Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:18]=[C:17]4[C:13]([CH:14]=[N:15][N:16]4S(C4C=CC(C)=CC=4)(=O)=O)=[C:12]([C:29]4[O:30][C:31]([CH2:34][N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)=[N:32][N:33]=4)[CH:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[Na+].Cl>C(O)(C)C>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:18]=[C:17]4[C:13]([CH:14]=[N:15][NH:16]4)=[C:12]([C:29]4[O:30][C:31]([CH2:34][N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)=[N:32][N:33]=4)[CH:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnc(CN5CCOCC5)o4)cc(-c4cccc5[nH]ccc45)cc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: c1cc(-c2cc(-c3nnc(CN4CCOCC4)o3)c3cn[nH]c3c2)c2cc[nH]c2c1

Procedure:
A stirred solution of 6-(1H-indol-4-yl)-1-[(4-methylphenyl)sulfonyl]-4-[5-(4-morpholinylmethyl)-1,3,4-oxadiazol-2-yl]-1H-indazole (25 mg, 0.045 mmol) and 2M sodium hydroxide (3 ml) in isopropanol (10 ml) was stirred at room temperature for 1 h. The solution was treated with 2M hydrochloric acid (3 ml) and evaporated to low bulk until the product was precipitated. The resulting solid was collected by filtration and washed with water to give the title compound as a cream coloured solid (15 mg).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:25][C:26]([CH3:35])([CH3:34])[CH2:27][CH:28]1[CH2:31][CH:30]([CH:32]=O)[CH2:29]1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.C1(C)C=CC=CC=1>[Br:2][C:1]([Br:5])=[CH:32][CH:30]1[CH2:31][CH:28]([CH2:27][C:26]([CH3:35])([CH3:34])[CH3:25])[CH2:29]1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)CC1CC(C=O)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)CC1CC(C=C(Br)Br)C1
Reaction time: 0.75 h

Procedure:
To a solution of carbon tetrabromide (205 g) in methylene chloride (600 mL) was added a solution of triphenylphosphine (325 g) in methylene chloride (350 mL) dropwise at ice temperature. After the mixture was stirred at ice temperature for 45 min, a solution of 3-(2,2-dimethylpropyl)cyclobutanecarbaldehyde in toluene was added to the reaction at ice temperature. The mixture was stirred at ice temperature for 1 hr and aqueous 10 w/v % sodium carbonate (660 mL) was added to the mixture dropwise at the same temperature. The resultant precipitate was filtered off and the filtrate was extracted with chloroform. The organic layer was washed with water and brine, then dried over sodium sulfate. After an addition of silica gel to the mixture, the mixture was stirred at RT. The sodium sulfate and silica gel were filtered off and the filtrate was concentrated in vacuo. The resultant residue was purified by silica gel column chromatography (Eluent: hexane) to give the title compound (120.33 g).
Reaction SMILES: [CH2:1]([NH:3][S:4](=[O:7])(=[O:6])[NH2:5])[CH3:2].Cl[C:9]1[C:14]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])=[C:13]([Cl:24])[N:12]=[C:11]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[N:10]=1>>[Cl:24][C:13]1[N:12]=[C:11]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[N:10]=[C:9]([NH:5][S:4](=[O:7])(=[O:6])[NH:3][C:1]2[CH:2]=[CH:13][CH:14]=[CH:9][N:10]=2)[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23]
Reactant: CCNS(N)(=O)=O
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1Cl
Product: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)Nc1ccccn1
Yield: 100.5 %

Procedure:
According to the procedure described in referential Example 1e), ethyl-sulfamic acid amide (40 mg, Referential Example 22) was reacted with 4,6-dichloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine (100 mg, Referential Example 1d)) to give pyridine-2-sulfamic acid-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-amide (70 mg). tR=4.40 min (LC); [M−H]+=434.28 (ES−);
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.[Cl-].[Na+]>CN(C=O)C>[CH3:13][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([Cl:12])[CH:9]=[C:10]([CH3:11])[C:2]=1[NH2:1]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1cc(Cl)cc(C)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1218.4 %

