Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[C:10]([F:17])([F:16])[S:11][CH2:12][CH2:13][O:14]C.F[C:26]1C=C(F)C=C[C:27]=1C(O)(CN1C=NC=N1)C(F)(F)SCCO.CI.C(I)C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([O:24][CH2:26][CH3:27])([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[C:10]([S:11][CH2:12][CH2:13][OH:14])([F:17])[F:16]
Reactant: OCCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: COCCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: CCI
Solvent: CI
Product: CCOC(Cn1cncn1)(c1ccc(F)cc1F)C(F)(F)SCCO

Procedure:
In a similar manner to Example 1 except that 2-(2,4-difluorophenyl)-1,1-difluoro-1-[(2-methoxyethyl)thio]-3-(1H-1,2,4-triazol-1-yl)-2-propanol was replaced with 2-(2,4-difluorophenyl)-1,1-difluoro-1-[(2-hydroxyethyl)thio]-3-(1H-1,2,4-triazol-1-yl)-2-propanol and methyl iodide was replaced with ethyl iodide, the experiment was carried out, whereby 2-{[2-(2,4-difluorophenyl)-2-ethoxy-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)propyl]thio}-1-ethanol was obtained as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N+:6]([O-])[CH:5]=[C:4]([O:9][CH3:10])[N:3]=1.P(Cl)(Cl)([Cl:13])=O>>[NH2:1][C:2]1[C:7]([Cl:13])=[N:6][CH:5]=[C:4]([O:9][CH3:10])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1c[n+]([O-])cc(N)n1
Product: COc1cnc(Cl)c(N)n1

Procedure:
A suspension of 2-amino-6-methoxypyrazine 4-oxide in freshly distilled phosphorus oxychloride is refluxed for one hour. Thin layer chromatography indicates that the starting material is no longer present. The excess of phosphorus oxychloride is removed in vacuo and the residue is treated with crushed ice. If decomposition is complete the solution is made alkaline with 10% sodium hydroxide and extracted with chloroform. The chloroform extracts are washed with water, dried over sodium sulfate and evaporated to give the product which may be recrystallized from a suitable solvent such as ethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:35][N:36]([CH3:40])[C:37](Cl)=[O:38].CCN(CC)CC.[Cl-]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:35][N:36]([CH3:40])[C:37](=[O:38])[NH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)Nc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Reaction time: 48 h

Procedure:
To a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (75 mg, 0.17 mmol) and dimethylcarbamic chloride (30 μL, 0.33 mmol) in CH2Cl2 (2 mL) was added Et3N (46 μL, 0.33 mmol) and catalytic amount of DMAP. The reaction mixture was stirred at RT for 2 h after which 2 equivalents each of dimethylcarbamic chloride and Et3N were added. After 2 h of stirring another 2 equivalents of both the chloride and Et3N were added. Upon the addition of the third addition of the chloride and the Et3N the temperature was raised to 45° C. The reaction mixture was stirred for 48 h. Concentrated in vacuo and the residue was purified by flash chromatography on silica (10:1 CH2Cl2:MeOH). The product tert-butyl 5-(2-(3-(3,3-dimethylureido)phenyl)-quinazolin-4-ylamino)-1H-indazole-1-carboxylate was isolated. (62 mg, 70%)
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:35]([O:36][CH3:37])=[CH:34][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:7]=2[CH:6]=1)[N:14]=[CH:13][C:12]([C:17]#[N:18])=[C:11]3[NH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][C:27]2[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=2)=[C:22]([Cl:33])[CH:21]=1.[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.[I-].[Na+]>>[Cl:33][C:22]1[CH:21]=[C:20]([NH:19][C:11]2[C:10]3[C:15](=[CH:16][C:7]4[CH:6]=[C:5]([O:4][CH2:3][CH2:2][N:42]5[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]5)[C:35]([O:36][CH3:37])=[CH:34][C:8]=4[CH:9]=3)[N:14]=[CH:13][C:12]=2[C:17]#[N:18])[CH:25]=[CH:24][C:23]=1[S:26][C:27]1[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=1
Reactant: COc1cc2cc3c(Nc4ccc(Sc5nccn5C)c(Cl)c4)c(C#N)cnc3cc2cc1OCCCl
Reactant: CN1CCNCC1
Agent: [I-]
Agent: [Na+]
Product: COc1cc2cc3c(Nc4ccc(Sc5nccn5C)c(Cl)c4)c(C#N)cnc3cc2cc1OCCN1CCN(C)CC1

