Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26](O)[CH3:27]>>[Cl:15][C:13]1[CH:14]=[C:9]2[C:10](=[CH:11][CH:12]=1)[NH:16][C:17](=[O:18])[N:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:1]2([O:8][CH2:26][CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=C(Nc1ccccc1)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Product: CCOC1(c2ccccc2)c2cc(Cl)ccc2NC(=O)N1c1ccccc1
Yield: 88 %

Procedure:
A solution of 10.0 g (0.285 mole) of 1-(2-benzoyl-4-chlorophenyl)-3-phenylurea in 50 ml ethanol was refluxed for 18 hr, and then cooled. The solid that formed was collected on a filter and washed with ethanol to give 9.46 g (88%) of 6-chloro-4-ethoxy-3,4-dihydro-3,4-diphenyl-2(1H)-quinazolinone as colorless crystals: mp 209°-211°. The 1H nmr spectrum shows the presence of an ethyl group in addition to aromatic hydrogens.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4](O)(=O)C.C=O.[CH3:10][C:11]1([CH3:24])[C:16]2=[CH:17][CH:18]=[CH:19][N:15]2[C:14]2[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=2[O:12]1>C(O)C>[CH3:1][N:2]([CH2:4][C:19]1[N:15]2[C:16]([C:11]([CH3:24])([CH3:10])[O:12][C:13]3[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=32)=[CH:17][CH:18]=1)[CH3:3]
Reactant: CC1(C)Oc2ccccc2-n2cccc21
Reactant: CNC
Reactant: CC(=O)O
Agent: C=O
Solvent: CCO
Product: CN(C)Cc1ccc2n1-c1ccccc1OC2(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 18 ml of 40% aqueous dimethylamine solution and 19.8 ml of acetic acid is treated with 9 ml of 37% formalin at 10° - 15° C. The resulting solution is added at once to 10 g of 4,4-dimethyl-4H-pyrrolo[2,1-c][1,4]benzoxazine (10. g, described in Example 78) in 30 ml of ethanol. The reaction mixture is stirred at ambient temperature for 18 hr. Ethanol is removed under reduced pressure, and the remaining oily suspension is extracted with chloroform. The combined extracts are dried (Na2SO4), filtered, and evaporated to yield the title compound, nmr (CDCl3) δ 1.56 (s, 6H), 2.67 (d, J = 4.5Hz, 6H), 4.70 (d, J = 4.5Hz, 2H), 6.08 and 6.85 (d, 2H), 6.95 - 7.70 (m, 4H), 12.4 (broad, 1H).
Reaction SMILES: [CH2:1]([N:8]([C@@H:28]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-])=O)=[CH:34][CH:33]=1)[CH2:29][OH:30])[CH2:9][C@H:10]([OH:27])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.O1CCOCC1.[Cl-].[NH4+]>[Fe].O>[NH2:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][C@H:28]([N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][C@H:10]([OH:27])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:15][CH:14]=2)[CH2:29][OH:30])=[CH:33][CH:34]=1
Reactant: O=[N+]([O-])c1ccc(C[C@@H](CO)N(Cc2ccccc2)C[C@H](O)COc2ccc(OCc3ccccc3)cc2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(C[C@@H](CO)N(Cc2ccccc2)C[C@H](O)COc2ccc(OCc3ccccc3)cc2)cc1
Reaction time: 0.5 h
Yield: 100.6 %

