Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[C:54]([C:57]1[N:58]=[N:59][NH:60][CH:61]=1)(O)=[O:55]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:54]([C:57]2[N:58]=[N:59][NH:60][CH:61]=2)=[O:55])[CH2:48]1
Reactant: O=C(O)c1c[nH]nn1
Reactant: O=C(C[C@@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@@H]1CCN(C(=O)c2c[nH]nn2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 87 %

Procedure:
The desired compound was prepared according to the procedure of Example D97, step A, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 4-carboxy-1,2,3-triazole as the starting materials in 87% yield. LCMS for C26H26ClN10O2 (M+H)+: m/z=545.0.
Reaction SMILES: [O:1]1[C:5]([C:6]2[S:10][C:9]([S:11](Cl)(=[O:13])=[O:12])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.[NH2:15][C:16]1[CH:17]=[C:18]([C:22]2[NH:26][N:25]=[N:24][N:23]=2)[CH:19]=[CH:20][CH:21]=1>>[O:1]1[C:5]([C:6]2[S:10][C:9]([S:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4[NH:26][N:25]=[N:24][N:23]=4)[CH:17]=3)(=[O:13])=[O:12])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)s1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(-c2cnco2)s1
Yield: 51.8 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting with 5-(1,3-oxazol-5-yl)thiophene-2-sulfonyl chloride (13.7 mg, 0.055 mmol) and 5-(3-amino-phenyl)tetrazole (8 mg, 0.05 mmol) yielding 9.7 mg (52%) of the title compound. MS (ESI+) calcd for C14H10N6O3S2 374.02558, found 374.02547.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[C:11]([N:15]=[N:16]/[C:17](/[CH3:24])=[CH:18]\[C:19]([O:21][CH2:22][CH3:23])=[O:20])([O:13][CH3:14])=[O:12].CCCCCC>C1COCC1>[CH2:22]([O:21][C:19](=[O:20])[CH:18]([NH:7][C:6]1[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:17](=[N:16][NH:15][C:11]([O:13][CH3:14])=[O:12])[CH3:24])[CH3:23]
Reactant: CCOC(=O)/C=C(/C)N=NC(=O)OC
Reactant: Nc1cccc([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C(Nc1cccc([N+](=O)[O-])c1)C(C)=NNC(=O)OC
Temperature: 70 °C
Yield: 71.1 %

Procedure:
3-Nitroaniline (2.92 g, 21.27 mmol) was added to a solution of ethyl 3-carbomethoxyazocrotonate (4.2 g, 21.13 mmol) (which is known in the literature) in THF (40 mL), and the mixture was stirred at 70° C. for a day and a night. After cooling to room temperature, hexane was added thereto, and the deposited precipitate was filtered out to yield the title compound (5.08 g, 71%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([Br:12])=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:13]([N:16]=[C:17]=[O:18])[CH2:14][CH3:15]>C(Cl)(Cl)Cl>[Br:12][C:9]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]([NH:1][C:17]([NH:16][CH2:13][CH2:14][CH3:15])=[O:18])=[N:11][CH:10]=1
Reactant: COC(=O)c1cc(N)ncc1Br
Reactant: CCCN=C=O
Solvent: ClC(Cl)Cl
Product: CCCNC(=O)Nc1cc(C(=O)OC)c(Br)cn1
Temperature: 55 °C
Yield: 94.2 %

Procedure:
Methyl 2-amino-5-bromoisonicotinate (100 g, 433 mmol) was dissolved in chloroform (600 mL) and placed into a 1 L sealed tube. Propyl isocyanate (122.5 mL, 1.29 mol) was then added. The reactor was heated at 55° C. for 72 h at which time the reaction was determined to be complete. The mixture was then cooled to room temperature, concentrated under reduced pressure, and the solid was dissolved in 2:1 ethyl acetate: tetrahydrofuran (3 L). This solution was washed with water (2×200 mL), and the water was back extracted with ethyl acetate (300 mL). The organic layers were then dried with sodium sulfate, filtered, and concentrated yielding 129 g (95%) of methyl 5-bromo-2-(3-propylureido)isonicotinate as a dark yellow solid.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([C:14]([NH:27][C:28]2[S:29][CH:30]=[C:31](/[C:33](=[N:37]/[OH:38])/[C:34]([OH:36])=[O:35])[N:32]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:39]1[O:50][C:49]2[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][C:41]=2[O:40]1>ClCCl>[C:8]1([C:14]([NH:27][C:28]2[S:29][CH:30]=[C:31](/[C:33](=[N:37]/[O:38][C:44](=[O:45])[C:43]3[CH:47]=[CH:48][C:49]4[O:50][CH2:39][O:40][C:41]=4[CH:42]=3)/[C:34]([OH:36])=[O:35])[N:32]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: O=C(O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)/C(=N\OC(=O)c1ccc2c(c1)OCO2)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.6 %

