Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]=[CH2:24])=[CH:19][CH:18]=3)[N:13]=2)[N:6]=1)([CH3:3])[CH3:2].[OH2:25].[OH2:26].C[N+]1([O-])CCOCC1>CC(C)=O.C(Cl)Cl.O=[Os](=O)(=O)=O>[CH:1]([NH:4][C:5]1[N:6]=[C:7]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH:23]([OH:26])[CH2:24][OH:25])=[CH:21][CH:22]=3)[N:13]=2)[CH:8]=[C:9]([CH3:11])[N:10]=1)([CH3:2])[CH3:3]
Reactant: O
Reactant: C=Cc1ccc(-c2noc(-c3cc(C)nc(NC(C)C)n3)n2)cc1
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cc1cc(-c2nc(-c3ccc(C(O)CO)cc3)no2)nc(NC(C)C)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of isopropyl-{4-methyl-6-[3-(4-vinyl-phenyl)-[1,2,4]oxadiazol-5-yl]-pyrimidin-2-yl}-amine (Intermediate 8: 2.78 g, 8.67 mmol) in acetone (45 mL) are added water (4 mL) and a 2.5% aq. solution of OsO4 (136 μL), followed by N-methyl-morpholine-N-oxide monohydrate (1.4 g, 10.4 mmol). The reaction mixture is stirred at rt for 18 h. Another 68 μL of 2.5% aq. solution of OsO4 is added and stirring is continued for another 3 h. The mixture is then diluted with DCM (150 mL), and washed with water (3×50 mL), dried over MgSO4, filtered and evaporated to give 0.97 g of racemic 1-{4-[5-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethane-1,2-diol as a brown solid; LC-MS: tR=0.84 min; [M+H]+=356.04. 1H NMR (CDCl3) δ 1.30 (d, J=6.5 Hz, 6H), 2.16 (s br, 1H), 2.49 (s, 3H), 2.74 (s br, 1H), 3.72 (dd, J=11.0, 8.0 Hz, 1H), 3.86 (dd, J=11.0, 3.3 Hz, 0H), 4.31 (m, 1H), 4.94 (dd, J=7.8, 3.3 Hz, 1H), 5.28 (s br, 1H), 7.30 (s, 1H), 7.55 (d, J=8.3 Hz, 2H), 8.20 (d, J=8.3 Hz, 2H).
Reaction SMILES: S(Cl)([Cl:3])=O.[N+:5]([C:8]1[CH:18]=[CH:17][C:11]2[NH:12][C:13]([CH2:15]O)=[N:14][C:10]=2[CH:9]=1)([O-:7])=[O:6]>C(Cl)Cl>[Cl:3][CH2:15][C:13]1[NH:12][C:11]2[CH:17]=[CH:18][C:8]([N+:5]([O-:7])=[O:6])=[CH:9][C:10]=2[N:14]=1
Reactant: O=[N+]([O-])c1ccc2[nH]c(CO)nc2c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2[nH]c(CCl)nc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
20 mL (275 mmol) thionyl chloride are added slowly to a solution of 6.4 g (33.1 mmol) (5-nitro-1H-benzimidazol-2-yl)-methanol in 100 mL DCM at 10° C. The reaction is stirred for 1 h at RT and the solvent is eliminated i.vac. The residue is triturated with DCM, suction filtered, washed with DCM and ether and dried in the circulating air dryer at 35° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH:19](=O)[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[OH:22]>>[OH:22][C:21]1[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=1[CH:19]=[C:13]1[C:12]2[C:16](=[CH:17][C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:10][CH:11]=2)[NH:15][C:14]1=[O:18]
Reactant: COc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Reactant: O=Cc1ccccc1O
Product: COc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2ccccc2O)c1

