Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][CH2:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[C:13]([NH2:22])[C:12]=2[N:11]=[C:10]1[CH2:23][CH2:24][CH2:25][CH3:26]>N1C=CC=CC=1>[NH2:22][C:13]1[C:12]2[N:11]=[C:10]([CH2:23][CH2:24][CH2:25][CH3:26])[N:9]([CH2:8][CH2:7][NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[C:21]=2[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCN
Solvent: c1ccncc1
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCNS(C)(=O)=O
Temperature: 25 °C
Yield: 28.7 %

Procedure:
Methanesulfonyl chloride (1.27 g, 11.1 mmol) was slowly added to a solution of 1-(2-aminoethyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (3.0 g, 10.6 mmol) in pyridine (60 mL). The reaction was maintained at ambient temperature overnight and then it was concentrated to dryness. The residue was combined with warm dichloroethane and water and then filtered to provide an off white solid. The dichloroethane layer was concentrated to provide an off white solid. The two solids were combined and then recrystallized from N,N-dimethylformamide to provide 1.1 g of N-[2-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]methanesulfonamide as a white solid, m.p. 210.0–211 .0° C. Analysis: Calculated for C17H23N5O2S: % C, 56.49; % H, 6.41; % N, 19.37. Found: % C, 56.45; % H, 6.49; % N, 19.50.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[F:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([CH3:17])[CH:11]=1.N1C=CN=C1>CN(C)C=O.CCOCC>[C:1]([Si:5]([O:16][C:13]1[CH:14]=[CH:15][C:10]([F:9])=[CH:11][C:12]=1[CH3:17])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(F)ccc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
t-Butyldimethylchlorosilane (14.34 g, 93.24 mmol) is combined with 4-fluoro-2-methylphenol (10.00 g, 77.70 mmol) and 1H-imidazole (13.32 g, 194.24 mmol) in dimethylformamide (100 mL) and stirred at room temperature overnight. The reaction is diluted with ether (200 mL) and washed with water (2×100 mL) and brine. The organic portion is dried with sodium sulfate, filtered, and concentrated to afford 18.9 g (100%) of the title compound. GC-ES m/z 240 [M]+, TR=4.06 min.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([N:10]1[CH:11]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[C:9]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])(=[O:21])[CH3:20]
Reactant: Cc1ccccc1-c1nc(-c2ccccc2)c[nH]1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)n1cc(-c2ccccc2)nc1-c1ccccc1C

Procedure:
0.702 g (0.003 mole) of the compound of Example 26 and 3 ml (0.00317 mole) of acetic anhydride were heated on an oil bath at 95° C. for 2 hours, then the excess of acetic anhydride was distilled under vacuum. The obtained residue was crystallized from tert-butylmethyl ether/light petroleum. Yield 0.69 g (83%) of the title compound M.p. 102°-4° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][CH:10]=2)[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]=1[C:22]([O:24][CH3:25])=[O:23].[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32](Cl)=[O:33])[CH:27]=1>>[CH3:25][O:24][C:22]([C:4]1[N:5]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:6]2[C:11]([C:12](=[O:13])[C:3]=1[CH2:2][NH:1][C:32]([C:28]1[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=1)=[O:33])=[CH:10][CH:9]=[C:8]([O:14][CH3:15])[CH:7]=2)=[O:23]
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(OC)cc2n1-c1ccccc1
Reactant: O=C(Cl)c1cccnc1
Product: COC(=O)c1c(CNC(=O)c2cccnc2)c(=O)c2ccc(OC)cc2n1-c1ccccc1

Procedure:
7-Methoxy-4-oxo-1-phenyl-3-{[(pyridine-3-carbonyl)-amino]-methyl}-1,4-dihydroquin-oline-2-carboxylic acid methyl ester was prepared starting from intermediate K and pyridine-3-carbonyl chloride. MS calcd. for C25H21N3O5 [(M+H)+] 444.2, obsd. 444.0.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([NH2:10])([CH3:9])([CH3:8])[CH3:7]>ClCCl>[C:6]([NH:10][S:2]([CH3:1])(=[O:4])=[O:3])([CH3:9])([CH3:8])[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)N
Solvent: ClCCl
Product: CC(C)(C)NS(C)(=O)=O
Reaction time: 0.08 h

