Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:33]=[CH:32][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][C:22]=3[O:30][CH3:31])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2].[NH2:34][C:35]1[S:36][CH:37]=[CH:38][N:39]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:11]1([N:10]2[C:6]3[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:33]=[CH:32][C:7]=3[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:28])[NH:34][C:35]4[S:36][CH:37]=[CH:38][N:39]=4)=[CH:23][C:22]=3[O:30][CH3:31])(=[O:20])=[O:19])[C:9]2=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: Nc1nccs1
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)O)cc1OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)Nc2nccs2)cc1OC
Yield: 7.7 %

Procedure:
This compound is prepared by the procedure described in EXAMPLE 100 starting from 1 g of the compound obtained in EXAMPLE 13, 0.3 g of 2-aminothiazole, 1.2 g of BOP, 1 ml of DIPEA and 20 ml of DCM. It is chromatographed on silica using a DCM/MeOH mixture (99.5/0.5; v/v) as the eluent to give 0.09 g of the expected product after crystallization from EtOH. M.p.=213° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]2[O:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:4][C:3]=1[O:17][CH3:18].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26]>>[CH3:26][C:25]1[O:24][C:23]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[N:22][C:21]=1[CH2:20][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]2[O:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:4][C:3]=1[O:17][CH3:18]
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: COc1cc(CCC2OC(=O)NC2=O)ccc1O
Product: COc1cc(CCC2OC(=O)NC2=O)ccc1OCc1nc(-c2ccccc2)oc1C

Procedure:
In substantially the same manner as in Working Example 9, 5-[2-(4-hydroxy-3-methoxyphenyl)ethyl]-2,4-oxazolidinedione was reacted with 4-chloromethyl-5-methyl-2-phenyloxazole to obtain 5-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-methoxyphenyl]ethyl]-2,4-oxazolidinedione, which was recrystallized from ethyl acetate-chloroform to give colorless prisms, m.p.194-195° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:24])[C:7](=[O:23])[C:8]3([CH2:22]C[CH2:20][CH2:19][CH2:18]3)[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:25][C:26]1[CH:41]=[CH:40][C:29]([C:30]([NH:32][CH:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=[O:31])=[CH:28][C:27]=1[O:42][CH3:43].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:22][CH2:20][CH2:19][CH2:18]3)[C:7](=[O:23])[N:6]([CH3:24])[C:5]3[CH:4]=[N:3][C:2]([NH:25][C:26]4[CH:41]=[CH:40][C:29]([C:30]([NH:32][CH:33]5[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]5)=[O:31])=[CH:28][C:27]=4[O:42][CH3:43])=[N:12][C:11]2=3)[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reactant: CN1C(=O)C2(CCCCC2)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)CC(C)O
Solvent: O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CCCC1)C(=O)N2C

Procedure:
2′-chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclohexane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 255; 80 mg, 0.24 mmol), 4-amino-3-methoxy-N-(1-methyl-4-piperidyl)benzamide (WO06/018220; 63 mg, 0.24 mmol) and p-toluenesulphonic acid monohydrate (114 mg, 0.60 mmol) were heated in 4-methyl-2-pentanol (3 mL) at 140° C. for 3 hours. The mixture was cooled and absorbed on to an SCX column, which was then washed with methanol and eluted with ammonia in methanol. Product containing fractions were evaporated and the residue purified on a silica column (2% 7N ammonia in methanol/DCM) to give the title compound as a white solid. (70 mg, 52%)
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1I)[CH3:2].FC1C=CC(B(O)O)=CC=1.[C:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)#[N:32]>>[C:31]([C:33]1[CH:38]=[CH:37][C:36]([C:7]2[NH:6][C:5]([CH:9]=[O:10])=[C:4]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[C:3]=2[CH2:1][CH3:2])=[CH:35][CH:34]=1)#[N:32]
Reactant: CCc1c(I)[nH]c(C=O)c1C(=O)OCc1ccccc1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: OB(O)c1ccc(F)cc1
Product: CCc1c(-c2ccc(C#N)cc2)[nH]c(C=O)c1C(=O)OCc1ccccc1

