Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].C(N(CC)CC)C.[F:12][C:13]1[C:14]([C:20](F)=[O:21])=[N:15][C:16]([F:19])=[CH:17][CH:18]=1>O>[F:12][C:13]1[C:14]([C:20]([O:4][CH:2]([CH3:3])[CH3:1])=[O:21])=[N:15][C:16]([F:19])=[CH:17][CH:18]=1
Reactant: O=C(F)c1nc(F)ccc1F
Reactant: CC(C)O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)c1nc(F)ccc1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 48 %

Procedure:
Anhydrous 2-propanol (0.361 g, 6 mmol) and anhydrous tri-ethylamine (0.405 g, 4 mmol) were added dropwise at room temperature to the 3,6-difluoropicolinoyl fluoride provided above. The mixture was stirred at room temperature for 6 hours, poured into a reparatory funnel with water and extracted with ethyl ether. The organic phase was then washed with water and dried over MgSO4. The solvent was removed with a rotary evaporator. The concentrated crude product was purified using column chromatography (silica gel) with ethyl acetate/hexanes mixture ( 1/10) as eluent to give 0.39 g (48% yield, 99% GC purity, 98% LC purity) of desired product as a pale yellow liquid. GC/MS results were consistent with the chemical formula of isopropyl 3,6-difluoropicolinate: 70 eV EIMS (GC) m/z=160 (41%), 142 (100%), 115 (43%), 114 (66%), 64 (31%), 43 (51%). 1H NMR (400 MHz, CDCl3) δ 7.69 to 7.63 (m, 1H), 7.16 to 7.12 (m), 5.33 (hept, J=6.3 Hz, 1H), 1.41 (d, J=6.3 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 161.41 (d, J=6.3 Hz), 158.80 (d, J=1.2 Hz), 158.26 (d, J=4.3 Hz), 156.41 (d, J=1.2 Hz), 155.62 (d, J=4.4 Hz), 134.05 (t, J=13.5 Hz), 131.06 (dd, J=23.9, 8.3 Hz), 114.86 (dd, J=41.7, 5.9 Hz), 70.34 (s), 21.71 (s). 19F NMR (376 MHz, CDCl3) δ −69.40 (d, J=26.9 Hz), −122.76 (d, J=27.4 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16](OS(C)(=O)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:28]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([N:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:27][CH3:28])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNc1ccccc1
Reactant: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)OS(C)(=O)=O
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)N(CC)c1ccccc1

Procedure:
Reaction and post-treatment were carried out according to Reference example 5(a) using 4.50 g of ethyl 3-(4-benzyloxyphenyl)-2-methanesulfonyloxypropionate and 5.6 ml of N-ethylaniline to obtain 6.30 g of a mixture of the desired compound and N-ethylaniline as a syrup.
Reaction SMILES: [OH:1][C@H:2]1[CH2:10][N:5]2[CH2:6][CH2:7][NH:8][CH2:9][C@@H:4]2[CH2:3]1.Cl[C:12]1[N:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:1][C@H:2]1[CH2:10][N:5]2[CH2:6][CH2:7][N:8]([C:12]3[N:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=3)[CH2:9][C@@H:4]2[CH2:3]1
Reactant: Fc1cnc(Cl)nc1
Reactant: O[C@@H]1C[C@H]2CNCCN2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O[C@@H]1C[C@H]2CN(c3ncc(F)cn3)CCN2C1
Yield: 85 %

