Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:32]([O:39][C:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C.CCOC(C)=O.C(N(CC)CC)C>[CH2:32]([O:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([C:3](=[O:5])[C@H:2]([OH:1])[CH2:6][CH:7]([CH3:9])[CH3:8])[CH2:44][CH2:43]1)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CC(C)C[C@@H](O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](O)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 4 h
Yield: 48.7 %

Procedure:
To (R)-2-hydroxy-4-methyl-pentanoic acid (1.71 g, 12.9 mmol) in 48 mL of DMF was added sequentially triethylamine (4.9 mL, 35. mmol), HOBt (1.75 g, 12.9 mmol), EDCI•HCl (2.48 g, 12.9 mmol) and piperazine-1-carboxylic acid benzyl ester (2.59 g, 11.8 mmol) at room temperature. The reaction mixture was stirred for 4 h and then diluted with EtOAc (50 mL) and extracted with 50 mL of water. The organic layer was separated and dried over Na2SO4, and the solvent was removed under reduced pressure to give an oil. The residue was subjected to purification by normal phase LC using 40-85% EtOAc-hexanes to give (1.92 g, 49% yield) of 4-(2(R)-hydroxy-4-methyl-pentanoyl)-piperazine-1-carboxylic acid benzyl ester the desired product. LC/MS: m/z 335.4 (M+H)+ at 2.96 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([CH3:41])[C:17]2[C:18]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[CH3:40])=[CH:19][C:20]([C@H:23]3[NH:27][C@@:26]([CH3:32])([C:28](OC)=[O:29])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH3:46]>CO>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([CH3:41])[C:17]2[C:18]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[CH3:40])=[CH:19][C:20]([C@H:23]3[NH:27][C@@:26]([CH3:32])([C:28]([NH2:46])=[O:29])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)=[O:15])[CH:4]=[C:3]([C:2]([F:44])([F:45])[F:1])[CH:8]=1
Reactant: COC(=O)[C@@]1(C)CC[C@@H](c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)N1
Reactant: N
Solvent: CO
Product: Cc1cc(F)ccc1-c1cc([C@@H]2CC[C@](C)(C(N)=O)N2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 48 h
Yield: 92 %

Procedure:
Methyl (5S)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinate (Intermediate 20, 30 mg, 0.047 mmol) was dissolved in 7N ammonia solution in MeOH (3 ml) and the reaction mixture was stirred for 48 hours at 50° C. The solvent was evaporated affording the title compound (27 mg, 0.043 mmol, 92% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.31 (s, 1 H) 8.04 (s, 1 H) 7.89-7.99 (m, 1 H) 7.60-7.87 (m, 2 H) 7.44 (s, 1 H) 6.90-7.24 (m, 4 H) 4.39-4.60 (m, 1 H) 3.21-3.32 (m, 1 H) 2.53 (s, 3 H) 2.21 (s, 3 H) 1.45 (s, 6 H) 1.38 (s, 3 H) 1.16-2.37 (m, 4 H) The spectrum of the sample consists of a mixture of conformers (broad lines in the spectrum at r.t). The relative stereochemistry syn was confirmed by dipolar correlation between: —CH3(8) at 1.31 ppm and CH(5) at 4.48 ppm. UPLC: Rt 0.75 min (broad peak), m/z 625 [M+H]+. HPLC: Rt 5.06 min.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([CH3:22])[C:11](N2[C@@H](C(C)C)COC2=O)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[Li].O.S([O-])([O-])=[O:27].[Na+].[Na+]>C1COCC1.O>[C:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([CH3:22])[C:11]([OH:12])=[O:27])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)[C@H](C)CCCc1ccccc1
Reactant: O=S([O-])[O-]
Agent: [Li]O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](CCCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
(4S)-3-((2R)-5-Phenyl-2-methyl-1 -oxopentyl)-4-isopropyl-1,3-oxazolidin -2-one (0.25 g, 0.83 mmol), prepared by the method described in J. Org. Chem. 59: 2261, (1994), was dissolved in 4.2 mL of 4:1 THF:H2O, cooled to 0° C. and purged with N2. 30% Hydrogen peroxide (0.34 mL) was added dropwise, followed by a dropwise addition of a solution of LiOH·H2O (31.9 mg, 1.3 mmol) and 1.7 mL H2O. The reaction mixture was stirred at 0° C. for 1 hour, then a solution of sodium sulfite (0.42 g, 3.3 mmol) in 2.5 mL of H2O was added. THF was evaporated in vacuo, and H2O was added to the residue. This mixture was washed with CH2Cl2 (3×). The aqueous layer was cooled to 0° C., acidified with aqueous hydrochloric acid and extracted (5×) with EtOAc. The combined EtOAc extracts were dried (MgSO4), filtered, and concentrated in vacuo to afford the title compound (0.11 g) as a colorless oil. 1HNMR (300 MHz, CDCl3) δ 1.18 (d, 3H), 1.50 (m, 3H), 1.60-1.80 (m, 3H), 2.5 (m, 1H), 2.62 (t, 2H), 7.08 (m, 3H), 7.29 (m, 2H). MS (DCl/NH3) m/e 210 (M+NH4)+.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1>>[CH3:1][NH:2][CH:3]1[CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:4]1
Reactant: CNC1CCNC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: CNC1CCN(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 110 °C

