Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([C:16]3[S:20][C:19]([N:21]4[CH2:26][CH2:25][CH:24]([C:27]([O:29]CC)=[O:28])[CH2:23][CH2:22]4)=[N:18][CH:17]=3)[CH:13]=[CH:14][CH:15]=2)[N:4]=1.[OH-].[Li+]>O1CCCC1.CO.CC1CCCO1>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([C:16]3[S:20][C:19]([N:21]4[CH2:26][CH2:25][CH:24]([C:27]([OH:29])=[O:28])[CH2:23][CH2:22]4)=[N:18][CH:17]=3)[CH:13]=[CH:14][CH:15]=2)[N:4]=1
Reactant: CCOC(=O)C1CCN(c2ncc(-c3cccc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CC1CCCO1
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1CCN(c2ncc(-c3cccc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Temperature: 90 °C

Procedure:
To a solution of ethyl 1-[5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-4-carboxylate (22 mg, 0.046 mmol) in tetrahydrofuran (0.5 mL) and methanol (0.5 mL) was added 1M aqueous lithium hydroxide (0.5 mL, 0.5 mmol) and the mixture was heated to 90° C. for 90 minutes. The mixture was cooled to room temperature, diluted with 2-methyltetrahydrofuran (30 mL), and, washed with 1 N aqueous hydrochloric acid (30 mL) and brine (30 mL). The aqueous layers were further extracted with 2-methyltetrahydrofuran (30 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to provide 1-[5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-4-carboxylic acid as a white solid. MS APCI: [M+H]+ m/z 450.1.
Reaction SMILES: [Mg].[CH:2]([C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=1Br)([CH3:4])[CH3:3].BrCCBr.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1F.[Li]CCCC.[I:38]I>C1COCC1>[I:38][C:25]1[C:24]([O:23][CH3:22])=[CH:29][CH:28]=[C:27]([O:30][CH3:31])[C:26]=1[C:6]1[C:5]([CH:2]([CH3:4])[CH3:3])=[CH:10][C:9]([CH:11]([CH3:13])[CH3:12])=[CH:8][C:7]=1[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)c1cc(C(C)C)c(Br)c(C(C)C)c1
Reactant: COc1ccc(OC)c(F)c1
Reactant: II
Agent: [Li]CCCC
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: COc1ccc(OC)c(-c2c(C(C)C)cc(C(C)C)cc2C(C)C)c1I
Temperature: 25 °C
Yield: 72 %

Procedure:
An oven-dried three-neck 500 mL round-bottom flask, which was equipped with a magnetic stir bar and charged with magnesium shavings (2.8 g, 116 mmol), was fitted with a reflux condenser, glass stopper, and rubber septum. The flask was purged with argon and then THF (100 mL) and 2,4,6-triisopropylbromobenzene (24.3 mL, 96 mmol) were added via syringe. The reaction mixture was heated to reflux and 1,2-dibromethane (40 uL) was added via syringe. The reaction was allowed to stir at reflux for 1.5 h and was then cooled to room temperature. A separate oven-dried 2 L round bottom flask, which was equipped with a magnetic stir bar and fitted with a septum, was purged with argon and then THF (500 mL) and 1,4-dimethoxy-2-fluorobenzene (7.49 g, 48 mmol) were added to the flask via syringe. The reaction mixture was cooled to −78° C. and n-BuLi (2.5 M in Hexane, 19.4 mL, 48.5 mmol) was added in a dropwise fashion over a 40 min period. The solution was stirred for 1 h and the Grignard reagent, which was prepared in the first reaction vessel, was added via cannula over a 30 min period and allowed to stir at −78° C. for 1 h. The reaction mixture was warmed to room temperature slowly where it was stirred for an additional 12 h. The mixture was then cooled to 0° C. and a solution of Iodine in THF (1 M, 96 mL, 96 mmol) was added via syringe over a 15 min period and then the dark red solution was warmed to room temperature and stirred for 1 h. The solvent was removed via a rotary evaporator, and the remaining dark brown oil was taken up in Et2O, washed with a saturated solution of sodium sulfite, and washed with brine. The organic layer was then dried over MgSO4, filtered, and the solvent was removed via rotary evaporator to give a yellow solid. The crude material was triturated with hexanes and filtered to give the desired product as an off-white solid (16.199 g, 72%, mp 189-191° C.). 