were collected and evaporated to give 4-(N-butylcarbamoyl)methylidene-2-methoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene (115.3 mg).
Reaction SMILES: C([N:8]1[CH2:15][CH:14]2[CH2:16][CH:10]([CH2:11][N:12]([C:17]([O:19][C:20]([CH2:23][CH3:24])([CH3:22])[CH3:21])=[O:18])[CH2:13]2)[CH2:9]1)C1C=CC=CC=1>CCO.[Pd]>[CH:14]12[CH2:16][CH:10]([CH2:9][NH:8][CH2:15]1)[CH2:11][N:12]([C:17]([O:19][C:20]([CH2:23][CH3:24])([CH3:21])[CH3:22])=[O:18])[CH2:13]2
Reactant: CCC(C)(C)OC(=O)N1CC2CC(CN(Cc3ccccc3)C2)C1
Agent: [Pd]
Solvent: CCO
Product: CCC(C)(C)OC(=O)N1CC2CNCC(C2)C1

Procedure:
tert-Pentyl 7-benzyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (8.67 g; from step (a) above) was dissolved in EtOH (45 mL) and hydrogenated over 5% Pd/C at 1 atm. for 10 h. The catalyst was removed by filtration and the residue was concentrated giving the sub-title compound.
Reaction SMILES: CC(C)(OC([NH:7][CH:8]1[CH2:11][N:10]([C:12](=[O:20])[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9]1=[O:21])=O)C.CCOCC.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[NH2:7][CH:8]1[CH2:11][N:10]([C:12](=[O:20])[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9]1=[O:21]
Reactant: CCOC(=O)C=CC(=O)N1CC(NC(=O)OC(C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CCOC(=O)C=CC(=O)N1CC(N)C1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
[1(E); 3S]-4-[3-[[(1,1-Dimethylethoxy)-carbonyl]amino]-2-oxo-1-azetidinyl]-4-oxo-2-butenoic acid, ethyl ester (2 g) was dissolved in 15 ml of trifluoroacetic acid and stirred for 15 minutes at 0° C. After adding ether, the title compound crystallized quantitatively from the solution as white crystals, melting point 138° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[C:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)#[N:18]>>[C:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=2)[C:5]([CH:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]2)=[O:6])=[O:24])=[CH:21][CH:20]=1)#[N:18]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccc(C#N)cc3)c2)CC1
Yield: 121.1 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 4-cyanobenzoyl chloride (38 mg, 0.229 mmol), 48.4 mg (>100%) of the title compound were recovered.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@@H:4]([N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[CH2:10][CH2:9]1)[CH2:5][CH:6]=O.[CH2:24]1[C:26]2([CH2:31][CH2:30][NH:29][CH2:28][C@H:27]2[OH:32])[CH2:25]1>>[ClH:22].[CH3:1][O:2][C:3](=[O:23])[C@@H:4]([N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[CH2:10][CH2:9]1)[CH2:5][CH2:6][N:29]1[CH2:30][CH2:31][C:26]2([CH2:24][CH2:25]2)[C@H:27]([OH:32])[CH2:28]1
Reactant: COC(=O)[C@H](CC=O)N1CCN(c2cccc(Cl)c2)CCC1=O
Reactant: O[C@@H]1CNCCC12CC2
Product: COC(=O)[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1CCN(c2cccc(Cl)c2)CCC1=O
Product: Cl

Procedure:
In analogy to the procedure described in example 1K, (S)-2-[4-(3-chloro-phenyl)-7-oxo-[1,4]diazepan-1-yl]-4-oxo-butyric acid methyl ester and (S)-6-aza-spiro[2.5]octan-4-ol; hydrochloride (intermediate 2) gave the title compound as light yellow foam. MS: 450.3 (MH+, 1Cl).
Reaction SMILES: [CH2:1]([C:9]1[CH:26]=[CH:25][CH:24]=[CH:23][C:10]=1[CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(C1C=CC(C(O)=O)=CN=1)CC1C=CC=CC=1CCC1C=CC=CC=1)C>>[CH2:1]([C:9]1[CH:26]=[CH:25][CH:24]=[CH:23][C:10]=1[CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(CCc2ccccc2CCc2ccccc2)cc1
Agent: CCN(Cc1ccccc1CCc1ccccc1)c1ccc(C(=O)O)cn1
Product: O=C(O)c1ccc(CCc2ccccc2CCc2ccccc2)cc1

