Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)=O.[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([NH2:17])=[O:16]>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]([C:15]2[O:16][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=3)[N:17]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: NC(=O)c1cccc(Cl)c1
Reactant: O=C(CBr)c1ccccn1
Solvent: Cc1ccccc1
Product: Clc1cccc(-c2nc(-c3ccccn3)co2)c1
Yield: 24.7 %

Procedure:
Using the procedures of Kelly et al., J. Org. Chem., (1996) 61:4623-4633, a solution of 2-bromoacetylpyridine (120 mg, 0.6 mmol) in toluene (5 mL) was treated with 3-chlorobenzamide (300 mg, 1.9 mmol) and the mixture heated in a sealed vial at reflux for 60 hours. The mixture was then cooled and the solvent was removed in vacuo. Silica gel chromatography using a gradient of hexane to ethyl acetate afforded 38 mg (9%) of 2-[3-chlorophenyl]-4-[pyridin-2-yl]-1,3-oxazole as a pale yellow solid. 1H-NMR (CDCl3), δ (ppm): 8.62 (d, 1H), 8.35 (s, 1H), 8.15 (m, 1H), 8.00 (m, 2H), 7.80 (td, 1H), 7.42 (m, 2H), 7.23 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([OH:10])[C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[CH:21](O)[CH2:20]2>>[NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([OH:10])[C:7]([O:9][CH:21]2[CH:22]3[CH2:25][CH2:26][N:19]([CH2:24][CH2:23]3)[CH2:20]2)=[O:8])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(O)(C(=O)O)c2ccccc2)cc1
Reactant: OC1CN2CCC1CC2
Product: Nc1ccc(C(O)(C(=O)OC2CN3CCC2CC3)c2ccccc2)cc1

Procedure:
The 4-aminobenzil may be prepared according to the method of Augl et al, Annu. Conf., SPE, Reinf. Plastic/Compos. Div. Proc., 26th, 19D, 1 (1971). The 4-aminobenzil is rearranged to yield 4-aminobenzilic acid which is in turn esterfied to produce the ethyl ester. The ethyl ester of the 4-aminobenzilic acid is then reacted with quinuclidin-3-ol to give the expected 3-quinuclidinyl 4-aminobenzilate (4-amino-QNB). The purified 4-amino-QNB is then converted to the 4-triazeno-QNB according to the procedure reported by Tewson et al, J. Nucl. Med. 20, 671 (1979). The purified 4-triazeno-QNB is then reacted with iodide or a desired gamma-emitting radionuclide to produce the desired product.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[NH:6][C:5]1=[O:15])=[N+:2]=[N-:3].[H-].[Na+].Br[CH2:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>CN(C)C=O.C1(C)C=CC=CC=1>[N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]([CH2:19][C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[C:5]1=[O:15])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC1CCc2ccccc2NC1=O
Reactant: O=C(CBr)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1CCc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 3-azido-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (8.7 g, 0.043 mol), in dry dimethylformamide (75 ml) was added during 30 min to a stirred suspension of sodium hydride [from a 60% mineral oil dispersion (1.9 g) washed with petroleum ether (3×150 ml)] in dry dimethylformamide (250 ml) maintained at 0° C. under a nitrogen atmosphere. Stirring was continued for an additional 1.5 hours, then benzyl bromoacetate (10.8 g; 0.047 mol) in dry dimethylformamide (75 ml) was added during 45 minutes, the temperature being maintained at 0°. The reaction mixture is then allowed to warm to room temperature while stirring for an additional 18 hours. The dimethylformamide was removed under reduced pressure and the residue partitioned between water (500 ml) and dichloromethane (500 ml). The aqueous phase was extracted with additional dichloromethane (3×500 ml). The combined extracts were dried over sodium sulfate and the solvent was removed under reduced pressure to give the crude ester-azide as an oil. This material was dissolved in toluene (500 ml) and silica gel (48 g) was added. Filtration and removal of the solvent under reduced pressure gave 3-azido-1-benzyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one, as an oil, used without further purification in the next synthetic step.
