Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][CH2:25][C:26]([F:38])([F:37])[C:27]([F:36])([F:35])[C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])[CH:6]=1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:47])C=1>C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16]([CH2:17][C:18]([F:21])([F:20])[F:19])=[O:47])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][CH2:25][C:26]([F:37])([F:38])[C:27]([F:35])([F:36])[C:28]([F:34])([F:33])[C:29]([F:30])([F:31])[F:32])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cc(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(S(=O)CC(F)(F)F)c(C)cc1F
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
0.2 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(2,2,3,3,4,4,5,5,5-nonafluoropentyloxy)pyrazole was dissolved in 10 mL of chloroform, and 77 mg of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for 30 minutes under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous potassium carbonate solution, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 0.19 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-3-(2,2,3,3,4,4,5,5,5-nonafluoropentyloxy)pyrazole.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][C:3]=1[CH3:9].[C:10]1([S:16](Cl)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1>[C:10]1([S:16]([O:1][C:2]2[C:7](=[O:8])[CH:6]=[CH:5][O:4][C:3]=2[CH3:9])(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1occc(=O)c1O
Solvent: c1ccncc1
Product: Cc1occc(=O)c1OS(=O)(=O)c1ccccc1
Yield: 71 %

Procedure:
3-Hydroxy-2-methyl-4H-pyran-4-one (1.0 g, 7.9 mmol) was reacted with benzenesulfonyl chloride (3.0 mL, 23.7 mmol) in 75 mL of pyridine to afford PZBG-2a in 71% yield (1.50 g, 5.6 mmol). 1H NMR (500 MHz, CDCl3) δ=8.12 (d, J=8.6 Hz, 2H), 7.69 (t, J=7.5 Hz, 1H), 7.65 (d, J=5.8 Hz, 1H), 7.58 (t, J=8.0 Hz, 2H), 6.33 (d, J=5.2 Hz, 1H), 2.46 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3) δ=172.1, 163.1, 154.3, 138.4, 136.6, 134.7, 129.2, 129.0, 117.7, 16.3. ESI-MS(+): m/z 267.06 [M+H]+, 289.03 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH:19]([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.Cl[C:32]1[CH:33]=[CH:34][C:35]2[N:36]([CH:38]=[C:39]([NH:41][C:42](=[O:44])[CH3:43])[N:40]=2)[N:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1.O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:32]2[CH:33]=[CH:34][C:35]3[N:36]([CH:38]=[C:39]([NH:41][C:42](=[O:44])[CH3:43])[N:40]=3)[N:37]=2)=[CH:6][C:7]=1[NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH:19]([F:20])[F:21])[CH:13]=1)(=[O:10])=[O:11]
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3cccc(OC(F)F)c3)c2)OC1(C)C
Reactant: CC(=O)Nc1cn2nc(Cl)ccc2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1cn2nc(-c3cnc(Cl)c(NS(=O)(=O)c4cccc(OC(F)F)c4)c3)ccc2n1
Temperature: 100 °C
Yield: 29.5 %