Procedure:
The title compound was prepared from methyl 4-[2-(phenethyl)phenethyl]benzoate using a similar method to that of Example 24 paragraph (A).
Reaction SMILES: [CH2:1]([C:3]1[CH:15]=[C:14]([C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[C:25]([CH3:27])[C:24]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:23][N:22]=3)[O:18][N:17]=2)[CH:13]=[C:12]([CH3:32])[C:4]=1[O:5][CH2:6][C@@H:7]([OH:11])[CH2:8][NH:9]C)[CH3:2].[K+].[CH2:34]([S:36]([NH-])(=[O:38])=[O:37])[CH3:35]>CN(C=O)C>[CH2:1]([C:3]1[CH:15]=[C:14]([C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[C:25]([CH3:27])[C:24]([CH2:28][CH:29]([CH3:30])[CH3:31])=[CH:23][N:22]=3)[O:18][N:17]=2)[CH:13]=[C:12]([CH3:32])[C:4]=1[O:5][CH2:6][C@@H:7]([OH:11])[CH2:8][NH:9][S:36]([CH2:34][CH3:35])(=[O:38])=[O:37])[CH3:2]
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OC[C@@H](O)CNC
Reactant: CCS([NH-])(=O)=O
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OC[C@@H](O)CNS(=O)(=O)CC

Procedure:
A solution of the epoxide intermediate of Example 57 (step a, 25 mg, 61 μmol) and ethanesulfonamide potassium salt (27 mg, 184 μmol) in DMF (2 mL) is stirred at 60° C. for 18 h. The solvent is removed in vacuo and the crude product is purified by prep. HPLC to give the title compound (8 mg) as a colourless oil; LC-MS: tR=1.07 min, [M+H]+=517.12.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](Cl)(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Br:11][C:8]1[CH:9]=[CH:10][C:2]2[N:1]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: O=C(Cl)c1ccccc1
Product: O=c1oc(-c2ccccc2)nc2ccc(Br)cc12
Temperature: 25 °C
Yield: 97.4 %

Procedure:
The 2-amino-5-bromobenzoic acid (5 g, 23.1 mmol) was treated with benzoyl chloride (237 mL, 2.04 mol) at 140° C. for 3 h. After the reaction mixture was cooled to rt, the crystals that formed were collected by filtration and were washed with hexanes to provide 64 as light brown needles (6.8 g, 97%): 1H NMR (CDCl3) δ 7.51–7.2 (m, 4H), 7.9 (dd, 1H, J=2.3, 8.6 Hz), 8.30–8.33 (m, 2H), 8.8 (d, 1H, J=2.2 Hz); 13C NMR (CDCl3) δ 158.19, 157.35, 145.75, 139.58, 132.82, 130.97, 129.77, 128.82, 128.73, 128.29, 121.37, 118.27; MS (EI) m/e (relative intensity) 303 (M+, 36), 301 (M+, 36), 259 (14), 257 (14), 226 (6), 224 (6), 178 (9), 170 (9), 168 (9), 151 (4), 105 (100).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[CH3:54][O:55][C:56]1[CH:63]=[CH:62][C:59]([NH:60][CH3:61])=[CH:58][CH:57]=1>CN(C=O)C.CCOC(C)=O>[Br:20][C:16]1[CH:15]=[C:14]([CH2:13][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([N:60]([C:59]2[CH:62]=[CH:63][C:56]([O:55][CH3:54])=[CH:57][CH:58]=2)[CH3:61])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(Br)c1)C(=O)O
Reactant: CNc1ccc(OC)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(N(C)C(=O)[C@H](Cc2cccc(Br)c2)NC(=O)OC(C)(C)C)cc1
Reaction time: 8 h
Yield: 86.5 %

