Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:18]([CH2:19][CH2:20][CH2:21]O)=[CH:17][N:16]=[CH:15]2)=[CH:9][CH:8]=1)#[N:6]>C(Cl)Cl>[Cl:3][CH2:21][CH2:20][CH2:19][C:18]1[N:14]([CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:5]#[N:6])=[CH:8][CH:9]=2)[CH:15]=[N:16][CH:17]=1
Reactant: O=S(Cl)Cl
Reactant: N#Cc1ccc(Cn2cncc2CCCO)cc1
Solvent: ClCCl
Product: N#Cc1ccc(Cn2cncc2CCCCl)cc1

Procedure:
To a solution of 5.2 g of thionyl chloride in 80 ml of methylene chloride is added 8.4 g of 1-(p-cyanophenylmethyl)-5-(3-hydroxypropyl)-1H-imidazole as a solid in portions. The rate of addition is regulated to control the foaming that occurs. When addition is complete, the solution is refluxed for 1.5 h, cooled in ice and filtered to obtain the hydrochloride salt of the title compound (c) as a buff-colored solid, m.p. 190°-191°. The salt is partitioned between methylene chloride and saturated sodium bicarbonate solution. The organic extracts are washed with water, dried over sodium sulfate and evaporated to yield the free base as an oil.
Reaction SMILES: [C:1]1([C:7]([C:9]2[N:10]=[C:11]([O:25][CH2:26][CH2:27][CH3:28])[C:12]3[N:17]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=4)[O:15][C:13]=3[N:14]=2)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Pd]>[C:1]1([CH:7]([C:9]2[N:10]=[C:11]([O:25][CH2:26][CH2:27][CH3:28])[C:12]3[N:17]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=4)[O:15][C:13]=3[N:14]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=C(c1ccccc1)c1nc(OCCC)c2nc(-c3cccc(C)c3)oc2n1
Agent: [Pd]
Solvent: CO
Product: CCCOc1nc(C(C)c2ccccc2)nc2oc(-c3cccc(C)c3)nc12

Procedure:
The 5-(1-phenyl-vinyl)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine obtained in step (a) was dissolved in 20 ml of methanol. 10% palladium on charcoal was added and the mixture was hydrogenated under a hydrogen pressure of about 1 bar. After 5 h the catalyst was filtered off and the solvents were removed in vacuo. Preparative HPLC (method HPLC2) of the residue yielded 125 mg of the title compound.
Reaction SMILES: O[CH2:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][CH2:8][C:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:22])=O>>[Cl:22][CH2:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][CH2:8][C:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: OCc1ccc(CCc2cccc3cncn23)cc1
Reactant: O=S(Cl)Cl
Product: ClCc1ccc(CCc2cccc3cncn23)cc1

Procedure:
5-[p-(hydroxymethyl)phenethyl]imidazo[1,5-a]pyridine (2.52 g) is refluxed in 20 ml of thionyl chloride for 2 hours. Excess thionyl chloride is evaporated and the residue is partitioned between ethyl acetate and dilute sodium bicarbonate solution. The organic phase is dried over sodium sulfate and evaporated to yield 5-[p-(chloromethyl)-phenethyl]imidazo[1,5-a]pyridine.
Reaction SMILES: N.ClC1[N:4]=CN(C2C=CC(N=C=S)=CC=2OC)C=1.[Cl:19][C:20]1[N:24]=[CH:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[S:33])=[CH:27][C:26]=2[O:34][CH3:35])[N:21]=1>>[Cl:19][C:20]1[N:24]=[CH:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH2:4])=[S:33])=[CH:27][C:26]=2[O:34][CH3:35])[N:21]=1
Reactant: COc1cc(N=C=S)ccc1-n1cnc(Cl)n1
Reactant: COc1cc(N=C=S)ccc1-n1cnc(Cl)c1
Agent: N
Product: COc1cc(NC(N)=S)ccc1-n1cnc(Cl)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.3 %