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]1[O:21][C:20]2[CH:19]=[CH:18][C:9]([CH2:10][C:11]3[O:17][C:14]([CH2:15]O)=[CH:13][CH:12]=3)=[CH:8][C:7]=2[O:6]1.[OH-].[Na+]>CCOCC>[CH2:5]1[O:21][C:20]2[CH:19]=[CH:18][C:9]([CH2:10][C:11]3[O:17][C:14]([CH2:15][Br:2])=[CH:13][CH:12]=3)=[CH:8][C:7]=2[O:6]1
Reactant: OCc1ccc(Cc2ccc3c(c2)OCO3)o1
Reactant: BrP(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: BrCc1ccc(Cc2ccc3c(c2)OCO3)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6.6 g. of phosphorus tribromide in 50 ml. of ether was added dropwise to a solution of 15 g. of 5-(3,4-methylenedioxybenzyl)furfuryl alcohol in 150 ml. of ether held at 0° C. After the addition was completed, the mixture was stirred for one hour at room temperature and then shaken with 20 ml. of 50% aqueous sodium hydroxide for 15 minutes. The organic layer was separated, washed with water, dried over potassium hydroxide and concentrated. The resulting product was used directly in the next reaction.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH3:23][O:24][C:25]1[CH:46]=[CH:45][C:28]([CH2:29][O:30][C:31]([NH:33][C:34]2[CH:39]=[CH:38][N:37]([CH2:40][C:41](O)=[O:42])[C:36](=[O:44])[N:35]=2)=[O:32])=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[C:41](=[O:42])[CH2:40][N:37]1[CH:38]=[CH:39][C:34]([NH:33][C:31]([O:30][CH2:29][C:28]2[CH:45]=[CH:46][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[O:32])=[N:35][C:36]1=[O:44])[CH3:2]
Reactant: COc1ccc(COC(=O)Nc2ccn(CC(=O)O)c(=O)n2)cc1
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1ccc(NC(=O)OCc2ccc(OC)cc2)nc1=O
Yield: 86.8 %

Procedure:
The title compound (2.86 g, 87%) was synthesized by the reaction of N-[2-(benzothiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester (1.72 g, 5 mmol) and [4-N-(4-methoxybenzyloxycarbonyl)-cytosin-1-yl]-acetic acid (1.67 g, 5 mmol) as per the procedure of Example 20. 1HNMR (500 MHz; DMSO-d6) δ 10.71 (s, 1H), 8.26 (dd, 1H), 8.16 (dd, 1H), 7.90 (d, 0.6H), 7.82 (d, 0.4H), 7.68˜7.60 (m, 2H), 7.34 (d, 2H), 7.00 (t, 1H), 6.93 (d, 2H), 5.10 (s, 2H), 4.82 (s, 1.2H), 4.61 (s, 0.8H), 4.34 (s, 0.8H), 4.13 (q, 0.8H), 4.05 (s, 1.2H), 4.03 (q, 1.2H), 3.74 (s, 3H), 3.56 (t, 1.2H), 3.40˜3.30 (m, 2H), 3.19 (t, 0.8H), 1.19 (t, 1.2H), 1.12 (t, 1.8H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C@@H:16]([CH2:17][CH3:18])[C:15](=O)[C:14]3[NH:20][N:21]=[CH:22][C:13]=3[C@H:12]2[CH2:23][CH3:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CC([O-])=O.[Na+].Cl.[NH2:31][OH:32]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C@@H:16]([CH2:17][CH3:18])/[C:15](=[N:31]/[OH:32])/[C:14]3[NH:20][N:21]=[CH:22][C:13]=3[C@H:12]2[CH2:23][CH3:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC[C@@H]1c2cn[nH]c2C(=O)[C@H](CC)N1S(=O)(=O)c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC[C@@H]1c2cn[nH]c2/C(=N\O)[C@H](CC)N1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of compound 62 (67 mg, 0.17 mmol) in a mixture of MeOH/H2O (5:1, 9 mL) was added NaOAc (141 mg, 1.7 mmol) followed by hydroxylamine hydrochloride (131.6 mg, 1.9 mmol). The resulting solution was stirred at room temperature for a weekend. The solvent was removed by rotary evaporation and the residue was taken up in EtOAc. The organic phase was washed with water, brine and dried (MgSO4). After removal of the solvent under reduced pressure, the crude product was purified by flash chromatography to give a white solid as the product 63 1H NMR (CDCl3) δ 10.28 (bs, 1H), 7.56 (d, J=9.0 Hz, 2H), 7.45 (s, 1H), 7.20 (d, J=9.0 Hz, 2H), 5.48 (dd, J=4.5, 10.5 Hz, 1H), 4.97 (t, J=7.5 Hz, 1H), 2.06-1.96 (m, 1H), 1.91-1.77 (m, 2H), 1.68-1.57 (m, 1H), 1.22 (t, J=6.9 Hz, 3H), 114 (t, J=7.2 Hz, 3H); MS (m/z) 383.0 (M+H)+.