Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:22]=[C:21]4[C:16]([CH2:17][CH2:18][CH:19]([C:23]([NH:25][C:26]5[CH:27]=[C:28]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=5)[CH2:29][NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:20]4)=[CH:15][CH:14]=3)[CH:9]=[CH:8][N:7]=2)[CH:3]=[N:2]1.Cl>O1CCOCC1>[NH2:30][CH2:29][C:28]1[CH:27]=[C:26]([NH:25][C:23]([CH:19]2[CH2:18][CH2:17][C:16]3[C:21](=[CH:22][C:13]([O:12][C:10]4[CH:9]=[CH:8][N:7]=[C:6]([C:4]5[CH:3]=[N:2][NH:1][CH:5]=5)[CH:11]=4)=[CH:14][CH:15]=3)[CH2:20]2)=[O:24])[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=1
Reactant: CC(C)(C)OC(=O)NCc1cc(NC(=O)C2CCc3ccc(Oc4ccnc(-c5cn[nH]c5)c4)cc3C2)cc(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Product: NCc1cc(NC(=O)C2CCc3ccc(Oc4ccnc(-c5cn[nH]c5)c4)cc3C2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl [3-{[(7-{[2-(1H-pyrazol-4-yl)pyridin-4-yl]oxy}-1,2,3,4-tetrahydronaphthalen-2-yl)carbonyl]amino}-5-(trifluoromethyl)benzyl]carbamate (0.238 g, 0.39 mmol) and 4M of HCl in dioxane (4 mL) was allowed to stir at rt for 1 h. The solvents were evaporated to give N-[3-(aminomethyl)-5-(trifluoromethyl)phenyl]-7-{[2-(1H-pyrazol-4-yl)-pyridin-4-yl]oxy}-1,2,3,4-tetrahydronaphthalene-2-carboxamide I-252. 1H NMR (400 MHz, d6-DMSO, HCl salt) δ: 10.83 (s, 1H), 8.71 (br s, 2H), 8.36-8.56 (m, 4H), 8.09 (s, 1H), 8.03 (s, 1H), 7.89 (s, 1H), 7.60 (s, 1H), 7.29 (d, 1H), 7.04-7.13 (m, 2H), 6.93-6.97 (m, 1H), 4.05-4.12 (m, 2H), 2.79-3.01 (m, 5H), 2.09-2.17 (m, 1H), and 1.76-1.88 (m, 1H). LCMS: (FA) ES+508.3, ES−506.4.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[C:13]([N+:14]([O-])=O)=[CH:12][C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=1.C(O)C.Cl.N>[Fe].O>[F:18][C:2]([F:1])([F:17])[O:3][C:4]1[C:13]([NH2:14])=[CH:12][C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=1
Reactant: Nc1nc2cc([N+](=O)[O-])c(OC(F)(F)F)cc2s1
Agent: [Fe]
Agent: Cl
Agent: N
Solvent: O
Solvent: CCO
Product: Nc1nc2cc(N)c(OC(F)(F)F)cc2s1
Yield: 62.2 %