Procedure:
Step E (5): Methanolic ammonia (1.0 M, 25 mL, 25 mmol) was added to a flask charged with 3-chloro-1-(4-isothiocyanato-2-methoxyphenyl)-1H-1,2,4-triazole 4-chloro-1-(4-isothiocyanato-2-methoxy-phenyl)-1H-imidazole (525 mg, 1.968 mmol) in a ice-water bath. After the addition was complete, the resulting slurry was stirred for 10 min and then allowed to warm to rt. After 24 h, the reaction mixture was concentrated to dryness in vacuo to afford 1-(4-(3-chloro-1H-1,2,4-triazol-1-yl)-3-methoxyphenyl)thiourea (560 mg, 100% yield) as a white solid. LC-MS (M+H)+ 284.1.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C@@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[F:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38]>CN(C=O)C>[F:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH:38][C:17]([C@H:14]1[CH2:13][CH2:12][C@@H:11]([CH2:10][C:2]2[NH:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH2:16][CH2:15]1)=[O:19]
Reactant: O=C(O)[C@H]1CC[C@@H](Cc2nc3ccccc3[nH]2)CC1
Reactant: NCc1ccccc1F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(NCc1ccccc1F)[C@H]1CC[C@@H](Cc2nc3ccccc3[nH]2)CC1

Procedure:
To a solution of (E) cis-4-(1H-benzimidazol-2-ylmethyl)-cyclohexanecarboxylic acid (271 mg, 1.05 mmol), EDC (200 mg, 1.05 mmol) and HOAt (142 mg, 1.05 mmol) in anhydrous DMF (4 mL) was added 2-fluorobenzylamine (131 mg, 1.05 mmol) and the reaction mixture was stirred for lh. The reaction mixture was partitioned between saturated aqueous NaHCO3 and EtOAc and the organic layer washed 2× with water. The EtOAc was dried with MgSO4 and concentrated to give a yellow solid. The crude material was triturated with 2:2:1 water/CH3CN/DMSO and the resultant white solid filtered off. Repetitive concentration and trituration of the filtrate in the same manner gave cis-4-(1H-benzimidazol-2-ylmethyl)-cyclohexanecarboxylic acid 2-fluoro-benzylamide (F) (230 mg, 60%) as a white solid. The (F) compound was stirred in 1M HCl/ether (10 ML) for 1 h and concentrated to give the HCl salt of Ex. 7 (250 mg): 1H NMR (400 MHz, CD3OD) δ 7.50 (br s 2H), 7.35-7.25 (m, 2H), 7.22-7.05 (m, 4H), 4.43 (s, 2H), 2.92 (d, 2H), 2.41 (m, 1H), 2.23 (m, 1H), 1.93 (m, 2H), 1.60 (m, 6H); mass spectrum m/z 366 [(M+H)+; calcd for C22H25N3OF: 366].
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:19][N:6]2[CH2:7][CH2:8][N:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[CH2:10][C@@H:5]2[CH2:4]1.[F:20][C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:1][CH2:2][C@@H:3]2[CH2:19][N:6]3[CH2:7][CH2:8][N:9]([C:11]4[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=4)[CH2:10][C@@H:5]3[CH2:4]2)=[CH:23][CH:22]=1
Reactant: Oc1ccc(F)cc1
Reactant: N#Cc1ccc(N2CCN3C[C@@H](CO)C[C@H]3C2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(N2CCN3C[C@@H](COc4ccc(F)cc4)C[C@H]3C2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
A solution of 0.25 g (0.97 mmol) of (7S,8aS)-7-hydroxymethyl-2-(4-cyanophenyl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 16), 0.164 g (1.46 mmol) of 4-fluorophenol, 0.31 g (1.15 mmol) of triphenylphosphine in 10 mL of THF was treated with 0.18 mL (1.15 mmol) of diethyl azodicarboxylate and the solution stirred at ambient temperature for 16 hours. The solvent was removed by rotary evaporation, and the residue partitioned between chloroform and 1M sodium hydroxide. The layers were separated, and the organic phase was dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 1:1 ethyl acetate:hexane gave 0.225 g (66%) of the title compound. Mp (.HCl) 81-85° C. HRMS calc'd for C21H23FN3O (MH+): 352.1825, found: 352.1817.
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[CH3:15])[N:11]=[C:10]([N:16]1[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[CH:18]=[N:17]1)[NH:9][C:8]2=O.[CH2:32]([NH:34][CH3:35])[CH3:33]>>[CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[CH3:15])[N:11]=[C:10]([N:16]1[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[N:17]1)[N:9]=[C:8]2[N:34]([CH2:32][CH3:33])[CH3:35]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(C)c(Oc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Reactant: CCNC
Product: CCN(C)c1nc(-n2cc(C(=O)O)cn2)nc2cc(C)c(Oc3c(C)cccc3C)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-(2,6-dimethylphenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and N-ethyl-N-methylamine in step E. MS (ESI/CI): predicted mass C25H24N5O3, 431.2.
Reaction SMILES: [Br:1]Br.[BrH:3].[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([CH2:13][C:14]([O:16][CH:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[O:15])=[N:5]1>C(O)(=O)C.O>[BrH:1].[Br:3][CH:13]([C:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:4][N:5]=1)[C:14]([O:16][CH:17]1[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]1)=[O:15]
Reactant: CN1CCC(OC(=O)Cc2noc3ccccc23)CC1
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CN1CCC(OC(=O)C(Br)c2noc3ccccc23)CC1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 87.3 %

