Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1.[Cl:22][CH2:23][CH:24]=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[CH:24][CH2:23][Cl:22])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1
Reactant: O=CCCl
Product: ClCC=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1

Procedure:
In the manner given in Example 1, 7-chloro-2-hydrazino-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can be reacted with α-chloroacetaldehyde to give 7-chloro-2-[(2-chloroethylidene)hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: C(O)(=O)CC(CC(O)=O)(C(O)=O)O.F[C:15]1[CH:39]=[CH:38][C:18]([C:19]([NH:21][C:22]2[CH:37]=[CH:36][CH:35]=[CH:34][C:23]=2[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=2)=[O:25])=[O:20])=[C:17]([O:40][CH:41]2[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH2:42]2)[CH:16]=1.[OH:54][CH:55]1[CH2:59][CH2:58][NH:57][CH2:56]1>>[C:50]([O:49][C:47]([N:44]1[CH2:45][CH2:46][CH:41]([O:40][C:17]2[CH:16]=[C:15]([N:57]3[CH2:58][CH2:59][CH:55]([OH:54])[CH2:56]3)[CH:39]=[CH:38][C:18]=2[C:19]([NH:21][C:22]2[CH:37]=[CH:36][CH:35]=[CH:34][C:23]=2[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=2)=[O:25])=[O:20])[CH2:42][CH2:43]1)=[O:48])([CH3:52])([CH3:51])[CH3:53]
Reactant: OC1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)ccc2C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCC(O)C3)ccc2C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1

Procedure:
Using methods substantially equivalent to those described in example 4-F except that the workup used saturated aqueous citric acid instead of water, 2-[2-(1-tert-butoxy-carbonylpiperidin-4-yloxy)-4-(3-hydroxypyrrolidin-1-yl)benzoylamino]-N-(5-chhloro-pyridin-2-yl)benzamide (160 mg, 0.25 mmol, 47%) was prepared from 2-[4-fluoro-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)-benzamide and 3-hydroxypyrrolidine.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])([F:13])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)=O)C.CO>ClCCCl>[F:21][C:15]1[C:16]([F:20])=[CH:17][CH:18]=[CH:19][C:14]=1[C:10]1([F:13])[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: Fc1cccc(C2(F)CCN(Cc3ccccc3)C2)c1F
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Solvent: CO
Product: Fc1cccc(C2(F)CCNC2)c1F
Yield: 19.3 %

Procedure:
To a solution of 1-benzyl-3-(2,3-difluorophenyl)-3-fluoropyrrolidine (1.6 g, 5.5 mmol) in dry 1,2-dichloroethane (10 mL) under nitrogen was added 1-chloroethylchloroformate (600 μl, 5.5 mmol). The mixture was stirred at ambient temperature for 7 h after which methanol was added and the mixture was evaporated. Methanol (10 mL) was added and the mixture was heated at reflux for 4 h. The mixture was evaporated and purified by column chromatography on silica gel (ethyl acetate/methanol, 1:0 to 1:1) to give the title compound (214 mg). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 136° C.; MS m/z (relative intensity, 70 eV) 201 (M+, 35), 151 (bp), 158 (69), 138 (45), 133 (42).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][S:10]([C:13]1[N:17]=[C:16]([NH2:18])[NH:15][N:14]=1)(=[O:12])=[O:11].C(O)(=O)C.[C:23](OCC)(=[O:28])[CH2:24][C:25]([CH3:27])=O>CO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][S:10]([C:13]1[N:17]=[C:16]2[N:18]=[C:25]([CH3:27])[CH:24]=[C:23]([OH:28])[N:15]2[N:14]=1)(=[O:12])=[O:11]
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1nc(S(=O)(=O)Nc2c(Cl)cccc2Cl)n[nH]1
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(O)n2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2n1
Reaction time: 24 h
Yield: 74.8 %

Procedure:
A solution of 5.0 g (14.3 mmol) of N-(2,6-dichlorophenyl)-5-amino-1,2,4-triazol-3-sulfonamide, 0.5 ml of acetic acid, and 2.0 ml (15.6 mmol) of ethyl acetoacetate in 100 ml of absolute methanol was heated at reflux for 48 hr. After 24 hr a solid began to form. The solution was cooled and the solid collected. After drying, 4.0 g (75 percent) of the desired product was obtained as a white powder; mp 302° C. decomposes.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:15][C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[O:19][C:20]1[C:25]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:23]=[CH:22][N:21]=1>CN(C=O)C>[O:7]([CH2:15][C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[O:19][C:20]1[C:25]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:23]=[CH:22][N:21]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: COC(=O)Cc1cccnc1Oc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccnc1Oc1cccc(COc2ccccc2)c1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 58.9 %