Procedure:
6-Trifluoromethoxy-5-nitro-2-benzothiazolamine (7.2 g), ethanol (25 cc), water (25 cc), iron powder (8.7 g) and concentrated hydrochloric acid (d=1.19) (1.1 cc) are heated to reflux for 2 hours. After returning to a temperature in the region of 20° C., the mixture is alkalinized with 28% strength ammonia solution (10 cc) and extracted 4 times with ethyl acetate (350 cc in total). The organic solution is evaporated at 50° C. under reduced pressure (20 mm Hg; 2.7 kPa). The product obtained (6.4 g) is purified by chromatography on a column of silica (800 g; particle size: 0.063-0.200 mm), eluting with an ethyl acetate/cyclohexane mixture (90:10 by volume), and recrystallized in toluene (320 cc). 6-Trifluoromethoxy-2,5-benzothiazolediamine (4 g), m.p. 175° C., is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([N:11]2[CH2:15][CH2:14][C@H:13]([NH:16]C(=O)OC(C)(C)C)[CH2:12]2)(=[O:10])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:25][O:26][C:27]1[CH:36]=[C:35]2[C:30]([C:31]([N:37]3[CH2:43][C:42]4[CH:44]=[C:45](B(O)O)[CH:46]=[CH:47][C:41]=4[O:40][CH2:39][CH2:38]3)=[N:32][CH:33]=[N:34]2)=[CH:29][CH:28]=1>>[NH2:16][C@H:13]1[CH2:14][CH2:15][N:11]([S:8]([C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:45]3[CH:46]=[CH:47][C:41]4[O:40][CH2:39][CH2:38][N:37]([C:31]5[C:30]6[C:35](=[CH:36][C:27]([O:26][CH3:25])=[CH:28][CH:29]=6)[N:34]=[CH:33][N:32]=5)[CH2:43][C:42]=4[CH:44]=3)[CH:6]=2)(=[O:9])=[O:10])[CH2:12]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cc(Br)cnc2N)C1
Reactant: COc1ccc2c(N3CCOc4ccc(B(O)O)cc4C3)ncnc2c1
Product: COc1ccc2c(N3CCOc4ccc(-c5cnc(N)c(S(=O)(=O)N6CC[C@H](N)C6)c5)cc4C3)ncnc2c1

Procedure:
Synthesized according to the method of example 5 using (S)-tert-butyl 1-(2-amino-5-bromopyridin-3-ylsulfonyl)pyrrolidin-3-ylcarbamate (reagent preparation 25) and {4-[7-(methyloxy)quinazolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}boronic acid (reagent preparation 23) in step 1 and BOC group deprotection. 1H NMR (400 MHz, d6-DMSO): 8.80 (s, 1H), 8.65 (d, 1H), 8.41 (m, 2H), 8.22 (m, 1H), 8.04 (d, 1H), 7.78 (s, 1H), 7.53 (d, 1H), 7.35 (m, 2H), 6.98 (br m, 2H), 5.43 (S, 2H), 4.62 (s, 2H), 4.49 (s, 2H), 3.92 (s, 3H), 3.79 (m, 1H), 3.69 (m, 1H), 3.55-3.45 (m, 3H), 3.32 (m, 2H), 2.20 (m, 1H), 1.91 (M, 1H); MS (EI) for C27H29N7O4S: 548 (MH+).
Reaction SMILES: [CH2:1]([C:8]1[CH2:12][CH2:11][CH2:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:13][S:14]([C:16]1[CH:25]=[CH:24][C:19]([C:20](=O)[CH2:21]Br)=[CH:18][CH:17]=1)=[O:15].C([O-])(O)=O.[Na+].BrC(Br)=O>CO.C(Cl)Cl.O.CCCCCC.CCOCC>[CH3:13][S:14]([C:16]1[CH:25]=[CH:24][C:19]([C:20]2[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:8]3[N:9]([CH:21]=2)[CH2:10][CH2:11][CH2:12]3)=[CH:18][CH:17]=1)=[O:15]
Reactant: CS(=O)c1ccc(C(=O)CBr)cc1
Reactant: c1ccc(CC2=NCCC2)cc1
Agent: O=C(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: O
Product: CS(=O)c1ccc(-c2cn3c(c2-c2ccccc2)CCC3)cc1
Yield: 11.7 %

