Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[C:15]2([OH:19])[CH2:18][CH2:17][CH2:16]2)[CH2:3][CH2:2]1.Cl.[O:21]=[S:22]1(=[O:30])[CH2:26][CH:25]([C:27]([NH2:29])=[O:28])[NH:24][CH2:23]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:24]3[CH:25]([C:27]([NH2:29])=[O:28])[CH2:26][S:22](=[O:30])(=[O:21])[CH2:23]3)=[O:14])[CH:9]=[CH:8][C:7]=2[C:15]2([OH:19])[CH2:18][CH2:17][CH2:16]2)[CH2:2][CH2:3]1
Reactant: NC(=O)C1CS(=O)(=O)CN1
Reactant: O=C(O)c1ccc(C2(O)CCC2)c(OCC2CC2)n1
Agent: Cl
Product: NC(=O)C1CS(=O)(=O)CN1C(=O)c1ccc(C2(O)CCC2)c(OCC2CC2)n1
Yield: 9 %

Procedure:
In analogy to the procedure described in Example 127 e), 6-(cyclopropylmethoxy)-5-(1-hydroxycyclobutyl)pyridine-2-carboxylic acid (CAN 1415899-53-4, 50 mg, 190 μmol) was reacted with 1,1-dioxo-1,3-thiazolidine-4-carboxamide hydrochloride (Example 127 d, 45.7 mg, 228 μmol) to give the title compound (7 mg, 8%) as colorless oil, MS (EI): m/e=410.5 [MH+].
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:11]([C:1]1[O:10][N:4]=[C:3]2[C:2]=1[CH:8]=[CH:7][CH:6]=[CH:5]2)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1C(=O)O
Product: CC(=O)c1onc2ccccc12

Procedure:
reacting the anthranilic acid compound of step (3) with acetic anhydride to form an acetylanthranil compound of the formula ##STR44##
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:39])[C:10]1[CH:15]=[CH:14][C:13](B2OC(C)(C)C(C)(C)O2)=[C:12]([CH2:25][N:26]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:27][CH3:28])[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:42][C:43](=[O:52])[CH2:44][C:45]1[CH:46]=[N:47][CH:48]=[C:49](Br)[CH:50]=1)C.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9](=[O:39])[C:10]1[CH:15]=[CH:14][C:13]([C:49]2[CH:48]=[N:47][CH:46]=[C:45]([CH2:44][C:43]([OH:42])=[O:52])[CH:50]=2)=[C:12]([CH2:25][N:26]([C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:30])[CH2:27][CH3:28])[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1cncc(Br)c1
Reactant: CCN(Cc1cc(C(=O)OCc2ccccc2)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCN(Cc1cc(C(=O)OCc2ccccc2)ccc1-c1cncc(CC(=O)O)c1)C(=O)OCc1ccccc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
3-[(N-Benzyloxycarbonyl-N-ethyl-amino)-methyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid benzyl ester (1.96 g, 3.7 mmol), (5-bromo-pyridin-3-yl)-acetic acid ethyl ester (0.99 g, 4.1 mmol), and potassium carbonate (1.79 g, 13.0 mmol) were combined in DME (40 mL) and H2O (30 mL), and the solution was purged with N2 for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.427 g, 0.37 mmol) was added, and the reaction was stirred at 70° C. overnight. The mixture was quenched with 1N aqueous HCl (13 mL) and extracted with EtOAc. The combined organic layers were washed with H2O, and then dried and concentrated to give 3-[(N-benzyloxycarbonyl-N-ethyl-amino)-methyl]-4-(5-carboxymethyl-pyridin-3-yl)-benzoic acid benzyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:34](=[O:35])[N:33]([CH3:36])[C:11]3[N:12]([CH3:32])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19](=O)[CH2:20][C:21](=O)[CH2:22][O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.O.[NH2:38][NH2:39]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:34](=[O:35])[N:33]([CH3:36])[C:11]3[N:12]([CH3:32])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[NH:38][N:39]=[C:21]([CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH:20]=2)=[CH:15][CH:14]=4)=[CH:6][CH:7]=1
Reactant: Cn1c(=O)c(-c2ccc(Br)cc2)cc2c3cc(C(=O)CC(=O)COC4CCCCO4)ccc3n(C)c21
Reactant: NN
Solvent: O
Product: Cn1c(=O)c(-c2ccc(Br)cc2)cc2c3cc(-c4cc(COC5CCCCO5)n[nH]4)ccc3n(C)c21