Procedure:
A solution of (2S)-2-[N-benzyl-N-[(2S)-3-[4-(benzyloxy)phenoxy]-2-hydroxypropyl]amino]-3-(4-nitrophenyl)-1-propanol (2.00 g) in a mixed solvent of ethanol (7.5 ml) and 1,4-dioxane (7.5 ml) was added dropwise to a stirred suspension of iron powder (2.00 g) and ammonium chloride (0.24 g) in a mixed solvent of ethanol (5 ml) and water (5 ml) at 85° C. over 10 minutes and the resulting mixture was stirred at the same temperature for 30 minutes. The insoluble solid was filtered off and washed with dioxane, and the filtrate was concentrated in vacuo. The residue was partitioned between saturated aqueous sodium hydrogencarbonate solution and ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated to give (2S)-3-(4-aminophenyl)-2-[N-benzyl-N-[(2S)-3-[4-(benzyloxy)phenoxy]-2-hydroxypropyl]-amino]-1-propanol (1.90 g) as a pale yellow oil.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1.[C:35]([O:39][C:40]([NH:42][S:43]([C:46]1[CH:54]=[CH:53][CH:52]=[CH:51][C:47]=1[C:48](O)=[O:49])(=[O:45])=[O:44])=[O:41])([CH3:38])([CH3:37])[CH3:36].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:20][CH2:21][N:22]([C:48]([C:47]5[CH:51]=[CH:52][CH:53]=[CH:54][C:46]=5[S:43]([NH:42][C:40](=[O:41])[O:39][C:35]([CH3:37])([CH3:36])[CH3:38])(=[O:44])=[O:45])=[O:49])[CH2:23][CH2:24]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)c1ccccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
To a solution of endo 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride II (238 mg, 0.47 mmol, 1 eq.) in dimethylformamide (14 mL) was added 2-{[(tert-butoxycarbonyl)amino]sulfonyl}benzoic acid 1b (140 mg, 0.47 mmol, 1 eq.) and N,N-diisopropylethyl amine (0.3 mL, 1.41 mmol, 3 eq.). After stirring at RT for several minutes, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (179 mg, 1.41 mmol, 1 eq.) was added and the reaction was stirred for 2 h. The mixture was partitioned between dichloromethane and water. The organic layer was dried and concentrated to provide crude tert-butyl {2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]phenyl}sulfonylcarbamate 1c. The crude product was used without further purification.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)(=O)[CH3:2].P(Cl)(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[ClH:19].[CH3:16][O:15][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][C:10]=1[O:13][CH3:14])[C:1]([CH3:2])=[N:4][CH2:5][CH2:6]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(CCNC(C)=O)cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)C(C)=NCC2
Product: Cl
Temperature: 25 °C

Procedure:
To a stirred solution of N-acetyl-3,4-dimethoxyphenethylamine (112.1 g, 0.502 m) in toluene (600 ml) maintained at 90°-95° was added dropwise phosphorusoxychloride (180.9 g, 112 ml, 1.179 mole) over a period of 1 hour. The mixture was heated to reflux for 2 hr, cooled to ambient temperature, and the solid hydrochloride salt collected by filtration, 170.4 g (wet with toluene). m.p. (after drying) 202°-203°.
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].[Na].C(O)C.[CH3:9][N:10]1[C:18]2[N:17]=[CH:16][N:15]([CH2:19][C:20](=[N:22]O)[NH2:21])[C:14]=2[C:13](=[O:24])[NH:12][C:11]1=[O:25]>C(OCC)(=O)C>[CH3:9][N:10]1[C:18]2[N:17]=[CH:16][N:15]([CH2:19][C:20]3[N:22]=[C:2]([CH3:1])[O:3][N:21]=3)[C:14]=2[C:13](=[O:24])[NH:12][C:11]1=[O:25]
Reactant: CC[O-]
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2CC(N)=NO
Agent: [Na+]
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1nc(Cn2cnc3c2c(=O)[nH]c(=O)n3C)no1
Reaction time: 4 h

