Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@:10]1([CH2:25][O:26]CC1C=CC=CC=1)[O:11][C@H:12]2[N:16]1[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]1=[O:18])C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[OH:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@:10]1([CH2:25][OH:26])[O:11][C@H:12]2[N:16]1[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]1=[O:18]
Reactant: Cc1cn([C@@H]2O[C@@]3(COCc4ccccc4)CO[C@@H]2[C@@H]3OCc2ccccc2)c(=O)[nH]c1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cc1cn([C@@H]2O[C@@]3(CO)CO[C@@H]2[C@@H]3O)c(=O)[nH]c1=O
Reaction time: 4 h

Procedure:
A solution of nucleoside 36 (97 mg, 0.215 mmol) in ethanol (1.5 cm3) was stirred at room temperature and 20% palladium hydroxide over carbon (50 mg) was added. The mixture was degassed several times with argon and placed in a hydrogen atmosphere with a baloon. After stirring for 4 h, the mixture was purified by silica gel column chromatography using dichloromethane-methanol (97:3, v/v) as eluent to give nucleoside 37 as a white solid material (57 mg, 98%). δH ((CD3)2SO) 11.33 (1H, br s, NH), 7.62 (1H, d, J 1.1 Hz, 6-H), 5.65 (1H, d, J 4.4 Hz, 3′-OH), 5.41 (1H, s, 1′-H), 5.19 (1H, t, J 5.6 Hz, 5′-OH); 4.11 (1H, s, 2′-H), 3.91 (1H, d, J 4.2 Hz, 3′-H), 3.82 (1H, d, J 7.7 Hz, 1″-Ha), 3.73 (1H, s, H′-5a), 3.76 (1H, s, 5′-Hb), 3.63 (1 H, d, J 7.7 Hz, 1″-Hb), 1.78 (3H, d, J 0.7 Hz, CH3). δC (CDCl3) 166.7 (C-4), 152.1 (C-2), 137.0 (C-6), 110.9 (C-5), 90.5, 88.4 (C-1′, C-4″), 80.9, 72.5, 70.4 (C-2′, C-3′, C-5′), 57.7 (C-1″), 12.6 (CH3). EI-MS m/z 270 [M]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.[Pd]>[N:14]1[CH:13]=[CH:12][C:11]([NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([NH2:1])[CH:5]=2)=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1cccc(Nc2ccncc2)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(Nc2ccncc2)c1
Reaction time: 2 h
Yield: 87 %

Procedure:
A suspension of compound A3 (7.26 g, 33.7 mmol) and 10% Pd/C in MeOH was hydrogenated for 2 h, filtered through a pad of Celite, and solvent evaporated. The residue was recrystallized from MeOH/H2O to give A4 as a pale yellow powder (5.43 g, 83%): mp. (MeOH/H2O) 170-171° C. 1H NMR [(CD3)2SO] δ8.48 (bs, 1 H, NH), 8.14-8.12 (m, 2 H, H-2′&6′), 6.96 (t, J=7.9 Hz, 1 H, H-5), 6.86-6.84 (m, 2 H, H-3′ & 6′), 6.43 (t, J=2.0 Hz, 1 H, H-2), 6.32 (dd, J=7.8, 1.3H, 1 H, H-6), 6.26 (dd, J=7.8, 1.5 Hz, 1 H, H-4) 5.07 (br s, 2 H, NH2); HRMS (EI+) calc. for C11H11N3 (M+) m/z 185.0953, found 185.0945; Anal. calc. for C11H11N3.0.125 H2O: C, 70.5; H, 6.1; N, 22.5; found, C, 70.6; H, 6.0; N, 22.7%.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([I:23])[CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.Cl.C[O:26][C:27](=[O:38])[C@@H:28]([NH2:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Br:36])[CH:31]=1>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([I:23])[CH:20]=[CH:19][C:15]=3[C:16]([NH:37][C@@H:28]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Br:36])[CH:31]=3)[C:27]([OH:26])=[O:38])=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: COC(=O)[C@@H](N)Cc1cccc(Br)c1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Product: O=C(N[C@@H](Cc1cccc(Br)c1)C(=O)O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoic acid was coupled to (S)-2-amino-3-(3-bromo-phenyl)-propionic acid methyl ester hydrochloride as in EXAMPLE 1, Part C. The methyl ester was hydrolyzed as in EXAMPLE 2, Part E, to afford the title compound. HPLC: RT=9.91 min. MS (ESI−): mass calcd. for C22H16BrIN4O5S2, 687.3; m/z found, 686 [M−H]−. 1H NMR (400 MHz, DMSO-d6): 13.05 (s, 1H), 11.77 (s, 1H), 9.03 (d, J=7.8, 1H), 8.45-8.35 (m, 2H), 7.92-7.86 (m, 1H), 7.82 (d, J=1.5, 1H), 7.53-7.51 (br m, 1H), 7.47-7.38 (m, 2H), 7.36-7.34 (m, 1H), 7.31-7.19 (m, 2H), 4.65-4.54 (m, 1H), 3.19 (dd, J=14.0, 4.7, 1H), 3.00 (dd, J=13.7, 10.8, 1H).
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:15][CH3:16])[O:7][CH2:6]1)[CH:2]=[CH2:3].[CH2:17](I)[CH2:18][CH3:19].C([O-])([O-])=O.[K+].[K+].C(#N)C>CCOCC>[CH2:1]([N:4]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:15][CH3:16])[O:7][CH2:6]1)[CH2:17][CH2:18][CH3:19])[CH:2]=[CH2:3]
Reactant: C=CCNC1COc2cccc(OC)c2C1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: C=CCN(CCC)C1COc2cccc(OC)c2C1
Temperature: 47 °C
Reaction time: 120 h
Yield: 80.4 %