Procedure:
N-methylpyrrolidin-3-amine (0.788 g, 7.87 mmol) was added to 1-fluoro-4-nitrobenzene (1.11 g, 7.87 mmol) slowly (CAUTION: extreme exotherm!!!). The resulting mixture was heated at 110° C. for 10 min. After cooling down to room temperature, another portion of amine (0.156 g) was added to the reaction mixture. The resulting mixture was heated at 110° C. for 1 h. After cooling down to room temperature, the obtained black solid product (Example 43A) was used for next step without further purification. LCMS (ES): m/z 252.3 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][C:6]([NH:10][CH2:11][C:12]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:13])=[C:5]([CH2:20][CH3:21])[CH:4]=1.CCN(CC)CC.[C:29](Cl)(=[O:32])[CH:30]=[CH2:31]>C(Cl)Cl>[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][C:6]([NH:10][CH2:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:29](=[O:32])[CH:30]=[CH2:31])[CH2:16][CH2:15]2)=[O:13])=[C:5]([CH2:20][CH3:21])[CH:4]=1
Reactant: C=CC(=O)Cl
Reactant: CCc1cc(Cl)c(Cl)cc1NCC(=O)N1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCN(C(=O)CNc2cc(Cl)c(Cl)cc2CC)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.2 %

Procedure:
To a mixture of above crude 2-(4,5-dichloro-2-ethylphenylamino)-1-(piperazin-1-yl)ethanone hydrochloride (82 mg) and Et3N (69 mg, 0.686 mmol) in DCM (3 mL) 0° C., a solution of acryloyl chloride (23 mg, 0.251 mmol) in DCM (1 mL) was added. The resulting mixture was stirred at room temperature for 1 h and then was quenched withed saturated NaHCO3 solution. The mixture was diluted with ethyl acetate, washed with saturated NaHCO3 solution and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (DCM/MeOH=30:1) to afford the desired product (20 mg, 18.76% yield, 2 steps) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ: 7.11 (s, 1H), 6.58 (dd, J=10.4, 16.4 Hz, 1H), 6.54 (s, 1H), 6.36 (dd, J=1.6, 16.4 Hz, 1H), 5.79 (dd, J=1.6, 10.4 Hz, 1H), 5.08 (bs., 1H), 3.89-3.52 (m, 10H), 2.52 (q, J=7.2 Hz, 2H), 1.29-1.26 (t, J=7.6 Hz, 3H). ESI-MS m/z: 370.2[M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2[CH2:20][C:19]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[O:18][N:17]=2)[CH:12]=[C:13](Br)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])(=[O:39])[CH:37]=[CH2:38].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2[CH2:20][C:19]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[O:18][N:17]=2)[CH:12]=[C:13](/[CH:38]=[CH:37]/[C:36]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CC1(C(=O)OC(C)(C)C)CC(c2cc(Br)cc(OCc3ccccc3)c2)=NO1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)/C=C/c1cc(OCc2ccccc2)cc(C2=NOC(CC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)C2)c1
Reaction time: 48 h
Yield: 50.1 %

