Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@H:2]([C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH3:28]>C1COCC1>[NH:1]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@H:2]([C:10]([NH:12][C@H:13]([C:15]([NH2:28])=[O:17])[CH3:14])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: N
Reactant: C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(N)=O

Procedure:
The above described procedure was repeated using 5.65 g of Cbz-Phe-Ala-OH and excess anhydrous ammonia in THF to obtain 7.16 g of crude Cbz-Phe-Ala-NH2. The crude product was then subjected to hydrogenolysis in MeOH over 10% Pd/C to afford 3.42 g (95% yield) of Phe-Ala-NH2 as a yellow solid after flash chromatography (EtOAc-MeOH, 10:1). Characteristic analytical data are as follows: mp 95°-97° C.; RF 0.10 (1:2 MeOH:EtOAc); 1H NMR (300 MHz, CDCl3) δ7.80-7.72 (br, 1H, H-N), 7.35-7.18 (m, 5H, Ph), 6.58-6.45 (br, 1H, H-N), 5.70-5.60 (br, 1H, H-N), 4.46 (quint, J=7 Hz, 1H, Hα-(Ala)), 3.62 (dd, J=4, 9 Hz, 1H, Hα-(Phe)), 3.21 (dd, J=4, 11 Hz, 1H, Hβ-(Phe)), 2.72 (dd, J=9, 11 Hz, 1H, Hβ -(Phe)), 1.35 (d, J=7 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3) δ175.3 (C=O), 174.8 (C=O), 137.6 (C-Ph), 129.4 (CH-Ph), 128.8 (CH-Ph), 127.0 (CH-Ph), 56.0 (CH-α), 48.0 (CH-α), 40.5 (CH2), 17.7 (CH3); [α]25D -25.6° (c=1.90, EtOH).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([CH2:13]O)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:34]N1C(=O)CCC1=O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C:10]1([CH2:13][Br:34])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1(COCc2ccccc2)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCC1(COCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
58.9 g of 1-benzyloxymethyl-1-(hydroxymethyl)cyclopropane and 88.5 g of triphenylphosphine are dissolved in 600 ml of methylene chloride, and 60 g of N-bromosuccinimide are added in portions at 0° C. The reaction mixture is stirred at room temperature for 16 h and concentrated and the residue is purified by means of FC over 3 kg of silica gel with a 1:1 mixture of methylene chloride and hexane as the eluting agent. This gives 68 g of the pure title compound: Rf (1:1 mixture from methylene chloride and hexane)=0.50.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:7]1[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][N:8]=1)[CH2:5]Br.[CH:15]1([NH2:18])[CH2:17][CH2:16]1.O>C(#N)C>[CH3:1][O:2][N:3]=[C:4]([C:7]1[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][N:8]=1)[CH2:5][NH:18][CH:15]1[CH2:17][CH2:16]1
Reactant: CON=C(CBr)c1ncc(Cl)cc1Cl
Reactant: NC1CC1
Solvent: CC#N
Solvent: O
Product: CON=C(CNC1CC1)c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.9 %

Procedure:
To 700 mg of 2-bromo-1-(3,5-dichloropyridin-2-yl)ethanone-O-methyloxime prepared in the same manner as in Steps 1 to 3 in Synthetic Example 2 in 10 ml of acetonitrile, 402 mg of cyclopropylamine in 5 ml of acetonitrile was added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was mixed with 30 ml of water and extracted with ethyl acetate (40 ml×2, the resulting organic layers were combined, washed with water (30 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 3:7 to 5:5) as the eluent to obtain 450 mg of the desired product as a colorless resinous substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9](I)[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:5]2.[C-:25]#[N:26].[Na+]>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[F:1][C:2]1[CH:10]=[C:9]([C:25]#[N:26])[C:8]2[C:7](=[O:12])[N:6]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH2:5][C:4]=2[CH:3]=1
Reactant: O=C1c2c(I)cc(F)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Reactant: [C-]#N
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CC#N
Product: N#Cc1cc(F)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 80 °C
Reaction time: 18 h
Yield: 45.4 %

