Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:17][C@H:16]2[N+:18]([O-])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CC(O)C.[Zn]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]2[CH2:17][C@H:16]2[NH2:18])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])[C@@H]1C[C@H]1c1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Zn]
Solvent: CC(C)O
Product: N[C@@H]1C[C@H]1c1ccc(OCc2ccccc2)cc1
Yield: 69.6 %

Procedure:
Zn dust (1.97 g, 30 mol) was added in small portions, over a period of 30 min, to a vigorously stirred solution of 1-(benzyloxy)-4-[(trans)-2-nitrocyclopropyl]benzene (Intermediate C, 0.81 g, 3.0 mmol) in i-PrOH (25 mL) and HCl (11 mL of aqueous solution 2.7 N, 30 mmol). After 17 h the mixture was filtered through a pad of celite that was washed with 10 mL of methanol. The filtrate was concentrated and 10 mL of water were added, washing with CH2Cl2 (3×15 mL). The organic layers were dried over anhydrous Na2SO4 and filtered. After removal of the solvent, the crude product was purified by column chromatography on silica gel (10% MeOH/CH2Cl2) affording 0.50 g of (trans)-2-[4-(benzyloxy)phenyl]cyclopropanamine [Rf=0.2 (10% MeOH/CH2Cl2), white solid, 70% yield]. 1H NMR δ (ppm): MeO 400 MH: 7.45-7.27 (m, 5H, ArH); 6.96 (d, J=8.5 Hz, 2H, ArH); 6.86 (d, J=8.5 Hz, 2H, ArH); 5.03 (s, 2H, CH2); 2.41-2.34 (m, 1H, CH); 1.86-1.76 (m, 1H, CH); 0.98-0.85 (m, 2H, CH2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5]([CH2:7][Cl:8])=[O:6].C([C:12]1[CH2:13][S:14][CH2:15][CH2:16][CH:17]=1)=O.S1CCCCC1C([O-])=O>N1CCCCC1.C(O)(=O)C.C(Cl)Cl>[S:14]1[CH2:15][CH2:16][CH2:17][CH2:12][C:13]1=[C:4]([C:5](=[O:6])[CH2:7][Cl:8])[C:3]([O:2][CH3:1])=[O:9]
Reactant: COC(=O)CC(=O)CCl
Reactant: O=CC1=CCCSC1
Agent: O=C([O-])C1CCCCS1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: ClCCl
Product: COC(=O)C(C(=O)CCl)=C1CCCCS1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Methyl-4-chloroacetoacetate (0.45g) in dry methlene dichlorode (5 ml) containing 4A molecular sieve (3g) was treated with tetrahydrothiapyran-2-carboxylate (0.4g) and then piperidine (2 drops) and acetic acid (2 drops). The mixture was stirred at room temperature for 45 min. The solution was diluted with methylene dichloride and the organic solution washed with water and brine. After drying over anhydrous magnesium sulphate the solvent was evaporated. Chromatography of the residue on silica gel using ethyl acetate-hexane (1:5) as eluant gave the title product as a 2:1 (Z/E) mixture of isomers (0.43g). νmax (CHCl3) 1710 and 1625 cm-1.
Reaction SMILES: C(OCl)(C)(C)C.[N+:7]([C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)([O-:9])=[O:8].[CH3:17][S:18][CH3:19].C[O-].[Na+]>C(Cl)Cl.C(#N)C.CO>[N+:7]([C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[C:12]([CH2:17][S:18][CH3:19])[CH:11]=1)([O-:9])=[O:8]
Reactant: CSC
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: CC(C)(C)OCl
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: CO
Product: CSCc1cc([N+](=O)[O-])ccc1N

