Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([O:15][CH3:16])[NH:14][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:17]>CO>[CH3:16][O:15][C:13]1[NH:14][C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:17])[C:11]=2[N:12]=1
Reactant: N
Reactant: COc1nc2c(Cl)nc3ccccc3c2[nH]1
Solvent: CO
Product: COc1nc2c(N)nc3ccccc3c2[nH]1
Temperature: 150 °C

Procedure:
4-Chloro-2-methoxy-1H-imidazo[4,5-c]quinoline (700 mg) was added to a high-pressure vessel with ammonia (40 mL of a 7 N solution in methanol), and the vessel was sealed and heated at 150° C. for 24 hours, allowed to cool, and concentrated under reduced pressure. The crude product was purified twice by automated flash chromatography (silica cartridge, eluting with aqueous ammonium hydroxide:methanol:dichloromethane first in a gradient from 0:0:100 to 0.3:4.7:95 and secondly in a gradient from 0:0:100 to 0.2:3.8:96) to provide 20 mg of 2-methoxy-1H-imidazo[4,5-c]quinolin-4-amine as a white solid. The compound was further purified by prep HPLC according to the method described in Examples 8-55. The observed accurate mass (M+H) for the isolated trifluoroacetate salt was 215.0931.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH2:12][C:13]([F:16])([F:15])[F:14])[CH2:7][CH:8]([CH2:10][CH3:11])[O:9][C:4]=2[CH:3]=1.CCO[C:22]([CH3:24])=[O:23]>>[CH2:10]([CH:8]1[O:9][C:4]2[C:5](=[CH:17][C:18]3[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:24][C:22](=[O:23])[NH:1][C:2]=3[CH:3]=2)[N:6]([CH2:12][C:13]([F:16])([F:15])[F:14])[CH2:7]1)[CH3:11]
Reactant: CCOC(C)=O
Reactant: CCC1CN(CC(F)(F)F)c2ccc(N)cc2O1
Product: CCC1CN(CC(F)(F)F)c2cc3c(C(F)(F)F)cc(=O)[nH]c3cc2O1

Procedure:
(±)-7-Amino-2-ethyl-3,4-dihydro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine (Structure 5 of Scheme I, where R6=Et, Rx=CF3). This compound was prepared by General Method 4 (EXAMPLE 1) from (±)-2-ethyl-3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine (170 mg, 0.6 mmol) and purified by flash chromatography (CH2Cl2/MeOH, 20:1) to afford 151 mg (99%) of (±)-7-amino-2-ethyl-3,4-dihydro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine. Data for (±)-7-amino-2-ethyl-3,4-dihydro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine: Rf 0.62 (3:2 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 6.56 (d, 1H, J=8.0), 6.25-6.20 (m, 2H), 3.93 (m, 1H), 3.70-3.64 (m, 3H), 3.43 (br s, 1H), 3.31 (m, 1H), 3.12 (dd, 1H, J=11.9, 8.1), 1.74-1.59 (m, 2H), 1.04 (t, 3H, J=7.5).
Reaction SMILES: C(O)CC.Cl.[CH3:6][O:7][NH2:8].[CH3:9][C:10]1[CH:14]=[C:13]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][O:24][C:25]2[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=2[CH3:32])=O)[O:12][N:11]=1>O>[CH3:6][O:7][N:8]=[C:15]([C:13]1[O:12][N:11]=[C:10]([CH3:9])[CH:14]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][O:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1[CH3:32]
Reactant: CON
Reactant: Cc1ccc(C)c(OCc2ccccc2C(=O)c2cc(C)no2)c1
Agent: Cl
Solvent: O
Solvent: CCCO
Product: CON=C(c1cc(C)no1)c1ccccc1COc1cc(C)ccc1C
Yield: 42.8 %