Procedure:
A mixture of tert-butyl 3-(3-(benzyloxy)-5-bromophenyl)-5-(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (500 mg), tert-butyl acrylate (586 mg), palladium acetate (10.27 mg), tris(2-methylphenyl)phosphine (41.8 mg), triethylamine (0.383 mL), and DMF (5 mL) was stirred at 100 C for 2 days under an argon atmosphere. To the reaction mixture, water was added, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure to obtain the title compound (272 mg).
Reaction SMILES: Cl.C(=N)(OCC)C.[F:8][C:9]([F:13])([F:12])[CH2:10][NH2:11].C1(N2[C:21]([CH:22]=[O:23])=[CH:20][N:19]=[C:18]2[CH3:24])CC1>>[CH3:24][C:18]1[N:11]([CH2:10][C:9]([F:13])([F:12])[F:8])[C:21]([CH:22]=[O:23])=[CH:20][N:19]=1
Reactant: NCC(F)(F)F
Reactant: Cc1ncc(C=O)n1C1CC1
Agent: CCOC(C)=N
Agent: Cl
Product: Cc1ncc(C=O)n1CC(F)(F)F

Procedure:
2-Methyl-3-(2,2,2-trifluoro-ethyl)-3H-imidazole-4-carbaldehyde was prepared from ethyl acetimidate hydrochloride and 2,2,2-trifluoroethylamine in the same manner as 3-cyclopropyl-2-methyl-3H-imidazole-4-carbaldehyde (Example 45).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(OCC)(=O)C>[C:1]1([CH:7]2[CH2:11][CH2:10][CH2:9][CH:8]2[NH:12][C:20](=[O:22])[CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC(C)=O
Reactant: N[C@@H]1CCC[C@H]1c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)NC1CCCC1c1ccccc1
Reaction time: 1 h

Procedure:
4.45 g of trans-2-phenyl-cyclopentylamine and 4.2 ml of triethylamine were dissolved in 50 ml of ethyl acetate. 2.86 ml of acetic anhydride was added slowly and the mixture stirred for 1 hour and washed with 40 ml of water. After drying the organic layer with sodium sulfate, filtration and evaporation 4.7 g of a crude solid was obtained that was used without further purification.
Reaction SMILES: F[C:2]1[C:10]([CH:11]=O)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[NH:13]([CH2:15][CH2:16][OH:17])[NH2:14].[CH3:18]O>C(OCC)(=O)C>[OH:17][CH2:16][CH2:15][N:13]1[C:2]2[C:10](=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([O:6][CH3:18])=[O:5])[CH:11]=[N:14]1
Reactant: O=Cc1cccc(C(=O)[O-])c1F
Reactant: CO
Reactant: NNCCO
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2cnn(CCO)c12
Temperature: 25 °C
Yield: 95 %

Procedure:
To a stirred solution of 2-fluoro-3-formylbenzoate (0.5 g, 2.8 mmol) in methanol (4 mL) was added 2-hydrazinoethanol (0.2 mL, 2.8 mmol) and the mixture was stirred at room temperature. After the starting material was consumed, the solution was transferred to a microwave tube and microwaved at 150° C. for 5 h. The crude reaction was diluted with ethyl acetate, washed with water, dried (Na2SO4), filtered, concentrated under reduced pressure and purified by column chromatography (silica gel, 0% to 50% ethyl acetate in hexanes) to afford methyl 1-(2-hydroxyethyl)-1H-indazole-7-carboxylate (0.6 g, 95%): 1H NMR (500 MHz, CDCl3) δ 8.04-8.02 (m, 1H), 8.00-7.98 (m, 1H), 7.95-7.93 (m, 1H), 4.87-4.80 (m, 2H), 4.14-4.10 (m, 2H), 3.99 (s, 3H); MS (ESI+) m/z 221 (M+H).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH2:2]1.[NH4+:9].[OH-]>CO>[NH2:9][CH2:2][C:3]1([OH:1])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: [NH4+]
Reactant: C1CC2(CCO1)CO2
Agent: [OH-]
Solvent: CO
Product: NCC1(O)CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41 %

