Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:11]([NH2:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:24][CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: NC(c1ccccc1)c1ccccc1
Product: c1ccc(C(Nc2nc3ccccc3[nH]2)c2ccccc2)cc1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and benzhydrylamine by Procedure A. The product was isolated by preparative LCMS to give the title compound as the free base (white solid, mp 255-258° C.). MS(ES+) m/z 300 ([M+1]+, 100). 1NMR (DMSO-d6) δ 6.20 (d, 1H), 6.75-7.65 (m, 15H), 10.5 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][CH2:9][CH3:10])=[CH:6][N:5]=[C:4]([C:11](=[O:13])[CH3:12])[CH:3]=1.[S:14]1[CH:18]=[CH:17][N:16]=[C:15]1[C:19]1[N:20]([CH2:24][C:25](O)=O)[CH:21]=[CH:22][N:23]=1.CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[CH2:9]([N:8]1[C:7]2[CH:6]=[N:5][C:4]([C:11](=[O:13])[CH3:12])=[CH:3][C:2]=2[N:1]=[C:25]1[CH2:24][N:20]1[CH:21]=[CH:22][N:23]=[C:19]1[C:15]1[S:14][CH:18]=[CH:17][N:16]=1)[CH3:10]
Reactant: O=C(O)Cn1ccnc1-c1nccs1
Reactant: CCNc1cnc(C(C)=O)cc1N
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: CCn1c(Cn2ccnc2-c2nccs2)nc2cc(C(C)=O)ncc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 1-(4-amino-5-ethylamino-pyridin-2-yl)-ethanone (54 mg, 0.3 mmol), (2-thiazol-2-yl-imidazol-1-yl)-acetic acid (61 mg, 0.3 mmol), EDCI (60 mg, 0.3 mmol) and pyridine (2 mL) is stirred at room temperature for 72 hr and then poured into water. The aqueous layer is extracted with ethyl acetate and the combined organic layers are dried over Na2SO4. Solvent is evaporated in vacuo and the residue is taken up in acetic acid (5 mL). The mixture is heated to reflux for 16 hr and saturated NaHCO3 solution is added to neutralize the reaction. The aqueous solution is extracted with ethyl acetate and the combined organic layers are dried over Na2SO4. Solvent is removed in vacuo and purification by preparative TLC provides the product as white solid. 1H NMR (CDCl3) δ 8.79 (d, 2H), 8.47 (d, 1H), 7.83 (d, 1H), 7.40 (d, 1H), 7.19 (d, 1H), 7.15 (d, 1H), 6.39 (s, 2H), 4.02 (q, 2H), 2.77 (s, 3H), 1.86 (t, 3H). LRMS 353.2 (MH+).
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].CCN(CC)CC.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([O-:15])=[O:14]>C(Cl)Cl>[CH2:1]([NH:5][S:22]([C:19]1[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][CH:20]=1)(=[O:23])=[O:24])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a solution of isobutylamine (5 mL, 0.052 mol) in CH2Cl2 (100 mL) was added Et3N (5.07 mL) and 4-nitrobenzenesulfonyl chloride (11.7 g, 0.052 mol) and the mixture was stirred at room temperature overnight. The resulting solution was washed with H2O (3×), dried and concentrated to afford the desired product (9.41 g, 70%).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:58][C@@H:59]1[CH2:64][CH2:63][CH2:62][CH2:61][C@H:60]1[OH:65]>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:58][C@@H:59]5[CH2:64][CH2:63][CH2:62][CH2:61][C@H:60]5[OH:65])=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N[C@@H]2CCCC[C@H]2O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and trans-(±)-2-aminocyclohexanol. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11-1.93 (m, 18 H) 3.32 (s, 1 H) 3.45 (m, 1 H) 3.64 (m, 1 H) 3.95 (s, 3 H) 4.07 (t, J=13.39 Hz, 2 H) 4.48 (m, 1 H) 4.64 (br. s., 1 H) 7.49 (d, J=8.0 Hz, 1 H) 7.55 (s, 1 H) 7.90 (s, 1 H) 8.03 (d, J=8.08 Hz, 1 H) 8.22 (s, 1 H) 8.28 (d, J=8.34 Hz, 1 H). [M+H] calculated for C28H36F2N6O4, 559; found 559.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:5]2[N:6]=[C:7]([CH3:14])[CH:8]=[C:9]([NH:10][CH2:11][CH2:12][NH2:13])[N:4]2[N:3]=1.[C:16]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:16]1([NH:13][CH2:12][CH2:11][NH:10][C:9]2[N:4]3[N:3]=[C:2]([CH3:1])[CH:15]=[C:5]3[N:6]=[C:7]([CH3:14])[CH:8]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1cc(NCCN)n2nc(C)cc2n1
Reactant: O=C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(NCCNC2CCCC2)n2nc(C)cc2n1
Reaction time: 1 h
Yield: 128 %