Procedure:
3-(N-Allylamino)-5-methoxychroman (1.3 g, 5.9 mmol) prepared analogous to example 26, n-propyl iodide (2.1 mL, 21 mmol) , anhyrous K2CO3 (3.0 g, 21 mmol) and acetonitrile (5.5 mL) were stirred under N2 at 47° C. (oilbath temp) for five days until GC indicated complete reaction. Ether (40 mL) was added, the salts were filtered off by suction and the clear filtrate was concentrated in vacuo to afford 3-(N-allyl-N-n-propylamino)-5-methoxy chroman (1.24 g, 81% yield) as an oil. The base was precipitated from an ether solution by adding a slight excess of HCl (approx. 3M in ether). Crystallization of the crude HCl salt afforded colourless needles. Mp 117°-118° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1.O>CN(C=O)C>[Si:18]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1)([C:15]([CH3:17])([CH3:16])[CH3:14])([CH3:20])[CH3:19]
Reactant: COC(=O)Cc1ccc(CO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
To a solution of methyl p-hydroxymethylphenylacetate (3.30 g, 18.3 mmol, prepared according to the method of G. Biagi et al., E. Ed. Farmaco., 43, 597 (1988)) in 6.6 ml DMF was added TBDMS-Cl (3.31 g, 22.0 mmol) and imidazole (3.12 g, 45.8 mmol), and the resulting solution was stirred at ambient temperature for 18 hours. The mixture was poured into 100 ml H2O and extracted (EtOAc, 4×50 ml). The combined extracts were dried (MgSO4), filtered and concentrated. The crude material was chromatographed (EtOAc:hexane, 5:95) to afford the title compound (5.0 g, 92% yield) as an oil.
Reaction SMILES: [CH2:1]([N:4]([CH2:13][CH:14]=[CH2:15])[S:5]([C:8]1[N:12]=[CH:11][NH:10][N:9]=1)(=[O:7])=[O:6])[CH:2]=[CH2:3].[CH2:16]([N:18]([CH2:22][CH3:23])[C:19](Cl)=[O:20])[CH3:17].C(N(CC)CC)C>O1CCCC1>[CH2:16]([N:18]([CH2:22][CH3:23])[C:19]([N:10]1[CH:11]=[N:12][C:8]([S:5](=[O:7])(=[O:6])[N:4]([CH2:1][CH:2]=[CH2:3])[CH2:13][CH:14]=[CH2:15])=[N:9]1)=[O:20])[CH3:17]
Reactant: C=CCN(CC=C)S(=O)(=O)c1nc[nH]n1
Reactant: CCN(CC)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCN(CC=C)S(=O)(=O)c1ncn(C(=O)N(CC)CC)n1

