Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]([Mg]Br)[CH2:9][CH:10]([CH3:12])[CH3:11].[Mg].C(Br)CC(C)C>CCOCC.[Cu]I>[CH3:3][C:2]([CH3:5])([C:1](=[O:6])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH3:4]
Reactant: CC(C)CC[Mg]Br
Reactant: CC(C)(C)C(=O)Cl
Agent: [Cu]I
Agent: [Mg]
Solvent: CC(C)CCBr
Solvent: CCOCC
Product: CC(C)CCC(=O)C(C)(C)C
Reaction time: 16 h

Procedure:
To a stirred mixture of pivaloyl chloride (6.02 g, 0.05 m) and copper (I) iodide (0.10 g, 0.6 mm) in dry ether (50 mls) at -60° C. under nitrogen was added dropwise isoamyl magnesium bromide [prepared from magnesium turnings (1.8 g, 0.075 m) and isoamyl bromide (7.55 g, 0.05 m) in dry ether (70 mls]. The cooling bath was removed and the reaction mixture stirred for 16 hours then poured cautiously into ice-cold dilute hydrochloric acid and extracted with ether. The combined ethereal extracts were washed with saturated aqueous sodium hydrogen carbonate solution, brine, dried (anhydrous MgSO4) and evaporated. The residue was chromatographed on silica using gradient elution (dichloromethane (0-30%) in petrol) to give the ketone as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@H:4]([OH:28])[CH2:5][N:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)[NH:7]C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])[C@H:4]([OH:28])[CH2:5][N:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)[NH2:7]
Reactant: COC(=O)[C@H](O)CN(Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](O)CN(N)Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
(R)-3-(N-biphenyl-4-ylmethyl-N′-t-butoxycarbonylhydrazino)-2-hydroxypropionic acid methyl ester (300 mg, 749 μmol, 1.0 eq.) was dissolved in DCM (3.0 mL). TFA (3.0 mL) was added and the mixture was stirred at room temperature until the reaction was complete (approximately 1 hour). The mixture was concentrated to yield the title compound, which was used without further purification.
Reaction SMILES: [C:1]([C:6]1([CH3:14])[CH2:10][C:9]([CH3:11])=[C:8]([OH:12])[C:7]1=[O:13])([O:3]CC)=[O:2].[OH-].[Na+].S(=O)(=O)(O)O>>[C:1]([C:6]1([CH3:14])[CH2:10][C:9]([CH3:11])=[C:8]([OH:12])[C:7]1=[O:13])([OH:3])=[O:2]
Reactant: CCOC(=O)C1(C)CC(C)=C(O)C1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC1=C(O)C(=O)C(C)(C(=O)O)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.5 %

Procedure:
4.8 g (24 mmol) of the foregoing 2-carboethoxy-2,4-dimethylcyclopent-4-en-5-olone are treated with 48 ml of 2 N sodium hydroxide solution and the mixture is stirred at room temperature for 1.5 hours. For the working-up, the mixture is adjusted to pH 3 with 10% sulphuric acid and extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulphate, concentrated and dried in a high vacuum for 2 hours. There are obtained 3 g (58.5%) of 2-carboxy-2,4-dimethylcyclopent-4-en-5-olone of melting point 98°-105° C., with elimination of carbon dioxide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2([C:13]3([CH3:21])[CH2:16][C:15]([F:18])([F:17])[C:14]3([F:20])[Cl:19])[CH2:12][O:11]2)=[CH:4][CH:3]=1.[NH:22]1[CH:26]=[N:25][CH:24]=[N:23]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]([C:13]2([CH3:21])[CH2:16][C:15]([F:18])([F:17])[C:14]2([F:20])[Cl:19])([OH:11])[CH2:12][N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)=[CH:4][CH:3]=1
Reactant: CC1(C2(C#Cc3ccc(Cl)cc3)CO2)CC(F)(F)C1(F)Cl
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C(O)(C#Cc2ccc(Cl)cc2)Cn2cncn2)CC(F)(F)C1(F)Cl
Yield: 77.4 %