1H NMR (300 MHz, CDCl3) δ: 7.07 (s, 2H), 6.90 (d, J=9.0 Hz, 1H), 6.81 (d, J=9.0 Hz, 1H), 3.90 (s, 3H), 3.67 (s, 3H), 2.98 (septet, J=7.0 Hz, 1H), 2.39 (septet, J=7.0 Hz, 2H), 1.33 (d, J=7.0 Hz, 6H), 1.20 (d, 7.0 Hz, 6H), 1.02 (d, J=7.0 Hz, 6H) ppm. 13C NMR (75 MHz, CDCl3) δ: 152.7, 152.5, 148.4, 145.9, 136.4, 136.1, 121.0, 110.3, 109.4, 96.6, 57.0, 55.8, 34.3, 31.1, 24.8, 24.3, 23.9 ppm. IR (neat, cm−1): 2957, 2865, 1567, 1460, 1428, 1257, 1032, 755. Anal. Calcd. for C23H31IO2: C, 59.23; H, 6.70. Found: C, 59.23; H, 6.72.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.C([Mg]Br)(C)C.C[Si]([N:21]=[C:22]=[S:23])(C)C.Cl>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([C:22](=[S:23])[NH2:21])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: Cc1cnc2c(c1)CCCC2
Reactant: C[Si](C)(C)N=C=S
Agent: CC(C)[Mg]Br
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cnc2c(c1)CCCC2C(N)=S
Temperature: 25 °C
Reaction time: 12 h
Yield: 5 %

Procedure:
3-Methyl-5,6,7,8-tetrahydroquinoline (7.3g, 0.05 mol.) was added to a solution of isopropylmagnesium bromide [prepared from isopropylbromide (6.15g, 0.05 mol), magnesium (1.44g, 0.06 mol) in ether (10 ml.)] and the solution heated at 60° to remove the ether by distillation. Toluene (5 ml.) was added and the reaction mixture was heated at 120° for 2 hours, cooled, diluted with toluene (30 ml) and this solution was added to a solution of trimethylsilyl isothiocyanate (7.85 g, 0.06 mol) in toluene (50 ml.) at 0° C. The reaction mixture was stirred at room temperature for 12 hours, diluted with water (15 ml.) and the pH adjusted to 2.0 with Conc. HCl. The aqueous solution was extracted with ether and the extracts discarded. The aqueous solution was adjusted to pH 9.0 with Na2CO3 and extracted with chloroform (3 × 50 ml.). The combined extracts were washed with brine, dried and the solvent removed to give a mixture of 3-methyl-5,6,7,8-tetrahydroquinoline and the title compound (5%) which was isolated by chromatography and identified by comparison with authentic material.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][O:7][C:8]([CH:10]1[CH2:19][CH:18]2[CH:13]([CH:14]=[C:15]([O:22][CH3:23])[C:16]([O:20][CH3:21])=[CH:17]2)[CH:12]([C:24]2[CH:32]=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=2)[NH:11]1)=[O:9].CCN(CC)CC>C(Cl)Cl>[CH3:6][O:7][C:8]([CH:10]1[CH2:19][CH:18]2[CH:13]([CH:14]=[C:15]([O:22][CH3:23])[C:16]([O:20][CH3:21])=[CH:17]2)[CH:12]([C:24]2[CH:32]=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=2)[N:11]1[C:3](=[O:4])[CH2:2][Cl:1])=[O:9]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)C1CC2C=C(OC)C(OC)=CC2C(c2ccc3c(c2)OCO3)N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CC2C=C(OC)C(OC)=CC2C(c2ccc3c(c2)OCO3)N1C(=O)CCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Chloroacetyl chloride (0.23 mL), 2.88 mmol) was added dropwise to a mixture of Intermediate 7 (0.82 g, 2.21 mmol) and Et3N (0.71 mL, 5.09 mmol) in CH2Cl2 (15 mL) at 0° C. under a nitrogen blanket. The resulting mixture was warmed to room temperature and stirred for about 0.5 hour. The reaction was quenched with 1 N HCl (2 mL), and diluted with CH2Cl2 (50 mL) and-water (10 mL). The layers were separated and the organic was washed with saturated NaCl and dried over anhydrous Na2SO4. Filtration and concentration in vacuo afforded Intermediate 8 (1.5 g), which was used without further purification. TLC Rf (10% EtOAc/CH2Cl2)=0.55; MS (API) m/z 448 (M+H), 472 (M+Na).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][C@H:4]([OH:32])[C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C@@H:41]([CH2:58][CH3:59])[C@H:42]([NH:46][C:47]([N:49]([CH3:57])[CH2:50][C:51]1[N:52]=[C:53]([CH3:56])[S:54][CH:55]=1)=[O:48])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:30][O:29][C:28](=[O:31])[NH:27][C@@H:22]([C:23]([CH3:25])([CH3:26])[CH3:24])[C:20](=[O:21])[NH:19][C@@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[C@@H:4]([OH:32])[CH2:3][C@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[NH:1][C:43](=[O:44])[C@H:42]([CH:41]([CH2:58][CH3:59])[CH3:40])[NH:46][C:47](=[O:48])[N:49]([CH3:57])[CH2:50][C:51]1[N:52]=[C:53]([CH3:56])[S:54][CH:55]=1
