Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3]1[CH:12]=[CH:11][C:6]([O:7][CH2:8][CH2:9][OH:10])=[CH:5][CH:4]=1.Cl[C:14]1C(C2C=CC=CC=2)=C(C=CC=1)C(O)=O.[S:29](=[O:32])(O)[O-:30].[Na+]>C(Cl)Cl>[CH3:14][S:29]([C:3]1[CH:12]=[CH:11][C:6]([O:7][CH2:8][CH2:9][OH:10])=[CH:5][CH:4]=1)(=[O:32])=[O:30]
Reactant: O=C(O)c1cccc(Cl)c1-c1ccccc1
Reactant: CSc1ccc(OCCO)cc1
Reactant: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(OCCO)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 14.1 g (0.77 mole) of 2-[4-(methylthio)phenoxy]ethanol (from Preparation 35) and 31.2 g (0.18 mole) of m-chlorophenylbenzoic acid in 800 ml of methylene chloride was stirred at room temperature overnight. A saturated, aqueous solution (300 ml) of sodium bisulfite was added, and the mixture was stirred at room temperature for 0.5 hr. The phases were separated, the mthylene chloride solution was dried over magnesium sulfate, and the volume reduced to approximately 100 ml in vacuo. n-Hexane was added until the solution became cloudy, and 9.40 g (56.8%) of the product precipitated as a white, crystalline solid, m.p. 96°-98° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[Cl:21]N1C(=O)CCC1=O.C(OCC)(=O)C>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][C:3]=1[Cl:21]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)cc2)C1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)c(Cl)c2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
In a 150 mL round-bottomed flask, (S)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate (5 g, 18 mmol) was dissolved in dimethylformamide (30 ml). N-Chlorosuccinimide (2.4 g, 18 mmol) was added and the mixture was stirred at 60° C. for 1 h. The reaction mixture was poured into ethyl acetate and extracted with saturated sodium chloride solution. The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 100 g, 30% ethyl acetate in heptane) to yield a light yellow solid (4.0 g, 71%) MS (ISP): 313.1 ([{35Cl}M+H]+), 315.1 ([{37Cl}M+H]+).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[C:43]([CH2:47][CH2:48][O:49]S(C)(=O)=O)[CH:44]=[CH:45][CH:46]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:54][N:55]1[CH2:61][CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1.C1C[O:65]CC1>>[CH:48]([OH:49])=[O:65].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][CH2:48][N:58]3[CH2:59][CH2:60][CH2:61][N:55]([CH3:54])[CH2:56][CH2:57]3)[CH:42]=2)[N:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: C1CCOC1
Reactant: CN1CCCNCC1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(CCOS(C)(=O)=O)c4)c4ccccc43)cn12
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(CCN5CCCN(C)CC5)c4)c4ccccc43)cn12
Product: O=CO

Procedure:
A solution of Intermediate 131d (44.5 mg, 0.06 mmol) and N-methylhomopiperazine (34.3 mg, 0.300 mmol) in THF (1 mL) was stirred at 60° C. for 20 h in a sealed tube. The mixture was concentrated in vacuo and the residue purified by MDAP (Method 7) to give an off-white solid (22 mg). Prep HPLC (Gemini C18, 20-60% MeCN in water, 0.1% HCO2H, 20 min) and concentration of the desired fractions removed the MeCN. The aqueous was washed with DCM (30 mL), then basified with aq. NaOH solution (1M, 0.5 mL) and extracted with DCM (2×10 mL). The combined organics were passed through a hydrophobic fit, then HCO2H (0.01 mL) added and the mixture concentrated in vacuo to leave the title compound as a clear film that became a solid on standing (10.6 mg, 23%). LCMS (Method 5): Rt 3.19 min, m/z 759.7 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.3 Hz), 1.28 (9H, s), 1.48-1.55 (2H, m), 1.64-1.74 (4H, m), 1.77-1.96 (4H, m), 2.00-2.16 (2H, m), 2.29 (3H, s), 2.58-2.62 (4H, m), 2.69-2.80 (8H, m), 2.91 (1H, ddd, J=12.4, 9.3, 4.3 Hz), 3.16 (1H, dt, J=11.9, 4.3 Hz), 3.28-3.34 (1H, m), 4.82 (1H, td, J=9.0, 5.7 Hz), 5.52 (1H, t, J=4.3 Hz), 6.33 (1H, s), 7.09 (1H, d, J=8.6 Hz), 7.19 (1H, dd, J=9.8, 2.2 Hz), 7.24-7.42 (8H, m), 7.64 (1H, dd, J=9.8, 0.8 Hz), 7.69 (1H, dd, J=2.2, 0.9 Hz), 8.10 (1H, s), 8.19 (1.4H, s).
Reaction SMILES: [NH3:1].[C:2]([C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[S:11](Cl)(=[O:13])=[O:12])#[N:3]>O1CCOCC1.O>[NH2:3][C:2]1[C:4]2[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=2[S:11](=[O:13])(=[O:12])[N:1]=1
Reactant: N
Reactant: N#Cc1c(Cl)cccc1S(=O)(=O)Cl
Solvent: C1COCCO1
Solvent: O
Product: NC1=NS(=O)(=O)c2cccc(Cl)c21