Procedure:
A mixture of 5-fluoro-7-iodo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.100 g, 0.22 mmol), Pd(PPh3)4 (0.022 g, 0.24 mmol), sodium cyanide (0.014 g, 0.285 mmol), and CuI (0.004 g, 0.022 mmol) in acetonitrile (5 mL) was stirred at 80° C. for 18 h. Workup and silica gel column chromatography using 2:1 hexanes-ethyl acetate afforded 6-fluoro-3-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-4-carbonitrile (0.035 g, 45%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.32 (s, 2H), 4.80 (s, 2H), 7.20 (d, 2H), 7.37 (m, 3H), 7.49 (d, 1H). GC-MS: m/z 350 (M)+.
Reaction SMILES: BrC1C=CC(C2C=CC3C4C(=CC=CC=4)C=CC=3C=2)=CC=1.[CH:22]1[C:35]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[C:24](B(O)O)[CH:23]=1.[Br:39][C:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][CH:44]=[C:45](Br)[CH:46]=2)[CH:41]=1>>[Br:39][C:40]1[CH:41]=[C:42]2[C:47](=[CH:48][CH:49]=1)[CH:46]=[C:45]([C:33]1[CH:34]=[CH:35][C:26]3[CH:25]=[CH:24][C:23]4[C:28]([C:27]=3[CH:32]=1)=[CH:29][CH:30]=[CH:31][CH:22]=4)[CH:44]=[CH:43]2
Reactant: OB(O)c1ccc2ccc3ccccc3c2c1
Reactant: Brc1ccc2cc(Br)ccc2c1
Agent: Brc1ccc(-c2ccc3c(ccc4ccccc43)c2)cc1
Product: Brc1ccc2cc(-c3ccc4ccc5ccccc5c4c3)ccc2c1

Procedure:
Synthesis was performed in the same manner as in the synthesis of 2-(4-bromophenyl)phenanthrene except that: phenanthrene-3-boronic acid was used instead of phenanthrene-2-boronic acid; and 2,6-dibromonaphthalene was used instead of 4-bromoiodobenzene.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2.[Se](=O)=[O:13]>C(OCC)(=O)C>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([CH:1]=[O:13])=[CH:11][CH:10]=2)[N:5]=[CH:6][CH:7]=1
Reactant: O=[Se]=O
Reactant: Cc1ccc2nccnc2c1
Solvent: CCOC(C)=O
Product: O=Cc1ccc2nccnc2c1
Temperature: 25 °C
Yield: 64.7 %

Procedure:
6-Methylquinoxaline (500 mg, 3.47 mmol) and selenium dioxide (423 mg, 3.81 mmol) in a sealed vessel were stirred at 160° C. for 7 h. After cooled to room temperature, the reaction mixture was dissolved in ethyl acetate. The solution was washed with brine twice, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20 to 60/40) to obtain the title compound as a pale brown solid (355 mg, 64%).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[C:16]2([CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:15][CH2:14][CH:13]1C(O)=O)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].CC(C)[C@H](NC(OC)=O)C(N1C([C:45]([NH:47][CH2:48][C:49]([C:51]2[CH:56]=[CH:55][C:54]([C:57]3[CH:62]=[CH:61][C:60]([C:63]4[N:64]=[C:65]([C@@H:68]5[CH2:72][CH2:71][CH2:70][N:69]5[C:73](=[O:83])[C@@H:74]([NH:78][C:79]([O:81][CH3:82])=[O:80])[CH:75]([CH3:77])[CH3:76])[NH:66][CH:67]=4)=[CH:59][CH:58]=3)=[CH:53][CH:52]=2)=[O:50])=[O:46])CC2(CN(C(OC(C)(C)C)=O)C2)C1)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl>[CH3:76][CH:75]([CH3:77])[C@H:74]([NH:78][C:79](=[O:80])[O:81][CH3:82])[C:73]([N:69]1[CH2:70][CH2:71][CH2:72][C@H:68]1[C:65]1[NH:66][CH:67]=[C:63]([C:60]2[CH:59]=[CH:58][C:57]([C:54]3[CH:55]=[CH:56][C:51]([C:49](=[O:50])[CH2:48][NH:47][C:45]([CH:13]4[CH2:14][CH2:15][C:16]5([CH2:21][CH2:20][O:19][CH2:18][CH2:17]5)[N:12]4[C:10](=[O:11])[C@@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH:7]([CH3:9])[CH3:8])=[O:46])=[CH:52][CH:53]=3)=[CH:62][CH:61]=2)[N:64]=1)=[O:83]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(CC1C(=O)NCC(=O)c1ccc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)C(C)C)n4)cc3)cc1)CN(C(=O)OC(C)(C)C)C2)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1C(C(=O)O)CCC12CCOCC2)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(C(=O)CNC(=O)C4CCC5(CCOCC5)N4C(=O)[C@@H](NC(=O)OC)C(C)C)cc3)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
To a solution of 1-{N-[(methyloxy)carbonyl]-L-valyl}-8-oxa-1-azaspiro[4.5]decane-2-carboxylic acid (168) (52 mg, 1.5 mmol) and methyl {(1S)-1-[((2S)-2-{4-[4′-(aminoacetyl)-4-biphenylyl]-1H-imidazol-2-yl}-pyrrolidinyl)carbonyl]-2-methylpropyl}carbamate dihydrochloride (1) (88 mg, 0.15 mmol) and HATU (58 mg, 0.15 mmol) in anhydrous dichloromethane (1.2 mL) was added Hunig's base (0.12 mL, 0.68 mmol) and the reaction stirred at room temperature for 1 h. The reaction was concentrated in vacuo and purified by HPLC eluting with 10-90% water/acetonitrile/0.2% NH4OH to afford the title compound as an off-white solid (73 mg, 58% yield).
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.[C:21]([CH:23]([C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)[CH2:24][C:25]([O:27]C)=[O:26])#[N:22]>>[C:21]([CH:23]([C:29]1[CH:34]=[CH:33][C:32]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5]/[C:4](=[N:3]\[O:2][CH3:1])/[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:8][CH:9]=2)=[CH:31][CH:30]=1)[CH2:24][C:25]([OH:27])=[O:26])#[N:22]
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Reactant: COC(=O)CC(C#N)c1ccc(O)cc1
Product: CO/N=C(\COc1ccc(COc2ccc(C(C#N)CC(=O)O)cc2)cc1)c1ccccc1
Yield: 34.7 %