Procedure:
31.8 g of 2-[2-(4-chlorophenyl)-ethin-1-yl]-2-(2,3,3-trifluoro- 2-chloro-1-methylcyclobut-1-yl)-oxirane are added at room temperature to a stirred mixture of 6.4 g of 1,2,4-triazole, 12.6 g of ground potassium carbonate and 300 ml of acetonitrile. The reaction mixture is refluxed for 12 hours, and then cooled and filtered. The filtrate is concentrated under reduced pressure, and the remaining residue is purified by column chromatography (ethyl acetate) on silica gel. 29 g (75.5% of theory) of 1-(4-chlorophenyl)-3-(2,3,3-trifluoro-2-chloro-1-methyl-cyclo-but-1-yl)-4-(1,2,4-triazol-1-yl)-but-1-in-3-ol are obtained in form of a viscous oil.
Reaction SMILES: CN1C(=O)N(C)CC1.[Br:9][C:10]1[CH:16]=[C:15]([C:17]([F:29])([C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[C:18]([F:21])([F:20])[F:19])[CH:14]=[C:13]([Br:30])[C:11]=1[NH2:12].[Cl:31][C:32]1[C:40]([N+:41]([O-:43])=[O:42])=[CH:39][CH:38]=[CH:37][C:33]=1[C:34](Cl)=[O:35].O>C(OCC)(=O)C>[Cl:31][C:32]1[C:40]([N+:41]([O-:43])=[O:42])=[CH:39][CH:38]=[CH:37][C:33]=1[C:34]([NH:12][C:11]1[C:10]([Br:9])=[CH:16][C:15]([C:17]([F:29])([C:22]([F:27])([F:28])[C:23]([F:24])([F:25])[F:26])[C:18]([F:19])([F:20])[F:21])=[CH:14][C:13]=1[Br:30])=[O:35]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1Cl
Reactant: Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1Br
Solvent: CN1CCN(C)C1=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1Br)c1cccc([N+](=O)[O-])c1Cl
Temperature: 140 °C
Reaction time: 4 h
Yield: 39.9 %

Procedure:
To 27 ml of DMI were added 9.90 g (21.1 mmol) of 2,6-dibromo-4-(perfluorobutan-2-yl)aniline and 4.60 g (20.9 mmol) of 2-chloro-3-nitrobenzoyl chloride, followed by stirring at 140° C. for 4 hours. To the reaction solution were added water and ethyl acetate, and the organic phase was extracted, and washed with 1 mol/L of an aqueous sodium hydroxide solution, saturated brine, and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent solvent; hexane:ethyl acetate=20:1→10:1→5:1→3:1) to prepare 5.44 g (yield 40%) of a target compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:10]2[N:22](C(OCC3C=CC=CC=3)=O)[CH2:23][CH2:24][CH:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[CH:10]2[NH:22][CH2:23][CH2:24][CH:9]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(OCc2ccc(F)cc2)C2C1CCN2C(=O)OCc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(OCc2ccc(F)cc2)C2NCCC21
Reaction time: 1.5 h
Yield: 123.5 %

Procedure:
To a solution of 44 (3.40 g, 7.22 mmol) in MeOH (70 mL) was added NH4OAc (280 mg, 3.61 mmol) and 10% Pd-on-carbon (wet, 770 mg, 0.70 mmol). The reaction flask was evacuated and backfilled with hydrogen (4×) and then maintained under a balloon of hydrogen gas. After 90 min, the catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was dissolved in Et2O and washed successively with saturated aqueous NaHCO3, and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 3.0 g of 45 as a colorless oil which was used in the next step without further purification. Mass spectrum, m/z [336.7] (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C@H:9]([N:12]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][OH:11])=[O:4].Cl[C:39]([O:41][CH2:42][CH3:43])=[O:40]>>[CH2:42]([O:41][C:39](=[O:40])[NH:1][C@H:2]([C:3](=[O:4])[NH:5][CH2:6][CH2:7][CH2:8][C@H:9]([N:12]([S:17]([C:20]1[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=1)(=[O:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][OH:11])[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[CH3:43]
Reactant: CCOC(=O)Cl
Reactant: CC(C)CN([C@H](CO)CCCNC(=O)[C@@H](N)Cc1cccc2ccccc12)S(=O)(=O)c1ccc(N)cc1
Product: CCOC(=O)N[C@@H](Cc1cccc2ccccc12)C(=O)NCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,4S)-2-amino-N-{4-[(4-amino-benzenesulfonyl)-isobutyl-amino]-5-hydroxy-pentyl}-3-naphthalen-1-yl-propionamide (product of example 8) as described in general procedure D using ethyl chloroformate. The final product was obtained in 60% yield.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([N:16]([CH3:36])[CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[C@H:26]([CH2:30][C:31]([O:33]CC)=[O:32])[CH2:25][CH2:24]5)[N:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.O.O[Li].O>C1COCC1.C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([N:16]([CH3:36])[CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[C@H:26]([CH2:30][C:31]([OH:33])=[O:32])[CH2:25][CH2:24]5)[N:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCN(C)c3nccc(-c4ccc5c(c4)OCO5)n3)ccc21
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CN(CCCOc1ccc2c(c1)CC[C@H]2CC(=O)O)c1nccc(-c2ccc3c(c2)OCO3)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.5 %

