Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K].[C:2]([O:7][CH3:8])(=[O:6])/[CH:3]=[CH:4]/[CH3:5].[CH:9]([C:11]1[S:15][C:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:13][CH:12]=1)=O.S([O-])(O)(=O)=O.[K+]>C(O)(C)(C)C.C(OCC)C.C(OCC)C.C(O)(C)(C)C>[C:19]([O:18][C:16]([C:14]1[S:15][C:11]([CH2:9][CH2:5][CH2:4][CH2:3][C:2]([O:7][CH3:8])=[O:6])=[CH:12][CH:13]=1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: C/C=C/C(=O)OC
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)s1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [K]
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: COC(=O)CCCCc1ccc(C(=O)OC(C)(C)C)s1
Temperature: 20 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
In an atmosphere of argon gas, potassium (25 g) was added to dried tert-butanol (820 ml) and refluxed for 3 hrs to give a solution. To the solution cooled to 20° C. was added diethyl ether (300 ml) and then slowly added a solution of methyl crotonate (63.93 g) and tert-butyl 5-formyl-2-thiophenecarboxylate (73.1 g) in tert-butanol/diethyl ether (2:1, 300 ml) keeping an inner temperature to 10° C. The mixture was stirred for 2 hrs at the same temperature and adjusted to pH 4 by adding 1N-potassium hydrogen sulfate aqueous solution (750 ml) under cooling. The mixture was extracted with diethyl ether, and the extract was washed with water and then saturated saline solution and distilled under reduced pressure to remove the solvent. The residue was dissolved in ethyl acetate (100 ml), to which 5% Pd-C (15 g:commercially available from Engelhard) was added. The mixture was vigorously stirred for 3 hrs at room temperature under hydrogen pressure of 4 kg/cm2. The reaction mixture was filtered to remove the catalyst and the filtrate was distilled under reduced pressure to remove the solvent. To the resulting residue were added dry methanol (200 ml), 4-(N,N-dimethylamino)pyridine (30 mg) and dichloromethane (250 ml), to which a solution of 1,3-dicyclohexylcarbodiimide (132 g) in dichloromethane (250 ml) was added slowly dropwise at 0° C. The mixture was stirred for 18 hrs at room temperature and cooled to 0° C. After adding acetic acid (30 ml), the mixture was stirred for 30 mins at 0° C. and for 30 mins at room temperature. The resulting precipitate was filtered off and the filtrate was concentrated to dryness under reduced pressure. Ethyl acetate (100 ml) was added to the residue and allowed to stand for 2 hrs at 0° C. Again, the resulting precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using diethyl ether-hexane=1:15→1:5, to obtain the captioned compound (61.4 g).
Reaction SMILES: B1C2CCCC1CCC2.[CH2:10]([C:13]1[N:14]=[N+:15]([O-:35])[C:16]2[CH:25]=[C:24]3[C:20]([CH2:21][CH:22]([CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:23]3)=[CH:19][C:17]=2[N:18]=1)[CH:11]=[CH2:12].C([O-])(=[O:38])C.[Na+].OO>C1COCC1.CO>[Si:28]([O:27][CH2:26][CH:22]1[CH2:21][C:20]2[C:24](=[CH:25][C:16]3[N+:15]([O-:35])=[N:14][C:13]([CH2:10][CH2:11][CH2:12][OH:38])=[N:18][C:17]=3[CH:19]=2)[CH2:23]1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:29])[CH3:30]
Reactant: CC(=O)[O-]
Reactant: C=CCc1nc2cc3c(cc2[n+]([O-])n1)CC(CO[Si](C)(C)C(C)(C)C)C3
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC1Cc2cc3nc(CCCO)n[n+]([O-])c3cc2C1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
