Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]([N:12]3[CH2:18][C:17]4([CH3:20])[CH2:19][CH:13]3[CH2:14][C:15]([CH3:22])([CH3:21])[CH2:16]4)=[O:11])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].Br[CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28]>CN(C=O)C>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][CH2:32][N:1]1[C:9]2[C:4](=[C:5]([C:10]([N:12]3[CH2:18][C:17]4([CH3:20])[CH2:19][CH:13]3[CH2:14][C:15]([CH3:22])([CH3:21])[CH2:16]4)=[O:11])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH3:31]
Reactant: CCOC(=O)C(C)Br
Reactant: CC1(C)CC2CC(C)(CN2C(=O)c2cccc3[nH]ccc23)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1ccc2c(C(=O)N3CC4(C)CC3CC(C)(C)C4)cccc21
Temperature: 60 °C
Reaction time: 72 h
Yield: 27.1 %

Procedure:
To a solution of (1H-indol-4-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone (82 mg, 0.27 mmol) in dry DMF (2 mL) at room temperature under an inert atmosphere of nitrogen was added sodium hydride (17 mg, 0.69 mmol, 60% dispersion in oil), and after stirring for 30 min ethyl bromopropionate (100 mg, 0.55 mmol) was added, and the reaction mixture was stirred for 72 h at 60° C. The reaction was quenched by the addition of water (20 mL) followed by extraction with DCM (3×50 mL). The combined organic phases were dried (MgSO4), filtered, and evaporated in vacuo. The resulting solid was purified by preparative HPLC, dried in vacuo at 50° C. affording 29 mg (27%) of the title compound as a solid. MS-ESI m/z 397; 1H NMR (400 MHz, DMSO) δ 0.88-1.08 (m, 6H), 1.14-1.22 (m, 7H), 1.28-1.29 (m) and 1.58-1.67 (m, 1H), 1.37-1.43 (m, 3H), 1.77-1.81 (m, 1H), 2.32-2.36 (m) and 3.10-3.20 (m, 1H), 2.81 (t, 2H), 3.35 (dd) and 3.75 (dd, 1H), 4.02-4.04 (m) and 4.68-4.70 (m, 1H), 4.11 (q, 2H), 4.46 (t, 2H), 6.44-6.50 (m, 1H), 7.10-7.13 (m, 1H), 7.17-7.26 (m, 2H), 7.38 (d, 1H).
Reaction SMILES: C([N:8]1[CH2:16][C@H:14]([OH:15])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])(OC(C)(C)C)=O.[CH:17]([N:20](CC)[CH:21](C)C)(C)C.[ClH:26].CNC>ClCCl.CN(C)C1C=CN=CC=1.Cl.O1CCOCC1>[CH2:13]1[C@@H:9]([C:10]([OH:12])=[O:11])[NH:8][CH2:16][C@@H:14]1[OH:15].[ClH:26].[CH3:17][N-:20][CH3:21]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Agent: CNC
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[N-]C
Product: O=C(O)[C@@H]1C[C@@H](O)CN1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
To a solution of BOC-hydroxyproline (2.99 g, 13.89 mmol) in dichloromethane (100 ml) were added N,N-diisopropylethylamine (3.7 ml, 21.24 mmol), 4-(dimethylamino)pyridine (1.74 g, 14.24 mmol), dimethylamine hydrochloride (1.72 g, 21.09 mmol) and WSCDI (3.17 g, 16.68 mmol). The mixture was stirred at room temperature for 30 hr. The mixture was diluted with dichloromethane (100 ml) and washed with 0.3M KHSO4, saturated sodium bicarbonate solution and brine, dried over MgSO4, and concentrated in vacuo to give a colourless gum. This crude material was taken up in 4N HCl/dioxan (50 ml) and stirred at room temperature for 1 hr and then concentrated in vacuo. The residue was azeotroped with toluene and diethyl ether to give a white solid; yield 0.45 g (17%).