Procedure:
A mixture of 6.9 g. 3-diallylsulphamoyl-1,2,4-triazole, 4.5 g. diethylcarbamoyl chloride, 6 ml. triethylamine and 25 ml. dry tetrahydrofuran was refluxed under anhydrous conditions for 1.5 hours. The cooled reaction mixture was filtered to remove triethylamine hydrochloride and the filtrate was evaporated to remove solvent. The solid residue was recrystallized from petroleum ether, b.p. 60° - 80°C., to give 1-diethylcarbamoyl-3-diallylsulphamoyl-1,2,4-triazole, m.p. 49° - 51°C. Elemental analysis satisfactory.
Reaction SMILES: CN(C)[C:3]1[S:7][C:6]2[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:5]=2[CH:4]=1.Cl.[O:16]1CCCC1>>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:5]2[CH2:4][C:3]([S:7][C:6]=2[CH:8]=1)=[O:16]
Reactant: COc1ccc2cc(N(C)C)sc2c1
Reactant: C1CCOC1
Agent: Cl
Product: COc1ccc2c(c1)SC(=O)C2
Yield: 80 %

Procedure:
To tetrahydrofuran (200 mL) containing 2-dimethylamino-6-methoxybenzo-[b]-thiophene (cf. U.S. Pat. No. 5,420,349)(20.00 g, 96.5 mmol) was added 1N aqueous HCl (200 mL) and the resulting mixture was heated to reflux for 3 h. The mixture was cooled, the layers were separated, and the aqueous layer was extracted with dichloromethane (300 mL). The combined organic layers washed with water (250 mL), dried (MgSO4), filtered and concentrated to give crude product, which was recrystallized from 3A-ethanol, and dried in vacuo at room temperature to afford the title compound (13.89 g, 77.0 mmol, 80%): mp 80-82° C.; IR (KBr) 1713, 1605, 1485, 1287, 1015, 865, 813 cm-1 ; 1H NMR (DMSO-d6) δ 7.22 (d, 1 H, J=8.4 Hz), 7.11 (s, 1 H), 6.78 (d, 1 H, J=8.4 Hz), 4.06 (s, 2 H), 3.71 (s, 3 H); 13C NMR (DMSO-d6) δ 203.5, 159.0, 136.9, 125.6, 124.6, 112.3, 108.4, 55.3, 46.2. Anal. Calcd. for C9H8O2S: C, 59.98; H, 4.47; S, 17.78. Found: C, 60.19; H, 4.57; S, 18.03.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:6][C:5](=[O:7])[O:4][C:3]1=[O:8].[CH2:10]([OH:12])[CH3:11]>>[CH2:10]([O:12][C:5](=[O:7])[CH2:6][C:2]([CH3:9])([CH3:1])[C:3]([OH:8])=[O:4])[CH3:11]
Reactant: CC1(C)CC(=O)OC1=O
Reactant: CCO
Product: CCOC(=O)CC(C)(C)C(=O)O