Procedure:
To a 500 mL round-bottom flask, 0.2 mol of 2-amino-3-methyl-5-chlorobenzoic acid having the structural formula of IV-5, 300 mL of DMF and 2.0 grams of potassium carbonate were added, stirred at room temperature for 0.5 hour, dimethyl sulfate was dripped, reacted at 110° C. for 7 hours, and cooled to room temperature, poured into a saturated sodium chloride solution, extracted with acetate ethyl, dried over anhydrous sodium sulfate, filtered and the solvent was removed to obtain a crude product, 35.2 grams of 2-amino-3-methyl-5-chlorobenzoic acid methyl ester having a structural formula of VIII-3 was obtained by column chromatography, and the yield was 88.4%;
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][O:26][CH2:27][CH:28]([NH2:30])[CH3:29]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:30][CH:28]([CH3:29])[CH2:27][O:26][CH3:25])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: COCC(C)N
Product: COCC(C)NC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3C)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-methoxypropan-2-amine 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (d, J=6.82 Hz, 3 H) 2.44 (s, 3 H) 3.29 (s, 3 H) 3.30-3.33 (m, 1 H) 3.44 (dd, J=9.47, 6.44 Hz, 1 H) 4.15-4.32 (m, 1 H) 7.67 (d, J=8.08 Hz, 1 H) 7.74 (s, 1 H) 7.78 (br. s., 1 H) 8.19 (br. s., 1 H) 8.43 (d, J=6.82 Hz, 1 H) 8.50 (d, J=7.83 Hz, 2 H) 8.87-8.96 (m, 1 H) 13.19 (br. s., 1 H). MS m/z [M+H]+ 392.2
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15]Cl)=[CH:9][CH:8]=1)C.[OH:20][C:21]1[CH:36]=[CH:35][C:24]2[C:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[CH:26][O:27][C:23]=2[CH:22]=1>>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C:25]2[C:24]3[CH:35]=[CH:36][C:21]([O:20][CH2:15][C:14]#[C:13][C:10]4[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:12][CH:11]=4)=[CH:22][C:23]=3[O:27][CH:26]=2)=[CH:29][CH:30]=1
Reactant: Oc1ccc2c(-c3ccc(F)cc3)coc2c1
Reactant: CCOC(=O)[C@H](Cc1ccc(C#CCCl)cc1)OC
Product: CO[C@@H](Cc1ccc(C#CCOc2ccc3c(-c4ccc(F)cc4)coc3c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Chloro-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 5, Step A and 6-hydroxy-3-(4-fluorophenyl)benzofurane in a manner analogous to that described for Example 5, Step B. MS(ES) for C27H21FO5 [M−H]−: 443.2.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:10][O:9][CH2:8][C@H:7]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C@@H:6]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C@H:5]([CH3:21])[O:4][C:3]1=[O:22].[OH:23][C:24]1[C:25]([C:32](O)=[O:33])=[N:26][CH:27]=[CH:28][C:29]=1[O:30][CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>C(Cl)Cl>[CH2:12]([O:11][C@@H:7]1[C@@H:6]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C@H:5]([CH3:21])[O:4][C:3](=[O:22])[C@@H:2]([NH:1][C:32](=[O:33])[C:25]2[C:24]([OH:23])=[C:29]([O:30][CH3:31])[CH:28]=[CH:27][N:26]=2)[CH2:10][O:9][CH2:8]1)[CH:13]([CH3:14])[CH3:15]
Reactant: CC(C)CO[C@H]1[C@H](C)OC(=O)[C@@H](N)COC[C@@H]1OCC(C)C
Reactant: COc1ccnc(C(=O)O)c1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccnc(C(=O)N[C@H]2COC[C@H](OCC(C)C)[C@@H](OCC(C)C)[C@H](C)OC2=O)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.1 %