A solution of 9-BBN (0.5 M, 32.5 mL, 16.3 mmol) in THF was added to a stirred solution of alkene 137 (4.02 g, 10.8 mmol) in THF (50 mL) at 20° C. under N2 and the mixture was stirred at 20° C. for 30 min. The mixture was cooled to 0° C., a solution of sodium acetate (3 M, 25 mL, 75 mmol) and then H2O2 (70%, 25 mL, 468 mmol) were added carefully and stirred for 10 min. MeOH (100 mL) was added and the mixture stirred at 20° C. for 20 min. The mixture was partitioned between aqueous Na2CO3 solution and EtOAc. The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, using a gradient (50-70%) of EtOAc/pet. ether, to give alcohol 138 (2.08 g, 49%) as a pale yellow solid: mp (EtOAc/pet. ether) 93-94° C.; 1H NMR δ 8.22 (s, 1H, H-9), 7.72 (s, 1H, H-5), 3.79 (br q, J=5.1 Hz, 2H, CH2O), 3.59-3.67 (m, 2H, CH2OSi), 3.12-3.24 (m, 4H, CH2), 2.93-3.03 (m, 2H, CH2), 2.73-2.84 (m, 1H, H-7), 2.30 (br s, 1H, OH), 2.11-2.21 (m, 2H, CH2), 0.87 [s, 9H, SiC(CH3)3], 0.04 [s, 6H, Si(CH3)2]; 13C NMR δ 165.7, 154.2, 148.3, 147.3, 132.3, 122.8, 114.5, 65.4, 62.2, 42.0, 35.8, 35.5, 34.0, 30.6, 25.8 (3), 18.3, −5.41 (2). Anal. calcd for C20H31N3O3S.¼H2O: C, 61.7; H, 8.0; N, 10.8. Found: C, 61.5; H, 7.8; N, 10.9%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20](O)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)C)=O)=O)(C)C.C1(C)C=CC=CC=1>O1CCCC1>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=Cc1cccc(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C=O)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.2 %

Procedure:
3-Hydroxybenzaldehyde (0.98 g), 1-t-butoxycarbonyl-4-hydroxypiperidine (2.41 g) and triphenylphosphine (3.15 g) were suspended in tetrahydrofuran (10 mL). To the mixture was added dropwise 40% azodicarboxylic acid diisopropyl ester-toluene solution (6.1 mL) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/3) to give the title compound (0.74 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=2)[CH2:3]1.N1C=CC=CC=1.[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>ClCCl>[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([CH:4]3[CH2:3][C:2]([CH3:20])([CH3:1])[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=4)[NH:5]3)[CH:14]=2)(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(N)c1)N2
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2cccc(C3CC(C)(C)c4cc(C)ccc4N3)c2)cc1
Yield: 31.9 %

Procedure:
To a stirred mixture of 3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (135 mg, 0.5 mmol) in dichloromethane (3 mL) was added pyridine (60 mg, 0.75 mmol) in dichloromethane (2 mL) and 4-methyl-benzenesulfonyl chloride (108 mg, 0.56 mmol) under nitrogen. The resultant mixture was stirred for 16 h. The reaction mixture was diluted with dichloromethane, washed with water (twice), saturated brine, and dried over magnesium sulfate. Magnesium sulfate was removed by filtration, and after evaporation, the residue was purified on chromatography column (silica gel, petroleum ether:ethyl acetate=15:1) to afford 67 mg of 4-methyl-N-[3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-benzenesulfonamide as yellow solid (Yield: 32%). MS (ESI+APCI) M+1=421.2.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](S(C)=O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:27][C:28]1[CH:39]=[CH:38][C:31]2[N:32]([CH3:37])[C:33](=[O:36])[CH2:34][O:35][C:30]=2[CH:29]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:27][C:28]4[CH:39]=[CH:38][C:31]5[N:32]([CH3:37])[C:33](=[O:36])[CH2:34][O:35][C:30]=5[CH:29]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1C(=O)COc2cc(N)ccc21
Reactant: CS(=O)c1ncc2ccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2n1
Product: CN1C(=O)COc2cc(Nc3ncc4ccc(-c5cccc(S(=O)(=O)NC(C)(C)C)c5)n4n3)ccc21