Procedure:
A glass microwave reaction vessel was charged with N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-3-(difluoromethoxy)benzenesulfonamide (1.1 g, 2.4 mmol), N-(6-chloroimidazo[1,2-b]pyridazin-2-yl)acetamide (0.25 g, 1.2 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (87 mg, 0.012 mmol, Strem Chemical, Inc., Newburyport, Mass.), sodium carbonate (0.25 g, 2.4 mmol), and dioxane-H2O (5 mL, 4:1). Ar was bubbled in the solution for 1 minute. The reaction mixture was sealed and heated at 100° C. for 2 h and then was concentrated in vacuo. Purification by silica gel chromatography (5-20% MeOH/CH2Cl2), followed by further purification by preparative HPLC (Phenomenex Synergi 4μ MAX-RP 150×21.2 mm, 30 to 80% CH3CN/H2O, 0.1% TFA, over 12 min) (Phenomenex, Torrance, Calif.) provided the title compound (0.18 g, 30% yield) as a tan solid. MS (ESI positive ion) m/z: 524 (M+1). 1H NMR (400 MHz, MeOH-d): δ ppm 2.22 (s, 3H), 6.88 (t, J=73.07 Hz, 1H), 7.43 (dd, J=8.12, 1.86 Hz, 1H), 7.54-7.62 (m, 2H), 7.63-7.68 (m, 1H), 7.74 (d, J=9.59 Hz, 1H), 7.98 (d, J=9.59 Hz, 1H), 8.44 (s, 1H), 8.57 (d, J=2.15 Hz, 1H), 8.82 (d, J=2.35 Hz, 1H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:11](=[O:12])[CH:10]=[CH:9][C:7](=[O:8])[C:5]=2[CH:6]=1.C(O[CH:17]=[CH:18][CH:19]=[CH2:20])(=O)C.CN(C)C=O>C(O)(=O)C>[CH:17]1[C:10]2[C:11](=[O:12])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7](=[O:8])[C:9]=2[CH:20]=[CH:19][CH:18]=1
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: C=CC=COC(C)=O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)c2ccccc21
Temperature: 125 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
15.8 parts by weight of naphthoquinone and 13.0 parts by weight of 1-acetoxybutadiene in 40 parts by volume of dimethylformamide and 10 parts by volume of acetic acid are stirred for 6 hours under nitrogen at 45° - 50° C. Air is then passed in and the batch is stirred for 2 hours at 125° C. After cooling, the anthraquinone which has precipitated is filtered off and washed with dimethylformamide. 18.0 g (90% of theory) of anthraquinone of melting point 284° C are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N:4]=1)#[N:2]>CO.N.[Ni]>[NH2:2][CH2:1][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N:4]=1
Reactant: Cc1ccnc(C#N)c1
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cc1ccnc(CN)c1

Procedure:
g 2 (0.0169 moles) of 2-cyano-4-methyl pyridine [J. Am. Chem. Soc. 78, 5842-5843 (1956)] dissolved in 400 ml of methanol containing 12% W/W of ammonia, were hydrogenated on 2 g of Ni-Raney at room temperature and 20 psi, until the theoretical amount of hydrogen was consumed.
Reaction SMILES: CO[C:3](=[O:23])[C@H:4]([CH2:13][CH2:14][O:15]CC1C=CC=CC=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]>[Pd].CO>[C:9]([O:8][C:6]([NH:5][C@H:4]1[CH2:13][CH2:14][O:15][C:3]1=[O:23])=[O:7])([CH3:10])([CH3:11])[CH3:12]
Reactant: COC(=O)[C@H](CCOCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CCOC1=O
Temperature: 25 °C
Reaction time: 14.5 h

Procedure:
A mixture of N-tert-butoxycarbonyl-O-benzyl-L-homoserine methyl ester (A, 3.13 g) and 10% palladium on activated carbon (0.93 g) in methanol (160 mL) was stirred at room temperature for 14.5 hr under hydrogen. The catalysts were removed by filtration and washed with methanol. The combined organic layers were evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:methanol=40:1 to 20:1, v/v) to afford the title compound (1.65 g) as a white powder: 1H NMR (400 MHz, CDCl3) δ 1.4-1.5 (m, 9H), 2.20 (m, 1H), 2.77 (m, 1H), 4.25 (m, 1H), 4.35 (m, 1H), 4.45 (t, J=8.8 Hz, 1H), 5.07 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@@H:12]2[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[CH2:14][C@H:13]2[NH:25][CH:26]([CH3:28])[CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.O1CCOCC1.BrC1[S:38][C:39]2[C:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:44][CH:43]=[CH:42][C:40]=2[N:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:38][C:39]4[C:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:44][CH:43]=[CH:42][C:40]=4[N:41]=3)[CH2:14][C@H:13]2[NH:25][CH:26]([CH3:27])[CH3:28])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1cccc2nc(Br)sc12
Reactant: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NC(C)C)nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc2nc(N3CC[C@@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](NC(C)C)C3)sc12
Yield: 28.1 %

