Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:10]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([C:14]([F:17])=[CH:15][CH:16]=1)[C:12]#[N:13].Cl.CN(C)CCCN=C=NCC.C1C=NC2N(O)N=NC=2C=1.[C:47]([O:51][C:52]([NH:54][C@@H:55]([CH2:59][CH3:60])[C:56](O)=[O:57])=[O:53])([CH3:50])([CH3:49])[CH3:48]>C(Cl)Cl>[C:47]([O:51][C:52](=[O:53])[NH:54][C@H:55]([C:56](=[O:57])[NH:8][C:9]1[CH:16]=[CH:15][C:14]([F:17])=[C:11]([C:12]#[N:13])[C:10]=1[NH:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:59][CH3:60])([CH3:48])([CH3:49])[CH3:50]
Reactant: N#Cc1c(F)ccc(N)c1Nc1ccccc1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)c(C#N)c1Nc1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Triethylamine (0.55 mL, 3.96 mmol) was added to a stirred mixture of 3-amino-6-fluoro-2-phenylaminobenzonitrile (0.30 g, 1.32 mmol), (S)-(2-tert-butoxycarbonylamino)butyric acid (0.30 g, 1.45 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.28 g, 1.45 mmol) and HOAt (0.20 g, 1.45 mmol) in DCM at 0° C. under nitrogen. The resultant mixture was stirred at 0° C. for 5 minutes then 20° C. for 16 h. The reaction mixture was re-cooled to 0° C. and (S)-2-tert-butoxycarbonylaminobutyric acid (0.30 g, 1.45 mmol), N-(3-dimethylaminopropyl)-N′ ethylcarbodiimide hydrochloride (0.28 g, 1.45 mmol), HOAt (0.20 g, 1.45 mmol) and triethylamine (0.55 mL, 3.96 mmol) added sequentially, and the resultant mixture stirred at 20° C. for 24 h. The mixture was partitioned between saturated aqueous NaHCO3 (20 mL) and DCM (3×20 mL). The combined DCM extracts were washed with water, dried (Na2SO4) and concentrated in vacuo to give the title compound as an off white foam (0.64 g). LCMS (method H): Rt 2.93 min, [M+H]+ 413.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[C:4](Cl)=[O:5].[CH2:15]([NH2:17])[CH3:16]>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[C:4]([NH:17][CH2:15][CH3:16])=[O:5]
Reactant: CCN
Reactant: C[Si](C)(C)c1cccc(Br)c1C(=O)Cl
Product: CCNC(=O)c1c(Br)cccc1[Si](C)(C)C
Yield: 92 %

Procedure:
The compound of Example d (38.19 g, 0.13 mol) was reacted with 70% aqueous ethylamine (53 mL) according to General Method E1 and recrystallized from methylcyclohexane to afford the title compound as light tan crystals in 92% yield. m.p. 121°-122° C.
Reaction SMILES: COC1C=CC2CC3C(=O)C(C)(C=2C=1)CCCC3.Cl[CH2:20][CH2:21][CH2:22][CH2:23][C:24]1([CH3:37])[C:33]2[C:28](=[C:29]([O:34][CH3:35])[CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][C:25]1=[O:36]>>[CH3:35][O:34][C:29]1[C:28]2[CH2:27][CH:26]3[C:25](=[O:36])[C:24]([CH3:37])([C:33]=2[CH:32]=[CH:31][CH:30]=1)[CH2:23][CH2:22][CH2:21][CH2:20]3
Reactant: COc1cccc2c1CCC(=O)C2(C)CCCCCl
Agent: COc1ccc2c(c1)C1(C)CCCCC(C2)C1=O
Product: COc1cccc2c1CC1CCCCC2(C)C1=O

Procedure:
Using a procedure analogous to that described in Example X for the preparation of 6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-one, there is obtained from 40.5 g. of 1-(4-chlorobutyl)-1-methyl-5-methoxy-2-tetralone, 21.5 g. of the title product, b.p. 130° to 135° C. (0.3 mm.).
Reaction SMILES: Br[C:2]1[N:19]([CH2:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]2)[C:5]2[C:6]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=3)=[N:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[N:3]=1.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:18][C:16]1[CH:17]=[C:12]([C:6]2[C:5]3[N:19]([CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]4)[C:2]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[N:3][C:4]=3[CH:9]=[C:8]([C:10]#[N:11])[N:7]=2)[CH:13]=[N:14][CH:15]=1
Reactant: Nc1ccccn1
Reactant: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C[C@H]1CC[C@H](Cn2c(Nc3ccccn3)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 100 °C

