Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH3:24])=[CH:6][CH:7]=1
Reactant: Cc1ccccc1O
Reactant: Cc1nccn1-c1nc(-c2ccc(F)cc2)c(CCCCO)o1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccccc1OCCCCc1oc(-n2ccnc2C)nc1-c1ccc(F)cc1
Reaction time: 1 h

Procedure:
To a mixture of 4-(4-fluorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolebutanol (315 mg), 2-methylphenol (216 mg), tributylphosphine (405 mg) and tetrahydrofuran (5ml) was added 1,1′-(azodicarbonyl)dipiperidine (505mg) at room temperature, and the resulting mixture was stirred for 1 hour. After the reaction mixture was concentrated, the residue was subjected to silica gel column chromatography, and 4-(4-fluorophenyl)-2-(2-methyl-1-imidazolyl)-5-[4-(2-methylphenoxy)butyl]oxazole was obtained as an oil (367 mg, 91%) from an ethyl acetate-hexane (1:1, v/v)-eluted fraction.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30]>>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:18][CH2:19][N:20]([CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:21][CH2:22]1
Reactant: CC(C)CCBr
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCNCC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCN(CCC(C)C)CC3)c2n1

Procedure:
Prepared similarly to Example 80 from 2-(butyloxy)-8-(methyloxy)-9-[2-(4-piperidinyl)ethyl]-9H-purin-6-amine and 1-bromo-3-methylbutane.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([C:17]1[N:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]3=[N:19][N:18]=1)[CH:13]=[CH:12]2)(=O)=O.[NH2:28][CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:19]1[N:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]3[C:16](=[C:7]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:34]4)[CH:8]=[CH:9][CH:10]=3)[N:15]=2)[N:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=12
Reactant: O=S(=O)(Oc1cccc2ccc(-c3nnc4ccccn34)nc12)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccc3ccc(-c4nnc5ccccn45)nc23)CC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 96.3 %

Procedure:
2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yl trifluoromethanesulfonate (0.100 g, 0.25 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (0.102 g, 0.51 mmol), Pd2 dba3 (0.023 g, 0.025 mmol), BINAP (0.032 g, 0.05 mmol) and cesium carbonate (0.124 g, 0.38 mmol) were combined in a capped vial and stirred at 100° C. for 16 hours. The cooled mixture was filtered through GF paper and the filtrate partitioned between saturated NaHCO3 and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (CH2Cl2 followed by 1% MeOH/CH2Cl2) to provide 0.107 g (95%) of desired product as an orange foam.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[NH:10][CH:11]=[CH:12][C:3]=12.[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O>C(O)CO>[CH:13]1([NH:19][C:2]2[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]3[NH:10][CH:11]=[CH:12][C:3]=23)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=Cc1cnc2[nH]ccc2c1Cl
Reactant: NC1CCCCC1
Solvent: O
Solvent: OCCO
Product: O=Cc1cnc2[nH]ccc2c1NC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
4-Chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (845 mg, 4.68 mmol) and cyclohexylamine (2.5 mL, 22 mmol) in ethylene glycol (2 mL) were stirred at 170° C. for 1 hour under microwave irradiation. The reaction mixture was allowed to cool to room temperature and, after addition of water, extracted with chloroform. The organic layer was stirred with 2 M hydrochloric acid (20 mL) for 1 hour, and the organic layer was separated. The aqueous layer was adjusted to pH 9 or above with 10 M aqueous sodium hydroxide and extracted with chloroform. The organic layers were combined, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=10/1 (v/v)) to give the title compound as a pale yellow oil (804 mg, yield 71%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9](OC(N2C=CN=C2)=S)[C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[CH3:8].C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH3:8])[CH2:9][C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: Cc1ccc(C(OC(=S)n2ccnc2)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(C[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1F
Temperature: 25 °C
Yield: 57 %

