Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:5]2[N:13]3[C:8]([C:9](=[O:14])[NH:10][CH:11]=[N:12]3)=[CH:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1.[I:15]N1C(=O)CCC1=O>CN(C=O)C>[CH:1]1([C:5]2[N:13]3[C:8]([C:9](=[O:14])[NH:10][CH:11]=[N:12]3)=[C:7]([I:15])[N:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C1CCC(=O)N1I
Reactant: O=c1[nH]cnn2c(C3CCC3)ncc12
Solvent: CN(C)C=O
Product: O=c1[nH]cnn2c(C3CCC3)nc(I)c12
Temperature: 55 °C

Procedure:
A solution of 7-cyclobutyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (789 mg, 4.15 mmol) and N-iodosuccinimide (NIS, 933 mg, 4.15 mmol) in anhydrous DMF (40 mL) was stirred overnight at rt. An additional 4 eq. of NIS was added and reaction was heated to 55° C. for 6 h. The reaction mixture was concentrated in vacuo and partitioned between DCM and H2O and separated. The aqueous layer was washed with DCM (3×) and the combined organic fractions were washed with 1M sodium thiosulfate (Na2S2O3) (1×), brine (1×), dried over sodium sulfate (Na2SO4), filtered, and concentrated in vacuo. The solid was triturated with 20% EtOAc in DCM and filtered through a fritted Buchner funnel resulting in the title compound as an off-white solid; 1H NMR (DMSO-d6, 400 MHz) δ 1.84-1.96 (m, 1H), 1.98-2.13 (m, 1H), 2.25-2.43 (m, 4H), 3.84-3.96 (m, 1H), 7.87 (s, 1H); MS (ES+): m/z 317.02 (100) [MH+], HPLC: tR=2.62 min (MicromassZQ, polar—5 min).
Reaction SMILES: [CH3:1][C:2]1[CH:29]=[C:28]([CH3:30])[C:5]2[N:6]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:7][CH2:8][CH2:9]/[C:10](=[N:11]/[C:12]3[N:13]=[N:14][N:15]([CH3:17])[N:16]=3)/[C:4]=2[CH:3]=1.CC1C=C(C)C2N(C(OCC3C=CC=CC=3)=O)CCC=C(NC3N=NN(C)N=3)C=2C=1.C1(C)C=CC=CC=1>>[CH3:1][C:2]1[CH:29]=[C:28]([CH3:30])[C:5]2[N:6]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:7][CH2:8][CH2:9][C@H:10]([NH:11][C:12]3[N:13]=[N:14][N:15]([CH3:17])[N:16]=3)[C:4]=2[CH:3]=1
Reactant: Cc1cc(C)c2c(c1)/C(=N\c1nnn(C)n1)CCCN2C(=O)OCc1ccccc1
Agent: Cc1cc(C)c2c(c1)C(Nc1nnn(C)n1)=CCCN2C(=O)OCc1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cc(C)c2c(c1)[C@@H](Nc1nnn(C)n1)CCCN2C(=O)OCc1ccccc1
Temperature: 100 °C

