Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]1[C:5]([NH:11][C@@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][C:23]([F:26])([F:25])[F:24])[CH:20]=3)[O:15][C:14]([CH3:28])([CH3:27])[C@H:13]2[OH:29])=[N:6][S:7](=[O:10])(=[O:9])[N:8]=1)C.[F:30][C:31]([F:41])([F:40])[C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1>>[O:10]=[S:7]1(=[O:9])[N:8]=[C:4]([NH:37][CH2:36][C:35]2[CH:34]=[CH:33][C:32]([C:31]([F:30])([F:40])[F:41])=[CH:39][CH:38]=2)[C:5]([NH:11][C@@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][C:23]([F:25])([F:26])[F:24])[CH:20]=3)[O:15][C:14]([CH3:27])([CH3:28])[C@H:13]2[OH:29])=[N:6]1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: CCOC1=NS(=O)(=O)N=C1N[C@@H]1c2cc(OC(F)(F)F)ccc2OC(C)(C)[C@H]1O
Product: CC1(C)Oc2ccc(OC(F)(F)F)cc2[C@@H](NC2=NS(=O)(=O)N=C2NCc2ccc(C(F)(F)F)cc2)[C@@H]1O

Procedure:
In a method similar to Example 5, the product of Example 1, Step 2 (0.250 g, 0.572 mmol) was converted to the title compound with 4-(trifluoromethyl)benzylamine (0.09 mL, 0.629 mmol) to afford 0.25 g (77%) of product as a white solid: mp 283°-284° C.; 1H NMR (DMSO-D6): δ 8.94 (d, 1H), 8.92 (t, 1H), 7.78 (d, 2H), 7.64 (d, 2H), 7.32 (d, 1H), 7.21 (dd, 1H), 6.90 (d, 1H), 6.00 (d, 1H), 4.80 (t, 1H), 4.62 (d, 2H), 3.62 (m, 1H), 1.40 (s, 3H), 1.20 (s, 3H); IR (KBr) 3300, 1610 cm-1 ; MS (m/z) 567 (MH+, 100%); [α]D25 =-44.8 (THF).
Reaction SMILES: C([Li])CCC.O1CCCC1.Br[C:12]1[CH:13]=[C:14]([O:20][CH3:21])[C:15]([O:18][CH3:19])=[CH:16][CH:17]=1.[S:22]1[CH:26]=[CH:25][C:24]([CH:27]=[O:28])=[CH:23]1>CCCCCC.O>[OH:28][CH:27]([C:24]1[CH:25]=[CH:26][S:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1
Reactant: O=Cc1ccsc1
Reactant: COc1ccc(Br)cc1OC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C(O)c2ccsc2)cc1OC
Temperature: 25 °C

Procedure:
24 ml of 2.5M n-butyl lithium in hexane are added dropwise to a tetrahydrofuran solution of 10.85 g 4-bromoveratrole under cooling. After stirring the mixture, 5.61 g of 3-thiophenecarboaldehyde are added thereto, and warmed to room temperature. Water is added thereto, and the mixture is extracted with ethyl acetate. The extract is dried and evaporated under reduced pressure to remove the solvent, whereby 3-(α-hydroxy-3,4-dimethoxybenzyl)thiophene is obtained. 2.8 g of sodium hydride are added to a solution of the product in dimethylformamide, and the mixture is stirred at room temperature. 4.7 ml of methyl iodide are added thereto, and the mixture is stirred. A small amount of water is added thereto, and the mixture is evaporated under reduced pressure to remove the solvent. Water is added to the residue and the mixture is extracted with ethyl acetate. The extract is dried and evaporated under reduced pressure to remove the solvent. The residue is purified by using silica gel column, whereby 10.5 g of 3-(α-methoxy-3,4-dimethoxybenzyl)thiophene are obtained.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:5]1([C:16]2[N:17]=[CH:18][NH:19][CH:20]=2)[C:13](=O)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=O)[CH3:4].[H][H]>[Pd]>[ClH:1].[CH2:3]([C:5]1([C:16]2[NH:17][CH:18]=[N:19][CH:20]=2)[CH2:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13]1)[CH3:4]
Reactant: CCC1(c2c[nH]cn2)C(=O)c2ccccc2C1=O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Product: CCC1(c2cnc[nH]2)Cc2ccccc2C1
Temperature: 82.5 °C
Reaction time: 6 h