Yield: 35.7 %

Procedure:
The titled compound was prepared in analogous fashion as Example 113 using N-tert-butyl-3-(2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide and 7-amino-4-methyl-4H-benzo[1,4]oxazin-3-one to give N-tert-butyl-3-[2-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-ylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-benzenesulfonamide as a light tan solid (51.6 mg, 35.7% yield). M.p=242-246° C. LCMS (E/I+) 507 (M+H). 1H NMR (400 MHz, CDCl3) δ 8.68 (d, 2H, J=6.8 Hz), 8.20 (d, 1H, J=8 Hz), 7.84 (d, 1H, J=8.1 Hz), 7.49 (t, 1H, J=7.9 Hz), 7.21 (m, 2H), 7.10 (s, 1H), 6.99 (m, 2H), 6.82 (d, 1H, J=4.8 Hz), 5.13 (s, 1H), 4.59 (s, 2H), 3.17 (s, 3H), 1.24 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[O:25]=[S:26]1(=[O:41])[CH2:31][CH2:30][CH:29]([N:32]2[CH2:37][CH2:36][CH:35]([C:38](O)=[O:39])[CH2:34][CH2:33]2)[CH2:28][CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:38]([CH:35]3[CH2:34][CH2:33][N:32]([CH:29]4[CH2:30][CH2:31][S:26](=[O:41])(=[O:25])[CH2:27][CH2:28]4)[CH2:37][CH2:36]3)=[O:39])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Reactant: O=C(O)C1CCN(C2CCS(=O)(=O)CC2)CC1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(C3CCS(=O)(=O)CC3)CC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound {(3S,4R)-4-(4-chloro-phenyl)-1-[1-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 1-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-piperidine-4-carboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as an off-white foam. MS m/e: 592.2 [M]+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([C:12](=[O:25])[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[CH:3]=1.C(OC([N:33]1[CH:37]=[CH:36][CH:35]=[C:34]1B(O)O)=O)(C)(C)C>>[NH:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([C:12](=[O:25])[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: COc1cc(C(=O)c2cc(I)ccc2NC(C)=O)cc(OC)c1OC
Product: COc1cc(C(=O)c2cc(-c3ccc[nH]3)ccc2NC(C)=O)cc(OC)c1OC

Procedure:
In the same manner as in the synthesis of Compound 457, Compound 19 shown in Reaction 5 and (1-(tert-butoxycarbonyl)-1H-pyrrole-2-yl)boronic acid were subjected to the Suzuki reaction to obtain N-(4-(1H-pyrrole-2-yl)-2-(3,4,5-trimethoxybenzoyl)phenyl)acetamide. Thus obtained N-(4-(1H-pyrrole-2-yl)-2-(3,4,5-trimethoxybenzoyl)phenyl)acetamide (20 mg, 0.05 mmol) was dissolved in methanol (3 ml), and NaOMe (30 μl, 0.5 mmol, 1.0 M/tetrahydrofuran) was added thereto at room temperature. The mixture was refluxed with stirring for 3 hours at 80° C. After completion of the reaction, the reaction mixture was cooled to room temperature, and diluted with an EtOAc solution. The organic layer was washed with water, and brine. The extracted organic layer was dried over anhydrous MgSO4, and the solid substance was filtered off. The filtrate was vacuum concentrated. The resulting residue was purified by column chromatography (SiO2, n-Hex/EA=2/1→1/2) to obtain Compound 597 (8 mg, 45%) in a form of a yellow solid.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[S:8]([O-:35])([O:11][N:12]1[C:18](=[O:19])[N:17]2[CH2:20][C@H:13]1[CH2:14][CH2:15][C@H:16]2[C:21]1[CH:25]=[C:24]([CH2:26][NH:27]C(OC(C)(C)C)=O)[O:23][N:22]=1)(=[O:10])=[O:9].[Na+]>C(Cl)Cl.C(OCC)C>[S:8]([OH:35])([O:11][N:12]1[C:18](=[O:19])[N:17]2[CH2:20][C@H:13]1[CH2:14][CH2:15][C@H:16]2[C:21]1[CH:25]=[C:24]([CH2:26][NH2:27])[O:23][N:22]=1)(=[O:10])=[O:9].[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2]