Procedure:
Phenol (0.16 g) and potassium carbonate (0.12 g) were stirred together in DMF (6 ml) under nitrogen at room temperature. After 20 minutes, a solution of methyl 2-(3-chloromethylphenoxy)-3-pyridinylacetate (0.5 g) in DMF was added and stirring continued. Copper-bronze (cat.) was added and the reaction mixture heated at 100° C. for a total of 5 hours. GC analysis indicated complete reaction. The reaction mixture was cooled and filtered, and then poured into water (50 ml). The aqueous mixture was extracted with ether (×3) and the combined extracts washed with dilute sodium hydroxide solution. The ether solution was then dried, filtered and evaporated to give methyl 2-(3-phenoxymethylphenoxy)-3-pyridinylacetate as a yellow oil (0.35 g, 59%), mass spectrum m/e 349 (M+); 1H NMR (CDCl3) inter alia delta 3.69 (3H, s); 3.76 (2H, s); 5.07 (2H, s) ppm, contained with traces of DMF. In a separate experiment, the chloromethyl compound (2.73 g, prepared as above) yielded a further 2.00 g of methyl 2-(3-phenoxymethylphenoxy)-3-pyridinylacetate.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=1)[CH2:3][OH:4].C(N(CC)CC)C.[CH3:28][O:29][C@@:30]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:34]([F:37])([F:36])[F:35])[C:31](Cl)=[O:32]>C(Cl)Cl>[CH3:28][O:29][C@:30]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:34]([F:37])([F:36])[F:35])[C:31]([NH:1][CH:2]([CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:11][CH:12]=1)[CH2:3][OH:4])=[O:32]
Reactant: CO[C@@](C(=O)Cl)(c1ccccc1)C(F)(F)F
Reactant: CCCCCCCCc1ccc(CCC(N)CO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCc1ccc(CCC(CO)NC(=O)[C@@](OC)(c2ccccc2)C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
2-Amino-4-(4-octylphenyl)butanol (30 mg), N,N-dimethyl-p-aminopyridine (52.6 mg), anhydrous triethylamine (34.2 μl) and anhydrous methylene chloride (1 ml) were mixed and the mixture was stirred under a nitrogen atmosphere at room temperature. Thereto was added (S)-α-methoxy-α-trifluoromethylphenylacetyl chloride (50.4 μl) and the mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by thin layer chromatography (eluent; chloroform:methanol=9:1) to give the two diastereomer mixtures. Moreover, the mixture was purified by high performance liquid chromatography (eluent; methanol:water=88:12, flow rate; 8.0 ml /minute) to give the subject oily substance (31.6 mg) of 67.8 minutes at retention time and the subject oily substance (31.9 mg) of 71.6 minutes at retention time.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[I-].[CH3:11][S+](C)C.[OH-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[CH2:11][O:5]1
Reactant: O=Cc1ccccc1Cl
Reactant: C[S+](C)C
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Clc1ccccc1C1CO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloro-benzaldehyde (5 mL, 44 mmol) was dissolved in dichloromethane (45 mL) and treated with trimethylsulfonium iodide (10.25 g, 49.28 mmol) and aqueous sodium hydroxide solution (50%, 44 g) subsequently. The mixture was stirred vigorously at room temperature for overnight. The organic phase was separated and concentrated to give clear oil, which was stored in the refrigerator and used directly without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[N+:25]([O-])=O)[NH:7][C:8](=[O:21])[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([O-])=O.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=2)[CH2:31][CH2:30]1>>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:42]=[CH:41][C:38]([C:39]3[NH:25][C:24]4[CH:23]=[CH:22][C:6]([NH:7][C:8](=[O:21])[C:9]5[CH:14]=[CH:13][C:12]([N:15]6[CH2:20][CH2:19][O:18][CH2:17][CH2:16]6)=[CH:11][CH:10]=5)=[CH:5][C:4]=4[N:1]=3)=[CH:37][CH:36]=2)[CH2:31][CH2:30]1
Reactant: CN1CCN(c2ccc(C=O)cc2)CC1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCOCC2)cc1
Product: CN1CCN(c2ccc(-c3nc4cc(NC(=O)c5ccc(N6CCOCC6)cc5)ccc4[nH]3)cc2)CC1