Procedure:
n-Propanol (2 ml) and methoxyamine hydrochloride (0.25 g, 3 mmol) were added to 2-(2,5-dimethylphenoxymethyl)-phenyl 3-methylisoxazol-5-yl ketone (0.33 g, 1 mmol), and the mixture was stirred under reflux for 15 hours. After completion of the reaction, water (200 ml) was added, the mixture was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give isomer A (0.18 g, 51.4%, as colorless crystals) and isomer B (0.15 g, 42.8%, as colorless crystals) of 2-(2,5-dimethylphenoxymethyl)phenyl 3-methylisoxazol-5-yl ketone O-methyloxime. One of the isomers A and B is the E-isomer and the other is Z-isomer.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([OH:5])=[O:4].S(OCC)(O[CH2:12][CH3:13])(=O)=O.C1(C(=CC(=C(C=1)C)C)C)C>O.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([O:5][CH2:12][CH3:13])=[O:4]
Reactant: O=C(O)C(Cl)(Cl)Cl
Reactant: CCOS(=O)(=O)OCC
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: Cc1cc(C)c(C)cc1C
Agent: [Cl-]
Solvent: O
Product: CCOC(=O)C(Cl)(Cl)Cl
Temperature: 60 °C

Procedure:
A solution of trichloroacetic acid (3.33 g, 20 millimoles, Sigma, 99.0+%) in water (171.02 g) was introduced into a three-necked 500 mL flask and warmed up to 60° C. when mechanically stirred (600 rpm). Next, the organic phase consisting of diethyl sulfate (15.49 g, 100 millimoles, Aldrich, 99+%), Adogen 464 (0.90 g, 2 millimoles, Aldrich), and durene (chromatographic standard, 0.652 g, 5 millimoles. Aldrich, 98%) was added to the flask. The organic phase:aqueous phase weight ratio was 1:10. Since diethyl sulfate decomposes in water, the reaction mixture was stirred at 60° C. for 30 minutes. Then, the reaction was stopped and an aliquot of the organic phase was centrifuged to remove the aqueous phase and injected into the gas chromatographic column. The yield of ethyl trichloroacetate based on the limiting reactant (trichloroacetic acid) was 15%. No other products were present in the chromatogram.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5][CH2:4][C:3]1=[O:19].[CH2:20]=[O:21].[OH-].[Na+]>C(OCC)(=O)C>[OH:21][CH2:20][CH:4]1[N:5]=[C:6]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:2]([CH3:1])[C:3]1=[O:19]
Reactant: CN1C(=O)CN=C(c2ccccc2)c2ccccc21
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CN1C(=O)C(CO)N=C(c2ccccc2)c2ccccc21
Yield: 15 %

Procedure:
A reaction mixture of 1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (J. Org. Chem. 52, 3232, (1987)) (12.6 g, 50 mmol), formaline-solution (37% in water, 75 mL) and sodium hydroxide (4.4 g, 110 mmol) was heated to reflux for 4.5 hours. Then additional formaline solution (35 mL) and sodium hydroxide (2.2 g) was added and the reaction mixture was heated for 4 hours. The cooled suspension was diluted with ethyl acetate, the organic layer separated, washed with water and dried over Na2SO4. The organicsolution was evaporated in vacuum and the residue flash-chromatographed on silica gel using toluene/ethanol (3.5%) as eluant to give 1,3-dihydro-3-hydroxymethyl-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (2.15 g, 15%).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][O:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH3:23].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[O:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH3:23]
Reactant: O=C1COC(=O)N1CCCCSc1cccc2nccn12
Reactant: CC=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CC=C1OC(=O)N(CCCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.527 g (5.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]oxazolidine-2,4-dione and 0.311 ml (5.0 mmol) of acetaldehyde in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 17 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=3/1) to yield 77 mg (4.65%, yellow oily substance) of the desired product.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[CH:20]=[CH:19][CH:18]=[CH:17][C:5]=1[C:6]([C:8]1[O:12][C:11]([C:13]([O:15]C)=[O:14])=[CH:10][CH:9]=1)=[O:7].[OH-].[Na+]>O.CO>[CH3:3][C:4]1[CH:20]=[CH:19][CH:18]=[CH:17][C:5]=1[C:6]([C:8]1[O:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][CH:9]=1)=[O:7]
Reactant: COC(=O)c1ccc(C(=O)c2ccccc2C)o1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccccc1C(=O)c1ccc(C(=O)O)o1
Reaction time: 1 h
Yield: 96.9 %