Procedure:
A solution of bromine (1.48 g) in glacial acetic acid (3 ml) was added dropwise with stirring to a solution of 1-methyl-4-piperidyl 1,2-benzisoxazole-3-acetate hydrobromide (3.0 g) in glacial acetic acid (6 ml). After the reaction mixture was stirred for 40 minutes at 60° C., it was diluted with water (100 ml) and extracted with two 100-ml portions of chloroform. The chloroform solution was dried over anhydrous sodium sulfate and evaporated to give crude 1-methyl-4-piperidyl 2-bromo-2-(1,2-benzisoxazol-3-yl)acetate hydrobromide (3.2 g). The hydrobromide thus obtained was dissolved in chloroform (15 ml) and thereto was added heptamethyleneimine (4.5 ml). The resulting mixture was stirred overnight at room temperature and evaporated in vacuo to give a residue, to which water (50 ml) was added. The resulting mixture was extracted with two 100-ml portions of toluene. The toluene layer was extracted with 5% hydrochloric acid (70 ml). The aqueous layer was made alkaline with aqueous ammonia solution and extracted with toluene. The toluene layer was dried over anhydrous sodium sulfate and evaporated in vacuo to give an oily residue (2.25 g). The residue and oxalic acid (0.74 g) were dissolved in ethanol (10 ml). The solution was concentrated in vacuo to about a half volume. To the residue was added diethyl ether until it became turbid. The crystals precipitated were collected by filtration and recrystallized from ethanol-diethyl ether to give 1-methyl-4-piperidyl 2-heptamethyleneimino-2-(1,2-benzisoxazol-3-yl)acetate oxalate (2.41 g), m.p. 170°-173° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([NH:7][C:8]1[C:9]([N:15]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1)=[O:6].[C:25](#[N:27])[CH3:26]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([NH:7][C:8]1[C:9]([N:15]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:26][CH2:25][N:27]3[CH2:4][CH2:3][CH2:2][CH2:24][CH2:23]3)[CH2:17][CH2:16]2)=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1)=[O:6]
Reactant: O=C(Nc1cc(Cl)cnc1N1CCCNCC1)c1cccc(Cl)c1
Reactant: CC#N
Product: O=C(Nc1cc(Cl)cnc1N1CCCN(CCN2CCCCC2)CC1)c1cccc(Cl)c1
Temperature: 175 °C
Yield: 9 %

