Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([CH2:11][OH:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH3:13][C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[CH2:16][O:17][C:18](Cl)=[O:19].C(=O)([O-])[O-].[Na+].[Na+]>O.C(OCC)(=O)C>[CH3:13][C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[CH2:16][O:17][C:18]([NH:1][C@H:2]([CH2:11][OH:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)=[O:19]
Reactant: Cc1ccccc1COC(=O)Cl
Reactant: N[C@H](CO)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccccc1COC(=O)N[C@H](CO)Cc1ccc(O)cc1
Yield: 72.9 %

Procedure:
In a mixture of 10 ml of water and 20 ml of ethyl acetate, 1.6 g of tyrosinol was dissolved. To the solution were added dropwise 2 g of 2-methylbenzyloxycarbonyl choride and 10 ml of an aqueous solution containing 1.3 g of sodium carbonate alternately with stirring while cooling with ice. After stirring for two hours at room temperature, the ethyl acetate layer was collected and washed with 5% hydrochloric acid and then with water. The layer was dried and concentrated to dryness. The residue was crystallized from ethyl acetate-petroleum either to give 2.2 g of N-(2-methylbenzyloxycarbonyl)-tyrosinol with a mp. 78°-81° C in a yield of 70%. Analysis, calculated for C18H21O4N C 68.55, H 6.72, N 4.44, found C 68.88, H 6.84, N 4.42.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=2[N:6]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32](Cl)=[O:33])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32](=[O:33])[NH:1][C:2]2[S:3][C:4]3[C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=3[N:6]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Cl)CC1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)C3CCN(C(=O)OC(C)(C)C)CC3)nc12

Procedure:
Using 2-amino-4-methoxy-7-morpholin-4-yl-benzothiazol and 4-chlorocarbonyl-piperidine-1-carboxylic acid tert-butyl ester the title compound was obtained as a white solid (3%), MS: m/e=477(M+H+).
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[N:14]1[C:18](=[O:19])[CH2:17][C@:16]([CH:23]([CH3:25])[CH3:24])([C:20]([OH:22])=O)[CH2:15]1.C(N(CC)C(C)C)(C)C.[F:35][C:36]([F:49])([F:48])[C:37]1[CH:38]=[C:39]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[NH2:40].Cl>C1COCC1.C(Cl)Cl>[F:35][C:36]([F:48])([F:49])[C:37]1[CH:38]=[C:39]([NH:40][C:20]([C@@:16]2([CH:23]([CH3:24])[CH3:25])[CH2:17][C:18](=[O:19])[N:14]([C:8]3[C:7]([CH3:6])=[CH:12][CH:11]=[CH:10][C:9]=3[CH3:13])[CH2:15]2)=[O:22])[CH:41]=[C:42]([C:44]([F:45])([F:47])[F:46])[CH:43]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1cccc(C)c1N1C[C@](C(=O)O)(C(C)C)CC1=O
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C)c1N1C[C@](C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(C(C)C)CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
Methanesulfonyl chloride (167 mg, 1.45 mmol) was added dropwise to a solution of enantiopure (3R)-1-(2,6-dimethylphenyl)-3-isopropyl-5-oxo-pyrrolidine-3-carboxylic acid (182 mg, 0.661 mmol, prepared in step a above), N,N-diisopropylethylamine (374 mg, 2.90 mmol) and 3,5-bis(trifluoromethyl)aniline (331 mg, 1.45 mmol) in THF (4 mL). Stirring at room temperature for 1 h allowed the reaction to reach completion, whereupon 5 mL of 0.3 M aqueous hydrochloric acid and 10 mL of DCM were added and the mixture was stirred vigorously for 5 min. The separated organic phase was concentrated in vacuo on silica gel and purified by flash chromatography (SiO2, 25-60% EtOAc/hexanes) to give an off-white residue, which was recrystallized from a mixture of hot ethyl acetate (2 mL) and hexanes (7 mL) to give 203 mg of the desired compound (63% yield) as colorless crystals. 1H NMR (400 MHz, CDCl3) δ □1.09 (d, J=7.4, 3H), 1.11 (d, J=7.4, 3H), 2.13 (s, 3H), 2.23 (s, 3H), 2.26 (qq, J=7.4, 7.4, 1H), 2.81 (d, J=17.2, 1H), 3.09 (d, J=17.2, 1H), 3.61 (d, J=10.4, 1H), 4.17 (d, J=10.4, 1H), 7.02-7.18 (m, 3H), 7.64 (s, 1H), 7.86 (s, 1H), 8.05 (s, 2H). LC-MS: Rt (retention time)=3.10 min, MS: (ES) m/z 487 (M+H+).