Procedure:
The starting material is prepared as follows: The solution of 23.4 g of t-butylhypochlorite in 20 ml of methylene chloride is added to that of 30.0 g of 4-nitroaniline and 27.0 g of dimethyl thioether in 650 ml of acetonitrile and 200 ml of methylene chloride while stirring at -40° under nitrogen. After 4 hours the temperature is raised to -20° and maintained there for three hours. After the addition of 30 g of sodium methoxide in 100 ml of methanol the mixture is refluxed for 15 hours, cooled, filtered and evaporated. The residue is dissolved in diethyl ether and filtered through a silica gel column to remove any unreacted 4-nitroaniline as its benzenesulfonate following addition of 17.4 g of benzenesulfonic acid. The filtrate is evaporated and the residue recrystallized from ethanol, to yield the 4 -nitro-2-methylmercaptomethylaniline melting at 72°-77°.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].O>CN(C)C=O>[C:27]([O:26][C:24]([CH2:23][N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(OCc1ccccc1)c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1ccc2cc(C(=O)OCc3ccccc3)ccc21
Reaction time: 0.5 h
Yield: 108.2 %

Procedure:
Sodium hydride (115 mg) was added to a solution of benzyl 1H-indole-5-carboxylate (600 mg) in N,N-dimethylformamide (2 ml) with ice cooling, and the mixture was stirred for 30 minutes. t-Butyl bromoacetate (562 mg) was added thereto and stirred for 2 hours. Water was added thereto, and the aqueous phase was neutralized and then extracted with dichloromethane. The organic phase was dried over sodium sulfate anhydrous. The product was concentrated under reduced pressure to give benzyl 1-t-butoxycarbonylmethyl-1H-indole-5-carboxylate (944 mg, Y.: quant.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].BrC1C=CC(S(O[CH2:26][C@@H:27]2[O:41][C:31]3=[C:32]4[C:37](=[CH:38][CH:39]=[C:30]3[O:29][CH2:28]2)[N:36]=[C:35]([CH3:40])[CH:34]=[CH:33]4)(=O)=O)=CC=1>>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:10][CH2:11][N:12]([CH2:26][C@@H:27]3[O:41][C:31]4=[C:32]5[C:37](=[CH:38][CH:39]=[C:30]4[O:29][CH2:28]3)[N:36]=[C:35]([CH3:40])[CH:34]=[CH:33]5)[CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Reactant: Cc1ccc(N2CCNCC2)cc1C
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CN1CCN(c2ccc(C)c(C)c2)CC1)O3
Yield: 55.9 %

Procedure:
This compound was prepared as described for Example 10, using 1-(3,4-dimethylphenyl)-piperazine (1.01 g, 5.33 mmol), and 804 mg (1.79 mmol) of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl 4-bromobenzene-sulfonate, to afford 404 mg (68%) of the title compound as a white foam: mp 118–120° C.; MS (ESI) m/z404 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][Si:5]([CH3:8])([CH3:7])[CH3:6].[OH:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:6][Si:5]([CH3:8])([CH3:7])[CH2:4][CH2:3][CH2:2][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1
Reactant: C[Si](C)(C)CCCCl
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCCOc1ccc(C=O)cc1
Temperature: 120 °C
Yield: 85.7 %

Procedure:
3-chloropropyltrimethylsilane (33.14 g, 0.22 mol) was added dropwise over 10 minutes to a mixture of 4-hydroxybenzaldehyde (24.4 g, 0.2 mol) and potassium carbonate (30.4 g, 0.22 mol) in 150 ml of dry DMF maintained at 120° C. under nitrogen. The mixture was maintained for 2 hours, 30 minutes, at 120°-130° C. The reaction mixture was cooled and poured into ice-cold water. The aqueous phase was extracted 3 times with dichloromethane. The organic phases were dried over sodium sulfate and concentrated under vacuum. After distillation under vacuum (0.2 mmHg), 40.5 g (yield: 86%) of 4-(3-trimethylsilanylpropyloxy) benzaldehyde were obtained in the form of a colorless oil distilling at 110-114° C. and employed without further purification in the following step.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][CH3:6].[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]=O>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH3:6])[CH:12]1[C:8]1[S:7][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1cccs1
Reactant: CNCCNC
Solvent: Cc1ccccc1
Product: CN1CCN(C)C1c1cccs1