Procedure:
Tert-butyl (2S)-2-{(3-fluoro-4-methylphenyl)[(1H-imidazol-1-yl carbonothioyl)oxy]methyl}pyrrolidine-1-carboxylate (0.83 g, 1.98 mmol), which had been obtained in Example 1 (1c), and a solution of tributyl tin hydride (1.73 g, 5.94 mmol) and 2,2′-azobis(isobutyronitrile) (0.07 g, 0.40 mmol) in toluene (4 mL) were stirred with heating under reflux for 6 hours. The reaction solution was cooled to room temperature. Water (20 mL) was added to the reaction solution, which was then extracted with ethyl acetate (20 mL×3). After that, the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to give the title compound as a colorless oily substance (0.33 g, yield 57%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[O:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:27][CH:24]2[CH2:25][CH2:26][O:21][CH2:22][CH2:23]2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: NC1CCOCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc(Cl)nc1NC1CCOCC1
Temperature: -64 °C
Reaction time: 5 h
Yield: 78.1 %

Procedure:
To a solution of 2,4-dichloro-5-nitropyrimidine (1.03 g, 5.15 mmol) in THF (40 mL) at −78° C., DIPEA (2.0 mL, 11.86 mmol) and tetrahydro-2H-pyran-4-amine (0.54 mL, 5.15 mmol) were added. The reaction mixture was stirred from −78 to −50° C. for 5 h. The crude mixture was quenched with H2O (50 mL), extracted with EtOAc (3×40 mL) and the combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated. The crude product thus obtained was chromatographed over silica gel using EtOAc/hexanes mixtures of increasing polarity as eluent, to afford 1.04 g of the desired compound (78% yield).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].Cl[C:7]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[C:9](=[C:10]([I:19])[CH:11]=[CH:12][CH:13]=2)[N:8]=1>C1COCC1>[C:1]([NH:5][C:7]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[C:9](=[C:10]([I:19])[CH:11]=[CH:12][CH:13]=2)[N:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(Cl)nc2c(I)cccc2c1=O
Reactant: CC(C)(C)N
Solvent: C1CCOC1
Product: Cn1c(NC(C)(C)C)nc2c(I)cccc2c1=O
Temperature: 50 °C
Yield: 89.7 %

Procedure:
A heterogeneous mixture of tert-butylamine (22.83 mL, 217 mmol) and 2-chloro-8-iodo-3-methylquinazolin-4(3H)-one (700) (4.64 g, 14.48 mmol) in 2 mL of THF in a 100 mL RBF fitted with a reflux condenser was heated in an oil bath at 50° C. for 4 h. The reaction mixture was concentrated under reduced pressure and the brown solid was dissolved in 300 mL of EtOAc, washed sequentially with 10 mL of water, 10 mL of sat. NaHCO3 solution and 10 mL of brine. The organic solution was concentrated. The residue was purified on a silica gel column (25-55% EtOAc in hexanes) to afford 2-(tert-butylamino)-8-iodo-3-methylquinazolin-4(3H)-one (4.64 g, 12.99 mmol, 90% yield) as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.12 (1H, dd, J=7.5, 1.3 Hz), 7.93 (1H, dd, J=7.8, 1.2 Hz), 6.89 (1H, t, J=7.6 Hz), 6.02 (1H, s), 3.41 (3H, s), 1.60 (9H, s). m/z (ES, +ve) 358.1 (M+H)+.
Reaction SMILES: [OH-].[K+].[CH:3]1([C:6]([CH:14]2[CH2:16][CH2:15]2)([C:8]2[S:9][C:10]([SH:13])=[N:11][N:12]=2)[OH:7])[CH2:5][CH2:4]1.Br[C:18]1[CH:27]=[C:26]2[C:21]([C:22]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)=[CH:23][C:24](=[O:28])[O:25]2)=[CH:20][CH:19]=1>CO>[CH:14]1([C:6]([CH:3]2[CH2:5][CH2:4]2)([OH:7])[C:8]2[S:9][C:10]([S:13][C:18]3[CH:27]=[C:26]4[C:21]([C:22]([C:29]5[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=5)=[CH:23][C:24](=[O:28])[O:25]4)=[CH:20][CH:19]=3)=[N:11][N:12]=2)[CH2:15][CH2:16]1
Reactant: O=c1cc(-c2cccnc2)c2ccc(Br)cc2o1
Reactant: OC(c1nnc(S)s1)(C1CC1)C1CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=c1cc(-c2cccnc2)c2ccc(Sc3nnc(C(O)(C4CC4)C4CC4)s3)cc2o1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
KOH (0.089 g, 1.59 mmol) was added to a solution of dicyclopropyl(5-mercapto-1,3,4-thiadiazol-2-yl)methanol (0.363 g, 1.60 mmol) in dry MeOH. When a solution was obtained, the reaction mixture was concentrated to dryness. Dry toluene was then added and the mixture was concentrated to dryness again. The residue was dissolved in NMP, 7-bromo-4-pyridin-3-yl-2H-chromen-2-one (400 mg, 1.32 mmol) was added and the resulting mixture was stirred at 120° C. for 16 h. The reaction mixture was cooled and partitioned between aqueous NH4OAc and EtOAc. The organic phase was washed with brine, dried over anhydrous Na2SO4, concentrated and purified on silica gel column (toluene-acetone, 90:10 to 70:30) to give the title compound. 1H NMR (400 MHz, CDCl3): δ 8.82 (d, 1H), 8.72 (s,1H), 7.81 (dt, 1H), 7.64 (s, 1H), 7.58-7.50 (m, 1H), 7.48-7.41 (m, 2H), 6.46 (s, 1H), 2.57 (s, 1H), 1.40-1.31 (m, 2H), 0.69-0.57 (m, 6H), 0.50-0.44 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([C:23]5[N:28]=[CH:27][C:26]([C:29](=[NH:31])[NH2:30])=[CH:25][C:24]=5[C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[CH:19][CH:18]=4)[CH2:12][CH2:11]3)[NH:7][C:6]=2[CH:38]=1.Cl[CH2:40][CH:41]=O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([C:23]5[C:24]([C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)=[CH:25][C:26]([C:29]6[NH:30][CH:40]=[CH:41][N:31]=6)=[CH:27][N:28]=5)=[CH:19][CH:18]=4)[CH2:12][CH2:11]3)[NH:7][C:6]=2[CH:38]=1
Reactant: O=CCCl
Reactant: N=C(N)c1cnc(-c2ccc(CN3CCC(c4nc5ccc(F)cc5[nH]4)CC3)cc2)c(-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Fc1ccc2nc(C3CCN(Cc4ccc(-c5ncc(-c6ncc[nH]6)cc5-c5ccccc5)cc4)CC3)[nH]c2c1
Temperature: 110 °C

