Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:37])=[C:6]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([S:18]([NH2:21])(=[O:20])=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:22]([N:24]2[CH2:29][CH2:28][CH:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:26][CH2:25]2)=[O:23])[CH:7]=1.[C:38](O)(=[O:40])[CH3:39]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:37])=[C:6]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([S:18]([NH:21][C:38](=[O:40])[CH3:39])(=[O:19])=[O:20])=[C:13]3[N:12]=[CH:11][C:10]=2[C:22]([N:24]2[CH2:25][CH2:26][CH:27]([C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)[CH2:28][CH2:29]2)=[O:23])[CH:7]=1
Reactant: NS(=O)(=O)c1cnn2c(Nc3cc(Cl)ccc3F)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Reactant: CC(=O)O
Product: CC(=O)NS(=O)(=O)c1cnn2c(Nc3cc(Cl)ccc3F)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 87.7 %

Procedure:
Using 7-(5-chloro-2-fluorophenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.050 g, 0.091 mmol) obtained in step 5 and acetic acid (0.026 mL, 0.457 mmol) instead of cyclopropanecarboxylic acid, and in the same manner as in Example 1 step 6, the title compound (0.047 g, 87%) was obtained.
Reaction SMILES: [CH3:1][NH2:2].O.F[C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15]>CN(C=O)C>[CH3:1][NH:2][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15]
Reactant: CN
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: O
Solvent: CN(C)C=O
Product: CNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 100 %

Procedure:
A 40% solution of methylamine in water (11 mL; 128 mmol) (or any other primary amine) was slowly added to a stirring suspension of 4-fluoro-3-nitrobenzoic acid (278, 6.1 g; 32.9 mmol) in DMF (20 mL) at room temperature. After the addition was completed the mixture was stirred at the same temperature for 60 min; concentrated in vacuo, and suspended in 5% KHSO4 (final pH=2). The suspension was stirred overnight; the precipitate was collected by filtration, washed with water, then with ether and dried to afford the title compound 279 (6.5 g; 100% yield). 1H NMR: (400.2 MHz, DMSO) δ (ppm): 12.8 (bs; 1H), 8.59 (d, J=2.0 Hz; 1H); 8.55 (q, J=5.0 Hz; 1H); 7.96 (dd, J=2.0, 9.1 Hz; 1H); 7.04 (d, J=9.1 Hz; 1H); 3.00 (d, J=5.0 Hz; 3H). MS: calc: 196.2; found: 197.1 (M+H)
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[N:7]=1.[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[S:18](Cl)(=[O:20])=[O:19]>>[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[S:18]([NH:9][C:3]1[C:2]([Cl:1])=[N:7][C:6]([Cl:8])=[CH:5][N:4]=1)(=[O:20])=[O:19]
Reactant: Nc1ncc(Cl)nc1Cl
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Product: O=S(=O)(Nc1ncc(Cl)nc1Cl)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 3,5-dichloro-2-pyrazinamine (2.0 g) and 2,3-dichloro benzenesulphonyl chloride (2.94 g). Yield 3.0 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:12]([C:13](=[O:30])[CH2:14][NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][C:26]([O:28]C)=[O:27])[CH:20]=2)=[O:17])[CH:11]([C:31](=[O:37])[NH:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:10][CH:9]1[S:38]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)(=[O:40])=[O:39].[OH-].[K+]>O.CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:12]([C:13](=[O:30])[CH2:14][NH:15][C:16](=[O:17])[NH:18][C:19]2[CH:20]=[C:21]([CH2:25][C:26]([OH:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:11]([C:31](=[O:37])[NH:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:10][CH:9]1[S:38]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)(=[O:39])=[O:40]
Reactant: COC(=O)Cc1cccc(NC(=O)NCC(=O)N2C(C(=O)NCC(C)C)CC(S(=O)(=O)c3ccccc3)C2c2ccccc2F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)CNC(=O)C1CC(S(=O)(=O)c2ccccc2)C(c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(CC(=O)O)c1
Yield: 50.1 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 3, but from 3.75 g of (2RS,4SR,5RS)-5-(2-flurophenyl)-2-isobutylcarbamoyl-1-{2-[3-(3-(methoxycarbonylmethyl)phenyl)ureido]acetyl}-4-(phenylsulphonyl)pyrrolidine and 0.32 g of potassium hydroxide in a mixture of 55 cm3 of distilled water and 140 cm3 of methanol. After treatment, there are obtained 1.84 g of (2RS,4SR,5RS)-3-{3-[2-(5-(2-fluorophenyl)-2-isobutylcarbamoyl-4-phenylsulphonyl-1-pyrrolidinyl)-2-oxoethyl]ureido}phenylacetic acid [Rf =0.73; eluent: methylene chloride/methanol (80/20)].
Reaction SMILES: [N:1]([CH:4]([CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:1][CH:4]([CH2:11][O:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1
Reactant: COc1ccc(COCC(Cn2ccnc2)N=[N+]=[N-])cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(COCC(N)Cn2ccnc2)cc1
Yield: 77.6 %

