Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27](=[O:33])[C:28]1[CH:32]=[CH:31][S:30][CH:29]=1)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:20][C:25](=[O:24])[CH2:26][C:27](=[O:33])[C:28]1[CH:32]=[CH:31][S:30][CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)c1ccsc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)CC(=O)c1ccsc1
Yield: 81.3 %

Procedure:
Prepared from (3-amino-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G9) (144 mg, 0.51 mmol) and 3-oxo-3-thiophen-3-yl-propionic acid ethyl ester (FR 7191887) (151 mg, 0.76 mmol) according to the general procedure K. Obtained as a yellow foam (181 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][N:10]=[C:9]([CH3:13])[C:5]2=[N:6][C:7]=1[Cl:8].[CH:14]1([NH2:17])[CH2:16][CH2:15]1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:8][C:7]1[N:6]=[C:5]2[C:9]([CH3:13])=[N:10][CH:11]=[CH:12][C:4]2=[N:3][C:2]=1[NH:17][CH:14]1[CH2:16][CH2:15]1
Reactant: NC1CC1
Reactant: Cc1nccc2nc(Cl)c(Cl)nc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1nccc2nc(NC3CC3)c(Cl)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.8 %

Procedure:
2,3-Dichloro-5-methylpyrido[3,4-b]pyrazine (1.700 g, 7.94 mmol) was added to dioxane (15.88 mL), then cyclopropanamine (0.864 mL, 12.71 mmol) and DIPEA (2.24 mL, 13.50 mmol) were added sequentially. The mixture was stirred for 12 h at room temperature then concentrated under reduced pressure. Column chromatography using a gradient of 10% to 75% EtOAc in hexanes provided 3-chloro-N-cyclopropyl-5-methylpyrido[3,4-b]pyrazin-2-amine (1.3 g) as a brown solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:31]=[CH:30][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[CH:17][C:18]([O:25][S:26]([CH3:29])(=[O:28])=[O:27])=[C:19]([CH:24]=3)[C:20]([O:22][CH3:23])=[O:21])[O:12][C:13]=2[CH3:14])=[C:5]([O:32][CH3:33])[CH:4]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:43])=O>C(OCC)(=O)C>[Cl:43][CH2:2][C:3]1[CH:31]=[CH:30][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[CH:17][C:18]([O:25][S:26]([CH3:29])(=[O:28])=[O:27])=[C:19]([CH:24]=3)[C:20]([O:22][CH3:23])=[O:21])[O:12][C:13]=2[CH3:14])=[C:5]([O:32][CH3:33])[CH:4]=1
Reactant: COC(=O)c1cc(-c2nc(COc3ccc(CO)cc3OC)c(C)o2)ccc1OS(C)(=O)=O
Reactant: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)ccc1OS(C)(=O)=O
Yield: 67.4 %

Procedure:
To a mixture of methyl 5-{4-[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-methanesulfonyloxybenzoate (0.20 g) and toluene (10 mL) was added thionyl chloride (0.055 g), and the mixture was heated under reflux for 1 hr. After concentration of the reaction mixture, ethyl acetate was added to the residue. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give methyl 5-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-methanesulfonyloxybenzoate (0.14 g, yield 67%) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 146-147° C.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([C@H:12]1[CH2:16][O:15][C:14]2([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[O:13]1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([Mg]Cl)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[CH2:1]([O:8][C@@H:9]([C@H:12]1[CH2:16][O:15][C:14]2([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[O:13]1)[CH:10]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C[C@@H](OCc1ccccc1)[C@H]1COC2(CCCCC2)O1
Reactant: Cl[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC(c1ccccc1)[C@@H](OCc1ccccc1)[C@H]1COC2(CCCCC2)O1
Temperature: -5 °C
Reaction time: 2 h