Procedure:
To a stirred solution of N-(2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl)-ethane-1,2-diamine (3.2 g, 16 mmol) and cyclopentanone (2.7 mL, 30 mmol) in methanol (30 mL)/acetic acid (3 mL) was added sodium cyanoborohydride (0.94 g, 15 mmol), portionwise. After stirring 1 hour the reaction was concentrated under reduced pressure and then extracted from saturated aqueous sodium bicarbonate with ethyl acetate. The combined extracts were dried (Na2SO4), concentrated under reduced pressure to give the crude product as a brown oil (5.6 g): +APcI MS (M+1)+ 274; 1H NMR (CDCl3) δ: 6.11 (s, 1H), 6.76 (s, 1H), 3.21 (t, 2H), 3.21 (m, 1H ), 3.04 (t, 1H), 2.42 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22]>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[CH:23]=[CH:24][CH:25]=1
Reactant: COc1cccc(N)c1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: COc1cccc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)c1
Yield: 78.4 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 3-methoxyaniline (107 mg, 0.87 mmol) to provide 193 (107 mg, 78% yield) as a white solid. LC-MS (M+H=318, obsd.=318).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[O:15][C:16]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[CH:17][N:18]=3)[CH:5]=[CH:4][C:3]1=2.C([O:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)(=O)C.[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[O:15][C:16]([CH:19]4[CH2:24][CH2:23][N:22]([CH2:33][CH2:32][CH2:31][CH2:30][OH:29])[CH2:21][CH2:20]4)=[CH:17][N:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC(=O)OCCCCBr
Reactant: CC1(C)CCC(C)(C)c2cc(-c3ncc(C4CCNCC4)o3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3ncc(C4CCN(CCCCO)CC4)o3)ccc21

Procedure:
The preparation was carried out as already described starting from 150 mg (0.44 mmol) of 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)oxazol-5-yl]piperidine and 96 μl (0.67 mmol) of 4-bromobutyl acetate. The protecting group was cleaved off by means of a 1N NaOH solution in methanol. The product was purified by means of preparative HPLC and converted into the hydrochloride by treatment with methanolic HCl.
Reaction SMILES: [N:1]([CH:4]([CH3:19])[CH2:5][O:6][C:7]1[C:8]([CH3:18])=[C:9]2[N:14]([CH:15]=1)[N:13]=[CH:12][N:11]=[C:10]2SC)=[N+:2]=[N-:3].[F:20][C:21]1[C:26]([OH:27])=[CH:25][N:24]=[C:23]2[NH:28][CH:29]=[CH:30][C:22]=12>>[N:1]([CH:4]([CH3:19])[CH2:5][O:6][C:7]1[C:8]([CH3:18])=[C:9]2[N:14]([CH:15]=1)[N:13]=[CH:12][N:11]=[C:10]2[O:27][C:26]1[C:21]([F:20])=[C:22]2[CH:30]=[CH:29][NH:28][C:23]2=[N:24][CH:25]=1)=[N+:2]=[N-:3]
Reactant: CSc1ncnn2cc(OCC(C)N=[N+]=[N-])c(C)c12
Reactant: Oc1cnc2[nH]ccc2c1F
Product: Cc1c(OCC(C)N=[N+]=[N-])cn2ncnc(Oc3cnc4[nH]ccc4c3F)c12