Procedure:
Following procedure 1 of Example 149, a mixture of 0.15 g (0.3 mmol) of 8-(2-chloroethoxy)-4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxybenzo[g]quinoline-3-carbonitrile, 0.5 mL of 1-methylpiperazine and 0.02 g of sodium iodide is heated under reflux for 16 hours. Purification of the material is carried out by silica gel flash chromatography, utilizing a 90:10 to 85:15 gradient of methylene chloride/methanol to give 0.052 g of 4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8-[2-(4-methylpiperazin-1-yl)ethoxy]-benzo[g]quinoline-3-carbonitrile as a yellow solid, mp 184–186° C.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH2:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]3([OH:20])[CH2:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:24]>CO>[NH2:24][C:2]1[C:11]2[N:12]=[C:13]([CH2:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]3([OH:20])[CH2:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: N
Reactant: CCCc1nc2c(Cl)nc3ccccc3c2n1CC1(O)CCC1
Solvent: CO
Product: CCCc1nc2c(N)nc3ccccc3c2n1CC1(O)CCC1
Temperature: 150 °C

Procedure:
1-[(4-Chloro-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutanol (1.56 g) was combined with a solution of ammonia in methanol (23 mL). The mixture was heated at 150° C. in a pressure vessel for 2 days. A portion of the solvent was removed under vacuum and then the mixture was diluted with additional methanol. A solid was isolated by filtration, washed with methanol, triturated with acetonitrile, and then dried. The material was suspended in water (70 mL). Concentrated hydrochloric acid (1.4 mL) was added and the mixture was heated at 90° C. for 30 minutes. The hot solution was neutralized with solid sodium bicarbonate. The solution was allowed to cool to ambient temperature. A precipitate was isolated by filtration, washed well with water, and then dried to provide 1-[(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutanol as a white powder, mp 228.0-229.0° C. Anal. Calcd for C18H22N4O C, 69.65; H, 7.14; N, 18.05; Found: C, 69.36; H, 7.24; N, 18.03.
Reaction SMILES: F[C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:19])[C:14]([C:16]([OH:18])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH:5]([CH3:21])[N:6]3[CH3:20].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>C(#N)C>[F:12][C:11]1[C:2]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:3]2[C:8]3=[C:9]([C:13](=[O:19])[C:14]([C:16]([OH:18])=[O:17])=[CH:15][N:7]3[N:6]([CH3:20])[CH:5]([CH3:21])[CH2:4]2)[CH:10]=1
Reactant: C1CCNC1
Reactant: CC1Cc2c(F)c(F)cc3c(=O)c(C(=O)O)cn(c23)N1C
Solvent: CC#N
Product: CC1Cc2c(N3CCCC3)c(F)cc3c(=O)c(C(=O)O)cn(c23)N1C
Yield: 59.6 %

