Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](=[C:3]([C:10](=[O:21])[C@@H:11]([C@@H:13]1[C@@H:16]([C@H:17]([OH:19])[CH3:18])[C:15](=[O:20])[NH:14]1)[CH3:12])[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5])=[N-]>ClCCl.C(#N)C.C([O-])(=O)CCCCCCC.[Rh+2].C([O-])(=O)CCCCCCC>[OH:19][C@@H:17]([C@H:16]1[C:15](=[O:20])[N:14]2[C@@H:13]1[C@@H:11]([CH3:12])[C:10](=[O:21])[CH:3]2[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5])[CH3:18]
Reactant: C=CCOC(=O)C(=[N+]=[N-])C(=O)[C@H](C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O
Agent: [Rh+2]
Agent: CCCCCCCC(=O)[O-]
Solvent: ClCCl
Solvent: CC#N
Product: C=CCOC(=O)C1C(=O)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12

Procedure:
To a solution of allyl (4R)-2-diazo-4-[(2R,3S)-3-{(1R)-1-hydroxyethyl}-4-oxoazetidin-2-yl]-3-oxopentanoate (0.36 g) in dichloromethane (2.25 ml) was added rhodium (II) octanoate (6 mg) under reflux. After refluxing for 20 minutes, to the solution was added rhodium (II) octanoate (6 mg). The mixture was refluxed for 40 minutes. The reaction mixture was cooled and evaporated in vacuo to give a residue. The residue was dissolved in anhydrous acetonitrile (4.5 ml) and then evaporated. This operation was repeated once again and the resulting residue was dried in vacuo to give allyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate. The residue containing the compound obtained above was dissolved in anhydrous acetonitrile (4.5 ml) and cooled to 0°-5° C. under an atmosphere of nitrogen. To this solution were added diphenyl phosphorochloridate (0.35 ml) and N,N-diisopropyl-N-ethylamine (0.32 ml) successively and the solution was stirred at 0°-5° C. for 1 hour. To the resulting solution were added dropwise a solution of (2S,4S)-1-allyloxycarbonyl-4-mercapto-2-[(ureidocarbonylmethyl)oxymethyl]pyrrolidine (0.35 g) in a mixture of dimethylformamide (1 ml) and acetonitrile (3 ml), and N,N-diisopropyl-N-ethylamine (0.35 ml) successively with stirring at 0°-5° C., and the stirring was continued at the same temperature for 3 hours. To a reaction mixture was added ethyl acetate (50 ml) and water (50 ml) with stirring, and the organic layer was separated.
Reaction SMILES: [OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[C:12](=[O:15])([O-])[O-].[K+].[K+].C=O.S(OC)(O[CH3:24])(=O)=O>CN(C=O)C.O.C(OCC)(=O)C>[OH:15][CH2:12][C:3]1[C:4]([C:8]([F:11])([F:10])[F:9])=[N:5][N:6]([CH3:7])[C:2]=1[O:1][CH3:24]
Reactant: Cn1nc(C(F)(F)F)cc1O
Reactant: COS(=O)(=O)OC
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1c(CO)c(C(F)(F)F)nn1C
Temperature: 25 °C
Yield: 84.3 %

Procedure:
In 100 ml of DMF were suspended 16.6 g (0.10 mole) of the 5-hydroxy-1-methyl-3-trifluoromethylpyrazole synthesized in Reference Example 1 and 20.9 g (0.15 mole) of potassium carbonate. In this suspension being stirred at room temperature was placed 4.5 g (0.15 mole) of paraformaldehyde, followed by stirring at the same temperature for 1 hour. Then, 41.8 g (0.30 mole) of potassium carbonate was added. Thereto was dropwise added 25.2 g (0.20 mole) of dimethyl sulfate, followed by stirring at room temperature for 2 hours to give rise to a reaction. After the reaction, 200 ml of ethyl acetate and 200 ml of water were added. The organic layer, which appeared by phase separation, was separated. The aqueous layer was subjected to re-extraction with 50 ml of ethyl acetate. The two organic layers were combined and washed with 50 ml of water, 30 ml of a saturated aqueous ammonium chloride solution and 30 ml of a saturated aqueous sodium chloride solution in this order. The resulting organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 23.5 g (purity: 75.4%, yield: 84.3%) of a crude solution of title compound. The crude solution was subjected to vacuum distillation to obtain a title compound. The compound showed spectra identical to those indicated in Example 2.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:12]1([S:18][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH2:6][CH2:5]3)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCc2cc(F)ccc21
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1CCc2cc(Sc3ccccc3)ccc21