Procedure:
To a mixture of (3S,7S,8S,9S)-3-amino-7,8-diisobutoxy-9-methyl-1,5-dioxonan-2-one (170 mg, 0.536 mmol), 3-hydroxy-4-methoxypicolinic acid (136 mg, 0.803 mmol) and HATU (336 mg, 0.857 mmol) in a vial was added CH2Cl2 (3 mL), followed by 4-methylmorpholine (0.353 mL, 3.21 mmol), and the resulting suspension was stirred at room temperature for 3 h. The resulting orange solution was directly purified by flash chromatography (SiO2) to afford the title compound as a white solid (176 mg, 70%): 1H NMR (400 MHz, CDCl3) δ11.95 (s, 1H), 8.68 (d, J=8.0 Hz, 1H), 8.00 (d, J=5.2 Hz, 1H), 6.87 (d, J=5.2 Hz, 1H), 5.10-5.00 (m, 1H), 4.97 (dt, J=12.6, 6.3 Hz, 1H), 4.10-4.01 (m, 1H), 3.94 (s, 3H), 3.87-3.78 (m, 2H), 3.71 (dd, J=8.4, 6.1 Hz, 1H), 3.66-3.57 (m, 1H), 3.38-3.28 (m, 2H), 3.28-3.17 (m, 3H), 1.90-1.76 (m, 2H), 1.45 (t, J=5.8 Hz, 3H), 0.98-0.88 (m, 12H); 13C NMR (101 MHz, CDCl3) δ 170.33, 168.95, 155.38, 148.76, 140.66, 130.23, 109.58, 84.84, 83.75, 80.60, 77.74, 75.32, 73.97, 73.23, 56.11, 52.19, 29.13, 28.89, 19.60, 19.48, 19.47, 19.39, 18.66; ESIMS m/z 469.4 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:3]=1[O:4][C:5]1[C:14]([C:15]2[C:16]3[CH:25]=[CH:24][N:23](S(C4C=CC(C)=CC=4)(=O)=O)[C:17]=3[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=2)=[CH:13][C:8]2[NH:9][C:10](=[O:12])[NH:11][C:7]=2[CH:6]=1.C(O)C.[OH-].[Na+].O>>[F:1][C:2]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:3]=1[O:4][C:5]1[C:14]([C:15]2[C:16]3[CH:25]=[CH:24][NH:23][C:17]=3[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=2)=[CH:13][C:8]2[NH:9][C:10](=[O:12])[NH:11][C:7]=2[CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cc5[nH]c(=O)[nH]c5cc4Oc4ccc(F)cc4F)cn(C)c(=O)c32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1cc(-c2cc3[nH]c(=O)[nH]c3cc2Oc2ccc(F)cc2F)c2cc[nH]c2c1=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
A solution of 5-(2,4-difluorophenoxy)-6-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one (0.024 g, 0.035 mmol) in ethanol (0.4 mL, 7 mmol) was treated with 1.0 M sodium hydroxide in water (0.18 mL, 0.18 mmol) and stirred at 80° C. for 30 min. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water 0.1% ammonium hydroxide, at flow rate of 30 mL/min) gave the desired product (3 mg, 20%). 1H NMR (500 MHz, DMSO-d6) δ 11.93 (br s, 1H), 10.62 (br s, 2H), 7.34-7.26 (m, 1H), 7.22 (d, J=2.8 Hz, 1H), 7.17 (s, 1H), 7.02-6.87 (m, 3H), 6.52 (s, 1H), 6.17 (d, J=2.7 Hz, 1H), 3.50 (s, 3H); LCMS calculated for C21H15F2N4O3 (M+H)+: m/z=409.1. found: 409.1.
Reaction SMILES: Cl[C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[CH3:17][NH2:18].O>C(O)C>[N+:11]([C:5]1[CH:4]=[C:3]([N+:14]([O-:16])=[O:15])[C:2]([NH:18][CH3:17])=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8])([O-:13])=[O:12]
Reactant: NC(=O)c1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CN
Solvent: CCO
Solvent: O
Product: CNc1cc(C(N)=O)c([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 98 %