Procedure:
A mixture of the crude (7R,8aS)-7-hydroxy-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]-pyrazine, 9.96 g (52.5 mmol) of 2-chloro-5-fluoropyrimidine (Dunaiskis, A. et al., Org. Prep. Proc. Int., 1995, 27, 600-602), 13.4 g (126 mmol) of sodium carbonate and 450 mL of water was heated at 95° C. for 72 hours. The mixture was cooled, extracted with chloroform (2×), and the combined organic phase was dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 95:5 ethyl acetate:methanol gave 8.54 g (85%) of the title compound. 13C NMR (base, CDCl3): δ 39.1, 43.7, 48.7, 51.0, 60.2, 62.9, 69.4, 144.95, 145.24, 149.9, 153.2,158.9. m/z (MH+) 239.
Reaction SMILES: C([N:4]1[CH2:9][C:8](=[O:10])[N:7]([CH3:11])/[C:6](=[CH:12]\[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)/[C:5]1=[O:21])(=O)C.[H-].[Na+].[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.C(OCC)(=O)C>[CH:24](=[C:9]1/[C:8](=[O:10])[N:7]([CH3:11])/[C:6](=[CH:12]\[C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)/[C:5](=[O:21])[NH:4]/1)\[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(/C=C2/C(=O)N(C(C)=O)CC(=O)N2C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(/C=c2/c(=O)[nH]/c(=C\c3ccccc3)c(=O)n2C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (3Z)-1-Acetyl-3-(4-methoxybenzylidene)-4-methyl-2,5-piperazinedione (10) (200 mg, 0.69 mmol) and sodium hydride (60% dispersion in oil, 28 mg, 0.69 mmol) in dry DMF (10 ml) was stirred at room temperature for 18 h. Benzaldehyde (71 μl, 0.69 mmol) was then added and the reaction mixture stirred at room temperature for 18 h. It was then diluted with ethyl acetate (100 ml) and washed with brine (4×50 ml). The organic phase was separated, dried (MgSO4), and the solvent removed in vacuo. The residue was purified by flash chromatography (silica, dichloromethane containing 1% MeOH) to give 48 mg (21 w) of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[CH:23]([C:25]1[NH:29][C:28]([CH3:30])=[C:27]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:26]=1[CH3:36])=O.N1CCCCC1>C(O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:25]1[NH:29][C:28]([CH3:30])=[C:27]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:26]=1[CH3:36])(=[O:12])=[O:11]
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CCC(=O)O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 5-(2,6-dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one(1 g, 2.82 mmol), 3-(5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)-propionic acid (548 mg, 1 eq.) and piperidine (0.416 mL, 1.5 eq.) in ethanol (5 mL) was stirred at rt for 5 days. The reaction was concentrated, acidified with 2M HCl (pH 3), stirred for 15 mins, diluted with water and filtered. The solid was washed with water and triturated with ethanol to give the titled compound as a pale orange solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:10]([OH:12])=O)([CH3:4])([CH3:3])[CH3:2].[CH2:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:31])[CH2:26][CH2:27][CH3:28].C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C.C(OCC)(=O)C>[CH2:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:10](=[O:12])[C@@H:9]([NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:24])[CH2:34][CH2:33]1)=[O:31])[CH2:26][CH2:27][CH3:28]
Reactant: CCCCOC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)CC1
Reaction time: 12 h

Procedure:
To a solution of 9.06 g (S)-2-Benzyloxycarbonylamino-pentanedioic acid 5-tert-butyl ester in 100 ml DMF were added 5.00 g piperazine-1-carboxylic acid butyl ester hydrotrifluoroacetate, 13.7 ml N-ethylmorpholine and 8.8 g TOTU. After stirring for 12 h the solution was diluted with ethyl acetate and subsequently washed with aqueous LiCl (4%) and saturated NaHCO3. The crude product obtained after evaporation of the solvent was used without further purification. Yield: 15.8 g.
Reaction SMILES: ClC1C=C(S([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[C:25]([F:32])[CH:24]=4)=[O:21])[CH:18]=3)[CH2:13][CH2:12]2)(=O)=O)C=CC=1.[CH2:33](OC(=O)C1C=CC(N)=CC=1F)[CH3:34]>>[CH2:33]([O:29][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][C:23]([NH:22][C:20]([C:17]2[CH:18]=[C:19]3[C:14]([CH:13]=[CH:12][NH:11]3)=[CH:15][CH:16]=2)=[O:21])=[CH:24][C:25]=1[F:32])[CH3:34]
Reactant: CCOC(=O)c1ccc(N)cc1F
Reactant: O=C(Nc1ccc(C(=O)O)c(F)c1)c1ccc2c(c1)N(S(=O)(=O)c1cccc(Cl)c1)CC2
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3cc[nH]c3c2)cc1F

