Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH:9]1([CH2:15][CH2:16]C2C=CC=CC=2O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:16][CH2:15][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:3]=1
Reactant: Oc1ccccc1CCC1CCCCC1
Reactant: Oc1cccc(Br)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Brc1cccc(OCCC2CCCCC2)c1
Yield: 93.7 %

Procedure:
To a solution of 3-bromophenol (15.0 g, 86.7 mmol), 2-cyclohexylethylphenol (12.0 ml, 86.7 mmol) and triphenylphosphine (23.0 g, 86.7 mmol) in tetrahydrofuran (200 ml) was added slowly a 40% solution of diethyl azodicarboxylate in toluene (38.0 ml, 86.7 mmol) in portions at 0° C. with stirring, and then the resulting mixture was stirred at room temperature for 7 hours. After stirring, the reaction mixture was evaporated in vacuo, and hexane was added to the residue. After filtration, the filtrate was evaporated in vacuo once again, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:100) as the eluent to afford 1-bromo-3-(2-cyclohexylethoxy)benzene (23.0 g, yield: 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]2[CH2:7][NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=1.[H-].[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CS(C)=O>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][N:8]1[CH2:7][C:6]2[CH:16]=[CH:17][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]1=2)[CH3:26]
Reactant: COc1ccc2c(c1)Oc1ccccc1NC2
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)CN1Cc2ccc(OC)cc2Oc2ccccc21
Temperature: 25 °C

Procedure:
A solution of 1-4 (2.04 g, 8.97 mmol) in DMSO (10 mL) was cooled to 0° C. and treated with sodium hydride (450 mg of 60% in oil, 11.2 mmol). The reaction mixture was warmed to room temperature for 15 min, followed by addition of ethyl bromoacetate (1.67 g, 10.0 mmol) and warming to 50° C. overnight. The solvent was removed in vacuo and the residue diluted with water and extracted with three portions of dichloromethane. The combined organic extracts were washed with brine and dried (Na2SO4). The solvent was removed in vacuo. Preparative centrifugal chromatography (SiO2, 6 mm, 50% EtOAc, 50% hexane) afforded 1-5.
Reaction SMILES: [CH:1]1[C:2]2[C:17](=[O:18])[C:16]([C:19]([OH:21])=[O:20])=[CH:15][N:14]([CH:22]3[CH2:24][CH2:23]3)[C:3]=2[CH:4]=[C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:6]=1[F:7].[P:25](=O)([OH:28])([OH:27])[OH:26]>P([O-])([O-])([O-])=O>[CH:22]1([N:14]2[C:3]3[C:2](=[CH:1][C:6]([F:7])=[C:5]([N:8]4[CH2:9][CH2:10][N:11]([P:25]([OH:28])([OH:27])=[O:26])[CH2:12][CH2:13]4)[CH:4]=3)[C:17](=[O:18])[C:16]([C:19]([OH:21])=[O:20])=[CH:15]2)[CH2:23][CH2:24]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Reactant: O=P(O)(O)O
Agent: O=P([O-])([O-])[O-]
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCN(P(=O)(O)O)CC3)c(F)cc2c1=O

Procedure:
To a stirred solution of 2.34 g of the product of Example 40 in 25 ml of methylene chloride under argon was added 2.57 g of N,O-bis(trimethylsilyl)triflouroacetamide and then (after 10 minutes) 2.68 g of bromotrimethylsilane. After 17 hours, the solution was evaporated to dryness at 40° C./0.02 mm. The evaporation was then repeated twice after redissolving the residue in 25 ml portions of methylene chloride. A solution of the residual solid in 25 ml of methylene chloride was added to a stirred solution of 1 ml of water in 100 ml of acetone and then stirred for 15 minutes, to hydrolyze silyl ester groups. The resulting solid was collected and washed with acetone to give 2.24 g of cream-colored solid, m.p. 246°-252° (dec.); 31P--NMR (in DMSO with 5% triethylamine) δ 9.34 compared to δ 0.54 (at 50° C.) for a salt of ciprofloxacin with an equimolar amount of phosphoric acid, and δ 0.35 for phosphoric acid. The product was soluble in 0.1M phosphate buffer, pH 7.5, unlike ciprofloxacin.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C[O:12][C:13]([C:15]1[C:16]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][Br:28])=[CH:23][CH:22]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=O.Cl>C1(C)C=CC=CC=1>[Br:28][CH2:27][C:24]1[CH:23]=[CH:22][C:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:13][OH:12])=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Product: OCc1ccccc1-c1ccc(CBr)cc1
Reaction time: 2 h
Yield: 94.6 %