Procedure:
To a solution of ethyl ((1S)-5-{3-[[4-(1,3-benzodioxol-5-yl)-2-pyrimidinyl](methyl)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 292, 35 mg, 0.071 mmol) in THF (2 mL), ethanol (1 mL), and water (2 mL) was added LiOH.H2O (7 mg, 0.29 mmol), and the mixture was stirred at rt for 16 h. The reaction mixture was then extracted with Et2O (2×), organic layers discarded, and the remaining aqueous solution was acidified to pH ˜5 using HCl (1 M aqueous solution). The aqueous solution was then extracted with EtOAc. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to give 9 mg (27%) of the product. 1H NMR (400 MHz, CDCl3): δ 1.70-1.80 (m, 1H), 2.15-2.20 (m, 2H), 2.32-2.50 (m, 2H), 2.71 (dd, 1H), 2.83-2.95 (m, 2H), 3.30 (s, 3H), 3.51-3.64 (m, 1H), 3.72 (q, 2H), 3.99 (t, 2H), 6.00 (s, 2H), 6.62 (d, 1H), 6.54 (s, 1H), 6.80 (d, 2H), 7.05 (d, 1H), 7.61 (s, 2H), 8.30 (d, 1H); LC-MS: RT=2.50 min, (M+H)+ 462.3.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:22])=[C:5]([CH2:7][NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[N:6]=1.C1CCN2C(=NCCC2)CC1.[C:34](=O)([O-])[O-:35].[K+].[K+]>ClCCl>[CH3:1][C:2]1[N:6]2[C:34](=[O:35])[N:8]([CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:11][CH2:10]3)[CH2:7][C:5]2=[C:4]([CH3:22])[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1nc(CNC2CCN(C(=O)OC(C)(C)C)CC2)c(C)[nH]1
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: Cc1nc(C)n2c1CN(C1CCN(C(=O)OC(C)(C)C)CC1)C2=O
Yield: 97 %

Procedure:
tert-Butyl 4-(((2,5-dimethyl-1H-imidazol-4-yl)methyl)amino)-1-piperidinecarboxylate (8.0 g) obtained in Example 88a) was dissolved in dichloromethane (100 ml), DBU (3.6 ml) and N,N′-carbonyldiimidazole (3.9 g) were added thereto. The reaction solution was mixed for 15 hours, and then the reaction solution was poured into an aqueous potassium carbonate solution and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and then the residue was purified with silica gel column to obtain a pale yellow oily title compound (7.8 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[Cl:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36][NH2:37]>>[Cl:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36][NH:37][C:21](=[O:23])[C:20]1[CH:24]=[CH:25][CH:26]=[C:18]([C:16]2[CH:15]=[N:14][C:10]3[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]4[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:28]([F:30])([F:29])[F:31])[C:9]=3[CH:17]=2)[CH:19]=1
Reactant: NCc1cccc(Cl)c1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(NCc1cccc(Cl)c1)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 3-chlorobenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=570.99 (M+H+); retention time=0.99 minutes.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([O:17][C:18]([C:20]1[N:21]=[C:22]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[N:23]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[C:24]=1[CH2:25][CH:26]=O)=[O:19])[CH3:16].[CH:42]1([NH2:47])[CH2:46][CH2:45][CH2:44][CH2:43]1.C(O)(=O)C>ClCCCl>[CH2:15]([O:17][C:18]([C:20]1[N:21]=[C:22]([C:35]2[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=2)[N:23]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[C:24]=1[CH2:25][CH2:26][NH:47][CH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1)=[O:19])[CH3:16]
Reactant: NC1CCCC1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2)n(-c2ccccc2Cl)c1CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2)n(-c2ccccc2Cl)c1CCNC1CCCC1
Yield: 55.4 %