Procedure:
A warm solution of potassium hydroxide (28 g.) in water (60 ml.) and methanol (120 ml.) was added to a warm solution of methyl 5-(2-methylbenzoyl)-2-furoate [prepared as described in (c) above; 110 g.] in methanol (550 ml.) and the mixture was allowed to stand at ambient temperature for 1 hour. The solution was then basified by the addition of 2N aqueous sodium hydroxide solution (50 ml.) and allowed to stand at ambient temperature overnight. The alkaline solution thus obtained was evaporated to dryness and the residue was dissolved in water. The aqueous solution was magnetically stirred whilst it was made strongly acid by the addition of concentrated hydrochloric acid. The precipitate was collected and washed with water to give 5-(2-methylbenzoyl)-2-furoic acid (100.5 g.), m.p. 155°-157° C.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[CH:10](=O)C1C=CC=CC=1.O>C1(C)C=CC=CC=1>[CH3:10][NH:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1
Reactant: O=Cc1ccccc1
Reactant: NC1CN2CCC1CC2
Solvent: Cc1ccccc1
Solvent: O
Product: CNC1CN2CCC1CC2
Temperature: 0 °C

Procedure:
A mixture of 50 g of 3-amino quinuclidine and 40 ml of benzaldehyde in 1000 ml of toluene is brought to reflux for 45 minutes, while eliminating the water formed. Then the solvent is evaporated, the residue is dissolved in 800 ml of methanol and 15 g of potassium borohydride are added within 3 hours while maintaining the temperature at 0° C. Then the solvent is evaporated, the residue is taken up in water, the mixture obtained is extracted with ethyl acetate (or with chloroform), dried on sodium (or magnesium) sulfate, filtered and the filtrate is evaporated. Thus 85 g (yield ≃100%) of the pure expected product are obtained (one spot in TLC) which is in liquid form.
Reaction SMILES: Cl[C:2]1[C:3]([C:18]#[N:19])=[N:4][CH:5]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=2[CH3:17])[CH:7]=1.[CH3:20][C:21]1[CH:22]=[CH:23][C:24](B2OC(C)(C)C(C)(C)O2)=[C:25]([NH:27]C(=O)OC(C)(C)C)[CH:26]=1>>[CH3:17][C:11]1[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:10]=1[C:9]#[C:8][C:6]1[CH:5]=[N:4][C:3]2[C:2]([CH:7]=1)=[C:24]1[CH:23]=[CH:22][C:21]([CH3:20])=[CH:26][C:25]1=[N:27][C:18]=2[NH2:19]
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(NC(=O)OC(C)(C)C)c1
Reactant: Cc1ccc(C#Cc2cnc(C#N)c(Cl)c2)c(C)c1
Product: Cc1ccc(C#Cc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1

Procedure:
2-((2,4-Dimethylphenyl)ethynyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine was prepared from 3-chloro-5-((2,4-dimethylphenyl)ethynyl)picolinonitrile (from Example 47/Step 3) and tert-butyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (from Example 5/Step 2) following the procedures described for Example 44, step 4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([NH:20][C:21]1[CH:27]=[C:26]([O:28][CH2:29][CH2:30][CH2:31][N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])[CH:25]=[C:24]([O:37][CH2:38][CH2:39][CH2:40][N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])[C:22]=1[NH2:23])[CH2:17][CH2:18][CH3:19]>C(O)C>[CH2:16]([N:20]1[C:21]2[CH:27]=[C:26]([O:28][CH2:29][CH2:30][CH2:31][N:32]([CH2:33][CH3:34])[CH2:35][CH3:36])[CH:25]=[C:24]([O:37][CH2:38][CH2:39][CH2:40][N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])[C:22]=2[N:23]=[C:14]1[CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCNc1cc(OCCCN(CC)CC)cc(OCCCN(CC)CC)c1N
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Solvent: CCO
Product: CCCCn1c(C2CCN(C(=O)OC(C)(C)C)CC2)nc2c(OCCCN(CC)CC)cc(OCCCN(CC)CC)cc21
Yield: 69 %