Procedure:
Charge an autoclave with a mixture of (Z)-benzyl 7,9-dimethyl-5-(2-methyl-2H-tetrazol-5-ylimino)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-carboxylate and (E)-benzyl 7,9-dimethyl-5-(2-methyl-2H-tetrazol-5-ylamino)-2,3-dihydro-1H-benzo[b]azepine-1-carboxylate (4.04 g, 10 mmole), S-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl ((S)-BINAP, 60 mg, 96.3 μmoles), KI (415 mg 24 mmoles, KI can be deleted if desired) and di chloro-bis((1,2,5,6 eta)-1,5-cyclooctadiene)diiridium (Ir2Cl2(COD)2 (927 mg 40.2 μmoles). Purge the autoclave with nitrogen. While maintaining an oxygen free environment, add degassed toluene (50 mL, 472.8 mmol) and seal the autoclave. Heat to 100° C. under 500 psi H2 for 66 h. Cool the reaction mixture to RT and vent. Filter the solids and collect the organic mixture. Wash the organic mixture with water (2×25 mL); dry over Na2SO4, and filter. Collect the filtrate and remove the solvent under vacuum to provide the title compound (3.99 g, 88.7% ee by HPLC).
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[CH2:5]([Li])[CH2:6][CH2:7][CH3:8].[O:10]=[C:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH2:12]1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH2:5]([C:11]1([OH:10])[CH2:12][CH2:13][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH2:15][CH2:16]1)[CH2:6][CH2:7][CH3:8]
Reactant: [Li]CCCC
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Agent: [Ce+3]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCC1(O)CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under nitrogen atmosphere, anhydrous cerium chloride (4.63 g) was added to anhydrous tetrahydrofuran (50 ml), and the mixture was stirred at room temperature for 2 hours. After the suspension was cooled to −78° C., 1.6 M butyl lithium in hexane (6.40 ml) was added to the suspension and then the mixture was stirred for 1 hour. A solution of t-butyl 4-oxocyclohexylcarbamate (2.36 g) in anhydrous tetrahydrofuran (50 ml) was added to the reaction mixture over 10 minutes, and the mixture was gradually warmed to about 25° C. and then stirred overnight. After a saturated aqueous ammonium chloride was added to the reaction mixture, the mixture was filtrated through Celite. The filtrate was extracted with ethyl acetate, and the organic layer was washed with brine, dried over sodium sulfate, and the solvent was removed in vacuo. The residue was purified by a silica gel chromatography (eluent: chloroform/methanol=100/1) to give 2.53 g of t-butyl 4-butyl-4-hydroxycyclohexylcarbamate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=2[N+:24]([O-])=O)[C:9](OC)=[O:10])=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:9](=[O:10])[NH:24][C:15]3[C:14](=[CH:23][CH:22]=[C:17]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=3)[NH:13]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(NC(C(=O)OC)c2ccc(F)cc2)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)NC(=O)C(c1ccc(F)cc1)N2
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed methyl 4-(1-(4-fluorophenyl)-2-methoxy-2-oxoethylamino)-3-nitrobenzoate (3.5 g, 9.67 mmol, 1.00 equiv), methanol (50 mL), and palladium on carbon (10%) (500 mg). Hydrogen gas was introduced to the reaction and it was stirred overnight at 30° C. in an oil bath. Then the solids were filtered off and the filtrate was concentrated in vacuo. This resulted in 2.6 g (90%) of methyl 2-(4-fluorophenyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate as a light yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:39])[C@H:4]([CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1)[NH:5][C:6](=[O:28])[CH2:7][CH2:8][C:9](=[O:27])[C@@H:10]([NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1COCC1.CO.[Li+].[OH-]>C(O)(=O)C>[C:19]([NH:18][C@@H:10]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:9](=[O:27])[CH2:8][CH2:7][C:6]([NH:5][C@H:4]([C:3]([OH:39])=[O:2])[CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1)=[O:28])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)CCC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CCC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
To a stirred solution of the compound (5S)-5-[(N-benzoyl)amino]-4-oxo-6-phenyl-hexanoyl-L-tryptophan methyl ester (170 mg, 0.3222 mmol, 1.0 eq.) in a mixture THF-MeOH (ratio 3:2) (10 mL) was added 0.5N LiOH (5.0 mL). The resulting yellowish mixture was stirred at room temperature for 30 min during which TLC shows the complete disappearance of the starting material. The reaction mixture was then neutralized with glacial acetic acid and the extracted with EtOAc (3×25 mL), dried over anhydrous MgSO4 and evaporation of the solvent gave a crude residue, which was subjected to column chromatography on silica gel elution with 30% MeOH-EtOAc afforded the free acid (5S)-5-[(N-benzoyl)amino]-4-oxo-6-phenyl-hexanoyl-L-tryptophan 5b as a pale yellow solid (0.158 g, 95%); mp 171-173° C.; Rf 0.38 (30% MeOH-EtOAc); IR (KBr) ν 1720 (CO), 3250 (broad, COOH) cm−1; 1H NMR (400 MHz, CDCl3) δH 2.31 (2H, m, —CH2CO), 2.70 (2H, m, —CH2CO), 2.96 (1H, m, —CHαPh), 3.24 (3H, m, —CHβPh and —CH2Trp),), 4.84 (1H, m, —CH—), 4.90 (1H, m, —CH—), 6.49 (1H, t, J=7.2 Hz, —NH), 6.92-7.66 (16H, m, Ar—H and —NH) and 8.48 (1H, d, J=6.0 Hz, —NH); 13C NMR (100 MHz, CDCl3) δC 27.2, 29.5, 35.0, 35.1, 36.5, 53.2, 59.5, 59.6, 109.5, 111.4, 118.5, 119.6, 122.0, 123.5, 127.0, 127.1 (2C), 127.4, 128.6, 128.7 (2C), 129.2, 132.0, 133.5, 136.1, 167.7, 172.4, 174.6 and 207.8; HRMS m/z calcd for C30H29N3O5 (M+) 511.21072, found 511.21072. [± The carboxylic acid and amide protons were not observed, presumably, due to rapid exchange with water in the deuteriated NMR solvent.]
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]([CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1)[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)C1C=CC=CC=1.Cl>C(O)C.C(OCC)(=O)C.O.[Pd]>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([N:11]([CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:30][CH:31]=2)[CH2:10][CH2:9][OH:8])=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccc(OCCCN(CCOCc2ccccc2)c2ccc(Cl)cc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(OCCCN(CCO)c2ccc(Cl)cc2)cc1
Reaction time: 27 h
Yield: 43.1 %