Reaction SMILES: [OH-].[Na+].CC(C)=O.Cl.[OH:8][C:9]1[C:10]([CH2:15][OH:16])=[N:11][CH:12]=[CH:13][CH:14]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[CH2:17]([O:8][C:9]1[C:10]([CH2:15][OH:16])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: OCc1ncccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: OCc1ncccc1OCc1ccccc1
Yield: 104.9 %

Procedure:
Sodium hydroxide (31.5 grams, 0.78 mole) was dissolved in 100 ml water and 100 ml of acetone was added followed by 3-hydroxy-2(hydroxymethyl)pyridine hydrochloride (63.8 grams; 0.39 mole). 250 ml of acetone was added followed by benzyl bromide (74.1 grams; 51.5 ml; 0.43 mole). The mixture was refluxed for a period of 4.5 hours and the acetone evaporated in vacuo. The aqueous layer was extracted with CH2Cl2 (three times 150 ml) and the extracts dried (anhydrous Na2SO4) and concentrated to yield 88.1 grams of a brown liquid. The brown liquid (88.1 grams) was dissolved in ether and ether-HCl added to form the hydrochloride salt. The HCl salt was filtered and the filter cake dissolved in water. The aqueous solution was basified to afford a brown pasty precipate which on trituration with ether afforded 58.7 grams of material. Recrystallization from ethanol yielded 31.6 grams of a tan solid, m.p. 79°-80° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])=[O:7].[H-].[Na+]>CN(C=O)C>[O:7]=[C:6]1[CH2:5][CH2:4][CH2:3][CH2:2][N:8]1[C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cccc(NC(=O)CCCCBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(N2CCCCC2=O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.2 %

Procedure:
The bromide of Example 36 (1.50 g, 4.88 mmol) was taken up in dry DMF (40 ml) and treated with NaH (160 mg, 80% disp. in oil) at 0° C. The mixture was stirred at r.t. under nitrogen for 10 min, then KI (80 mg) added and the mixture heated at 70° C. for 4 h. The mixture was evaporated and partitioned between EtOAc and 1M HCl. The organic portion was washed with 5% KHCO3 and brine, filtered (Whatman® 1 PS, phase separator) and evaporated. The residue was chromatographed (eluant 2% MeOH in EtOAc) to provide a colourless oil (640 mg, 56%).
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][CH:18]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[C@H:2]([C:11](O)=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].C1CCC(N=C=NC2CCCCC2)CC1.[NH2:46][C@H:47]([C:58]([O:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)=[O:59])[CH2:48][C:49]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[NH:51][CH:50]=1.Cl.C(N(CC)CC)C>C(Cl)Cl>[NH:1]([C:14]([O:16][CH2:17][CH:18]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[C@H:2]([C:11]([NH:46][C@H:47]([C:58]([O:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)=[O:59])[CH2:48][C:49]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[NH:51][CH:50]=1)=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:7])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 41 mg portion of Fmoc-Asp(Ot-Bu)-OH was dissolved in 1, ml of methylene chloride, and 12 mg of HONSu and 21 mg of DCC were added thereto at 0° C. and stirred at 0° C. for 30 minutes. Then, 1 ml of a methylene chloride solution containing 33 mg of H-Trp-OBzl hydrochloride and 14 μl of triethylamine were added thereto and stirred at 0° C. for 3 hours. The insoluble substances were removed by filtration and washed with cold methylene chloride, and the filtrate was collected. The solvent was removed from the filtrate by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (50 g of Wakogel C-200, eluted with chloroform/methanol=25/1) to obtain 67 mg of Fmoc-Asp(Ot-Bu)-Trp-OBzl as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:19]([OH:21])=[O:20])[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22](=O)(O)[O-].[Na+].CI>CN(C)C=O>[CH3:22][O:20][C:19](=[O:21])[C@@H:9]([CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 95.4 %

Procedure:
To a solution of t-butyloxycarbonyl-O-benzyl-D-serine (25.0 g, 84.7 mmol) stirring in dimethylformamide (500 mL) at room temperature was added sodium bicarbonate (14.2 g, 169 mmol) followed by methyl iodide (26.4 mL, 424 mmol). After 18 h, the reaction mixture was concentrated to approximately 100 mL. Ethyl acetate was added and the mixture washed with aqueous sodium bicarbonate and brine. The organic extract was dried and concentrated to give the desired compound (25 g, 96%) as a light yellow oil: 1H NMR (300 MHz, CDCl3) d 1.45 (s, 9H), 3.70 (m, 1H), 3.75 (s, 3H), 3.85 (m, 1H), 4.50 (m, 3H), 7.30 (m, 5H); MS (FD) m/e 310; Anal. calc'd for C16H23NO5: C, 62.12; H, 7.49; N, 4.53. Found: C, 62.31; H, 7.49; N, 4.43.