Procedure:
5-Fluoro-1-indanone from Aldrich Sigma Chemical Co. (Cat No. 18,566-3) was treated with benzenethiol in the presence of potassium carbonate using the procedure of step 4 of Example 1 to afford 5-phenylsulfanyl-indan-1-one. MS: 241 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH2:27]([NH2:29])[CH3:28]>C(O)C>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([NH:29][CH2:27][CH3:28])[CH:3]=1)=[O:15]
Reactant: CCN
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Solvent: CCO
Product: CCNc1cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c2cnn(C(C)C)c2n1
Temperature: 25 °C

Procedure:
To a 10 mL microwave vial equipped with stir bar, septum cap and nitrogen inlet were added 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (23 mg, 0.062 mmol) and ethanol (1 mL). Added next to the stirring suspension was ethylamine (0.100 mL, 1.230 mmol) via syringe at once. The sealed reaction mixture was irradiated (microwave) at 110° C. for 40 min, followed by addition of 0.1 mL ethylamine and further irradiation for 7 hr at 130° C. After cooling to room temperature, about 50% of the volatiles were removed by a stream of nitrogen. The reaction mixture was diluted with water (20 mL) and stirred for 10 min. The mixture was then filtered and the collected solid washed with water. The solid was dried in vacuum oven at 50° C. for 18 h, to afford the title compound as 0.17 g (71%). LCMS E-S (M+H)=383.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (t, J=7.07 Hz, 3H), 1.43 (d, J=6.57 Hz, 6H), 2.12 (s, 3H), 2.21 (s, 3H), 3.35-3.39 (m, 2H), 4.31 (d, J=5.05 Hz, 2H), 4.89-5.01 (m, 1H), 5.89 (s, 1H), 6.61 (s, 1H), 7.18 (t, J=5.31 Hz, 1H), 7.83 (s, 1H), 8.44 (t, J=5.05 Hz, 1H), 11.55 (br. s., 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.[C:19]1([NH:25][CH2:26][CH:27]([NH2:29])[CH3:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:29][CH:27]([CH3:28])[CH2:26][NH:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1
Reactant: CC(N)CNc1ccccc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CC(CNc1ccccc1)Nc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 1-phenylamino-2-amino-propane hydrochloride and DBU in DME. ES-MS m/e (%): 335 (M+H+, 100).
Reaction SMILES: C(/C(/[CH:11]=[CH:12]/[C:13](/[C:21]#[N:22])=[C:14](\O)/[C:15]([O:17][CH2:18][CH3:19])=[O:16])=C(/O)\C(OCC)=O)#N.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:23]([N:30]1[CH:11]=[CH:12][C:13]([C:21]#[N:22])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)/C(O)=C(C#N)/C=C/C(C#N)=C(\O)C(=O)OCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C#N)ccn1Cc1ccccc1
Temperature: 95 °C
Yield: 58 %

Procedure:
A solution of (2E,4E,6E)-diethyl 3,6-dicyano-2,7-dihydroxyocta-2,4,6-trienedioate (18 g, 58.8 mmol) in N,N-Dimethylformamide (DMF) (100 mL) and Ethyl acetate (100 mL), was treated with benzylamine (15.44 mL, 141 mmol) and the resultant was heated at 95° C. for 3 hours. The dark mixture was concentrated and purified on silica gel (0-70% ethyl acetate/hexanes) to afford ethyl 1-benzyl-3-cyano-1H-pyrrole-2-carboxylate (8.7 g, 34.1 mmol, 60% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.25-7.45 (m, 3H) 7.11-7.16 (m, 2H) 6.84-6.87 (m, 1H) 6.53-6.58 (m, 1H) 5.59 (s, 2H) 4.37 (q, J=7.04 Hz, 2H) 1.40 (t, J=7.13 Hz, 3H); LCMS (m/z) ES+=255 (M+1).
Reaction SMILES: [Br:1][CH2:2][C:3]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH2:12]([N:26]([CH3:28])[CH3:27])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[Br-:1].[O:5]([C:3]([CH2:2][N+:26]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([CH3:27])[CH3:28])=[O:4])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCCCCCCCCCCCCCN(C)C
Reactant: O=C(CBr)Oc1ccccc1
Product: CCCCCCCCCCCCCC[N+](C)(C)CC(=O)Oc1ccccc1
Product: [Br-]
Reaction time: 72 h

