Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([CH3:14])[CH:10]=[C:9]2[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.CS(O[CH2:28][C:29]1[C:34]([Cl:35])=[CH:33][CH:32]=[C:31]([N:36]([CH3:51])[C:37](=[O:50])[CH2:38][N:39]2[C:43](=[O:44])[C:42]3=[CH:45][CH:46]=[CH:47][CH:48]=[C:41]3[C:40]2=[O:49])[C:30]=1[Cl:52])(=O)=O.O>CN(C)C=O>[Cl:52][C:30]1[C:31]([N:36]([CH3:51])[C:37](=[O:50])[CH2:38][N:39]2[C:40](=[O:49])[C:41]3=[CH:48][CH:47]=[CH:46][CH:45]=[C:42]3[C:43]2=[O:44])=[CH:32][CH:33]=[C:34]([Cl:35])[C:29]=1[CH2:28][O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([CH3:14])[CH:10]=[C:9]2[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: Cc1cc(OCc2ccccn2)c2cccc(O)c2n1
Reactant: CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)c(COS(C)(=O)=O)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2ccccn2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN4C(=O)c5ccccc5C4=O)c3Cl)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
To a suspension of sodium hydride (59.5 mg) in N,N-dimethylformamide (0.5 ml) was added a solution of 8-hydroxy-2-methyl-4-(2-pyridylmethoxy)quinoline (600 mg) in N,N-dimethylformamide (5 ml) in ice water bath under nitrogen atmosphere, and the mixture was stirred for 30 minutes at the same condition. To the mixture was dropwise added a solution of 2,6-dichloro-3-[N-methyl-N-(phthalimidoacetyl)amino]benzyl methanesulfonate (1 g) in N,N-dimethylformamide (25 ml) in ice water bath under nitrogen atmosphere, and the mixture was stirred for 2 hours at the same temperature and for 1 day at ambient temperature. The reaction mixture was poured into water and extracted with chloroform. The organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform-methanol) to give 8-[2,6-dichloro-3-[N-methyl-N-(phthalimidoacetyl)amino]benzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline (772 mg) as amorphous powder.
Reaction SMILES: CO[C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[C:7]([CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[N:6]=1)=[O:4].Cl.[CH3:18][NH:19][C:20]([C:22]1[C:26]([NH2:27])=[CH:25][N:24]([CH3:28])[N:23]=1)=[O:21]>>[NH2:11][C:10]1[C:5]([C:3]([NH:27][C:26]2[C:22]([C:20](=[O:21])[NH:19][CH3:18])=[N:23][N:24]([CH3:28])[CH:25]=2)=[O:4])=[N:6][C:7]([CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)=[CH:8][N:9]=1
Reactant: CNC(=O)c1nn(C)cc1N
Reactant: COC(=O)c1nc(C2CCCO2)cnc1N
Agent: Cl
Product: CNC(=O)c1nn(C)cc1NC(=O)c1nc(C2CCCO2)cnc1N
Yield: 64 %

Procedure:
According to the procedure described in step 2 of example 14, 3-amino-6-(tetrahydrofuran-2-yl)pyrazine-2-carboxylic acid methyl ester was reacted with 4-amino-1-methyl-1H-pyrazole-3-carboxylic acid methylamide hydrochloride to obtain the title compound as yellow solid (64%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](Cl)=[CH:11][C:10]=1[Br:16])([CH3:4])([CH3:3])[CH3:2].BrC1C(O)=CC=C(C)[N:20]=1>>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[C:10]([Br:16])=[N:20][C:12]([CH3:11])=[CH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(O)c(Br)n1
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Product: Cc1ccc(OCC(=O)OC(C)(C)C)c(Br)n1
Yield: 79 %