Procedure:
Palladium catalyst (1.4 g of 10% Pd/C) was suspended in the hydrochloric acid solution of 2-ethyl-2-(1H-imidazol-4-yl)indan-1,3-dione hydrochloride. The obtained suspension was poured into a hydrogenation autoclave. Hydrogen was supplied to autoclave to 3.0 bar. The reaction mixture was stirred and heated to 80-85° C. The typical hydrogenation time was 6 hours. After hydrogenation the reaction mixture was filtered to remove the catalyst. The filtrate was cooled to (−5)° C., the precipitates were separated by filtration. The obtained crude 5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole hydrochloride was dried at 50° C. under reduced pressure. The yield was 3.7 g of a white powder.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:7]([NH:9][C@H:10]([C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=O)=[O:13])[CH3:11])=[O:8])[CH3:6])(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:37]([O:39][C:40](=[O:44])[N:41]([CH3:43])[NH2:42])[CH3:38]>O1CCCC1>[CH2:37]([O:39][C:40](=[O:44])[N:41]([CH3:43])[NH:42][C:16](=[O:18])[C@@H:15]1[CH2:19][CH2:20][CH2:21][N:14]1[C:12](=[O:13])[C@H:10]([CH3:11])[NH:9][C:7](=[O:8])[C@H:5]([CH3:6])[NH:4][C:1](=[O:3])[CH3:2])[CH3:38]
Reactant: CC(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CCOC(=O)N(C)N
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCOC(=O)N(C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@H](C)NC(C)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of acetylalanylalanylproline (2 mmole) and N-methylmorpholine (2 mmole) in dry tetrahydrofuran (20 ml) at -20° to -25° C. is added isobutyl chloroformate (2 mmole). After 5 minutes a solution of 2-azaalanine ethyl ester (2 mmole) in tetrahydrofuran (3 ml) is added dropwise and the reaction mixture is allowed to warm to room temperature over a period of 1 hour and stirred for a further 4 hours. The precipitate is filtered off and the filtrate is evaporated to dryness. Chromatography on silica gel (50 gm) and elution with 10% methanol in chloroform gives pure acetylalanylalanylprolyl-2-azaalanine ethyl ester.
Reaction SMILES: [NH2:1][C:2]1([C:21](O)=[O:22])[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=2)[CH2:3]1.[BH4-].[Na+].II>C1COCC1>[NH2:1][C:2]1([CH2:21][OH:22])[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:11][CH:12]=2)[CH2:3]1
Reactant: CCCCCCCCc1ccc(C2CCC(N)(C(=O)O)C2)cc1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc(C2CCC(N)(CO)C2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 21.4 %

Procedure:
63.4 mg (0.2 mmol) of 5 and 27 mg (0.6 mmol) sodium borohydride were dissolved in 3 mL of THF. After the solution was cooled to 0° C., 51 mg (0.2 mmol) I2 was dissolved in 1 mL THF and added dropwise. Then the vessel was fitted with a condenser and the reaction mixture was refluxed under N2 for 5 hrs. Excess NaBH4 was quenched with methanol. After removal of solvent, 2 mL water and 5 mL methylene chloride was added, the mixture was stirred for about 1 hr until the organic layer became clear. The organic phase was collected and aqueous phase was further extracted twice with methylene chloride. The combined organic extraction was dried and concentrated to provide 43 mg (71%) of the crude product. Further purification on TLC with methanol/chloroform (5:95) provided 13 mg of clear oil. J. Org. Chem., 1993, 58, 3568-3571. 1H NMR (CD3OD) δ 7.11 (m, 4H, ArH), 3.80 (t, J=7.5 Hz, 1H, c-pentyl-CH2O), 3.67 (t, J=7.5 Hz, 1H, c-pentyl-CH2O), 3.01 (m, 1H, ArCHCC), 2.55 (t, J=7.5 Hz, 2H, ArCH2), 2.29-1.69 (m, 6H, cyclo-pentyl), 1.57 (m, 2H, ArCH2CH2), 1.38-1.28 (m, 10H, CH2), 0.89 (t, J=7.5 Hz, 3H, CH3); 13C NMR (CD3COCD3) δ 141, 128, 127, 96, 45, 44, 43, 35, 35, 33, 33, 32, 32, 29, 29, 29, 23, 13.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[N:20]=[C:19]3[S:21][C:22]([NH:24][C:25]([CH:27]4[CH2:29][CH2:28]4)=[O:26])=[N:23][C:18]3=[CH:17][CH:16]=2)[CH:9]=1)(C)(C)C.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[NH2:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[O:14][C:15]1[N:20]=[C:19]2[S:21][C:22]([NH:24][C:25]([CH:27]3[CH2:29][CH2:28]3)=[O:26])=[N:23][C:18]2=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c1
Yield: 78.7 %