Procedure:
(S)-2-(tert-Butoxycarbonylamino)-3-(3-bromophenyl)propanoic acid (660 mg, 1.92 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 803 mg, 2.1 mmol) and DIPEA (0.43 ml, 2.5 mmol) were dissolved in DMF (10 ml) and treated with 4-methoxy-N-methylaniline (316 g, 2.3 mmol). The mixture was stirred vigorously overnight. The mixture was diluted with EtOAc (100 ml) and washed with brine (2×50 ml). The organic layer was dried over Na2SO4, filtered and concentrated. The oily crude product was introduced to a silica gel loading column and purified by column chromatography (15-38% EtOAc/hexanes) to provide the desired product (770 mg, 1.66 mmol), 86.5%. MS (m/z) 463 [M+H]+.
Reaction SMILES: C(S[C:5]1[N:6]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:19][CH:18]=2)[C:7](=[O:16])[C:8]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:9]=2[N:10]=1)CC.[O-:29][CH2:30][CH3:31].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[CH2:30]([O:29][C:5]1[N:6]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:27])([F:28])[F:26])=[CH:19][CH:18]=2)[C:7](=[O:16])[C:8]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:9]=2[N:10]=1)[CH3:31]
Reactant: CCCSc1nc2c(=O)[nH]ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reactant: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1nc2c(=O)[nH]ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of 2-(propylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]-3,7-dihydropyrido[3,4-d]pyrimidine-4,8-dione (535 mg) in N,N-dimethylformamide (5 ml) was added sodium ethoxide (20% ethanol solution, 0.863 ml), and the mixture was stirred at 60° C. for 4 hr. The reaction mixture was allowed to be cooled to room temperature, saturated brine was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (140 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:45]=[CH:44][C:9]([CH2:10][C@H:11]([NH:32][C:33](=[O:43])[O:34][C@@H:35]2[C@H:42]3[C@H:38]([O:39][CH2:40][CH2:41]3)[O:37][CH2:36]2)[C@H:12]([OH:31])[CH2:13][N:14]([S:19]([C:22]2[CH:30]=[CH:29][C:25]3[O:26][CH2:27][O:28][C:24]=3[CH:23]=2)(=[O:21])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:8][CH:7]=1.Cl[C:47]1[CH:52]=[CH:51][C:50]([C:53]#[N:54])=[CH:49][N:48]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[O:26]1[C:25]2[CH:29]=[CH:30][C:22]([S:19]([N:14]([CH2:15][CH:16]([CH3:17])[CH3:18])[CH2:13][C@@H:12]([OH:31])[C@@H:11]([NH:32][C:33](=[O:43])[O:34][C@@H:35]3[C@H:42]4[C@H:38]([O:39][CH2:40][CH2:41]4)[O:37][CH2:36]3)[CH2:10][C:9]3[CH:44]=[CH:45][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:1][C:47]4[CH:52]=[CH:51][C:50]([C:53]#[N:54])=[CH:49][N:48]=4)=[CH:7][CH:8]=3)(=[O:21])=[O:20])=[CH:23][C:24]=2[O:28][CH2:27]1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCN)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCNc2ccc(C#N)cn2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 81.3 %

Procedure:
A solution of 35 mg (0.054 mmol) of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-[4-(3-aminopropoxy)benzyl]-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxypropylcarbamate, 22 mg (0.16 mmol) of 2-chloro-5-cyanopyridine, and 38 μL (0.22 mmol) of N,N-diisopropylethylamine in 0.5 mL of anhydrous DMF was heated to 80° C. with stirring. After 6 hours the solution was cooled to RT and concentrated to dryness in vacuo. The residue was purified by flash chromatography (SiO2, 95:5 CH2Cl2/MeOH) to afford 33 mg (80%) of the desired compound as a white foam. 1H NMR (CDCl3): 8.30 (s, 1H), 7.50 (d, 1H), 7.29 (d, 1H), 7.13 (s, 1H), 7.09 (d, 2H), 6.84 (d, 1H), 6.78 (d, 2H), 6.37 (d, 1H), 6.04 (s, 2H), 5.62 (d, 1H), 5.44 (br s, 1H), 4.96 (m, 2H), 4.00 (t, 2H), 3.91 (m, 1H), 3.80 (m, 3H), 3.71-3.49 (m, 5H), 3.18-2.65 (m, 7H), 2.08 (m, 2H), 1.80 (m, 1H), 1.61 (m, 1H), 1.50 (m, 1H), 0.90 (d, 3H), 0.81 (d, 3H). MS(ESI): 752(M+H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]([N:14]1[CH2:20][C@H:19]([NH:21]C(OC(C)(C)C)=O)[C:18](=[O:29])[N:17]([CH2:30][CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:16]2[CH:40]=[CH:41][CH:42]=[CH:43][C:15]1=2)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:44]>O1CCOCC1>[ClH:44].[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]([N:14]1[CH2:20][C@H:19]([NH2:21])[C:18](=[O:29])[N:17]([CH2:30][CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:16]2[CH:40]=[CH:41][CH:42]=[CH:43][C:15]1=2)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(C(=O)OCCOCc2ccccc2)c2ccccc2N(CCOCc2ccccc2)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CN(C(=O)OCCOCc2ccccc2)c2ccccc2N(CCOCc2ccccc2)C1=O