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([Br:24])=[CH:22][N:23]=3)[N:20]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>CO>[ClH:1].[ClH:1].[Br:24][C:21]1[N:19]2[N:20]=[C:15]([N:12]3[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]3)[CH:16]=[CH:17][C:18]2=[N:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3ncc(Br)n3n2)CC1
Agent: Cl
Solvent: CO
Product: Brc1cnc2ccc(N3CCNCC3)nn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Concentrated hydrochloric acid (6.4 mL) was added to a solution of 4-(3-bromo-imidazo[1,2-b]pyridazin-6-yl)-piperazine-1-carboxylic acid tert-butyl ester 2.9 g, 7.6 mmol) in methanol (150 mL), allowed to stir at ambient temperature overnight, then evaporated to dryness. The resultant yellow solid was dissolved in methanol and the stirred solution diluted with diethyl ether to precipitate 3-bromo-6-piperazin-1-yl-imidazo[1,2-b]pyridazine dihydrochloride as 2.6 g of white powder, mp. 275-276° C. (dec.). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.24 (br. s., 4H) 3.82-3.92 (m, 4H) 7.57 (d, J=10.11 Hz, 1H) 8.05 (s, 1H) 8.12 (d, J=10.10 Hz, 1H) 9.70 (br. s., 1H). 13C NMR (100 MHz, DMSO-d6) δ ppm 41.86, 42.37, 101.30, 114.15, 124.22, 127.20, 134.76, 155.43. LRMS (ESI) m/z 282.1/284.1 [(M+H)]+, calc'd for C10H12BrN5: 282.14.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Cl:23])C(=O)C1.Cl(O)(=O)(=O)=O.O>C(Cl)(Cl)Cl>[Cl:23][C:9]1[S:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:11]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=1
Reactant: COC(=O)c1ccsc1-c1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Cl)sc1-c1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-phenylthiophene-3-carboxylate and NCS in CHCl3 was added perchloric acid, followed by stirring at 50° C. for overnight. To the reaction mixture was added water, and the aqueous layer was extracted with EtOAc. The organic layer was washed with water and brine in this order, dried over MgSO4, and then concentrated under reduced pressure. The residue obtained was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, hexane:EtOAc) to obtain methyl 5-chloro-2-phenylthiophene-3-carboxylate as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[N:3]=1.C1N2CN3CN(C2)C[N:11]1C3.[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[N:3]=[C:4]([CH2:8][NH2:11])[CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1cccc(Br)n1
Reactant: C1N2CN3CN1CN(C2)C3
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: NCc1cccc(Br)n1
Temperature: 25 °C

Procedure:
2-Bromo-6-bromomethyl-pyridine (2.67 g, 10.63 mmol) was combined with hexamethylenetetramine (3.00 g, 21.30 mmol) in chloroform (50 ml) and the resulting reaction mixture was stirred at reflux for 14 hours. The reaction mixture was then cooled to room temperature and the white solid was collected by filtration. The white solid was suspended in ethanol (50 ml) and concentrated HCl (12 ml) was added. The resulting reaction mixture was stirred at 90° C. for 14 hours. Adjustment of pH to 12 was done by the addition of aq 5N NaOH. The reaction mixture was extracted with dichloromethane several times. The combined organic layers were concentrated to yield the title compound. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ 3.95 (s, 2H) 7.19-7.28 (m, 2H) 7.62 (t, J=7.82 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[C:22](OC)=[O:23].[NH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32].C[O-].[Na+].CO>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[C:22]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:23]