Procedure:
The same operation as in Example (196c) was performed using tert-butyl trans(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-(isopropylamino)piperidine-1-carboxylate obtained in Example (211a) (20.0 mg, 0.048 mmol), 4 N hydrochloric acid/1,4-dioxane (2 mL), ethyl 2-bromo-1,3-benzothiazole-7-carboxylate obtained in Example (1f) (15 mg, 0.053 mmol) and sodium carbonate (51 mg, 0.483 mmol), to obtain 7 mg of the title compound (28%) as a colorless solid.
Reaction SMILES: [C:1]([O:20]C(C)C)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]CCCCCCCCC.[CH3:24]C(C)=O>>[CH3:24][C@@H:1]([OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CC(C)=O
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC(C)C
Product: CCCCCCCC[C@@H](C)O
Temperature: 5 °C
Yield: 72 %

Procedure:
In a 300 ml separable flask were put 1 g of Lipase QL and 40 g of (R,S)-2-decanol, and the mixture was subjected to ultrasonication with the same ultrasonic wave generating equipment as used in Example 1 at room temperature and 90 kHz for 1 minute. To the dispersion was added 60 g of isopropyl stearate, followed by stirring at 95° C. and 250 rpm for 20 hours to carry out interesterification while evaporating by-produced isopropyl alcohol under reduced pressure. The water content of the reaction system was 0.02% by weight, and 96% of the lipase particles had a particle size of 10 to 40 μm. Gas chromatographic analysis of the reaction mixture revealed that 58 mol % of (R,S)-2-decanol had been converted to 2-decyl stearate. Lipase was removed by filtration in the same manner as in Example 1, and the filtrate was subjected to simple distillation at 70° C. under reduced pressure of 5 mmHg to give (S)-(+)-2-decanol (yield: 73.5%; chemical purity: 99.9%; optical purity: 98.5% ee). The residue, i.e., a mixture of (R)-(-)-2-decanol stearic acid ester and unreacted isopropyl stearate was acid-hydrolyzed in the same manner as in Example 2, and 1000 ml of acetone was added to the reaction mixture, followed by cooling to 5° C. The precipitated stearic acid was removed by filtration, and methanol was evaporated from the filtrate under reduced pressure to give (R)-(-)-2-decanol (yield: 72%; chemical purity: 99.6%; optical purity: 84% ee).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.Cl.Cl.[CH3:18][NH:19][CH2:20][CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>>[CH3:18][N:19]([CH2:20][CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[C:13]([C:9]1[CH:10]=[N:11][O:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)=[O:15]
Reactant: CNCCc1cccnc1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Agent: Cl
Product: Cc1ccc(-c2oncc2C(=O)N(C)CCc2cccnc2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3-[2-(methylamino)ethyl]pyridine dihydrochloride (12.5 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (4.6 mg). Calcd for C19H19N3O2: 321.1477, found 321.1491.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH2:18][NH:19][CH:20]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]3)[CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[Cl:35][C:36]1[C:37]2[C:47]([F:48])=[CH:46][CH:45]=[C:44]([F:49])[C:38]=2[S:39][C:40]=1[C:41](Cl)=[O:42]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH2:18][N:19]([C:41]([C:40]3[S:39][C:38]4[C:44]([F:49])=[CH:45][CH:46]=[C:47]([F:48])[C:37]=4[C:36]=3[Cl:35])=[O:42])[CH:20]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:22][CH2:21]3)[CH:11]=2)=[CH:8][CH:9]=1)(=[O:3])[NH2:2]
Reactant: COc1ccc(-c2ccc(C(N)=O)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Product: COc1ccc(-c2ccc(C(N)=O)cc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 55 (80 mg, 0.17 mmol) is treated with acid chloride 8 (55 mg, 0.21 mmol) using Method D to give the title compound.
Reaction SMILES: C([N:8]1[CH2:12][C@:11]2([O:23][CH3:24])[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@H:10]2[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:24][O:23][C@@:11]12[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@H:10]1[CH2:9][NH:8][CH2:12]2
Reactant: CO[C@]12CN(Cc3ccccc3)C[C@H]1CN(C(=O)OC(C)(C)C)C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CO[C@]12CNC[C@H]1CN(C(=O)OC(C)(C)C)C2
Temperature: 45 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
To a solution of (+/−)-cis-tert-butyl 5-benzyl-3a-methoxyhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (1.5 g, 4.5 mmol) in MeOH (100 mL) was added Pd(OH)2/C (300 mg) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen three times. The mixture was stirred at 40-50° C. under hydrogen (45 psi) overnight. TLC (petroleum ether/EtOAc=2/1) showed the reaction was complete. The mixture was filtered, concentrated and purified by column chromatography (CH2Cl2/MeOH=15/1) to afford the title compound (454 mg, 41% yield) as a yellow gum. 1H NMR (400 MHz, CDCl3) δ 3.95 (brs., 2 H), 3.51-3.78 (m, 3 H), 3.36-3.50 (m, 2 H), 3.14-3.35 (m, 4 H), 2.83-3.08 (m, 2 H), 2.75 (brs., 1 H), 1.45 (s, 9 H). m/z (APCI+) for C12H22N2O3 [M−56+H]+.
Reaction SMILES: [F:1][CH:2]([F:18])[N:3]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][C:10]=2[F:16])[N:5]=[C:4]1[CH3:17].Cl[CH2:20][C:21]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:22]=1[O:23][CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:18][CH:2]([F:1])[N:3]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15][CH2:20][C:21]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:22]=3[O:23][CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:11][C:10]=2[F:16])[N:5]=[C:4]1[CH3:17]
Reactant: COC(=O)C(C)Oc1cc(Cl)ccc1CCl
Reactant: Cc1nn(-c2ccc(S)cc2F)c(=O)n1C(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cc(Cl)ccc1CSc1ccc(-n2nc(C)n(C(F)F)c2=O)c(F)c1
Yield: 22 %

