Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][NH:4][C:5](=[NH:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CO[C:16](=O)[CH:17]([NH:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([N:38]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[NH:40][C:39]2=[O:48])[CH2:34][CH2:33]1)=[O:31])[CH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[C:26]([CH3:28])[CH:27]=1)[NH:24][N:23]=[CH:22]2>O1CCCC1>[CH2:6]([C:5]1[N:13]=[C:16]([CH:17]([NH:29][C:30]([N:32]2[CH2:33][CH2:34][CH:35]([N:38]3[CH2:47][C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[NH:40][C:39]3=[O:48])[CH2:36][CH2:37]2)=[O:31])[CH2:18][C:19]2[CH:20]=[C:21]3[C:25](=[C:26]([CH3:28])[CH:27]=2)[NH:24][N:23]=[CH:22]3)[O:3][N:4]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)C(Cc1cc(C)c2[nH]ncc2c1)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Reactant: N=C(Cc1ccccc1)NO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2nc(Cc3ccccc3)no2)cc2cn[nH]c12
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (8 mg, 0.366 mmol) was added to a solution of N-hydroxy-2-phenyl-acetamidine (50 mg, 0.366 mmol) in tetrahydrofuran (15 mL). The solution was stirred at 60° C. for 15 min. A solution of (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid methyl ester (60 mg, 0.122 mmol) in tetrahydrofuran (5 mL) was added. The reaction mixture was stirred at 60° C. for 18 h. The reaction was then cooled to room temperature and the solvent removed under reduced pressure. The residue was dissolved with methylene chloride and partitioned with water and extracted with methylene chloride (3×50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduce pressure. Purification was carried out by preparative HPLC. LC/MS: tR=1.79 min, 591 (MH)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:34][C:35]1[CH:36]=[N:37][C:38]([S:44][CH2:45][CH2:46][S:47]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)(=[O:49])=[O:48])=[C:39]([CH:43]=1)[C:40]([OH:42])=O.[S:56]1[CH:60]=[CH:59][CH:58]=[C:57]1[CH2:61][NH2:62]>CN(C=O)C.CC(=O)OCC.CCCCCC.CC(=O)OCC>[C:50]1([S:47]([CH2:46][CH2:45][S:44][C:38]2[N:37]=[CH:36][C:35]([CH3:34])=[CH:43][C:39]=2[C:40]([NH:62][CH2:61][C:57]2[S:56][CH:60]=[CH:59][CH:58]=2)=[O:42])(=[O:49])=[O:48])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: NCc1cccs1
Reactant: Cc1cnc(SCCS(=O)(=O)c2ccccc2)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cnc(SCCS(=O)(=O)c2ccccc2)c(C(=O)NCc2cccs2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
456 mg (1.2 mmol) of HATU and 680 μl (4.0 mmol) of DIPEA were added at 0° C. to a solution of 337 mg (1.0 mmol) of 5-methyl-2-(2-(phenylsulfonyl)ethylthio)nicotinic acid in DMF (3 ml). After stirring for a further 15 min at 0° C., 113 mg (1.0 mmol) of thiophen-2-ylmethylamine were added and stirring was carried out for 16 hours at RT. The mixture was then diluted with EA and washed in succession with sat. aq. citric acid solution, saturated aqueous Na2CO3 solution and brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. CC (hexane/EA 7:3) of the residue yielded 418 mg (0.97 mmol, 97%) of 2-[2-(benzenesulfonyl)ethylthio]-5-methyl-N-(2-thienylmethyl)-nicotinamide. MS: m/z 433.1 [M+H]+
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C@@H:11]([OH:21])[C@H:12]([NH:19][CH3:20])[CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:9]=[CH:10][C:2]1=2.CCN(C(C)C)C(C)C.[C:31](Cl)(=[O:40])[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1.CCOC(C)=O>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C@@H:11]([OH:21])[C@H:12]([N:19]([CH3:20])[C:31](=[O:40])[CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:13][N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)[CH:9]=[CH:10][C:2]1=2
Reactant: CN[C@H](CN1CCCC1)[C@H](O)c1ccc2c(c1)OCCO2
Reactant: O=C(Cl)CCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C(=O)CCc1ccccc1)[C@H](CN1CCCC1)[C@H](O)c1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
To a 0° C. solution of compound 5 (0.2 g, 0.72 mmol) in THF (4 mL) was added Hunig's Base (0.09 g, 0.72 mmol) followed by hydrocinnamoyl chloride (0.12 g, 0.72 mmol) dropwise. The resulting mixture was allowed to stir overnight at room temperature, diluted with EtOAc and washed with satd. aq. NaHCO3, satd. aq. NaCl and dried over MgSO4. Purification by flash silica chromatography (MeOH/CH2Cl2) gave a yellow oil (0.12 g, 0.29 mmol, 41% yield). HPLC purity 98.4% (tR=5.02 min). NMR (500 MHz, CDCl3) δ 7.2 (s, 1H), 7.1-7.2 (m, 4H), 6.8-6.9 (m, 3H), 4.8 (s, 1H), 4.3 (s, 4H), 2.9 (s, 3H), 2.8-3.2 (m, 4H), 2.5-2.6 (m, 2H), 1.8-2.1 (m, 2H), 1.5-1.8 (m, 4H). ESI-MS m/z 425.1 (M+H+).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C@@H:12]3[O:34][C@H:33]([CH2:35][O:36]C(=O)C4C=CC=CC=4)[C@@H:23]([O:24]C(=O)C4C=CC=CC=4)[C@@:13]3([CH3:45])[O:14]C(=O)C3C=CC=CC=3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:46]>O1CCOCC1>[NH2:46][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C@@H:12]3[O:34][C@H:33]([CH2:35][OH:36])[C@@H:23]([OH:24])[C@@:13]3([CH3:45])[OH:14])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: N
Reactant: C[C@@]1(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1cc(I)c2c(Cl)ncnc21
Solvent: C1COCCO1
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc(I)c2c(N)ncnc21
Temperature: 120 °C
Reaction time: 10 h
Yield: 69 %