Procedure:
Compound 423 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-morpholinobenzoyl)aniline and 4-(4-methylpiperazino)benzaldehyde. [M+H]+ calcd for C29H32N6O2: 497.26; found: 496.98.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[N:3]=1.[Cl-].[NH4+]>CC(C)=O.O.[Zn]>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[N:3]=1
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1)CCC2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CC(C)=O
Solvent: O
Product: Clc1ncc2c(n1)C(c1ccccc1)CCC2
Temperature: 90 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
A mixture of 2,4-dichloro-8-phenyl-5,6,7,8-tetrahydroquinazoline (51.9 mg, 0.186 mmol), ammonium chloride (13.0 mg, 0.243 mmol) and zinc (130 mg, 1.988 mmol) in acetone (0.75 mL) and water (0.75 mL) was heated at 90° C. with stirring for 2 h. The reaction mixture was filtered through a short plug of diatomaceous earth (Celite®). The solvent was removed in vacuum, and the residue was partitioned between dichloromethane and water. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum and the residue was purified by column chromatography on silica gel to give 2-chloro-8-phenyl-5,6,7,8-tetrahydroquinazoline (24.1 mg, 0.097 mmol, 52.4% yield) as white solid. LC-MS (M+H)+=245.1. 1H NMR (500 MHz, CDCl3) δ ppm 8.39 (1H, s), 7.27 (2H, t, J=7.6 Hz), 7.16-7.23 (1H, m), 6.95 (2H, d, J=7.3 Hz), 4.21 (1H, t, J=6.0 Hz), 2.72-2.91 (2H, m), 2.14-2.26 (1H, m), 1.95-2.06 (1H, m), 1.81-1.93 (1H, m), 1.71-1.81 (1H, m).
Reaction SMILES: [H-].[Na+].[CH:3]1([CH:6]([OH:33])[C:7]2[N:11]([CH3:12])[C:10]3[CH:13]=[C:14]([N:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)=[CH:19][C:18]4=[O:32])[CH:15]=[CH:16][C:9]=3[N:8]=2)[CH2:5][CH2:4]1.IC.[CH3:36]N(C=O)C>C1COCC1>[CH:3]1([CH:6]([O:33][CH3:36])[C:7]2[N:11]([CH3:12])[C:10]3[CH:13]=[C:14]([N:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)=[CH:19][C:18]4=[O:32])[CH:15]=[CH:16][C:9]=3[N:8]=2)[CH2:5][CH2:4]1
Reactant: Cn1c(C(O)C2CC2)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc21
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(c1nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc2n1C)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaH (40% oil dispersion, 5.2 mg) was added to a solution of 1-(2-(cyclopropyl(hydroxy)methyl)-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (30 mg) and iodomethane (0.013 ml) in THF (2 ml)-DMF (1 ml) at room temperature. The mixture was stirred at room temperature for 30 min. The mixture was quenched with water and extracted with EtOAc twice. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The resulting solid was washed with Et2O to give the title compound (23.6 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClC(Cl)(Cl)Cl>[Br:12][CH2:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(F)c(CBr)c1
Reaction time: 16 h

Procedure:
186 g (1.2 mol) of 2-fluoro-5-nitrotoluene are dissolved in 1.2 l of tetrachloromethane and admixed with 214 g (1.20 mol) of N-bromosuccinimide. 19.7 g (120 mmol) of azodiisobutyronitrile are added and the mixture is heated under reflux. After 16 h, the mixture is allowed to cool, filtered and concentrated to dryness under reduced pressure. The residue is dissolved in 300 ml of dichloromethane and admixed with 300 g of Seesand. Then the mixture is concentrated to dryness under reduced pressure again, and the residue is applied to a 1 kg silica gel column. It is chromatographed with a 20:1 mixture of cyclohexane and ethyl acetate, and the product fractions are concentrated to dryness under reduced pressure. The residue is crystallized with cyclohexane and dried under reduced pressure. This affords 92 g (32% of theory) of the desired product.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[Cl:28][C:29]1[CH:30]=[C:31]([NH:35][NH2:36])[CH:32]=[CH:33][CH:34]=1>>[Cl:28][C:29]1[CH:30]=[C:31]([N:35]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:15]=[CH:16][C:17]([S:20]([C:23]([F:26])([F:24])[F:25])(=[O:22])=[O:21])=[CH:18][CH:19]=4)[N:8]=3)=[CH:4][CH:3]=[N:36]2)[CH:32]=[CH:33][CH:34]=1
Reactant: NNc1cccc(Cl)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(S(=O)(=O)C(F)(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(S(=O)(=O)C(F)(F)F)cc2)nc1-c1ccnn1-c1cccc(Cl)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethansulfonyl-phenyl)-1H-pyridazin-4-one (A-27) and 3-chloro-phenylhydrazine according to the method described for example 1. MS: M=481.1 (M+H)+
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C[O-].[Na+]>C(#N)C>[N+:9]([C:5]1[C:6]([NH2:8])=[N:7][C:2]([O:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3][CH:4]=1)([O-:11])=[O:10]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Product: Nc1nc(Oc2ccccc2)ccc1[N+](=O)[O-]
Yield: 68.8 %