Procedure:
A mixture of 55 g (0.26 mol) phenyl bromoacetate and 62 g (0.26 mol) of tetradecyldimethylamine was allowed to stand at room temperature for three days. The resultant crystalline mass was washed well with ether and dried to 114 g. Recrystallized from ethyl acetate and vacuum dried, the compound melted at 87°-91.5°.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=C[C:17]2[N:22]([OH:23])N=NC=2C=1.[CH2:24](N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:4]([O:3][C:1]([NH:8][C@@H:9]([CH3:10])[C:11]([N:22]([O:23][CH3:24])[CH3:17])=[O:13])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: On1nnc2ccccc21
Reactant: CCN(CC)CC
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 81.5 %

Procedure:
To a solution of Boc-alanine (20 grams, 105.7 mmol) in dichloromethane (170 ml) was added HOBT (14.28 g, 105.7 mmol) and N, O-dimethylhydroxylamine hydrochloride (10.31 g, 105.7 mmol). The mixture was chilled with an ice water bath then triethylamine (30 ml, 211.4 mmol) and 1,3-dicyclohexylcarbodiimide (21.81 g, 105.7 mmol) were added. The reaction was stirred in the ice water bath for 1 hour and then allowed to warm to room temperature overnight. The crude reaction was then chilled in an ice water bath and the precipitate filtered. The resulting organic solution was then washed twice with 1N aqueous sodium hydroxide (50 mL), twice with 10% aqueous citric acid (50 mL), and once with brine. The solution was then dried over anhydrous sodium sulfate, filtered, and the solvent evaporated. The resulting residue was purified by chromatography on a normal phase silica gel column with 30-100% ethyl acetate in hexanes. Fractions containing clean product were combined and the solvent evaporated to give the title compound (20 g, 81%): ES-MS (m/z) 233.2 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:17])([S:13](F)(=[O:15])=[O:14])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].CCN(CC)CC.[CH2:25]([CH:32]1[C:40]2[C:35](=[CH:36][C:37]([F:42])=[C:38]([OH:41])[CH:39]=2)[CH2:34][CH:33]1[NH:43][C:44](=[O:48])[O:45][CH2:46][CH3:47])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[F:1][C:2]([F:17])([S:13]([O:41][C:38]1[CH:39]=[C:40]2[C:35](=[CH:36][C:37]=1[F:42])[CH2:34][CH:33]([NH:43][C:44]([O:45][CH2:46][CH3:47])=[O:48])[CH:32]2[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:15])=[O:14])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6]
Reactant: CCOC(=O)NC1Cc2cc(F)c(O)cc2C1Cc1ccccc1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NC1Cc2cc(F)c(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2C1Cc1ccccc1
Temperature: 25 °C

Procedure:
Perfluorobutanesulfonyl fluoride (0.392 ml, 2.004 mmol) and Et3N (0.419 ml, 3.01 mmol) in abs. dichloromethane (10 ml) was added dropwise to the intermediate ethyl 1-benzyl-5-fluoro-6-hydroxy-2,3-dihydro-1H-inden-2-ylcarbamate (330 mg, 1.002 mmol), dissolved in dichloromethane and stirred at room temperature over night. Evaporated and purified by flash silica gel chromatography on 12 g SiO2-cartridge using dichloromethane to afford 3-benzyl-2-(ethoxycarbonylamino)-6-fluoro-2,3-dihydro-1H-inden-5-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate as a yellow product. M=389 mg (63%)
Reaction SMILES: [CH3:1][C:2]1[O:7][C:6]([CH3:9])([CH3:8])[C:5]2=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=[C:4]2[N:3]=1.Cl[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=1.CN(C=O)C>O.C(OCC)(=O)C>[CH3:1][C:2]1[O:7][C:6]([CH3:8])([CH3:9])[C:5]2[C:10]([O:14][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=3)=[CH:11][CH:12]=[CH:13][C:4]=2[N:3]=1
Reactant: CC1=Nc2cccc(O)c2C(C)(C)O1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC1=Nc2cccc(Oc3ccc([N+](=O)[O-])cn3)c2C(C)(C)O1
Temperature: 70 °C
Yield: 27.8 %