Reactant: CC(C)(C)OC(=O)NCc1cc([C@@H]2CC[C@@H]3CN2C(=O)N3OS(=O)(=O)[O-])no1
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1cc([C@@H]2CC[C@@H]3CN2C(=O)N3OS(=O)(=O)O)no1
Temperature: 0 °C

Procedure:
TFA (0.40 mL) was added to a 0° C. solution of sodium (2S,5R)-2-(5-(tert-butoxycarbonylaminomethyl)isoxazol-3-yl)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-6-yl sulfate (54 mg, 0.12 mmol) in dry DCM (1.2 mL). The reaction mixture was stirred at 0° C. for 30 minutes to 1 h and then diluted with diethyl ether. The precipitate was collected via centrifugation, washed with ether (3×) and further dried under high vacuum to provide (2S,5R)-2-(5-(aminomethyl)isoxazol-3-yl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate as a TFA salt (˜30 mg). ESI-MS (EI+, m/z): 319.2. The TFA salt (˜30 mg) was further purified by prep-HPLC using ammonium formate buffer to provide (2S,5R)-2-(5-(aminomethyl)isoxazol-3-yl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate (601, 10 mg, 26%) as a white solid. ESI-MS (EI+, m/z): 319.21. 1H NMR (300 MHz, D2O) δ 6.61 (s, 1H), 4.68-4.65 (m, 1H), 4.35 (s, 2H), 4.17-4.14 (m, 1H), 3.14-3.10 (m, 1H), 2.95-2.91 (m, 1H), 2.31-1.80 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:15][CH2:14][C@@H:13]([NH:16][CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])[CH2:12]1>[Pd]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[CH2:15][CH2:14][C@@H:13]([NH:16][CH2:17][C:18]([CH3:19])([OH:20])[CH3:21])[CH2:12]2)=[C:2]([F:1])[CH:7]=1
Reactant: CC(C)(O)CN[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2F)C1
Agent: [Pd]
Product: CC(C)(O)CN[C@@H]1CCN(c2ccc(N)cc2F)C1

Procedure:
1-[(R)-1-(2-Fluoro-4-nitro-phenyl)-pyrrolidin-3-ylamino]-2-methyl-propan-2-ol was reduced according to Method F using Pd/C. In this way the product was obtained with molecular weight 267.17 (C14H22FN30); MS (ESI): 268 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[N:13][N:14]([CH2:15][C@@H:16]([NH:18]C(=O)OCC4C=CC=CC=4)[CH3:17])[C:8]=3[C:6]=2[N:7]=1>CO.[Pd]>[CH3:1][O:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[N:13][N:14]([CH2:15][C@@H:16]([NH2:18])[CH3:17])[C:8]=3[C:6]=2[N:7]=1
Reactant: COc1nc2c(ccc3cnn(C[C@H](C)NC(=O)OCc4ccccc4)c32)o1
Agent: [Pd]
Solvent: CO
Product: COc1nc2c(ccc3cnn(C[C@H](C)N)c32)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the product from Step E (60 mg, 0.157 mmol) in methanol (10 mL) was added 10% palladium-on-carbon (20 mg) and the mixture was stirred under an atmosphere of hydrogen at room temperature for 18 h. The reaction mixture was filtered and evaporated to a colorless oil (30 mg): LC/MS m/z 247.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C(N(C(C)C)CC)(C)C.[N:18]1([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)CCC>[N:18]1([CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][N:28]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=3)[CH2:29][CH2:30]2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: Nc1cc(Cl)ncn1
Reactant: C1CCN(CCN2CCNCC2)C1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(N2CCN(CCN3CCCC3)CC2)ncn1
Temperature: 125 °C
Reaction time: 18 h

Procedure:
6-Chloropyrimidin-4-amine 7-2 (0.317 g, 2.44 mmol) and diisopropylethylamine (0.0.316 g, 2.44 mmol) were suspended in n-butanol and 1-(2-pyrrolidin-1-ylethyl)piperazine 11-1 (0.448 g, 2.44 mmol) was added. The reaction was stirred at 125° C. for 18 hours. Upon cooling the reaction was purified on a silica column (DCM:MeOH:NH4OH) to afford 11-2. 1NMR (CD3OD): 7.96 ppm (s, 1H); 5.71 ppm (s, 1H); 3.53 ppm (t, 4H); 2.69 ppm (m, 2H); 2.58 ppm (m, 10H); 1.82 ppm (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[N:19]=[C:18]([CH2:20]Cl)[O:17][N:16]=4)=[C:10]3[C@@H:9]3[CH2:22][CH2:23][N:8]3[C:7](=[O:24])[C:6]=2[CH:25]=1.[CH2:26]([NH2:29])[CH2:27][CH3:28]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[N:19]=[C:18]([CH2:20][NH:29][CH2:26][CH2:27][CH3:28])[O:17][N:16]=4)=[C:10]3[C@@H:9]3[CH2:22][CH2:23][N:8]3[C:7](=[O:24])[C:6]=2[CH:25]=1
Reactant: CCCN
Reactant: O=C1c2cc(Cl)ccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Solvent: CN(C)C=O
Product: CCCNCc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2cc(Cl)ccc2-3)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.2 %

Procedure:
A suspension of 1.13 g (3.0 mmol) of (S)-7-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one in 15 ml of N,N-dimethylformamide was treated with 0.74 ml (9.0 mmol) of propylamine and stirred at room temperature under argon for 3 hrs. The solution was evaporated, the residue was taken up in 20 ml of water and the aqueous phase was extracted with methylene chloride. The combined extracts were washed twice with water, dried with sodium sulfate, filtered and evaporated. The crude product was chromatographed on 30 g of silica gel (methylene chloride/acetone 4:1, then 2:1 and finally methylene chloride/methanol 9:1). There were obtained 840 mg of (S)-7-chloro-1-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted in acetonitrile in the presence of fumaric acid into the fumarate. By recrystallization from acetonitrile there were obtained 588 mg (35%) of (S)-7-chloro-1-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one fumarate (1:1.4) of m.p. 135°-140° (dec.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:28](OCC)=[O:29])=[N:4][N:5]([CH2:7][C@H:8]2[CH2:13][CH2:12][C@H:11]([NH:14][C:15](=[O:27])[C:16]3[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=3[Cl:26])[CH2:10][CH2:9]2)[CH:6]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:26][C:17]1[CH:18]=[CH:19][C:20]([C:22]([F:23])([F:25])[F:24])=[CH:21][C:16]=1[C:15]([NH:14][C@H:11]1[CH2:12][CH2:13][C@H:8]([CH2:7][N:5]2[CH:6]=[C:2]([Cl:1])[C:3]([CH2:28][OH:29])=[N:4]2)[CH2:9][CH2:10]1)=[O:27]
Reactant: CCOC(=O)c1nn(C[C@H]2CC[C@H](NC(=O)c3cc(C(F)(F)F)ccc3Cl)CC2)cc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(N[C@H]1CC[C@H](Cn2cc(Cl)c(CO)n2)CC1)c1cc(C(F)(F)F)ccc1Cl
Temperature: 0 °C

Procedure:
A cooled (0° C.) solution of ethyl 4-chloro-1-((trans-4-(2-chloro-5-(trifluoromethyl)benzamido)cyclohexyl)methyl)-1H-pyrazole-3-carboxylate (step 1)(40 mg, 0.081 mmol) in THF (1 ml) was treated with LiAlH4 (6.1 mg, 0.162 mmol) and stirred at 0° C. After 3 h a grey suspension formed. The reaction was quenched by dropwise addition water (0.1 ml in THF 5 ml), followed by 1 M NaOH (0.1 ml) and water (0.3 ml). The reaction mixture was stirred and allowed to warm to RT overnight. The resulting mixture was filtered and the filtrate was concentrated in vacuo. The crude product was triturated with Et2O to afford the title compound as a white solid; 1H NMR (400 MHz, DMSO-d6) δ 8.5 (1H, d), 7.9 (1H, s), 7.8 (1H, d), 7.7 (2H, d), 5.0 (1H, s), 4.4 (2H, s), 3.9 (2H, d), 3.7 (1H, m), 1.9 (2H, d), 1.7 (1H, m), 1.6 (2H, d), 1.2 (2H, m), 1.1 (2H, m). LC-MS: Rt 2.47 mins; MS m/z 450.5 [M+H]+; Method LowpH_v002.