Procedure:
A mixture of compound 10 from Step 1 (200 mg, 0.27 mmol) and aq ammonia (25% w/w, 3 ml) in dioxane (3 ml) was stirred in a sealed tube at 120° C. for 10 h. After cooling the volatiles were evaporated and crude product was purified by chromatography on silica (CHCl3→CHCl3MeOH, 8:2) and then re-purified by reverse phase chromatography (0→100% MeOH in water) to afford title compound 6 as white solid (76 mg, 69%). Compound was recrystallized from MeOH/MeCN. Mp 207° C. [α]20D −39.0 (c 0.274, MeOH). 1H NMR (600 MHz, DMSO-d6): 0.67 (s, 3H, CH3); 3.65 (ddd, 1H, Jgem=12.1, J5′b,OH=4.8, J5′b,4′=2.7, H-5′b); 3.81 (ddd, 1H, Jgem=12.1, J5′a,OH=4.8, J5′a,4′=2.0, H-5′a); 3.79 (ddd, 1H, J4′,3′=9.1, J4,5=2.7, 2.0, H-4′); 3.93 (bd, 1H, J3′,4′=9.1, H-3′); 5.14 (s, 1H, OH-2′); 5.16 (bs, 1H, OH-3′); 5.22 (t, 1H, JOH,5′=4.8, OH-5′); 6.10 (s, 1H, H-1′); 6.67 (bs, 2H, NH2); 7.82 (s, 1H, H-6); 8.10 (s, 1H, H-2). 13C NMR (151 MHz, DMSO-d6): 19.89 (CH3); 51.68 (C-5); 59.46 (CH2-5′); 71.76 (CH-3′); 78.87 (C-2′); 82.39 (CH-4′); 90.71 (CH-1′); 103.11 (C-4a); 126.81 (CH-6); 149.88 (C-7a); 152.23 (CH-2); 157.43 (C-4). IR (Mk): 3474, 3429, 3392, 3366, 1631, 1582, 1553, 1504, 1440, 1343, 1295, 1147, 1128, 1070, 1045, 789. MS (FAB): m/z 407 (M+H). HRMS (FAB) for C12H16H4O4 [M+H] calcd: 407.0216. found: 407.0225. Anal. Calcd for C12H15IN4O4: C, 35.48; H, 3.72; N, 13.79. Found: C, 35.37; H, 3.72; N, 13.39.
Reaction SMILES: [N:1]([CH3:4])=[C:2]=[S:3].[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]=[C:14]2[NH:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][NH:31][C:32]3[S:33][CH:34]=[CH:35][N:36]=3)[CH2:25][CH2:24]2)=[CH:8][CH:7]=1>O1CCCC1>[F:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]=[C:14]2[NH:22][CH:23]2[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][N:31]([C:32]3[S:33][CH:34]=[CH:35][N:36]=3)[C:2]([NH:1][CH3:4])=[S:3])[CH2:27][CH2:28]2)=[CH:10][CH:11]=1
Reactant: CN=C=S
Reactant: Fc1ccc(Cn2c(NC3CCN(CCNc4nccs4)CC3)nc3ccccc32)cc1
Solvent: C1CCOC1
Product: CNC(=S)N(CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1)c1nccs1
Yield: 44.5 %