Procedure:
2-Benzyl-1-pyrroline (2.0 g, 80% strength, 10 mmol), dissolved in MeOH (30 ml), is treated with a solution of 4-methylsulphinylphenacyl bromide (2.1 g, 8 mmol) in CH2Cl2 (10 ml) and then with NaHCO3 (1.5 g, 18 mmol) and the mixture is stirred at RT until a TLC sample (Al2O3, hexane/ether 9:1) indicates the complete reaction of the bromoketone (Rf 0.75) and an adequate formation of product (Rf=0.2) (48 h). After addition of water (50 ml), the mixture is extracted with diethyl ether (3×30 ml), and the combined extracts are dried over Na2SO4 sicc. and concentrated. The residue is purified by CC (Al2O3, hexane/ether 1:1). 0.3 g (12%) of the compound sought is isolated.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([Cl:21])[C:6]2[N:7]([C:9]([CH2:19]Cl)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1.[CH3:22][C:23]1[CH:24]=[CH:25][C:26](=[O:29])[NH:27][N:28]=1>>[Cl:2][C:3]1[CH:4]=[C:5]([Cl:21])[C:6]2[N:7]([C:9]([CH2:19][N:27]3[C:26](=[O:29])[CH:25]=[CH:24][C:23]([CH3:22])=[N:28]3)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1
Reactant: Cc1ccc(=O)[nH]n1
Reactant: Cc1ccc(-c2nc3c(Cl)cc(Cl)cn3c2CCl)cc1
Agent: Cl
Product: Cc1ccc(-c2nc3c(Cl)cc(Cl)cn3c2Cn2nc(C)ccc2=O)cc1

Procedure:
The title compound was prepared according to Method B and the experimentals described for compound 91 from 6,8-dichloro-3-(chloromethyl)-2-p-tolylimidazo[1,2-a]pyridine hydrochloride and 6-methylpyridazin-3(2H)-one. m/e+ 399 for C20H17Cl2N4O [M+H]+; 1H-NMR (300 MHz, CDCl3) δ 8.72 (d, J=1.8 Hz, 1H), 8.01 (d, J=8.1 Hz, 2H), 7.30 (m, 3H), 7.10 (d, J=9.3 Hz, 1H), 6.96 (d, J=9.3 Hz, 1H), 5.70 (s, 2H), 2.43 (s, 3H), 2.29 (s, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[N:16]([C@@H:17]2[CH2:22][CH2:21][C@H:20]([C:23]([O:25][CH3:26])=[O:24])[CH2:19][CH2:18]2)[C:15]2[CH:27]=[C:28]([CH2:31][O:32][Si:33]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][C:14]=2[N:13]=1>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[N:16]([C@@H:17]3[CH2:22][CH2:21][C@H:20]([C:23]([O:25][CH3:26])=[O:24])[CH2:19][CH2:18]3)[C:15]3[CH:27]=[C:28]([CH2:31][O:32][Si:33]([CH:34]([CH3:36])[CH3:35])([CH:40]([CH3:42])[CH3:41])[CH:37]([CH3:39])[CH3:38])[CH:29]=[CH:30][C:14]=3[N:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COC(=O)[C@H]1CC[C@@H](n2c(N)nc3ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cc32)CC1
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@@H](n2c(NC(=O)c3ccc(F)cc3)nc3ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cc32)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
A solution of 4-fluorobenzoyl chloride (0.113 mL, 0.957 mmol) in DCM (2.90 mL) was cooled to 0° C. under nitrogen. To this was added cis-methyl 4-(2-amino-6-((triisopropylsilyloxy)methyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate (0.4 g, 0.870 mmol) followed by TEA (0.482 mL, 3.48 mmol). The resulting mixture was stirred at 0° C. for 30 minutes. The ice bath was removed, and the mixture was stirred for 2 hours. The reaction mixture was diluted with DCM (20 mL) and washed with water (10 mL). The organic layer was collected, dried over sodium sulfate, concentrated, and dried under vacuum to afford cis-methyl 4-(2-(4-fluorobenzamido)-6-((triisopropylsilyloxy)methyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate (0.5 g, 100% yield).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]1=[O:26].[OH-].[Na+]>>[O:26]=[C:12]1[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:27])=[O:2])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)CCCCCCCn1c(=O)n(-c2ccccc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCCCn1c(=O)n(-c2ccccc2)c2ccccc21