Procedure:
A solution of 1-[2-azido-3-[(4-methoxyphenyl)methoxy]propyl]-1H-imidazole (5.1 g, 0.018M) in dry tetrahydrofuran (10 ml) was added dropwise to a stirred slurry of lithium aluminium hydride (0.68 g, 0.018M) in dry tetrahydrofuran (40 ml) at room temperature under a stream of dry nitrogen. When the addition was complete the reaction mixture was heated under reflux for 18 hours. The solvent was evaporated off under reduced pressure and the residue was extracted with ethyl acetate, washed with saturated aqueous ammonium chloride solution and dried (MgSO4). The solvent was evaporated off under reduced pressure to give 1-[2-amino-3-[(4-methoxyphenyl)methoxy]propyl]-1H-imidazole as an oil (3.6 g) which was used directly without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:16][CH2:17][C:18]#[CH:19])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22](=[O:43])[CH2:23][CH:24]1[CH2:33][C:32]2[C:27](=[CH:28][C:29](OS(C(F)(F)F)(=O)=O)=[CH:30][CH:31]=2)[NH:26][C:25]1=[O:42].CCOC(C)=O.CCCCCC>CN1CCCC1.[Cu]I>[CH3:20][O:21][C:22](=[O:43])[CH2:23][CH:24]1[CH2:33][C:32]2[C:27](=[CH:28][C:29]([C:19]#[C:18][CH2:17][CH2:16][N:8]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:30][CH:31]=2)[NH:26][C:25]1=[O:42]
Reactant: C#CCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: COC(=O)CC1Cc2ccc(OS(=O)(=O)C(F)(F)F)cc2NC1=O
Agent: [Cu]I
Agent: CN1CCCC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)CC1Cc2ccc(C#CCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2NC1=O
Temperature: 60 °C
Reaction time: 22 h
Yield: 61.8 %

Procedure:
A suspension of N-but-3-ynyl-imidodicarbonic acid di-tert-butyl ester (4.65 g, 17.3 mmol), [2-oxo-7-(trifluoro-methanesulfonyloxy)-1,2,3,4-tetrahydro-quinolin-3-yl]-acetic acid methyl ester (6.36 g, 17.3 mmol), tetrakis (triphenylphosphine)palladium (2.0 g, 1.7 mmol) and copper (I) iodide (0.49 g, 2.6 mmol) in N-methylpyrrolidine (50 mL; purged with N2) was heated to 60° C. The resulting solution was treated with the original amounts of both catalysts, two additional times, at 1.5 h intervals. After 22 h, the reaction mixture was filtered and concentrated. The resulting dark oil was treated with saturated aqueous NH4Cl (250 mL), extracted with chloroform (3×250 mL), dried (MgSO4) and concentrated to give a dark mixture of oil and foam (16.2 g). Flash chromatography (260 g silica; 5%, then 10%, then 20%, then 40% EtOAc-hexane) gave the title compound (5.2 g, 62% yield) as an impure yellow foam.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH2:15][OH:16])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[NH2:20][CH2:21][CH2:22][CH2:23][NH2:24]>O1CCOCC1>[NH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH2:15][OH:16])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: NCCCN
Reactant: O=C1CC(CO)C(c2ccc(Cl)c([N+](=O)[O-])c2)=NN1
Solvent: C1COCCO1
Product: NCCCNc1ccc(C2=NNC(=O)CC2CO)cc1[N+](=O)[O-]

