Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:43])=[N:14][C:15]([CH3:42])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CCO.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:43])=[N:14][C:15]([CH3:42])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCCc3ccc(F)cc3)cc2)c1N1CCC(C)(C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(C)(C)CC2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Yield: 93.3 %

Procedure:
A mixture of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (0.009 g, 0.015 mmol) and LiOH (3.65 mg, 0.152 mmol) in 9:1 EtOH/H2O (1 mL) was refluxed for 3 h. Then, cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetic acid (0.0081 g, 0.014 mmol, 94% yield) as white solid. Alternatively, to a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (0.302 g, 0.5 mmol) in ethanol (5 mL) and water (0.500 mL) was added KOH (0.281 g, 5.00 mmol). The solution was heated at 75° C. for 8 h. The solvent in the mixture was evaporated. The remaining residue was treated with water (5 mL), and acidified with 1 N HCl (5.1 mL) to pH˜2. The resulting mixture was stirred for 1 h. The solid was collected on a filter, washed with water, dried under vacuum to give (0.281 g, 100%) as beige solid. 1H NMR (500 MHz, CDCl3) δ 7.27-7.32 (m, 2H), 7.12-7.18 (m, 1H), 7.01-7.09 (m, 3H), 6.95-7.00 (m, 2H), 5.95 (br. s., 1H), 4.16-4.29 (m, 2H), 3.61 (br. s., 1H), 3.13 (t, J=6.9 Hz, 2H), 2.77-3.02 (m, 1H), 2.66 (s, 3H), 2.22 (s, 3H), 1.99-2.37 (m, 2H), 1.25 (s, 9H), 1.07-1.40 (m, 4H), 0.88 (br.s., 3H), 0.68 (br. s., 3H). LCMS (M+H)=563.3.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[CH2:4][O:5][CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[F:21][C:22]([F:43])([F:42])[C:23]1[CH:41]=[CH:40][C:26]([O:27][C:28]2[CH:39]=[CH:38][C:31]([O:32][CH:33]([CH3:37])[C:34](Cl)=[O:35])=[CH:30][CH:29]=2)=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[F:21][C:22]([F:42])([F:43])[C:23]1[CH:41]=[CH:40][C:26]([O:27][C:28]2[CH:39]=[CH:38][C:31]([O:32][CH:33]([CH3:37])[C:34]([O:8][CH2:7][CH2:6][O:5][CH2:4][C:3]3[C:2]([Cl:1])=[CH:12][CH:11]=[CH:10][C:9]=3[Cl:13])=[O:35])=[CH:30][CH:29]=2)=[CH:25][CH:24]=1
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)Cl
Reactant: OCCOCc1c(Cl)cccc1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)OCCOCc1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
22.1 g of 2-(2,6-dichlorobenzyloxy)ethanol and 10.1 g of triethylamine were dissolved in 200 ml of toluene, then cooled to 0° C. To this solution was dropwise added a solution of 34.5 g of 2-[4-(4-trifluoromethylphenoxy)phenoxy]propionyl chloride in 50 ml of toluene at 0° to 10° C. After the dropwise addition, the reaction mixture was gradually heated and, at 40° C., it was stirred for one hour to complete the reaction. After cooling the reaction solution to room temperature, it was washed successively with 1% strength by weight sodium hydroxide aqueous solution and water, then dehydrated. After distilling off toluene under reduced pressure, the resulting colorless, viscous, oily product was allowed to stand for about 1 month to obtain 49.2 g of crystalline 2-(2,6-dichlorobenzyloxy)ethyl 2-[4-(4-trifluoromethylphenoxy)phenoxy]propionate. m.p. 51° to 53° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[NH2:15][C@@H:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C@H:17]1[CH2:29][CH3:30].CC(O)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:15][C@@H:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:18][C@H:17]3[CH2:29][CH3:30])=[C:8]([C:11](=[O:12])[NH2:13])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 90 °C
Yield: 75 %