Reactant: COC(=O)c1ncc2cc(NCc3ccc(OC)cc3)ccc2c1O
Reactant: NCCCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNc2ccc3c(O)c(C(=O)NCCCCC(=O)O)ncc3c2)cc1
Temperature: 25 °C

Procedure:
A mixture of methyl 4-hydroxy-7-(4-methoxybenzylamino)isoquinoline-3-carboxylate (21.0 mg, 0.06 mmol), 5-aminovaleric acid (269.3 mg, 2.3 mmol, Sigma-Aldrich) and NaOMe in MeOH (3.0 mL, 1.5 mmol, 0.5 M solution, Sigma-Aldrich) was heated to reflux for 20 hours before cooling to room temperature. The solvent was removed in vacuo and the residue was dissolved in H2O (10 mL) and EtOAc (10 mL). To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-30% MeOH/CH2Cl2) to give the title compound in 14 mg. MS: (−) m/z 422.13 (M−1).
Reaction SMILES: [CH:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[O:18])[CH2:9][N+:8]=2[O-])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20]([O:23]C(=O)C)(=[O:22])[CH3:21]>C(Cl)(Cl)Cl>[C:20]([O:23][CH:9]1[N:8]=[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10]1=[O:18])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1C[N+]([O-])=C(C2CCCCC2)c2ccccc2N1
Solvent: ClC(Cl)Cl
Product: CC(=O)OC1N=C(C2CCCCC2)c2ccccc2NC1=O
Temperature: 70 °C

Procedure:
To a suspension of 5-cyclohexy-2,3-dihydro-1H-1,4-benzodiazepin-2-one-4-oxide (0.70 g) in chloroform (10 ml) was added acetic anhydride (3.7 ml) at ambient temperature and the mixture was heated for 4 hours at 70° C. After cooling, the mixture was concentrated in vacuo. The residue was taken up with chloroform. The organic layer was washed with saturated aqueous sodium carbonate, dried over magnesium sulfate, filtered off and concentrated in vacuo to give a crude product. The crude product was purified by column chromatography on silica gel with chloroform to give (3RS)-3-acetoxy-5-cyclohexyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:24][CH3:25])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])=[O:34])=[CH:29][CH:28]=1>>[CH:1]1([CH:7]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:34])=[CH:31][CH:32]=2)[C:9]2[C:10]([CH2:24][CH3:25])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: CCc1nn(-c2ccc(C(F)(F)F)cc2)cc1C(O)C1CCCCC1
Product: CCc1nn(-c2ccc(C(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Yield: 5.9 %

Procedure:
Using cyclohexyl{3-ethyl-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}methanol (0.90 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.75 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (82 mg, 6%) was obtained as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:16]([C:19]3[C:20]([NH2:35])=[N:21][CH:22]=[C:23]([C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[N:30]([CH3:34])[CH:29]=[CH:28]5)[CH:24]=3)=[N:17][N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C([SiH](CC)CC)C.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.O>[CH3:34][N:30]1[C:31]2[C:27](=[CH:26][C:25]([C:23]3[CH:24]=[C:19]([C:16]4[O:15][C:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[N:18][N:17]=4)[C:20]([NH2:35])=[N:21][CH:22]=3)=[CH:33][CH:32]=2)[CH2:28][CH2:29]1