Procedure:
Procedures given in Tetrahedron Lett, 1977, 1977, and JACS, 1999, 3637 were modified. Thus, a 10 mL flask was charged with 1-(5-methyl-4-methylsulfanylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)-propan-2-ol (249 mg, 0.98 mmol), and tetrahydrofuran (4.91 mL) and cooled to 0° C. Triphenylphosphine (516 mg, 1.96 mmoles), diethyl azodicarboxylate (310 μL, 1.96 mmol) and diphenylphosphoryl azide (424 μL, 1.96 mmol) were added in order. The mixture was stirred at 23° C. for 15 h and then concentrated in vacuo. The crude material was purified by flash chromatography eluting with a mixture of 20% ethyl acetate in hexane to give (156 mg, 57%) of 6-(2-azidopropoxy)-5-methyl-4-methylsulfanylpyrrolo[2,1-f][1,2,4]triazine as white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.19 (1H, s), 7.85 (1H, s), 4.16 (1H, dd, J=2.8, 9.6 Hz), 4.05-3.96 (m, 2H), 2.60 (3H, s), 2.37 (3H, s), 1.21 (3H, d, J=6.3 Hz). LCMS m/z 254 (M+H+). B. 6-(2-Azido-propoxy)-5-methyl-4-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine and 4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-ol were reacted together according to the procedure described in Example 7 to afford 6-(2-azido-propoxy)-4-(4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-5-methyl-pyrrolo[2,1-f][1,2,4]triazine. The crude material was purified by preparative HPLC. 1H NMR (400 MHz, DMSO-d6) δ 12.18 (1H, s), 8.32 (1H, d, J=9.6 Hz), 8.02 (1H, s) 7.96 (1H, s), 6.60 (1H, d, J=3.6 Hz), 4.21 (1H, d, J=7.0 Hz), 4.09-4.02 (2H, m), 2.42 (3H, s), 1.23 (3H, d, J=6.3 Hz). LCMS m/z 382 (M+H+). C. A solution of 6-(2-azido-propoxy)-4-(4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-5-methyl-pyrrolo[2,1-f][1,2,4]triazine (20 mg, 0.05 mmol) in ethyl acetate (2.0 mL) was stirred in the presence of hydrogen (14 psi) and 10% Pd/C (10 mg) for 12 h. Excess hydrogen was removed and the mixture was filtered through Celite® and evaporated. The residue was purified by preparative HPLC to afford (10 mg, 54%) of the title compound. LCMS: m/z 357 (M+H+). Dihydrochloride salt: 1H NMR (400 MHz, DMSO-d6) δ 12.19 (1H, s), 8.31 (1H, d, J=8.9 Hz), 8.16 (2H, br. s), 8.05 (1H, m), s), 7.97 (1H, s), 7.60 (1H, s), 6.60 (1H, s), 4.19 (2H, m), 4.03 (2H, m), 3.65 (1H, m), 1.30 (3H, d, J=6.8 Hz).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([CH2:13][CH2:14][N:15]1[CH:23]=[N:22][C:21]2[C:16]1=[N:17][C:18]([NH2:25])=[N:19][C:20]=2Cl)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-:27].[Na+]>O1CCCC1>[CH2:1]([O:8][CH2:9][C@@H:10]([CH2:13][CH2:14][N:15]1[CH:23]=[N:22][C:21]2[C:20](=[O:27])[NH:19][C:18]([NH2:25])=[N:17][C:16]1=2)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: Nc1nc(Cl)c2ncn(CC[C@@H](CO)COCc3ccccc3)c2n1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc2c(ncn2CC[C@@H](CO)COCc2ccccc2)c(=O)[nH]1
Temperature: 60 °C

Procedure:
To a stirred solution of the chloropurine (13a) (325 mg, 0.9 mmol) in tetrahydrofuran (15 ml) was added hydrochloric acid (2M, 15 ml) and stirred at 60° C. under argon, for 26H. The reaction mixture was cooled in a water bath and sodium hydroxide solution (10M) added until pH9. The aqueous phase was extracted with methanol:ethyl acetate. (7:93, 4×35 ml). The organic phase was dried over sodium sulphate, filtered and evaporated in vacuo to give an oil (150 mg). On standing a white solid crystallised from the aqueous phase which was filtered off, washed with water (5 ml) and diethylether and dried in vacuo to give the title compound (14a) (175 mg, 56.8%). 1H NMR (400 MHz, DMSO-d6) 10.55 (1H, s), 7.66 (1H, s), 7.40 to 7.22 (5H, m), 6.44 (2H, bs), 4.51 (1H, t), 4.42 (2H, t), 4.00 (2H, t), 3.49 to 3.30 (4H, m), 1.76 (2H, q), 1.64 (1H, m). HPLC purity (Method) 98.3%, chiral HPLC (Method D) 89.6% e.e., retention time major peak 10.3 mins, minor peak 6.9 minutes. (C17H11N5O3,−7.7 ppm, NH3Cl) m/z 343.1617. The oil was purified by column chromatography on silica gel eluting with an increasing gradient of methanol (8–22%) in methylene chloride to yield (14a) (87 mg, 28.2%) as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1.[H][H]>CO.[Pd]>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:2]2([CH3:1])[CH2:11][CH2:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[O:3]2)=[CH:15][CH:16]=1
Reactant: [H][H]
Reactant: CC1(COc2ccc([N+](=O)[O-])cc2)C=Cc2ccccc2O1
Agent: [Pd]
Solvent: CO
Product: CC1(COc2ccc(N)cc2)CCc2ccccc2O1
Yield: 70.8 %