Procedure:
12.5 ml of 25% ammonia were added at approx. 60° C. to a solution of 11,8 g of 2-cyano-3-chlorobenzenesulphonylchloride in 20 ml of dioxane. After heating on a steam bath for 30 minutes the reaction mixture was cooled and diluted with water. The resulting crystalline product was sucked off, washed with water and dried. The desired product was obtained in a yield of 8.9 g. After recrystallization from ethanol, the product melted at 261°-263° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:13]=[C:12]([CH2:14][N:15]2[CH:19]=[CH:18][CH:17]=[N:16]2)[CH:11]=[CH:10][C:5]=1[O:6][CH2:7][CH2:8][OH:9].F[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>CN(C)C=O>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:9][CH2:8][CH2:7][O:6][C:5]1[CH:10]=[CH:11][C:12]([CH2:14][N:15]2[CH:19]=[CH:18][CH:17]=[N:16]2)=[CH:13][C:4]=1[Cl:3]
Reactant: OCCOc1ccc(Cn2cccn2)cc1Cl
Reactant: Fc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cc(Cn2cccn2)ccc1OCCOc1ccccn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91.2 %

Procedure:
To a mixture of 10 ml of anhydrous N,N-dimethylformamide and 24 mg of sodium hydride (60% oil dispersion) was added dropwise an anhydrous N,N-dimethylformamide (5 ml) solution of 500 mg of 2-[2-chloro-4-(1-pyrazolyl)methylphenoxy]-ethanol (produced in Reference Production Example 3 described below) under stirring over 10 minutes. After stirring at 60° to 70° C. for 2 hours, the mixture was cooled to 5° to 10° C., to which an anhydrous N,N-dimethylformamide (5 ml) solution of 250 mg of 2-fluoropyridine was added dropwise over 30 minutes. The mixture was then stirred at room temperature overnight and then at 60° to 70° C. for further 2 hours. After completion of the reaction, the reaction mixture was poured into 50 ml of ice water, which was extracted with twice with 30 ml of toluene. The organic layers were combined, washed with water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, which afforded 595 mg of 2-chloro-4-(1-pyrazolyl)methylphenyl 2-(2-pyridyloxy)ethyl ether (compound 8). Yield, 91%.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][NH:6][CH2:5][C@H:4]1[C:8]1[NH:9][C:10](=[O:23])[C:11]2[CH:16]=[N:15][N:14]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:12]=2[N:13]=1)[CH3:2].C(O)(=O)C.[CH3:28][C:29]1[N:30]=[CH:31][C:32]([CH:35]=O)=[N:33][CH:34]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O>[CH2:1]([C@@H:3]1[CH2:7][N:6]([CH2:28][C:29]2[CH:34]=[N:33][C:32]([CH3:35])=[CH:31][N:30]=2)[CH2:5][C@H:4]1[C:8]1[NH:9][C:10](=[O:23])[C:11]2[CH:16]=[N:15][N:14]([CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[C:12]=2[N:13]=1)[CH3:2]
Reactant: CC[C@@H]1CNC[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1
Reactant: Cc1cnc(C=O)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC[C@@H]1CN(Cc2cnc(C)cn2)C[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
To a solution of 6-[(3S,4S)-4-ethylpyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (4.4 g) in dimethylformamide (62 mL) was added acetic acid (2.4 mL), 5-methylpyrazine-2-carbaldehyde (2 g) and sodium triacetoxyborohydride (5.27 g). The reaction mixture stirred for 2 h at ambient temperature and was carefully quenched with saturated sodium bicarbonate solution, extracted 3× with methylene chloride, dried with magnesium sulfate, filtered and concentrated. Purification via Biotage MPLC chromatography eluting with 1-4% methanolmethylene chloride/0.5% saturated ammonium hydroxide provided the title compound (3.9 g). 400 MHz 1H NMR (CDCl3) δ 8.52-8.48 (m, 1H), 8.38 (s, 1H), 8.02 (s, 1H), 4.81-4.75 (m, 1H), 4.11-4.01 (m, 3H), 3.79-3.75 (m, 1H), 3.60-3.53 (m, 2H), 3.40-3.32 (m, 1H), 3.10-3.08 (m, 1H), 2.94 (m, 1H), 2.63-2.57 (m, 1H), 2.53 (d, J=7.5 Hz, 1H), 2.37-2.18 (m, 4H), 1.90-1.83 (m, 2H), 1.67-1.60 (m, 1H), 1.54-1.47 (m, 1H), 0.95-0.92 (m, 3H). MS: (M+H m/z 424.2).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]([C:12]3[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=3)=[O:11])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClCCCl.O>[CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]([C:12]3[CH:19]=[CH:18][C:15]([CH2:16][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:14][CH:13]=3)=[O:11])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=Cc1ccc(C(=O)N2CCN(C3CC3)CC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O
Product: O=C(c1ccc(CN2CCOCC2)cc1)N1CCN(C2CC2)CC1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(4-cyclopropyl-piperazine-1-carbonyl)-benzaldehyde (56.0 g) in 1,2-dichloroethane (550 mL) was added morpholine (37.8 mL) dropwise over 5 min. The mixture was cooled to 10° C. and was treated with NaBH(OAc)3 (64.3 g) in portions over 1 h. After a further 2 h, the mixture was warmed to room temperature, and a water bath was used to keep the temperature below 20° C. After 18 h, water (60 mL) was added while the temperature was kept under 20° C. by the addition of small amounts of ice. After 20 min, the mixture was basified to pH˜10 with 1 N NaOH (450 mL) and the mixture was stirred for 10 min. The layers were separated, and the organic layer was washed with 1 N NaOH (150 mL). The combined aqueous layers were extracted with CH2Cl2 (200 mL). The combined organic layers were washed with brine (200 mL), dried (Na2SO4), and concentrated to yield the title compound as pale yellow viscous oil.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][C:13]#[N:14]>>[C:1]([NH:14][CH2:13][CH2:12][C:11]#[N:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCCN
Reactant: O=C(Cl)c1ccccc1
Product: N#CCCNC(=O)c1ccccc1