Procedure:
A solution of 5-chloro-2,4-dinitrobenzamide (6.14 g, 25 mmol) [Goldstein, H.; Stamm, R.; Helv. Chim. Acta, 1952, 35, 1330-1333] and 40% aqueous methylamine (20 mL) in ethanol (80 mL) is heated in a sealed pressure vessel at 100° C. for 2 h. After cooling, dilution with water gives 2,4-dinitro-5-methylaminobenzamide (5.89 g, 98%). 1H NMR (DMSO) δ8.88 (1H, q, J=4.9 Hz), 8.76 (1H, s), 8.07 (1H, brs), 7.77 (1H, brs), 6.98 (1H,s), 3.07 (3H, d, J=5.0 Hz).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][C:18]=3[CH3:28])[C:12]([NH2:29])=[CH:11][CH:10]=2)=[N:3]1.[C:30]1(=[O:40])[C@@H:38]2[C@@H:33]([CH2:34][CH2:35][CH2:36][CH2:37]2)[C:32](=O)[O:31]1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:29]=[C:32]([C@H:33]4[CH2:34][CH2:35][CH2:36][CH2:37][C@H:38]4[C:30]([OH:40])=[O:31])[N:15]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][C:24]([F:25])([F:26])[F:27])=[CH:19][C:18]=4[CH3:28])[C:13]=3[CH:14]=2)=[N:3]1
Reactant: Cc1cc(OC(F)(F)F)ccc1CNc1cc(OCc2ccn(C)n2)ccc1N
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Product: Cc1cc(OC(F)(F)F)ccc1Cn1c([C@H]2CCCC[C@H]2C(=O)O)nc2ccc(OCc3ccn(C)n3)cc21

Procedure:
The title compound was prepared using analogous conditions described in Example 92 using 5-((1-methyl-1H-pyrazol-3-yl)methoxy)-N1-(2-methyl-4-(trifluoromethoxy)benzyl)benzene-1,2-diamine and cis-hexahydroisobenzofuran-1,3-dione in Step D. MS (ESI): mass calcd. for C28H29F3N4O4, 542.20; m/z found, 543.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 7.71 (d, J=7.7, 1H), 7.58 (d, J=2.2, 1H), 7.35 (s, 1H), 7.24 (s, 1H), 7.15 (s, 1H), 7.01 (d, J=10.0, 1H), 6.42 (d, J=8.8, 1H), 6.18 (d, J=2.2, 1H), 5.72-5.60 (m, 2H), 4.96 (s, 2H), 3.76 (s, 3H), 3.65 (s, 1H), 2.72 (s, 1H), 2.51 (s, 3H), 2.22-1.66 (m, 5H), 1.62-1.33 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([OH:16])=O)=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([CH2:12][CH3:13])[CH:6]=2.[NH2:17][C:18]1[C:19]([N:27]2[CH2:32][CH2:31][CH2:30][C@H:29]([NH:33]C(=O)OC(C)(C)C)[CH2:28]2)=[C:20]2[CH2:26][CH2:25][O:24][C:21]2=[N:22][CH:23]=1.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>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:14]([NH:17][C:18]2[C:19]([N:27]3[CH2:32][CH2:31][CH2:30][C@H:29]([NH2:33])[CH2:28]3)=[C:20]3[CH2:26][CH2:25][O:24][C:21]3=[N:22][CH:23]=2)=[O:16])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([CH2:12][CH3:13])[CH:6]=2
Reactant: CCc1ccc2cc(N)c(C(=O)O)nc2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3c2CCO3)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1ccc2cc(N)c(C(=O)Nc3cnc4c(c3N3CCC[C@H](N)C3)CCO4)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 11.7 %