Procedure:
In an analogous manner to that described in Example 1d), the treatment of the (S)-5-(2-benzyloxy-ethyl)-3-tert-butoxycarbonylamino-4-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepine-1-carboxylic acid 2-benzyloxy-ethyl ester with hydrochlorid acid (37%) in dioxane yielded quantitatively the title compound as a viscous light yellow oil; MS (m/e): 490 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]2[CH:9]=[C:8]3[O:18][CH2:19][O:20][C:7]3=[CH:6][C:5]=2[O:4]1.[Cl:23]Cl>C(O)(C(F)(F)F)=O.[Zn]>[Cl:23][C:9]1[C:10]2[CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:3]([C:2]([F:21])([F:1])[F:22])[O:4][C:5]=2[CH:6]=[C:7]2[O:20][CH2:19][O:18][C:8]=12
Reactant: ClCl
Reactant: CCOC(=O)C1=Cc2cc3c(cc2OC1C(F)(F)F)OCO3
Agent: [Zn]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1=Cc2c(cc3c(c2Cl)OCO3)OC1C(F)(F)F
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 6-(trifluoromethyl)-6H-[1,3]dioxolo[4,5-g]chromene-7-carboxylate (500 mg, 1.58 mmoles) in 6 mL of TFA was added a solution of Cl2 6 mL, 0.28M) in TFA. After 30 min, another 6 mL of Cl2 solution was added and stirring continued. Zn dust (1.00 g, 15.3 mg-atm) was added, and stirred overnight. After concentration, the residue was chromatographed over silica gel using 20% EtOAc—hexane as eluent to give the title compound, 460 mg, as a yellow solid.
Reaction SMILES: [CH3:1][C:2](=[N:4][NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH3:3]>[Pd].C(O)(=O)C>[CH:2]([NH:4][NH:5][C:6]([O:8][C:9]([CH3:11])([CH3:10])[CH3:12])=[O:7])([CH3:3])[CH3:1]
Reactant: CC(C)=NNC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)NNC(=O)OC(C)(C)C

Procedure:
1-Methylethylidene-2-tert-butoxycarbonylhydrazine, glacial acetic acid (150 mL) and 10% palladium on carbon (2.0 g) were placed in a 500 mL Parr flask. The bottle was placed on a Parr apparatus, and after evacuating and flushing the bottle with nitrogen three times, the flask was charged with hydrogen to 40 psi. After hydrogen uptake ceased, the flask was evacuated and flushed with nitrogen. Filtration through celite, eluting with ethyl acetate, and concentration afforded the crude 1-(isopropyl)-2-tert-butoxycarbonylhydrazine as an acetic acid salt.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([O:13]C(=O)C)[C@H:10]([N:17]=[N+:18]=[N-:19])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li+].[OH-]>C1COCC1.CO>[C:1]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([N:17]=[N+:18]=[N-:19])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(=O)O[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1N=[N+]=[N-]
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](N=[N+]=[N-])C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (3R,4R)—N-Boc-3-azido-4-acetoxypyrrolidine (1.0 g, 3.4 mmol) in THF-MeOH (3:1, 8 mL) at 0° C. was added 1N LiOH (4 mL) dropwise. The reaction mixture was stirred at room temperature overnight, then it was evaporated under reduced pressure. Ethyl acetate (20 mL) was added to the residue and the solution was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash column (50% ethyl acetate in hexane) to give (3R,4R)—N-Boc-3-azido-4-hydroxypyrrolidine: 1H NMR (300 MHz, CDCl3) identical to that of the (3S,4S) isomer; [α]20D=−26.8° (c=1.0, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[CH3:22])[N:15]([C:23](=[O:32])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C@@H:14]([CH3:33])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.NC1C=CC=CC=1.COC1C=CC(C(Cl)=O)=CC=1.CN(C)C1C=CC(C(Cl)=O)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][C:18]([CH3:19])=[CH:22][CH:20]=3)[N:15]([C:23](=[O:32])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C@@H:14]([CH3:33])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)N2c3cccc(C)c3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: CN(C)c1ccc(C(=O)Cl)cc1
Agent: COc1ccc(C(=O)Cl)cc1
Solvent: Nc1ccccc1
Product: COc1ccc(C(=O)N2c3cc(C)ccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1

Procedure:
(±)-Cis-N-(4-chloro-phenyl)-N-[1-(4-methoxy-benzoyl)-2,5-dimethyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide was made following general procedure B, substituting 3-toluidine for aniline and 4-methoxybenzoyl chloride for 4-dimethylaminobenzoyl chloride. The reaction was non-selective and also (±)-cis-N-(4-chloro-phenyl)-N-[1-(4-methoxy-benzoyl)-2,7-dimethyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide was obtained in a 1:1 mixture with the product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=3)[C:16]([O:18]C)=[O:17])[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>O.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=3)[C:16]([OH:18])=[O:17])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc(-c2cc(-c3ccc(Cl)cc3)on2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-c2cc(-c3ccc(Cl)cc3)on2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
A mixture of methyl 3-[5-(4-chlorophenyl)-3-isoxazolyl]benzoate (1.10 g), 1 M aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (15 ml) and methanol (15 ml) was stirred at 60° C. for 1 hr. After cooling, the reaction mixture was poured into water, and 1 M hydrochloric acid (5 ml) was added. The crystals were collected by filtration and recrystallized from tetrahydrofuran-hexane to give 3-[5-(4-chlorophenyl)-3-isoxazolyl]benzoic acid (0.91 g, yield 87%) as colorless crystals. melting point: 298–299° C.