Procedure:
Triethylamine (6.7 ml) was added with stirring to an ice-cooled suspension of 10 g of 2-(2-triphenylmethylamino-4-thiazolyl)-2-(Z-hydroxyimino)acetic acid in 140 ml of anhydrous dichloromethane. The suspension turned to a clear, faint yellow solution after ten minutes. A solution of 3,4-methylenedioxybenzoyl chloride (3.4 g) in 25 ml of dichloromethane was dropwise added and the mixture was stirred at room temperature for one hour. The insoluble crystals were removed by filtration and the filtrate was washed twice with 20 ml of 1N hydrochloric acid and 30 ml of saturated sodium chloride solution each, and dried over anhydrous sodium sulfate. The dried filtrate was concentrated under reduced pressure, and the viscous brown residue (14.2 g) was purified by silica gel column chromatography using chloroform/methanol (20-10:1) as eluent, affording 2.3 g of the objective compound as light brown crystals.
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C@@H:16]([C@H:19]1[CH2:21][O:20]1)[CH2:17][CH3:18]>CO>[C:2]1([CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:14]2[CH2:21][C@@H:19]([OH:20])[C@@H:16]2[CH2:17][CH3:18])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: CC[C@@H](Br)[C@H]1CO1
Solvent: CO
Product: CC[C@H]1[C@H](O)CN1C(c1ccccc1)c1ccccc1
Yield: 48.6 %

Procedure:
Benzhydrylamine (1.04 mL, 6.06 mmol) was added to a solution of (2R*)-2-[(1R*)-1-bromopropyl]oxirane obtained in Example (234a) (1.00 g, 6.06 mmol) in methanol (6 mL), and the mixture was heated under reflux for 17 hours. The reaction solution was concentrated under reduced pressure. Saturated aqueous sodium carbonate solution was added to the resulting residue, followed by extraction with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate. Following filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=2/1) to obtain 787 mg of the title compound as a colorless oily substance (49%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].S(Cl)([Cl:19])(=O)=O>C(OCC)C>[Cl:19][CH:9]([C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CC(=O)c1ccccc1F
Reactant: O=S(=O)(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)C(Cl)C(=O)c1ccccc1F
Yield: 97.2 %

Procedure:
Using ethyl 3-(2-fluorophenyl)-3-oxopropanoate (1.0 g, 4.75 mmol), sulfuryl chloride (771 mg, 5.7 mmol) and diethyl ether (50 mL) as starting materials and in the same manner as in Example 20-B (i), the title compound (1.13 g, 97%) was obtained as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:25][CH:26]([CH2:37][CH3:38])[CH2:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1.C1(C)C=CC=CC=1>N1C=CC=CC=1>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:28]([CH2:27][CH:26]([CH3:25])[CH2:37][CH3:38])=[CH:29][CH:30]=3)=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCOc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCC(C)Cc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCOc1ccc(-c2ccc(OC(=O)c3ccc(CC(C)CC)cc3)cc2)cc1
Temperature: 25 °C
Yield: 39.1 %