Procedure:
The product is produced as described in example 22 from 15 g. of 8-(2-oxo-3-phenyl-benzimidazolin-1-yl)-caprylic acid methyl ester and 1.64 g. of NaOH.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12]Cl)[N:6]=[CH:5]2.Cl.[C@H:15]12[CH2:21][C@H:18]([NH:19][CH2:20]1)[CH2:17][O:16]2.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][N:19]1[CH2:20][C@@H:15]3[CH2:21][C@H:18]1[CH2:17][O:16]3)[N:6]=[CH:5]2
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: ClCCn1ncc2cc(Br)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc2c(cnn2CCN2C[C@@H]3C[C@H]2CO3)c1
Temperature: 90 °C
Reaction time: 19 h
Yield: 38.9 %

Procedure:
5-Bromo-1-(2-chloroethyl)-1H-indazole (183 mg, 0.703 mmol) was added to a suspension of (1S,4S)-(+)-5-aza-2-oxabicyclo[2.2.1]heptane hydrochloride (286 mg, 2.11 mmol), K2CO3 (485 mg, 3.52 mmol) and KI (117 mg, 0.703 mmol) in DMF (10 mL) under N2. The resulting suspension was stirred at 90° C. for 19 h. The suspension was cooled, and H2O (10 mL) was added. The aqueous solution was extracted with EtOAc, and the combined organic extracts were washed with brine. The organic solution was dried over Na2SO4 and concentrated under reduced pressure to afford clear viscous oil. Flash chromatography on silica gel (100:0 to 0:100 hexanes/(9:0.9:0.1 CH2Cl2/MeOH/NH4OH)) gave the title compound (88 mg, 39%) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.95-7.92 (m, 1H), 7.87-7.84 (m, 1H), 7.45 (dd, J=8.7, 1.8 Hz, 1H), 7.34 (d, J=8.7 Hz, 1H), 4.43 (t, J=6.7 Hz, 2H), 4.34 (br s, 1H), 3.92 (d, J=7.8 Hz, 1H), 3.56 (dd, J=7.8, 1.5 Hz, 1H), 3.34 (br s, 1H), 3.15-3.01 (m, 2H), 2.92 (d, J=21.9 Hz, 1H), 2.81 (dd, J=9.9, 1.5 Hz, 1H), 2.47 (br d, J=9.9 Hz, 1H), 1.79-1.60 (m, 1H).
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)=[O:14])=O)C1C=CC=CC=1.[Br:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1>[Pd]>[Br:36][C:37]1[CH:42]=[CH:41][C:40]([S:43]([NH:11][CH:12]([CH2:28][O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:21]=2)=[O:14])(=[O:45])=[O:44])=[CH:39][CH:38]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COC2CCCCO2)NC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Product: CCOC(=O)Cc1ccc(NC(=O)C(COC2CCCCO2)NS(=O)(=O)c2ccc(Br)cc2)cc1
Yield: 67.2 %

Procedure:
The procedure described in Example 15 was repeated, except that (RS)-2-(benzyloxycarbonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (2.0 g) was hydrogenolyzed in the presence of 10% Pd-C, and then, reacted with 4-bromobenzenesulfonyl chloride (2.08 g) to obtain (RS)-2-(4-bromobenzenesulfonyl-amino)-N-(4-(ethoxycarbonylmethyl) phenyl)-3-(tetrahydro-pyran-2-yloxy)propanamide (1.58 g).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:11]2[N:6]([C:7]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][C:17]4=[O:22])=[CH:12][C:8]=3[O:9][CH2:10]2)[C:5](=[O:23])[O:4]1.[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:1][CH2:2][C@H:3]2[C@H:11]3[N:6]([C:7]4[CH:15]=[CH:14][C:13]([N:16]5[CH2:21][CH2:20][O:19][CH2:18][C:17]5=[O:22])=[CH:12][C:8]=4[O:9][CH2:10]3)[C:5](=[O:23])[O:4]2)=[O:30])=[CH:27][CH:26]=1
Reactant: NC[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(NC[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12)c1ccc(Cl)cc1
Yield: 83.68 %