Procedure:
A solution of tert-butyl[3-({2-[(cyclopropylcarbonyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)phenyl]carbamate (900 mg, 2.11 mmol) and anisole (1 mL) in trifluoroacetic acid (10 mL) was stirred at 0° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to the residue, and the mixture was extracted with tetrahydrofuran-ethyl acetate mixture (1:1, 50 mL, 15 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was washed with a tetrahydrofuran-ethyl acetate mixture to give the title compound (542 mg, 79%) as a pale-yellow solid.
Reaction SMILES: [C:1]([N:8]([CH3:17])[C@H:9]([C:14](O)=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].B.C1COCC1.O.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[C:4]([O:3][C:1](=[O:2])[N:8]([C@H:9]([CH2:14][OH:15])[C@@H:10]([CH3:11])[CH2:12][CH3:13])[CH3:17])([CH3:5])([CH3:7])[CH3:6]
Reactant: CC[C@H](C)[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: B
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC[C@H](C)[C@@H](CO)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
39.3 g Boc-MeIle-OH (0.160 mol; Synthetech) were dissolved in 160 ml THF and cooled to 0° C. 240 ml 1M BH3-THF (0.24 mol; Fluka) were added at 0° C. over 1 h and the clear, colorless reaction mixture was warmed up and stirred at RT for 1 h. The reaction mixture was again cooled to 0° C., 100 ml deionized water were carefully added at 0-5° C. over 0.5 h and after warming up to RT stirring was continued for 1 h. To the colorless solution were added 250 ml 10% Na2CO3 all at once and after stirring for 1 h the reaction mixture was extracted with 1000 ml and 500 ml ethyl acetate. The organic layers were washed with brine and dried (Na2SO4). Removal of the solvent by rotary evaporation gave 36.9 g (99.7%) product as colorless oil.
Reaction SMILES: [N:1]1([CH:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][NH:10]2)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:22]1([S:32](Cl)(=[O:34])=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1>ClCCl>[C:22]1([S:32]([N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]2[CH:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH3:8])(=[O:34])=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: CC(C1CCCCN1)N1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C1CCCCN1S(=O)(=O)c1cccc2ccccc12)N1CCCCC1
Reaction time: 24 h
Yield: 58.2 %

Procedure:
To a stirred solution of 2-[1-(piperidinyl)ethyl]piperidine (196 mg, 1 mmol) and triethylamine (0.14 ml, 1 mmol) in dichloromethane (10 ml) cooled by an ice bath, was added dropwise a solution of 1 -naphthalene sulfonyl chloride (226 mg, 1 mmol) in dichloromethane. Stirring continued, allowing the solution to reach room temperature for 24 hours. The solution was washed thoroughly (10% NaOH), and brine, dried (Na2SO4) and concentrated in vacuo to afford a pale yellow oil (225 mg, 58%) M+=387.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([NH2:14])=[S:13])=[N:9][CH:10]=1.Br[CH:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:17](OC)OC.Cl.C([O-])([O-])=O.[Na+].[Na+]>CCO.O>[C:22]1([C:16]2[S:13][C:12]([NH:11][C:8]3[N:9]=[CH:10][C:5]([CH2:4][CH2:3][CH2:2][OH:1])=[CH:6][CH:7]=3)=[N:14][CH:17]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(OC)C(Br)c1ccccc1
Reactant: NC(=S)Nc1ccc(CCCO)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCCCc1ccc(Nc2ncc(-c3ccccc3)s2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
[5-(3-Hydroxy-propyl)-pyridin-2-yl]-thiourea (7-4), 2.20 g (10.4 mmol) was stirred in 20 mL EtOH. (1-Bromo-2,2-dimethoxy-ethyl)-benzene (3.83 g, 15.6 mmol) was added, dissolved in 12 mL EtOH. The reaction was heated to reflux. After 30 min, 8 mL of concentrated HCl (aq) was added. After 7 h the reaction was cooled to RT, and diluted with water. Na2CO3 (s) was added to pH 9. The resulting precipitate was filtered, and washed with water. To solid was added ether, the mixture was sonicated and filtered, washing with ether. Afford the titled compound as a white solid. 1H NMR (CDCl3): δ 8.74 (bs, 1H), 8.25 (d, 1H, J=2.2 Hz), 7.57 (dd, 2H, J=1.7, 9.0 Hz)7.49 (dd, 1H, J=2.4, 8.4 Hz), 7.38 (t, 2H, J=7.7 Hz), 6.83 (d, 1H, J=8.2 Hz), 3.71 (m, 2H), 2.70 (t, 2H, J=6.7 Hz), 1.89 (m, 2H). Mp 153-154° C. MS [M+H]+=312.2.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:15][CH3:16])[S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:17])=[CH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:25][C:26]1[O:30][C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:28][CH:27]=1>CN(C=O)C>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:15][CH3:16])[S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:17][CH2:25][C:26]3[O:30][C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:28][CH:27]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: CCc1nc2c(N)nc3cc(O)ccc3c2s1
Reactant: CCOC(=O)c1ccc(CCl)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(COc2ccc3c(c2)nc(N)c2nc(CC)sc23)o1
Temperature: 60 °C