Procedure:
To a solution of methanesulfonyl chloride (7.7 ml) in dichloromethane (100 ml) was added dropwise tert-butylamine (23.1 ml) at 0° C., and the mixture was stirred for 5 minutes. Subsequently, the mixture was filtered and the filtrate was washed with 1 N hydrochloric acid (100 ml), dried with magnesium sulfate, filtered and concentrated under reduced pressure. This gave the product (14.7 g) with a molecular weight of 151.3 g/mol (C5H13NO2S).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25])[CH3:21].O[C:29]1[CH:38]=[C:37]2[C:32]([C:33]([O:39][C:40]3[CH:41]=[C:42]4[C:46](=[CH:47][CH:48]=3)[NH:45][C:44]([CH3:49])=[CH:43]4)=[N:34][CH:35]=[N:36]2)=[CH:31][C:30]=1[O:50][CH3:51].N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[CH2:20]([N:22]([CH2:23][CH2:24][O:25][C:29]1[CH:38]=[C:37]2[C:32]([C:33]([O:39][C:40]3[CH:41]=[C:42]4[C:46](=[CH:47][CH:48]=3)[NH:45][C:44]([CH3:49])=[CH:43]4)=[N:34][CH:35]=[N:36]2)=[CH:31][C:30]=1[O:50][CH3:51])[CH2:26][CH3:27])[CH3:21]
Reactant: CCN(CC)CCO
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCN(CC)CCOc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
Triphenylphosphine (262 mg, 1 mmol) and N,N-diethylethanolamine (88 mg, 0.75 mmol) were added to a suspension of 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (160 mg, 0.5 mmol), (prepared as described in Example 49), in methylene chloride (5 ml), followed by the addition, in portions, of diethyl azodicarboxylate (165 μl, 1 mmol). After stirring for 1 hour at ambient temperature, the volatiles were removed under vacuum. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5) followed by methylene chloride/3M ammonia in methanol (90/10) to give 7-(2-(N,N-diethylamino)ethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (147 mg, 70%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1.CCOCC.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][O:9]1
Reactant: C1=COCCC1
Reactant: OCCCCCCCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: ClCCCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 15 h
Yield: 86.6 %

Procedure:
To a mixture of 15 g of 6-chlorohexanol, 100 ml of methylenechloride and 0.2 g of p-toluenesulphonic acid were added dropwise 12 g of dihydropyrane in 40 ml of methylenechloride. The reaction mixture was stirred for 15 h at room temperature and then distributed between ether and saturated sodium bicarbonate solution. The ether phase was washed with water, dried over sodium sulphate, filtered and concentrated to dryness. Chromatography of the residue on silica using hexane/ether (3:1) gave 21 g of the product as a colourless oil.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:38])=[C:23]([NH:25][C:26]([C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[N:34]=[CH:33][CH:32]=[CH:31]3)=[O:27])[CH:24]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH3:38])=[C:23]([NH:25][C:26]([C:28]3[CH:29]=[C:30]4[C:35](=[CH:36][CH:37]=3)[N:34]=[CH:33][CH:32]=[CH:31]4)=[O:27])[CH:24]=2)=[O:14])=[CH:11][CH:10]=1
Reactant: Cc1ccc(N)cc1NC(=O)c1ccc2ncccc2c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccc(Cl)cc2)cc1NC(=O)c1ccc2ncccc2c1
Yield: 49.5 %

Procedure:
Triethylamine (0.28 ml) was added to a stirred mixture of 4-chlorobenzoyl chloride (0.29 g), N-(5-amino-2-methylphenyl)quinoline-6-carboxamide (0.28 g) and methylene chloride (10 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The precipitate was isolated, washed with water and with methylene chloride. There was thus obtained the title compound as a solid (0.208 g); NMR Spectrum: (DMSOd6) 2.24 (s, 3H), 7.24 (d, 1H), 7.52-7.62 (m, 4H), 7.87 (s, 1H), 7.98 (d, 2H), 8.12 (d 1H) 8.46 (d, 1H), 8.52 (d, 1H), 8.65 (s, 1H) 9.00 (s, 1H), 10.15 (s, 1H) 10.31 (s, 1H); Mass Spectrum: M+H+ 416.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][N:13]=1)[C:5](N(OC)C)=[O:6].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[Cl:24].[Li]CCCC.[NH4+].[Cl-]>C1COCC1>[Cl:24][C:17]1[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:16]=1[CH2:15][C:5]([C:4]1[CH:11]=[CH:12][N:13]=[C:2]([Cl:1])[CH:3]=1)=[O:6]
Reactant: CON(C)C(=O)c1ccnc(Cl)c1
Reactant: COc1ccc(CBr)c(Cl)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)c2ccnc(Cl)c2)c(Cl)c1
Temperature: -72 °C
Reaction time: 0.25 h