Procedure:
By the method of Example 1, Step I, 1.35 g (0.0049 mole) of 4-(4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-on-1-yl)-3-fluorothiophenol and 3.0 g (0.011 mole) of methyl 2-(2-chloromethyl-5-chlorophenoxy)propionate (Example 2, Step E) were reacted in the presence of 1.02 g (0.0074 mole) of anhydrous potassium carbonate in 75 mL of N,N-dimethylformamide, yielding 0.54 g of methyl 2-[2-[4-(4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-on-1-yl)-3-fluorophenylthiomethyl]-5-chlorophenoxy]propionate as a yellow syrup. The NMR spectrum was consistent with the proposed structure. NMR: 1.65 (d, 3H, JHH =8.0 Hz); 2.44 (s, 3H); 3.78 (s, 3H); 4.20 (dd, 2H, JHH =13.0 Hz); 4.78 (q, 1H, JHH =8.0 Hz); 6.70-7.38 (m, 7H) .
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:26])[CH3:25])[CH2:20][CH2:19]2)[CH:12]=[CH:13][C:14]=1[N+:15]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[NH2:15][C:14]1[CH:13]=[CH:12][C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:26])[CH3:25])[CH2:20][CH2:19]2)=[CH:10][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)N1CCN(c2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N1CCN(c2ccc(N)c(OCc3ccccc3)c2)CC1
Reaction time: 2 h