Procedure:
A solution of 4.30 g (0.015 mmol) of α(S)-benzyloxy-1,4-dioxaspiro[4,5]decane-2(R)-acetaldehyde in 50 ml of anhydrous diethyl ether was cooled to -8° C. and 15 ml of a 2M solution of phenylmagnesium chloride in tetrahydrofuran were added dropwise over a period of 1 hour. The mixture was stirred at -5° C. for 2 hours, then allowed to warm to room temperature and poured into 50 ml of 10% ammonium chloride solution. The mixture was extracted twice with 100 ml of ethyl acetate each time. The ethyl acetate extracts were dried over anhydrous magnesium sulphate and evaporated. The residue was subjected to flash chromatography on silica gel using 5% methanol in dichloromethane for the elution. There were obtained 2.47 g of β(R)-benzyloxy-α(RS)-phenyl-1,4-dioxaspiro[4,5]decane-2(R)-ethanol in the form of a colourless gum; MS (C.I.): m/e 369 [M+H]+.
Reaction SMILES: I[C:2]1[S:6][C:5]([NH:7][C:8](=[O:10])[CH3:9])=[N:4][C:3]=1[CH3:11].Br[C:13]1[CH:14]=[C:15]([S:19]([NH:22][CH2:23][CH2:24][OH:25])(=[O:21])=[O:20])[CH:16]=[N:17][CH:18]=1>>[OH:25][CH2:24][CH2:23][NH:22][S:19]([C:15]1[CH:14]=[C:13]([C:2]2[S:6][C:5]([NH:7][C:8](=[O:10])[CH3:9])=[N:4][C:3]=2[CH3:11])[CH:18]=[N:17][CH:16]=1)(=[O:21])=[O:20]
Reactant: CC(=O)Nc1nc(C)c(I)s1
Reactant: O=S(=O)(NCCO)c1cncc(Br)c1
Product: CC(=O)Nc1nc(C)c(-c2cncc(S(=O)(=O)NCCO)c2)s1
Yield: 23 %

Procedure:
Using an analogous method to that described in Example 7, N-(5-iodo-4-methyl-1,3-thiazol-2-yl)acetamide was reacted with 5-bromo-N-(2-hydroxyethyl)pyridine-3-sulfonamide to give the title compound (Method A HPLC: retention time 4.0 minutes; 10 mg, 23%); 1H NMR Spectrum: (DMSOd6) 12.22 (1H, br s); 8.92 (1H, d); 8.86 (1H, d); 8.16 (1H, t); 7.96 (1H, br s); 4.73 (1H, t); 3.39 (2H, br q); 2.89 (2H, br t); 2.40 (3H, s); 2.17 (3H, s); Mass Spectrum: M+H+ 357.
Reaction SMILES: [Br-:1].O[C@@H:3]1[CH2:8][CH2:7][CH2:6][N+:5]([CH2:10][C:11](=[O:18])[NH:12][C:13]2[CH:17]=[CH:16][O:15][N:14]=2)([CH3:9])[CH2:4]1.CN1CCC([OH:26])CC1>>[Br-:1].[OH:26][CH:8]1[CH2:7][CH2:6][N+:5]([CH2:10][C:11](=[O:18])[NH:12][C:13]2[CH:17]=[CH:16][O:15][N:14]=2)([CH3:9])[CH2:4][CH2:3]1
Reactant: C[N+]1(CC(=O)Nc2ccon2)CCC[C@@H](O)C1
Reactant: CN1CCC(O)CC1
Agent: [Br-]
Product: C[N+]1(CC(=O)Nc2ccon2)CCC(O)CC1