Procedure:
Following the procedures described in Example 5, replacing of methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate with benzyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate and 4-fluorophenylboronic acid with 4-cyanophenylboronic acid, the title compound was obtained. Proton NMR for the product was consistent with the title compound. HRMS (ES) exact mass calculated for C22H19N2O3 (M+H): 359.1390. Found 359.1387
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1[C:25]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[C:24]([S:36]([CH3:39])(=[O:38])=[O:37])[CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20].[CH3:40][C:41]([N:44]1[C:48]([OH:49])=[CH:47][CH:46]=[N:45]1)([CH3:43])[CH3:42].C(N(CC)CC)C.CC(C)(O)C#N>C(#N)C>[CH3:40][C:41]([N:44]1[C:48]([OH:49])=[C:47]([C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:24]([S:36]([CH3:39])(=[O:37])=[O:38])=[C:25]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:28][CH:27]=3)[C:17]=2[CH3:16])[CH:46]=[N:45]1)([CH3:43])[CH3:42]
Reactant: CC(C)(C)n1nccc1O
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1-c1ccc(S(C)(=O)=O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(O)C#N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)c2cnn(C(C)(C)C)c2O)ccc(S(C)(=O)=O)c1-c1ccc(S(C)(=O)=O)cc1
Reaction time: 3 h

Procedure:
A solution of 560 mg (2.7 mmol) of 1,3-dicyclohexylcarbodiimide in 5 mL of acetonitrile was added with stirring to a mixture of 2-methyl-4-methylsulfonyl-3-(4-methylsulfonylphenyl)benzoic acid and 378 mg (2.7 mmol) of 1-(1,1-dimethylethyl)-5-hydroxypyrazole in 15 mL of acetonitrile. The mixture was allowed to react for 1 hour and was then filtered. The solids were washed with a little acetonitrile. Triethylamine (1.13 mL, 8.1 mmol) and 274 microliters (2.7 mmol) of acetone cyanohydrin were added with stirring to the combined filtrate and acetonitrile wash. After 3 hours, the mixture was diluted with dichloromethane and the resulting solution was washed with 2N aqueous hydrochloric acid, filtered, and concentrated by evaporation under reduced pressure. The residue was dissolved in the minimum amount of hot ethanol and the solution was then cooled. The precipitate that formed was collected by filtration and dried to obtain the title compound as a pale yellow powder melting at 187-188° C.
Reaction SMILES: C(O[C@H:5]1[C@H:10]2[C:11]([CH2:14]OC(=O)C)=[CH:12][CH2:13][C@@H:9]2[C:8]([C:19]([O:21][CH3:22])=[O:20])=[CH:7][O:6]1)(=O)C.[H][H]>C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[CH3:14][CH:11]1[C@H:10]2[CH2:5][O:6][CH:7]=[C:8]([C:19]([O:21][CH3:22])=[O:20])[C@H:9]2[CH2:13][CH2:12]1
Reactant: [H][H]
Reactant: COC(=O)C1=CO[C@@H](OC(C)=O)[C@H]2C(COC(C)=O)=CC[C@H]12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COC(=O)C1=COC[C@@H]2C(C)CC[C@H]12
Yield: 81.5 %

Procedure:
After methyl (1S, 4aS, 7aR)-1-acetoxy-7-(acetoxymethyl)-1,4a,5,7a-tetrahydrocyclopenta[c]pyran-4-carboxylate (100 mg, 0.0003 mol) obtained in Example 21 was dissolved in 5 ml of ethyl acetate, 20% Pd(OH)2 - C (5 mg) was added to the solution, and the reaction mixture was stirred for 24 hours in a hydrogen gas atmosphere of 1 atm. The catalyst was removed by celite filtration and the filtrate was concentrated. The residual substance was purified by chromatography using silica gel, and the solvent of the fraction obtained from hexane:ether=2:8 eluent was distilled, and a colorless oily substance was obtained, i.e., methyl (4aS, 7aR)-1,4a,5,6,7,7a-hexahydro-7-methylcyclopenta[c]pyran-4-carboxylate (48 mg, yield=30.4%). This methyl (4aS, 7aR)-1,4a,5,6,7,7a-hexahydro-7-methylcyclopenta[c]pyran-4-carboxylate had the following physicochemical properties.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:13][CH2:12][C:11]([NH2:14])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[CH3:17][O:18][C:19]1[CH:25]=[CH:24][C:22](N)=[CH:21][CH:20]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl>CCOCC>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:13][CH2:12][C:11]([NH:14][C:22]3[CH:24]=[CH:25][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(N)cc1
Reactant: NC1=NN(c2cccc(C(F)(F)F)c2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(NC2=NN(c3cccc(C(F)(F)F)c3)CC2)cc1
Yield: 29.7 %