Procedure:
14.0 g (50 mmol) of 6-(4-chloro-3-nitro-phenyl)-4,5-dihydro-5-hydroxymethyl-3(2H)-pyridazinone are heated to 60° C. together with 50 ml of 1,3-diaminopropane in 40 ml of dioxane for 8 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:20]([C:22]1[NH:26][C:25]([CH3:27])=[C:24]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:23]=1[CH3:33])=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:20][C:22]4[NH:26][C:25]([CH3:27])=[C:24]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:23]=4[CH3:33])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)c(C)c1CCC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.5 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (6.3 mg, 0.0226 mmol), 3-(5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)-propionic acid (4.9 mg, 0.0249 mmol) and piperidine (4 drops) in ethanol (1 mL) was stirred at room temperature for 24 hours. The reaction was concentrated and purified (reversed phase HPLC) to give 5.2 mg (51%) of the title compound. MS 456.4 [M++1].
Reaction SMILES: Cl.[Si]([O:19][CH2:20][CH2:21][C:22]1[C:23](=[O:51])[N:24]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:38][C@H:37]([CH2:39][NH:40][C:41]([C:43]4[S:44][C:45]([Cl:48])=[CH:46][CH:47]=4)=[O:42])[O:36][C:35]3=[O:49])=[CH:30][C:29]=2[CH3:50])[CH:25]=[CH:26][CH:27]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>CO.ClCCl>[Cl:48][C:45]1[S:44][C:43]([C:41]([NH:40][CH2:39][C@@H:37]2[O:36][C:35](=[O:49])[N:34]([C:31]3[CH:32]=[CH:33][C:28]([N:24]4[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][CH2:20][OH:19])[C:23]4=[O:51])=[C:29]([CH3:50])[CH:30]=3)[CH2:38]2)=[O:42])=[CH:47][CH:46]=1
Reactant: Cc1cc(N2C[C@H](CNC(=O)c3ccc(Cl)s3)OC2=O)ccc1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(N2C[C@H](CNC(=O)c3ccc(Cl)s3)OC2=O)ccc1-n1cccc(CCO)c1=O
Reaction time: 1 h

Procedure:
With ice-cooling, 400 ml of 1.25N hydrochloric acid in methanol are added to 43.8 g (60.3 mmol) of the compound from Example 17A. After 1 h, the mixture is diluted with dichloromethane, and the aqueous phase is then separated off. The organic phase is washed twice with water, dried over sodium sulphate and, after filtration, concentrated to dryness under reduced pressure. The residue is applied to silica gel and chromatographed using a gradient of cyclohexane and ethyl acetate. The product-containing fractions are combined and concentrated to dryness under reduced pressure. This gives 19.6 g (66% of theory) of the desired product.
Reaction SMILES: C1C=CC(C(NC2C3NC=NC=3N=CN=2)=[O:8])=CC=1.C(N[C:23]1[CH:44]=[CH:43][N:26]([C@@H:27]2[O:42][C@H:36]([CH2:37][O:38]C(=O)C)[C@@H:31]([O:32]C(=O)C)[C@H:28]2[O:29]C)[C:25](=[O:45])[N:24]=1)(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C(#N)C.ClCCl>[C@@H:27]1([N:26]2[CH:43]=[CH:44][C:23](=[O:8])[NH:24][C:25]2=[O:45])[O:42][C@H:36]([CH2:37][OH:38])[C@@H:31]([OH:32])[C@H:28]1[OH:29]
Reactant: CO[C@@H]1[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@H]1n1ccc(NC(C)=O)nc1=O
Reactant: O=C(Nc1ncnc2nc[nH]c12)c1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Solvent: ClCCl
Product: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Temperature: 75 °C
Yield: 50 %