Procedure:
This compound is prepared by an analogous method to (1R/S,3R)-3-Hydroxy-1-(isoxazol-3-ylcarbamoylmethyl)-1-methyl-piperidinium bromide (Intermediate C) by replacing (R)-1-methyl-piperidin-3-ol (step C3) with 1-methyl-piperidin-4-ol.
Reaction SMILES: [ClH:1].C(O[C:5](=[NH:26])[C:6]1[CH:11]=[CH:10][C:9]([C@@:12]2([CH3:25])[C:16](=[O:17])[N:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:14](=[O:23])[N:13]2[CH3:24])=[CH:8][CH:7]=1)C.[NH3:27].C(OCC)C>C(O)(C)C>[ClH:1].[NH2:27][C:5](=[NH:26])[C:6]1[CH:11]=[CH:10][C:9]([C@@:12]2([CH3:25])[C:16](=[O:17])[N:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:14](=[O:23])[N:13]2[CH3:24])=[CH:8][CH:7]=1
Reactant: N
Reactant: CCOC(=N)c1ccc([C@@]2(C)C(=O)N(CC(=O)OC)C(=O)N2C)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Product: COC(=O)CN1C(=O)N(C)[C@@](C)(c2ccc(C(=N)N)cc2)C1=O
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
2.26 g of methyl (S)-(4-(4-(ethoxy-imino-methyl)phenyl)-3,4-dimethyl-2,5-dioxoimidazolidin-1-yl)acetate hydrochloride (6.4 mmol) were suspended in 25 ml of isopropanol and treated with 7.2 ml of a 2N solution of ammonia in isopropanol. The reaction mixture was stirred at 50° C. for 2.5 hours. The mixture was cooled and then treated with 200 ml of diethyl ether. The precipitate was filtered off with suction and dried in a high vacuum.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([OH:11])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:19][O:20][CH2:21][CH2:22]Br>CC(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([O:11][CH2:22][CH2:21][O:20][CH3:19])[CH:5]=1
Reactant: COCCBr
Reactant: COC(=O)c1ccc(N)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCOc1cc(C(=O)OC)ccc1N
Temperature: 120 °C
Reaction time: 1 h

Procedure:
The reaction was repeated in two batches as follows. To a solution of Methyl3-hydroxy-4-aminobenzoate (135 mg, 0.81 mmol) in acetone (4 ml), in a microwave tube. Was added Potassium Carbonate (185 mg, 1.34 mmol) and Methoxyethyl bromide (115 μl, 1.22 mmol) The reaction was heated to 120° C. in a microwave and held for 1 hour. The reactions was cooled, treated with a further aliquot of methoxyethyl bromide (58 μl, 0.62 mmol) and re-heated to 120° C. holding for a further hour.
Reaction SMILES: BrCC1C=C[C:6]([C:7]([C:9]2[CH:28]=[CH:27][C:12]([CH2:13][N:14]3[C:22]4[C:21](=[O:23])[N:20]([CH3:24])[C:19](=[O:25])[N:18]([CH3:26])[C:17]=4[N:16]=[CH:15]3)=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[C:37]1([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C.O>[CH3:24][N:20]1[C:21](=[O:23])[C:22]2[N:14]([CH2:13][C:12]3[CH:27]=[CH:28][C:9]([C:7](=[O:8])[C:6]4[CH:5]=[CH:4][C:40]([C:39]5[CH:38]=[CH:7][CH:6]=[CH:5][CH:4]=5)=[CH:41][C:42]=4[CH2:37][N:43]4[CH2:44][CH2:45][NH:46][CH2:47][CH2:48]4)=[CH:10][CH:11]=3)[CH:15]=[N:16][C:17]=2[N:18]([CH3:26])[C:19]1=[O:25]
Reactant: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(CBr)cc3)cc2)n(C)c1=O
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(-c4ccccc4)cc3CN3CCNCC3)cc2)n(C)c1=O
Yield: 14.7 %

Procedure:
A solution of 7-[4-(4-bromomethylbenzoyl)benzyl]-1,3-dimethylxanthine (232 mg), potassium carbonate (109 mg) and 1-phenylpiperazine (92 mg) in DMF (10 ml) was stirred at 60° C. for 5 hours. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane: triethylamine =3:1:0.1) and recrystallized from chloroform-isopropyl ether to provide the title compound as colorless solid (20 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:12][CH2:13][CH2:14][CH3:15])=[C:7]([CH:11]=1)[C:8]([NH2:10])=[O:9].[F:16][B-:17]([F:20])([F:19])[F:18].[CH2:21]([O+](CC)CC)[CH3:22]>>[F:16][B-:17]([F:20])([F:19])[F:18].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:12][CH2:13][CH2:14][CH3:15])=[C:7]([CH:11]=1)[C:8](=[NH:10])[O:9][CH2:21][CH3:22]
Reactant: CCCOc1ccc(OC)cc1C(N)=O
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Product: CCCOc1ccc(OC)cc1C(=N)OCC
Yield: 124.6 %