Procedure:
A mixture of 1-(3-trifluoromethylphenyl)-4,5-dihydro-1H-pyrazol-3-amine (0.23 g), 4-methoxyaniline (0.37 g) and p-toluenesulphonic acid (0.17 g) was heated in an oil bath at 140° under nitrogen for 15 minutes. The reaction was cooled, dilute hydrochloric acid and ether added and the organic phase separated, dried over sodium sulphate, filtered and evaporated to leave a yellow solid, which on trituration with pentane gave the colourless title compound (0.1 g) m.p. 127°-8°.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[O:28]1[C:32]2[CH:33]=[CH:34][C:35]([C:37](O)=[O:38])=[CH:36][C:31]=2[O:30][CH2:29]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:37]([C:35]5[CH:34]=[CH:33][C:32]6[O:28][CH2:29][O:30][C:31]=6[CH:36]=5)=[O:38])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)c1ccc2c(c1)OCO2

Procedure:
The title compound, white solid (107 mg, 89%), MS (ISP) m/z=479.3 [(M+H)+], mp 243.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and benzo[1,3]dioxole-5-carboxylic acid.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[O:8]=[C:9]1[NH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[CH2:24]([N:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:9]1=[O:8])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1nc2ccccc2[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2ccccc2n(Cc2ccccc2)c1=O
Reaction time: 0.17 h
Yield: 83.2 %

Procedure:
Sodium hydride (60% dispersion in oil; 0.8 g) was added to a DMF (20 ml) solution of ethyl 3,4-dihydro-3-oxo-2-quinoxalinecarboxylate (4.4 g) under ice-cooling. The reaction mixture was stirred for 10 minutes, to which was added benzyl bromide (2.4 g). The reaction mixture was stirred at room temperature for 3 hours, poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain the entitled compound (3.6 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.C(N1CCOCC1)C.[CH2:35]([NH2:40])[CH2:36][CH2:37][CH2:38][CH3:39]>O1CCCC1>[CH2:35]([NH:40][C:13](=[O:15])[C@@H:12]1[CH2:16][CH2:17][CH2:18][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CCCCCN
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: C1CCOC1
Product: CCCCCNC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 16 h

Procedure:
12.46 g (0.05 mol) of N-benzyloxycarbonyl-L-proline were dissolved in 100 ml of dry tetrahydrofuran and the solution was cooled to -10° C. The solution was stirred and there were added thereto 6.56 ml (0.05 mol) of isobutyl chloroformate and 6.35 ml (0.05 mol) of N-ethylmorpholine. The mixture was then stirred at -10° C. for 15 minutes. 5.76 ml (0.05 mol) of n-pentylamine were then added and the resulting mixture was stirred at 0° C. for 1 hour and then at room temperature for 16 hours. The mixture was evaporated to an oil and 400 ml of water were added. The resulting mixture was extracted with two 150 ml portions of ethyl acetate, the organic layers were combined and washed successively with two 100 ml portions of 5% citric acid solution, once with 100 ml of water, twice with 100 ml portions of 5% sodium bicarbonate solution and once with 100 ml of water. The organic layer was dried over sodium sulphate, evaporated to an oil and triturated with 350 ml of petroleum ether. On scratching, the product crystallized out, was filtered off and washed with 100 ml of petroleum ether. There were thus obtained 10.16 g (64%) of N-benzyloxycarbonyl-L-proline n-pentylamide of melting point 74°-76° C. A second crop (0.800 g) of melting point 76°-79° C. was obtained from the mother liquor.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.O[CH2:16][CH2:17][N:18]1[C:27]2[C:26](=[O:28])[N:24]([CH3:25])[C:23](=[O:29])[N:22]([CH3:30])[C:21]=2[N:20]=[CH:19]1.O.C(=O)(O)[O-].[Na+]>C1(C)C(C)=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([O:10][CH2:16][CH2:17][N:18]2[C:27]3[C:26](=[O:28])[N:24]([CH3:25])[C:23](=[O:29])[N:22]([CH3:30])[C:21]=3[N:20]=[CH:19]2)=[O:9])=[CH:13][CH:14]=1
Reactant: Cn1c(=O)c2c(ncn2CCO)n(C)c1=O
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: Cn1c(=O)c2c(ncn2CCOC(=O)C(C)(C)Oc2ccc(Cl)cc2)n(C)c1=O
Yield: 55.1 %