Procedure:
Benzoyl chloride and aminoethylcyanide are reacted to give N-benzoyl-aminoethylcyanide, which is reacted with hydrogen sulfide in ammonia to yield the thioamide, which is reacted with an appropriate a-halo ketone to yield the desired thiazole. Treatment with 5N hydrochloric acid removes the protecting benzoyl group to wive the desired amine product.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:10]([OH:11])[CH3:17])[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(C)O)cc1OC1CCCC1
Temperature: 25 °C

Procedure:
A solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (10.00 g, 45.40 mM) in dried tetrahydrofuran (100 ml) was cooled to 0° C., a tetrahydrofuran solution of methyl magnesium bromide (136.20 mM) was dropped into this solution, and the resultant mixture was stirred at that temperature for 2 hours. A aqueous ammonium chloride was added to the solution obtained, which was then warmed to room temperature and extracted with ethyl acetate. The extract was successively washed with brine and water. The organic solution was dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to obtain crude product of 1-(3-cyclopentyloxy-4-methoxyphenyl)ethanol 10.67 g as a light yellow oil. The crude product thus obtained of 1-(3-cyclopentyloxy-4-methoxyphenyl)ethanol (10.67 g) was dissolved in dried methylene chloride (200 ml). Manganese dioxide (39.2 g) was added to this solution. The resultant product was stirred vigorously at room temperature for 16 hours. The undissolved material in the solution was removed by filtration through Celite, then the filtrate was concentrated in vacuo to obtain residue as a yellow oil. The residue was purified by flash chromatography (SiO2: eluted by 25% ethyl acetate/hexane). The solvent was removed in vacuo and the resultant product was dried to obtain 3-cyclopentyloxy-4-methoxyacetophenone 10.00 g (yield 94.4%) as a yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]Br.CN(C)C=O.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:24]([CH:29]=1)[C:25]([O:27][CH3:28])=[O:26]>C(OCC)(=O)C.O>[CH2:31]([O:30][C:23]1[CH:22]=[CH:21][C:20]([N:19]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCCCCCBr
Reactant: COC(=O)c1cc(N)ccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(N2CCCCC2)ccc1OCc1ccccc1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
Potassium carbonate (5.1 g) and 1,5-dibromopentane (2.5 mL) were sequentially added to an N,N-dimethylformamide (23 mL) solution of methyl 5-amino-2-(benzyloxy)benzoate (4.6 g), followed by stirring at 50 to 55° C. for 1 hour, at 55 to 60° C. for 1 hour, at 70° C. for 1 hour and 30 minutes, and then at 75 to 80° C. for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-65% hexane/ethyl acetate] to obtain 4.3 g of methyl 2-(benzyloxy)-5-(piperidin-1-yl)benzoate as a light yellow oily substance.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[N:7]([C:15]([O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)=[O:16])[CH2:6][C@@H:5]1[CH3:22])(=[O:3])[CH3:2].CC1(C)OB([C:29]2[CH:30]=[N:31][N:32](C(OC(C)(C)C)=O)[CH:33]=2)OC1(C)C.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:29]3[CH:30]=[N:31][NH:32][CH:33]=3)=[CH:11][CH:12]=2)[N:7]([C:15]([O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)=[O:16])[CH2:6][C@@H:5]1[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(=O)N1c2ccc(Br)cc2N(C(=O)OCC2CC2)C[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N1c2ccc(-c3cn[nH]c3)cc2N(C(=O)OCC2CC2)C[C@@H]1C