Procedure:
4-Aminomethyl-tetrahydro-pyran-4-ol is prepared from 1,6-dioxa-spiro[2.5]octane. A MeOH (3.5 mL) solution of 1,6-dioxa-spiro[2.5]octane (0.19 g, 1.7 mmol) is added to concentrated aqueous NH4OH (4.3 mL) at 0° C. The reaction mixture is warmed to room temperature and stirred for 16 hours. The reaction mixture is concentrated under reduced pressure and purified by column chromatography (10% MeOH, 2% Et3N in DCM) to afford 90 mg (41%) of the desired product as a white solid.
Reaction SMILES: [N:1]([C@H:4]1[C@@H:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:8]([O:18][CH2:19]C2C=CC=CC=2)[C@@H:7]([CH2:26][O:27]CC2C=CC=CC=2)[O:6][C@@H:5]1[CH2:35][P:36]([O:41][CH2:42][CH3:43])(=[O:40])[O:37][CH2:38][CH3:39])=[N+:2]=[N-:3].C(Cl)Cl>CC(O)=O.CC(OC(C)=O)=O.OS(O)(=O)=O.CC(OC(C)=O)=O>[C:5]([O:27][CH2:26][C@H:7]1[O:6][C@H:5]([CH2:35][P:36]([O:37][CH2:38][CH3:39])(=[O:40])[O:41][CH2:42][CH3:43])[C@@H:4]([N:1]=[N+:2]=[N-:3])[C@@H:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:8]1[O:18][CH2:19][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:6])[CH3:4]
Reactant: CCOP(=O)(C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1N=[N+]=[N-])OCC
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCOP(=O)(C[C@H]1O[C@H](COC(C)=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1N=[N+]=[N-])OCC
Reaction time: 8 h
Yield: 169.2 %

Procedure:
Compound 3 (3.2 g, 5.2 mmol) was dissolved in HOAc/Ac2O (1:1, 32 mL). Ten drops of 1% H2SO4 in Ac2O was added. After stirring overnight the mixture was poured into a separation funnel containing ice and CH2Cl2. The organic phase was separated, filtered through a plug of silica and concentrated. The residue was purified by column chromatography to give 4 (2.48 g, 4.4 mmol, 84%). 13C-NMR (CDCl3) 170.41, 137.41, 136.95, 128.34-127.75, 77.77, 77.60, 74.01, 73.39, 72.17, 71.89, 69.26, 62.47, 61.82, 61.73, 60.50, 60.37, 27.57 (d, J=141 Hz), 20.59, 16.27, 16.19; 31P-NMR (CDCl3) 27.50; [α]D+37 (c 1.0, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]3[O:10][CH:9]2O)[CH:5]=[CH:6][CH:7]=1.[N:18]1(C(OC(C)(C)C)=O)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(Cl)Cl>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]2[OH:10])[CH2:9][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: OC1OC2CCCCC2C1c1cccc(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: Cl
Product: OC1CCCCC1C(CN1CCNCC1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 274.6 %