Procedure:
Using compound (3S,3aS)-3-aminomethyl-7-(3-oxomorpholin-4-yl)-3a,4-dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-1(3H)-one (the product of step (e) in Example 1) (60 mg, 0.188 mmol), p-chlorobenzoic acid (35 mg, 0.225 mmol), HATU (107 mg, 0.282 mmol), and TEA (38 mg, 0.376 mmol) as starting materials, preparation following the method as described in Example 11 (g) afforded white solid compound 72 mg, yield: 83.68%.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](O)=O)[C:7]([CH3:16])=[CH:6]2)#[N:2].[F:21][C:22]([F:34])([F:33])[C:23]1[N:28]=[CH:27][C:26]([C:29]([NH:31][NH2:32])=[O:30])=[CH:25][CH:24]=1>>[CH3:16][C:7]1[N:8]([CH2:12][C:13]2[O:30][C:29]([C:26]3[CH:27]=[N:28][C:23]([C:22]([F:33])([F:21])[F:34])=[CH:24][CH:25]=3)=[N:31][N:32]=2)[C:9]2[C:5]([CH:6]=1)=[C:4]([C:17]([F:19])([F:18])[F:20])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=2
Reactant: NNC(=O)c1ccc(C(F)(F)F)nc1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=O)O
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1nnc(-c2ccc(C(F)(F)F)nc2)o1

Procedure:
Synthesized as described in Example 35C using [5-cyano-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl]acetic acid and 6-(trifluoromethyl)-3-pyridinecarbohydrazide: 1H NMR (400 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.54 (d, J=8.3 Hz, 1H), 8.11 (d, J=8.3 Hz, 1H), 8.08 (d, J=8.3 Hz, 1H), 7.78 (d, J=8.3 Hz, 1H), 6.66 (s, 1H), 6.03 (s, 2H), 2.58 (s, 3H); MS (ES) m/z 474 (M+Na).
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.COC1C=C(OC)C=CC=1C[N:21]1[CH2:27][CH2:26][C:25]([F:29])([F:28])[CH2:24][C@@H:23]([N:30]([CH2:40][C:41]2[CH:42]=[N:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=2)[S:31]([CH2:34][CH2:35][C:36]([F:39])([F:38])[F:37])(=[O:33])=[O:32])[C:22]1=[O:49]>ClCCl>[F:29][C:25]1([F:28])[CH2:26][CH2:27][NH:21][C:22](=[O:49])[C@H:23]([N:30]([CH2:40][C:41]2[CH:42]=[N:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=2)[S:31]([CH2:34][CH2:35][C:36]([F:38])([F:39])[F:37])(=[O:33])=[O:32])[CH2:24]1
Reactant: COc1ccc(CN2CCC(F)(F)C[C@@H](N(Cc3ccc(OC)nc3)S(=O)(=O)CCC(F)(F)F)C2=O)c(OC)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CN([C@@H]2CC(F)(F)CCNC2=O)S(=O)(=O)CCC(F)(F)F)cn1

Procedure:
A mixture containing trifluoroacetic acid/trifluoromethanesulfonic acid (5:2 v/v, 0.76 ml) was added to 3,3,3-trifluoro-propane-1-sulfonic acid [(R)-1-(2,4-dimethoxy-benzyl)-5,5-difluoro-2-oxo-azepan-3-yl]-(6-methoxy-pyridin-3-ylmethyl)-amide (0.2 g, 0.24 mmol) in dichloromethane (10 ml). After 2 h the reaction mixture was concentrated under reduced pressure and the residue taken up in ethyl acetate and washed with water, saturated aqueous sodium bicarbonate and brine, dried (Na2SO4), filtered, concentrated under reduced pressure and purified over silica gel (heptane-ethyl acetate, 9:1-0:1): white solid 72 mg (69%);
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:26][C:27]2[CH:35]=[CH:34][C:30]3[O:31][CH2:32][O:33][C:29]=3[CH:28]=2)[C:7](=[O:25])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([C:21]([O:23]C)=[O:22])=[CH:10][CH:9]=2)=[O:4].CO.[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:26][C:27]2[CH:35]=[CH:34][C:30]3[O:31][CH2:32][O:33][C:29]=3[CH:28]=2)[C:7](=[O:25])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([C:21]([OH:23])=[O:22])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1ccc2c(=O)n(Cc3ccc4c(c3)OCO4)c(C(=O)OC)c(-c3ccccc3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2)c2cc(C(=O)O)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Reaction time: 12 h
Yield: 79 %