Procedure:
4-[3-[N-(2-Benzyloxyethyl)-N-(4-chlorophenyl)amino]propoxy]benzoic acid (3.5 g) was dissolved in a mixed solvent of ethanol (60 ml) and ethyl acetate (15 ml), and thereto were added conc. hydrochloric acid (0.7 ml) and 10 % palladium/carbon (0.35 g), and the mixture was stirred under hydrogen and atmospheric pressure at room temperature for 27 hours. The reaction mixture was diluted with water, filtered, and neutralized with lN aqueous sodium hydroxide solution, and then, the mixture was concentrated under reduced pressure. The residue was washed with water, and crystallized from about 50 % aqueous methanol and collected by filtration. The resultant was further recrystallized from a mixed solvent of ethyl acetate/n-hexane [1:10 (v/v)] to give the desired product (1.20 g). mp. 120°-122° C.
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1Cl)=[CH:8][CH:7]=[CH:6][CH:5]=2.C([O-])([O-])=O.[K+].[K+].[CH3:21][NH:22][C:23]([NH2:25])=[S:24]>C(O)(C)C>[CH3:21][NH:22][C:23]1[S:24][C:11]2[C:10](=[O:13])[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[C:3](=[O:14])[C:2]=2[N:25]=1
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Reactant: CNC(N)=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CNc1nc2c(s1)C(=O)c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 0.9 %

Procedure:
A mixture of 2,3-dichloronaphthalene-1,4-dione 10.0 g (0.044 mol,), 18.0 g K2CO3 (0.13 mol, 3.0 eq) and 1-methylthiourea (0.056 mol, 1.2 eq) in 100 ml isopropanol was stirred at room temperature under N2 for 20 h. After removing all solvents under reduced pressure, the residue was diluted with CH2Cl2 and the K2CO3 was removed by filtration, the organic layer was concentrated, the residue was purified by chromatography to afford 0.1 g 2-(methylamino-) naphtho[2,3-d]thiazole-4,9-dione as black solid in a yield of 0.93%. 1HNMR (300 MHz, DMSO) δ3.59 (s, 3H); 7.78-7.81 (m, 2H); 7.89-7.93 (m, 1H); 7.98-8.01 (m, 1H); 9.06 (br, 1H) ppm. MS-ESI: cal. 244; found: 285 (M+Na+H2O).
Reaction SMILES: [CH:1]([C@@H:4]1[C:9]2=[CH:10][C:11]3[CH:12]=[CH:13][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6][N:5]1[C:21]1[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[C:24]([C:31](=[O:33])[CH3:32])=[CH:23][N:22]=1)([CH3:3])[CH3:2].[CH3:34][Mg]Cl>C1COCC1>[CH:1]([C@@H:4]1[C:9]2=[CH:10][C:11]3[CH:12]=[CH:13][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6][N:5]1[C:21]1[N:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[C:24]([C:31]([OH:33])([CH3:34])[CH3:32])=[CH:23][N:22]=1)([CH3:3])[CH3:2]
Reactant: C[Mg]Cl
Reactant: CC(=O)c1cnc(N2CCn3c(cc4ccc(S(C)(=O)=O)cc43)[C@H]2C(C)C)nc1C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)[C@@H]1c2cc3ccc(S(C)(=O)=O)cc3n2CCN1c1ncc(C(C)(C)O)c(C(F)(F)F)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 24.2 %