Procedure:
The compound prepared in Step 2 was dissolved in ethanol, added with 10% Pd/C and stirred under hydrogen atmosphere for 2 hours. Upon completion of the reaction, the Pd/C in the reaction mixture was removed using celite and the solvent was removed under reduced pressure. The thus obtained compound was used in the subsequent reaction without further purification.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:23])[C:6]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[C:8]([C:15](=[O:22])[N:16]([O:18][CH2:19][CH:20]=[CH2:21])[CH3:17])[CH:7]=1)[CH:2]=[CH2:3].O.O.[Sn](Cl)Cl.N>C(OCC)(=O)C>[CH2:1]([O:4][C:5](=[O:23])[C:6]1[CH:7]=[C:8]([C:15](=[O:22])[N:16]([O:18][CH2:19][CH:20]=[CH2:21])[CH3:17])[CH:9]=[C:10]([NH2:12])[CH:11]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1cc(C(=O)N(C)OCC=C)cc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: N
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)c1cc(N)cc(C(=O)N(C)OCC=C)c1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
A mixture of (8(b)) (0.523 g), tin(II) chloride dihydrate (1.84 g) and ethyl acetate (50 ml) was heated under reflux for 6 hours. The mixture was allowed to cool to ambient temperature and ammonia solution (sp. g. 0.880) was added dropwise until the solution reached pH 8. The white precipitate which had formed was filtered off. washed with ethyl acetate (2×50 ml) and the combined washings and filtrate evaporated to dryness to give the desired starting material (8(c)) as a yellow oil (0.472 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.CCN(CC)CC.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:39][CH2:40][CH:41]([OH:53])[CH2:42][N:43]1[CH2:52][CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:39][CH2:40][CH:41]([OH:53])[CH2:42][N:43]1[CH2:52][CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1)=[O:7]
Reactant: O=C(O)c1cccc(Br)c1
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 77 %

Procedure:
To a solution of 3-bromobenzoic acid (200 mg, 1.0 mmol) in DCM (8 mL) was added Et3N (303 mg, 3.0 mmol), EDCI (383 mg, 2.0 mmol), HOBt (270 mg, 2.0 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (247 mg, 1.2 mmol). The mixture was stirred at 25° C. for 6 h. The mixture was treated with water and extracted with EA. The organic layer was washed with NaHCO3, brine, dried over Na2SO4 and concentrated to give the title compound which was used in next step without further purification (300 mg, Yield 77%). LCMS (m/z): 390.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:11][CH2:12][CH3:13])[NH:10][C:6]=2[CH:5]=[C:4]([CH2:14][OH:15])[CH:3]=1.[H-].[Na+].[CH3:18][O:19][C:20](=[O:30])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Br)=[CH:23][C:22]=1[F:29]>CN(C=O)C>[CH3:18][O:19][C:20](=[O:30])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:10]2[C:6]3[CH:5]=[C:4]([CH2:14][OH:15])[CH:3]=[C:2]([CH3:1])[C:7]=3[N:8]=[C:9]2[CH2:11][CH2:12][CH3:13])=[CH:23][C:22]=1[F:29]
Reactant: COC(=O)c1ccc(CBr)cc1F
Reactant: CCCc1nc2c(C)cc(CO)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)cc(CO)cc2n1Cc1ccc(C(=O)OC)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43.2 %

Procedure:
(7-Methyl-2-propyl-3H-benzoimidazol-5-yl)methanol (3 g, 15 mmol; prepared as described in Preparation 7) was dissolved in 20 mL of dry DMF. The solution was cooled to 0° C. and sodium hydride (598 mg, 15 mmol, 60 wt % in mineral oil) was added. The mixture was stirred for 30 minutes. 4-Bromomethyl-2-fluorobenzoic acid methyl ester (3.7 g, 15 mmol; prepared as described in Preparation 3) in 50 mL of DMF was added, and the mixture was warmed to room temperature and stirred for 10 minutes. The solution was partitioned between EtOAc (300 mL) and 150 mL 10% LiCl (aqueous). The organic layer was separated, dried over MgSO4 and concentrated. The concentrate was flash chromatographed to produce Intermediate (8a) as a clear oil (2.4 g). MS m/z: [M+H+] calcd for C21H23FN2O3, 371.7. found 371.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:26]([O:28]C)=O)[CH:15]([OH:25])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>C(OCC)(=O)C.[Fe]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH:15]([OH:25])[C:16]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:22][C:26]2=[O:28])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)C(C1CCN(C(=O)OC(C)(C)C)CC1)C(O)c1ccccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(C2C(=O)Nc3ccccc3C2O)CC1
Temperature: 80 °C
Yield: 77 %