Procedure:
100 mg (0.34 mmol) of the compound (157) obtained in Example 35 and 88 mg (1.24 mmol) of pyrrolidine were added to 1 ml of acetonitrile, and the solution was heated at reflux for 3 hours. Then, the solvent was removed by distillation, and the residue was extracted with 20 ml of chloroform, and after drying over magnesium sulfate, the solvent was removed by distillation. The residue was solidified with ether and the solids were filtered off to obtain 70 mg of the subject compound (160) in a 60% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[C:23]([C:22]1[CH:25]=[C:18]([NH:17][C:14]([C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]=2[CH3:13])=[O:16])[CH:19]=[CH:20][C:21]=1[N:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)[CH2:28][CH2:27]1)#[N:24]
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(F)cc1
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(C#N)c2)cnn1-c1ccc(F)cc1
Yield: 29.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-fluorophenyl)-5-methylpyrazole-4-carboxylic acid (0.8 g) and 5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (0.6 g), the title compound (0.3 g) was obtained, melting point: 226° C.(decomposition).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:21])[C:5]2[S:10][C:9](=[O:11])[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])[C:6]=2[N:7]=1.[OH-].[Na+]>CC(O)=O>[NH2:1][C:2]1[NH:3][C:4](=[O:21])[C:5]2[S:10][C:9](=[O:11])[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:6]=2[N:7]=1
Reactant: CCOC(=O)CCCCn1c(=O)sc2c(=O)[nH]c(N)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1nc2c(sc(=O)n2CCCCC(=O)O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 5-amino-3-[4-(ethoxycarbonyl)butyl]thiazolo[4,5-d]pyrimidine-2,7(3H,6H)-dione (312 mg, 1 mmol) and 1 N NaOH (5 mL) was stirred at ambient temperature for 1.5 h. The mixture was acidified (pH=4) with AcOH and then refrigerated for 16 h. The solid was collected by filtration, crystallized from a MeOH:H2O mixture and dried under vacuum at 80° C. for 16 h; 220 mg (0.774 mmol, 77%), mp 263-265° C. Ir (KBr): ν3410, 3315 and 3180 (NH, NH2), 1725 (C=O) and 1640 (C=O), and 1640 (C=O, C=N) cm-1. Uv, νmax (nm), (ε×10-3): pH 1, 302 (9.79), 250 (8.52), 222 (31.0); MeOH, 302 (9.48), 250 (8.79), 222 (30.40); pH 11, 292 (8.26), 250 (8.15), 224 (12.20). 1H nmr (DMSO-d6): δ1.43-1.50 (m, 2H, CH2), 1.60-1.67 (m, 2H, CH2), 2.24 (t, 2H, CH2), 3.76 (t, 2H, NCH2), 6.91 (br s, 2H, NH2), 11.1 (br s, 1H, NH), and 12.0 (br s, 1H, COOH) Anal. Calc'd for C10H12N4O4S (284.30): C, 42.25; H, 4.25; N, 19.71. Found: C, 42.32; H, 4.22; N, 19.69.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:18]I>CN(C)C=O>[CH3:18][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:10]1
Reactant: CI
Reactant: c1ccc(-c2c[nH]c3ccccc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccccc2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
Sodium hydride (60% in mineral oil, 200 mg, 5 mmol) was added at 0° C. to a solution of 3-phenyl-1H-indole (1a) (940 mg, 4.86 mmol) in N,N-dimethylformamide (20 mL) under a nitrogen atmosphere. The suspension was stirred for 15 minutes at 0° C. and methyliodide (311 μL, 5 mmol) was then added. The reaction mixture was warmed to room temperature, stirred for 6 hours and then concentrated in vacuo. The residue was partitioned between ethyl acetate (30 mL) and water (10 mL). The organic layer was washed with water (2×10 mL), brine (10 mL), dried over sodium sulfate, filtered and evaporated to dryness to give the desired product (1b) as a yellow oil (1 g, 4.86 mmol, 100%) which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:16][C:17]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=1[CH2:19]Cl.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[Cl:16][C:17]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=1[CH2:19][NH:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(C(=O)OC)c(NCc2ccc(Cl)cc2Cl)c1
Yield: 42.8 %