Procedure:
To a solution of 2-bromo-4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Preparative Example 3.1) (0.5 g, 1.128 mmol) in toluene (5 mL) in a pyrex tube, 2-aminopyridine (0.127 g, 1.35 mmol), and BINAP (35 mg, 0.056 mmol) were added, and the reaction mixture was degassed with argon for 5 minutes. Pd2(dba)3 (51 mg, 0.056 mmol) and potassium tert-butoxide (0.189 g, 1.69 mmol) were added, and the tube was capped and heated to 100° C. for 17 h. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure, The residue was dissolved in ethyl acetate (20 mL), washed with water (5 mL) and brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on a silica gel column using 40% ethyl acetate/petroleum ether as eluent to give 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(pyridin-2-ylamino)-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ES/APCl calc'd. for C25H24ClN7 [M+H]+ 458. found 458.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[Br-:21].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)C>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:5]([Br:21])=[CH:4][N:3]=1
Reactant: Nc1nccnc1Cc1ccccc1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: Nc1ncc(Br)nc1Cc1ccccc1
Yield: 89 %

Procedure:
To a solution of 3-benzyl-2-aminopyrazine 12 (1.38 g, 7.40 mmol) in chloroform (40 mL), pyridine (1.80 mL, 22.00 mmol) and tetrabutylamoniumtribromide TBATB (3.57 g, 7.40 mmol) were added at room temperature. After 1 h the reaction mixture was washed with 20% aqueous solution of NaCl, the organic layer was then dried over Na2SO4, filtered and the solvent removed under reduced pressure. The crude was purified by flash chromatography (EtOAc-dichloromethane, 80:20) to get 1.75 g (89% yield) of the title compound 13 as a pale brown solid and subsequent recrystallization (n-exane/diethyl ether) gave colorless crystals suitable for crystallographic studies. 1H-NMR (CDCl3): 3.97 (s, 2H), 4.74 (br s, 2H), 7.10-7.24 (m, 5H), 7.89 (s, 1H). MS (ESI): m/z 265 (M+H). The crystallography of compound 13 is shown in FIG. 3, demonstrating its purity.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][C@H:11]([C@@H:15]([OH:27])[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[O:17])[C:10]2=[O:28])[CH:5]=[CH:6][C:7]=1[CH3:8].C(N(CC)CC)C.[C:36]([O:39][CH2:40][C:41](Cl)=[O:42])(=[O:38])[CH3:37].CCOC(C)=O>C(Cl)Cl.O>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16](=[O:17])[C@@H:15]([C@H:11]2[O:12][CH2:13][CH2:14][N:9]([C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH:3]=3)[NH:1][C:41](=[O:42])[CH2:40][O:39][C:36](=[O:38])[CH3:37])[C:10]2=[O:28])[OH:27])=[CH:20][CH:21]=1)#[N:26]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1ccc(N2CCO[C@H]([C@@H](O)C(=O)Nc3ccc(C#N)cc3)C2=O)cc1N
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)OCC(=O)Nc1cc(N2CCO[C@H]([C@@H](O)C(=O)Nc3ccc(C#N)cc3)C2=O)ccc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of compound 9-5 (16.5 mg) in CH2Cl2 (1 mL), were added triethylamine (6.7 microL) and acetoxyacetyl chloride (5.1 microL) at 0° C. The reaction mixture was stirred at room temperature for 30 minutes. Then EtOAc and water were added into the mixture and it was extracted with EtOAc. The organic layer was washed with H2O, 1N HCl, sat. NaHCO3 aq. and brine, respectively and dried with anhydr. Na2SO4. The solvent was removed under reduced pressure to obtain compound 9-6 (20 mg) as a pale yellow amorphous solid.
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH:35]([O:38][CH3:39])[O:36][CH3:37])[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1)=[CH:18][C:17]=2[OH:34])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.[CH3:53][O:54][CH2:55][CH:56](O)[CH3:57].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH2:1]([S:8][CH:9]([CH:35]([O:38][CH3:39])[O:36][CH3:37])[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][CH:25]=1)=[CH:18][C:17]=2[O:34][CH:56]([CH3:57])[CH2:55][O:54][CH3:53])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCC(C)O
Reactant: COC(OC)C(CNC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(O)c2[nH]1)SCc1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COCC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(=O)NCC(SCc3ccccc3)C(OC)OC)[nH]c12
Temperature: 50 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
To a stirred solution of N-[2-(benzylsulfanyl)-3,3-dimethoxypropyl]-7-hydroxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxamide (1.73 g), tributylphosphine (1.4 mL) and 1-methoxypropan-2-ol (0.59 mL) in tetrahydrofuran (50 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.53 g) at room temperature under argon atmosphere. The whole mixture was stirred at 50° C. for 4 h, and tributylphosphine (1.4 mL), and 1-methoxypropan-2-ol (0.59 mL) and 1,1′-(azodicarbonyl)dipiperidine (1.53 g) were added thereto. After stirred at 50° C. for 3 h, the reaction mixture was concentrated in vacuo. The residue was diluted with diethyl ether and the insoluble materials were removed by filtration and washed with diethyl ether. The combined filtrate and washings were concentrated in vacuo and the residue was purified by silica gel chromatography (ethyl acetate:hexane=35:65 to 60:40) to give a light yellow oil. The oil was partitioned between ethyl acetate and water. The organic layer was washed with successively water and brine, dried (MgSO4), filtered, and concentrated to give a yellow oil, which was purified by silica gel chromatography (ethyl acetate:hexane=35:65 to 70:30, volume ratio) to give the title compound (1.6 g, 82%) as a pale yellow oil. MS 641 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([CH3:22])[C:19]([C:23](OC)=[O:24])=[C:18]([NH:27][C:28]2[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=2)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Se](=O)=O.[CH3:38][O:39][C:40]1[CH:45]=[C:44]([O:46][CH3:47])[CH:43]=[CH:42][C:41]=1[CH2:48][NH2:49].C([BH3-])#N.[Na+]>O1CCOCC1.CO>[CH3:38][O:39][C:40]1[CH:45]=[C:44]([O:46][CH3:47])[CH:43]=[CH:42][C:41]=1[CH2:48][N:49]1[C:23](=[O:24])[C:19]2[C:18]([NH:27][C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)=[N:17][C:16]([NH:15][C@@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]3[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[N:21][C:20]=2[CH2:22]1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: COC(=O)c1c(C)nc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cccc(C)c1
Agent: O=[Se]=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(CN2Cc3nc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(Nc4cccc(C)c4)c3C2=O)c(OC)c1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 36.9 %