Procedure:
A mixture of 1.1 parts of isothiocyanatomethane, 6.76 parts of 1-[(4-fluorophenyl)methyl]-N-[1-[2-[2-thiazolylamino]ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine and 90 parts of tetrahydrofuran was stirred and refluxed for one week. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from methanol, yielding 3.5 parts (44.5%) of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-N'-methyl-N-(2-thiazolyl)thiourea; mp. 188.5° C. (compound 104).
Reaction SMILES: N.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[N:10]=[CH:9][N:8](COC(=O)C(C)(C)C)[C:7]2=[O:30]>C(O)C.C(Cl)Cl>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[N:10]=[CH:9][NH:8][C:7]2=[O:30]
Reactant: COCCOCCOc1cc2ncn(COC(=O)C(C)(C)C)c(=O)c2cc1OC
Agent: N
Solvent: CCO
Solvent: ClCCl
Product: COCCOCCOc1cc2nc[nH]c(=O)c2cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.2 %

Procedure:
Saturated methanolic ammonia (20 ml) was added to a solution of 6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (2.26 g, 5.5 mmol) in a mixture of ethanol (40 ml) and methylene chloride (15 ml). The mixture was stirred for 24 hours at ambient temperature, and further methanolic ammonia (20 ml) was added. The mixture was stirred for a further 24 hours at ambient temperature and the volatiles were removed by evaporation. The residue was triturated with ether, collected by filtration, dried under vacuum to give 6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-3,4-dihydroquinazolin-4-one (975 mg, 78%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:11][C:10]2[C:9](=O)[NH:8][C:7]([NH2:13])=[N:6][C:5]=2[N:4]=1.P(Cl)(Cl)([Cl:18])=O>>[NH2:13][C:7]1[N:6]=[C:5]2[C:10]([NH:11][C:3]([C:2]([F:15])([F:14])[F:1])=[N:4]2)=[C:9]([Cl:18])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc2nc(C(F)(F)F)[nH]c2c(=O)[nH]1
Product: Nc1nc(Cl)c2[nH]c(C(F)(F)F)nc2n1

Procedure:
A suspension of 8-trifluoromethylguanine (Pfleiderer and Shanshal, Liebigs Ann. Chem., 726, 201-215 (1969)) (2.0 g, 9.1 mmol) in phosphorous oxychloride (20 mL) was refluxed for 3 h. Excess phosphorous oxychloride was evaporated under reduced pressure. The resulting residue was mixed with ice-water (100 g), and the pH was adjusted to 3-4 with a concentrated aqueous NaOH solution. The resulting solution was mixed with MeOH (100 mL) and approximately half (i.e., 100 mL) of the aqueous methanol solution was loaded on a 3×80 cm Sephadex LH-20 column eluted with methanol/water (1:1) at 1 mL/min. Column eluent was continuously monitored at 280 nm and fractions (10 mL) were collected. The remainder of the reaction mixture in MeOH/H2O was chromatographed separately under identical conditions. The desired product eluted in fractions 73-85. Evaporation of solvent from the pooled fractions 73-85 from both chromatographic runs afforded analytically pure 2-amino-6-chloro-8-trifluoromethylpurine: yield, 0.94 g (43%); mp >225° C. dec.; UV (pH 1) λmax 245 nm (ε=0.501×104), 314 (0.746×104); (pH 6.9) 270 (0.265×104), 315 (0.612×104); (pH 13) 272 (0.269×104), 314 (0.612×104); 1H NMR δ 7.19 (s, 2H, NH2, exchange with D2O), 14.25 (br s, 1H, NH, exchanges with D2O); MS (EI) calcd. m/z for C6H3N5F335Cl 237.0029, found 237.0011; calcd. m/z for C6H3N5F337Cl 239.0000, found 238.9987; Anal. (C6H3N5F3C) C, HI N, F, Cl.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[C:15]([C:16](OC)=[O:17])=[CH:14][N:13]=1.[BH4-].[Na+]>CO.O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:13]=[CH:14][C:15]([CH2:16][OH:17])=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:21]=1
Reactant: COCCCc1ccccc1-c1cc(C(F)(F)F)c(C(=O)OC)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCCCc1ccccc1-c1cc(C(F)(F)F)c(CO)cn1
Temperature: 65 °C
Reaction time: 12 h