Procedure:
Following the general method as outlined in Intermediate 1, starting from 2-Bromo-6-methylpyridin-3-ol (Activate Scientific), the title compound was obtained in 79% yield as a yellow liquid after purification by flash column chromatography (silica), eluting with chloroform and methanol (98:2).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:7]([CH:8]=[C:9]([Cl:11])[CH:10]=1)=[N:6][N:5]([CH2:12][C:13](=O)[CH3:14])[CH:4]=2.[Si](OC(C)[CH2:25][N:26]1C=C2C(C=C(Cl)C=C2Cl)=N1)(C(C)(C)C)(C)C.[Si]([O:45][CH:46]([CH3:61])[CH2:47][NH:48][CH2:49][C:50]1[C:55]([N+:56]([O-])=O)=[CH:54][C:53]([Cl:59])=[CH:52][C:51]=1[Cl:60])(C(C)(C)C)(C)C>>[NH2:48][C:13]([CH3:14])([CH2:12][N:5]1[CH:4]=[C:3]2[C:7]([CH:8]=[C:9]([Cl:11])[CH:10]=[C:2]2[Cl:1])=[N:6]1)[C:25]#[N:26].[Cl:60][C:51]1[C:50]2[C:55]([CH:54]=[C:53]([Cl:59])[CH:52]=1)=[N:56][N:48]([CH2:47][C:46](=[O:45])[CH3:61])[CH:49]=2
Reactant: CC(CNCc1c(Cl)cc(Cl)cc1[N+](=O)[O-])O[Si](C)(C)C(C)(C)C
Reactant: CC(Cn1cc2c(Cl)cc(Cl)cc2n1)O[Si](C)(C)C(C)(C)C
Agent: CC(=O)Cn1cc2c(Cl)cc(Cl)cc2n1
Product: CC(N)(C#N)Cn1cc2c(Cl)cc(Cl)cc2n1
Yield: 54 %

Procedure:
2-Amino-3-(4,6-dichloro-2H-indazol-2-yl)-2-methylpropionitrile (88 mg, 54%) was prepared using a procedure similar to that described in Example 1, part b, except starting from 1-(4,6-dichloro-2H-indazol-2-yl)propan-2-one (146 mg). 1-(4,6-Dichloro-2H-indazol-2-yl)propan-2-one was prepared using a procedure similar to that described in Example 105 part c and d except starting from 2-[2-(tert-butyldimethylsilanyloxy)propyl]-4,6-dichloro-2H-indazole that was prepared using a procedure similar to that described in Example 132 part a except starting from [2-(tert-butyldimethylsilanyloxy)propyl]-(2,4-dichloro-6-nitrobenzyl)amine described in Example 116.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]1[C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C=O)C>[CH2:21]([O:20][C:18]([C:10]1[NH:9][C:17]2[C:12]([C:11]=1[Br:1])=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:19])[CH3:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]c2ccccc2c1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.4 %

Procedure:
A solution of N-bromosuccinimide (4.94 g, 27.7 mmol) in DMF (20 mL) was added dropwise to a stirred solution of ethyl 1H-indole-2-carboxylate (5.0 g, 26.4 mmol) in DMF (15 mL) at 0˜5° C. After the addition was completed, the reaction was warmed to room temperature and stirring was continued for an additional 1.5 h. The reaction mixture was poured over ice water and the resulting precipitate was collected and dried to give 3-bromo-1H-indolecarboxylic acid ethyl ester (6.68 g, 81%) as a white solid: 1H NMR (DMSO-d6) δ 1.37 (t, J=7.2 Hz, 3H), 4.38 (q, J=7.2 Hz, 2H), 7.18-7.22 (m, 1H), 7.34-7.38 (m, 1H), 7.50 (dd, J=8.3, 0.8 Hz, 1H), 7.55 (dd, J=8.3, 0.8 Hz, 1H), 12.22 (br s, 1H); MS (ESI) m/z 268 (MH+); 266 ([M−H]−).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=2[N:10]=[C:9]1[CH:18]([N:22]([CH2:32][CH2:33][CH2:34][N:35]1C(=O)C2C(=CC=CC=2)C1=O)[C:23](=[O:31])[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN>C(O)C>[NH2:35][CH2:34][CH2:33][CH2:32][N:22]([CH:18]([C:9]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:12]2[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=2[N:10]=1)[CH:19]([CH3:21])[CH3:20])[C:23](=[O:31])[C:24]1[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=1
Reactant: Cc1ccc(C(=O)N(CCCN2C(=O)c3ccccc3C2=O)C(c2nc3cc(C)ccc3n2Cc2ccccc2)C(C)C)cc1
Agent: NN
Solvent: CCO
Product: Cc1ccc(C(=O)N(CCCN)C(c2nc3cc(C)ccc3n2Cc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
To a solution of N-[1-(1-benzyl-5-methyl-1H-benzimidazol-2-yl)-2-methyl-propyl]-N-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-4-methyl-benzamide (0.302 mmol) in ethanol at room temperature, was added hydrazine (0.19 mL, 6 mmol). The reaction was stirred at room temperature for 1 h. The crude product was purified via reverse phase chromatography to give N-(3-amino-propyl)-N-[1-(1-benzyl-5-methyl-1H-benzimidazol-2-yl)-2-methyl-propyl]-4-methyl-benzamide (129 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:6]=1[CH:14]=[CH2:15])([CH3:4])([CH3:3])[CH3:2].C(C1C(C=C)=C(N)C=CC=1)(C)(C)C>[Pd].CO>[C:1]([C:5]1[C:6]([CH2:14][CH3:15])=[C:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cc1c([N+](=O)[O-])cccc1C(C)(C)C
Agent: [Pd]
Agent: C=Cc1c(N)cccc1C(C)(C)C
Solvent: CO
Product: CCc1c(N)cccc1C(C)(C)C