Procedure:
This 4-hydroxy-4'-n-decyloxybiphenyl (0.5 g) was dissolved in dry pyridine (20 ml), followed by dropwise adding to the solution, commercially available (+)-p-(2-methylbutyl)benzoyl chloride (0.4 g), further pouring dry toluene (15 ml) in the mixture, sufficiently shaking at room temperature, further heating on a water bath at 60° C. for 3 hours, cooling down to room temperature, adding toluene (50 ml), twice washing with 6N hydrochloric acid (100 ml), further twice washing with a 2N alkali aqueous solution, several times washing with saturated NaCl aqueous solution to make the liquid neutral, drying over sodium sulfate, distilling off toluene, filtering through active carbon on heating using a mixed solvent of ethanol (20 ml) and ethyl acetate (20 ml), recrystallizing, filtering crystals deposited in a refrigerator, and drying to obtain the objective 4-n-decyloxy-4'-(p-(2-methylbutyl)benzoyloxy)biphenyl (0.3 g). Its phase transition points are shown in Table 3, sample No. 10. Further, its values of elemental analysis accorded well with its theoretical values as follows:
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[C:13]2[CH2:12][S:11][N:10]=[C:9]([N:14](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:8]3=[N:29][N:30]([CH2:32][C:33]4[C:38]([CH3:39])=[C:37]([O:40][CH3:41])[C:36]([CH3:42])=[CH:35][N:34]=4)[N:31]=[C:6]([C:7]=23)[CH2:5]1.[CH3:43]N(C)C=O.CI>O>[CH3:43][O:3][CH:4]1[C:13]2[CH2:12][S:11][N:10]=[C:9]([NH2:14])[C:8]3=[N:29][N:30]([CH2:32][C:33]4[C:38]([CH3:39])=[C:37]([O:40][CH3:41])[C:36]([CH3:42])=[CH:35][N:34]=4)[N:31]=[C:6]([C:7]=23)[CH2:5]1
Reactant: CN(C)C=O
Reactant: COc1c(C)cnc(CN2N=C3CC(O)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COc1c(C)cnc(CN2N=C3CC(OC)C4=C3C(=N2)C(N)=NSC4)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
Sodium hydride (6.7 mg) was added to a mixture of di-tert-butyl {8-hydroxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 32 (40 mg) and dehydrated N,N-dimethylformamide (1 mL), and then the mixture was stirred at room temperature for one hour. Methyl iodide (6.5 μL) was added to the reaction mixture, followed by stirring for 1.5 hours. Then, water (20 mL) was added. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL) were added to the resulting residue, and the mixture was stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reversed phase liquid chromatography to obtain the title compound (4.8 mg, 18%) as a solid.
Reaction SMILES: [BH3-]C#N.[Na+].C(OC([NH:12][C:13]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:14]=1[C:15]([NH:17][CH2:18][C:19]([NH:21][CH2:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:20])=[O:16])=O)(C)(C)C.[CH2:35]([O:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][C:45]=1[O:46][CH2:47][CH3:48])[CH:41]=O)[CH3:36].CO>C(O)(=O)C>[NH2:12][C:13]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:14]=1[C:15]([NH:17][CH2:18][C:19]([NH:21][CH2:22][CH:23]1[CH2:24][CH2:25][N:26]([CH2:41][C:40]2[CH:43]=[CH:44][C:45]([O:46][CH2:47][CH3:48])=[C:38]([O:37][CH2:35][CH3:36])[CH:39]=2)[CH2:27][CH2:28]1)=[O:20])=[O:16]
Reactant: CCOc1ccc(C=O)cc1OCC
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOc1ccc(CN2CCC(CNC(=O)CNC(=O)c3cc(F)c(F)cc3N)CC2)cc1OCC
Temperature: 50 °C
Reaction time: 8 h

Procedure:
NaBH3CN (0.25 mmol) was added to a mixture of 4-[[N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl]aminomethyl]piperidine (0.050 mmol) with 3,4-diethoxybenzaldehyde (0.15 mol), methanol (1.2 mL) and acetic acid (0.050 mL), and the obtained mixture was stirred at 50° C. overnight, cooled to room temperature, loaded onto a Varian™ SCX column and washed with methanol (5 mL×2). The obtained product was eluted with a 2 M methanol solution of NH3 (5 mL) and concentrated. Dichloromethane (2 mL) and phenyl isocyanate (0.10 mL) were added to the obtained residue, and the resulting mixture was stirred at room temperature for 1 hour, loaded onto a Varian™ SCX column and washed with methanol (5 mL). The obtained product was eluted with a 2 M methanol solution of NH3 (5 mL) and concentrated. The residue was dissolved in methanol (0.25 mL); and a 4 M dioxane solution of HCl (0.125 mL) was added to the resulting solution. The obtained mixture was stirred at room temperature overnight and concentrated. The resulting residue was dissolved in methanol, loaded onto a Varian™ SCX column and washed with methanol (5 mL×2). The obtained crude product was eluted with a 2 M methanol solution of NH3 (5 mL) and concentrated to thereby afford 4-[[N-(2-amino-4,5-difluorobenzoyl)glycyl]aminomethyl]-1-(3,4-diethoxybenzyl)piperidine (Compd. No. 2065) (21.2 mg, 84%). The purity was determined by RPLC/MS (97%). ESI/MS m/e 505.2 (M++H, C26H34F2N4O4).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([F:28])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)[N:12]=1.[CH3:29][C:30]([OH:34])([CH:32]=[CH2:33])[CH3:31].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[F:28][C:4]1[CH:5]=[C:6]2[C:10](=[C:2](/[CH:33]=[CH:32]/[C:30]([CH3:31])([OH:34])[CH3:29])[CH:3]=1)[NH:9][CH:8]=[C:7]2[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]2[CH2:19][C:20]([CH3:27])([CH3:26])[NH:21][C:22]([CH3:25])([CH3:24])[CH2:23]2)[N:12]=1
Reactant: C=CC(C)(C)O
Reactant: CC1(C)CC(Nc2nccc(-c3c[nH]c4c(Cl)cc(F)cc34)n2)CC(C)(C)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC(C)(O)/C=C/c1cc(F)cc2c(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)c[nH]c12