Procedure:
A mixture of a sodium ethylate solution prepared from 6.76 g of metallic sodium and 290 ml of anhydrous ethanol, 35 g of 2-(3-methyl-xanthine-7-yl)-acetamidoxime and 43.0 g of ethyl acetate is heated to boiling under stirring for 4 hours. The hot reaction mixture is filtered, the filtrate is evaporated in vacuo and the residue is dissolved in 200 ml of water. The pH of the solution is adjusted to 7 by adding 10% hydrochloric acid, the precipitate is filtered by suction and crystallized twice from water. Thus, 18.0 g of 3,7-dihydro-3-methyl-7-([5-methyl-1,2,4-oxadiazole-3-yl]-methyl)-1H-purine-2,6-dione are obtained, m.p.: 262°-264° C.
Reaction SMILES: O[CH:2]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.S(Cl)([Cl:17])=O>C1C=CC=CC=1>[Cl:17][CH:2]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: O=S(Cl)Cl
Reactant: OC1c2ccccc2-c2ccccc21
Solvent: c1ccccc1
Product: ClC1c2ccccc2-c2ccccc21
Temperature: 25 °C

Procedure:
To a cold (0° C.) suspension of 9-hydroxyfluorene (49 g) in benzene (650 mL) was added thionylchloride (70 mL). This solution was allowed to stir while warming up to room temperature overnight. The benzene was distilled off and the product was recrystallized from isopropylether to give 41 g of the title compound as a white solid: m.p. 87°-89° C.
Reaction SMILES: CN1CCOCC1.[CH2:8]([O:15][C:16](=[O:31])[CH:17]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18][CH2:19][C:20]([OH:22])=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CN([C:35]([O:39][N:40]1N=NC2C=CC=N[C:41]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CNOC>CN(C)C=O>[CH2:8]([O:15][C:16](=[O:31])[CH:17]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18][CH2:19][C:20](=[O:22])[N:40]([O:39][CH3:35])[CH3:41])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NC(CCC(=O)O)C(=O)OCc1ccccc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CON(C)C(=O)CCC(NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Yield: 100.6 %

Procedure:
4-Methylmorpholine (9.77 mL, 88.9 mmol) was added to a suspension of 2-tert-butoxycarbonylamino-pentanedioic acid 1-benzyl ester (6 g, 17.7 mmol), and HATU (8.11 g, 21.3 mmol) in dimethylformamide (20 mL). After 5 minutes N,O-dimethylhydroxylamine hydrochloride (2.60 g, 26.7 mmol), was added to the solution. After 1 hour the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (150 mL), and washed with water (100 mL), aqueous hydrogen chloride (0.5 N, 2×100 mL), saturated sodium bicarbonate (100 mL), and saturated sodium chloride (100 mL). The organic phase was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was subjected to flash chromatography with eluent of ethyl acetate and hexane. The product-containing fractions were combined and the solvent was removed under reduced pressure to yield 2-tert-butoxycarbonylamino-4-(methoxy-methyl-carbamoyl)-butyric acid benzyl ester (6.8 g, 17.8 mmol, 99%). C19H28N2O6 calculated 380.2 observed [M+1]+381.2; rt=2.48 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=[C:5]([CH:12]([OH:14])[CH3:13])[CH:4]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=[C:5]([C:12](=[O:14])[CH3:13])[CH:4]=1
Reactant: COc1cc(C(C)O)cc2c1OCO2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1cc(C(C)=O)cc2c1OCO2

Procedure:
Manganese dioxide (5 g, molar excess) was added to a solution of 2 (0.89 g, 4.5 mmol) in dichloromethane (10 mL). The resulting mixture was heated at reflux for 3 hours then filtered through Celite®. The filtrate was concentrated in vacuo to afford 3 as a tan solid.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH2:29][C:28]([C:34]4[CH:39]=[C:38]([Cl:40])[C:37]([Cl:41])=[C:36]([Cl:42])[CH:35]=4)([C:30]([F:33])([F:32])[F:31])[O:27][N:26]=3)=[CH:21][C:20]=2Br)([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN([CH:47]=[O:48])C>O.[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]([N:14]1[CH2:17][C:16]2([C:19]3[C:20](=[CH:21][C:22]([C:25]4[CH2:29][C:28]([C:34]5[CH:39]=[C:38]([Cl:40])[C:37]([Cl:41])=[C:36]([Cl:42])[CH:35]=5)([C:30]([F:33])([F:32])[F:31])[O:27][N:26]=4)=[CH:23][CH:24]=3)[C:47](=[O:48])[O:18]2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: OC1(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2Br)CN(C(c2ccccc2)c2ccccc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: O=C1OC2(CN(C(c3ccccc3)c3ccccc3)C2)c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc21
Temperature: 150 °C
Yield: 58 %