Procedure:
To a solution of 6-(4-{[4-(6-fluoro-1H-benzimidazol-2-yl)piperidin-1-yl]methyl)phenyl)-5-phenylpyridine-3-carboximidamide (3-2, 0.030 g, 0.059 mmol) in Dioxane (1.5 mL) was added chloroacetaldehyde (50% solution in H2O, 0.019 mL, 0.119 mmol) followed by sodium carbonate (0.016 mg, 0.149 mmol). The reaction was heated to 110° C. for 1 hr. The mixture was cooled and partitioned between saturated aqueous sodium bicarbonate and CH2Cl2 and extracted 3×. The combined organics were dried (anhd. Na2SO4), filtered and concentrated. The residue was purified by silica gel chromatography (6-8% MeOH in CH2Cl2). 1H-NMR (500 MHz, d6 DMSO) δ 12.83 (s, 1H), 12.31 (s, 1H), 9.21 (d, J=1.95, 1H), 8.74 (s, 1H), 8.30 (d, J=2.2, 1H), 7.08-7.42 (m, 12H), 6.97 (bs, 1H), 3.61 (bs, 2H), 3.50 (bs, 1H), 3.13 (bs, 2H), 2.87 (bs, 2H), 1.98 (bs, 2H), 1.84 (bs 2H). HRMS m/z (M+H) Calcd: 529.2511, found: 529.2532.
Reaction SMILES: [N+]([C:4]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[C:5]=1[CH:6]=[CH:7][N:8]1CCCC1)([O-])=O.O.NN>C1C=CC=CC=1.[Ni]>[Cl:19][C:13]1[C:14]([O:17][CH3:18])=[CH:15][CH:16]=[C:4]2[C:5]=1[CH:6]=[CH:7][NH:8]2
Reactant: COc1ccc([N+](=O)[O-])c(C=CN2CCCC2)c1Cl
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc2[nH]ccc2c1Cl
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
A solution of 2-nitro-5-methoxy-6-chloro-β-pyrrolidinostyrene (5.28 g, 18.7 mmol) in benzene (100 ml) was stirred under nitrogen at 20° C. Raney nickel (0.50 ml) was added, followed by hydrazine hydrate (1.6 ml). After 30 minutes, more hydrazine hydrate was added (1.6 ml), and the mixture was stirred for a further 11/2 hours. After filtration through celite, the filtrate was evaporated to dryness to leave a dark yellow crystalline residue, which was purified by chromatography (SiO2 ; CHCl3), then recrystallised from benzene/hexane to give 4-chloro-5-methoxyindole (2.85 g) m.p. 112°-3° C.
Reaction SMILES: [CH:1]1([C:6]2[C:7]([O:22]S(C3C=CC(C)=CC=3)(=O)=O)=[N:8][N:9]3[C:14]=2[C:13]([CH3:15])=[N:12][N:11]=[C:10]3[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:33]([N:35]1[C:39]([CH2:40]O)=[N:38][CH:37]=[N:36]1)[CH3:34].[H-].[Na+].O>CN(C=O)C>[CH:1]1([C:6]2[C:7]([O:22][CH2:40][C:39]3[N:35]([CH2:33][CH3:34])[N:36]=[CH:37][N:38]=3)=[N:8][N:9]3[C:14]=2[C:13]([CH3:15])=[N:12][N:11]=[C:10]3[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCn1ncnc1CO
Reactant: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4ccccc4)nnc(C)c3c2C2CCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1ncnc1COc1nn2c(-c3ccccc3)nnc(C)c2c1C1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To toluene-4-sulfonic acid 3-cyclopentyl-4-methyl-7-phenylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester (300 mg, 0.67 mmol) and (2-ethyl-2H-[1,2,4]triazol-3-yl)methanol (102 mg, 1.2 molar eq; prepared as