Procedure:
A solution of 1-(t-butyloxycarbonyl)piperdine-4-carboxaldehyde (235 mg; 1.1 mmol) and 2-butylamino-4,6-di(3-diethylaminopropoxy)aniline (synthesized via General Procedures J1 and J2 and I) (424 mg; 1 mmol) in ethanol (5 mL) was subjected to General Procedure K. The crude product was purified by silica gel column chromatography using 10% MeOH in DCM with a gradual increment of triethylamine (0.2 to 1.0%) as eluent to afford 425 mg of tert-butyl {4-[1-butyl-4,6-di(3-diethylaminopropoxy)-1H-benzimidazol-2-yl]}piperidine-1-carboxylate.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]([O:29][CH2:30][CH3:31])=[C:8]([CH:28]=1)[C:9]([NH:11][C:12]1[C:13]([C:25]([NH2:27])=[O:26])=[N:14][N:15]([CH:19]2[CH2:22][N:21]([CH2:23][CH3:24])[CH2:20]2)[C:16]=1[CH2:17][CH3:18])=O)(=[O:3])[CH3:2].[CH2:32](O)[CH2:33]CC>>[C:1]([C:4]1[CH:28]=[C:8]([C:9]2[NH:27][C:25](=[O:26])[C:13]3[C:12](=[C:16]([CH2:17][CH3:18])[N:15]([CH:19]4[CH2:22][N:21]([CH2:23][CH3:24])[CH2:20]4)[N:14]=3)[N:11]=2)[C:7]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[N:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCOc1ncc(C(C)=O)cc1C(=O)Nc1c(C(N)=O)nn(C2CN(CC)C2)c1CC
Reactant: CCCCO
Product: CCCCOc1ncc(C(C)=O)cc1-c1nc2c(CC)n(C3CN(CC)C3)nc2c(=O)[nH]1

Procedure:
To a stirred suspension of 5-Acetyl-N-[3-(aminocarbonyl)-5-ethyl-1-(1-ethyl-3-azetidinyl)-1H-pyrazol-4-yl]-2-ethoxynicotinamide, the title compound of Preparation 2(e), (0.41 g, 0.96 mMol) in n-butanol (4 mL) under nitrogen atmosphere at room temperature was added n-butyl acetate (1.92 mMol, 0.25 mL) followed by potassium tert-butoxide (14.4 mMol, 162 mg) as a single solid portion. The reaction was left to stir at room temperature for 5 minutes before being heated to reflux overnight. The reaction was not complete so further n-butyl acetate (1.92 mMol, 0.25 mL) and potassium tert-butoxide (1.92 mMol, 215 mg) were added and the reaction was heated to reflux for a further 2 h. The reaction was allowed to cool to room temperature and then reduced to low volume (ca 1 mL) at reduced pressure. The crude concentrate was then diluted with DCM (50 mL) and washed with water (50 mL). The bi-phasic mixture was then passed through a pad of celite and the cake was washed with further DCM (50 mL). The two phases were then treated with brine (20 mL) and separated. The aqueous phase was then extracted with DCM (3×40 mL). The combined organics were then evaporated at reduced pressure to afford a dark brown oil that appeared to contain residual n-butanol. The crude residue was triturated with hexane (10 mL) and the resultant tan solid isolated by decanting the liquors to afford the title compound, 0.50 g, yield by HPLC=50%. M/Z=439 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([CH3:28])=[C:6]2[C:11](=[C:12]([CH3:15])[C:13]=1[CH3:14])[O:10][C:9]([CH3:27])([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=1)[CH2:8][CH2:7]2)[CH3:2].CO>[Pd].C1C=CC=CC=1>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:16][C:9]2([CH3:27])[CH2:8][CH2:7][C:6]3[C:11](=[C:12]([CH3:15])[C:13]([CH3:14])=[C:4]([O:3][CH2:1][CH3:2])[C:5]=3[CH3:28])[O:10]2)=[CH:19][CH:20]=1
Reactant: CCOc1c(C)c(C)c2c(c1C)CCC(C)(COc1ccc([N+](=O)[O-])cc1)O2
Agent: [Pd]
Solvent: c1ccccc1
Solvent: CO
Product: CCOc1c(C)c(C)c2c(c1C)CCC(C)(COc1ccc(N)cc1)O2

Procedure:
The procedure described in Preparation 62 was repeated, except that 11 g of 6-ethoxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman (prepared as described in Preparation 61), 2.2 g of 10% w/w palladium-on-carbon, 100 ml of methanol and 30 ml of benzene were used as the starting materials to give the title compound, melting at 121°-123° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[N:7]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]([CH2:32][CH2:33][CH3:34])[CH2:29][CH2:30][CH3:31])=[CH:18][CH:17]=1)[CH2:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45].O>ClCCl>[C:1]([O:5][C:6](=[O:35])[N:7]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][N:23]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]([CH2:29][CH2:30][CH3:31])[CH2:32][CH2:33][CH3:34])[S:44]([CH3:43])(=[O:46])=[O:45])=[CH:20][CH:21]=1)[CH2:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCN(CCC)CCCCNCc1ccc(CN(Cc2nccn2C)C(=O)OC(C)(C)C)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCN(CCC)CCCCN(Cc1ccc(CN(Cc2nccn2C)C(=O)OC(C)(C)C)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (182.6 mg) obtained in Example 21-4 was dissolved in dichloromethane (5.3 ml) and added with triethylamine (0.105 ml) and methanesulfonyl chloride (43.6 μl), and the whole was stirred at room temperature for 0.5 hours. The reaction solution was added with water, subjected to extraction with chloroform, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (148.0 mg) as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([CH:10]2[CH2:12][CH2:11]2)[OH:9])[C:3]=1[O:13][CH3:14]>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])[C:3]=1[O:13][CH3:14]
Reactant: COc1c(Cl)ccnc1C(O)C1CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1c(Cl)ccnc1C(=O)C1CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 96.2 %