Procedure:
To a suspension of 2,4,4-trimethyl-4H-3,1-benzoxazin-5-ol (Intermediate 202, 500 mg, 2.61 mmol) and 2-chloro-5-nitropyridine (410 mg, 2.58 mmol) in dry DMF (4 mL) potassium carbonate (400 mg, 2.89 mmol) was added and the resulting mixture was heated in a MW apparatus at 70° C. for 40 min. The mixture was diluted with water and ethyl acetate, phases were separated and the aqueous was back-extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (2×20 mL), dried over Na2SO4, filtered and concentrated and the residue was purified by flash chromatography on silica gel using cyclohexane/ethyl acetate from 70:30 to 50:50 as eluents affording the title compound (225 mg) as yellow foam.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH:5][C:6](=[O:8])[CH3:7].[H-].C([Al+]CC(C)C)C(C)C>COCCOC.C1(C)C=CC=CC=1>[C:6]([NH:5][C@H:4]([CH:3]=[O:2])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])[CH3:7]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(C)=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: CC(=O)N[C@H](C=O)Cc1ccccc1
Temperature: -70 °C
Reaction time: 2 h
Yield: 74.3 %

Procedure:
N-Acetylphenylalanine methyl ester (4.2 g, 19 mmol) is dissolved in ethylene glycol dimethyl ether. The solution is cooled to −70° C. and diisobutylaluminum hydride (25.3 mL of a 1.5M solution in toluene, 39 mmol) is added. The resulting reaction mixture is stirred at −70° C. for 2 hours. The reaction is quenched by addition of 2N hydrochloric acid. The mixture is extracted 4 times with cold ethyl acetate and 4 times with toluene. The extracts are combined, washed with brine and dried over magnesium sulfate. Concentration in vacuo followed by silica gel chromatography furnishes 2.7 g of a white solid. The NMR is as reported in the literature, Biochemistry, 18: 921–926 (1979).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:13]([N:20]1C=CN=C1)([N:15]1C=CN=C1)=O.C(=O)=O.[F:28][C:29]([F:48])([F:47])[C:30]1[C:35]2[C:36](=[O:46])[N:37]3[CH2:45][CH2:44][C@H:38]3[C:39]3[N:40]([CH:41]=[N:42][CH:43]=3)[C:34]=2[CH:33]=[CH:32][CH:31]=1>CN(C)C=O>[C:1]([NH:8][CH2:9][C:10]1[O:12][N:20]=[C:13]([C:43]2[N:42]=[CH:41][N:40]3[C:34]4[CH:33]=[CH:32][CH:31]=[C:30]([C:29]([F:28])([F:47])[F:48])[C:35]=4[C:36](=[O:46])[N:37]4[CH2:45][CH2:44][C@H:38]4[C:39]=23)[N:15]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: O=C1c2c(cccc2C(F)(F)F)-n2cncc2[C@@H]2CCN12
Agent: O=C=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c-3cccc2C(F)(F)F)no1
Reaction time: 8 h
Yield: 72.5 %