Procedure:
The title compound was prepared by the general Heck procedure described in Example 256, using the SEM-protected intermediate of Example 254 and 2-methyl-but-3-en-2-ol, followed by TBAF deprotection of the SEM group.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH2:23][NH:24]C(=O)OC(C)(C)C)=[N:21][N:22]=3)[N:19]=2)[S:11][N:10]=1>C(Cl)Cl>[CH3:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH2:23][NH2:24])=[N:21][N:22]=3)[N:19]=2)[S:11][N:10]=1
Reactant: Cc1cc(-c2ccc3nnc(CNC(=O)OC(C)(C)C)n3n2)sn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc3nnc(CN)n3n2)sn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 68.5 %

Procedure:
Trifluoroacetic acid (2889 μl, 37505 μmol) was added to a stirred suspension of tert-butyl (6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (464 mg, 1339 μmol) in DCM (10 mL) at RT. The reaction mixture was stirred at RT for 45 min. and then concentrated in vacuo. 2M NH3 in MeOH was added. Purification by MPLC (DCM/MeOH+1% NH4OH) afforded the title compound (226 mg, 69% yield). MS m/z=247.1 [M+H]+. Calc'd for C, 10; H, 10; N, 6; S: 246.30.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][S:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:31])=[O:30])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNS(=O)(=O)c1ccccc1
Yield: 61 %

Procedure:
Using the general method of Example 242, 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.53 g, 5.11 mmol) was reacted with benzenesulfonyl chloride (993 mg, 5,62 mmol) to provide 1.37 g of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}benzenesulfonamide as a white powder, m.p. 149-151° C. Analysis: Calculated for C22H25N5O3S: % C, 60.12; % H, 5.73; % N, 15.93; Found: % C, 60.40; % H, 5.82; % N, 15.85.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([CH2:10][CH3:11])[CH:3]=1.[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.[K].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:16]2[C:12](=[O:22])[C:13]3[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:15]2=[O:17])=[C:4]([CH2:10][CH3:11])[CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCc1cc(Br)ccc1CBr
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc(Br)ccc1CN1C(=O)c2ccccc2C1=O
Temperature: 80 °C

Procedure:
To 4-bromo-1-bromomethyl-2-ethyl-benzene (4.0 g, 14.2 mmol) in dimethylformamide (100 mL) at room temperature was added potassium phthalimide (2.9 g, 15.6 mmol), and the solution was heated at 80° C. for 5 h. The solution was cooled to room temperature and poured into water. The aqueous solution was extracted with ethyl acetate. The pooled organics were washed with saturated sodium chloride, dried (Na2SO4), filtered, and concentrated in vacuo to a yellow solid (4.0 g, 82%). 1H NMR (300 MHz, CDCl3): δ ppm 1.27 (t, J=7.54 Hz, 3H) 2.85 (q, J=7.60 Hz, 2H) 4.84 (s, 2H) 7.14-7.18 (m, 1H) 7.24-7.27 (m, 1H) 7.34 (d, J=2.07 Hz, 1H) 7.73 (dd, J=5.46, 3.01 Hz, 2H) 7.86 (dd, J=5.56, 3.11 Hz, 2H).
Reaction SMILES: [CH3:1][Li].[CH3:3][O:4][C:5]([CH3:17])([CH3:16])[CH2:6][CH2:7][CH:8]1[CH2:13][C:12]([CH3:14])=[CH:11][C:10](=[O:15])[CH2:9]1>O1CCCC1.C(OCC)C.[Cu]I>[CH3:3][O:4][C:5]([CH3:17])([CH3:16])[CH2:6][CH2:7][CH:8]1[CH2:13][C:12]([CH3:1])([CH3:14])[CH2:11][C:10](=[O:15])[CH2:9]1
Reactant: COC(C)(C)CCC1CC(=O)C=C(C)C1
Reactant: [Li]C
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(C)(C)CCC1CC(=O)CC(C)(C)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of copper(I) iodide (6.0 g, 0.032 mol) in tetrahydrofuran (120 mL) cooled to 0° C. was added a methyllithium solution (45 mL of a 1.4M solution in diethyl ether, 0.063 mol). After stirring 0.5 hour, 3-(3-methoxy-3-methylbutyl)-5-methylcyclohex-5-en-1-one (2.0 g, 0.0095 mL) in tetrahydrofuran (80 mL) was slowly added. After stirring 2.5 hours, the mixture was added to ice cold dilute hydrochloric acid. Subsequent workup yielded 3-(3-methoxy-3-methylbutyl)-5,5-dimethylcyclohexan-1-one, bp0.5 125°-130° C. (1.3 g); NMR (CDCl3)δ0.9(s,3H), 1.1(s,3H), 1.1(s,6H), 1.2-1.6(m,6H), 1.6-2.5(m,5H), 3.2(s,3H); IR(neat) 2960, 1715, 1365, 1085 cm-1. MS(m/e) 41, 55, 73, 138, 161, 211, 212.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][NH2:25]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:25][CH2:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH3:17])[N:3]=1
Reactant: COCCOCCCN
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: COCCOCCCNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-[3-(2-methoxyethoxy)propylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 3-(2-methoxyethoxy)propylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)(O)[CH3:13])[C:6]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:5]=3[C:4]=2[CH:3]=1.C(N(S(F)(F)[F:32])CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([F:32])([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[CH3:13])[C:6]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(C)(O)c2ccncc2)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(C)(F)c2ccncc2)C1
Temperature: 2.5 °C