Procedure:
107.3 g (0.5 mol) 2-(p-chlorophenoxy) isobutyric acid and 56.0 g (0.25 mol) 7-hydroxyethyltheophylline were suspended together in 250 ml xylene and heated for 15 hours in a water separator after addition of 1.5 g p-toluenesulfonic acid. The solution was next agitated with dilute sodium bicarbonate solution (0.5 mol NaHCO3), waterwashed and evaporated in a rotary evaporator. The residue was crystallized from isopropanol, yielding 58.0 g (55% yield) 1-(7-theophyllinyl)-2-ethyl [2-(p-chlorophenoxy)-isobutyrate] with a melting point 131°-132°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH:9]=2)[C:4]=1/[CH:21]=[CH:22]/[C:23]([OH:25])=O.[CH3:26][NH2:27]>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH:9]=2)[C:4]=1/[CH:21]=[CH:22]/[C:23]([NH:27][CH3:26])=[O:25]
Reactant: CN
Reactant: COc1cccc(-c2ccc3c(/C=C/C(=O)O)c(OC)ccc3c2)c1
Product: CNC(=O)/C=C/c1c(OC)ccc2cc(-c3cccc(OC)c3)ccc12

Procedure:
The compound was prepared by reaction of (E)-3-(2-methoxy-6-(3-methoxyphenyl)naphthalene-1-yl)acrylic acid (200 mg, 0.60 mmol, 1 eq) with 33% methylamine (1 eq) according to method D. Purification by column chromatography was not necessary. The desired compound was obtained in quantitative yield.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[C:7](CC#N)=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].Cl.[C:25]([OH:28])(=[O:27])[CH3:26]>>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[C:7]([CH2:26][C:25]([OH:28])=[O:27])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CC#N)n1Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)O
Agent: Cl
Product: CCCCc1nc(Cl)c(CC(=O)O)n1Cc1ccc([N+](=O)[O-])cc1

Procedure:
2-Butyl-4-chloro-5-(cyanomethyl)-1-(4-nitrobenzyl)imidazole (7.08 g) and a 1:1 mixture of 12N HCl and glacial acetic acid (175 mL) were mixed and refluxed for 6 hours. The solvents were removed by rotary evaporation and water (300 mL) was then added to the residue. After a few minutes, the product precipitated and was collected and dried to give 7.35 g of a solid; m.p. 207.0°-210.0°. NMR (200 MHz, DMSO-d6 /CDCl3) δ 8.20 (d, 2H, J=10 Hz); 7.22 (d, 2H, J=10 Hz); 5.28 (s, 2H); 3.42 (s, 2H); 2.52 (t, 2H, J=7 Hz); 1.64 (m, 2H); 1.34 (m, 2H); 0.86 (t, 3H, J=7 Hz). Anal. Calcd. for C16H18ClN3O4 ; C, 54.63; H, 5.16; N, 11.94. Found C, 54.52; H, 5.05; N, 12.21.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]#[CH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>C(Cl)Cl>[CH2:1]([N:8]([CH2:9][C:10]#[CH:11])[C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: C#CCNCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCN(Cc1ccccc1)C(=O)C(C)(C)C

Procedure:
To a stirred solution of N-benzylprop-2-yn-1-amine (472 mg, 3.25 mmol) and triethylamine (493 mg, 4.88 mmol) in DCM (16 mL), cooled to 0° C. was added pivaloyl chloride (451 mg, 3.74 mmol). After 1 hour the reaction mixture was applied directly to the top of a silica gel column for purification, eluting with a gradient of 60-100% DCM in hexanes to give the title compound. MS: m/z=230 (M+1).
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[C:16](OC)[CH:15]=[CH:14][C:13]=3OCOC)[O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:24][O:25][CH2:26][O:27]C1C=CC(C2OC3C=CC=C(C)C=3N=2)=CC=1>>[Br:1][CH2:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([O:27][CH2:26][O:25][CH3:24])=[CH:16][CH:17]=3)[O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COCOc1ccc(-c2nc3c(C)cccc3o2)cc1
Reactant: COCOc1ccc(OC)cc1-c1nc2c(CBr)cccc2o1
Product: COCOc1ccc(-c2nc3c(CBr)cccc3o2)cc1