Procedure:
In a hydrogenation apparatus, a mixture of 1,5 g (8,55 mmol) 1-tert-butyl-2-vinyl-3-nitrobenzene and 250 mg 5% Pd/C and 20 ml of absolute methanol is hydrogenated at room temperature for 2,5 hours. The catalyst is filtered off and the solvent is evaporated in a water jet vacuum. The crude reaction product can be used directly for further chemical transformations. This gives 1,5 g 3-tert-butyl-2-vinyl-phenylamine in the form of a slightly brownish liquid (98% of theory).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][N:16]2[C:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[C:25]([O:32][CH:33]5[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]5)[CH:26]=[CH:27][CH:28]=4)[N:23]=3)=[CH:20][N:21]=[C:15]2[CH:14]=1>ClCCl>[CH3:8][O:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][N:16]2[C:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[C:25]([O:32][CH:33]5[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]5)[CH:26]=[CH:27][CH:28]=4)[N:23]=3)=[CH:20][N:21]=[C:15]2[CH:14]=1
Reactant: COCCOc1ccn2c(-c3ccc4cccc(OC5CCN(C(=O)OC(C)(C)C)CC5)c4n3)cnc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCOc1ccn2c(-c3ccc4cccc(OC5CCNCC5)c4n3)cnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
Trifluoroacetic acid 0.0862 ml, 1.12 mmol) was added to a solution of tert-butyl 4-(2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-yloxy)piperidine-1-carboxylate (0.029 g, 0.0559 mmol) in dichloromethane (0.50 mL). After stirring overnight at ambient temperature, the reaction mixture was concentrated under reduced pressure and partitioned between dichloromethane and saturated NaHCO3. The organic layer was washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified via flash column chromatography (40:1 dichloromethane/MeOH followed by 5:1 dichloromethane/MeOH followed by 2:1 dichloromethane/MeOH) provided 10.0 mg of the desired compound. MS APCI (+) m/z 419.2 (M+1) detected.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][S:17][C:11]=2[N:10]=[C:9]1[CH:19](Br)[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:23]>CO>[NH2:23][CH:19]([C:9]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][S:17][C:11]=2[N:10]=1)[CH2:20][CH3:21]
Reactant: N
Reactant: CCC(Br)c1nc2snc(C)c2c(=O)n1Cc1ccccc1
Solvent: CO
Product: CCC(N)c1nc2snc(C)c2c(=O)n1Cc1ccccc1
Temperature: 120 °C
Yield: 100 %

Procedure:
A mixture of 32 (160 mg, 0.42 mmol) and 7N ammonia in MeOH (7.5 mL) was heated in a sealed tube at 120° C. for 2 h, and cooled to room temperature. Solvent was removed to give a yellow solid 36 (136 mg, 100%), which was used without further purification. 1H-NMR (400 MHz, CDCl3): δ 7.07–7.28 (m, 5H), 5.39 (s 2H), 4.23 (brs, 2H), 4.15 (t, J=5.99 Hz, 1H), 2.72 (s, 3H), 1.46–1.66 (m, 2H), 0.75 (t, J=7.37 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]([Cl:32])([Cl:31])[CH2:3][O:4][C:5]([NH:7][C@@H:8]1[CH2:25][C@@:23]2([CH3:24])[C@@H:19]([CH2:20][CH2:21][C@@H:22]2[C:26]([O:28][CH3:29])=[O:27])[C@H:18]2[C@H:9]1[C@:10]1([CH3:30])[C@@H:15]([CH2:16][CH2:17]2)[CH2:14][CH:13]=[CH:12][CH2:11]1)=[O:6].BrCC(N)=[O:36].Cl(O)(=O)(=O)=O.[OH-].[Na+]>O1CCCC1.O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].CO>[O:36]1[C@@H:13]2[CH2:14][C@H:15]3[C@:10]([CH3:30])([CH2:11][C@H:12]12)[C@@H:9]1[C@H:18]([C@H:19]2[C@@:23]([CH2:25][C@H:8]1[NH:7][C:5]([O:4][CH2:3][C:2]([Cl:31])([Cl:32])[Cl:1])=[O:6])([CH3:24])[C@@H:22]([C:26]([O:28][CH3:29])=[O:27])[CH2:21][CH2:20]2)[CH2:17][CH2:16]3
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3[C@H](NC(=O)OCC(Cl)(Cl)Cl)C[C@]12C
Reactant: NC(=O)CBr
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H]5O[C@H]5C[C@]4(C)[C@H]3[C@H](NC(=O)OCC(Cl)(Cl)Cl)C[C@]12C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.2 %