Reactant: CC[C@H](C)[C@H](NC(=O)N(C)Cc1csc(C)n1)C(=O)O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)[C@@H](O)C[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(C)[C@H](NC(=O)N(C)Cc1csc(C)n1)C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.8 %

Procedure:
A solution containing the product from Example 23S (0.025 g, 0.047 mmol) in THF (0.5 mL) was treated with the product from Example 109E (0.018 g, 0.061 mmol), DEPBT (0.021 g, 0.071 mmol), and N,N-diisopropylethylamine (0.041 mL, 0.235 mmol), stirred at 25° C. for 2 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 0-100% ethyl acetate/dichloromethane, followed by 0-10% methanol in ethyl acetate. The product was then purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA). The product was partitioned between ethyl acetate and saturated NaHCO3, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound (0.011 g, 29% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.64 (d, J=6.62 Hz, 3 H), 0.72 (t, J=7.35 Hz, 3 H), 0.83 (s, 9 H), 0.93 (m, 1 H), 1.28 (m, 2 H), 1.49 (m, 2 H), 1.60 (m, 1 H), 2.61 (s, 3 H), 2.73 (m, 3 H), 2.84 (s, 3 H), 3.50 (s, 3 H), 3.62 (m, 1 H), 3.91 (m, 2 H), 4.10 (m, 2 H), 4.41 (m, 2 H), 4.80 (d, J=5.52 Hz, 1 H), 6.01 (d, J=8.46 Hz, 1 H), 6.76 (d, J=9.93 Hz, 1 H), 7.12 (m, 6 H), 7.31 (m, 3 H), 7.60 (m, 2 H), 7.86 (m, 4 H), 8.63 (d, J=4.41 Hz, 1 H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>N1C=CC=CC=1.C(Cl)(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][O:8][S:15]([C:12]1[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: OCCc1ccco1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OCCc2ccco2)cc1
Temperature: 60 °C
Yield: 53.6 %

Procedure:
To a stirred solution of 2-furan-2-yl-ethanol (1.6 g, 14.0 mmol) in a mixture of pyridine (5 mL) and chloroform (15 mL) was added para-toluenesulfonyl chloride (5.5 g, 28.0 mmol) and heated at 60° C. for 3 hrs. The reaction was cooled and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water, sat. sodium bicarbonate solution and dried over anhydrous sodium sulfate. The filtrate was concentrated, and the crude compound purified by column chromatography over silica gel (60-120 mesh) using 10% ethyl acetate/petroleum ether as eluent to afford toluene-4-sulfonic acid 2-furan-2-yl-ethyl ester (2.0 g, 32%) as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[N:3]1.[C:11]([CH2:13][C:14]1([N:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[N:27][N:26]4[C:29]([C:32]5[CH:33]=[C:34]([NH:38][C:39]([NH:41][CH2:42][C:43]([F:46])([F:45])[F:44])=[O:40])[CH:35]=[CH:36][CH:37]=5)=[CH:30][N:31]=[C:25]4[CH:24]=3)[CH:20]=[N:19]2)[CH2:17][NH:16][CH2:15]1)#[N:12].C(N(CC)CC)C>C(#N)C.CO>[C:11]([CH2:13][C:14]1([N:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[N:27][N:26]4[C:29]([C:32]5[CH:33]=[C:34]([NH:38][C:39]([NH:41][CH2:42][C:43]([F:45])([F:46])[F:44])=[O:40])[CH:35]=[CH:36][CH:37]=5)=[CH:30][N:31]=[C:25]4[CH:24]=3)[CH:20]=[N:19]2)[CH2:15][N:16]([S:7]([C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)(=[O:9])=[O:8])[CH2:17]1)#[N:12]
Reactant: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CNC1
