Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH:4]([NH:7][C:8](=[O:10])[CH3:9])[CH:5]=O.O=S(Cl)Cl>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:4]1[N:7]=[C:8]([CH3:9])[O:10][CH:5]=1)=[O:11]
Reactant: COC(=O)C(C=O)NC(C)=O
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1coc(C)n1
Temperature: 0 °C

Procedure:
A solution of the respective 2-acetylamino-3-oxo-propionic acid methyl ester derivative (0.63 mmol, 1.0 eq.) in CHCl3 (0.4 mL) was cooled to 0° C. in an ice/NaCl bath. SOCl2 (0.88 mmol, 1.4 eq.) was added to the stirred solution and the temperature was maintained at 0° C. for 30 minutes. Then the solution was stirred and refluxed for one hour. Another 0.25 eq. of SOCl2 was added and the reaction mixture was refluxed for another hour. The excess SOCl2 was quenched with 1M aq. K2CO3. The aq. layer was extracted twice with ether. The combined organic phases were washed once with water and dried over MgSO4, filtered and concentrated yielding the corresponding 2-methyl-oxazole-4-carboxylic acid methyl ester derivative. The respective 2-methyl-oxazole-4-carboxylic acid methyl ester derivative was dissolved in a mixture of EtOH (0.7 ml) and 2N aq. NaOH (0.7 mL, 2.5 eq.). The mixture was stirred at rt for 2 hours. The reaction mixture was washed once with ether and this organic layer was discarded. The aq. layer was then acidified with conc. HCl and extracted twice with ether. Both organic layers were combined, dried over MgSO4 and concentrated in vacuo to afford the corresponding 2-methyl-oxazole-4-carboxylic acid derivatives.
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[Cl:44][C:45]1[C:50]([CH3:51])=[CH:49][C:48]([NH2:52])=[C:47]([O:53][CH3:54])[CH:46]=1>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]2[CH:41]=[C:40]([NH:52][C:48]3[CH:49]=[C:50]([CH3:51])[C:45]([Cl:44])=[CH:46][C:47]=3[O:53][CH3:54])[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: COc1cc(Cl)c(C)cc1N
Product: COc1cc(Cl)c(C)cc1Nc1ccc(F)c([C@@]2(C)N=C(N)N(C)C(=O)C2(C)C)c1

Procedure:
The coupling (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 4-chloro-2-methoxy-5-methyl-phenylamine according to procedure B followed by deprotection yielded the title compound as an off-white solid. MS (ESI): m/z=433.3 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[N:8]3[C:9](=[N:14][C:15]([CH3:16])=[C:7]3[C:6]1=[O:17])[CH:10]=[CH:11][CH:12]=2.C(N(CC)CC)C.[F:25][C:26]([F:33])([F:32])[CH2:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:16][C:15]1[N:14]=[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[N:8]2[C:7]=1[C:6](=[O:17])[N:5]3[CH2:4][CH2:3][CH2:2][NH:1][S:28]([CH2:27][C:26]([F:33])([F:32])[F:25])(=[O:30])=[O:29]
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: Cc1nc2cccc3n(CCCN)c(=O)c1n23
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2cccc3n(CCCNS(=O)(=O)CC(F)(F)F)c(=O)c1n23
Yield: 58.5 %

Procedure:
To a solution of 0.43 g (1.87 mmol) of 1-[3-(amino)propan-1-yl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one and 0.39 ml (2.80 mmol) of triethylamine in 30 ml of methylene chloride was added, while stirring under ice-cooling, 0.41 g (2.26 mmol) of 2,2,2-trifluoroethanesulfonyl chloride. The mixture was stirred for 30 minutes at the same temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, which was then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to give 412 mg of the desired compound (58.6%, white powdery).
Reaction SMILES: Cl.[CH2:2]([C:6]1[N:7]([NH2:19])[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=1)[CH2:3][CH2:4][CH3:5].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)(C)C>[CH:20](=[N:19][N:7]1[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=[C:6]1[CH2:2][CH2:3][CH2:4][CH3:5])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCCCc1nc2cnc3ccccc3c2n1N
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CC(C)O
Product: CCCCc1nc2cnc3ccccc3c2n1N=Cc1ccccc1
Yield: 96.2 %