Procedure:
3,3-Dimethyl-dihydro-furan-2,5-dione (6.4 g) was heated at 50° C. in ethanol (150 mL) overnight. The solvent was removed in vacuo and the residue triturated with hexane to yield 2,2-Dimethyl-succinic acid 4-ethyl ester (4.66 g) which was used without further purification. t-Butanol (7.5 mL) was added to a mixture of 2,2-Dimethyl-succinic acid 4-ethyl ester (2.74 g, 15.7 mmol) in dichloromethane (62 mL) containing magnesium sulfate (7.5 g) and conc. sulfuric acid (0.85 mL) and the mixture was stirred at room temperature overnight. Saturated sodium bicarbonate solution was added and the product was extracted into dichloromethane, washed with brine solution, dried and concentrated to yield the diested as a colorloess oil (1.89 g). The ethyl ester was hydrolyzed by trating the crude sample with potassium hydroxide (2.75 g) in a mixture of ethanol (50 mL) and water (25 mL) at room temperatire for 2 h. The reaction was acidified using 1N HCl (aq) and extracted into ether, dried and concentrated to yield 2,2-Dimethyl-succinic acid 1-tert-butyl ester (1.4 g). This acid was treated under the conditions of Example 320 (step 1) to yield 3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2,2-dimethyl-propionic acid tert-butyl ester (1.9 g). This t-Bu ester was deprotected using formic acid (19 mL) at 50° C. for 20 min. The crude product was concentrated and triturated with a mixture of ether and hexane to yield 3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2,2-dimethyl-propionic acid (1.12 g). To a solution of 3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2,2-dimethyl-propionic acid (561 mg, 2 mmol) and triethylamine (1.1 mL, 8 mmol) in THF (9 ml), isobutyl chloroformate (0.31 mL, 2.4 mmol) was added dropwise at −78° C. After being stirred for 1 h, hydrazine hydrate (1 mL, 11 mmol) was added. The reaction mixture was stirred at room temperature for 1 h and concentrated. A small amount of ice was added to quence any excess reagent and precipitate the product, which was collected by filtration to give 482 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:16]=1)[CH2:7][O:8][Si](C(C)(C)C)(C)C.C([Mg]Cl)(C)C.[CH:23]1[N:24]=[CH:25][N:26]2[CH2:31][CH2:30][CH2:29][C:28](=[O:32])[C:27]=12.Cl>O1CCCC1.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]2([OH:32])[CH2:29][CH2:30][CH2:31][N:26]3[CH:25]=[N:24][CH:23]=[C:27]23)=[C:6]([CH2:7][OH:8])[CH:16]=1
Reactant: O=C1CCCn2cncc21
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(Br)ccc1I
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: OCc1cc(Br)ccc1C1(O)CCCn2cncc21
Reaction time: 1 h

Procedure:
A solution of 6.55 mmol of (5-bromo-2-iodo-benzyloxy)-tert-butyl-dimethyl-silane in 20 ml of tetrahydrofuran is cooled to −20° C. 6.55 mmol of an isopropymagnesium chloride solution (2M in tetrahydrofuran) is added dropwise and stirring continued for 1 h at −20° C. A solution of 4.37 mmol of 6,7-dihydro-5H-imidazo[1,5-a]pyridin-8-one [426219-51-4] in 40 ml of tetrahydrofuran is added dropwise and the reaction mixture stirred for 40 minutes at −20° C. The reaction mixture is poured into a mixture of 0.1N aqueous HCl and dichloromethane and the layers are separated. The aqueous layer is basified with sodium bicarbonate and extracted with ethyl acetate. The combined organic layers are dried over sodium sulfate, filtered and concentrated under reduced pressure. The title compound is obtained as a white foam and used for the next step without further purification. Rt=4.61 (gradient II).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([C:15]3([CH:19]=[O:20])[CH2:18][CH2:17][CH2:16]3)[NH:8][CH2:7][CH2:6][C:5]2=1.[CH2:21]([Mg]Br)[CH3:22]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([C:15]3([CH:19]([OH:20])[CH2:21][CH3:22])[CH2:18][CH2:17][CH2:16]3)[NH:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=CC1(C2NCCc3c2[nH]c2ccc(Cl)cc32)CCC1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)C1(C2NCCc3c2[nH]c2ccc(Cl)cc32)CCC1

Procedure:
2.32 g of the compound obtained in Step A of Example 115 in 150 ml of tetrahydrofuran are stirred for 4 hours at −30° C., under an inert atmosphere, in the presence of 15 ml of a 1M solution of ethylmagnesium bromide in tetrahydrofuran. After returning to ambient temperature, the mixture is worked up in conventional manner, then concentrated under reduced pressure, enabling the expected product to be isolated.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:22])[C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([CH2:32]O)[CH:27]=1.C(P(CCCC)CCCC)CCC.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:22])[C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:32][C:28]4[CH:27]=[C:26]([O:25][CH3:24])[CH:31]=[CH:30][N:29]=4)=[CH:19][CH:20]=3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(O)cc1
Reactant: COc1ccnc(CO)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: COc1ccnc(COc2ccc(C(=O)Nc3cc(C(=O)NC4CC4)ccc3C)cc2)c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 36.2 %