Reactant: Cn1ccc(S(=O)(=O)Cl)n1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cn1ccc(S(=O)(=O)N2CC(CC#N)(n3cc(-c4cnn5c(-c6cccc(NC(=O)NCC(F)(F)F)c6)cnc5c4)cn3)C2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-Methyl-1H-pyrazole-3-sulfonyl chloride (5.5 mg, 0.030 mmol) (Maybridge and Cat. No. CC 48303) was added to a mixture of N-[3-(7-{1-[3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (10.0 mg, 0.0202 mmol) and triethylamine (8.4 μL, 0.060 mmol) in acetonitrile (1.0 mL) and MeOH (0.2 mL). The reaction mixture was stirred at r.t. for 30 min. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=640.2.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[C:28](OC(=O)C)(=[O:30])[CH3:29]>C1COCC1>[C:28]([NH:1][CH2:2][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[C:4]1[CH:5]=[CH:6][C:7]([Cl:10])=[CH:8][CH:9]=1)(=[O:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)NC(CN)c1ccc(Cl)cc1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCC(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.7 %

Procedure:
A solution of tert-butyl 2-amino-1-(4-chlorophenyl)ethylcarbamate (Intermediate 73) (0.208 g, 0.77 mmol) and N-ethyldiisopropylamine (0.266 mL, 1.54 mmol) in THF (5 mL) was treated with acetic anhydride (0.102 mL, 1.08 mmol). The resulting solution was stirred at ambient temperature for 2 hours. The mixture was partitioned between DCM and sodium bicarbonate solution. The organic layer was concentrated and the residue was purified by flash column chromatography on silica using gradient elution (10% ethyl acetate/DCM to 40% ethyl acetate/DCM). The desired product, tert-butyl 2-acetamido-1-(4-chlorophenyl)ethylcarbamate (0.151 g, 62.7%), was thus isolated as a colourless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:12]=2)=[CH:4][CH:3]=1.[C:30]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31]>>[C:30]([C:34]1[CH:39]=[CH:38][C:37]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[NH:9][C:10]([C:21]4[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=4)=[C:11]([C:13]4[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=4[Cl:20])[N:12]=3)=[CH:4][CH:3]=2)=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: O=[N+]([O-])c1ccc(-c2[nH]c(-c3ccc(Br)cc3)nc2-c2ccc(Cl)cc2Cl)cc1
Product: CC(C)(C)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)cc4Cl)c(-c4ccc([N+](=O)[O-])cc4)[nH]3)cc2)cc1

Procedure:
2-(4-Bromo-phenyl)-4-(2,4-dichloro-phenyl)-5-(4-nitro-phenyl)-1H-imidazole (prepared according to general procedure A) (979 mg, 2 mmol) was treated as described in general procedure G using 4-tert-butylphenylboronic acid (712 mg, 4 mmol) to give 2-(4′-tert-butyl-biphenyl-4-yl)-4-(2,4-dichloro-phenyl)-5-(4-nitro-phenyl)-1H-imidazole, which was treated as described in general procedure L using 2-(trimethylsilyl)ethoxymethyl chloride (0.7 mL, 4 mmol) to give 2-(4′-tert-butyl-biphenyl-4-yl)-4-(2,4-dichloro-phenyl)-5-(4-nitro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH:11]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)[C:9]1=[O:36])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][C@@H:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:24][CH:23]=2)[C:9]1=[O:36])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C(=O)C(c2ccc(OCc3ccccc3)cc2)=C[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C(=O)[C@H](c2ccc(OCc3ccccc3)cc2)C[C@@H]1CO[Si](C)(C)C(C)(C)C
Yield: 99.7 %

Procedure:
A solution of (5R)-3-(4-benzyloxyphenyl)-5-(tert-butyldimethylsilanyloxymethyl)-2-oxo-2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester (2.0 g, 3.92 mmol) in ethyl acetate (40 mL) and hexane (40 mL) was treated with 20% palladium hydroxide on carbon (200 mg) and hydrogenated in a Parr™ shaker at 3 atmospheres pressure for 2 hours. The catalyst was removed by filtration and the solvent was evaporated to provide the title compound as a yellow oil (2.0 g, 100%).