Procedure:
To a solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Intermediate 2, 334 mg, 1.217 mmol) and (3R,4R)-tert-butyl 4-amino-3-ethylpiperidine-1-carboxylate (1.2 eq., Intermediate 8), AcOH (351 mg, 1.217 mmol) in DMF (3.0 ml) was added DIEA (1275 μl, 7.30 mmol). The reaction was heated at 90° C. for 5 hrs. The reaction was diluted with ethyl acetate (100 ml), and washed with water (3×100 ml), dried with sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified via medium pressure chromatography (silica gel column, EtOAc/hexanes eluent, 0-100% gradient elution) to afford (3R,4R)-tert-butyl 4-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-3-ethylpiperidine-1-carboxylate (428.4 mg, 0.919 mmol, 75.0% yield) as a faint yellow solid. LCMS (Method K) m/z 468.2 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[NH:8][C:4]=2[CH:3]=1.[OH-].[Na+].[CH2:14](Cl)/[CH:15]=[C:16](/[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])\[CH3:17]>CO>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7]([S:9][CH2:14]/[CH:15]=[C:16](\[CH3:17])/[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)=CCC/C(C)=C/CCl
Reactant: Sc1nc2ccc(Cl)cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)=CCC/C(C)=C/CSc1nc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 23.4 %

Procedure:
To a solution of the 5-chloro-2-mercaptobenzimidazole (0.665 g, 3.6 mmol) in methanol (10 mL) and 2N NaOH (7 mmol) was added geranyl chloride (0.775 g, 4.5 mmol). The reaction mixture was stirred at ambient temperature for 24 hours, evaporated in vacuo, dissolved in CH2Cl2, washed with water, and dried over Na2SO4. Evaporation and flash chromatography (Merck Kieselgel, CH2Cl2) gave an oil which was crystallized with pentane to yield a white solid of the title compound (270 mg). m.p. 102°-104° C. NMR (CDCl3)δ7.45-7.0(m,3H), 5.37(t, J=7 Hz,1H), 5.03(t,J=7Hz, 1H), 3.93(d,J=8 Hz,2H), 2.02(m,4H), 1.67(s,3H), 1.66(s,3H), 1.58(s,3H).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[C:3]=1[C:4]#[N:5].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.C(OCC)(=O)C>C1COCC1>[NH2:5][CH2:4][C:3]1[C:2]([NH2:1])=[N:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][C:6]=1[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23]
Reactant: N#Cc1c(-c2ccc(Cl)cc2Cl)cc(-c2ccccc2)nc1N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: NCc1c(-c2ccc(Cl)cc2Cl)cc(-c2ccccc2)nc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under an atmosphere of argon, a solution of 2-amino-4-(2,4-dichloro-phenyl)-6-phenyl-nicotinonitrile (580 mg, 1.71 mmol) in THF (2 ml) is added slowly to a suspension of LiAlH4 (324 mg, 8.52 mmol) in THF (2 ml). After stirring for 2 h at room temperature, the reaction mixture is cooled to −20° C. and water (0.4 ml) is added. After 15 min, ethyl acetate is added and the mixture is filtered through Decalite. The organic phase is then separated, washed with water, and dried over sodium sulfate. Purification by flash chromatography (silica gel, methanol, dichloromethane) affords the title compound, MS: m/e=343.8 (M+H+), as a light yellow solid (36 mg, 6%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[NH:5][C:6]([C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[N:14]=[C:15]([NH:23][CH:24]2[CH2:26][CH2:25]2)[C:16]([CH3:22])=[N:17]3)=[CH:7][C:8]=1[C:9](O)=[O:10].[CH2:27](Cl)Cl.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C=O)C>[CH3:22][C:16]1[C:15]([NH:23][C:24]2([CH3:27])[CH2:25][CH2:26]2)=[N:14][C:13]2[C:18](=[CH:19][CH:20]=[CH:21][C:12]=2[C:6]2[NH:5][C:4]3[CH2:3][NH:2][C:9](=[O:10])[C:8]=3[CH:7]=2)[N:17]=1
Reactant: ClCCl
Reactant: Cc1nc2cccc(-c3cc(C(=O)O)c(CN)[nH]3)c2nc1NC1CC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(-c3cc4c([nH]3)CNC4=O)c2nc1NC1(C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
To a 25-mL round-bottomed flask was added 2-(aminomethyl)-5-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (363c) (0.19 g, 0.52 mmol), DCM (6 mL), DMF (6 mL), DIEA (0.27 mL, 1.57 mmol), and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.30 g, 0.58 mmol) (Sigma-Aldrich Chemical Company, Inc.). The reaction mixture was stirred at RT for 16 h, concentrated to half of its volume, and poured over water. The yellow solid obtained was filtered, washed with water, ether, and dried in a vacuum over at 50° C. for 16 h. 2-(2-Methyl-3-((1-methylcyclopropyl)amino)-quinoxalin-5-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (363) (0.13 g, 77% yield) was obtained a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 13.16 (s, 1H), 8.01 (dd, J=0.68, 7.53 Hz, 1H), 7.63 (s, 1H), 7.61 (dd, J=0.78, 8.02 Hz, 1H), 7.53 (s, 1H), 7.36 (t, J=7.73 Hz, 1H), 7.04 (d, J=1.17 Hz, 1H), 4.31 (s, 2H), 2.89 (br. s, 1H), 2.52 (s, 3H), 0.87-0.94 (m, 2H), 0.67-0.74 (m, 2H). m/z (ESI, +ve) 320.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[C:14]1([CH3:23])[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.C([O-])([O-])=O.[K+].[K+].CCO>[Pd].O>[F:10][C:9]([F:12])([F:11])[CH:8]([C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH3:23])[CH:15]=1)[OH:13]
Reactant: OC(c1ccc(Br)cc1)C(F)(F)F
Reactant: Cc1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1cccc(-c2ccccc2C(O)C(F)(F)F)c1
Temperature: 80 °C
Yield: 71.5 %

