Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:64])=[CH:43][CH:44]2[CH2:49][CH2:48][C:47]([OH:61])([CH2:50][C:51]([O:53][CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)=[O:52])[CH:46]([O:62][CH3:63])[CH2:45]2)[CH:7]([CH3:65])[CH:6]([O:66][Si](C(C)(C)C)(C)C)[CH2:5][C:4]1=[O:74])[CH3:2]>C(#N)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:64])=[CH:43][CH:44]2[CH2:49][CH2:48][C:47]([OH:61])([CH2:50][C:51]([O:53][CH2:54][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)=[O:52])[CH:46]([O:62][CH3:63])[CH2:45]2)[CH:7]([CH3:65])[CH:6]([OH:66])[CH2:5][C:4]1=[O:74])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)(CC(=O)OCc4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Solvent: CC#N
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)(CC(=O)OCc4ccccc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Yield: 82.4 %

Procedure:
A solution of 0.200 g (0.191 mmole) of 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-4"-[benzyloxycarbonylmethyl]-3"-methoxycyclohexyl)-1'-methylvinyl]-14-tert-butyldimethylsilyloxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone in 5 mL of 10% (48% aqueous HF)-acetonitrile was stirred at room temperature for 16 h. The reaction was quenched by addition of 5 mL of trimethylethoxy-silane and the solution was concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 1.5 cm×10 cm) using acetone-hexane and the product lyophilized from benzene to afford 0.148 g (82%) of the title compound as a colorless solid; MS (FAB) 946 (M+Li).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[CH3:18][N:19]1[C:23]([CH3:24])=[CH:22][C:21]([C:25](O)=[O:26])=[N:20]1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:25]([C:21]3[CH:22]=[C:23]([CH3:24])[N:19]([CH3:18])[N:20]=3)=[O:26])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Reactant: Cc1cc(C(=O)O)nn1C
Product: Cc1cc(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)OC[C@@H]3F)c2)nn1C

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (CAS 5744-59-2) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=364.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[N:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].C.[C:25](=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:13]=[C:12]([C:14]([O:16][CH3:25])=[O:15])[N:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc(OCc2ccccc2)nn1-c1ccccc1
Agent: C
Agent: Cl
Agent: [I-]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccccc2)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
A mixture of 3-benzyloxy-1-phenyl-1H-pyrazole-5-carboxylic acid (33.00 g), methane iodide (8.5 ml), potassium carbonate (18.88 g) and N,N-dimethylformamide (300 ml) was stirred overnight at room temperature. The reaction mixture was poured into dilute hydrochloric acid and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-benzyloxy-1-phenyl-1H-pyrazole-5-carboxylate (33.48 g, yield 97%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 53–54° C.
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8](O)=[O:9])[CH:5]=[N:4][N:3]=[N:2]1.[Cl-].[NH4+].Cl.C[N:19](C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[N:1]1([C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([NH2:19])=[O:9])[CH:5]=[N:4][N:3]=[N:2]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccccc1-n1cnnn1
Agent: Cl
Agent: On1nnc2cccnc21
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1-n1cnnn1

Procedure:
A solution of 2-Tetrazol-1-yl-benzoic acid (1.0 g, 5.2 mmol), ammonium chloride (0.56 g, 10.4 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.0 g, 10.4 mmol), 1-hydroxy-7-azabenzotriazole (1.4 g, 10.4 mmol) and diisopropylethylamine (3.6 ml, 20.8 mmol) in N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. Water was added and the reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with brine. Drying and solvent evaporation gave 2-Tetrazol-1-yl-benzamide; 1H NMR (CD3OD, 400 MHz) δ 9.44 (s, 1H), 7.72 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([F:11])=[CH:4][C:3]=1[CH3:12].[H][H]>[Ni].C(O)C>[Br:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([F:11])=[C:6]([CH:7]=1)[NH2:8]
Reactant: [H][H]
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1Br
Agent: [Ni]
Solvent: CCO
Product: Cc1cc(F)c(N)cc1Br
Yield: 63.2 %