Procedure:
4-{[1-(3-Chloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-2-fluoro-benzoic acid, m/z (ES+): 475.18 (M+H+.), was prepared in analogy to example 1, steps 1 to 5. Step 2 was performed using 4-amino-2-fluorobenzoic acid ethyl ester and yielded 2-fluoro-4-[(1H-indole-6-carbonyl)-amino]-benzoic acid ethyl ester. This was reduced to 4-[(2,3-dihydro-1H-indole-6-carbonyl)-amino]-2-fluoro-benzoic acid ethyl ester in step 3. Step 4 was performed using 3-chloro-benzenesulfonyl chloride, yielding 4-{[1-(3-chloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, which was hydrolyzed in step 5.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.C(N(CC)C(C)C)(C)C.Br[C:26]1[S:30][C:29]([C:31]#[N:32])=[N:28][N:27]=1.[NH4+].[Cl-]>O1CCOCC1>[Br:1][C:2]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:3]=1[O:4][CH:5]1[CH2:6][CH2:7][N:8]([C:26]2[S:30][C:29]([C:31]#[N:32])=[N:28][N:27]=2)[CH2:9][CH2:10]1
Reactant: Fc1ccc(Br)c(OC2CCNCC2)c1
Reactant: N#Cc1nnc(Br)s1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1nnc(N2CCC(Oc3cc(F)ccc3Br)CC2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(2-bromo-5-fluorophenoxy)piperidine (15.16 g, 52.5 mmol) in 1,4-dioxane (80 mL) was added N,N-diisopropylethylamine (Hünig's base or DIPEA) (20 mL, 115 mmol) followed by 5-bromo-1,3,4-thiadiazole-2-carbonitrile (10.02 g, 52.7 mmol). The mixture was stirred 1 h at room temperature. The reaction mixture was then poured into saturated aqueous NH4Cl, extracted with EtOAc, washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel (eluting with 10-40% EtOAc/hexanes) to afford the desired product as a colorless oil.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[OH:33])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH: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.C(=O)([O-])[O-].[K+].[K+].Br[CH:41]1[CH2:45][CH2:44][NH:43][C:42]1=[O:46].O>CS(C)=O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH:41]2[CH2:45][CH2:44][NH:43][C:42]2=[O:46])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NCCC1Br
Reactant: CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)/C(=N\OC1CCNC1=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85.7 %

Procedure:
15.8 g of ethyl (Z)-2-(2-tritylaminothiazol-4-yl)-2-hydroxyiminoacetate are dissolved in 70 ml of dimethylsulfoxide, and 5.8 g of anhydrous potassium carbonate are added thereto. The mixture is stirred at room temperature for 20 minutes. 6.6 g of 3-bromo-2-pyrrolidone are added to said mixture, and the mixture is stirred at room temperature for 20 hours. The mixture is poured into 800 ml of water, and crystalline precipitates are collected by filtration and washed with water. The crystals are dissolved in chloroform, washed with water and then dried. Then, the chloroform solution is evaporated under reduced pressure to remove solvent. 100 ml of ethyl acetate are added to the residue, and allowed to stand at room temperature. Crystalline precipitates thus obtained are collected by filtration and dried. 16.0 g of ethyl (Z)-2-(2-tritylaminothiazol-4-yl)-2-[(2-pyrrolidon-3-yl)oxyimino]acetate are obtained.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[NH2:21][CH2:22][C@@H:23]1[O:27][C:26](=[O:28])[N:25]([C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][C:36]3=[O:41])=[CH:31][CH:30]=2)[CH2:24]1.O>CN(C1C=CN=CC=1)C.ClCCl>[CH:33]1[C:32]([N:35]2[C:36](=[O:41])[CH2:37][O:38][CH2:39][CH2:40]2)=[CH:31][CH:30]=[C:29]([N:25]2[C:26](=[O:28])[O:27][C@@H:23]([CH2:22][NH:21][C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:9])[CH2:24]2)[CH:34]=1
Reactant: NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Reactant: O=C(O)c1ccc(Cl)s1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: ClCCl
Product: O=C(NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1
Reaction time: 0.17 h
Yield: 85.6 %