Procedure:
Sodium triacetoxyborohydride (32 mg, 0.152 mmol) was added to a solution of 2-(4-chloro-phenyl)-1-(2-chloro-phenyl)-5-(2-oxo-ethyl)-1H-imidazole-4-carboxylic acid ethyl ester I-5h (34 mg, 0.084 mmol), cyclopentylamine (12 μl, 0.118 mmol), and acetic acid (5 μl, 0.09 mmol) in 1,2-dichlorethane (2 ml) at room temperature. The reaction mixture was quenched with 1N NaOH and extracted with CH2Cl2 (3×). The combined CH2Cl2 extracts were washed with sat'd aq NaCl, dried, and concentrated in vacuo. The crude residue was purified on a 1 mm chromatotron plate using 100% EtOAc to give I-5i as a colorless oil (22 mg): +APCI MS (M+1) 472.2.
Reaction SMILES: [CH3:1][O:2][CH:3]1[O:7][C@@H:6]([CH2:8][O:9][Si](C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:5][CH2:4]1.C(O)=O.CCOC(C)=O>CO>[CH3:1][O:2][CH:3]1[O:7][C@@H:6]([CH2:8][OH:9])[CH2:5][CH2:4]1
Reactant: COC1CC[C@H](CO[Si](C)(c2ccccc2)c2ccccc2)O1
Solvent: CCOC(C)=O
Solvent: O=CO
Solvent: CO
Product: COC1CC[C@H](CO)O1
Yield: 100 %

Procedure:
((R)-5-Methoxy-tetrahydro-furan-2-ylmethoxy)-methyl-diphenylsilane (Pilli, R. A.; Riatto, V. B. Tet. Asymm. (2000)), 11, 3675) (0.80 g, 2.25 mmol) was dissolved in 35 mL of anhydrous MeOH and 5 mL of formic acid was added to the mixture. The mixture was stirred at room temperature for 30 minutes at which point TLC (9:1 hexanes:EtOAc) indicated complete conversion to the product. Volatiles were removed in vacuo and 0.83 g, 100% of the title compound was obtained as clear oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]([OH:19])=O)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=[N:30]C=2C=1.N>CN(C=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]([NH2:30])=[O:19])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(C(=O)O)cc2C1
Reactant: On1nnc2ccccc21
Agent: N
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1Cc2ccc(C(N)=O)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
A mixture of N-t-butoxycarbonyl-5-carboxyisoindoline (D13) (240 mg), EDC (350 mg), HOBT (140 mg), triethylamine (0.32 ml) and 0.880 ammonia solution (1 ml) in DMF (10 ml) was stirred overnight at rt and then evaporated. The residue was partitioned between EtOAc (10 ml) and 5% citric acid (10 ml). The organic layer was collected, washed with water (10 ml), saturated NaHCO3 solution (10 ml), water (10 ml), brine (10 ml), dried (MgSO4) and evaporated to give the title compound (D14) (154 mg). MS electrospray (+ion) 263 (MH+). 1H NMR δ (CDCl3), 7.73 (2H, m), 7.26 (1H, m), 6.88 (2H, m), 4.72 (2H, s), 4.69 (2H, s),1.52 (9H, s).
Reaction SMILES: [CH2:1]([C:7]1[C:8]([C:32](OCC)=[O:33])=[C:9]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:11]([C:13](OCC)=[O:14])[CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([C:7]1[C:8]([CH2:32][OH:33])=[C:9]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:11]([CH2:13][OH:14])[CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cc(C(=O)OCC)c(-c2ccc(F)cc2)c(-c2ccc(F)cc2)c1C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCc1cc(CO)c(-c2ccc(F)cc2)c(-c2ccc(F)cc2)c1CO
Temperature: 25 °C
Yield: 94 %