Procedure:
A scintillation vial was charged with 4-amino-2-ethylthiazolo[4,5-c]quinolin-7-ol (1.0 eq., 1.0 mmol) and anhydrous DMF (2 mL). The mixture was warmed until a solution was obtained. An additional amount of DMF (1 mL) was added. To this stirred orange solution was added cesium carbonate (3.0 eq., 3.0 mmol) and a solution of ethyl 5-(chloromethyl)-2-furancarboxylate (1.0 eq., 1.0 mmol) dissolved in DMF (2 mL). Additional DMF (1 mL) was used to rinse the vial. The vial was capped and heated to 60° C. overnight. The reaction was monitored by HPLC. The reaction was quenched by adding the reaction mixture drop-wise to water (60 mL) with stirring. A precipitate formed. Crude ethyl 5-{[(4-amino-2-ethylthiazolo[4,5-c]quinolin-7-yl)oxy]methyl}-2-furoate was isolated as a solid by vacuum filtration. The solid was then dissolved in methanol and adsorbed onto silica gel (6 g) for purification by HPFC (0-15% CMA in chloroform, 1440 mL). Pure fractions were combined and concentrated to provide a solid which analysis indicated was the methyl ester. This material was recrystallized from acetonitrile to provide methyl 5-{[(4-amino-2-ethylthiazolo[4,5-c]quinolin-7-yl)oxy]methyl}-2-furoate as a light yellow crystalline solid, mp 184-186° C. MS (APCI) m/z 384 (M+H)+. Anal. calcd for C19H17N3O4S.0.30CH3CN: C, 59.49; H, 4.56; N, 11.68. Found: C, 59.35; H, 4.22; N, 11.71.
Reaction SMILES: C(OC(N(C)[C@@H](C)C(N[C@@H](C(C)(C)C)C(N1C[C@@H](C2C=C3C(C[C@@H](C(=O)N[C@H]4C5C(=CC=CC=5)CCC4)N(C(=O)[C@@H](NC(=O)[C@@H](N(C(OC(C)(C)C)=O)C)C)C(C)(C)C)C3)=CC=2)C[C@H]1C(N[C@@H](CC1C=CC=CC=1)C(O)=O)=O)=O)=O)=O)(C)(C)C.FC(F)(F)S(O[C:91]1[CH2:95][N:94]([C:96]([O:98][C:99]([CH3:102])([CH3:101])[CH3:100])=[O:97])[C@H:93]([C:103]([O:105][CH3:106])=[O:104])[CH:92]=1)(=O)=O.CC1(C)C(C)(C)OB([C:117]2[CH:126]=[C:125]3[C:120]([CH2:121][C@@H:122]([C:134]([O:136][CH3:137])=[O:135])[N:123]([C:127]([O:129][C:130]([CH3:133])([CH3:132])[CH3:131])=[O:128])[CH2:124]3)=[CH:119][CH:118]=2)O1>>[C:99]([O:98][C:96]([N:94]1[C@H:93]([C:103]([O:105][CH3:106])=[O:104])[CH:92]=[C:91]([C:117]2[CH:126]=[C:125]3[C:120]([CH2:121][C@@H:122]([C:134]([O:136][CH3:137])=[O:135])[N:123]([C:127]([O:129][C:130]([CH3:131])([CH3:132])[CH3:133])=[O:128])[CH2:124]3)=[CH:119][CH:118]=2)[CH2:95]1)=[O:97])([CH3:102])([CH3:101])[CH3:100]
Reactant: COC(=O)[C@@H]1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN1C(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H]1C=C(OS(=O)(=O)C(F)(F)F)CN1C(=O)OC(C)(C)C
Agent: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](c2ccc3c(c2)CN(C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)(C)C)[C@H](C(=O)N[C@@H]2CCCc4ccccc42)C3)C[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)O)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Product: COC(=O)[C@@H]1C=C(c2ccc3c(c2)CN(C(=O)OC(C)(C)C)[C@H](C(=O)OC)C3)CN1C(=O)OC(C)(C)C
Yield: 69.9 %