Procedure:
A solution of N6-benzoylaminopurine (Lancaster) (1.23 g, 5.16 mmol) stirring in anhydrous acetonitrile under an argon atmosphere was treated with BSA (3.82 ml, 15.48 mmol) at reflux for 3 hours. Upon cooling, a solution of N4-acetyl-5′,3′-di-O-acetyl-2′-O-methyl cytidine (2) (see above) (0.66 g, 1.72 mmol) in 20 ml anh. acetonitrile was added to the reaction mixture followed by TMStriflate (1.03 ml, 5.16 mmol). The reaction mixture was then heated to 75° C. for 16 hours while stirring under positive pressure argon. Upon cooling, an additional 1.03 ml (5.16 mmol) of TMStriflate was added, and the reaction heated to 75° C. for an additional 20 hours. Once cool, the reaction mixture was diluted with two volumes of dichloromethane and washed with sat. NaHCO3. The organic layer was then dried over Na2SO4 and evaporated in vacuo. Flash chromatography employing a gradient of 10 to 80% ethyl acetate/hexanes afforded (1) as a white foam; 0.403 g, 50% yield. 1H NMR (CDCl3): 8.88 (br s, 1H, NH), 8.81 (s, 1H, H8), 8.31 (s, 1H, H2), 8.11-7.53 (m, 5H, benzoyl), 6.18 (d, J1′,2′=4.8, 1H, H1′), 5.41 (t, J3′,2′=4.8, J3′,4′=4.8, 1H, H3′), 4.75 (t, J2′,1′=4.8, J2′,3′=4.8, 1H, H2′), 4.50-4.34 (m, 3H, H4′, H5′, H5″), 3.44 (s, 3H, OCH3), 2.19 (s, 3H, OAc), 2.14 (s, 3H, OAc).
Reaction SMILES: C[O-].[Na+].[O:4]=[C:5]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[O:8][C:7]2([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH2:6]1.[CH:27](OCC)=[O:28].O>C1COCC1>[OH:28][CH:27]=[C:6]1[C:7]2([CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)[O:8][C:9]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[C:5]1=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1ncccc1O2
Reactant: CCOC=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1cccnc1C(=O)C2=CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.2 %

Procedure:
To a suspension of sodium methoxide (594 mg, 11.0 mmol) in THF (5 mL) was added a suspension of tert-butyl 4′-oxo-3′,4′-dihydrospiro[piperidine-4,2′-pyrano[3,2-b]pyridine]-1-carboxylate (1.0 g, 3.1 mmol) in THF (10 mL), followed by ethyl formate (2.5 mL, 31 mmol) and the reaction mixture was stirred at 25° C. for 3 hours. Additional sodium methoxide (170 mg, 3.1 mmol) and ethyl formate (0.25 mL, 3.1 mmol) were added and the reaction mixture was stirred at 25° C. for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate (4×). The aqueous layer was saturated with solid NaCl and was extracted with ethyl acetate (5×). The organic layers were combined and dried over sodium sulfate. The precipitate formed was filtered and washed with ether (2×). The solid product was dissolved in hot dichloromethane/MeOH (1:1) and filtered, and the filter cake was rinsed with additional hot dichloromethane/MeOH (1:1) (4×) to dissolve all product and remove solid sodium sulfate. The combined filtrates were evaporated to afford tert-butyl 3′-(hydroxymethylene)-4′-oxo-3′,4′-dihydrospiro-[piperidine-4,2′-pyrano[3,2-b]pyridine]-1-carboxylate (560 mg, 52%) as a yellow solid. ESI-MS m/z calc. 346.2. found 347.5 (M+1)+; Retention time: 0.98 minutes (3 min run).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][C:13]1[C:14]([Cl:19])=[N:15][CH:16]=[CH:17][CH:18]=1>C(COC)OC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Zn]>[Cl:19][C:14]1[C:13]([CH2:12][C:6]([C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)=[O:7])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: Clc1ncccc1CBr
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: O=C(Cc1cccnc1Cl)c1ccc(F)cc1
Reaction time: 20 h
Yield: 12.6 %