Procedure:
reaction of 5-methoxy-2-propoxybenzamide (10.88 g) with triethyloxonium tetrafluoroborate (0.07 mol) yielded ethyl 5-methoxy-2-propoxybenzimidate tetrafluoroborate (21.0 g);
Reaction SMILES: [Cl:1][C:2]1[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2[CH:6]=[N:7][NH:8][C:9](=[O:10])[C:4]=2[C:3]=1I.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>C(O)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2[CH:6]=[N:7][NH:8][C:9](=[O:10])[C:4]=2[C:3]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OB(O)c1ccccc1
Reactant: C[Si](C)(C)CCOCn1c(Cl)c(I)c2c(=O)[nH]ncc21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1c(Cl)c(-c2ccccc2)c2c(=O)[nH]ncc21
Temperature: 80 °C
Reaction time: 16 h
Yield: 83.5 %

Procedure:
To 206 mg (0.484 mmol) of 2-chloro-3-iodo-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 30-(b) were added 71 mg (0.58 mmol) of phenylboronic acid, 54 mg of tetrakistriphenylphosphine palladium, 6 ml of toluene, 4 ml of ethanol and 1 ml of 2M aqueous sodium carbonate solution, the mixture was degassed under reduced pressure and replaced with argon, and the mixture was stirred at 80° C. for 16 hours. After completion of the reaction, a saturated aqueous solution of sodium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; toluene:ethyl acetate=1:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 152 mg of the title compound as a pale yellowish solid. (Yield: 84%)
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][N:19]([C:22]([NH:24][CH2:25][C:26]([OH:28])=O)=[O:23])[CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:29]([NH2:33])([CH3:32])([CH3:31])[CH3:30].Cl.C(N=C=NCCCN(C)C)C.O>ClCCl>[C:29]([NH:33][C:26](=[O:28])[CH2:25][NH:24][C:22]([N:19]1[CH2:18][CH2:17][C:16](=[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)[CH2:21][CH2:20]1)=[O:23])([CH3:32])([CH3:31])[CH3:30]
Reactant: O=C(O)CNC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Reactant: CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)NC(=O)CNC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
300 mg (0.801 mmol) of ({[4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-piperidinyl]carbonyl}amino)acetic acid, 1.0 ml (0.961 mmol) of t-butylamine and 230 mg (1.20 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride were dissolved in 10 ml of dichloromethane. The obtained solution was stirred at room temperature for 1 hour. Water was added to the reaction mixture. After extracting with dichloromethane, the dichloromethane layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue thus obtained was purified by the silica gel chromatography (dichloromethane: methanol=4:1 to 1:9) to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=O)[C:3]=1[C:11]([OH:13])=[O:12].[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]2[C:5]([O:13][C:11](=[O:12])[C:3]=12)=[O:7])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(C(=O)O)c1C(=O)O
Product: CC(=O)Nc1cccc2c1C(=O)OC2=O
Temperature: 2.5 °C
Yield: 61 %

Procedure:
A 1 L 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with 3-aminophthalic acid (108 g, 596 mmol) and acetic anhydride (550 mL). The reaction mixture was heated to reflux for 3 hours and cooled to about 25° C. and further to 0-5° C. for another 1 hour. The crystalline solid was collected by vacuum filtration and washed with ether. The solid product was dried in vacuo at ambient temperature to a constant weight, giving 75 g (61% yield) of 3-acetamidopthalic anhydride as a white product. 1H-NMR (CDCl3) δ: 2.21 (s, 3H), 7.76 (d, 1H), 7.94 (t, 1H), 8.42 (d, 1H), 9.84 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[CH2:4][O:3]1.[ClH:24]>C(Cl)Cl.O1CCOCC1>[ClH:24].[ClH:24].[CH3:1][CH:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[CH2:4][O:3]1
Reactant: CC1OCc2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC1OCc2ncnc(N3CCNCC3)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-(5-methyl-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (0.28 g, 0.87 mmol) in DCM (15 mL) was added 4N HCl in dioxane (5 mL). The mixture was stirred at room temperature overnight and then concentrated to give 5-methyl-4-(piperazin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidine dihydrochloride salt as an off white solid. 1H NMR (DMSO-d6, 400 MHz) δ 9.62 (bs, 2H), 8.72 (s, 1H), 5.72-5.71 (m, 1H), 5.55-5.00 (bs, 1H), 4.99-4.89 (m, 2H), 4.05-4.00 (m, 2H), 3.81-3.75 (m, 2H), 3.19-3.18 (m, 4H), 1.32 (d, J=8.4 Hz, 3H). LCMS (APCI+) m/z 221 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[C:5]([N+:17]([O-])=O)[CH:4]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]2)=[C:5]([CH:4]=1)[NH2:17]
Reactant: [H][H]
Reactant: COc1ccc(CN2CCN(C)CC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(CN2CCN(C)CC2)c(N)c1
Yield: 75 %