Procedure:
Combine crude 1-bromo-4-fluoro-2-methyl-5-nitrobenzene (32.4 g, 138 mmol), ethanol (100 mL) and Raney Nickel (1.00 g, 17.04 mmol) in a shaker flask. Charge the flask with hydrogen (275 kPa) and agitate until the absorption of hydrogen ceases. De-pressurize the reaction vessel, remove the catalyst by filtration, and evaporate the filtrate to dryness. Add MTBE, then filter again and evaporate the filtrate. Stir residue in hexanes. Collect the solids by filtration, wash with cold hexanes and dry in vacuo to provide the title compound (17.8 g, 63% yield) as a dark solid. MS (m/z): 204.0 (M+1)/206.0 (M+3).
Reaction SMILES: [C:1]([C@H:3]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][C@H:4]1[C:15]([O:17]CC)=[O:16])#[N:2].[OH-].[K+].Cl>CO.O>[C:1]([C@@H:3]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][C@@H:4]1[C:15]([OH:17])=[O:16])#[N:2]
Reactant: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1C#N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#C[C@@H]1CN(Cc2ccccc2)C[C@@H]1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 182.5 %

Procedure:
Dissolve ethyl(3S,4R)-4-cyano-1-(phenylmethyl)-3-pyrrolidinecarboxylate (2.0 g, 7.72 mmol) in 4:1 methanol/water (50 mL). The solution was cooled to 0 degrees C. and potassium hydroxide (0.867 g, 15.4 m, mol) was added. The reaction was allowed to stir at 0 degrees C. for 1 hour. 1 N HCl was added with cooling and the solution brought to pH=7. The solvent was removed under reduced pressure yielding a crude solid (3.244 g) which was taken on to the next step. LCMS: m/z 231.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.Cl[C:11]1[CH:16]=[C:15]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:14]=[C:13]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[N:12]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:11]2[CH:16]=[C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[N:14]=[C:13]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[N:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: Clc1cc(N2CCCC2)nc(N2CCCC2)n1
Product: COc1ccc(Nc2cc(N3CCCC3)nc(N3CCCC3)n2)cc1
Reaction time: 18 h