Reaction SMILES: [CH2:1]1[CH2:10][C@@H:9]2[N:4]([CH2:5][C@H:6]3[C@H:13]4[CH2:14][CH2:15][CH2:16][C:17](=O)[N:12]4[CH2:11][C@@H:8]2[CH2:7]3)[CH2:3][CH2:2]1.[BH4-].[Na+].II.[OH-].[OH-].[K+]>C1COCC1.CCOCC>[CH2:1]1[CH2:10][C@H:9]2[N:4]([CH2:5][C@@H:6]3[C@@H:13]4[CH2:14][CH2:15][CH2:16][CH2:17][N:12]4[CH2:11][C@H:8]2[CH2:7]3)[CH2:3][CH2:2]1
Reactant: O=C1CCC[C@@H]2[C@H]3C[C@@H](CN12)[C@@H]1CCCCN1C3
Agent: II
Agent: [BH4-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C1CCN2C[C@H]3C[C@H](CN4CCCC[C@@H]34)[C@H]2C1
Temperature: 80 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
To a solution of Lupanine (49.6 mg) in THF (3 mL) as ether was added NaBH4 (7.6 mg, 1.0 eq) and I2 (25.4 mg, 0.5 eq). The mixture was stirred at 80° C. for 16 hours and then cooled to room temperature. As alcohol MeOH (10 mL) was added and the mixture was subsequently poured into 50 mL of 5% aqueous alkaline hydroxide KOH. The resulting solution was extracted with Et2O (5×40 mL) as organic solvent, the organic extracts were dried over Na2SO4 and then concentrated to afford Sparteine as a colorless oil (41.2 mg, 88% yield).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1.FC(F)(F)S(O[CH2:21][C:22]([F:25])([F:24])[F:23])(=O)=O.O>CN(C)C=O>[F:23][C:22]([F:25])([F:24])[CH2:21][O:3][CH:4]1[CH2:5][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(OCC(F)(F)F)C1
Reaction time: 0.5 h
Yield: 47.4 %

Procedure:
Sodium hydride (60 wt % dispersion in liquid paraffin, 151 mg, 3.46 mmol) in N,N-dimethylformamide (5 mL) was mixed with tert-butyl 3-hydroxyazetidine-1-carboxylate (500 mg, 2.89 mmol) in N,N-dimethylformamide (3 mL) under cooling with ice and stirred for 30 minutes, and the resulting reaction mixture was mixed with 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.499 mL, 3.46 mmol) under cooling with ice and then stirred at room temperature for 5 hours. After addition of water, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1→1/1(v/v)) to give the title compound as a colorless solid (350 mg, yield 48%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C@@H:10]2[C@@H:16]3[CH2:17][CH2:18][C@@H:12]([C@@H:13]4[C@H:15]3[CH2:14]4)[C@@H:11]2[C:19](OC)=[O:20])=[CH:4][CH:3]=1.[CH3:23][S:24]([NH:27][C:28]1[CH:43]=[CH:42][C:31]2[NH:32][C:33]([CH2:38][C:39](O)=[O:40])=[N:34][S:35](=[O:37])(=[O:36])[C:30]=2[CH:29]=1)(=[O:26])=[O:25].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:39](=[O:40])[C:38]([C:33]3[NH:32][C:31]4[CH:42]=[CH:43][C:28]([NH:27][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:29][C:30]=4[S:35](=[O:37])(=[O:36])[N:34]=3)=[C:19]([OH:20])[C@@H:11]3[C@H:10]2[C@@H:16]2[CH2:17][CH2:18][C@H:12]3[C@@H:13]3[C@H:15]2[CH2:14]3)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: COC(=O)[C@H]1[C@H]2CC[C@H]([C@@H]3C[C@@H]32)[C@H]1NCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@H]3[C@H]4CC[C@H]([C@@H]5C[C@@H]54)[C@H]3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 25 °C
Yield: 81.6 %

Procedure:
rac-Methyl (1R,2R,4S,5S,6S,7R)-7-{[(4-fluorophenyl)methyl]amino}tricyclo[3.2.2.02,4]nonane-6-carboxylate (0.15 g, 0.49 mmol) was dissolved in anhydrous N,N-dimethylformamide (8 mL). (7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1g, 0.16 g, 0.49 mmol) was added followed by N-methylmorpholine (0.11 mL, 1.03 mmol). The mixture was stirred until everything dissolved, approximately 5 min. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.10 g, 0.51 mmol) was added and the mixture was stirred at 25° C. for 4 h. Triethylamine (0.20 mL, 1.47 mmol) was added and the mixture was stirred at 50° C. for 16 h. Upon cooling to 25° C., the solution was diluted with ethyl acetate (50 mL) and washed with 1.0 M aqueous hydrochloric acid solution (2×50 mL), saturated aqueous brine solution (20 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a golden oil. Purification by flash column chromatography (Teledyne Isco RediSep column; 0 to 20% ethyl acetate in dichloromethane) afforded the desired product, rac-N-{3-[(1R,2R,7S,8S,9S,11R)-3-[(4-Fluorophenyl)methyl]-6-hydroxy-4-oxo-3-azatetracyclo[6.3.2.02,7.09,11]tridec-5-en-5-yl]-1,1-dioxo-4H-1λ6,2,4-benzothiadiazin-7-yl}methanesulfonamide (0.23 g, 0.40 mmol, 82%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 0.44-1.28 (10H, m), 2.29 (1H, bs), 3.06 (3H, s), 3.82 (1H, d, J=11.6 Hz), 4.40 (1H, d, J=14.0 Hz), 4.98 (1H, d, J=15.6 Hz), 7.12-7.60 (7H, m), 10.19 (1H, s). LC-MS (ESI) calcd for C27H27FN4O6S2 586.65, found 587.5 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][CH2:8][N:7]([C:12](=[O:14])[CH3:13])[C:6]=2[CH:15]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:34])=[CH:19][N:18]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)(O)[O-].[Na+].ClC1N=CC=CN=1>C(O)(C)C.O>[C:12]([N:7]1[C:6]2[CH:15]=[C:2]([NH:1][C:17]3[N:22]=[C:21]([NH:23][C:24]4[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=4[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:34])=[CH:19][N:18]=3)[CH:3]=[CH:4][C:5]=2[O:11][CH2:10][CH2:9][CH2:8]1)(=[O:14])[CH3:13]
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CC(=O)N1CCCOc2ccc(N)cc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: Clc1ncccn1
Agent: O=C([O-])O
Solvent: CC(C)O
Solvent: O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)N(C(C)=O)CCCO3)ncc1Cl
Yield: 42.8 %

Procedure:
1-(2-Amino-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-ethanone (55 mg, 0.27 mmol), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (85 mg, 0.29 mmol), and 10-Camphorsulfonic acid (12 mg, 0.052 mmol) in Isopropyl alcohol (2 mL) was irradiated in a CEM microwave (120° C., 40 min). The contents were neutralized with 1 mL satd. sodium bicarbonate and diluted with 4 mL water to afford a turbid solution. This solution was added to stirring water (10 mL) resulting in ppt of the target and the chloropyrimidine traces. The solid was chromatographed (SiO2, 0-100% EtOAc:Hex) to afford 2-[2-(9-Acetyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-ylamino)-5-chloro-pyrimidin-4-ylamino]-N-methyl-benzamide as a light yellow foam (54 mg, 43%). LCMS: 467 (M+H); 1H-NMR (DMSO): 11.51 (s, 1H), 9.50 (s, 1H), 8.75 (s, 1H), 8.64 (s, 1H), 8.24 (s, 1H), 7.73 (m, 2H), 7.45 (m, 2H), 7.14 (m, 1H), 7.03 (d, 1H, J=8.8 Hz), 4.60 (m, 1H), 4.30 (m, 1H), 3.62 (m, 1H), 2.91 (d, 1H, J=4 Hz), 2.77 (m, 1H), 1.93 (m, 1H), 1.74 (m, 4H).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[CH:11]=[CH:10][C:9]([C@@H:12]([NH:14][C:15](=[O:17])[CH3:16])[CH3:13])=[CH:8][CH:7]=2)[CH2:3]1.Br[C:19]1[N:24]=[C:23]([N:25]([CH3:31])[CH2:26][C:27]([CH3:30])([OH:29])[CH3:28])[CH:22]=[CH:21][CH:20]=1.CC([O-])(C)C.[Na+].O>O1CCOCC1.CN(C=O)C>[OH:29][C:27]([CH3:30])([CH3:28])[CH2:26][N:25]([CH3:31])[C:23]1[N:24]=[C:19]([O:1][CH:2]2[CH2:3][N:4]([C:6]3[CH:7]=[CH:8][C:9]([C@@H:12]([NH:14][C:15](=[O:17])[CH3:16])[CH3:13])=[CH:10][CH:11]=3)[CH2:5]2)[CH:20]=[CH:21][CH:22]=1