Procedure:
To a solution of (4-chloro-3-methoxy-2-pyridyl)-cyclopropyl-methanol (700 mg, 3.28 mmol) in DCM (20 ml), manganese (IV) oxide (4.6 g, 58 mmol) was added and stirred for 14 h at room temperature. The reaction mixture was filtered over Celite and the filtrate evaporated to dryness to obtain (4-chloro-3-methoxy-2-pyridyl)-cyclopropyl-methanone as a yellow oil (668 mg, 96%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]([O:7][CH2:8][CH2:9][NH2:10])=[CH:5][CH:4]=1.[CH:15](OCC)=[O:16]>>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:12]=[CH:11][C:6]([O:7][CH2:8][CH2:9][NH:10][CH:15]=[O:16])=[CH:5][CH:4]=1
Reactant: NCCOc1ccc(C(F)(F)F)cc1
Reactant: CCOC=O
Product: O=CNCCOc1ccc(C(F)(F)F)cc1
Yield: 97 %

Procedure:
A mixture of 2-(4-trifluoromethylphenoxy)ethylamine (1.38 g, 6.72 mmol) prepared in Reference Example 159 and ethyl formate (10 ml) was heated under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) to afford N-[2-(4-trifluoromethylphenoxy)ethyl]formamide (1.51 g, yield 97%) as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)[C:13](=O)[CH2:14][CH3:15])=[CH:6][CH:5]=1)([O-])=O>CCO.[Pd]>[C:25]1([N:22]2[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][N:12]([CH2:13][CH2:14][CH3:15])[CH2:11][CH2:10][C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=3)[CH2:20][CH2:21]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCC(=O)N(CCc1ccc([N+](=O)[O-])cc1)CCN1CCN(c2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCCN(CCc1ccc(N)cc1)CCN1CCN(c2ccccc2)CC1
Reaction time: 8 h

Procedure:
N-[2-(4-nitro-phenyl)-ethyl]-N-[2-(4-phenyl-piperazin-1-yl)-ethyl]-propionamide 28a (0.33 g, 0.80 mmol) was dissolved in dry EtOH (20 mL) and 10 wt % Pd/C (0.05 g) was added. The mixture was stirred for overnight under H2 at 1 atm. Pressure. The reaction mixture was filtered through celite and filtrate was concentrated under reduced pressure and kept under vacuum for 1 h to give the corresponding aniline. In to the solution of the crude product in 15 ml dry THF was added 1(M) BH3/THF (7 mL, 7 mmol). The reaction mixture was refluxed for 6 h. After the solution was cooled to room temperature, methanol (5 mL) was added slowly. The solvent was removed under reduced pressure and 10% HCl/MeOH (25 mL) was added into the residue and the solution was refluxed for 1 h. Solid NaHCO3 was added and the methanol was removed in vacuo. The mixture was extracted with EtOAc. The combined organic phase was dried over Na2SO4 and evaporated to give the crude product which was purified by chromatography (EtOAc/MeOH=9/1) to give 29a as a colorless oil: 0.23 g (78% yield). 1H NMR (CDCl3, 300 MHz): δ 0.89 (3H, t, J=7.2 Hz, CH3), 1.50 (2H, q, J=7.2 Hz, CH2), 2.48-2.57 (4H, m, CH2Ar, (CH2)N), 2.63-2.75 (10H, m, (CH2)3N, (CH2)2N), 3.20 (4H, t, J=4.8 Hz, (CH2)2NPh), 3.56 (2H, bs, NH2), 6.62 (2H, d, J=8.7 Hz, ArH), 6.85 (1H, t, J=9.6 Hz, ArH), 6.91-6.99 (4H, m, ArH), 7.25 (2H, t, J=9 Hz, ArH). Free base was converted into its hydrochloride salt, mp 262-264° C. Elemental analysis calculated for C23H38N4Cl4,1.05H2O:C, 51.99; H, 7.60; N, 10.54. Found C, 52.37; H, 7.89; N, 10.12.
Reaction SMILES: O.[NH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([SH:10])[N:4]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Cl>>[NH2:2][C:3]1[N:4]=[C:5]([S:10][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[C:12]([Cl:11])[CH:13]=2)[NH:6][C:7](=[O:9])[CH:8]=1
Reactant: ClCc1cccc(Cl)c1
Reactant: Nc1cc(O)nc(S)n1
Solvent: O
Product: Nc1cc(=O)[nH]c(SCc2cccc(Cl)c2)n1