Procedure:
To a stirred suspension of 4-fluorobenzoyl chloride (2.89 mL, 24.5 mmol), bis(triphenylphosphine)palladium (II) chloride (1.08 g, 1.54 mmol) and zinc dust (3.20 g, 49 mmol) in anhydrous dimethoxyethane (50 mL) was added a solution of the title compound of Step B (5.06 g, 24.5 mmol) in dimethoxyethane (50 mL) at room temperature under N2 over 45 min. After 20 h, the suspension was filtered through Celite® washed with ethyl acetate. The filtrate was washed with water and saturated aqueous NaCl, dried over MgSO4, and concentrated in vacuo to a yellow solid. Purification by flash chromatography eluting with 17-60% ethyl acetate/hexanes afforded the title compound of Step C as a yellow solid (0.77 g) which was somewhat impure by 1H NMR. 1H NMR (CDCl3, 300 MHz) δ8.30 (dd, 1H), 8.10 (m,2H), 7.6 (dd, 1H), 7.0-7.4 (m,3H), 4.40 (s,2H).
Reaction SMILES: [C:1]([C:9]1[CH:19]=[CH:18][C:12]2[N:13]=[C:14]([CH2:16]Cl)[NH:15][C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:27]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=1)[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][NH:36][CH:37]2[C:46]3[N:45]=[CH:44][CH:43]=[CH:42][C:41]=3[CH2:40][CH2:39][CH2:38]2)=[CH:31][CH:30]=1)=O)(C)(C)C.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:49]1[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[CH2:47][NH:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][N:36]([CH2:16][C:14]2[NH:13][C:12]3[CH:18]=[CH:19][C:9]([C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][C:11]=3[N:15]=2)[CH:37]2[C:46]3[N:45]=[CH:44][CH:43]=[CH:42][C:41]=3[CH2:40][CH2:39][CH2:38]2)=[CH:33][CH:34]=1
Reactant: O=C(c1ccccc1)c1ccc2nc(CCl)[nH]c2c1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(CNC2CCCc3cccnc32)cc1)Cc1ccccn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccccc1)c1ccc2[nH]c(CN(Cc3ccc(CNCc4ccccn4)cc3)C3CCCc4cccnc43)nc2c1
Yield: 75.9 %