described in EP-A-170073) in DMF (10 ml) was added sodium hydride (29.5 mg of a 60% dispersion in mineral oil; 1.2 molar eq) and the mixture was stirred at room temperature for 1 h. Water (90 ml) was added then the solution was extracted with diethyl ether (4×60 ml). The combined ether layers were washed with brine (1×100 ml), dried (Na2SO4), the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel eluting with 0 to 50% ethyl acetate in dichloromethane. 3-Cyclopentyl-2-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-4-methyl-7-phenylpyrazolo[1,5-d][1,2,4]triazine was isolated as a gum, which solidified upon trituration under diethyl ether/isohexane (144 mg, mp=112° C.). 1H NMR (360 MHz, CDCl3) δ 1.42 (3H, t, J=7.3 Hz), 1.66-1.95 (8H, m), 2.87 (3H, s), 3.43 (1H, m), 4.20 (2H, q, J=7.3 Hz), 5.55 (2H, s), 7.51-7.61 (3H, m), 7.93 (1H, s), 8.28-8.31 (2H, m); MS (ES+) m/e 403 [MH]+. Anal. Found C, 65.10; H, 6.06; N, 24.19%. C22H25N7O requires C, 65.49; H, 6.25; N, 24.06%.
Reaction SMILES: [CH3:1][C:2]1[NH:20][C:5]2=[N:6][C:7]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:4]2[N:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[CH3:30].C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C>[Cl:29][C:25]1[C:24]([CH3:30])=[C:23]([CH:28]=[CH:27][CH:26]=1)[CH2:22][N:20]1[C:5]2=[N:6][C:7]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:4]2[N:3]=[C:2]1[CH3:1]
Reactant: COC(=O)c1cc(N2CCOCC2)nc2[nH]c(C)nc12
Reactant: Cc1c(Cl)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(N2CCOCC2)nc2c1nc(C)n2Cc1cccc(Cl)c1C
Temperature: 80 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
A mixture of methyl 2-methyl-5-morpholino-3H-imidazo[4,5-b]pyridine-7-carboxylate (200 mg, 0.72 mmol), prepared as described in Example 3, step f, 1-(bromomethyl)-3-chloro-2-methylbenzene (237 mg, 1.08 mmol) and Na2CO3 (153 mg, 1.44 mmol) in DMF (10 mL) was stirred at 80° C. for 5 h. It was cooled to room temperature and poured into water (100 mL). It was extracted with EA (100 mL×2). The combined organic layers were washed with brine (100 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluted with MeOH/DCM=1/60 to afford the desired product as a black solid (239 mg, 80%); LC/MS: MS (ES+) m/e 415 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 2.39 (s, 3H), 2.44 (s, 3H), 3.42 (t, J=4.8 Hz, 4H), 3.69 (t, J=4.8 Hz, 4H), 3.92 (s, 3H), 5.45 (s, 2H), 6.37 (d, J=7.8 Hz, 1H), 7.07-7.12 (m, 2H), 7.36 (d, 1H).
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[C:12]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=CC=C[CH:13]=1.CC(O)C.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:12]([CH3:17])[CH3:13])=[C:4]([Cl:11])[N:3]=1
Reactant: Fc1nc(Cl)c2[nH]cnc2n1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(C)n1cnc2c(Cl)nc(F)nc21
Temperature: -10 °C
Reaction time: 18 h