Procedure:
A mixture of methyl 2-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-methyl-6-(m-tolylamino)pyrimidine-5-carboxylate (500 mg, 1.065 mmol) and selenium dioxide (236 mg, 2.130 mmol) in dioxane (10 mL) was heated at 100° C. for 24 h. The solution was subsequently cooled and filtered. The filtrate was concentrated under reduced pressure and dried to give a brown foam (534 mg; dihydroxyl form was observed via mass spectroscopy), which was used directly in the next step without further purification. A mixture of the unpurified intermediate (534 mg, 1.065 mmol) and (2,4-dimethoxyphenyl)methanamine (0.160 mL, 1.065 mmol) in MeOH (10 mL) was stirred at RT for 10 min, after which sodium cyanoborohydride (100 mg, 1.597 mmol) was added, and the reaction mixture was stirred at RT for 20 h. The reaction mixture was warmed to 50° C. and stirred for an additional 2 h to complete the reaction. The mixture was cooled to RT and the solid filtered and washed with MeOH to give the title compound as a pinkish solid (237 mg, 37%). [M+H] calc'd for C33H42N6O5, 603. found, 603.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24](O)(=[O:35])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@@:9]([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)([O:23][C:24](=[O:35])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: CCCCCCCCCCC(=O)O
Product: CCCCCCCCCCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and undecanoic acid to yield (3aR,4S,7aR)-4-m-tolylethynyl-4-undecanoyloxy-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H]=296 (ester elimination ion); RT=1.77 min; UPLC Method I
Reaction SMILES: [N:1]1([CH2:9][C:10]([O:12]C(=O)C2C=CC=CC=2)=[O:11])[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3].[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1>[C:21]([NH:6][C:5]1[CH:7]=[CH:8][N:1]([CH2:9][C:10]([OH:12])=[O:11])[C:2](=[O:3])[N:4]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccn(CC(=O)OC(=O)c2ccccc2)c(=O)n1
Solvent: c1ccncc1
Product: O=C(O)Cn1ccc(NC(=O)c2ccccc2)nc1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1) (10 g, 38 mmol) in 10 mL pyridine was added 6.6 g (47 mmol) of benzoyl chloride and stirred overnight at room temperature. The solution was evaporated under reduced pressure. The residue was dissolved in 1 M KOH and stirred for 3 h after which the Ph was adjusted to 2 with conc. HCl. The target compound (2) precipitated out. Yield: 9.3 g (90%). 1H NMR (d6-DMSO): δ 4.59 (s, 2 H, CH2O), 7.31 (d, 1 H, H5), 7.5-8.2 (7 H, aromatic, NH, H6). MS (FAB) m/z 273 (M+H)+ (calcd 273).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]([NH2:23])=O)[NH:6]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>O1CCCC1>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21](=[S:33])[NH2:23])[NH:6]2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(N)=O)cc12
Solvent: C1CCOC1
Product: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(N)=S)cc12
Temperature: 60 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
A mixture of 4-methyl-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (1.78 g), Lawesson's reagent (2.26 g) and tetrahydrofuran (120 ml) was stirred at 60° C. for 2 hr. The reaction solution was concentrated under reduced pressure, and the obtained oil was crystallized from dichloromethane-toluene to give the title compound (1.56 g, yield 84%) as pale-yellow crystals. MS: 366(MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13](OC)=[O:14])[CH2:11][C@H:10]([NH:17][C:18]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][C:19]=2[C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=2)=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[Li+].[BH4-].[Na+]>O1CCCC1.C(O)C>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][OH:14])[CH2:11][C@H:10]([NH:17][C:18]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][C:19]=2[C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=2)=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1C[C@H](Nc2ccc([N+](=O)[O-])cc2C(=O)NCc2ccc(OC)c(OC)c2)CN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2N[C@H]2C[C@@H](CO)N(C(=O)OC(C)(C)C)C2)cc1OC
Reaction time: 24 h
Yield: 85.4 %