Procedure:
Methyl 11α-(2,2,2-trichloroethoxycarbonylamino)5α-androst-2-ene-17β-carboxylate (507 mg) in tetrahydrofuran (15 ml) and water (7.5 ml) was treated with N bromoacetamide (193 mg) and 60% perchloric acid (0.15 ml) and stirred at room temperature for 30 minutes. The reaction mixture was diluted with 5% sodium metabisulphite solution (30 ml) and water (50 ml). The suspension was extracted with ether (3×). The ether extracts were washed with water, dried and evaporated to give a foam. This was dissolved in methanol (50 ml), treated with 2M sodium hydroxide solution (10 ml), and stirred at room temperature for 30 minutes. The solution was concentrated by evaporation, diluted with water (100 ml) and extracted with ethyl acetate (3×). The extracts were washed with water (1×), dried and evaporated to give a white foam. This was purified by preparative t.l.c. in ethyl acetate/petrol (1:2) and crystallised from ether to give the title compound (90 mg) m.p. 153°-155° C., [α]D +25.2°.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C:9]1([CH:19]=[CH2:20])[CH2:14][O:13][C:12]([CH2:17][F:18])([CH2:15][F:16])[O:11][CH2:10]1)=[O:8])C.Cl.[Cl-].[Na+]>O.O1CCCC1.CO>[F:16][CH2:15][C:12]1([CH2:17][F:18])[O:11][CH2:10][C:9]([CH:19]=[CH2:20])([C:7]([OH:8])=[O:6])[CH2:14][O:13]1
Reactant: C=CC1(C(=O)OCC)COC(CF)(CF)OC1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C=CC1(C(=O)O)COC(CF)(CF)OC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
A solution of lithium hydroxide monohydrate (311 mg, 7.42 mmol) in water (8 mL) was added to a stirred solution of 2,2-bis-fluoromethyl-5-vinyl-[1,3]dioxane-5-carboxylic acid ethyl ester (619 mg, 2.47 mmol) in tetrahydrofuran/methanol (12 mL, 4:1). The reaction mixture was stirred at room temperature for 1 h and then cooled to 0° C. before acidifying to pH 4 with hydrochloric acid (1 M). The mixture was saturated with sodium chloride and then extracted with dichloromethane (3×10 mL). The extract was filtered through a hydrophobic frit and evaporated to give the title product (390 mg, 71%) as a colorless gum. 1H NMR (300 MHz, CDCl3) δ 4.00 (d, J=12.0 Hz, 2H), 4.35-4.73 (m, 6H), 5.30-5.43 (m, 2H), 5.68-5.81 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[CH:5][CH:6]=[N:7]2.[OH-].[Na+]>C(O)C>[NH2:12][C:11]1[C:2]([CH3:1])=[C:3]2[C:8](=[CH:9][CH:10]=1)[N:7]=[CH:6][CH:5]=[N:4]2
Reactant: Cc1c([N+](=O)[O-])ccc2nccnc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(N)ccc2nccnc12

Procedure:
A mixture of 5-methyl-6-nitroquinoxaline (1.4 g), ethanol (100 mL) and stannous chloride dihydrate (7.2 g) is heated at reflux for three hours, cooled to below room temperature in an ice bath and treated with 1.0 N NaOH solution (120 mL). The mixture is then extracted with chloroform (2×1000 mL). The combined extracts are dried over potassium carbonate, filtered, and rotary evaporated to give 6-amino-5-methylquinoxaline.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]([OH:6])=O.C(N(C(C)C)C(C)C)C.ClC(OCC(C)C)=O.[Cl:24][C:25]1[C:29]([NH:30][CH3:31])=[CH:28][N:27]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[N:26]=1>C(Cl)Cl>[Cl:24][C:25]1[C:29]([N:30]([CH3:31])[C:4](=[O:6])[CH2:3][S:2][CH3:1])=[CH:28][N:27]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[N:26]=1
Reactant: CNc1cn(-c2cccnc2)nc1Cl
Reactant: CSCC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CSCC(=O)N(C)c1cn(-c2cccnc2)nc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 66 %