Procedure:
To a solution of (R)-1-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (5 mg, 0.01 mmol) in THF (1 mL) was added LaCl3-2LiCl (0.2 mL, 0.12 mmol, 0.6M) at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 1 h. MeMgCl (0.3 mL, 0.9 mmol, 3M) was added to the formed mixture and then the reaction mixture was stirred at 0° C. for 1 h. The reaction was quenched with sat. NH4Cl (5 mL) at 0° C. and then extracted with EtOAc (30 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated, purified by preparative TLC eluting with PE/EtOAc 1:1 and then by SFC separation to afford (R)-2-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-ol (1.20 mg, 24.68% yield, Isomer 1) as a colorless oil. Analytical chiral HPLC: tR=6.394 min in 15 min chromatography (Method: OJ-H_3_5_40_2.35 ML). LC-MS m/z 497.3 [M+H]+. 1H NMR (CDCl3 400 MHz): δ 8.75 (s, 1H), 7.93 (s, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.62 (d, J1=8.4 Hz, J2=1.6 Hz, 1H), 6.48 (s, 1H), 5.89 (d, J=8.8 Hz, 1H), 5.16-5.12 (m, 1H), 4.32-4.28 (m, 1H), 4.14-4.07 (m, 1H), 3.86-3.77 (m, 1H), 3.07 (s, 3H), 2.34-2.25 (m, 1H), 1.92 (s, 1H), 1.68 (s, 6H), 1.18 (d, J=7.2 Hz, 3H), 1.06 (d, J=7.2 Hz, 3H)
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)[CH:2]([CH3:4])[CH3:3].[CH2:14]([NH2:22])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([NH:22][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:10])[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)Cc1cccc(C(=O)O)c1
Reactant: NCCc1ccccc1
Product: CC(C)Cc1cccc(C(=O)NCCc2ccccc2)c1

Procedure:
Using preparation method 1, 94B (131 mg, 0.74 mmol) was reacted with phenethylamine (138 μL, 133 mg, 1.1 mmol). Purification by flash chromatography on SiO2 using CH2Cl2/hexanes 50:50 then CH2Cl2 100% afforded white crystals were obtained (177 mg, 86%). NMR 1H (ppm, CDCl3): 7.50 (s, 1H), 7.47 (dt, J3=7.0 Hz, J4=1.8 Hz, 1H), 7.33-7.21 (m, 7H), 6.28 (br. s, 1H), 3.72-3.66 (m, 2H), 2.92 (t, J3=7.0 Hz, 2H), 2.48 (d, J3=7.2 Hz, 2H), 1.90-1.81 (m, 1H), 0.88 (d, J3=6.6 Hz, 6H).
Reaction SMILES: [H-].[Na+].Cl.[F:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[NH:10])=[CH:7][CH:6]=1.[CH:14]([CH:16]([CH3:21])[C:17](OC)=O)=[O:15]>C(O)C>[F:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]2[NH:11][C:14](=[O:15])[C:16]([CH3:21])=[CH:17][N:10]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(C)C=O
Reactant: N=C(N)c1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cnc(-c2ccc(F)cc2)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.52 g, 13 mmol) is added to 20 mL of anhydrous ethanol and stirred for 30 minutes at ambient temperature. To this, 4-fluorobenzamidine hydrochloride (1.47 g, 8.5 mmol) (from example 40) is added and the mixture is stirred for further 30 minutes. Methyl 2-formylpropionate (1 g, 10.6 mmol) is added dropwise and the reaction mixture is left for 4 days under stirring at ambient temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([CH:17]=O)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([CH2:17][N:29]4[CH2:28][CH2:27][C:26]([C:23]5[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=5)([OH:32])[CH2:31][CH2:30]4)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: OC1(c2ccc(F)cc2)CCNCC1
Reactant: O=CC12CC(c3ccccc31)c1ccc(Cl)cc12
Product: OC1(c2ccc(F)cc2)CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Yield: 27 %