Reaction SMILES: Cl.O1CCOCC1.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][N:15]1[C:23]2[C:18](=[CH:19][C:20]([NH2:24])=[CH:21][CH:22]=2)[CH:17]=[N:16]1.Cl[C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[F:36])[N:29]=[CH:28][N:27]=1>C(#N)C>[F:36][C:34]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:35]=1[C:26]([NH:24][C:20]1[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=1)[N:15]([CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][N:8]=1)[N:16]=[CH:17]3)=[N:27][CH:28]=[N:29]2
Reactant: Fc1cccc2ncnc(Cl)c12
Reactant: Nc1ccc2c(cnn2Cc2ccccn2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: Fc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 71.7 %

Procedure:
4N Hydrogen chloride in dioxane (9.6 ml, 38.4 mmol) was added to a mixture of 1-(pyridin-2-ylmethyl)-1H-indazol-5-amine (8.78 g, 39.2 mmol) and 4-chloro-5-fluoroquinazoline (7 g, 38.4 mmol; prepared as described in WO 2001/094341) in acetonitrile (100 ml). The mixture was stirred at 75° C. for 1.5 hours. After cooling, the mixture was evaporated to dryness. The residue was diluted in 6N methanolic ammonia. The mixture was evaporated to dryness and was diluted in DCM. After filtration of the solids, the filtrate was evaporated to dryness. The residue was purified by chromatography on silica gel (eluant: methanol in DCM) to give 5-fluoro-N-[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]quinazolin-4-amine as a beige solid (10.2 g, 72%); NMR spectrum (CDCl3) 5.76 (s, 2H), 6.89 (d, 1H), 7.22-7.18 (m, 2H), 7.58-7.45 (m, 3H), 7.72 (m, 2H), 8.11 (s, 1H), 8.21 (s, 1H), 8.47 (m, 1H), 8.60 (d, 1H), 8.68 (s, 1H); Mass spectrum MH+ 371.
Reaction SMILES: O=P(Cl)(Cl)Cl.[Br:6]Br.P(Br)(Br)Br.[C:12]1([CH2:18][CH2:19][CH2:20][N:21]2[C:25]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[C:24]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[NH:23][C:22]2=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N>C(OCC)(=O)C>[F:38][C:35]1[CH:36]=[CH:37][C:32]([C:24]2[N:23]=[C:22]([Br:6])[N:21]([CH2:20][CH2:19][CH2:18][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:25]=2[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:33][CH:34]=1
Reactant: O=c1[nH]c(-c2ccc(F)cc2)c(-c2ccncc2)n1CCCc1ccccc1
Reactant: BrBr
Agent: BrP(Br)Br
Agent: N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2nc(Br)n(CCCc3ccccc3)c2-c2ccncc2)cc1
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
A reaction vessel was charged with POCl3 (1500.0 g, 9.78 mol). Br2 (184.9 g, 1.157 mol) was then added in one portion at ambient temperature. The reaction mixture was cooled to 10° C. and then PBr3 (313.0 g, 1,157 mol) was added over 25 min. under vigorous stirring. The temperature of the reaction mixture increased to 20° C. After addition, stirring was continued for another 1.5 h, maintaining the temperature in the range of 10–20° C. The formed PBr5 precipitated as a yellow solid. The reaction mixture was warmed to 25° C. and 1,3-dihydro-1-(3-phenylpropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-imidazol-2-one (150.0 g 0,386 mol) was added in one portion. After addition, the reaction mixture was heated to about 30° C. and stirring was continued for 24 h. The suspension changed to a dark solution. The POCl3 was distilled off under vacuum at a temperature below 35° C., to yield a viscous oil. This oil was added to a mixture of ethyl acetate (1000 g) and aqueous ammonia (25 w %, 1000 g) over about 1.25 hours, with cooling. The resulting two phases were separated, the aqueous phase was extracted with ethyl acetate (500 g) and the combined organic phases were washed with water (200 g) at 70° C. The organic phase was concentrated to approximately 30% of the original volume. To the warmed reaction mixture, was then added triethylamine (600 g) and an additional amount of the solvent (about 150 g) was removed in vacuo, resulting in the crystallization of the desired product. The reaction mixture was cooled to 0° C. and stirred for 12 h. The product was filtered off, washed with triethylamine (50 g) and dried at 40° C. under vacuum, to yield the crude product.