Procedure:
3-Amino-7-ethylquinoline-2-carboxylic acid (24.5 mg, 0.113 mmol), tert-butyl [(3S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate (38.3 mg, 0.114 mmol) and HATU (136.1 mg, 0.3579 mmol), DMF (2.00 mL) was added, followed by DIPEA (152.9 mg, 1.183 mmol). The reaction mixture was stirred at room temperature for 3 h and then concentrated under reduced pressure. To the resulting residue DCM (2.0 mL) was added followed by T (2.0 mL). The mixture was stirred at room temperature for 30 min. and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a yellow solid (5.7 mg, 12%). LCMS calc. for C24H29N6O2 (M+H)+: m/z=433.2. found 433.2. 1H NMR (500 MHz, DMSO-d6) δ 8.82 (s, 1H), 7.65-7.61 (m, 2H), 7.51 (s, 1H), 7.37 (dd, J=8.6, 1.5 Hz, 1H), 6.81 (s, 2H), 4.52 (t, J=8.6 Hz, 2H), 3.46-3.39 (m, 2H), 3.22-3.17 (m, 1H), 3.17-3.10 (m, 1H), 3.07-3.00 (m, 1H), 2.88-2.81 (m, 1H), 2.76 (q, J=7.5 Hz, 2H), 2.67-2.59 (m, 1H), 2.00-1.92 (m, 1H), 1.92-1.79 (m, 2H), 1.28 (t, J=7.5 Hz, 3H), 1.26-1.20 (m, 1H) ppm.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([O:25]COC)=[C:6]([O:23][CH3:24])[CH:7]=[C:8]2/[CH:13]=[CH:14]/[C:15]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16])[CH3:2].O>CC(C)=O.Cl>[CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([OH:25])=[C:6]([O:23][CH3:24])[CH:7]=[C:8]2/[CH:13]=[CH:14]/[C:15]([N:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)=[O:16])[CH3:2]
Reactant: CCc1cccc2c(/C=C/C(=O)N3CCCCC3)cc(OC)c(OCOC)c12
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CCc1cccc2c(/C=C/C(=O)N3CCCCC3)cc(OC)c(O)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.4 %

Procedure:
960 mg of (E)-1-[3-(5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthyl)-1-oxo-2-propenyl]piperidine was dissolved in 50 ml of acetone, to which 1 ml of concentrated hydrochloric acid was gradually added at room temperature. After stirring at room temperature for 5 hours, the reaction mixture was slowly poured into water. The resultant crystals were collected by filtration, washed with water and dried to obtain 760 mg of the titled compound as yellow crystals.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[S:13][CH2:14][CH2:15][NH3+:16].[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH:22]=O>>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[S:13][CH2:14][CH2:15][NH:16][CH2:22][C:18]1[O:17][CH:21]=[CH:20][CH:19]=1
Reactant: [NH3+]CCSc1ccc2ccccc2c1Cl
Reactant: O=Cc1ccco1
Agent: [Cl-]
Product: Clc1c(SCCNCc2ccco2)ccc2ccccc12
Yield: 57 %

Procedure:
The reductive amination step of 2-[(1-chloronaphthalen-2-yl)sulfanyl]ethanaminium chloride with furan-2-carbaldehyde was performed as described for compound I to obtain 2-[(1 chloronaphthalen-2-yl)sulfanyl]-N-(furan-2-ylmethyl)ethanamine in 57% yield.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].CC1(C)C(C)(C)O[B:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([OH:28])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)O1>O1CCOCC1>[CH3:1][C:2]1([CH3:7])[CH2:5][O:6][B:11]([C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:23]([OH:28])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)[O:4][CH2:3]1
Reactant: CC(C)(CO)CO
Reactant: CC1(C)OB(c2ccc(-c3ccccc3O)cc2)OC1(C)C
Solvent: C1COCCO1
Product: CC1(C)COB(c2ccc(-c3ccccc3O)cc2)OC1
Yield: 99 %