Procedure:
Compound 16 was synthesized from (4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}phenyl) methanol (0.264 g, 0.98 mmol) and methyl 3-cyano-3-(4-hydroxyphenyl)propanoate (0.2 g, 0.98 mmol) by following the procedure described in Scheme 5 (0.15 g, yield: 34.7%); Purity: 98.2%:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[C:13]3[NH:19][N:18]=[C:17]([I:20])[C:14]3=[N:15][CH:16]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1.CS(O)(=O)=O>C(Cl)Cl.O1CCCC1>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([C:11]2[CH:12]=[C:13]3[N:19]([CH:22]4[CH2:23][CH2:24][CH2:25][CH2:26][O:21]4)[N:18]=[C:17]([I:20])[C:14]3=[N:15][CH:16]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(OC)cc(-c2cnc3c(I)n[nH]c3c2)c1
Reactant: C1=COCCC1
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(OC)cc(-c2cnc3c(I)nn(C4CCCCO4)c3c2)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
A mixture of 6-(3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-b]pyridine (0.54 g, 1.4 μmmol), dihydropyran (0.39 mL, 4.2 mmol) and methanesulfonic acid (18 μL, 0.28 mmol) in methylene chloride (6 mL) and tetrahydrofuran (2 mL) in a sealed reaction vial was stirred at 50° C. for 3 h. After cooling it was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.60 g). LCMS (M+H)+=465.9.
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O-]CC.[Na+].[Cl:15][C:16]1[CH:33]=[CH:32][CH:31]=[CH:30][C:17]=1[C:18]([C:20](=[CH:26]N(C)C)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=O>C(O)C>[Cl:15][C:16]1[CH:33]=[CH:32][CH:31]=[CH:30][C:17]=1[C:18]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][N:10]=[C:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:9]=1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1Cl
Reactant: N=C(N)c1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2ccccc2)nc1-c1ccccc1Cl
Reaction time: 0.17 h
Yield: 77.8 %

Procedure:
To a stirred solution of 3.45 g of benzamidine hydrochloride in 50 cc of ethanol was added 1.50 g of sodium ethoxide at room temperature and the mixture was stirred for 10 minutes. The resulting suspension was added to 6.2 g of compound D in 50 cc of ethanol and the resulting mixture was heated under reflux for 6 hours. After cooling, the solvent was distilled off, and AcOEt and water were added to the residue. The organic layer was further washed with a saturated aqueous sodium bicarbonate solution and dried over magnesium sulfate. The solvent was distilled off and the crude product thus obtained was purified by a silica gel column chromatography (eluent: ethyl acetate/hexane=1/8) to obtain 5.80 g of compound E. Yield: 77.6%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([OH:13])[CH:12]=1)[O:9][C:8]([CH3:15])([CH3:14])[CH2:7][C:6]2([CH3:17])[CH3:16])#[CH:2].[CH3:18][O:19][C:20](=[O:31])[C:21]([C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1)([CH3:23])[CH3:22].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:18][O:19][C:20](=[O:31])[C:21]([C:24]1[CH:25]=[CH:26][C:27]([C:2]#[C:1][C:3]2[CH:4]=[C:5]3[C:10](=[C:11]([OH:13])[CH:12]=2)[O:9][C:8]([CH3:15])([CH3:14])[CH2:7][C:6]3([CH3:17])[CH3:16])=[CH:28][CH:29]=1)([CH3:23])[CH3:22]
Reactant: C#Cc1cc(O)c2c(c1)C(C)(C)CC(C)(C)O2
Reactant: COC(=O)C(C)(C)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: COC(=O)C(C)(C)c1ccc(C#Cc2cc(O)c3c(c2)C(C)(C)CC(C)(C)O3)cc1