Procedure:
A solution of 3-(3-chlorophenyl)octahydro-1-benzofuran-2-ol (175 mg, 0.69 mmol) and tert-butyl 1-piperazinecarboxylate (128 mg, 0.69 mmol) in dichloroethane (3 mL) was treated with sodium trisacetoxyborohydride (220 mg, 1.04 mmol). The reaction was allowed to stir at room temperature for 16 h. The reaction was then diluted with methylene chloride and washed with a saturated aqueious solution of ammonium chloride (3 times). The organic layer was dried over magnesium sulfate and concentrated in vacuo and the product was purified via Biotage Horizon (FLASH 25 M, silica, gradient from 0% EtOAc/hexane to 30% EtOAc/hexane). This material was dissolved in methanol (0.5 mL) and treated with a saturated methanolic solution of hydrochloric acid (0.5 mL) followed by diethyl ether. After crystallizing in the refrigerator for 16 h, the resulting solid was collected, washed with diethyl ether and dried in vacuo to yield 250 mg (83%) 2-[1-(3-chlorophenyl)-2-piperazin-1-ylethyl]cyclohexanol dihydrochloride as a white solid. HRMS: calcd for C18H27ClN2O+H, 323.18901. found (ESI, [M+H]+), 323.1891.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](O)([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[CH:4][CH2:3]1.[CH3:29][S:30][CH2:31][CH2:32][NH2:33]>CO.C(Cl)Cl>[CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:16])([NH:33][CH2:32][CH2:31][S:30][CH3:29])[CH3:15])[CH:11]=[CH:10][C:9]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[CH:4][CH2:3]1
Reactant: CSCCN
Reactant: CC1(C)CC=C(c2cc(C(C)(C)O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Solvent: ClCCl
Solvent: CO
Product: CSCCNC(C)(C)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCC(C)(C)CC2)c1
Yield: 50.3 %

Procedure:
The title compound was prepared by the procedure of Example 14, step (e) using 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-amide (as prepared in Example 14, step (d), 120 mg, 0.317 mmol) and 2-methylsulfanyl-ethylamine (69.0 μL, 0.951 mmol). Silica gel chromatography (1-4% MeOH/DCM) afforded the title compound (72 mg, 50%) as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.26 (d, 1H, J=8.6 Hz), 7.94 (s, 1H), 7.39 (dd, 1H, J=8.6, 2.3 Hz), 7.32 (d, 1H, J=2.3 Hz), 5.75 (m, 1H), 2.51-2.61 (m, 4H), 2.29-2.36 (m, 2H), 2.05-2.12 (m, 2H), 1.91 (s, 3H), 1.60 (t, 2H, J=6.3 Hz), 1.54 (s, 6H), 1.09 (s, 6H). Mass spectrum (ESI-neg, m/z): Calcd. for C25H33N5OS, 450.4 (M−H). found 450.2.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:11])[C:3]=1F.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[F:30][P-](F)(F)(F)(F)F.[NH2:37][CH:38]1[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]1.CCN(C(C)C)C(C)C.[OH-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([C:6]([NH:37][CH:38]2[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]2)=[O:7])=[C:9]([F:30])[CH:10]=1
Reactant: O=C(O)c1ccc(Br)c(F)c1F
Reactant: CN1CCC(N)CC1
Reactant: F[P-](F)(F)(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)c2c(F)cc(Br)cc2F)CC1
Reaction time: 48 h
Yield: 0 %