Procedure:
A mixture of 2.44 g of p-anisidine is heated to 135° (oil bath). The molten mixture is treated with 4-chloro-2,6-di-1-pyrrolidinylpyrimidine V, J. Med. Chem., 33,1145 (1990), 500 mg! and the reaction is stirred at 135° for 18 hr. The reaction mixture is allowed to cool and is then partitioned between chloroform and water. The organic layer is separated, washed with saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product (1.93 g) is chromatographed on 180 g of mesh silica gel. The column is packed and eluted with dichloromethane/ethyl acetate (9/1). An initial fraction of 2000 ml is collected. The solvent system is then changed to ethyl acetate/dichloromethane (9/1) and 10 ml fractions are then collected. Based on their TLC homogeneity, fractions 5-25 are combined to give the title compound, which is recrystallized from ethanol/water and dried (18 hours, 0.01 mm, 40°), mp 162°-163°; IR (mineral oil) 3273, 2953, 2925, 2865, 2854, 1609, 1586, 1571, 1549, 1505, 1478, 1453, 1427, 1409, 1377, 1343, 1313, 1303, 1294, 1236, 1219, 1171, 1043, 821 and 788 cm-1 ; NMR (CDCl3, TMS) 7.30-7.20, 6.90-6.80, 6.19, 4.99, 4.03, 3.60-3.30 and 2.00-1.80δ; CMR (CDCl3, TMS) 161.9, 160.3, 155.6, 133.1, 123.9, 114.1, 72.6, 55.3, 46.1, 45.8, 25.4 and 25.1δ; MS M+ found=339, other ions 324, 311, 297, 283, 270, 242, 169, 148, 121, 70 and 55.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:10]1([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][NH:28][C:29](=[O:35])[CH2:30][S:31][CH2:32][CH2:33][OH:34])[CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>N1C=CC=CC=1>[N:10]1([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][NH:28][C:29](=[O:35])[CH2:30][S:31][CH2:32][CH2:33][O:34][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C(CSCCO)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(CSCCOC(=O)c1ccccc1)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
0.24 ml of benzoyl chloride was added, whilst ice-cooling, to a mixture of 0.40 g of N-[4-(4-piperidinomethyl -2-pyridyloxy)-cis-2-butenyl]-2-(2-hydroxyethylthio)acetamide (prepared as described in Example 1) and 1.02 ml of pyridine, and the resulting mixture was stirred at room temperature for 2 hours. At the end of this time, the mixture was concentrated by evaporation under reduced pressure. The concentrate was diluted with water and made alkaline by the addition of an aqueous ammonia solution, after which it was extracted with ethyl acetate. The extract was concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 1:40 by volume mixture of methanol and ethyl acetate as the eluent, to give 0.31 g of the title compound in a 61% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[C:27](C)[CH:26]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=NC(C#C)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.BrC1C=CC(C(F)(F)F)=CC=1[Cl:71]>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=2[Cl:71])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(Br)c(Cl)c1
Reactant: Cc1cc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)ccc1C(F)(F)F
Agent: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Product: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c(Cl)c1
Yield: 75 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-((3-methyl-4-(trifluoromethyl)phenyl)-ethynyl)pyridazine (Intermediate 74) from 3,4-bis(benzyloxy)-6-ethynylpyridazine (Intermediate 5) and 1-bromo-2-chloro-4-(trifluoromethyl)benzene in 75% yield.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[C:7]([C:9]3[N:14]=[C:13](N)[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][CH:10]=3)[N:8]=2)[CH2:3][CH2:2]1.[OH:27]S(O)(=O)=O.N([O-])=O.[Na+].OP([O-])(O)=O.[Na+].[OH-].[Na+]>CS(C)=O.O>[CH:1]1([C:4]2[NH:5][C:6]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[C:7]([C:9]3[N:14]=[C:13]([OH:27])[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][CH:10]=3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1nc(-c2nc(C3CC3)[nH]c2-c2ccc(F)cc2F)ccc1[N+](=O)[O-]
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2nc(C3CC3)[nH]c2-c2ccc(F)cc2F)nc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
6-[2-Cyclopropyl-5-(2,4-difluorophenyl)-1H-imidazol-4-yl]-3-nitro-pyridin-2-amine (5.51 g, 15.41 mmol) is suspended in dimethyl sulfoxide (DMSO, 32 mL), water (25 mL), and concentrated H2SO4 (6 mL). The suspension is cooled at 0° C. and sodium nitrite (2.13 g, 30.81 mmol) is added portionwise at such a rate that the temperature is maintained below 5° C. The mixture is stirred at 0° C. for 30 min, and then is allowed to warm to RT, and is stirred until liquid chromatography/mass spectrometry (LC/MS) shows complete conversion of the starting material (1 hour). A 0.8 M aqueous solution of sodium phosphate monobasic (200 mL) is added to the mixture. A yellow suspension is formed. Aqueous 1 N NaOH is then added until the pH rises to 8. The mixture is stirred for 30 h, filtered, and the solid is rinsed with water, and then dried under reduced pressure to afford the title compound (4.53 g, 82%). LC-ES/MS m/z 358.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([N+:8]([O-])=O)=[CH:6][N:5]([C@H:11]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12]2)[N:4]=1>[Pd].CO>[CH3:1][O:2][C:3]1[C:7]([NH2:8])=[CH:6][N:5]([C@H:11]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12]2)[N:4]=1
Reactant: COc1nn([C@H]2CCN(C)C2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1nn([C@H]2CCN(C)C2)cc1N
Reaction time: 16 h

Procedure:
A nitrogen-flushed round bottom flask was charged with (S)-3-methoxy-1-(1-methylpyrrolidin-3-yl)-4-nitro-1H-pyrazole (300 mg, 1.33 mmol, 1.00 eq), 10% Pd/C (200 mg) and methanol (20 mL). The reaction mixture was sparged with hydrogen for 10 min then stirred vigorously under hydrogen atmosphere for 16 hr. The reaction mixture was then sparged with nitrogen, filtered through Celite®, and concentrated to give an oil that was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.99 (s, 1H), 4.51 (tdd, J=4.8, 7.3, 9.3 Hz, 1H), 3.74 (s, 3H), 3.36 (br. s., 2H), 2.71-2.61 (m, 2H), 2.57 (dd, J=4.8, 9.5 Hz, 1H), 2.40 (dt, J=6.5, 8.3 Hz, 1H), 2.25 (s, 3H), 2.23-2.14 (m, 1H), 1.94-1.84 (m, 1H). m/z (APCI+) for C9H17N4O 197.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][NH:8][C:7](=O)[C:6]=2[CH:17]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][NH:8][C:7](=[S:19])[C:6]=2[CH:17]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cc1nnc2n1-c1ccc(Cl)cc1C(=O)NC2
Solvent: c1ccncc1
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(=S)NC2