Procedure:
6-Chloro-3-nitro-2-pyridine amine (1.2 g), phenol (3.1 g) and sodium methoxide (0.4 g) were dissolved in acetonitrile (20 ml), and the solution was heated for 12 hours under reflux. After the completion of the reaction, the solvent was distilled off under reduced pressure. The residue was distributed into ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The organic layer was washed with water and dried over MgSO4. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. The fraction eluted with ethyl acetate-hexane (1:10, v/v) was concentrated under reduced pressure. The resulting crystals were collected by filtration to obtain 3-nitro-6-phenoxy-2-pyridine amine (1.1 g, 66%).
Reaction SMILES: C([O:8][C:9](=[O:32])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:31])[C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21](=[O:30])[C@H:22]([CH3:29])[NH:23][S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])C1C=CC=CC=1.[H][H]>CO.O.[C].[Pd]>[CH2:27]([S:24]([NH:23][C@H:22]([C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:16]1[C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([OH:32])=[O:8])=[O:31])=[O:30])[CH3:29])(=[O:25])=[O:26])[CH3:28]
Reactant: [H][H]
Reactant: CCS(=O)(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CCS(=O)(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Yield: 72.5 %

Procedure:
N-ethanesulfonyl-L-alanyl-L-prolyl-L-proline benzylester (2.00 g, 4.29 m mole) was dissolved in a mixture of methanol (10 ml) and water (10 ml), and then hydrogen gas was passed through the solution in the presence of 5% palladium carbon for 1.5 hours at room temperature. Cellite was added to the reaction solution and the solution was filtered and this operation was repeated again. The catalyst was completely removed and the filtrate was concentrated under reduced pressure. The thus produced crystals were obtained by filtration, washed sufficiently with ethyl acetate, and then dried under reduced pressure to give white crystals of N-ethanesulfonyl-L-alanyl-L-prolyl-L-proline (1.17 g).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3](=[O:11])[O:2]1.[BrH:12]>O>[Br:12][CH2:1][C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:4][C:3]([OH:2])=[O:11]
Reactant: Br
Reactant: O=C1Cc2ccccc2CO1
Solvent: O
Product: O=C(O)Cc1ccccc1CBr
Reaction time: 0.17 h

Procedure:
3-Isochromanone (30 g), Mann, F. G. and Stewart, F. H., Journal of the Chemical Society 2819 (1954) is added with swirling to 150 ml of hydrobromic acid (48%) at 80° C. The resulting mixture is then heated on a steam bath with occasional swirling for 10 min and thereafter poured into a mixture of crushed ice and water (750 g). The resulting mixture is then extracted with ethyl acetate and the ethyl acetate extracts washed with a mixture of water and brine (1:1) and dried over magnesium sulfate. Concentration under reduced pressure yields a residue of crude o-(bromomethyl)phenylacetic acid. (Crystallization of the crude product from methylene chloride yields a product with melting point 130°-131° C. and a C:H ratio of 46.90:4.09). The crude o-(bromomethyl)phenylacetic acid, 400 ml of benzene and 38 g of triphenylphosphine is stirred at 80° C. for 5 hr and cooled and filtered to yield 57 g of title product, melting point 248°-249° C. The C:H:Br:P ratio is 66.22:4.94:16.16:6.49.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.C([NH2:21])=O.N.[OH-].[Na+]>CO>[CH3:17][CH:16]([CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:21])[C:11]=2[N:12]=[CH:13]1)[CH3:18]
Reactant: NC=O
Reactant: CC(C)Cn1cnc2c(Cl)nc3ccccc3c21
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Cn1cnc2c(N)nc3ccccc3c21
Temperature: 145 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
A mixture of 4-chloro-1-isobutyl-1H-imidazo[4,5-c]quinoline (100.0 g, 0.385 mole) and formamide (250 ml, 6.27 mole, 16.3 equiv.) was heated to 145° C. under nitrogen atmosphere. Then, ammonia (gas) (92 g, 5.29 mole, 14 equiv.) was bubbled (4-5 g per hour) into the reaction mixture at this temperature during a period of 20 hours. Then, the reaction mixture was cooled to ambient temperature and stirred at this temperature for 3 hours. A colorless solid was collected by filtration, washed with methanol (3×100 ml), water (3×100 ml) and again with methanol (3×50 ml) and dried at 50° C. under reduced pressure overnight to give a crude Imiquimod (74.1 g, 80.2% yield, purity by HPLC: 99.3%). The crude compound (74.1 g) was slurried in a boiling mixture of methanol (500 ml) and 47% aqueous sodium hydroxide solution (about 6 ml) for 4 hours. The hot mixture was filtered and the thus obtained cake was washed with methanol (3×40 ml), water (3×50 ml) and again with methanol (3×40 ml) and dried at 50° C. under reduced pressure to yield 72.2 g of Imiquimod in 77.9% yield, having a purity of 99.85% (by HPLC)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([F:9])[CH:3]=1.[C:10]([NH:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O)(=[O:17])=[O:16])([CH3:13])([CH3:12])[CH3:11]>[Pd]>[F:9][C:4]1[CH:3]=[C:2]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[S:15](=[O:17])(=[O:16])[NH:14][C:10]([CH3:11])([CH3:13])[CH3:12])[CH:7]=[CH:6][C:5]=1[CH3:8]
Reactant: Cc1ccc(Br)cc1F
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Agent: [Pd]
Product: Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Yield: 92 %