Procedure:
4.2 g (24 mmol) of BOC-glycine were dissolved in 40 ml of N,N-dimethylformamide and treated portionwise with 4.05 g (25 mmol) of 1,1'-carbonyldiimidazole. After completion of the CO2 evolution the solution was stirred at 50° for 20 min. Then, 7.7 g (22 mmol) of (S)-8-trifluoromethyl-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine were added and the mixture was stirred at 90° overnight. The reaction mixture was concentrated and the residue was dissolved in methylene chloride. By washing, drying and evaporating the organic phase there were obtained 7.82 g (72%) of (S)-1-[5-(N-BOC-aminomethyl)-1,2,4-oxadiazol-3-yl]-8-trifluoromethyl-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: [CH2:1]=O.[CH3:3][NH:4][CH3:5].[NH:6]([C:13]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15](=[O:21])[CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CO.C(O)(=O)C>[NH:6]([C:13]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15](=[O:21])[C:14]=1[CH2:3][N:4]([CH3:1])[CH3:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C=O
Reactant: CC1(C)CC(=O)C=C(Nc2ccccc2)C1
Reactant: CNC
Solvent: CO
Solvent: CC(=O)O
Product: CN(C)CC1=C(Nc2ccccc2)CC(C)(C)CC1=O
Reaction time: 1 h

Procedure:
In 10 volume parts of methanol is dissolved 2.15 parts of 3-anilino-5,5-dimethyl-2-cyclohexen-1-one under warming and, then, to the resulting solution 0.9 part of a 37 weight % aqueous solution of formaldehyde, 1.12 part of a 40 weight % aqueous solution of dimethylamine and 1 drop of glacial acetic acid are added. The whole mixture is allowed to stand at room temperature for 1 hour, after which time the methanol is distilled off under reduced pressure. A small amount of isopropanol is added to the resulting residue and the whole mixture is cooled, whereupon colorless crystals separate. The crystals are collected by filtration and recrystallized from isopropyl ether to obtain colorless prisms of 3-anilino-5,5-dimethyl-2-dimethylaminomethyl-2-cyclohexen-1-one. Melting point: 111°-112°C. Elementary analysis: C17H24N2O Calcd. C, 74.95; H, 8.88; N, 10.28 Found C, 75.28; H, 8.96; N, 10.50.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24]OS(C)(=O)=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH2:30][CH2:31][CH2:32][CH2:33][N:34]1[CH:38]=[CH:37][N:36]=[CH:35]1>>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][NH:30][CH2:31][CH2:32][CH2:33][N:34]2[CH:38]=[CH:37][N:36]=[CH:35]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:16][CH:10]([CH2:11][CH:12]([CH2:13]3)[CH2:17]1)[CH2:9]2)=[O:5]
Reactant: CS(=O)(=O)OCCCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reactant: NCCCn1ccnc1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCCNCCCn2ccnc2)ccc1Cl

Procedure:
Synthesized from 2-chloro-5-[3-[(methylsulfonyl)oxy]propyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 6e, 1 mg,) and 1-(3-aminopropyl)imidazole according to the procedure described in Example 6f to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:12])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:12])[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
(S)-(−)-2-(tert-Butoxycarbonylamino)-1-propanol (523 mg, 2.98 mmol, 1.0 equiv.) was dissolved in 45 mL methylene chloride in a 100 mL r.b. flask with a magnetic stir bar. To this clear homogeneous solution, Dess-Martin periodinane (1.523 g, 3.591 mmol, 1.2 equiv.) was added in one part and the cloudy white reaction mixture was allowed to stir at room temperature for 2 h. Thin-layer chromotography monitored the reaction to completion. The reaction mixture was diluted with 100 mL ethyl acetate. Sodium bisulfite solution (2 M, 20 mL) was added to the reaction mixture and the organic layer was separated. The aqueous layer was washed with 3×30 mL EtOAc. The combined organic layers were washed with 50 mL 1 M NaOH, followed by saturated NaCl (30 mL) and dried over MgSO4. Filtration and rotary evaporation produced the desired product as a yellow oil (475 mg, 92% yield, Rf=0.63, 1:1 hexanes/ethyl acetate).
Reaction SMILES: [OH-:1].[Na+].[CH3:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10]1[CH:17]=[CH:16][C:13]([C:14]#N)=[CH:12][C:11]=1[C:18]([F:21])([F:20])[F:19].Cl.C[OH:24]>>[CH3:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10]1[CH:17]=[CH:16][C:13]([C:14]([OH:24])=[O:1])=[CH:12][C:11]=1[C:18]([F:21])([F:20])[F:19]
Reactant: [OH-]
Reactant: CO
Reactant: CC1CCCCN1c1ccc(C#N)cc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Product: CC1CCCCN1c1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 0 °C
Yield: 91 %