Procedure:
A mixture of 0.035 g (0.096 mmol) of 3-chloro-N-(5-chloro-2-[1,4]diazepan-1-yl-pyridin-3-yl)-benzamide in 0.053 g (0.29 mmol) of 2-pyridino-1-ethylchloride hydrochloride in acetonitrile (2 mL) is heated at 175° C. in a microwave reactor for 30 minutes. The mixture is cooled to room temperature and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography to provide 0.004 g (9%) of the title compound (108) as a red solid. [M+H]+=476.2.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][O:9][C:10]([CH:12]2[N:16]3[C:17](=[O:21])[C:18](Br)([Br:19])[C@H:15]3[S:14](=[O:22])[C:13]2([CH3:24])[CH3:23])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(C(OC(C2N3C(=O)C(Br)(Br)[C@H]3S(=O)C2(C)C)=O)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[NH4+].[Bi](Cl)(Cl)Cl.[Al]>ClCCl.CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([CH:12]2[N:16]3[C:17](=[O:21])[CH:18]([Br:19])[C@H:15]3[S:14](=[O:22])[C:13]2([CH3:23])[CH3:24])=[O:11])=[CH:25][CH:26]=1)([O-:3])=[O:2]
Reactant: CC1(C)C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(Br)(Br)[C@H]2S1=O
Agent: CC1(C)C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(Br)(Br)[C@H]2S1=O
Agent: Cl[Bi](Cl)Cl
Agent: [Al]
Solvent: ClCCl
Solvent: CO
Product: CC1(C)C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(Br)[C@H]2S1=O

Procedure:
A 82.6 g quantity of 6,6-dibromo-2,2-dimethylpenam-3-carboxylic acid 1-oxide p-nitrobenzyl ester (Compound 4) [compound of the formula (1) wherein X═Y═Br, R=p-nitrobenzyl, n=1] was dissolved in 300 mL of dichloromethane. To the solution was added 115 mL of 20% aqueous solution of ammonium chloride and 36 mL of methanol with stirring. After adding 1.6 g of bismuth chloride and 10 g of aluminum powder at one time, the mixture was reacted at 40° C. for 8 hours. An organic layer was separated and concentrated by an evaporator to give 6-bromo-2,2-dimethylpenam-3-carboxylic acid 1-oxide p-nitrobenzyl ester (Compound 5) [compound of the formula (1b) wherein X═Br, Y═H, R=p-nitrobenzyl, n=1] in a yield of 65%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:10])[CH:8]=[C:5]([CH3:4])[O:10][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)Cc2ccc(F)cc2)cc1
Solvent: CC(=O)O
Product: Cc1cc(=O)c(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)o1
Temperature: 140 °C

Procedure:
To a solution of 2-(4-fluorophenyl)-1-(4-methanesulfonylphenyl)ethanone (1 g; 3.4 moles) in glacial acetic acid (15 ml), polyphosphoric acid (10 g) was added and then heated at 140° C. for 16 hours. After cooling, the reaction was poured into ice-water, extracted with ethyl acetate (2×50 ml), the organic solution dried (Na2SO4) and the solvent removed under reduced pressure. The residual oil was purified by column chromatography with silica gel and ethyl acetate as eluent. 3-(4-fluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one was obtained (0.5 g) m.p. 237° C. (Compound 2 in Table 4).
Reaction SMILES: [F:1][C:2]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:8]([F:19])[C:7]=1[F:20].C([Li])(CC)C.[F:31][C:32]1[C:37]([F:38])=[C:36]([O:39][CH2:40][CH3:41])[CH:35]=[CH:34][C:33]=1[CH:42]1[CH2:47][CH2:46][C:45](=O)[CH2:44][CH2:43]1.Cl>C(OCC)(=O)C.C1COCC1>[F:20][C:7]1[C:8]([F:19])=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][C:3]1[CH:21]=[CH:22][C:23]([C:45]2[CH2:46][CH2:47][CH:42]([C:33]3[CH:34]=[CH:35][C:36]([O:39][CH2:40][CH3:41])=[C:37]([F:38])[C:32]=3[F:31])[CH2:43][CH:44]=2)=[C:24]([F:25])[C:2]=1[F:1]
Reactant: CCCCCCOc1ccc(CCc2cccc(F)c2F)c(F)c1F
Reactant: CCOc1ccc(C2CCC(=O)CC2)c(F)c1F
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCOc1ccc(CCc2ccc(C3=CCC(c4ccc(OCC)c(F)c4F)CC3)c(F)c2F)c(F)c1F
Temperature: 30 °C
Reaction time: 2 h