Procedure:
Using a procedure similar to that described in example 21 except starting with 2-chloro-9-formyl-9,10-dihydro-9,10-methanoanthracene (described in example 1i) and 4-(4-fluorophenyl)-4-hydroxypiperidine, the title compound hydrochloride salt was obtained in 27% yield as a white powder, mp 280°-281° C. elemental
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[CH2:16]([O:18][C:19](=[O:23])[CH2:20][CH2:21][NH2:22])[CH3:17].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:22][CH2:21][CH2:20][C:19]([O:18][CH2:16][CH3:17])=[O:23])=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: CCOC(=O)CCN
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 0 °C
Reaction time: 4 h
Yield: 111.3 %

Procedure:
4-Chloro-3-nitroquinoline (76.1 g, 365 mmol) was treated with β-alanine ethyl ester hydrochloride (50.0 g, 326 mmol) in the presence of triethylamine (94.5 mL, 678 mmol) and potassium carbonate (37.45 g, 271.2 mmol) according to a modification of the method described in Part A of Example 15. Before the addition of β-alanine ethyl ester hydrochloride, the reaction was cooled to 0° C. After this addition, the reaction was stirred for four hours at ambient temperature and subjected to the work-up procedure to provide 105 g of ethyl N-(3-nitroquinolin-4-yl)-β-alaninate.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=O.[C:17]([O:21][C:22]([N:24]1[CH2:30][CH2:29][CH2:28][C@H:27]([NH2:31])[C:26]2[CH:32]=[C:33]([CH2:40][CH3:41])[C:34]([C:36]([F:39])([F:38])[F:37])=[CH:35][C:25]1=2)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[C:17]([O:21][C:22]([N:24]1[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31][CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:16])([F:15])[F:1])[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=2)[C:26]2[CH:32]=[C:33]([CH2:40][CH3:41])[C:34]([C:36]([F:39])([F:37])[F:38])=[CH:35][C:25]1=2)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 82.2 %

Procedure:
Add 3,5-bistrifluoromethylbenzaldehyde (4.30 g, 24.22 mmol) to a solution of (S)-5-amino-7-ethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester (4.91 g, 13.70 mmol) in dichloromethane (100 mL) and glacial acetic acid (6 mL) at room temperature under nitrogen and stir for 2 h. Add sodium triacetoxyborohydride (6.01 g, 28.35 mmol) and stir the mixture for 2 h. Remove the solvents under reduced pressure and dilute the residue with dichloromethane (50 mL) and water (50 mL). Collect the organic layer and extract the aqueous layer with dichloromethane (3×30 mL). Wash the combined organic extracts with water (20 mL) and brine (20 mL) and dry over anhydrous sodium sulfate. Filter and remove the solvents under reduced pressure to provide the title compound as an amber oil (6.58 g, 75%), which is used in the next step without purification. 1H NMR (CDCl3, 300 MHz) δ 1.21-2.30 (m, 19H), 2.83-2.89 (m, 2H), 4.78-4.80 (m, 3H), 6.89-7.60 (m, 3H), 7.70-7.91 (m, 2H); APCI MS m/z 585 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([CH3:7])[C:4]([OH:6])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:41][C:42]([C:44]([F:47])([F:46])[F:45])=[O:43].[F:48][CH:49]([F:77])[CH2:50][NH:51][C:52]1[N:57]=[C:56]2[CH2:58][NH:59][CH2:60][CH2:61][C:55]2=[N:54][C:53]=1[N:62]1[CH2:67][CH2:66][CH:65]([O:68][C:69]2[CH:74]=[CH:73][C:72]([F:75])=[CH:71][C:70]=2[F:76])[CH2:64][CH2:63]1>CN(C=O)C>[F:77][CH:49]([F:48])[CH2:50][NH:51][C:52]1[N:57]=[C:56]2[CH2:58][N:59]([C:4](=[O:6])[C@@H:3]([O:2][CH3:1])[CH3:7])[CH2:60][CH2:61][C:55]2=[N:54][C:53]=1[N:62]1[CH2:63][CH2:64][CH:65]([O:68][C:69]2[CH:74]=[CH:73][C:72]([F:75])=[CH:71][C:70]=2[F:76])[CH2:66][CH2:67]1.[C:42]([OH:43])([C:44]([F:47])([F:46])[F:45])=[O:41]
Reactant: CO[C@@H](C)C(=O)O
Reactant: Fc1ccc(OC2CCN(c3nc4c(nc3NCC(F)F)CNCC4)CC2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CO[C@@H](C)C(=O)N1CCc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NCC(F)F)nc2C1
Reaction time: 8 h