Procedure:
To a stirred solution of N-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide (200 mg, 0.64 mmol) and 4-methoxy-2-hydroxymethylpyridine (500 mg, 3.6 mmol) in dry THF (25 mL) under an argon atmosphere was added successively tributylphosphine (500 mg, 2.5 mmol) and di-isopropyl azodicarboxylate (500 mg, 2.5 mmol). The mixture was stirred at 20° C. for 16 hours, then the solvent was evaporated at reduced pressure and the residue purified by silica column chromatography, eluting with a gradient of 0 to 10% methanol in ethyl acetate to give the title compound as a white solid (100 mg); NMR Spectrum: (DMSOd6) 1.55 (m, 2H), 1.65 (m, 2H), 2.25 (s, 3H), 2.85 (m, 1H), 3.85 (s, 3H), 5.20 (s, 2H), 6.95 (dd, 1H), 7.05 (d, 1H), 7.15 (d, 2H), 7.30 (d, 1H), 7.60 (dd, 1H), 7.80 (s, 1H), 7.95 (d, 2H), 8.35 (d, 1H), 8.40 (broad s, 1H), 9.80 (s, 1H); Mass Spectrum: M+H+ 432.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:12][CH2:11][CH2:10][C:8]3=2)[C:3](=O)[C:2]1=O.[BH4-].[Na+].B(F)(F)F.CCOCC>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:12][CH2:11][CH2:10][C:8]3=2)[CH:3]=[CH:2]1
Reactant: O=C1Nc2c(ccc3c2CCO3)C1=O
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: c1cc2ccc3c(c2[nH]1)CCO3
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 42 %

Procedure:
A solution of 2,3,7,8-tetrahydro-1H-furo[2,3-g]indole-2,3-dione (9.05 g, 47.9 mmol) in tetrahydrofuran (100 mL) was stirred at −20° C. under an argon atmosphere. Solid sodium borohydride was added portionwise and the reaction was stirred for 20 min at −20° C. Boron trifluoride etherate (11.9 mL, 96 mmol) was added dropwise over 90 min, then the mixture was warmed to 0° C. and stirred for 1 h. The reaction was quenched with water (100 mL) and the solution was extracted with ethyl acetate (3×150 mL). The organic extracts were combined, dried (magnesium sulphate) and concentrated in vacuo to afford a yellow solid which was purified by column chromatography [SiO2; heptane-ethyl acetate (5:1)] to afford the title compound (3.2 g, 42.8%); analytical data as described above.
Reaction SMILES: FC(F)(F)[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[N:7]([CH:15]([CH3:17])[CH3:16])[CH:6]=1)=[O:4].[OH-:20].[Na+]>>[Br:14][C:10]1[CH:9]=[C:8]2[C:13]([C:5]([C:3]([OH:4])=[O:20])=[CH:6][N:7]2[CH:15]([CH3:17])[CH3:16])=[CH:12][CH:11]=1
Reactant: CC(C)n1cc(C(=O)C(F)(F)F)c2ccc(Br)cc21
Reactant: [OH-]
Agent: [Na+]
Product: CC(C)n1cc(C(=O)O)c2ccc(Br)cc21
Temperature: 25 °C
Yield: 94 %

Procedure:
A solution of 2,2,2-trifluoro-1-(6-bromo-1-isopropyl-1H-indol-3-yl)-ethanone (3.30 g, 9.88 mmol) in a 20% aqueous sodium hydroxide solution (35 mL) was heated at 110° C. for 18 h. At this time, the reaction was cooled to 25° C., partitioned between water (100 mL) and ethyl acetate (100 mL), and treated with a 1N aqueous hydrochloric acid solution (60 mL). The organic layer was then washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 6-bromo-1-isopropyl-1H-indole-3-carboxylic acid (2.63 g, 94%) as a yellow solid: mp 207-209° C.; EI-HRMS m/e calcd for C12H12BrNO2 (M+) 281.0051, found 281.0047.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.C(O)C.[NH2:18][C:19]1[CH:24]=[C:23]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:22]=[CH:21][C:20]=1[S:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1>>[O:26]([CH2:25][C:23]1[CH:22]=[CH:21][C:20]([S:33][C:34]2[CH:35]=[CH:36][C:37]([OH:40])=[CH:38][CH:39]=2)=[C:19]([NH:18][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:24]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Reactant: Nc1cc(COc2ccccc2)ccc1Sc1ccc(O)cc1
Solvent: CCO
Product: CCCc1ccc2c(Nc3cc(COc4ccccc4)ccc3Sc3ccc(O)cc3)ccnc2n1
Temperature: 80 °C