Procedure:
A solution of 5-benzoyl-2-chloromethylbenzimidazole (284 mg, 1.05 mmol), N-(tert-butoxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (476 mg, 1.04 mmol) and N,N-diisopropylethylamine (0.36 mL, 2.08 mmol) were stirred at 80□ C in DMF (4 mL) for 16 hours. The reaction was then cooled, concentrated under reduced pressure and diluted with CH2Cl2 (35 mL) and saturated aqueous NaHCO3 (40 mL). The phases were separated and the aqueous phase was washed with CH2Cl2 (2×25 mL). The combined organic extracts were washed with saturated aqueous NaHCO3 (1×40 mL), dried (NaSO4), filtered and concentrated under reduced pressure. Purification of the resultant oil by flash chromatography on silica gel (96:4 CH2Cl2/MeOH) provided the desired alkylated product (468 mg, 65%) as an orange oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][N:10]=[C:9]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[C:19]1([C:9]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([C:27]4[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=4)=[CH:3][CH:4]=3)[C:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[N:11][N:10]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Brc1ccc(-n2c(-c3ccccc3)nnc2-c2ccccc2)cc1
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: c1ccc(-c2nnc(-c3ccccc3)n2-c2ccc(-c3cccnc3)cc2)cc1
Temperature: 95 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
Into a 100 mL three-neck flask were put 2.0 g (5.3 mmol) of 4-(4-bromophenyl)-3,5-diphenyl-4H-1,2,4-triazole, 0.98 g (8.0 mmol) of 3-pyridineboronic acid, and 0.28 g (1.1 mmol) of tetrakis(triphenylphosphine)palladium(0), and 10 mL of 1,2-dimethoxyethane (DME) and 10 mL of a 2M sodium carbonate aqueous solution were added to the mixture. This mixture was degassed under reduced pressure. After that, the air in the flask was replaced with nitrogen. This mixture was stirred at 95° C. for 3 hours. After the stir, dichloromethane was added to the reacted mixture, and the suspension was washed with 1M diluted hydrochloric acid, a saturated sodium hydrogen carbonate solution, and saturated saline. The organic layer and the aqueous layer were separated. Magnesium sulfate was added to the organic layer to dry the organic layer. After the drying, this mixture was subjected to suction filtration through Celite (Catalog No. 531-16855, manufactured by Wako Pure Chemical Industries, Ltd.) to obtain the filtrate. The obtained filtrate was concentrated and purified by silica gel column chromatography. For the column chromatography, first toluene and then a mixed solvent of toluene and ethyl acetate (toluene:ethyl acetate=1:3) were used as developing solvents. The obtained fraction was concentrated to give a solid. The obtained solid was recrystallized with a mixed solvent of ethanol and hexane to give 1.5 g of a powdery white solid, which was the object of the synthesis, at a yield of 76%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1.[OH-].[K+].[CH2:12](I)[CH3:13]>C(O)C>[CH2:12]([N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]1=[O:9])[CH3:13]
Reactant: CCI
Reactant: COc1ccc[nH]c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCn1cccc(OC)c1=O

Procedure:
A mixture of 3-methoxy-2(1H)-pyridone (12.5 g., 0.10 moles), potassium hydroxide (8.0 g., 0.12 moles) and ethyl iodide (31.2 g., 0.02 moles) in 200 ml. ethanol is heated at reflux for 4 hours. Proceeding as previous preparations affords 1-ethyl-3-methoxy-2(1H)-pyridone as a clear yellow oil (14.1 g., 92%).
Reaction SMILES: [C:1]([NH:14][C@H:15]([C:19]([OH:21])=[O:20])[CH:16]([CH3:18])[CH3:17])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].S(=O)(=O)(O)O.[CH:27](O)([CH3:29])[CH3:28]>>[CH:27]([O:20][C:19](=[O:21])[C@H:15]([CH:16]([CH3:18])[CH3:17])[NH:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])([CH3:29])[CH3:28]
Reactant: CCCCCCCCCCCC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Product: CCCCCCCCCCCC(=O)N[C@H](C(=O)OC(C)C)C(C)C

Procedure:
Forty-nine(49) grams of N-lauroylvaline and 197 g of isopropanol were charged into a 500-milliliter flask. Further, 1.61 g of conc. sulfuric acid were added as the catalyst. The mixture was heated under reflux for reaction for 6 hours.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][CH:22]4[NH:27][CH:28]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]>C(O)(C(F)(F)F)=O>[CH:10]([O:9][C:8]1[CH:7]=[CH:6][C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][CH:22]4[NH:27][CH:28]3[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]3)[N:14]=2)=[CH:4][C:3]=1[C:1]#[N:2])([CH3:12])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC4NC3CCN(C(=O)OC(C)(C)C)CC3)no2)cc1C#N
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC4NC3CCNCC3)no2)cc1C#N
Yield: 90.2 %

Procedure:
A solution of tert-butyl 4-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidine-1-carboxylate (15.7 mg, 0.03 mmol) in neat TFA (1 mL) was stirred for 30 min and concentrated to provide 12 mg (99%) of 2-isopropoxy-5-(3-(1-(piperidin-4-ylamino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)benzonitrile. LCMS-ESI (m/z) calculated for C26H29N5O2: 443.5; found 444.2 [M+H]+, tR=5.31 min (Method 2).