Procedure:
1-(4-Bromophenyl)-2,2,2-trifluoroethanol (0.13 g, 0.525 mmol), m-tolylboronic acid (0.1 g, 0.736 mmol), Fibercat (4.28% Pd, 47 mgs, 0.0157 mmol Pd), K2CO3 (0.22 g, 1.576 mmol), EtOH (3 mls), and H2O (0.5 mls) were combined and heated at 80° C. for 4 hours. The reaction was shown complete by TLC(CH2Cl2). The mixture was cooled, filtered, concentrated, slurried in CH2Cl2, and chromatographed over silica gel (CH2Cl2) to give 0.1 g of 2,2,2-trifluoro-1-(3′-methylbiphenyl-2-yl)ethanol. Yield: 72%.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][CH2:8][CH2:9]OC1C=C2C(=CC=1)N(CC1C=CC=CC=1)C(Br)=C2CC(N)=O)(=[O:6])[O:4][CH3:5].[Br:32]C1N(CC2C=CC=CC=2)C2C(C=1CC(N)=O)=CC(O)=CC=2.[H-].[Na+]>>[CH3:5][O:4][P:3]([CH2:7][CH2:8][CH2:9][Br:32])(=[O:6])[O:2][CH3:1]
Reactant: NC(=O)Cc1c(Br)n(Cc2ccccc2)c2ccc(O)cc12
Reactant: COP(=O)(CCCOc1ccc2c(c1)c(CC(N)=O)c(Br)n2Cc1ccccc1)OC
Agent: [H-]
Agent: [Na+]
Product: COP(=O)(CCCBr)OC

Procedure:
[3-[[3-(2-Amino-2-oxoethyl)-2-bromo-1-(phenylmethyl)-1H-indol-5-yl]oxy]propyl]phosphonic acid dimethyl ester. Using the procedure described in Example 81, Part A, 1.35 g (3.8 mmol) of 2-bromo-5-hydroxy-1-(phenylmethyl)-1H-indole-3-acetamide was reacted with 170 mg (4.2 mmol) of NaH/mineral oil and then 970 mg (4.2 mmol) of (3-bromopropyl)phosphonic acid dimethyl ester to give a product that was chromatographed on silica gel (eluted with a gradient, 1% MeOH/methylene chloride→3% MeOH/methylene chloride). There was obtained 520 g (27% yield) of 3-[[3-(2-amino-2-oxoethyl)-2-bromo-1-(phenylmethyl)-1H-indol-5-yl]oxy]propyl]phosphonic acid dimethyl ester, melting approximately at 100° C. after crystallizing from methylene chloride/ether.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=O)C.[OH-].[K+].Cl>O>[N:9]1([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][N:13]=2)[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]1
Reactant: CCOC(=O)N1CCN(c2ccc(C(=O)O)cn2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(N2CCNCC2)nc1
Yield: 81.8 %