Procedure:
To a solution of 1-benzhydryl-3-(2-bromo-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidin-3-ol (500 mg, 0.7 mmol) in DMF (12 mL) was added Zn(CN)2 (180 mg, 1.5 mmol) and the reaction was degassed with N2 purge. Pd(PPh3)4 (40 mg, 0.04 mmol) was added and the reaction mixture was heated at 150° C. for 15 minutes under microwave irradiation. The reaction mixture was diluted with water, extracted with EtOAc, dried, and concentrated under vacuum. The crude material was chromatographed (40 g Redi-Sep column) eluting from 100% heptane to 50:50 EtOAc:heptane to afford the intermediate (268 mg, 58%) as a glass. 1HNMR (CDCl3) δ ppm: 8.32 (1H), 8.18 (1H), 7.95 (1H), 7.68 (2H), 7.51 (4H), 7.35-7.23 (6H), 4.55 (1H), 4.15 (1H), 3.79-3.69 (3H), 3.60 (2H); m/z (CI) 657 ([M+H]+.
Reaction SMILES: [O:1]=[S:2]1(=[O:32])[CH2:6][C@@H:5]([NH:7][C@@H](C2C=CC=CC=2)C)[C@H:4]([C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:19]2)=[O:17])[CH2:3]1>[OH-].[Pd+2].[OH-].CO>[NH2:7][C@@H:5]1[CH2:6][S:2](=[O:1])(=[O:32])[CH2:3][C@H:4]1[C:16]([N:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:19]1)=[O:17]
Reactant: C[C@@H](N[C@@H]1CS(=O)(=O)C[C@H]1C(=O)N1CCC[C@@H](Cc2ccc(F)cc2)C1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: N[C@@H]1CS(=O)(=O)C[C@H]1C(=O)N1CCC[C@@H](Cc2ccc(F)cc2)C1
Reaction time: 20.5 h
Yield: 108.3 %

Procedure:
[1,1-Dioxo-(3R,4S)-4-[(R)-1-phenyl-ethylamino]-tetrahydrothiophen-3-yl]-[(S)-3-(4-fluoro-benzyl)-piperidin-1-yl]-methanone (790 mg, 1.72 mmol), palladium hydroxide (20 weight % on carbon, dry basis; 1.1 g) and methanol (50 mL) were combined in a pressure bottle and shaken under a hydrogen atmosphere (55-60 psig) for 20.5 h. The mixture was filtered through Celite, and the solids were washed thoroughly with methanol. The filtrate was concentrated to give the product as a solid (660 mg, quantitative), used without further purification.
Reaction SMILES: [C:1]([OH:6])#[C:2][CH2:3][CH2:4][CH3:5].C(Cl)Cl.[C:10](Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11]>CN(C1C=CN=CC=1)C.CCN(CC)CC>[C:10]([O:6][CH2:1][CH2:2][CH2:3][C:4]#[CH:5])(=[O:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCCC#CO
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCCCOC(=O)c1ccccc1
Temperature: 0 °C
Yield: 89.2 %