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:48](=[O:68])[C:49]4[C:54]([O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:53]3[N:63]([CH3:67])[N:64]=[C:65]([Cl:66])[C:52]3=[CH:51][CH:50]=4)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(O)(C(F)(F)F)=O>CO.O.Cl>[ClH:66].[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:48](=[O:68])[C:49]4[C:54]([O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:53]3[N:63]([CH3:67])[N:64]=[C:65]([Cl:66])[C:52]3=[CH:51][CH:50]=4)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: Cn1nc(Cl)c2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c21
Agent: Cl
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CO
Product: Cn1nc(Cl)c2ccc3c(=O)c(-c4ccc(C5(N)CCC5)cc4)c(-c4ccccc4)oc3c21
Yield: 36 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(3-chloro-1-methyl-6-oxo-8-phenyl-1,6-dihydro-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was treated with TFA. The resultant free base was dissolved in a mixture of MeOH (1.5 mL), water (3.5 mL) and 1 M HCl (0.15 mL) and chromatographed on a 2 g C18 cartridge {gradient 30 to 65% MeOH in water+1 M HCl (60 μL in each 5 mL of eluent)} to give the title compound (10 mg, 36%, 2 steps) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.38 (br s, 3H), 7.82 (d, J=8.6 Hz, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.56-7.53 (m, 2H), 7.51-7.44 (m, 3H), 7.41-7.37 (m, 2H), 7.31 (d, J=8.2 Hz, 2H), 4.38 (s, 3H), 2.62-2.49 (m, 4H), 2.22-2.12 (m, 1H), 1.86-1.75 (m, 1H). LCMS (Method E): RT=3.51 min, [M+H]+=456/458.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([C@@H:10]3[CH2:12][C@H:11]3[NH2:13])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[CH:14]([CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([C@@H:10]3[CH2:12][C@H:11]3[NH:13][CH2:14][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:24]=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=4)[CH2:18][CH2:17]3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(CN2CCC(C=O)CC2)cc1
Reactant: N[C@@H]1C[C@H]1c1ccc(C2CC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CN2CCC(CN[C@@H]3C[C@H]3c3ccc(C4CC4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
To a solution of trans-2-(4-cyclopropylphenyl)cyclopropanamine (90 mg, 0.519 mmol) in methanol (2 mL) were added methyl 4-((4-formylpiperidin-1-yl)methyl)benzoate (156 mg, 0.597 mmol) and acetic acid (8.92 μL, 0.156 mmol), and the mixture was stirred at room temperature for 1 h. Sodium cyanoborohydride (52.2 mg, 0.831 mmol) was added and the mixture was stirred at room temperature for 18 h. The reaction was quenched with 10% NaHCO3 aqueous solution and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was purified using reverse-phase HPLC to give 120 mg of product as off-white solid. MS: (M+H)+=419.4. 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.56-0.71 (m, 2H), 0.89-1.07 (m, 2H), 1.32-1.43 (m, 1H), 1.51-1.77 (m, 3H), 1.83-1.94 (m, 1H),1.97-2.25 (m, 3H), 2.53 (ddd, J=10.11, 6.44, 3.41 Hz, 1H), 2.93-3.25 (m, 5H), 3.49-3.64 (m, 2H), 3.86-4.00 (m, 3H), 4.43 (s, 2H), 6.97-7.17 (m, 4H), 7.72 (d, J=8.08 Hz, 2H), 8.14 (d, J=8.08 Hz, 2H).