Procedure:
Dimethyl 2-aminoterephthalate (10.45 g), 2,4-dichlorobenzyl chloride (11.74 g), potassium iodide (8.33 g) and potassium carbonate (13.82 g) in a mixed solvent of toluene (50 ml) and water (30 ml) were heated under reflux for 20 hr. After cooling, toluene (50 ml) was added and the precipitated yellow crystals were collected by filtration. The crystals were washed with water and toluene and dried to give the objective compound (7.87 g). The mother liquor was concentrated and crystallized from ethyl acetate to give the second crystals (4.43 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:22]3[CH2:27][CH2:26][N:25]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)=[O:29])[CH2:24][CH2:23]3)=[CH:7][C:8]([NH:12][CH2:13][CH2:14][NH:15]C(C(F)(F)F)=O)=[N:9]2)=[CH:4][CH:3]=1.C1COCC1.[OH-].[K+]>CO>[NH2:15][CH2:14][CH2:13][NH:12][C:8]1[CH:7]=[C:6]([N:22]2[CH2:27][CH2:26][N:25]([C:28]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[O:29])[CH2:24][CH2:23]2)[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: O=C(Nc1ccc(F)cc1)N1CCN(c2cc(NCCNC(=O)C(F)(F)F)nc3cc(Cl)ccc23)CC1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: NCCNc1cc(N2CCN(C(=O)Nc3ccc(F)cc3)CC2)c2ccc(Cl)cc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 7-Chloro-4-[4-(4-fluorphenylaminocarbonyl)piperazin-1-yl]-2-[2-(trifluoroacetamino)ethylamino]quinoline (13 mg, 0.024 mmol) was added THF (0.5 mL) and 0.5 N KOH (2.0 eq, 0.14 mL), the mixture was stirred at rt. for 2 h, additional 0.5 N KOH (0.5 mL, 10 eq.) was added and the reaction mixture was heated at 50° C. for 30 min, MeOH (0.2 ml) was added and heated at the same temperature for 30 min. Evaporation and dilution with AcOEt, washing with brine, usual workup gave the residue, which was purified by preparative TLC with 20% MeOH in DCM with 0.5% hydroxylamine by twice developing the plate to afford the title compound.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.O.[C:11](Cl)(Cl)=[S:12]>C(Cl)Cl>[I:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[C:11]=[S:12])=[C:4]([CH3:9])[CH:3]=1
Reactant: S=C(Cl)Cl
Reactant: Cc1cc(I)ccc1N
Solvent: ClCCl
Solvent: O
Product: Cc1cc(I)ccc1N=C=S
Reaction time: 8 h
Yield: 90.9 %

Procedure:
To a stifling solution of 4-iodo-2-methylaniline (1.0 g, 4.2 mmol) in DCM (50 mL) was added water (20 mL) followed by thiophosgene (490 mg, 4.2 mmol). The reaction mixture was stirred overnight before the layers were separated and the organic layer dried (Na2SO4) and evaporated in vacuo to give the desired product as a brown solid (1.05 g, 89%). δH (CDCl3) 7.75 (1H, d, J=1.2 Hz), 7.62 (1H, dd, J 1.2, 8.3 Hz), 7.15 (1H, d, J=8.3 Hz), 2.20 (3H, s).
Reaction SMILES: Cl.[O:2]=[C:3]1[N:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[CH2:6][C:5]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:4]1.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][C:25]=1[O:32][C:33]([F:36])([F:35])[F:34]>>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:20]2[CH2:21][CH2:22][C:5]3([O:4][C:3](=[O:2])[N:7]([C:8]4[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=4)[CH2:6]3)[CH2:18][CH2:19]2)=[CH:26][C:25]=1[O:32][C:33]([F:34])([F:36])[F:35]
Reactant: O=Cc1ccc(Cl)c(OC(F)(F)F)c1
Reactant: COC(=O)c1ccc(N2CC3(CCNCC3)OC2=O)cc1
Agent: Cl
Product: COC(=O)c1ccc(N2CC3(CCN(Cc4ccc(Cl)c(OC(F)(F)F)c4)CC3)OC2=O)cc1