Procedure:
4-(N,N-dimethylamino)pyridine (36.6 g, 0.3 mol) was added to a stirred suspension of 5-chlorothiophene-2-carboxylic acid (16.25 g, 0.1 mol) in dichloromethane (162 ml) at 0-5° C. and the resulting solution was stirred for 10 minutes. A mixture of p-toluenesulfonyl chloride (19.05 g, 0.1 mol) and dichloromethane (50 ml) was added to the above solution at −5° C. The resulting solution was stirred for 1 hour at −5° C. to produce a reaction mass containing the sulfonyl ester intermediate, followed by portion wise addition of 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (29.1 g, 0.1 mol, chiral purity: 99.9%). The reaction mixture was stirred for 2 hours at 25-30° C., followed by the addition of water (162 ml) and then stirring for 15 minutes. The separated solid was filtered, washed with dichloromethane (50 ml) and water (100 ml), and the resulting wet material was dried at 80-85° C. for 3 to 5 hours to produce 37.3 g of pure rivaroxaban as a white crystalline solid (Theoretical Yield: 85.6%; Purity by HPLC: 99.9%; and Chiral Purity by HPLC: 99.9%).
Reaction SMILES: C[O-].[Na+].[CH2:4]([SH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:12][S:13]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1Br)(=[O:15])=[O:14]>CN(C)C=O>[CH3:12][S:13]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[S:11][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:15])=[O:14]
Reactant: SCc1ccccc1
Reactant: CS(=O)(=O)c1sccc1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1sccc1SCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2 g of sodium methoxide in 100 ml of dimethylformamide was added 6 ml of benzyl mercaptan followed by 10 g of 3-bromo-2-thienyl methyl sulfone. The temperature rose to 70°. The mixture was stirred at room temperature for 16 hours and then at 70° for 1 hour. Most of the dimethylformamide was evaporated at reduced pressure and ice-water was added to the residue. The resulting solid was filtered, washed with ice-water and hexane to afford 14 g of crude XXVII. A dried sample of this material had m.p. 95°-97° and peak at 4.2 in the NMR spectrum (CDCl3), consistent with an aromatic benzyl sulfide.
Reaction SMILES: [C:1]([CH2:4][S:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:12](=[O:16])[CH2:13][CH2:14][CH:15]=1)([OH:3])=[O:2].[C:17]1(C)C=CC(S(O)(=O)=O)=C[CH:18]=1>C(O)C>[C:1]([CH2:4][S:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:12](=[O:16])[CH2:13][CH2:14][CH:15]=1)([O:3][CH2:17][CH3:18])=[O:2]
Reactant: O=C(O)CSCCCCCC1=CCCC1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)CSCCCCCC1=CCCC1=O