Procedure:
To 60.8 ml (0.0735 mol) of diisobutylaluminium hydride in toluene (20 wt % solution) at 0° C. under argon atmosphere 10.8 g (0.0354 mol) of 4′-bromomethylbiphenyl-2-carboxylic acid methyl ester is added dropwise in a period of 30 minutes. Stirring is continued for 2 hours at the temperature between 0° C. and −5° C. Thereafter 300 ml of 1 M hydrochloric acid and 100 ml of toluene are added under stirring, layers are separated and organic layer washed 3 times with 150 ml of water. After drying with MgSO4 and evaporating under reduced pressure, 9.28 g of white crystalline powder is isolated.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([OH:30])=O)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1.[NH2:32][C@@H:33]([CH2:37][OH:38])[C@@H:34]([CH3:36])[OH:35].C1C=CC2N(O)N=NC=2C=1.O.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.[Cl-].[Na+].O>[OH:35][C@H:34]([CH3:36])[C@@H:33]([NH:32][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][C:13]3[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=3)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:30])[CH2:37][OH:38]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Reactant: C[C@@H](O)[C@@H](N)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)N[C@@H](CO)[C@@H](C)O)[nH]2)c1
Reaction time: 5.5 h
Yield: 80.9 %

Procedure:
5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxylic acid (1.47 g, 3.29 mmol) synthesized in Example (78k), commercially available D-allo-threoninol (0.52 g, 4.94 mmol), HOBT.H2O (0.49 g, 3.62 mmol) and N-methylmorpholine (0.72 mL, 6.58 mmol) were dissolved in N,N-dimethylformamide (10 mL), and WSCI.HCl (0.76 g, 3.95 mmol) was added at room temperature, followed by stirring for 5.5 hours under nitrogen atmosphere. To the reaction solution, saturated brine (40 mL) was added, and extraction was carried out with ethyl acetate (70 mL). After washed with saturated brine, drying was carried out over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-6%) to afford the desired compound (1.42 g, 81%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:8][C:9]([O:11]CC2C=CC=CC=2)=[O:10])=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:8][C:9]([OH:11])=[O:10])=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N(CC(=O)OCc1ccccc1)Cc1ccc(Br)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CC(=O)O)Cc1ccc(Br)cc1
Temperature: 25 °C
Yield: 101.5 %

Procedure:
To a solution of 81A (325 mg, 0.75 mmol) in THF (5 mL) was added LiOH (0.5 mL, 3 mmol). The mixture was stirred rt over night, then concentrated. Water (20 mL) was added to the residue, and the organic phase washed with CH2Cl2 (2×20 mL). The aqueous layer was acidified with 1N HCl, and was extracted with EtOAc (2×20 mL). The combined organic layer washed with brine, dried (Na2SO4) and concentrated to give 81B (262 mg, 100%). 1H NMR (400 MHz, CD3OD) δ ppm 1.36-1.51 (m, 9 H) 3.76-3.99 (m, 2 H) 4.44 (d, J=5.71 Hz, 2 H) 7.18 (d, J=8.35 Hz, 2 H) 7.41-7.49 (m, 2 H).
Reaction SMILES: N#N.[CH3:3][O:4][CH2:5][C:6]1[O:7][CH:8]=[C:9]([CH2:11][OH:12])[N:10]=1.CCN(CC)CC.[S:20](Cl)([CH3:23])(=[O:22])=[O:21]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:23][S:20]([O:12][CH2:11][C:9]1[N:10]=[C:6]([CH2:5][O:4][CH3:3])[O:7][CH:8]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: COCc1nc(CO)co1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCc1nc(COS(C)(=O)=O)co1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.6 %