Procedure:
The title compound was prepared from methyl 4-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)benzoate hydrochloride salt (50 mg, 0.153 mmol; Example 1, Step 2) and 4-chloro-3-trifluoromethoxybenzaldehyde (43.7 mg, 0.199 mmol) following essentially the same procedure described in Step 1 of Example 7-6. The title compound was obtained as a yellow oil (76 mg) that was used without any further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[K+].[OH-].[K+].[C:11]1([C:17]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH2:20][CH2:21]Br)[C:18]#[N:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O>[C:23]1([C:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)([CH2:20][CH2:21][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:18]#[N:19])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: N#CC(CCBr)(c1ccccc1)c1ccccc1
Reactant: C1CCNCC1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: N#CC(CCN1CCCCC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 86.1 %

Procedure:
To 1.96 parts of piperidine is added 1.91 parts of potassium iodide and 25 parts deionized water under a nitrogen atmosphere. The mixture is gently warmed and 1.65 parts of potassium hydroxide and 7.51 parts of 2,2-diphenyl-4-bromobutyronitrile are added. The temperature is raised to reflux and maintained thereat for 4.5 hours. After cooling to room temperature, the reaction mixture is extracted three times with 14 part portions of ethyl ether. The ether extracts are combined, and extracted four times with 25 parts by volume portions of a dilute acetic acid solution. The acid extracts are combined, neutralized to about pH 10 with 50% sodium hydroxide solution, and extracted again with ethyl ether. The ether extracts are combined, washed twice with 50 parts by volume portions of a saturated sodium chloride solution, and dried over anhydrous potassium carbonate. The solvent is removed under reduced pressure to afford, as an off-white solid, in 86.1% yield, 2,2-diphenyl-4-piperidinobutyronitrile. This compound melts at 74° - 77° C., and is represented by the following structural formula. ##STR16##
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:21][C:20]=2[N+:32]([O-])=O)=[C:4]([Cl:17])[CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH:7]2[C:12]([O:14][CH2:15][CH3:16])=[O:13].[Cl-].[NH4+]>O1CCCC1.[Zn]>[NH2:32][C:20]1[CH:21]=[C:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH:23]=[CH:24][C:19]=1[O:18][C:3]1[C:2]([Br:1])=[C:11]2[C:6]([CH:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:9][O:10]2)=[CH:5][C:4]=1[Cl:17]
Reactant: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-])c2Br
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)OC(C)(C)C)cc1N)c2Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To a stirred solution of ethyl 8-bromo-7-(4-(tert-butoxycarbonyl)-2-nitrophenoxy)-6-chlorochroman-4-carboxylate (2.00 g, 3.59 mmol) in tetrahydrofuran (15 mL) at ambient temperature was added zinc dust (4.70 g, 71.8 mmol), followed by saturated ammonium chloride solution (7.5 mL). The resulting mixture was stirred at ambient temperature for 1 hour. The mixture was filtered through a glass microfibre filter to remove the insoluble zinc solids, and the solids were washed twice with tetrahydrofuran. The combined filtrate and washings were concentrated to remove most of the tetrahydrofuran, and the residue was partitioned between ethyl acetate (100 mL) and water (50 mL). The organic layer was washed with brine (50 mL), then dried over sodium sulfate and concentrated to afford ethyl 7-(2-amino-4-(tert-butoxycarbonyl)phenoxy)-8-bromo-6-chlorochroman-4-carboxylate as a light brown glass (1.61 g, 85% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([O:13][CH3:14])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:20](O)[CH3:21]>>[CH3:14][O:13][C@@H:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[C:10]([O:12][CH2:20][CH3:21])=[O:11]
Reactant: CCO
Reactant: CO[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)OC
Temperature: 25 °C