Procedure:
A stirred mixture of 8-chloro-5,6-dihydro-1-methyl-4H-s-triazolo[4,3-a][1,4]benzodiazepin-6-one (VIIa) (24.87 g., 0.1 mole) and dry pyridine (1420 ml.) was treated with phosphorus pentasulfide (24.45 g., 0.11 mole) and refluxed for 2.5 hours, under nitrogen. The mixture was cooled, concentrated in vacuo, and the residue mixed with water and chloroform. The mixture was neutralized with sodium bicarbonate and the solid collected by filtration. This solid was washed with chloroform and recrystallized from a chloroform/methanol/ethyl acetate mixture to give 20.31 g., melting point 303°-308° of the titled product (VIIIa). Additional product was obtained from the chloroform filtrates which were washed with brine, dried (Na2SO4) and concentrated. The residue was crystallized from a chloroform/methanol/ethyl acetate mixture to give 2.93 g., melting point 298°-303°; and 0.78 g., melting point 302°-305° of the title compound (VIIIa) (91% overall yield). The analytical sample was recrystallized from methylene chloride/methanol and had: melting point 306°-308°; uv (EtOH) λ max 223 mμ (ε31,500), 316 (7700). The ir and nmr spectra support the proposed structure.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:26])[CH2:10][C@@:11]1([C:20]2[S:21][C:22]([Br:25])=[CH:23][CH:24]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33](O)=[O:34].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:26])[CH2:10][C@@:11]1([C:20]2[S:21][C:22]([Br:25])=[CH:23][CH:24]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:14]([C:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=2)=[O:34])[CH2:13][CH2:12]1
Reactant: O=C(O)c1ccccn1
Reactant: O=C(C[C@]1(c2ccc(Br)s2)CCNCCS1(=O)=O)NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(C[C@]1(c2ccc(Br)s2)CCN(C(=O)c2ccccn2)CCS1(=O)=O)NOC1CCCCO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
A mixture of N-(2-tetrahydropyranyloxy)-2-[(S)-7-(5-bromo-2-thienyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (2.40 g), 2-pyridinecarboxylic acid (695 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.48 g) and 1-hydroxybenzotriazole (1.04 g) in anhydrous dimethylformamide (24 ml) was stirred at 0° C. for 2 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of chloroform and methanol (50:1) to give N-(2-tetrahydropyranyloxy)-2-[(S)-7-(5-bromo-2-thienyl)-4-(2-pyridinecarbonyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide as a colorless amorphous powder (2.68 g).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[O:19]1[C:23]2=[CH:24][CH:25]=[CH:26][C:27]([NH2:28])=[C:22]2[N:21]=[CH:20]1>>[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([NH:28][C:15](=[O:17])[CH2:14][C:9]3[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:8]=3)[C:22]=2[N:21]=[CH:20]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1cccc2ocnc12
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc2ocnc12
Yield: 54.6 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 260 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 268 mg of 1,3-benzoxazol-4-amine in place of the 2,4-difluoroaniline. 193 mg of N-(1,3-benzoxazol-4-yl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of an ecru solid, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>N1C=CC=CC=1>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:28](=[O:30])[CH3:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Solvent: c1ccncc1
Product: COc1ccc(N2CCN(C(C)=O)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reaction time: 16 h
Yield: 97 %