Procedure:
1-(2,3-Difluorophenethyl)-2,3-difluoro-4-(hexyloxy)benzene (s-24) (3.6 g) and THF (100 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and cooled to −74° C. sec-Butyllithium (1.00M; n-hexane and cyclohexane solution; 12 ml) was added dropwise in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. 1-(2,3-Difluoro-4-ethoxyphenyl)-cyclohexan-4-one (s-25) (2.6 g) in a THF (50 ml) solution was added dropwise in the temperature range of −75° C. to −70° C., and the stirring was continued for 8 hours while the mixture was allowed to return to 25° C. The resulting reaction mixture was poured into a vessel containing a 1N-HCl aqueous solution (100 ml) and ethyl acetate (100 ml) and mixed with them. The mixture was then allowed to stand until it had separated into organic and aqueous layers, and the extraction was carried out. The resulting organic layers were separated, and washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. p-Toluenesulfonic acid (0.19 g) and toluene (100 ml) were added, and the mixture was heated to reflux for 2 hours, while distilled water was removed. After the reaction solution had been cooled to 30° C., water (200 ml) and toluene (100 ml) were added and mixed with it. The mixture was then allowed to stand until it had separated into two layers of organic and aqueous layers, and the extraction into an organic layer was carried out. The resulting organic layers were separated, and washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The resulting solution was purified by column chromatography using silica gel as a stationary phase powder and toluene as an eluent, and further purified by recrystallization from a mixed solvent of Solmix A-11 and heptane (Solmix A-11:heptane=1:2 by volume) and dried to give 1-(2,3-difluoro-4-(hexyloxy)phenethyl)-4-(4-(4-ethoxy-2,3-difluorophenyl)cyclohex-1-enyl)-2,3-difluorobenzene (No. 487) (3.1 g). The yield based on the compound (s-24) was 33.8%.
Reaction SMILES: C(=[N:14][C:15]1[N:16]=[C:17]2[C:23]([CH3:24])=[CH:22][N:21]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:18]2=[N:19][CH:20]=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])=O.[Na+].NO.Cl>CO>[CH3:24][C:23]1[C:17]2[C:18](=[N:19][CH:20]=[C:15]([NH2:14])[N:16]=2)[N:21]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:32])[CH3:31])[CH:22]=1
Reactant: Cc1cn(COCC[Si](C)(C)C)c2ncc(N=C(c3ccccc3)c3ccccc3)nc12
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: CO
Product: Cc1cn(COCC[Si](C)(C)C)c2ncc(N)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
Benzhydrylidene-[7-methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-amine (91 mg, 0.206 mmol), NaOAc (41 mg, 0.494 mmol) and NH2OH HCl (26 mg, 0.371 mmol) were dissolved in MeOH (2 mL) and stirred at RT overnight, and partitioned between EtOAc and brine. The organic layer was dried (MgSO4), filtered, concentrated, and purified by SiO2 chromatography (12 g SiO2, hexanes/EtOAc 0-90% EtOAc) to give 41 mg of 7-methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamine as a yellow solid (71% yield).
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH3:22])([CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][N:14]=2)[CH2:9][CH2:8]1)[CH3:6])C.[OH-].[Na+]>O1CCCC1.CO>[CH3:22][C:5]([CH:7]1[CH2:8][CH2:9][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][N:14]=2)[CH2:11][CH2:12]1)([CH3:6])[C:4]([OH:23])=[O:3]
Reactant: CCOC(=O)C(C)(C)C1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C(=O)O)C1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 140 °C
Yield: 71.6 %

Procedure:
To a solution of 2-methyl-2-(5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-propionic acid ethyl ester (321 mg, 1.0 mmol) in tetrahydrofuran (2 mL) and methanol (6 mL) was added sodium hydroxide solution (1N, 2 mL). The mixture was heated in a microwave at 140° C. for 1.5 hr. The mixture was evaporated and the residue was dissolved in hot methanol and water. The clear solution was then acidified with 1N hydrochloric acid (2.5 mL). The resulting pale yellow precipitate was filtered and dried to give 2-methyl-2-(5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-propionic acid (210 mg). LC-MS calcd. for C14H19N3O4 (m/e) 293.1, obsd 294.1
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][CH3:23])[N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:24])=[CH:5][C:4]=2[N:3]=1.Br[CH2:26][C:27]([N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:28].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O>[CH2:22]([C:13]1[N:14]([CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:10]2[C:9]3[CH:8]=[CH:7][C:6]([O:24][CH2:26][C:27]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:28])=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=1)[CH3:23]
Reactant: O=C(CBr)N1CCOCC1
Reactant: CCc1nc2c(N)nc3cc(O)ccc3c2n1CC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc2c(N)nc3cc(OCC(=O)N4CCOCC4)ccc3c2n1CC1CCOCC1
Temperature: 70 °C
Yield: 52.2 %