Procedure:
Anhydrous tetrahydrofuran (60 mL) is added to a flame-dried flask under N2 containing 2-fluoro-6-chloropurine (1.8 g, 10.4 mmol) and triphenylphosphine (6 g, 20.8 mmol). To this anhydrous 2-propanol (1.6 ml, 20.8 mmol) is added, and the mixture is then cooled to −10° C. After dropwise addition of 40% (W/V) diethyl azodicarboxylate in tetrahydrofuran (9 ml, 20.8 mmol), the mixture is warmed gradually to room temperature. After 18 h, the reaction mixture is quenched with 1 ml of water and the solvent is removed in vacuo. The resulting yellow oil is purified by column chromatography. The resulting solid is triturated with methanol (to remove the diethyl hydrazine-N,N′-dicarboxylate ester by-products) to yield 1.1 g (49%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C@@H:8]([CH:12]=[N:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[C:21](=[O:30])[NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>O1CCOCC1.C(O)CO>[C:1]([O:5][C:6](=[O:31])[NH:7][C@@H:8]([C:12]1[N:22]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:21](=[O:30])[C:15]2[C:14](=[CH:19][C:18]([Cl:20])=[CH:17][CH:16]=2)[N:13]=1)[CH:9]([CH3:11])[CH3:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)[C@H](C=Nc1cc(Cl)ccc1C(=O)NCc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: OCCO
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A dry 3-necked, round bottomed flask, equipped with a magnetic stirrer, nitrogen inlet, heating mantle and a water condenser, is charged with 60 mL of 1,4-dioxane/ethylene glycol (2:1), 4.60 g (10 mmol) of (R)-{1-[(2-benzylcarbamoyl-5-chloro-phenylimino)-methyl]-2-methyl-propyl}-carbamic acid tert-butyl ester (a compound of Formula 106, obtained as described in Example 5.3), and 0.46 g (11 mmol) of lithium hydroxide monohydrate. The mixture is heated to reflux and the reaction is monitored by TLC (hexanes/ethyl acetate 7:3). After 4 h of refluxing the reaction appears to be complete. The mixture is allowed to cool to room temperature and is slowly acidified to pH=5 by adding 1N hydrochloric acid. The mixture is stirred for 1 h and the white suspension is separated by filtration and dried in high vacuum to afford the title compound of Formula 107, (R)-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methylpropyl]-carbamic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([C:11]12[CH2:17][CH:14]([CH:15]=[CH:16]1)[CH2:13][CH:12]2[C:18](Cl)=[O:19])[CH:9]=[CH2:10]>>[CH2:1]([NH:7][C:18]([CH:12]1[CH2:13][CH:14]2[CH2:17][C:11]1([CH2:8][CH:9]=[CH2:10])[CH:16]=[CH:15]2)=[O:19])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccco1
Reactant: C=CCC12C=CC(CC1C(=O)Cl)C2
Product: C=CCC12C=CC(CC1C(=O)NCc1ccco1)C2