Procedure:
A mixture of 2,2-dimethylpropane-1,3-diol (4.0 g, 38 mmol) and 4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-ol (1.0 g, 3.4 mmol) in 1,4-dioxane (2 mL) was subjected to microwave irradiation at 210° C. for 1 hour. The cooled reaction mixture was partitioned between water (50 mL) and 1:1 EtOAc/heptane (25 mL:25 mL). The organic layer was washed with water (30 mL) and brine (30 mL), dried over Na2SO4 and concentrated in vacuo to give the title compound (0.95 g, 99% yield). GC/MS, M=282 at 5.31 min. 1H NMR (500 MHz, CDCl3) δ 7.94 (d, J=7.81 Hz, 2H), 7.48 (d, J=7.81 Hz, 2H), 7.31-7.26 (m, 2H), 7.03-6.98 (m, 2H), 3.82 (s, 4H), 1.08-1.04 (m, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]([CH3:22])([C:19]([OH:21])=[O:20])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([OH:18])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:31][C:32]1[O:33][C:34](=[O:38])[O:35][C:36]=1[CH3:37]>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@:9]([CH3:22])([C:19]([O:21][CH2:37][C:36]1[O:35][C:34](=[O:38])[O:33][C:32]=1[CH3:31])=[O:20])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([OH:18])[CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(Cc1ccc(O)c(O)c1)C(=O)O
Reactant: Cc1oc(=O)oc1CBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1oc(=O)oc1COC(=O)[C@](C)(Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C
Yield: 31 %

Procedure:
A solution of N-(t-butoxycarbonyl)-3-hydroxy-α-methyltyrosine (760 mg, 2.44 mmol), triethylamine (263 mg, 2.60 mmol) and 4-bromomethyl-5-methyl-1,3-dioxol-2-one (500 mg, 2.60 mmol) in dimethylformamide, 10 mL, is stirred at 60° C. for 3 hours under nitrogen. Most of the dimethylformamide is removed at 50°-60° C. and 0.1 mm and the residue is partitioned between saturated sodium bicarbonate solution, 10 mL, and ethyl acetate, 50 mL. The ethyl acetate extract is washed with water saturated with sodium sulfate, filtered and concentrated at 40°-45° C. and 15 mm. Flash chromatography of the residue over 40 g of silica gel 60 (230-400 mesh) with 3% methanol-97% chloroform as eluent affords 320 mg of the desired ester.
Reaction SMILES: [NH:1]([C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][OH:20])[O:13]2)=[C:5]([NH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[N:4]=1)[NH2:2].[CH:27]([CH:29]([CH:35]=O)[C:30]([O:32][CH2:33][CH3:34])=[O:31])=O.C(N(C(C)C)CC)(C)C>C(O)C>[OH:17][C@@H:16]1[C@H:15]([OH:18])[C@@H:14]([CH2:19][OH:20])[O:13][CH:12]1[N:9]1[CH:8]=[N:7][C:6]2[C:10]1=[N:11][C:3]([N:1]1[CH:35]=[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:27]=[N:2]1)=[N:4][C:5]=2[NH:21][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: NNc1nc(NC2CCCC2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reactant: CCOC(=O)C(C=O)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2nc(NC3CCCC3)c3ncn(C4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Temperature: 25 °C