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:12](Cl)=[O:13])[CH2:8]2.[CH3:15][O:16][C:17](=[O:31])[C@@:18]([CH3:30])([CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)[NH2:19].C(N(CC)CC)C>C1COCC1>[CH3:15][O:16][C:17](=[O:31])[C@@:18]([CH3:30])([CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)[NH:19][C:12]([O:11][CH:2]1[CH:3]2[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][CH:1]1[CH2:8]3)[CH2:4]2)=[O:13]
Reactant: COC(=O)[C@](C)(N)Cc1c[nH]c2ccccc12
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@](C)(Cc1c[nH]c2ccccc12)NC(=O)OC1C2CC3CC(C2)CC1C3
Reaction time: 0.25 h
Yield: 86.5 %

Procedure:
To a stirred solution of 2-adamantylchloroformate (0.965 g, 4.5 mmol) in dry THF (10 mL) was added a solution of α-methyl-D-tryptophan methyl ester (0.928 g, 4 mmol) in dry THF (20 mL) followed by a solution of triethylamine (0.808 g, 8 mmol) in dry THF (20 mL) dropwise. After 15 minutes, the reaction mixture was filtered, the solvent removed in vacuo and column chromatographed using 2% MeOH:98% CH2Cl2 as eluant to yield the title compound (1.42 g, 89%) as a syrup. IR (film) 1740-1695 b.r cm-1 ; NMR (CDCl3) δ1.50-1.60 (2H, m), 1.67 (3H, s), 1.70-2.10 (12H, m), 3.38 (1H, d, J =14.5Hz), 3.50-3.60 (1H, br.s), 3.68 (3H, s), 4.86 (1H, br.s), 5.28 (1H, br.s), 6.93 (1H, d, J 2.4Hz); 7.04-7.10 (2H, m), 7.33 (1H, d, J 8.2Hz) 7.54 (1H, d, J 7.8Hz), 8.18 (1H, br.s).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([NH:11][S:12]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[F:22])(=[O:14])=[O:13])[CH:3]=1.Cl.[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]([CH3:36])[CH2:34][NH2:35])=[CH:29][CH:28]=1)([O-:26])=[O:25].[N+](C1C=CC(CC#N)=CC=1)([O-])=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:35][CH2:34][CH:33]([C:30]2[CH:31]=[CH:32][C:27]([N+:24]([O-:26])=[O:25])=[CH:28][CH:29]=2)[CH3:36])=[O:7])=[C:4]([NH:11][S:12]([C:15]2[C:16]([F:22])=[CH:17][CH:18]=[CH:19][C:20]=2[F:21])(=[O:14])=[O:13])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1c(F)cccc1F
Reactant: CC(CN)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: N#CCc1ccc([N+](=O)[O-])cc1
Product: CC(CNC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1c(F)cccc1F)c1ccc([N+](=O)[O-])cc1

Procedure:
This compound was prepared from 4-chloro-2-(2,6-difluoro-benzenesulfonylamino)-benzoic acid and 2-(4-nitro-phenyl)-propylamine hydrochloride (prepared as in EXAMPLE 5, substituting 4-nitrophenylacetonitrile in Part A) as in Example 1, Part C. HPLC: RT=10.37 min. MS (ESI−): mass calcd. for C22H18ClF2N3O5S, 509.9; m/z found, 509 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.63 (s, 1H), 8.18 (d, J=8.6, 1H), 7.69 (d, J=1.7, 1H), 7.56-7.46 (m, 1H), 7.42 (d, J=8.6, 2H), 7.15 (d, J=8.5, 1H), 7.02-6.94 (m, 1H), 6.19-6.17 (br m, 1H), 3.79-3.70 (m, 1H), 3.57-3.49 (m, 1H), 3.33-3.23 (m, 1H), 1.38 (d, J=6.9, 3H).