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (2-(methoxymethyl)oxazol-4-yl)methanol (76 mg, 0.53 mmol) in dry CH2Cl2 (5 mL) was treated at 0° C. with Et3N (0.10 mL, 0.69 mmol) followed by DMAP (6.6 mg, 0.05 mmol) and Ms-Cl (0.05 mL, 0.67 mmol). After stirring at 0° C. for 30 min, the reaction was quenched with water (5 mL). The org. layer was dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give 118 mg of crude (2-(methoxymethyl)oxazol-4-yl)methyl methanesulfonate as a brown oil. LC-MS-conditions 07: tR=0.51 min, [M+H]+=222.02. A solution of this crude material (118 mg) in DMF (1.3 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (635 mg of a 9.6% solution in DMF, 0.53 mmol) in DMF (1.3 mL) pre-treated for 30 min with DIPEA (0.18 mL, 1.07 mmol) and the reaction mixture was stirred for 24 h at 50° C. Water (10 mL), followed by EA (10 mL) was added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (1:1 hept-EA) gave the title compound as a yellow oil: TLC: rf (1:1 hept-EA)=0.31. LC-MS-conditions 07: tR=0.62 min, [M+H]+=240.10.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[O:14])[CH2:9][CH2:8]1)=[O:6])[CH3:3].[BH4-].[Na+]>CO>[CH3:3][C:2]([CH3:21])([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[OH:14])[CH2:9][CH2:8]1)=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2cccnc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2cccnc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
A solution of 1-(1,1-dimethylethyloxycarbonyl)-4-(3-pyridinoyl)piperidine (5.0 g, 17.22 mmol) in methanol (75 mL) was cooled to 0° C. and sodium borohydride (1.30 g, 34.44 mmol) was added in four portions. The mixture was stirred at 0° C. for 1 h. The solvent was evaporated and the residue was partitioned between water (25 mL) and ethyl acetate (100 mL, 2×50 mL). The organic extracts were washed sequentially with 1N aqueous sodium hydroxide (25 mL) and brine (25 mL), combined, dried over Na2SO4, filtered and evaporated to afford the title alcohol as a white foam (5.02 g, 17.17 mmol, 99%). 1H NMR: δ8.45 (brs, 2H, H--C(2'), H--C(6')), 7.85 (brd, J=8.4 Hz, 1H, H--C(4')), 7.28 (dd, J=4.9, 8.4 Hz, 1H, H--C(5')), 4.43 (d, J=7.1 Hz, 1H, CHOH), 4.08 (m, 2H, eq-H--C(2)), 3.28 (exs, 1H, CHOH), 2.62 (m, 2H, ax-H--C(2)), 1.90 (m, 2H, eq-H--C(3)), 1.77 (m, 1H, H--C(4)), 1.43 (s, 9H, (CH3)3C), 1.28 (m, 2H, ax-H--C(3)). CIMS: m/z 293 (87%, (M+H)+ for C16H24N2O3), 265 (19), 237 (100), 219 (14), 175 (24).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([C:11]2[S:12][C:13](S(C)(=O)=O)=[N:14][N:15]=2)[CH:8]=[C:7]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:6]=1[OH:24])([CH3:4])[CH3:3].[CH2:25]([CH2:27][NH2:28])[OH:26]>C(O)(C)C>[CH3:1][C:2]([C:5]1[CH:10]=[C:9]([C:11]2[S:12][C:13]([NH:28][CH2:27][CH2:25][OH:26])=[N:14][N:15]=2)[CH:8]=[C:7]([C:20]([CH3:22])([CH3:21])[CH3:23])[C:6]=1[OH:24])([CH3:3])[CH3:4]
Reactant: NCCO
Reactant: CC(C)(C)c1cc(-c2nnc(S(C)(=O)=O)s2)cc(C(C)(C)C)c1O
Solvent: CC(C)O
Product: CC(C)(C)c1cc(-c2nnc(NCCO)s2)cc(C(C)(C)C)c1O
Yield: 84 %