Procedure:
A mixture of 74 g. (0.306 mols) of 2-(7-carboxy-6-thiaheptyl)-2-cyclopentenone, 1200 ml. of ethanol and 1 g. p-toluenesulfonic acid is stirred and refluxed for 18 hours. The resulting solution is concentrated and the residue is dissolved in ether. The organic phase is washed with water, sodium bicarbonate solution and saline, dried (MgSO4) and evaporated. The residue is distilled to give a light yellow oil, o.p. 147°-150° C. (0.07 Torr).
Reaction SMILES: C(C(CC)(C1C=CC=CC=1OCC1C=CC=CC=1)N)C.[CH:21]1([NH:24][C:25](=[O:53])[C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([N:33]3[CH:38]=[CH:37][N:36]=[C:35]([NH:39][C:40]([CH2:50][CH3:51])([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=4[OH:49])[CH2:41][CH3:42])[C:34]3=[O:52])[CH:27]=2)[CH2:23][CH2:22]1.C1(O)C=CC=CC=1.Br[CH2:62][CH2:63][Cl:64]>>[Cl:64][CH2:63][CH2:62][O:49][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=1[C:40]([NH:39][C:35]1[C:34](=[O:52])[N:33]([C:28]2[CH:27]=[C:26]([CH:31]=[CH:30][C:29]=2[CH3:32])[C:25]([NH:24][CH:21]2[CH2:23][CH2:22]2)=[O:53])[CH:38]=[CH:37][N:36]=1)([CH2:41][CH3:42])[CH2:50][CH3:51]
Reactant: CCC(CC)(Nc1nccn(-c2cc(C(=O)NC3CC3)ccc2C)c1=O)c1ccccc1O
Reactant: ClCCBr
Agent: CCC(N)(CC)c1ccccc1OCc1ccccc1
Solvent: Oc1ccccc1
Product: CCC(CC)(Nc1nccn(-c2cc(C(=O)NC3CC3)ccc2C)c1=O)c1ccccc1OCCCl

Procedure:
α,α-Diethyl-2-(phenylmethoxy)-benzenemethanamine (Example 266d) was converted to N-cyclopropyl-3-[3-[[1-ethyl-1-(2-hydroxyphenyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide using the method described in Example 134. This phenol was alkylated with 1-bromo-2-chloroethane as described in example 167e to afford the subtitle product.
Reaction SMILES: [N:1]1[N:5]2[C:6]3[C:14]4[CH:15]=[N:16][NH:17][C:13]=4[N:12]=[CH:11][C:7]=3[C:8](=[O:10])[NH:9][C:4]2=[N:3][CH:2]=1.C(N1C2N=CC3C(=O)NC4N(N=CN=4)C=3C=2C=N1)C.[CH2:37](I)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CI>>[C:38]1([CH2:37][N:9]2[C:8](=[O:10])[C:7]3[CH:11]=[N:12][C:13]4[NH:17][N:16]=[CH:15][C:14]=4[C:6]=3[N:5]3[N:1]=[CH:2][N:3]=[C:4]23)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=c1[nH]c2ncnn2c2c1cnc1[nH]ncc12
Reactant: ICc1ccccc1
Agent: CCn1ncc2c1ncc1c(=O)[nH]c3ncnn3c12
Solvent: CI
Product: O=c1c2cnc3[nH]ncc3c2n2ncnc2n1Cc1ccccc1

Procedure:
By substituting the 4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one of Example 11 for the 8-ethyl -4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]-triazolo[1,5-a]pyrimidin-5(8H)-one and benzyl iodide for the methyl iodide in the procedure of Example 4, 4-phenylmethyl4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]1([CH2:21][O:22][CH2:23][CH2:24][CH2:25][Mg]Cl)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.ClCCCOCC1C=CC=CC=1.[Cl-].[NH4+]>O.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH:10]([OH:11])[CH2:25][CH2:24][CH2:23][O:22][CH2:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: Cl[Mg]CCCOCc1ccccc1
Agent: ClCCCOCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(O)CCCOCc1ccccc1
Reaction time: 0.25 h