Procedure:
A solution of (2S)-3-(4-hydroxyphenyl)-2-methoxypropanoic acid (35 g) in 140 ml of ethanol was mixed with 5.66 ml of concentrated sulfuric acid and stirred at room temperature until complete as indicated by HPLC. The ethanol was removed via vacuum distillation (55° C./28″Hg) and 110 ml of water was added. The pH was adjusted to about 7 to 8 with sodium bicarbonate, and the mixture was extracted with add 50 ml ethyl acetate (3×50 ml). The organic layers were combined, washed with 50 ml 20% NaCl solution, dried with 15 g of magnesium sulfate, and concentrate product to afford ethyl (2S)-2-methoxy-3-(4-hydorxyphenyl)propanoate as an oil. 1H-NMR (CDCl3): 7.1 (d, 2H); 6.7(d, 2H); 4.2(m, 2H); 3.9(m, 1H); 3.6(s, 3H); 2.95(m, 2H); 1.25(t, 3H). MS (ES): 223.2 (M−1).
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH3:6][NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C(OCC)(=O)C>[CH2:18]([O:17][C:15]([N:7]([CH3:6])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)CNC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A rapidly stirred mixture of ethyl acetate and saturated aqueous sodium bicarbonate containing commercially available commercially available 2 ethyl 2-(methylamino)acetate (1.91 g, 12.4 mmol, HCl salt) was cooled to 0° C. and treated dropwise with benzyl chloroformate (4.10 mL, 12.3 mmol). After stirring overnight warming to room temperature, the aqueous layer was removed and the organic layer concentrated in vacuo. Purification of the residue by flash chromatography (silica gel, DCM) yielded the product.
Reaction SMILES: [NH:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5]([NH2:14])[C:4]=2[N:3]=[CH:2]1.[H-].[Na+].[CH2:17](Br)[CH:18]([CH3:20])[CH3:19]>CN(C)C=O.O>[CH3:17][CH:18]([CH3:20])[CH2:19][N:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5]([NH2:14])[C:4]=2[N:3]=[CH:2]1
Reactant: Nc1nc2ccccc2c2[nH]cnc12
Reactant: CC(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1cnc2c(N)nc3ccccc3c21
Temperature: 100 °C

Procedure:
To a stirred suspension of 1.0 g (0.0054 mole) of 1H-imidazo[4,5-c]quinolin-4-amine in 10 mL of N,N-dimethylformamide was added 0.15 g (0.0059 mole) of sodium hydride. To this stirred mixture was added 0.74 g (0.0054 mole) of isobutyl bromide. After 30 minutes the mixture was heated at about 100° C. for one hour. The mixture was cooled to about 20° C., diluted with 20 mL of water, and the solid was separated by filtration. Recrystallization from N,N-dimethylformamide provided the known antiviral agent 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([NH:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23][CH3:24])=[O:22])[CH2:16]1)=[O:13].[C:25]1([O:31][CH2:32][CH2:33][CH2:34]/[CH:35]=[CH:36]\[C:37]2[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][CH2:45]Br)=[CH:39][CH:38]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:24][O:23][C:21]([CH:17]1[CH2:18][CH2:19][CH2:20][CH:15]([NH:14][C:12]([C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=2[O:1][CH2:45][CH2:44][CH2:43][C:40]2[CH:41]=[CH:42][C:37](/[CH:36]=[CH:35]\[CH2:34][CH2:33][CH2:32][O:31][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:38][CH:39]=2)[C:6]([O:8][CH3:9])=[O:7])=[O:13])[CH2:16]1)=[O:22]
Reactant: BrCCCc1ccc(/C=C\CCCOc2ccccc2)cc1
Reactant: COC(=O)c1ccc(O)c(C(=O)NC2CCCC(C(=O)OC)C2)c1
Product: COC(=O)c1ccc(OCCCc2ccc(/C=C\CCCOc3ccccc3)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1

Procedure:
Preparation takes place in analogy to Example 22 from the (+)-B-enantiomer of methyl 4-hydroxy-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate (see Example IX, method 2) and (4Z)-5-[4-(3-bromopropyl)phenyl]pent-4-en-1-yl phenyl ether.