Procedure:
A solution of 2-butyl-1H-imidazo[4,5-c]quinolin-1-amine hydrochloride (503 mg, 1.82 mmol) in 10 mL of isopropanol was treated with benzaldehyde (220 μL, 2.17 mmol) and 200 mg of DOWEX W50-X1 acid resin. The reaction mixture was heated to reflux overnight. The reaction mixture was filtered, and the filtrate was treated with 0.5 mL of triethylamine and concentrated under reduced pressure. The resulting oil was dissolved in 75 mL of CH2Cl2 and washed with saturated NaHCO3 solution, H2O and brine. The organic was dried over Na2SO4, filtered and concentrated to give N-benzylidene(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)amine (575 mg) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([OH:21])[CH:19]=4)[CH2:14][CH2:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[C:24]([NH:31][CH2:32][CH2:33]Br)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CN(C)C=O>[C:27]([O:26][C:24](=[O:25])[NH:31][CH2:32][CH2:33][O:21][C:18]1[CH:19]=[C:20]2[C:15]([CH2:14][CH2:13][N:12]=[C:11]2[C:8]2([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:10][CH2:9]2)=[CH:16][CH:17]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: Oc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CC1)=NCC2
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CC1)=NCC2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1-[1-(4-chlorophenyl)cyclopropyl]-3,4-dihydroisoquinolin-7-ol (120 mg, 0.4 mmol) was added in several portions to a suspension of sodium hydrid (NaH, 1.3 mmol, activated by removal of oil) in dimethylformamide (DMF, 5 ml). 2-(Boc-amino)ethyl bromide was added after one hour and the resulting mixture stirred for 3 days at room temperature. DMF was evaporated, the residue diluted with ethylacetate and extracted with water. Removal of the solvents from the dried (Na2SO4) extract afforded an oil which was further purified by chromatography. Yield: 100 mg (0.23 mmol, 56%)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[O:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1C(=O)C2C(=CC=CC=2)C1=O)([O-:3])=[O:2].NN>C(O)C.ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[O:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])([O-:3])=[O:2]
Reactant: O=C1c2ccccc2C(=O)N1CCCCOc1cccc([N+](=O)[O-])c1
Agent: NN
Solvent: CCO
Solvent: ClCCl
Product: NCCCCOc1cccc([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A solution of 17.0 g (50 mmol) of 2-[4-(3-nitro-phenoxy)-butyl]-isoindole-1,3-dione in 1000 ml of ethanol is mixed with 25 ml of hydrazine and stirred for 2 hours at 70° C. After cooling, the precipitate that is formed is suctioned off, and the filtrate is spun in. The residue is taken up in dichloromethane. It is filtered again, and the filtrate is fully concentrated by evaporation. 5.8 g (28 mmol, corresponding to 56% of theory) of the product is obtained.
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:44]=[CH:43][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=5)[C:38]#[N:39])[O:32][C:33]=4[CH3:34])=[C:25]([O:45][CH3:46])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=1)[CH3:2].[N-:47]=[N+:48]=[N-:49].[Na+].[Cl-].[NH4+].CN(C)C=O>O>[CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:44]=[CH:43][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:36]=[C:37]([C:38]6[NH:49][N:48]=[N:47][N:39]=6)[CH:40]=[CH:41][CH:42]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:45][CH3:46])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:14]=2)[N:7]=1)[CH3:2]
Reactant: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4cccc(C#N)c4)oc3C)c(OC)c2)cs1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4cccc(-c5nnn[nH]5)c4)oc3C)c(OC)c2)cs1
Temperature: 120 °C
Reaction time: 6 h
Yield: 28.3 %