Temperature: 100 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
A 100-mL round-bottom flask was purged with nitrogen and charged with cyclopropylmethyl (3S)-4-acetyl-7-bromo-3-methyl-1,2,3,4-tetrahydroquinoxaline-1-carboxylate (1 g, 2.72 mmol), tert-butyl 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-carboxylate (953 mg, 3.24 mmol), sodium carbonate (573 mg, 5.41 mmol), [1,1′bis(diphenylphosphino) ferrocene]dichloropalladium(II) dichloromethane complex (265 mg, 0.326 mmol), 1,4-dioxane (9 mL), and water (3 mL). The resulting mixture was stirred overnight at 100° C. After cooling to room temperature, the reaction mixture was poured into water (20 mL). The aqueous layer was separated and extracted with ethyl acetate (4×40 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 1:1, ethyl acetate/petroleum ether) to afford cyclopropylmethyl (3S)-4-acetyl-3-methyl-7-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxylate (400 mg, 41%) of as a yellow solid. MS (ESI, pos. ion) m/z 355 [M+H]+.
Reaction SMILES: [C:1]([NH:8][C@H:9]1[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[CH2:12][NH:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(=O)(O)[O-].[Na+].C1COCC1.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>CCOC(C)=O.O>[C:4]([O:3][C:1]([NH:8][C@H:9]1[CH2:14][C@@H:13]([C:15]([F:17])([F:16])[F:18])[CH2:12][N:11]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:10]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H](C(F)(F)F)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.4 %

Procedure:
To a round bottom flask containing cis-3-(Boc-amino)-5-(trifluoromethyl)piperidine (Molbridge, 10.00 g, 37.27 mmol) and sodium bicarbonate (18.8 g, 224 mmol), THF (200 mL) was added, followed by water (200 mL). Benzyl chloroformate (20.1, g, 112 mmol) was then added dropwise over a period of 30 min. via a syringe pump. The mixture was stirred at room temperature for 2 h. The mixture was then diluted with EtOAc and water. The layers were separated and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (340 g, 15% EtOAc in hexanes) to give a white foamy solid which was subjected to chiral HPLC separation (Phenomenex Lux Cellulose C-1, 5 μm, 21.2×250 mm column, eluting with 15% EtOH in hexanes, at flow rate of 18 mL/min., with a loading of 100 mg in 1000 μL at 220 nm wavelength) to give the sub-title compound (retention time: 9.1 min.) as a white foamy solid (6.51 g, 43%). LCMS calc. for C19H25F3N2NaO4 (M+Na)+: m/z=425.2. found: 425.2. The sub-title compound is assigned as the (3S,5R) isomer. The alternative (3R,5S) isomer can be obtained from the same separation.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([C:14]1[C:15]#[C:16][CH:17]=[CH:18][CH:19]=1)[CH3:13].B(F)(F)F>>[CH2:12]([C:14]1[CH:15]=[CH:16][C:17]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])=[CH:18][CH:19]=1)[CH3:13]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCc1c#cccc1
Agent: FB(F)F
Product: CCc1ccc(C(=O)c2ccccc2C(=O)O)cc1