Procedure:
21.4 g of furfurylamine and 39.3 g of allylbicyclo[2.2.1]hept-5-ene-2-carbonyl chloride are reacted in accordance with process A, affording 38.1 g (73.8% of theory) of a reddish brown liquid resin; η25 =1287.2 m Pas.
Reaction SMILES: [O:1]1[CH:7]([C:8]([OH:10])=[O:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:12]1[N:17]=[CH:16][C:15]([B:18]([OH:20])[OH:19])=[CH:14][N:13]=1>>[B:18]([C:15]1[CH:14]=[N:13][C:12]([N:4]2[CH2:5][CH2:6][CH:7]([C:8]([OH:10])=[O:9])[O:1][CH2:2][CH2:3]2)=[N:17][CH:16]=1)([OH:20])[OH:19]
Reactant: O=C(O)C1CCNCCO1
Reactant: OB(O)c1cnc(Cl)nc1
Product: O=C(O)C1CCN(c2ncc(B(O)O)cn2)CCO1

Procedure:
The title compound was prepared from 1,4-oxazepane-7-carboxylic acid and (2-chloropyrimidin-5-yl)boronic acid in accordance with General Method C.
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][CH2:20][Cl:21])=[C:11]([NH:22][C:23]([C:25]2[NH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([O:34][CH3:35])=[C:29]([O:36][CH3:37])[C:28]=3[O:38][CH3:39])=[O:24])[CH:10]=1)C1C=CC=CC=1>C1COCC1.[Pd]>[Cl:21][CH2:20][CH2:19][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([OH:8])=[CH:10][C:11]=1[NH:22][C:23]([C:25]1[NH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([O:34][CH3:35])=[C:29]([O:36][CH3:37])[C:28]=2[O:38][CH3:39])=[O:24]
Reactant: COc1cc2cc(C(=O)Nc3cc(OCc4ccccc4)c4ccccc4c3CCCl)[nH]c2c(OC)c1OC
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1cc2cc(C(=O)Nc3cc(O)c4ccccc4c3CCCl)[nH]c2c(OC)c1OC
Reaction time: 8 h
Yield: 91.3 %

Procedure:
A solution of 2-[4-benzyloxy-2-(5,6,7-trimethoxyindole-2-carboxamido)naphthalen-1-yl]ethyl chloride (70 mg, 0.13 mmol) in THF (10 mL) was added to a suspension of 10% Pd/C (50 mg) in chilled THF (10 mL) and the suspension was hydrogenated under H2 atmosphere at room temperature overnight. The suspension was filtered over Celite and the filtrate was concentrated in reduced pressure. The residue was crystallized with diethylether to yield 4-(2-chloroethyl)-3-(5,6,7-trimethoxyindole-2-carboxamido)-1-naphthol (54 mg, 91%) as a white solid: mp 212° C. (decomp.); 1H NMR (CDCl3, 500 MHz) δ 9.55 (s, 1H), 8.76 (s, 1H), 8.33 (d, 8.0, 1H), 7.82 (d, 8.5, 1H), 7.78 (brs, 1H), 7.71 (s, 1H), 7.57 (t, 7.0, 1H), 7.48 (t, 7.5, 1H), 7.03 (s, 1H), 6.88 (s, 1H), 4.13 (s, 3H), 4.06 (t, 6.0, 1H), 3.97 (s, 3H), 3.93 (s, 3H), ), 3.61 (t, 6.0, 2H); FABMS (NBA) m/z 455 (M+H+), FABHR (NBA) m/z 454.1290 (M+H+, C24H23ClN2O5 requires 454.1296); IR (neat) νmax 3416, 3193, 3149, 2936, 1621, 1592, 1524, 1435, 1411, 1383, 1328, 1267, 1244, 1197, 1126, 1096, 1054, 852, 821, 758, 743 cm1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH3:20])[C:11]3[N:12]([C:14]([C:17]([OH:19])=O)=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.O[NH:22][C:23]([C:25]1[S:26][C:27]([S:30](=[O:33])(=[O:32])[NH2:31])=[CH:28][CH:29]=1)=[NH:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH3:20])[C:11]3[N:12]([C:14]([C:17]4[O:19][N:24]=[C:23]([C:25]5[S:26][C:27]([S:30]([NH2:31])(=[O:33])=[O:32])=[CH:28][CH:29]=5)[N:22]=4)=[CH:15][N:16]=3)[CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)cn2c(C(=O)O)cnc12
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)s1
Product: Cc1cc(-c2ccc(Cl)cc2)cn2c(-c3nc(-c4ccc(S(N)(=O)=O)s4)no3)cnc12

Procedure:
The title compound was prepared from 6-(4-chloro-phenyl)-8-methyl-imidazo[1,2-a]pyridine-3-carboxylic acid (example C.33) (143 mg, 0.5 mmol) and N-hydroxy-5-sulfamoyl-thiophene-2-carboxamidine (example B.2) (166 mg, 0.75 mmol) according to general procedure II. Obtained after trituration with water and further purification by crystallization (MeOH/diethyl ether) as an off-white solid (159 mg, 67%). MS (ISN) 470.0 [(M−H)−]; mp 271° C.