Reactant: Cn1ccc2cc(-c3cnc(N)c(-c4nnc(C5CCN(C(=O)OC(C)(C)C)CC5)o4)c3)ccc21
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN1CCc2cc(-c3cnc(N)c(-c4nnc(C5CCNCC5)o4)c3)ccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 4-{5-[2-amino-5-(1-methyl-1H-indol-5-yl)-pyridin-3-yl]-[1,3,4]oxadiazol-2-yl}-piperidine-1-carboxylic acid tert-butyl ester (300 mg, 0.63 mmol) in TFA (2.0 mL) at 0° C. was added triethylsilane (146 mg, 1.26 mmol) drop-wise over a period of 5 min, and stirred for 2 h at 0° C. The reaction was diluted with water (20 mL), neutralized with saturated aqueous NaHCO3 solution and extracted with ethyl acetate (3×20 mL). The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude product. Crude product was purified by washing with diethyl ether and hexane to afford the title compound as a yellow solid:
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]([NH:11][C:12](=[O:21])[C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:26]O>>[Br:1][C:2]1[S:6][C:5]([CH:7]([NH:11][C:12](=[O:21])[C:13]2[C:14]([F:20])=[CH:15][CH:16]=[CH:17][C:18]=2[F:19])[C:8]([O:10][CH3:26])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NC(C(=O)O)c1ccc(Br)s1)c1c(F)cccc1F
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C(NC(=O)c1c(F)cccc1F)c1ccc(Br)s1

Procedure:
An amount of 3.415 g (9 mmol) of the product of Step B was dissolved in 19 mL of methanol. It was cooled in an ice-bath and 1.13 mL of thionyl chloride was added dropwise. The mixture was heated at reflux for 30 min. It was cooled and the methanol removed under reduced pressure. A saturated solution of sodium bicarbonate was carefully added to the residue, then extracted with ether. The combined ether extracts were washed with brine, dried (MgSO4) and concentrated to give a white solid: mp 123°-124° C. 1H-NMR (DMSO-d6) δ9.90 (d, 1H), 7.55 (m, 1H), 7.20 (m,3H), 7.00 (d, 1H), 5.90 (d, 1H), 3.75 (s,3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][CH3:19])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([NH2:16])[CH3:15])=[CH:10][CH:9]=2)[CH:7]=1.C(N(CC)CC)C.[Cl:27][C:28]1[N:32]([CH3:33])[N:31]=[C:30]([CH3:34])[C:29]=1[S:35](Cl)(=[O:37])=[O:36]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][CH3:19])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]([NH:16][S:35]([C:29]3[C:30]([CH3:34])=[N:31][N:32]([CH3:33])[C:28]=3[Cl:27])(=[O:36])=[O:37])[CH3:15])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: CCOc1ccc(Cl)cc1-c1ccc(C(C)N)cc1
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccc(Cl)cc1-c1ccc([C@@H](C)NS(=O)(=O)c2c(C)nn(C)c2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
A suspension of 5-chloro-2-ethoxyphenylboronic acid (601 mg, 3.0 mmol), palladium (II) acetate (33 mg, 0.15 mmol) and (R)-1-(4-bromophenyl)ethylamine (295 mg, 1.5 mmol) in water (4 ml) was heated for 5 min at 200° C. in a Smithcreator microwave oven. The reaction mixture was diluted with dichloromethane and purified on a Strata™ 5 g/20 ml SCX column (eluted with 2M ammonia in methanol) to give (R)-1-(5′-chloro-2′-ethoxy-biphenyl-4-yl)-ethylamine (341 mg, 1.2 mmol, 82%). To a solution of 1-(5′-chloro-2′-ethoxy-biphenyl-4-yl)-ethylamine (30 mg, 0.1 mmol) in dichloromethane (0.75 ml) was added triethylamine (36 mg, 0.35 mmol) and 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride (30 mg, 0.13 