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([CH:19]=O)[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].CC(O)=O.Cl.[CH3:26][NH:27][CH3:28].[BH3-]C#N.[Na+]>C1COCC1>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([CH2:19][N:27]([CH3:28])[CH3:26])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(c2nc3ccc(C=O)cc3s2)CC1
Reactant: CNC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)N1CCN(c2nc3ccc(CN(C)C)cc3s2)CC1
Temperature: 63 °C
Yield: 32.4 %

Procedure:
To a solution of 2-(4-isopropylpiperazin-1-yl)benzothiazole-6-carboxaldehyde (0.7 g, 2.42 mmol) and AcOH (291 mg, 4.84 mmol) in THF, dimethylamine hydrochloride (397 mg, 4.84 mmol) and NaCNBH3 (245 mg, 3.88 mmol) were added in turn. The reaction mixture was heated at 63° C. for 12 hours. The solvent was removed and the residue was extracted with ethyl acetate, washed with water and brine and dried (MgSO4). The volatiles were evaporated and the residue was purified by preparative HPLC to yield 250 mg (32%) of [2-(4-isopropylpiperazin-1-yl)benzothiazol-6-ylmethyl]dimethylamine as a trifluoroacetate salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[C:12]([NH2:19])=[CH:11]2)[C:4]=1[CH3:20].C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[CH:46]1([CH2:49][C:50](O)=[O:51])[CH2:48][CH2:47]1>ClCCl.O>[CH:46]1([CH2:49][C:50]([NH:19][C:12]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:18]3[N:10]([CH2:9][C:5]3[C:4]([CH3:20])=[C:3]([O:2][CH3:1])[N:8]=[CH:7][N:6]=3)[CH:11]=2)=[O:51])[CH2:48][CH2:47]1
Reactant: O=C(O)CC1CC1
Reactant: COc1ncnc(Cn2cc(N)c3ncccc32)c1C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ncnc(Cn2cc(NC(=O)CC3CC3)c3ncccc32)c1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-amine (25d) (0.1 g, 0.37 mmol) in dichloromethane (10 mL) were added triethylamine (0.15 mL, 1.11 mmol), T3P (0.35 g, 1.11 mmol) and 2-cyclopropylacetic acid (0.037 g, 0.37 mmol and the mixture was stirred for 16 h at room temperature. Then the reaction mixture was poured into water (20 mL) and extracted with dichloromethane (2×50 mL). The combined organic layer was washed with brine and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography using 50% ethylacetate in hexane to afford 2-cyclopropyl-N-(1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)acetamide as off-white solid; yield: 25 mg (19%). ES+MS m/z: 352 (M+1). 1H NMR (400 MHz, DMSO-d6): δ ppm 2.25 (s, 3H), 3.67-3.69 (m, 1H), 3.73-3.76 (m, 1H), 4.50-4.52 (m, 1H), 4.62-4.64 (m, 1H), 5.49 (s, 2H), 6.94-6.96 (m, 3H), 7.27-7.30 (m, 1H), 8.08 (d, J=8.2 Hz), 8.45 (s, 1H), 8.50 (d, J=3.88 Hz), 8.92 (t, J=5.6 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[C:28]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].FC(F)(F)C(O)=O.C(Cl)[Cl:44]>>[ClH:44].[CH3:12][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[C:28]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)[N:14]=2)=[CH:4][C:3]=1[C:1]#[N:2])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCN(C(=O)OC(C)(C)C)CC4)no2)cc1C#N
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCNCC4)no2)cc1C#N
Product: Cl
Yield: 100 %

Procedure:
1,1-Dimethylethyl 6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (Preparation 16) (505 mg, 1.064 mmol) was dissolved in DCM (40 ml) and treated with trifluoroacetic acid (4 ml, 51.9 mmol). The resulting mixture was heated at reflux for 1 hour then evaporated. The resulting residue was partitioned between DCM (20 ml) and 2N NaOH (20 ml). The DCM layer was collected, dried (hydrophobic frit) and evaporated. The free-base was dissolved in 4M HCl in dioxane and evaporated to give the HCl salt, 2-[(1-methylethyl)oxy]-5-[3-(2,3,4,5-tetrahydro-1H-3-benzazepin-6-yl)-1,2,4-oxadiazol-5-yl]benzonitrile hydrochloride (438 mg, 1.066 mmol, 100% yield) as an off-white powder. δH (400 MHz, CDCl3) 10.15 (1H, br.s), 8.39 (1H, s), 8.33-8.31 (1H, m), 7.75-7.85 (1H, m), 7.45-7.3 (2H, m), 7.14 (1H, d), 4.84-4.76 (1H, m), 3.90-3.30 (8H, m) 1.48 (6H, d); MS (ES) C22H22N4O2 requires 374; found 375 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3]([I:19])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[N:6]=[CH:5]2.[C:20]([CH:24]1[CH2:29][CH2:28][CH:27](OS(C)(=O)=O)[CH2:26][CH2:25]1)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+].C(O)(C)(C)C.CC(=O)CC>C(Cl)Cl>[C:20]([C@H:24]1[CH2:29][CH2:28][C@H:27]([O:1][C:2]2[C:3]([I:19])=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([C@:12]2([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]2)[N:6]=[CH:5]3)[CH2:26][CH2:25]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)C1CCC(OS(C)(=O)=O)CC1
Reactant: C[C@@]1(c2ncc3c(I)c(O)ccc3n2)COC(=O)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)(C)O
Solvent: CCC(C)=O
Solvent: ClCCl
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc([C@]4(C)COC(=O)N4)ncc3c2I)CC1
Temperature: 80 °C

Procedure:
(R)-4-(6-Hydroxy-5-iodo-quinazolin-2-yl)-4-methyl-oxazolidin-2-one (350.0 mg, 0.0009431 mol), methanesulfonic acid 4-tert-butyl-cyclohexyl ester (884.0 mg, 0.003772 mol) and cesium carbonate (921.8 mg, 0.002829 mol) were dissolved in a mixture of tert-butyl alcohol (19.9 mL, 0.208 mol) and 2-butanone (6.6 mL, 0.074 mol). The reaction mixture was heated at 80° C. for 1 hour (MW), an additional methanesulfonic acid 4-tert-butyl-cyclohexyl ester (500 mg) was added, and the mixture was heated at 80° C. for an additional for 1 hour. LC/MS indicated that reaction was completed. Removal of solvents gave a solid mixture, which was treated with DCM and filtered. The filtrate was then washed with water, brine and dried over Na2SO4. The crude mixture was then purified via chromatography (SiO2, 24 gm, 0-100% ethyl acetate/hexanes) to give 451 mg desired product (94%). 1H NMR (CHLOROFORM-d) δ: 9.55 (s, 1H), 7.94 (d, J=9.3 Hz, 1H), 7.61 (d, J=9.3 Hz, 1H), 6.07 (s, 1H), 5.16 (d, J=8.8 Hz, 1H), 4.50 (d, J=8.8 Hz, 1H), 4.24-4.42 (m, 1H), 2.24 (d, J=12.0 Hz, 2H), 1.92 (d, J=9.5 Hz, 2H), 1.76 (s, 3H), 1.63 (d, J=11.3 Hz, 1H), 1.22-1.39 (m, 2H), 1.15 (br. s., 2H), 0.81-0.98 (m, 9H). MS (M+1): 510.10.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([C:7](=O)[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=O)=[CH:3][CH:2]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[C:20]=1[NH2:26]>CCO.CC(O)=O>[C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([C:7]2[N:25]=[C:21]3[CH:22]=[CH:23][CH:24]=[N:19][C:20]3=[N:26][C:8]=2[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(C(=O)C(=O)c2ccc(C)cc2)cc1
Reactant: Nc1cccnc1N
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(-c2nc3cccnc3nc2-c2ccc(C)cc2)cc1
Temperature: 85 °C

Procedure:
A solution of 1,2-dip-tolylethane-1,2-dione (commercially available) (175 g, 733 mmol) and pyridine-2,3-diamine (80 g, 733 mmol) in EtOH (1609 ml) and AcOH (179 ml) was heated to reflux (bath at 85° C.) for 1.5 h. The mixture was allowed to cool and concentrated in vacuo. The crude material was dissolved in DCM (500 ml) and filtered through silica to remove baseline impurities. The silica was washed with EtOAc (2 L). The combined filtrate layers were concentrated in vacuo to give a brown solid. The material was triturated in 1:1 TBME/heptane (300 ml). The solid was removed by filtration and washed with 1:1 TBME/heptane (200 ml) before drying at RT over 2 days to afford the title compound as an AcOH salt (1 eq).