Procedure:
A solution of the bis-hydrochloride salt of (S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine in pyridine (1 mL) was treated with acetic anhydride (32 μL, 0.34 mmol) and stirred for 16 h. The reaction mixture was evaporated and partitioned between EtOAc (2 mL) and a saturated aqueous NaHCO3 solution (2 mL). The organic component was separated, dried over MgSO4, filtered, and evaporated to residue which was purified by silica gel flash chromatography with EtOAc as eluant to afford the title compound as an oil (45 mg, 97%). LC/MS (Method A) 6.88 min, [M+1]+ 409.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[CH2:18][O:17]1.O>CN(C)C=O>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]([OH:17])([CH2:19][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1)[CH2:18][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: c1c[nH]cn1
Reactant: Clc1ccc(C2(Cn3cncn3)CO2)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OC(Cn1ccnc1)(Cn1cncn1)c1ccc(Cl)cc1Cl
Temperature: 80 °C

Procedure:
Sodium hydride (50% suspension in oil--2.23 g) was suspended in dimethylformamide (30 ml) under an atmosphere of argon, and cooled in a water bath while imidazole (3.2 g) was added in portions. A solution of 2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)oxirane (6.4 g) in dimethylformamide (30 ml) was added, and the mixture was heated at 80° C. for 2 hours. The mixture was cooled, poured into water (200 ml) and extracted with methylene dichloride. The organic extract was washed with water twice and with brine twice, dried over sodium sulphate and filtered. The solvent was evaporated under reduced pressure, and the residue was chromatographed on a K60 silica column, eluting with 0 to 7% of methanol in methylene dichloride, to give 2-(2,4-dichlorophenyl)-1-(imidazol-1-yl)-3-(1,2,4-triazol-1-yl)-2-propanol, m.p. 169°-170° C.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[O:10]1[CH:14]=[CH:13][CH2:12][CH2:11]1>N1C=CC=CC=1>[O:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: C1=COCC1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: c1ccncc1
Product: O=c1[nH]c(=O)n(C2CCCO2)cc1F
Temperature: 70 °C
Yield: 97.5 %

Procedure:
In an autoclave, 520 g of 5-fluorouracil, 1400 g of 2,3-dihydrofuran and 1.56 l of pyridine were heated together at 185° C. for 3 hours. After cooling, the reaction mixture was concentrated to dryness under reduced pressure and the residue was dissolved in 6 l of ethanol-water(1:1). The solution was heated at 70° C. for 2 hours, after which it was treated with activated charcoal. After filtration, the solution was concentrated under reduced pressure to about one-half of its original volume. After cooling, the resultant crystals were recovered by filtration and dried. By the above procedure was obtained 780 g of 1-(tetrahydro-2-furyl)-5-fluorouracil. If necessary, this product may be recrystallized from ethanol. Recrystallization yielded 600 g of colorless needles, melting point: 167.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH2:10])=[O:4].[CH2:11]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Sn](CCCC)(CCCC)(Cl)Cl.C1([SiH3])C=CC=CC=1>C1COCC1>[CH2:11]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH:10][C:9]2[CH:8]=[CH:7][S:6][C:5]=2[C:3]([O:2][CH3:1])=[O:4])[CH2:23][CH2:22]1)=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1sccc1N
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1sccc1NC1CCN(C(=O)OCc2ccccc2)CC1
Yield: 101.4 %

Procedure:
Reductive amination of 3-amino-thiophene-2-carboxylic acid methyl ester (3.0 g, 19.1 mmol) and 4-oxo-piperidine-1-carboxylic acid benzyl ester (4.46 g, 19.1 mmol) in THF (4.6 mL) employing Bu2SnCl2 (0.598 g, 1.92 mmol) and PhSiH3 (2.58 mL, 21.6 mmol) was carried out as described for example 19, step 1 gave 4-(2-methoxycarbonyl-thiophen-3-ylamino)-piperidine-1-carboxylic acid benzyl ester (7.25 g, quantitative). NMR 1H (CDCl3, 400 MHz): 7.4-7.3 (m, 6H), 6.9-6.78 (m, 1H), 6.7-6.6 (m, 1H), 5.14 (s, 2H), 4.15-4.0 (m, 2H), 3.81 (s, 3H), 3.6-3.45 (m), 3.1 (brt, 2H), 2.1-1.9 (m, 2H), 1.6-1.45 (m, 2H).