Procedure:
A 250 mL 3 neck round-bottom flask equipped with a condenser was flushed with nitrogen and then loaded with diethyl 5-hexyl-2,3-di-(4-fluorophenyl)-1,4-benzenedicarboxylate (4 g, 8.1 mmol), anhydrous THF (40 mL) and then cooled in an ice/water bath. Lithium aluminum hydride (1.23 9, 32.4 mmol) followed by THF (40 mL) was added to the reaction mixture with stirring. The mixture was warmed to room temperature and then refluxed for 6 hours. This was then cooled to room temperature and the excess lithium aluminum hydride was destroyed by dropwise addition of water. NaOH (1.5 g in 10 mL of water) was then added and stirred for 15 min. The solvent was then removed by rotary evaporation and then 10% sulfuric acid (80 mL) was added to the white gelatinous product and stirred overnight. The white precipitate was filtered and washed with water and air-dried (3.12 g, 94.0% yield).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1COCC1.[CH3:16][N:17]1[CH2:22][CH2:21][CH2:20][CH:19]([OH:23])[CH2:18]1.F[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=1>CCO.[Pd].O>[CH3:16][N:17]1[CH2:22][CH2:21][CH2:20][CH:19]([O:23][C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH2:18]1
Reactant: CN1CCCC(O)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [Pd]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CN1CCCC(Oc2ccc(N)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
KHMDS (1.1 equivalent) was added to a THF solution of 1-methylpiperidin-3-ol (1 equivalent) at 0° C. and stirred until H2 evolution ceased. 1-fluoro-4-nitrobenzene (1 equivalent) was then added and the solution was allowed to warm to room temperature. After 2 hours, water was added and the mixture was extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, and concentrated in vacuo to give a bright yellow oil which was directly used in the reduction step. The oil (1 equivalent) and a catalytic amount of 10% Pd/C were suspended in anhydrous EtOH at room temperature. The reaction flask was evacuated and subsequently filled with H2. After stirring for 18 hours, the mixture was filtered through Celite, and the solvent was concentrated in vacuo to yield 4-(1-methyl-3-piperidyloxy)phenylamine. LC/MS (m/z) 207.2 (MH+), Rt 0.47 minutes.
Reaction SMILES: [NH2:1][CH:2]([C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][C:25]=1[F:36])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][S:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][CH:6]1[CH2:19][C:20]([O:22]C)=[O:21].[OH-].[Na+].O1CCOCC1>O>[NH2:1][CH:2]([C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][C:25]=1[F:36])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][S:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][CH:6]1[CH2:19][C:20]([OH:22])=[O:21]
Reactant: COC(=O)CC1CN(CCSc2cccs2)CCC1CCC(N)c1c(F)cnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2ncc(F)c(C(N)CCC3CCN(CCSc4cccs4)CC3CC(=O)O)c2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
A mixture of 0.355 g of methyl (3RS,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-acetate in 1.66-cm3 of a 1 N aqueous sodium hydroxide solution and 5-cm3 of dioxane was heated at a temperature in the region of 60° C., with stirring, for 2 hours. After cooling to about 20° C., the reaction mixture was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 50° C. The evaporation residue obtained was taken up in 30-cm3 of water and 30-cm3 of diethyl ether, the aqueous phase was separated after settling out and neutralized with 1.66-cm3 of a 1 N aqueous hydrochloric acid solution and was then extracted twice with 100-cm3 of ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and then concentrated to dryness according to the same conditions above. 0.238 g of (3RS,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-acetic acid were obtained in the form of a white solid.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH2:27][CH2:28][CH:29]4[CH2:33][O:32]C(C)(C)[O:30]4)[N:18]=3)=[CH:15][N:16]=[C:11]2[N:10](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH2:27][CH2:28][CH:29]([OH:30])[CH2:33][OH:32])[N:18]=3)=[CH:15][N:16]=[C:11]2[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3nn(CCC4COC(C)(C)O4)c4cc(F)ccc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(CCC(O)CO)c4cc(F)ccc34)nc12
Reaction time: 2 h
Yield: 54.5 %

Procedure:
To a stirred solution of N-tert-butyl-2-(1-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-6-fluoro-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (90 mg, 0.125 mmol) in dichloromethane (2 mL) was added drop-wise trifluoroacetic acid (2 mL) at room temperature and the reaction mixture was stirred for 2 hours. The solvent was removed under reduced pressure. The residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 30% acetonitrile/70% water (0.1% trifluoroacetic acid, v/v) initially, and then proceed to 70% acetonitrile/30% water (0.1% trifluoroacetic acid, v/v) in a linear fashion after just 9 min.) to give N-tert-butyl-2-(1-(3,4-dihydroxybutyl)-6-fluoro-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (30 mg, 54.5%) as a white solid. LCMS: (M+H)+=441, (M+Na)+=463; 1H NMR (300 MHz, DMSO): δ12.81 (s, 1H), 9.06 (s, 1H), 8.47-8.42 (m, 1H), 8.37 (s, 1H), 7.91 (s, 1H), 7.64 (d, 1H, J=9.9 Hz), 7.14 (dd, 1H, J1=9.0 Hz, J2=1.8 Hz), 4.57 (t, 2H, J=6.5 Hz), 3.46-3.24 (m, 5H), 2.10-2.08 (m, 1H), 2.06-1.77 (m, 1H), 1.51 (s, 9H).