Procedure:
4-bromo-difluorobenzoic acid (Fluorochem; 3.0 g, 12.66 mol) and HBTU (5.3 g, 13.92 mol) were added to DMF (80 mL), to this was added the required 4-amino-1-methylpiperidine (Fluorochem; 1.59 g, 13.93 mol) and DIPEA (5.0 mL, 27.85 mol), the reaction was stirred for 48 hours, after which the solvent was removed in vacuo to yield a brown gum. The gum was treated with 2.0 M NaOH (50 mL) and extracted with DCM (3×200 ml). Combined extracts were dried and solvent removed in vacuo to yield a dark orange gum which was recrystallised from hot acetonitrile to give the title compound as a white solid (1.9 g, 45%)
Reaction SMILES: [C:1](NCC(O)=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N1C=CN=C1)([N:15]1[CH:19]=[CH:18]N=C1)=O.C(=O)=O.[Cl:28][C:29]1[C:34]2[C:35](=[O:49])[N:36]3[CH2:48][CH2:47][C@H:37]3[C:38]3[N:39]([CH:40]=[N:41][C:42]=3[C:43](=[N:45][OH:46])[NH2:44])[C:33]=2[CH:32]=[CH:31][C:30]=1[F:50]>CN(C)C=O>[C:1]([CH:19]([NH2:15])[C:18]1[O:46][N:45]=[C:43]([C:42]2[N:41]=[CH:40][N:39]3[C:33]4[CH:32]=[CH:31][C:30]([F:50])=[C:29]([Cl:28])[C:34]=4[C:35](=[O:49])[N:36]4[CH2:48][CH2:47][C@H:37]4[C:38]=23)[N:44]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: NC(=NO)c1ncn2c1[C@@H]1CCN1C(=O)c1c-2ccc(F)c1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: O=C=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(N)c1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c-3ccc(F)c2Cl)no1
Reaction time: 8 h
Yield: 85.2 %

Procedure:
17.08 g (97 mmol) of BOC-glycine were dissolved in 165 ml of N,N-dimethylformamide and treated portionwise with 16.9 g (104 mmol) of 1,1'-carbonyldiimidazole. After completion of the CO2 evolution the solution was stirred at 50° for 30 min. Then, 30.8 g (91mmol) of (S)-8-chloro-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamidoxime were added and the mixture was stirred at 90° overnight. By evaporation of the solution and chromatography of the residue on 1.5 kg of silica gel while eluting with methylene chloride/methanol 19/1 there were obtained 36.8 g (84%) of (S)-1-[5-(BOC-aminomethyl)-1,2,4-oxadiazol-3-yl]-8-chloro-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]([O:18][CH3:19])(=[O:17])[C@@H:14]([CH3:16])O.C(OCC)(=O)CO>>[CH3:19][O:18][C:13](=[O:17])[C@@H:14]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[CH3:16]
Reactant: COC(=O)[C@@H](C)O
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Agent: CCOC(=O)CO
Product: COC(=O)[C@H](C)Oc1ccc(C=O)cc1[N+](=O)[O-]

Procedure:
The title compound was synthesized in a manner analogous to intermediate 7 using 4-hydroxy-3-nitrobenzaldehyde and methyl (R)-(+)-lactate instead of 5-nitrovanillin and ethyl glycolate. MS: M+−87=166.1 Da.
Reaction SMILES: Cl.[Si]([O:9][C@@H:10]([CH2:20][C@H:21]([O:61][Si](C(C)(C)C)(C)C)/[CH:22]=[CH:23]\[C@H:24]([CH3:60])[C@H:25]([O:52][Si](C(C)(C)C)(C)C)[C@@H:26]([CH3:51])[CH2:27][C@@H:28]([CH3:50])[CH2:29][CH2:30][C@@H:31]([O:42][Si](C(C)(C)C)(C)C)[C@H:32]([CH3:41])[C@@H:33]([OH:40])[C@@H:34]([CH3:39])/[CH:35]=[CH:36]\[CH:37]=[CH2:38])[C@H:11]([CH3:19])/[CH:12]=[CH:13]/[CH:14]=C\C(O)=O)(C(C)(C)C)(C)C.C[CH2:70][O:71][C:72]([CH3:74])=[O:73]>C1COCC1.O>[CH3:70][O:71][C:72](=[O:73])/[CH:74]=[CH:14]\[CH:13]=[CH:12]\[C@@H:11]([CH3:19])[C@@H:10]([OH:9])[CH2:20][C@H:21]([OH:61])/[CH:22]=[CH:23]\[C@H:24]([CH3:60])[C@H:25]([OH:52])[C@@H:26]([CH3:51])[CH2:27][C@@H:28]([CH3:50])[CH2:29][CH2:30][C@@H:31]([OH:42])[C@H:32]([CH3:41])[C@@H:33]([OH:40])[C@@H:34]([CH3:39])/[CH:35]=[CH:36]\[CH:37]=[CH2:38]
Reactant: CCOC(C)=O
Reactant: C=C/C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](CC[C@H](C)C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C)/C=C/C=C\C(=O)O)O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C=C/C=C\[C@H](C)[C@H](O)[C@@H](C)[C@H](O)CC[C@H](C)C[C@H](C)[C@@H](O)[C@@H](C)/C=C\[C@@H](O)C[C@H](O)[C@H](C)/C=C/C=C\C(=O)OC
Reaction time: 24 h
Yield: 36 %