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:3][C@H:4]([OH:26])[C@@H:5]([NH:13][C:14]([C@@H:16]([NH:21][C:22](=[O:25])[O:23][CH3:24])[C@@H:17]([CH3:20])[CH2:18][CH3:19])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:34][C@@H:35]([CH2:54][CH3:55])[C@H:36]([N:40]1[CH2:44][CH2:43][N:42]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([CH3:52])[N:47]=2)[C:41]1=[O:53])[C:37](O)=[O:38].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:6]([C@H:5]([NH:13][C:14]([C@@H:16]([NH:21][C:22](=[O:25])[O:23][CH3:24])[CH:17]([CH3:20])[CH2:18][CH3:19])=[O:15])[C@@H:4]([OH:26])[CH2:3][C@@H:2]([NH:1][C:37](=[O:38])[C@@H:36]([N:40]1[CH2:44][CH2:43][N:42]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([CH3:52])[N:47]=2)[C:41]1=[O:53])[CH:35]([CH3:34])[CH2:54][CH3:55])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](N)Cc1ccccc1
Reactant: CC[C@H](C)[C@@H](C(=O)O)N1CCN(Cc2cccc(C)n2)C1=O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)[C@H](C(C)CC)N1CCN(Cc2cccc(C)n2)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
A solution containing the product from Example 9B (0.36 g, 0.79 mmol) in THF (8 mL) was treated with the product from Example 7B (0.33 g, 0.79 mmol), DEPBT (0.355 g, 1.19 mmol), and N,N-diisopropylethylamine (0.70 mL, 4.02 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-50% acetone/dichloromethane to give the title compound (0.264 g, 45% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.75 (m, 12 H), 0.94 (m, 2 H), 1.29 (m, 2 H), 1.46 (m, 2 H), 1.62 (m, 1 H), 1.80 (m, 1 H), 2.43 (m, 4 H), 2.68 (m, 3 H), 2.88 (m, 1 H), 3.08 (m, 3 H), 3.56 (m, 4 H), 3.84 (m, 2 H), 4.15 (m, 2 H), 4.34 (s, 2 H), 4.84 (d, J=5.88 Hz, 1 H), 7.03 (m, 7 H), 7.15 (m, 6 H), 7.39 (d, J=9.19 Hz, 1 H), 7.66 (t, J=7.72 Hz, 1 H), 7.83 (d, J=8.82 Hz, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](O)=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.CN1CCOCC1.Cl.[CH3:43][O:44][C:45](=[O:60])[C@@H:46]([NH:49][C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH2:47][NH2:48].C[Si](C)(C)NC(=O)C>O1CCCC1>[CH3:43][O:44][C:45](=[O:60])[C@@H:46]([NH:49][C:50]([O:52][CH2:53][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)=[O:51])[CH2:47][NH:48][C:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]2)[CH2:19]1)=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCC[C@@H](C(=O)O)C2)CC1
Reactant: COC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Agent: CC(=O)N[Si](C)(C)C
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CNC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 83.2 %

Procedure:
To a stirred solution of (R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidine carboxylic acid (1.0 g) in tetrahydrofuran (20 ml) was added dropwise isobutyl chloroformate (356 μl) and 4-methylmorpholine (300 μl) at −15° C. under a nitrogen atmosphere. To an ice cooled solution of 2(S)-benzyloxycarbonylamino-β-alanine methyl ester hydrochloride (783 mg) and N-(trimethylsilyl)acetamide (1.78 g) in tetrahydrofuran (30 ml) was added dropwise the above solution with stirring under a nitrogen atmosphere. The reaction mixture was allowed to warm to ambient temperature, and stirred for 2 hours, which was partitioned between ethyl acetate and water. The organic layer was separated, washed in turn with water, aqueous 5% KHSO4, aqueous 5% NaHCO3 and brine, and dried over MgSO4. Evaporation of the solvent gave a residue, which was purified by silica-gel column chromatography eluting with n-hexane-ethyl acetate (from 1:6 to ethyl acetate only) to give N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-benzyloxycarbonylamino-β-alanine methyl ester (1.36 g) as a foam, which is the same compound obtained in Preparation 7.