Procedure:
2-Chloro-N-methoxy-N-methyl-isonicotinamide (24.6 g, 0.127 mol) and 1-bromomethyl-2-chloro-4-methoxy-benzene [CAS Reg. No. 54788-17-9] (34.7 g, 0.147 mol) were dissolved in THF (720 ml), cooled down to −72° C. and treated over a period of 1.3 h with 1.6 M n-BuLi in hexanes (157 ml, 0.251 mol) without exceeding −70° C. The reaction mixture was stirred at −72° C. for 15 min, warmed up to −20° C. (duration: 35 min) and treated with saturated aqueous NH4Cl (400 ml). After 5 min, the reaction mixture was extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous NH4Cl, dried over MgSO4, filtered off and concentrated in vacuo to yield an orange oil (46.5 g). The residue was purified by flash chromatography (600 g silica gel, ethyl acetate/heptane 1:1) to give the title compound as orange viscous oil (17.1 g). MS (m/e, neg. ion)=294.2 [M−H+].
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C1C(=O)N([Br:18])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:10][C:4]1[C:5]([O:8][CH3:9])=[N:6][CH:7]=[C:2]([I:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ncc(I)cc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ncc(I)cc1CBr
Reaction time: 3 h
Yield: 54.9 %

Procedure:
A solution containing 5-iodo-3-methyl-2-methoxy-pyridine (1.00 g, 4.00 mmol) and NBS (0.78 g, 4.40 mmol) in CCl4 (20 mL) is warmed to reflux. AIBN is added in 5 mg portions (0.03 mmol) every hour. After 3 h, the reaction mixture is cooled and then concentrated in vacuo. The residue is dissolved in EtOAc (150 mL) and washed successively with aqueous Na2S2O3 (100 mL), water (100 mL), brine then dried over anhydrous Na2SO4, filtered and concentrated. The crude product ispurified by silica gel flash column chromatography (hexane/diethyl ether, 19:1) to provide 0.72 g (55%) of the title compound as a white solid. 1H NMR (300 MHz, CDCl3) δ3.97 (s, 3H), 4.38 (s, 2H), 7.83 (d, J=2.2 Hz, 1H), 8.27 (d, J=2.2 Hz, 1H) ppm; MS (EI): m/z 327 (M+).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH3:10])[N:8]([CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:7](=[NH:18])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[F:26][C:27]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:28]=1[C:29](Cl)=[O:30]>C1COCC1>[C:1]([C:5]1[N:9]([CH3:10])[N:8]([CH2:11][CH:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)/[C:7](=[N:18]/[C:29](=[O:30])[C:28]2[CH:32]=[C:33]([C:36]([F:37])([F:38])[F:39])[CH:34]=[CH:35][C:27]=2[F:26])/[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Reactant: Cn1c(C(C)(C)C)cc(=N)n1CC1CCOCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2F)n1CC1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.4 %