Procedure:
6-(3-Methoxyphenyl)-1,3-dihydroindol-2-one was condensed with salicylaldehyde using method B to give 3-(2-hydroxybenzylidene)-6-(3-methoxyphenyl)-1,3-dihydro-indol-2-one as a yellow solid which was reducted using method E to give 0.03 g (66%) of 3-(2-hydroxy-benzyl)-6-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as a white solid.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:11]([N:18]1[CH2:23][CH2:22][C:21]2([NH:10][C:1](=[O:9])[C:2]3[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=3[O:4]2)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: NC(=O)c1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1NC2(CCN(Cc3ccccc3)CC2)Oc2ccccc21
Temperature: 25 °C

Procedure:
Salicylamide (7.24 g), 1-benzylpiperidin-4-one (10.0 g) and p-toluenesulfonic acid hydrate (500 mg) were suspended in toluene (200 mL), and the suspension was stirred under reflux overnight while removing the water in the reaction system using a Dean-Stark tube. The mixture was cooled to room temperature, and the resulting precipitate was collected by filtration and washed with water, ethanol and diethyl ether to give 1′-benzylspiro[1,3-benzoxazine-2,4′-piperidin]-4(3H)-one as a crude product (9.7 g). The obtained crude 1′-benzylspiro[1,3-benzoxazine-2,4′-piperidin]-4(3H)-one (5.0 g) and 10% palladium-carbon (1.0 g) were suspended in ethanol (50 mL), and the suspension was stirred at 50° C. for 5 hr under a hydrogen atmosphere. The catalyst was removed by filtration through celite and the solvent was evaporated under reduced pressure. The resulting precipitate was collected by filtration, and washed with ethanol and diethyl ether to give the object product (2.7 g, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:14])[CH3:13])[CH2:8][CH2:7]1)=O.Cl.[NH2:21][OH:22].C([O-])(=O)C.[NH4+].C(O)C>O>[C:12]([N:9]1[CH2:10][CH2:11][CH:6]([C:4](=[N:21][OH:22])[C:3]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:2]=2[Cl:1])[CH2:7][CH2:8]1)(=[O:14])[CH3:13]
Reactant: CC(=O)N1CCC(C(=O)c2ccc(Cl)cc2Cl)CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(=O)N1CCC(C(=NO)c2ccc(Cl)cc2Cl)CC1
Yield: 31.1 %

Procedure:
A mixture of 13.0 g of 4-(2,4-dichlorobenzoyl)-N-acetyl-piperidine, 6.8 g of hydroxylamine hydrochloride, 13.5 g of ammonium acetate, 127 ml of ethanol and 43 ml of water was stirred and heated at 130° for 24 hrs. The reaction mixture was evaporated and 1.3 l of water was added to the residue. The water was decanted from the oil and the oil was dissolved in about 150 ml dichloromethane. After washing with about 150 ml of water, drying over anhydrous magnesium sulfate and evaporating the solvent, an oil was obtained, which after crystallization from methanol/ether gave 4.25 g (31.1%) of product, mp, 167°-168°.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH3:32])[C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21]([N:24]5[C@H:28]([CH2:29][OH:30])[CH2:27][O:26][C:25]5=[O:31])=[CH:20][CH:19]=4)=[O:17])[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:33]I>>[CH:1]1([C:4]2[CH:5]=[C:6]([CH3:32])[C:7]([N:10]3[CH2:11][CH2:12][N:13]([C:16]([C:18]4[CH:19]=[CH:20][C:21]([N:24]5[C@H:28]([CH2:29][O:30][CH3:33])[CH2:27][O:26][C:25]5=[O:31])=[CH:22][CH:23]=4)=[O:17])[CH2:14][CH2:15]3)=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3CO)cc2)CC1
Reactant: CI
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)cc1
Yield: 86.2 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 93 and using (R)-3-{4-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-4-hydroxymethyloxazolidin-2-one (655 mg) described in Example 299 and methyl iodide (255 mg), the title compound (583 mg) was obtained.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:16][C:17]([C:19]2[NH:20][N:21]=[N:22][CH:23]=2)=[O:18])[CH2:9][C@@H:10]([CH2:14][OH:15])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.Cl.[CH3:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37]O>O1CCOCC1>[CH3:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:12][C:11](=[O:13])[C@H:10]([CH2:14][OH:15])[CH2:9][C@H:8]([NH:16][C:17]([C:19]1[NH:20][N:21]=[N:22][CH:23]=1)=[O:18])[CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:2][CH:3]=1
Reactant: O=C(N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@H](CO)C(=O)O)c1cnn[nH]1
Reactant: COCCOCCO
Agent: Cl
Solvent: C1COCCO1
Product: COCCOCCOC(=O)[C@H](CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Temperature: 60 °C