Procedure:
The process is carried out as in Example 43 above, with compound A, 1-[3-(4-bromo-phenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-6-yl]-4-(tetrahydropyran-2-yloxy)butane-1,3-dione and hydrazine monohydrate.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: NOC1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NOC1CCOCC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.204 g, 0.74 mmol) in dry DCM (20 mL) were added 4-(aminooxy)tetrahydro-2H-pyran 31 (0.131 g, 1.11 mmol, J. Med. Chem., 2008, 51, 4601-4608), 1-hydroxybenzotriazole (0.142 g, 1.11 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.201 g, 1.11 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by column chromatography to give (2S,5R)-6-(benzyloxy)-7-oxo-N-(tetrahydro-2H-pyran-4-yloxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 32 (0.26 g, 93%) as a clear thick oil.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[C:6](Cl)=[N:5][S:4][N:3]=1.[CH3:10][O-:11].[Na+]>CO>[Cl:1][C:2]1[C:7](=[O:8])[C:6]([O:11][CH3:10])=[N:5][S:4][N:3]=1
Reactant: C[O-]
Reactant: O=c1c(Cl)nsnc1Cl
Agent: [Na+]
Solvent: CO
Product: COc1nsnc(Cl)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3.66 g of 3,5-dichloro-4H-1,2,6-thiadiazin-4-one in 30 ml of methanol is kept at 0°-5° C. and stirred while a solution of 2.40 g of sodium methoxide in 30 ml of methanol is added dropwise to it. The reaction mixture is stirred at room temperature 2 hours longer, then mixed with 200 ml of ice water. The precipitate is collected, washed with water, dried, and recrystallized from hexane to yield pale yellow needles, mp 159°-161°.
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[CH:5]=[C:4]([Cl:11])[N:3]=1.CCN(C(C)C)C(C)C.[C:21]([O:25][C:26]([NH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>CN(C=O)C>[C:21]([O:25][C:26](=[O:27])[NH:28][CH:29]1[CH2:34][CH2:33][N:32]([C:2]2[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[CH:5]=[C:4]([Cl:11])[N:3]=2)[CH2:31][CH2:30]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CCn1c(Cl)nc(Cl)cc1=O
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(Cl)cc1=O
Yield: 35.9 %

Procedure:
A solution of 2,6-dichloro-3-ethyl-3H-pyrimidin-4-one (320 mg, 1.64 mmol), DIEA (423 mg, 3.28 mmol) and (tert-butoxy)-N-(4-piperidyl)carboxamide (328 mg, 1.64 mmol) in DMF (10 mL) was heated to 120° C. for 1 h. The solvent was concentrated in vacuo and the residue was purified by silica chromatography (1:5, EA:PE) to give 210 mg (36%) of the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 1.25-1.32 (m 2H), 1.35 (t, J=7.2 Hz, 3H), 1.96-2.02 (m, 2H), 2.98-3.06 (m, 2H), 3.70 (br, 1H), 4.30 (q, J=5.2 Hz, 2H), 4.44 (br, 1H), 4.57-4.61 (m, 2H), 5.95 (s, 1H). [M+H] Calc'd for C16H25ClN4O3, 357, 359. Found, 357, 359.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28].C(N(CC)CC)C.C1COCC1>C(Cl)(Cl)Cl>[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([NH:20][C:16]1[CH:15]=[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)[CH:19]=[CH:18][CH:17]=1)=[O:28]
Reactant: O=C(Cl)CCCCCBr
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(N)c2)CC1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(NC(=O)CCCCCBr)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.6 %