Procedure:
To a solution of methyl 6-[2-(3-methoxypropyl)phenyl]-4-(trifluoromethyl)nicotinate (1 eq.) from step 1, in MeOH (0.14M) was added portion wise sodium borohydride (9.3 eq.). The mixture was stirred at 65° C. for 12 h, cooled to room temperature, poured in water and extracted with EtOAc. The organic extract was washed with brine, dried over MgSO4 filtered and concentrated. Purification by column chromatography on silica gel, eluting with Hex/EtOAc 20% afforded the desired compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:49]([O:56][C:57]([NH:59][CH2:60][CH2:61][C@H:62]([NH2:73])[C:63]1[NH:67][C:66]2[CH:68]=[CH:69][C:70]([Cl:72])=[CH:71][C:65]=2[N:64]=1)=[O:58])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.ClCl>CN(C)C=O.ClCCl.C(O)C>[CH2:49]([O:56][C:57]([NH:59][CH2:60][CH2:61][C@H:62]([NH:73][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([C:11]([N:13]2[CH2:17][CH:16]=[CH:15][CH2:14]2)=[O:12])=[C:2]([CH3:1])[CH:3]=1)[C:63]1[NH:67][C:66]2[CH:68]=[CH:69][C:70]([Cl:72])=[CH:71][C:65]=2[N:64]=1)=[O:58])[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CC=CC1
Reactant: N[C@@H](CCNC(=O)OCc1ccccc1)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc(C(=O)N[C@@H](CCNC(=O)OCc2ccccc2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CC=CC1
Yield: 100 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(2,5-dihydropyrrol-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine and (1S)-3-(benzyloxycarbonylamino)-1-(5-chloro-1H-benzimidazol-2-yl)propylamine in dimethylformamide. Yield: 100%; Rf value: 0.50 (silica gel; dichloromethane/ethanol=9:1); C31H30ClN5O4 (572.06); mass spectrum: (M+H)+=572/574 (chlorine isotope).
Reaction SMILES: [B-]C#N.[Na+].C(O)(=O)C.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19](=[N:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]3[N:46]=[C:45]([CH3:47])[O:44][N:43]=3)=[CH:38][CH:37]=2)[C:20]2[NH:24][C:23](=[O:25])[N:22]([C:26]3[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=3[C:28]([OH:30])=[O:29])[N:21]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18].Cl>CO.O.C(OCC)(=O)C.C1COCC1>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:19]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]3[N:46]=[C:45]([CH3:47])[O:44][N:43]=3)=[CH:38][CH:37]=2)[C:20]2[NH:24][C:23](=[O:25])[N:22]([C:26]3[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=3[C:28]([OH:30])=[O:29])[N:21]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COc1ccc(C(=Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ccccc3C(=O)O)c(=O)[nH]2)cc1OC
Agent: Cl
Agent: [B-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ccccc3C(=O)O)c(=O)[nH]2)cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.2 %

Procedure:
After adding 16.3 mg of sodium cyanotrihydroborate and 0.0074 ml of acetic acid to a solution of 34 mg of 2-(3-{(3,4-dimethoxyphenyl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)benzoic acid in 6 ml of a methanol:THF=2:1 mixed solvent, the mixture was stirred at room temperature for 20 hours. Next, 0.1 ml of 5N hydrochloric acid was added to the reaction mixture and the mixture was stirred at room temperature for 10 minutes, after which 10 ml of ethyl acetate and 5 ml of water were added and filtration was performed with celite. The aqueous layer was extracted with 10 ml of ethyl acetate, and the organic layers were combined and dried over anhydrous magnesium sulfate. The desiccating agent was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-dichloromethane) to give the title compound (25 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]=1[C:20]([NH2:22])=[O:21].F[C:24]1[CH:37]=[C:36]([N+:38]([O-:40])=[O:39])[CH:35]=[CH:34][C:25]=1[CH2:26][O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC#N>[NH2:1][C:2]1[N:6]([C:24]2[CH:37]=[C:36]([N+:38]([O-:40])=[O:39])[CH:35]=[CH:34][C:25]=2[CH2:26][O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[N:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C:3]=1[C:20]([NH2:22])=[O:21]
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Reactant: O=[N+]([O-])c1ccc(COC2CCCCO2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn(-c2cc([N+](=O)[O-])ccc2COC2CCCCO2)c1N
Temperature: 80 °C
Reaction time: 16 h
Yield: 75.5 %