Procedure:
To a solution of 2-(benzo[1,3]dioxol-5-ylmethyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3,6-dicarboxylic acid dimethyl ester (300 mg) in THF (3 ml) were added methanol (3 ml) and 8N-aqueous sodium hydroxide solution (0.16 ml) at room temperature, and the mixture was stirred for 12 hrs. The reaction mixture was concentrated under reduced pressure, and 1N-hydrochloric acid was added to the residue. The aqueous layer of the mixture was acidified, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to give the title compound (230 mg).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1.[CH3:18][O:19][CH2:20][CH2:21]O.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOC(C)=O>[C:14]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:21][CH2:20][O:19][CH3:18])=[CH:9][CH:8]=2)[N:5]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: COCCO
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(O)cc2)n1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCOc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-(5-amino-3-tert-butyl-pyrazol-1-yl)phenol (500 mg, 2.16 mmol), 2-methoxyethanol (164.5 mg, 2.16 mmol), ADDP (818.2 mg, 3.24 mmol, 1.5 eq), and triphenylphosphine (850.5 mg, 3.24 mmol, 1.5 eq) in anhydrous THF was stirred at ambient temperature under nitrogen for 18 h. The reaction mixture was poured into EtOAc, and the organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated at reduced pressure. Purification by MPLC (eluting with 25% EtOAc/hexane) gave an oil which solidified upon standing, 507 mg (81%). 1H-NMR (DMSO-d6) δ 7.39 (dd, J=6.6, 2.4 Hz, 2H), 6.97 (dd, J=6.9, 2.7 Hz, 2H), 5.30 (s, 1H), 5.02 (broad s, 2H), 4.09 to 4.06 (m, 2H), 3.65 to 3.62 (m, 2H), 3.28 (s, 3H), 1.16 (s, 9H); MS LC-MS [M+H]+=290, RT=1.35 min.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][C:5]2[S:16][CH:17]=[C:18]([C:19]([CH3:21])=[CH2:20])[C:4]=2[O:3]1>C1COCC1.CO.[Pd]>[CH3:1][CH:2]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])[CH2:6][C:5]2[S:16][CH:17]=[C:18]([CH:19]([CH3:21])[CH3:20])[C:4]=2[O:3]1
Reactant: C=C(C)c1csc2c1OC(C)CN(C(=O)OC(C)(C)C)C2
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC1CN(C(=O)OC(C)(C)C)Cc2scc(C(C)C)c2O1
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a solution of tert-butyl 2-methyl-8-(1-methylethenyl)-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (269 mg) in THF-MeOH (2:1, 15 ml) was added 10% palladium on carbon (30 mg), and the mixture was stirred for 2 hr under a hydrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→10% ethyl acetate/hexane) to give the title compound (243 mg, 90%) as a colorless oil.
Reaction SMILES: C[Si]([C:5]1[NH:13][C:12]2[C:11](=[O:14])[NH:10][C:9]([N:15]([Si](C)(C)C)[Si](C)(C)C)=[N:8][C:7]=2[N:6]=1)(C)C.[C:24]([O:32][CH2:33][CH2:34][O:35][CH2:36]Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:24]([O:32][CH2:33][CH2:34][O:35][CH2:36][N:6]1[CH:5]=[N:13][C:12]2[C:11](=[O:14])[NH:10][C:9]([NH2:15])=[N:8][C:7]1=2)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C[Si](C)(C)c1nc2nc(N([Si](C)(C)C)[Si](C)(C)C)[nH]c(=O)c2[nH]1
Reactant: O=C(OCCOCCl)c1ccccc1
Product: Nc1nc2c(ncn2COCCOC(=O)c2ccccc2)c(=O)[nH]1
Yield: 32 %