Procedure:
2.8 g of 6-(4-ethoxycarbonyl-1-piperazinyl)nicotinic acid obtained in Example 1 and 2 g of potassium hydroxide were dissolved in 20 ml of water. The solution was heated under reflux for 2 hours. After cooled, the reaction mixture was neutralized with concentrated hydrochloric acid and crystals precipitated were filtered, washed with water and dried to give 1.7 g of 6-(1-piperazinyl)nicotinic acid (yield 82%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Cl[CH2:6][C:7](Cl)=[O:8].[OH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[C:12]=1[C:13]([OH:15])=[O:14].C(OCC)(=O)C>[N+](C1C=CC=CC=1)([O-])=O>[OH:10][C:11]1[CH:19]=[CH:18][C:17]2[C:7](=[O:8])[CH2:6][O:20][C:16]=2[C:12]=1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1c(O)cccc1O
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1COc2c1ccc(O)c2C(=O)O
Temperature: 0 °C
Yield: 95.5 %

Procedure:
A suspension of aluminum chloride (2.7 g, 21 mmol) in nitrobenzene (6.0 mL) was cooled to 0° C., and stirred. The suspension was added with chloroacetyl chloride (0.60 g, 6.2 mmol), and then added portionwise with a suspension of 2,6-dihydroxybenzoic acid (0.064 g, 4.1 mmol) in nitrobenzene (6.0 mL). After completion of the addition, the reaction mixture was stirred at 40° C. for 12 hours. The reaction mixture was added with ethyl acetate and ice water, the mixture was stirred at room temperature for 1 hour, and then the organic layer was separated. The organic layer was extracted with 2 N aqueous sodium hydroxide, and the aqueous layer was made acidic with 3 N hydrochloric acid. The precipitated solid was collected by filtration and dried to obtain 6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-carboxylic acid (0.76 g, 89%).
Reaction SMILES: [F:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[Br:11]Br>CCOCC.C(Cl)(Cl)Cl>[Br:11][CH:2]([F:1])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: BrBr
Reactant: O=C(CF)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: O=C(c1ccccc1)C(F)Br

Procedure:
To a solution of 2.76 g of 2-fluoroacetophenone in 50 ml of ether is added dropwise over 30 minutes a solution of 3.2 g of bromine in 10 ml of chloroform. Evaporation of the reaction mixture under reduced pressure affords α-bromo-2-fluoroacetophenone.
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]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:2]1C=CC=C[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C(Br)C=C>C(O)C.C(#N)C.[C].[Pd]>[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]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:2]=[CH2:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Solvent: C=CCBr
Product: C=CCON1C(=O)N2C[C@H]1CC[C@H]2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.2 %

Procedure:
140 mg (0.421 mmol) of (2S,5R)-tert-butyl 6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate was dissolved in ethanol (3.1 mL), and 14 mg of 10% palladium-carbon (50% water content) was added, followed by stirring at room temperature for 1 hour under hydrogen atmosphere. The catalyst of the reaction mixture was filtered through celite, and the residue resulting from concentration of the solvent under reduced pressure was dissolved in acetonitrile (4.1 mL), and 62 mg (0.449 mmol) of anhydrous potassium carbonate and 70 μL (0.809 mmol) of allyl bromide were added, followed by stifling at room temperature for 3 hours. After the reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate and washed sequentially with water, saturated aqueous ammonium chloride solution and saturated brine, subsequently the organic layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The resulting residue was applied to silica gel column chromatography (n-hexane/ethyl acetate=5/2) to afford 60.8 mg of the title compound (yield 54%). Enantiomeric excess: 99.9% ee or more (CHIRALPAK AD-H, 4.6×150 mm, hexane/ethanol=2/1, UV 210 nm, flow rate 1 mL/min., retention time 4.8 min.).
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH:4]([OH:28])[C@@H:5]([NH:8]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:6][CH3:7])[CH3:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@@H:5]([CH2:6][CH3:7])[CH:4]([OH:28])[C:2]([CH3:29])([CH3:3])[CH3:1]
Reactant: CC[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(O)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](N)C(O)C(C)(C)C
Reaction time: 1 h