Procedure:
To a solution of Example 95E (0.53 g, 2.1 mmol) and Et3N (0.88 mL, 6.3 mmol) in THF (10 mL) was added 2-fluoro-5-(trifluoromethyl)benzoyl chloride (0.320 mL, 2.108 mmol). The mixture was stirred at ambient temperature for 4 h then was quenched with saturated aqueous NaHCO3 (10 mL) and diluted with EtOAc (10 mL). The layers were separated and the aqueous phase was extracted EtOAc (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, 50% hexanes in EtOAc) afforded the title compound (0.48 g, 1.1 mmol, 52% yield). MS (DCI/NH3) m/z 442 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C@@H:14]([C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([C:64]2[CH:69]=[CH:68][C:67]([NH:70][C:71](=[O:94])[C@H:72]([CH2:81][CH2:82][NH:83][C:84]([O:86][CH2:87][C:88]3[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=3)=[O:85])[NH:73]C(OC(C)(C)C)=O)=[CH:66][CH:65]=2)[C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:40](=[O:63])[C@H:41]([CH2:50][CH2:51][NH:52][C:53]([O:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[O:54])[NH:42]C(OC(C)(C)C)=O)=[CH:35][CH:34]=2)=[CH:28][CH:27]=1)=[O:24])[NH:15]C(OC(C)(C)C)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:95].O1CCOCC1>O1CCCC1>[ClH:95].[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C@@H:14]([C:23]([NH:25][C:26]1[CH:27]=[CH:28][C:29]([CH:32]([C:64]2[CH:69]=[CH:68][C:67]([NH:70][C:71](=[O:94])[C@H:72]([CH2:81][CH2:82][NH:83][C:84]([O:86][CH2:87][C:88]3[CH:89]=[CH:90][CH:91]=[CH:92][CH:93]=3)=[O:85])[NH2:73])=[CH:66][CH:65]=2)[C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:40](=[O:63])[C@H:41]([CH2:50][CH2:51][NH:52][C:53]([O:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[O:54])[NH2:42])=[CH:35][CH:34]=2)=[CH:30][CH:31]=1)=[O:24])[NH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCNC(=O)OCc1ccccc1)C(=O)Nc1ccc(C(c2ccc(NC(=O)[C@H](CCNC(=O)OCc3ccccc3)NC(=O)OC(C)(C)C)cc2)c2ccc(NC(=O)[C@H](CCNC(=O)OCc3ccccc3)NC(=O)OC(C)(C)C)cc2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: N[C@@H](CCNC(=O)OCc1ccccc1)C(=O)Nc1ccc(C(c2ccc(NC(=O)[C@@H](N)CCNC(=O)OCc3ccccc3)cc2)c2ccc(NC(=O)[C@@H](N)CCNC(=O)OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The tris[4-(β-benzyloxycarbonylaminomethyl-N-t-butoxycarbonyl-L-alanyl)aminophenyl]methane (the total amount obtained in the previous reaction) was dissolved in tetrahydrofuran (4 mL), and a hydrochloric acid/dioxane solution (2 N, 4 mL) was added while cooling on ice. The mixture was raised to room temperature and stirred for 4 hours, and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([CH2:7]COC(=O)[O-])=[CH:3][CH:2]=1.[S].N1C2C(=CC=CC=2)C=CC=1.[O:25]1CCCC1>[Pd]>[CH3:13][C:1]1[CH:2]=[CH:3][C:4]([CH:7]=[O:25])=[CH:5][CH:6]=1
Reactant: C1CCOC1
Reactant: Cc1ccc(CCOC(=O)[O-])cc1
Agent: [Pd]
Agent: [S]
Solvent: c1ccc2ncccc2c1
Product: Cc1ccc(C=O)cc1
Yield: 88 %

Procedure:
To a solution containing 20.8 g (0.10 moles) of p-toluylethyl-carbonate in 300 ml of tetrahydrofuran there are added 10.4 g of Pd on BaSO4 10% and 0.1 cc of a solution of sulfur and quinoline 1:3000. Proceeding as in Example I, step (6), 10.5 g of p-methylbenzaldehyde (yield 88%) are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=3)[N:7]([CH2:20][CH2:21][CH2:22][C:23](OCC)=[O:24])[C:6]=2[C:5]([CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:4][CH:3]=1.[BH4-].[Li+].O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=3)[N:7]([CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[C:6]=2[C:5]([CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCn1c(Nc2cc(Cl)cc(Cl)c2)nc2c(Cl)ccc(C(CC)CC)c21
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3cc(Cl)cc(Cl)c3)n(CCCCO)c12
Temperature: 25 °C
Reaction time: 36 h
Yield: 93.8 %