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:15][CH2:16][CH3:17])[NH:8][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:4])[CH3:3].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:27]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:22][CH:21]=1>>[C:35]([O:34][C:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:8]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([C:2]([OH:1])([CH3:4])[CH3:3])[N:6]=[C:7]2[CH2:15][CH2:16][CH3:17])=[CH:21][CH:22]=1)=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 73.6 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 0.845 g of ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate (prepared as described in Preparation 9) and 1.22 g of t-butyl 4'-bromomethylbiphenyl-2-carboxylate, 1.31 g of the title compound were obtained as a gum. This compound was allowed to stand at room temperature, which caused it to crystallize. It was then recrystallized from a mixture of diisopropyl ether and hexane, to give pure title compound, melting at 90°-91° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([CH:9]=[C:10](C(O)=O)[N:11]=2)[CH:6]=[CH:7][CH:8]=1.CN([C:18]([O:22]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:39]1[CH:43]=[CH:42][N:41]=[C:40]1[NH:44][C:45]([C:47]1[C:55]2[NH:54][C:53]([NH2:56])=[N:52][C:51]=2[CH:50]=[CH:49][CH:48]=1)=[O:46]>CN(C=O)C.CCN(C(C)C)C(C)C.[Cl-].[Na+].O>[NH:41]1[CH:42]=[CH:43][N:39]=[C:40]1[NH:44][C:45]([C:47]1[C:55]2[N:54]=[C:53]([NH:56][C:18]([C:9]3[N:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]4=[N:11][CH:10]=3)=[O:22])[NH:52][C:51]=2[CH:50]=[CH:49][CH:48]=1)=[O:46]
Reactant: COc1cccn2cc(C(=O)O)nc12
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccn2c(C(=O)Nc3nc4c(C(=O)Nc5ncc[nH]5)cccc4[nH]3)cnc12
Yield: 39.4 %

Procedure:
300 mg (3.0 mmol) of the above 8-methoxy-imidazo[1,2-a]pyridine-2-carboxylic acid and 200 mg (0.5 mmol) of HBTU in a mixture of 1.5 mL of DMF and 0.6 mL of DIEA was reacted with 60 mg (0.25 mmol) of the 2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide (Intermediate B) as described in general procedure A. After the reaction was complete, it was diluted with brine (20 mL), and the resulting solid was filtered, washed with water, ethyl acetate and dried under vacuum to give 41 mg (40%) of 2-[(8-methoxy-imidazo[1,2-a]pyridine-3-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide as a solid. LCMS: 417 (M+1)+.