Procedure:
To a solution of 2,6-bis(1,1-dimethylethy)-4-[5-(methylsulfonyl)-1,3,4-thiadiazole-2-yl]phenol (4.0 g, 0.0109 mole) in isopropyl alcohol (15 ml) is added ethanolamine (1.9 g, 0.0326 mole). The resulting mixture is heated to reflux for 18 hours. The reaction is cooled and concentrated in vacuo. The resulting solid is recrystallized from methanol/water to give 3.2 g (3.8 g theor., 83%) of 2,6-bis(1,1-dimethylethyl)-4-[5-[(2-hydroxyethyl)amino]-1,3,4-thiadiazol-2-yl]phenol after drying in vacuo at 65° C., mp 212°-213.5° C.
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=O)(C)(C)C.[C:17]([O:21][C:22]([NH:24][C@@H:25]([C:27]([OH:29])=O)[CH3:26])=[O:23])([CH3:20])([CH3:19])[CH3:18].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[C:17]([O:21][C:22]([NH:24][C@@H:25]([C:27]([NH:8][C@@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:29])[CH3:26])=[O:23])([CH3:18])([CH3:19])[CH3:20]
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Product: CC(C)C[C@@H](NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 18 h

Procedure:
Nα-t-Butoxycarbonyl-D-leucine resin (53 g., 42.9 mmol) is deprotected as in part (b), and Nα-t-butoxycarbonyl-D-alanine (8.5 g., 45 mmol) is added followed by the addition of dicyclohexylcarbodiimide, 9.3 g., 45 mmol in chloroform, after 15 to 30 minutes, followed by agitation for 18 hours. The product is separated by filtration and washed three times with dichloromethane, 250 ml., and dried.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:11][C:12]([NH:14][C:15](C)=O)=[O:13].C=O>S(=O)(=O)(O)O>[CH3:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[CH2:15][NH:14][C:12](=[O:13])[CH3:11]
Reactant: Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)NC(C)=O
Agent: C=O
Agent: O=S(=O)(O)O
Product: CC(=O)NCc1cc([N+](=O)[O-])ccc1C
Temperature: 55 °C
Reaction time: 19 h
Yield: 64.8 %

Procedure:
To a solution of p-nitrotoluene (2.74 g; 0.02 mol) and diacetamide (4.24 g; 0.04 mol) in concentrated sulfuric acid (20 ml) is added aqueous formaldehyde (37%; 1.6 g; 0.02 mol) dropwise with stirring. The reaction mixture is stirred at room temperature for 17 hours, heated to 55° C. for 8 hours and then to 85° C. for 19 hours. The mixture is then poured onto ice. The resulting colorless precipitate is removed by filtration and recrystallized from aqueous ethanol to give 2.7 g of product (65% yield) having a melting point of 133° to 137.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.[Br:19]N1C(=O)CCC1=O.C(N(CC)CC)C.O>C(#N)C>[Br:19][CH:9]=[CH:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[N:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(/C=C/B2OC(C)(C)C(C)(C)O2)cn1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: Cc1ccc(C=CBr)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (E)-2-methyl-5-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)-pyridine (1.0 g, 4.08 mmol; Example 23B) in acetonitrile (10 mL) was treated with N-bromosuccinimide (0.346 mL, 4.08 mmol; Aldrich) and triethylamine (0.625 mL, 4.49 mmol; Aldrich) and stirred at room temperature for 16 hours. Water was added and the mixture was extracted several times with ethyl acetate. The combined organic extracts were concentrated, and the resulting material was purified by flash chromatography (silica gel, hexane/ethyl acetate, 3:1) to afford the title compound as a 1.2:1 Z/E mixture: 1H NMR (300 MHz, CDCl3) δ ppm 2.54 (s, 3H), 2.57 (s, 3.6H), 6.52 (d, J=14 Hz, 1.2H), 6.75-6.85 (d, J=14 Hz, 1H), 7.01-7.22 (m, 4.4H), 7.52 (dd, J=8, 2 Hz, 1H), 8.07 (dd, J=8, 2 Hz, 1.2H), 8.43 (d, J=2 Hz, 1H), 8.66 (d, J=2 Hz, 1.2H); MS (DCI/NH3) m/z 198/200 (M+H)+.
Reaction SMILES: [NH:1]([C:8]1[CH:14]=[C:13]([CH2:15][CH3:16])[C:12]([Cl:17])=[CH:11][C:9]=1[NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][CH2:19][C:20](O)=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:2]1([N:1]2[C:8]3[CH:14]=[C:13]([CH2:15][CH3:16])[C:12]([Cl:17])=[CH:11][C:9]=3[N:10]=[C:20]2[CH2:19][Cl:18])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1cc(Nc2ccccc2)c(N)cc1Cl
Reactant: O=C(O)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCc1cc2c(cc1Cl)nc(CCl)n2-c1ccccc1
Temperature: 130 °C