Procedure:
A 5N aqueous solution of sodium hydroxide (336 mL, 1.68 mol) was added into a solution of 4-(2-methylpiperidin-1-yl)-3-(trifluoromethyl)benzonitrile (28.0 g, 104.4 mmol) in MeOH (280 mL) and the resulting mixture was heated at reflux for 7 hours. The reaction mixture was cooled to 0° C. and acidified to pH 2 with a 5N aqueous solution of HCl. The precipitate was filtered, washed with water and dried under vacuum to give the title compound as a white powder (27.5 g, 91%). HPLC (Method A), Rt 5.4 min (purity: 99.8%). UPLC/MS, M+(ESI): 288.2, M−(ESI): 286.2. 1H NMR (DMSO-d6, 300 MHz) δ 13.30 (bs, 1H), 8.17 (m, 2H), 7.68 (d, J=8.2 Hz, 1H), 3.08 (m, 1H), 3.08 (m, 1H), 2.88 (m, 1H), 2.57 (m, 1H), 1.77-1.25 (m, 6H), 0.72 (d, J=6.0 Hz, 3H).
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[C:8]2[CH:9]=[C:10]([O:14][CH2:15][C:16]([OH:18])=[O:17])[C:11](Br)=[CH:12][C:7]=2[N:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:5][C:4]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:25][CH3:26])[CH2:3]1.C([O-])([O-])=O.[Cs+].[Cs+].[C:38]([O:42][CH2:43][CH3:44])(=[O:41])[CH2:39][SH:40].Cl>O.CN(C=O)C>[O:1]=[S:2]1(=[O:31])[C:8]2[CH:9]=[C:10]([O:14][CH2:15][C:16]([OH:18])=[O:17])[C:11]([S:40][CH2:39][C:38]([O:42][CH2:43][CH3:44])=[O:41])=[CH:12][C:7]=2[N:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:5][C:4]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:25][CH3:26])[CH2:3]1
Reactant: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(OCC(=O)O)cc2S(=O)(=O)C1
Reactant: CCOC(=O)CS
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC1(CC)CN(c2ccccc2)c2cc(SCC(=O)OCC)c(OCC(=O)O)cc2S(=O)(=O)C1
Yield: 100.2 %

Procedure:
1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 9; 50 mg, 0.098 mmol) and Cs2CO3 (51 mg, 0.15 mmol) were added to DMF (2.0 ml) and ethyl thioglycolate (0.02 ml, 0.15 mmol) was added. The reaction mixture was subjected to microwave irradiation in a Smith Synthesiser at 150° C. for 5 min. The reaction mixture was diluted with water (100 ml), made acidic with HCl (1 M), extracted with DCM (3×10 ml) and the collected organic layers were dried (MgSO4) to give the crude title compound (54 mg). M/z 550.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].N1C=CC=CC=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH2:14]([O:13][C:11]([CH:10]1[CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][N:8]([S:23]([CH3:22])(=[O:25])=[O:24])[CH2:9]1)=[O:12])[CH3:15]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C1CNCC1C(=O)OCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1CN(S(C)(=O)=O)CC1C(=O)OCC
Reaction time: 2 h
Yield: 57.5 %

Procedure:
To a solution of (3RS,4RS)-pyrrolidine-3,4-dicarboxylic acid diethyl ester (2.04 g, 9.48 mmol) [Bull. Soc. Chim. Fr. 1988, 579] in dichloromethane (30 ml) was added pyridine (1.12 g, 14.22 mmol), N,N-dimethylaminopyridine (10 mg) and methanesulfonyl chloride (1.30 g, 11.38 mmol) and stirred for 2 h at RTThe solution was washed with 0.5 M aqueous HCl and water, dried and evaporated. Flash chromatography (EtOAc/hexane 1:1) gave 1.6 g (42%) of (3RS,4RS)-1-methanesulfonyl-pyrrolidine-3,4-dicarboxylic acid diethyl ester as a colorless solid, MS: 310 (M+NH4)+.