Procedure:
To an ice cold solution of 2-(methylthio)acetic acid (0.092 g, 0.863 mmol) in DCM (2 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.111 g, 0.863 mmol) followed by isobutyl chloroformate (0.099 ml, 0.767 mmol). Stirring was continued for 10 minutes. Next, the mixed anhydride was added to a solution of 3-chloro-N-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine (0.08 g, 0.383 mmol) in DCM (0.66 mL) and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated and purified using reverse phase C-18 column chromatography (0-100% CH3CN/H2O) to yield the title compound as a pale yellow oil (0.075 g, 66%): 1H NMR (400 MHz, CDCl3) δ 8.95 (d, J=2.5 Hz, 1H), 8.62 (dd, J=4.8, 1.4 Hz, 1H), 8.13 (s, 1H), 8.04 (ddd, J=8.3, 2.7, 1.4 Hz, 1H), 7.50-7.43 (m, 1H), 3.26 (s, 3H), 3.12 (s, 2H), 2.24 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 170.00, 148.61, 140.15, 140.03, 135.68, 126.56, 126.42, 125.33, 124.15, 37.16, 34.94, 16.22; ESIMS m/z 297 ([M+H]+).
Reaction SMILES: [C@@H:1]1([N:9]2[C:13]3[N:14]=[C:15]([NH2:19])[NH:16][C:17](=[O:18])[C:12]=3[N:11]=[N:10]2)[O:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1.C(O[CH:23](OCC)[N:24]([CH3:26])[CH3:25])C>CN(C=O)C>[C@@H:1]1([N:9]2[C:13]3[N:14]=[C:15]([N:19]=[CH:23][N:24]([CH3:26])[CH3:25])[NH:16][C:17](=[O:18])[C:12]=3[N:11]=[N:10]2)[O:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1
Reactant: CCOC(OCC)N(C)C
Reactant: Nc1nc2c(nnn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Solvent: CN(C)C=O
Product: CN(C)C=Nc1nc2c(nnn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
3-(2-Deoxy-β-D-erythropentofuranosyl)-5-amino-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-(6H)-one (8-aza-2'-deoxyguanosine (1)) (290 mg; 1.06 mmol) was dissolved in abs. DMF (7 ml), and N,N-dimethylformamide diethyl acetal (5 ml) was added. After the mixture had been stirred at room temperature for 24 hours, it was subjected to rotary evaporation in vacuo, and the residue was coevaporated with toluene. The residue was purified by means of chromatography on silica gel (column: 20×4 cm, 0.5 bar, CH2 Cl2 /MeOH 8:2). Compound (2) (320 mg, 92%) was obtained as a colorless foam which crystallized from MeOH. M.p. 236° C. TLC (CH2Cl2 /MeOH 8:2): Rf 0.7. UV (MeOH): 301 (26500), 244(15500).
Reaction SMILES: Br[C:2]1[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=[C:6]([Br:8])[N:7]=1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[NH:21][CH2:20][CH2:19]2>>[Br:8][C:6]1[N:7]=[C:2]([N:21]2[C:22]3[C:18](=[CH:17][C:16]([Cl:15])=[CH:24][C:23]=3[Cl:25])[CH2:19][CH2:20]2)[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=1
Reactant: CCC(CC)n1cc(Br)nc(Br)c1=O
Reactant: Clc1cc(Cl)c2c(c1)CCN2
Product: CCC(CC)n1cc(Br)nc(N2CCc3cc(Cl)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dibromo-1-(1-ethylpropyl)-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 158–160° C.; 1H NMR (300 MHz, CDCl3): 7.18 (d, J=1.8 Hz, 1 H), 7.11 (d, J=2.2 Hz, 1 H), 6.85 (s, 1 H), 4.80–4.75 (m, 1 H), 4.34 (t, J=8.1 Hz, 2 H), 3.13 (t, J=8.1 Hz, 2 H), 1.88–1.74 (m, 2 H), 1.70–1.60 (m, 2 H), 0.88 (t, J=7.3 Hz, 6 H); HRMS (ESI) calcd for C17H19N3OBrCl2 (M+H)+: 430.0089; found m/z 430.0109.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C@H:6]([NH:20][C:21](OC(C)(C)C)=[O:22])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH3:2].C(O)(C(F)(F)F)=O.C1(=O)[O:41][C:39](=[O:40])[CH2:38][CH2:37]1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C@H:6]([NH:20][C:21](=[O:22])[CH2:37][CH2:38][C:39]([OH:41])=[O:40])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.2 %