Procedure:
To a solution of ethyl 4-[4-chloro-2-[(3,5-dichlorophenyl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (250 mg, 0.50 mmol) in tetrahydrofuran (5 mL) was added lithium borohydride (33 mg, 1.51 mmol) portionwise at 0° C. The mixture was warmed to room temperature and stirred for 36 hr. Water was added and the resulting precipitate was collected by filtration to afford the title compound (213 mg, 0.469 mmol, 94%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][C@@H:11]2[CH2:13][C@H:8]1[C:9](=[O:14])[S:10]2)=[O:6])[CH:2]=[CH2:3].[CH3:15][NH:16][CH3:17]>O1CCCC1>[CH3:15][N:16]([CH3:17])[C:9]([C@@H:8]1[CH2:13][C@H:11]([SH:10])[CH2:12][N:7]1[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])=[O:14]
Reactant: CNC
Reactant: C=CCOC(=O)N1C[C@@H]2C[C@H]1C(=O)S2
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@@H](S)C[C@H]1C(=O)N(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1S,4S)-5-allyloxycarbonyl-2-thia-5-azabicyclo[2.2.1]heptan-3-one (37.3 mg) in tetrahydrofuran (0.3 ml) was added an aqueous 40% dimethylamine solution (39.2 mg). The mixture was stirred for 2 hours at room temperature. After the reaction was over, the same post-treatment as in Example 5-(1) was conducted, thereby to give oily (2S,4S)-N,N-dimethyl-1-allyloxycarbonyl -4-mercapto-2-pirrolidinecarboxamide.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH2:6][NH:5][CH2:4]1.C(N(C(C)C)CC)(C)C.[Cl:22][C:23]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:24]=1[CH:25]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:22][C:23]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:24]=1[CH2:25][N:5]1[CH2:6][C@H:7]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[C@@H:3]([CH:2]=[O:1])[CH2:4]1
Reactant: OC[C@H]1CNC[C@@H]1c1ccsc1
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C[C@H]1CN(Cc2ccc(Cl)cc2Cl)C[C@@H]1c1ccsc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2.4 g (13.1 mmol) of 3-(R)-hydroxymethyl-4-(S)-(3-thienyl)pyrrolidine, 6.8 mL (39 mmol) of diisopropylethylamine, and 4.1 g (23.4 mmol) of 2,4-dichlorobenzaldehyde (Aldrich) in 60 mL of CH2Cl2 at rt was added 5.5 g (26 mmol) of sodium triacetoxyborohydride in several small portions and the reaction mixture was stirred at rt for 3 h. To the reaction was added 50 mL of sat'd NaHCO3 solution and the mixture was extracted with CH2Cl2. The combined organic fractions were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:acetone, 4:1) to give the title compound. Mass Spectrum (ESI) m/e=342 (M+1 35Cl, 35Cl), 344 (M+1 35Cl, 37Cl), and 346 (M+1 37Cl, 37Cl). 1H-NMR (CDCl3, 500 MHz): 7.38 (m, 2H), 7.30 (m, 1H), 7.23 (m, 1H), 7.03 (m, 2H), 3.65-3.77 (m, 3H), 3.34 (m, 1H), 3.21 (t, J=8.5 Hz, 1H), 2.82 (m, 2H), 2.70 (m, 1H), 2.52 (t, J=8 Hz, 1H), 2.38 (m, 1H). 13C-NMR (CDCl3, 125 MHz): 145.0, 134.7, 134.6, 133.3, 131.3, 129.3, 127.0, 126.9, 126.0, 119.8, 66.2, 61.7, 57.8, 56.1, 48.0, 41.7.). [α]D=+3.0 (c=1.75, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH2:10]([NH:12][CH2:13][CH3:14])[CH3:11].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:12]([CH2:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: CCNCC
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCN(CC)c1cc(Cl)nc(Cl)n1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2.0 g (10.90 mmols) of 2,4,6-trichloropyrimidine in 25 mL of anhydrous ethanol at 0° C., was added drop wise a solution 0.79 g (10.90 mmols) of diethylamine in 5 mL of ethanol. This was followed by the addition of 2.3 mL (16.35 mmols) of triethylamine and the mixture was stirred for further 30 min. The mixture was then concentrated and 25 mL of CH2Cl2 and 25 mL of water were added. The organic layer was separated and the aqueous layer was extracted by additional amount of dichloromethane (2×10 mL) and the extracts were combined, dried over anhydrous Na2SO4 and concentrated. Column chromatography on silica gel afforded 1.48 g (62%) of L as colorless solid.
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[CH3:21][C:22]1[C:23]([CH:31](O)[CH3:32])=[CH:24][C:25]2[O:29][CH2:28][O:27][C:26]=2[CH:30]=1>C1C=CC=CC=1>[CH3:21][C:22]1[C:23]([CH:31]([S:1][CH2:2][C:3]([OH:5])=[O:4])[CH3:32])=[CH:24][C:25]2[O:29][CH2:28][O:27][C:26]=2[CH:30]=1
Reactant: Cc1cc2c(cc1C(C)O)OCO2
Reactant: O=C(O)CS
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: c1ccccc1
Product: Cc1cc2c(cc1C(C)SCC(=O)O)OCO2
Yield: 93 %