Procedure:
(2S,4S)-5-Biphenyl-4-yl-2-hydroxymethyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid (20 mg, 39 μmol, 1.0 eq.) was dissolved in 2-(2-methoxyethoxy)-ethanol, (3 mL) followed by the addition of 4 M of HCl in dioxane (295.0 μL). The mixture was heated and maintained at 60° C. for 4 hours. The mixture was concentrated and purified by preparative HPLC to yield the title compound (13 mg; purity 95%). MS m/z [M+H]+ calc'd for C26H32N4O6, 497.23. found 497.6.
Reaction SMILES: I[CH2:2][C:3]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][NH2:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][NH:30][CH2:2][C:3]2([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]2)=[CH:25][CH:24]=1
Reactant: COc1ccc(CN)cc1
Reactant: CCOC(=O)C1(CI)CCCN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CNCc2ccc(OC)cc2)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 145 °C
Yield: 20.3 %

Procedure:
1-tert-butyl 3-ethyl 3-(iodomethyl)piperidine-1,3-dicarboxylate (C1) (4.13 mmol, 1.64 g) was dissolved in THF (5 mL), (4-methoxyphenyl)methanamine (6.19 mmol, 0.81 mL) and cesium carbonate (6.19 mmol, 2.02 g) were added and the mixture was heated for 8 h at 145° C. in the microwave. The mixture was filtered over a PE-filter and concentrated in vacuo. The crude was purified by flash chromatography (heptane/EtOAc: 0 to 45% yielding the title compound (C2) (340 mg, 20%). 1H NMR (400 MHz, DMSO, 300K): δ=1.23 (3H, t, J=7.2 Hz), 1.43 (9H, s), 1.55 (2H, m), 1.67 (1H, m), 1.89 (1H, m), 2.64 (1H, d, J=11.9 Hz), 2.77 (1H, d, J=11.9 Hz), 3.21 (1H, m), 3.51 (2H, m), 3.62 (1H, m), 3.70 (2H, m), 3.79 (3H, s), 4.14 (2H, q, J=7.2 Hz), 6.84 (2H, d, J=8.6 Hz), 7.20 (2H, d, J=8.6 Hz).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCOCC1.C(N(CC)C(C)C)(C)C.[Cl:23][C:24]1[N:29]=[C:28](Cl)[C:27]([Cl:31])=[CH:26][N:25]=1>>[CH:1]1([NH:7][C:26]2[C:27]([Cl:31])=[CH:28][N:29]=[C:24]([Cl:23])[N:25]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Clc1ncc(Cl)c(NC2CCCCC2)n1
Temperature: 100 °C
Yield: 87.3 %