Procedure:
Following General Procedure B and using 6-ethynyl-8-hydroxy-2,2,4,4-tetramethyl-chroman (Intermediate 19, 0.057 g, 0.25 mmol), methyl-2-(4-iodophenyl)-2-methyl-propionate (Reagent-2, 0.112 g, 0.37 mmol), triethyl amine (3 mL), copper(I)iodide (0.020 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by flash column chromatography over silica gel (230–400 mesh) and preparative normal phase HPLC using 5% ethyl acetate in hexane as the mobile phase, the title compound was obtained as a brown oil (0.035 g, 35%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3([CH2:20][CH2:19]3)[CH2:7][N:8](C(OC(C)(C)C)=O)[CH2:9]2)=[CH:4][CH:3]=1.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>C(Cl)Cl>[CH2:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([NH2:1])[CH:11]=2)[C:6]2([CH2:20][CH2:19]2)[CH2:7][NH:8]1.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(N)ccc2C2(CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc2c(c1)CNCC21CC1
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 7′-amino-1′H-spiro[cyclopropane-1,4′-isoquinoline]-2′(3′H)-carboxylate (0.350 g, 1.276 mmol) in CH2Cl2 (8 ml) was added trifluoroacetic acid (0.983 ml, 12.76 mmol). The reaction was stirred overnight and concentrated to provide the title compound as a trifluoroacetic acid salt.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:9]([N:28]([CH3:30])[CH3:29])=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[CH:19]=1)=[CH:15][C:14]([Cl:27])=[CH:13][CH:12]=2)=[O:7])(C)(C)C.Cl>O1CCOCC1>[Cl:27][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([N:28]([CH3:29])[CH3:30])[C:8]([C:6]([OH:7])=[O:5])=[C:17]2[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[CH:19]=1
Reactant: CC(C)c1cccc(-c2c(C(=O)OC(C)(C)C)c(N(C)C)nc3ccc(Cl)cc23)c1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)c1cccc(-c2c(C(=O)O)c(N(C)C)nc3ccc(Cl)cc23)c1

Procedure:
The title compound was prepared in analogy to example 78 step E from 6-chloro-2-dimethylamino-4-(3-isopropyl-phenyl)-quinoline-3-carboxylic acid tert-butyl ester (75 mg, 0.18 mmol) and 4N HCl in dioxane. Off white solid (45 mg, 69%). LC-MS (ESI): 369 (M+H)+.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:40])[CH2:15][C:16]1[CH:17]=[C:18]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[CH:19]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:42][C:43]([CH3:45])=[CH2:44]>C1COCC1>[CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:40])[CH:15]([C:16]1[CH:17]=[C:18]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:38])([F:39])[F:37])=[CH:34][CH:35]=2)[CH:19]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=1)[CH2:44][C:43]([CH3:45])=[CH2:42])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)CBr
Reactant: O=C(Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1)N1C(=O)OCC1Cc1ccccc1
Solvent: C1CCOC1
Product: C=C(C)CC(C(=O)N1C(=O)OCC1Cc1ccccc1)c1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a colorless solution of 4-benzyl-3-[2-(5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetyl]-oxazolidin-2-one from the previous step (6.0 g, 11.00 mmol) in dry THF (22 mL) at −78° C. was added sodium bis(trimethylsiyl)amide (NaHMDS) (1 M in THF solution, 12.11 mL, 12.11 mmol), drop-wise, maintaining the internal temperature below −75° C. The resulting red solution was stirred at −78° C. for 30 minutes. To this was added 3-bromo-2-methyl propene (4.44 mL, 44 mmol) maintaining the temperature below −75° C. When the addition was near completion, the reaction mixture turned green. At this point the dry-ice bath was quickly removed and replaced with water-ice bath, and the addition was completed. The reaction mixture was stirred at 0° C. for an additional 30 min and quenched with saturated aqueous NH4Cl solution. The system was diluted with EtOAC (100 mL) and the organic phase was washed with saturated aqueous NaHCO3 solution (3×50 mL) and dried (MgSO4). Solvent was removed in vacuo and the crude mixture was purified by ISCO silica gel column to yield 4-benzyl-3-[2-(5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pent-4-enoyl]-oxazolidin-2-one (6.3 g, 95%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]([NH:12][NH2:13])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9].[CH2:14]([O:16][C:17](=[O:24])[C:18](=O)[CH2:19][C:20](=O)[CH3:21])[CH3:15]>CC(O)=O>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([N:12]2[C:20]([CH3:21])=[CH:19][C:18]([C:17]([O:16][CH2:14][CH3:15])=[O:24])=[N:13]2)=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: NNc1ccc(Br)cc1C(=O)O
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C)n(-c2ccc(Br)cc2C(=O)O)n1
Yield: 100.4 %