Procedure:
A mixture of 2-anilino-4-ethyl-5-chloroaniline (3.3 g, 13.4 mmol) prepared in the preceding step (a), polyphosphoric ester (8.9 g) and monochloroacetic acid (1.3 g, 13.4 mmol) was heated for 1 hour at 130° C. under stirring. Water was added to the reaction mixture to decompose an excess of the ester and they were neutralized with sodium carbonate and the occurred oily substance was extracted with chloroform, which was washed, dried, and concentrated in vacuo.
Reaction SMILES: [C@@H:1]12[CH2:7][NH:6][C@@H:5]1[CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2]2.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][N:20]=1>>[Cl:18][C:19]1[N:20]=[CH:21][C:22]([N:6]2[CH2:7][C@@H:1]3[C@H:5]2[CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:2]3)=[CH:23][CH:24]=1
Reactant: Clc1ccc(Br)cn1
Reactant: O=C(OCc1ccccc1)N1C[C@@H]2CN[C@@H]2C1
Product: O=C(OCc1ccccc1)N1C[C@@H]2CN(c3ccc(Cl)nc3)[C@@H]2C1
Yield: 50.5 %

Procedure:
The product of Example 40A (0.8 g, 3.4 mmol) and 2-chloro-5-bromopyridine (0.98 g, 5.1 mmol) was processed according to the procedure described in Example 1E. The crude product was purified by chromatography (SiO2, hexane:ethyl acetate, 60:40, Rf0.3) to provide the title compound (0.59 g, 51% yield). 1H NMR (MeOH-d4, 300 MHz) δ 3.24 (dd, J=12.9, 4.1 Hz, 1H), 3.30 (m, 1H), 3.40 (m, 1H), 3.65 (dd, J=7.8, 3.4 Hz, 1H), 4.08-3.92 (m, 3H), 4.70 (dd, J=5.7, 3.7 Hz, 1H), 5.10 (m, 2H), 6.90 (dd, J=8.5, 3.1 Hz, 1H), 7.20 (d, J=8.8 Hz, 1H), 7.25 (m, 3H), 7.35 (m, 2H), 7.54 (d, J=3.0 Hz, 1H); MS (DCI/NH3) m/z 346 (M+2+H)+, 344 (M+H)+.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][O:29][CH2:28][C:27]3[CH:36]=[CH:37][C:38]([O:39][CH3:40])=[C:25]([O:24][CH3:23])[CH:26]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1ccc(COCCCCCBr)cc1OC
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1ccc(COCCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)cc1OC