Procedure:
To a solution of 2-[(3S, 5S)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)pyrrolidin-3-ylamino]-N-(3,4-dimethoxylbenzyl)-5-nitrobenzamide (492 mg) in tetrahydrofuran (5 mL) was added lithium chloride (75 mg), and then a solution of sodium borohydride (67 mg) in ethanol (10 mL) at ambient temperature. After stirring for one day, the mixture was evaporated and the residue was partitioned between ethyl acetate and 10% citric acid aqueous solution. The organic layer was separated, washed with water and brine and dried over magnesium sulfate. The residue was subjected to a silica gel column chromatography eluting with a mixture of ethyl acetate and hexane (1:1 to 2:1) to give 2-[(3S,5S)-1-(tert-butoxycarbonyl)-5-(hydroxymethyl)pyrrolidin-3-ylamino]-N-(3,4-dimethoxylbenzyl)-5-nitrobenzamide (399 mg) as pale yellow foams.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:33]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:26]=[C:25](Cl)[C:24]=2[N:23]=[CH:22]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>>[CH2:1]([NH:8][C:25]1[C:24]2[N:23]=[CH:22][N:21]([CH2:20][CH2:19][CH2:18][CH2:17][NH:16][C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[C:33]=2[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCCCn1cnc2c(Cl)nc3ccccc3c21
Reactant: NCc1ccccc1
Product: CC(C)(C)OC(=O)NCCCCn1cnc2c(NCc3ccccc3)nc3ccccc3c21
Temperature: 150 °C
Reaction time: 3 h

Procedure:
2 ml of benzylamine was added to 70 mg (0.187 mmol) of 1-[4-(tert-butoxycarbonylamino)butyl]-4-chloro-1H-imidazo-[4,5-c]quinoline. The resulting mixture was heated at 150° C. and stirred for 3 hours. An excess amount of benzylamine was distilled off under reduced pressure and 1N hydrochloric acid and brine were added thereto. The resulting solution was extracted twice with methylene chloride. The organic phase was washed with a saturated sodium hydrogencarbonate aqueous solution and dried (Na2SO4). The solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=150:1 (v/v)) to obtain 79 mg (0.177 mmol) of 4-benzylamino-1-[4-(tert-butoxycarbonylamino)butyl]-1H-imidazo[4,5-c]quinoline shown below as white powder (mp: 151 to 153.5° C.). ##STR46## Its spectroscopic data are as follows: IR (KBr) cm-1 : 3380, 3310, 2930, 1680, 1595, 1540, 1245, 1160.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].Br[CH2:19][CH2:20][CH2:21][C:22]([O:24]CC)=[O:23].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>O.O1CCCC1.Cl>[C:4]([C:3]1[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:2]=1[O:1][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])(=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)CCCBr
Reactant: COc1ccc(C(=O)c2ccccc2)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2ccccc2)c(OCCCC(=O)O)c1
Reaction time: 20 h