Procedure:
4-bromomethyl-2-(4-methoxymethoxyphenyl)benzoxazole (F15) was prepared in a similar manner for the preparation of 4-bromomethyl-2-(5-methoxy-2-methoxymethoxyphenyl)benzoxazole (F12) by using 2-(4-methoxymethoxyphenyl)-4-methylbenzoxazole (F11) (4.04 g, 15 mmol) instead of 2-(5-methoxy-2-methoxymethoxyphenyl)-4-methylbenzoxazole (F8) in 80% (4.16 g): 1H-NMR (500 MHz, CDCl3) δ3.60 (s, 3H), 3.97 (s, 3H), 3.99 (s, 3H), 4.96 (s, 2H), 5.31 (s, 2H), 6.85 (s, 1H), 7.30 (t, 1H, J=8.0 Hz), 7.40 (d, 1H, J=8.0 Hz), 7.51 (d, 1H, J=8.0 Hz), 7.66 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[F:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(F)cc1)N1CCOCC1

Procedure:
20 g of morpholine were added dropwise to a solution, cooled with ice, of 19.5 g of 4-fluorobenzenesulfonyl chloride in 100 ml of toluene, and the mixture was heated under reflux for 1 hour. After cooling, the mixture was concentrated under reduced pressure, the residue was stirred with water and the precipitate was filtered off with suction, washed with water and recrystallized from isopropanol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:13][NH2:14])=[N:4][C:5]([Cl:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(O[CH:18]=[C:19]([C:22]#[N:23])[C:20]#[N:21])C>C(O)C>[NH2:23][C:22]1[N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:10])([F:11])[F:9])=[C:5]([Cl:12])[N:4]=2)[N:14]=[CH:18][C:19]=1[C:20]#[N:21]
Reactant: NNc1nc(Cl)c(C(F)(F)F)cc1Cl
Reactant: CCOC=C(C#N)C#N
Solvent: CCO
Product: N#Cc1cnn(-c2nc(Cl)c(C(F)(F)F)cc2Cl)c1N
Temperature: 20 °C

Procedure:
24.6 g (0.1 mol) of 3,6-dichloro-2-hydrazino-5-trifluoromethylpyridine were added to a mixture of 12.2 g (0.1 mol) of ethoxymethylenemalononitrile and 200 ml of ethanol with stirring at 20° C. and it was stirred at 78° C. for 10 hours. After cooling, the reaction mixture was concentrated under reduced pressure and the residue was taken up in methylene chloride. It was extracted 3× with water and the organic phase separated off was dried over magnesium sulfate, filtered off with suction through neutral alumina and then concentrated under reduced pressure. After stirring in ether/pentane, 13.3 g (41.3% of theory) of the title compound of m.p. 168-171° C. were obtained (Active Compound Example No. 2a.002).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]2[N:13]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:14][CH:15]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=4)[NH:18][CH:17]=3)[CH:9]12)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:25][C:21]1[CH:20]=[C:19]2[C:24]([C:16]([CH:15]3[CH2:14][N:13]([S:26]([CH3:29])(=[O:27])=[O:28])[CH:10]4[CH2:11][CH2:12][NH:8][CH:9]34)=[CH:17][NH:18]2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2S(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)N1CC(c2c[nH]c3cc(F)ccc23)C2NCCC21
Reaction time: 5 h
Yield: 95.5 %

Procedure:
To a solution containing 62 (2.47 g, 5.83 mmol) in DCM (10 mL) was added TFA (5 mL) at 0° C. After 5 h, the reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc and the resultant organic solution was washed successively with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 1.8 g (95%) of 63 as a white solid which was used without further purification. Mass spectrum, m/z [324.2] (M+H)+.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][CH:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:22]([OH:25])[CH2:23][N:24]=2)=[CH:15][CH:14]=1)([O-:12])=[O:11]>ClCCCl>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([C:19]2[O:20][CH:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:22]([O:25][C:8](=[O:9])[NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:23][N:24]=2)=[CH:17][CH:18]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(C2=NCC(O)C(c3ccccc3)O2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCCl
Product: O=C(Nc1ccccc1)OC1CN=C(c2ccc([N+](=O)[O-])cc2)OC1c1ccccc1
Yield: 24.1 %

Procedure:
Phenyl isocyanate (1.6 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, o[(5RS, 6SR)-2-(4-nitrophenyl)-6-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (4.1 g) in 1,2-dichloroethane (45 cc). The solution obtained is heated to reflux for 4 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by chromatography on silica (0.063-0.2 mm; 100 g) contained in a column 2.5 cm in diameter [eluent: dichloromethane/methanol (97:3 by volume)], collecting 20-cc fractions. Fractions 10 to 31 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in acetonitrile, (5RS, 6SR)-2-(4-nitrophenyl)-6-phenyl-5-phenylcarbamoyloxy-5,6-dihydro-4H-1,3-oxazine (1.35 g), m.p. 170° C., is obtained.