Procedure:
A mixture of 3-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzonitrile (350 mg), sodium azide (55 mg), ammonium chloride (59 mg) and N,N-dimethylformamide (10 mL) was stirred at 120° C. for 6 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:5-1:2-1:1, v/v) to give 5-{3-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}-1H-tetrazole (106 mg, yield 28%) as colorless crystals. Recrystallization from ethyl acetate-diethyl ether gave colorless prism crystals. melting point: 144-147° C.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([NH2:20])[CH2:18][CH3:19]>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:20][CH2:17][CH2:18][CH3:19])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CCCN
Product: CCCNC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, light yellow solid, m.p. 90° C. and MS: m/e=254 (M+) was prepared in accordance with the general method of example 1 from diphenylacetyl chloride and propylamine.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][C:5]([N:7]1[CH2:11][CH2:10][S:9][CH:8]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[CH2:23][CH2:22]1)=[O:6].[C:34](Cl)(=[O:36])[CH3:35]>CN(C)C=O.CCOCC>[C:34]([N:4]([CH3:3])[C:5]([N:7]1[CH2:11][CH2:10][S:9][CH:8]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[CH2:25][CH2:26]1)=[O:6])(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: CNC(=O)N1CCSC1c1ccccc1OCCN1CCN(c2cccc(F)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)N(C)C(=O)N1CCSC1c1ccccc1OCCN1CCN(c2cccc(F)c2)CC1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
0.1 g of sodium hydride (60% oil dispersion) is added to a solution of one g of N-methyl-2-{2-[2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxy]phenyl}thiazolidine-3-carboxamide in 30 ml of dimethylformamide, and a solution of 0.19 g of acetyl chloride in 5 ml of ether is added thereto. After the mixture is stirred at 50° C. for 20 hours, the mixture is concentrated under reduced pressure to remove solvent. Water is added to the residue, and the aqueous mixture is extracted with ethyl acetate. The extract is washed with water, dried and then concentrated under reduced pressure to remove solvent. The residue is purified by silica gel chromatography (solvent, ethyl acetate:n-hexane=4:1). 0.32 g of N-acetyl-N-methyl-2-{2-[2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxy]phenyl}thiazolidine-3-carboxamide is obtained as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[C:10](=O)([O-])[O-:11].[K+].[K+].C(Cl)(Cl)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:10](=[O:11])[O:9][C:3]=2[CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc(F)cc1O
Agent: O=C(Cl)Cl
Agent: [K+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=c1[nH]c2ccc(F)cc2o1
Temperature: 25 °C
Yield: 96 %

Procedure:
To 5.0 g (39.3 mmol) 2-amino-5-fluorophenol in 150 ml of CH2Cl2 at 0° C. was added 13.4 (98 mmol) of potassium carbonate and 23 g (47 mmol) of 20 wt. % phosgene in toluene. After warming to room temperature, the reaction was stirred an additional hour before quenching onto 200 ml ice/water. The layers were separated and the aqueous phase was extracted with EtOAc (1×100 ml) before the organics were combined and dried over Na2SO4. The solvent was removed in vacuo to give 5.76 g (96% yield) of the desired product as determined by 1H NMR.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:16]1[NH:20][N:19]=[N:18][N:17]=1)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].Br[CH2:22][CH2:23][CH2:24][CH:25]=[CH2:26].C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:16]1[N:17]=[N:18][N:19]([CH2:26][CH2:25][CH2:24][CH:23]=[CH2:22])[N:20]=1)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(=O)c2cc(-c3nnn[nH]3)ccc2[nH]1
Reactant: C=CCCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CCCCn1nnc(-c2ccc3[nH]c(CCCC)nc(=O)c3c2)n1
Yield: 53.2 %

Procedure:
A mixture of 3.0 g of 2-butyl-6-(1H-tetrazol-5-yl)-4(1H)-quinazolinone, 2.2 g of 5-bromo-1-pentene and 2 ml of N,N-diisopropylethylamine in 50 ml of tetrahydrofuran is refluxed for 24 hours. The volatiles are evaporated in vacuo to a residue which is partitioned between chloroform and water. The organic layer is dried over MgSO4, filtered and evaporated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 3:2 ethyl acetate-hexanes to give a residue which crystallizes from ethyl acetate-hexanes to give 2.0 g of the desired product as a solid, m.p. 130° C.
Reaction SMILES: Cl.[CH:2]12[NH:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][C:4](=[O:10])[CH2:3]2.Cl[C:12]1[N:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C([O-])(O)=O.[Na+]>C(O)(C)C>[N:13]1[CH:14]=[CH:15][CH:16]=[N:17][C:12]=1[N:9]1[CH:6]2[CH2:7][CH2:8][CH:2]1[CH2:3][C:4](=[O:10])[CH2:5]2
Reactant: O=C1CC2CCC(C1)N2
Reactant: Clc1ncccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: O=C1CC2CCC(C1)N2c1ncccn1
Yield: 63.7 %