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([F:21])=[C:15]([F:20])[CH:16]=2)[N:11]([CH3:22])[C:10]1=[O:23])C1C=CC=CC=1.[H][H]>C1COCC1.CO.[Pd]>[F:20][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][C:14]=1[F:21])[N:11]([CH3:22])[C:10](=[O:23])[N:9]([OH:8])[C:18]2=[O:19]
Reactant: [H][H]
Reactant: Cn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(F)cc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(=O)n(O)c(=O)c2cc(F)c(F)cc21
Yield: 98.4 %

Procedure:
Twenty percent Pd/C (0.2 g) was added to a solution of 3-benzyloxy-6,7-difluoro-1-methyl-1H-quinazoline-2,4-dione (Example K, 1.55 g, 4.9 mmol) in 25 mL of THF and 25 mL of methanol. The mixture was shaken under 50 PSI of hydrogen for 1.5 hours, and filtered. The catalyst was rinsed with 200 mL of a 50/50 mixture of THF and methanol and concentrated to afford 1.1 g of the title compound as a solid, mp 239-241° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21][NH2:22])[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21][NH:22][S:31]([CH3:30])(=[O:33])=[O:32])[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: NC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To a solution of C—[(R)-7-(3-Fluoro-benzenesulfonyl)-chroman-2-yl]-methylamine (0.28 g, 0.871 mmol) in methylene chloride (10 mL) was added triethylamine (0.363 mL, 0.26 mmol.) and methanesulfonyl chloride (0.071 g, 0.915 mmol) The mixture was stirred at room temperature for two hours, and was then quenched by addition of water. The mixture was extracted with methylene chloride, and the combined organic layers were washed with water and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. Purification of the residue by flash chromatography (hexanes:EtOAc 1:1) gave 0.296 g of N-[(R)-7-(3-fluoro-benzenesulfonyl)-chroman-2-ylmethyl]-methanesulfonamide as a foam. MS (M+H)=400.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]([O:14][CH3:15])=[O:13])[C:6](O)=[O:7].C(Cl)(=O)C([Cl:19])=O>ClCCl.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]([O:14][CH3:15])=[O:13])[C:6]([Cl:19])=[O:7]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)c1ccc(C(=O)O)cc1OC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)Cl)cc1OC
Yield: 100 %

Procedure:
To a stirred suspension of 3-methoxy-4-methoxycarbonylbenzoic acid (4.1 g, 19.5 mmol) and oxalyl chloride (2.4 ml, 27.3 mmol) in dry dichloromethane (100 ml) was added 2 drops of dimethylformamide. After 3 h at room temperature the clear solution was evaporated to an oil. The oil was redissolved in dry dichloromethane and evaporated, this procedure was repeated to give 3-methoxy-4-methoxycarbonylbenzoyl chloride as an oil (100%) which was used immediately in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[C:4]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1.[H-].[Na+].Cl[CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29].O>C1COCC1.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]2[C:5](=[N:9][S:28](=[O:30])(=[O:29])[CH2:27][CH2:26]2)[C:4]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:12][CH:11]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: COc1ccnc(N)c1-c1ccc(Oc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC1=C(c2ccc(Oc3ccccc3)cc2)C2=NS(=O)(=O)CCN2C=C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-methoxy-3-(4-phenoxyphenyl)pyridin-2-amine (124 mg) in THF (dry) (5 mL) was added to a suspension of NaH (60%, 85.0 mg) and 2-chloroethanesulfonyl chloride (0.133 ml) in THF (dry) (5 mL) at 0° C. The mixture was stirred at room temperature overnight. Water and hexane were added to give a white precipitate. The precipitate was collected by filtration and washed with water and EtOAc then crystallized from THF-IPE to give the title compound (60.0 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:10]2[C:14]3[CH:15]([CH2:19][C:20]([O:22]CC4C=CC=CC=4)=[O:21])[CH2:16][CH2:17][CH2:18][C:13]=3[N:12]=[C:11]2[CH:30]([CH3:32])[CH3:31])[CH3:9])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[NH3:10].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:10]2[C:14]3[CH:15]([CH2:19][C:20]([OH:22])=[O:21])[CH2:16][CH2:17][CH2:18][C:13]=3[N:12]=[C:11]2[CH:30]([CH3:32])[CH3:31])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)c1nc2c(n1[C@H](C)c1ccc(Cl)cc1)C(CC(=O)OCc1ccccc1)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1nc2c(n1[C@H](C)c1ccc(Cl)cc1)C(CC(=O)O)CCC2
Product: N
Temperature: 25 °C

Procedure:
Intermediate 69 (147 mg) was dissolved in Methanol (4 mL). NaOH (2 mL) was added to the stirred reaction mixture as a 3.3 N aqueous soln and the reaction mixture stirred at room temperature. After stirring overnight, LCMS of the reaction mixture demonstrated full consumption of the starting material and the formation of the desired acid product. The reaction mixture was conc in vacuo and taken up in acetonitrile/water. The soln was taken to pH4-5 by the addition of 2 M aqueous HCl and loaded onto an SCX column. After washing with water and acetonitrile, the product was eluted with 2 M ammonia soln in methanol. The washings were conc in vacuo to afford the ammonium salt of the desired product: LC/MS MH+ 361, Rt 2.02 mins (5 min run).