Procedure:
780 mg of 2-methyl-2-(4-nitrophenoxymethyl)-2H-chromene (prepared as described in Preparation 3) were dissolved in 20 ml of methanol, and 160 mg of 10% w/w palladium-on-carbon were added to the solution. The solution was then hydrogenated at room temperature at a hydrogen pressure of about one atmosphere for about 10 hours. At the end of this time, the catalyst was filtered off, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography eluted with a 2:1 by volume mixture of hexane and ethyl acetate, to afford 500 mg of the title compound as a pale yellow oily substance.
Reaction SMILES: C([O:8][C:9]1[C:10]([F:33])=[C:11]([CH:18](C(OC(C)(C)C)=O)[C:19]([O:21]C(C)(C)C)=[O:20])[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])C1C=CC=CC=1.Cl>C(O)(=O)C>[F:33][C:10]1[C:9]([OH:8])=[C:14]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:12][C:11]=1[CH2:18][C:19]([OH:21])=[O:20]
Reactant: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1F
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc([N+](=O)[O-])c(O)c1F
Temperature: 25 °C

Procedure:
Di-tert-butyl (3-benzyloxy-2-fluoro-4-nitrophenyl)malonate (6.87 g, 14.9 mmol), acetic acid (200 ml) and concentrated hydrochloric acid (35 ml) were stirred at 120° C. for 6 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, whereby the title compound was obtained as a brown oil (this compound was provided for the subsequent reaction without further purification).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH2:20][CH2:19][CH2:18]2)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: COC(=O)[C@H](Cc1ccc2ncccc2c1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: COC(=O)[C@H](Cc1ccc2c(c1)CCCN2)NC(=O)OC(C)(C)C
Yield: 78.9 %

Procedure:
A suspension of #213 (1.5 g, 4.55 mmol, 1 eq.) and palladium on carbon (150 mg) in ethanol (20 mL) was stirred at 50° C. under 30 psi of hydrogen overnight. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The residue was purified by silica column chromatography (Gradient: 40% ethyl acetate in petroleum ether) to afford #214 (1.2 g, 80%) as an oil. 1H NMR (400 MHz, CDCl3): δ 6.70 (d, 2H), 6.40 (m, 1H), 4.95 (m, 1H), 4.49 (m, 1H), 3.77 (s, 3H), 3.28 (m, 2H), 2.97 (m, 2H), 2.71 (m, 2H), 1.95 (m, 2H), 1.26 (s, 9H), HPLC (Protocol Y): m/z 357.0 [M+Na+] retention time=5.304 minutes (purity >98%). Chiral HPLC retention time: 4.64 min (purity=98%)(Column: Chiralcel OJ-H, 150×4.6 mm, 5 μm; Mobile phase: ethanol (0.05% diethylamine) in CO2 from 5% to 40% over 15 minutes; Flow rate: 2.5 mL/minute.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[N:12]=[C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH:25]=[N:24][N:23]=[N:22]4)=[N:19][CH:20]=3)[CH:10]=[N:9]2)[CH2:4][CH2:3]1.[C:26]1([CH2:32][S:33](Cl)(=[O:35])=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:32]([S:33]([N:2]1[CH2:3][CH2:4][CH:5]([N:8]2[N:12]=[C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH:25]=[N:24][N:23]=[N:22]4)=[N:19][CH:20]=3)[CH:10]=[N:9]2)[CH2:6][CH2:7]1)(=[O:35])=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: c1cc(-n2cnnn2)ncc1OCc1cnn(C2CCNCC2)n1
Agent: Cl
Product: O=S(=O)(Cc1ccccc1)N1CCC(n2ncc(COc3ccc(-n4cnnn4)nc3)n2)CC1