Procedure:
23.5 g (267 mmol) of N,N′-dimethylethylenediamine were dissolved in 300 ml of toluene and treated with 29.8 g (266 mmol) of thiophene-2-carbaldehyde. The clear mixture was refluxed for 4 hours using a Dean-Stark trap. After that time 4.9 ml of water had separated in the trap. After cooling, the solution was filtered and evaporated. The oily residue was destined in vacuo. Yield: 45 g.
Reaction SMILES: [C:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[NH:8][C:9](=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)#[N:2].C(Cl)Cl.C(N(CC)CC)C.Cl.[NH2:31][OH:32]>C(O)C.C(=O)(O)[O-].[Na+]>[OH:32][NH:31][C:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[NH:8][C:9](=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[NH:2]
Reactant: NO
Reactant: COc1ccc(CC(=O)Nc2sccc2C#N)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(CC(=O)Nc2sccc2C(=N)NO)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-(3-cyanothiophen-2-yl)-2-(4-methoxyphenyl)acetamide (234 mg, 0.859 mmol) in a mixture of ethanol (5 mL), methylene chloride (0.5 mL) and triethylamine (202 4, 1.46 mmol) was added hydroxylamine hydrochloride (90 mg, 1.29 mmol). The resulting solution was stirred at room temperature for 18 h and was subsequently diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phases were combined, dried (Na2SO4), filtered, concentrated under vacuum and purified on a silica gel column (eluant hexane/ethyl acetate, 7/3 to 2/8) to give N-(3-(N-hydroxycarbamimidoyl)thiophen-2-yl)-2-(4-methoxyphenyl)acetamide. Retention time (min)=1.161, method [1], MS (ESI) 306.1 (M+H).
Reaction SMILES: [O:1]([C:8]1[C:9]([NH:21][C:22]2[S:26][N:25]=[C:24]([CH:27]3[CH2:32][CH2:31][N:30]([S:33]([CH2:36][CH2:37][N:38]4C(=O)C5C(=CC=CC=5)C4=O)(=[O:35])=[O:34])[CH2:29][CH2:28]3)[N:23]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CCO>[NH2:38][CH2:37][CH2:36][S:33]([N:30]1[CH2:29][CH2:28][CH:27]([C:24]2[N:23]=[C:22]([NH:21][C:9]3[C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][C:12]([S:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=4)=[CH:11][N:10]=3)[S:26][N:25]=2)[CH2:32][CH2:31]1)(=[O:35])=[O:34]
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)N1CCC(c2nsc(Nc3ncc(Sc4ccccn4)cc3Oc3ccccc3)n2)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCS(=O)(=O)N1CCC(c2nsc(Nc3ncc(Sc4ccccn4)cc3Oc3ccccc3)n2)CC1
Temperature: 25 °C
Yield: 14.5 %

Procedure:
2-(2-(4-(5-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-ylsulfonyl)ethyl)isoindoline-1,3-dione (0.110 g, 0.157 mmol) and hydrazine monohydrate (0.0236 g, 0.472 mmol) were dissolved in EtOH (25 mL) and heated to reflux for 8 hours. The reaction was cooled to ambient temperature and the solids filtered and triturated with EtOH to afford the title compound (0.013 g, 14.5% yield). 1H NMR (d6-DMSO) δ 8.38 (d, 1H), 8.36 (m, 1H), 7.66 (dt, 1H), 7.45 (d, 1H), 7.41 (t, 2H), 7.20-7.10 (m, 5H), 3.61 (d, 2H), 3.12 (t, 2H), 3.01-2.89 (m, 5H), 2.09 (d, 2H), 1.79 (m, 2H).
Reaction SMILES: [I:1](O)(=O)(=O)=O.S(=O)(=O)(O)O.[I-:11].[K+].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1>>[Br:13][C:14]1[CH:19]=[C:18]([I:11])[C:17]([Br:20])=[CH:16][C:15]=1[I:1]
Reactant: [O-][I+3]([O-])([O-])O
Reactant: Brc1ccc(Br)cc1
Reactant: [I-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Brc1cc(I)c(Br)cc1I
Temperature: -25 °C
Reaction time: 36 h
Yield: 101.1 %