Procedure:
3.7 g of mercaptoacetic acid and a catalytic amount of D-10-camphorsulfonic acid were added to 3.2 g of 1-(6-methyl-1,3-benzodioxol-5-yl)ethanol and the mixture was heated under reflux in 100 ml of benzene for 1 h. The reaction mixture was washed with water and then extracted with a 1 1Nsodium hydroxide solution. The aqueous layer was washed with ethyl acetate, acidified with 1Nhydrochloric acid and extracted with chloroform. The organic layer was dried over magnesium sulfate and the solvent was distilled off to obtain a crystalline residue. After recrystallization from diisopropyl ether, 4.2 g of the intended compound was obtained in the form of white crystals.
Reaction SMILES: [C:1]([N:9]1[C:13]2([CH2:18][CH2:17][CH:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[S:12][CH2:11][C@H:10]1[C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36]CC1C=CC=CC=1)=[O:35])=[O:30])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(OCC)(=O)C.Cl>C(O)C>[C:1]([N:9]1[C:13]2([CH2:14][CH2:15][CH:16]([O:19][C:20]3[CH:21]=[CH:22][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:24][CH:25]=3)[CH2:17][CH2:18]2)[S:12][CH2:11][C@H:10]1[C:29]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(OC2CCC3(CC2)SC[C@@H](C(=O)NCCC(=O)OCc2ccccc2)N3C(=O)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)c1ccc(OC2CCC3(CC2)SC[C@@H](C(=O)NCCC(=O)O)N3C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.9 %

Procedure:
In 8 ml of ethanol was dissolved 0.38 g of benzyl 3-({[(3R)-4-benzoyl-8-(4-isopropylphenoxy)-1-thia-4-azaspiro[4.5]decan-3-yl]carbonyl}amino)-propionate. Then, 1.90 ml of 1 mol/L aqueous solution of sodium hydroxide was added at 0-5° C., and the resulting mixture was stirred at ambient temperature for 4 hours. The reaction mixture was poured into a mixture of ice water and ethyl acetate, and the aqueous layer was separated. Ethyl acetate was added to the aqueous layer thus obtained, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer thus obtained was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Thus, 0.30 g of 3-({[(3R)-4-benzoyl-8-(4-isopropylphenoxy)-1-thia-4-azaspiro[4.5]-decan-3-yl]carbonyl}amino)-propionic acid was obtained as a colorless oily product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].Cl[C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:15][N:13]([CH3:14])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:3]=2)[NH:7][CH:6]=1
Reactant: CN(C)CCc1c[nH]c2ccc(N)cc12
Reactant: Clc1ncccn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(C)CCc1c[nH]c2ccc(Nc3ncccn3)cc12
Yield: 11 %

Procedure:
5-Amino-3-(2-dimethylaminoethyl)-1H-indole and 2-chloropyrimidine were used, Sodium acetate was used as base, acetic acid was used as solvent, and the reaction was heated at reflux for 12 hours. Column chromatography afforded the title compound (11%) as a yellow solid: 13C NMR (CD3OD) δ162.6, 159.2, 135.4, 132.2, 128.9, 124.0, 118.6, 113.7, 112.6, 112.4, 112.3, 61.3, 45.4, 24.3; HRMS calculated for C16H19N5 281.1642, found 281.1660. Anal. calcd for C16H19N5.0.5C2H4O2 [acetic acid]: C, 65.62; H, 6.80; N, 22.51. Found: C, 65.74; H, 6.68; N, 22.60.