Procedure:
To a stirred solution of (3RS,4S)-2,2-dimethyl-4-(trityl-amino)-hexan-3-ol (0.47 g, 1 eq, 1.21 mmol) in DCM (10 mL) under an argon atmosphere at room temperature, was added CF3COOH (5 mL) dropwise, and the solution was stirred at this temperature for 1 h. The solvent was evaporated in vacuo, the residue was precipitated: from Et2O (3 mL) with hexane (20 mL) with stirring to give a yellow oil. The solvent was decanted from the oil, and the oil was washed-with hexane (20 mL) and dried in vacuo to afford the title compound as a light yellow oil. Yield: 0.18 g (99%). (53% de 3R,4S: 47% de 3S,4S). 1H-NMR (d6-DMSO, 250 MHz): δ 0.86-0.99 (m, 3H, NH2CH(CH2 CH3)CH(C(CH3)3)OH), 1.25-1.30 (m, 9H, NH2CH(CH2CH3) CH(C(CH3)3OH), 1.20-1.67 (m, 2H, NH2CH(CH2CH3)CH(C(CH3)3)OH), 3.14 (m, 1H, NH2CH(CH2CH3) CH(C(CH3)3)OH), 3.38 (m, 1H, NH2CH(CH2CH3) CH(C(CH3)3)OH, 3.64 (m, 1, NH2CH(CH2CH3)CH(C(CH3)3)OH), 7.41, 7.73 & 8.44 (3×bs, 2H, NH2CH(CH2CH3) CH(CH(CH3)2)OH).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH2:9][CH2:10][CH2:11][CH:12]2[C:17]([N:19]([CH2:29][C:30]1[CH:31]=[N:32][N:33]([CH2:35][CH3:36])[CH:34]=1)[C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=1)=[O:18].Cl.[CH3:38][NH:39][CH3:40].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:38][N:39]([CH3:40])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH2:9][CH2:10][CH2:11][CH:12]2[C:17]([N:19]([CH2:29][C:30]1[CH:31]=[N:32][N:33]([CH2:35][CH3:36])[CH:34]=1)[C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=1)=[O:18]
Reactant: CCn1cc(CN(C(=O)C2CCCc3c(OCCCCBr)cccc32)c2ccc(C(C)C)cc2)cn1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCn1cc(CN(C(=O)C2CCCc3c(OCCCCN(C)C)cccc32)c2ccc(C(C)C)cc2)cn1
Yield: 55.5 %