Procedure:
3N HCl (10 mL, prepared by adding 2.5 mL of conc. HCl to 7.5 mL MeOH) was added to a stirred solution of the macrolactonization precursor 48 (23 mg, 23 μmol) in THF (3 mL) at 0° C. After 24 h at room temperature, the reaction mixture was diluted with EtOAc (4 mL) and H2O (4 mL). The organic phase was retained and aqueous phase was extracted with EtOAc (2×4 mL). The combined organic phase was washed with saturated aqueous NaHCO3 (10 mL), dried with MgSO4, filtered and concentrated. The residue was purified by flash chromatography (EtOAc/hexane 3:2) to yield the product 50 (4.5 mg, 36%) as a colorless oil: IR (CHCl3) 3399, 2917, 2849, 1713, 1635, 1600, 1461, 1439, 1197, 1178, 970, 757 cm−1; 1H NMR (600 MHz, CD3OD) δ 7.36 (dd, J=15.3, 11.2 Hz, 1H), 6.67 (ddd, J=16.9, 11.1, 10.6 Hz, 1H), 6.63 (dd, J=11.3, 11.3 Hz, 1H), 6.14 (dd, J=15.4, 8.3 Hz, 1H), 6.03 (dd, J=11.0, 1.0 Hz, 1H), 5.59 (d, J=11.4 Hz, 1H), 5.43 (dd, J=10.7, 10.7 Hz, 1H), 5.42 (dd, J=10.8, 9.2 Hz, 1H), 5.32 (dd, J=10.4, 10.4 Hz, 1H), 5.17 (dd, J=16.8, 2.0 Hz, 1H), 5.08 (d, J=10.2 Hz, 1H), 4.61 (ddd, J=12.9, 8.5, 4.6 Hz, 1H), 3.80 (ddd, J=8.9, 4.4, 4.4 Hz, 1H), 3.69 (s, 3H), 3.63 (m, 1H), 3.46 (t, J=5.8 Hz, 1H), 3.13 (dd, J=8.0, 3.2 Hz, 1H), 2.93 (m, 1H), 2.71 (m, 1H), 2.38 (m, 1H), 1.73 (m, 1H), 1.56-1.53 (m, 3H), 1.52-1.46 (m, 2H), 1.44-1.36 (m, 3H), 1.09 (d, J=6.9 Hz, 3H), 0.98 (d, J=6.8 Hz, 3H), 0.96 (d, J=6.6 Hz, 3H), 0.95 (m, 2H), 0.94 (d, J=6.9 Hz, 3H), 0.87 (d, J=6.6 Hz, 3H), 0.86 (d, J=6.8 Hz, 3H); 13C NMR (150 MHz, CD3OD) δ 168.4, 148.5, 146.9, 135.7, 135.4, 133.85, 133.82, 130.6, 128.2, 117.7, 116.2, 79.2, 78.5, 74.8, 72.4, 65.8, 51.5, 45.1, 43.2, 43.0, 41.0, 37.2, 36.5, 34.0, 33.3, 33.1, 31.0, 20.7, 18.6, 18.4, 16.7, 13.8, 7.8; LRMS (ESI) 587.5 [M+Na]+, 559.2, 485.2, 413.3, 355.1, 212.1; HRMS (ESI) calcd for C33H56O7Na 587.3924 [M+Na]+, found 587.3953; [α]20D+8.7 (c 0.30, CDCl3).