Procedure:
1-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-4-yl)propan-2-ol (300 mg) was dissolved in DCM (10 mL) and the solution was cooled to 0 to 5° C. Diethylaminosulfur trifluoride (0.3 mL) was added and the reaction mixture was allowed to warm to RT for 30 min The reaction mixture was quenched with saturated aqueous sodium bicarbonate, the organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by HPLC.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[OH-].[Na+].[CH2:17]([O:20][C:21](Cl)=[O:22])[CH:18]=[CH2:19]>O.O1CCOCC1>[CH2:17]([O:20][C:21]([NH:1][C@@H:2]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[N:14])=[CH:11][CH:12]=1)[C:3]([OH:5])=[O:4])=[O:22])[CH:18]=[CH2:19]
Reactant: C=CCOC(=O)Cl
Reactant: N#Cc1ccc(C[C@H](N)C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C=CCOC(=O)N[C@@H](Cc1ccc(C#N)cc1)C(=O)O
Yield: 51.1 %

Procedure:
A suspension of 50 g (0.221 mol) of (S)-2-amino-3-(4-cyanophenyl)propionic acid in 150 ml of water was adjusted to pH=8 with 1N NaOH. 26.6 g (0.221 mol) of allylchloroformate in 225 ml of dioxane were slowly added at 0 to 5° C. (pH kept at 8 by addition of 1N NaOH). After completion of the reaction (thin layer chromatography (TLC) control) the mixture was extracted with DCM and the aqueous layer was acidified to pH=2 with KHSO4. The precipitate was dissolved in DCM, dried (Na2SO4), and evaporated. The residue was recrystallized from ether/petroleum benzene to give 31 g (51%) of the title compound. MS=275.1 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:15][CH2:16][CH:17]=[CH2:18]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]([CH2:4][CH2:3][CH:2]=[CH2:10])([CH2:15][CH2:16][CH:17]=[CH2:18])[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: C=CCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCC1(CCC=C)Cc2ccc(Br)cc2C1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 32.4 %

Procedure:
To a stirred solution of 6-bromo-1-indanone (0.5330 g, 2.52 mmol) in dry THF (10 mL) was added NaH (0.3380 g, 60% in a mineral oil, 8.45 mmol) at 0° C. under nitrogen. After being stirred for 10 min, 4-iodobut-1-ene (1.3450 g, 7.39 mmol) was added and then the mixture was stirred at ambient temperature for 20 h. The reaction mixture was cooled to 0° C., quenched with 1 N HCl, extracted with ethyl acetate, and dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/ethyl acetate to afford 0.1304 g of 6-bromo-2,2-di(but-3-en-1-yl)-2,3-dihydro-1H-inden-1-one. LC-MS tR=2.33 min in 3 min chromatography, m/z 319, 321 (MH1); 1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.67 (d, J=8 Hz, 1H), 7.33 (d, J=8 Hz, 1H), 5.76-5.66 (m, 2H), 4.94-4.87 (m, 4H), 2.98 (s, 2H), 1.98-1.63 (m, 8H); 13C NMR (100 MHz, CDCl3) δ 209.23, 151.43, 138.85, 137.85, 137.54, 127.94, 126.75, 121.55, 114.81, 52.87, 37.28, 36.58, 28.54.