Procedure:
A solution of 8-aza-bicyclo[3.2.1]octan-3-one hydrochloric acid (5.0 g, 30.9 mmol), 2-chloro-pyrimidine (4.95 g, 43.2 mmol), NaHCO3(7.78 g, 92.7 mmol) and isopropanol (200 ml) was maintained at reflux over weekend. The resulting reaction mixture was concentrated and purified by ISCO to afford 8-pyrimidin-2-yl-8-aza-bicyclo[3.2.1]octan-3-one (4.0 g, 52.9%) as a white solid: MS (M+1)=204. 1H NMR (MeOH) 8.36 (d, J=12 Hz 2H), 6.75 (m, 1H), 4.97 (m, 2H), 2.75 (d, J=12 Hz, 1H), 2.71 (d, J=12 Hz, 1H), 2.32 (d, J=50 Hz, 2H), 2.22 (m, 2H), 1.87 (m, 2H).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:12])[CH2:9][C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[OH:22])[CH:17]=O>>[C:1]1([NH:7][C:8](=[O:12])[C:9]([C:10]#[N:11])=[CH:17][C:16]2[CH:19]=[CH:20][C:21]([OH:22])=[C:14]([OH:13])[CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCC(=O)Nc1ccccc1
Reactant: O=Cc1ccc(O)c(O)c1
Product: N#CC(=Cc1ccc(O)c(O)c1)C(=O)Nc1ccccc1

Procedure:
Following the procedure as set forth in Example 6 above, N-phenylcyanoacetamide was condensed with 3,4-dihydroxybenzaldehyde to yield the title compound, m.p. 258° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[N+:15]([CH2:18][CH3:19])([O-:17])=[O:16].C([O-])(=O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH:5]=[C:18]([N+:15]([O-:17])=[O:16])[CH3:19]
Reactant: COc1ccc(C=O)c(OC)c1OC
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(C=C(C)[N+](=O)[O-])c(OC)c1OC
Yield: 85.4 %

Procedure:
A mixture of 3.9 g of 2,3,4-trimethoxybenzaldehyde, 3.7 g of nitroethane, 2.5 g of Amberlite IR-45 acetate and 200 ml of toluene is refluxed for 20 hours while removing the resultant water. After the reaction is completed, the reaction mixture is filtered, and the filtrate is evaporated to remove solvent. The residue thus obtained is recrystallized from a mixture of isopropyl ether and hexane. 4.3 g of 1-(2,3,4-trimethoxyphenyl)-2-nitropropene are thereby obtained as yellow cubes. M.p. 57°-58° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[S:16](=[O:18])(=[O:17])[CH2:15][CH2:14][CH2:13][S:12]2(=[O:20])=[O:19])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].[CH2:23]([CH:25]1[O:27][CH2:26]1)Cl.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:23][CH:25]3[O:27][CH2:26]3)[S:12](=[O:19])(=[O:20])[CH2:13][CH2:14][CH2:15][S:16]2(=[O:17])=[O:18])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: ClCC1CO1
Reactant: COc1ccc(C2S(=O)(=O)CCCS2(=O)=O)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C2(CC3CO3)S(=O)(=O)CCCS2(=O)=O)cc1OC
Temperature: 100 °C