Procedure:
A 25-mL RB-flask, charged with tert-butyl-4-[3-(amino)phenyl]-1-piperidinecarboxylate (2.00 mmol, 0.553 g), 6-bromohexanoyl chloride (0.427 g, 2.00 mmol, 1.0 eq.), triethylamine (0.404 g, 4.00 mmol) and THF (8.00 mL) was stirred at room temperature for 4 h. The reaction mixture was diluted with chloroform (50 mL) and washed with water (100 mL), brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography (silica gel, hexanes/EtOAc 10:1) to yield the desired product (0.921 g, 95.8%). 1H NMR (400 MHz, CDCl3) δ 7.47 (s, 1H), 7.28-7.22 (m, 2H), 7.11 (s, 1H), 6.5 (d, 1H, J=7.0 Hz), 3.45-3.39 (m, 2H), 2.85-2.70 (m, 2H), 2.68-2.58 (m, 1H), 2.37 (t, 2H, J=7.4 Hz), 1.96-1.71 (m, 7H), 1.68-1.50 (m, 5H), 1.48 (s, 9H); ESMS m/e: 355.4, 476.6.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)#[N:11].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:43]1([C@H:47]([NH:54][CH3:55])[CH2:48][N:49]2[CH2:52][CH:51]([OH:53])[CH2:50]2)[CH2:46][CH2:45][CH2:44]1>C(Cl)Cl>[C:10]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([N:54]([C@@H:47]([CH:43]2[CH2:46][CH2:45][CH2:44]2)[CH2:48][N:49]2[CH2:50][CH:51]([OH:53])[CH2:52]2)[CH3:55])=[O:18])=[CH:19][CH:20]=1)#[N:11]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: CN[C@H](CN1CC(O)C1)C1CCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ccc(C#N)cc1)[C@H](CN1CC(O)C1)C1CCC1
Reaction time: 0.08 h
Yield: 64.9 %

Procedure:
DIPEA (2.504 mL, 14.38 mmol) was added to a stirred suspension of 4-cyanobenzoic acid (0.670 g, 4.55 mmol) and TBTU (1.462 g, 4.55 mmol) in DCM (10 mL) at rt. The suspension was stirred for 5 min before it was cooled on an ice-bath. A solution of (S)-1-(2-cyclobutyl-2-(methylamino)ethyl)azetidin-3-ol (Compound Z2.1) (0.960 g, 4.79 mmol) in DCM (10 mL) was added over 5 min. The ice-bath was removed after 10 min and the reaction was stirred at rt for 3 h. The reaction mixture was diluted with DCM (20 mL), washed with NaHCO3 (8% aq., 35 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC. The selected fractions were concentrated and NaHCO3 (saturated, 40 mL) was added. The water layer was extracted with DCM (3×75 mL) and the combined organic layers were filtered through a phase separator and concentrated under reduced pressure to give the title compound (0.925 g, 62%). Mixture of rotamers: 1H NMR (400 MHz, DMSO-d6) δ 1.32-1.62, 1.65-1.97, 1.97-2.08, 2.17-2.28, 2.32-2.60, 2.62-2.74, 3.16-3.27, 3.39-3.45, 3.46-3.52, 4.07-4.18, 4.40-4.52, 5.19-5.24, 7.42-7.46, 7.57-7.62, 7.87-7.95.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([OH:11])=[C:6]([CH3:12])[CH:5]=1.Br[CH2:14][C:15]([OH:17])=[O:16]>C1COCC1>[Br:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([O:11][CH2:14][C:15]([OH:17])=[O:16])=[C:6]([CH3:12])[CH:5]=1
Reactant: O=C(O)CBr
Reactant: Cc1cc(Br)cc(C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(C)c1OCC(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85.4 %