Procedure:
A solution of (S)-2-methoxypropanoic acid (2.9 mg, 0.028 mmol), DIPEA (3.9 mg, 0.028 mmol), and HATU (10.6 mg, 0.028 mmol) in DMF (278 μL) was stirred at room temperature for 10 min then treated with N-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (15 mg, 0.028 mmol). Stirring was continued overnight. The crude reaction mixture was diluted in DMF, filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR), and purified via HPLC Method A to give the title compound as a TFA salt (3 mg) as a clear oil. 1H NMR (400 MHz, methanol-d4, mixture of rotamers) δ ppm 1.32 (d, J=6.6 Hz, 1.3H), 1.38 (d, J=6.6 Hz, 1.7H), 1.91-2.04 (m, 2H), 2.09-2.19 (m, 2H), 2.76 (t, J=6.2 Hz, 0.9H), 2.84 (t, J=5.4 Hz, 1.1H), 2.95-3.05 (m, 2H), 3.33 (s, 3H), 3.35-3.43 (m, 2H), 3.78 (td, J=14.6, 4.3 Hz, 2H), 3.83-3.98 (m, 2H), 4.32-4.41 (m, 1H), 4.42-4.49 (m, 1H), 4.56 (m, 1.1H), 4.68 (m, 0.9H), 5.89-6.22 (m, 1H), 6.85-6.91 (m, 1H), 6.98 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 512.4.
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][C:4]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=3[C:8]=2[C:7]([CH:20]=[O:21])=[CH:6][CH:5]=1.[Mn]([O-])(=O)(=O)=[O:24].[K+]>CC(C)=O.O>[F:22][CH:2]([F:1])[O:3][C:4]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=3[C:8]=2[C:7]([C:20]([OH:24])=[O:21])=[CH:6][CH:5]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O=Cc1ccc(OC(F)F)c2oc3ccc([N+](=O)[O-])cc3c12
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1ccc(OC(F)F)c2oc3ccc([N+](=O)[O-])cc3c12
Temperature: 65 °C
Yield: 64.5 %

Procedure:
Intermediate 50 (150 mg, 0.48 mmol) in acetone (20 ml) and water (5 ml) was heated to 60-70° C. for 10 min. To the above solution was added dropwise a solution of potassium permanganate (150 mg, 0.973 mmol) in water (5 ml) for 10 min. The reaction was heated to 60-70° C. for 30 min., and filtered hot through celite bed. Acidification of the filterate resulted in a precipitate which on filteration and washing with water yielded 4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1-carboxylic acid (100 mg) as white solid; mp: >270° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([Br:10])[CH:9]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:17]([NH:20][CH2:21][CH:22]=[CH2:23])[CH:18]=[CH2:19].O>C(#N)C>[Br:10][C:8]1[CH:9]=[C:5]([C:3](=[O:4])[CH2:2][N:20]([CH2:21][CH:22]=[CH2:23])[CH2:17][CH:18]=[CH2:19])[S:6][CH:7]=1
Reactant: O=C(CBr)c1cc(Br)cs1
Reactant: C=CCNCC=C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C=CCN(CC=C)CC(=O)c1cc(Br)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 1-(4-bromothiophen-2-yl)ethanone (10 g, 48.8 mmol) in methanol (98 mL) and dichloromethane (163 mL) is added tetra-n-butylammonium tribromide (28.8 g, 58.5 mmol). The reaction mixture is concentrated under reduced pressure at 50° C. to give a residue which is purified by silica gel chromatography, eluting with dichloromethane to give crude 2-bromo-1-(4-bromo-2-thienyl)ethanone. To a solution of the crude 2-bromo-1-(4-bromo-2-thienyl)ethanone in acetonitrile (200 ml) is added potassium carbonate (20.2 g, 146 mmol) and diallylamine (9.48 g, 97.5 mmol). The reaction is stirred at room temperature for 2 hours. Water is added and the solution is extracted with ethyl acetate. The organic phases are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude title compound. ES/MS (m/e): (79Br/81Br) 300/302 (M+H).