Procedure:
To a flame-dried round-bottomed flask was added pentynol (1 equiv., 24 mmol, 2.0 g) and CH2Cl2 (80 mL). The solution was cooled to 0° C. and BzCl (1.2 equiv., 28 mmol, 3.3 mL) was added dropwise, followed by DMAP (0.1 equiv., 2.4 mmol, 300 mg), and Et3N (7 mL). The reaction was warmed to ambient temperature over 12 h, quenched with 2N HCl (10 mL), extracted with EtOAc (2×40 mL), washed with brine (40 mL) and dried over Na2SO4. The purified product was isolated by concentrating in vacuo and purifying by flash chromatography (2.5% EtOAc/Hex) to afford pent-4-yn-1-yl benzoate (4.02 g, 21.4 mmol, 89%). TLC Rf=0.57 (10% EtOAc/Hex); 1HNMR (600 MHz): δ 8.03-8.07 (2H), 7.53-7.60 (1H), 7.42-7.48 (2H), 4.44 (t, 2H, J=6.1 Hz), 2.40 (td, 2H, J=7.3, 2.7 Hz), 1.98-2.05 (overlapping signals, 3H); 13CNMR (150 MHz): δ166.5, 132.9, 130.3, 129.6, 128.3, 83.0, 69.1, 63.4, 27.7, 15.4.
Reaction SMILES: C[O:2]C1C=C(CNCCCNCCCCNCCCN)C=CC=1O.[Cl:25][C:26]1[CH:27]=[C:28](N2CC(=O)NC2=O)[CH:29]=[CH:30][CH:31]=1.COC1C=C(CNCCCNCCCCNCCCN)C=CC=1O.ClC1C=CC([N:70]2[CH2:76][C:74](=[O:75])[NH:73][C:71]2=[O:72])=CC=1>>[C:71]([NH:70][CH:76]([C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([Cl:25])[CH:27]=1)[C:74]([OH:75])=[O:2])(=[O:72])[NH2:73]
Reactant: O=C1CN(c2ccc(Cl)cc2)C(=O)N1
Reactant: O=C1CN(c2cccc(Cl)c2)C(=O)N1
Reactant: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Product: NC(=O)NC(C(=O)O)c1cccc(Cl)c1

Procedure:
Further, the same large scale reaction as in Example 10 was repeated except that DL-5-(3-chlorophenyl)hydantoin and Agrobacterium rhizogenes IFO 13259 were employed instead of DL-5-(4-chlorophenyl)hydantoin and Pseudomonas chlororaphis IFO 3904, respectively. From 1.0 g. of DL-5-(3-chlorophenyl)hydantoin 267 mg. of N-carbamoyl-2-(3-chlorophenyl)glycine was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[OH2:10].[C:11]1(C)C=[CH:15][C:14](S(O)(=O)=O)=[CH:13][CH:12]=1>O1C=CCCC1.C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:9][CH:15]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1cccc(O)c1
Agent: C1=COCCC1
Solvent: CCOCC
Product: COc1cccc(OC2CCCCO2)c1
Reaction time: 1 h
Yield: 24786.6 %