Procedure:
Following a procedure analogous to that for the synthesis of Compound D of Example 22, (S)-1-tert-butyl 2-methyl 4-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrrole-1,2(2H,5H)-dicarboxylate (585 mg, 1.56 mmol) and (S)-2-tert-butyl 3-methyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate (650 mg, 1.56 mmol) were converted to the title compound (563 mg, 70%). MS (ESI+) m/z 517.4 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.[H-].[Na+].[CH2:8](Cl)[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C=O)C.CCOC(C)=O>[CH2:10]([O:9][CH2:8][N:1]1[CH:5]=[N:4][N:3]=[N:2]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1nnn[nH]1
Reactant: ClCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1ccc(COCn2cnnn2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 35.6 %

Procedure:
To a mixture of tetrazole (500 mg, 7.13 mmol) in 14 mL DMF at 0° C. was added NaH (60%, 286 mg, 7.13 mmol). The mixture was stirred at 0° C. for 20 min, then was treated with BOM-Cl (80%, 1.35 mL, 7.84 mmol). The mixture was stirred at rt for 2 h, then was diluted with EtOAc. The organic phase was washed with H2O (3×) and brine, dried (Na2SO4), filtered through 1″ SiO2 and concentrated. The crude product was purified by flash chromatography (0 to 50% EtOAc/hexanes gradient) to afford 483 mg of Intermediate 12.1 as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([N+:14]([O-])=O)([CH3:13])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:12])[CH3:11])[CH2:6][CH2:5]1.[ClH:17]>CO.O>[ClH:17].[ClH:17].[NH2:14][C:2]([CH3:13])([CH3:1])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:12])[CH3:11])[CH2:6][CH2:5]1
Reactant: CC(=O)N1CCN(CC(C)(C)[N+](=O)[O-])CC1
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(=O)N1CCN(CC(C)(C)N)CC1
Reaction time: 0.08 h
Yield: 81 %

Procedure:
A solution of 1-(4-(2-methyl-2-nitropropyl)piperazin-1-yl)ethanone (7.2 g, 19.4 mmol) in a mixture of methanol and water (50:10 mL) was added to a steel pressure vessel equipped with a magnetic stir bar. The vessel was flushed with nitrogen while Raney nickel (50% aqueous suspension, 1.0 mL) was added in one portion. The vessel was sealed and pressurized with hydrogen (100 psi). The suspension was stirred for 5 min and the hydrogen released until the pressure was just above 0 psi. This was repeated once more and the vessel was finally pressurized to 500 psi. The reaction was stirred at room temperature for 17 h. The hydrogen was released and the suspension was filtered through Celite®. The solid was washed with small portions of water (5×40 mL) to give a colorless filtrate. The filtrate was brought to pH 2 with 6N HCl. The filtrate was concentrated in vacuo to a yellow oil. The oil was purified by Prep-LC utilizing a gradient of methanol and water with 0.05% acetic acid as a modifier. Fractions were pooled and concentrated to give foamy solid (6.91 g, 81%). 1H NMR (CDCl3, 400 MHz): δ 1.33 (s, 6H), 2.12 (s, 3H), 2.58 (s, 2H), 2.63-2.72 (dt, J=4.8, 4H), 3.57-3.60 (m, 4H). LRMS (ESI+) for C10H21N3O (199.1); Found: 200 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:13](O)(=[O:33])[CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].CCN=C=NCCCN(C)C.CN(C1C=CC=CN=1)C>ClCCl>[OH:12][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:13](=[O:33])[CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(N)ccc1O
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)Nc1ccc(O)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
To a solution of methyl 5-amino-2-hydroxybenzoate (0.27 g, 1.6 mmol) in dichloromethane (10 mL) was added arachidonic acid (0.5 g, 1.6 mmol), EDCI (0.32 g, 1.7 mmol) and dimethylaminopyridine (0.020 g, 0.2 mmol). The reaction was stirred (RT, 2 h), and then partitioned between DCM and brine. The aqueous layer was extracted with DCM, and the combined organic layers were washed with 1N HCl, water, saturated aqueous NaHCO3 and water, and then dried over MgSO4. The crude product was purified by silica gel chromatography (0-5% MeOH/DCM) to afford 0.6 g of methyl 2-hydroxy-5-(5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenamidobenzoate as a brown oil. Mass calculated for C28H39NO4=453.61; found: [M+H]+=454.3.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][C:16]1[CH:26]=[CH:25][C:19]([CH:20]=[CH:21][C:22](O)=O)=[CH:18][CH:17]=1>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:22](/[CH:21]=[CH:20]/[C:19]3[CH:25]=[CH:26][C:16]([CH3:15])=[CH:17][CH:18]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: Cc1ccc(C=CC(=O)O)cc1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(C)cc3)nc2n(CC)c1=O
Yield: 53.9 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 3.00 g (15.1 mmol) of 5,6-diamino-1,3-diethyluracil and 2.70 g (16.7 mmol) of 4-methylcinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane to give 2.64 g (yield 54%) of Compound 151 as pale yellow needles.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.Cl[C:16]([O:18][CH2:19][CH3:20])=O>N1C=CC=CC=1>[CH2:19]([O:18][C:16]1[O:13][C:12](=[O:14])[C:3]2[CH:4]=[C:5]3[C:10]([CH2:9][CH2:8][CH2:7][CH2:6]3)=[CH:11][C:2]=2[N:1]=1)[CH3:20]
Reactant: CCOC(=O)Cl
Reactant: Nc1cc2c(cc1C(=O)O)CCCC2
Solvent: c1ccncc1
Product: CCOc1nc2cc3c(cc2c(=O)o1)CCCC3
Reaction time: 20 h