Procedure:
A mixture of 4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-ol (500 mg, 1.53 mmol), 2-bromo-1-(morpholin-4-yl)ethanone (351 mg, 1.69 mmol), cesium carbonate (1.5 g, 4.59 mmol) and anhydrous DMF was heated at 70° C. overnight. The reaction mixture was cooled, poured into water (350 mL), and then extracted with dichloromethane (2×100 mL). The combined organics were dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was dissolved in dichloromethane and filtered. The filtrate was purified by chromatography on a HORIZON HPFC system (eluting with a gradient of 0 to 8% methanol in dichloromethane). The product was recrystallized from acetonitrile to provide 362 mg of 2-ethyl-7-(2-morpholin-4-yl-2-oxoethoxy)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, mp 245-247° C. Anal. calcd for C24H31N5O4: C, 63.56; H, 6.89; N, 15.44. Found: C, 63.20; H, 6.78; N, 15.31.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[CH2:21][NH2:22])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]([F:31])([F:30])[CH2:25][S:26](Cl)(=[O:28])=[O:27].C(=O)([O-])[O-].[K+].[K+]>ClCCCl.N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[CH2:21][NH:22][S:26]([CH2:25][C:24]([F:31])([F:30])[F:23])(=[O:28])=[O:27])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1cnccc1-c1cccc(OCc2ccccc2)c1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: c1ccncc1
Product: O=S(=O)(CC(F)(F)F)NCc1cnccc1-c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-(4-(3-benzyloxyphenyl)pyridin-3-ylmethylamine (1.0 equiv.) in 2:1 DCE/Pyridine (0.15 M) was cooled to 0° C. and treated with 2,2,2-trifluoroethanesulfonyl chloride (1.8 equiv.). The mixture was allowed to warm to ambient temperature and stir overnight. The reaction was treated with anhydrous potassium carbonate, stirred for 40 min, and filtered. The filtrate was purified via preparative HPLC eluting with 70:30 to 60:40 DCM/ethyl acetate, evaporated, and then triturated with diethyl ether to give the title compound. Anal Calcd for C21H19F3N2O3S: C, 57.79; H, 4.39; N, 6.42. Found: C, 57.60; H, 4.47; N, 6.41. 1H NMR (400 MHz) 3.77 (2H, q, J=9.0 Hz), 4.86 (2H, d), 4.99 (2H, d), 6.82 (2H, m), 6.95 (1H, m), 7.25 (2H, m), 7.34-7.40 (5H, m), 7.67 (1H, td, J=2.0, 8.0 Hz), 8.32 (1H, bs), 8.50 (1H, d, J=4.0 Hz). MS found 437.1 [M+H]+
Reaction SMILES: ClC[C:3](=[O:27])[C@:4]1(OC=O)[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[C:28](=O)(O)[O-:29].[K+]>CO.O>[OH:29][CH2:28][C:3](=[O:27])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(OC=O)C(=O)CCl
Reactant: O=C([O-])O
Agent: [K+]
Solvent: CO
Solvent: O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)CO
Temperature: 0 °C

Procedure:
At room temperature, 1.6 g of 21-chloro-17- formyloxy-4-pregnene-3,20-dione is stirred in a mixture of 60 ml of methanol and 9 ml of water with 500 mg of potassium bicarbonate After one hour, the reaction mixture is stirred into ice water. The thus-precipitated product is suctioned off, washed with water, and dried over sodium sulfate, yielding 1.3 g of 21-chloro-17™hydroxy-4-pregnene-3,20-dione; mp 239.4° C.