Procedure:
To a suspension of sodium hydride (60%, 437 mg, 10.9 mmol) in THF (10 mL) at rt, was added a solution of 4-bromo-2,6-dimethylphenol (1.00 g, 4.97 mmol) in THF (10 mL), over 5 min. The reddish suspension was stirred at rt for 10 min, then a solution of bromoacetic acid (691 mg, 4.97 mmol) in 5 mL THF was added. The suspension was stirred at rt for 20 h. The volatile solvent was evaporated in vacuo, then the mixture was diluted with 20 mL H2O. The pH was adjusted to 7 with 1N HCl, then the aqueous phase was extracted with Et2O (2×). The aqueous phase was acidified to pH=2 with 1N HCl, then was extracted with EtOAc (2×). The combined organic extract washed with brine, dried (Na2SO4) and concentrated to afford 1.10 g (85%) of 79A as a colorless solid. MS (ESI) m/z 259.0 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:39])[CH:16]([NH:31][C:32](=O)[O:33]C(C)(C)C)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])[N:19]=2)=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+].[C:45]1(C(O)=O)[CH:46]=[CH:47][CH:48]=[C:49]2[CH2:55][CH2:54][CH2:53][CH:52]=[CH:51][C:50]=12.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([OH:39])[CH:16]([NH:31][C:32]([C:48]2[CH:47]=[CH:46][CH:45]=[C:50]3[CH2:51][CH2:52][CH2:53][CH:54]=[CH:55][C:49]=23)=[O:33])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])[N:19]=2)=[CH:13][CH:14]=1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Reactant: CC(C)(C)OC(=O)NC(Cc1cccc(OC(F)(F)C(F)F)n1)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)n1)C(O)c1ccc(F)cc1)c1cccc2c1C=CCCC2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Trifluoroacetic acid (3 ml) was added to tert-butyl (1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-{[6-(1,1,2,2-tetrafluoroethoxy)pyridin-2-yl]methyl}ethylcarbamate (300 mg, 0.65 mmol) at 0° C., and the mixture was stirred at 0° C. for 10 min. To the reaction solution was added saturated aqueous sodium hydrogen carbonate and the mixture was extracted with ethyl acetate (20 ml×2). The extract was washed with saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. To a solution of the residue in acetonitrile (25 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (122 mg, 0.65 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (187 mg, 0.97 mmol) and 1-hydroxybenzotriazole hydrate (99 mg, 0.65 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-1:1). Recrystallization from ethyl acetate-hexane gave the objective substance (196 mg, 57%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[N:14]3[CH:15]=[C:16]([O:19][C@H:20]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[C@@H:23]([NH2:30])[CH2:22][CH2:21]4)[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)[CH2:4][CH2:3]1.ClC(Cl)(Cl)C[O:34][C:35](=[O:53])[NH:36][C:37]1[N:38]([C:46]2[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=2)[N:39]=[C:40]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:41]=1.CCN(C(C)C)C(C)C.C(O)=O>O1CCOCC1>[CH:35]([OH:53])=[O:34].[C:42]([C:40]1[CH:41]=[C:37]([NH:36][C:35]([NH:30][C@@H:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:20]([O:19][C:16]3[CH:17]=[CH:18][C:13]4[N:14]([C:10]([CH2:9][CH2:8][N:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)=[N:11][N:12]=4)[CH:15]=3)[CH2:21][CH2:22]2)=[O:34])[N:38]([C:46]2[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=2)[N:39]=1)([CH3:45])([CH3:43])[CH3:44]
Reactant: CN1CCN(CCc2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: C1COCCO1
Solvent: O=CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(CCN5CCN(C)CC5)n4c3)c3ccccc32)cc1
Temperature: 60 °C