Procedure:
A 100 mL mini-block tube equipped with a magnetic stir bar was charged with 4.56 g (20.0 mmol) of 2-hydroxy-4-methoxybenzophenone, 2.70 mL (3.68 g, 18.9 mmol) of ethyl 4-bromobutyrate and 40 mL of dimethylformainide (DMF). Potassium carbonate (2.96 g, 21.4 mmol) was added to the clear solution. The reaction mixture was heated to 80 C. After stirring for 20 hr at 25 C, the clear reaction mixture was diluted with water. The resulting solid was isolated by filtration. This solid was taken up in 30 mL of tetrahydrofuran (THF) and treated with 3.10 g (24.0 mmol) of potassium trimethylsilanoate. The orange solution was stirred for 20 hr at 25 C, diluted with aqueous 4% hydrochloric acid to pH 7.5 and washed with MTBE. The organic phase was extracted with aqueous 3% sodium bicarbonate solution. The combined aqueous phases were acidified to pH 2 with aqueous 4% hydrochloric acid and extracted with 60 mL of MTBE. This organic phase was washed with brine (1×40 mL), dried over sodium sulfate and concentrated. The resulting solid was purified by trituration using MTBE/hexanes. More of the product was isolated from the mother liquor. LC-MS analysis: m+1 peak confirmed (315). 1H NMR Analysis: (d6-DMSO): δ 12.0, bs, 1H (COOH); δ 7.6, d, 2H, (phenyl H's, o to CO); δ 7.56, t, 1H (phenyl H, p to CO); δ 7.44, t, 2H (phenyl H's, m to CO); δ 7.35, d, 1H (aryl H, o to CO); δ 6.64, m, 2H (aryl H's, m to CO); δ 3.88, t, 2H, (CH2 α to O); δ 3.82, s, 3H, (CH3O); δ 1.84, t, 2H (CH2 α to COOH); δ1.53, p, 2H (middle CH2 in chain). 13C NMR (d6-DMSO): 195.08, 173.91, 163.17, 158.33, 138.84, 132.37, 131.37, 128.67, 128.24, 120.87, 105.87, 99.02, 66.89, 55.53, 29.45, 23.79.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH:13]=O)=[CH:11][N:10]=[C:9]([S:15][CH3:16])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([CH2:19][C:20](O)=[O:21])#N.C(N)C1C=CC=CC=1>C(O)(=O)C>[CH:1]1([N:6]2[C:7]3[N:8]=[C:9]([S:15][CH3:16])[N:10]=[CH:11][C:12]=3[CH:13]=[CH:19][C:20]2=[O:21])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSc1ncc(C=O)c(NC2CCCC2)n1
Reactant: N#CCC(=O)O
Solvent: CC(=O)O
Solvent: NCc1ccccc1
Product: CSc1ncc2ccc(=O)n(C3CCCC3)c2n1
Temperature: 25 °C

Procedure:
A mixture of 4-cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (9), (1 g, 4.2 mmol), 1.2 equivalent of cyanoacetic acid, and a catalytic amount of benzylamine was taken into acetic acid and refluxed for about 6 h. After completion of the reaction by TLC, the reaction mixture was cooled to room temperature and product precipitated from the reaction mixture. Additional product was precipitated from the reaction mixture via the addition of hexane. The resultant solid was collected, washed with saturated NaHCO3, water, and subsequently dried under vacuum. The resultant crude product (10) was recrystallized in 2-propanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[CH2:13][C:14]([O:16][CH3:17])=[O:15].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Br:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1.Cl>C1COCC1.CN1C(=O)N(C)CCC1>[Br:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[C:6]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:7]2[CH3:12])=[CH:31][CH:30]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: COC(=O)Cc1c(C)[nH]c2ccc(OC)cc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)Cc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Temperature: 0 °C
Yield: 48 %

Procedure:
To a solution of ester from Step 1 (13.8 g, 59 mmol) in THF (300 mL) and DMPU (40 mL) at -78° C. was added KHMDS solution (0.64M/toluene, 95 mL, 60 mmol). The reaction mixture was warmed to 0° C. and was then recooled to -78° C., at which point a solution of 4-bromobenzyl bromide (17.0 g, 68 mmol) in THF (80 mL) was added via double-tipped needle. The reaction was allowed to warm to r.t., and was then poured into 1M HCl (500 mL). The product was extracted with Et2O and the organic phase was washed with H2O and brine. After drying (MgSO4), filtration, and removal of solvent, the crude product was purified by flash chromatography (1:20 EtOAc/toluene). The resulting prodeuct was recrystallized from CH2Cl2 /hexane to give 11.4 g of the title compound.