Procedure:
To a solution of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide (27.6 mg, 0.1 mmol) in DMF (3 mL) and CH3CN (5 mL) was added 2-(2-fluoro-4-nitrobenzyloxy)-tetrahydro-2H-pyran (25.5 mg, 0.1 mmol) and K2CO3 (27.6 mg, 0.2 mmol). After stirring at 80° C. under N2 for 16 hr, the mixture was concentrated and recrystallized with PE/EA to afford 40 mg (80%) of 5-amino-1-(5-nitro-2-((tetrahydro-2H-pyran-2-yloxy)methyl)phenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide as a yellow solid. MS (ESI) m/e [M+1]+ 512.2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>ClCCl>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:21](=[O:22])[O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (9.3 mg, 36 μmol) in 10 mL of dichloromethane was cooled to −5° C. and a solution of phenyl chloroformate (7 mg, 45 μmol) in 1.5 mL of dichloromethane was added, with argon bubbling to facilitate mixing. The mixture was then allowed to warm to room temp while being vortexed for 10 min. Aminomethylpolystyrene (ca. 80 mg, 1 meq/g, 100–200 mesh, Bachem) was added to quench excess chloroformate, and the mixture was refluxed and vortexed for several hours. The mixture was chromatographed through a short plug of silica gel with 10:1 dichloromethane-methanol as eluant to isolate the product as a solid. 1H NMR (500 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.06 (d, J=7.6 Hz, 1H), 7.76 (t, J=5.6 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.45 (t, J=7 Hz, 1H), 7.34 (t, J=8.2 Hz, 2H), 7.27 (t, J=7.5 Hz, 1H), 7.18 (t, J=7.3 Hz, 1H), 7.00 (d, J=8.6 Hz, 2H), 6.65 (bs, 2H), 4.64 (t, J=7 Hz, 2H), 3.10 (q, J=6 Hz, 2H), 1.92 (quintet, J=7 Hz, 2H), 1.52 (quintet, J=7 Hz, 2H). MS (APCI) m/e 376.15 (M+H).
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH:72]1[CH2:77][CH2:76][NH:75][CH2:74][C:73]1=[O:78].C(N(CC)CC)C>ClCCl>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:36][CH2:37][N:38]([CH2:41][C:42]([N:75]4[CH2:76][CH2:77][NH:72][C:73](=[O:78])[CH2:74]4)=[O:43])[CH2:39][CH2:40]3)=[O:34])[C@@:14]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:4])([CH3:3])[CH3:5]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Reactant: O=C1CNCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCNC(=O)C2)CC1
Reaction time: 2 h
Yield: 23.1 %

Procedure:
{4-[(4S,5R)-2-(6-tert-Butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride salt (31.5 mg, 0.47 mmol, example 99), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 19.7 mg, 0.052 mmol, Advchemtech), piperazin-2-one (12 mg, ) and triethylamine (0.05 mL) was mixed in dichloromethane (2 ml) and stirred for 2 h. The mixture was diluted with dichloromethane (5 mL) and was washed with sodium hydroxide (0.1 N solution), saturated sodium chloride solution and water. Dichloromethane solution was dried over anhydrous magnesium sulfate. The solids were filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by preparative HPLC (reversed phase, eluting with acetonitrile and water) gave the title compound (20.7 mg). HR-MS (ES, m/z) calculated for C39H48Cl2N7O4 [(M+H)+] 748.314, observed 748.3138.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][C:13](=[O:15])[CH2:12][C:11](=[O:16])[CH2:10]1.[C:17](O)(=[O:19])[CH3:18].CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[C:17]([CH:12]1[C:11](=[O:16])[CH2:10][CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:14][C:13]1=[O:15])(=[O:19])[CH3:18]
Reactant: COc1ccccc1C1CC(=O)CC(=O)C1
Reactant: CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Product: COc1ccccc1C1CC(=O)C(C(C)=O)C(=O)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.8 %

Procedure:
To a solution of 5-(2-methoxyphenyl)-1,3-cyclohexanedione (2.0 g), acetic acid (0.99 g) and dimethylaminopyridine (1.7 g) in dimethylformamide (100 ml) was added dicyclohexylcarbodiimide (2.5 g), and the mixture was stirred at room temperature for 15 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added ethyl acetate. The solution was washed with potassium hydrogen sulfate solution and water, and to the solution was added 1N sodium hydroxide solution. The aqueous layer was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was recrystallized from diisopropylether/hexane to give colorless crystals of 2-acetyl-5-(2-methoxyphenyl)cyclohexane-1,3-dione (2.0 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22](=[O:27])N(OC)C)=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22]([C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1)=[O:27])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: c1ccc2occc2c1
Reactant: CON(C)C(=O)C1CCCN1C(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)c1cc2ccccc2o1

Procedure:
The title compound (2.7 g) was prepared from benzofuran (2.29 g) and (RS)-2-(methoxy-methyl-carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, D79 (5.00 g) according to a procedure similar to that for Description 2.