Procedure:
Intermediate 2c (85.0 mg, 0.21 mmol) was dissolved in 1,4-dioxane (2 mL) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 96.0 mg, 0.24 mmol) and DIPEA (75.0 μL, 0.43 mmol) were added. The reaction was heated to 60° C. for 18 h. After cooling, the mixture was partitioned between EtOAc (50 mL) and water (50 mL), and extracted into EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, then further purified by HPLC (C18 X-select column, 10-40% MeCN in H2O, 0.1% formic acid) to give the title compound mainly as formic acid salt (43.0 mg, 0.065 mmol, 31%). LCMS (Method 5) Rt 3.54 mins, m/z 662 [MH+]. 1H NMR (400 MHz, d4-MeOD): 1.30 (9H, s), 1.90-2.05 (2H, m), 2.06-2.15 (1H, m), 2.20-2.30 (1H, m), 2.38 (3H, s), 2.40 (3H, s), 2.55-2.75 (8H, br s), 2.90-2.95 (2H, t, J 7.4), 3.29-3.32 (2H, t, J 7.4), 4.86-4.92 (1H, dd, J 8.8, 5.6), 5.43-5.47 (1H, t, J 4.2), 6.33 (1H, s), 7.21-7.35 (11H, m), 7.60-7.64 (1H, d, J 9.9), 8.07-8.09 (1H, d, J 1.9), 8.40-8.50 (0.4H, br s, formate).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:14][C@H:15]1[CH2:21][S:20][C@H:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)[CH2:18][N:17]([CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])[C:16]1=[O:35])[C:7]([O:9]C(C)(C)C)=[O:8].[ClH:36]>O1CCOCC1>[ClH:36].[ClH:36].[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:14][C@H:15]1[CH2:21][S:20][C@H:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)[CH2:18][N:17]([CH2:27][C:28]([OH:30])=[O:29])[C:16]1=[O:35])[C:7]([OH:9])=[O:8]
Reactant: CC(C)(C)OC(=O)CN1C[C@@H](c2cccs2)SC[C@H](N[C@@H](CCCCN)C(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: NCCCC[C@H](N[C@H]1CS[C@H](c2cccs2)CN(CC(=O)O)C1=O)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
302 mg of t-butyl α-{6(R)-[5-amino-1(S)-t-butoxycarbonylpentylamino]-5-oxo-2(S)-(2-thienyl)perhydro-1,4-thiazepin-4-yl}acetate (prepared as described in Example 2) were mixed with 3 ml of a 4N solution of hydrogen chloride in dioxane, and the mixture was stirred for 16 hours at room temperature. At the end of this time, the dioxane was distilled off under reduced pressure, and the residue was triturated with diethyl ether and filtered to yield 278 mg of the title compound as a powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[O:18]1[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19]1>>[O:18]1[CH:22]=[CH:21][C:20]([C:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:24])=[CH:19]1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: O=C(O)c1ccoc1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccoc4)cc3c2C1
Yield: 47.2 %

Procedure:
Beginning with 8.7 mg (0.038 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 10.0 mg (0.089 mMol) furan-3-carboxylic acid, 5.8 mg (47%) of the title compound were recovered as a beige solid.
Reaction SMILES: CC([C:4]1[C:12]2[O:11][C@H:10]3[CH2:13][C@@H:14]([OH:26])[C@H:15]([NH:16][S:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:19])=[O:18])[C@H:9]3[C:8]=2[CH:7]=[CH:6][CH:5]=1)=O.C(=O)([O-])O.[Na+].ClC1C=CC=[C:35]([C:39]([O:41]O)=[O:40])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:39]([O:41][C:4]1[C:12]2[O:11][C@H:10]3[CH2:13][C@@H:14]([OH:26])[C@H:15]([NH:16][S:17]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)(=[O:18])=[O:19])[C@H:9]3[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:40])[CH3:35]
Reactant: CC(=O)c1cccc2c1O[C@H]1C[C@@H](O)[C@H](NS(=O)(=O)c3ccccc3)[C@@H]21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Oc1cccc2c1O[C@H]1C[C@@H](O)[C@H](NS(=O)(=O)c3ccccc3)[C@@H]21
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
(1R, 2R, 3aS, 8bR)-1-benzenesulfonamido-2-hydroxy-2,3,3a,8b-tetrahydro-1H-cyclopenta [b]benzofuran-5-yl methyl ketone (111) (219 mg) was dissolved in methylene chloride (4 ml) followed by the addition of sodium hydrogencarbonate (197 mg, 2.3 mmol) and metachloroperbenzoic acid (potency: 70%, 289 mg) and stirring for 2 hours at room temperature. A 3% aqueous solution of sodium sulfite (15 ml) was added to the reaction mixture followed by extraction with methylene chloride (15 ml+10 ml×2). The organic layer was washed with water (15 ml) and saturated brine (15 ml) and concentrated after drying with anhydrous magnesium sulfate. The residue was purified with column chromatography (silica gel: cyclohexane/ethyl acetate 1:2) to obtain (1R, 2R, 3aS, 8bR)-1-benzenesulfonamido-2-hydroxy-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-5-yl acetate (190 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][CH:22]=[C:21](F)[C:4]=1[C:5]([NH:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)=[O:9])=[O:6].[CH3:26][NH:27][CH3:28]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][CH:22]=[C:21]([N:27]([CH3:28])[CH3:26])[C:4]=1[C:5]([NH:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)=[O:9])=[O:6]
Reactant: COc1cccc(F)c1C(=O)NC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: CNC
Solvent: CN(C)C=O
Product: COc1cccc(N(C)C)c1C(=O)NC(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 100 °C