Procedure:
The palladium (0)-catalyzed coupling of 4-bromo-2-fluorotoluene with 2-(N-t-butylsulfamoyl)phenylboronic acid was carried out according to the procedure of Example 28 Step F. Purification of the crude product by flash chromatography (elution with hexane-EtOAc) gave a 92% yield of the title compound as an off-white foam (TLC in 4:1 hexane-EtOAc); mass spectrum (FAB) m/e 322 (M+1)+.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[N:29][CH:30]=1>>[CH:11]1[C:12]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20]([C:25]5[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[N:29][CH:30]=5)([OH:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: COc1ccc(Br)cn1
Product: COc1ccc(C2(O)CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)cn1
Yield: 81 %

Procedure:
Using a procedure similar to that described in example 1 except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and employing 5-bromo-2-methoxypyridine, the title compound was formed in 81% yield as a white solid, mp 218°-222° C. free base: 1H NMR (CDCl3, 250 MHz) 8.28 (d, J=2.5 Hz, 1H), 7.69 (dd, J=2.6, 8.7 Hz, 1H), 7.22 (m, 4H), 6.95 (m, 4H), 6.71 (d, J=8.7 Hz, 1H), 4.28 (s, 1H), 3.93 (s, 3H), 3.48 (s, 2H), 2.91 (m, 2H), 2.78 (dt, J=2.4, 11.7 Hz, 2H), 2.62 (d, J=1.4 Hz, 2H), 2.07 (dt, J=4.4, 12.8 Hz, 2H), 1.75 (m, 2H), 1.59 (s, 1H) MS (CI, CH4) m/z 413 (M+1,100), 441 (M+29,12), 395 (19) hydrochloride salt: Analysis for C27H28N2O2.2HCl.0.5H2O: Calculated: C, 65.59; H, 6.32; N, 5.67 Found: C, 65.48; H, 6.14; N, 5.35
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(C)(C)C.[CH:19]1([CH2:24][CH2:25]O)[CH2:23][CH2:22][CH:21]=[CH:20]1>>[CH:19]1([CH2:24][CH2:25][O:16][C:13]2[CH:12]=[CH:11][C:10]([C:9]([NH:8][CH2:7][C:6]([OH:5])=[O:18])=[O:17])=[CH:15][CH:14]=2)[CH2:23][CH2:22][CH:21]=[CH:20]1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(O)cc1
Reactant: OCCC1C=CCC1
Product: O=C(O)CNC(=O)c1ccc(OCCC2C=CCC2)cc1
Yield: 72 %

Procedure:
The same reaction as in Example 1 (1b) was conducted using N-(4-hydroxybenzoyl)glycine tert-butyl ester (157 mg, 0.625 mmol) prepared in Example 1 (1a) and 2-cyclopenta-2-en-1-ylethanol (which is the compound disclosed in J. Org. Chem., (2000), 65, 4241-4250, 85 mg, 0.75 mmol) to give 128 mg of the title compound (white powder, yield: 72%).