Procedure:
The subtitle compound was prepared according to the procedure of Example 1 step i) treating 4-amino-6-hydroxy-2-mercaptopyrimidine monohydrate (10.00 g) with 3-chlorobenzyl chloride (9.98 g) to afford the subtitle compound as a white solid. Yield: 15.00 g.
Reaction SMILES: [CH2:1](I)[CH3:2].[CH3:4][O:5][CH:6]1[C:11](=[O:12])[NH:10][C:9](=[S:13])[NH:8][C:7]1=[O:14].[OH-].[Na+]>O>[CH2:1]([S:13][C:9]1[NH:8][C:7](=[O:14])[CH:6]([O:5][CH3:4])[C:11](=[O:12])[N:10]=1)[CH3:2]
Reactant: CCI
Reactant: COC1C(=O)NC(=S)NC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCSC1=NC(=O)C(OC)C(=O)N1

Procedure:
Ethyl iodide (11.2 ml) was added dropwise to a stirred mixture of the product from step (i) (23 g) and sodium hydroxide (6 g) in water (400 ml). After 16 h the mixture was filtered, the filtrate acidified to pH1 and the precipitate filtered, washed with water and dried. Yield 17.8 g
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:6][C:5](=[O:7])[CH2:4]1.CN1C=CN=C1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(OCC)C>CN(C)C=O.O>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:1][CH2:2][C@@H:3]2[CH2:4][C:5](=[O:7])[NH:6]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1C[C@@H](CO)N1
Agent: Cn1ccnc1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CC(=O)N2)cc1
Reaction time: 2 h
Yield: 26 %

Procedure:
(4S)-4-(hydroxymethyl)azetidin-2-one a39 (0.41 g, 4.6 mmol, 1 eq) and N-methylimidazole (1.1 ml, 14 mmol, 3.5 eq) are dissolved in dimethylformamide (5 ml) at 0° C. A solution of p-toluenesulfonyl chloride a40 (0.85 g, 4.4 mmol, 4 eq) in dimethylformamide (1 ml) is added dropwise. After 2 h, diethyl ether and water are added. The organic phase is separated, dried over magnesium sulfate and concentrated under reduced pressure to give 0.27 g of crude [(2S)-4-oxoazetidin-2-yl]methyl 4-methylbenzenesulfonate a41.
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:25])([CH3:24])[CH3:23])=[CH:17][CH:16]=2)=[CH:11][C:10]1=[O:26])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1.O>[OH:25][C:22]([CH3:24])([CH3:23])[CH2:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][C:12]2[CH2:13][N:9]([C@@H:4]([CH2:5][CH:6]([CH3:7])[CH3:8])[C:3]([OH:27])=[O:2])[C:10](=[O:26])[CH:11]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)[C@H](CC(C)C)N1CC(Oc2ccc(CC(C)(C)O)cc2)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)O)N1CC(Oc2ccc(CC(C)(C)O)cc2)=CC1=O
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 83 %

Procedure:
A solution of (S)-2-{4-[4-(2-hydroxy-2-methyl-propyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid methyl ester (0.150 g, 0.40 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was treated with lithium hydroxide monohydrate (0.017 g 0.40 mmol). The mixture was stirred at room temperature for 1.75 h and then partitioned between ethyl acetate and water. The water layer was made acidic with 1N aqueous hydrochloric acid (pH=1) and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford (S)-2-{4-[4-(2-hydroxy-2-methyl-propyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid (0.120 g, 83%) as a white solid.