Procedure:
A mixture of guanine (2.0 g), ammonium sulfate (1.5 g), and hexamethyldisilazane (126 g) was heated at reflux under nitrogen overnight. Excess hexamethyldisilazane was removed by distillation at reduced pressure. Dry benzene (10 ml) was added to the residual oil and any remaining ammounium sulfate removed by filtration. To this solution was added triethylamine (4 ml) and a solution of 2-benzoyloxyethoxymethyl chloride (2.8 g) in dry benzene (15 ml) and the mixture heated at reflux under nitrogen overnight. The solvent was evaporated in a rotary evaporator at reduced pressure and the residue dissolved in 95% ethanol. The solution was warmed on a steam bath for 1/2 hour to effect hydrolysis of the silyl groups. The ethanol was then evaporated and the residual solid was thoroughly washed with water, filtered and dried. Recrystallization from methanol and then from water (residual guanine was insoluble in the hot solvents and was removed by filtration) afforded 9-(2-benzoyloxyethoxymethyl)guanine (0.58 g., 14% of theroetical), m.p. 222°-226° C. A later condensation of the tris-(trimethylsilyl) guanine with a 60% excess of 2-benzoyloxyethoxymethyl chloride gave a 32% yield of 9-(2-benzoyloxyethoxymethyl)guanine.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].FC1C([O:38][C:39](=O)[CH2:40][CH2:41][CH2:42][CH2:43][O:44][N+:45]([O-:47])=[O:46])=C(F)C(F)=C(F)C=1F>CN(C1C=CN=CC=1)C>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:7]([CH2:11][O:12][C:39]([CH2:40][CH2:41][CH2:42][CH2:43][O:44][N+:45]([O-:47])=[O:46])=[O:38])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: O=C(CCCCO[N+](=O)[O-])Oc1c(F)c(F)c(F)c(F)c1F
Agent: CN(C)c1ccncc1
Product: CCCCc1nc(Cl)c(COC(=O)CCCCO[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Using the same procedure described in Example 1 but starting from 2-Butyl-4-chloro-1-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol (Losartan) (0.93 g, 2.19 mmol) and 5-(nitrooxy)pentanoic acid pentafluorophenyl ester (0.72 g, 2.19 mmol) TEA (0.30 ml, 2.19 mmol), DMAP (0.27 g, 2.19 mmol) after purification with Flash chromatography of the residue (CH2Cl2/MeOH 98:2) the title compound (0.72 g, 60%) was obtained as a white foam.
Reaction SMILES: O1C[CH2:4][CH2:3][CH2:2]1.[CH2:6]([C:19]1[NH:23][CH:22]=[C:21]([C:24]([OH:26])=[O:25])[CH:20]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C>C(O)CC>[CH2:6]([C:19]1[NH:23][CH:22]=[C:21]([C:24]([O:26][CH2:2][CH2:3][CH3:4])=[O:25])[CH:20]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C1CCOC1
Reactant: CCCCCCCCCCCCCc1cc(C(=O)O)c[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CCCO
Product: CCCCCCCCCCCCCc1cc(C(=O)OCCC)c[nH]1
Temperature: 60 °C
Yield: 73 %

Procedure:
To 25 ml of tetrahydrofuran were added 1.50 g (5.11 mmol) of 5-tridecylpyrrole-3-carboxylic acid and 1.27 g (6.15 mmol) of dicyclohexylcarbodiimide, followed by adding 3.8 ml of n-propyl alcohol and 62 mg of dimethylaminopyridine. Then the mixture was heated at 60° C. for 10 hours under stirring. After cooling, the resulting precipitates were filtered off and washed well with ether. The filtrate and the washing liquid were combined and concentrated. The residue was purified by subjecting it to column chromatography over silica gel (eluent: ethyl acetate/hexane=1/20) to obtain 1.26 g (73% yield) of propyl 5-tridecylpyrrole-3-carboxylate, m.p. 51°-52° C.