Procedure:
The title compound was synthesized using Intermediate 15 and phenylmethanesulfonyl chloride in a similar manner as described in Example 39. 1H NMR (DMSO-d6): δ 10.07 (1H, s), 8.41 (1H, d), 8.00 (1H, d), 7.96 (1H, s), 7.86 (1H, dd), 7.36 (5H, m), 5.35 (2H, s), 4.68 (1H, m), 4.43 (2H, s) 3.54 (2H, m), 2.99 (2H, m), 2.12 (2H, m), 1.91 (2H, m).
Reaction SMILES: [CH2:1]([O:3][C:4](Cl)=[O:5])[CH3:2].[CH3:7][N:8]([CH2:10][C:11]1[S:15][C:14]([CH2:16][S:17][CH2:18][CH2:19][NH:20][C:21]2[N:25]([CH3:26])[N:24]=[C:23]([NH2:27])[N:22]=2)=[CH:13][CH:12]=1)[CH3:9].C(=O)([O-])[O-].[Na+].[Na+].O>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:5])[NH:27][C:23]1[N:22]=[C:21]([NH:20][CH2:19][CH2:18][S:17][CH2:16][C:14]2[S:15][C:11]([CH2:10][N:8]([CH3:7])[CH3:9])=[CH:12][CH:13]=2)[N:25]([CH3:26])[N:24]=1)[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CN(C)Cc1ccc(CSCCNc2nc(N)nn2C)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)Nc1nc(NCCSCc2ccc(CN(C)C)s2)n(C)n1
Yield: 56.2 %

Procedure:
A cooled mixture of ethylchloroformate (0.45 g) in pyridine was treated with a solution of N5 -[2-[[[5-[(dimethylamino)methyl]-2-thienyl]methyl]thio]ethyl]-1-methyl-1H-1,2,4-triazole-3,5-diamine (0.7 g) in pyridine (8 ml). Sodium carbonate (2 g) and water (10 ml) were added and the mixture evaporated in vacuo. The residue was dissolved in water (15 ml) and extracted with hot isopropanol (30 ml). The extract was evaporated and the residue purified by column chromatography (silica:methanol:0.88 ammonia; 79:1) to give the title compound (0.48 g).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH2:16])(=[O:15])=[O:14].CO>C(Cl)Cl>[OH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH2:16])(=[O:14])=[O:15]
Reactant: COc1ccccc1S(N)(=O)=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: NS(=O)(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
22.2 ml of boron tribromide are added dropwise, under nitrogen and at room temperature, over 15 minutes to a suspension of 39 g of 2-methoxyphenylsulfonamide in 210 ml of dry methylene chloride. The reaction mixture is then stirred for 1 hour at room temperature. After the mixture has been cooled to 0° C., 200 ml of methanol are added over 15 minutes and the clear solution is concentrated. The oily residue is taken up in ethyl acetate and the solution is washed twice with water, dried over sodium sulfate, and evaporated to dryness. The residue is triturated with petroleum ether, affording 25.1 g of 2-hydroxyphenylsulfonamide with a melting point of 136°-138° C. The hydroxyphenylsulfonamides of the formula VIII listed in the following Table 1 are obtained in analogous manner:
Reaction SMILES: COC(=O)CO[C:6]1[N:11]=[C:10]2[S:12][C:13]([C:16](=[O:18])[NH2:17])=[C:14]([NH2:15])[C:9]2=[C:8](C)[CH:7]=1.[N+:21]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)([O-:23])=[O:22]>O1CCOCC1>[NH2:15][C:14]1[C:9]2[C:10](=[N:11][CH:6]=[CH:7][C:8]=2[NH:28][C:27]2[CH:29]=[CH:30][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=2)[S:12][C:13]=1[C:16]([NH2:17])=[O:18]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)COc1cc(C)c2c(N)c(C(N)=O)sc2n1
Solvent: C1COCCO1
Product: NC(=O)c1sc2nccc(Nc3ccc([N+](=O)[O-])cc3)c2c1N
Yield: 9.9 %