Procedure:
In a 3 neck flask fitted with a nitrogen inlet, thermometer, and a mechanical stirrer, 4-[2-hydroxy-1-methoxycarbonyl-2-(2-nitro-phenyl)-ethyl]-piperidine-1-carboxylic acid tert-butyl ester (9.93 g, 24.3 mmoles) was dissolved in acetic acid (1.75 moles, 100 mL). Iron powder (8.90 g, 159 mmoles) was added to the vessel with stirring. The stirred mixture was slowly heated to 80° C. for 30 min and then cooled to room temperature. It was then diluted with ethyl acetate and filtered through a pad of celite. Solids were washed with 20% methanol/ethyl acetate, and then with methanol. The filtrate was concentrated and the residue partitioned between ethyl acetate and aqueous sodium bicarbonate. The layers were separated. The resulting aqueous phase was extracted twice with ethyl acetate. The organic layers were combined. The mixture was washed twice with water and the aqueous phase was discarded. The material was dried (magnesium sulfate) filtered, and concentrated to dryness. Silica gel chromatography afforded the title compound as light yellow foam in 77% yield. MS m/e (M−H)−=345.1.
Reaction SMILES: [OH:1][C:2]([CH2:9][CH3:10])([CH2:7][CH3:8])[C:3]([O:5]C)=[O:4].[H-].[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:21][C:22]([CH2:26]Cl)=[C:23]([CH3:25])[N:24]=2)=[CH:16][CH:15]=1.[I-].[Na+].[OH-].[Na+]>C(COC)OC.O.C(O)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[O:21][C:22]([CH2:26][O:1][C:2]([CH2:9][CH3:10])([CH2:7][CH3:8])[C:3]([OH:5])=[O:4])=[C:23]([CH3:25])[N:24]=2)=[CH:18][CH:19]=1
Reactant: CCC(O)(CC)C(=O)OC
Reactant: Cc1nc(-c2ccc(Cl)cc2)oc1CCl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: CCC(CC)(OCc1oc(-c2ccc(Cl)cc2)nc1C)C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 35.5 %

Procedure:
A solution of 0.8 g (5.5 mmol) of methyl 2-hydroxy-2-ethylbutyrate in 2 ml of dimethoxyethane was added over a period of about 10 minutes to a stirred suspension of 0.24 g (6 mmol) of a 60% sodium hydride dispersion in mineral oil in 4 ml of dry dimethoxyethane. The solution was stirred at room temperature for 10 minutes and then a solution of 1.21 g (5 mmol) of 2-(4-chlorophenyl)-4-methyl-5-chloromethyloxazole in 5 ml of dry dimethoxyethane was added. A small crystal of sodium iodide was added and the mixture was stirred at room temperature overnight under an argon atmosphere. The mixture was heated at 65° C. for 1 hour, cooled and 2 ml of water were added. The majority of the solvent was removed by evaporation under reduced pressure and the residue was partitioned between 100 ml of diethyl ether and 100 ml of water. The organic phase was separated, washed with 50 ml of water and dried over magnesium sulphate. After filtration the filtrate was evaporated and the residue was combined with 25 ml of ethanol, 0.3 g (7.5 mmol) of sodium hydroxide and 10 ml of water. The solution was heated at reflux for 40 minutes, cooled and the majority of the solvent was removed under reduced pressure. The residue was dissolved in 100 ml of water and extracted twice with 100 ml of diethyl ether. The aqueous was acidified to pH 2 with concentration hydrochloric acid and extracted three times with 35 ml of dichloromethane each time. The combined dichloromethane extracts were dried over magnesium sulphate, filtered and evaporated to give a crude solid which was recrystallized twice from ethyl acetate/hexane. There was obtained 0.6 g (33%) of 2-[[2-(4-chlorophenyl)-4-methyl-5-oxazolyl]methoxy]-2-ethylbutyric acid of melting point 157° C.