mmol) in dichloromethane (0.5 ml). The reaction mixture was then agitated at room temperature for 16 h and quenched with acetic acid (200 μl). Purification by preparatory LCMS and removal of solvent under reduced pressure gave the title compound (21 mg, 0.04 mmol, 40%): 1H NMR (400 MHz, DMSO-d6): δ 8.25 (d, 1H), 7.32-7.37 (m, 3H), 7.21-7.24 (m, 3H), 7.10 (d, 1H), 4.35 (m, 1H), 4.05 (m, 2H), 2.20 (s, 3H), 1.26-1.35 (m, 6H) ppm; MS (ESI) m/z: value [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:4][CH2:3]1.Br[CH2:16][C:17]#[N:18]>>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH2:16][C:17]#[N:18])[CH2:11][CH2:10]2)[CH2:4][CH2:3]1
Reactant: CN1CCC(CN2CCNCC2)CC1
Reactant: N#CCBr
Product: CN1CCC(CN2CCN(CC#N)CC2)CC1

Procedure:
The title compound is synthesized by coupling of 1-(1-Methyl-piperidin-4-ylmethyl)-piperazine (commercially available from CHESS GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+H=237.3.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7](Cl)=[O:8].[NH2:10][CH2:11][C@H:12]1[O:16][C@@H:15]([N:17]2[CH:24]=[C:23]([CH2:25][CH3:26])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:14][C@@H:13]1[OH:27].[OH-].[Na+]>O>[CH2:25]([C:23]1[C:21](=[O:22])[NH:20][C:18](=[O:19])[N:17]([CH:24]=1)[C@@H:15]1[O:16][C@H:12]([CH2:11][NH:10][C:7](=[O:8])[CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C@@H:13]([OH:27])[CH2:14]1)[CH3:26]
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CN)O2)c(=O)[nH]c1=O
Reactant: O=C(Cl)Cc1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CNC(=O)Cc3cccs3)O2)c(=O)[nH]c1=O
Reaction time: 0.17 h
Yield: 52.8 %

Procedure:
0.18 g of 2-thiopheneacetylchloride was added to a solution of 0.255 g of 5'-amino-2',5'-dideoxy-5-ethyluridine in 5 ml of water containing 1.2 ml of 1M sodium hydroxide solution and the resulting mixture was shaken vigorously for 10 minutes. The resulting white solid was collected by filtration, washed with water, dried at 50° C. in vacuo over phosphorus pentoxide and recrystallized from ethanol to give 0.2 g of 2',5'-dideoxy-5-ethyl-5'-[2-(2-thienyl)acetamido]uridine of melting point 215°-217° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1.[CH2:12]([O:14][C:15]([C:17]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=[C:19](Cl)[N:18]=1)=[O:16])[CH3:13].O>O1CCCC1>[CH2:12]([O:14][C:15]([C:17]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=[C:19]([O:9][CH2:8][C:7]2[CH:10]=[CH:11][C:4]([F:3])=[CH:5][CH:6]=2)[N:18]=1)=[O:16])[CH3:13]
Reactant: CCOC(=O)c1ccc(Cl)nc1C(=O)OCC
Reactant: OCc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc(OCc2ccc(F)cc2)nc1C(=O)OCC
Temperature: 60 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A mixture of sodium hydride (55% in mineral oil, 254 mg, 0.6 mmol) and 4-fluorobenzylalcohol in tetrahydrofuran (30 mL) was heated at 60° C. for 30 min and then after cooling at 0° C. a solution of 6-chloro-pyridine-2,3-dicarboxylic acid diethyl ester (1.3 g. 0.5 mmol) in tetrahydrofuran (20 mL) was added over 10 min. The resulting mixture was kept at 0° C. for 1 h and then water was added. The mixture was then extracted with ethylacetate and the combined organic extracts washed with water, brine and then dried over sodium sulfate. Filtration and evaporation gave a residue which was purified by chromatography (SiO2, heptane-EtOAc 9:1 to 3:1) to afford the title compound (1.3 g, 74%) as a colorless oil. MS: m/e=348.4 (M+H+).