Procedure:
1-(2-methoxy-6-fluorobenzoyl)-3-(3-trifluoromethylphenyl)urea is dissolved in an amount of 1.0 g in 6 ml of dimethylformamide. The starting compound is obtained by the method as described in Example VI. Liquified dimethylamine in an amount of 0.5 ml is added and the reaction mixture is heated on 100° C. for 4 hours in a sealed tube. After cooling down to room temperature the reaction mixture is poured on ice-water. The formed precipitate is filtered off and washed with water. The desired compound is obtained in a yield of 0.8 g; melting point 180° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)([CH2:7][O:8][CH2:9][CH:10]=[CH2:11])[C:4](=[O:20])[NH:3]1.Br[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([C:30]([F:33])([F:32])[F:31])[CH:23]=1>CC(N(C)C)=O.[Cu-]=O>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([C:5]2([CH2:7][O:8][CH2:9][CH:10]=[CH2:11])[C:4](=[O:20])[N:3]([C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([C:30]([F:31])([F:33])[F:32])[CH:23]=3)[C:2](=[O:1])[NH:6]2)=[CH:13][CH:14]=1)#[N:17]
Reactant: C=CCOCC1(c2ccc(C#N)cc2)NC(=O)NC1=O
Reactant: N#Cc1ccc(Br)cc1C(F)(F)F
Agent: O=[Cu-]
Solvent: CC(=O)N(C)C
Product: C=CCOCC1(c2ccc(C#N)cc2)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Temperature: 130 °C

Procedure:
To a solution of 675 mg of 4-[2,5-dioxo-4-[(2-propenyloxy)methyl]imidazolidin-4-yl]benzonitrile and 622 mg of 4-bromo-2-trifluoromethylbenzonitrile in DMAC (2.5 mL) 214 mg of copper (I) oxide is added. The mixture is refluxed overnight at 130° C. The mixture is concentrated, taken in DCM, washed with a 10% aqueous ammonia solution and brine. The organic phase is dried over magnesium sulfate, concentrated under vacuum and purified on silica gel (ethyl acetate/cyclohexane: 0/100 to 50/50) to give the desired compound.
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([O:8][CH3:9])[CH2:5][N:4]1C(OCC1C=CC=CC=1)=O.[H][H]>C(OCC)(=O)C.[Pd]>[F:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([O:8][CH3:9])[CH2:5][NH:4]1
Reactant: [H][H]
Reactant: CO[C@@H]1C[C@@H](CF)N(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CO[C@H]1CN[C@H](CF)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To benzyl (2S,4R)-2-(fluoromethyl)-4-methoxypyrrolidine-1-carboxylate (529 mg, 1.98 mmol) dissolved in ethyl acetate (12.9 mL) was added palladium on carbon (211 mg, 0.2 mmol). Hydrogen gas was added via balloon, and the reaction was stirred at room temperature for 3 hours. The mixture was filtered over celite and concentrated under reduced pressure to afford (2S,4R)-2-(fluoromethyl)-4-methoxypyrrolidine. 1H NMR (500 MHz, CDCl3) δ 4.44-4.19 (m, 2H), 3.29 (s, 3H), 3.09-2.93 (m, 2H), 2.02-1.92 (m, 1H), 1.78 (s, 2H), 1.62-1.56 (m, 1H), 1.25 (s, 1H).