Procedure:
To a solution of 1-(4-methoxy-2-nitrobenzyl)-4-methylpiperazine (6 g; 25.5 mmol; 1 eq) in methanol (100 mL) was added palladium on charcoal (0.6 g; 10%) and the mixture is hydrogenated under atmospheric pressure of hydrogen for 3 h. The catalyst is filtered off and the filtrate is evaporated under vacuum. The crude residue is purified via column chromatography (eluent chloroform/methanol [9/1]) to afford 4.5 g (84%) of the title compound as a viscous liquid. 1H NMR (CDCl3, 400 MHz) δ 6.90-6.88 (m, 1H), 6.24-6.22 (m, 2H), 5.32 (br s, 2H), 3.82 (s, 3H), 3.47 (s, 2H), 2.46-2.30 (m, 8H), 2.25 (s, 3H). HPLC (max plot) 99%. LC/MS(ES+): 236.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=2)=[C:11]([CH3:24])[N:10]=[N:9]1.[CH3:25][C:26]1([NH2:30])[CH2:29][O:28][CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH:30][C:26]3([CH3:25])[CH2:29][O:28][CH2:27]3)=[O:21])=[CH:17][N:16]=2)=[C:11]([CH3:24])[N:10]=[N:9]1
Reactant: Cc1nnn(-c2ccccc2F)c1COc1ccc(C(=O)O)cn1
Reactant: CC1(N)COC1
Product: Cc1nnn(-c2ccccc2F)c1COc1ccc(C(=O)NC2(C)COC2)cn1
Yield: 21 %

Procedure:
As described for example 67, 6-((1-(2-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)nicotinic acid (78 mg, 0.24 mmol), was converted, using 3-methyloxetan-3-amine instead of isopropylamine, to the title compound (20 mg, 21%) which was obtained as an off white foam. MS: m/e=398.2 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][C:8](O)([CH3:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:12]>>[C:1]1([CH2:7][C:8]([Cl:12])([CH3:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(O)Cc1ccccc1
Reactant: Cl
Product: CC(C)(Cl)Cc1ccccc1
Reaction time: 1 h

Procedure:
A mixture of 5.92 g (40 mmol) of 1-phenyl-2-hydroxy-2-methylpropane and 50 mL of conc. hydrochloric acid was stirred at ice bath temperature for 1 h and at RT for 3 h. The reaction mixture was then extracted with ether. The organic layer was dried over MgSO4. Solvent removal gave 1-phenyl-2-chloro-2-methylpropane.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].C(N(CC)CC)C.[CH3:14][C:15]1[CH:51]=[CH:50][CH:49]=[CH:48][C:16]=1[CH2:17][NH:18][C:19]([C@@H:21]1[C:25]([CH3:27])([CH3:26])[S:24][CH2:23][N:22]1[C:28](=[O:47])[C@@H:29]([OH:46])[C@@H:30]([NH:38][C:39](=[O:45])[C@H:40]([CH:42]([CH3:44])[CH3:43])[NH2:41])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:20]>C(OCC)(=O)C>[CH3:14][C:15]1[CH:51]=[CH:50][CH:49]=[CH:48][C:16]=1[CH2:17][NH:18][C:19]([C@@H:21]1[C:25]([CH3:27])([CH3:26])[S:24][CH2:23][N:22]1[C:28](=[O:47])[C@@H:29]([OH:46])[C@@H:30]([NH:38][C:39](=[O:45])[C@@H:40]([NH:41][C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH:42]([CH3:44])[CH3:43])[CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:20]
Reactant: Cc1ccccc1CNC(=O)[C@H]1N(C(=O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@@H](N)C(C)C)CSC1(C)C
Reactant: CCOC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)N1CSC(C)(C)[C@H]1C(=O)NCc1ccccc1C)C(C)C
Reaction time: 8 h