Reactant: CN(CC(C)(C)O)c1cccc(Br)n1
Reactant: CC(=O)N[C@@H](C)c1ccc(N2CC(O)C2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](C)c1ccc(N2CC(Oc3cccc(N(C)CC(C)(C)O)n3)C2)cc1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
23 mg (0.10 mmol) (S)—N-{1-[4-(3-Hydroxy-azetidin-1-yl)-phenyl]ethyl}-acetamide (V.1) in 1,4-dioxane (2.0 mL) is added to 31 mg (0.12 mmol) 1-[(6-bromo-pyridin-2-yl)-methyl-amino]-2-methyl-propan-2-ol. 38 mg (0.40 mmol) NaOtBu is added followed by 7.4 mg (0.01 mmol) chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II). The mixture is stirred for 12 h at 50° C. 7.8 mg (0.01 mmol) chloro(2-dicyclohexylphosphino-2′,4′,6′-triisoporpyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) is added and the mixture is stirred for 12 h at 100° C. After cooling to room temperature water (0.5 mL) and DMF (2.0 mL) are added and the mixture is filtered and concentrated. The residue is purified by HPLC (acetonitrile/water (+0.1% NH4OH)) to yield the desired product.
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[H-].[Na+].FC(F)(F)S(OC1[CH:21]=[C:22]2[C:26](=[C:27]([Cl:30])[C:28]=1[Cl:29])[C:25](=[O:31])[C:24]([CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)([CH3:32])[CH2:23]2)(=O)=O>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:29][C:28]1[C:27]([Cl:30])=[C:26]2[C:22]([CH2:23][C:24]([CH2:33][CH:34]3[CH2:35][CH2:36][CH2:37][CH2:38]3)([CH3:32])[C:25]2=[O:31])=[CH:21][C:3]=1[CH2:2][C:1]([OH:9])=[O:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC1(CC2CCCC2)Cc2cc(OS(=O)(=O)C(F)(F)F)c(Cl)c(Cl)c2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC1(CC2CCCC2)Cc2cc(CC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
Diethyl malonate (18.3 g., 0.114 mole) is added with stirring under nitrogen at 10°-15° C. to a suspension of sodium hydride (56% in mineral oil, 4.89 g., 0.114 mole) in dry dimethylformamide (85 ml.). The reaction mixture is stirred for 1 hour at room temperature, cooled to 5° C. and then 6,7-dichloro-2-cyclopentylmethyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl trifluoromethanesulfonate (18.8 g., 0.0426 mole dissolved in dry toluene (20 ml.) is added over 1 hour at 5°-7° C. After stirring at room temperature for 18 hours, the reaction mixture is poured into ice water (1000 ml.) and extracted with ether (4×150 ml.) and then with methylene chloride (2×50 ml.). The combined organic extracts are washed three times with water and concentrated under vacuum. The residual oil is dissolved in ethanol (150 ml.) and added to a solution of 20 g. of sodium hydroxide in water (150 ml.). The mixture is refluxed for 3 hours, cooled and the ethanol removed under vacuum. The residue is diluted with water, extracted with hexane and then acidified with hydrochloric acid. The gum that separates is extracted with ether. The combined etheral extracts are washed with water and then extracted