Procedure:
To a solution of 3-amino-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (1-2) (5.0 g, 26 mmol, 1 equiv) in pyridine (50 mL) at −10° C. under nitrogen was added ethyl chloroformate (10 mL, 11 g, 100 mmol, 4.0 equiv) dropwise over 1 h. The resulting solution was stirred from −10° C. to 23° C. over 20 h. The solvent was evaporated under reduced pressure and the solid residue was suspended in water (100 mL) with stirring for 1 h. The precipitate was filtered, washed with water and dried to yield 2-ethoxy-6,7,8,9-tetrahydro-4H-naphtho[2,3-d][1,3]oxazin-4-one (1-3) as a yellow solid. LRMS m/z (M+H) 246.4 found, 246.1 required.
Reaction SMILES: C(OC(=O)[NH:7][C:8](=[NH:37])[C:9]1[S:10][C:11]([S:35][CH3:36])=[C:12]([S:14]([C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([OH:34])[C:30]([F:33])([F:32])[F:31])[CH:24]=3)[CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH:13]=1)(C)(C)C.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[CH3:36][S:35][C:11]1[S:10][C:9]([C:8]([NH2:37])=[NH:7])=[CH:13][C:12]=1[S:14]([C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([OH:34])[C:30]([F:32])([F:33])[F:31])[CH:24]=2)[CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2cccc(C(O)C(F)(F)F)c2)c1
Solvent: O=C(O)C(F)(F)F
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2cccc(C(O)C(F)(F)F)c2)c1
Yield: 86 %

Procedure:
(Imino-{5-methylsulfanyl-4-[3′-(2,2,2-trifluoro-1-hydroxy-ethyl)-biphenyl-3-sulfonyl]-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester (25 mg, 0.043 mmol, as prepared in Example 28, step c) was treated with trifluoroacetic acid (50% in DCM) for 1 hr at rt. The reaction mixture was concentrated in vacuo and the residue obtained was purified using C18-HPLC (10–80% CH3CN in H2O (0.1% TFA) over 25 min) to give 18 mg (86%) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz) δ 8.33 (s, 1H), 8.30 (t, 1H, J=1.7), 7.97–8.05 (m, 2H), 7.91 (br s, 1H), 7.68–7.74 (m, 2H), 7.53–7.56 (m, 2H), 5.15 (q, 1H, J=7.0 Hz), 2.74 (s, 3H). 19F-NMR (CD3OD; 400 MHz) δ −80.09 (d, J=6.9 Hz). ESI-MS (m/z): Calcd. for C20H17F3N2O3S3: 487.6 (M+H); found: 487.3.