Procedure:
To a solution of (R)-4-biphenyl-4-yl-3-tert-butoxycarbonylamino-butyric acid ethyl ester (400 mg, 1.04 mmol) in DCM (10 mL) at room temperature is added TFA (2.009 mL, 26.1 mmol) and the mixture is stirred at room temperature for 1 hour. The mixture is concentrated under reduced pressure. To the obtained TFA salt in DCM (10 mL) at ice bath temperature is added succinic anhydride (125 mg, 1.25 mmol) and followed by TEA (0.363 mL, 2.61 mmol). The reaction is stirred at room temperature for 16 hours. The mixture is concentrated under reduced pressure. The obtained residue is purified by flash chromatography (silica gel, 2% to 5% EtOH/DCM) give (R)-4-biphenyl-4-yl-3-(3-carboxy-propionylamino)-butyric acid ethyl ester (200 mg). HPLC retention time=1.53 minutes (condition C); MS=384 (m+1).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9])=[N+:2]=[N-:3].N1C=CC=CC=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=1)(=[O:24])=[O:23])=[N+:2]=[N-:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: [N-]=[N+]=NCCOCCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCOCCN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.2 %

Procedure:
A solution of 2-(2-azido-ethoxy)-ethanol 2 (14.1 g, 0.108 mol) and pyridine (13 ml, 1.5 equiv.) in CH2Cl2 (150 ml) was cooled in an ice bath. p-Toluenesulfonyl chloride (30.7 g, 1.5 equiv.) then DMAP (173 mg, 0.01 equiv.) were added. The reaction mixture was stirred at RT for 72 h, then washed with a 1 M HCl aqueous solution (3×50 ml), dried over MgSO4, filtrated then concentrated under reduced pressure. Purification by flash column chromatography (eluent: pet. ether/AcOEt 9:1 then 7:3) afforded tosylate 3 as a colorless oil (23.8 g, 78%). 1H and 13C NMR spectra matched the literature data (Gill, H. et al. J. Med. Chem. 2009, 52, 5816-5825).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:7]=[C:6]([CH2:8][C:9]([OH:11])=O)[NH:5][N:4]=1.[NH2:12][C@@H:13]([CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15]>>[CH2:33]([O:32][CH2:31][C@H:13]([NH:12][C:9](=[O:11])[CH2:8][C:6]1[NH:5][N:4]=[C:3]([CH3:2])[CH:7]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: Cc1cc(CC(=O)O)[nH]n1
Agent: Cl
Product: Cc1cc(CC(=O)N[C@@H](COCc2ccccc2)C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)[nH]n1
Yield: 49 %

Procedure:
Proceeding as in Example 1, but substituting 2-(3-methyl-1H-pyrazol-5-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 166, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(3-methyl-1H-pyrazol-5-yl)acetamido)propanamide (48 mg, 49%). 1H-NMR (400 MHz, DMSO-D6): σ 12.07 (s, 1H), 10.18 (s, 1H), 8.38 (s, 1H), 7.65-7.58 (m, 2H), 7.35-7.17 (m, 6H), 7.06-6.95 (m, 4H), 5.86 (s, 1H), 4.73-4.64 (m, 1H), 4.52 (s, 2H), 3.66 (d, 2H), 3.46 (s, 2H), 2.15 (s, 3H). MS (EI) for C28H27FN4O4. found 503.0 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[C:6]#[N:7].[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=1)[C:28]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:29]>>[C:6]([C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:3][CH2:2][N:22]([CH3:21])[CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=1)[C:28]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:29])#[N:7]
Reactant: COc1ccc(C(C#N)(CCCBr)C(C)C)cc1OC
Reactant: CCCCOC(=O)c1cccc(CCNC)c1
Product: CCCCOC(=O)c1cccc(CCN(C)CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)c1

Procedure:
Reaction of 1f with 2m produced 3ar. MS found M+H=495. The oxalate salt of 3ar was recrystallized from methanol/ether; mp 97-103° C.