Procedure:
Into a round bottom flask was added cyclohexanamine (1.0 mL, 8.7 mmol) and 1,4-dioxane (30 mL, 380 mmol). N,N-Diisopropylethylamine (1.83 mL, 10.5 mmol) was added followed by 2,4,5-trichloro-pyrimidine (1.20 mL, 10.5 mmol) and the mixture was heated at 100° C. overnight and then concentrated under reduced pressure. The residue was taken up in DCM (100 mL) and washed with water (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-20% EtOAc/hex as the eluting solvent to obtain cyclohexyl-(2,5-dichloro-pyrimidin-4-yl)-amine as a white solid (1.87 g, 87%). m.p.=93-94° C.; LCMS (m/e) 246 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.01 (s, 1H), 5.45-5.30 (m, 1H), 4.13-4.00 (m, 1H), 2.10-1.99 (m, 2H), 1.85-1.74 (m, 2H), 1.74-1.63 (m, 1H), 1.55-1.39 (m, 2H), 1.36-1.18 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:30]([O:32]CC)=[O:31])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:17][CH2:16]1)=[CH:9][C:8]([O:35][CH3:36])=[CH:7][CH:6]=2.[OH-].[Na+]>O1CCOCC1.CO>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:30]([OH:32])=[O:31])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][S:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:17][CH2:16]1)=[CH:9][C:8]([O:35][CH3:36])=[CH:7][CH:6]=2
Reactant: CCOC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CCN(CCSc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc2ncc(F)c(CCCC3(C(=O)O)CCN(CCSc4ccccc4)CC3)c2c1
Temperature: 70 °C
Reaction time: 17 h
Yield: 81.4 %

Procedure:
A mixture of 0.39 g of ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(2-phenylthioethyl)piperidine-4-carboxylate in 3 cm3 of dioxane, 3 cm3 of methanol and 2.3 cm3 of aqueous SN sodium hydroxide solution was stirred at a temperature in the region of 70° C. for 17 hours. After cooling to about 20° C., the reaction mixture was concentrated to dryness under a pressure gradually reduced from 30 kPa to 2.5 kPa and at a temperature in the region of 45° C. The residue was taken up in 5 cm3 of a dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume) and was then purified by chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200μ; mass 10 g), eluting with a dichloromethane/methanol/aqueous ammonia mixture (90/9/0.9 by volume) and then with a chloroform/methanol/aqueous ammonia mixture (77.5/19.5/3). The fractions containing the product were combined, concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. and dried in a desiccator (10 kPa). 0.3 g of 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(2-phenylthioethyl)piperidine-4-carboxylic acid was obtained in the form of a white solid.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][C:13]3([CH2:20][CH2:19][NH:18][C:17](=[O:21])[CH2:16]3)[C:12]2=[O:22])=[CH:7][CH:6]=1.[CH3:25][C:26]([CH3:32])([CH3:31])[CH2:27][C:28](Cl)=[O:29]>>[CH3:25][C:26]([CH3:32])([CH3:31])[CH2:27][C:28]([N:18]1[CH2:19][CH2:20][C:13]2([C:12](=[O:22])[N:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][C:2]([F:1])([F:23])[F:24])=[CH:6][CH:7]=3)[CH2:15][CH2:14]2)[CH2:16][C:17]1=[O:21])=[O:29]
Reactant: O=C1CC2(CCN1)CCN(c1ccc(OCC(F)(F)F)cc1)C2=O
Reactant: CC(C)(C)CC(=O)Cl
Product: CC(C)(C)CC(=O)N1CCC2(CCN(c3ccc(OCC(F)(F)F)cc3)C2=O)CC1=O

Procedure:
This material was prepared as a white solid in analogy to example 3) from 2-(4-(2,2,2-trifluoroethoxy)phenyl)-2,8-diazaspiro[4.5]decane-1,7-dione and 3,3-dimethyl-butyryl chloride. MS (ESI): 441.19 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12].[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[S:23](Cl)(=[O:25])=[O:24].C(N(CC)CC)C>ClCCl>[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[S:23]([NH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[S:11](=[O:13])(=[O:12])[NH2:14])(=[O:25])=[O:24]
Reactant: COc1cc(N)c(S(N)(=O)=O)cc1F
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(S(N)(=O)=O)cc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 5.9 %