Procedure:
(4S,2R,3R,5R)-2-[2-hydrazino-6-(cyclopentylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol (0.2 mmol) and ethyl 2,2-diformylacetate (0.28 mmol) were suspended in 3 mL of ethanol and to the suspension was added 5 mmol of diisopropylethylamine. The mixture was heated at reflux for 3 hours. Upon cooling to room temperature, the precipitate thus formed was collected by filtration, and washed with ethanol and ether to afford ethyl 1-{9-[(4S,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}pyrazole-4-carboxylate, a compound of Formula I.
Reaction SMILES: [C:1]([NH:4][NH2:5])([NH2:3])=[NH:2].Cl.[C:7]([CH:10]([C:14](=O)[CH3:15])[C:11](=O)[CH3:12])(=[O:9])[CH3:8]>CO>[C:7]([C:10]1[C:11]([CH3:12])=[N:5][N:4]([C:1]([NH2:3])=[NH:2])[C:14]=1[CH3:15])(=[O:9])[CH3:8]
Reactant: CC(=O)C(C(C)=O)C(C)=O
Reactant: N=C(N)NN
Agent: Cl
Solvent: CO
Product: CC(=O)c1c(C)nn(C(=N)N)c1C
Temperature: -10 °C
Reaction time: 24 h
Yield: 16 %

Procedure:
1.86 g of aminoguanidine hydrochloride were added to a solution of 3.0 g of triacetylmethane and 30 ml of methanol with cooling at -10° C., and the reaction mixture was stirred for one day with cooling with ice. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel chromatography (eluent: chloroform/methanol=5/1) and then recrystallized from ether-chloroform to obtain 484 mg of 4-acetyl-3,5-dimethyl-1H-pyrazole-1-carboxamidine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH3:19])[CH2:10][NH:11]C(=O)OC(C)(C)C)[CH:5]=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>ClCCl>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[NH2:11][CH2:10][CH:9]([NH:8][C:6]1[N:7]=[C:2]([NH2:1])[C:3]([N+:20]([O-:22])=[O:21])=[CH:4][CH:5]=1)[CH3:19]
Reactant: CC(CNC(=O)OC(C)(C)C)Nc1ccc([N+](=O)[O-])c(N)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(CN)Nc1ccc([N+](=O)[O-])c(N)n1

Procedure:
N6-(2-Amino-1-methylethyl)-3-nitropyridine-2,6-diamine trifluoracetate (Example 40A) is prepared in analogy to Example 40A from tert-butyl {2-[(6-amino-5-nitropyridin-2-yl)amino]propyl}carbamate (Example 39A) (560 mg, 1.8 mmol), trifluoroacetic acid (2.0 ml, 27 mmol) in dichloromethane (20 ml). 900 mg of the crude product are obtained thus as a solid.
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH2:14][C:15]2=O)=[CH:10][CH:9]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH2:14][C:15]2=[CH2:1])=[CH:10][CH:9]=1
Reactant: [Li]CCCC
Reactant: COc1ccc2c(c1)C(=O)CCC2
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCCc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
n-Butyl lithium (1.6M, 6.2 mL, 9.92 mmol) was added dropwise to a THF (20 mL) solution containing methyltriphenylphosphonium bromide (3.65 g, 10.22 mmol) cooled in an ice bath. The solution was stirred at room temperature for 3 hours. A THF (5 mL) solution of 7-methoxy-3,4-dihydronaphthalen-1(2H)-one (1 g, 5.68 mmol) was added dropwise. The solution was then stirred at 60° C. overnight. The solution was partitioned between ethyl ether and water. The organic phase was washed with water (3×) and brine and dried over MgSO4. The filtered solution was concentrated and the residue purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. 1H NMR (500 MHz, CDCl3): δ 7.25 (d, J=2.6 Hz, 1H); 7.10 (d, J=8.3 Hz, 1H); 6.86 (dd, J=2.6, 8.4 Hz, 1H); 5.55 (s, 1H); 5.05 (s, 1H); 3.88 (s, 3H); 2.86 (t, J=6.3 Hz, 2H); 2.61 (t, J=6.2 Hz, 2H); 1.96-1.92 (m, 2H). LCMS1 3.79 min. (M+1)=175