Procedure:
To a 1 L three-necked flask fitted with a mechanical stirrer were added 16.7 g (73.0 mmol) of periodic acid and 525 ml of sulfuric acid. After periodic acid was dissolved, 36.4 g (219 mmol) of potassium iodide was added portionwise. The content was cooled to a temperature of −30° C. and 34.5 g (146 mmol) of 1,4-dibromobenzene was added over a period of 5 minutes. The resulting mixture was stirred at −30 to −20° C. for 36 hours. After the reaction mixture was poured into ice (2 kg), the whole was filtrated and a solid was taken out. The solid was dissolved in chloroform, the solution was washed with a 5% aqueous sodium hydroxide solution and water, and the organic phase was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was recrystallized from chloroform to obtain white crystals of 1,4-dibromo-2,5-diiodobenzene (36.0 g, yield 50%).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH3:10][O:11][C:12]([C:14]1([CH:17](O)[CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][O:15]1)=[O:13]>C(Cl)Cl>[CH3:10][O:11][C:12]([C:14]1([CH:17]([F:7])[CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][O:15]1)=[O:13]
Reactant: COC(=O)C1(C(O)CCCCc2ccccc2)CO1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1(C(F)CCCCc2ccccc2)CO1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2.44 g (15 mmol; 2.01 ml) of diethylaminosulfur trifluoride in 50 ml of methylene chloride cooled to -78° C. under a nitrogen atmosphere is added dropwise a solution of 2.00 (7.6 mmol) of 2-[1-hydroxy-5-phenylpentyl]-2-oxiranecarboxylic acid methyl ester (isomer A) in 50 ml of methylene chloride over 30 minutes. The mixture is stirred at -78° C. for 90 minutes and then is allowed to come to room temperature. The mixture is stirred at room temperature for 1.5 hours, is quenched with a saturated aqueous solution of sodium bicarbonate and is extracted with ethyl ether. The combined ethereal extracts are dried over magnesium sulfate, filtered and rotoevaporated. The resulting oil is purified chromatographically (silica gel; hexane:ethyl acetate (9:1)) to give 1.19 g of the title compound (Rf 0.54 in hexane:ethyl ether (3:2)): IR (neat) γ1750 cm-1 ; NMR (CDCl3) δ1.40-1.96 (6H, m), 2.64 (2H, t, J=8 Hz), 3.07 (1H, dd, J=4, 6 Hz), 3.15 (1H, d, J=6 Hz), 3.79 (3H, s), 5.14 (1H, ddd, JHF =49 Hz, J=10, 3 Hz), 7.21 (2H, d, J=8 Hz) and 7.31 (2H, d, J=8 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].C(Cl)(Cl)Cl.O.Cl>C(O)C.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(OC)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)O)c(OC)c1
Temperature: 32.5 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
53 g of methyl 2,4-dimethoxybenzoate was dissolved in 160 mL of ethanol, to which 104 mL of a 5M aqueous solution of sodium hydroxide was added, and this mixture was stirred for 2 hours at 25 to 40° C. Then, chloroform and water were added to the reaction mixture, which was adjusted to pH 2 with 6M hydrochloric acid, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure to yield 45 g of 2,4-dimethoxybenzoic acid as white solid.
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](SC2C=CC(S(O)(=O)=O)=CC=2)=[CH:4][C:3]=1OC1C=CC(S(O)(=O)=O)=C(N)C=1.N1C(Cl)=NC(Cl)=NC=1Cl.[Cl-].[Na+]>>[CH:9]1[C:8]2[C:7](=[O:17])[C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1cc(Oc2cc(Sc3ccc(S(=O)(=O)O)cc3)c3c(c2N)C(=O)c2ccccc2C3=O)ccc1S(=O)(=O)O
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: [Cl-]
Agent: [Na+]
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
1-Amino-2-(3'-amino-4'-sulfophenoxy)-4-(4'-sulfophenylthio)anthraquinone (6 parts) and cyanuric chloride (1.8 parts) were subjected to condensation reaction in an aqueous medium in a conventional manner, followed by a condensation reaction with 1-aminobenzene-3-β-sulfatoethylsulfone (2.8 parts) at 20° to 40° C. under weak acid conditions. Thereafter, salting out of the reaction mixture with sodium chloride gave an anthraquinone compound of the following formula (free acid form). ##STR27##
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:13][CH2:14][NH-:15])[CH:7]=[C:8]2[O:12][CH2:11][O:10][C:9]=12.[OH-].[Na+].[CH:18](O)=[O:19]>O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:13][CH2:14][NH:15][CH:18]=[O:19])[CH:7]=[C:8]2[O:12][CH2:11][O:10][C:9]=12
Reactant: O=CO
Reactant: COc1cc(CC[NH-])cc2c1OCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(CCNC=O)cc2c1OCO2
Yield: 81.8 %