Procedure:
The product from Example 2g as a 4.1M solution in ethanol (0.050 mL, 0.205 mmol) was reacted with the product from Example 221d (0.066 g, 0.205 mmol) for 16.5 h following the procedure from Example 1g. Consumption of starting material required a second addition of the product from Example 2g (0.025 mL, 0.102 mmol) and continued heating at 80° C. (12 h). The crude title compound was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (0.0269 g, 21.5%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J=7.54 Hz, 3H) 1.76-1.99 (m, 2H) 3.00 (t, J=7.35 Hz, 2H) 5.12 (s, 2H) 6.31 (d, J=6.99 Hz, 1H) 6.79 (d, J=8.82 Hz, 2H) 6.91-7.07 (m, 4H) 7.17-7.37 (m, 4H) 7.43-7.55 (m, 2H) 7.84 (d, J=8.82 Hz, 1H) 8.47 (d, J=7.35 Hz, 1H) 9.04 (d, J=8.46 Hz, 1H) 9.97 (s, 1H); MS (ESI+) m/z 494.2 (M+H)+; (ESI−) m/z 492.2 (M−H)−.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[CH:14]2)([O-])=O>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[CH:14]2
Reactant: O=[N+]([O-])c1ccncc1Nc1ccc2[nH]ncc2c1
Solvent: CCO
Product: Nc1ccncc1Nc1ccc2[nH]ncc2c1

Procedure:
A suspension of N-(4-nitro-3-pyridinyl)-1H-indazol-5-amine, N5 -oxide (7 g) in 250 ml ethanol containing 0.5 g platinum oxide was hydrogenated at 60 psi for sixty hours and thereafter filtered through Celite and concentrated to 3.3 g solid. This solid was purified by HPLC (silica, 25% methanol in dichloromethane) to give 2.1 g solid. This solid was recrystallized twice from acetonitrile to give 1.5 g crystals, m.p. 198°-199°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17](=[O:31])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24]C(=O)C(F)(F)F)[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.C(=O)([O-])[O-].[K+].[K+].CO>O>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH2:24])=[O:31])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1CN1CCC(CC(=O)c2ccccc2NC(=O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ncccc1CN1CCC(CC(=O)c2ccccc2N)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
150 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-oxo-2-(2-trifluoroacetylaminophenyl)ethyl]piperidine obtained in Example 63 and 141 mg of potassium carbonate were suspended in a mixed solvent of 3 ml of methanol and 3 ml of water, and the mixture was stirred at room temperature for one hour. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, to give the title compound as a yellow oil (quantitatively).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([F:10])=[C:4](Cl)[N:3]=1.C(O)C.[H][H]>[Pd].C(N(CC)CC)C>[NH2:9][CH2:8][C:7]1[CH:2]=[N:3][CH:4]=[C:5]([F:10])[CH:6]=1
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: NCc1cncc(F)c1
Reaction time: 18 h

Procedure:
In a Parr Bottle add 2,6-dichloro-3-cyano-5-fluoropyridine (20 g, 0.105 mol), ethanol (336 mL), triethylamine (24 mL), and 5% Pd/C (4 g). Place on a Parr Shaker Apparatus under 60 psi hydrogen for 1 h at ambient temperature. Filter the reaction mixture and bubble ammonia gas into filtrate for 10 min. Add Raney® nickel (5.2 g) and place on a Parr Shaker Apparatus under 500 psi hydrogen for 18 h at 60-70° C. Filter the reaction mixture and concentrate in vacuo. Dissolve in methanol and add 1N hydrogen chloride in ether until form a precipitate. Cool in an ice bath, filter off the precipitate, wash the solid several times with ether, and dry to give the title compound as the hydrochloride salt (12 g, 70%). MS (ES+) m/z: 127 (M+H)+. Dissolve the hydrochloride salt in water, add 0.1 N aqueous NaOH to adjust to pH 10, extract with DCM, dry the organic layer over Na2SO4, filter and concentrate to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CCCOc1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1ccccc1N

Procedure:
A solution of (3) (1.27 g, 5.0 mM) in 15 mL ethyl acetate containing 200 mg of 5% palladium on carbon is reacted in a hydrogen atmosphere (40 psig.) at room temperature until hydrogen uptake ceases. The mixture is then filtered and concentrated in vacuo to yield 1.0+ g of (4) as an oil/low melting solid.