repeatedly with dilute sodium bicarbonate. The combined aqueous extracts are acidified with hydrochloric acid and extracted with ether. The ether extracts are washed with brine, dried over magnesium sulfate an concentrated under vacuum to obtain the crude (6,7-dichloro-2-cyclopentylmethyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)acetic acid, 9.3 g., m.p. 145.5°-148° C., in 62% yield. Recrystallization from butyl chloride affords material which melts at 149°-151° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:13][CH:12]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:24]1(=[O:30])[O:29][C:27](=[O:28])[CH2:26][CH2:25]1.CCN(C(C)C)C(C)C>ClCCl>[Cl:23][C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][C@@H:3]([NH:2][C:24](=[O:30])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:12][CH:13]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=C1CCC(=O)O1
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)CCC(=O)O
Reaction time: 2.5 h
Yield: 54 %

Procedure:
A solution of (R)-ethyl 3-amino-4-(3′-chlorobiphenyl-4-yl)butanoate hydrochloride (400 mg, 1.13 mmol), succinic anhydride (136 mg, 1.36 mmol) and DIPEA (0.237 mL, 1.36 mmol) in dichloromethane (5 mL) is allowed to stir for 2.5 hours. The reaction is quenched with 1 M aqueous HCl and extracted with dichloromethane. The organic layer is separated and concentrated under reduced pressure. The resulting residue is purified by preparative HPLC using a gradient of 20% MeCN/water (0.1% TFA) to 100% MeCN to give (R)-4-(1-(3′-chlorobiphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoic acid (255 mg). HPLC retention time=1.15 minutes (condition B); MS (m+1)=418.0; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (t, J=7.08 Hz, 3 H) 2.46-2.58 (m, 4 H) 2.64-2.67 (m, 2 H) 2.87 (A of ABX, Jab=13.6 Hz, Jbx=7.8 Hz, 1 H) 2.99 (B of ABX, Jab=13.6 Hz, Jbx=6.6 Hz, 1 H) 4.12-4.24 (m, 2 H) 4.47-4.55 (m, 1 H) 6.50 (br d, J=8.8 Hz, 1 H) 7.24-7.37 (m, 4 H) 7.43-7.46 (m, 1 H) 7.48-7.52 (m, 2H) 7.55-7.56 (m, 1 H).
Reaction SMILES: [CH3:1][O:2]C1C=CC([N+]([O-])=O)=C(C=1)N.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[C:23]2[CH:24]=[CH:25][C:26](C(F)(F)F)=[CH:27][C:22]=2[N:21]=[C:20]1/[CH:32]=[CH:33]/[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[C:40]([OH:45])(=[O:44])[C:41]([OH:43])=[O:42]>C(OCC)(=O)C>[C:40]([OH:45])(=[O:44])[C:41]([OH:43])=[O:42].[CH3:1][O:2][C:25]1[CH:26]=[CH:27][C:22]2[N:21]=[C:20](/[CH:32]=[CH:33]/[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=3)[C:23]=2[CH:24]=1
Reactant: FC(F)(F)c1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Reactant: COc1ccc([N+](=O)[O-])c(N)c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc2nc(/C=C/c3ccccc3)n(-c3ccccn3)c2c1

Procedure:
Free base of the titled compound was prepared from 5-methoxy-2-nitroaniline according to the preparation of (E)-1-(2-pyridyl)-2-styryl-5-trifluoromethyl-1H-benzimidazole (Example 57). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate-hexane yielded the titled compound. MW: 417.42; mp: 172.0-174.0° C.; 1H-NMR (DMSO) δ: 8.78-8.76 (1H, m), 8.18 (1H, td, J=7.8, 2.1 Hz), 7.78 (1H, d, J=16.1 Hz), 7.74 (1H, d, J=8.1 Hz), 7.66-7.55 (4H, m), 7.41-7.32 (3H, m), 7.11 (1H, d, J=15.8 Hz), 6.98-6.91 (2H, m), 3.75 (3H, s).