Procedure:
Ethyl chloroformate (32 μel), triethylamine (46 μl) were added to a solution of H-Val-Apns-Dmt-NHBzl(2-Me) (162 mg) obtained in the step 2 of Example 8 in ethyl acetate (3 ml) and the mixture was stirred overnight. After the addition of ethyl acetate, the reaction mixture was washed with 3% Na2CO3, 1N HCl, and 5% NaCl and dried over MgSO4. After filtration and concentration, the residue was purified using silica gel column chromatography and reprecipitated from ethyl acetate/n-hexane to obtain the title compound (149 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:10]([C:14]1[CH:19]=[CH:18][C:17]([O:20][S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])=[C:16]([O:28][CH3:29])[CH:15]=1)(O)[CH2:11][CH3:12])[CH3:9].[C:30]1([CH3:37])[C:35]([OH:36])=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:8]([C:10]([C:14]1[CH:19]=[CH:18][C:17]([O:20][S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])=[C:16]([O:28][CH3:29])[CH:15]=1)([C:32]1[CH:33]=[CH:34][C:35]([OH:36])=[C:30]([CH3:37])[CH:31]=1)[CH2:11][CH3:12])[CH3:9]
Reactant: CCC(O)(CC)c1ccc(OS(=O)(=O)C(F)(F)F)c(OC)c1
Reactant: Cc1ccccc1O
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(OS(=O)(=O)C(F)(F)F)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
Trifluoromethanesulfonic anhydride (0.8 mL, 4.76 mmol) was added to a solution of 4-(1-ethyl-1-hydroxy-propyl)-2-methoxy-phenol (Example 176-(3); 1.0 g, 4.76 mmol) in pyridine (4 mL) at room temperature, and the mixture was stirred at room temperature for one hour. The reaction solution was extracted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid aqueous solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane only to hexane:ethyl acetate=1:1) to give trifluoromethanesulfonic acid 4-(1-ethyl-1-hydroxy-propyl)-2-methoxy-phenyl ester (1.51 g, 93%). Trifluoroacetic acid (0.1 mL) was added to a mixture of trifluoromethanesulfonic acid 4-(1-ethyl-1-hydroxy-propyl)-2-methoxy-phenyl ester (100 mg, 0.292 mmol) with o-cresol (68.2 mg, 585 mmol) at room temperature, and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure. Then, the resulting residue was purified by silica gel chromatography (hexane only to hexane:ethyl acetate=4:1) to give the title compound (0.12 g, 95%).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[S:31][C:32]([CH:35]([OH:37])[CH3:36])=[CH:33][N:34]=3)[C@H:14]2[CH3:38])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:41][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1.CI>[F:40][C:2]([F:1])([F:39])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[S:31][C:32]([CH:35]([O:37][CH3:41])[CH3:36])=[CH:33][N:34]=3)[C@H:14]2[CH3:38])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC(O)c1cnc(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)s1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(C)c1cnc(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)s1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a 0° C. solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[5-(1-hydroxyethyl)-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (Example 154) (13.2 mg, 0.0221 mmol) in THF (1 mL) was added NaHMDS (26.5 μL of a 1M solution in THF, 0.0265 mmol) followed by MeI (1 drop). After 1.5 hours, additional NaHMDS (15 μL of a 1M solution in THF, 0.015 mmol) and MeI (1 drop) were added to the reaction. The reaction was warmed to room temperature for 20 minutes and then quenched by pouring into saturated NH4Cl (10 mL). The mixture was extracted with EtOAc (35 mL) and the organic layer was washed with water and brine (15 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (15 to 75% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[5-(1-methoxyethyl)-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.37 (40% EtOAc/hexanes). LCMS=613.0 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.87 (s, 1H), 7.74-7.82 (m, 5H), 7.67 (d, J=8.0 Hz, 1H), 6.63-5.66 (m, 1H), 5.08-5.14 (m, 1H), 4.83-4.88 (m, 1H), 4.64-4.68 (m, 1H), 4.01-4.08 (m, 1H), 3.34 (m, 3H), 1.60 (d, J=6.4 Hz, 3H), 0.69 (d, J=6.7 Hz, 3H).