Procedure:
A THF solution (20 ml) of N-(tert-butoxycarbonyl)-L-prolinal (4.50 g) was dropwise added to a THF solution (30 ml) of 3-(phenylmethyloxy)propyl magnesium chloride prepared from 1-chloro- 3-(phenylmethyloxy)propane (5.00 g), at -78° C. After stirring for 15 minutes, saturated ammonium chloride (10 ml) was added, and the reaction mixture was allowed to reach room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with 10% citric acid, saturated sodium hydrogencarbonate and saturated brine in order, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluent: n-hexane-ethyl acetate) to give two stereoisomers (1.89 g of low polar isomer and 3.05 g of high polar isomer).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].Cl.Cl.[CH3:29][N:30]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][NH2:41])=[CH:35][CH:34]=1)[CH3:31].C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](=[O:19])[NH:41][CH2:40][CH2:39][C:36]3[CH:37]=[CH:38][C:33]([CH2:32][N:30]([CH3:31])[CH3:29])=[CH:34][CH:35]=3)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2]
Reactant: CN(C)Cc1ccc(CCN)cc1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(CN(C)C)cc4)cc3)c(C#N)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a stirred suspension of 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (0.10 g, 0.28 mmol), 2-(4-((dimethylamino)methyl)phenyl)ethanamine dihydrochloride (0.056 g, 0.31 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′-tetramethyluronium hexafluorophosphate (0.13 g, 0.34 mmol) in N,N-dimethylformamide (1.4 mL) at ambient temperature was added N,N-diisopropylethylamine (0.25 mL, 1.4 mmol). The resulting solution was stirred at ambient temperature for 60 minutes, then partitioned between water (15 mL) and ethyl acetate (10 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel, eluting with 90/10 chloroform/(90/10 methanol/concentrated ammonium hydroxide), to afford methyl 6-cyano-7-(4-(4-((dimethylamino)methyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate as a colorless film (0.083 g, 57% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[CH3:14][C:15]1([CH3:23])[C:20](=[O:21])[CH2:19][C:18](=[O:22])[CH2:17][O:16]1.C(N(CC)CC)C.CC(C)(O)C#N>[Cl-]>[N+:1]([C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:5]=1[C:6]([CH:19]1[C:18](=[O:22])[CH2:17][O:16][C:15]([CH3:23])([CH3:14])[C:20]1=[O:21])=[O:7])([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CC1(C)OCC(=O)CC1=O
Agent: CC(C)(O)C#N
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: CC1(C)OCC(=O)C(C(=O)c2ccc(Cl)cc2[N+](=O)[O-])C1=O
Temperature: 25 °C
Yield: 43 %

Procedure:
2-Nitro-4-chlorobenzoyl chloride (2.2 g, 10 mmol) and 2,2-dimethyl-2H-pyran-3,5-(4H,6H)-dione (1.4 g, 10 mmol) were dissolved in 150 milliliters (ml) chloride. Triethylamine (3 ml, 22 mmol) was added and the resulting solution stirred at room temperature for fifteen minutes. The solution was washed with dilute hydrochloric acid, 5% potassium carbonate and saturated sodium chloride, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was dissolved in 10 ml acetonitrile. Triethylamine (3 ml, 22 mmol) and acetone cyanohydrin (0.2 g) were added and the mixture stirred at room temperature for 2 hours. After dilution with ether, the solution was washed with dilute hydrochloric acid and extracted with 5% potassium carbonate. The basic extract was acidified with hydrochloric acid and extracted with ether. The ether extract was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate and concentrated under vacuum, yielding 1.4 g of the desired product as a viscous oil. It was identified as such by nuclear magnetic resonance spectroscopy, infrared spectroscopy and mass spectroscopy.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([CH2:14][CH3:15])[N:4]=[CH:3]1.S(O)(O)(=O)=O.[NH2:22][OH:23].S(=O)(=O)(O)O>O>[CH3:1][C:2]([CH3:16])([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([CH2:14][CH3:15])[NH2:4])[CH:3]=[N:22][OH:23]
Reactant: NO
Reactant: CCC1CCCCCCCCC(C)(C)C=N1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCC(N)CCCCCCCCC(C)(C)C=NO
Yield: 191 %

Procedure:
The procedure described in Example 1(b) is repeated, except that 223 g (1 mol) of 3,3-dimethyl-12-ethyl-1-aza-cyclododecene, 82 g (0.5 mol) of hydroxylamine sulfate, 150 g of sulfuric acid and 400 ml of water are used. Distillation yields 245 g (0.955 mol) of 2,2-dimethyl-11-ethyl-11-amino-undecanal oxime; yield 95.5% of theory; boiling point 155°-160° C./7 Pa.