Procedure:
To a solution of 5-bromo-2-hydrazinylbenzoic acid hydrochloride (60.0 g, 225.6 mmol) in AcOH (600 mL) was added ethyl-2,4-dioxovalerate (35.67 g, 225.6 mmol) followed by refluxing for 3 h. AcOH was evaporated invacuo and the residue was co-distilled with toluene (100 mL), twice. The residue was dissolved in EtOAc and washed with water until the aq. layer became neutral. The organic layer was dried over sodium sulphate and concentrated invacuo. The gummy material was triturated with diethyl ether to afford the title compound as a brown colored oil 80 g (100%), which was used without further purification for the next step. Rf=0.23 (10% MeOH in DCM); 1H NMR (400 MHz, DMSO-d6): δ 13.80-12.80 (brs, 1H), 8.08 (d, J=1.9 Hz, 1H), 7.96 (dd, J=2.4&8.3 Hz, 1H), 7.53 (d, J=8.3 Hz, 1H), 6.70 (s, 1H), 4.26 (q, J=7.2 Hz, 2H), 2.13 (s, 3H), 1.28 (t, J=7.1 Hz, 3H); ES-MS: m/z 353.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[CH2:15]([CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:32])[C:29](Cl)=[O:30])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)(Cl)Cl>[CH2:15]([CH:22]1[CH2:23][CH2:24][N:25]([C:28](=[O:32])[C:29]([NH:1][C:2]2[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]3[NH:6][C:7](=[O:9])[O:8][C:4]=3[CH:3]=2)=[O:30])[CH2:26][CH2:27]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Cl)C(=O)N1CCC(Cc2ccccc2)CC1
Reactant: Nc1cc2oc(=O)[nH]c2cc1[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Product: O=C(Nc1cc2oc(=O)[nH]c2cc1[N+](=O)[O-])C(=O)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of 3.23 g (16.56 mmol) of 6-amino-5-nitro-3H-benzoxazole-2-one (step a), 2.58 ml (18.5 mmol) of trethylamine and 100 ml of chloroform 5.25 g (19.75 mmol) of (4-benzylpiperidin-1-yl)oxoacetyl chloride in 20 ml of chloroform is added dropwise at 20° C., then the mixture is stirred at room temperature for 2 h. The mixture is washed with water, the organic layer is dried and concentrated. The residue is purified by column chromatography using Kieselgel 60 as adsorbent (Merck) and toluene:methanol=4:1 as eluent to yield 3.3 g (47%) of the title compound. Mp.: foam.
Reaction SMILES: C(Cl)Cl.[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].[O:17]([C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:31](=[O:32])[NH:30][C:27]2[CH:26]=[CH:25][C:24]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:29][CH:28]=2)[CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Nc2ccc(Oc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.5 %

Procedure:
To a methylene chloride solution (25 mL) of N-tert-butoxycarbonylpiperazine (2.50 g, 13.4 mmol), 4-phenoxyphenyl isocyanate (2.83 mL, 13.4 mmol) was added, followed by stirring at room temperature overnight. Methanol was added to the reaction solution, and the solvent was evaporated to give the target compound (5.71 g, 14.4 mmol).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:18][CH:17]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:31])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(NC(=O)c3ccccn3)cc1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(NC(=O)c2ccccn2)cc1
Yield: 79.4 %

Procedure:
A mixture of methyl 3,3-dimethyl-2-(4-(picolinamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (67 mg, 0.16 mmol) in methanol (8 mL) and aqueous sodium hydroxide solution (1 M, 1.2 mL, 1.2 mmol) was heated to reflux for 5 h, LC-MS showed the reaction was complete. The solvent was removed in vacuo and the residue was acidified with 2 M hydrochloric acid solution until lots of yellow solid precipitated, which was collected by filtration to afford 51 mg of 3,3-dimethyl-2-(4-(picolinamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid. Yield: 80%. MS (ESI+APCI) M+1=402.