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 5-(3,4-dimethoxybenzyloxy)-pentyl bromide are reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-N-((1-(5-(3,4-dimethoxybenzyloxy)pentyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: CC([O-])(C)C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([OH:15])[CH:11]=[CH:12][C:13]=1[Cl:14].Cl[C:17]1[N:22]=[C:21]([C:23]#[N:24])[C:20]([S:25][CH2:26][CH3:27])=[CH:19][CH:18]=1.C>C(Cl)Cl.CS(C)=O.C1COCC1>[Cl:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:13]=1[Cl:14])[O:15][C:17]1[N:22]=[C:21]([C:23]#[N:24])[C:20]([S:25][CH2:26][CH3:27])=[CH:19][CH:18]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CCSc1ccc(Cl)nc1C#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCSc1ccc(Oc2ccc(Cl)c(Cl)c2)nc1C#N
Temperature: 0 °C
Yield: 77.8 %

Procedure:
In a reaction flask were placed 110 ml of THF, 10 ml of DMSO and 5.6 g of t-BuOK. 3,4-Dichlorophenol (8.2 g) was added and the mixture was stirred until solution was achieved. To this was added 9.9 g of 6-chloro-3-ethylthio-2-pyridinecarbonitrile and the reaction mixture was heated at reflux temperature for about 5 hours. After cooling, the contents of the flask were poured onto 500 g of ice, stirred until the ice had melted and then filtered. The solid obtained by filtration was dissolved in CH2Cl2, treated with charcoal, dried and was concentrated. Upon dilution with hexane, 12.6 g (77.5%) of 6-(3,4-dichlorophenoxy)-3-ethylthio-2-pyridinecarbonitrile was obtained as a tan crystalline material, m.p. 64°-66° C. Subsequent analysis by differential scanning calorimetry indicated that the compound obtained was polymorphic and existed in two crystalline forms: one melting at 66°-69° C., and the other at 81°-87° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:23])=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[O:20][CH3:21])=[O:8].[N:24]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][C:30]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:31])=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:13]=[CH:12][C:11]=1[O:20][CH3:21])=[O:8]
Reactant: COc1ccc(C(F)(F)F)cc1NC(=O)c1cc(Br)ccc1O
Reactant: O=C(Cl)N1CCOCC1
Product: COc1ccc(C(F)(F)F)cc1NC(=O)c1cc(Br)ccc1OC(=O)N1CCOCC1
Yield: 94.9 %

Procedure:
Using 5-bromo-2-hydroxy-N-[2-methoxy-5-(trifluoromethyl)phenyl]benzamide and morpholine-4-carbonyl chloride as the raw materials, the same operation as the Example 71 gave the title compound.
Reaction SMILES: Cl.Cl.[CH3:3][S:4]([CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]1)(=[O:6])=[O:5].N1([O:26][C:27](=O)[C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[C:30]([O:35][CH3:36])[CH:29]=2)C2C=CC=CC=2N=N1.CN(C)C=O.C(N(CC)CC)C>ClCCl>[NH2:34][C:31]1[CH:32]=[CH:33][C:28]([C:27]([NH:16][CH:13]2[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][CH2:7][S:4]([CH3:3])(=[O:6])=[O:5])[CH2:11][CH2:12]2)=[O:26])=[CH:29][C:30]=1[O:35][CH3:36]
Reactant: CS(=O)(=O)CCCN1CCC(N)CC1
Reactant: COc1cc(C(=O)On2nnc3ccccc32)ccc1N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(CCCS(C)(=O)=O)CC2)ccc1N
Temperature: 25 °C
Reaction time: 20 h
Yield: 69 %

Procedure:
To a mixture of 2.3 g of 1-(3-methanesulfonyl-propyl)-piperidin-4-ylamine dihydrochloride, 2.7 g (0.0095 mole) of 4-amino-3-methoxy-benzoic acid benzotriazol-1-yl ester and 15 mL of dimethylformamide was added 4.0 g (0.0395 mole) of triethylamine. The mixture was stirred at room temperature for 20 hours, then diluted with 150 mL of dichloromethane. The mixture was washed twice with 100 mL of sodium bicarbonate, once with 50 mL of water, once with 50 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-80:20) to give 2.0 g of 4-amino-N-[1-(3-methanesulfonyl-propyl)-piperidin-4-yl]-3-methoxy-benzamide.