Procedure:
A solution of 20 mg trifluoromethanesulfonic acid 3-amino-2-carbamoyl-thieno[2,3-b]pyridin-4-yl ester (see Example 19) and 40.5 mg 4-nitroaniline in 1 mL of dry dioxane was heated at 95° C. overnight under N2. The reaction was concentrated and applied to a 2 mm silica gel prep plate that was developed twice in 7.5% MeOH—CH2Cl2. The band was eluted with 20% MeOH—CH2Cl2, concentrated in vacuo, re-dissolved in 5% MeOH—CH2Cl2, filtered, concentrated, and dried in vacuo at 60° overnight to get 2.2 mg of the title compound as an orange solid.
Reaction SMILES: [CH:1]1[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.[C:17](Cl)([CH3:20])([CH3:19])[CH3:18].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.O>[C:17]([C:8]1[C:7]2[C:16]3=[C:15]4[C:4](=[CH:5][CH:6]=2)[CH:3]=[CH:2][CH:1]=[C:14]4[CH:13]=[CH:12][C:11]3=[CH:10][CH:9]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: c1cc2ccc3cccc4ccc(c1)c2c34
Reactant: CC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1ccc2ccc3cccc4ccc1c2c34
Temperature: 0 °C
Reaction time: 2 h
Yield: 51.1 %

Procedure:
In a reaction vessel, 50.0 g (0.25 mol) of pyrene, 27.6 g (0.30 mol) of tert-butyl chloride, and 200 ml of methylene chloride were charged, and the resulting mixture was cooled to 0° C. Next, 35.3 g (0.27 mol) of aluminum chloride was charged, followed by stirring at room temperature for 2 hours. Then, iced water and methylene chloride were added, and an organic layer was extracted, washed with water, dried over magnesium sulfate, and recrystallized to produce 33 g of tert-butylpyrene crystals in a yield of 51%.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([N+:16]([O-])=O)=[C:14]([CH3:19])[N:13]=[C:12]([NH:20][C@H:21]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[CH2:22][OH:23])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[NH4+].[Cl-]>[Zn].CO.C1COCC1>[NH2:16][C:15]1[C:10]([NH:9][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[NH:8][N:7]=2)=[N:11][C:12]([NH:20][C@H:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:22][OH:23])=[N:13][C:14]=1[CH3:19]
Reactant: Cc1nc(N[C@@H](CO)c2ccc(F)cc2)nc(Nc2cc(C3CC3)[nH]n2)c1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(N[C@@H](CO)c2ccc(F)cc2)nc(Nc2cc(C3CC3)[nH]n2)c1N
Reaction time: 3 h

Procedure:
To a suspension of (R)-2-[4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6-methyl-5-nitropyrimidin-2-ylamino]-2-(4-fluorophenyl)ethanol (Method 1, 1.0 g, 2.4 mmol) and zinc dust (0.79 g, 12.0 mmol) in the mixture of MeOH:THF (1:1, 70 ml) was slowly added saturated NH4Cl solution (10 ml). After 3 hours, the reaction was treated with saturated aqueous NH4OAc solution (40 ml), and the resulting mixture was stirred for 30 minutes. The reaction was then filtered through a plug of celite with EtOAc (100 ml). The resulting aqueous layer was extracted with EtOAc (2×100 ml), dried, filtered, and concentrated to give (0.8 g, 90%). MS: Calcd.: 383; Found: [M+H]+ 384.
Reaction SMILES: [CH:1]([CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:13])[C:5]1=[O:14])([CH3:3])[CH3:2].[N+:15]([O-])([OH:17])=[O:16]>S(=O)(=O)(O)O>[CH:1]([CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=2)[N:6]([CH3:13])[C:5]1=[O:14])([CH3:3])[CH3:2]
Reactant: CC(C)C1C(=O)N(C)c2ccccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(C)C1C(=O)N(C)c2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (rac)-3-isopropyl-1-methyl-1,3-dihydro-indol-2-one (4.5 g) (J. Chem. Soc. Chem. Commun. 1986, 115-116) in concentrated sulfuric acid (7 ml) is added drop-wise a mixture of nitric acid (65%, 1.7 ml) and concentrated sulfuric acid (2.8 ml) at 0° C. over a period of 30 min. The reaction mixture is stirred at this temperature for 30 min and then poured into ice-water. The precipitate is collected by filtration and washed with water to give the title compound (3.4 g).