Procedure:
2-Amino-5-fluoro-4-methoxybenzenesulfonamide (200 mg, 0.91 mmol) and 2,3-dichlorobenzene-1-sulfonyl chloride (290 mg, 1.18 mmol) were dissolved in anhydrous dichloromethane (5 mL). Anhydrous triethylamine (0.290 mL, 2.09 mmol) was added and the reaction was stirred at room temperature for 48 hours under an inert atmosphere. The reaction was quenched using 2 M hydrochloric acid (20 mL) and was extracted with dichloromethane. The combined organic phase were washed with water, dried over magnesium sulfate and concentrated under vacuum. Purification by preparative HPLC gave 23 mg (6% yield) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[C:11]([F:18])[CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C(O)(=O)C>O1CCCC1>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([F:18])[CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:19]1[CH:20]=[CH:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc2c1C(c1ccc(C(F)(F)F)cc1)N(Cc1ccccc1)C=C2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Fc1cccc2c1C(c1ccc(C(F)(F)F)cc1)N(Cc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A 250-mL round-bottomed flask containing a solution of 2-benzyl-8-fluoro-1-(4-(trifluoromethyl)phenyl)-1,2-dihydroisoquinoline (1.0 g, 2.6 mmol) in anhydrous tetrahydrofuran (20 mL) was treated with sodium borohydride (0.3 g, 8.4 mmol) at RT. After 20 min, acetic acid (3.3 mL) was added and the reaction was stirred at RT for 2.5 h. The reaction mixture was concentrated and the resulting residue was taken up in ethyl acetate (150 mL), water (25 mL), 1N sodium hydroxide, and brine (35 mL). The ethyl acetate layer was separated, dried over anhydrous sodium sulfate, and concentrated to yield the crude product. The crude product was purified by silica gel chromatography (20-30% EtOAc in hexanes) to give 2-benzyl-8-fluoro-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline as a colorless oil. MS (ESI, pos. ion) m/z: 386 (M+1).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([OH:19])[C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C>[CH2:28]([O:19][C:13]1[C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:8]2[CH2:7][CH2:6][N:5]([C:3](=[O:4])[C:2]([F:1])([F:20])[F:21])[CH2:11][CH2:10][C:9]=2[CH:12]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(N1CCc2cc(O)c([N+](=O)[O-])cc2CC1)C(F)(F)F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(N1CCc2cc(OCc3ccccc3)c([N+](=O)[O-])cc2CC1)C(F)(F)F
Reaction time: 3 h

Procedure:
1.30 g (4.27 mmol) 2,2,2-trifluoro-1-(7-hydroxy-8-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethanone are placed in 20 ml DMF and at room temperature 0.65 g (4.70 mmol) potassium carbonate and 0.508 ml (4.27 mmol) benzylbromide are added and the mixture is stirred for 3 h. Then it is filtered and the filtrate is concentrated by evaporation i.vac., the residue is triturated with water, suction filtered and dried at 45° C. in the circulating air dryer.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:31])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:17]([N+:28]([O-])=O)[CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.CO.[C].[Pd]>[NH2:28][C:17]1[CH:16]=[C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:31])[CH:27]=[CH:26][C:18]=1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]
Reactant: CN(C(=O)OC(C)(C)C)c1ccccc1-c1ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)c1ccccc1-c1ccc(C(=O)OC(C)(C)C)c(N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.5 %

Procedure:
To a solution mixture of tert-butyl 4-(2-((tert-butoxycarbonyl)(methyl)amino)phenyl)-2-nitrobenzoate (0.057 g) in ethyl acetate (2.5 mL) and methanol (2.5 mL), 10% palladium-carbon (0.011 g) was added. The mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 95-85% hexane/ethyl acetate] to obtain 0.048 g of tert-butyl 2-amino-4-(2-((tert-butoxycarbonyl)(methyl)amino)phenyl)benzoate as a white solid.
Reaction SMILES: [Li+].[OH-].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C:13]([N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]3[N:30]=[C:29]([C:31]([O:33]C)=[O:32])[C:28]([O:35][CH2:36][CH2:37][CH2:38][O:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:27][CH:26]=3)[CH:23]=2)[N:18]([CH3:46])[CH2:17][CH2:16]1)=[O:14].Cl>CO.O>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C:13]([N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]3[N:30]=[C:29]([C:31]([OH:33])=[O:32])[C:28]([O:35][CH2:36][CH2:37][CH2:38][O:39][C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)=[CH:27][CH:26]=3)[CH:23]=2)[N:18]([CH3:46])[CH2:17][CH2:16]1)=[O:14]
Reactant: COC(=O)c1nc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCN3C)ccc1OCCCOc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN1CCN(C(=O)Nc2nc3ccccc3s2)c2cc(-c3ccc(OCCCOc4ccccc4)c(C(=O)O)n3)ccc21
Temperature: 55 °C
Yield: 61.4 %