Procedure:
6.95 g (30 mmol) of 2-(3-methoxy-4,5-methylenedioxyphenyl)ethylamide hydrochloride was dissolved in 30 ml of water, and the mixture was made basic with 25% sodium hydroxide aqueous solution. The mixture was extracted with 30 ml of toluene. The toluene layer was washed with 10 ml of water, added with 2.73 g (59.3 mmol) of formic acid, refluxed under heating for 2 hours at normal pressure to distill off about 15 ml of the toluene while separating the produced water by an azeotropic distillation and then cooled. The deposited crystal was filtered out, washed with 3 ml of toluene and dried to obtain 5.48 g of N-[2-(3-methoxy-4,5-methylenedioxyphenyl)ethyl]formamide (C). Yield: 83%; melting point: 108°-110° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:47]1([C@@H:53]([NH2:55])[CH3:54])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([NH:55][C@H:53]([CH:47]4[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]4)[CH3:54])=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](N)C1CCCCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N[C@@H](C)C2CCCCC2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with N-((S)-1-cyclohexyl-ethyl)amine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C44H58Cl2N5O3 [(M+H)+] 774.391 1, observed 774.3913.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17](C=O)[CH:16]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+]>C(O)C.O>[C:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH2:16][C:17](=[N:26][OH:27])[C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: NO
Reactant: COc1ccc(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1C=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC1=CC=C(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)CC1=NO
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.7 %

Procedure:
Intermediate (b) N-BOC-(R)-2-(3-formyl-4-hydroxybenzyl)morpholine (0.192 g, 0.06 mmol) was dissolved in dry acetone (5 mL) with potassium carbonate (0.165 g, 1.19 mmol), under an atmosphere of nitrogen and iodomethane (0.074 mL, 1.19 mmol) added in one portion. The resulting mixture was stirred at room temperature for 18 hrs and then concentrated in vacuo. The residue was dissolved in water (10 mL) and extracted with diethyl ether (10 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The orange oil was purified by column chromatography (silica; 35% ethyl acetate/isohexane) to yield the desired product as a yellow oil (0.157 g, 78%). The material was used directly in the next step. N-BOC-(R)-2-(3-formyl-4-methoxybenzyl)morpholine (0.157 g, 0.468 mmol) was dissolved in ethanol (5 mL) and added to a solution of hydroxylamine hydrochloride (42 mg, 0.61 mmol) and sodium acetate (88 mg, 1.08 mmol) in ethanol (5 mL) at room temperature. The resulting mixture was stirred at room temperature for 18 hrs and then heated at 80° C. for 72 hrs. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (20 mL×2). Combined organic layers were washed with brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo to yield the desired intermediate (a), N-BOC-(R)-2-(3-hydroxyimino-4-methoxybenzyl)morpholine as a yellow oil (85 mg).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[Br-].[Li+].[CH2:18]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1.O.CCCCCC>[CH2:18]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31]([OH:34])([C:15]2[C:10]([F:9])=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:30][CH2:29]1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Fc1ccccn1
Agent: CC(C)[N-]C(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(O)(c2cccnc2F)CC1
Temperature: -50 °C