Procedure:
To a solution of 5-(4-bromobutoxy)-N-[(l-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.52 g) in acetonitrile (10 mL) were added dimethylamine hydrochloride (0.69 g) and potassium carbonate (1.30 g), and the mixture was heated under reflux for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between water and chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give 5-[4-(dimethylamino)butoxy]-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.27 g).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:42])[N:10]([C@@H:16]([CH2:36][CH2:37][CH:38]([F:41])[CH2:39][NH2:40])[CH2:17][O:18][Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[CH3:48][O:49][C:50]([NH:52][C@H:53]([C:67](ON1C(=O)CCC1=O)=[O:68])[CH:54]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:51]>C1COCC1.O.[Cl-].[Na+].O>[CH2:1]([O:8][C:9](=[O:42])[N:10]([C@@H:16]([CH2:36][CH2:37][CH:38]([F:41])[CH2:39][NH:40][C:67](=[O:68])[C@H:53]([CH:54]([C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)[NH:52][C:50]([O:49][CH3:48])=[O:51])[CH2:17][O:18][Si:19]([C:32]([CH3:35])([CH3:33])[CH3:34])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CCN(C(=O)OCc1ccccc1)[C@@H](CCC(F)CN)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)ON1C(=O)CCC1=O)C(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)NCC(F)CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N(CCC(C)C)C(=O)OCc1ccccc1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
To a stirred solution of the material from Step 10 (86 mg, 0.145 mmol) in THF (1 mL) and water (333 μL) at 0° C. was added NaHCO3 (49 mg, 0.58 mmol) and followed by portionwise addition of 2,5-dioxopyrrolidin-1-yl N-(methoxycarbonyl)-β-phenyl-L-phenylalaninate (63 mg, 0.16 mmol). The reaction mixture was stirred at room temperature overnight, poured into brine, and extracted with EtOAc (2×). The combined organics were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using EtOAc-hexanes to afford 110 mg of the title compound. 1H NMR (DMSO-d6): δ 8.24-8.12 (m, 1H), 7.67-7.53 (m, 4H), 7.51-7.37 (m, 6H), 7.37-7.20 (m, 11H), 7.19-7.07 (m, 2H), 7.03-6.91 (m, 1H), 5.15-4.90 (m, 3H), 4.29-4.19 (m, 1H), 3.96-3.76 (m, 1H), 3.74-3.47 (m, 2H), 3.06 (s, 3H), 3.16-2.97 (m, 4H), 2.96-2.76 (m, 1H), 1.55-1.28 (m, 5H), 1.27-1.01 (m, 2H), 0.97 (s, 9H), 0.85 (d, J=4.2 Hz, 3H), 0.77 (d, J=4.20 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13](=O)[CH2:14][Cl:15])=[CH:4][C:5]([CH3:12])=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[Cl:1][C:2]1[C:3]([CH2:13][CH2:14][Cl:15])=[CH:4][C:5]([CH3:12])=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1
Reactant: CC(=O)Nc1cc(Cl)c(C(=O)CCl)cc1C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1cc(Cl)c(CCCl)cc1C
Temperature: 60 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To a solution of N-[5-Chloro-4-(2-chloro-acetyl)-2-methyl-phenyl]-acetamide (10 g, 38.44 mmol) in trifluoroacetic acid (100 mL) at <20° C. was added portionwise, triethylsilane (15.35 mL, 96.1 mmol). The reaction was heated to 60° C. and stirred overnight. The reaction was cooled to rt and poured over ice/H2O and stirred for 30 min as a grey precipitate formed. The precipitate was collected by filtration and dried in vacuo overnight to give desired product (8.35 g, 33.92 mmol). Yield=88%; MS (APCI): 246 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.05 (s, 1H), 6.93 (bs, 1H, NH), 3.69 (t, J=7.26 Hz, 2H), 3.10 (t, J=7.26 Hz, 2H), 2.20 (d, J=4.48 Hz, 3H).
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.I[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1.[CH:34]([C:36]1[CH:37]=[N:38][CH:39]=[C:40]([CH:43]=1)[C:41]#[N:42])=[CH2:35]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu]I>[F:31][C:30]([F:33])([F:32])[C:26]1[CH:25]=[C:24]([CH:35]=[CH:34][C:36]2[CH:37]=[N:38][CH:39]=[C:40]([CH:43]=2)[C:41]#[N:42])[CH:29]=[CH:28][CH:27]=1
Reactant: FC(F)(F)c1cccc(I)c1
Reactant: C=Cc1cncc(C#N)c1
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: N#Cc1cncc(C=Cc2cccc(C(F)(F)F)c2)c1
Yield: 54 %

Procedure:
Prepare essentially as described in EXAMPLE 15 using palladium(II) acetate (0.002 g, 0.01 mmol), tri-o-tolylphosphine (0.06 g, 0.02 mmol), copper (I) iodide (0.001 g, 0.005 mmol), 1-iodo-3-trifluoromethylbenzene (0.140 mL, 1 mmol) and 5-vinylnicotinonitrile, (prepared essentially as described in PREPARATION 51), (0.195 g, 1.5 mmol) at 100° C. for 7 h to give the title compound (0.149 g, 54%).