Procedure:
The title compound 6-(4-(benzo[d]thiazol-2-ylcarbamoyl)-1-methyl-1,2,3,4-tetrahydroquinoxalin-6-yl)-3-(3-phenoxypropoxy)picolinic acid (26) was prepared by the following procedure: LiOH (12 mg, 10 eq) was added to a mixture of Methyl 6-(4-(benzo[d]thiazol-2-ylcarbamoyl)-1-methyl-1,2,3,4-tetrahydroquinoxalin-6-yl)-3-(3-phenoxypropoxy)picolinate (26E) (25 mg, 0.041 mmol) in MeOH (0.5 mL) and water (0.25 mL) at rt. The mixture was heated to 55° C. for 14 hours, cooled to 0° C. and acidified with 1N HCl to pH˜4. The resulting precipitate was filtered, washed with water and dried in vacuo to provide 15 mg (61%) of the desired product 6-(4-(benzo[d]thiazol-2-ylcarbamoyl)-1-methyl-1,2,3,4-tetrahydroquinoxalin-6-yl)-3-(3-phenoxypropoxy)picolinic acid (26): 1H NMR (300 MHz, DMSO-d6) δ 8.13 (1H, bs), 7.83 (1H, d), 7.80 (1H, d), 7.65 (2H, m), 7.37 (1H, t), 7.32-7.18 (4H, m), 6.94 (3H, m), 6.79 (1H, d), 4.26 (2H, t), 4.15 (2H, t), 4.02 (2H, t), 3.41 (2H, t), 2.97 (3H, s), 2.17 (2H, t). MS (ESI(+)): m/z 596.1 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]=[N:12][C:11]=2[C:22]([O:24]CC)=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH3:27].CO>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:13]=[N:12][C:11]=2[C:22]([NH2:27])=[O:24])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)c1nnc(-c2ccccc2)cc1-c1cccc([N+](=O)[O-])c1
Reactant: N
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1nnc(-c2ccccc2)cc1-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of ethyl 4-(3-nitrophenyl)-6-phenyl-3-pyridazinecarboxylate (1 g) in methylene chloride (10 ml) was added ammonia-methanol solution (60 ml) which was prepared by bubbling an ammonia gas (14 g) into methanol (120 ml), and the mixture was stirred for 24 hours at ambient temperature. After evaporating the solvent, the residue was recrystallized from methanol to give 4-(3-nitrophenyl)-6-phenyl-3-pyridazinecarboxamide (0.78 g).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])=[CH:6][CH:5]=1)([O-])=O>C(OCC)(=O)C.[C].[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[C:14]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:15])=[CH:6][CH:5]=1
Reactant: O=C(Oc1ccccc1)C1CCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)C(C(=O)Oc1ccccc1)CCC2

Procedure:
A 1.0-g portion of the phenyl 7-nitro-1,2,3,4-tetrahydro-1-naphthoate obtained above was catalytically reduced with 5% palladium-carbon in ethyl acetate. After removal of the catalyst by filtration, the ethyl acetate was removed by distillation under reduced pressure. The residue was recrystallized from methanol to obtain 550 mg of phenyl 7-amino-1,2,3,4-tetrahydro-1-naphthoate, m.p. 89°-90° C.