Procedure:
A complex of ortho-(4-ethylbenzoyl)benzoic acid (OEBB acid) is prepared according to U.S. Pat. No. 4,379,092 by reacting 26.6 g phthalic anhydride, 19.07 g ethylbenzyne, 35.9 g HF, and 121.77 g BF3 for 30 minutes at -40° C. After reaction and degassing at -40° C., 144.4 g of a complex solution in HF is obtained. This solution is injected over a 20 minute period into the column described in Example 1. The same temperature and pressure conditions were used and methylene chloride was again selected as the solvent. The methylene chloride reflux rate was 3.8 kg/h. After introducing the complex solution, the solvent reflux was maintained for 20 minutes before evaporating the solvent in the boiler. 43.31 g of crude OEBB acid which contained 39.07 g of OEBB acid was recovered. Also, the recovery rates for BF3 and HF were 99.3% and 99.6%, respectively.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O-:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:23](N(CC)C(C)C)(C)C.[C:32]1([CH2:38][C:39](Cl)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(OCC)(=O)C>ClCCl>[CH3:23][O:21][C:20]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:39](=[O:40])[CH2:38][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:3]=1)[C:17]([CH3:18])([CH3:19])[CH2:16]2)=[O:22]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC1(C)Cc2cc(C(=O)[O-])ccc2NC1c1cccc(N)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)Cc3ccccc3)c1)N2
Yield: 67.6 %

Procedure:
To a solution of 2-(3-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (150 mg, 0.48 mmol) and N,N-diisopropylethylamine (0.16 mL, 0.97 mmol) in dichloromethane (10 mL) was added 2-phenylacetyl chloride (0.1 mL, 0.63 mmol) with ice cooling. The resultant mixture was kept 0° C. for 10 h. Thin layer chromatography (petroleum ether:ethyl acetate=3:1, Rf=0.4) showed the reaction was complete. Solvent was removed in vacuo and the residue was purified by Prep. Thin layer chromatography (petroleum ether:ethyl acetate=3:1) to afford 139 mg of methyl-3,3-dimethyl-2-(3-(2-phenylacetamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxy late as a off-white solid. Yield: 67.1%. MS (ES+APCI) M+1-CH3O=397.1.
Reaction SMILES: [NH2:1][C@H:2]([C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)=[O:18])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl.[N:35]1([CH2:40][C:41](O)=[O:42])[CH:39]=[N:38][CH:37]=[N:36]1>>[N:35]1([CH2:40][C:41]([NH:1][C@H:2]([C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)=[CH:24][CH:25]=2)=[O:18])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:42])[CH:39]=[N:38][CH:37]=[N:36]1
Reactant: O=C(O)Cn1cncn1
Reactant: N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(Cn1cncn1)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 20 %

Procedure:
Proceeding as in Example 1, but substituting (S)-benzyl 4-amino-5-(4-(4-fluorophenoxy)phenylamino)-5-oxopentylcarbamate and 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride, gave Compound 165, (S)-benzyl 4-(2-(1H-1,2,4-triazol-1-yl)acetamido)-5-(4-(4-fluorophenoxy)phenylamino)-5-oxopentylcarbamate (90.1 mg, 20%). 1H-NMR (400 MHz, DMSO-D6): σ 10.19 (s, 1H), 8.69 (d, 1H), 8.48 (s, 1H), 7.96 (s, 1H), 7.60 (d, 2H), 7.39-7.29 (m, 5H), 7.21 (m, 2H), 7.04-6.96 (m, 4H), 5.00-4.97 (m, 4H), 4.46-4.39 (m, 1H), 3.04-2.99 (m, 2H), 1.75-1.39 (m, 4H). MS (EI) for C29H29FN6O5. found 560.9 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[N:7][N:8]=[CH:9]2)([O-])=O.O.NN>C(O)C.C1COCC1.[Ni].O>[CH:9]1[C:10]2[C:5](=[C:4]([NH2:1])[CH:13]=[CH:12][CH:11]=2)[CH:6]=[N:7][N:8]=1
Reactant: O=[N+]([O-])c1cccc2cnncc12
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Nc1cccc2cnncc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.8 %

Procedure:
A reaction vessel was charged with the 5-nitrophthalazine (1.9 g, 10.9 mmol) prepared above, dissolved in a mixture of 60 mL of ethanol:THF (5:1). Hydrazine hydrate (2.5 g, 25 mmol) was added to the reaction mixture followed by a catalytic amount of Raney nickel as a slurry in water. The reaction mixture was stirred at ambient temperature for 4 hours. The reaction mixture was then passed through a pad of silica gel/celite which was washed with ethanol. The ethanol fractions were combined and evaporated to yield 1.2 g (79%) of the title compound of formula (Z).