Procedure:
A solution of 22 gm (177.4 mMol) 3-methoxyphenol in 30 mL dihydropyran was added dropwise to a solution of 100 mg (0.525 mMol) p-toluenesulfonic acid monohydrate in 10 mL dihydropyran while cooling in an ice/water bath. After stirring for 1 hour the reaction mixture was diluted with 300 mL diethyl ether and then washed sequentially with 100 mL 0.1 N sodium hydroxide and 100 mL saturated aqueous sodium chloride. The remaining organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The resulting oil was distilled. The fraction distilling at 110-130° C. was collected and then partitioned between 5 N sodium hydroxide and diethyl ether. The organic phase was separated, washed sequentially with water and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure to provide 27.1 gm (73%) of tetrahydropyran-2-yl 3-methoxyphenyl ether.
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15]C=2)=O)=[CH:6][CH:5]=1.[O:21]1[CH2:26]COCC1.Cl.[CH3:28][NH:29][C:30]([NH2:32])=[NH:31].C([O-])([O-])=O.[Na+].[Na+]>O.CCO>[NH2:32][C:30]1[N:29]([CH3:28])[C:26](=[O:21])[C:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][CH:2]([F:1])[F:20])=[CH:9][CH:8]=2)([C:11]2[CH:13]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:31]=1
Reactant: CNC(=N)N
Reactant: O=C(C(=O)c1ccc(OC(F)F)cc1)c1ccccc1
Reactant: C1COCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN1C(=O)C(c2ccccc2)(c2ccc(OC(F)F)cc2)N=C1N
Temperature: 95 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
Into a mixture of 1-[4-(difluoromethoxy)phenyl]-2-phenylethane-1,2-dione (3.7 g, 13.4 mmol), dioxane (180 mL) and EtOH (240 mL) were added 1-methylguanidine hydrochloride (6.6 g, 60.3 mmol), and a solution of Na2CO3 (6.4 g, 60.3 mmol) in H2O (20 mL). The new mixture was stirred at 95° C. for 3 hours. Then, the volatiles were removed under vacuum and the residue was taken in water and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification on silica gel (ISCO) using MeOH/EtOAc (1/20) as the eluting solvent gave 2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one as a white solid (3.65 g, 94% yield). MS m/e (M+H)+ 332; 1H NMR (400 MHz, DMSO-d6) 2.93 (s, 3H), 6.61 (brs, 2H), 7.1 (d, J=8.54 Hz, 2H), 7.15-7.31 (m, 4H), 7.38 (m, 2H), 7.42 (d, J=8.54 Hz, 2H).
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[C:32]([O:36][C:37](=[O:47])[NH:38][C:39]1[C:44]([CH:45]=[O:46])=[CH:43][CH:42]=[CH:41][N:40]=1)([CH3:35])([CH3:34])[CH3:33]>C1COCC1>[C:32]([O:36][C:37](=[O:47])[NH:38][C:39]1[C:44]([CH:45]([C:2]2[C:7]([N:8]([S:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=3)(=[O:11])=[O:10])[CH2:23][O:24][CH3:25])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=2)[OH:46])=[CH:43][CH:42]=[CH:41][N:40]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)Nc1ncccc1C=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(O)c1cccnc1NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
To a solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (3.27 g, 6.64 mmol) in THF (20 mL) under nitrogen atmosphere at 0° C. was added dropwise isopropylmagnesium chloride (2 M solution in THF, 6.62 mL, 13.25 mmol). The mixture was then stirred for 30 min at 0° C. followed by the addition of a solution of (3-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (590 mg, 2.65 mmol) in THF (3 mL) at 0° C. The mixture was stirred at room temperature for 3 hours, quenched with saturated aqueous NH4Cl solution (10 mL) and extracted with EtOAc (2×50 mL). Combined organic layers were washed with saturated aqueous NH4Cl solution (50 mL), brine (50 mL), dried (anhydrous Na2SO4) and concentrated under reduced pressure. Obtained residue was column purified (SiO2, 50% EtOAc-hexanes) to obtain [3-({5-chloro-3-[(4-chloro-3-trifluoromethyl-benzene sulfonyl)-methoxymethyl-amino]-pyridin-2-yl}-hydroxy-methyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (750 mg) in 44% yield as yellow solid. ESMS m/z (relative intensity): 637 (M+H)+ (100).
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:14]=1[C:15](O)=[O:16]>>[CH3:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:14]=1[C:15]([NH:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:16]
Reactant: Cc1cccc(C)c1C(=O)O
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Product: Cc1cccc(C)c1C(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, white solid, MS: m/e=287.3 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2,6-dimethyl benzoic acid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.Br[CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:1][C:2]1[N:3]([CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)[C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrCC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(CC2CCCCO2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
A mixture of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 2-(bromomethyl)tetrahydro-2H-pyran (0.45 mL), potassium carbonate (0.60 g) and N,N-dimethylformamide (10 mL) was stirred at 90° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.64 g, 48%).