Procedure:
9.6 of 2-(3,4-dimethoxyphenyl)-m-dithiane-1,1,3,3-tetraoxide (prepared as described in Example 2) are dissolved in 35 ml of dimethylformamide and, with stirring under argon, treated with 1.2 g of sodium hydride at room temperature. The suspension is stirred at 40° C for a further 0.5 hour, then cooled and treated with 2.8 g of epichlorohydrin. The mixture is then heated at 100° C for 16 hours. After cooling to room temperature, the suspension is poured on to water and the oily material extracted with chloroform. After evaporation of the solvent, the residue is chromatographed on silica gel with chloroform/ethanol (98:2). The 2-(3,4-dimethoxyphenyl)-2-(2,3-epoxypropyl)-m-dithiane-1,1,3,3-tetraoxide obtained is recrystallized from methylene chloride/ethanol and has a melting point of 175°-176° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@H:15]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][C:17]([OH:19])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([O:32][C:33](=[O:49])[NH:34][CH2:35][CH2:36][CH2:37][C@H:38]([NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:39][NH2:40])([CH3:31])([CH3:30])[CH3:29].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][CH2:14][C@H:15]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][C:17]([NH:40][CH2:39][C@@H:38]([NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37][CH2:36][CH2:35][NH:34][C:33]([O:32][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:49])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)CC(=O)O
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CN)NC(=O)OC(C)(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCC[C@@H](CNC(=O)C[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under argon, 0.1 g (0.263 mmol) of (3S)-6-{[(benzyloxy)carbonyl]amino}-3-[(tert-butoxycarbonyl)amino]hexanoic acid (Bioorg. Med. Chem. Lett. (1998) 8:1477-1482) and 0.108 g (0.342 mmol) of tert-butyl{(4S)-5-amino-4-[(tert-butoxycarbonyl)amino]pentyl}carbamate (Example 86A) are dissolved in 6 ml of dimethylformamide. Then, at 0° C. (ice bath), 0.066 g (0.342 mmol) of EDC and 0.011 g (0.079 mmol) of HOBt are added. The mixture is slowly warmed to RT and stirred at RT for 12 h. The solution is concentrated in vacuo and the residue is taken up with ethyl acetate. The organic phase is washed successively with saturated sodium bicarbonate and sodium chloride solutions, dried over magnesium sulfate and evaporated in vacuo. The remaining solid is dried to constant weight under high vacuum.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([OH:13])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([C:11]([OH:13])=[O:12])=[C:2]1[CH3:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1[nH]c2ccccc2c1C(=O)O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)O)c2ccccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
To a stirred solution of 0.50 g (3.1 mmol) 2-methyl-1H-indole-3-carboxylic acid (described in J. Heterocyclic Chem. 1977, 14, 1123) in 5 ml DMF were added 0.27 g (6.75 mmol) of NaH (60% in oil). The mixture was stirred at RT for 30 min. and then 0.39 ml (3.28 mmol) of benzyl bromid were added. The mixture was stirred an additional hour and then poured onto water and extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Crystallization in Et2O afforded 0.61 g (78%) of 1-benzyl-2-methyl-1H-indole-3-carboxylic acid as a white solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[CH:19]=[C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[N:21]=[CH:22][C:15]=2[N:14]([CH3:31])[C:13]1=[O:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[Cl:41][C:42]1[CH:49]=[CH:48][C:45]([CH:46]=[O:47])=[CH:44][CH:43]=1>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH:46]([C:45]3[CH:48]=[CH:49][C:42]([Cl:41])=[CH:43][CH:44]=3)[OH:47])=[C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[N:21]=[CH:22][C:15]=2[N:14]([CH3:31])[C:13]1=[O:32])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2cc(Oc3cccc(Cl)c3)ncc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Oc3cccc(Cl)c3)ncc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 28.8 %

Procedure:
To a solution of 3-(3-(tert-butyldimethylsilyloxy)propyl)-6-(3-chlorophenoxy)-1-methyl pyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (150 mg, 0.315 mmol) in THF (4 mL) at −78° C. was added LDA (2.0 M in THF, 0.79 mL, 1.58 mmol) dropwise. The reaction was stirred at −78° C. for 1 h then a solution of 4-chlorobenzaldehyde (88 mg, 0.625 mmol) in THF (1 mL) was added. The reaction was stirred at −78° C. for 30 min, quenched with aq. NH4Cl (3 mL) then diluted EA (20 mL) and water (20 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography PE/EA (2:1) to give 3-(3-(tert-butyldimethylsilyloxy)propyl)-6-(3-chlorophenoxy)-5-((4-chlorophenyl)(hydroxy)methyl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (56 mg, 29% yield) as a solid. LCMS: (M+-OH) 598 and TR=2.221 min.
Reaction SMILES: [F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3(SC)[S:21][CH3:22])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:26])[CH:4]=[CH:5][C:6](=[O:25])[CH:7]=1>C(C1C=CC=CC=1CC)C>[F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH:14]=[C:15]3[S:21][CH3:22])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:26])[CH:4]=[CH:5][C:6](=[O:25])[CH:7]=1
Reactant: CSC1(SC)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Agent: CCc1ccccc1CC
Product: CSC1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Yield: 91.7 %

Procedure:
A suspension of 9-fluoro-11β-hydroxy-17,17-bis(methylthio)androsta-1,4-diene-3-one (3.6 g) in diethylbenzene (250 ml) is slowly distilled from a bath at 220° C. In a few minutes, a clear solution results and the starting material disappears. On cooling in an ice bath, the solution deposits small needles of the analytical specimen of the title compound, (2.9 g), melting point 268° C (dec.). (discoloration starts at 263° C).