Procedure:
To a solution of lithium diisopropylamide (0.31 mol) in 300 mL of anhydrous tetrahydrofuran:hexane at -78° C. was added a solution of 2-fluoropyridine (24.6 mL) in 40 mL of anhydrous tetrahydrofuran. The reaction mixture was allowed to warm to -50° C., cooled back to -74° C. and treated dropwise with a solution of lithium bromide (55.5 g) and 1-benzyloxycarbonyl-4-oxopiperidine (55.5 g) in 300 mL of anhydrous tetrahydrofuran so that the temperature of the reaction mixture remained below -70° C. After the addition was complete, the reaction mixture was allowed to warm to -30° C. and then treated with water. The organic layer was separated and the aqueous layer was extracted with two portions of ether. Combined organic layers were dried and evaporated to afford the crude product. This material was purified by column chromatography to afford the pure product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]([CH2:16][C:17]3[N:21]([CH2:22][CH2:23][O:24]COC)[C:20]4[CH:28]=[C:29]([Cl:33])[C:30]([Cl:32])=[CH:31][C:19]=4[N:18]=3)[CH3:15])=[O:13])[C:6]=2[CH:34]=1.Cl.CCOC(C)=O>CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]([CH2:16][C:17]3[N:21]([CH2:22][CH2:23][OH:24])[C:20]4[CH:28]=[C:29]([Cl:33])[C:30]([Cl:32])=[CH:31][C:19]=4[N:18]=3)[CH3:15])=[O:13])[C:6]=2[CH:34]=1
Reactant: COCOCCn1c(CN(C)C(=O)Cn2c(=O)oc3ccc(Cl)cc32)nc2cc(Cl)c(Cl)cc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(Cc1nc2cc(Cl)c(Cl)cc2n1CCO)C(=O)Cn1c(=O)oc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 156.8 %

Procedure:
To a mixture of 2-(5-chloro-2-oxo-1,3-benzoxazol-3(2H)-yl)-N-({5,6-dichloro-1-[2-(methoxymethoxy)ethyl]-1H-benzimidazol-2-yl}methyl)-N-methylacetamide (110 mg) and MeOH (0.22 mL) was added 4 M hydrogen chloride/EtOAc (521 μL), followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The obtained solid was washed with EtOAc to obtain 2-(5-chloro-2-oxo-1,3-benzoxazol-3(2H)-yl)-N-{[5,6-dichloro-1-(2-hydroxyethyl)-1H-benzimidazol-2-yl]methyl}-N-methylacetamide hydrochloride (85 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][C:10]([O:12]C)=[O:11])=[C:4]([O:18][CH3:19])[CH:3]=1.[CH3:20][O:21][CH2:22][CH2:23][CH2:24]OS(C1C=CC(C)=CC=1)(=O)=O>CCOCC>[CH3:20][O:21][CH2:22][CH2:23][CH2:24][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][C:10]([OH:12])=[O:11])=[C:4]([O:18][CH3:19])[CH:3]=1
Reactant: COCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CCCCC(CC(=O)OC)c1ccc(O)cc1OC
Solvent: CCOCC
Product: CCCCC(CC(=O)O)c1ccc(OCCCOC)cc1OC

Procedure:
Following a similar procedure to that described in Preparation 45A(i), but using methyl 3-(4-hydroxy-2-methoxyphenyl)heptanoate (prepared as described in Preparation 58A), and 3-methoxy-1-tosyloxypropane, the corresponding ether derivative was obtained. Hydrolysis of this derivative and subsequent treatment of the reaction mixture were conducted in a similar manner to that described in Preparation 7 to give the title compound as an oily substance.